Rh(III)-Catalyzed C-H Amidation of Indoles with Isocyanates

Article abstract of DOI:10.1021/acs.joc.5b00763

The rhodium(III)-catalyzed direct amidation of indoles and pyrroles with aryl and alkyl isocyanates is described. These transformations provide a facile and efficient construction of C2-amidated N-heterocyclic scaffolds. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.joc.5b00763

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Note
Rh(III)-Catalyzed C–H Amidation of Indoles with Isocyanates
Taejoo Jeong, Sangil Han, Neeraj Kumar Mishra, Satyasheel Sharma, Seok-
Yong Lee, Joa Sub Oh, Jong Hwan Kwak, Young Hoon Jung, and In Su Kim
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 24 Jun 2015
Downloaded from http://pubs.acs.org on June 25, 2015
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The Journal of Organic Chemistry
Rh(III)-Catalyzed C–H Amidation of Indoles with Isocyanates
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Taejoo Jeong,a,† Sangil Han,a,† Neeraj Kumar Mishra,a Satyasheel Sharma,a Seok-Yong Lee,a Joa
Sub Oh,b Jong Hwan Kwak,a Young Hoon Jung,a and In Su Kim*,a
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a School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
b College of Pharmacy, Dankook University, Cheonan 330-714, Republic of Korea
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* Corresponding author. Tel.: +82-31-290-7788; fax: +82-31-292-8800; e-mail: insukim@skku.edu
† These authors equally contributed.
Abstract
The rhodium(III)-catalyzed direct amidation of indoles and pyrroles with aryl and alkyl isocyanates
is described. These transformations provide the facile and efficient construction of C2-amidated N-
heterocyclic scaffolds.
Indoles and pyrroles are among the most interesting heterocycles in nature and have been recognized
as privileged structural motifs in drug discovery.1 Consequently, there are many powerful methods for the
synthesis and functionalization of these scaffolds.2 In particular, C2-amidated indoles and pyrroles are
known to have diverse biological profiles, including androgen receptor inhibition, protein kinase
inhibition, DPP-4 inhibition, allosteric modulation of cannabinoid receptor, selective inhibition of β-
amyloid (Figure 1).3 The synthetic methods for the formation of C2-amidated indoles and pyrroles relies
on the traditional approaches such as amidation reaction between carboxylic acid derivatives and amines,4
coupling reactions of dilithioindoles with isocyanates,5 Beckmann rearrangement of indoles with an
oxime group at the C2-position,6 and the palladium-catalyzed carbonylation of C2-halogenated indoles
using amines and carbon monoxide.7 However, these protocols have inherent limitations including the
preparation of prefunctionalized indoles, stoichiometric use of metallic reagents, harsh reaction conditions
as well as the use of hazardous CO gas. In complement to previous protocols, it is desirable to develop
more efficient methodologies for synthesizing indole-2-carboxamides and pyrrole-2-carboxamides with
fewer synthetic steps that avoid waste formation.
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Figure 1. Selected examples for bioactive C2-amidated indoles and pyrroles.
In last decades, a great deal of effort has been devoted to the transition-metal-catalyzed direct
functionalization of inactive C–H bonds with various coupling partners.8 In this context, there has been
recent progress in the area of the transition-metal-catalyzed direct additions of C(sp2)–H bonds to
polarized C–O9 and C–N10 multiple bonds. For example, Murai demonstrated the Ir-catalyzed coupling
reaction of imidazoles with aldehydes in the presence of trialkylsilanes to quench the C–O bonds to
facilitate the catalytic cycle.9a Larock disclosed the Pd-catalyzed arene C–H activation and intermolecular
carbopalladation of nitriles.10a,b Kuninobu and Takai reported the Re-catalyzed intermolecular reaction of
aromatic aldimines with alkynes and isocyanates to give indene and phthalimidine derivatives via
insertion of unsaturated compounds and intramolecular annulation reaction.10c Ellman and Bergman11 and
Shi12 independently described the Rh(III)-catalyzed redox-neutral imine insertion of aryl C–H bonds to
deliver amine products. In addition, Li,13 Kim,14 Shi,15 and Zhou and Li16 reported the Rh(III)-catalyzed
direct addition of C–H bonds to aldehydes to afford ketones and alcohols. Thus, these protocols represent
a catalytic alternative to transcend the barriers imposed by classical Grignard reaction.
Recently, further exploration of this reactivity mode revealed that various directing groups can also
facilitate the arylation of polar C–N π-bond of isocyanates. In this area, acetanilides,17 phenylpyridines,18
oximes,19 and benzoic acid derivatives20 were efficiently coupled with isocyanates to afford the
corresponding ortho-amidated products under Rh, Ru and Re catalysis. Inspired by our recent study on
the site-selective functionalization of heterocycles21 and in consideration of the biological importance of
C2-amidated indoles and pyrroles, we herein present the Rh(III)-catalyzed direct C2-addition of indoles
and pyrroles to isocyanates via C–H bond activation.
Our study was initiated by examining the coupling of 1-(pyrimidin-2-yl)-1H-indole (1a) and n-butyl
isocyanate (2a) under rhodium catalysis (Table 1). Initial experiments indicated that the cationic rhodium
complex, derived from [RhCp*Cl2]2 and AgSbF6, was found to catalyze the coupling of 1a and 2a in
o
dichloroethane (DCE) at 100 C for 24 h to provide C2-amidated indole 3a in 60% yield (Table 1, entry
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1). However, cationic ruthenium and cobalt catalysts are found to be ineffective for this transformation
(Table 1, entries 2 and 3). Exclusion of either Rh catalyst or AgSbF6 additive resulted in no formation of
the desired product 3a (Table 1, entries 4 and 5). After screening of a range of solvents, DCE was found
to exhibit the highest reactivity (Table 1, entries 6–9). Screening of silver salts revealed that AgSbF6
additive was found to be the most effective in this coupling reaction (Table 1, entries 10 and 11). Further
study revealed that acetate additives failed to facilitate high levels of conversion reaction (Table 1, entries
12 and 13). To our delight, the optimal result was obtained by use of increased amount of Rh catalyst and
Ag additive to afford our desired product 3a in 81% yield (Table 1, entry 14). However, a decreased
loading of isocyanate 2a under otherwise identical conditions led to a decreased formation of 3a (Table 1,
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entry 15). In addition, this reaction can proceed under air conditions or at lower temperature (60 C) to
give 3a, albeit in relatively low yields (Table 1, entries 16 and 17).
Table 1. Selected optimization of reaction conditions.a
Entry
Catalyst (mol %)
Additive (mol %)
Solvent
Yield (%)b
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2
[RhCp*Cl2]2 (2.5)
[Ru(p-Cy)Cl2]2 (2.5)
CoCp*(CO)I2 (2.5)
[RhCp*Cl2]2 (2.5)
AgSbF6 (10)
AgSbF6 (10)
AgSbF6 (10)
DCE
DCE
DCE
DCE
DCE
THF
60
N.R.
12
3
4
N.R.
N.R.
54
5
AgSbF6 (10)
AgSbF6 (10)
6
[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (5)
[RhCp*Cl2]2 (5)
[RhCp*Cl2]2 (5)
[RhCp*Cl2]2 (5)
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AgSbF6 (10)
MeCN
DMSO
PhCl
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
50
8
AgSbF6 (10)
N.R.
35
9
AgSbF6 (10)
10
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14
15c
16d
AgNTf2 (10)
52
AgBF4 (10)
48
AgSbF6 (10) + NaOAc (30)
AgSbF6 (10) + Cu(OAc)2 (30)
AgSbF6 (20)
51
24
81
AgSbF6 (20)
64
AgSbF6 (20)
60
17e
AgSbF6 (20)
52
a
Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), catalyst (quantity noted), additive (quantity noted),
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o
solvent (1 mL) under N2 atmosphere at 100 C for 24 h in reaction tubes. Isolated yield by flash column
b
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chromatography. c 2a (0.4 mmol, 2 equiv.). d Under air conditions. e 60 oC.
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With the optimal reaction conditions in hands, various directing groups on indoles 1b–1e were
examined for C2-amidation with n-butyl isocyanate (2a), as shown in Table 2. Indole 1b containing a
pyridinyl directing group provided our desired product 3b in 48% yield. However, indoles 1c–1e with
carbonyl directing groups, such as pivaloyl, benzoyl and N,N-dimethylcarbamoyl groups, did not deliver
the coupling product. These results suggest that nitrogen-containing heterocyclic directing groups are
very crucial for this transformation.
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Table 2. Screening of directing groups.a
a Reaction conditions: 1a–1e (0.2 mmol), 2a (0.6 mmol), [RhCp*Cl2]2 (5 mol %), AgSbF6 (20 mol %), DCE (1
mL) under N2 atmosphere at 100 oC for 24 h in reaction tubes. b Isolated yield by flash column chromatography.
To evaluate the scope and limitation of this process, various indoles 1f–1n were screened under the
optimal reaction conditions, as shown in Table 3. Indoles 1f–1k bearing electron-rich and electron-
deficient groups (OMe, NO2, Br, Cl and F) at the C4-, C5- and C6-positions were found to undergo
coupling with n-butyl isocyanate (2a) affording the corresponding products 3f–3k, whereas C7-
substituted indole 1l was found to be less reactive under these reaction conditions. Notably, the bromo
and chloro moieties on amidated indoles 3h and 3i offer the opportunity for further transformations by
empolying other traditional cross-coupling reactions. In addition, sterically congested C3-substituted
indole 1m and 2,3-disubstituted pyrrole 1n also participated in this catalytic amidation reaction to furnish
3m and 3n in moderate yields. Finally, 2-(1H-pyrrol-1-yl)pyrimidine (1o) and 2-(3-methyl-1H-pyrrol-1-
yl)pyrimidine (1p) underwent bis-amidation reaction under slightly modified reaction conditions to afford
3o and 3p in high yields, respectively.
Table 3. Scope of indoles and pyrroles.a
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a Reaction conditions: 1f–1p (0.2 mmol), 2a (0.6 mmol), [RhCp*Cl2]2 (5 mol %), AgSbF6 (20 mol %), DCE (1
b
mL) under N2 atmosphere at 100 oC for 24 h in reaction tubes. Isolated yield by flash column chromatography. c
60 oC, 1 h.
Table 4. Scope of isocyanates.a
a Reaction conditions: 1a (0.2 mmol), 2a–2m (0.6 mmol), [RhCp*Cl2]2 (5 mol %), AgSbF6 (20 mol %), DCE
(1 mL) under N2 atmosphere at 100 oC for 24 h in reaction tubes. b Isolated yield by flash column chromatography.
To further explore the scope of this transformation, the optimal reaction conditions were applied to a
range of alkyl-, aryl- and arylsulfonyl isocyanates 2b–2m (Table 4). In case of alkyl isocyanates 2b–2f,
the desired indolic C2-amidation adducts were obtained in moderate to good yields. Exceptionally, benzyl
isocyanate (2g) and cyclopentyl isocyanate (2h) exhibited the slightly decreased reactivity. In addition,
aryl isocyanates 2i–2l with electron-rich and electron-deficient groups (Me, Br and CF3) were tolerated
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under current reaction conditions to afford the corresponding products 4i–4l. However, highly electron-
deficient phenylsulfonyl isocyanate (2m) did not deliver the corresponding coupling product.
Based on the above results, we considered that the moderate to low yields obtained from aryl
isocyanates 2i–2l might be possibly attributed to the reversibility of amidation. Thus we performed the
reversibility experiment using 4k under the standard reaction conditions, which provided 1a in 50% yield
(Scheme 1, eq. 1). Previously, the similar reversible process was observed by Bergman and Ellman in the
Rh(III)-catalyzed coupling reaction between 2-phenylpyridines and N-Boc-imines.11a In addition, this
reversible reaction was further confirmed by the treatment of n-butyl acrylate (5a) to afford C2-
alkenylated indole 6a in 65% yield (Scheme 1, eq. 2).22
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Scheme 1. Reversibility experiments.
Meanwhile, the deprotection of a pyrimidyl directing group on C2-amidated indoles 3a and 4k was
carried out, as shown in Scheme 2. First, treatment of 3a under the standard reaction condition (NaOEt,
o
DMSO, 100 C)23 afforded the desired product 7a in low yield (16%). After further optimization, the
cleavage of pyrimidinyl directing group was found to increase by additional use of EtOH affording C2-
amidated free-(NH)-indoles 7a (42%) and 7b (52%).24
Scheme 2. Removal of directing group on indoles.
A plausible reaction mechanism for the Rh(III)-catalyzed amidation reaction of indoles with
isocyanates is depicted in Scheme 3. Cationic Rh(III) catalyst,25 derived from [RhCp*Cl2]2 and AgSbF6,
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can coordinate to pyrimidinyl nitrogen atom, which can reversibly activate the C–H bond at the indolic
C2-position providing cyclorhodated intermediate A26 (see Supporting Information for H/D exchange
experiment) and the release of one equivalent of proton (H+). Subsequent coordination of isocyanate
furnishes intermediate B, which on migratory insertion into the Rh–C bond deliver the complex C.
Finally, protonation of C affords our desired product and the regeneration of active Rh(III) catalyst.
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1/2 [RhCp*Cl2]2
O
H
N
AgSbF6
HN
R
N
N
N
N
N
[RhCp*]2+
3
1
H+
+
O
Cp*
R
Rh
N
N
N
N
Rh
N
Cp*
N
N
A
C
O
C
N
R
Cp*
Rh
2
N
O
C N
N
R
N
B
Scheme 3. Proposed reaction mechanism.
In conclusion, we disclosed a selective C2-amidation of indoles and pyrroles with isocyanates under
rhodium catalysis. These transformations have been applied to a wide range of substrates, and typically
proceed with excellent levels of chemoselectivity as well as with high functional group tolerance.
Experimental Section
General procedure for the synthesis of heteroarenes substrates (1a, 1b and 1f–1p): Indoles and
pyrroles containing a 2-pyrimidinyl and 2-pyridinyl directing groups were prepared as described in
previous literatures.27
Typical procedure for C2-amidation of indoles and pyrrole 1a–1p with isocyanates 2a–2m: To
an oven-dried sealed tube charged with 1-(pyrimidin-2-yl)-1H-indole (1a) (39.1 mg, 0.2 mmol, 100
mol %), [RhCp*Cl2]2 (6.2 mg, 0.01 mmol, 5 mol %), and AgSbF6 (13.7 mg, 0.04 mmol, 20 mol %) were
added n-butyl isocyanate (2a) (67.5 µL, 0.6 mmol, 300 mol %) and DCE (1 mL) under N2 atmosphere.
The reaction mixture was allowed to stir at 100 oC for 24 h and cooled to room temperature. The reaction
mixture was diluted with EtOAc (3 mL) and concentrated in vacuo. The residue was purified by flash
column chromatography (n-hexanes/EtOAc = 2:1) to afford 48 mg of 3a in 81% yield.
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N-Butyl-1-(pyrimidin-2-yl)-1H-indole-2-carboxamide (3a): 48.0 mg (81%); Brown solid; mp =
241.7–244.6 °C; 1H NMR (700 MHz, CDCl3) δ 8.69 (d, J = 4.2 Hz, 2H), 8.26 (d, J = 8.4 Hz, 1H), 7.57 (d,
J = 7.7 Hz, 1H), 7.34 (t, J = 8.4 Hz, 1H), 7.21 (t, J = 7.0 Hz, 1H), 7.10 (t, J = 4.9 Hz, 1H), 6.89 (s, 1H),
6.34 (s, 1H), 3.38 (q, J = 7.0 Hz, 2H), 1.57–1.55 (m, 2H), 1.42–1.38 (m, 2H), 0.94 (t, J = 7.7 Hz, 3H); 13C
NMR (175 MHz, CDCl3) δ 162.8, 157.9, 157.2, 137.5, 134.7, 127.8, 125.2, 122.3, 121.5, 117.5, 113.8,
109.1, 39.4, 31.5, 19.9, 13.7; IR (KBr) υ 3249, 2927, 2870, 1637, 1556, 1417, 1344, 1286, 1233, 1192,
1145, 1058, 977, 817, 742 cm-1; HRMS (quadrupole, EI) calcd for C17H18N4O [M]+ 294.1481, found
294.1479.
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N-Butyl-1-(pyridin-2-yl)-1H-indole-2-carboxamide (3b): 28.2 mg (48%); White solid; mp = 96.5–
99.4 °C; 1H NMR (700 MHz, CDCl3) δ 8.59 (d, J = 4.2 Hz, 1H), 7.87 (t, J = 7.7 Hz, 1H), 7.64 (d, J = 7.7
Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.33 (t, J = 6.3 Hz, 1H), 7.27 (t, J = 7.0 Hz,
1H), 7.19 (t, J = 7.7 Hz, 1H), 6.44 (s, 1H), 3.35 (q, J = 7.0 Hz, 2H), 1.52–1.50 (m, 2H), 1.36–1.32 (m,
2H), 0.92 (t, J = 7.7 Hz, 3H); 13C NMR (175 MHz, CDCl3) δ 161.7, 151.5, 149.1, 138.5, 138.2, 134.0,
127.0, 124.8, 122.5, 121.9, 121.6, 121.3, 111.1, 107.4, 39.3, 31.5, 20.0, 13.7; IR (KBr) υ 3284, 3054,
2924, 2855, 1641, 1546, 1467, 1447, 1387, 1350, 1273, 1225, 1148, 809, 739 cm-1; HRMS (quadrupole,
EI) calcd for C18H19N3O [M]+ 293.1528, found 293.1522.
N-Butyl-4-methoxy-1-(pyrimidin-2-yl)-1H-indole-2-carboxamide (3f): 39.6 mg (61%); Light
yellow solid; mp = 142.5–147.5 °C; 1H NMR (700 MHz, CDCl3) δ 8.74 (d, J = 4.2 Hz, 2H), 7.80 (d, J =
8.4 Hz, 1H), 7.27 (t, J = 7.7 Hz, 1H), 7.16 (t, J = 4.9 Hz, 1H), 7.07 (s, 1H), 6.64 (d, J = 8.4 Hz, 1H), 6.17
(s, 1H), 3.96 (s, 3H), 3.44–3.41 (m, 2H), 1.62–1.59 (m, 2H), 1.45–1.42 (m, 2H), 0.96 (t, J = 7.7 Hz, 3H);
13C NMR (175 MHz, CDCl3) δ 162.6, 158.0, 157.5, 153.6, 139.0, 133.3, 126.3, 118.4, 117.8, 106.6, 106.4,
102.2, 55.4, 39.4, 31.6, 20.2, 13.8; IR (KBr) υ 3297, 2923, 2854, 1637, 1541, 1432, 1360, 1296, 1255,
1227, 1183, 1109, 1080, 985, 853, 822, 757, 722 cm-1; HRMS (quadrupole, EI) calcd for C18H20N4O2
[M]+ 324.1586, found 324.1586.
N-Butyl-4-nitro-1-(pyrimidin-2-yl)-1H-indole-2-carboxamide (3g): 35.3 mg (52%); Dark brown
solid; mp = 160.5–164.2 °C; 1H NMR (700 MHz, CDCl3) δ 8.79 (d, J = 4.2 Hz, 2H), 8.52 (d, J = 8.4 Hz,
1H), 8.16 (d, J = 7.7 Hz, 1H), 7.60 (s, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.27 (t, J = 4.9 Hz, 1H), 6.54 (s, 1H),
3.46 (q, J = 7.0 Hz, 2H), 1.67–1.64 (m, 2H), 1.48–1.45 (m, 2H), 0.99 (t, J = 7.7 Hz, 3H); 13C NMR (175
MHz, CDCl3) δ 161.7, 158.3, 156.7, 140.8, 138.9, 138.3, 124.2, 122.1, 120.6, 119.6, 118.8, 107.5, 39.7,
31.6, 20.0, 13.7; IR (KBr) υ 3291, 2928, 1644, 1549, 1505, 1420, 1333, 1286, 1226, 991, 824, 760, 733
cm-1; HRMS (quadrupole, EI) calcd for C17H17N5O3 [M]+ 339.1331, found 339.1326.
5-Bromo-N-butyl-1-(pyrimidin-2-yl)-1H-indole-2-carboxamide (3h): 38.1 mg (51%); Light
yellow solid; mp = 180.0–182.5 °C; 1H NMR (700 MHz, CDCl3) δ 8.72 (d, J = 3.5 Hz, 2H), 8.18 (d, J =
8.4 Hz, 1H), 7.71 (s, 1H), 7.41 (d, J = 9.1 Hz, 1H), 7.17 (t, J = 3.5 Hz, 1H), 6.82 (s, 1H), 6.21 (s, 1H),
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3.43 (q, J = 5.6 Hz, 2H), 1.63–1.59 (m, 2H), 1.46–1.42 (m, 2H), 0.97 (t, J = 6.3 Hz, 3H); 13C NMR (175
MHz, CDCl3) δ 162.5, 158.0, 157.0, 136.1, 135.8, 129.6, 128.1, 124.0, 117.9, 115.6, 115.5, 108.1, 39.5,
31.5, 20.0, 13.8; IR (KBr) υ 3265, 2921, 2852, 1637, 1554, 1426, 1378, 1333, 1290, 1210, 1051, 863, 801,
754, 717 cm-1; HRMS (quadrupole, EI) calcd for C17H17BrN4O [M]+ 372.0586, found 372.0580.
N-Butyl-5-chloro-1-(pyrimidin-2-yl)-1H-indole-2-carboxamide (3i): 40.1 mg (61%); Light
yellow solid; mp = 167.4–171.8 °C; 1H NMR (700 MHz, CDCl3) δ 8.72 (d, J = 4.9 Hz, 2H), 8.23 (d, J =
9.1 Hz, 1H), 7.54 (s, 1H), 7.28 (dd, J = 8.4, 2.1 Hz, 1H), 7.16 (t, J = 4.9 Hz, 1H), 6.82 (s, 1H), 6.23 (s,
1H), 3.43 (q, J = 7.0 Hz, 2H), 1.63–1.59 (m, 2H), 1.46–1.41 (m, 2H), 0.97 (t, J = 7.7 Hz, 3H); 13C NMR
(175 MHz, CDCl3) δ 162.6, 158.0, 157.0, 136.0, 135.8, 129.0, 127.9, 125.5, 120.9, 117.8, 115.2, 108.2,
39.5, 31.5, 20.0, 13.8; IR (KBr) υ 3276, 2927, 2871, 1642, 1556, 1425, 1335, 1290, 1229, 1067, 879, 804,
713, 656 cm-1; HRMS (quadrupole, EI) calcd for C17H17ClN4O [M]+ 328.1091, found 328.1092.
N-Butyl-5-nitro-1-(pyrimidin-2-yl)-1H-indole-2-carboxamide (3j): 30.5 mg (45%); Light brown
solid; mp = 205.0–206.8 °C; 1H NMR (700 MHz, CDCl3) δ 8.77 (d, J = 4.9 Hz, 2H), 8.50 (s, 1H), 8.31 (d,
J = 9.1 Hz, 1H), 8.18 (d, J = 9.1 Hz, 1H), 7.26 (t, J = 4.9 Hz, 1H), 7.0 (s, 1H), 6.30 (s, 1H), 3.45 (q, J =
7.0 Hz, 2H), 1.65–1.63 (m, 2H), 1.48–1.44 (m, 2H), 0.98 (t, J = 7.0 Hz, 3H); 13C NMR (175 MHz,
CDCl3) δ 161.9, 158.2, 156.6, 143.5, 140.0, 137.8, 127.5, 120.3, 118.7, 118.2, 114.3, 109.2, 39.7, 31.5,
20.0, 13.7; IR (KBr) υ 3271, 2926, 1642, 1565, 1511, 1422, 1332, 1296, 1280, 1072, 896, 812, 731, 655
cm-1; HRMS (quadrupole, EI) calcd for C17H17N5O3 [M]+ 339.1331, found 339.1333.
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N-Butyl-6-fluoro-1-(pyrimidin-2-yl)-1H-indole-2-carboxamide (3k): 34.4 mg (55%); Light
yellow solid; mp = 146.3–148.1 °C; 1H NMR (700 MHz, CDCl3) δ 8.73 (d, J = 4.9 Hz, 2H), 8.05 (d, J =
10.5 Hz, 1H), 7.53 (t, J = 8.4 Hz, 1H), 7.17 (t, J = 4.2 Hz, 1H), 6.99 (td, J = 9.8, 2.1 Hz, 1H), 6.89 (s, 1H),
6.15 (s, 1H), 3.43 (q, J = 7.0 Hz, 2H), 1.63–1.59 (m, 2H), 1.46–1.43 (m, 2H), 0.97 (t, J = 7.0 Hz, 3H); 13C
NMR (175 MHz, CDCl3) δ 162.6, 161.5 (d, JC-F = 239.4 Hz), 158.0, 157.1, 137.9, 135.3 (d, JC-F = 4.2 Hz),
124.2, 122.4 (d, JC-F = 10.1 Hz), 117.8, 111.2 (d, JC-F = 24.3 Hz), 109.0, 101.1 (d, JC-F = 28.3 Hz), 39.5,
31.6, 20.0, 13.8; IR (KBr) υ 3272, 2927, 2869, 1644, 1617, 1552, 1473, 1423, 1357, 1291, 1234, 1211,
1134, 977, 858, 834, 736, 673 cm-1; HRMS (quadrupole, EI) calcd for C17H17FN4O [M]+ 312.1386, found
312.1383.
N-Butyl-7-methyl-1-(pyrimidin-2-yl)-1H-indole-2-carboxamide (3l): 16.1 mg (26%); Light
yellow solid; mp = 130.2–131.6 °C; 1H NMR (700 MHz, CDCl3) δ 9.11 (d, J = 4.9 Hz, 2H), 7.78 (d, J =
8.4 Hz, 1H), 7.66 (t, J = 4.9 Hz, 1H), 7.52 (s, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.28 (t, J = 7.0 Hz, 1H), 6.53
(s, 1H), 3.57 (q, J = 7.0 Hz, 2H), 2.15 (s, 3H), 1.80–1.78 (m, 2H), 1.64–1.60 (m, 2H), 1.18 (t, J = 7.7 Hz,
3H); 13C NMR (175 MHz, CDCl3) δ 161.4, 159.8, 158.0, 137.5, 133.5, 127.4, 127.3, 122.3, 121.6, 120.2,
119.9, 106.2, 39.3, 31.6, 20.0, 19.1, 13.7; IR (KBr) υ 3327, 2924, 1636, 1549, 1421, 1282, 1243, 911, 829,
772, 728 cm-1; HRMS (quadrupole, EI) calcd for C18H20N4O [M]+ 308.1637, found 308.1632.
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N-Butyl-3-methyl-1-(pyrimidin-2-yl)-1H-indole-2-carboxamide (3m): 33.4 mg (54%); Yellow
solid; mp = 176.4–181.3 °C; 1H NMR (700 MHz, CDCl3) δ 8.68 (d, J = 4.9 Hz, 2H), 8.45 (d, J = 8.4 Hz,
1H), 7.57 (d, J = 7.7 Hz, 1H), 7.35 (t, J = 7.0 Hz, 1H), 7.26 (t, J = 9.1 Hz, 1H), 7.06 (t, J = 4.9 Hz, 1H),
5.84 (s, 1H), 3.47 (q, J = 7.0 Hz, 2H), 2.44 (s, 3H), 1.63–1.60 (m, 2H), 1.45–1.41 (m, 2H), 0.97 (t, J = 7.7
Hz, 3H); 13C NMR (175 MHz, CDCl3) δ 163.7, 157.8, 157.5, 136.6, 131.3, 129.9, 125.4, 122.2, 119.6,
117.7, 116.7, 114.6, 39.6, 31.6, 20.1, 13.8, 9.3; IR (KBr) υ 3285, 2926, 2868, 2363, 1698, 1623, 1558,
1424, 1348, 1280, 1224, 1159, 1074, 947, 759, 744, 700 cm-1; HRMS (quadrupole, EI) calcd for
C18H20N4O [M]+ 308.1637, found 308.1642.
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N-Butyl-4-oxo-1-(pyrimidin-2-yl)-4,5,6,7-tetrahydro-1H-indole-2-carboxamide (3n): 28.2 mg
(45%); Yellow oil; 1H NMR (700 MHz, CDCl3) δ 8.79 (d, J = 4.9 Hz, 2H), 7.34 (t, J = 4.9 Hz, 1H), 6.98
(s, 1H), 6.11 (s, 1H), 3.30 (q, J = 7.0 Hz, 2H), 2.87 (t, J = 5.6 Hz, 2H), 2.52 (t, J = 6.3 Hz, 2H), 2.14 (t, J
= 6.3 Hz, 2H), 1.54–1.52 (m, 2H), 1.39–1.35 (m, 2H), 0.92 (t, J = 7.7 Hz, 3H); 13C NMR (175 MHz,
CDCl3) δ 194.6, 160.8, 158.4, 156.8, 147.7, 130.0, 120.9, 120.0, 109.1, 39.2, 37.8, 31.6, 23.3, 22.9, 20.0,
13.7; IR (KBr) υ 3298, 2923, 2854, 2139, 1640, 1554, 1416, 1296, 1223, 1129, 1087, 997, 898, 817, 751,
718 cm-1; HRMS (quadrupole, EI) calcd for C17H20N4O2 [M]+ 312.1586, found 312.1585.
N,N'-Dibutyl-1-(pyrimidin-2-yl)-1H-pyrrole-2,5-dicarboxamide (3o): 64.5 mg (94%); White
solid; mp = 244.7–246.2 °C; 1H NMR (700 MHz, CDCl3) δ 8.78 (d, J = 4.9 Hz, 2H), 7.35 (t, J = 4.9 Hz,
1H), 6.60 (s, 2H), 6.17 (br s, 2H), 3.26 (q, J = 7.0 Hz, 4H), 1.51–1.46 (m, 4H), 1.34–1.31 (m, 4H), 0.90 (t,
J = 7.0 Hz, 6H); 13C NMR (175 MHz, CDCl3) δ 160.2, 158.5, 158.0, 131.6, 120.2, 111.1, 39.2, 31.6, 20.6,
13.7; IR (KBr) υ 3322, 3301, 2924, 1643, 1542, 1414, 1283, 822, 739 cm-1; HRMS (quadrupole, EI)
calcd for C18H25N5O2 [M]+ 343.2008, found 343.2009.
N,N'-Dibutyl-3-methyl-1-(pyrimidin-2-yl)-1H-pyrrole-2,5-dicarboxamide (3p): 65.0 mg (91%);
Light yellow oil; 1H NMR (700 MHz, CDCl3) δ 8.68 (d, J = 4.9 Hz, 2H), 7.27 (t, J = 4.9 Hz, 1H), 6.87 (br
s, 1H), 6.33 (s, 1H), 6.30 (br s, 1H), 3.24–3.21 (m, 2H), 3.18–3.15 (m, 2H), 2.15 (s, 3H), 1.46–1.40 (m,
4H), 1.31–1.26 (m, 4H), 0.88–0.84 (m, 6H); 13C NMR (175 MHz, CDCl3) δ 161.2, 160.5, 158.2, 157.7,
129.7, 129.0, 121.5, 119.7, 114.2, 39.1, 39.0, 31.5, 20.0, 19.9, 13.6, 12.3; IR (KBr) υ 3309, 3203, 1708,
1636, 1561, 1520, 1428, 1413, 1255, 1147, 817, 756 cm-1; HRMS (quadrupole, EI) calcd for C19H27N5O2
[M]+ 357.2165, found 357.2166.
N-Ethyl-1-(pyrimidin-2-yl)-1H-indole-2-carboxamide (4b): 41.0 mg (77%); Yellow sticky solid;
1H NMR (700 MHz, CDCl3) δ 8.76 (br s, 2H), 8.28 (d, J = 7.7 Hz, 1H), 7.62 (d, J = 7.0 Hz, 1H), 7.36 (t, J
= 7.0 Hz, 1H), 7.26–7.23 (m, 1H), 7.17 (s, 1H), 6.94 (s, 1H), 6.20 (s, 1H), 3.47 (s, 2H), 1.26 (s, 3H); 13C
NMR (175 MHz, CDCl3) δ 162.8, 157.9, 157.3, 137.6, 134.7, 127.9, 125.3, 122.4, 121.6, 117.7, 113.9,
109.3, 34.7, 14.7; IR (KBr) υ 3283, 2924, 1642, 1556, 1419, 1345, 1284, 1231, 1148, 931, 810, 741, 657
cm-1; HRMS (quadrupole, EI) calcd for C15H14N4O [M]+ 266.1168, found 266.1174.
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N-Pentyl-1-(pyrimidin-2-yl)-1H-indole-2-carboxamide (4c): 37.6 mg (61%); Yellow oil; 1H NMR
(700 MHz, CDCl3) δ 8.74 (d, J = 4.2 Hz, 2H), 8.28 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.34 (t, J
= 7.0 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.16 (t, J = 4.9 Hz, 1H), 6.94 (s, 1H), 6.17 (s, 1H), 3.43 (q, J = 7.0
Hz, 2H), 1.64–1.62 (m, 2H), 1.40–1.37 (m, 4H), 0.93 (t, J = 7.0 Hz, 3H); 13C NMR (175 MHz, CDCl3) δ
162.9, 158.0, 157.4, 137.6, 134.8, 127.9, 125.3, 122.4, 121.6, 117.6, 113.9, 109.2, 39.8, 29.2, 29.0, 22.4,
14.0; IR (KBr) υ 3272, 2925, 2856, 1639, 1548, 1146, 1426, 1348, 1290, 1266, 1233, 1149, 1026, 817,
739, 708 cm-1; HRMS (quadrupole, EI) calcd for C18H20N4O [M]+ 308.1637, found 308.1638.
N-Hexyl-1-(pyrimidin-2-yl)-1H-indole-2-carboxamide (4d): 47.7 mg (74%); Yellow solid; mp =
117.6–120.4 °C; 1H NMR (700 MHz, CDCl3) δ 8.73 (d, J = 4.9 Hz, 2H), 8.28 (d, J = 8.4 Hz, 1H), 7.61 (d,
J = 7.7 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.23 (t, J = 7.0 Hz, 1H), 7.15 (t, J = 4.9 Hz, 1H), 6.93 (s, 1H),
6.15 (s, 1H), 3.43 (q, J = 6.3 Hz, 2H), 1.64–1.62 (m, 2H), 1.42–1.40 (m, 2H), 1.34–1.33 (m, 4H), 0.91 (t,
J = 7.0 Hz, 3H); 13C NMR (175 MHz, CDCl3) δ 162.9, 158.0, 157.4, 137.7, 134.9, 128.0, 125.3, 122.5,
121.6, 117.6, 113.9, 109.2, 39.8, 31.5, 29.5, 26.6, 22.6, 14.0; IR (KBr) υ 3274, 2924, 2855, 1643, 1558,
1419, 1347, 1287, 1233, 1149, 807, 744, 657 cm-1; HRMS (quadrupole, EI) calcd for C19H22N4O [M]+
322.1794, found 322.1795.
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N-Octyl-1-(pyrimidin-2-yl)-1H-indole-2-carboxamide (4e): 36.4 mg (52%); Yellow solid; mp =
103.3–105.4 °C; 1H NMR (700 MHz, CDCl3) δ 8.74 (d, J = 4.9 Hz, 2H), 8.28 (d, J = 8.4 Hz, 1H), 7.62 (d,
J = 7.7 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.15 (t, J = 4.9 Hz, 1H), 6.94 (s, 1H),
6.14 (s, 1H), 3.43 (q, J = 7.0 Hz, 2H), 1.64–1.61 (m, 2H), 1.42–1.38 (m, 2H), 1.35–1.27 (m, 8H), 0.89 (t,
J = 7.0 Hz, 3H); 13C NMR (175 MHz, CDCl3) δ 162.9, 158.0, 157.5, 137.7, 134.9, 128.0, 125.3, 122.5,
121.6, 117.6, 113.9, 109.2, 39.9, 31.8, 29.7, 29.6, 29.2, 26.9, 22.6, 14.0; IR (KBr) υ 3273, 2921, 2851,
1644, 1557, 1420, 1347, 1288, 1234, 1213, 1150, 804, 744, 720 cm-1; HRMS (quadrupole, EI) calcd for
C21H26N4O [M]+ 350.2107, found 350.2106.
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NMR (700 MHz, CDCl3) δ 8.73 (d, J = 4.9 Hz, 2H), 8.28 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H),
7.37–7.32 (m, 3H), 7.28 (d, J = 7.0 Hz, 2H), 7.26–7.22 (m, 2H), 7.15 (t, J = 4.9 Hz, 1H), 6.84 (s, 1H),
6.26 (s, 1H), 3.69 (q, J = 6.3 Hz, 2H), 2.95 (t, J = 7.0 Hz, 2H); 13C NMR (175 MHz, CDCl3) δ 162.8,
158.0, 157.3, 139.0, 137.6, 134.6, 128.9, 128.6, 127.8, 126.5, 125.4, 122.5, 121.6, 117.6, 113.9, 109.4,
41.0, 35.5; IR (KBr) υ 3285, 2923, 2854, 1642, 1556, 1421, 1346, 1284, 1231, 1151, 809, 742, 697 cm-1;
HRMS (quadrupole, EI) calcd for C21H18N4O [M]+ 342.1481, found 342.1485.
N-Benzyl-1-(pyrimidin-2-yl)-1H-indole-2-carboxamide (4g): 24.9 mg (38%); Light yellow solid;
mp = 175.2–176.9 °C; 1H NMR (700 MHz, CDCl3) δ 8.70 (d, J = 4.9 Hz, 2H), 8.31 (d, J = 8.4 Hz, 1H),
7.61 (d, J = 7.7 Hz, 1H), 7.43 (d, J = 7.7 Hz, 2H), 7.38–7.35 (m, 3H), 7.31 (t, J = 6.3 Hz, 1H), 7.24 (dt, J
= 7.7, 1.4 Hz, 1H), 7.14 (t, J = 4.9 Hz, 1H), 6.98 (s, 1H), 6.52 (s, 1H), 4.64 (d, J = 5.6 Hz, 2H); 13C NMR
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(175 MHz, CDCl3) δ 162.8, 158.0, 157.3, 138.2, 137.7, 134.4, 128.6, 127.9, 127.8, 127.5, 125.5, 122.5,
121.7, 117.6, 114.0, 109.6, 43.7; IR (KBr) υ 3315, 2919, 1649, 1552, 1421, 1338, 1240, 1078, 975, 836,
754, 695 cm-1; HRMS (quadrupole, EI) calcd for C20H16N4O [M]+ 328.1324, found 328.1319.
N-Cyclopentyl-1-(pyrimidin-2-yl)-1H-indole-2-carboxamide (4h): 18.3 mg (30%); Light yellow
solid; mp = 185.0–190.0 °C; 1H NMR (700 MHz, CDCl3) δ 8.75 (d, J = 4.9 Hz, 2H), 8.29 (d, J = 8.4 Hz,
1H), 7.62 (d, J = 8.4 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.16 (t, J = 4.2 Hz, 1H),
6.94 (s, 1H), 6.08 (s, 1H), 4.38–4.35 (m, 1H), 2.09–2.04 (m, 2H), 1.73–1.70 (m, 2H), 1.68–1.64 (m, 2H),
1.58–1.57 (m, 2H); 13C NMR (175 MHz, CDCl3) δ 162.6, 158.0, 157.4, 137.5, 134.9, 128.0, 125.3, 122.5,
121.6, 117.6, 113.9, 109.1, 51.6, 32.9, 23.7; IR (KBr) υ 3319, 3046, 2953, 2865, 1626, 1557, 1425, 1350,
1295, 1150, 1079, 823, 803, 740, 664 cm-1; HRMS (quadrupole, EI) calcd for C18H18N4O [M]+ 306.1481,
found 306.1476.
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N-Phenyl-1-(pyrimidin-2-yl)-1H-indole-2-carboxamide (4i): 32.1 mg (51%); Light yellow solid;
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mp = 173.9–176.0 °C; H NMR (700 MHz, CDCl3) δ 8.74 (d, J = 4.9 Hz, 2H), 8.28 (d, J = 8.4 Hz, 1H),
8.11 (br s, 1H), 7.61–7.59 (m, 3H), 7.38 (t, J = 8.4 Hz, 1H), 7.33 (t, J = 7.7 Hz, 2H), 7.24–7.23 (m, 1H),
7.16 (t, J = 4.2 Hz, 1H), 7.13 (t, J = 7.0 Hz, 1H), 7.08 (s, 1H); 13C NMR (175 MHz, CDCl3) δ 160.5,
158.1, 157.3, 138.0, 137.9, 134.4, 129.0, 127.7, 125.8, 124.4, 122.7, 121.9, 119.9, 117.8, 113.9, 110.3; IR
(KBr) υ 3016, 1653, 1600, 1564, 1538, 1444, 1425, 1353, 1310, 1236, 1191, 1150, 819, 744, 690 cm-1;
HRMS (quadrupole, EI) calcd for C19H14N4O [M]+ 314.1168, found 314.1173.
N-(4-Bromophenyl)-1-(pyrimidin-2-yl)-1H-indole-2-carboxamide (4j): 34.6 mg (44%); Light
yellow solid; mp = 223.3–225.9 °C; 1H NMR (700 MHz, CDCl3) δ 8.74 (d, J = 4.9 Hz, 2H), 8.29 (d, J =
8.4 Hz, 1H), 8.10 (br s, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.49–7.48 (m, 2H), 7.43 (d, J = 9.1 Hz, 2H), 7.39 (t,
J = 8.4 Hz, 1H), 7.26–7.24 (m, 1H), 7.17 (t, J = 4.9 Hz, 1H), 7.08 (s, 1H); 13C NMR (175 MHz, CDCl3) δ
160.5, 158.2, 157.2, 137.9, 137.0, 134.0, 132.0, 127.6, 126.0, 122.8, 121.9, 121.4, 117.8, 117.0, 113.9,
110.5; IR (KBr) υ 3292, 2920, 2850, 1659, 1588, 1538, 1184, 1424, 1396, 1305, 1239, 1194, 1069, 938,
819, 737, 655 cm-1; HRMS (quadrupole, EI) calcd for C19H13BrN4O [M]+ 392.0273, found 392.0269.
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1-(Pyrimidin-2-yl)-N-(p-tolyl)-1H-indole-2-carboxamide (4k): 20.3 mg (31%); Colorless oil; H
NMR (700 MHz, CDCl3) δ 8.75 (d, J = 4.9 Hz, 2H), 8.31 (d, J = 8.4 Hz, 1H), 7.96 (br s, 1H), 7.64 (d, J =
7.7 Hz, 1H), 7.49 (br s, 2H), 7.39 (t, J = 7.7 Hz, 1H), 7.28–7.26 (m, 2H), 7.16–7.15 (m, 2H), 7.09 (s, 1H),
2.35 (s, 3H); 13C NMR (175 MHz, CDCl3) δ 158.1, 157.4, 137.9, 135.5, 134.7, 134.1, 129.5, 127.9, 125.7,
122.7, 121.8, 120.0, 117.7, 114.0, 110.1, 20.8; IR (KBr) υ 3256, 2921, 1660, 1602, 1564, 1534, 1422,
1348, 1313, 1240, 1191, 1149, 814, 734 cm-1; HRMS (quadrupole, EI) calcd for C20H16N4O [M]+
328.1324, found 328.1328.
1-(Pyrimidin-2-yl)-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (4l): 32.9
mg
(43%); Light yellow solid; mp = 241.7–244.6 °C; 1H NMR (700 MHz, CDCl3) δ 8.75 (d, J = 4.2 Hz, 2H),
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8.30 (d, J = 8.4 Hz, 1H), 8.23 (s, 1H), 7.70 (d, J = 7.7 Hz, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.4
Hz, 2H), 7.41 (dt, J = 7.7, 1.4 Hz, 1H), 7.27–7.25 (m, 1H), 7.18 (t, J = 4.9 Hz, 1H), 7.12 (s, 1H); 13C
NMR (175 MHz, CDCl3) δ 160.7, 158.2, 157.2, 141.0, 138.0, 133.8, 127.6, 126.4 (q, JC-F = 2.6 Hz), 126.3
(q, JC-F = 32.2 Hz), 126.2, 124.0 (q, JC-F = 269.3 Hz), 122.9, 122.0, 119.5, 117.9, 114.0, 110.8; IR (KBr) υ
3261, 2918, 2359, 1666, 1602, 1542, 1423, 1315, 1249, 1158, 1107, 1065, 937, 835, 739 cm-1; HRMS
(quadrupole, EI) calcd for C20H13F3N4O [M]+ 382.1041, found 382.1039.
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Experimental procedure for reversibility experiment of 4k: To a mixture of 1-(pyrimidin-2-yl)-
N-(p-tolyl)-1H-indole-2-carboxamide (4k) (65.6 mg, 0.2 mmol, 100 mol %), [RhCp*Cl2]2 (6.2 mg, 0.01
mmol, 5 mol %) and AgSbF6 (13.7 mg, 0.04 mmol, 20 mol %) was added DCE (1 mL) under N2
atmosphere. The reaction mixture was allowed to stir at 100 oC for 24 h and cooled to room temperature.
The reaction mixture was diluted with EtOAc (3 mL) and concentrated in vacuo. The residue was purified
by flash column chromatography (n-hexanes/EtOAc = 10:1) to afford 19.6 mg of 1a in 50% yield.
Reaction of 4k with n-butyl acrylate (5a): To a stirred solution of 1-(pyrimidin-2-yl)-N-(p-tolyl)-
1H-indole-2-carboxamide (4k) (65.6 mg, 0.2 mmol, 100 mol %), [RhCp*Cl2]2 (6.2 mg, 0.01 mmol, 5
mol %), AgSbF6 (13.7 mg, 0.04 mmol, 20 mol %) and Cu(OAc)2 (72.6 mg, 0.4 mmol, 200 mol %) in
DCE (1 mL) was added n-butyl acrylate (5a) (57.3 µL, 0.4 mmol, 200 mol %). The reaction mixture was
allowed to stir at 110 oC for 24 h and cooled to room temperature. The reaction mixture was diluted with
EtOAc (3 mL) and concentrated in vacuo. The residue was purified by flash column chromatography (n-
hexanes/EtOAc = 4:1) to afford 42 mg of 6a in 65% yield.
(E)-Butyl 3-(1-(pyrimidin-2-yl)-1H-indol-2-yl)acrylate (6a): Light yellow solid; mp = 85.1–
1
88.3 °C; H NMR (700 MHz, CDCl3) δ 8.82 (d, J = 4.9 Hz, 2H), 8.34 (d, J = 8.4 Hz, 1H), 8.24 (d, J =
16.1 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.33 (dt, J = 7.7, 1.4 Hz, 1H), 7.24 (dt, J = 7.7, 1.4 Hz, 1H), 7.19
(t, J = 4.9 Hz, 1H), 7.13 (s, 1H), 6.47 (d, J = 16.1 Hz, 1H ), 4.10 (t, J = 6.3 Hz, 2H), 1.71–1.66 (m, 2H),
13
1.46–1.43 (m, 2H), 0.96 (t, J = 7.7 Hz, 3H); C NMR (175 MHz, CDCl3) δ 167.1, 158.3, 157.5, 137.8,
136.2, 135.4, 128.6, 124.9, 122.6, 121.1, 117.8, 117.4, 114.2, 108.8, 64.3, 30.7, 19.1, 13.7; IR (KBr) υ
2956, 2926, 2870, 1703, 1624, 1561, 1447, 1419, 1340, 1302, 1261, 1223, 1159, 964, 806, 739 cm-1;
HRMS (quadrupole, EI) calcd for C19H19N3O2 [M]+ 321.1477, found 321.1477.
General procedure and characterization for deprotection of 3a and 4k: To a stirred solution of
N-butyl-1-(pyrimidin-2-yl)-1H-indole-2-carboxamide (3a) (58.8 mg, 0.2 mmol, 100 mol %) in DMSO
(1.5 mL) was added NaOEt (40.8 mg, 0.6 mmol, 300 mol %) in EtOH (0.3 mL) at room temperature. The
o
reaction mixture was allowed to stir for 20 h at 100 C under nitrogen atmosphere. The reaction mixture
was diluted with EtOAc (10 mL) and washed with H2O (2 × 25 mL). The aqueous layer was extracted
with EtOAc (2 × 25 mL). The combined organic layer was dried over Mg2SO4 and concentrated in vacuo.
The residue was purified by flash column chromatography (n-hexanes/EtOAc = 10:1) to afford 18.1 mg
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of 7a in 42% yield.
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N-Butyl-1H-indole-2-carboxamide (7a): 18.2 mg (42%); Light yellow solid; mp = 164.8–167.8 °C;
1H NMR (700 MHz, CDCl3) δ 9.53 (s, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.44 (d, J = 7.7 Hz, 1H), 7.28 (t, J =
7.7 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H), 6.81 (s, 1H), 6.18 (s, 1H), 3.50 (q, J = 7.0 Hz, 2H), 1.66–1.61 (m,
2H), 1.46–1.42 (m, 2H), 0.97 (t, J = 7.0 Hz, 3H); 13C NMR (175 MHz, CDCl3) δ 161.6, 136.2, 130.8,
127.6, 124.3, 121.8, 120.6, 111.9, 101.4, 39.4, 31.8, 20.1, 13.7; IR (KBr) υ 3333, 3266, 2922, 2852, 1610,
1551, 1416, 1338, 1252, 1216, 1154, 842, 811, 776, 714 cm-1; HRMS (quadrupole, EI) calcd for
C13H16N2O [M]+ 216.1263, found 216.1267.
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N-(p-Tolyl)-1H-indole-2-carboxamide (7b): 26.1 mg (52%); Light yellow solid; mp = 235.6–
237.4 °C; 1H NMR (700 MHz, CDCl3) δ 9.27 (s, 1H), 7.81 (s, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.53 (d, J =
8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.20–7.16 (m, 3H), 6.98 (s, 1H), 2.35 (s,
3H); 13C NMR (175 MHz, CDCl3) δ 159.3, 136.4, 134.8, 134.3, 130.8, 129.7, 127.6, 124.9, 122.0, 120.9,
120.1, 111.9, 102.3, 20.9; IR (KBr) υ 3406, 3332, 3050, 2916, 2851, 1729, 1644, 1593, 1512, 1403, 1301,
1233, 934, 883, 809, 740 cm-1; HRMS (quadrupole, EI) calcd for C16H14N2O [M]+ 250.1106, found
250.1108.
Acknowledgment
This research was supported by the National Research Foundation of Korea (NRF) grant funded by
the Korea Government (MSIP) (Nos. 2013R1A2A2A01005249 and 2013R1A1A2058800).
Supporting Information Available: Spectroscopic data for all compounds and deuterium
exchange experiments. This material is available free of charge via the internet at http://pubs.acs.org.
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