Copper-Catalyzed Direct C2-Benzylation of Indoles with Alkylarenes

Article abstract of DOI:10.1021/acs.joc.5b01935

The copper-catalyzed regioselective cross-dehydrogenative coupling of N-pyrimidylindoles with benzylic C(sp³)-H bonds has been developed. Di-tert-butyl peroxide was employed as a mild oxidant, and benzaldehyde proved to be an effective additive. This reaction provides a direct and pratical route to a variety of 2-benzylindoles.

Full text of DOI:10.1021/acs.joc.5b01935

Article
pubs.acs.org/joc
Copper-Catalyzed Direct C2-Benzylation of Indoles with Alkylarenes
Hui-Jun Zhang,* Feng Su, and Ting-Bin Wen*
Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, Fujian, P. R. China
S
* Supporting Information
ABSTRACT: The copper-catalyzed regioselective cross-de-
hydrogenative coupling of N-pyrimidylindoles with benzylic
C(sp3)−H bonds has been developed. Di-tert-butyl peroxide
was employed as a mild oxidant, and benzaldehyde proved to
be an effective additive. This reaction provides a direct and
pratical route to a variety of 2-benzylindoles.
(hetero)arylation, and the acylation of indoles has been
investigated.7 Moreover, the unique activity of relatively
cheap and abundant copper salts in C−H functionalization
has recently attracted plenty of interest.8,9 Several examples
concerning the copper-promoted C2−H functionalization of
indoles have been already reported.10,11 In 2008, Gaunt et al.
developed a direct and site-selective C3- and C2-arylation of
indoles with diaryliodine(III) reagents under mild conditions.10
In 2012, Miura and co-workers reported the first copper-
catalyzed oxidative coupling reaction between N-(2-pyrimidyl)-
indoles and 1,3-azoles.11a,b Subsequently, Zhu et al. developed a
copper-mediated C2-cyanation of indoles with acetonitrile.11d
Continuing with our interest in the regioselective C−H
functionalization of indoles,12 we envisioned that the synthesis
of 2-benzylindoles could be readily accomplished employing a
copper-catalyzed regioselective CDC reaction between indoles
and benzylic Csp3−H bonds. To this end, we herein report the
Cu(OAc)2-catalyzed direct C2-benzylation of N-(2-pyrimidyl)-
indoles with alkylarenes (Scheme 1).
INTRODUCTION
■
Indoles are important structural motifs found ubiquitously in
biologically active compounds and pharmaceuticals.1 Therefore,
the construction and functionalization of indole skeletons has
attracted considerable attention.2 Furthermore, the synthesis of
2-benzylindole frameworks is of particular interest, as this
structural motif has been incorporated into a number of
bioactive compounds including luzindole.3−5 Recently, a few
strategies for the construction of 2-benzylindole derivatives
based on the cyclization of suitable substrates were
disclosed.4a−d For example, in 2014, Ghorai et al. reported an
efficient method for the synthesis of 3-substituted 2-
benzylindoles via Pd-catalyzed intramolecular oxidative annu-
lation of o-allylanilines.4b Utilizing more classical methods,
syntheses of 2-benzylindoles based on the regioselective
lithiation of the C2-position of indoles have been extensively
investigated (Scheme 1).5 Unfortunately, however, these
multistep approaches suffer from relatively low yields and
require the use of air- and moisture-sensitive organolithium
reagents.
RESULTS AND DISCUSSION
■
In recent years, cross-dehydrogenative coupling (CDC) has
emerged as an atom-economic and sustainable process.6 In this
context, the transition-metal-catalyzed direct alkenylation,
Our initial study began with the reactions of N-(2-pyrimidyl)-
indole 1a with toluene (2a) in the presence of different
transition-metal catalysts and oxidants. After a careful screening
of reaction conditions (see the Supporting Information), we
found that the direct cross coupling between 1a and 2a took
place in the presence of 10 mol % of Cu(OAc)2, 2 equiv of
DTBP, and 1 equiv of benzaldehyde at 120 °C to afford the
desired product 3aa in 45% yield after 12 h (Table 1). The
homocoupling of 1a that provided the corresponding 2,2′-
bisindole derivative was observed to account for the relatively
low yield of 3aa.11c With the optimized reaction conditions in
hand, the scope of the reaction in regard to both the
arylmethane and indole substrates was surveyed (Table 1). It
was observed that the presence of electron-withdrawing groups
(−Cl, −Br, −CN) on the phenyl ring of arylmethanes slightly
increased the yields of the reaction process to afford the
Scheme 1. 2-Benzylation of Indoles
Received: August 6, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01935
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a,b
Table 1. Scope of Indoles.
a
Reaction conditions: 1a (0.2 mmol), ArMe (2 mL), Cu(OAc)2 (10 mol %), DTBP (2 equiv), and PhCHO (1 equiv) under Ar atmosphere at 120
b
c
°C, sealed tube, 20 h. Isolated yields for the reactions in the absence of PhCHO are shown in parentheses. 12 h.
corresponding products (3ab,ac,af−ah). In addition, substitu-
ents on the phenyl ring of the indole had little effect on the
oxidative cross couplings between 1 and 4-chlorotoluene 2f
(Table 1, 3bf−ff). Notably, the reaction also worked in the
absence of benzaldehyde, whereas the desired products 3 were
isolated in lower yields even after a prolonged reaction times
(Table 1, 3ae−ah).
Subsequently, to prevent the undesired homocoupling of N-
(2-pyrimidyl)indoles 1, the reactions of several C3-substituted
N-(2-pyrimidyl)indoles (1g−k) with 4-chlorotoluene 2f were
performed (Scheme 2, eq 1). To our delight, a series of
toluene, p-xylene, o-xylene, and mesitylene, respectively, to
afford the corresponding products 3ia, 3id, 3ii, and 3ij in high
yields (82−89%). Moreover, the reactions of several aryl-
methanes bearing electron-withdrawing groups (−Cl, −F, −Br,
−CN, −CO2Me, −COMe) with 1i also led to the formation of
the desired 2-benzylation products 3ib−ic,ie,ig,ih,ik,il in good
yields (54−97%). Notably, several C2-benzylation reactions
were performed in the absence of benzaldehyde and still gave
the desired products 3ia,ic,ig,ih in high yields, which may be
ascribed to the inhibition of homocoupling of indoles by the
introduction of bromo group at the C-3 position. Besides
toluene derivatives, 2-methylthiophene (2m) also reacted with
1i, providing the desired product 3im in 63% yield. When
ethylbenzene (2n) was reacted with 1i, the corresponding
benzylation product 3in was obtained in only 37% yield.13
Furthermore, both the electron-rich and electron-deficient
substituents (−OMe, −Me, and −CO2Me) on the phenyl ring
of 3-bromo-N-pyrimidylindoles 1 were compatible, and the
corresponding products 3lf−nf were obtained in good yields
(Table 2, 66−88%).
Scheme 2. Benzylation of 3-Substituted Indoles
Having established the reaction scope, several experiments
were conducted to study the reaction mechanism (Scheme 3).
First, 3-bromo-N-pyrimidylindole 1i alone underwent homo-
coupling in DCE to give 2,2′-bisindole 1i′ in 59% yield, which
suggested the involvement of chelation-assisted C−H cupration
of N-pyrimidylindole in the reaction process (eq 3, also see the
Supporting Information).11c Furthermore, treatment of 1a with
Cu(OAc)2 in the presence of AcOH-d4 at 120 °C led to the
incorporation of deuterium at the C2-position selectively (12 h,
18% D; 24 h, 28% D; eq 4). Exposure of 1i to the same reaction
system led to increased deuterium incorporation (12 h, 35% D;
24 h, 46% D; eq 5), consistent with the improved performance
of 3-bromo-N-pyrimidylindole 1i over 1a in the coupling.
Subsequently, the kinetic isotope effect experiment on 1i and
1i-d (98% D) with toluene was carried out under the standard
conditions resulting in a KIE value of 1.4 (see the Supporting
Information), which indicated that the C2-H cleavage is not
likely to be the rate-limiting step (eq 6). Furthermore, the
intermolecular competing reactions of 1i with toluene and
deuterated toluene exhibited a kinetic isotopic effect of 7.3,
which suggested that the benzylic C−H bond cleavage is more
likely to be involved in the rate-determining step (eq 7). It was
also observed that, upon addition of 1.5 equiv of TEMPO to
substituents at the C3-position of indoles had a significant effect
on the yield of the reaction. Among the five substituents (−Me,
−Cl, −Br, −COMe, −CN) that we tested, the N-
pyrimidylindole with the bromo substituent at the C3-position
gave the best result, and the corresponding product 3if was
obtained in 88% yield. To further explore this reaction process,
3-bromo-1-phenyl-1H-indole 1′ and 4-chlorotoluene 2f were
subjected to the same reaction conditions (eq 2). The
corresponding benzylation product 3′ was not observed,
indicating that the 2-pyrimidinyl directing group is essential
for C2−H bond activation during the reaction process.
Next, the scope of the reaction of 3-bromo-substituted
indoles 1 with various alkylarenes 2 was investigated (Table 2).
Initially, 3-bromo-N-(2-pyrimidyl)indole 1i was reacted with
B
DOI: 10.1021/acs.joc.5b01935
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a,b
Table 2. Benzylation of 3-Bromo-Substituted Indoles
a
Reaction conditions: 1 (0.2 mmol), 2 (2 mL), Cu(OAc)2 (10 mol %), DTBP (2 equiv), and PhCHO (1 equiv) under Ar atmosphere at 120 °C,
b
c
sealed tube, 20 h. Isolated yields for the reactions in the absence of PhCHO are shown in parentheses. 24 h.
the reaction of 1i with toluene, the desired product was only
isolated in 11% yield (see the Supporting Information), which
confirmed the involvement of a radical process.14 The addition
of benzaldehyde in the catalytic system significantly enhanced
the transformation, which might be attributed to the
involvement of benzoyl radical. Subsequently, the cross-
coupling reaction between 1i and 2f using t-BuOOCOPh
instead of DTBP as oxidant was performed, which provided the
corresponding product 3if in only 56% yield (eq 8). Therefore,
the real effect of benzaldehyde in the reaction remains unclear;
however, it is worth mentioning that, in contrast to the previous
results,12a the direct C2-acylation of 1 with benzaldehyde was
not observed under our standard conditions.
On the basis of these observations and the previous
reports,11,15 a tentative mechanism is proposed (Scheme 4).
First, the Cu(OAc)2 precatalyst is transformed to the CuI
catalyst A via disproportionation or reduction by the aldehyde.
The CuI catalyst A could then be reoxidized by DTBP to afford
the active CuII species B and tert-butoxy radical.16 The
coordination-directed C−H cupration of N-(2-pyrimidyl)-
indoles 1 with CuII species affords the metalacycle intermediate
C.17 The benzyl radical that arises from the reaction between
toluene and tert-butoxy radical could interact with intermediate
C to form the desired benzylation product 3 and CuI
species.18−20
Subsequently, we investigated the synthetic applications of
the benzylation product 3ia (Scheme 5). For example, 3-
arylindole 4 was generated in 49% yield from phenylboronic
acid via Suzuki coupling. Application of a Heck reaction
enabled generation of 3-styrylindole 5 in 87% yield.
Furthermore, treatment of 3ia with 3 equiv of benzaldehyde
in the presence of 5 mol % Pd(OAc)2 and 4 equiv of TBHP in
toluene at 120 °C gave rise to 7-benzoylindole derivative 6 in
44% yield. Similar reaction of 3ia with 4 equiv of 4-
chlorobenzaldehyde produced the corresponding 7-acylation
product 7 in 66% yield. In addition, as illustrated in eq 9,
removal of a pyrimidyl group from 2-benzylindole 3aa could be
achieved easily by treating 3aa with NaOEt in DMSO at 110
°C, and the desired product 8 was isolated in 83% yield.
CONCLUSIONS
■
In summary, we have developed an efficient regioselective
copper-catalyzed direct coupling of N-pyrimidylindoles with
alkylarenes. A substituent at the C3-position of indoles has a
significant effect on the reaction selectivity. 3-Bromo-N-
pyrimidylindoles were reacted with various alkylarenes to
afford a series of C2-benzylated indoles in moderate to good
yields. Furthermore, due to the involvement of bromo and
pyrimidyl substituents, the benzylation product 3ia was readily
further functionalized through Pd-catalyzed cross-coupling
C
DOI: 10.1021/acs.joc.5b01935
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Scheme 3. Preliminary Mechanism Study
Scheme 5. Applications of 3-Bromo-Substituted Indole 3ia
indole 1 (0.2 mmol, 1 equiv), Cu(OAc)2 (0.02 mmol, 10 mol %),
benzaldehyde (0.2 mmol, 1 equiv), and 2 mL of alkylarene 2 under the
argon atmosphere. After the reaction mixture was stirred at room
temperature for 2 min, DTBP (0.4 mmol, 2 equiv) was added
dropwise. Then the tube was sealed with a Teflon lined cap, and the
reaction mixture was stirred at 120 °C for 20 h. Subsequently, the
resulting mixture was concentrated under vacuum. The residue was
purified by column chromatography on silica gel (petroleum ether/
ethyl acetate = 30:1−5:1) to afford the product 3.
2-Benzyl-1-(pyrimidin-2-yl)-1H-indole (3aa): white solid; mp 104−
106 °C; yield 45% (25.8 mg); 1H NMR (500 MHz, CDCl3) δ 8.74 (d,
J = 4.8 Hz, 2H), 8.29 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H),
7.26−7.22 (m, 3H), 7.22−7.15 (m, 4H), 7.09 (t, J = 4.8 Hz, 1H), 6.35
(s, 1H), 4.60 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 158.1, 157.9,
140.5, 139.4, 137.1, 129.1, 129.0, 128.2, 126.0, 122.7, 121.8, 119.9,
116.9, 113.9, 107.9, 36.0; HRMS m/z (ESI) calcd for C19H15N3Na (M
+ Na)+ 308.1164, found 308.1156.
Scheme 4. Proposed Mechanism
2-(2-Chlorobenzyl)-1-(pyrimidin-2-yl)-1H-indole (3ab): brown
1
solid; mp 97−98 °C; yield 46% (29.2 mg); H NMR (500 MHz,
CDCl3) δ 8.73 (d, J = 4.8 Hz, 2H), 8.39 (d, J = 8.3 Hz, 1H), 7.55 (d, J
= 7.6 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.29 (dd, J = 9.8, 5.5 Hz, 1H),
7.23 (t, J = 7.4 Hz, 1H), 7.17−7.08 (m, 3H), 7.06 (t, J = 4.8 Hz, 1H),
6.33 (s, 1H), 4.72 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 158.1,
157.9, 138.8, 137.5, 137.1, 134.0, 130.4, 129.2, 129.2, 127.5, 126.7,
122.9, 121.9, 119.9, 116.8, 114.3, 108.2, 33.8; HRMS m/z (ESI) calcd
for C19H14ClN3Na (M + Na)+ 342.0774, found 342.0770.
2-(3-Chlorobenzyl)-1-(pyrimidin-2-yl)-1H-indole (3ac): brown
1
liquid; yield 50% (32 mg); H NMR (500 MHz, CDCl3) δ 8.73 (d,
reactions. The present protocol would provide a useful
synthetic strategy to access to various biologically active 2-
benzylindoles.
J = 4.8 Hz, 2H), 8.33 (dd, J = 8.2, 0.7 Hz, 1H), 7.56 (d, J = 7.1 Hz,
1H), 7.28 (ddd, J = 8.5, 7.3, 1.4 Hz, 1H), 7.24−7.20 (m, 2H), 7.15
(dd, J = 5.0, 1.8 Hz, 2H), 7.10 (t, J = 4.8 Hz, 1H), 7.08−7.05 (m, 1H),
6.40 (s, 1H), 4.58 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 158.1,
158.0, 141.6, 139.4, 137.2, 133.9, 129.4, 129.1, 129.0, 127.1, 126.3,
123.0, 122.0, 120.0, 117.0, 114.2, 108.3, 35.7; HRMS m/z (ESI) calcd
for C19H14ClN3Na (M + Na)+ 342.0774, found 342.0769.
EXPERIMENTAL SECTION
General Information. All reactions were carried out under Ar
■
atmosphere. Toluene was distilled from sodium. All other commercial
reagents were used without further purification. H and 13C NMR
1
2-(4-Methylbenzyl)-1-(pyrimidin-2-yl)-1H-indole (3ad): brown
1
liquid; yield 48% (28.5 mg); H NMR (500 MHz, CDCl3) δ 8.75
spectra were recorded at 500 MHz in CDCl3 as solvent. High-
resolution mass spectra were recorded on an FT-MS instrument using
the ESI technique.
General Procedures for Direct C2-Benzylation of Indoles
with Alkylarenes. To a 25 mL tube were added N-(2-pyrimidyl)-
(d, J = 4.8 Hz, 2H), 8.29 (d, J = 8.3 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H),
7.27−7.23 (m, 1H), 7.20 (t, J = 7.3 Hz, 1H), 7.11−7.04 (m, 5H), 6.33
(s, 1H), 4.55 (s, 2H), 2.31 (s, 3H); 13C NMR (126 MHz, CDCl3) δ
158.2, 158.0, 140.9, 137.2, 136.2, 135.5, 129.2, 128.9, 122.7, 121.8,
D
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119.8, 116.9, 113.9, 107.7, 35.5, 21.0; HRMS m/z (ESI) calcd for
C20H17N3Na (M + Na)+ 322.1320, found 322.1314.
107.5, 105.0, 35.2; HRMS m/z (ESI) calcd for C20H13ClN4Na (M +
Na)+ 367.0726, found 367.0722.
2-(4-Fluorobenzyl)-1-(pyrimidin-2-yl)-1H-indole (3ae): brown
liquid; yield 46% (28.1 mg); H NMR (500 MHz, CDCl3) δ 8.73
Methyl 2-(4-chlorobenzyl)-1-(pyrimidin-2-yl)-1H-indole-5-car-
boxylate (3ff): brown solid; mp 100−102 °C; yield 49% (37 mg);
1H NMR (500 MHz, CDCl3) δ 8.74 (d, J = 4.8 Hz, 2H), 8.28 (dd, J =
5.0, 3.5 Hz, 2H), 7.96 (dd, J = 8.9, 1.2 Hz, 1H), 7.20 (d, J = 8.3 Hz,
2H), 7.14 (t, J = 4.8 Hz, 1H), 7.08 (d, J = 8.3 Hz, 2H), 6.43 (s, 1H),
4.55 (s, 2H), 3.95 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 167.8,
158.1, 157.6, 141.3, 139.7, 137.4, 131.9, 130.2, 128.6, 128.4, 124.3,
123.8, 122.4, 117.6, 113.6, 108.4, 51.8, 35.2; HRMS m/z (ESI) calcd
for C21H16ClN3O2Na (M + Na)+ 400.0829, found 400.0826.
1
(dd, J = 4.7, 1.2 Hz, 2H), 8.30 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 7.6 Hz,
1H), 7.26 (d, J = 8.1 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 7.16−7.12 (m,
2H), 7.09 (t, J = 4.7 Hz, 1H), 6.92 (t, J = 8.0 Hz, 2H), 6.36 (s, 1H),
4.57 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 161.3 (d, J = 243.8 Hz),
158.1, 158.0, 140.2, 137.2, 135.0 (d, J = 3.2 Hz), 130.3 (d, J = 7.9 Hz),
129.0, 122.9, 121.9, 119.9, 117.0, 114.9 (d, J = 21.2 Hz), 114.0, 107.9,
35.2; HRMS m/z (ESI) calcd for C19H14FN3Na (M + Na)+ 326.1069,
found 326.1064.
2-(4-Chlorobenzyl)-3-methyl-1-(pyrimidin-2-yl)-1H-indole (3gf):
1
yellow solid; yield 56% (37.2 mg); H NMR (500 MHz, CDCl3) δ
2-(4-Chlorobenzyl)-1-(pyrimidin-2-yl)-1H-indole (3af): yellow
1
8.65 (d, J = 4.8 Hz, 2H), 8.34−8.28 (m, 1H), 7.62−7.60 (m, 1H),
7.33−7.26 (m, 2H), 7.13−7.10 (m, 2H), 7.01 (t, J = 4.8 Hz, 1H), 6.97
(d, J = 8.6 Hz, 2H), 4.64 (s, 2H), 2.38 (s, 3H); 13C NMR (126 MHz,
CDCl3) δ 158.0, 157.9, 138.6, 136.4, 134.1, 131.3, 130.2, 129.4, 128.1,
123.3, 121.6, 118.2, 116.6, 114.8, 113.9, 31.5, 9.0; HRMS m/z (ESI)
calcd for C20H16ClN3Na (M + Na)+ 356.0930, found 356.0923.
3-Chloro-2-(4-chlorobenzyl)-1-(pyrimidin-2-yl)-1H-indole (3hf):
solid; mp 109−110 °C; yield 53% (33.6 mg); H NMR (500 MHz,
CDCl3) δ 8.73 (d, J = 4.7 Hz, 2H), 8.31 (d, J = 8.3 Hz, 1H), 7.54 (d, J
= 7.8 Hz, 1H), 7.29−7.25 (m, 1H), 7.23−7.18 (m, 3H), 7.13−7.08 (m,
3H), 6.37 (s, 1H), 4.57 (s, 2H); 13C NMR (126 MHz, CDCl3) δ
158.0, 157.9, 139.7, 138.0, 137.1, 131.8, 130.2, 129.0, 128.3, 122.9,
121.9, 119.9, 117.0, 114.1, 108.1, 35.4; HRMS m/z (ESI) calcd for
C19H14ClN3Na (M + Na)+ 342.0774, found 342.0770.
1
white solid; mp 99−100 °C ; yield 77% (54.7 mg); H NMR (500
2-(4-Bromobenzyl)-1-(pyrimidin-2-yl)-1H-indole (3ag): brown
1
MHz, CDCl3) δ 8.67 (d, J = 4.8 Hz, 2H), 8.38−8.32 (m, 1H), 7.72−
7.67 (m, 1H), 7.39−7.31 (m, 2H), 7.14−7.09 (m, 2H), 7.07 (t, J = 4.8
Hz, 1H), 7.01 (d, J = 8.6 Hz, 2H), 4.74 (s, 2H); 13C NMR (126 MHz,
CDCl3) δ 158.0, 157.5, 137.4, 135.3, 134.2, 131.6, 129.5, 128.2, 126.7,
124.4, 122.5, 117.9, 117.3, 114.4, 111.6, 31.4; HRMS m/z (ESI) calcd
for C19H13Cl2N3Na (M + Na)+ 376.0384, found 376.0380.
solid; mp 112−113 °C; yield 54% (39.2 mg); H NMR (500 MHz,
CDCl3) δ 8.73 (d, J = 4.8 Hz, 2H), 8.32 (d, J = 8.2 Hz, 1H), 7.54 (d, J
= 7.1 Hz, 1H), 7.39−7.32 (m, 2H), 7.29−7.25 (m, 1H), 7.21 (td, J =
7.4, 0.9 Hz, 1H), 7.10 (t, J = 4.8 Hz, 1H), 7.06 (d, J = 8.3 Hz, 2H),
6.37 (s, 1H), 4.55 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 158.1,
158.0, 139.6, 138.5, 137.2, 131.3, 130.6, 129.0, 123.0, 122.0, 119.93,
119.85, 117.0, 114.1, 108.2, 35.5; HRMS m/z (ESI) calcd for
C19H14BrN3Na (M + Na)+ 386.0269, found 386.0265.
3-Bromo-2-(4-chlorobenzyl)-1-(pyrimidin-2-yl)-1H-indole (3if):
1
yellow solid; mp 115−117 °C; yield 88% (70.2 mg); H NMR (500
MHz, CDCl3) δ 8.67 (d, J = 4.8 Hz, 2H), 8.35−8.30 (m, 1H), 7.68−
7.65 (m, 1H), 7.39−7.33 (m, 2H), 7.15−7.11 (m, 2H), 7.07 (t, J = 4.8
Hz, 1H), 7.01 (d, J = 8.6 Hz, 2H), 4.76 (s, 2H); 13C NMR (126 MHz,
CDCl3) δ 158.0, 157.4, 137.3, 135.90, 135.88, 131.6, 129.5, 128.2,
128.1, 124.4, 122.6, 119.0, 117.4, 114.3, 99.7, 32.5; HRMS m/z (ESI)
calcd for C19H13BrClN3Na (M + Na)+ 419.9879, found 419.9877.
2-(4-Chlorobenzyl)-1-(pyrimidin-2-yl)-1H-indole-3-carbonitrile
(3kf): white solid; yield 77% (53.2 mg); 1H NMR (500 MHz, CDCl3)
δ 8.77 (d, J = 4.8 Hz, 2H), 8.19−8.10 (m, 1H), 7.81−7.74 (m, 1H),
7.41−7.35 (m, 2H), 7.24 (t, J = 4.8 Hz, 1H), 7.14−7.07 (m, 2H), 6.96
(d, J = 8.5 Hz, 2H), 4.80 (s, 2H); 13C NMR (126 MHz, CDCl3) δ
158.4, 156.7, 147.4, 136.0, 135.7, 132.3, 129.6, 128.5, 127.0, 125.0,
123.7, 119.1, 118.9, 115.4, 114.4, 92.4, 33.2; HRMS m/z (ESI) calcd
for C20H13ClN4Na (M + Na)+ 367.0726, found 367.0721.
4-((1-(Pyrimidin-2-yl)-1H-indol-2-yl)methyl)benzonitrile (3ah):
1
yellow liquid; yield 58% (36 mg); H NMR (500 MHz, CDCl3) δ
8.70 (d, J = 4.6 Hz, 2H), 8.36 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 7.7 Hz,
1H), 7.51 (d, J = 7.9 Hz, 2H), 7.31−7.23 (m, 4H), 7.08 (t, J = 4.7 Hz,
1H), 6.43 (s, 1H), 4.67 (s, 2H); 13C NMR (126 MHz, CDCl3) δ
158.0, 157.9, 145.5, 138.2, 137.1, 132.0, 129.5, 128.9, 123.3, 122.1,
120.0, 119.0, 117.0, 114.4, 109.9, 108.8, 36.2; HRMS m/z (ESI) calcd
for C20H14N4Na (M + Na)+ 333.1116, found 333.1111.
2-(4-Chlorobenzyl)-5-methoxy-1-(pyrimidin-2-yl)-1H-indole
(3bf): brown liquid; yield 45% (31.8 mg); 1H NMR (500 MHz,
CDCl3) δ 8.69 (d, J = 4.8 Hz, 2H), 8.30 (d, J = 9.1 Hz, 1H), 7.22−7.19
(m, 2H), 7.12 (d, J = 8.5 Hz, 2H), 7.05 (t, J = 4.8 Hz, 1H), 7.02 (d, J =
2.5 Hz, 1H), 6.91 (dd, J = 9.1, 2.6 Hz, 1H), 6.29 (s, 1H), 4.57 (s, 2H),
3.88 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 158.0, 157.9, 155.5,
140.5, 138.1, 132.0, 131.7, 130.2, 129.8, 128.3, 116.7, 115.4, 111.9,
108.2, 102.3, 55.7, 35.7; HRMS m/z (ESI) calcd for C20H16ClN3ONa
(M + Na)+ 372.0880, found 372.0875.
2-Benzyl-3-bromo-1-(pyrimidin-2-yl)-1H-indole (3ia): pale yellow
solid; mp 115−117 °C; yield 82% (59.8 mg, for the reaction without
1
PhCHO); H NMR (500 MHz, CDCl3) δ 8.69 (d, J = 4.8 Hz, 2H),
8.26−8.20 (m, 1H), 7.65−7.60 (m, 1H), 7.35−7.30 (m, 2H), 7.12 (t, J
= 7.3 Hz, 2H), 7.10−7.06 (m, 2H), 7.05−7.01 (m, 2H), 4.79 (s, 2H);
13C NMR (126 MHz, CDCl3) δ 158.0, 157.5, 138.7, 136.5, 136.0,
128.23, 128.15, 128.1, 125.9, 124.2, 122.5, 119.0, 117.4, 114.0, 99.5,
33.0; HRMS m/z (ESI) calcd for C19H14BrN3Na (M + Na)+ 386.0269,
found 386.0266.
2-(4-Chlorobenzyl)-5-methyl-1-(pyrimidin-2-yl)-1H-indole (3cf):
brown liquid; yield 37% (24.6 mg); H NMR (500 MHz, CDCl3) δ
1
8.70 (d, J = 4.8 Hz, 2H), 8.24 (d, J = 8.5 Hz, 1H), 7.33 (s, 1H), 7.23−
7.17 (m, 2H), 7.13−7.08 (m, 3H), 7.05 (t, J = 4.8 Hz, 1H), 6.31 (s,
1H), 4.57 (s, 2H), 2.47 (s, 3H); 13C NMR (126 MHz, CDCl3) δ
158.1, 157.9, 139.8, 138.1, 135.4, 131.7, 131.3, 130.2, 129.3, 128.3,
124.3, 119.8, 116.7, 114.0, 108.0, 35.5, 21.3; HRMS m/z (ESI) calcd
for C20H16ClN3Na (M + Na)+ 356.0930, found 356.0926.
3-Bromo-2-(4-methylbenzyl)-1-(pyrimidin-2-yl)-1H-indole (3id):
1
pale brown solid; mp 86−88 °C; yield 89% (67.3 mg); H NMR
(500 MHz, CDCl3) δ 8.70 (d, J = 4.8 Hz, 2H), 8.27−8.23 (m, 1H),
7.66−7.62 (m, 1H), 7.35−7.32 (m, 2H), 7.08 (t, J = 4.8 Hz, 1H), 6.93
(s, 4H), 4.76 (s, 2H), 2.23 (s, 3H); 13C NMR (126 MHz, CDCl3) δ
158.0, 157.5, 136.8, 136.0, 135.6, 135.3, 128.8, 128.2, 128.0, 124.1,
122.4, 119.0, 117.4, 114.0, 99.3, 32.5, 20.9; HRMS m/z (ESI) calcd for
C20H16BrN3Na (M + Na)+ 400.0425, found 400.0423.
5-Chloro-2-(4-chlorobenzyl)-1-(pyrimidin-2-yl)-1H-indole (3df):
1
yellow solid; mp 75−78 °C; yield 45% (31.5 mg); H NMR (500
MHz, CDCl3) δ 8.72 (d, J = 4.8 Hz, 2H), 8.26 (d, J = 8.9 Hz, 1H),
7.49 (d, J = 2.1 Hz, 1H), 7.21 (d, J = 8.4 Hz, 3H), 7.11 (dd, J = 11.4,
6.6 Hz, 3H), 6.29 (s, 1H), 4.56 (s, 2H); 13C NMR (126 MHz, CDCl3)
δ 158.0, 157.8, 141.3, 137.6, 135.5, 131.9, 130.2, 130.1, 128.4, 127.4,
123.0, 119.3, 117.3, 115.4, 107.4, 35.5; HRMS m/z (ESI) calcd for
C19H13Cl2N3Na (M + Na)+ 376.0384, found 376.0380.
3-Bromo-2-(2-methylbenzyl)-1-(pyrimidin-2-yl)-1H-indole (3ii):
1
white solid; mp 182−186 °C; yield 87% (66.0 mg); H NMR (500
MHz, CDCl3) δ 8.61 (d, J = 4.8 Hz, 2H), 8.34−8.25 (m, 1H), 7.70−
7.62 (m, 1H), 7.40−7.32 (m, 2H), 7.09 (d, J = 7.4 Hz, 1H), 6.99 (dd, J
= 10.1, 5.5 Hz, 2H), 6.89 (t, J = 7.4 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H),
4.72 (s, 2H), 2.41 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 157.9,
157.5, 136.9, 136.0, 135.9, 135.6, 129.6, 128.3, 127.2, 125.78, 125.76,
124.2, 122.5, 118.9, 117.3, 114.1, 100.0, 30.6, 19.7; HRMS m/z (ESI)
calcd for C20H16BrN3Na (M + Na)+ 400.0425, found 400.0424.
2-(4-Chlorobenzyl)-1-(pyrimidin-2-yl)-1H-indole-5-carbonitrile
1
(3ef): pale yellow solid; mp 110−111 °C; yield 42% (28.8 mg); H
NMR (500 MHz, CDCl3) δ 8.78 (d, J = 4.8 Hz, 2H), 8.32 (d, J = 8.7
Hz, 1H), 7.85 (d, J = 1.1 Hz, 1H), 7.49 (dd, J = 8.7, 1.6 Hz, 1H),
7.24−7.18 (m, 3H), 7.09 (d, J = 8.4 Hz, 2H), 6.39 (s, 1H), 4.56 (s,
2H); 13C NMR (126 MHz, CDCl3) δ 158.3, 157.4, 142.5, 138.8,
137.0, 132.2, 130.2, 128.8, 128.5, 126.0, 124.9, 120.3, 118.1, 114.8,
E
DOI: 10.1021/acs.joc.5b01935
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3-Bromo-2-(3,5-dimethylbenzyl)-1-(pyrimidin-2-yl)-1H-indole
(3ij): brown liquid; yield 88% (69.4 mg); 1H NMR (500 MHz, CDCl3)
δ 8.71 (d, J = 4.8 Hz, 2H), 8.26−8.20 (m, 1H), 7.67−7.63 (m, 1H),
7.36−7.31 (m, 2H), 7.09 (t, J = 4.8 Hz, 1H), 6.71 (s, 1H), 6.65 (s,
2H), 4.72 (s, 2H), 2.17 (s, 6H); 13C NMR (126 MHz, CDCl3) δ
158.0, 157.6, 138.5, 137.5, 136.8, 136.0, 128.2, 127.6, 126.0, 124.1,
122.4, 119.0, 117.4, 113.9, 99.1, 32.7, 21.2; HRMS m/z (ESI) calcd for
C21H18BrN3Na (M + Na)+ 414.0582, found 414.0573.
117.5, 114.4, 100.1, 33.4, 26.5; HRMS m/z (ESI) calcd for
C21H16BrN3ONa (M + Na)+ 428.0374, found 428.0373.
3-Bromo-1-(pyrimidin-2-yl)-2-(thiophen-2-ylmethyl)-1H-indole
1
(3im): yellow solid; mp 92−93 °C; yield 63% (46.5 mg); H NMR
(500 MHz, CDCl3) δ 8.77 (d, J = 4.8 Hz, 2H), 8.35−8.30 (m, 1H),
7.64−7.59 (m, 1H), 7.37−7.29 (m, 2H), 7.15 (t, J = 4.8 Hz, 1H), 7.01
(dd, J = 5.1, 1.2 Hz, 1H), 6.78 (dd, J = 5.1, 3.5 Hz, 1H), 6.73−6.69 (m,
1H), 4.98 (d, J = 0.8 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 158.1,
157.6, 141.2, 136.0, 135.8, 128.2, 126.4, 125.1, 124.4, 123.6, 122.6,
119.1, 117.5, 114.4, 99.1, 27.9; HRMS m/z (ESI) calcd for
C17H12BrN3SNa (M + Na)+ 391.9833, found 391.9829.
3-Bromo-2-(2-chlorobenzyl)-1-(pyrimidin-2-yl)-1H-indole (3ib):
1
pale yellow solid; mp 163−164 °C; yield 71% (56.3 mg); H NMR
(500 MHz, CDCl3) δ 8.64 (d, J = 4.8 Hz, 2H), 8.42−8.34 (m, 1H),
7.70−7.62 (m, 1H), 7.40−7.34 (m, 2H), 7.32 (dd, J = 7.9, 1.3 Hz,
1H), 7.07−6.94 (m, 3H), 6.82 (dd, J = 7.7, 1.4 Hz, 1H), 4.85 (s, 2H);
13C NMR (126 MHz, CDCl3) δ 158.0, 157.4, 136.6, 135.8, 135.1,
133.4, 129.0, 128.8, 128.2, 127.1, 126.6, 124.4, 122.6, 119.0, 117.2,
114.6, 100.6, 31.1; HRMS m/z (ESI) calcd for C19H13BrClN3Na (M +
Na)+ 419.9879, found 419.9876.
3-Bromo-2-(1-phenylethyl)-1-(pyrimidin-2-yl)-1H-indole (3in):
pale brown liquid; yield 37% (29.4 mg); 1H NMR (500 MHz,
CDCl3) δ 8.72 (d, J = 4.8 Hz, 2H), 7.92 (dd, J = 5.8, 3.3 Hz, 1H), 7.60
(dd, J = 5.7, 3.2 Hz, 1H), 7.29 (dt, J = 4.1, 2.3 Hz, 2H), 7.23 (d, J = 7.8
Hz, 2H), 7.19 (t, J = 7.6 Hz, 2H), 7.14 (t, J = 4.8 Hz, 1H), 7.10 (t, J =
7.1 Hz, 1H), 5.17 (q, J = 7.2 Hz, 1H), 1.98 (d, J = 7.3 Hz, 3H); 13C
NMR (126 MHz, CDCl3) δ 158.3, 157.5, 142.9, 140.5, 135.7, 128.5,
127.8, 127.3, 125.7, 124.0, 122.3, 118.8, 118.0, 112.8, 97.1, 36.5, 18.0;
HRMS m/z (ESI) calcd for C20H16BrN3Na (M + Na)+ 400.0425,
found 400.0421.
3-Bromo-2-(3-chlorobenzyl)-1-(pyrimidin-2-yl)-1H-indole (3ic):
yellow solid; mp 96−98 °C; yield 79% (62.7 mg, for the reaction
without PhCHO); 1H NMR (500 MHz, CDCl3) δ 8.70 (d, J = 4.8 Hz,
2H), 8.35−8.25 (m, 1H), 7.69−7.60 (m, 1H), 7.40−7.30 (m, 2H),
7.15−7.01 (m, 4H), 6.96−6.91 (m, 1H), 4.75 (s, 2H); 13C NMR (126
MHz, CDCl3) δ 158.1, 157.5, 140.9, 135.9, 135.6, 133.9, 129.4, 128.39,
128.2, 126.3, 126.1, 124.4, 122.6, 119.1, 117.5, 114.3, 99.9, 32.9;
HRMS m/z (ESI) calcd for C19H13BrClN3Na (M + Na)+ 419.9879,
found 419.9874.
3-Bromo-2-(4-chlorobenzyl)-5-methoxy-1-(pyrimidin-2-yl)-1H-in-
1
dole (3lf): white solid; mp 123−124 °C, yield 66% (56.9 mg); H
NMR (500 MHz, CDCl3) δ 8.65 (d, J = 4.8 Hz, 2H), 8.26 (d, J = 9.1
Hz, 1H), 7.14−7.10 (m, 2H), 7.07 (d, J = 2.5 Hz, 1H), 7.05 (t, J = 4.8
Hz, 1H), 7.01 (d, J = 8.5 Hz, 2H), 6.97 (dd, J = 9.1, 2.6 Hz, 1H), 4.74
(s, 2H), 3.94 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 157.9, 157.4,
156.1, 137.4, 136.4, 131.6, 130.6, 129.5, 128.9, 128.2, 117.2, 115.8,
113.9, 100.9, 99.7, 55.8, 32.8; HRMS m/z (ESI) calcd for
C20H15BrClN3ONa (M + Na)+ 449.9985, found 449.9985.
3-Bromo-2-(4-fluorobenzyl)-1-(pyrimidin-2-yl)-1H-indole (3ie):
1
white solid; mp 106−107 °C; yield 97% (73.9 mg); H NMR (500
MHz, CDCl3) δ 8.69 (d, J = 4.8 Hz, 2H), 8.26 (ddd, J = 5.0, 2.3, 0.6
Hz, 1H), 7.67−7.59 (m, 1H), 7.34 (ddd, J = 4.8, 2.1, 1.1 Hz, 2H), 7.09
(t, J = 4.8 Hz, 1H), 7.03−6.98 (m, 2H), 6.85−6.78 (m, 2H), 4.75 (s,
2H); 13C NMR (126 MHz, CDCl3) δ 161.2 (d, J = 243.8 Hz), 158.1,
157.5, 136.3, 135.9, 134.3 (d, J = 3.2 Hz), 129.5 (d, J = 7.9 Hz), 128.2,
124.3, 122.6, 119.1, 117.5, 114.9 (d, J = 21.3 Hz), 114.1, 99.5, 32.3;
HRMS m/z (ESI) calcd for C19H13BrFN3Na (M + Na)+ 404.0175,
found 404.0169.
3-Bromo-2-(4-chlorobenzyl)-5-methyl-1-(pyrimidin-2-yl)-1H-in-
1
dole (3mf). white solid; mp 109−110 °C; yield 75% (62.3 mg); H
NMR (500 MHz, CDCl3) δ 8.66 (d, J = 4.8 Hz, 2H), 8.21 (d, J = 8.5
Hz, 1H), 7.43 (s, 1H), 7.17 (d, J = 8.5 Hz, 1H), 7.11 (d, J = 8.4 Hz,
2H), 7.05 (t, J = 4.8 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 4.75 (s, 2H),
2.53 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 157.9, 157.5, 137.5,
135.9, 134.2, 132.3, 131.5, 129.5, 128.3, 128.2, 125.9, 118.8, 117.2,
114.3, 99.6, 32.7, 21.3; HRMS m/z (ESI) calcd for C20H15BrClN3Na
(M + Na)+ 434.0036, found 434.0033.
3-Bromo-2-(4-bromobenzyl)-1-(pyrimidin-2-yl)-1H-indole (3ig):
pale yellow solid; mp 133−134 °C; yield 86% (76.0 mg, for the
reaction without PhCHO); 1H NMR (500 MHz, CDCl3) δ 8.67 (d, J
= 4.8 Hz, 2H), 8.32 (dd, J = 6.0, 3.2 Hz, 1H), 7.66 (dd, J = 5.9, 3.2 Hz,
1H), 7.41−7.32 (m, 2H), 7.28 (d, J = 8.1 Hz, 2H), 7.07 (t, J = 4.8 Hz,
1H), 6.95 (d, J = 8.2 Hz, 2H), 4.74 (s, 2H); 13C NMR (126 MHz,
CDCl3) δ 158.1, 157.4, 137.8, 135.9, 135.8, 131.2, 129.9, 128.1, 124.4,
122.6, 119.7, 119.1, 117.5, 114.3, 99.8, 32.7; HRMS m/z (ESI) calcd
for C19H13Br2N3Na (M + Na)+ 463.9374, found 463.9367.
4-((3-Bromo-1-(pyrimidin-2-yl)-1H-indol-2-yl)methyl)benzonitrile
(3ih): white solid; mp 123−125 °C; yield 78% (60.4 mg, for the
reaction without PhCHO); 1H NMR (500 MHz, CDCl3) δ 8.67 (d, J
= 4.8 Hz, 2H), 8.38−8.33 (m, 1H), 7.66−7.62 (m, 1H), 7.47−7.43 (m,
2H), 7.39−7.33 (m, 2H), 7.19 (d, J = 8.5 Hz, 2H), 7.10 (t, J = 4.8 Hz,
1H), 4.82 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 158.1, 157.4,
144.7, 135.9, 134.7, 132.0, 128.9, 128.1, 124.7, 122.8, 119.2, 118.9,
117.5, 114.6, 109.8, 100.5, 33.6; HRMS m/z (ESI) calcd for
C20H13BrN4Na (M + Na)+ 411.0221, found 411.0216.
Methyl 3-bromo-2-(4-chlorobenzyl)-1-(pyrimidin-2-yl)-1H-indole-
5-carboxylate (3nf): white solid; mp 141−143 °C; yield 88% (80.1
1
mg); H NMR (500 MHz, CDCl3) δ 8.70 (d, J = 4.8 Hz, 2H), 8.35
(dd, J = 1.7, 0.5 Hz, 1H), 8.25 (dd, J = 8.8, 0.5 Hz, 1H), 8.02 (dd, J =
8.8, 1.8 Hz, 1H), 7.14 (t, J = 4.8 Hz, 1H), 7.10 (d, J = 8.5 Hz, 2H),
6.96 (d, J = 8.6 Hz, 2H), 4.72 (s, 2H), 3.99 (s, 3H); 13C NMR (126
MHz, CDCl3) δ 167.4, 158.2, 157.1, 138.5, 137.5, 136.8, 131.8, 129.4,
128.3, 127.9, 125.6, 124.6, 121.5, 118.1, 114.0, 99.9, 52.0, 32.5; HRMS
m/z (ESI) calcd for C21H15BrClN3O2Na (M + Na)+ 477.9934, found
477.9939.
3,3′-Dibromo-1,1′-di(pyrimidin-2-yl)-1H,1′H-2,2′-biindole (1i′).
1
yellow solid; mp 222−223 °C; yield 59% (32.1 mg); H NMR (500
MHz, CDCl3) δ 8.58 (d, J = 8.4 Hz, 2H), 8.38 (d, J = 4.8 Hz, 4H),
7.70 (d, J = 7.9 Hz, 2H), 7.47−7.44 (m, 2H), 7.41−7.35 (m, 2H), 6.87
(t, J = 4.8 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 157.7, 157.3,
135.6, 129.0, 128.6, 125.1, 122.6, 119.6, 116.7, 115.4, 102.4; HRMS m/
z (ESI) calcd for C24H14Br2N6Na (M + Na)+ 566.9544, found
566.9547.
Methyl 4-((3-bromo-1-(pyrimidin-2-yl)-1H-indol-2-yl)methyl)-
benzoate (3ik): white solid; mp 167−168 °C; yield 80% (67.5 mg);
1H NMR (500 MHz, CDCl3) δ 8.65 (d, J = 4.8 Hz, 2H), 8.32−8.30
(m, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.67−7.62 (m, 1H), 7.38−7.31 (m,
2H), 7.13 (d, J = 8.0 Hz, 2H), 7.07 (t, J = 4.5 Hz, 1H), 4.83 (s, 2H),
3.86 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 167.0, 158.0, 157.3,
144.4, 135.9, 135.4, 129.4, 128.4, 128.1, 127.8, 124.4, 122.6, 119.0,
117.4, 114.3, 99.9, 51.9, 33.4; HRMS m/z (ESI) calcd for
C21H16BrN3O2Na (M + Na)+ 444.0324, found 444.0320.
1-(4-((3-Bromo-1-(pyrimidin-2-yl)-1H-indol-2-yl)methyl)phenyl)-
ethanone (3il): brown solid; mp 104−106 °C; yield 66% (53.6 mg);
1H NMR (500 MHz, CDCl3) δ 8.66 (d, J = 4.7 Hz, 2H), 8.34−8.29
(m, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.66−7.62 (m, 1H), 7.38−7.32 (m,
2H), 7.16 (d, J = 8.2 Hz, 2H), 7.08 (t, J = 4.7 Hz, 1H), 4.83 (s, 2H),
2.51 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 197.8, 158.1, 157.4,
144.7, 135.9, 135.4, 135.1, 128.30, 128.28, 128.2, 124.5, 122.7, 119.1,
Experimental Procedure for the Synthesis of 2-Benzyl-3-
phenyl-1-(pyrimidin-2-yl)-1H-indole (4). To a 25 mL tube were
added 3ia (0.2 mmol, 1 equiv), PhB(OH)2 (0.8 mmol, 4 equiv),
Pd(PPh3)4 (0.01 mmol, 5 mol %), K3PO4 (0.6 mmol, 3 equiv), and 1
mL of 1,4-dioxane under Ar atmosphere. The tube was sealed with a
Teflon-lined cap, and the reaction mixture was stirred at 70 °C for 18
h. The resulting mixture was concentrated under vacuum, and the
residue was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1−10:1) to afford the desired
product 4: 35.3 mg, yield 49%; white solid; mp 140−141 °C; 1H NMR
(500 MHz, CDCl3) δ 8.65 (d, J = 4.8 Hz, 2H), 8.22 (d, J = 8.3 Hz,
1H), 7.65 (d, J = 7.9 Hz, 1H), 7.59 (dd, J = 8.1, 1.2 Hz, 2H), 7.49 (t, J
= 7.7 Hz, 2H), 7.38 (t, J = 7.4 Hz, 1H), 7.34−7.29 (m, 1H), 7.27−7.23
F
DOI: 10.1021/acs.joc.5b01935
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(m, 1H), 7.06 (t, J = 7.3 Hz, 2H), 7.03−6.97 (m, 2H), 6.92 (d, J = 7.0
Hz, 2H), 4.74 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 158.0, 157.9,
140.0, 136.5, 135.1, 134.4, 130.2, 129.1, 128.6, 127.98, 127.96, 126.9,
125.5, 123.5, 122.9, 121.7, 119.2, 117.1, 113.5, 32.4; HRMS m/z (ESI)
calcd for C25H19N3Na (M + Na)+ 384.1477, found 384.1476.
Experimental Procedure for the Synthesis of 2-Benzyl-1-
(pyrimidin-2-yl)-3-styryl-1H-indole (5). To a 25 mL tube were
added 3ia (0.2 mmol, 1 equiv), styrene (0.8 mmol, 4 equiv),
Pd(PPh3)4 (0.02 mmol, 10 mol %), Et3N (2 mmol, 10 equiv), and 1.5
mL of DMF under Ar atmosphere. Then the tube was sealed with a
Teflon lined cap, and the reaction mixture was stirred at 100 °C for 36
h. The resulting mixture was concentrated under vacuum, and the
residue was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give the desired product
5: 67.6 mg, yield 87%; pale yellow liquid; 1H NMR (500 MHz,
CDCl3) δ 8.70 (d, J = 4.8 Hz, 2H), 8.23−8.20 (m, 1H), 8.12−8.10 (m,
1H), 7.57 (d, J = 7.3 Hz, 2H), 7.46 (d, J = 16.4 Hz, 1H), 7.40 (t, J =
7.7 Hz, 2H), 7.38−7.27 (m, 4H), 7.15 (t, J = 7.3 Hz, 2H), 7.11−7.02
(m, 4H), 4.83 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 158.0, 157.7,
139.4, 138.4, 137.5, 137.0, 129.1, 128.6, 128.2, 128.1, 127.5, 127.0,
126.0, 125.8, 123.5, 122.3, 120.9, 119.9, 117.4, 116.9, 113.6, 32.0;
HRMS m/z (ESI) calcd for C27H21N3Na (M + Na)+ 410.1633, found
410.1631.
Experimental Procedures for the C7-Acylation of 3ia with
Aldehydes. To a 25 mL tube were added 3ia (0.2 mmol, 1 equiv),
aldehyde (PhCHO: 0.6 mmol; p-Cl-PhCHO: 0.8 mmol), Pd(OAc)2
(0.02 mmol, 10 mol %), TBHP in decane (0.8 mmol, 4 equiv), and 0.4
mL of toluene under Ar atmosphere. Then the tube was sealed with a
Teflon lined cap, and the reaction mixture was stirred at 120 °C for 18
h. Finally, the resulting mixture was concentrated under vacuum, and
the residue was purified by column chromatography on silica gel or by
PTLC (petroleum ether/ethyl acetate = 5:1) to afford the desired
product.
128.7, 126.7, 121.3, 120.0, 119.7, 110.4, 101.1, 34.7; HRMS m/z (ESI)
calcd for C15H13NNa (M + Na)+ 230.0946, found 230.0946.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01935.
■
S
Text, figures, and tables giving optimization and
mechanism study details; NMR spectra for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: meghjzhang@xmu.edu.cn.
*E-mail: chwtb@xmu.edu.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the Natural Science
Foundation of China (No. 21302157), Program for Changjiang
Scholars and Innovative Research Team in University
(PCSIRT), and Fundamental Research Funds for the Central
Universities (No. 2013121015). We also thank Dr. Daniel
Priebbenow (Monash University, Australia) for useful dis-
cussions.
REFERENCES
■
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66% (66.4 mg); H NMR (500 MHz, CDCl3) δ 8.29 (d, J = 4.8 Hz,
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Experimental Procedure for the Synthesis of 2-Benzyl-1H-
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