An annulative electrophilic amination approach to 3-aminobenzoheteroles

Article abstract of DOI:10.1021/jo202207s

A copper-catalyzed annulative amination approach to 3-aminobenzofurans and -indoles from o-alkynylphenols and -anilines has been developed. The Cu-based catalysis is based on an umpolung, electrophilic amination with O-benzoyl hydroxylamines and enables t

Full text of DOI:10.1021/jo202207s

Article
pubs.acs.org/joc
An Annulative Electrophilic Amination Approach to
3-Aminobenzoheteroles
Naoki Matsuda, Koji Hirano,* Tetsuya Satoh, and Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
S
* Supporting Information
ABSTRACT: A copper-catalyzed annulative amination ap-
proach to 3-aminobenzofurans and -indoles from o-alkynyl-
phenols and -anilines has been developed. The Cu-based
catalysis is based on an umpolung, electrophilic amination with
O-benzoyl hydroxylamines and enables the mild and
convergent synthesis of various 3-aminobenzoheteroles of bio-
logical and pharmaceutical interest. Some mechanistic
investigations and an application of this protocol to construction of more complex tricyclic framework are also described.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
Heteroarylamines constitute an important class of compounds
in organic chemistry as a result of their ubiquity in pharmaceuticals
and biologically active compounds. In particular, 3-aminobenzo-
furans and -indoles have received significant attention as a pro-
mising structural candidate for the drug design directed toward a
variety of diseases.1 Such compounds are traditionally prepared by
sequential nitration of the parent benzofuran or indole/reduction
into amine/alkylation with appropriate electrophiles (Scheme 1,
route a).2 However, the nitration often suffers from harsh con-
ditions and difficulties in controlling the reactivity and regio-
selectivity. The palladium-catalyzed cross-coupling reaction of the
corresponding halides and amines, also known as Buchwald−
Hartwig amination, has recently been developed and has largely
displaced the above conventional strategy (route b).3 Despite the
advance, high utilities of these amines necessitate further
developments of more efficient and versatile synthetic method-
ologies for their preparation. In this context, we envisioned an
annulative amination of o-alkynylphenols and -anilines with an
electrophilic aminating reagent as the third approach (route c).
Our working scenario is illustrated in Scheme 2. An initial
activation of the alkyne moiety through coordination to a soft,
π-acidic metal (MXn) triggers an intramolecular attack of a
pendant nucleophile, that is anti-oxymetalation or -amino-
metalation (B), to generate the benzoheterolyl metal species C
with concomitant elimination of HX.4 If an appropriate base
suppressed the protonation of resultant organometallics via a
proton transfer (C to D), the subsequent coupling with the
electrophilic aminating reagent would occur to afford the desired
3-aminobenzoheteroles E along with the regeneration of the
starting metal catalyst A.5 The catalysis allows both C−Y and
C−N bonds to be formed efficiently in one synthetic operation so
as to provide a concise and complementary access to the target
motifs. We have now found that a common and bench-stable
Cu(OTf)2 salt is the suitable promoter for this type of trans-
formation. The detailed substrate scope and mechanistic
investigations are reported herein.6
We chose 2-(phenylethynyl)phenol (1a) and O-benzoyl-N,N-
diethylhydroxylamine (2a)7 as model substrates and began our
studies with a Cu(acac)2/dtbpy (dtbpy = 4,4′-di(tert-butyl)-2,2′-
bipyridine) catalyst and LiO-t-Bu base (Table 1). Initial
investigation into solvent systems revealed that polar, aprotic
DMSO and amides resulted in a detectable amount of
3-aminobenzofuran 3aa even at room temperature (entries
1−4), whereas less polar THF and toluene were ineffective
(entries 5 and 6). Although the yield was moderate, our
postulated catalytic cycle could be indeed operative. With the
preliminary but intriguing results, we next evaluated various
ligands to support the Cu catalyst. The modification of
substituents on the bipyridine ring gave minor effects on yield
(entries 7 and 8), while phenanthroline derivatives and
phosphorus ligands tested were less efficient or formed no
product (entries 9−16). Interestingly, such ancillary ligands
were not necessary for the reaction (entry 17). Moreover,
copper salts bearing less coordinating counteranions such as
hfac (hfac = hexafluoroacetylacetonate), OAc, and OTf showed
higher catalytic activity than Cu(acac)2, CuCl2, and CuCN
(entries 17−22). These trends are in good agreement with our
working hypothesis: the alkynyl moiety would be effectively
activated as the metal center become more π-acidic. However,
under Cu(hfac)2·OH2 or Cu(OAc)2·OH2 catalysis, the yields
varied from 60% to 92% (GC) probably due to presence of
water (entries 18 and 19). Thus, Cu(OTf)2 proved to be most
reliable and reproducible (entry 20). Some bases other than
LiO-t-Bu were detrimental. Both more basic Na- and KO-t-Bu
and less basic Cs2CO3 largely diminished the yield (entries 23−
25). In the absence of any copper salts, the reaction did not
proceed at all (entry 26). On the other hand, the corresponding
chloroamine8 did not act as the nitrogen source under con-
ditions employed for entry 20 (data not shown).
Received: October 26, 2011
Published: December 1, 2011
© 2011 American Chemical Society
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Scheme 1. Approaches to 3-Aminobenzofurans and -indoles
Scheme 2. Working Hypothesis
Scheme 3. Copper-Catalyzed Annulative Electrophilic
Amination of o-Alkynylphenols 1 with O-Benzoyl
a
Hydroxylamines 2 Leading to 3-Aminobenzofurans 3
With the optimized conditions in hand, we investigated
the substrate scope of the annulative amination approach to
3-aminobenzofurans (Scheme 3). In many cases, an increase in
the amount of hydroxylamines 2 to 2.0 equiv gave a better
result. At the alkyne terminus, electron-donating methoxy as
well as electron-withdrawing trifluoromethyl and chloro func-
tions were compatible (3ba−3da). In general, electron-rich
compounds tended to show higher reactivity. The benzofuran−
thiophene linkage was constructed without any difficulties
(3ea). The conjugated enyne moiety was transformed into the
alkenyl-substituted aminobenzofuran 3fa with the olefinic
moiety left intact. In addition to the above sp2 carbon sub-
stituents, the Cu-based catalysis accommodated the alkyl side
chains. The primary, secondary, and tertiary alkyl groups were
equally tolerated toward the reaction (3ga−3ia). The synthesis
of multisubstituted benzofuran cores was also successful
(3ja−ka). Especially, Cl substituents that remained unaffected
in 3ja are useful synthetic handles for further structural manipu-
lations via palladium-catalyzed cross-coupling reactions. Not
only diethylamine 2a but also acyclic allyl- and benzylamines
could participate in the annulative amination (3gb−gc). The
aminobenzofurans 3gb−gc obtained could enjoy additional and
orthogonal functionalizations after the selective deprotection of
allylic and benzylic groups.9 Cyclic frameworks involving piperidine,
a
With 1.0 mmol of 2.
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Table 1. Optimization Studies for Annulative Amination of 2-(Phenylethynyl)phenol (1a) and O-Benzoyl-N,
a
N-diethylhydroxylamine (2a)
b
entry
Cu/ligand
base
solvent
3aa, yield (%)
1
Cu(acac)2/dtbpy
Cu(acac)2/dtbpy
Cu(acac)2/dtbpy
Cu(acac)2/dtbpy
Cu(acac)2/dtbpy
Cu(acac)2/dtbpy
Cu(acac)2/bpy
Cu(acac)2/MeO-bpy
Cu(acac)2/phen
Cu(acac)2/bathophen
Cu(acac)2/2PPh3
Cu(acac)2/dppbz
Cu(acac)2/dppe
Cu(acac)2/dppf
Cu(acac)2/DPEphos
Cu(acac)2/Xantphos
Cu(acac)2
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
NaO-t-Bu
KO-t-Bu
Cs2CO3
DMSO
DMF
DMAc
NMP
THF
(14)
(18)
(27)
(39)
trace
trace
(38)
(41)
(20)
(14)
(20)
0
2
3
4
5
6
toluene
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
0
trace
(5)
(2)
(47)
(65)−(92)
(60)−(92)
Cu(hfac)2·OH2
Cu(OAc)2·OH2
Cu(OTf)2
c
(92) 61
CuCl2
(9)
(11)
(11)
trace
0
CuCN
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
none
LiO-t-Bu
0
a
A mixture of Cu salt (0.050 mmol), base (1.0 mmol), 1a (0.50 mmol), and 2a (0.60 mmol) in solvent (3.0 mL) was stirred at room temperature for
b
c
4 h under N2. Yield in parentheses determined by GC. The lower isolated yield is due to the partial decomposition of 3aa during chromatographic
purification, while the compound is stable after isolation.
morpholine, tetrahydroisoquinoline, and N-Boc-piperazine also
could be employed albeit with somewhat lower efficiencies in
some cases (3gd−gf and 3eg).
resulted in a lower yield of 5aa probably due to steric reasons
(entry 20).
By using conditions employed for entry 2 in Table 2, the
reaction with an array of o-alkynylanilines was performed
(Scheme 4). Compared to 4a, cyclohexyl- and tert-butyl-
substituted anilines resulted in lower efficiencies because of
their steric reasons (5ba and 5ca-H). The formation of 5ca-H
arose from concomitant deprotection of the corresponding
N-mesylindole during the reaction course.10 The annulative
amination could be applicable to aromatic systems. The
introduction of electron-donating groups increased the reactivity
(5da−fa), whereas that of electron-withdrawing chloro and
trifluoromethyl functions dropped the yield (5ga and 5ha).
Especially, the conversion of trifluoromethyl-containing substrate
was not complete, and about half of the starting material remained
unchanged. Similar trends were also observed in the case of
phenols 1 (vide supra). The reactivity differences can be explained
as follows (Scheme 5). In the anti-oxy- or aminometalation step
corresponding to the transformation from B to C in Scheme 2,
the productive coordination mode F would be preferable with R
of electron-neutral or -donating natures. However, the presence of
electron-withdrawing R lowers an electron density of alkyne so
that the competitive, unproductive O- or N-bound mode of type
G would be predominant. Thus, the copper catalyst is poisoned,
and its turnover is disturbed.
On the basis of the above success, we then turned our
attention to o-alkynylanilines for the synthesis of 3-amino-
indoles (Table 2). We were pleased to find that under identical
conditions, the annulative amination of N-Ms-aniline 4a with
2a proceeded to form the desirable 3-aminoindole derivative
5aa (entry 1). Extensive screening of solvents (entries 2−10)
identified DMF to be optimal, and 5aa was obtained in 93%
yield (entry 2). In contrast to phenol derivatives 1, stronger and
milder bases, NaO-t-Bu, Cs2CO3, K2CO3, and K3PO4, also
promoted the reaction (entries 11−14). The choice of
substituents on nitrogen was critical. The free aniline 4a-H
afforded the simply cyclized 2-butylindole (6) as the sole
detectable product (entry 15). The corresponding acetate
4a-Ac and benzoate 4a-Bz were relatively instable under
standard conditions and partially deprotected, en route to the
same indole 6, although 4a-Bz gave 5aa-H with only 16% yield
(entries 16 and 17). The change of base into mild K3PO4
suppressed the problematic deprotection, but the yield was not
satisfactory (entry 18). On the other hand, an analogous
tosylate 4a-Ts showed comparable reactivity, and the
corresponding 5aa-Ts was obtained in 84% yield (entry 19).
The use of N,N-diethyl-O-pivaloylhydroxylamine instead of 2a
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Table 2. Optimization Studies for Annulative Amination of 2-(1-Hexyn-1-yl)anilines 4 and O-Benzoyl-N,
a
N-diethylhydroxylamine (2a)
b
entry
R, 4
base
solvent
5, yield (%)
1
Ms (4a)
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
NaO-t-Bu
Cs2CO3
K2CO3
NMP
DMF
DMAc
DMSO
THF
5aa, 42
2
4a
5aa, 93
3
4a
5aa, (68)
5aa, (79)
5aa, (64)
5aa, (38)
5aa, (53)
5aa, (49)
5aa, (10)
5aa, (24)
5aa, (49)
5aa, (34)
5aa, (20)
5aa, (65)
4
4a
5
4a
6
4a
dioxane
DME
MeCN
CH2Cl2
toluene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
7
4a
8
4a
9
4a
10
11
12
13
14
15
16
17
18
19
4a
4a
4a
4a
4a
K3PO4
c
H (4a-H)
Ac (4a-Ac)
Bz (4a-Bz)
4a-Bz
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
K3PO4
5aa-H, 0
c
5aa-Ac, 0
c
5aa-H, (16)
5aa-Bz, (9)
5aa-Ts, 84
5aa, (61)
Ts (4a-Ts)
4a
LiO-t-Bu
LiO-t-Bu
d
20
a
A mixture of Cu salt (0.025 mmol), base (0.50 mmol), 4 (0.25 mmol), and 2a (0.30 mmol) in solvent (1.5 mL) was stirred at room temperature for
b
c
1
6−24 h under N2 Yields estimated by H NMR in parentheses. In place of 5, 2-butylindole (6) was detected as a major product (ca. 20−30%).
d
With N,N-diethyl-O-pivaloylhydroxylamine instead of 2a.
On the other hand, 1-naphthyl and heteroaromatic 3-thienyl
substitution patterns were suitable (5ia and 5ja). Unfortu-
nately, an introduction of substituents on the benzene ring of
aniline generally decreased the reactivity (5ka−ma). We then
tested some hydroxylamines other than 2a. For the synthesis of
3-(diallylamino)indole 5eb and 3-(allylmethyl)indole 5eh, the
use of NaO-t-Bu instead of LiO-t-Bu gave a better result. The
current limitation of the present methodology was found to be
lack of generality for cyclic amines: while the piperidine deri-
vative reacted moderately (5ed), the annulative aminations
with the hydroxylmorpholine and -piperazine were sluggish
(5ee and 5eg). In these unsuccessful cases, the simple cyclization pre-
dominantly occurred to form the corresponding C3-unsubstituted
indole as a major product.5a
radical cyclization was detected by GC and GC−MS analyses.
These outcomes could exclude the radical process. Another
possibility is a copper-catalyzed direct C3-amination of
benzofurans and indoles with hydroxylamines,11 but it is also
ruled out by the control experiments illustrated in Scheme 8.
Thus, our proposed pathway is considered to be reasonable at
this stage, while further efforts are essential for elucidation of
the detailed mechanism.
Finally, we applied the annulative amination methodologies
to the synthesis of benzofuro[3,2-b]azepine core, which is
found in potent inhibitors of bone resorption (Scheme 9).12
Treatment of 1l with 2h under identical Cu(OTf)2/LiO-t-Bu
systems furnished the expected aminobenzofuran 3lh in 51%
yield, leaving the two terminal olefins untouched. The
subsequent cycloisomerization catalyzed by a ruthenium
hydride13 constructed the desired tricyclic framework 7 in
77% yield.
Although our initial scenario (Scheme 2) can account for
some observed reactivity profiles of phenols 1 and anilines 4, an
alternative pathway including a nitrogen-centered radical
species might be plausible. Gottlich reported a copper-catalyzed
̈
CONCLUSION
intramolecular oxyamination of alkenes and proposed a
formation of aminyl radical intermediate, which was also
supported by the fact the reaction was initiated by a catalytic
amount of AIBN as well as Cu(I) (Scheme 6).7c To determine
whether similar radical species are involved in our catalytic
cycle, we carried out the reaction of 4a with 2a in the presence
of radical scavengers TEMPO and galvinoxyl (Scheme 7).
However, these additives gave no effect on reaction rate and
product yield. Furthermore, AIBN instead of the Cu(OTf)2/
LiO-t-Bu did not promote the reaction at all. An additional
experiment with 4-pentenylhydroxylamine 2i produced the
usual annulative amination product 5ei exclusively. No
pyrrolidine-containing compound arising from the conceivable
■
We have developed a copper-catalyzed annulative amination of
o-alkynylphenols and -anilines with O-acylated hydroxylamines
for the synthesis of 3-aminobenzofurans and -indoles. The
copper-based catalyses proceed even at room temperature and
provide a unique, complementary access to the above hetero-
arylamines of biological and pharmaceutical interest. Some
mechanistic investigations are suggestive of nonradical, electro-
philic amination of the heteroarylcopper species in the C−N
bond-forming step. Our ongoing work seeks to overcome the
current limitation for the coupling of anilines with cyclic amines
and to apply the annulative electrophilic amination strategy to
construction of other heterocyclic amines.
620
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Scheme 4. Copper-Catalyzed Annulative Electrophilic
Scheme 6. Radical Intramolecular Oxyamination of Alkenes
Reported by Gottlich7c
Amination of o-Alkynylanilines 4 with O-Benzoyl
̈
a
Hydroxylamines 2 Leading to 3-Aminoindoles 5
Scheme 7
Scheme 8. Control Experiments
a
With 20 mol % of Cu(OTf)2.
b
With NaO-t-Bu instead of LiO-t-Bu.
Scheme 5. Explanation for Reactivity Differences
Scheme 9
EXPERIMENTAL SECTION
(18 mg, 0.050 mmol) and LiO-t-Bu (80 mg, 1.0 mmol) were placed
in a 20 mL two-necked reaction flask, which was filled with nitrogen
using the standard Schlenk technique. NMP (1.0 mL) was added,
and the suspension was stirred for 10 min at room temperature.
■
Typical Procedure for Copper-Catalyzed Annulative Amina-
tion of o-Alkynylphenols with O-Acylated Hydroxylamines.
Synthesis of 3aa (Table 1, entry 20) is representative. Cu(OTf)2
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A solution of 2-(phenylethynyl)phenol (1a, 97.1 mg, 0.50 mmol) and
O-benzoyl-N,N-diethylhydroxylamine (2a, 116 mg, 0.60 mmol) in NMP
(2.0 mL) was then added dropwise. After being stirred for 4 h at the
same temperature, the resulting mixture was poured into saturated aq
NaCl and extracted with dichloromethane. The combined organic layer
was dried over sodium sulfate and concentrated in vacuo. Subsequent silica
gel column purification with hexane/Et3N (200/1, v/v) afforded N,N-
diethyl-2-phenylbenzofuran-3-amine (3aa, 81 mg, 0.31 mmol) in 61% yield.
N,N-Diethyl-2-phenylbenzofuran-3-amine (3aa). Oil; 1H
NMR (400 MHz, CDCl3) δ 1.05 (t, J = 7.4 Hz, 6H), 3.26 (q, J =
7.4 Hz, 4H), 7.16 (t, J = 7.3 Hz, 1H), 7.26−7.31 (m, 2H), 7.40−7.49
(m, 3H), 7.66 (d, J = 7.8 Hz, 1H), 8.40 (d, J = 7.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 13.7, 48.8, 111.7, 121.0, 122.0, 124.0, 125.9,
127.1, 127.7, 127.9, 128.2, 131.1, 149.2, 153.3; HRMS m/z (M+) calcd
for C18H19NO 265.1467, found 265.1466.
(100 MHz, CDCl3) δ 14.1, 26.0, 26.4, 31.2, 34.9, 49.4, 111.4, 120.0,
121.5, 122.2, 122.6, 126.6, 153.4, 159.7; HRMS m/z (M+) calcd for
C18H25NO 271.1936, found 271.1935.
2-(tert-Butyl)-N,N-diethylbenzofuran-3-amine (3ia). Oil; 1H
NMR (400 MHz, CDCl3) δ 1.04 (t, J = 7.3 Hz, 6H), 1.44 (s, 9H), 3.12
(bs, 4H), 7.09 (t, J = 7.3 Hz, 1H), 7.16 (t, J = 7.3 Hz, 1H), 7.36 (d, J =
7.8 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
14.1, 29.6, 34.0, 48.9, 111.3, 120.8, 121.3, 122.7, 124.5, 127.6, 152.6,
160.1; HRMS m/z (M+) calcd for C16H23NO 245.1780, found
245.1782.
2-Butyl-5,7-dichloro-N,N-diethylbenzofuran-3-amine (3ja). Oil;
1H NMR (400 MHz, CDCl3) δ 0.96 (t, J = 7.3 Hz, 9H), 1.38−1.47
(m, 2H), 1.67−1.74 (m, 2H), 2.77 (t, J = 7.7 Hz, 2H), 3.07 (q, J = 7.3
Hz, 4H), 7.19 (d, J = 2.2 Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 13.8, 13.9, 22.6, 25.6, 30.0, 49.1, 117.3, 118.1,
122.9, 124.8, 127.5, 129.5, 147.7, 158.6; HRMS m/z (M+) calcd for
C16H21Cl2NO 313.1000, found 313.1002.
N,N-Diethyl-2-(4-methoxylphenyl)benzofuran-3-amine
1
(3ba). Oil; H NMR (400 MHz, CDCl3) δ 1.04 (t, J = 7.4 Hz, 6H),
3.24 (q, J = 7.4 Hz, 4H), 3.85 (s, 3H), 6.95 (dt, J = 8.7, 1.8 Hz, 2H),
7.14 (t, J = 7.3 Hz, 1H), 7.21 (t, J = 8.2 Hz, 1H), 7.45 (d, J = 7.8 Hz,
1H), 7.64 (d, J = 7.8 Hz, 1H), 8.34 (dt, J = 8.7, 2.3 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 13.7, 48.8, 55.2, 111.5, 113.6, 120.7, 121.9,
123.5, 124.0, 125.3, 127.4, 128.0, 149.5, 153.1, 159.2; HRMS m/z
(M+) calcd for C19H21NO2 295.1572, found 295.1571.
N,N-Diethyl-2-{(4-trifluoromethyl)phenyl}benzofuran-3-
amine (3ca). Oil; 1H NMR (400 MHz, CDCl3) δ 1.05 (t, J = 7.3 Hz,
6H), 3.27 (q, J = 7.3 Hz, 4H), 7.19 (t, J = 7.8 Hz, 1H), 7.28−7.32 (m,
1H), 7.50 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 7.8
Hz, 1H), 8.52 (d, J = 8.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
13.6, 48.8, 112.0, 121.3, 122.4, 124.2 (q, J = 270.8 Hz), 124.9, 125.1
(q, J = 3.8 Hz), 125.8, 127.6, 129.1 (q, J = 32.4 Hz), 129.2, 134.4,
147.6, 153.5; 19F NMR (373 MHz, CDCl3) δ −62.5; HRMS m/z
(M+) calcd for C19H18F3NO 333.1340, found 333.1338.
2-(4-Chlorophenyl)-N,N-diethylbenzofuran-3-amine (3da). Oil;
1H NMR (400 MHz, CDCl3) δ 1.04 (t, J = 7.3 Hz, 6H), 3.25 (q, J =
7.3 Hz, 4H), 7.17 (t, J = 7.3 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 7.38 (dt,
J = 8.8, 2.2 Hz, 2H), 7.47 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 7.3 Hz, 1H),
8.35 (dt, J = 8.8, 2.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 13.6,
48.8, 111.8, 121.0, 122.2, 124.3, 127.1, 127.5, 127.7, 128.4, 129.6,
133.3, 148.2, 153.3; HRMS m/z (M+) calcd for C18H18ClNO
299.1077, found 299.1070.
5,7-Di-tert-butyl-2-butyl-N,N-diethylbenzofuran-3-amine
1
(3ka). Oil; H NMR (400 MHz, CDCl3) δ 0.94 (t, J = 7.3 Hz, 3H),
0.99 (t, J = 7.3 Hz, 6H), 1.37 (s, 9H), 1.40−1.44 (m, 2H), 1.50 (s,
9H), 1.66−1.70 (m, 2H), 2.76 (t, J = 7.3 Hz, 2H), 3.13 (q, J = 7.3 Hz,
4H), 7.15 (d, J = 1.8 Hz, 1H), 7.39 (d, J = 1.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 13.9, 14.3, 22.5, 25.4, 30.0, 30.3, 32.0, 34.3, 34.7,
49.2, 113.9, 117.5, 124.1, 126.8, 133.5, 144.0, 149.8, 154.5; HRMS m/z
(M+) calcd for C24H39NO 357.3032, found 357.3027.
1
N,N-Diallyl-2-butylbenzofuran-3-amine (3gb). Oil; H NMR
(400 MHz, CDCl3) δ 0.95 (t, J = 7.3 Hz, 3H), 1.29−1.43 (m, 2H),
1.64−1.72 (m, 2H), 2.76 (t, J = 7.3 Hz, 2H), 3.69 (d, J = 6.6 Hz, 4H),
5.00−5.03 (m, 2H), 5.07−5.13 (m, 2H), 5.83 (ddt, J = 16.5, 10.2, 6.2
Hz, 2H), 7.12−7.18 (m, 2H), 7.34−7.36 (m, 1H), 7.55−7.57 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 13.9, 22.5, 25.7, 30.2, 57.3, 111.2,
116.8, 119.7, 121.8, 122.8, 126.1, 127.2, 136.0, 153.2, 154.3; HRMS m/z
(M+) calcd for C18H23NO 269.1780, found 269.1781.
N-Benzyl-2-butyl-N-methylbenzofuran-3-amine (3gc). Oil;
1H NMR (400 MHz, CDCl3) δ 0.91 (t, J = 7.3 Hz, 3H), 1.26−1.38
(m, 2H), 1.51−1.59 (m, 2H), 2.68 (t, J = 7.7 Hz, 2H), 2.83 (s, 3H),
4.21 (s, 2H), 7.14−7.37 (m, 8H), 7.62−7.64 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 13.8, 22.5, 25.8, 30.2, 42.3, 61.3, 111.3, 119.7, 121.7,
122.9, 126.8, 127.0, 128.0, 128.2, 128.8, 139.2, 152.8, 153.2; HRMS m/z
(M+) calcd for C20H23NO 293.1780, found 293.1775.
N,N-Diethyl-2-(3-thienyl)benzofuran-3-amine (3ea). Oil; 1H
NMR (400 MHz, CDCl3) δ 1.04 (t, J = 7.3 Hz, 6H), 3.24 (q, J = 7.3
Hz, 4H), 7.15 (t, J = 7.3 Hz, 1H), 7.21−7.25 (m, 1H), 7.34 (dd, J =
5.0, 3.2 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H),
7.99 (d, J = 5.0 Hz, 1H), 8.05 (d, J = 3.2 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 13.8, 48.8, 111.7, 120.7, 122.06, 122.07, 123.8, 125.1,
125.4, 126.1, 127.5, 132.0, 147.9, 153.3; HRMS m/z (M+) calcd for
C16H17NOS 271.1031, found 271.1032.
1-(2-Butylbenzofuran-3-yl)piperidine (3gd). Oil; 1H NMR
(400 MHz, CDCl3) δ 0.94 (t, J = 7.3 Hz, 3H), 1.35−1.43 (m, 2H),
1.58−1.60 (m, 2H), 1.64−1.70 (m, 6H), 2.79 (t, J = 7.3 Hz, 2H),
3.08−3.11 (m, 4H), 7.11−7.18 (m, 2H), 7.34 (d, J = 7.3 Hz, 1H), 7.60
(d, J = 7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.8, 22.3, 24.4,
26.0, 26.9, 30.5, 53.7, 111.1, 119.8, 121.6, 122.7, 127.0, 129.3, 151.2,
153.1; HRMS m/z (M+) calcd for C17H23NO 257.1780, found
257.1777.
4-(2-Butylbenzofuran-3-yl)morpholine (3ge). Oil; 1H NMR
(400 MHz, CDCl3) δ 0.95 (t, J = 7.3 Hz, 3H), 1.38 (tq, J = 7.3, 7.4 Hz,
2H), 1.65 (tt, J = 7.3, 7.4 Hz, 2H), 2.80 (t, J = 7.3 Hz, 2H), 3.15 (t, J =
4.6 Hz, 4H), 3.85 (t, J = 4.6 Hz, 4H), 7.14−7.21 (m, 2H), 7.37 (d, J =
7.8 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
13.8, 22.3, 25.7, 30.4, 52.6, 67.8, 111.4, 119.6, 121.9, 123.0, 126.4,
127.9, 152.4, 153.2; HRMS m/z (M+) calcd for C16H21NO2 259.1572,
found 259.1573.
2-(1-Cyclohexen-1-yl)-N,N-diethylbenzofuran-3-amine
1
(3fa). Oil; H NMR (400 MHz, CDCl3) δ 1.01 (t, J = 7.3 Hz, 6H),
1.59−1.69 (m, 2H), 1.71−1.77 (m, 2H), 2.2.4−2.27 (m, 2H), 2.64−
2.66 (m, 2H), 3.15 (q, J = 7.3 Hz, 4H), 6.67−6.70 (m, 1H), 7.09 (t, J =
8.0 Hz, 1H), 7.17 (t, J = 8.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.58 (d,
J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.8, 22.1, 22.7, 25.6,
25.7, 48.7, 111.3, 120.6, 121.6, 123.3, 125.2, 127.6, 128.0, 128.7, 151.6,
152.8; HRMS m/z (M+) calcd for C18H23NO 269.1780, found
269.1783.
2-(2-Butylbenzofuran-3-yl)-1,2,3,4-tetrahydroisoquinoline
1
1
2-Butyl-N,N-diethylbenzofuran-3-amine (3ga). Oil; H NMR
(3gf). Oil; H NMR (400 MHz, CDCl3) δ 0.92 (t, J = 7.3 Hz, 3H),
(400 MHz, CDCl3) δ 0.95 (t, J = 7.3 Hz, 3H), 0.97 (t, J = 7.3 Hz, 6H),
1.38−1.44 (m, 2H), 1.60−1.73 (m, 2H), 2.76 (t, J = 7.3 Hz, 2H), 3.12
(q, J = 7.3 Hz, 4H), 7.11 (td, J = 7.3, 1.4 Hz, 1H), 7.17 (td, J = 7.3,
1.4 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 6.9 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 13.9, 14.1, 22.6, 25.4, 30.2, 49.3, 111.3,
119.9, 121.6, 122.7, 124.2, 126.8, 153.5, 155.8; HRMS m/z (M+) calcd
for C16H23NO 245.1780, found 245.1782.
1.34−1.40 (m, 2H), 1.67−1.71 (m, 2H), 2.80 (t, J = 7.3 Hz, 2H), 3.01
(bs, 2H), 3.47 (bs, 2H), 4.34 (s, 2H), 7.04−7.06 (m, 1H), 7.13−7.23
(m, 5H), 7.39 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 7.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 13.8, 22.3, 25.8, 30.1, 30.4, 50.4, 54.5, 111.3,
119.6, 121.9, 123.0, 125.7, 126.1, 126.3, 126.6, 128.1, 129.1, 134.6,
135.4, 152.5, 153.3; HRMS m/z (M+) calcd for C21H23NO 305.1780,
found 305.1778.
2-Cyclohexyl-N,N-diethylbenzofuran-3-amine (3ha). Oil;
1H NMR (400 MHz, CDCl3) δ 0.96 (t, J = 7.3 Hz, 6H), 1.26−1.44
(m, 4H), 1.65−1.85 (m, 6H), 3.01 (tt, J = 11.4, 3.6 Hz, 1H), 3.12 (q,
J = 7.3 Hz, 4H), 7.10 (td, J = 7.3, 0.9 Hz, 1H), 7.17 (td, J = 7.3, 1.3 Hz,
1H), 7.38 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H); 13C NMR
tert-Butyl 4-[2-(thiophen-3-yl)benzofuran-3-yl]piperazine-1-
carboxylate (3eg). Oil; 1H NMR (400 MHz, CDCl3) δ 1.52
(s, 9H), 3.22 (bs, 4H), 4.32 (bs, 4H), 7.17 (t, J = 7.3 Hz, 1H), 7.25
(t, J = 7.8 Hz, 1H), 7.38 (dt, J = 5.0, 3.2 Hz, 1H), 7.45 (d, J = 8.7 Hz,
1H), 7.70 (d, J = 7.8 Hz, 1H), 7.90−7.91 (m, 1H), 7.98−7.99
622
dx.doi.org/10.1021/jo202207s | J. Org. Chem. 2012, 77, 617−625

The Journal of Organic Chemistry
Article
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 28.4, 51.6, 79.9, 111.7,
120.7, 122.1, 122.3, 124.0, 125.65, 125.69, 126.6, 127.7, 131.6, 145.2,
153.1, 154.9; HRMS m/z (M+) calcd for C21H24N2O3S 384.1508,
found 384.1504.
Hz, 6H), 2.75 (s, 3H), 3.01 (q, J = 7.3 Hz, 4H), 3.85 (s, 3H), 6.95 (d,
J = 8.2 Hz, 2H), 7.28−7.35 (m, 2H), 7.40 (d, J = 8.2 Hz, 2H), 7.67 (d,
J = 8.2 Hz, 1H), 8.13 (d, J = 8.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 14.1, 39.7, 48.0, 55.3, 113.1, 116.1, 120.3, 123.8, 123.9,
125.0, 129.7, 132.7, 132.8, 134.6, 136.4, 159.9; HRMS m/z (M+) calcd
for C20H24N2O3S 372.1508, found 372.1505.
Typical Procedure for Copper-Catalyzed Annulative Amination
of o-Alkynylanilines with O-Acylated Hydroxylamines. Synthesis
of 5aa is representative (Table 2, entry 2). Cu(OTf)2 (9.0 mg,
0.025 mmol) and LiO-t-Bu (40.0 mg, 0.50 mmol) were placed in a 20
mL two-necked reaction flask, which was filled with nitrogen by using
the standard Schlenk technique. DMF (0.50 mL) was then added to
the flask, and the suspension was stirred for 15 min at ambient
temperature. Finally, a solution of 2-hexynylaniline 4a (63 mg, 0.25
mmol), O-benzoyl-N,N-diethylhydroxylamine (2a, 58 mg, 0.30 mmol),
and 1-methylnaphthalene (ca. 25 mg, internal standard) in DMF (1.0 mL)
was added dropwise. The solution was stirred at ambient temperature for
additional 6 h. The resulting mixture was quenched with water. An
aqueous solution of 4 M HCl (60 mL) was added to the mixture. The
aqueous layer was washed four times with Et2O, neutralized with 6 M aq
NaOH, and then extracted four times with Et2O. The combined organic
layer was dried over sodium sulfate. Concentration in vacuo and
subsequent purification by column chromatography on silica gel with
hexane/ethyl acetate (5:1, v/v) as an eluent gave 2-butyl-N,N-diethyl-1-
(methanesulfonyl)indol-3-amine (5aa, 75 mg, 0.23 mmol) in 93% yield.
2-Butyl-N,N-diethyl-1-(methanesulfonyl)indol-3-amine
2-(4-Chlorophenyl)-N,N-diethyl-1-(methanesulfonyl)indol-3-
1
amine (5ga). Mp 86.0−87.0 °C; H NMR (400 MHz, CDCl3) δ
0.92 (t, J = 7.3 Hz, 6H), 2.74 (s, 3H), 3.04 (q, J = 7.3 Hz, 4H), 7.30−
7.44 (m, 6H), 7.69 (d, J = 8.3 Hz, 1H), 8.13 (d, J = 8.3 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 14.1, 39.3, 48.1, 116.3, 120.7, 124.2, 125.5,
127.9, 129.5, 130.2, 132.7, 133.7, 133.9, 134.7, 136.8; HRMS m/z
(M+) calcd for C19H21ClN2O2S 376.1012, found 376.1010.
N,N-Diethyl-1-methanesulfonyl-2-[4-(trifluoromethyl)-
1
phenyl]indol-3-amine (5ha). Oil; H NMR (400 MHz, CDCl3) δ
0.91 (t, J = 7.3 Hz, 6H), 2.74 (s, 3H), 3.06 (q, J = 7.3 Hz, 4H), 7.34 (t,
J = 8.3 Hz, 1H), 7.40 (t, J = 8.3 Hz, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.67
(d, J = 8.3 Hz, 2H), 7.72 (d, J = 8.3 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 14.1, 39.1, 48.3, 116.4, 121.0, 124.37
(q, J = 272.4 Hz), 124.41, 124.5 (q, J = 3.8 Hz), 125.9, 129.4, 130.3 (q,
J = 32.7 Hz), 131.7, 133.9, 134.4, 135.5 (q, J = 1.5 Hz), 137.0; HRMS
m/z (M+) calcd for C20H21F3N2O2S: 410.1276, found 410.1274.
N,N-Diethyl-1-methanesulfonyl-2-(1-naphthyl)indol-3-
amine (5ia). Oil; 1H NMR (400 MHz, CDCl3) δ 0.87 (t, J = 7.3 Hz,
6H), 2.82 (s, 3H), 2.85−2.96 (m, 4H), 7.33−7.56 (m, 6H), 7.69 (d,
J = 8.3 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.88 (d, J = 8.3 Hz, 1H),
7.93 (d, J = 8.3 Hz, 1H), 8.16 (d, J = 8.3 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 14.3, 40.2, 47.5, 115.5, 120.5, 123.8, 124.8, 125.2,
126.1, 126.39, 126.42, 128.5, 129.70, 129.72, 129.8, 129.9, 131.4,
133.4, 134.2, 134.4, 136.1; HRMS m/z (M+) calcd for C23H24N2O2S
392.1558, found 392.1561.
1
(5aa). Oil; H NMR (400 MHz, CDCl3) δ 0.95 (t, J = 7.3 Hz, 3H),
0.99 (t, J = 7.3 Hz, 6H), 1.38−1.48 (m, 2H), 1.58−1.68 (m, 2H), 2.87
(s, 3H), 2.94 (t, J = 7.8 Hz, 2H), 3.17 (q, J = 7.3 Hz, 4H), 7.20−7.28
(m, 2H), 7.60 (d, J = 8.3 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 14.1, 14.6, 23.25, 25.6, 32.9, 39.4, 49.0, 115.3,
120.0, 123.4, 124.1, 128.9, 130.2, 136.0, 140.0; HRMS m/z (M+) calcd
for C17H26N2O2S 322.1715, found 322.1714.
2-Butyl-N,N-diethyl-1-(p-toluenesulfonyl)indol-3-amine
N,N-Diethyl-1-methanesulfonyl-2-(3-thienyl)indol-3-amine
1
1
(5aa-Ts). Oil; H NMR (400 MHz, CDCl3) δ 0.81 (t, J = 7.3 Hz,
(5ja). Oil; H NMR (400 MHz, CDCl3) δ 0.94 (t, J = 7.3 Hz, 6H),
6H), 0.96 (t, J = 7.3 Hz, 3H), 1.40−1.49 (m, 2H), 1.66−1.74 (m, 2H),
2.26 (s, 3H), 3.01 (t, J = 7.8 Hz, 3H), 3.06 (q, J = 7.3 Hz, 3H), 7.07−
7.24 (m, 4H), 7.45−7.49 (m, 3H), 8.20 (d, J = 8.3 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ14.1, 14.2, 21.6, 23.2, 26.1, 33.1, 48.9, 116.3,
119.6, 123.3, 123.8, 126.4, 129.1, 129.6, 130.8, 135.4, 136.6, 140.1, 144.5;
HRMS m/z (M+) calcd for C23H30N2O2S 398.2028, found 398.2025.
2-Cyclohexyl-N,N-diethyl-1-(methanesulfonyl)indol-3-amine
2.77 (s, 3H), 3.03 (q, J = 7.3 Hz, 4H), 7.24−7.36 (m, 4H), 7.44−7.45
(m, 1H), 7.66 (d, J = 8.3 Hz, 1H), 8.13 (d, J = 8.3 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 14.0, 39.6, 47.9, 116.1, 120.3, 123.9, 124.2,
125.3, 127.0, 129.4, 129.5, 130.9, 131.2, 133.6, 136.5; HRMS m/z
(M+) calcd for C17H20N2O2S2: 348.0966, found 348.0968.
N,N-Diethyl-1-methanesulfonyl-5-methyl-2-phenylindol-3-
amine (5ka). Oil; 1H NMR (400 MHz, CDCl3) δ 0.92 (t, J = 7.3 Hz,
6H), 2.47 (s, 3H), 2.73 (s, 3H), 3.01 (q, J = 7.3 Hz, 4H), 7.17 (d, J =
8.2 Hz, 1H), 7.39−7.48 (m, 6H), 8.00 (d, J = 8.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 14.1, 21.6, 39.2, 48.1, 116.0, 120.4, 126.6, 127.5,
128.6, 130.0, 131.5, 131.9, 133.0, 133.8, 134.9, 135.1; HRMS m/z
(M+) calcd for C20H24N2O2S 356.1558, found 356.1556.
1
(5ba). Mp 98.0−100.0 °C; H NMR (400 MHz, CDCl3) δ 1.05 (t,
J = 7.3 Hz, 6H), 1.26−1.43 (m, 4H), 1.72−1.84 (m, 4H), 2.21 (q, J =
12.4 Hz, 2H), 2.93 (s, 3H), 3.18 (q, J = 7.3 Hz, 4H), 3.54 (t, J = 12.4
Hz, 1H), 7.17−7.25 (m, 2H), 7.59 (d, J = 8.2 Hz, 1H), 8.09 (d, J = 8.2
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.5, 26.3, 27.5, 31.6, 37.3,
40.1, 48.9, 115.7, 120.3, 123.2, 124.1, 129.0, 131.9, 136.2, 142.9;
HRMS m/z (M+) calcd for C19H28N2O2S 348.1871, found 348.1870.
2-(tert-Butyl)-N,N-diethylindol-3-amine (5ca-H). Oil; 1H
NMR (400 MHz, CDCl3) δ 1.06 (t, J = 7.3 Hz, 6H), 1.47 (s, 9H),
3.19 (q, J = 7.3 Hz, 4H), 6.98 (t, J = 8.3 Hz, 1H), 7.07 (t, J = 8.3 Hz,
1H), 7.26 (d, J = 8.3 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.67 (bs, 1H);
13C NMR (100 MHz, CDCl3) δ 14.6, 30.6, 32.9, 49.4, 111.0, 118.6,
120.4, 120.7, 123.6, 126.9, 133.4, 141.5; HRMS m/z (M+) calcd for
C16H24N2 244.1939, found 244.1940.
2-Butyl-N,N-diethyl-1-methanesulfonyl-5-methylindol-3-
amine (5la). Oil; 1H NMR (400 MHz, CDCl3) δ 0.95 (t, J = 7.3 Hz,
3H), 0.98 (t, J = 7.3 Hz, 6H), 1.38−1.47 (m, 2H), 1.59−1.67 (m, 2H),
2.43 (s, 3H), 2.83 (s, 3H), 2.94 (d, J = 7.6 Hz, 2H), 3.16 (q, J = 7.3
Hz, 4H), 7.07 (d, J = 8.3 Hz, 1H), 7.38 (s, 1H), 7.92 (d, J = 8.3 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 14.1, 14.6, 21.6, 23.2, 25.6, 32.8,
39.0, 49.0, 115.1, 120.0, 125.4, 129.1, 130.1, 133.1, 134.3, 140.1;
HRMS m/z (M+) calcd for C18H28N2O2S 336.1871, found 336.1869.
2-Butyl-5-chloro-N,N-diethyl-1-(methanesulfonyl)indol-3-
1
amine (5ma). Oil; H NMR (400 MHz, CDCl3) δ 0.95 (t, J = 7.3
N,N-Diethyl-1-methanesulfonyl-2-phenylindol-3-amine
1
Hz, 3H), 0.98 (t, J = 7.3 Hz, 6H), 1.37−1.47 (m, 2H), 1.59−1.67 (m,
2H), 2.88 (s, 3H), 2.95 (t, J = 7.8 Hz, 2H), 3.14 (q, J = 7.3 Hz, 4H), 7.21
(dd, J = 8.3, 2.3 Hz, 1H), 7.56 (d, J = 2.3 Hz, 1H), 7.97 (d, J = 8.3 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 14.1, 14.6, 23.3, 25.7, 32.8, 39.7,
48.9, 116.3, 119.5, 124.2, 129.3, 129.7, 130.2, 134.3, 141.5; HRMS m/z
(M+) calcd for C17H25ClN2O2S 356.1325, found 356.1323.
(5da). Oil; H NMR (400 MHz, CDCl3) δ 0.91 (t, J = 7.3 Hz, 6H),
2.76 (s, 3H), 3.01 (q, J = 7.3 Hz, 4H), 7.29−7.49 (m, 7H), 7.69 (d, J =
8.3 Hz, 1H), 8.14 (d, J = 8.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
14.1, 39.7, 48.1, 116.1, 120.5, 124.0, 125.2, 127.6, 128.7, 129.7, 131.6,
131.8, 133.0, 134.8, 136.5; HRMS m/z (M+) calcd for C19H22N2O2S
342.1402, found 342.1400.
N,N-Diethyl-1-methanesulfonyl-2-(4-methylphenyl)indol-3-
amine (5ea). Oil; 1H NMR (400 MHz, CDCl3) δ 0.93 (t, J = 7.3 Hz,
6H), 2.41 (s, 3H), 2.76 (s, 3H), 3.01 (q, J = 7.3 Hz, 4H), 7.21−7.36
(m, 6H), 7.68 (d, J = 8.3 Hz, 1H), 8.13 (d, J = 8.3 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 14.1, 21.7, 39.7, 48.1, 116.1, 120.4, 123.9, 125.1,
128.4, 128.8, 129.8, 131.4, 132.8, 135.0, 136.5, 138.6; HRMS m/z
(M+) calcd for C20H24N2O2S 356.1558, found 356.1556.
N,N-Diallyl-1-methanesulfonyl-2-(4-methyphenyl)indol-3-
1
amine (5eb). Mp 108.0−111.0 °C; H NMR (400 MHz, CDCl3) δ
2.42 (s, 3H), 2.75 (s, 3H), 3.55 (d, J = 6.4 Hz, 4H), 4.99 (dd, J = 9.2,
1.4 Hz, 2H), 5.01 (dd, J = 16.9, 1.4 Hz, 2H), 5.70 (ddt, J = 16.9, 9.2,
6.4 Hz, 2H), 7.22−7.36 (m, 6H), 7.67 (dd, J = 7.1, 2.3 Hz, 1H), 8.11
(dd, J = 7.1, 2.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.7, 39.7,
56.1, 116.1, 117.0, 120.1, 124.1, 125.2, 128.5, 128.6, 129.6, 131.6,
133.5, 133.8, 135.8, 136.3, 138.8; HRMS m/z (M+) calcd for
C22H24N2O2S 380.1558, found 380.1560.
N,N-Diethyl-1-methanesulfonyl-2-(4-methoxyphenyl)indol-
1
3-amine (5fa). Oil; H NMR (400 MHz, CDCl3) δ 0.93 (t, J = 7.3
623
dx.doi.org/10.1021/jo202207s | J. Org. Chem. 2012, 77, 617−625

The Journal of Organic Chemistry
Article
N-Allyl-N-methyl-1-methanesulfonyl-2-(4-methylphenyl)-
AUTHOR INFORMATION
■
1
indol-3-amine (5eh). Oil; H NMR (400 MHz, CDCl3) δ 2.42 (s,
Corresponding Author
*E-mail: k_hirano@chem.eng.osaka-u.ac.jp; miura@chem.eng.
osaka-u.ac.jp.
3H), 2.58 (s, 3H), 2.77 (s, 3H), 3.52 (d, J = 6.4 Hz, 2H), 5.07 (dd, J =
9.2, 1.4 Hz, 1H), 5.11 (dd, J = 16.9, 1.4 Hz, 1H), 5.78 (ddt, J = 16.9,
9.2, 6.4 Hz, 1H), 7.22−7.25 (m, 2H), 7.30−7.37 (m, 4H), 7.65 (dd,
J = 6.4, 2.3 Hz, 1H), 8.12 (dd, J = 7.3, 2.3 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 21.7, 39.9, 41.2, 59.0, 116.1, 117.1, 119.9, 124.0,
125.3, 128.5, 128.8, 128.9, 131.3, 131.9, 135.2, 135.8, 136.2, 138.9;
HRMS m/z (M+) calcd for C20H22N2O2S 354.1402, found 354.1404.
1-Methanesulfonyl-2-(4-methylphenyl)-3-(1-piperidinyl)-
ACKNOWLEDGMENTS
■
This work was supported by Grants-in-Aid for Scientific
Research from MEXT and JSPS, Japan. K.H. acknowledges
Kansai Research Foundation for the Promotion of Science.
1
indole (5ed). Mp 163.0−165.0 °C; H NMR (400 MHz, CDCl3) δ
1.42−1.48 (m, 2H), 1.54−1.59 (m, 4H), 2.42 (s, 3H), 2.76 (s, 3H),
2.82 (t, J = 5.0 Hz, 4H), 7.21 (d, J = 8.3 Hz, 2H), 7.31−7.36 (m, 4H),
7.64 (d, J = 8.3 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 21.7, 24.4, 27.0, 39.9, 53.3, 116.0, 119.7, 124.0, 125.3,
128.3, 129.0, 129.1, 129.6, 132.1, 136.0, 136.2, 138.8; HRMS m/z
(M+) calcd for C21H24N2O2S 368.1558, found 368.1559.
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N-Butyl-1-methanesulfonyl-2-(4-methylphenyl)-N-(4-pent-
en-1-yl)indol-3-amine (5ei). Mp 48.0−49.5 °C; 1H NMR (400
MHz, CDCl3) δ 0.80 (t, J = 7.3 Hz, 3H), 1.12−1.21 (m, 2H), 1.29−
1.44 (m, 4H), 1.89 (q, J = 7.3 Hz, 2H), 2.41 (s, 3H), 2.78 (s, 3H), 2.91
(t, J = 7.3 Hz, 2H), 2.93 (t, J = 7.3 Hz, 2H), 4.87 (dd, J = 9.2, 1.4 Hz,
1H), 4.88 (dd, J = 16.9, 1.4 Hz, 1H), 5.68 (ddt, J = 16.9, 9.2, 6.4 Hz,
1H), 7.21−7.23 (m, 2H), 7.25−7.29 (m, 4H), 7.67 (d, J = 7.3 Hz,
1H), 8.13 (d, J = 7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.2,
20.5, 21.7, 28.0, 31.0, 31.4, 39.9, 53.6, 54.3, 114.6, 116.1, 120.3, 123.9,
125.1, 128.4, 128.7, 129.6, 131.5, 133.7, 134.3, 136.4, 138.7, 138.8;
HRMS m/z (M+) calcd for C25H32N2O2S 424.2184, found 424.2187.
Synthesis of 7 (Scheme 9). With Cu(OTf)2 (36 mg, 0.10 mmol),
under otherwise identical conditions mentioned above, the oxy-
amination of 2-(3-methylbut-3-en-1-yn-1-yl)phenol (1l, 79 mg, 0.50
mmol) with N-allyl-O-benzoyl-N-methylhydroxylamine (2h, 191.2 mg,
1.0 mmol) proceeded to furnish N-allyl-N-methyl-2-(1-propen-2-
yl)benzofuran-3-amine (3lh, 58 mg, 0.26 mmol) in 51% yield.
N-Allyl-N-methyl-2-(1-propen-2-yl)benzofuran-3-amine
(3lh). Oil; 1H NMR (600 MHz, CDCl3) δ 2.25 (s, 3H), 2.84 (s, 3H),
3.74 (d, J = 6.2 Hz, 2H), 5.09 (dd, J = 10.2, 1.4 Hz, 1H), 5.17−5.20
(m, 1H), 5.20 (s, 1H), 5.81 (s, 1H), 5.88 (ddt, J = 17.0, 10.2, 6.2 Hz,
1H), 7.15 (t, J = 7.3 Hz, 1H), 7.23 (t, J = 7.3 Hz, 1H), 7.39 (d, J = 8.2
Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ
20.5, 41.5, 59.6, 111.6, 114.9, 117.1, 120.8, 121.9, 124.1, 127.3, 130.0,
134.3, 135.7, 148.6, 152.7; HRMS m/z (M+) calcd for C15H17NO
227.1310, found 227.1307.
Grubbs second generation catalyst (3.7 mg, 4.4 μmol) was placed in
a 5 mL Schlenk tube, which was then filled with nitrogen. Trimethyl-
(vinyloxy)silane (0.013 mL, 0.087 mmol) and a solution of 3lh
(20 mg, 0.087 mmol) in toluene (1.0 mL) were subsequently added
dropwise. The solution was heated at 110 °C for 2 h. The resulting
mixture was allowed to cool to room temperature and filtered through a
pad of neutral alumina. Concentration under reduced pressure followed
by column chromatography on silica gel with hexane/EtOAc/Et3N
(400/20/2.5, v/v/v) produced 1,3,5-trimethyl-2,3-dihydro-1H-benzofuro-
[3,2-b]azepine (7, 15 mg, 0.067 mmol) in 77% yield.
1,3,5-Trimethyl-2,3-dihydro-1H-benzofuro[3,2-b]azepine
(7). Oil; 1H NMR (400 MHz, CDCl3) δ 1.22 (d, J = 7.4 Hz, 3H), 2.22
(t, J = 1.8 Hz, 3H), 2.38−2.50 (m, 1H), 2.58 (dd, J = 13.3, 7.8 Hz,
1H), 2.99 (s, 3H), 3.12 (dt, J = 13.3, 1.4 Hz, 1H), 5.55−5.56 (m, 1H),
7.17 (td, J = 6.8, 0.9 Hz, 1H), 7.23 (td, J = 7.8, 1.4 Hz, 1H), 7.38 (d, J =
7.8 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
20.4, 20.6, 32.0, 43.6, 59.6, 111.4, 119.6, 121.7, 124.1, 125.9, 130.4, 132.5,
142.0, 152.8 (one sp2 13C signal was overlapped by another one); HRMS
m/z (M+) calcd for C15H17NO 227.1310, found 227.1308.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for products. This material is available
free of charge via the Internet at http://pubs.acs.org.
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