Condensation of Carboxylic Acids with Non-Nucleophilic N-Heterocycles and Anilides Using Boc2O

Article abstract of DOI:10.1021/acs.joc.6b02097

A novel condensation reaction of carboxylic acids with various non-nucleophilic N-heterocycles and anilides was developed. The reaction proceeds in the presence of di-tert-butyl dicarbonate (Boc₂O), catalytic 4-(dimethylamino)pyridine (DMAP), a

Full text of DOI:10.1021/acs.joc.6b02097

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Note
Condensation of Carboxylic Acids with Non-
Nucleophilic N-Heterocycles and Anilides Using Boc2O
Atsushi Umehara, Hirofumi Ueda, and Hidetoshi Tokuyama
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02097 • Publication Date (Web): 21 Oct 2016
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dimethylaminopyridinium ion and naked tꢀbutoxide.8d On the
Condensation of Carboxylic Acids with Non-Nucleophilic
other hand, a combination of Boc2O, DMAP, and tertiary
amines or pyridine is effective for condensation of carboxylic
acids with primary amines,9a anilines,9b ammonia,9c alcohols,9dꢀ
N-Heterocycles and Anilides Using Boc2O
Atsushi Umehara, Hirofumi Ueda, Hidetoshi Tokuyama*
g
or phenols,9d in which the corresponding mixed anhydride is
Graduate School of Pharmaceutical Sciences, Tohoku
University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578,
Japan
initially formed.
We reasoned that upon mixing a nonꢀnucleophilic nitrogen
compound, such as indole (1), and a carboxylic acid in the
presence of Boc2O and DMAP, the above Bocꢀmediated
processes would facilitate acylation to form Nꢀacylated
product 6 by activation of the carboxylic acid as a mixed
anhydride 2 or Nꢀacylꢀdimethylaminopyridinium ion 3 and
activation of the nonꢀnucleophilic nitrogen compound as an
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anionic species (Scheme 1).10 A competing process would be
8c, 8e, 8f
the formation of NꢀBocꢀindole8b,
7 and/or a tꢀbutyl
9g
ester9e,
8 via reaction of the indole anion with NꢀBocꢀ
dimethylaminopyridinium ion 5 or reaction of tꢀbutoxide with
mixed anhydride 2 or Nꢀacylꢀdimethylaminopyridinium ion 3,
respectively. To the best of our knowledge, Bocꢀmediated
condensation has only been applied to intrinsically
nucleophilic compounds9 and there is no report on nonꢀ
nucleophilic nitrogen compounds. Herein, we report a novel
direct condensation of carboxylic acids with various nonꢀ
ABSTRACT: A novel condensation reaction of carboxylic
acids with various nonꢀnucleophilic Nꢀheterocycles and
anilides was developed. The reaction proceeds in the
presence of diꢀtertꢀbutyl dicarbonate (Boc2O), catalytic 4ꢀ
(dimethylamino)pyridine (DMAP), and 2,6ꢀlutidine and is
applicable to the acylation of a wide range of nonꢀ
nucleophilic nitrogen compounds, including indoles,
pyrroles, pyrazole, carbazole, lactams, oxazolidinones, and
anilides with high functional group compatibility. The
scope of indoles, carboxylic acids, and anilides was also
studied.
nucleophilic
aromatic
Nꢀheterocycles,
lactams,
oxazolidinones, and anilides under metalꢀfree mild conditions
using Boc2O.
Scheme 1. Working Hypothesis.
The amide group is one of the most important and
fundamental functional groups present in naturally occurring
compounds, proteins, synthetic polymers, and pharmaceutical
agents. Therefore, the development of amide formation
reactions has a long history, and numerous reaction conditions
have so far been reported.1 However, methodologies for the
direct condensation of carboxylic acids with aromatic Nꢀ
heterocycles such as indole, pyrrole, pyrazole, and carbazole
are limited2 due the low nucleophilicity of these substrates,
which is attributed to the participation of the nitrogen lone pair
electrons in the aromatic system. Direct condensation of
lactams or anilides is also inefficient, due to the low
nucleophilicity of nitrogen by delocalization of the nitrogen
lone pair electrons into the carbonyl group.
Keeping these considerations in mind, we examined the
proposed Boc2Oꢀmediated amide formation using monoꢀ
methyl succinate (9a) and indole (1) as test substrates (Table
1). First, we tested the conditions required for Boc protection
of the indole N–H (entry 1). Thus, 1 was treated with 9a in the
presence of Boc2O and 5 mol% DMAP. To our satisfaction,
we obtained a moderate yield of the expected Nꢀacylindole
10a along with a trace amount of NꢀBocꢀindole 7, without the
tꢀbutyl ester of 9a being formed. Reactions with other amine
catalysts such as Nꢀmethylimidazole (NMI), 1,4ꢀ
In order to conduct condensation reactions of these nonꢀ
nucleophilic nitrogen compounds with carboxylic acids, prior
formation of an anionic species by deprotonation of the N–H
by a stoichiometric strong metal base such as nꢀbutyllithium or
NaH and/or the use of an activated carboxylic acid derivative
such as an acid halide or activated ester3,4,5 is usually required.
For example, Snider reported Nꢀacylation of a tryptophan
derivative by using a pꢀnitrophenyl ester as an acylation
reagent.6 Sarpong has recently demonstrated that
carbonylazoles are effective for a highly chemoselective Nꢀ
acylation of indoles and oxazolidinones.7
To consider a direct condensation of carboxylic acids and
nonꢀnucleophilic nitrogen compounds, we focused on the
function of diꢀtertꢀbutyl dicarbonate (Boc2O). Installation of a
tertꢀbutyloxycarbonyl (Boc) group on a variety of nonꢀ
nucleophilic nitrogen compounds including indoles, pyrroles,
and lactams proceeds smoothly with a combination of Boc2O
and 4ꢀ(dimethylamino)pyridine (DMAP).8 This process should
diazabicyclo[2.2.2]octane
(DABCO),
and
1,8ꢀ
diazabicyclo[5.4.0]undecꢀ7ꢀene (DBU) (entries 2–4) did not
give amide 10a in better yields. Considering that protonation
of DMAP with the carboxylic acid would prevent smooth
conversion, we then added additional base to the reaction. A
significant acceleration was observed when we added 10
mol% triethylamine to give 10a in 87% yield (entry 5).
Extensive examination revealed that 2,6ꢀlutidine yielded the
best result, thus affording the desired Nꢀacylindole 10a in 92%
yield (entry 7). In addition, the reaction using inorganic bases
proceeded smoothly to provide the desired product 10a in high
include
in
situ
generation
of
a
NꢀBocꢀ
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yields (entries 8–11). The reaction did not proceed without
purity. Due to the relatively lower reactivity, reaction of
aromatic carboxylic acids 9u–w required increased amounts of
the bases (20 mol% DMAP and 30 mol% 2,6ꢀlutidine).
DMAP at all (entry 12), thus indicating that it plays a crucial
role in this condensation reaction. The yield decreased when
CH2Cl2 was used as the solvent instead of MeCN (entry 13).
Excess indole and Boc2O are also necessary for the highꢀ
yielding and selective formation of Nꢀacylindole 10a. Thus, a
reaction using an equimolar amount of 1 with Boc2O (1.5
equiv.) gave 10a in 65% yield along with NꢀBocꢀindole 7
(14%) and recovery of 1 (21%) (entry 14). Moreover, we
performed this reaction using 5 gram of carboxylic acid 9a.
The reaction proceeded uneventfully to afford the target acyl
indole 10a in almost quantitative yield (entry 15).
Notably,
heteroaromatic
carboxylic
acids,
2ꢀ
pyridinecarboxylic acid (9v), and 2ꢀquinolinecarboxylic acid
(9w), reacted smoothly to provide Nꢀacylindoles 10v and 10w
in good to excellent yields.
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Next, the scope of nonꢀnucleophilic nitrogen compounds
was studied using 4ꢀphenylbutyric acid (9j) (Table 3).
Reaction of 6ꢀ, 5ꢀ, or 3ꢀsubstituted indoles bearing halogen or
electronꢀwithdrawing groups proceeded well under the
optimal conditions to provide N-acylindoles (12a–e) in
excellent yields. Significantly, 2ꢀ and 7ꢀsubstituted indoles,
which usually behave as poor nucleophiles due to steric
hindrance,3f,7 gave the corresponding Nꢀacylindoles (12f–j) in
excellent yields, except for 2ꢀphenylindole (11h). In addition
to these indole derivatives, analogous nonꢀnucleophilic Nꢀ
heteroaromatic compounds such as pyrroles, pyrazole, and
carbazole proved to be suitable substrates to give Nꢀacyl
products 12k–n in good to excellent yields.
Table 1. Optimization of Reaction Conditions.
yield (%)a
Table 2. Scope of Carboxylic Acids.a
entry
1
catalyst
DMAP
NMI
additive
–
42
33
2
–
3
DABCO
DBU
–
Trace
0
4
–
5
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
–
Et3N
87
6
pyridine
2,6-lutidine
NaHCO3
Na2CO3
K2CO3
Cs2CO3
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
88
7
92
8
81
9
79
10
11
12
13b
14c
15e
89
91
0
DMAP
DMAP
DMAP
69
65 (82)d
97
aIsolated yield. bCH2Cl2 was used instead of MeCN. cIndole (1
equiv.) and Boc2O (1.5 equiv.) were used. dBased on the
recovered starting indole.eThis reaction was performed on 5
gram scale of 9a.
Having established the optimal conditions, we then
investigated the substrate scope of carboxylic acids (Table 2).
Reactions using a series of functionalized linear carboxylic
acids (9b–q) demonstrated that a variety of functional groups,
including ketone, ester, silyl ether, alkenyl, alkynyl,
bromoalkyl, substituted phenyl, and thienyl groups, were
compatible with the reaction conditions to give the
corresponding Nꢀacylindoles 10b–q in good to excellent
yields. Sterically hindered βꢀ (9r) or αꢀbranched (9s and 9t)
carboxylic acids were feasible in the reaction to give 10r, 10s,
and 10t in good yields. In particular, Nꢀbenzyloxycarbonylꢀ
proline derivative 10t was obtained without loss of optical
aIsolated yield. bDMAP (20 mol%) and 2,6ꢀlutidine (30 mol%)
were used. c>99% ee, determined by HPLC analysis.
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Table 3. Scope of Indole Derivatives and N-
furnish the desired amide. Smooth acylation of nonꢀ
nucleophilic nitrogen compounds 17 should be based on dual
activation, namely, activation of carboxylic acid by conversion
Heteroaromatic Compounds.a
7
8
to the Nꢀacylꢀdimethylaminopyridinium ion
3
and
deprotonation of N–H by naked tꢀbutoxide (4). The key to the
selective formation of amides, while circumventing possible
competing processes (i.e., formation of NꢀBoc nitrogen
compounds and tꢀbutyl esters), is attributed to the higher
reactivity of 3 among the three acyl donors 2, 3, and 5 due to
steric as well as electronic reasons. According to the series of
experiments in Table 1, we consider that the role of the
additional base (2,6ꢀlutidine) would be as a proton scavenger
to prevent protonation of DMAP (Scheme 2b).
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Table 4. Scope of Lactams, Oxazolidinones, and Anilides.a
aIsolated yield.
Furthermore, we found that this reaction was applicable to
other nonꢀnucleophilic nitrogen compounds including γꢀ
lactams, oxazolidinones, and anilides. Thus, γꢀlactams (13a
and 13b) and oxazolidinones (13c–e) reacted smoothly to
provide the corresponding Nꢀacyl products 14a, 14b, and 14c–
e (Table 4). The anilides (13f–p) bearing substituents at the
orthoꢀ, metaꢀ or paraꢀpositions on the benzene ring gave the
corresponding imides (14f–p) in nearly quantitative yields.
Importantly, the sterically hindered substrate 13n derived from
2,6ꢀdimethylaniline reacted uneventfully to furnish the desired
imide 14n in a high yield. Finally, 1ꢀaminonaphthalene
derivative 13o and 2ꢀpyridylamide 13p served as good
substrates to give the desired products (14o and 14p) in
excellent and satisfactory yields, respectively. In the case of
oxazolidinones (13d and 13e) and anilides (13k, 13l, and 13o),
reaction using an equimolar amount of the nucleophiles with
Boc2O (1.5 equiv.) gave the products in high (80–91%) yields.
Plausible reaction mechanisms based on the above
observations and related reports9 are depicted in Scheme 2.
The initial nucleophilic attack of DMAP on Boc2O should
give NꢀBocꢀdimethylaminopyridinium ion 5 with concomitant
generation of a naked tꢀbutoxide anion (4), which deprotonates
carboxylic acid 15 to give carboxylate 16, followed by
addition of 16 to 5, which would afford mixed anhydride 2.
Subsequent nucleophilic attack of DMAP on 2 should produce
Nꢀacylꢀdimethylaminopyridinium ion 3 with formation of
naked tꢀbutoxide (4). At this point, nonꢀnucleophilic nitrogen
compound 17 should be deprotonated by 4 to afford a highly
nucleophilic anion 18. Finally, anion 18 would attack 3 to
aIsolated yield. bNucleophile (1 equiv.) and Boc2O (1.5 equiv.)
were used.
To demonstrate the practical synthetic utility of the direct
condensation, we performed a multiꢀgram scale reaction
(Scheme 3). Thus, acid 9j and an equimolar amount of anilide
13o with Boc2O (1.5 equiv.) were subjected to the reaction
conditions. As expected, the condensation took place smoothly
to furnish the desired product 14o in 94% yield.
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silica gel (63–210 µm), and flash column chromatography was
Scheme 2. Proposed Mechanism.
performed on spherical neutral silica gel (40–50 ꢀm) using the
indicated eluent. Analytical TLC was performed on glass
plates precoated with a 0.25 mm thickness of silica gel. All
melting points were determined on a micro melting point
apparatus and are uncorrected. 1HꢀNMR and 13CꢀNMR spectra
were recorded at 400 and 600 MHz for 1HꢀNMR and (100 and
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1
150 MHz for 13CꢀNMR. For HꢀNMR spectra, chemical shifts
are given from tetramethylsilane (0 ppm) or chloroform (7.24
ppm) as an internal standard. For 13CꢀNMR spectra, chemical
shifts are given from chloroform (77.0 ppm) as an internal
standard. Mass spectra were realized by ESI method using a
timeꢀofꢀflight mass spectrometer.
General Synthetic Procedure of Condensation Reaction.
Methyl 4-(1H-indol-1-yl)-4-oxobutanoate (10a)
A 10 mL threaded Pyrex test tube equipped with a magnetic
stirring bar, a rubber septum, and argon inlet needle was
charged with Boc2O (223 mg, 1.02 mmol). A solution of
monoꢀmethyl succinate (9a) (54.0 mg, 0.409 mmol), indole (1)
(120 mg, 1.02 mmol), DMAP (2.5 mg, 0.02 mmol), and 2,6ꢀ
lutidine (4.7 ꢀL, 0.04 mmol) in MeCN (0.9 mL) were added to
the test tube at room temperature. Then, the reaction mixture
was warmed to 28 ºC by water bath. After stirring at 28 °C for
24 h, the resulting mixture was concentrated under reduced
pressure to give a crude oil, which was purified by silica gel
column chromatography (hexanes/AcOEt = 5:1) to give Nꢀ
acylindole 10a (87.1 mg, 0.377 mmol, 92%); a white solid;
Mp 82ꢀ83 °C (hexanesꢀAcOEt); IR (neat) 2953, 1738, 1708,
1454, 1310, 1207, 910, 752 cmꢀ1; 1H NMR (600 MHz, CDCl3)
δ 8.43 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.50 (d, J
= 3.6 Hz, 1H), 7.34 (dd, J = 7.8, 6.6 Hz, 1H), 7.28 (dd, J = 8.4,
6.6 Hz, 1H), 6.66 (d, J = 3.6 Hz, 1H), 3.74 (s, 3H), 3.27 (t, J =
6.6 Hz, 2H), 2.86 (t, J = 6.6 Hz, 2H); 13C NMR (150 MHz,
CDCl3) δ 172.8, 169.8, 135.6, 130.3, 125.2, 124.3, 123.7,
120.9, 116.5, 109.5, 52.0, 30.7, 28.3; HRMS Calcd. for
C13H13NNaO3 [M+Na+] 254.0793, found 254.0790.
Scheme 3. Multi-Gram Scale Reaction.
In conclusion, we have developed a direct condensation of
carboxylic acids with a wide variety of nonꢀnucleophilic Nꢀ
heterocycles such as indoles, pyrroles, pyrazole, carbazole,
lactams, and oxazolidinones using the Boc2O/DMAP/2,6ꢀ
lutidine system. Furthermore, various anilides were also
amenable to this reaction and generated imides. The
Boc2O/DMAP/2,6ꢀlutidine system played a crucial role in the
in situ dual activation of both carboxylic acids as the Nꢀacylꢀ
dimethylaminopyridinium ion and of nonꢀnucleophilic
nitrogen compounds through the generation of the
corresponding anion with naked tꢀbutoxide. This condensation
reaction is performed using a simple operation that does not
involve prior formation of the anion by deprotonation of the
nitrogen nucleophile using a metal base and preparation of an
activated carboxylic acid such as an acid halide or activated
ester.
1-(1H-Indol-1-yl)-4-phenylbutane-1,4-dione (10b)
According to the general procedure described for 10a, Nꢀ
acylindole 10b (79.4 mg, 0.287 mmol, 68%) was obtained
from 3ꢀbenzolypropionic acid (9b) (75.0 mg, 0.421 mmol) and
indole (1) (123 mg, 1.05 mmol); a white solid; Mp 146ꢀ148 °C
(hexanesꢀAcOEt); IR (neat) 2949, 1703, 1678, 1453, 1399,
1360, 1311, 1227, 1212, 773, 764, 751 cmꢀ1; 1H NMR (600
MHz, CDCl3) δ 8.43 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 7.2 Hz,
2H), 7.60 (d, J = 4.2 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.57
(d, J = 8.4 Hz, 1H), 7.49 (dd, J = 8.4, 7.2 Hz, 2H), 7.33 (dd, J
= 8.4, 6.6 Hz, 1H), 7.27 (dd, J = 8.4, 6.6 Hz, 1H), 6.68 (d, J =
4.2 Hz, 1H), 3.54 (t, J = 6.6 Hz, 2H), 3.41 (t, J = 6.6 Hz, 2H);
13C NMR (150 MHz, CDCl3) 198.0, 170.4, 136.5, 135.7,
133.4, 130.4, 128.7, 128.1, 125.1, 124.6, 123.7, 120.8, 116.6,
109.4, 32.8, 29.8; HRMS Calcd. for C18H15NNaO2 [M+Na+]
300.1000, found 300.0993.
Experimental Section
General Remarks
1-(1H-Indol-1-yl)-5-phenylpentane-1,5-dione (10c)
Materials were obtained from commercial suppliers and used
without further purification unless otherwise mentioned. All
reactions were carried out in ovenꢀdried glassware under a
slight positive pressure of argon unless otherwise noted.
Column chromatography was performed on spherical neutral
According to the general procedure described for 10a, Nꢀ
acylindole 10c (71.4 mg, 0.245 mmol, 73%) was obtained
from 4ꢀbenzoylbutyric acid (9c) (64.0 mg, 0.335 mmol) and
indole (1) (98.0 mg, 0.836 mmol); a white solid; Mp 98ꢀ100
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°C (hexanesꢀAcOEt); IR (neat) 2949, 1704, 1685, 1451, 1388,
According to the general procedure described for 10a, Nꢀ
1338, 1308, 1224, 1209, 768, 750, 690 cmꢀ1; 1H NMR (600
MHz, CDCl3) δ 8.47 (d, J = 7.8 Hz, 1H), 7.99 (d, J = 7.8 Hz,
2H), 7.58–7.55 (m, 3H), 7.47 (dd, J = 8.4, 7.8 Hz, 2H), 7.35
(dd, J = 7.8, 7.8 Hz, 1H), 7.27 (dd, J = 7.8, 7.8 Hz, 1H), 6.64
(d, J = 3.6 Hz, 1H), 3.21 (t, J = 7.2 Hz, 2H), 3.07 (t, J = 7.2
Hz, 2H), 2.30 (tt, J = 7.2, 7.2 Hz, 2H); 13C NMR (150 MHz,
CDCl3) 199.5, 171.1, 136.7, 135.6, 133.2, 130.4, 128.6,
128.0, 125.1, 124.7, 123.6, 120.8, 116.6, 109.2, 37.2, 34.9,
19.0; HRMS Calcd. for C19H17NNaO2 [M+Na+] 314.1157,
found 314.1152.
acylindole 10g (67.3 mg, 0.319 mmol, 91%) was obtained
from 5ꢀhexynoic acid acid (9g) (39.0 mg, 0.350 mmol) and
indole (1) (103 mg, 0.875 mmol); a white solid; Mp 69ꢀ70 °C
(hexanesꢀAcOEt); IR (neat) 2954, 1705, 1452, 1389, 1308,
1205, 752 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 8.46 (d, J = 8.4
Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 3.6 Hz, 1H),
7.35 (dd, J = 8.4, 7.8 Hz, 1H), 7.27 (dd, J = 7.8, 7.8 Hz, 1H),
6.65 (d, J = 3.6 Hz, 1H), 3.08 (t, J = 7.2 Hz, 2H), 2.41 (dt, J =
7.2, 2.4 Hz, 2H), 2.07 (tt, J = 7.2, 7.2 Hz, 2H), 2.02 (t, J = 2.4
Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 170.8, 135.6, 130.3,
125.1, 124.5, 123.6, 120.8, 116.6, 109.2, 83.2, 69.5, 34.2,
23.1, 17.8; HRMS Calcd. for C14H14NO [M++H] 212.1075,
found 212.1076.
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Methyl 5-(1H-indol-1-yl)-5-oxopentanoate (10d)
According to the general procedure described for 10a, Nꢀ
acylindole 10d (79.5 mg, 0.324 mmol, 92%) was obtained
from glutaric acid monoꢀmethyl ester (9d) (52.0 mg, 0.355
mmol) and indole (1) (104 mg, 0.887 mmol); a white solid;
Mp 49ꢀ51 °C (hexanesꢀAcOEt); IR (neat) 2953, 1735, 1706,
11-Bromo-1-(1H-indol-1-yl)undecan-1-one (10h)
According to the general procedure described for 10a, Nꢀ
acylindole 10h (76.3 mg, 0.210 mmol, 71%) was obtained
from 11ꢀbromoundecanoic acid (9h) (79.0 mg, 0.297 mmol)
and indole (1) (87.0 mg, 0.742 mmol); a white solid; Mp 52ꢀ
54 °C (hexanesꢀAcOEt); IR (neat) 2925, 2853, 1709, 1452,
1386, 1338, 1308, 1205, 767, 750 cmꢀ1; 1H NMR (600 MHz,
CDCl3) δ 8.47 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H),
7.47 (d, J = 3.6 Hz, 1H), 7.35 (dd, J = 8.4, 6.6 Hz, 1H), 7.27
(dd, J = 7.8, 6.6 Hz, 1H), 6.64 (d, J = 3.6 Hz, 1H), 3.40 (t, J =
7.2 Hz, 2H), 2.91 (t, J = 7.2 Hz, 2H), 1.87–1.81 (m, 4H),
1.47–1.30 (m, 12H); 13C NMR (150 MHz, CDCl3) δ 171.6,
135.6, 130.3, 125.1, 124.6, 123.5, 120.8, 116.6, 109.0, 35.9,
34.0, 32.8, 29.33, 29.31, 29.2, 28.7, 28.1, 24.6 (One signal is
missing due to overlap); HRMS Calcd. for C19H27BrNO
[M++H] 364.1276, found 364.1272.
1
1453, 1310, 1207, 752 cmꢀ1; H NMR (600 MHz, CDCl3)
δ 8.46 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.49 (d, J
= 3.6 Hz, 1H), 7.35 (dd, J = 7.8, 7.8 Hz, 1H), 7.27 (dd, J = 8.4,
7.8 Hz, 1H), 6.64 (d, J = 3.6 Hz, 1H), 3.70 (s, 3H), 3.01 (t, J =
6.6 Hz, 2H), 2.53 (t, J = 6.6 Hz, 2H), 2.17 (tt, J = 6.6, 6.6 Hz,
2H); 13C NMR (150 MHz, CDCl3) δ 173.5, 170.7, 135.6,
130.3, 125.1, 124.5, 123.7, 120.8, 116.6, 109.2, 51.7, 34.7,
32.8, 19.7; HRMS Calcd. for C14H15NNaO3 [M+Na+]
268.0950, found 268.0934.
4-((tert-Butyldimethylsilyl)oxy)-1-(1H-indol-1-yl)butan-1-
one (10e)
According to the general procedure described for 10a, Nꢀ
acylindole 10e (69.2 mg, 0.218 mmol, 57%) was obtained
from carboxylic acid 9e11 (84.0 mg, 0.385 mmol) and indole
(1) (113 mg, 0.964 mmol); a colorless oil; IR (neat) 2949,
1709, 1453, 1206, 1100, 837, 775, 749 cmꢀ1; 1H NMR (600
MHz, CDCl3) δ 8.47 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 7.8 Hz,
1H), 7.52 (d, J = 4.2 Hz, 1H), 7.35 (dd, J = 8.4, 7.2 Hz, 1H),
7.27 (dd, J = 7.8, 7.2 Hz, 1H), 6.64 (d, J = 4.2 Hz, 1H), 3.76
(t, J = 6.0 Hz, 2H), 3.03 (t, J = 7.2 Hz, 2H), 2.06 (tt, J = 7.2,
6.0 Hz, 2H), 0.90 (s, 9H), 0.06 (s, 6H); 13C NMR (150 MHz,
CDCl3) δ 171.6, 135.6, 130.4, 125.0, 124.8, 123.5, 120.8,
116.6, 109.0, 61.7, 32.2, 27.8, 25.9, 18.3, –5.4; HRMS Calcd.
for C18H28NO2Si [M++H] 318.1889, found 318.1873.
(Z)-4-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1-(1H-indol-1-
yl)hex-4-en-1-one (10i)
According to the general procedure described for 10a, Nꢀ
acylindole 10i (105 mg, 0.281 mmol, 87%) was obtained from
carboxylic acid 9i (88.0 mg, 0.324 mmol) and indole (1) (95.0
mg, 0.810 mmol); a colorless oil; IR (neat) 2953, 1710, 1452,
1205, 835, 749 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 8.46 (d, J
= 8.4 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 3.6 Hz,
1H), 7.35 (dd, J = 8.4, 7.2 Hz, 1H), 7.27 (dd, J = 7.8, 7.2 Hz,
1H), 6.64 (d, J = 3.6 Hz, 1H), 5.39 (q, J = 6.6 Hz, 1H), 3.67 (t,
J = 7.8 Hz, 2H), 3.01 (t, J = 7.8 Hz, 2H), 2.54 (t, J = 7.8 Hz,
2H), 2.35 (t, J = 7.8 Hz, 2H), 1.62 (d, J = 6.6 Hz, 3H), 0.89 (s,
9H), 0.06 (s, 6H); 13C NMR (150 MHz, CDCl3) 171.2, 135.6,
135.1, 130.3, 125.1, 124.6, 123.6, 121.8, 120.8, 116.6, 109.0,
61.8, 35.0, 33.8, 32.2, 25.9, 18.3, 13.5, –5.3; HRMS Calcd. for
C22H34NO2Si [M++H] 372.2359, found 372.2350.
1-(1H-Indol-1-yl)pent-4-en-1-one (10f)
According to the general procedure described for 10a, Nꢀ
acylindole 10f (93.4 mg, 0.469 mmol, 87%) was obtained
from 4ꢀpentenoic acid (9f) (54.0 mg, 0.537 mmol) and indole
(1) (157 mg, 1.34 mmol); a colorless oil; IR (neat) 2953, 1708,
1453, 1387, 1363, 1320, 1307, 1206, 930, 767, 751 cmꢀ1; 1H
NMR (600 MHz, CDCl3) δ 8.47 (d, J = 7.8 Hz, 1H), 7.56 (d, J
= 8.4 Hz, 1H), 7.46 (d, J = 3.6 Hz, 1H), 7.35 (dd, J = 8.4, 7.2
Hz, 1H), 7.27 (dd, J = 7.8, 7.2 Hz, 1H), 6.64 (d, J = 3.6 Hz,
1H), 5.94 (dddd, J = 17.1, 10.2, 6.0, 6.0 Hz, 1H), 5.14 (d, J =
17.1 Hz, 1H), 5.07 (d, J = 10.2 Hz, 1H), 3.02 (t, J = 6.6 Hz,
2H), 2.62–2.58 (m, 2H); 13C NMR (150 MHz, CDCl3) δ
170.7, 136.5, 135.6, 130.3, 125.1, 124.5, 123.6, 120.8, 116.6,
116.0, 109.1, 35.1, 28.4; HRMS Calcd. for C13H14NO [M++H]
200.1075, found 200.1070. Spectroscopic date matched those
previously reported.12
1-(1H-Indol-1-yl)-4-phenylbutan-1-one (10j)
According to the general procedure described for 10a, Nꢀ
acylindole 10j (112 mg, 0.426 mmol, 89%) was obtained from
4ꢀphenylbutyric acid (9j) (79.0 mg, 0.478 mmol) and indole
(1) (141 mg, 1.20 mmol); a white solid; Mp 47ꢀ49 °C
(hexanesꢀAcOEt); IR (neat) 2953, 1705, 1452, 1386, 1339,
1308, 1205, 767, 750, 700 cmꢀ1; 1H NMR (600 MHz, CDCl3)
δ 8.46 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.37–7.29
(m, 4H), 7.26 (dd, J = 8.4, 7.8 Hz, 1H), 7.23–7.20 (m, 3H),
6.61 (d, J = 4.2 Hz, 1H), 2.90 (t, J = 7.2 Hz, 2H), 2.79 (t, J =
7.2 Hz, 2H), 2.19 (tt, J = 7.2, 7.2 Hz, 2H); 13C NMR (150
MHz, CDCl3) δ 171.2, 141.2, 135.6, 130.3, 128.5, 126.1,
125.1, 124.5, 123.6, 120.8, 116.6, 109.0, 35.0, 34.8, 26.0 (One
1-(1H-Indol-1-yl)hex-5-yn-1-one (10g)
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signal is missing due to overlap); HRMS Calcd. for C18H18NO
Methyl 4-(3-(1H-indol-1-yl)-3-oxopropyl)-3-nitrobenzoate
(10o)
[M++H] 264.1388, found 264.1364.
3-(2-Bromophenyl)-1-(1H-indol-1-yl)propan-1-one (10k)
According to the general procedure described for 10a, Nꢀ
acylindole 10k (106 mg, 0.325 mmol, 87%) was obtained
from 3ꢀ(2ꢀbromophenyl)propionic acid (9k) (86.0 mg, 0.376
mmol) and indole (1) (110 mg, 0.939 mmol); a white solid;
Mp 88ꢀ90 °C (hexanesꢀAcOEt); IR (neat) 2948, 1706, 1451,
1327, 1205, 767, 748 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 8.48
(d, J = 7.8 Hz, 1H), 7.51–7.55 (m, 2H), 7.46 (d, J = 3.6 Hz,
1H), 7.37–7.34 (m, 2H), 7.29–7.24 (m, 2H), 7.11 (dd, J = 7.8,
7.8 Hz, 1H), 6.62 (d, J = 3.6 Hz, 1H), 3.30–3.23 (m, 4H); 13C
NMR (150 MHz, CDCl3) δ 170.3, 139.6, 135.6, 133.0, 130.9,
130.3, 128.3, 127.8, 125.2, 124.5, 124.3, 123.7, 120.8, 116.6,
109.3, 35.9, 31.3; HRMS Calcd. for C17H15BrNO [M++H]
328.0337, found 328.0316.
3-(3-Bromophenyl)-1-(1H-indol-1-yl)propan-1-one (10l)
According to the general procedure described for 10a, Nꢀ
acylindole 10l (87.5 mg, 0.268 mmol, 85%) was obtained
from 3ꢀ(3ꢀbromophenyl)propionic acid (9l) (72.0 mg, 0.315
mmol) and indole (1) (92.0 mg, 0.785 mmol); a white solid;
Mp 59ꢀ61 °C (hexanesꢀAcOEt); IR (neat) 2953, 1707, 1452,
1326, 1205, 767, 751 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 8.46
(d, J = 7.8 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.44 (s, 1H), 7.42
(d, J = 4.2 Hz, 1H), 7.37–7.35 (m, 2H), 7.29–7.17 (m, 3H),
6.63 (d, J = 4.2 Hz, 1H), 3.22 (t, J = 7.8 Hz, 2H), 3.14 (t, J =
7.8 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 170.0, 142.7,
135.6, 131.5, 130.3, 130.2, 129.6, 127.2, 125.2, 124.3, 123.7,
122.6, 120.9, 116.6, 109.4, 37.3, 30.0; HRMS Calcd. for
C17H15BrNO [M++H] 328.0337, found 328.0320.
According to the general procedure described for 10a, Nꢀ
acylindole 10o (81.4 mg, 0.231 mmol, 72%) was obtained
from 9o (81.0 mg, 0.321 mmol) and indole (1) (94.0 mg, 0.802
mmol); a white solid; Mp 155ꢀ157 °C (hexanesꢀAcOEt); IR
(neat) 2949, 1716, 1536, 1453, 1319, 1261, 764 cmꢀ1; 1H NMR
(600 MHz, CDCl3) δ 8.62 (s, 1H), 8.44 (d, J = 7.8 Hz, 1H),
8.20 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.56 (d, J =
8.4 Hz, 1H), 7.44 (d, J = 3.6 Hz, 1H), 7.36 (dd, J = 8.1, 7.8
Hz, 1H), 7.28 (dd, J = 8.4, 8.1 Hz, 1H), 6.64 (d, J = 3.6 Hz,
1H), 3.96 (s, 3H), 3.48 (t, J = 7.2 Hz, 2H), 3.37 (t, J = 7.2 Hz,
2H); 13C NMR (150 MHz, CDCl3) δ 169.6, 164.8, 149.3,
140.3, 135.6, 133.8, 133.1, 130.3, 130.2, 126.2, 125.3, 124.2,
123.8, 120.9, 116.5, 109.6, 52.7, 36.3, 28.3; HRMS Calcd. for
C19H16N2NaO5 [M+Na+] 375.0957, found 375.0939.
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22
23
24
25
26
27
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29
30
31
32
33
34
35
36
37
38
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45
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59
60
1-(1H-Indol-1-yl)-3-(6-nitrobenzo[d][1,3]dioxol-5-
yl)propan-1-one (10p)
According to the general procedure described for 10a, Nꢀ
acylindole 10p (103 mg, 0.302 mmol, 70%) was obtained
from 9p (103 mg, 0.431 mmol) and indole (1) (127 mg, 1.08
mmol); a white solid; Mp 147ꢀ148 °C (hexanesꢀAcOEt); IR
(neat) 2949, 1704, 1519, 1327, 1256, 1206, 1037, 752 cmꢀ1; 1H
NMR (600 MHz, CDCl3) δ 8.46 (d, J = 8.4 Hz, 1H), 7.56 (d, J
= 8.4 Hz, 1H), 7.54 (s, 1H), 7.48 (d, J = 3.6 Hz, 1H), 7.36 (dd,
J = 8.4, 7.2 Hz, 1H), 7.27 (dd, J = 8.4, 7.2 Hz, 1H), 6.94 (s,
1H), 6.63 (d, J = 3.6 Hz, 1H), 6.09 (s, 2H), 3.38 (t, J = 7.2 Hz,
2H), 3.33 (t, J = 7.2 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ
170.2, 152.0, 146.9, 142.8, 135.6, 133.0, 130.4, 125.2, 124.5,
123.7, 120.9, 116.6, 111.4, 109.4, 105.8, 102.9, 36.6, 29.2;
HRMS Calcd. for C18H15N2O5 [M++H] 339.0981, found
339.0984.
1-(1H-Indol-1-yl)-3-(thiophen-2-yl)propan-1-one (10q)
According to the general procedure described for 10a, Nꢀ
acylindole 10q (51.3 mg, 0.201 mmol, 82%) was obtained
from 3ꢀ(2ꢀthienyl)propionic acid (9q) (38.0 mg, 0.244 mmol)
and indole (1) (71.0 mg, 0.606 mmol); a white solid; Mp 65ꢀ
66 °C (hexanesꢀAcOEt); IR (neat) 2953, 1705, 1452, 1324,
1205, 767, 751, 698 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 8.47
(d, J = 7.8 Hz, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.43 (d, J = 3.0
Hz, 1H), 7.36 (dd, J = 7.8, 7.5 Hz, 1H), 7.27 (dd, J = 7.5, 7.2
Hz, 1H), 7.15 (d, J = 4.8 Hz, 1H), 6.93 (dd, J = 4.8, 4.2 Hz,
1H), 6.91 (d, J = 4.2 Hz, 1H), 6.63 (d, J = 3.0 Hz, 1H), 3.39 (t,
J = 7.2 Hz, 2H), 3.29 (t, J = 7.2 Hz, 2H); 13C NMR (150 MHz,
CDCl3) δ 170.0, 142.8, 135.6, 130.3, 127.0, 125.2, 125.0,
124.3, 123.7, 120.9, 116.6, 109.4, 37.8, 24.6 (One signal is
missing due to overlap); HRMS Calcd. for C15H14NOS
[M++H] 256.0796, found 256.0785.
4-(3-(1H-Indol-1-yl)-3-oxopropyl)benzonitrile (10m)
According to the general procedure described for 10a, Nꢀ
acylindole 10m (70.8 mg, 0.258 mmol, 78%) was obtained
from 3ꢀ(4ꢀcyanophenyl)propionic acid (9m) (58.0 mg, 0.330
mmol) and indole (1) (97.0 mg, 0.828 mmol); a white solid;
Mp 121ꢀ122 °C (hexanesꢀAcOEt); IR (neat) 2953, 2226, 1705,
1452, 1389, 1328, 1206, 767, 752 cmꢀ1; 1H NMR (600 MHz,
CDCl3) δ 8.46 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H),
7.44–7.42 (m, 4H), 7.29–7.17 (m, 3H), 6.63 (d, J = 4.2 Hz,
1H), 3.22 (t, J = 7.8 Hz, 2H), 3.14 (t, J = 7.8 Hz, 2H); 13
C
NMR (150 MHz, CDCl3) δ 169.7, 146.0, 135.6, 132.4, 130.3,
129.3, 125.3, 124.1, 123.8, 120.9, 118.8, 116.5, 110.4, 109.6,
36.7, 30.3; HRMS Calcd. for C18H15N2O [M++H] 275.1184,
found 275.1170.
1-(1H-Indol-1-yl)-3-(4-nitrophenyl)propan-1-one (10n)
According to the general procedure described for 10a, Nꢀ
acylindole 10n (84.9 mg, 0.289 mmol, 76%) was obtained
from 3ꢀ(4ꢀnitrophenyl)propionic acid (9n) (75.0 mg, 0.387
mmol) and indole (1) (113 mg, 0.964 mmol); a white solid;
Mp 149ꢀ151 °C (hexanesꢀAcOEt); IR (neat) 2953, 1707, 1509,
1453, 1345, 1333, 1206, 1112, 752 cmꢀ1; 1H NMR (600 MHz,
CDCl3) δ 8.44 (d, J = 7.8 Hz, 1H), 8.17 (d, J = 9.0 Hz, 2H),
7.56 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 9.0 Hz, 2H), 7.42 (d, J =
3.6 Hz, 1H), 7.36 (dd, J = 7.8, 7.5 Hz, 1H), 7.28 (dd, J = 7.8,
7.5 Hz, 1H), 6.65 (d, J = 3.6 Hz, 1H), 3.29 (s, 4H); 13C NMR
(150 MHz, CDCl3) δ 169.6, 148.1, 146.7, 135.6, 130.3, 129.4,
125.3, 124.1, 123.9, 121.0, 116.5, 109.7, 36.6, 30.0 (One
signal is missing due to overlap); HRMS Calcd. for
C17H15N2O3 [M++H] 295.1083, found 295.1077.
1-(1H-Indol-1-yl)-2-(1,4-dioxaspiro[4.5]decan-8-
yl)ethanone (10r)
According to the general procedure described for 10a, Nꢀ
acylindole 10r (52.5 mg, 0.175 mmol, 56%) was obtained
from 9r (63.0 mg, 0.315 mmol) and indole (1) (92.0 mg, 0.788
mmol); a white solid; Mp 96ꢀ98 °C (hexanesꢀAcOEt); IR
(neat) 2953, 1704, 1452, 1317, 1204, 1105, 752 cmꢀ1; 1H NMR
(600 MHz, CDCl3) δ 8.48 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 7.8
Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 7.35 (dd, J = 8.4, 7.8 Hz,
1H), 7.21 (dd, J = 7.8, 7.8 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H),
3.95 (s, 4H), 2.82 (d, J = 7.2 Hz, 2H), 2.15–2.08 (m, 1H),
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1.90–1.88 (m, 2H), 1.78–1.76 (m, 2H), 1.65–1.59 (m, 2H),
222.0913. Spectroscopic date matched those previously
1.45–1.39 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 170.7,
135.6, 130.4, 125.1, 124.7, 123.6, 120.8, 116.7, 109.0, 108.5,
64.3, 64.2, 42.2, 34.3, 33.3, 30.2; HRMS Calcd. for
C18H22NO3 [M++H] 300.1600, found 300.1579.
reported.3h
(1H-Indol-1-yl)(pyridin-2-yl)methanone (10v)
According to the general procedure described for 10a, Nꢀ
acylindole 10v (73.3 mg, 0.330 mmol, 98%) was obtained
from 2ꢀpyridinecarboxylic acid (9v) (42.0 mg, 0.337 mmol)
and indole (1) (99.0 mg, 0.844 mmol) in the presence of
DMAP (8.20 mg, 0.0674 mmol), and 2,6ꢀlutidine (12 ꢀL, 0.10
mmol); a white solid; Mp 79ꢀ81 °C (hexanesꢀAcOEt); IR
(neat) 2949, 1684, 1539, 1451, 1437, 1382, 1347, 1205, 1193,
890, 767, 747, 698 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 8.74
(dd, J = 4.8, 1.2 Hz, 1H), 8.54 (d, J = 7.8 Hz, 1H), 8.09 (d, J =
7.2 Hz, 1H), 7.98 (d, J = 4.2 Hz, 1H), 7.94 (ddd, J = 7.5, 7.2,
1.2 Hz, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.51 (ddd, J = 7.5, 4.8,
1.2 Hz, 1H), 7.39 (dd, J = 7.8, 7.5 Hz, 1H), 7.32 (dd, J = 7.5,
7.2 Hz, 1H), 6.64 (d, J = 4.2 Hz, 1H); 13C NMR (150 MHz,
CDCl3) δ 165.7, 152.4, 148.5, 137.4, 136.4, 130.7, 128.4,
126.1, 125.7, 124.9, 124.1, 120.7, 116.9, 109.1; HRMS Calcd.
for C14H11N2O [M++H] 223.0871, found 223.0869.
Spectroscopic date matched those previously reported.3h
(1H-Indol-1-yl)(quinolin-2-yl)methanone (10w)
According to the general procedure described for 10a, Nꢀ
acylindole 10w (78.3 mg, 0.288 mmol, 70%) was obtained
from 2ꢀquinolinecarboxylic acid (9w) (71.0 mg, 0.411 mmol)
and indole (1) (121 mg, 1.03 mmol) in the presence of DMAP
(10.0 mg, 0.0819 mmol), and 2,6ꢀlutidine (14 ꢀL, 0.12 mmol);
a white solid; Mp 125ꢀ127 °C (hexanesꢀAcOEt); IR (neat)
2953, 1684, 1451, 1383, 1349, 1206, 902, 825, 771, 761, 749
cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 8.60 (d, J = 8.4 Hz, 1H),
8.39 (d, J = 8.4 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.16 (d, J =
4.2 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H),
7.83 (dd, J = 8.4, 7.5 Hz, 1H), 7.70 (dd, J = 8.4, 7.5 Hz, 1H),
7.61 (d, J = 7.8 Hz, 1H), 7.41 (dd, J = 8.4, 7.2 Hz, 1H), 7.33
(d, J = 7.8, 7.2 Hz, 1H), 6.66 (d, J = 4.2 Hz, 1H); 13C NMR
(150 MHz, CDCl3) δ 165.9, 151.9, 146.6, 137.5, 136.5, 130.8,
130.5, 130.3, 128.7, 128.6, 127.7, 125.0, 124.2, 121.6, 120.7,
117.0, 109.2 (One signal is missing due to overlap); HRMS
Calcd. for C18H13N2O [M++H] 273.1028, found 273.1021.
1-(6-Bromo-1H-indol-1-yl)-4-phenylbutan-1-one (12a)
According to the general procedure described for 10a, Nꢀ
acylindole 12a (80.6 mg, 0.236 mmol, 88%) was obtained
from 4ꢀphenylbutyric acid (9j) (44.0 mg, 0.268 mmol) and 6ꢀ
bromoindole (11a) (131 mg, 0.668 mmol); a white solid; Mp
93ꢀ94 °C (hexanesꢀAcOEt); IR (neat) 2953, 1713, 1449, 1428,
1301, 1200, 886, 699 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 8.69
(s, 1H), 7.41–7.37 (m, 2H), 7.33–7.29 (m, 3H), 7.22–7.20 (m,
3H), 6.57 (d, J = 3.6 Hz, 1H), 2.88 (t, J = 7.8 Hz, 2H), 2.79 (t,
J = 7.8 Hz, 2H), 2.18 (tt, J = 7.8, 7.8 Hz, 2H); 13C NMR (150
MHz, CDCl3) δ 171.1, 141.0, 136.2, 129.0, 128.53, 128.48,
126.9, 126.2, 124.9, 121.8, 119.7, 118.8, 108.7, 34.9, 34.7,
25.8; HRMS Calcd. for C18H17BrNO [M++H] 342.0494, found
342.0474.
Cyclopent-3-en-1-yl(1H-indol-1-yl)methanone (10s)
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According to the general procedure described for 10a, Nꢀ
acylindole 10s (46.7 mg, 0.221 mmol, 76%) was obtained
from 3ꢀcyclopentenecarboxylic acid (9s) (33.0 mg, 0.291
mmol) and indole (1) (85.0 mg, 0.725 mmol); a white solid;
Mp 76ꢀ77 °C (hexanesꢀAcOEt); IR (neat) 2953, 1700, 1451,
1360, 1339, 1309, 1289, 1224, 1206, 767, 750, 717 cmꢀ1; 1H
NMR (600 MHz, CDCl3) δ 8.51 (d, J = 7.8 Hz, 1H), 7.57 (d, J
= 7.2 Hz, 1H), 7.49 (d, J = 4.2 Hz, 1H), 7.35 (dd, J = 7.8, 7.5
Hz, 1H), 7.27 (dd, J = 7.5, 7.2 Hz, 1H), 6.65 (d, J = 4.2 Hz,
1H), 5.74 (s, 2H), 3.85 (tt, J = 9.6, 6.0 Hz, 1H), 2.93 (dd, J =
14.7, 6.0 Hz, 2H), 2.81 (dd, J = 14.7, 9.6 Hz, 2H); 13C NMR
(150 MHz, CDCl3) δ 174.0, 135.9, 130.3, 128.8, 125.1, 124.7,
123.6, 120.7, 116.8, 109.1, 42.0, 36.9; HRMS Calcd. for
C14H14NO [M++H] 212.1075, found 212.1060.
(S)-Benzyl
2-(1H-indole-1-carbonyl)pyrrolidine-1-
carboxylate (10t)
According to the general procedure described for 10a, Nꢀ
acylindole 10t (101 mg, 0.292 mmol, 72%, >99% ee) was
obtained from CbzꢀLꢀproline 9t (101 mg, 0.405 mmol) and
indole (1) (118 mg, 1.01 mmol) in the presence of DMAP (10
mg, 0.082 mmol), and 2,6ꢀlutidine (14 ꢀL, 0.12 mmol); a
white solid; Mp 31ꢀ32 °C (hexanesꢀAcOEt); Enantiomeric
excess was determined by HPLC analysis (CHIRALCEL OJꢀ
H column, nꢀhexaneꢀisopropanol (80:20 v/v as an eluent), 0.8
mL/min, λ = 254 nm, 25 °C, the retention times of (+)ꢀisomer
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and (–)ꢀisomer are 27 min and 50 min, respectively); [α]D
–
109.3 (c 0.81, CHCl3); IR (neat) 2954, 1700, 1452, 1415,
1355, 1308, 1204, 1123, 765, 751 cmꢀ1; 1H NMR (600 MHz,
CDCl3, a mixture of two rotamers) δ 8.48–8.45 (m, 1H), 7.58–
7.26 (m, 7H), 7.12–7.00 (m, 2H), 6.68–6.62 (m, 1H), 5.23–
5.01 (m, 3H), 3.81–3.79 (m, 1H), 3.68–3.59 (m, 1H), 2.44–
2.38 (m, 1H), 2.15–2.10 (m, 2H), 2.01–2.00 (m, 1H); 13C
NMR (150 MHz, CDCl3, a mixture of two rotamers) δ 170.7,
170.4, 155.0, 154.1, 136.6, 136.2, 135.94, 135.88, 128.5,
128.2, 128.0, 127.9, 127.7, 127.6, 125.4, 125.2, 124.0, 123.9,
123.6, 120.84, 120.80, 116.9, 116.8, 109.8, 67.23, 67.19, 59.5,
59.0, 47.2, 46.6, 31.4, 30.4, 24.3, 23.5; HRMS Calcd. for
C21H20N2NaO3 [M+Na+] 371.1372, found 371.1354.
(1H-Indol-1-yl)(phenyl)methanone (10u)
According to the general procedure described for 10a, Nꢀ
acylindole 10u (31.0 mg, 0.140 mmol, 42%) was obtained
from benzoic acid (9u) (41.0 mg, 0.337 mmol) and indole (1)
(99.0 mg, 0.844 mmol) in the presence of DMAP (8.20 mg,
0.0674 mmol), and 2,6ꢀlutidine (12 ꢀL, 0.10 mmol); a white
solid; Mp 61ꢀ62 °C (hexanesꢀAcOEt); IR (neat) 2949, 1686,
1450, 1340, 1205, 887, 750, 700 cmꢀ1; 1H NMR (600 MHz,
CDCl3) δ 8.40 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 7.2 Hz, 2H),
7.65–7.60 (m, 2H), 7.53 (dd, J = 8.1, 7.2 Hz, 2H), 7.39 (dd, J
= 8.1, 7.8 Hz, 1H), 7.33–7.30 (m, 2H), 6.62 (d, J = 3.6 Hz,
1H); 13C NMR (150 MHz, CDCl3) δ 168.7, 136.0, 134.6,
131.9, 130.8, 129.1, 128.6, 127.6, 124.9, 123.9, 120.9, 116.4,
108.5; HRMS Calcd. for C15H12NO [M++H] 222.0919, found
1-(4-Phenylbutanoyl)-1H-indole-5-carbaldehyde (12b)
According to the general procedure described for 10a, Nꢀ
acylindole 12b (65.5 mg, 0.225 mmol, 84%) was obtained
from 4ꢀphenylbutyric acid (9j) (44.0 mg, 0.268 mmol) and
indoleꢀ5ꢀcarbaldehyde (11b) (97.0 mg, 0.668 mmol); a white
solid; Mp 69ꢀ70 °C (hexanesꢀAcOEt); IR (neat) 2974, 1715,
1691, 1381, 1308, 1194, 1156, 700 cmꢀ1; 1H NMR (600 MHz,
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CDCl3) δ 10.1 (s, 1H), 8.60 (d, J = 7.8 Hz, 1H), 8.10 (s, 1H),
cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 8.00 (d, J = 8.4 Hz, 1H),
7.89 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 3.6 Hz, 1H), 7.33–7.30
(m, 2H), 7.23–7.21 (m, 3H), 6.73 (d, J = 3.6 Hz, 1H), 2.93 (t, J
= 7.2 Hz, 2H), 2.80 (t, J = 7.2 Hz, 2H), 2.20 (tt, J = 7.2, 7.2
Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 192.0, 171.3, 140.9,
139.0, 132.4, 130.5, 128.6, 128.5, 126.33, 126.29, 126.23,
123.6, 117.0, 109.4, 34.88, 34.85, 25.8; HRMS Calcd. for
C19H18NO2 [M++H] 292.1338, found 292.1320.
7.62 (d, J = 8.4 Hz, 1H), 7.42 (dd, J = 8.4, 6.6 Hz, 1H), 7.31
(s, 1H), 7.28–7.23 (m, 3H), 7.18–7.12 (m, 3H), 4.34 (q, J =
7.8 Hz, 2H), 2.87 (t, J = 7.8 Hz, 2H), 2.66 (t, J = 7.8 Hz, 2H),
2.11 (tt, J = 7.8, 7.8 Hz, 2H), 1.37 (t, J = 7.8 Hz, 3H); 13
C
NMR (150 MHz, CDCl3) δ 174.3, 161.7, 141.2, 138.2, 129.5,
128.42, 128.39, 127.7, 127.2, 126.0, 123.5, 122.4, 117.6,
114.7, 61.6, 38.9, 35.0, 27.0, 14.2; HRMS Calcd. for
C21H21NNaO3 [M+Na+] 358.1419, found 358.1409.
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1-(5-Nitro-1H-indol-1-yl)-4-phenylbutan-1-one (12c)
According to the general procedure described for 10a, Nꢀ
acylindole 12c (77.3 mg, 0.251 mmol, 93%) was obtained
from 4ꢀphenylbutyric acid (9j) (45.0 mg, 0.271 mmol) and 5ꢀ
nitroindole (11c) (110 mg, 0.678 mmol); a pale yellow solid;
Mp 89ꢀ90 °C (hexanesꢀAcOEt); IR (neat) 2974, 1717, 1518,
1339, 1308, 1198, 770, 742 cmꢀ1; 1H NMR (600 MHz, CDCl3)
δ 8.58 (d, J = 8.4 Hz, 1H), 8.47 (s, 1H), 8.23 (d, J = 8.4 Hz,
1H), 7.53 (d, J = 3.6 Hz, 1H), 7.33–7.30 (m, 2H), 7.26–7.21
(m, 3H), 6.75 (d, J = 3.6 Hz, 1H), 2.94 (t, J = 7.2 Hz, 2H),
1-(2-Iodo-1H-indol-1-yl)-4-phenylbutan-1-one (12g)
According to the general procedure described for 10a, Nꢀ
acylindole 12g (130 mg, 0.333 mmol, 90%) was obtained
from 4ꢀphenylbutyric acid (9j) (61.0 mg, 0.370 mmol) and 2ꢀ
iodoindole (11g)13 (225 mg, 0.926 mmol); a pale yellow solid;
Mp 49ꢀ50 °C (hexanesꢀAcOEt); IR (neat) 2949, 1711, 1438,
1259, 746 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 7.94 (d, J = 7.2
Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.30–7.19 (m, 7H), 7.02 (s,
1H) 3.18 (t, J = 7.2 Hz, 2H), 2.77 (t, J = 7.8 Hz, 2H), 2.19 (tt,
J = 7.8, 7.2 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 173.0,
141.1, 137.8, 131.1, 128.53, 128.48, 126.1, 124.7, 123.4,
123.2, 119.6, 114.8, 73.2, 39.2, 35.0, 26.9; HRMS Calcd. for
C18H16INNaO [M+Na+] 412.0174, found 412.0167.
4-Phenyl-1-(2-phenyl-1H-indol-1-yl)butan-1-one (12h)
According to the general procedure described for 10a, Nꢀ
acylindole 12h (35.3 mg, 0.104 mmol, 33%) was obtained
from 4ꢀphenylbutyric acid (9j) (52.0 mg, 0.320 mmol) and 2ꢀ
phenylindole (11h) (154 mg, 0.798 mmol); a colorless oil; IR
(neat) 2929, 1703, 1451, 1370, 1329, 1283, 1268, 1164, 749,
699 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 8.30 (d, J = 8.4 Hz,
1H), 7.55 (d, J = 7.2 Hz, 1H), 7.56–7.39 (m, 5H), 7.36–7.26
(m, 2H), 7.19–7.12 (m, 3H), 6.90 (d, J = 6.6 Hz, 2H), 6.60 (s,
1H), 2.38 (t, J = 7.8 Hz, 2H), 2.26 (t, J = 7.8 Hz, 2H), 1.87 (tt,
J = 7.8, 7.8 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 174.7,
141.0, 139.4, 137.6, 134.2, 129.0, 128.71, 128.69, 128.5,
128.34, 128.28, 125.8, 125.0, 123.5, 120.4, 115.6, 111.3, 39.1,
34.8, 26.8; HRMS Calcd. for C24H22NO [M++H] 340.1701,
found 340.1683.
2.81 (t, J = 6.6 Hz, 2H), 2.21 (tt, J = 7.2, 6.6 Hz, 2H); 13
C
NMR (150 MHz, CDCl3) δ 171.3, 144.2, 140.8, 138.5, 130.1,
128.6, 128.5, 127.4, 126.3, 120.3, 117.0, 116.8, 109.4, 34.80,
34.77, 25.7; HRMS Calcd. for C18H16N2NaO3 [M+Na+]
331.1059, found 331.1032.
1-(4-Phenylbutanoyl)-1H-indole-3-carbaldehyde (12d)
According to the general procedure described for 10a, Nꢀ
acylindole 12d (97.8 mg, 0.336 mmol, 96%) was obtained
from 4ꢀphenylbutyric acid (9j) (57.0 mg, 0.350 mmol) and
indoleꢀ3ꢀcarbaldehyde (11d) (127 mg, 0.875 mmol); a white
solid; Mp 87ꢀ88 °C (hexanesꢀAcOEt); IR (neat) 2973, 1727,
1676, 1550, 1447, 1187, 1126, 752, 700 cmꢀ1; 1H NMR (600
MHz, CDCl3) δ 10.1 (s, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.26 (d,
J = 8.4 Hz, 1H), 7.94 (s, 1H), 7.44 (dd, J = 8.4, 7.8 Hz, 1H),
7.40 (dd, J = 8.4, 7.8 Hz, 1H), 7.34–7.31 (m, 2H), 7.26–7.22
(m, 3H), 2.97 (t, J = 7.8 Hz, 2H), 2.81 (t, J = 7.8 Hz, 2H), 2.22
(tt, J = 7.8, 7.8 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 185.6,
171.2, 140.7, 136.4, 134.5, 128.6, 128.5, 126.8, 126.4, 125.9,
125.3, 122.5, 121.9, 116.4, 34.7, 34.6, 25.7; HRMS Calcd. for
C19H18NO2 [M++H] 292.1338, found 292.1318.
1-(3-Acetyl-1H-indol-1-yl)-4-phenylbutan-1-one (12e)
According to the general procedure described for 10a, Nꢀ
acylindole 12e (92.6 mg, 0.303 mmol, 97%) was obtained
from 4ꢀphenylbutyric acid (9j) (51.0 mg, 0.313 mmol) and 3ꢀ
acetylindole (11e) (125 mg, 0.785 mmol); a white solid; Mp
101ꢀ103 °C (hexanesꢀAcOEt); IR (neat) 2949, 1718, 1665,
1545, 1448, 1388, 1197, 1148, 1016, 753 cmꢀ1; 1H NMR (600
MHz, CDCl3) δ 8.38 (d, J = 7.8 Hz, 1H), 8.33 (d, J = 7.2 Hz,
1H), 7.93 (s, 1H), 7.42–7.37 (m, 2H), 7.34–7.31 (m, 2H),
7.26–7.22 (m, 3H), 2.96 (t, J = 7.8 Hz, 2H), 2.82 (t, J = 7.8
Hz, 2H), 2.53 (s, 3H), 2.22 (tt, J = 7.8, 7.8 Hz, 2H); 13C NMR
(150 MHz, CDCl3) δ 193.7, 171.3, 140.8, 136.0, 130.5, 128.6,
128.5, 127.1, 126.3, 126.2, 125.1, 122.4, 121.8, 116.2, 34.75,
34.71, 27.9, 25.8; HRMS Calcd. for C20H20NO2 [M++H]
306.1494, found 306.1483.
1-(2-(4-((tert-Butyldiphenylsilyl)oxy)but-1-yn-1-yl)-1H-
indol-1-yl)-4-phenylbutan-1-one (12i)
According to the general procedure described for 10a, Nꢀ
acylindole 12i (234 mg, 0.411 mmol, 98%) was obtained from
4ꢀphenylbutyric acid (9j) (69.0 mg, 0.418 mmol) and indole
11i (440 mg, 1.04 mmol); a pale yellow solid; Mp 73ꢀ75 °C
(hexanesꢀAcOEt); IR (neat) 2950, 1707, 1449, 1284, 1110,
742, 701 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 8.43 (d, J = 8.4
Hz, 1H), 7.70–7.68 (m, 4H), 7.47–7.33 (m, 8H), 7.26–7.23 (m,
3H), 7.17–7.14 (m, 3H), 6.81 (s, 1H), 3.85 (t, J = 6.6 Hz, 2H),
3.22 (t, J = 7.2 Hz, 2H), 2.68–2.66 (m, 4H), 2.11 (tt, J = 7.2,
6.6 Hz, 2H), 1.08 (s, 9H); 13C NMR (150 MHz, CDCl3) δ
173.3, 141.5, 136.5, 135.6, 133.4, 129.8, 128.6, 128.44,
128.37, 127.7, 125.99, 125.97, 123.8, 120.2, 119.7, 117.5,
117.0, 95.9, 74.7, 61.9, 37.3, 35.1, 26.8, 26.4, 24.0, 19.2;
HRMS Calcd. for C38H40NO2Si [M++H] 570.2828, found
570.2785.
Ethyl 1-(4-phenylbutanoyl)-1H-indole-2-carboxylate (12f)
According to the general procedure described for 10a, Nꢀ
acylindole 12f (101 mg, 0.300 mmol, 91%) was obtained from
4ꢀphenylbutyric acid (9j) (54.0 mg, 0.330 mmol) and ethyl
indoleꢀ2ꢀcarboxylate (11f) (156 mg, 0.824 mmol); a colorless
oil; IR (neat) 2949, 1720, 1536, 1444, 1377, 1202, 747, 700
1-(7-(Benzyloxy)-1H-indol-1-yl)-4-phenylbutan-1-one (12j)
According to the general procedure described for 10a, Nꢀ
acylindole 12j (80.9 mg, 0.218 mmol, 93%) was obtained
from 4ꢀphenylbutyric acid (9j) (39.0 mg, 0.236 mmol) and 7ꢀ
benzyloxyindole (11j) (132 mg, 0.592 mmol); a pale yellow
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solid; Mp 42ꢀ43 °C (hexanesꢀAcOEt); IR (neat) 2953, 1726,
88 °C (hexanesꢀAcOEt); IR (neat) 2949, 1696, 1445, 1375,
1704, 1583, 1485, 1421, 1300, 1260, 1247, 1196, 1070, 788,
742, 722, 697 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 7.54 (d, J =
3.6 Hz, 1H), 7.45 (d, J = 7.8 Hz, 2H), 7.38–7.31 (m, 3H),
7.25–7.14 (m, 5H), 7.56 (d, J = 7.2 Hz, 2H), 6.89 (d, J = 7.8
Hz, 1H), 6.57 (d, J = 3.6 Hz, 1H), 5.18 (s, 2H), 2.95 (t, J = 7.8
Hz, 2H), 2.53 (t, J = 7.8 Hz, 2H), 1.98 (tt, J = 7.8, 7.8 Hz,
2H); 13C NMR (150 MHz, CDCl3) δ 172.9, 147.2, 141.4,
136.5, 134.2, 128.6, 128.4, 128.3, 128.1, 127.7, 127.5, 125.9,
124.7, 124.0, 114.2, 108.0, 107.6, 71.1, 37.3, 34.9, 27.0;
HRMS Calcd. for C25H24NO2 [M++H] 370.1807, found
370.1798.
1283, 1210, 1156, 753, 721 cmꢀ1; 1H NMR (600 MHz, CDCl3)
δ 8.14 (d, J = 7.8 Hz, 2H), 7.98 (d, J = 7.8 Hz, 2H), 7.44 (dd, J
= 7.8, 7.5 Hz, 2H), 7.37 (dd, J = 7.8, 7.5 Hz, 2H), 7.31 (dd, J =
7.5, 7.2 Hz, 2H), 7.26–7.20 (m, 3H), 3.13 (t, J = 7.8 Hz, 2H),
2.84 (t, J = 7.8 Hz, 2H), 2.27 (tt, J = 7.8, 7.8 Hz, 2H); 13C
NMR (150 MHz, CDCl3) δ 173.0, 141.4, 138.5, 128.6, 128.5,
127.3, 126.4, 126.1, 123.5, 119.8, 116.4, 38.3, 35.1, 26.3;
HRMS Calcd. for C22H20NO [M++H] 314.1545, found
314.1534.
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1-(4-Phenylbutanoyl)pyrrolidin-2-one (14a)
According to the general procedure described for 10a, imide
14a (46.4 mg, 0.201 mmol, 64%) was obtained from 4ꢀ
phenylbutyric acid (9j) (51.0 mg, 0.313 mmol) and 2ꢀ
pyrrolidone (13a) (67.0 mg, 0.787 mmol); a white solid; Mp
55ꢀ56 °C (hexanesꢀAcOEt); IR (neat) 2953, 1738, 1692, 1362,
1252, 747, 701 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 7.29–7.17
(m, 5H), 3.79 (t, J = 7.8 Hz, 2H), 2.94 (t, J = 7.8 Hz, 2H), 2.69
(t, J = 7.2 Hz, 2H), 2.58 (t, J = 8.4 Hz, 2H), 2.04–1.96 (m,
4H); 13C NMR (150 MHz, CDCl3) δ 175.3, 174.1, 141.8,
128.5, 128.3, 125.8, 45.4, 36.3, 35.2, 33.7, 25.8, 17.2; HRMS
Calcd. for C14H17NNaO2 [M+Na+] 254.1157, found 254.1153.
(S)-5-(((tert-Butyldimethylsilyl)oxy)methyl)-1-(4-
Ethyl
(12k)
1-(4-phenylbutanoyl)-1H-pyrrole-2-carboxylate
According to the general procedure described for 10a, Nꢀ
acylpyrrole 12k (65.3 mg, 0.229 mmol, 68%) was obtained
from 4ꢀphenylbutyric acid (9j) (55.0 mg, 0.335 mmol) and
ethyl pyrroleꢀ2ꢀcarboxylate (11k) (117 mg, 0.841 mmol); a
colorless oil; IR (neat) 2978, 1717, 1453, 1416, 1270, 1245,
1
1209, 1108, 756, 700 cmꢀ1; H NMR (600 MHz, CDCl3) δ
7.29–7.26 (m, 2H), 7.23 (dd, J = 2.4, 1.2 Hz, 1H), 7.21–7.17
(m, 3H), 6.93 (dd, J = 3.6, 1.2 Hz, 1H), 6.20 (dd, J = 3.6, 2.4
Hz, 1H), 4.29 (q, J = 7.8 Hz, 2H), 2.88 (t, J = 7.8 Hz, 2H),
2.71 (t, J = 7.8 Hz, 2H), 2.10 (tt, J = 7.8, 7.8 Hz, 2H), 1.34 (t,
J = 7.8 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 172.2, 161.2,
141.1, 128.4, 126.1, 125.5, 125.2, 122.0, 110.8, 61.0, 36.2,
34.8, 26.4, 14.2 (One signal is missing due to overlap); HRMS
Calcd. for C17H19NNaO3 [M+Na+] 308.1263, found 308.1265.
1-(2-acetyl-1H-pyrrol-1-yl)-4-phenylbutan-1-one (12l)
According to the general procedure described for 10a, Nꢀ
acylpyrrole 12l (60.0 mg, 0.235 mmol, 78%) was obtained
from 4ꢀphenylbutyric acid (9i) (49.0 mg, 0.300 mmol) and 2ꢀ
acecyl pyrrole (11l) (81.0 mg, 0.750 mmol); a colorless oil; IR
(neat) 2929, 1735, 1661, 1433, 1411, 1266, 747, 700 cmꢀ1; 1H
NMR (400 MHz, CDCl3) δ 7.29–7.14 (m, 6H), 6.98 (dd, J =
3.4, 1.6 Hz, 1H), 6.22 (dd, J = 3.4, 2.8 Hz, 1H), 2.81 (t, J = 7.2
Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H), 2.44 (s, 3H), 2.08 (tt, J =
7.6, 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 188.5, 174.1,
141.1, 133.7, 128.41, 128.36, 127.6, 126.0, 122.9, 110.5, 37.3,
34.8, 27.2, 26.6; HRMS Calcd. for C16H17NNaO2 [M+Na+]
278.1157, found 278.1146.
phenylbutanoyl)pyrrolidin-2-one (14b)
According to the general procedure described for 10a, imide
14b (68.1 mg, 0.181 mmol, 41%) was obtained from 4ꢀ
phenylbutyric acid (9j) (72.0 mg, 0.440 mmol) and lactam
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13b14 (252 mg, 1.10 mmol); pale yellow oil; [α]D –85.6 (c
1.00, CHCl3); IR (neat) 2953, 1739, 1692, 1362, 1256, 1231,
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1200, 1112, 837, 778 cmꢀ1; H NMR (600 MHz, CDCl3) δ
7.29–7.26 (m, 2H), 7.21–7.16 (m, 3H), 4.41–4.39 (m, 1H),
3.94 (dd, J = 10.5, 3.0 Hz, 1H), 3.65 (dd, J = 10.5, 2.4 Hz,
1H), 2.98–2.92 (m, 2H), 2.84–2.78 (m, 1H), 2.71–2.66 (m,
2H), 2.44–2.39 (m, 1H), 2.13–1.94 (m, 4H), 0.85 (s, 9H), 0.02
(s, 3H), –0.02 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 176.4,
174.0, 141.8, 128.5, 128.3, 125.8, 63.9, 58.0, 36.6, 35.3, 33.1,
25.9, 25.8, 21.2, 18.1, –5.6; HRMS Calcd. for C21H33NNaO3Si
[M+Na+] 398.2127, found 398.2112.
3-(4-Phenylbutanoyl)oxazolidin-2-one (14c)
According to the general procedure described for 10a, imide
14c (76.8 mg, 0.329 mmol, 91%) was obtained from 4ꢀ
phenylbutyric acid (9j) (59.0 mg, 0.361 mmol) and 2ꢀ
oxazolidone (13c) (79.0 mg, 0.907 mmol); a white solid; Mp
79ꢀ80 °C (hexanesꢀAcOEt); IR (neat) 2949, 1770, 1698, 1393,
4-Phenyl-1-(1H-pyrazol-1-yl)butan-1-one (12m)
According to the general procedure described for 10a, Nꢀ
acylpyrazole 12m (59.2 mg, 0.276 mmol, 85%) was obtained
from 4ꢀphenylbutyric acid (9j) (53.0 mg, 0.324 mmol) and
pyrazole (11m) (55.0 mg, 0.808 mmol); a white solid; Mp 34ꢀ
35 °C (hexanesꢀAcOEt); IR (neat) 2978, 1735, 1415, 1344,
1200, 923, 745, 700 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 8.25
(d, J = 3.0 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.31–7.18 (m,
5H), 6.43 (dd, J = 3.0, 1.8 Hz, 1H), 3.17 (t, J = 7.8 Hz, 2H),
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1113, 1038, 758, 702 cmꢀ1; H NMR (600 MHz, CDCl3) δ
7.29–7.17 (m, 5H), 4.38 (t, J = 7.8 Hz, 2H), 3.98 (t, J = 7.8
Hz, 2H), 2.96 (t, J = 7.2 Hz, 2H), 2.69 (t, J = 7.2 Hz, 2H), 2.01
(tt, J = 7.2, 7.2 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 173.2,
153.5, 141.5, 128.5, 128.3, 125.9, 62.0, 42.5, 35.1, 34.5, 25.8;
HRMS Calcd. for C13H15NNaO3 [M+Na+] 256.0950, found
256.0945.
2.75 (t, J = 7.8 Hz, 2H), 2.13 (tt, J = 7.8, 7.8 Hz, 2H); 13
C
NMR (150 MHz, CDCl3) δ 172.0, 143.9, 141.3, 128.5, 128.4,
128.2, 126.0, 109.5, 35.1, 33.3, 25.9; HRMS Calcd. for
C13H14N2NaO [M+Na+] 237.1004, found 237.0987.
(S)-4-Benzyl-3-(4-phenylbutanoyl)oxazolidin-2-one (14d)
According to the general procedure described for 10a, imide
14d (110 mg, 0.340 mmol, 98%) was obtained from 4ꢀ
phenylbutyric acid (9j) (57.0 mg, 0.348 mmol) and (S)ꢀ4ꢀ
benzylꢀ2ꢀoxazolidinone (13d) (154 mg, 0.869 mmol). The
reaction using equimolar amount of 13d with Boc2O (1.5 eq)
gave imide 14d in 80% yield; a white solid; Mp 78ꢀ80 °C
1-(9H-Carbazol-9-yl)-4-phenylbutan-1-one (12n)
According to the general procedure described for 10a, Nꢀ
acylcarbazole 12n (85.3 mg, 0.272 mmol, 87%) was obtained
from 4ꢀphenylbutyric acid (9j) (51.0 mg, 0.313 mmol) and
carbazole (11n) (131 mg, 0.783 mmol); a white solid; Mp 87ꢀ
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(hexanesꢀAcOEt); [α]D +50.2 (c 1.00, CHCl3); IR (neat)
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2953, 1781, 1698, 1386, 1352, 1211, 744, 701 cmꢀ1; 1H NMR
Mp 56ꢀ57 °C (hexanesꢀAcOEt); IR (neat) 2978, 1716, 1472,
(600 MHz, CDCl3) δ 7.34–7.18 (m, 10H), 4.66–4.62 (m, 1H),
4.19–4.14 (m, 2H), 3.28 (dd, J = 13.5, 3.6 Hz, 1H), 3.03–2.93
(m, 2H), 2.77–2.71 (m, 3H), 2.04 (tt, J = 7.8, 7.8 Hz, 2H); 13C
NMR (150 MHz, CDCl3) δ 173.0, 153.4, 141.5, 135.3, 129.4,
128.9, 128.5, 128.4, 127.3, 126.0, 66.2, 55.1, 37.9, 35.1, 35.0,
25.8; HRMS Calcd. for C20H21NNaO3 [M+Na+] 346.1419,
found 346.1418.
1366, 1235, 1215, 1129, 756, 700 cmꢀ1; 1H NMR (600 MHz,
CDCl3) δ 7.69 (dd, J = 8.1, 1.2 Hz, 1H), 7.41 (ddd, J = 8.4,
7.8, 1.2 Hz, 1H), 7.31–7.25 (m, 3H), 7.20–7.14 (m, 4H), 2.63
(t, J = 7.2 Hz, 2H), 2.54 (t, J = 7.8 Hz, 2H), 2.32 (s, 3H), 1.96
(tt, J = 7.8, 7.2 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 174.7,
172.2, 141.5, 138.5, 133.7, 130.7, 130.4, 128.8, 128.4, 128.3,
125.9, 123.9, 37.4, 35.0, 26.7, 26.0; HRMS Calcd. for
C18H18BrNNaO2 [M++H] 382.0419, found 382.0408.
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(S)-4-Isopropyl-3-(4-phenylbutanoyl)oxazolidin-2-one
(14e)
N-(2-Bromophenyl)-N-(4-phenylbutanoyl)benzamide (14i)
According to the general procedure described for 10a, imide
14i (177 mg, 0.420 mmol, 95%) was obtained from 4ꢀ
phenylbutyric acid (9j) (72.0 mg, 0.440 mmol) and 2ꢀ
(bromophenyl)benzamide (13i) (302 mg, 1.10 mmol); a
colorless oil; IR (neat) 2954, 1714, 1693, 1472, 1298, 699 cmꢀ
1; 1H NMR (600 MHz, CDCl3, a mixture of two rotamers) δ
7.66–7.62 (m, 2H), 7.44–7.14 (m, 12H), 2.75–2.62 (m, 4H),
2.08–2.02 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 175.8,
172.0, 141.5, 138.5, 135.2, 133.7, 131.8, 131.3, 130.0, 128.49,
128.46, 128.45, 128.36, 128.1, 125.9, 123.6, 37.1, 35.1, 26.4;
HRMS Calcd. for C23H20BrNNaO2 [M++H] 444.0575, found
444.0567.
N-Acetyl-N-(2-methoxyphenyl)-4-phenylbutanamide (14j)
According to the general procedure described for 10a, imide
14j (97.4 mg, 0.313 mmol, 87%) was obtained from 4ꢀ
phenylbutyric acid (9j) (59.0 mg, 0.359 mmol) and 2ꢀ
acetanisidine (13j) (148 mg, 0.897 mmol); a pale yellow solid;
Mp 36ꢀ37 °C (hexanesꢀAcOEt); IR (neat) 2954, 1711, 1499,
1367, 1280, 1248, 1224, 1023, 753 cmꢀ1; 1H NMR (600 MHz,
CDCl3) δ 7.38 (dd, J = 7.5, 7.2 Hz, 1H), 7.25 (dd, J = 7.5, 7.2
Hz, 2H), 7.18–7.13 (m, 3H), 7.05 (d, J = 7.2 Hz, 1H), 7.01
(dd, J = 8.4, 7.5 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 3.78 (s,
3H), 2.61 (t, J = 7.2 Hz, 2H), 2.52 (br m, 2H), 2.30 (s, 3H),
1.93 (tt, J = 7.2 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ
175.5, 173.0, 154.8, 141.7, 130.3, 130.0, 128.4, 128.3, 127.8,
125.8, 121.2, 111.9, 55.6, 37.0, 35.0, 26.5, 26.1; HRMS Calcd.
for C19H21NNaO3 [M+Na+] 334.1419, found 334.1424.
N-Acetyl-N-(3-methoxyphenyl)-4-phenylbutanamide (14k)
According to the general procedure described for 10a, imide
14k (101 mg, 0.324 mmol, 94%) was obtained from 4ꢀ
phenylbutyric acid (9j) (57.0 mg, 0.346 mmol) and 3ꢀ
acetanisidine (13k) (143 mg, 0.866 mmol). The reaction using
equimolar amount of 13k with Boc2O (1.5 eq) gave imide 14k
in 81% yield; a colorless oil; IR (neat) 2954, 1709, 1604,
1489, 1367, 1292, 1212, 1030, 698 cmꢀ1; 1H NMR (600 MHz,
CDCl3) δ 7.34 (dd, J = 8.4, 8.1 Hz, 1H), 7.27–7.25 (m, 2H),
7.19–7.13 (m, 3H), 6.95–6.94 (m, 1H), 6.70–6.68 (m, 1H),
6.63–6.62 (m, 1H), 3.80 (s, 3H), 2.61 (t, J = 7.8 Hz, 2H), 2.55
(t, J = 7.8 Hz, 2H), 2.33 (s, 3H), 1.94 (tt, J = 7.8, 7.8 Hz, 2H);
13C NMR (150 MHz, CDCl3) δ 175.5, 172.9, 160.6, 141.5,
140.1, 130.4, 128.4, 128.3, 125.9, 120.9, 114.6, 114.4, 55.4,
37.6, 35.0, 27.0, 26.2; HRMS Calcd. for C19H21NNaO3
[M+Na+] 334.1419, found 334.1418.
According to the general procedure described for 10a, imide
14e (106 mg, 0.384 mmol, 99%) was obtained from 4ꢀ
phenylbutyric acid (9j) (64.0 mg, 0.389 mmol) and (S)ꢀ4ꢀ
isopropylꢀ2ꢀoxazolidinone (13e) (125 mg, 0.968 mmol). The
reaction using equimolar amount of 13e with Boc2O (1.5 eq)
gave imide 14e in 85% yield; a white solid; Mp 26ꢀ27 °C
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(hexanesꢀAcOEt); [α]D +68.1 (c 1.00, CHCl3); IR (neat)
2946, 1781, 1701, 1387, 1206, 701 cmꢀ1; 1H NMR (600 MHz,
CDCl3) δ 7.30–7.18 (m, 5H), 4.41 (ddd, J = 9.0, 7.5, 2.4 Hz,
1H), 4.25 (dd, J = 9.0, 9.0 Hz, 1H), 4.19 (dd, J = 9.0, 2.4 Hz,
1H), 3.04–2.99 (m, 1H), 2.95–2.90 (m, 1H), 2.69 (t, J = 7.2
Hz, 2H), 2.39–2.33 (m, 1H), 2.05–1.94 (m, 2H), 0.91 (d, J =
6.6 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 173.0, 154.0, 141.5, 128.5, 128.3, 125.9, 63.3, 58.4,
35.1, 35.0, 28.4, 26.0, 18.0, 14.6; HRMS Calcd. for
C16H21NNaO3 [M+Na+] 298.1419, found 298.1412.
N-Acetyl-N-4-diphenylbutanamide (14f)
According to the general procedure described for 10a, imide
14f (142 mg, 0.504 mmol, quant) was obtained from 4ꢀ
phenylbutyric acid (9j) (83.0 mg, 0.504 mmol) and acetanilide
(13f) (170 mg, 1.26 mmol); a colorless oil; IR (neat) 2937,
1707, 1491, 1366, 1236, 1121, 697 cmꢀ1; 1H NMR (600 MHz,
CDCl3) δ 7.46–7.39 (m, 3H), 7.27–7.24 (m, 2H), 7.19–7.09
(m, 5H), 2.61 (t, J = 7.2 Hz, 2H), 2.52 (t, J = 7.2 Hz, 2H), 2.31
(s, 3H), 1.94 (tt, J = 7.2, 7.2 Hz, 2H); 13C NMR (150 MHz,
CDCl3) δ 175.5, 173.0, 141.5, 139.1, 129.7, 128.8, 128.4,
128.3, 125.9, 37.7, 35.0, 27.0, 26.2 (One signal is missing due
to overlap); HRMS Calcd. for C18H19NNaO2 [M+Na+]
304.1313, found 304.1291.
N-(2-Bromophenyl)-N-formyl-4-phenylbutanamide (14g)
According to the general procedure described for 10a, imide
14g (137 mg, 0.397 mmol, 94%) was obtained from 4ꢀ
phenylbutyric acid (9j) (69.0 mg, 0.420 mmol) and 2ꢀ
(bromophenyl)formamide (13g) (210 mg, 1.05 mmol); a white
solid; Mp 61ꢀ62 °C (hexanesꢀAcOEt); IR (neat) 2978, 1728,
1704, 1474, 1305, 1201, 1161, 751, 701 cmꢀ1; 1H NMR (600
MHz, CDCl3) δ 9.56 (s, 1H), 7.72 (dd, J = 7.8, 1.2 Hz, 1H),
7.42 (dd, J = 7.8, 6.0 Hz, 1H), 7.33 (ddd, J = 8.4, 7.8, 1.2 Hz,
1H), 7.27–7.24 (m, 2H), 7.18 (dd, J = 7.8, 7.8 Hz, 2H), 7.11
(d, J = 7.8 Hz, 2H), 2.66–2.57 (m, 2H), 2.21–2.20 (m, 2H),
2.00–1.94 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 174.4,
161.6, 141.0, 134.7, 133.9, 131.0, 130.6, 128.9, 128.41,
128.37, 126.1, 123.5, 34.9, 34.7, 25.3; HRMS Calcd. for
C17H16BrNNaO2 [M++H] 368.0262, found 368.0248.
N-Acetyl-N-(3-(methylthio)phenyl)-4-phenylbutanamide
(14l)
According to the general procedure described for 10a, imide
14l (112 mg, 0.342 mmol, 94%) was obtained from 4ꢀ
phenylbutyric acid (9j) (60.0 mg, 0.365 mmol) and anilide 13l
(165 mg, 0.912 mmol). The reaction using equimolar amount
N-Acetyl-N-(2-bromophenyl)-4-phenylbutanamide (14h)
According to the general procedure described for 10a, imide
14h (142 mg, 0.396 mmol, 99%) was obtained from 4ꢀ
phenylbutyric acid (9j) (66.0 mg, 0.400 mmol) and 2ꢀ
bromoacetanilide (13h) (213 mg, 1.00 mmol); a white solid;
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of 13l with Boc2O (1.5 equiv.) gave imide 14l in 85% yield; a
phenylbutyric acid (9j) (67.0 mg, 0.407 mmol) and 2ꢀ
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colorless oil; IR (neat) 2954, 1710, 1587, 1366, 1235, 1217,
1125, 698 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 7.35 (dd, J =
7.2, 7.2 Hz, 1H), 7.28–7.25 (m, 3H), 7.18 (dd, J = 7.2, 7.2 Hz,
1H), 7.13 (d, J = 6.6 Hz, 2H), 6.95 (dd, J = 2.4, 2.4 Hz, 1H),
6.85 (dd, J = 7.5, 2.4 Hz, 1H), 2.62 (t, J = 6.6 Hz, 2H), 2.52 (t,
J = 7.8 Hz, 2H), 2.47 (s, 3H), 2.33 (s, 3H), 1.94 (tt, J = 7.8, 6.6
Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 175.4, 172.9, 141.4,
140.8, 139.6, 129.9, 128.4, 128.3, 126.5, 126.3, 125.9, 125.2,
37.6, 34.9, 27.0, 26.2, 15.5; HRMS Calcd. for C19H21NNaO2S
[M+Na+] 350.1191, found 350.1193.
(pivaloylamino)pyridine (13p) (182 mg, 1.02 mmol); a
colorless oil; IR (neat) 2954, 1698, 1588, 1466, 1434, 1280,
1140, 747, 700 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 8.41 (d, J
= 4.8 Hz, 1H), 7.76 (ddd, J = 8.7, 7.2, 1.2 Hz, 1H), 7.36 (d, J =
7.2 Hz, 1H), 7.28–7.26 (m, 2H), 7.22–7.17 (m, 4H), 2.69 (t, J
= 7.2 Hz, 2H), 2.51 (t, J = 7.2 Hz, 2H), 2.06 (tt, J = 7.2, 7.2
Hz, 2H), 1.10 (s, 9H); 13C NMR (150 MHz, CDCl3) δ 186.5,
174.7, 152.0, 148.4, 141.5, 138.0, 128.5, 128.3, 125.9, 122.2,
121.8, 44.0, 35.7, 35.1, 28.4, 26.6; HRMS Calcd. for
C20H24N2NaO2 [M+Na+] 347.1735, found 347.1726.
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N-Acetyl-N-(4-methoxyphenyl)-4-phenylbutanamide (14m)
According to the general procedure described for 10a, imide
14m (79.5 mg, 0.256 mmol, 98%) was obtained from 4ꢀ
phenylbutyric acid (9j) (43.0 mg, 0.260 mmol) and 4ꢀ
acetanisidine (13m) (108 mg, 0.654 mmol); a colorless oil; IR
Procedure for Multi-Gram Scale Reaction
Caution! Because the reaction generates CO2 gas, the multi-
gram scale reaction should be conducted in flask equipped
with balloon or under the open-air condition.
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(neat) 2954, 1708, 1509, 1366, 1248, 1219, 1028 cmꢀ1; H
NMR (600 MHz, CDCl3, a mixture of two rotamers) δ 7.27–
7.25 (m, 2H), 7.19–7.13 (m, 3H), 7.01–6.98 (m, 2H), 6.95–
6.93 (m, 2H), 3.83 (s, 3H), 2.61 (t, J = 7.2 Hz, 2H), 2.52 (t, J =
7.8 Hz, 2H), 2.32 (s, 3H), 1.94 (tt, J = 7.8, 7.2 Hz, 2H); 13C
NMR (150 MHz, CDCl3) δ 175.8, 173.3, 159.6, 141.5, 131.6,
129.7, 128.4, 128.3, 125.9, 114.9, 55.4, 37.7, 35.0, 27.0, 26.2;
HRMS Calcd. for C19H21NNaO3 [M+Na+] 334.1419, found
334.1434.
Methyl 4-(1H-indol-1-yl)-4-oxobutanoate (10a)
A 500 mL flask equipped with a magnetic stirring bar, was
charged with Boc2O (20.6 g, 94.6 mmol). A solution of monoꢀ
methyl succinate (9a) (5.00 g, 37.8 mmol), indole (1) (11.0 g,
94.6 mmol), DMAP (231 mg, 1.89 mmol), and 2,6ꢀlutidine
(440 ꢀL, 3.78 mmol) in MeCN (83 mL) were added to the
flask at room temperature. Then, the reaction mixture was
warmed to 28 ºC by water bath. After stirring at 28 °C for 24 h
under argon atmosphere, the resulting mixture was
concentrated under reduced pressure to give a crude oil, which
was purified by silica gel column chromatography
(AcOEt/hexanes = 1:5) to give Nꢀacyl indole 10a (8.46 g, 36.6
mmol, 97%).
N-Acetyl-N-(2,6-dimethylphenyl)-4-phenylbutanamide
(14n)
According to the general procedure described for 10a, imide
14n (122 mg, 0.395 mmol, 84%) was obtained from 4ꢀ
phenylbutyric acid (9j) (77.0 mg, 0.467 mmol) and 2,6ꢀ
dimethylacetanilide (13n) (191 mg, 1.17 mmol); a white solid;
Mp 29ꢀ30 °C (hexanesꢀAcOEt); IR (neat) 2954, 1708, 1367,
N-Acetyl-N-(naphthalen-1-yl)-4-phenylbutanamide (14o)
A 500 mL flask equipped with a magnetic stirring bar and
argon balloon, was charged with Boc2O (10.6 g, 48.6 mmol).
A solution of 4ꢀphenylbutyric acid (9j) (5.32 g, 32.4 mmol), 1ꢀ
acetamidonaphthalene (13o) (6.00 g, 32.4 mmol), DMAP (200
mg, 1.64 mmol), and 2,6ꢀlutidine (380 ꢀL, 3.24 mmol) in
MeCN (80 mL) were added to the flask at room temperature.
Then, CH2Cl2 (100 mL) was added to a solution, and the
reaction mixture was warmed to 28 ºC by water bath. After
stirring at 28 °C for 24 h under argon atmosphere, the
resulting mixture was concentrated under reduced pressure to
give a crude oil, which was purified by silica gel column
chromatography (hexanes/AcOEt = 5:1) to give imide 14o
(10.1 g, 30.5 mmol, 94%).
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1254, 1224, 773, 700 cmꢀ1; H NMR (600 MHz, CDCl3) δ
7.27–7.12 (m, 8H), 2.62 (t, J = 7.2 Hz, 2H), 2.48 (t, J = 7.2
Hz, 2H), 2.27 (s, 3H), 2.09 (s, 6H), 1.95 (tt, J = 7.2, 7.2 Hz,
2H); 13C NMR (150 MHz, CDCl3) δ 175.1, 172.6, 141.5,
137.2, 135.6, 128.9, 128.8, 128.4, 128.3, 125.9, 36.9, 35.0,
26.3, 26.1, 17.8; HRMS Calcd. for C20H23NNaO2 [M+Na+]
332.1626, found 332.1656.
N-Acetyl-N-(naphthalen-1-yl)-4-phenylbutanamide (14o)
According to the general procedure described for 10a, imide
14o (120 mg, 0.362 mmol, 92%) was obtained from 4ꢀ
phenylbutyric acid (9j) (65.0 mg, 0.394 mmol) and 1ꢀ
acetamidonaphthalene (13o) (182 mg, 0.983 mmol). The
reaction using equimolar amount of 13o with Boc2O (1.5 eq)
gave imide 14o in 91% yield; a colorless oil; IR (neat) 2954,
1709, 1366, 1219, 776 cmꢀ1; 1H NMR (600 MHz, CDCl3, a
mixture of two rotamers) δ 7.93–7.91 (m, 2H), 7.65–7.63 (m,
1H), 7.55–7.50 (m, 3H), 7.29 (d, J = 7.2 Hz, 1H), 7.23 (dd, J =
7.8, 7.2 Hz, 2H), 7.15 (dd, J = 7.8, 7.2 Hz, 1H), 7.08 (d, J =
7.8 Hz, 2H), 2.67–2.53 (m, 3H), 2.49–2.44 (m, 1H), 2.34 (s,
3H), 1.96–1.90 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 175.8,
173.2, 141.5, 135.5, 134.5, 130.5, 129.5, 128.7, 128.4, 128.3,
127.7, 126.9, 126.7, 125.9, 125.6, 121.5, 37.3, 34.9, 26.7,
26.2; HRMS Calcd. for C22H21NNaO2 [M+Na+] 354.1470,
found 354.1480.
ASSOCIATED CONTENT
Supporting Information
1
Copies of H and 13CꢀNMR spectra of compounds 10a–10w,
12a–12n, and 14a–14p. Copy of HPLC chromatogram of 10t.
This materials is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
4-Phenyl-N-pivaloyl-N-(pyridin-2-yl)butanamide (14p)
According to the general procedure described for 10a, imide
14p (71.3 mg, 0.220 mmol, 54%) was obtained from 4ꢀ
Corresponding Author
*Eꢀmail: tokuyama@mail.pharm.tohoku.ac.jp.
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
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This work was supported by JSPS KAKENHI Grant Numbers
JP16H01127 in Middle Molecular Strategy, JP16H00999 in Precisely
Designed Catalysts with Customized Scaffolding, and JP15J03530, a
Grantꢀin aid for Scientific Research (A) (26253001), and Young
Scientists (B) (26860004).
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