Stereoselective Synthesis of 2-(2-Aminoalkyl)- and 1,3-Disubstituted Tetrahydro-1H-pyrido[4,3-b]- Benzofuran and Indole Derivatives

Article abstract of DOI:10.1021/acs.joc.6b01047

The addition of an allenyl indium intermediate to chiral N-tert-butanesulfinyl imines 7 proceeds with high levels of diastereocontrol. The resulting homopropargylic amine derivatives 10 were transformed into 2-(2-aminoalkyl)benzofuran and indole derivatives 13 and 19, after Sonogashira coupling with o-iodophenol or o-iodoaniline, followed by formation of the heteroaromatic ring through an intramolecular cyclization. Enantioenriched tetrahydropyrido-benzofuran and indole derivatives 16 and 21 were prepared through a Pictet-Spengler condensation of the free amines derived from compounds 15 and 20, involving the nucleophilic 3-position of the benzofuran or indole moiety.

Full text of DOI:10.1021/acs.joc.6b01047

Article
pubs.acs.org/joc
Stereoselective Synthesis of 2‑(2-Aminoalkyl)- and 1,3-Disubstituted
Tetrahydro‑1H‑pyrido[4,3‑b]- Benzofuran and Indole Derivatives
María Jesus García-Munoz,†,‡,§ Francisco Foubelo,*,†,‡,§ and Miguel Yus*,†,§
́
̃
†Departamento de Química Organ
‡Instituto de Síntesis Organ
ica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
§Centro de Innovacion
en Química Avanzada (ORFEO−CINQA), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
́
ica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
́
́
S
* Supporting Information
ABSTRACT: The addition of an allenyl indium intermediate to chiral
N-tert-butanesulfinyl imines 7 proceeds with high levels of diaster-
eocontrol. The resulting homopropargylic amine derivatives 10 were
transformed into 2-(2-aminoalkyl)benzofuran and indole derivatives 13
and 19, after Sonogashira coupling with o-iodophenol or o-iodoaniline,
followed by formation of the heteroaromatic ring through an
intramolecular cyclization. Enantioenriched tetrahydropyrido-benzofur-
an and indole derivatives 16 and 21 were prepared through a Pictet-
Spengler condensation of the free amines derived from compounds 15
and 20, involving the nucleophilic 3-position of the benzofuran or
indole moiety.
INTRODUCTION
■
A large percentage of drugs and drug candidates contain the
amine functionality,1 which is also widespread among natural
products, organocatalysts2 and ligands of organometallic
catalysts. Remarkably, in many of these compounds the
nitrogen atom is bonded to a stereogenic center, so the
development of general and versatile asymmetric method-
ologies for preparing enantioenriched chiral amines is of great
importance in synthesis.3 Compounds with the indole unit
bearing a 2-aminoalkyl substituent at the 3-position are part of
the family of these aminated compounds, which have attracted
the interest of chemists and pharmacologists mainly due to
their possible physiological activities. Many indole alkaloids
have been known for years and used in ancient cultures as
psychotropic, stimulants and poisons. All these natural products
derive from the amino acid tryptophan (1)4 and show wide
structural diversity, going from the simplest compound
tryptamine (2), a nonselective serotonin receptor agonist and
serotonin-norepinephrine-dopamine releasing agent,5 to, for
instance, harmine (3), a fluorescent harmala alkaloid which
reversibly inhibits monoamine oxidase, which shows also
cytotoxicity against different cell lines,6 and lysergic acid (4),
a precursor of different ergoline alkaloids. Amide derivatives of
4 were used as psychedelic drugs. Other representative indole
alkaloids with more complex structures are strychnine (5), a
poison which produces muscular convulsions isolated from the
seeds of the Strychnos nux-vomica tree,7 and the bisindole
derivative voacamine (6) found in Voacanga africana8 (Figure
1). Regioisomeric benzofurans and indoles with a 2-aminoalkyl
substituent at the 2-position with general structures I and II
Figure 1. Representative natural products bearing the 3-(2-
aminoalkyl)indole moiety.
(Figure 1) are less common compounds and have been
synthesize in order to explore their biological actitivity. Thus,
some benzofuran derivatives on type I were found to display a
potent and selective enhancement of the impulse propagation
mediated release of catecholamines and serotonin in the brain,9
and also, histamine H3 receptor antagonist activity;10 mean-
while, some indole derivatives of type II have been found to
inhibit intracellular Ca2+ release in human TT cells,11 or act as
serotonin-3 receptor antagonists.12
On the other hand, over the past decade, N-tert-
butanesulfinyl imines13 have been extensively used as electro-
Special Issue: Heterocycles
Received: May 5, 2016
© XXXX American Chemical Society
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Scheme 1. Retrosynthetic Analysis of Synthesis of 2-Aminoalkyl Indoles, Benzofurans and Tetrahydropyridoindole and Furan
Derivatives
Scheme 2. Diastereoselective Synthesis of Homopropargyl Amine Derivatives 10
philes in a wide range of synthetic applications due to easy
access to both enantiomers from commercially available tert-
butanesulfinamide at reasonable prices. Importantly, the tert-
butanesulfinyl group can be removed under mild reaction
conditions leading to free amines and, in addition, useful
synthetic procedures have been developed in order to recycle
the chiral tert-butanesulfinamide,14 being this process at the end
as a nonimmolative removal procedure of the chiral auxiliary.
Regarding our research in this area, we have described the
stereoselective indium promoted coupling of N-tert-butanesul-
finyl imines with allylic bromides15 and also with trimethylsilyl
propargyl bromide16 to give the corresponding homoallyl and
homopropargyl amine derivatives, respectively, which have
been used as precursors in the synthesis of natural products17
and other structurally diverse nitrogen-containing com-
pounds.18 Being aware of the potential interest of 2-aminoalkyl
benzofurans and indoles of type I and II with regard to
biological activity, we decided to explore new synthetic
pathways to access to these compounds and other polyheter-
ocyclic derivatives in an enantioenriched form, from N-tert-
butanesulfinyl homopropargylamines and ortho-iodoaniline or
ortho-iodophenol, through a tandem Sonogashira-cyclization
reaction and final Pictet−Spengler type intramolecular electro-
philic substitution (Scheme 1).
RESULTS AND DISCUSSION
■
We have already reported that the reaction of 3.3 equiv of
trimethylsilylpropargyl bromide 8 with different chiral N-tert-
butanesulfinyl aldimines 7 in the presence of 3.3 equiv of
indium metal under sonication for 7 h led to the formation of
B
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Table 1. Optimization of the Tandem Sonogashira-Cyclization Reaction of Terminal Alkyne 10d and ortho-Iodophenol (11)
a
entry
reaction conditions
12d:13d:14d ratio
1
2
3
4
5
6
Pd(PPh3)4 (2 mol %), CuI (2 mol %), Et3N, 23 °C, 14 h
Pd(PPh3)4 (2 mol %), CuI (2 mol %), Et3N, 40 °C, 6 h
Pd(PPh3)4 (2 mol %), CuI (2 mol %), Et3N, 60 °C, 14 h
Pd(PPh3)4 (2 mol %), CuI (2 mol %), Et3N, 60 °C (MW), 15 min
Pd(PPh3)4 (2 mol %), CuI (2 mol %), Et3N, 60 °C (MW), 30 min
Pd(PPh3)4 (2 mol %), CuI (2 mol %), Et3N, 60 °C (MW), 45 min
51:23:26
26:27:47
4:49:47
39:52:9
28:64:8
16:81:3
a
1
Ratio was determined from H NMR spectrum of the crude reaction mixture. In all cases total consumption of the starting compound 10d was
observed.
a
Scheme 3. Synthesis of 2-(2-Aminoalkyl)furan Derivatives 13 from Terminal Alkynes 10
a
12:13 ratio is given in parentheses and was determined from 1H NMR spectrum of the crude reaction mixture. Yield refers to isolated compounds
after column chromatography purification.
the corresponding silylated homopropargyl amine derivatives 9
in variable yields, but always with excellent diastereomeric
ratios. It is worth mentioning that enantiomerically pure
compounds 9 were isolated after column chromatography
purification in all cases (Scheme 2).16 Addition of silicon-
stabilized allenylindium intermediate took place predominantly
to the Si face of imines with RS configuration. In order to
explain that, we proposed a six-membered ring transition state
III, with the simultaneous coordination of the indium atom of
the to both the nitrogen and oxygen atoms of the imine, so
fixing a conformation in which nucleophilic attack proceeded at
the less hindered Si face for these imines (Scheme 2). The
silicon unit was selectively removed upon treatment of
compounds 9 with potassium carbonate in THF/methanol at
room temperature for 12 h, leading to terminal alkynes 10 in
high yields (Scheme 2). Under these mild reaction conditions
the sulfinyl group remained unaltered. This is important in
order not to perturb the desired further transformations.
All the attempts to perform a palladium(0)-catalyzed sila-
Sonogashira coupling of compounds 9d with ortho-iodophenol
(11) in the presence of CuCl in DMF,19 or on potassium
fluoride doped alumina under microwave irradiation,20 failed.
Decomposition of the starting compound 9d was always
observed. However, better results were obtained working with
desilylated compounds 10. Homopropargylamine derivative
10d was taken as a model compound for the optimization of
tandem Sonogashira-cyclization process with ortho-iodophenol
(11). The reaction of 10d with 11 in the presence of catalytic
amounts of Pd(PPh3)4 (2 mol %) and CuI (2 mol %), in Et3N
at room temperature for 14 h led to the cross-coupling product
C
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Table 2. Synthesis of Tetrahydro-1H-pyrido[4,3-b]benzofurans 16
12d as the major component of the reaction mixture, along
with the desired tandem coupling-cyclization product 13d, and
compound 14d, resulting from the homocoupling of the
terminal alkyne 10d (Table 1, entry 1). The formation of the
homocoupling product 14d is facilitated working at higher
temperatures. Thus, 14d became the major component of the
reaction mixture at 40 °C, meanwhile 12b and 13d were in an
almost 1:1 ratio (Table 1, entry 2). At 60 °C, compound 14d
was formed in a similar extension as at 40 °C, but we observed
that the initially formed Sonogashira coupling product 12d
underwent intramolecular cyclization leading to 13d (Table 1,
entry 3).21 Fortunately, formation of undesired compound 14d
was minimized working at 60 °C under microwave irradiation,
and the amount of the desired compound 13d increased by
increasing reaction time from 15 to 45 min (Table 1, entries 4
to 6). Longer reaction times under microwave irradiation led to
significant decomposition of the 2-(2-aminoalkyl)furan deriv-
ative 13d.
We studied next the scope of the reaction with different
homopropargylamine derivatives 10, by applying the optimized
conditions depicted in Table 1, entry 6. In all cases, the
corresponding benzofuran derivative 13 was obtained as the
major reaction product, the Sonogashira coupling product 12
being formed in a lesser extension. Importantly, for the
homoproparglylamines 10e and 10f derived from aldehydes
phenylacetaldehyde and benzaldehyde, compounds 12 were
neither isolated nor detected. Anyway, products 12 and 13 were
formed in ratios ranging from 26:74 to <5:95, and were purified
very easily by column chromatography (Scheme 3).
The previously commented methodology allow us an easy
access to N-tert-butanesulfinyl substituted 2-(2-aminoalkyl)-
furans 13, which can be transformed into the free amines 15 by
removal of the sulfinyl group upon treatment first of a
methanolic solution of compounds 13 with hydrogen chloride
4.0 M in dioxane, and then, with a saturated sodium
bicarbonate solution. After that, the crude amines 15 were
treated with an aldehyde in dichloromethane at room
D
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a
Scheme 4. Synthesis of 2-(2-Aminoalkyl)indole Derivatives 19 from Terminal Alkynes 10
a
Compound 19a could not be isolated.
temperature to form the corresponding imines. The progress of
the reaction could be follow by gas chromatography and it took
around 5 h to go to completion. Once the intermediate imine
was formed, anhydrous magnesium sulfate was added and after
filtration of the solid and removal of the solvent, the resulting
crude imine was treated with trifluoroacetic acid (TFA) in a
high pressure tube and heated at 90 °C for 24 h, leading to the
expected tetrahydropyridofuran derivatives 16 in variable yields,
after intramolecular electrophilic aromatic substitution at the
electron-rich 3-position of the indole system (Table 2). In the
case of formaldehyde, 1.5 equiv from a 37% aqueous solution of
formaldehyde was used in this Pictet−Spengler type cyclization
(Table 2, entries 1−3). Surprisingly, for the 2-(2-aminoalkyl)-
fenzofuran 13e, derived from the imine of phenylacetaldehyde,
along with the expected tetrahydropyridofuran 16ea, the
pentacyclic compound 16ea′, resulting from a double aromatic
electrophilic substitution involving also the phenyl group of the
starting phenylacetaldehyde, was also formed in a significant
amount (Table 2, entry 2). This double electrophilic
substitution was not observed starting from compound 13f,
derived from the imine of benzaldehyde. In this case, the Pictet-
Spengler cyclization involving the phenyl group leading to a
five-membered ring did not take place under the essayed
reaction conditions (Table 2, entry 3). Importantly, when other
aldehydes, such as isobutyraldehyde and benzaldehyde, were
used, the expected 1,3-disubstituted tetrahydropyridofurans 16
were obtained as a single diastereoisomer (Table 2, entries 4−
7). The relative configuration was unambiguously determined
to be cis by NOESY experiments in compounds 16. Moreover,
on the contrary to formaldehyde, 15e did not undergo double
electrophilic aromatic substitution when reacting with iso-
butyraldehyde and benzaldehyde (Table 2, entries 4 and 7).
Unfortunately, the reaction of homopropargylamine deriva-
tives 10 with ortho-iodoaniline (17) under the palladium-
catalyzed microwave irradiation conditions, which were found
to be optimal for the Sonogashira coupling and subsequent
cyclization in the case of ortho-iodophenol (11) in Table 1,
entry 6, led always to very low yields of the expected indole
E
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Table 3. Synthesis of Tetrahydro-1H-pyrido[4,3-b]indoles 21
derivative 19, taking place especially decomposition of the
starting homopropargylamines 10.22 Since the formation of the
2-(2-aminoalkyl)indole derivatives 19 from compounds 10 and
ortho-aniline (17) in a single synthetic operation failed, we
planned to perform first the Sonogashira coupling reaction
exclusively under thermal conditions and after that, the
intramolecular cyclization to produce the five-membered ring
of the indole system. The palladium-catalyzed coupling of
terminal alkynes 10 and ortho-iodoaniline (17) in Et3N at 60
°C produced compounds 18 in moderate yields. Further
treatment of orto-alkynylaniles 18 with 1 equiv of copper iodide
in DMF at 100 °C led to the expected 2-(2-aminoalkyl)indoles
19.23 Although TLC monitoring of this reaction reflected a
clean transformation (a single spot corresponding to the
reaction product was developed), compounds 19 were obtained
in relatively low isolated yields after column chromatography
purification. Even, for the aniline derivative 18a, the expected
indole 19 could not be isolated in a significant amount in order
to be characterized (Scheme 4).
Finally, tetrahydropyridoindoles 21 were prepared from
compounds 19, following the same strategy depicted in Table
2: first removal of the tert-butanesulfinyl group under acidic
conditions and then, reaction of the resulting free amine 20
with an aldehyde in trifluoroacetic acid (Table 3). Overall yields
are similar to those obtained in the case of furan derivatives 16.
Tetrahydropyridoindoles 21 with substituents at 1- and 3-
positions exhibited also cis relative configuration (Table 3).
In summary, 1,3-disubstituted tetrahydro-1H-pyrido[4,3-b]-
benzofuran and indole derivatives 16 and 21, respectively, were
prepared in a highly stereoselective fashion from tert-
butanesulfinamide, trimethylsilylpropargyl bromide, two alde-
hydes and ortho-iodophenol or ortho-iodoaniline. The method-
ology presented here comprised as key steps a diastereose-
lective addition of an allenyl indium intermediate to the chiral
sulfinyl imine 7, a Sonogashira coupling reaction of a terminal
alkyne and ortho-iodophenol or aniline, and a final Pictet−
Spengler condensation involving a five-membered heteroar-
omatic ring. Tetrahydropyridobenzofuran and indole deriva-
tives 16 and 21 with substituents at 1- and 3-positions exhibit
cis-relative configuration and since the addition of the allenyl
indium intermediate to the sulfinyl imine is stereospecific, the
stereochemistry of the reaction products is determined by the
configuration of the tert-butanesulfinamide.
EXPERIMENTAL SECTION
■
General Remarks. (RS)-tert-Butanesulfinamide was a gift of
Medalchemy (>99% ee by chiral HPLC on a Chiracel AS column,
90:10 n-hexane/i-PrOH, 1.2 mL/min, λ = 222 nm). TLC was
performed on silica gel 60 F254, using aluminum plates and visualized
with phosphomolybdic acid (PMA) stain. Flash chromatography was
carried out on handpacked columns of silica gel 60 (230- 400 mesh).
Melting points are uncorrected. Optical rotations were measured using
a polarimeter with a thermally jacketted 5 cm cell at approximately 20
°C and concentrations (c) are given in g/100 mL. Infrared analyses
were performed with a spectrophotometer equipped with an ATR
component; wavenumbers are given in cm−1. Low-resolution mass
spectra (EI) were obtained at 70 eV; and fragment ions in m/z with
relative intensities (%) in parentheses. High-resolution mass spectra
(HRMS) were also carried out using the electron impact mode (EI) at
70 eV with a Q-TOF analyzer. 1H NMR spectra were recorded at 300
1
or 400 MHz for H NMR and 75 or 100 MHz for 13C NMR, using
CDCl3 as the solvent and TMS as internal standard (0.00 ppm). The
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data are being reported as s = singlet, d = doublet, t = triplet, q =
quatriplet, h = heptet, m = multiplet or unresolved, br s = broad signal,
coupling constant(s) in Hz, integration. 13C NMR spectra were
recorded with 1H-decoupling at 100 MHz and referenced to CDCl3 at
77.16 ppm. DEPT-135 experiments were performed to assign CH,
CH2 and CH3. Microwave-assisted synthesis was performed using
microwave oven CEM Discover Intellivent Explorer in sealed reaction
vessels, and the temperature was monitored using a vertically focused
IR temperature sensor. Compounds 7a,24 7b,25 7c,26 7d,27 7e,26 and
7f26 were prepared from the corresponding aldehyde and (RS)-tert-
butanesulfinamide in THF in the presence of 2 equiv of titanium
tetraethoxide.
(3R,RS)-N-(tert-Butanesulfinyl)-1-phenyl-6-(trimethylsilyl)hex-5-
yn-3-amine (9d).16 The representative procedure was followed by
using imine 7d (118.5 mg, 0.50 mmol). Purification by column
chromatography (hexane/AcOEt, 5:1) yielded 9d (139.4 mg, 0.40
20
mmol, 80%) as a white solid: mp 51−52 °C (hexane/CH2Cl2); [α]D
−16.1 (c = 1.01, CH2Cl2); Rf 0.50 (hexane/EtOAc, 1:1); IR ν (film)
3271, 2959, 2928, 2175, 1250, 1032, 838, 759, 697 cm−1; δH 7.33−7.14
(m, 5H), 3.65 (d, J = 8.1 Hz, 1H), 3.45−3.31 (m, 1H), 2.79−2.62 (m,
2H), 2.71 (dd, J = 16.9, 5.9 Hz, 1H), 2.53 (dd, J = 16.8, 4.6 Hz, 1H),
2.01−1.87 (m, 2H), 1.26 (s, 9H), 0.16 (s, 9H); δC 141.4 (C), 128.5,
128.3, 126.0 (CH), 102.4, 88.4, 56.0 (C), 53.9 (CH), 36.6, 31.8, 28.0
(CH2), 22.7, 0.04 (CH3); LRMS (EI) m/z 293 (M+−C4H8, 5%), 246
(13), 245 (58), 140 (13), 91 (99), 75 (16), 73 (100).
General Procedure for the Propargylation of N-tert-
Butanesulfinylimines 7. Synthesis of Homopropargylamine
Derivatives 9. A mixture of N-tert-butanesulfinyl imine 7 (0.5
mmol), 3-bromo-1-trimethylsilyl-1-propyne (8; 313 mg, 0.275 mL,
1.65 mmol), and indium (189 mg, 1.65 mmol) was sonicated in dry
THF (2 mL) for 7 h. Then the resulting mixture was hydrolyzed with
H2O (5 mL) and extracted with EtOAc (3 × 15 mL). The organic
phase was washed with brine (3 × 10 mL), dried with anhydrous
MgSO4, and the solvent evaporated (15 Torr). The residue was
purified by column chromatography (silica gel, hexane/EtOAc) to
yield products 9. Yields, physical and spectroscopic data follow.
(4R,RS)-N-(tert-Butanesulfinyl)-1-(trimethylsilyl)dodec-1-yn-4-
amine (9a).16 The representative procedure was followed by using
imine 7a (122.5 mg, 0.50 mmol). Purification by column
chromatography (hexane/AcOEt, 5:1) yielded 9a (134.8 mg, 0.38
(2R,RS)-N-(tert-Butanesulfinyl)-1-phenyl-5-(trimethylsilyl)pent-4-
yn-2-amine (9e).16 The representative procedure was followed by
using imine 7e (446.0 mg, 2.00 mmol). Purification by column
chromatography (hexane/AcOEt, 5:1) yielded 9e (522.8 mg, 1.56
mmol, 78%) as a yellow oil: [α]D20 −21.1 (c = 1.06, CH2Cl2); Rf 0.53
(hexane/EtOAc, 1:1); IR ν (film) 3444, 3118, 3020, 2959, 2177, 1473,
1456, 1426, 1364, 1249, 1081, 1052, 1026, 1003, 839, 743, 698 cm−1;
δH 7.36−7.14 (m, 5H), 3.70−3.57 (m, 2H), 2.99 (dd, J = 13.6, 6.1 Hz,
1H), 2.86 (dd, J = 13.6, 6.7 Hz, 1H), 2.58 (dd, J = 16.9, 5.7 Hz, 1H),
2.48 (dd, J = 16.9, 4.6 Hz, 1H), 1.15 (s, 9H), 0.19 (s, 9H); δC 137.6
(C), 129.5, 128.4, 126.6 (CH), 102.6, 88.7, 56.0 (C), 55.9 (CH), 40.9,
26.9 (CH2), 22.5, 0.04 (CH3); LRMS (EI) m/z 279 (M+−C4H8, 1%),
231 (31), 188 (19), 167 (14), 140 (19), 104 (37), 98 (27), 91 (52), 75
(14), 73 (100), 71 (13); HRMS (ESI) Calculated for C14H21NSi
(M+−C4H8OS) 231.1443, found 231.1437.
20
mmol, 76%) as a colorless oil: [α]D −11.4 (c = 1.16, CH2Cl2); Rf
(1S,RS)-N-(tert-Butanesulfinyl)-1-phenyl-4-(trimethylsilyl)but-3-
yn-1-amine (9f).16 The representative procedure was followed by
using imine 7f (104.5 mg, 0.50 mmol). Purification by column
chromatography (hexane/AcOEt, 5:1) yielded 9f (106.0 mg, 0.33
0.65 (hexane/EtOAc, 1:1); IR ν (film) 3203, 2956, 2924, 2855, 2173,
1466,1363, 1249, 1052, 840, 759, 648 cm−1; δH 3.58 (d, J = 7.7 Hz,
1H), 3.38−3.27 (m, 1H), 2.65 (dd, J = 16.8, 5.7 Hz, 1H), 2.48 (dd, J =
16.8, 5.0 Hz, 1H), 1.65−1.50 (m, 2H), 1.39−1.24 (m, 12H), 1.23 (s,
9H), 0.88 (t, J = 6.8 Hz, 3H), 0.15 (s, 9H); δC 102.8, 88.2, 55.9 (C),
54.4 (CH), 34.7, 31.8, 29.4, 29.3, 29.2, 27.9, 25.6 (CH2), 22.7, 14.1,
0.04 (CH3); LRMS (EI) m/z 301 (M+−C4H8, 7%), 253 (29), 189
(26), 142 (12), 140 (25), 84 (13), 77 (11), 75 (16), 74 (10), 73 (100),
70 (24), 69 (13); HRMS (EI) Calculated for C15H31NOSSi (M+−
C4H8) 301.1896, found 301.1897.
20
mmol, 69%) as a white solid: mp 80−82 °C (hexane/CH2Cl2); [α]D
−133.1 (c = 1.00, CH2Cl2); Rf 0.52 (hexane/EtOAc, 1:1); IR ν (film)
3231, 3209, 2955, 2932, 2899, 2178, 1249, 1046, 1024, 837, 757, 697
cm−1; δH 7.40−7.28 (m, 5H), 4.56 (m, 1H), 4.15 (br. s, 1H), 2.74 (dd,
J = 16.9, 5.1 Hz, 1H), 2.64 (dd, J = 16.8, 8.3 Hz, 1H), 1.24 (s, 9H),
0.16 (s, 9H); δC 140.4 (C), 128.5, 128.0, 127.5 (CH), 102.2, 89.1 (C),
56.5 (CH), 55.7 (C), 30.3 (CH2), 22.6, 0.1 (CH3); LRMS (EI) m/z
217 (M+−C4H8, 22%), 202 (14), 153 (74), 144 (10), 136 (20), 129
(20), 128 (20), 77 (14), 75 (16), 74 (10), 73 (100).
(4R,RS)-N-(tert-Butanesulfinyl)-6-methyl-1-(trimethylsilyl)hept-1-
yn-4-amine (9b). The representative procedure was followed by using
imine 7b (283.5 mg, 1.50 mmol). Purification by column
chromatography (hexane/AcOEt, 5:1) yielded 9b (401.3 mg, 1.30
General Procedure for the Desilylation of Compounds 9.
Synthesis of Terminal Alkynes 10. A suspension of K2CO3 (5 mg,
0.036 mmol) in methanol (4 mL) was added dropwise to a solution of
the corresponding compound 9 (0.5 mmol) in THF (4 mL). The
reaction mixture was stirred for 12 h at rt, and then it was hydrolyzed
with a 1 N NH4Cl aqueous solution (8 mL) and extracted with methyl
tert-butyl ether (3 × 15 mL). The organic phase was dried with
anhydrous MgSO4 and the solvent evaporated (15 Torr). The residue
was purified by column chromatography (silica gel, hexane/EtOAc,
2:1) to yield products 10. Yields, physical and spectroscopic data
follow.
20
mmol, 89%) as a yellow oil: [α]D −5.2 (c = 1.72, CH2Cl2); Rf 0.52
(hexane/EtOAc, 1:1); IR ν (film) 3198, 2956, 2929, 2903, 2868, 2174,
1467, 1364, 1248, 1050, 838, 758 cm−1; δH 3.57 (d, J = 8.7 Hz, 1H),
3.49−3.35 (m, CH, 1H), 2.68 (dd, J = 16.8, 5.8 Hz, 1H), 2.49 (dd, J =
16.8, 4.3 Hz, 1H), 1.83−1.64 (m, 1H), 1.62−1.47 (m, 1H), 1.48−1.29
(m, 1H), 1.23 (s, 9H), 0.96−0.87 (m, 6H), 0.16 (s, 9H); δC 102.8,
88.2 (C), 55.9 (CH), 52.9 (C), 44.2, 28.4 (CH2), 24.5 (CH), 22.7,
22.6, 22.0, 0.03 (CH3); LRMS (EI) m/z 301 (M+, 0.5%), 197 (44),
149 (11), 140 (15), 133 (31), 86 (100), 73 (55), 57 (48), 43 (63);
HRMS (EI) Calculated for C11H22NSi (M+−C4H9OS) 196.1522,
found 196.1519.
(4R,RS)-N-(tert-Butanesulfinyl)dodec-1-yn-4-amine (10a). The
representative procedure was followed by using compound 9a
(357.0 mg, 1.00 mmol). Purification by column chromatography
(hexane/AcOEt, 6:1) yielded 10a (175.4 mg, 0.62 mmol, 62%) as a
(3S,RS)-N-(tert-Butanesulfinyl)-2-methyl-6-(trimethylsilyl)hex-5-
yn-3-amine (9c).16 The representative procedure was followed by
using imine 7c (87.5 mg, 0.50 mmol). Purification by column
chromatography (hexane/AcOEt, 5:1) yielded 9c (83.4 mg, 0.29
20
yellow oil: [α]D −15.7 (c = 1.61, CH2Cl2); Rf 0.42 (hexane/EtOAc,
1:1); IR ν (film) 3222, 2954, 2923, 2855, 1465, 1363, 1051, 720, 625
cm−1; δH 3.48 (d, J = 8.5 Hz, 1H), 3.44−3.26 (m, 1H), 2.66 (ddd, J =
16.7, 5.6, 2.6 Hz, 1H), 2.48 (ddd, J = 16.7, 4.5, 2.6 Hz, 1H), 2.06 (t, J =
2.6 Hz, 1H), 1.70−1.46 (m, 2H), 1.44−1.22 (m, 12H), 1.23 (s, 9H),
0.94−0.82 (m, 3H); δC 80.2 (C), 71.4 (CH), 56.0 (C), 54.8 (CH),
34.8, 31.8, 29.4, 29.3, 29.2, 26.6, 25.7 (CH2), 22.7 (CH3), 14.1 (CH3);
LRMS (EI) m/z 229 (M+−C4H8, 1%), 213 (12), 140 (18), 126 (44),
116 (13), 113 (100), 100 (47), 67 (11), 56 (13); HRMS (EI)
Calculated for C12H23NOS (M+−C4H8) 229.1500, found 229.1501.
(4R,RS)-N-(tert-Butanesulfinyl)-6-methylhept-1-yn-4-amine (10b).
The representative procedure was followed by using compound 9b
(150.5 mg, 0.50 mmol). Purification by column chromatography
(hexane/AcOEt, 6:1) yielded 10b (101.9 mg, 0.44 mmol, 90%) as a
20
mmol, 58%) as a white solid: mp 40−43 °C (hexane/CH2Cl2); [α]D
−8.3 (c = 1.01, CH2Cl2); Rf 0.60 (hexane/EtOAc, 1:1); IR ν (film)
3449, 3263, 3123, 2959, 2929, 2898, 2870, 2174, 1473, 1466, 1429,
1366, 1248, 1008, 838, 758, 698, 646 cm−1; δH 3.61 (d, J = 8.0 Hz,
1H), 3.17−3.06 (m, 1H), 2.65 (dd, J = 17.0, 5.8 Hz, 1H), 2.56 (dd, J =
17.0, 5.1 Hz, 1H), 2.06−1.94 (m, 1H), 1.24 (s, 9H), 0.94 (d, J = 6.8
Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.15 (s, 9H); δC 102.9, 88.2 (C),
59.8 (CH), 56.1 (C), 31.2 (CH), 25.0 (CH2), 22.8, 18.8, 18.4, 0.03
(CH3); LRMS (EI) m/z 231 (M+−C4H8, 7%), 188 (10), 184 (16),
183 (100), 140 (33), 120 (23), 119 (65), 102 (17), 83 (10), 75 (23),
73 (85), 72 (19), 59 (11), 57 (67), 56 (33), 55 (10); HRMS (ESI)
Calculated for C10H21NOSSi (M+−C4H8) 231.1113, found 231.1124.
G
DOI: 10.1021/acs.joc.6b01047
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
20
yellow oil: [α]D −10.5 (c = 1.00, CH2Cl2); Rf 0.32 (hexane/EtOAc,
HRMS (ESI) Calculated for C10H11NOS (M+−C4H8) 193.0561,
found 193.0553.
1:1); IR ν (film) 3217, 2955, 2929, 2868, 1468, 1388, 1364, 1050, 898,
632 cm−1; δH 3.49−3.39 (m, 2H), 2.77−2.62 (m, 1H), 2.53−2.45 (m,
1H), 2.06 (t, J = 2.6 Hz, 1H), 1.80−1.65 (m, 1H), 1.61−1.50 (m, 1H),
1.41−1.31 (m, 1H), 1.23 (s, 9H), 0.92 (d, J = 6.7 Hz, 3H), 0.90 (d, J =
6.5 Hz, 3H); δC 80.2 (C), 71.5 (CH), 56.1 (C), 53.2 (CH), 44.1
(CH2), 27.2 (CH2), 24.5 (CH), 23.0 (CH3), 22.7 (CH3), 21.2 (CH3);
LRMS (EI) m/z 229 (M+, 0.05%), 173 (18), 134 (38), 133 (100), 118
(13), 116 (41), 100 (13), 67 (16), 57 (79); HRMS (EI) Calculated for
C5H12NOS (M+−C7H11) 134.0640, found 134.0630.
General Procedure for the Tandem Sonogashira Coupling
Reaction and Cyclization of Terminal Alkynes 10 and o-
Iodophenol 11. Isolation of Compounds 12, 13 and 14. In a 10
mL vial containing a solution of the corresponding terminal alkyne 10
(0.3 mmol) in dry triethylamine (3 mL) was successively added ortho-
iodophenol (11, 66 mg, 0.3 mmol), copper(I) iodide (1.1 mg, 0.006
mmol) and Pd(PPh3)4 (6.9 mg, 0.006 mmol). The mixture was
irradiated for 45 min at 80 W power and 60 °C. After that, the reaction
mixture was cooled down to rt and filtered through a Celite path with
ethyl acetate (100 mL). The organic solution was washed with water
(5 × 30 mL), dried with anhydrous MgSO4, and the solvent
evaporated (15 Torr). The residue was purified by column
chromatography (silica gel, hexane/EtOAc) to yield mainly products
12 and 13. Yields, physical and spectroscopic data follow.
(3S,RS)-N-(tert-Butanesulfinyl)-2-methylhex-5-yn-3-amine (10c).
The representative procedure was followed by using compound 9c
(106.2 mg, 0.37 mmol). Purification by column chromatography
(hexane/AcOEt, 6:1) yielded 10c (69.4 mg, 0.32 mmol, 87%) as a
20
yellow oil: [α]D −23.5 (c = 1.33, CH2Cl2); Rf 0.35 (hexane/EtOAc,
1:1); IR ν (film) 3222, 2959, 2928, 2871, 1467, 1387, 1364, 1057, 889,
628 cm−1; δH 3.46 (d, J = 8.8 Hz, 1H), 3.16−3.05 (m, 1H), 2.64 (ddd,
J = 16.9, 5.8, 2.7 Hz, 1H), 2.58 (ddd, J = 16.9, 5.0, 2.6 Hz, 1H), 2.04 (t,
J = 2.6 Hz, 1H), 2.03−1.96 (m, 1H), 1.24 (s, 9H), 0.95 (d, J = 5.8 Hz,
3H), 0.93 (d, J = 5.8 Hz, 3H); δC 80.3 (C), 71.4 (CH), 60.4 (CH),
56.2 (C), 31.2 (CH), 24.0 (CH2), 22.8 (CH3), 19.1, 18.3 (CH3);
LRMS (EI) m/z 215 (M+, 0.6%), 197 (12), 159 (12), 149 (25), 133
(11), 120 (14), 119 (50), 116 (33), 83 (13), 73 (19), 70 (20), 57 (67),
43 (100), 41 (31); HRMS (ESI) Calculated for C7H13NOS (M+−
C4H8) 159.0718, found 159.0723.
(4R,RS)-N-(tert-Butanesulfinyl)-1-(2-hydroxyphenyl)dodec-1-yn-4-
amine (12a). The representative procedure was followed by using
compound 10a (85.5 mg, 0.30 mmol). Purification by column
chromatography (hexane/AcOEt, 5:1) yielded 12a (9.8 mg, 0.02
20
mmol, 9%) as a yellow oil: [α]D −39.1 (c = 0.98, CH2Cl2); Rf 0.45
(hexane/EtOAc, 2:1); IR ν (film) 3252, 2955, 2922, 2853, 1570, 1488,
1458, 1242, 1023, 1008, 749, 722 cm−1; δH 8.47 (m, 1H), 7.29−7.24
(m, 1H), 7.21−7.15 (m, 1H), 6.92 (dd, J = 8.3, 0.9 Hz, 1H), 6.78 (td, J
= 7.5, 1.1 Hz, 1H), 3.47−3.37 (m, 1H), 3.32 (d, J = 9.5 Hz, 1H), 2.95
(dd, J = 17.2, 3.8, 2.0 Hz, 1H), 2.54 (dd, J = 17.1, 7.3, 2.0 Hz, 1H),
1.61−1.48 (m, 2H), 1.37−1.15 (m, 21H), 0.88 (t, J = 6.8 Hz, 3H); δC
158.4 (C), 132.0, 129.8, 119.3, 116.2 (CH), 109.8, 91.5, 79.5 (C), 56.6
(CH), 56.5 (C), 36.7, 31.8, 29.4, 29.2, 28.2, 25.9 (CH2), 22.6 (CH3),
22.5 (CH2), 14.1 (CH3); LRMS (EI) m/z 377 (M+, 7%), 304 (12),
274 (15), 273 (79), 216 (15), 190 (46), 175 (19), 174 (58), 162 (28),
161 (100), 160 (57), 142 (38), 131 (51), 77 (19), 57 (56), 43 (27;
HRMS (EI) Calculated for C18H27NO (M+− C4H8OS) 273.2093,
found 273.2082.
(3R,RS)-N-(tert-Butanesulfinyl)-1-phenylhex-5-yn-3-amine
(10d).16 The representative procedure was followed by using
compound 9d (174.5 mg, 0.50 mmol). Purification by column
chromatography (hexane/AcOEt, 6:1) yielded 10d (115.2 mg, 0.41
mmol, 83%) as a yellow oil: [α]D20 −23.5 (c = 0.86, CH2Cl2); Rf 0.20
(hexane/EtOAc, 1:1); IR ν (film) 3219, 3061, 3025, 2978, 2948, 2864,
2111, 1602, 1495, 1455, 1363, 1175, 1054, 699 cm−1; δH 7.33−7.25
(m, 2H), 7.24−7.14 (m, 3H), 3.55 (d, J = 8.8 Hz, 1H), 3.47−3.32 (m,
1H), 2.82−2.61 m, CH2, 3H), 2.56−2.44 (m, 1H), 2.07 (t, J = 2.6 Hz,
1H), 2.03−1.88 (m, 2H), 1.26 (s, 9H); δC 141.3 (C), 128.5 (CH),
128.3 (CH), 126.0 (CH), 79.9 (C), 71.7 (C), 56.1 (C), 54.3 (CH),
36.7 (CH2), 32.0 (CH2), 26.7 (CH2), 22.6 (CH3); LRMS (EI) m/z
221 (M+−C4H8, 1%), 157 (11), 132 (53), 117 (51), 116 (28), 101
(16), 98 (16), 92 (10), 91 (100), 77 (16), 68 (32), 67 (28), 65 (19);
HRMS (ESI) Calculated for C12H15NOS (M+−C4H8) 221.0874,
found 221.0877.
(4R,RS)-N-(tert-Butanesulfinyl)-1-(2-hydroxyphenyl)-6-methyl-
hept-1-yn-4-amine (12b). The representative procedure was followed
by using compound 10b (68.7 mg, 0.30 mmol). Purification by
column chromatography (hexane/AcOEt, 5:1) yielded 12b (12.1 mg,
0.04 mmol, 12%) as a white solid: mp 143−145 °C (hexane/CH2Cl2);
20
[α]D −38.5 (c = 0.99, CH2Cl2); Rf 0.38 (hexane/EtOAc, 2:1); IR ν
(film) 3247, 2956, 2936, 2863, 1603, 1453, 1413, 1364, 1270, 1008,
934, 749, 644 cm−1; δH 8.50 (br s, 1H), 7.30−7.23 (m, 1H), 7.22−7.14
(m, 1H), 6.92 (dd, J = 8.3, 0.9 Hz, 1H), 6.78 (td, J = 7.5, 1.1 Hz, 1H),
3.59−3.45 (m, 1H), 3.29 (d, J = 9.9 Hz, 1H), 2.97 (dd, J = 17.1, 3.9
Hz, 1H), 2.51 (dd, J = 17.1, 6.9 Hz, 1H), 1.82−1.65 (m, 1H), 1.61−
1.47 (m, 1H), 1.37−1.28 (m, 1H), 1.25 (s, 9H), 0.93 (d, J = 8.1 Hz,
3H), 0.91 (d, J = 7.9 Hz, 3H); δC 158.5 (C), 131.9, 129.8, 119.3, 116.2
(CH), 109.8, 91.5, 79.6, 56.6 (C), 54.7 (CH), 45.7, 28.7 (CH2), 24.6
(CH), 23.0, 22.7, 21.6 (CH3); LRMS (EI) m/z 321 (M+, 5%), 162
(20), 161 (100), 160 (29), 134 (19), 131 (16), 77 (11), 57 (27);
HRMS (ESI) Calculated for C18H27NO2S (M+) 321.1762, found
321.1764.
(2R,RS)-N-(tert-Butanesulfinyl)-1-phenylpent-4-yn-2-amine (10e).
The representative procedure was followed by using compound 9e
(167.5 mg, 0.50 mmol). Purification by column chromatography
(hexane/AcOEt, 6:1) yielded 10e (120.6 mg, 0.46 mmol, 90%) as a
20
yellow oil: [α]D −16.5 (c = 1.16, CH2Cl2); Rf 0.25 (hexane/EtOAc,
1:1); IR ν (film) 3219, 2978, 2955, 2924, 2867, 1496, 1455, 1363,
1171, 1050, 902, 743, 700 cm−1; δH 7.34−7.27 (m, 2H), 7.25−7.19
(m, 3H), 3.72−3.60 (m, 1H), 3.54 (d, J = 8.3 Hz, 1H), 2.98 (dd, J =
13.7, 6.7 Hz, 1H), 2.89 (dd, J = 13.7, 7.0 Hz, 1H), 2.59 (ddd, J = 16.8,
6.0, 2.6 Hz, 1H), 2.48 (ddd, J = 16.9, 4.6, 2.7 Hz, 1H), 2.14 (t, J = 2.6
Hz, 1H), 1.14 (s, 9H); δC 137.5 (C), 129.5, 128.5, 126.6 (CH), 80.0
(C), 71.9 (CH), 56.2 (C), 56.1 (CH), 40.9, 25.7 (CH2), 22.5 (CH3);
LRMS (EI) m/z 263 (M+−C4H8, 0.5%), 208 (13), 207 (59), 168 (15),
167 (60), 149 (24), 128 (16), 116 (100), 104 (20), 91 (98), 68 (20),
57 (82), 55 (17), 41 (34); HRMS (ESI) Calculated for C11H13NOS
(M+−C4H8) 207.0718, found 207.0720.
(3S,RS)-N-(tert-Butanesulfinyl)-6-(2-hydroxyphenyl)-2-methylhex-
5-yn-3-amine (12c). The representative procedure was followed by
using compound 10c (64.5 mg, 0.30 mmol). Purification by column
chromatography (hexane/AcOEt, 5:1) yielded 12c (14.6 mg, 0.05
mmol, 15%) as a white solid: mp 146−148 °C (hexane/CH2Cl2);
20
(1S,RS)-N-(tert-Butanesulfinyl)-1-phenylbut-3-yn-1-amine (10f).
The representative procedure was followed by using compound 9f
(96.3 mg, 0.30 mmol). Purification by column chromatography
(hexane/AcOEt, 6:1) yielded 10f (64.2 mg, 0.26 mmol, 86%) as a
[α]D −75.7 (c = 1.21, CH2Cl2); Rf 0.40 (hexane/EtOAc, 2:1); IR ν
(film) 3271, 2957, 2927, 2868, 1484, 1363, 1244, 1030, 1011, 913, 756
cm−1; δH 8.64 (br s, 1H), 7.26 (dd, J = 7.7, 1.7 Hz, 1H), 7.18 (ddd, J =
8.3, 7.4, 1.7 Hz, 1H), 6.91 (dd, J = 8.3, 0.9 Hz, 1H), 6.78 (td, J = 7.5,
1.2 Hz, 1H), 3.39−3.23 (m, 2H), 2.92−2.80 (m, 1H), 2.65−2.55 (m,
1H), 1.89−1.75 (m, 1H), 1.27 (s, 9H), 0.99−0.93 (m, 6H); δC 158.3
(C), 132.1, 129.7, 119.3, 116.4 (CH), 109.9, 91.4, 79.5 (C), 61.8
(CH), 56.7 (C), 33.6 (CH), 25.4 (CH2), 22.8, 19.2, 17.9 (CH3);
LRMS (EI) m/z 307 (M+, 5%), 203 (29), 160 (100), 131 (19), 120
(13), 57 (26); HRMS (ESI) Calculated for C13H17NO2S (M+−C4H8)
251.0980, found 251.0982.
20
white solid: mp 85−86 °C (hexane/CH2Cl2); [α]D −7.7 (c = 1.12,
CH2Cl2); Rf 0.30 (hexane/EtOAc, 1:1); IR ν (film) 3210, 2958, 2937,
1454, 1428, 1348, 1202, 1049, 1050, 876, 776, 696, 638 cm−1; δH
7.40−7.29 (m, 5H), 4.58 (ddd, J = 8.3, 5.2, 3.4 Hz, 1H), 4.04 (d, J =
3.3 Hz, 1H), 2.75 (ddd, J = 16.8, 5.2, 2.6 Hz, 1H), 2.67 (ddd, J = 16.8,
8.0, 2.6 Hz, 1H), 2.12 (t, J = 2.6 Hz, 1H), 1.23 (s, 9H); δC 140.3 (C),
128.5, 128.1, 127.4 (CH), 79.8 (C), 72.1 (CH), 56.8 (CH), 55.8 (C),
28.7 (CH2), 22.6 (CH3); LRMS (EI) m/z 249 (M+, 0.3%), 193 (19),
154 (22), 153 (60), 129 (100), 128 (54), 104 (20), 57 (50), 43 (55);
(3R,RS)-N-(tert-Butanesulfinyl)-6-(2-hydroxyphenyl)-1-phenylhex-
5-yn-3-amine (12d). The representative procedure was followed by
H
DOI: 10.1021/acs.joc.6b01047
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
using compound 10d (83.1 mg, 0.30 mmol). Purification by column
chromatography (hexane/AcOEt, 5:1) yielded 12d (10.0 mg, 0.027
mmol, 9%) as a colorless wax: [α]D −28.7 (c = 1.48, CH2Cl2); Rf
14.9, 4.8, 0.7 Hz, 1H), 2.84−2.73 (m, 1H), 2.73−2.63 (m, 1H), 1.97−
1.85 (m, 1H), 1.85−1.73 (m, 1H), 1.25 (s, 9H); δC 154.8, 141.4, 128,6
(C), 128.5, 128.4, 126.0, 123.6, 122.7, 120.6, 110.9, 105.3 (CH), 56.1
(C), 55.0 (CH), 37.1, 35.4, 32.1 (CH2), 22.7 (CH3); LRMS (EI) m/z
369 (M+, 0.3%), 313 (31), 238 (20), 182 (22), 164 (43), 134 (37),
131 (60), 117 (100), 91 (60), 77 (11), 57 (27); HRMS (EI)
Calculated for C18H19NO2S (M+−C4H8) 313.1136, found 313.1134.
(2R,RS)-2-(2-Amino-3-phenylpropanyl)-N-(tert-butanesulfinyl)-
benzofuran (13e). The representative procedure was followed by
using compound 10e (78.9 mg, 0.30 mmol). Purification by column
chromatography (hexane/AcOEt, 5:1) yielded 13e (71.4 mg, 0.20
20
0.28 (hexane/EtOAc, 2:1); IR ν (film) 3187, 2971, 2962, 1487, 1292,
1264, 1241, 1031, 734 cm−1; δH 7.38−7.12 (m, 7H), 6.92 (dd, J = 8.3,
1.1 Hz, 1H), 6.78 (td, J = 7.5, 1.2 Hz, 1H), 3.54−3.43 (m, 2H), 3.07−
2.91 (m, 1H), 2.82−2.53 (m, 3H), 1.97−1.82 (m, 2H), 1.28 (s, 9H);
δC 158.4, 141.0 (C), 132.0, 130.0, 128.6, 128.3, 126.2, 119.4, 116.1
(CH), 109.8, 91.2, 79.7, 56.7 (C), 56.0 (CH), 38.4, 32.2, 28.2 (CH2),
22.8 (CH3); LRMS (EI) m/z 369 (M+, 3%), 162 (19), 161 (100), 160
(21), 131 (17), 117 (28), 91 (43), 57 (23); HRMS (EI) Calculated for
C18H19NO (M+−C4H8OS) 265.1467, found 265.1459.
20
mmol, 67%) as a yellow oil: [α]D + 0.9 (c = 1.19, CH2Cl2); Rf 0.15
(hexane/EtOAc, 2:1); IR ν (film) 3218, 3060, 3030, 2951, 2922, 2863,
1603, 1584, 1454, 1251, 1048, 740, 699 cm−1; δH 7.56−7.50 (m, 1H),
7.48−7.41 (m, 1H), 7.35−7.27 (m, 2H), 7.26−7.27 (m, 5H), 6.59 (d, J
= 0.9 Hz, 1H), 3.99−3.90 (m, 1H), 3.59 (d, J = 7.4 Hz, 1H), 3.18 (dd,
J = 14.7, 5.7 Hz, 1H), 3.13 (dd, J = 14.7, 5.3 Hz, 1H), 2.88−2.83 (m,
2H), 1.10 (s, 9H); δC 154.9, 137.9 (C), 129.6 (CH), 128.5 (C), 128.4,
126.5, 123.7, 122.7, 120.6, 110.9, 105.3, 56.7 (CH), 56.0 (C), 41.5,
34.6 (CH2), 22.4 (CH3); LRMS (EI) m/z 355 (M+−C4H8, 0.5%), 300
(12), 299 (59), 224 (17), 168 (100), 167 (55), 150 (17), 132 (23),
131 (95), 120 (74), 104 (26), 91 (42), 77 (17), 57 (44); HRMS (EI)
Calculated for C17H17NO2S (M+−C4H8) 299.0980, found 299.0979.
(2R,RS)-2-(2-Amino-2-phenylethyl)-N-(tert-butanesulfinyl)-
benzofuran (13f). The representative procedure was followed by
using compound 10f (74.7 mg, 0.30 mmol). Purification by column
chromatography (hexane/AcOEt, 5:1) yielded 13f (50.9 mg, 0.15
mmol, 50%) as a white solid: mp 157−160 °C (hexane/CH2Cl2);
(2R,RS)-2-(2-Aminodecyl)-N-(tert-butanesulfinyl)benzofuran
(13a). The representative procedure was followed by using compound
10a (85.5 mg, 0.30 mmol). Purification by column chromatography
(hexane/AcOEt, 5:1) yielded 13a (49.2 mg, 0.13 mmol, 45%) as a
20
yellow oil: [α]D −5.1 (c = 1.00, CH2Cl2); Rf 0.28 (hexane/EtOAc,
2:1); IR ν (film) 3208, 2953, 2923, 2854, 1598, 1589, 1454, 1251,
1172, 1050, 750, 722 cm−1; δH 7.52−7.49 (m, 1H), 7.44−7.39 (m,
1H), 7.26−7.15 (m, 2H), 6.56 (s, 1H), 3.67−3.58 (m, 1H), 3.49 (d, J
= 7.9 Hz, 1H), 3.17 (dd, J = 14.9, 5.8 Hz, 1H), 3.09 (dd, J = 14.9, 5.2
Hz, 1H), 1.60−1.34 (m, 4H), 1.33−1.23 (m, 10H), 1.22 (s, 9H), 0.87
(t, J = 6.8 Hz, 3H); δC 155.2, 154.8, 128.6 (C), 123.5, 122.6, 120.5,
110.9, 105.1 (CH), 55.9 (C), 55.4 (CH), 35.4, 35.1, 31.8, 29.5, 29.3,
29.2, 25.7 (CH2), 22.7, 14.1 (CH3); LRMS (EI) m/z 377 (M+, 0.4%),
321 (18), 246 (18), 190 (100), 189 (39), 142 (43), 131 (55), 57 (28);
HRMS (EI) Calculated for C18H27NO2S (M+−C4H8) 321.1762, found
321.1759.
20
[α]D −56.9 (c = 1.04, CH2Cl2); Rf 0.18 (hexane/EtOAc, 1:1); IR ν
(2R,RS)-2-(2-Amino-4-methylpentyl)-N-(tert-butanesulfinyl)-
benzofuran (13b). The representative procedure was followed by
using compound 10b (68.7 mg, 0.30 mmol). Purification by column
chromatography (hexane/AcOEt, 5:1) yielded 13b (47.2 mg, 0.15
mmol, 49%) as a yellow oil: [α]D20 + 10.6 (c = 1.09, CH2Cl2); Rf 0.21
(hexane/EtOAc, 2:1); IR ν (film) 3212, 2954, 2926, 2868, 1598, 1454,
1364, 1251, 1049, 795, 750 cm−1; δH 7.53−7.50 (m, 1H), 7.45−7.14
(m, 1H), 7.26−7.14 (m, 2H), 6.56 (d, J = 0.9 Hz, 1H), 3.79−3.62 (m,
1H), 3.46 (d, J = 9.1 Hz, 1H), 3.21 (dd, J = 14.9, 6.1 Hz, 1H), 3.10
(dd, J = 14.6, 4.5 Hz, 1H), 1.83−1.71 (m, 1H), 1.45−1.37 (m, 1H),
1.34−1.25 (m, 1H), 1.22 (s, 9H), 0.89 (d, J = 6.7 Hz, 3H), 0.88 (d, J =
6.6 Hz, 3H); δC 155.2, 154.8, 128.6 (C), 123.5, 122.6, 120.5, 110.9,
105.1 (CH), 55.9 (C), 55.4 (CH), 35.4, 35.1, 31.8, 29.5, 29.3, 29.2,
25.7 (CH2), 22.7, 14.1 (CH3); LRMS (EI) m/z 321 (M+, 0.5%), 265
(20), 190 (19), 134 (100), 133 (62), 131 (55), 86 (22), 57 (31);
HRMS (EI) Calculated for C14H19NO2S (M+−C4H8) 265.1136, found
265.1132.
(2R,RS)-2-(2-Amino-3-methylbutyl)-N-(tert-butanesulfinyl)-
benzofuran (13c). The representative procedure was followed by
using compound 10c (64.5 mg, 0.30 mmol). Purification by column
chromatography (hexane/AcOEt, 5:1) yielded 13c (44.3 mg, 0.14
mmol, 48%) as a yellow oil: [α]D20 −31.0 (c = 0.91, CH2Cl2); Rf 0.22
(hexane/EtOAc, 2:1); IR ν (film) 3163, 2957, 2926, 2868, 1589, 1455,
1364, 1252, 1060, 1004, 750 cm−1; δH 7.53−7.48 (m, 1H), 7.43−7.39
(m, 1H), 7.25−7.16 (m, 1H), 6.57 (d, J = 0.7 Hz, 1H), 3.53−3.40 (m,
2H), 3.18−3.12 (m, 2H), 1.86−1.74 (m, 1H), 1.24 (s, 9H), 0.99 (d, J
= 6.7 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H); δC 155.4, 154.8, 128.5 (C),
123.5, 122.6, 120.5, 110.8, 104.9 (CH), 60.7 (CH), 56.1 (C), 32.4
(CH2), 31.1 (CH), 22.7, 19.1, 18.0 (CH3); LRMS (EI) m/z 307 (M+,
0.7%), 251 (33), 176 (18), 133 (23), 131 (87), 120 (100), 119 (64),
72 (38), 57 (43); HRMS (EI) Calculated for C13H17NO2S (M+−
C4H8) 251.0980, found 251.0980.
(film) 3281, 3025, 2957, 2918, 2873, 1603, 1584, 1454, 1250, 1163,
1060 744, 697 cm−1; δH 7.50−7.46 (m, 1H), 7.44−7.39 (m, 1H),
7.38−7.33 (m, 4H), 7.33−7.29 (m, 1H), 7.25−7.17 (m, 2H), 6.46 (d, J
= 0.9 Hz, 1H), 4.85 (ddd, J = 8.2, 5.9, 2.4 Hz, 1H), 4.01 (d, J = 2.5 Hz,
1H), 3.30−3.21 (m, 2H), 1.19 (s, 9H); δC 154.8, 154.3, 140.8 (C),
128.6 (CH), 128.3 (C), 128.0, 127.5, 123.9, 122.7, 120.7, 110.9, 104.8,
57.1 (CH), 55.6 (C), 37.9 (CH2), 22.6 (CH3); LRMS (EI) m/z 341
(M+−C4H8, 0.1%), 221 (22), 210 (38), 154 (100), 153 (31), 131 (25),
77 (11), 57 (20); HRMS (ESI) Calculated for C16H13NO (M+−
C4H10SO) 235.0997, found 235.0997.
(3R,10R,3RS,10RS)-N,N′-Di-(tert-butanesulfinyl)-1,12-diphenyldo-
deca-5,7-diyne-3,10-diamine (14d). The representative procedure
was modified, performing the reaction at 40 °C for 4 h without
microway irradiation. Starting from compound 10d (83.1 mg, 0.30
mmol). Purification by column chromatography (hexane/AcOEt, 1:1)
yielded 14d (38.9 mg, 0.07 mmol, 47%) as a yellow oil: [α]D20 −3.1 (c
= 1.07, CH2Cl2); Rf 0.05 (hexane/EtOAc, 2:1); IR ν (film) 3321,
2947, 2927, 2868, 1454, 1438, 1363, 1178, 1038, 724, 698 cm−1; δH
7.3−7.04 (m, 10H), 3.47 (d, J = 9.2 Hz, 2H), 3.44−3.31 (m, 2H),
2.85−2.70 (m, 4H), 2.69−2.50 (m, 4H), 2.01−1.82 (m, 4H), 1.25 (s,
18H); δC 141.2 (C), 128.5, 128.3, 126.0 (CH), 73.5, 68.1, 56.2 (C),
54.7 (CH), 36.8, 32.0, 27.7 (CH2), 22.7 (CH3); LRMS (EI) m/z 497
(M+− C4H8, 1%), 495 (11), 243 (12), 238 (10), 223 (12), 222 (66),
212 (11), 211 (62), 166 (17), 164 (11), 134 (64), 132 (14), 117 (53),
91 (100), 71 (10), 57 (72), 44 (16). It was not possible to get HRMS
(ESI) for this compound.
General Procedure for the Sonogashira Coupling Reaction
and of Terminal Alkynes 10 and o-Iodoaniline 17. Isolation of
Compounds 18. To a solution of the corresponding terminal alkyne
10 (0.3 mmol) in dry triethylamine (3 mL) was successively added
ortho-iodoaniline (17, 66 mg, 0.3 mmol), copper(I) iodide (1.1 mg,
0.006 mmol) and Pd(PPh3)4 (6.9 mg, 0.006 mmol). The mixture was
stirred and 60 °C for 4 h. After that, the reaction mixture was cooled
down to rt and filtered through a Celite path with ethyl acetate (100
mL). The organic solution was washed with water (5 × 30 mL), dried
with anhydrous MgSO4, and the solvent evaporated (15 Torr). The
residue was purified by column chromatography (silica gel, hexane/
EtOAc) to yield products 18. The yields are given in Scheme 4, the
physical and spectroscopic data follow.
(2R,RS)-2-(2-Amino-4-phenylbutyl)-N-(tert-butanesulfinyl)-
benzofuran (13d). The representative procedure was followed by
using compound 10d (83.1 mg, 0.30 mmol). Purification by column
chromatography (hexane/AcOEt, 5:1) yielded 13d (54.9 mg, 0.15
20
mmol, 50%) as a yellow oil: [α]D −4.2 (c = 1.01, CH2Cl2); Rf 0.19
(hexane/EtOAc, 2:1); IR ν (film) 3208, 3060, 3020, 2951, 2922, 2864,
1603, 1454, 1251, 1050, 943, 742, 698 cm−1; δH 7.53−7.48 (m, 1H),
7.44−7.39 (m, 1H), 7.30−7.26 (m, 1H), 7.25−7.23 (m, 1H), 7.22−
7.13 (m, 5H), 6.55 (d, J = 0.9 Hz, 1H), 3.73−3.61 (m, 1H), 3.58 (d, J
= 8.3 Hz, 1H), 3.24 (ddd, J = 14.9, 8.0, 0.8 Hz, 1H), 3.13 (ddd, J =
(4R,RS)-1-(2-Aminophenyl)-N-(tert-butanesulfinyl)dodec-1-yn-4-
amine (18a). The representative procedure was followed by using
I
DOI: 10.1021/acs.joc.6b01047
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
compound 10a (59.3 mg, 0.21 mmol). Purification by column
chromatography (hexane/AcOEt, 3:1) yielded 18a (38.6 mg, 0.10
mmol, 50%) as a yellow oil: [α]D −2.0 (c = 0.78, CH2Cl2); Rf 0.33
mmol, 51%) as a yellow oil: [α]D20 −11.1 (c = 0.80, CH2Cl2); Rf 0.20
(hexane/EtOAc, 1:1); IR ν (film) 3203, 3026, 2951, 2908, 2859, 1615,
1493, 1455, 1045, 932, 743, 700 cm−1; δH 7.36−7.19 (m, 6H), 7.12
(ddd, J = 8.1, 7.4, 1.6 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 6.73 (td, J =
7.5, 1.1 Hz, 1H), 3.86 (d, J = 8.2 Hz, 1H), 3.81−3.65 (m, 1H), 3.07−
2.82 (m, 3H), 2.73 (dd, J = 16.9, 5.5 Hz, 1H), 1.13 (s, 9H); δC 146.9,
137.7 (C), 132.0, 129.5, 129.3, 128.5, 126.6, 118.6, 115.2 (CH), 108.9,
91.1, 80.6 (C), 57.0 (CH), 56.2 (C), 41.8, 26.9 (CH2), 22.6 (CH3);
LRMS (EI) m/z 354 (M+, 8%), 160 (11), 159 (100), 130 (38), 120
(21), 91 (15), 57 (15); HRMS (EI) Calculated for C21H26N2OS (M+)
354.1766, found 354.1772.
20
(hexane/EtOAc, 1:1); IR ν (film) 3330, 3212, 2954, 2924, 2854, 1618,
1493, 1456, 1314, 1050, 745 cm−1; δH 7.24 (dd, J = 7.6, 1.6 Hz, 1H),
7.09 (ddd, J = 8.1, 7.3, 1.6 Hz, 1H), 6.73−6.62 (m, 2H), 3.62 (d, J =
8.5 Hz, 1H), 3.49−3.38 (m, 1H), 2.97 (dd, J = 16.8, 5.2 Hz, 1H), 2.70
(dd, J = 16.8, 4.9 Hz, 1H), 1.69−1.55 (m, 2H), 1.47−1.24 (m, 12H),
1.23 (s, 9H), 0.92−0.83 (m, 3H); δC 148.0 (C), 132.0, 129.2, 117.8,
114.5 (CH), 108.3, 90.9, 80.5, 56.1 (C), 55.4 (CH), 35.5, 31.8, 29.5,
29.3, 29.2, 27.8, 25.8 (CH2), 22.7 (CH3), 22.6 (CH2), 14.1 (CH3);
LRMS (EI) m/z 376 (M+, 21%), 320 (10), 319 (15), 272 (45), 215
(15), 190 (28), 174 (14), 173 (42), 162 (17), 161 (23), 160 (80), 159
(46), 143 (12), 142 (61), 131 (26), 129 (100), 77 (14), 57 (40);
HRMS (EI) Calculated for C18H26N2OS (M+−C4H10) 318.1766,
found 318.1765.
(4R,RS)-1-(2-Aminophenyl)-N-(tert-butanesulfinyl)-6-methylhept-
1-yn-4-amine (18b). The representative procedure was followed by
using compound 10b (68.7 mg, 0.30 mmol). Purification by column
chromatography (hexane/AcOEt, 3:1) yielded 18b (52.7 mg, 0.16
mmol, 55%) as a yellow oil: [α]D20 + 13.1 (c = 0.88, CH2Cl2); Rf 0.26
(hexane/EtOAc, 1:1); IR ν (film) 3341, 3210, 2955, 2928, 2868, 1617,
1492, 1455, 1364, 1314, 1049, 910, 745, 646 cm−1; δH 7.26−7.21 (m,
1H), 7.13−7.05 (m, 1H), 6.73−6.62 (m, 2H), 3.58 (d, J = 9.4 Hz,
1H), 3.55−3.44 (m, 1H), 3.02 (dd, J = 16.8, 5.1 Hz, 1H), 2.68 (dd, J =
16.8, 4.1 Hz, 1H), 1.82−1.68 (m, 1H), 1.67−1.55 (m, 1H), 1.46−1.32
(m, 1H), 1.23 (s, 9H), 0.93 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.5 Hz,
3H); δC 148.1 (C), 132.0, 129.2, 117.7, 114.4 (CH), 108.2, 90.8, 80.6,
56.2 (C), 53.7 (CH), 44.7, 28.3 (CH2), 24.5 (CH3), 23.0 (CH), 22.7,
21.8 (CH3); LRMS (EI) m/z 320 (M+, 14%), 162 (10), 161 (17), 160
(100), 159 (30), 134 (18), 131 (13), 130 (53), 86 (21), 77 (12), 57
(26); HRMS (EI) Calculated for C18H28N2OS (M+) 320.1922, found
320.1921.
(1S,RS)-4-(2-Aminophenyl)-N-(tert-butanesulfinyl)-1-phenylbut-3-
yn-1-amine (18f). The representative procedure was followed by
using compound 10f (69.0 mg, 0.27 mmol). Purification by column
chromatography (hexane/AcOEt, 3:1) yielded 18f (43.0 mg, 0.13
mmol, 49%) as a white solid: mp 112−114 °C (hexane/CH2Cl2);
20
[α]D −84.1 (c = 0.63, CH2Cl2); Rf 0.25 (hexane/EtOAc, 1:1); IR ν
(film) 3311, 3065, 3035, 2981, 2951, 2922, 2853, 1623, 1494, 1456,
1316, 1030, 868, 746, 701 cm−1; δH 7.43−7.30 (m, 5H), 7.21 (dd, J =
7.7, 1.6 Hz, 1H), 7.09 (ddd, J = 8.1, 7.3, 1.6 Hz, 1H), 6.70 (d, J = 8.2
Hz, 1H), 6.66 (td, J = 7.5, 1.1 Hz, 1H), 4.73−4.65 (m, 1H), 4.20 (d, J
= 4.0 Hz, 1H), 3.05 (dd, J = 16.9, 5.4 Hz, 1H), 2.97 (dd, J = 16.9, 7.8
Hz, 1H), 1.23 (s, 9H); δC 147.6, 141.0 (C), 132.1, 129.4, 128.6, 128.0,
127.2, 118.1, 114.7 (CH), 108.0, 90.5, 80.8 (C), 57.9 (CH), 55.9 (C),
30.0 (CH2), 22.6 (CH3); LRMS (EI) m/z 340 (M+, 24%), 284 (14),
283 (18), 237 (17), 236 (100), 235 (33), 221 (20), 220 (57), 219
(25), 218 (25), 217 (15), 210 (43), 205 (15), 204 (19), 202 (13), 154
(92), 136 (37), 132 (19), 131 (32), 130 (83), 106 (43), 104 (25), 77
(33), 57 (55), 43 (20); HRMS (EI) Calculated for C16H16N2 (M+−
C4H8OS) 236.1313, found 236.1311.
General Procedure for the Synthesis of 2-(2-Aminoalkyl)-
indoles 19 from Compounds 18. To a solution of the
corresponding aminoalkyne 18 (0.1 mmol) in dry DMF (2 mL) was
added copper(I) iodide (10.3 mg, 0.1 mmol). The reaction mixture
was degassed and stirred at 100 °C for 7 h, and after that, it was cooled
down to rt, hydrolyzed with water (20 mL) and extracted with EtOAc
(3 × 15 mL). The combined organic phases were washed first with
brine (3 × 10 mL), dried with anhydrous MgSO4 and the solvent
evaporated (15 Torr). The residue was purified by column
chromatography (silica gel, hexane/EtOAc) to yield products 19.
The yields are given in Scheme 4, the physical and spectroscopic data
follow.
(3S,RS)-6-(2-Aminophenyl)-N-(tert-butanesulfinyl)-2-methylhex-
5-yn-3-amine (18c). The representative procedure was followed by
using compound 10c (68.2 mg, 0.32 mmol). Purification by column
chromatography (hexane/AcOEt, 3:1) yielded 18c (46.5 mg, 0.16
20
mmol, 51%) as a yellow oil: [α]D −7.2 (c = 1.96, CH2Cl2); Rf 0.32
(hexane/EtOAc, 1:1); IR ν (film) 3341, 3222, 2959, 2926, 1618, 1493,
1456, 1386, 1314, 1052, 893, 745 cm−1; δH 7.23 (dd, J = 7.6, 1.6 Hz,
1H), 7.08 (ddd, J = 8.1, 7.3, 1.6 Hz, 1H), 6.69 (dd, J = 8.2, 1.1 Hz,
1H), 6.65 (td, J = 7.5, 1.1 Hz, 1H), 3.60 (d, J = 8.3 Hz, 1H), 3.27−3.16
(m, 1H), 2.92 (dd, J = 17.0, 5.2 Hz, 1H), 2.79 (dd, J = 17.0, 5.8 Hz,
1H), 2.04−1.91 (m, 1H), 1.24 (s, 9H), 0.98 (d, J = 6.8 Hz, 3H), 0.97
(d, J = 6.8 Hz, 3H); δC 148.1 (C), 132.0, 129.2, 117.7, 114.5 (CH),
108.2, 90.9, 80.4 (C), 60.9 (CH), 56.3 (C), 32.1 (CH), 24.9 (CH2),
22.8, 19.0, 18.4 (CH3); LRMS (EI) m/z 306 (M+, 16%), 202 (16), 160
(19), 159 (100), 131 (13), 130 (51), 120 (13), 77 (10), 72 (18), 57
(22); HRMS (EI) Calculated for C17H26N2OS (M+) 306.1766, found
306.1763.
(2R,RS)-2-(2-Amino-4-methylpentyl)-N-(tert-butanesulfinyl)indole
(19b). The representative procedure was followed by using compound
18b (46.3 mg, 0.14 mmol). Purification by column chromatography
(hexane/AcOEt, 5:1) yielded 19b (6.4 mg, 0.02 mmol, 20%) as a
20
colorless wax: [α]D + 89.3 (c = 0.30, CH2Cl2); Rf 0.23 (hexane/
EtOAc, 4:1); IR ν (film) 3257, 2954, 2926, 2864, 1457, 1364, 1289,
1040, 919, 786, 734 cm−1; δH 9.97 (br s, 1H), 7.60−7.53 (m, 1H),
7.42−7.34 (m, 1H), 7.18−7.01 (m, 2H), 6.25 (s, 1H), 3.71−3.53 (m,
1H), 3.46 (dd, J = 14.3, 5.4 Hz, 1H), 3.03 (d, J = 11.4 Hz, 1H), 2.87
(dd, J = 14.3, 1.9 Hz, 1H), 1.72−1.59 (m, 2H), 1.50−1.35 (m, 1H),
1.22 (s, 9H), 0.90 (d, J = 6.9 Hz, 3H), 0.87 (d, J = 7.0 Hz, 3H); δC
136.1, 133.5, 128.4 (C), 121.0, 119.6, 119.3, 110.9, 102.4 (CH), 56.4
(C), 54.6 (CH), 43.4, 35.0 (CH2), 24.5 (CH), 23.0, 22.5, 21.4 (CH3);
LRMS (EI) m/z 320 (M+, 21%), 199 (14), 190 (22), 134 (51), 132
(27), 131 (57), 130 (100), 86 (19), 57 (23), 43 (15); HRMS (ESI)
Calculated for C18H28N2OS (M+) 320.1922, found 320.1923.
(3R,RS)-6-(2-Aminophenyl)-N-(tert-butanesulfinyl)-1-phenylhex-
5-yn-3-amine (18d). The representative procedure was followed by
using compound 10d (82.5 mg, 0.29 mmol). Purification by column
chromatography (hexane/AcOEt, 3:1) yielded 18d (51.0 mg, 0.14
mmol, 50%) as a yellow oil: [α]D20 −19.3 (c = 0.45, CH2Cl2); Rf 0.24
(hexane/EtOAc, 1:1); IR ν (film) 3208, 3030, 2924, 2853, 1616, 1492,
1455, 1313, 1157, 1052, 908, 730, 699 cm−1; δH 7.32−7.26 (m, 2H),
7.25−7.17 (m, 4H), 7.09 (ddd, J = 8.2, 7.3, 1.6 Hz, 1H), 6.71 (dd, J =
8.2, 1.1 Hz, 1H), 6.66 (td, J = 7.5, 1.1 Hz, 1H), 3.71 (d, J = 8.7 Hz,
1H), 3.52−3.43 (m, 1H), 3.01 (dd, J = 16.9, 5.4 Hz, 1H), 2.84−2.62
(m, CHH, 3H), 2.03−1.92 (m, 2H), 1.26 (s, 9H); δC 147.8, 141.3 (C),
132.0, 129.3, 128.5, 128.3, 126.0, 117.9, 114.6 (CH), 108.2, 90.6, 80.6,
56.3 (C), 54.9 (CH), 37.3, 32.1, 27.9 (CH2), 22.7 (CH3); LRMS (EI)
m/z 368 (M+, 8%), 311 (11), 161 (16), 160 (100), 159 (18), 134
(21), 131 (11), 130 (43), 117 (19), 91 (33), 57 (18); HRMS (EI)
Calculated for C22H28N2OS (M+) 368.1922, found 368.1921.
(2R,RS)-5-(2-Aminophenyl)-N-(tert-butanesulfinyl)-1-phenylpent-
4-yn-2-amine (18e). The representative procedure was followed by
using compound 10e (52.6 mg, 0.20 mmol). Purification by column
chromatography (hexane/AcOEt, 3:1) yielded 18e (35.0 mg, 0.10
(2R,RS)-2-(2-Amino-3-methylbutyl)-N-(tert-butanesulfinyl)indole
(19c). The representative procedure was followed by using compound
18c (43.7 mg, 0.14 mmol). Purification by column chromatography
(hexane/AcOEt, 6:1) yielded 19c (17.1 mg, 0.05 mmol, 40%) as a
20
colorless wax: [α]D −7.3 (c = 1.50, CH2Cl2); Rf 0.20 (hexane/
EtOAc, 4:1); IR ν (film) 3247, 2959, 2922, 2873, 1457, 1364, 1289,
1170, 1043, 1004, 885, 786, 734 cm−1; δH 9.93 (br s, 1H), 7.54 (d, J =
7.6 Hz, 1H), 7.38 (dd, J = 8.0, 1.0 Hz, 1H), 7.20−7.00 (m, 2H), 6.28
(d, J = 2.4 Hz, 1H), 3.40−3.07 (m, 4H), 1.72−1.55 (m, 1H), 1.23 (s,
9H), 1.09 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.7 Hz, 3H); δC 136.0,
133.8, 128.4 (C), 121.0, 119.6, 119.3, 110.9, 101.8, 63.1 (CH), 56.6
(C), 32.0 (CH2), 31.3 (CH), 22.6, 20.2, 19.8 (CH3); LRMS (EI) m/z
J
DOI: 10.1021/acs.joc.6b01047
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The Journal of Organic Chemistry
Article
306 (M+, 22%), 185 (17), 176 (19), 132 (23), 131 (54), 130 (100),
120 (34), 72 (21), 57 (25), 43 (20); HRMS (ESI) Calculated for
C17H26N2OS (M+) 306.1766, found 306.1768.
trifluoroacetic acid (0.6 mL) was placed in a high pressure tube and
heated at 90 °C for 24 h. Then, the reaction mixture was cooled down
and the solvent evaporated (15 Torr). A saturated sodium bicarbonate
aqueous solution (10 mL) was added to the resulting residue. Then, it
was extracted with EtOAc (3 × 15 mL), dried with anhydrous MgSO4
and the solvent evaporated (15 Torr). The residue was purified by
column chromatography (silica gel, hexane/EtOAc) to yield products
16 and 21. The yields are given in Tables 2 and 3, the physical and
spectroscopic data follow.
(2R,RS)-2-(2-Amino-4-phenylbutyl)-N-(tert-butanesulfinyl)indole
(19d). The representative procedure was followed by using compound
18d (43.1 mg, 0.12 mmol). Purification by column chromatography
(hexane/AcOEt, 4:1) yielded 19d (20.3 mg, 0.045 mmol, 39%) as a
20
colorless wax: [α]D −15.3 (c = 0.80, CH2Cl2); Rf 0.14 (hexane/
EtOAc, 4:1); IR ν (film) 3247, 2952, 2922, 2853, 1455, 1363, 1287,
1179, 1030, 788, 734, 699 cm−1; δH 9.89 (br s, 1H), 7.54 (dd, J = 8.0,
1.2 Hz, 1H), 7.38 (dd, J = 8.0, 1.0 Hz, 1H), 7.31−7.26 (m, 2H), 7.22−
7.04 (m, 5H), 6.28−6.25 (m, 1H), 3.62−3.51 (m, 1H), 3.46 (dd, J =
14.4, 5.4 Hz, 1H), 3.15 (d, J = 11.2 Hz, 1H), 2.93 (dd, J = 14.4, 1.9 Hz,
1H), 2.77−2.61 (m, 2H), 1.85−1.72 (m, 2H), 1.25 (s, 9H); δC 141.3,
136.1, 133.2 (C), 128.5 (CH), 128.4 (C), 128.3, 126.1, 121.1, 119.7,
119.3, 110.9, 102.4 (CH), 56.5 (C), 56.1 (CH), 36.6, 34.9, 32.6
(CH2), 22.6 (CH3); LRMS (EI) m/z 368 (M+, 16%), 247 (11), 238
(32), 164 (24), 156 (12), 134 (32), 132 (27), 131 (53), 130 (100),
117 (41), 91 (33), 57 (20); HRMS (ESI) Calculated for C22H28N2OS
(M+) 368.1922, found 368.1923.
(R)-3-Octyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]benzofuran
(16aa). The representative procedure was followed by using
compound 13a (31.0 mg, 0.08 mmol). Purification by column
chromatography (hexane/AcOEt, 2:1) yielded 16aa (9.2 mg, 0.03
mmol, 45%) as a yellow oil: [α]D20 −48.1 (c = 0.74, CH2Cl2); Rf 0.32
(hexane/EtOAc, 1:1); IR ν (film) 2953, 2923, 1642, 1451, 1184, 742,
722 cm−1; δH 7.45−7.35 (m, 2H), 7.25−7.16 (m, 2H), 4.11−4.03 (m,
2H), 4.03−3.94 (m, 1H), 3.10−2.98 (m, 1H), 2.90−2.79 (m, 1H),
2.59−2.45 (m, 1H), 1.75−1.55 (m, 2H), 1.53−1.41 (m, 2H), 1.39−
1.19 (m, 11H), 0.93−0.84 (m, 3H); δC 154.4, 152.6, 126.8 (C), 123.3,
122.4, 118.3 (CH), 112.1 (C), 111.0, 54.0 (CH), 41.2, 36.1, 31.9, 30.6,
29.7, 29.5, 29.3, 26.1, 22.7 (CH2), 14.1 (CH3); LRMS (EI) m/z 353
(M+, 8%), 349 (16), 348 (15), 221 (18), 220 (100), 219 (46); HRMS
(EI) Calculated for C19H27NO (M+) 285.2093, found 285.2094.
(R)-3-Benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]benzofuran
(16ea). The representative procedure was followed by using
compound 13e (45.0 mg, 0.13 mmol). Purification by column
chromatography (hexane/AcOEt, 1:2) yielded 16ea (15.5 mg, 0.06
(2R,RS)-2-(2-Amino-3-phenylpropanyl)-N-(tert-butanesulfinyl)-
indole (19e). The representative procedure was followed by using
compound 18e (29.0 mg, 0.08 mmol). Purification by column
chromatography (hexane/AcOEt, 4:1) yielded 19e (7.9 mg, 0.024
20
mmol, 30%) as a colorless wax: [α]D −23.1 (c = 0.70, CH2Cl2); Rf
0.13 (hexane/EtOAc, 4:1); IR ν (film) 3238, 2953, 2922, 2853, 1455,
1289, 1182, 1032, 1012, 789, 738, 700 cm−1; δH 9.94 (br s, 1H), 7.59
(d, J = 7.7 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 7.32−7.26 (m, 2H),
7.24−7.05 (m, 5H), 6.35 (d, J = 2.3 Hz, 1H), 3.92−3.78 (m, 1H), 3.43
(dd, J = 14.5, 5.5 Hz, 1H), 3.18 (d, J = 11.1 Hz, 1H), 3.00 (dd, J =
14.5, 2.1 Hz, 1H), 2.84 (dd, J = 14.0, 6.4 Hz, 1H), 2.68 (dd, J = 14.0,
8.7 Hz, 1H), 1.06 (s, 9H); δC 138.3, 136.2, 133.1 (C), 129.2, 128.4,
126.5, 121.1, 119.7, 119.4, 111.0, 102.7, 58.2 (CH), 56.4 (C), 40.8,
34.1 (CH2), 22.3 (CH3); LRMS (EI) m/z 354 (M+, 20%), 298 (12),
233 (18), 224 (23), 168 (31), 132 (21), 131 (54), 130 (100), 120
(39), 91 (15), 57 (24); HRMS (ESI) Calculated for C21H26N2OS
(M+) 354.1766, found 354.1757.
20
mmol, 47%) as a colorless oil: [α]D −41.8 (c = 1.20, CH2Cl2); Rf
0.26 (hexane/EtOAc, 1:1); IR ν (film) 3060, 3023, 2923, 2848, 1644,
1602, 1450, 1185, 742, 699 cm−1; δH 7.43−7.38 (m, 1H), 7.37−7.32
(m, 3H), 7.29−7.25 (m, 3H), 7.24−7.13 (m, 2H), 4.10−4.00 (m, 1H),
3.99−3.89 (m, 1H), 3.39−3.27 (m, 1H), 2.99−2.92 (m, 2H), 2.85−
2.73 (m, 1H), 2.71−2.57 (m, 1H), 2.30 (br s, 1H); δC 154.5, 152.2,
138.1 (C), 129.3, 128.7 (CH), 126.7 (C), 126.6, 123.3, 122.4, 118.3
(CH), 111.9 (C), 111.0, 55.0 (CH), 42.3, 41.2, 30.4 (CH2); LRMS
(EI) m/z 263 (M+, 1%), 173 (12), 172 (100), 170 (10), 145 (33), 144
(44), 115 (20), 91 (11); HRMS (EI) Calculated for C11H10NO (M+−
C7H7) 172.0762, found 172.0766.
(2R,RS)-2-(2-Amino-2-phenylethyl)-N-(tert-butanesulfinyl)indole
(19f). The representative procedure was followed by using compound
18f (39.5 mg, 0.12 mmol). Purification by column chromatography
(hexane/AcOEt, 2:1) yielded 19f (5.3 mg, 0.015 mmol, 15%) as a
(R)-6,6a,7,14-Tetrahydro-12H-benzofuro[2′,3′:4,5]pyrido[1,2-b]-
isoquinoline (16ea′). The representative procedure was followed by
using compound 13e (45.0 mg, 0.13 mmol). Purification by column
chromatography (hexane/AcOEt, 1:2) yielded 16ea′ (11.1 mg, 0.04
mmol, 33%) as a white solid: mp 148−150 °C (hexane/CH2Cl2);
20
colorless wax: [α]D −78.3 (c = 0.15, CH2Cl2); Rf 0.14 (hexane/
EtOAc, 2:1); IR ν (film) 3222, 2957, 2918, 2859, 1456, 1264, 1151,
1027, 734, 699 cm−1; δH 9.10 (br s, 1H), 7.49 (d, J = 7.7 Hz, 1H),
7.37−7.29 (m, 4H), 7.26−7.23 (m, 2H), 7.11 (ddd, J = 8.2, 7.1, 1.3
Hz, 1H), 7.09−7.00 (m, 1H), 6.11 (s, 1H), 4.86−4.78 (m, 1H), 3.83
(d, J = 6.9 Hz, 1H), 3.49 (dd, J = 14.7, 5.6 Hz, 1H), 3.30 (dd, J = 14.7,
5.4 Hz, 1H), 1.19 (s, 9H); δC 141.3, 136.5, 133.4 (C), 128.7 (CH),
128.5 (C), 127.8, 127.0, 121.5, 120.1, 119.6, 111.0, 102.9, 58.7 (CH),
56.3 (C), 37.4 (CH2), 22.7 (CH3); LRMS (EI) m/z 340 (M+, 8%),
220 (14), 219 (14), 218 (12), 210 (60), 154 (100), 153 (11), 136
(22), 132 (15), 131 (39), 130 (83), 106 (20), 103 (12), 77 (13), 57
(31), 43 (26); HRMS (ESI) Calculated for C11H16NOS (M+−C9H8N)
210.0953, found 210.0958.
20
[α]D −48.2 (c = 0.73, CH2Cl2); Rf 0.68 (hexane/EtOAc, 1:1); IR ν
(film) 3025, 2955, 2853, 2765, 1662, 1451, 1211, 1191, 1076, 1020,
745, 736 cm−1; δH 7.46−7.34 (m, 2H), 7.25−7.15 (m, 4H), 7.14−7.03
(m, 2H), 4.14−4.05 (m, 2H), 4.06−3.95 (m, 2H), 3.73−3.58 (m, 1H),
3.18−3.00 (m, 2H), 2.92 (dd, J = 16.8, 7.6 Hz, 1H), 2.78 (ddt, J =
17.0, 7.2, 2.1 Hz, 1H); δC 149.8, 145.6, 128.0, 127.5 (C), 123.9 (CH),
122.0 (C), 121.6, 121.5, 121.2, 118.5, 117.5, 113.3, 106.1 (CH), 104.7
(C), 48.5 (CH2), 48.0 (CH), 42.3, 27.2, 22.5 (CH2); LRMS (EI) m/z
275 (M+, 25%), 145 (14), 144 (100); HRMS (ESI) Calculated for
C19H17NO (M+) 275.1310, found 275.1303.
(S)-3-Phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]benzofuran
(16fa). The representative procedure was followed by using
compound 13f (34.1 mg, 0.10 mmol). Purification by column
chromatography (hexane/AcOEt, 4:1) yielded 16fa (12.1 mg, 0.048
mmol, 49%) as a white wax: [α]D20 −31.3 (c = 0.48, CH2Cl2); Rf 0.42
(hexane/EtOAc, 1:1); IR ν (film) 3025, 2955, 2853, 2765, 1662, 1451,
1211, 1191, 1076, 1020, 745, 736 cm−1; δH 7.55−7.33 (m, 9H), 7.25−
7.19 (m, 1H), 4.24 (t, J = 7.1 Hz, 1H), 4.20−4.11 (m, 2H), 3.16−3.08
(m, 2H); δC 154.6, 151.7 (C), 128.9, 128.2, 127.1 (CH), 126.5 (C),
123.7, 122.6, 118.4, 111.2 (CH), 111.0 (C), 58.1 (CH), 41.3, 31.5
(CH2); LRMS (EI) m/z 249 (M+, 16%), 145 (13), 144 (100), 115
(22); HRMS (ESI) Calculated for C17H15NO (M+) 249.1154, found
249.1153.
General Procedure for the Synthesis of Tetrahydro-1H-
pyrido[4,3-b]- Benzofuran and Indole Derivatives 16 and 21.
To a solution of the corresponding 2-(2-aminoalkyl)benzofuran or
indole derivative, 13 or 19 (0.1 mmol), respectively, in MeOH (1 mL)
was added under argon a 4 M HCl dioxane solution (0.3 mL) at 0 °C.
After 2 h of stirring at the same temperature, the solvent was
evaporated (15 Torr) and a saturated sodium bicarbonate aqueous
solution (10 mL) was added to the resulting residue. Then, it was
extracted with EtOAc (3 × 15 mL), washed with brine (2 × 10 mL),
dried with anhydrous MgSO4 and the solvent evaporated (15 Torr).
The resulting free amine 15 or 20 was dissolved in dry dichloro-
methane (1 mL) and then the corresponding aldehyde (0.13 mmol)
was added. The reaction was stirred at rt for 5 h (until no starting
material 15 or 20 was observed by GC). Then, anhydrous magnesium
sulfate (0.5 g) was added, after 10 min filtered off, and the solvent was
evaporated (15 Torr). A solution of the resulting residue in
(1S,3R)-3-Benzyl-1-isobutyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]-
benzofuran (16eb). The representative procedure was followed by
using compound 13e (35.5 mg, 0.10 mmol). Purification by column
chromatography (hexane/AcOEt, 9:1) yielded 16eb (9.9 mg, 0.03
K
DOI: 10.1021/acs.joc.6b01047
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
mmol, 30%) as a yellow wax: [α]D20 −60.5 (c = 0.44, CH2Cl2); Rf 0.42
(hexane/EtOAc, 1:1); IR ν (film) 3060, 3030, 2954, 2925, 2864, 1718,
1450, 1178, 742, 699 cm−1; δH 7.49−7.26 (m, 8H), 7.21−7.16 (m,
2H), 4.14 (d, J = 10.3 Hz, 1H), 3.36−3.19 (m, 1H), 3.06−2.87 (m,
1H), 2.76−2.66 (m, 2H), 2.07−1.89 (m, 2H), 1.71−1.57 (m, 1H),
0.95 (d, J = 6.4 Hz, 3H), 0.94 (d, J = 6.3 Hz, 3H); δC 154.73, 152.3,
138.1 (C), 129.1, 128.7, 126.7 (CH), 126.5 (C), 123.0, 122.2, 119.4,
111.2, 55.2, 51.1 (CH), 43.9, 42.2, 39.2 (CH2), 24.4 (CH), 24.1, 21.3
(CH3); LRMS (EI) m/z 319 (M+, 1%), 273 (32), 263 (20), 262
(100), 229 (11), 228 (68), 200 (17), 185 (13), 183 (17), 170 (30),
157 (18), 91 (15); HRMS (ESI) Calculated for C18H16NO (M+−
C4H9) 262.1232, found 262.1236.
(1S,3S)-1-Isobutyl-3-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]-
benzofuran (16fb). The representative procedure was followed by
using compound 13f (34.1 mg, 0.10 mmol). Purification by column
chromatography (hexane/AcOEt, 20:1) yielded 16fb (13.9 mg, 0.045
mmol, 46%) as a yellow oil: [α]D20 −87.0 (c = 0.95, CH2Cl2); Rf 0.62
(hexane/EtOAc, 9:1); IR ν (film) 2951, 2925, 2868, 1450, 1265, 1216,
1116, 1012, 844, 742, 698 cm−1; δH 7.57−7.49 (m, 3H), 7.48−7.30
(ArH, 5H), 7.25−7.19 (m, 2H), 4.38 (d, J = 10.3 Hz, 1H), 4.13 (t, J =
7.1 Hz, 1H), 3.01 (br s, 2H), 2.07−1.89 (m, 2H), 1.76−1.57 (m, 1H),
1.07 (d, J = 6.2 Hz, 3H), 0.97 (d, J = 6.2 Hz, 3H); δC 154.7, 128.7 (C),
127.8, 127.0 (CH), 126.5 (C), 123.1, 122.3, 119.5, 111.2, 58.1, 51.4
(CH), 44.0, 29.7 (CH2), 24.3 (CH3), 24.2 (CH), 21.5 (CH3); LRMS
(EI) m/z 305 (M+, 4%), 259 (27), 249 (19), 248 (100), 200 (41), 185
(18), 157 (33), 144 (14), 128 (12); HRMS (ESI) Calculated for
C21H23NO (M+) 305.1780, found 305.1772.
110.7, 51.6, 51.5 (CH), 45.8, 45.2, 31.3 (CH2), 24.8, 24.5, 24.3, 22.8,
21.4 (CH3, CH); LRMS (EI) m/z 284 (M+, 2%), 228 (17), 227 (100),
184 (11), 169 (11), 43 (24); HRMS (ESI) Calculated for C19H28N2
(M+) 284.2252, found 284.2245.
(1S,3S)-1-Isobutyl-3-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-
b]indole (21db). The representative procedure was followed by using
compound 19d (36.8 mg, 0.10 mmol). Purification by column
chromatography (hexane/AcOEt, 1:1) yielded 21db (18.2 mg, 0.055
mmol, 45%) as a yellow solid: mp 104−105 °C (hexane/CH2Cl2);
20
[α]D −73.6 (c = 0.15, CH2Cl2); Rf 0.37 (hexane/EtOAc, 1:2); IR ν
(film) 3400, 3056, 3026, 2950, 2924, 2865, 1608, 1453, 1319, 1239,
1128, 1018, 738, 698 cm−1; δH 7.82 (s, 1H), 7.54 (dd, J = 7.2, 1.7 Hz,
1H), 7.35−7.16 (m, 6H), 7.14−7.02 (m, 2H), 4.22 (dd, J = 10.6, 2.3
Hz, 1H), 3.03−2.88 (m, 1H), 2.87−2.75 (m, 2H), 2.75−2.49 (m, 2H),
2.14 (ddd, J = 13.6, 10.7, 2.6 Hz, 1H), 2.02−1.82 (m, 4H), 1.53 (ddd, J
= 13.9, 10.6, 3.4 Hz, 1H), 1.08 (d, J = 6.5 Hz, 3H), 0.97 (d, J = 6.6 Hz,
3H); δC 141.8, 135.9, 132.9 (C), 128.4, 128.3, 125.9 (CH), 125.5 (C),
120.8, 119.1, 119.0 (CH), 113.2 (C), 110.7, 53.2, 51.5 (CH), 45.2,
38.0, 32.6, 31.0 (CH2), 24.4, 24.3 (CH3), 21.5 (CH); LRMS (EI) m/z
141.8, 135.9, 132.9 (C), 128.4, 128.3, 125.9 (CH), 125.5 (C), 120.8,
119.1, 119.0 (CH), 113.2 (C), 110.7, 53.2, 51.5 (CH), 45.2, 38.0, 32.6,
31.0 (CH2), 24.4, 24.3 (CH3), 21.5 (CH); HRMS (ESI) Calculated
for C23H28N2 (M+) 332.2252, found 332.2231.
(1S,3R)-3-Isobutyl-1-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]-
indole (21bc). The representative procedure was followed by using
compound 19b (32.0 mg, 0.10 mmol). Purification by column
chromatography (hexane/AcOEt, 2:1) yielded 21bc (15.8 mg, 0.052
mmol, 52%) as a yellow solid: mp 84−85 °C (hexane/CH2Cl2);
(1S,3R)-3-Phenethyl-1-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-
b]benzofuran (16dc). The representative procedure was followed by
using compound 13d (40.1 mg, 0.10 mmol). Purification by column
chromatography (hexane/AcOEt, 9:1) yielded 16dc (19.2 mg, 0.054
20
[α]D −40.2 (c = 0.11, CH2Cl2); Rf 0.37 (hexane/EtOAc, 1:2); IR ν
(film) 3395, 3060, 2953, 2922, 1455, 1316, 1239, 737, 699 cm−1; δH
7.88 (s, 1H), 7.44−7.23 (m, 6H), 7.03 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H),
6.81 (td, J = 7.5, 1.0 Hz, 1H), 6.62 (d, J = 7.9 Hz, 1H), 5.19 (s, 1H),
3.34−3.16 (m, 1H), 2.81−2.57 (m, 2H), 1.91−1.75 (m, 1H), 1.72 (s,
1H), 1.63−1.38 (m, 2H), 0.97 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.5 Hz,
3H); δC 143.4, 135.8, 134.1 (C), 128.6, 128.5, 127.5 (CH), 125.7 (C),
120.9, 119.2, 119.1 (CH), 112.2 (C), 110.4, 59.4, 52.5 (CH), 45.9,
31.0 (CH2), 24.6 (CH), 22.9, 22.7 (CH3); LRMS (EI) m/z 304 (M+,
10%), 220 (18), 219 (95), 218 (100), 217 (23); HRMS (ESI)
Calculated for C21H24N2 (M+) 304.1939, found 304.1932.
20
mmol, 55%) as a white solid: mp 69−70 °C (hexane/CH2Cl2); [α]D
−26.2 (c = 1.69, CH2Cl2); Rf 0.33 (hexane/EtOAc, 9:1); IR ν (film)
3050, 3020, 2922, 2853, 1494, 1450, 1174, 1030, 819, 742, 698 cm−1;
δH 7.45−7.16 (m, 12H, NH), 7.20−7.07 (m, 1H), 6.94 (td, J = 7.6, 1.0
Hz, 1H), 6.59 (dt, J = 7.7, 1.0 Hz, 1H), 5.14−5.03 (m, 1H), 3.27−3.11
(m, 1H), 2.90 (ddd, J = 16.2, 4.0, 2.2 Hz, 1H), 2.84.2.65 (m, 3H),
2.08−1.87 (m, 2H); δC 154.5, 153.6, 141.5 (C), 128.6, 128.5, 128.4,
128.3, 128.0 (CH), 126.5 (C), 126.0, 123.0, 122.2, 119.6, 110.9, 58.3,
54.1 (CH), 32.3, 31.0, 29.7 (CH2); LRMS (EI) m/z 353 (M+, 8%),
349 (16), 348 (15), 221 (18), 220 (100), 219 (46); HRMS (ESI)
Calculated for C25H23NO (M+) 353.1780, found 353.1776.
(1S,3R)-3-Phenethyl-1-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-
b]indole (21dc). The representative procedure was followed by using
compound 19d (36.8 mg, 0.10 mmol). Purification by column
chromatography (hexane/AcOEt, 2:1) yielded 21dc (16.4 mg, 0.047
mmol, 47%) as a yellow solid: mp 80−82 °C (hexane/CH2Cl2);
(1S,3R)-3-Benzyl-1-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]-
benzofuran (16ec). The representative procedure was followed by
using compound 13e (35.5 mg, 0.10 mmol). Purification by column
chromatography (hexane/AcOEt, 9:1) yielded 16ec (16.2 mg, 0.05
mmol, 50%) as a white solid: mp 118−120 °C (hexane/CH2Cl2);
20
[α]D −45.1 (c = 0.30, CH2Cl2); Rf 0.42 (hexane/EtOAc, 1:2); IR ν
(film) 3193, 3025, 2927, 2838, 1494, 1453, 1317, 1238, 1028, 858,
839, 739, 698 cm−1; δH 7.87 (m, 1H), 7.41−7.15 (m, 11H), 7.04 (ddd,
J = 8.2, 7.1, 1.2 Hz, 1H), 6.81 (ddd, J = 8.1, 7.1, 1.0 Hz, 1H), 6.62 (dd,
J = 7.9, 1.0 Hz, 1H), 5.19−5.13 (m, 1H), 3.24−3.11 (m, 1H), 2.85−
2.75 (m, 3H), 2.71 (ddd, J = 15.5, 10.3, 2.6 Hz, 1H), 2.03−1.89 (m,
2H); δC 143.3, 141.8, 135.7, 133.9 (C), 128.6, 128.5, 128.4, 128.3,
127.6, 125.9 (CH), 125.7 (C), 121.0, 119.2, 119.1 (CH), 112.2 (C),
110.4, 59.2, 54.1 (CH), 38.2, 32.4, 30.7 (CH2); LRMS (EI) m/z 352
(M+, 11%), 220 (20), 219 (100), 218 (86), 217 (21); HRMS (ESI)
Calculated for C25H24N2 (M+) 352.1939, found 352.1943.
20
[α]D + 6.6 (c = 1.28, CH2Cl2); Rf 0.32 (hexane/EtOAc, 9:1); IR ν
(film) 3055, 3025, 2918, 2878, 2848, 1638, 1449, 1302, 1178, 1011,
835, 747, 700, 615 cm−1; δH 7.41−7.21 (m, 12H), 7.16−7.07 (m, 1H),
6.98−6.88 (m, 1H), 6.57 (d, J = 7.7 Hz, 1H), 5.07 (br s, 1H), 3.53−
3.40 (m, 1H), 3.03−2.85 (m, 2H), 2.83−2.70 (m, 2H); δC 154.6,
153.3, 138.1 (C), 129.2, 128.6, 128.5, 128.1, 126.6 (CH), 126.5 (C),
123.0, 122.2, 119.5, 110.9, 58.4, 56.0 (CH), 42.5, 31.0 (CH2); LRMS
(EI) m/z 339 (M+, 1%), 334 (22), 249 (19), 248 (100), 246 (11), 221
(11), 220 (41), 191 (11), 91 (13); HRMS (ESI) Calculated for
C18H16NO (M+−C6H5) 262.1232, found 262.1230.
(1S,3R)-1,3-Diisobutyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole
(21bb). The representative procedure was followed by using
compound 19b (32.0 mg, 0.10 mmol). Purification by column
chromatography (hexane/AcOEt, 1:1) yielded 21bb (12.9 mg, 0.045
mmol, 45%) as a yellow solid: mp 88−90 °C (hexane/CH2Cl2);
[α]D20 −129.4 (c = 0.18, CH2Cl2); Rf 0.28 (hexane/EtOAc, 1:2); IR ν
(film) 3400, 2952, 2927, 2868, 1461, 1366, 1316, 1126, 1018, 736
cm−1; δH 7.77 (s, 1H), 7.58−7.53 (m, 1H), 7.31−7.27 (m, 1H), 7.14−
7.03 (m, 2H), 4.27 (dd, J = 10.5, 2.4 Hz, 1H), 3.08−2.94 (m, 1H),
2.67 (ddd, J = 15.3, 3.7, 1.8 Hz, 1H), 2.56−2.42 (m, 1H), 2.22−2.11
(m, 1H), 2.01−1.91 (m, 1H), 1.87−1.77 (m, 1H), 1.60−1.39 (m, 3H),
1.09 (d, J = 6.5 Hz, 3H), 0.99 (d, J = 6.5 Hz, 3H), 0.96 (d, J = 6.6 Hz,
6H); δC 135.9, 133.2, 125.6 (C), 120.8, 119.1, 119.1 (CH), 113.3 (C),
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b01047.
1
Copies of H, 13C NMR and DEPT spectra for all the
reported compounds and NOESY spectra for com-
pounds 16fb, 16dc, 16ec, 21bb, 21db, 21bc and 21dc.
(PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: foubelo@ua.es.
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L
DOI: 10.1021/acs.joc.6b01047
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(17) See, for instance: (a) Gonzal
́
ez-Gom
́
ez, J. C.; Foubelo, F.; Yus,
*E-mail: yus@ua.es.
M. Synlett 2008, 2008, 2777. (b) Medjahdi, M.; Gonzal
C.; Foubelo, F.; Yus, M. Eur. J. Org. Chem. 2011, 2011, 2230.
(18) See, for instance: (a) Medjahdi, M.; Gonzalez-Gomez, J. C.;
Foubelo, F.; Yus, M. J. Org. Chem. 2009, 74, 7859. (b) Sirvent, A.;
Foubelo, F.; Yus, M. J. Org. Chem. 2014, 79, 1356.
(19) Nishihara, Y.; Inoue, E.; Ogawa, D.; Okada, Y.; Noyori, S.;
Takagi, K. Tetrahedron Lett. 2009, 50, 4643.
(20) Kabalka, G. W.; Wang, L.; Pagni, R. M. Tetrahedron 2001, 57,
8017.
(21) For other accounts of this palladium-catalyzed transformation
leading to benzofurans, see: (a) Wang, R.; Mo, S.; Lu, Y.; Shen, Z. Adv.
Synth. Catal. 2011, 353, 713. (b) Zhou, R.; Wang, W.; Jiang, Z.-J.;
Wang, K.; Zheng, X.-L.; Fu, H.-Y.; Chen, H.; Li, R.-X. Chem. Commun.
2014, 50, 6023.
(22) An attempt to synthesize indole derivative 19e under palladium
catalysis starting from N-trifluoroacetyl protected ortho-iodoaniline
and alkyne 10e following a known procedure failed: Barik, S. K.;
Rakshit, M.; Kar, G. K.; Chakrabarty, M. ARKIVOC 2014, No. v, 1.
(23) For recent examples of cycloisomerization of 2-alkynylanilines
to indoles, see: (a) Perea-Buceta, J. E.; Wirtanen, T.; Laukkanen, O.-
́ ́
ez-Gomez, J.
Notes
The authors declare no competing financial interest.
́
́
ACKNOWLEDGMENTS
■
We thank the continued financial support from our Ministerio
de Ciencia e Innovacion (MCINN; projects CTQ2010-20387,
́
CONSOLIDER INGENIO 2010-CDS2007-00006, CTQ2011-
́
24165), the Ministerio de Economia y Competitividad
(MINECO; projects CTQ2014-53695-P, CTQ2014-51912-
REDC), FEDER, the Generalitat Valenciana (PROMETEO
2009/039, PROMETEOII/2014/017) and the University of
Alicante.
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DOI: 10.1021/acs.joc.6b01047
J. Org. Chem. XXXX, XXX, XXX−XXX