Mechanically Induced Fe(III) Catalysis at Room Temperature: Solvent-Free Cross-Dehydrogenative Coupling of 3-Benzylic Indoles with Methylenes/Indoles

Article abstract of DOI:10.1021/acs.joc.6b02197

An Fe(III)-catalyzed solvent-free cross-dehydrogenative coupling of 3-benzylic indoles and compounds with acidic methylene groups has been achieved under high-speed ball-milling (HSBM) conditions at room temperature. The reactions afford desired 3-arylmet

Full text of DOI:10.1021/acs.joc.6b02197

Note
pubs.acs.org/joc
Mechanically Induced Fe(III) Catalysis at Room Temperature: Solvent-
Free Cross-Dehydrogenative Coupling of 3‑Benzylic Indoles with
Methylenes/Indoles
Jing-Bo Yu, Yang Zhang, Zhi-Jiang Jiang, and Wei-Ke Su*
National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation
Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. China
S
* Supporting Information
ABSTRACT: An Fe(III)-catalyzed solvent-free cross-dehydro-
genative coupling of 3-benzylic indoles and compounds with
acidic methylene groups has been achieved under high-speed ball-
milling (HSBM) conditions at room temperature. The reactions
afford desired 3-arylmethylindole derivatives in moderate to high
yields within 21 min of grinding. Besides, both N-substituted and
N-free indoles can take part in this mechanochemical reaction as
efficient nucleophiles to give bisindoles with satisfactory results. Remarkably, this protocol displays the possibility to induce high
activity when using iron catalysts under HSBM conditions.
ross-dehydrogenative coupling (CDC) reaction is one of
the most powerful tools for covalent bond direct
and compounds with acidic methylene groups as well as indoles
(Scheme 1).
C
construction and has been extensively studied over the past
decade.1 Besides widely used Cu catalysts, highly active metal
catalysts containing Pd, Rh, Ru, and Yb have also been applied
in different types of CDC reactions.2 However, the problems of
expense and toxicity are still challenging the chemists for
greener and cheaper covalent-bond construction. Recently, iron
as an earth-abundant element has received much attention from
the catalysis community due to its low cost and nontoxicity.3 A
flurry of iron-catalyzed CDC reactions have arisen since the
pioneering investigation by Li and co-workers.4 Although these
findings have revealed iron’s catalytic potential, further
development of which is plagued by its relatively low activity.
Hitherto, how to induce the high activity of iron-catalysts is still
one of the most crucial problems in the field of metal-catalyzed
synthesis.
Scheme 1. Indoles Synthesis via Fe-Catalyzed Mechanical
CDC Reactions
High-speed ball-milling (HSBM) is a green mechanical
technique which always promotes chemical reactions with high
efficiency, energy economy, and sometimes new reactivity.5 In
continuation of our research interest in HSBM promoted CDC
reactions,6 the realization of iron-catalyzed high-efficiency
reactions was hypothesized to be induced by mechanochem-
istry treatment. Initially, the functionalization of the methylene
position of 3-benzylic indoles was undertaken for its high utility
in pharmaceutical research.7 Previously, this transformation has
been studied successfully by placing a leaving group at the
methylene position,8 especially Xiao and Shao’s “on-water”
catalysis which represents the state-of-the-art of this trans-
formation.8f To the best of our knowledge, the only case of
direct coupling of benzylic indoles was reported by Gong et al.,
which was catalyzed by Cu to give asymmetric products and Yb
to afford symmetric ones.9 Herein, we reported our studies of
solvent-free iron-catalyzed CDC reactions of benzylic indoles
At the outset, the reactions between 2-phenyl-3-benzyl-1H-
indole (1a) and diethyl malonate (2a) were treated with
different combinations of catalysts and oxidants, where silica gel
was chosen as a helpful grinding auxiliary for better substrate
mixing on the basis of our previous research,6 and the selected
results were summarized in Table 1. To our delight, both
Fe(III) and Fe(II) catalysts could afford the desired product
3aa after 30 min of grinding, where Fe(III) worked much better
than Fe(II) (Table 1, entries 1−8). Fe(NO3)3 and Fe(NO3)3·
9H2O showed similar high activity (Table 1, entries 3 and 4),
and the latter was chosen for its easy handling. Gratifyingly,
Received: September 6, 2016
Published: October 25, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b02197
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
temperature, which verified our hypothesis that the HSBM
may induce high activity when using an Fe catalyst.
Table 1. Optimization of the Reaction Conditions
Mechanochemistry process parameters usually have a strong
influence on the outcomes, which were shown by us and others
previously.6a,d,10 Thus, the combined assessment of the
grinding time and vibration frequency was carried out
attentively, and the results were summarized in Figure 1. The
yields increased sharply when elevating the frequency from 15
to 25 Hz. However, slightly lower yields were obtained when
the reactions were performed under 30 Hz. In contrast to the
apparent influence of frequency, variation of grinding time did
not show any obvious difference at 25 and 30 Hz, where the
best result could be obtained by milling at 25 Hz within 21 min
(87% yield).11 However, the gentle growth trend in yields from
15 to 20 Hz might be explained by the insufficient mechanical
energy input.
With the optimal conditions in hand, the scopes and
limitations of this methodology were then investigated by
varying 3-benzylic indoles first. The results were presented in
Table 2. To our delight, both electron-withdrawing and
-donating aryl groups (involving oxidative sensitive OH
group) in 1 were tolerated to give moderate to excellent yields
(3aa−3ea). As expected, electron-rich substrates 1b−1e gave
better results than electron-deficient ones 1f−1i. Steric
hindrance was found to strongly influence product yields,
where o-methyl substituted substrate 1j afforded a low yield of
23%. Moderate to good yields were obtained by replacing the
phenyl group with a methyl (3ka−3ma) or p-chlorophenyl
(3na) group. Further examination of N-protected indole
substrate 1o showed that the reaction could also proceed
smoothly, but product 3oa was afforded in a relatively low yield
(52%). Besides, 3-thienylmethylindole 1p provided the desired
product 3pa with an excellent yield of 92%. Then, several
compounds with acidic methylene groups were examined to
further validate the power of this strategy. Gratifyingly, both of
the symmetric and asymmetric methylene compounds
proceeded successfully under the optimum conditions, furnish-
ing the desired products 3bb−3bg in moderate to high yields. It
was worth mentioning that coupling partners with sensitive
groups as malononitrile 2b and ethyl 4-chloroacetoacetate 2e
were well tolerated under this oxidative condition. However, 2h
and 2i failed to give the products, which was probably due to
the steric hindrance disturbance.
b
entry
catalyst
FeCl3
oxidant
yield (%)
1
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
TCQ
BQ
55
43
61
2
Fe2(SO4)3
3
Fe(NO3)3
c
d
4
Fe(NO3)3·9H2O
FeSO4
62 (58)
5
50
35
37
n.d.
23
14
6
6
FeCl2
7
FeCl2·4H2O
−
8
9
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Cu(OTf)2
10
11
12
Oxone
MnO2
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
10
75
83
83
70
trace
78
e
13
f
14
g
15
h
16
i
17
j
18
a
Unless otherwise noted, all reactions were carried out with 1a (1.0
mmol), 2a (1.0 mmol), catalyst (10 mol %), oxidant (1.0 mmol), and
silica gel (0.6 g) at 30 Hz for 30 min, using two stainless steel grinding
balls (14 mm diameter) in a 50 mL stainless steel vial (DDQ = 2,3-
dicyano-5,6-dichlorobenzoquinone, TCQ = Tetrachlorobenzo-
quinone, BQ = benzoquinone). Yield based on 1a. Fe(NO3)3·
9H2O was purchased from Sinopharm Chemical Reagent Co. Ltd.
(purity ≥98.5%), of which the copper content was determined to be
5.0 ppm (the major contaminant in this sample was calcium [162.8
ppm]). Fe(NO3)3·9H2O was purchased from Aldrich (purity
≥99.95%), of which the copper content was determined to be 0.4
ppm. DDQ was added in two portions during the milling interval
[2(15 min + 1 min break)]. DDQ was added in three portions during
the milling intervals [3(10 min + 1 min break)]. DDQ was added in
four portions during the milling intervals [4(7.5 min + 1 min break)].
5 mol % of the catalyst was used. Yield of the comparative
b
c
d
e
f
g
h
i
experiment: 1a (1.0 mmol), 2a (1.0 mmol), Fe(NO3)3·9H2O (10 mol
%), DDQ (1.0 mmol), and CH2Cl2 (30 mL) at room temperature.
Yield of the comparative experiment (see ref 9): 1a (1.0 mmol), 2a
j
With these positive results, we then turned our attention to
indoles as the nucleophile for further expansion of the substrate
scope (Scheme 2). We were delighted to find that not only N-
substituted but also N-free indoles could be tolerated under the
above-mentioned milling conditions to give the desired
bisindole derivatives (5ba−5bd). However, only a trace amount
of 5bb was obtained when the reaction of 1b and 4b was placed
under solvent-based conditions,12 where a high reaction
temperature (100 °C) and long reaction time (24 h) were
required.13 The results of electronic effects showed that an
indole bearing an electron-donating group (4d) gave a much
lower yield than that with electron-withdrawing groups (4a and
4c), which was consistent with the finding of Chen’s group.4g
Further application of this method to large-scale preparation
showed that 10.0 mmol of 2-phenyl-3-benzyl-1H-indole 1a
were converted into the corresponding 3aa in a low yield of
55% under the standard conditions, which was probably due to
the limited space of the milling vessel which hindered the
movement of the milling balls and therefore the energy input
was reduced.10c
(1.0 mmol), Cu(OTf)2 (10 mol %), DDQ (1.0 equiv), and CH2Cl2
(30 mL) at room temperature.
traces of metal impurities in Fe(NO3)3·9H2O had minimal
influence on the product yield (Table 1, entry 4). Next, several
kinds of oxidants were tested (Table 1, entries 9−12). The
reaction with DDQ gave the best result of 62%, while other
oxidants involving BQ and TCQ gave lower yields under the
same conditions. To further elevate the product yield, we
attempted to add DDQ in several portions to avoid the radical
polymerization. Gratefully, the strategy worked well giving the
best result of 83% yield by adding DDQ in three portions
(Table 1, entries 13−15). Decreasing the catalyst loadings to 5
mol % led to erosion in yield (Table 1, entry 16). Furthermore,
simple comparison of this protocol with a solvent-based
method was conducted (Table 2, entries 17 and 18), and it is
interesting to see that though a moderate yield of 3aa was
afforded when using Cu(OTf)2 as the catalyst, the reaction
could hardly be promoted by Fe(NO3)3·9H2O at room
B
DOI: 10.1021/acs.joc.6b02197
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
Table 2. Substrate Scope of Fe(III)-Catalyzed CDC Reactions of 3-Benzylic Indoles with Methylenes
a
Reactions were performed with 1 (1.0 mmol), 2 (1.0 mmol), Fe(NO3)3·9H2O (10 mol %), DDQ (1.0 mmol, added in 3 portions during the milling
intervals), and silica gel (0.6 g) at 25 Hz in mixer mill [3(7 min + 1 min break)], using two stainless steel grinding balls (14 mm diameter) in 50 mL
stainless steel vial. Yield based on 1.
Scheme 2. Fe(III)-Catalyzed CDC Reactions of 3-Benzylic
Indoles with Indoles
Figure 1. Optimization of mechanochemical parameters for the CDC
reaction (all the reactions were proceeded in three milling cycles
To gain insight into the mechanism, radical scavenger
[3(milling time + 1 min break)]).
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and 2,6-di-tert-
butyl-4-methylphenol (BHT) were added to the reaction
mixtures, respectively. Both reactions were inhibited and
C
DOI: 10.1021/acs.joc.6b02197
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
resolution MS instrument using ESI ionization. Traces of metal
impurities in Fe(NO3)3·9H2O were determined on an ICP-MS
instrument.
afforded only trace amounts of the product (Scheme 3a),
indicating the reaction may undergo a radical mechanism,
which was similar to that in literature reports (Scheme
3b),4c,g,14 but different from the Cu-catalyzed one.9
Typical Procedure for the Synthesis of Diethyl 2-(Phenyl(2-
phenyl-1H-indol-3-yl)methyl)malonate (3aa9). The following
components were added to the screw-capped stainless steel vial: 3-
benzyl-2-phenyl-1H-indole 1a (1 mmol, 283 mg), diethyl malonate 2a
(1 mmol, 160 mg), Fe(NO3)3·9H2O (0.1 mmol, 40 mg), silica gel (0.6
g), and DDQ (1/3 mmol, 76 mg), along with two stainless steel balls
(d = 14 mm). Then, the vial was placed in a vibrational micromill
(milling cycle: 7 min at 25 Hz, followed by 1 min break, in 3
repetitions); during the next two milling intervals, the other two 1/3
portions of DDQ were added, respectively (total amount of DDQ = 1
mmol). After the reaction was completed, the contents were scratched
off the vessel and purified directly by column chromatography on silica
gel using PE−EtOAc (15:1) as eluent to give desired products 3aa as a
Scheme 3. Possible Mechanism for the Fe(III)-Catalyzed
CDC Reaction
1
white solid (384 mg, 87% yield); mp 110−111 °C; H NMR (400
MHz, CDCl3) δ 8.06 (s, 1H), 7.83 (d, J = 7.2 Hz, 1H), 7.55 (d, J = 6.8
Hz, 2H), 7.45−7.34 (m, 3H), 7.30−7.23 (m, 3H), 7.18−7.04 (m, 5H),
5.24 (d, J = 12.0 Hz, 1H), 4.77 (d, J = 12.0 Hz, 1H), 4.01 (q, J = 7.2
Hz, 2H), 3.87−3.70 (m, 2H), 1.04 (t, J = 7.0 Hz, 3H), 0.71 (t, J = 7.0
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.0, 167.7, 142.0,
135.9, 135.8, 132.8, 128.9, 128.6, 128.1, 128.0, 127.6, 127.2, 126.2,
121.8, 120.6, 119.7, 112.2, 110.9, 61.4, 61.1, 56.4, 42.6, 13.9, 13.5;
HRMS (ESI) m/z: calcd for C28H27NO4Na [M + Na]+ 464.1832,
found 464.1836.
Diethyl 2-((2-Phenyl-1H-indol-3-yl)(p-tolyl)methyl)malonate
1
(3ba). White solid (414 mg, 91% yield); mp 102−103 °C; H NMR
(400 MHz, CDCl3) δ 8.04 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.56 (d, J
= 6.4 Hz, 1H), 7.46−7.34 (m, 3H), 7.27−7.20 (m, 1H), 7.16 (d, J =
7.6 Hz, 2H), 7.13−7.06 (m, 2H), 6.95 (d, J = 7.6 Hz, 2H), 5.21 (d, J =
12.0 Hz, 1H), 4.75 (d, J = 12.0 Hz, 1H), 4.02 (q, J = 7.2 Hz, 2H),
3.85−3.70 (m, 2H), 2.21 (s, 3H), 1.07 (t, J = 7.2 Hz, 3H), 0.69 (t, J =
7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.4, 167.2, 138.6,
135.4, 135.3, 132.4, 128.5, 128.3, 127.7, 127.0, 126.9, 121.5, 120.4,
119.3, 112.1, 110.6, 61.5, 61.2, 56.6, 42.4, 21.4, 14.4, 13.9; HRMS
(ESI) m/z: calcd for C29H29NO4Na [M + Na]+ 478.1989, found
478.1984.
Diethyl 2-((2-Phenyl-1H-indol-3-yl)(m-tolyl)methyl)malonate
1
(3ca). White solid (391 mg, 86% yield); mp 134−135 °C; H NMR
In summary, we have built up a protocol for inducing an
iron-catalyzed high-efficiency CDC reaction by using the
HSBM technique. The model reaction between benzylic
indoles and compounds with acidic methylene groups
proceeded smoothly and afforded the desired products in
moderate to high yields at room temperature, which could
hardly be operated in the solvent environment. Far more
important was that not only N-substituted indoles but also the
N-free ones could be tolerated in this mechanical Fe(III)
catalyzed CDC (coupling of sp3 C−H bond and sp2 C−H
bond) reaction to furnish bisindoles in satisfactory yields. The
successful development of this protocol showed the potential of
HSBM to induce high catalytic activities of low-active iron
metals, which provided a complement for HSBM in the field of
metal-catalyzed synthesis.
(400 MHz, CDCl3) δ 8.04 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.54 (d, J
= 7.2 Hz, 2H), 7.46−7.33 (m, 3H), 7.21−7.19 (m, 1H), 7.13−7.01 (m,
5H), 6.88 (d, J = 6.8 Hz, 1H), 5.21 (d, J = 12.0 Hz, 1H), 4.74 (d, J =
12.0 Hz, 1H), 4.01 (q, J = 7.2 Hz, 2H), 3.86−3.68 (m, 2H), 2.19 (s,
3H), 1.06 (t, J = 7.2 Hz, 3H), 0.70 (t, J = 7.2 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 168.0, 167.8, 141.8, 137.5, 135.8, 135.7, 132.8,
128.9, 128.5, 128.3, 128.0, 127.3, 127.0, 124.5, 121.7, 120.6, 119.6,
112.2, 110.8, 61.3, 61.4, 56.4, 42.4, 21.6, 14.0, 13.5; HRMS (ESI) m/z:
calcd for C29H29NO4Na [M + Na]+ 478.1989, found 478.2005.
Diethyl 2-((4-Hydroxyphenyl)(2-phenyl-1H-indol-3-yl)methyl)-
malonate (3da). White solid (402 mg, 88% yield); mp 176−178
°C; 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.83 (d, J = 7.6 Hz,
1H), 7.55 (d, J = 7.2 Hz, 2H), 7.48−7.34 (m, 3H), 7.28 (d, J = 7.2 Hz,
1H), 7.17−7.08 (m, 4H), 6.57 (d, J = 8.8 Hz, 2H), 5.16 (d, J = 12.0
Hz, 1H), 5.04 (brs, 1H), 4.71 (d, J = 12.0 Hz, 1H), 4.03 (q, J = 7.2 Hz,
2H), 3.87−3.71 (m, 2H), 1.08 (t, J = 7.0 Hz, 3H), 0.71 (t, J = 7.2 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.2, 167.8, 153.9, 135.7,
134.1, 132.7, 128.80 (2C), 128.75 (2C), 128.6 (2C), 128.1, 127.1,
121.8, 120.6, 119.7, 115.0 (2C), 112.3, 110.9, 61.5, 61.2, 56.7, 41.9,
14.0, 13.5; HRMS (ESI) m/z: calcd for C28H27NO5Na [M + Na]+
480.1781, found 480.1791.
Diethyl 2-((4-Methoxyphenyl)(2-phenyl-1H-indol-3-yl)methyl)-
malonate (3ea). White solid (410 mg, 87% yield); mp 118−120
°C; 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.82 (d, J = 8.0 Hz,
1H), 7.53 (d, J = 7.2 Hz, 2H), 7.43−7.33 (m, 3H), 7.25−7.18 (m,
3H), 7.14−7.06 (m, 2H), 6.68 (d, J = 8.4 Hz, 2H), 5.19 (d, J = 12.0
Hz, 1H), 4.72 (d, J = 12.0 Hz, 1H), 4.01 (q, J = 7.2 Hz, 2H), 3.84−
3.71 (m, 2H), 3.67 (s, 3H), 1.06 (t, J = 7.2 Hz, 3H), 0.69 (t, J = 7.2
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.1, 167.7, 157.8,
135.8, 134.3, 132.8, 128.8, 128.6, 128.0, 127.2, 121.7, 120.6, 119.6,
EXPERIMENTAL SECTION
■
General Information. All reagents were purchased from
commercial sources and used without purification, unless otherwise
indicated. 3-Benzylic indoles 1 were prepared according to the
literature method.15 A high-energy vibrational ball mill (mix-miller
MM 400 from Retsch) was employed. The reaction was performed in
a 50 mL stainless steel vial and milled with two stainless steel grinding
balls (14 mm diameter). TLC (Thin-Layer Chromatography) analysis
was performed using precoated glass plates. Melting points (mp) were
obtained on a digital melting point apparatus and uncorrected. 1H and
13C NMR were recorded at 400 (or 500) MHz and 100 (or 125)
MHz, respectively, and TMS was used as the internal standard. Mass
spectra were measured with an HRMS-ESI-Q-TOF and a low-
D
DOI: 10.1021/acs.joc.6b02197
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The Journal of Organic Chemistry
Note
113.6, 112.4, 110.9, 61.4, 61.0, 56.7, 55.1, 41.9, 14.0, 13.5; HRMS
(ESI) m/z: calcd for C29H29NO5Na [M + Na]+ 494.1938, found
494.1926.
Diethyl 2-((2-Methyl-1H-indol-3-yl)(p-tolyl)methyl)malonate
(3la). Pale red solid (330 mg, 84% yield); mp 112−113 °C; 1H
NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.66−7.60 (m, 1H), 7.24 (d,
J = 7.6 Hz, 2H), 7.14−7.08 (m, 1H), 6.99 (d, J = 8.4 Hz, 4H), 5.00 (d,
J = 12.0 Hz, 1H), 4.66 (d, J = 12.0 Hz, 1H), 4.08 (q, J = 7.0 Hz, 2H),
3.85−3.72 (m, 2H), 2.36 (s, 3H), 2.22 (s, 3H), 1.11 (t, J = 7.0 Hz,
3H), 0.74 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.1,
167.9, 138.7, 135.5, 135.1, 131.8, 128.8, 127.2, 120.5, 119.1, 119.0,
111.3, 110.2, 61.4, 61.1, 55.9, 42.1, 21.0, 14.0, 13.5, 12.3; HRMS (ESI)
m/z: calcd for C24H27NO4Na [M + Na]+ 416.1832, found 416.1844.
Diethyl 2-((2,5-Dimethyl-1H-indol-3-yl)(p-tolyl)methyl)malonate
Diethyl 2-((2-(4-Chlorophenyl)-1H-indol-3-yl)(phenyl)methyl)-
malonate (3fa). White solid (409 mg, 86% yield); mp 117−118
°C; 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.79 (d, J = 7.6 Hz,
1H), 7.55 (d, J = 7.2 Hz, 2H), 7.50−7.38 (m, 3H), 7.30 (d, J = 7.2 Hz,
1H), 7.21−7.09 (m, 6H), 5.21 (d, J = 12.0 Hz, 1H), 4.72 (d, J = 12.0
Hz, 1H), 4.05 (q, J = 7.2 Hz, 2H), 3.90−3.72 (m, 2H), 1.10 (t, J = 7.2
Hz, 3H), 0.73 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 167.2, 166.9, 140.2, 135.7, 135.3, 132.2, 131.6, 128.6, 128.4, 128.0,
126.7, 121.7, 120.1, 119.6, 111.5, 110.7, 61.7, 61.4, 56.4, 42.2, 14.5,
13.9; HRMS (ESI) m/z: calcd for C28H26ClNO4Na [M + Na]+
498.1443, found 498.1453.
1
(3ma). Light yellow solid (301 mg, 74% yield); mp 138−139 °C; H
NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.42 (s, 1H), 7.23 (d, J = 7.6
Hz, 2H), 6.99 (d, J = 8.0 Hz, 3H), 6.82 (d, J = 8.0 Hz, 1H), 4.97 (d, J
= 12.0 Hz, 1H), 4.65 (d, J = 12.0 Hz, 1H), 4.08 (q, J = 7.2 Hz, 2H),
3.87−3.72 (m, 2H), 2.40 (s, 3H), 2.32 (s, 3H), 2.22 (s, 3H), 1.11 (t, J
= 7.2 Hz, 3H), 0.77 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 168.2, 167.8, 138.9, 135.5, 133.5, 131.9, 128.8, 128.1, 127.7,
127.3, 122.1, 118.8, 111.1, 109.8, 61.4, 61.0, 56.1, 42.1, 21.7, 21.0, 14.0,
13.5, 12.5; HRMS (ESI) m/z: calcd for C25H29NO4Na [M + Na]+
430.1989, found 430.2007.
Diethyl 2-((4-Bromophenyl)(2-phenyl-1H-indol-3-yl)methyl)-
malonate (3ga). Light yellow solid (359 mg, 69% yield); mp 79−
1
82 °C; H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.78 (d, J = 7.6
Hz, 1H), 7.56−7.36 (m, 5H), 7.30−7.22 (m, 3H), 7.15−7.05 (m, 4H),
5.20 (d, J = 12.0 Hz, 1H), 4.71 (d, J = 12.0 Hz, 1H), 4.04 (q, J = 7.0
Hz, 2H), 3.87−3.71 (m, 2H), 1.09 (t, J = 7.0 Hz, 3H), 0.72 (t, J = 7.0
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.8, 167.5, 141.1,
136.1, 135.7, 132.6, 131.2, 129.3, 128.9, 128.7, 128.2, 126.9, 122.0,
120.3, 120.1, 119.8, 111.5, 111.0, 61.6, 61.2, 56.2, 42.0, 14.0, 13.5;
HRMS (ESI) m/z: calcd for C28H26BrNO4Na [M + Na]+ 542.0937,
found 542.0911.
Diethyl 2-((2-(4-Chlorophenyl)-1H-indol-3-yl)(p-tolyl)methyl)-
malonate (3na). White solid (337 mg, 69% yield); mp 123−125
1
°C; H NMR (400 MHz, CDCl3) δ 8.0 (s, 1H), 7.83 (d, J = 7.2 Hz,
1H), 7.49 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 7.2
Hz, 1H), 7.16−7.08 (m, 4H), 6.96 (d, J = 8.0 Hz, 2H), 5.13 (d, J =
12.0 Hz, 1H), 4.73 (d, J = 12.0 Hz, 1H), 4.03 (q, J = 7.2 Hz, 2H),
3.85−3.71 (m, 2H), 2.22 (s, 3H), 1.08 (t, J = 7.0 Hz, 3H), 0.71 (t, J =
7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.9, 167.8, 138.7,
135.8 (2C), 134.5, 134.0, 131.2, 130.1 (2C), 128.92 (2C), 128.86
(2C), 127.3 (2C), 127.0, 122.0, 120.7, 119.8, 112.7, 110.9, 61.5, 61.2,
56.3, 42.2, 21.1, 14.0, 13.5; HRMS (ESI) m/z: calcd for
C29H28ClNO4Na [M + Na]+ 512.1599, found 512.1612.
Diethyl 2-((4-Nitrophenyl)(2-phenyl-1H-indol-3-yl)methyl)-
1
malonate (3ha). Light yellow oil (248 mg, 51% yield); H NMR
(400 MHz, CDCl3) δ 8.08 (s, 1H), 8.01 (d, J = 8.8 Hz, 2H), 7.99 (d, J
= 8.4 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.58−7.42 (m, 5H), 7.38−
7.30 (m, 3H), 7.20−7.11 (m, 2H), 5.35 (d, J = 12.0 Hz, 1H), 4.78 (d, J
= 12.0 Hz, 1H), 4.14−4.01 (m, 2H), 3.94−3.77 (m, 2H), 1.12 (t, J =
7.2 Hz, 3H), 0.76 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (125 MHz,
CDCl3) δ 167.8, 167.5, 149.8, 146.4, 136.6, 135.8, 135.6, 132.5, 129.1,
129.0, 128.7, 128.4, 126.8, 123.6 (2C), 122.4, 120.3, 120.1, 111.2,
110.8, 110.7, 61.8, 61.5, 55.6, 42.1, 13.9, 13.4; HRMS (ESI) m/z: calcd
for C28H26N2O6Na [M + Na]+ 509.1683, found 509.1663.
Diethyl 2-((1-Methyl-2-phenyl-1H-indol-3-yl)(p-tolyl)methyl)-
1
malonate (3oa). Yellow oil (244 mg, 52% yield); H NMR (500
MHz, CDCl3) δ 7.96 (d, J = 6.0 Hz, 1H), 7.59−7.45 (m, 4H), 7.35−
7.17 (m, 4H), 7.11 (d, J = 6.4 Hz, 2H), 6.98 (d, J = 6.0 Hz, 2H), 5.00
(d, J = 10.0 Hz, 1H), 4.74 (d, J = 10.0 Hz, 1H), 4.08−4.01 (m, 2H),
3.97−3.83 (m, 2H), 3.48 (s, 1H), 2.26 (s, 1H), 1.08 (t, J = 6.0 Hz,
3H), 0.83 (t, J = 6.0 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ
168.2, 168.1, 139.4, 138.8, 137.1, 135.5, 131.8, 131.0 (2C), 128.8 (4C),
128.4, 128.3, 127.4 (3C), 126.2, 121.3, 120.3, 119.3, 61.2, 61.0, 56.3,
42.5, 30.6, 20.9, 13.8, 13.4; HRMS (ESI) m/z: calcd for C30H31NO4Na
[M + Na]+ 492.2145, found 492.2161.
Diethyl 2-((2-Phenyl-1H-indol-3-yl)(thiophen-2-yl)methyl)-
malonate (3pa). White solid (411 mg, 92% yield); mp 107−108
°C; 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.76 (d, J = 7.6 Hz,
1H), 7.55 (d, J = 7.2 Hz, 2H), 7.47−7.31 (m, 3H), 7.24 (d, J = 7.6 Hz,
1H), 7.15−7.01 (m, 3H), 6.87 (brs, 1H), 6.82−6.76 (m, 1H), 5.49 (d,
J = 11.6 Hz, 1H), 4.68 (d, J = 11.6 Hz, 1H), 4.15−4.05 (m, 2H), 3.79−
3.62 (m, 2H), 1.14 (t, J = 7.0 Hz, 3H), 0.63 (t, J = 7.0 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 167.8, 167.0, 146.0, 136.1, 135.9,
Diethyl 2-((3-Methoxyphenyl)(2-phenyl-1H-indol-3-yl)methyl)-
malonate (3ia). White solid (344 mg, 73% yield); mp 124−126 °C;
1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.83 (d, J = 6.8 Hz, 1H),
7.54 (d, J = 6.8 Hz, 2H), 7.44−7.32 (m, 3H), 7.26−7.20 (m, 1H),
7.15−7.02 (m, 3H), 6.87 (d, J = 7.6 Hz, 1H), 6.80 (s, 1H), 6.62 (dd, J
= 8.0, 1.6 Hz, 1H), 5.22 (d, J = 12.0 Hz, 1H), 4.76 (d, J = 12.0 Hz,
1H), 4.02 (q, J = 7.2 Hz, 2H), 3.84−3.71 (m, 2H), 3.62 (s, 3H), 1.07
(t, J = 7.2 Hz, 3H), 0.70 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 168.0, 167.7, 159.2, 143.6, 135.9, 135.8, 132.8, 129.1,
128.9, 128.6, 128.0, 127.2, 121.8, 120.5, 119.8, 119.6, 113.5, 112.0,
111.8, 110.9, 61.4, 61.1, 56.3, 55.0, 42.5, 14.0, 13.5; HRMS (ESI) m/z:
calcd for C29H29NO5Na [M + Na]+ 494.1938, found 494.1935.
Diethyl 2-((2-Phenyl-1H-indol-3-yl)(o-tolyl)methyl)malonate
1
(3ja). White solid (104 mg, 23% yield); mp 138−139 °C; H NMR
(400 MHz, CDCl3) δ 8.01−7.94 (m, 2H), 7.54 (d, J = 6.4 Hz, 2H),
7.44−7.34 (m, 4H), 7.28−7.23 (m, 1H), 7.16−7.09 (m, 2H), 6.97−
6.87 (m, 3H), 5.46 (d, J = 12.0 Hz, 1H), 4.82 (d, J = 12.0 Hz, 1H),
4.01−3.93 (m, 2H), 3.91−3.74 (m, 2H), 1.86 (s, 3H), 1.00 (t, J = 7.2
Hz, 3H), 0.76 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 168.1, 167.6, 139.6, 136.1, 135.7, 135.2, 133.0, 130.1, 129.0, 128.2,
127.8, 127.2, 126.0, 125.7, 125.1, 121.4, 120.3, 119.3, 111.3, 110.4,
61.0, 60.9, 56.3, 38.0, 19.6, 13.6, 13.2; HRMS (ESI) m/z: calcd for
C29H29NO4Na [M + Na]+ 478.1989, found 478.2004.
132.6, 128.8, 128.7, 128.1, 127.0, 126.2, 124.5, 123.9, 122.0, 120.8,
119.7, 111.8, 110.9, 61.6, 61.1, 57.9, 38.2, 14.0, 13.4; HRMS (ESI) m/
z: calcd for C26H25NSO4Na [M + Na]+ 470.1397, found 470.1418.
2-((2-Phenyl-1H-indol-3-yl)(p-tolyl)methyl)malononitrile (3bb).
1
White solid (282 mg, 78% yield); mp 183−184 °C; H NMR (400
MHz, CDCl3) δ 8.23 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.45 (brs, 4H),
7.36 (d, J = 8.0 Hz, 3H), 7.24−7.19 (m, 1H), 7.18−7.10 (m, 4H), 4.93
(d, J = 10.8 Hz, 1H), 4.67 (d, J = 10.8 Hz, 1H), 2.32 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 137.9, 137.7, 136.0, 134.5, 131.4, 129.6,
129.1, 129.0, 128.1, 128.1, 127.5, 127.2, 122.7, 120.6, 119.4, 112.5,
112.2, 111.7, 44.5, 28.6, 21.2; HRMS (ESI) m/z: calcd for
C25H19N3Na [M + Na]+ 384.1471, found 384.1453.
Diethyl 2-((2-Methyl-1H-indol-3-yl)(phenyl)methyl)malonate
1
(3ka). White solid (284 mg, 75% yield); mp 144−145 °C; H NMR
(400 MHz, CDCl3) δ 7.74 (s, 1H), 7.67−7.63 (m, 1H), 7.37 (d, J =
7.6 Hz, 2H), 7.24−7.15 (m, 3H), 7.11 (t, J = 7.2 Hz, 1H), 7.06−6.99
(m, 2H), 5.04 (d, J = 12.0 Hz, 1H), 4.68 (d, J = 12.0 Hz, 1H), 4.09 (q,
J = 7.2 Hz, 2H), 3.88−3.77 (m, 2H), 2.46 (s, 3H), 1.11 (t, J = 7.2 Hz,
3H), 0.78 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
168.0, 167.8, 141.6, 135.0, 131.9, 128.2 (2C), 127.4 (2C), 127.2, 126.2,
120.7, 119.2, 119.0, 111.3, 110.1, 61.5, 61.2, 55.8, 42.5, 14.0, 13.6, 12.5;
HRMS (ESI) m/z: calcd for C23H25NO4Na [M + Na]+ 402.1676,
found 402.1670.
Dibenzyl 2-((2-Phenyl-1H-indol-3-yl)(p-tolyl)methyl)malonate
(3bc9). White solid (318 mg, 55% yield); mp 125−126 °C; 1H
NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H),
7.45 (d, J = 6.8 Hz, 2H), 7.36 (d, J = 6.8 Hz, 3H), 7.27−7.19 (m, 4H),
7.16−7.02 (m, 9H), 6.90 (d, J = 7.2 Hz, 2H), 6.68 (d, J = 7.2 Hz, 2H),
5.23 (d, J = 12.0 Hz, 1H), 4.96 (brs, 2H), 4.90 (d, J = 12.0 Hz, 1H),
E
DOI: 10.1021/acs.joc.6b02197
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
4.78−4.70 (m, 2H), 2.20 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 167.8, 167.6, 138.7, 135.9, 135.8, 135.7, 135.1, 135.0, 132.6, 129.0,
128.9, 128.6, 128.2, 128.0, 127.9, 127.6, 127.6, 127.3, 127.0, 121.8,
120.6, 119.8, 112.0, 111.0, 67.1, 66.9, 56.3, 42.5, 21.1; HRMS (ESI)
m/z: calcd for C39H33NO4Na [M + Na]+ 602.2302, found 602.2287.
Ethyl 3-Oxo-2-((2-phenyl-1H-indol-3-yl)(p-tolyl)methyl)-
butanoate (3bd). White solid (403 mg, 95% yield). The ratio of
isolated diastereoisomers is 7.8; mp 156−157 °C; 1H NMR (400
MHz, CDCl3) δ 8.03 (s, 1H), 7.84 (d, J = 5.2 Hz, 1H), 7.56 (d, J = 6.8
Hz, 2H), 7.46−7.36 (m, 3H), 7.25−7.21 (m, 1H), 7.14−7.08 (m, 4H),
6.95 (d, J = 7.6 Hz, 2H), [5.21 major, 5.12 minor] (d, J = 12.0 Hz, J =
12.4 Hz 1H), 4.94 (d, J = 12.0 Hz, 1H), [(4.03−3.95) minor, (3.83−
3.70) major] (m, 2H), [2.23 minor, 2.20 major] (s, 3H), [2.12 minor,
2.11 major] (s, 3H), 0.70 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 202.1, 167.8, 138.9, 135.8, 135.7, 132.8, 129.1, 128.9,
128.6, 128.0, 127.4, 127.1, 121.9, 121.8, 120.6, 119.6, 112.6, 110.9, 64.2
major, 63.7 minor, 61.3 minor, 61.1 major, 42.0, 30.0 major, 21.0
minor, 13.5; HRMS (ESI) m/z: calcd for C28H27NO3Na [M + Na]+
448.1883, found 448.1888.
desired products 5ba in a light yellow solid (302 mg, 52% yield); mp
192−193 °C; 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.46 (d, J =
6.8 Hz, 2H), 7.42−7.34 (m, 3H), 7.30 (d, J = 8.0 Hz, 1H), 7.27−7.15
(m, 8H, including CDCl3), 7.13−7.05 (m, 2H), 7.05−6.90 (m, 5H),
6.83 (dd, J1 = 7.6 Hz, J2 = 7.6 Hz, 1H), 6.78 (s, 1H), 5.92 (s, 1H),
[5.15, 5.14] (s, 2H), 2.29 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 140.3, 137.3, 136.1, 135.3, 134.9, 132.8, 129.6, 129.0, 128.8, 128.6,
128.5, 128.3, 128.2, 128.0, 127.4, 126.0, 124.3, 122.3, 121.7, 121.2,
119.3, 118.5, 114.7, 112.3, 111.1, 110.7, 50.1, 38.9, 21.2; HRMS (ESI)
m/z: calcd for C37H29BrN2Na [M + Na]+ 603.1406, found 603.1379.
3-((1H-indol-3-yl)(p-tolyl)methyl)-2-phenyl-1H-indole (5bb). Yel-
1
low oil (144 mg, 35% yield); H NMR (400 MHz, CDCl3) δ 7.94 (s,
1H), 7.79 (s, 1H), 7.46−7.42 (m, 1H), 7.38−7.24 (m, 5H), 7.18−6.77
(m, 11H), 6.73 (s, 1H), [5.95 major, 6.05 minor] (s, 1H), [2.26 major,
2.33 minor] (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 140.9,
136.6, 136.3, 135.0, 133.1, 128.9, 128.8, 128.6, 128.4, 128.2, 128.1,
127.7, 127.5, 127.2, 125.1, 123.8, 121.8, 121.4, 119.8, 119.3, 119.2,
110.8, 110.6, 110.4, 39.3, 21.1; HRMS (ESI) m/z: calcd for
C30H24N2Na [M + Na]+ 435.1831, found 435.1847.
5-Nitro-3-((2-phenyl-1H-indol-3-yl)(p-tolyl)methyl)-1H-indole
Ethyl 4-Chloro-3-oxo-2-((2-phenyl-1H-indol-3-yl)(p-tolyl)methyl)-
butanoate (3be). Yellow solid (391 mg, 85% yield); mp 152−154 °C;
1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.77 (d, J = 7.2 Hz, 1H),
1
(5bc). Yellow solid (352 mg, 77% yield); mp 163−164 °C; H NMR
(400 MHz, CDCl3) δ 8.25 (s, 1H), 8.11 (s, 1H), 8.02−7.93 (m, 2H),
7.50−7.31 (m, 6H), 7.25−7.18 (m, 4H), 7.11−7.02 (m, 3H), 6.92−
6.82 (m, 2H), 5.96 (s, 1H), 2.31 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 141.6, 139.9, 139.4, 136.3, 135.7, 135.5, 132.8, 128.9, 128.8,
128.6, 128.5, 128.2, 128.1, 126.9, 126.2, 122.8, 121.9, 120.9, 119.5,
117.6, 117.0, 114.4, 110.9, 110.7, 39.3, 21.1; HRMS (ESI) m/z: calcd
for C30H23N3O2Na [M + Na]+ 480.1682, found 480.1676.
7.50 (d, J = 7.6 Hz, 2H), 7.46−7.35 (m, 3H), 7.26 (d, J = 7.6 Hz, 1H),
7.22−7.18 (m, 2H), 7.16−7.06 (m, 2H), 6.99 (d, J = 7.6 Hz, 2H), 5.16
(d, J = 12.0 Hz, 1H), 5.09 (d, J = 12.0 Hz, 1H), 4.03−3.89 (m, 3H,
including3.93 [d, J = 16.4 Hz, 1H]), 3.73 (d, J = 16.4 Hz, 1H), 2.23 (s,
3H), 1.04 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
195.1, 167.1, 138.5, 136.1, 135.9, 132.2, 129.0, 128.8, 128.7, 128.3,
127.3, 126.5, 122.2, 120.1, 119.8, 111.5, 111.1, 61.7, 60.3, 48.6, 42.4,
21.0, 13.9; HRMS (ESI) m/z: calcd for C28H26NClO3Na [M + Na]+
482.1493, found 482.1502.
Ethyl 2-Nitro-3-(2-phenyl-1H-indol-3-yl)-3-p-tolylpropanoate
(3bf). Yellow solid (347 mg, 81% yield); mp 148−149 °C; 1H
NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.87 (s, 1H), 7.41 (brs, 5H),
7.31−7.12 (m, 5H), 7.08−6.99 (m, 2H), 6.36 (brm, 1H), 5.36 (brm,
1H), 4.11−3.92 (m, 2H), 2.26 (s, 3H), 1.02 (t, J = 7.0 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 163.5, 137.1, 136.9, 135.8, 135.4,
7-Methyl-3-((2-phenyl-1H-indol-3-yl)(p-tolyl)methyl)-1H-indole
1
(5bd). White solid (102 mg, 24% yield); mp 121−123 °C; H NMR
(400 MHz, CDCl3) δ 7.83 (s, 1H), 7.63 (s, 1H), 7.42−7.38 (m, 2H),
7.33−7.25 (m, 4H), 7.11−6.99 (m, 5H), 6.97−6.91 (m, 3H), 6.87 (t, J
= 7.6 Hz, 2H), 6.67 (s, 1H), 5.93 (s, 1H), 2.45 (s, 3H), 2.25 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 140.3, 135.7, 135.5, 134.5, 134.3,
132.4, 128.2, 128.1, 128.0, 127.8, 127.7, 127.3, 126.9 126.4, 123.4,
121.9, 121.3, 121.2, 119.7, 119.0, 118.8, 117.2, 115.4, 113.8, 110.5,
39.1, 21.5, 17.1; HRMS (ESI) m/z: calcd for C31H26N2Na [M + Na]+
449.1988, found 449.2006.
132.1, 129.3, 128.9, 128.7, 128.5, 128.0, 126.4, 122.2, 120.3, 119.7,
111.4, 109.1, 90.5, 62.8, 44.6, 21.1, 13.7; HRMS (ESI) m/z: calcd for
C26H24N2O4Na [M + Na]+ 451.1628, found 451.1634.
ASSOCIATED CONTENT
■
Ethyl 2-Benzoyl-3-(2-phenyl-1H-indol-3-yl)-3-(p-tolyl)propanoate
(3bg). Light yellow solid (453 mg, 93% yield). The ratio of isolated
diastereoisomers is 2.3; mp 156−157 °C; 1H NMR (400 MHz,
CDCl3) δ [8.05 major, 8.03 minor] (s, 1H), 7.89−7.80 (m, 2H), [7.74
major, 7.65 minor] (d, J = 7.6, J = 7.2 Hz, 2H), 7.54 (d, J = 6.8 Hz,
2H), 7.50−7.34 (m, 5H), 7.30 (d, J = 8.0 Hz, 2H), 7.22−7.19 (m,
1H), 7.16−7.12 (m, 1H), 7.08−6.99 (m, 3H, including 7.02 major [d,
J = 8.0 Hz]), 6.86 minor (d, J = 8.0 Hz, 0.70H), [5.80 minor, 5.78
major] (d, J = 11.2, J = 11.6 Hz, 1H), [5.63 minor, 5.42 major] (d, J =
11.2, J = 11.6 Hz, 1H), 3.94 major (q, J = 7.2 Hz, 1.78H), (3.78−3.60)
minor (m, 0.85H), [2.25 major, 2.14 minor] (s, 3H), [0.97 major, 0.56
minor] (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
193.2, 168.1 major, 167.7 minor, 139.6, 136.7, 135.9, 135.7, 135.6,
133.1, 132.5, 129.1, 128.8, 128.5, 128.2, 128.0 (3C), 127.8, 127.5
major, 127.3 minor, 121.6, 120.3, 119.6, 112.8 minor, 112.7 major,
110.9, 61.3, 58.4, 42.4, 21.0, 14.3 minor, 13.9 major; HRMS (ESI) m/
z: calcd for C33H29NO3Na [M + Na]+ 510.2040, found 510.2046.
Typical Procedure for the Synthesis of 1-Benzyl-5-bromo-3-
((2-phenyl-1H-indol-3-yl)(p-tolyl)methyl)-1H-indole (5ba). The
following components were added to the screw-capped stainless steel
vial: 3-(4-methylbenzyl)-2-phenyl-1H-indole 1b (1 mmol, 297 mg), 1-
benzyl-5-bromo-1H-indole 4a (1 mmol, 286 mg), Fe(NO3)3·9H2O
(0.1 mmol, 40 mg), silica gel (0.6 g), DDQ (1/3 mmol, 76 mg), along
with two stainless steel balls (d = 14 mm). Then, the vial was placed in
a vibrational micromill (milling cycle: 7 min at 25 Hz, followed by 1
min break, in 3 repetitions); during the next two milling intervals, the
other two 1/3 portions of DDQ were added, respectively (total
amount of DDQ = 1 mmol). After the reaction was completed, the
contents were scratched off the vessel and purified directly by column
chromatography on silica gel using PE-EtOAc (15:1) as eluent to give
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b02197.
Optimization of mechanochemical parameters for CDC
1
reaction; copies of H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: pharmlab@zjut.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (No. 21406201) and the Special Program
for Key Basic Research of the Ministry of Science and
Technology of China (No. 2014CB460608) for financial
support.
REFERENCES
■
(1) (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335−344. (b) Girard, S. A.;
Knauber, T.; Li, C.-J. Angew. Chem., Int. Ed. 2014, 53, 74−100.
(2) (a) Bartoccini, F.; Cannas, D. M.; Fini, F.; Piersanti, G. Org. Lett.
2016, 18, 2762−2765. (b) Wencel-Delord, J.; Nimphius, C.; Wang,
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