Synthesis of multiply substituted 1,6-dihydropyridines through Cu(I)-catalyzed 6-endo cyclization

Article abstract of DOI:10.1039/c5ob00356c

Copper-catalyzed 6-endo cyclization of N-propargylic β-enaminocarbonyls was developed for the synthesis of oxidation-labile 1,6-dihydropyridines. This synthetic method allows flexible and regio-defined assembly of various substituents at the N1, C2, C3, C4, and C6 positions of 1,6-dihydropyridines under mild conditions.

Full text of DOI:10.1039/c5ob00356c

Organic &
Biomolecular Chemistry
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Synthesis of multiply substituted 1,6-
dihydropyridines through Cu(I)-catalyzed
6-endo cyclization†
Cite this: Org. Biomol. Chem., 2015,
13, 5955
Haruki Mizoguchi,a Ryo Watanabe,a Shintaro Minami,a Hideaki Oikawaa and
Hiroki Oguri*a,b
Received 21st February 2015,
Accepted 20th April 2015
Copper-catalyzed 6-endo cyclization of N-propargylic β-enaminocarbonyls was developed for the syn-
thesis of oxidation-labile 1,6-dihydropyridines. This synthetic method allows flexible and regio-defined
assembly of various substituents at the N1, C2, C3, C4, and C6 positions of 1,6-dihydropyridines under
mild conditions.
DOI: 10.1039/c5ob00356c
www.rsc.org/obc
Introduction
Dihydropyridines (DHPs) exhibit intriguing biological func-
tions, examples of which include the redox coenzymes NAD(P)
H and calcium channel blockers for the treatment of cardio-
vascular disease.1 From a synthetic point of view, DHPs have
significant potential as a versatile platform for the construc-
tion of densely functionalized piperidines and pyridines, the
most ubiquitous frameworks of natural products and medic-
inal drugs.2 In the biosynthesis of terpene indole alkaloids,
1,6-DHP could be exploited as a pluripotent intermediate for
divergent synthesis of natural products (Scheme 1a).3 Synthetic
methodologies for 1,6-DHPs (or 1,2-DHPs), however, remain
far more limited4,5 than those for the widely studied 1,4-DHP,
readily prepared via Hantzsch synthesis.1,6 The synthesis of
1,6-DHPs mainly relies on the nucleophilic addition onto pyri-
dinium salts, which often results in the formation of insepar-
able regio-isomeric mixtures of adducts at the C2, C4, or C6
positions (Scheme 1b). In recent years, different approaches to
the generation of oxidation-labile 1,6-DHPs (or 1,2-DHP) via
6π-electrocyclization of 1-azatrienes have emerged.7 For
example, Ellman and co-workers reported Rh(I)-catalyzed C–H
activation–alkyne coupling followed by electrocyclization.8,9
To develop an alternative method for access to sensitive 1,6-
DHPs with flexible and regio-controlled installation of substi-
tuents on the N1, C2, C3, C4, and C6 positions, we conceived
Cu(I)-catalyzed 6-endo cyclization of propargylic enaminocarbo-
aDivision of Chemistry, Graduate School of Science, Hokkaido University, N10 W8,
Sapporo 060-0810, Japan. E-mail: oguri@sci.hokudai.ac.jp
bJST, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan
†Electronic supplementary information (ESI) available: Experimental procedures
and spectral data including scanned images of 1H and 13C NMR spectra. See
DOI: 10.1039/c5ob00356c
Scheme 1
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nyls (1 → 2) (Scheme 1c). In a recent investigation, we found dentate phosphine necessitated gentle heating (45 °C) to
that N-alkylated 1,6-DHPs, with installation of an electron-with- produce 1,6-DHP 2a in moderate yield (entry 1), the use of
drawing carbonyl group at C3, showed stability to handling in bidentate phosphine ligands with wide bite angles allowed the
the laboratory as a solution and also allowed the biomimetic formation of 2a at room temperature with substantial improve-
synthesis of skeletally diverse alkaloids.10 Herein, we report the ment of the product yield (entries 2–4). Dichloromethane and
development of a potentially general synthetic protocol for 1,2-dichloroethane were found to be the optimal solvents. As
regio-defined synthesis of multiply substituted 1,6-DHPs shown in entry 4, treatment of 1a with 10 mol% [Cu(Xantphos)
16
through Cu(I)-catalyzed cyclization under mild conditions.
(CH3CN)]PF6
in dichloromethane at room temperature
afforded the desired 1,6-DHP 2a in 98% yield (calculated yield
1
based on H-NMR) as a labile compound that was not amen-
able to chromatographic isolation. Reducing the amount of
the catalyst to 5 mol% (entry 5) turned out to be acceptable for
the almost quantitative conversion. The attempt with 3 mol%
of the catalyst (entry 6) resulted in a longer reaction time
(24 h), giving a lower yield (54%). The reaction employing a
catalyst generated in situ by mixing CuCl and Xantphos
resulted in almost no conversion, which supported the impor-
tance of cationic cuprous species.
Having optimized the conditions, we next synthesized cycli-
zation precursors with various substitution patterns (R1–R5) as
shown in Scheme 2. The conjugate addition of benzyl amine 3
to methyl acrylate followed by N-propargylation gave tertiary
amine 4 as a common intermediate. Treatment of 4 with
methyl propiolate in the presence of 2,2,2-trifluoroethanol
effected Hoffman elimination to afford the enyne 1a in 90%
yield. This protocol could be efficiently applicable for installa-
tion of aryl sulfone and phenyl ketone groups at R3 of the pre-
Results and discussion
Exploration of the proposed 6-endo cyclization began with the
exposure of substrate 1a, bearing alkyne and enamine groups,
to copper complexes. Whilst a variety of transition metals,
such as gold,11 platinum,12 rhodium,13 and silver,14 have been
reported to promote chemo-selective activation of alkyne
groups, we focused on copper salts due to their broad toler-
ance to polar functional groups, as well as abundance. Cacchi
and Fabrizi reported CuBr-catalyzed cyclization of N-pro-
pargylic β-enaminones bearing
a tri-substituted Z-double
bond, which requires heating (60–80 °C) in DMSO and entails
oxidation of transiently generated DHPs to form pyridines.15
Despite the differences between the substrates, a more reactive
activator which was more tolerant of functional groups would
be required to obtain sensitive 1,6-DHPs (2) by suppressing
oxidation and undesired side reactions. We thus employed a
cationic cuprous catalyst and screened a series of phosphine
ligands (Table 1). While a copper complex composed of mono-
cursors (1c and 1d). N-Propargylation of
3 followed by
condensation of the resulting secondary amine 6 with 1,3-
Table 1 Optimization of Cu-catalyzed formation of 1,6-DHP (2a)
Entry
Ligand
Cu catalyst
Yielda
b
1
2
3
4
5
6
PPh3
10 mol%
10 mol%
10 mol%
10 mol%
5 mol%
42%
72%
95%
98%
98%
54%
BINAP
dppf
Xantphos
Xantphos
Xantphos
3 mol%
a Calculated yield based on 1H-NMR analysis with an internal
standard. b [Cu(CH3CN)4]PF6 (10 mol%), PPh3 (22 mol%), 45 °C.
Scheme 2 Reagents and conditions: (a) CH2vCHCO2Me, MeOH,
65 °C, 83%, (b) propargyl bromide, K2CO3, Et3N, CH3CN, 85 °C, 4 (75%),
(c) methyl propiolate, CF3CH2OH, ClCH2CH2Cl, 1a (90%), (d) ethynyl
p-tolylsulfone, CF3CH2OH, ClCH2CH2Cl, 1c (80%), (e) 5, CF3CH2OH,
ClCH2CH2Cl, 45 °C, 1d (92%), (f) propargyl bromide, toluene, 6 (89%), (g)
1,3-cyclohexanedione, p-TsOH, benzene, reflux, 1f (46%), (h) Pd(PPh3)4
(2 mol%), PhI, CuI, Et3N, CH3CN, 60 °C, (i) methyl propiolate, CF3CH2OH,
ClCH2CH2Cl, 1g (99% for 2 steps).
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cyclohexanedione produced 1f bearing substituents R2 and R3
The scope of 6-endo cyclization was then investigated with
in a moderate yield. Manipulation of the terminal alkyne of 4 the series of precursors, generating multiply substituted 1,6-
allowed installation of R4 and subsequent treatment with DHPs (Table 2). A range of electron-withdrawing groups at R3
methyl propiolate produced 1g in good yields.
were well tolerated, producing 1,6-DHPs containing acyl oxazo-
lidinone (2b), aryl sulfone (2c) at the C3 position in good to
excellent yields. Although cyclization of a substrate 1d bearing
a ketone conjugated to an enamine moiety required heating
(65 °C) for completion, 1,6-DHP 2d was formed in 93% yield.
The installation of methyl substituents for R2 was well tole-
rated, furnishing 2e at room temperature in good yield (80%).
A substrate composed of a cyclic enaminocarbonyl group was
also applicable to cyclization at 65 °C to give 2f in 94% yield.
Furthermore, both an internal phenyl alkyne and a diyne were
good substrates for cyclization, leading to 2g and 2h in greater
than 75% yield. Incorporation of geminal dimethyl substitu-
ents as R5 retarded cyclization, resulting in a requirement for
heating to 65 °C in 1,2-dichloroethane. Nonetheless, the
desired 2i, bearing a quaternary center, was formed in almost
quantitative yield. As expected, 2i without hydrogen at the C6
position was sufficiently stable for chromatographic purifi-
cation through silica gel, and thereby, it was isolated in 86%
yield. Furthermore, cyclization of a substrate 1j bearing substi-
tuents at the C2 and C4 positions also proceeded to give 2j in
good yield. As described above, its tolerance of different substi-
tuents at R1–R5 underscored the generality and potential of Cu
(I)-catalyzed cyclization for the construction of multiply substi-
tuted 1,6-DHPs.
Table 2 Substrate scope for Cu-catalyzed formation of 1,6-DHPs
N-Propargylenamine
1,6-DHP
Yielda
2b, 84%
2c, 99%
2d, 93%b
2e, 80%
2f, 94%b
2g, 82%
2h, 75%
On the basis of these results, we postulated a plausible
mechanism, which is shown in Scheme 3a. The reaction is
thought to be initiated by coordination and activation of the
2i, 99%b
(86%)c
2j, 89%
a Calculated yield based on 1H-NMR analysis with an internal
standard. b 65 °C in 1,2-dichloroethane. c Yield of the isolated product.
Scheme 3 (a) Proposed mechanism; (b) conversion with a deuterium-
labeled substrate.
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alkyne group with copper(I) to form the electrophilic Materials
π-complex A. The subsequent nucleophilic attack of the
Commercial solvents and reagents were used as received with
the following exceptions. The cationic Cu(I) complex,
[Cu(BINAP)(MeCN)]PF6, [Cu(dppf)(MeCN)]PF6, were prepared
with a modified protocol reported by Kim and co-workers18
and purified by precipitation from CH2Cl2/Et2O = 1/1 solution.
[Cu(Xantphos)(MeCN)]PF6,16 and (S)-4-benzyl-3-propioloyloxazo-
lidin-2-one19 were prepared by applying the reported protocols.
pendant enamine effects 6-endo cyclization. The resulting
ionic intermediate B undergoes a deprotonation and protode-
metallation sequence (B to C) to produce 1,6-DHP (2a) with
regeneration of the catalyst. To substantiate this hypothesis,
we then conducted cyclization of a deuterium-labeled sub-
strate, 1j–D (Scheme 3b). Actually, translocation of deuterium
from the β-position of enamine to the C5 position of 1,6-DHP
occurred. Whilst the substantial decrease (approximately
20–30%) of deuteration at the C5 position was reproducibly
observed,17 this result is consistent with the proposed mechan-
ism on the whole.
Synthesis of N-propargylenamines
Methyl
3-(benzyl(prop-2-yn-1-yl)amino)propanoate,
a
common intermediate for the synthesis of N-propargylen-
amines. A solution of benzyl amine (3) (1.83 ml, 16.8 mmol)
and methyl acrylate (1.66 ml, 18.5 mmol) in MeOH (5.0 ml)
was stirred at 65 °C for 10 min under microwave irradiation.
After the concentration of the mixture in vacuo, the residue
Conclusion
In summary, we have developed a copper(I)-catalyzed cycliza- was purified by silica-gel chromatography to afford methyl 3-
tion to form multiply substituted 1,6-dihydropyridines under (benzylamino)propanoate (2.68 g, 13.9 mmol, 83%). A solution
mild conditions. Substrates composed of alkyne and enamine of methyl 3-(benzylamino)propanoate (6.43 g, 33.3 mmol), pro-
were cyclized in a 6-endo manner with the chemoselective acti- pargyl bromide (3.16 ml, 36.6 mmol), K2CO3 (9.20 g,
vation of terminal and internal alkynes to furnish 1,6-DHP, 66.6 mmol), and Et3N (4.64 ml, 33.3 mmol) in acetonitrile
with a broad tolerance of substitution at the N1, C2, C3, C4, (133 ml) was stirred at 70 °C for 16 h. The resulting mixture
and C6 positions. We are currently exploring further synthetic was then treated with another portion of propargyl bromide
manipulation for the regio- and stereo-controlled synthesis of (1.44 ml, 16.7 mmol). After being stirred at 85 °C for 6 h, the
densely functionalized tetrahydropyridines and piperidines, mixture was concentrated in vacuo and then added with EtOAc
exploiting the versatile reactivity of 1,6-DHPs conjugated with and H2O. The organic phase was washed with water, brine and
a carbonyl group at the C3 position.
then dried over Na2SO4. After concentration, the residue was puri-
fied by silica-gel chromatography to afford methyl 3-(benzyl(prop-
2-yn-1-yl)amino)propanoate (4) (5.78 g, 25.0 mmol, 75%) as a
common intermediate for the synthesis of N-propargylen-
amines; H-NMR (500 MHz, CDCl3): δ 7.37–7.20 (5H, m), 3.68
(3H, s), 3.65 (2H, s), 3.32 (2H, d, J = 2.2 Hz), 2.91 (2H, t, J = 6.9
Experimental
General methods
1
All reactions were performed under a nitrogen atmosphere Hz), 2.53 (2H, t, J = 6.9 Hz), 2.24 (1H, t, J = 2.2 Hz); 13C-NMR
unless otherwise specified. Microwave reactions were per- (125 MHz, CDCl3): δ 172.92, 138.55, 129.14, 128.43, 127.35,
formed using a Biotage Initiator. NMR spectra were recorded 78.32, 73.47, 57.79, 51.74, 49.15, 41.44, 33.27; HRMS (ESI,
on a JEOL JNM-ECP 300 (1H/300 MHz, 13C/75 MHz) spectro- m/z): [M + H]+ calcd for C14H18NO2 232.1332; found 232.1330.
meter, a JEOL JNM-ECX 400 (1H/400 MHz, 13C/100 MHz)
spectrometer,
JEOL JNM-ECX 600 (1H/600 MHz, 13C/ solution of 3-(benzyl(prop-2-yn-1-yl)amino)propanoate (4)
(E)-Methyl 3-(benzyl(prop-2-yn-1-yl)amino)acrylate (1a). A
a
150 MHz) spectrometer and a Bruker VSP 500 (1H/500 MHz, (1.08 g, 4.67 mmol) and methyl propiolate (0.91 ml,
13C/125 MHz) spectrometer. Chemical shifts are reported in 10.2 mmol) in 1,2-dichloroethane/2,2,2-trifluoroethanol = 1/1
δ (ppm) using chloroform, acetonitrile as an internal standard (24 ml) was stirred at r.t. for 14 h. The mixture was treated
of δ 7.26, 1.94, and 77.16, 118.26 for 1H and 13C-NMR, respect- with saturated aqueous solution of NaHCO3 and extracted with
1
ively. Data for H-NMR are reported as follows: chemical shift EtOAc. The combined organic extracts were washed with brine
(number of hydrogens, multiplicity, coupling constant). Multi- and dried over Na2SO4. The residue was concentrated in vacuo
plicity is abbreviated as follows: s (singlet), d (doublet), and purified by silica-gel chromatography to afford 1a
t (triplet), q (quartet), quin (quintet), m (multiplet), br (broad). (962 mg, 4.20 mmol, 90%). 1a: TLC Rf = 0.35 (Hex : AcOEt =
1
ESI-Mass spectra were recorded on a JEOL AccuTOF LC-Plus 4 : 1); H NMR (500 MHz, CDCl3): δ 7.60 (1H, d, J = 13.1 Hz),
JMS-T100. The medium pressure liquid chromatography 7.38–7.27 (3H, m), 7.24 (2H, d, J = 6.9 Hz), 4.83 (1H, d, J = 13.1
(MPLC) purifications were performed on
a YAMAZEN Hz), 4.41 (2H, s), 3.81 (2H, d, J = 2.2 Hz), 3.68 (3H, s), 2.30 (1H,
YFLC-AI-580. Where necessary, solvents were distilled from t, J = 2.2 Hz); 13C-NMR (125 MHz, CDCl3): 169.83, 151.42,
appropriate drying agents prior to use. Reactions were moni- 135.70, 128.98, 128.16, 127.81, 87.43, 73.67, 50.87; HR-MS
tored by thin layer chromatography using Merck Millipore TLC (ESI, m/z): [M + H]+ calcd For C14H16NO2 230.1176; found
silica gel F254 plates (0.25 mm) which were visualized using UV 230.1216.
light, p-anisaldehyde stain and PMS stain. Flash column
chromatography was performed using Kanto Silica Gel 60N.
(E)-4-Benzyl-3-(3-((4-methoxybenzyl)(prop-2-yn-1-yl)amino)-
acryloyl)oxazolidin-2-one (1b). A solution of N-(4-methoxyben-
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zyl)prop-2-yn-1-amine20 (858 mg, 4.90 mmol) and (S)-4-benzyl- using a Dean–Stark apparatus. After cooling down to room
3-propioloyloxazolidin-2-one (1.12 g, 4.90 mmol) in CH2Cl2 temperature, the mixture was washed with aqueous 1 M solu-
(16 ml) was stirred at r.t. for 1.5 h. The residue was concen- tion of NaOH, water and brine, dried over Na2SO4. After fil-
trated in vacuo and purified by silica-gel chromatography to tration, the residue was concentrated in vacuo and purified by
afford 1b (1.91 g, 4.72 mmol, 96%). 1b: 1H-NMR (500 MHz, silica-gel chromatography to afford 1e (318 mg, 1.31 mmol,
CDCl3): δ 7.89 (1H, d, J = 12.6 Hz), 7.33 (2H, t, J = 7.3 Hz), 40%). 1e: TLC Rf = 0.60 (Hex : AcOEt = 1 : 1); 1H-NMR
7.29–7.18 (5H, m), 6.89 (2H, m), 6.40 (1H, br-d, J = 12.6 Hz), (500 MHz, CDCl3): δ 7.34 (2H, t, J = 7.3 H), 7.28 (1H, t, J = 7.3
4.75 (1H, m), 4.45 (2H, s), 4.14 (1H, dd, J = 16.4, 8.8 Hz), 4.11 Hz), 7.18 (2H, d, J = 7.3 Hz), 4.92 (1H, s), 4.53 (2H, s), 3.93 (2H,
(1H, dd, J = 8.8, 3.2 Hz), 3.89 (2H, br-s), 3.81 (3H, s), 3.37 (1H, d, J = 2.2 Hz), 3.63 (3H, s), 2.56 (3H, s), 2.28 (1H, t, J = 2.2 Hz);
dd, J = 13.2, 3.2 Hz), 2.78 (1H, dd, J = 13.2, 9.8 Hz), 2.35 (1H, 13C-NMR (125 MHz, CDCl3): 169.41, 160.38, 136.70, 128.93,
br-s); 13C-NMR (125 MHz, CDCl3): δ 166.61, 159.74, 154.17, 127.67, 126.82, 87.46, 78.24, 73.04, 53.05, 50.38, 39.35, 15.60;
153.13, 136.20, 129.68, 129.62, 128.98, 127.22, 114.43, 87.62, HR-MS (ESI, m/z): [M + H]+ calcd for C15H18NO2 244.1332,
65.86, 55.58, 55.45, 38.61; HRMS (ESI, m/z): [M + Na]+ calcd for found 244.1357.
C24H24N2O4Na, 427.1628; found, 427.1641.
(E)-N-Benzyl-N-(2-tosylvinyl)prop-2-yn-1-amine (1c). A solu- a solution of N-benzylprop-2-yn-1-amine (145 mg, 1.00 mmol)
tion of 3-(benzyl(prop-2-yn-1-yl)amino)propanoate (4) in benzene (10 ml) were added 1,3-cyclohexanedione (178 mg,
3-(Benzyl(prop-2-yn-1-yl)amino)cyclohex-2-en-1-one (1f). To
(62.4 mg, 0.270 mmol) and ethynyl p-tolylsulfone (58.6 mg, 1.60 mmol) and p-toluenesulfonic acid monohydrate (11.4 mg,
0.330 mmol) in 1,2-dichloroethane/2,2,2-trifluoroethanol = 1/1 0.06 mmol) and heated under reflux for 12 h using a Dean–
(540 μl) was stirred at r.t. for 12 h. The mixture was treated Stark apparatus. After cooling down to room temperature, the
with saturated aqueous solution of NaHCO3 at 0 °C and mixture was washed with aqueous 1 M solution of NaOH and
extracted with EtOAc. The combined organic extracts were brine, and dried over Na2SO4. The residue was concentrated
washed with saturated aqueous solution of NaHCO3, brine and in vacuo and purified by silica-gel chromatography to afford 1f
dried over Na2SO4. The residue was concentrated and purified (109 mg, 0.455 mmol, 46%). 1f: TLC Rf = 0.20 (Hex : AcOEt =
by silica-gel chromatography to afford 1c (70.1 mg, 1 : 5); 1H-NMR (500 MHz, CDCl3): δ 7.38–7.33 (2H, m),
0.215 mmol, 80%). 1c: TLC Rf = 0.61 (Hex : AcOEt = 1 : 1); 1H 7.32–7.27 (1H, m), 7.18 (2H, d, J = 7.9 Hz), 5.41 (1H, s), 4.56
NMR (500 MHz, CDCl3): δ 7.74 (2H, d, J = 8.2 Hz), 7.50 (1H, d, (2H, s), 3.97 (2H, d, J = 2.2 Hz), 2.55 (2H, t, J = 6.3 Hz),
J = 12.9 Hz), 7.37–7.29 (3H, m), 7.27 (2H, d, J = 8.2 Hz), 2.39–2.30 (2H, m), 2.31 (1H, s), 2.05–1.99 (2H, m); 13C NMR
7.23–7.19 (2H, m), 5.20 (1H, d, J = 12.9 Hz), 4.39 (2H, s), 3.77 (125 MHz, CDCl3): 197.62, 164.56, 136.15, 129.10, 127.95,
(2H, s), 2.41 (2H, s), 2.30 (1H, s); 13C NMR (125 MHz, CDCl3): 126.77, 101.21, 77.78, 73.60, 53.31, 39.53, 35.88, 27.10, 22.37;
149.19, 142.64, 141.68, 135.00, 129.61, 129.07, 128.37, 127.84, HRMS (ESI, m/z): calcd for C16H18NO [M + H]+ 240.1383, found
126.51, 96.64, 76.72, 74.32, 21.61; HRMS (ESI, m/z): [M + Na]+ 240.1388.
calcd for C19H19NO2SNa 348.1028, found 348.1044.
(E)-3-(Benzyl(prop-2-yn-1-yl)amino)-1-phenylprop-2-en-1-one
Methyl (E)-3-(benzyl(3-phenylprop-2-yn-1-yl)amino)acrylate
(1g). A mixture of 3-(benzyl(prop-2-yn-1-yl)amino)propanoate
(1d). A mixture of 3-(benzyl(prop-2-yn-1-yl)amino)propanoate (4) (762 mg, 3.29 mmol), Pd(PPh3)4 (87.7 mg, 0.076 mmol),
(4) (1.77 g, 7.65 mmol) and 1-phenyl-3-(trimethylsilyl)prop- CuI (43.4 mg, 0.228 mmol), Et3N (0.530 ml, 3.80 mmol) and
2-yn-1-one 5 (2.32 g, 11.5 mmol) in 1,2-dichloroethane/2,2,2- PhI (0.282 ml, 2.53 mmol) in MeCN (16.5 ml) was heated at
trifluoroethanol = 1/1 (26 ml) was stirred at 45 °C for 10 h 60 °C for 3 h. After concentration in vacuo, the residue was pur-
40 min. After concentration in vacuo, the residue was purified ified by silica-gel chromatography to afford methyl 3-(benzyl(3-
by silica-gel chromatography to afford 1d (1.93 g, 7.01 mmol, phenylprop-2-yn-1-yl)amino)propanoate (867 mg). To a solu-
92%). 1d: 1H-NMR (500 MHz, CDCl3): δ 7.95 (1H, d, J = 12.6 tion of 3-(benzyl(3-phenylprop-2-yn-1-yl)amino)propanoate
Hz), 7.89 (2H, d, J = 7.3 Hz), 7.49–7.45 (1H, m), 7.44–7.34 (4H, (867 mg) in 1,2-dichloroethane/2,2,2-trifluoroethanol = 1/1
m), 7.35–7.31 (1H, m), 7.30–7.26 (2H, m), 6.02 (1H, d, J = 12.6 (14.7 ml) was added methyl propiolate (0.277 ml, 3.10 mmol)
Hz), 4.54 (2H, s), 3.93 (2H, br-s), 2.36 (1H, s); 13C-NMR and stirred at r.t. for 12 h. The mixture was quenched with the
(125 MHz, CDCl3): δ 189.28, 152.59, 140.13, 135.24, 131.34, saturated aqueous solution of NaHCO3 and extracted with
129.01, 128.27, 127.83, 127.71, 94.55, 76.99, 74.08; HRMS (ESI, EtOAc. The combined organic extracts were washed with brine
m/z): [M + H]+ calcd for C19H18NO, 276.1383; found, 276.1385.
Methyl (E)-3-(benzyl(prop-2-yn-1-yl)amino)but-2-enoate was purified by silica-gel chromatography to afford 1g (775 mg,
and dried over Na2SO4. After concentration in vacuo, the residue
(1e). To a solution of benzyl amine (3) (4.26 ml, 39.0 mmol) in 2.54 mmol, quant. for 2 steps). 1g: TLC Rf = 0.35 (Hex : AcOEt =
toluene (6.3 ml) was added propargyl bromide (0.560 ml, 4 : 1); 1H-NMR (500 MHz, CDCl3): δ 7.68 (1H, d, J = 13.2 Hz),
6.50 mmol) and stirred at r.t. for 14 h. After concentration 7.43–7.26 (10H, m), 4.88 (1H, d, J = 13.2 Hz), 4.47 (2H, s), 4.05
in vacuo, the residue was purified by silica-gel chromatography (2H, br-s), 3.69 (3H, s); 13C-NMR (75 MHz, CDCl3): 169.85,
to afford N-benzylprop-2-yn-1-amine (6) (839 mg, 5.78 mmol, 151.49, 135.85, 131.79, 128.85, 128.62, 128.36, 127.97, 127.69,
89%). To a solution of N-benzylprop-2-yn-1-amine (475 mg, 122.33, 86.99, 85.45, 82.72, 55.68, 50.73, 40.81; HRMS (ESI, m/z):
3.27 mmol) and methyl acetoacetate (0.705 ml, 6.54 mmol) in calcd for C20H20NO2 [M + H]+ 306.1489, found 306.1489.
benzene (8.8 ml) was added p-toluenesulfonic acid mono-
Dimethyl 3,3′-(hexa-2,4-diyne-1,6-diylbis(benzylazanediyl))
hydrate (37.3 mg, 0.196 mmol) and stirred at 95 °C for 12 h (2E,2′E)-diacrylate (1h). To a solution of 3-(benzyl(prop-2-yn-1-
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yl)amino)propanoate (4) (565 mg, 2.44 mmol) in acetone based on the value of the integral for a signal of 4-nitrobenzo-
(2.0 ml) was added a solution of preliminarily mixed CuCl nitrile and that of the desired product.
(21.4 mg, 0.216 mmol) and N,N,N′,N′-tetramethyl-
Methyl 1-benzyl-4-phenyl-1,6-dihydropyridine-3-carboxylate
ethylenediamine (11 μl, 0.072 mmol) in acetone (2.0 ml) and (2a). A solution of N-propargylenamine 1a (251 mg,
stirred at r.t. for 12 h under an O2 atmosphere. After concen- 1.09 mmol) and [Cu(Xantphos)(MeCN)]PF6 (90.6 mg,
tration in vacuo, the residue was purified by silica-gel column 0.109 mmol) in CH2Cl2 (11 ml) was stirred at r.t. for 40 min.
chromatography to afford the corresponding dimer bearing a The reaction mixture was then treated with 1,10-phenanthro-
conjugated diyne linkage (553 mg, 1.20 mmol, 98%). To a solu- line (25.2 mg, 0.140 mmol) to deactivate the copper catalyst.
tion of the dimer (530 mg, 1.15 mmol) in 1,2-dichloroethane/ After concentration in vacuo, 4-nitrobenzonitrile (162 mg,
2,2,2-trifluoroethanol = 1/1 (9.0 ml) was added methyl propio- 1.09 mmol) was added. Due to the instability of 2a to silica-gel
late (383 μl, 4.60 mmol) and stirred at r.t. for 19 h. After con- chromatography, the yield of 2a (98%) was calculated based on
centration in vacuo, the residue was purified by silica-gel 1H-NMR. 2a: TLC Rf = 0.45 (Hex : acetone = 4 : 1); 1H-NMR
chromatography to afford 1h (423 mg, 0.927 mmol, 81%). 1h: (300 MHz, CDCl3): δ 7.43–7.28 (6H, m), 6.30 (1H, m), 4.96 (1H,
1H-NMR (500 MHz, CDCl3): δ 7.56 (2H, d, J = 12.9 Hz), dt, J = 10.1, 3.1 Hz), 4.20 (2H, s), 4.01 (2H, dd, J = 3.1, 1.9 Hz),
7.38–7.28 (6H, m), 7.22 (4H, d, J = 6.9 Hz), 4.83 (2H, d, J = 12.9 3.68 (3H, s); 13C-NMR (75 MHz, CDCl3): 167.00, 147.94, 134.95,
Hz), 4.39 (4H, s), 3.85 (4H, s), 3.68 (6H, s); 13C-NMR (125 MHz, 128.92, 128.20, 127.89, 122.20, 109.85, 96.04, 60.08, 50.63,
CDCl3): δ 169.66, 151.28, 135.45, 129.04, 128.29, 127.87, 87.94, 47.98; HR-MS (ESI): calcd for the corresponding pyridinium
72.81, 69.18, 56.25, 50.90, 40.08; HRMS (ESI, m/z): [M + H]+ salt C14H14NO2[M]+ 228.1019, found 228.1019.
calcd for C28H29N2O4, 457.2122; found, 457.2117.
4-Benzyl-3-(1-(4-methoxybenzyl)-1,6-dihydropyridine-3-carbo-
Methyl
(1i). To
(E)-3-(benzyl(2-methylbut-3-yn-2-yl)amino)acrylate nyl)oxazolidin-2-one (2b). A solution of N-propargylenamine
a solution of amine N-benzyl-2-methylbut-3-yn-2- 1b (63.7 mg, 0.170 mmol) and [Cu(Xantphos)(MeCN)]PF6
amine21 (182 mg, 1.25 mmol) in 1,2-dichloroethane/2,2,2-tri- (14.1 mg, 0.0170 mmol) in CH2Cl2 (1.7 ml) was stirred at r.t.
fluoroethanol = 1/1 (6 ml) was added methyl propiolate for 180 min. The reaction mixture was then treated with 1,10-
(209 μl, 2.51 mmol) and stirred at 45 °C for 19 h. After concen- phenanthroline (3.1 mg, 0.017 mmol) to deactivate the copper
tration in vacuo, the residue was purified by silica-gel chrom- catalyst. After concentration in vacuo, 4-nitrobenzonitrile
atography to afford 1i (263 mg, 0.970 mmol, 78%). 1i: 1H-NMR (26.8 mg, 0.181 mmol) was added. Due to the instability of 2b
(500 MHz, CDCl3): δ 8.06 (1H, d, J = 12.9 Hz), 7.30 (2H, t, J = to silica-gel chromatography, the yield of 2b (84%) was calcu-
1
7.6 Hz), 7.23 (1H, t, J = 7.6 Hz), 7.20 (2H, d, J = 7.6 Hz), 4.54 lated based on H-NMR. 2b: TLC Rf = 0.38 (Hex : AcOEt = 1 : 1);
(1H, d, J = 12.9 Hz), 4.52 (2H, s), 3.61 (3H, s), 2.47 (1H, s), 1.64 1H-NMR (500 MHz, CDCl3): δ 7.45 (1H, s), 7.32–7.17 (7H, m),
(6H, s); 13C-NMR (125 MHz, CDCl3): δ 169.97, 147.59, 137.01, 6.92 (2H, d, J = 8.5 Hz), 6.33 (1H, d, J = 10.4 Hz), 5.05 (1H, dt,
128.7, 127.1, 126.24, 88.45, 85.86, 72.94, 56.95, 50.69, 50.42, J = 10.1, 3.2 Hz), 4.90 (1H, ddd, J = 17.0, 8.5, 3.5 Hz), 4.30–4.24
29.57; HRMS (ESI, m/z): [M + H]+ calcd for C16H20NO2, (2H, m), 4.18 (1H, d, J = 14.5 Hz), 4.12–4.06 (3H, m), 3.18 (3H,
258.1489; found, 258.1482.
s), 3.26 (1H, dd, J = 13.6, 3.5 Hz), 2.83 (1H, dd, J = 13.6, 8.8
Methyl (E)-3-(benzyl(but-2-yn-1-yl)amino)-3-phenylacrylate Hz); 13C NMR (125 MHz, CDCl3): 164.98, 159.78, 155.33,
(1j). To a solution of N-benzylbut-2-yn-1-amine (195 mg, 152.49, 135.63, 129.59, 129.55, 128.73, 127.09, 125.84, 122.31,
1.23 mmol) in methanol (1.2 ml) was added methyl 3-phenyl- 114.42, 109.88, 98.58, 66.57, 60.38, 55.54, 55.37, 48.36, 37.89;
propiolate (0.19 ml, 1.29 mmol) at room temperature and then HR-MS (ESI): calcd for C24H24N2O4Na [M + Na]+ 427.1628,
stirred at 70 °C for 16 h. After concentration in vacuo, the found 427.1565.
residue was purified by silica-gel chromatography to afford 1j
1-Benzyl-5-tosyl-1,2-dihydropyridine (2c). A solution of
(176 mg, 0.551 mmol, 45%). 1j: TLC Rf = 0.38 (Hex : AcOEt = N-propargylenamine 1c (50.2 mg, 0.154 mmol) and [Cu(Xant-
2 : 1); 1H-NMR (500 MHz, CDCl3): δ 7.43–7.40 (3H, m), phos)(MeCN)]PF6 (13.0 mg, 0.0157 mmol) in CH2Cl2 (1.6 ml)
7.33–7.31 (4H, m), 7.29–7.25 (1H, m), 7.23 (1H, br-d, J = 7.4 was stirred at r.t. for 4 h. The reaction mixture was treated with
Hz), 5.13 (1H, s), 4.33 (2H, br-s), 3.74 (2H, br-s), 3.48 (3H, s), 1,10-phenanthroline (3.8 mg, 0.0211 mmol) to deactivate the
1.84 (3H, t, J = 2.2 Hz); 13C-NMR (75 MHz, CDCl3): 167.97, copper catalyst. After concentration in vacuo, 4-nitrobenzo-
162.56, 136.75, 136.08, 128.73 128.58, 128.48, 128.23, 127.40, nitrile (22.8 mg, 0.154 mmol) was added. The yield of 2c (99%)
89.75, 80.78, 73.36, 52.63, 50.20, 39.34, 3.52.
was calculated based on 1H-NMR. 2c: TLC Rf = 0.48 (Hex :
acetone = 2 : 1); 1H-NMR (500 MHz, CDCl3): δ 7.67 (2H, m),
7.32–7.18 (8H, m), 5.90 (1H, m), 4.90 (1H, dt, J = 10.2, 3.2 Hz),
4.13 (2H, s), 3.89 (2H, dd, J = 3.2, 1.9 Hz), 2.34 (3H, s);
General procedure for Cu(I)-catalyzed cyclization of N-
propargylenamine
A solution of N-propargylenamine (0.200 mmol) and [Cu(Xant- 13C-NMR (75 MHz, CDCl3): 145.57, 142.48, 140.76,
phos)(MeCN)]PF6 (0.020 mmol) in CH2Cl2 (2.0 ml) was stirred 134.35, 129.57, 128.93, 128.30, 127.92, 126.39, 119.35, 111.59,
at r.t. for several hours. The reaction mixture was then treated 104.29, 59.91, 47.77, 21.44; HR-MS (ESI): calcd for the corres-
with 1,10-phenanthroline (0.020 mmol) to deactivate the ponding pyridinium salt C19H18NO2[M]+ 324.1053, found
copper catalyst. After concentration in vacuo, 4-nitrobenzo- 324.1091.
nitrile (0.200 mmol) was added as an internal standard for
(1-Benzyl-1,6-dihydropyridin-3-yl)(phenyl)methanone (2d).
1H-NMR. The yield of the desired product was calculated A solution of N-propargylenamine 1d (100 mg, 0.364 mmol)
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and [Cu(Xantphos)(MeCN)]PF6 (30.2 mg, 0.0365 mmol) in 1,2- m), 7.37–7.30 (3H, m), 7.30–7.21 (3H, m), 7.20–7.16 (2H,
dichloroethane (3.6 ml) was stirred at 65 °C for 3 h. The reac- m), 4.91 (1H, t, J = 4.1 Hz), 4.32 (2H, s), 4.04 (2H, d, J =
tion mixture was then treated with 1,10-phenanthroline 4.1 Hz), 3.51 (3H, s); 13C-NMR (125 MHz, CDCl3): 166.67,
(11.2 mg, 0.0621 mmol) to deactivate the copper catalyst. After 150.11, 141.49, 137.28, 135.06, 129.02, 128.30, 128.00
concentration in vacuo, 4-nitrobenzonitrile (53.9 mg, 127.45, 127.29, 126.67, 110.60, 98.13, 59.88, 50.41, 48.07;
0.364 mmol) was added. The yield of 2d (93%) was calculated HR-MS (ESI): calcd for C20H19NO2Na [M + Na]+ 328.1308,
based on 1H-NMR. 2d: TLC Rf = 0.33 (Hex : AcOEt = 2 : 1); found 328.1311.
1H-NMR (500 MHz, CDCl3): δ 7.52–7.50 (2H, m), 7.40–7.33 (6H,
Dimethyl 1,1′-dibenzyl-1,1′,6,6′-tetrahydro-[4,4′-bipyridine]-
m), 7.23–7.17 (3H, m), 6.63 (1H, m), 5.14 (1H, dt, J = 10.2, 3.3 3,3′-dicarboxylate (2h). A solution of N-propargylenamine 1h
Hz), 4.19 (2H, s), 4.11 (2H, dd, J = 3.3, 1.9 Hz); 13C-NMR (53.1 mg, 0.116 mmol) and [Cu(Xantphos)(MeCN)]PF6
(125 MHz, CDCl3): 190.18, 152.71, 140.40, 134.41, 129.88, (19.2 mg, 0.0232 mmol) in CH2Cl2 (1.2 ml) was stirred at r.t.
129.12, 128.49, 128.34, 128.12, 127.90, 122.25, 111.70, 107.35, for 3 h. The reaction mixture was then treated with 1,10-phe-
60.46, 48.79; HRMS (ESI): calcd for C19H17NONa [M + Na]+ nanthroline (4.18 mg, 0.0232 mmol) to deactivate the copper
298.1202, found 298.1201.
catalyst. After concentration in vacuo, 4-nitrobenzonitrile
Methyl 1-benzyl-2-methyl-1,6-dihydropyridine-3-carboxylate (17.9 mg, 0.121 mmol) was added. The yield of 2h (75%) was
1
(2e). A solution of N-propargylenamine 1e (48.0 mg, calculated based on H-NMR. 2h: TLC Rf = 0.28 (Hex : AcOEt =
0.197 mmol) and [Cu(Xantphos)(MeCN)]PF6 (16.7 mg, 1 : 1); 1H-NMR (500 MHz, CDCl3): δ 7.50 (2H, s), 7.39–7.27
0.0202 mmol) in CH2Cl2 (2.0 ml) was stirred at r.t. for 2 h. The (10H, m), 4.78 (2H, t, J = 3.5 Hz), 4.28 (2H, br-d, J = 14.8 Hz),
reaction mixture was then treated with 1,10-phenanthroline 4.16 (2H, br-d, J = 14.8 Hz), 4.02 (2H, br-d, J = 14.2 Hz), 3.95
(4.7 mg, 0.0261 mmol) to deactivate the copper catalyst. After (2H, br-d, J = 14.2 Hz), 3.59 (6H, s); 13C-NMR (125 MHz,
concentration in vacuo, 4-nitrobenzonitrile (29.2 mg, CDCl3): 166.48, 147.83, 137.24, 135.39, 128.91, 128.08, 127.97,
0.197 mmol) was added. The yield of 2e (80%) was calculated 108.67, 98.98, 59.96, 50.38, 48.17; HR-MS (ESI): calcd for
based on 1H-NMR due to the instability of 2e to silica-gel C28H28N2O4Na [M + Na]+ 479.1898, found 479.1871.
chromatography. 2e: TLC Rf = 0.38 (Hex : acetone = 5 : 1);
Methyl 1-benzyl-6,6-dimethyl-1,6-dihydropyridine-3-carboxy-
1H-NMR (500 MHz, CDCl3): δ 7.40–7.37 (2H, m), 7.32–7.24 (3H, late (2i). A solution of N-propargylenamine 1i (47.0 mg,
m), 6.54 (1H, m), 5.00 (1H, dt, J = 9.8, 3.7 Hz), 4.50 (2H, s), 0.183 mmol) and [Cu(Xantphos)(MeCN)]PF6 (15.7 mg,
4.01 (2H, m), 3.70 (3H, s), 2.52 (3H, s); 13C-NMR (75 MHz, 0.0190 mmol) in 1,2-dichloroethane (1.8 ml) was stirred at
CDCl3): 167.85, 157.65, 136.19, 128.96, 127.59, 126.46, 125.45, 65 °C for 20 h. The reaction mixture was then treated with
107.19, 97.54, 54.44, 50.63, 50.57, 16.16; HR-MS (ESI): calcd for 1,10-phenanthroline (5.6 mg, 0.0311 mmol) to deactivate the
C15H17NO2Na [M + Na]+ 266.1151, found 266.1120.
copper catalyst. After concentration in vacuo, 4-nitrobenzo-
1-Benzyl-2,6,7,8-tetrahydroquinolin-5(1H)-one (2f). A solu- nitrile (27.7 mg, 0.187 mmol) was added. The yield of 2i (99%)
1
tion of N-propargylenamine 1f (138 mg, 0.578 mmol) and [Cu- was calculated based on H-NMR spectra. After concentration
(Xantphos)(MeCN)]PF6 (48.5 mg, 0.0586 mmol) in 1,2-dichlor- of the mixture, the residue was purified by silica-gel chromato-
oethane (6.0 ml) was stirred at 65 °C for 2 h. The reaction graphy to afford 2i (40.5 mg, 0.157 mmol, 86%). 2i: TLC Rf =
mixture was treated with 1,10-phenanthroline (13.8 mg, 0.29 (Hex : AcOEt
=
4 : 1); 1H-NMR (500 MHz, CDCl3):
0.0767 mmol) to deactivate the copper catalyst. After concen- δ 7.38–7.35 (2H, m), 7.31–7.25 (3H, m), 6.35 (1H, dd, J = 9.8,
tration in vacuo, 4-nitrobenzonitrile (85.6 mg, 0.578 mmol) was 1.3 Hz), 4.85 (1H, d, J = 9.8 Hz), 4.45 (2H, s), 3.68 (3H, s), 1.28
added. The yield of 2f (94%) was calculated based on 1H-NMR. (6H, s); 13C NMR (125 MHz, CDCl3): 167.11, 147.60, 138.74,
2f: TLC Rf = 0.36 (Hex : acetone = 1 : 2); 1H-NMR (500 MHz, 128.93, 127.69, 126.94, 120.46, 120.13, 97.70, 58.01, 53.35,
CDCl3): δ 7.37–7.21 (5H, m), 6.60 (1H, m), 5.08 (1H, dt, J = 50.77, 28.59; HRMS (ESI, m/z): calcd for C16H20NO2 [M + H]+
10.1, 3.3 Hz), 4.41 (2H, s), 4.13 (2H, dd, J = 3.3, 1.7 Hz), 2.47 258.1489, found 258.1485.
(2H, t, J = 6.3 Hz), 2.28 (2H, t, J = 6.3 Hz), 1.90 (2H, quin, J =
Methyl
1-benzyl-4-methyl-2-phenyl-1,6-dihydropyridine-3-
6.3 Hz); 13C-NMR (75 MHz, CDCl3): 191.24, 161.45, 135.25, carboxylate (2j). A solution of N-propargylenamine 1j
129.08, 127.81, 126.33, 121.06, 110.71, 106.32, 53.97, 51.41, (70.4 mg, 0.221 mmol) and [Cu(Xantphos)(MeCN)]PF6
35.42, 26.28, 21.23; HR-MS (ESI): calcd for C16H18NO [M + H]+ (18.3 mg, 0.022 mmol) in 1,2-dichloroethane (2.2 ml) was
240.1383, found 240.1382.
stirred at r.t. for 3 h. The reaction mixture was then treated
Methyl 1-benzyl-4-phenyl-1,6-dihydropyridine-3-carboxylate with 1,10-phenanthroline (4.9 mg, 0.0272 mmol) to deactivate
(2g). A solution of N-propargylenamine 1g (70.4 mg, the copper catalyst. After concentration in vacuo, 4-nitrobenzo-
0.231 mmol) and [Cu(Xantphos)(MeCN)]PF6 (20.0 mg, nitrile (32.7 mg, 0.221 mmol) was added as an internal stan-
1
0.0241 mmol) in CH2Cl2 (2.3 ml) was stirred at r.t. for dard. The yield of 2j (89%) was calculated based on H-NMR.
110 min. The reaction mixture was then treated with 1,10-phe- 2j: TLC Rf = 0.50 (Hex : AcOEt = 2 : 1); 1H-NMR (500 MHz,
nanthroline (4.14 mg, 0.0230 mmol) to deactivate the copper CDCl3): δ 7.36–7.16 (10H, m), 4.81–4.77 (1H, m), 4.11 (2H, s),
catalyst. After concentration in vacuo, 4-nitrobenzonitrile 3.93–3.91 (2H, m), 3.22 (3H, s), 2.06–2.03 (3H, m); 13C-NMR
(28.7 mg, 0.194 mmol) was added. The yield of 2g (82%) was (75 MHz, CDCl3): 168.82, 156.49, 137.81, 136.83, 133.66,
1
calculated based on H-NMR. 2g: TLC Rf = 0.45 (Hex : AcOEt = 128.85, 128.69, 128.58, 128.26, 127.38, 127.05, 106.83, 105.17,
4 : 1); 1H-NMR (500 MHz, CDCl3): δ 7.70 (1H, s), 7.42–7.37 (2H, 55.21, 50.20, 48.85, 21.01.
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Cu-catalyzed cyclization of a deuterium labeled
N-propargylenamine
2007, 9, 2167; (c) K. Oshima, T. Ohmura and M. Suginome,
J. Am. Chem. Soc., 2012, 134, 3699; (d) C. Challa, M. John
and R. S. Lankalapalli, Tetrahedron Lett., 2013, 54, 3810;
(e) Y. Hoshimoto, T. Ohata, M. Ohashi and S. Ogoshi,
Chem. – Eur. J., 2014, 20, 4105.
6 (a) M. G. P. Buffat, Tetrahedron, 2004, 60, 1701;
(b) J. A. Bull, J. J. Mousseau, G. Pelletier and A. B. Charette,
Chem. Rev., 2012, 112, 2642.
7 (a) D. F. Maynard and W. H. Okamura, J. Org. Chem., 1995,
60, 1763; (b) D. Tejedor, G. Mendez-Abt and F. Garcia-
Tellado, Chem. – Eur. J., 2010, 16, 428; (c) H. Wei, Y. Wang,
B. Yue and P.-F. Xu, Adv. Synth. Catal., 2010, 352, 2450;
(d) K. Tanaka, K. Fukase and S. Katsumura, Synlett, 2011,
2115; (e) T. Harschneck and S. F. Kirsch, J. Org. Chem.,
2011, 76, 2145; (f) X. Xin, D. Wang, F. Wu, X. Li and
B. Wan, J. Org. Chem., 2013, 78, 4065.
8 (a) D. A. Colby, R. G. Bergman and J. A. Ellman, J. Am.
Chem. Soc., 2008, 130, 3645; (b) D. A. Colby, R. G. Bergman
and J. A. Ellman, Chem. Rev., 2010, 110, 624;
(c) S. Duttwyler, C. Lu, A. L. Rheingold, R. G. Bergman and
J. A. Ellman, J. Am. Chem. Soc., 2012, 134, 4064;
(d) S. Duttwyler, S. Chen, M. K. Takase, K. B. Wiberg,
R. G. Bergman and J. A. Ellman, Science, 2013, 339, 678;
(e) M. A. Ischay, M. K. Takase, R. G. Bergman and
J. A. Ellman, J. Am. Chem. Soc., 2013, 135, 2478;
(f) T. Mesganaw and J. A. Ellman, Org. Process Res. Dev.,
2014, 18, 1097.
N-Benzyl prop-2-yn-1-amine-d1. To a solution of benzyl
amine (3) (2.34 ml, 21.4 mmol) in toluene (4.2 ml) was added
1-bromo-2-butyne (0.380 ml, 4.34 mmol) and stirred at r.t. for
14 h. After concentration in vacuo, the residue was purified by
silica-gel chromatography to afford N-benzyl but-2-yn-1-amine
(636 mg, 3.99 mmol, 92%). This amine (301 mg, 1.89 mmol)
was then dissolved in CH3OD (3.5 ml) and stirred at r.t. for
1 h, and after concentrated in vacuo, treated again with CH3OD
(3.0 ml) at r.t. for further 1 h. Removal of the solvent in vacuo
afforded N-benzyl but-2-yn-1-amine-d1 (240 mg, 1.50 mmol,
79%).
Methyl
1-benzyl-4-methyl-2-phenyl-1,6-dihydropyridine-3-
carboxylate-5-d1 (2j–D). To a solution of N-benzyl but-2-yn-1-
amine-dl (274 mg, 1.71 mmol) in CD3OD (1.6 ml) was added
methyl 3-phenylpropiolate (0.260 ml, 1.76 mmol) and stirred
at 70 °C for 10 h. After concentration in vacuo, the residue was
purified by silica-gel chromatography to afford 1j–D (482 mg,
1.51 mmol, 88%). Deuterium incorporation (80%) at the C3
1
proton was determined based on H-NMR analysis. A solution
of N-propargylenamine 1j–D (70.1 mg, 0.219 mmol) and [Cu-
(Xantphos)(MeCN)]PF6 (18.3 mg, 0.0219 mmol) in dichloro-
methane (2.2 ml) was stirred at r.t. for 3 h. The reaction
mixture was then treated with 1,10-phenanthroline (5.0 mg,
0.0277 mmol) to deactivate the copper catalyst. After concen-
tration in vacuo, 4-nitrobenzonitrile (32.4 mg, 0.219 mmol) was
added as an internal standard. The yield of 2j–D (83%) as well
as the percentage of deuteration of the C5 proton (66%) were
calculated based on 1H-NMR.
9 Related cyclization with the cobalt catalyst: T. Yamakawa
and N. Yoshikai, Org. Lett., 2012, 15, 196.
10 H. Mizoguchi, H. Oikawa and H. Oguri, Nat. Chem., 2014,
6, 57.
11 (a) L. Zhang, J. Sun and S. A. Kozmin, Adv. Synth. Catal.,
2006, 348, 2271; (b) A. S. K. Hashmi, Chem. Rev., 2007, 107,
3180; (c) E. Jiménez-Núñez and A. M. Echavarren, Chem.
Rev., 2008, 108, 3326.
12 (a) A. Fürstner and P. W. Davies, Angew. Chem., Int. Ed.,
2007, 46, 3410; (b) E. Soriano and J. Marco-Contelles, Acc.
Chem. Res., 2009, 42, 1026.
13 H. Kim and C. Lee, J. Am. Chem. Soc., 2006, 128, 6336.
14 M. A. P. Martins, M. Rossatto, C. P. Frizzo, E. Scapin,
L. Buriol, N. Zanatta and H. G. Bonacorso, Tetrahedron
Lett., 2013, 54, 847.
Acknowledgements
We are grateful for financial support from the Japan Science
and Technology Agency (JST) “Precursory Research for Embryo-
nic Science and Technology (PRESTO)” for a project of “Mole-
cular technology and creation of new functions”, and JSPS
KAKENHI (grant no. 23310156). This work was also inspired
by the international and interdisciplinary environments of the
JSPS Asian CORE Program, “Asian Chemical Biology
Initiative”.
15 S. Cacchi, G. Fabrizi and E. Filisti, Org. Lett., 2008, 10,
2629.
16 M. F. Cain, R. P. Hughes, D. S. Glueck, J. A. Golen,
C. E. Moore and A. L. Rheingold, Inorg. Chem., 2010, 49,
7650.
Notes and references
1 R. J. Lavilla, J. Chem. Soc., Perkin Trans. 1, 2002, 1141.
2 J. P. Michael, Nat. Prod. Rep., 2008, 25, 139.
3 (a) E. M. Stocking and R. M. Williams, Angew. Chem., Int.
Ed., 2003, 42, 3078; (b) S. E. O’Connor and J. J. Maresh,
Nat. Prod. Rep., 2006, 23, 532.
4 For a review, see: E. M. P. Silva, P. A. M. M. Varandas and
A. M. S. Silva, Synthesis, 2013, 3053.
5 For recent examples, see: (a) B. Brunner, N. Stogaitis and
M. Lautens, Org. Lett., 2006, 8, 3473; (b) M. Motamed,
E. M. Bunnelle, S. W. Singaram and R. Sarpong, Org. Lett.,
17 Taking the decrease of deuteration at C5 into account, we
hypothesized that the acetonitrile bound to the copper
catalyst might be a competitive proton source for the proto-
demetallation step and thus, prepared a deuterated catalyst
[Cu(Xantphos)(CD3CN)]PF6. However, in contrast to our
assumption, we observed no deference in the deuteration
percentages of the products 2j–D (or 2j) between the cycli-
zations of 1j–D (or 1j) with the use of catalysts either
[Cu(Xantphos)(CD3CN)]PF6 or [Cu(Xantphos)(CH3CN)]PF6.
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This suggests that the acetonitrile bound to catalysts could 19 N. A. Eddy, P. D. Morse, M. D. Morton and G. Fenteany,
be excluded for the competitive proton source. At this Synlett, 2011, 699.
stage, a more detailed reaction mechanism involving com- 20 M. Yoshida, T. Mizuguchi and K. Shishido, Chem. – Eur. J.,
petitive or alternative pathways remains unclear. 2012, 18, 15578.
18 H.-S. Kim, J.-W. Kim, S.-C. Kwon, S.-C. Shim and T.-J. Kim, 21 B. Gabriele, P. Plastina, G. Salerno, R. Mancuso and
J. Organomet. Chem., 1997, 545–546, 337.
M. Costa, Org. Lett., 2007, 9, 3319.
This journal is © The Royal Society of Chemistry 2015
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