Radical Mediated Aza-Pauson-Khand Reaction of Acetylenes, Imines, and CO Leading to Five-Membered Unsaturated Lactams

Article abstract of DOI:10.1002/hlca.201900186

Formal [2+2+1] cycloaddition reaction involving acetylenes, aromatic imines, and CO was achieved by radical chain reaction, which gave five-membered unsaturated lactams in modest to good yields. When we used 5-chloropentyne, sequential carbonylation took

Full text of DOI:10.1002/hlca.201900186

DOI: 10.1002/hlca.201900186
FULL PAPER
Radical Mediated Aza-Pauson-Khand Reaction of Acetylenes, Imines,
and CO Leading to Five-Membered Unsaturated Lactams
Takahide Fukuyama,a Takuma Okada,a Nao Nakashima,a and Ilhyong Ryu*a, b
a
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531,
Japan, e-mail: ryu@c.s.osakafu-u.ac.jp
Department of Applied Chemistry, National Chiao Tung University, Hsinchu 30010, Taiwan
b
Dedicated to Professor Philippe Renaud on the occasion of 60th birthday
Formal [2+2+1] cycloaddition reaction involving acetylenes, aromatic imines, and CO was achieved by
radical chain reaction, which gave five-membered unsaturated lactams in modest to good yields. When we used
5-chloropentyne, sequential carbonylation took place accompanied with double annulation events to give a
cyclohexanone-fused lactam in excellent stereoselectivity.
Keywords: cycloaddition, alkynes, CO, aromatic imines, lactams.
behave as nucleophilic radicals towards electron-poor
alkenes. However, deeming that acyl radicals may act
Introduction
Carbonylation reactions with CO, irrespective of the as pseudo-carbonyl species, we observed acyl radicals
reactive species, provide a straightforward means to to behave as electrophilic radicals. Previously, we
access
cyclic
and
heterocyclic
carbonyl found that acyl radicals, generated by the addition of
compounds.[1–5] Acyl radicals[6] are the first intermedi- alkyl and alkenyl radicals to CO, underwent N-philic
ates in radical carbonylation with CO,[7–11] which acyl radical cyclization onto imine nitrogen providing
an annulation method for the synthesis of
lactams.[12–21] The N-philic acyl radical cyclization can
be rationalized by dual orbital interactions between
the π* orbital of the acyl radical or ketenyl radical[22,23]
Scheme 1. Dual polar reactivity of acyl radicals.
Scheme 2. Concept of radical-mediated aza-Pauson-Khand reac-
tion.
Supporting information for this article is available on the
WWW under https://doi.org/10.1002/hlca.201900186
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Helv. Chim. Acta 2019, 102, e1900186
and the lone pair of the imine nitrogen and the SOMO
of the acyl radical and the π* orbital of the imine
(Scheme 1).[24–27]
Having successful examples of the intramolecular
reaction using imines, we also reported on intermolec-
ular trapping of acyl radicals by N=C double bonds of
amidines,[28] which gave five membered unsaturated
lactams in good yields through the [2+2+1] cyclo-
addition reaction of acetylenes, amidines, and CO
(Scheme 2). The overall transformation represents a
radical-mediated aza-Pauson-Khand reaction.[29,30] In
this article, we report the results on the extension of
[2+2+1] cycloaddition reaction with a variety of
aromatic imines as coupling partner, leading to five-
membered unsaturated lactams, whose structure are
often found in biologically active molecules (Scheme 2,
Eqn. 2).[31]
Results and Discussion
Unlike amidine C=N double bond,[28] the reactivity of
imine C=N double bond towards acyl radicals was
rather modest. For example, the reaction of 1-octyne
(1a), CO, and five equivalents of aromatic imine 2a
gave the desired [2+2+1] cycloaddition product 3a
only in 23% yield (Scheme 3). To encourage the
Scheme 3. [2+2+1] Cycloaddition of 1-octyne 1a, CO, and
aromatic imines, 2a, 2b, and 2c under radical conditions.
Scheme 4. Radical-mediated [2+2+1] cycloaddition of acetylenes 1, CO, and aromatic imines 2.
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Helv. Chim. Acta 2019, 102, e1900186
intermolecular addition onto imine, we increased the
amount of 2a to ten- and twenty-fold excess, which
caused the increase of the yield of 3a to 31% and
45%, respectively. Since acyl radicals, the initial
intermediates of the reaction, have polar nature
consisting of nucleophilic SOMO and electrophilic
carbonyl π*,[24–27] we also tested imines 2b and 2c for
a comparison. The reaction using ten equivalents of
these imines gave lactams 3b and 3c in 15% and 51%
yield, respectively. Unlike the cases of amidines,[28] the
reaction gave poor results when we used lesser
amounts of tin hydride. All these results suggested
that electron-donating substituents, such as MeO and
Me2N group, effectively enhanced the reactivity of
imines towards the attack of acyl radicals.
Then, several acetylenes 1 and imines 2 were
exposed to similar radical carbonylation conditions
(Scheme 4). 4-Phenyl-1-butyne also reacted with imine
2c to give the corresponding lactam 3d. Acetylenes
bearing functional groups such as chlorine, silyloxy or
cyano group also participated in the [2+2+1] cyclo-
addition reaction to give corresponding lactams 3e,
3f, and 3g. The reaction of imine 2a with the acetoxy-
functionalized alkyne gave the corresponding 3h in a
39% yield. An imine derived from 3,4,5-trimethoxy-
benzaldehyde gave the corresponding lactam 3i,
albeit in a modest yield. The reaction of a ketimine
derived from p-methoxyacetophenone also reacted
with alkyne 1a to give lactam 3k, having a quaternary
center, in 35% yield.
Scheme 5. Radical-mediated hybrid radical/polar reaction
mechanism.
A possible reaction mechanism for the present
radical mediated [2+2+1] cycloaddition is shown in single stereoisomer, whose structure was confirmed by
Scheme 5. The addition of tributyltin radical to the X-ray diffraction analysis (Scheme 6)1.
acetylene terminus generates a β-stannyl-substituted
alkenyl radical. This radical reacts with CO to afford
α,β-unsaturated acyl radical A, which is in equilibrium
Conclusions
with isomeric α-ketenyl radical B.[22,23] Intermolecular
trapping of the α-ketenyl radical B by imine nitrogen In summary, we have reported a radical mediated [2+
gives an intermediate C, which can be drawn in a 2+1] cycloaddition reaction comprising terminal
canonical form D. 5-Endo cyclization of C or 6π acetylenes, aromatic imines, and CO, which leads to
electrocyclization[32,33] of D gives intermediate E. The the formation of five-membered unsaturated lactams
subsequent β-fission gives α,β-unsaturated lactam 3 in modest to good yields. In this reaction, intermolec-
and tributyltin radical.
ular ionic trapping of α-ketenyl radical by an imine
Lactam 3e having chloropentenyl-substructure is
suitable for further radical transformation because of
the CÀ Cl bond. Indeed, the consecutive radical medi-
ated [2+2+1] cyclization and carbonylative 6-endo
cyclization gave bicyclic lactam 4e in 51% yield as a
1 CCDC-1947806 contains the supplementary crystallo-
graphic data for compound 4e. These data can be
obtained free of charge through www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ ccdc.cam.
ac.uk, or by contacting The Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44 1223 336033.
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Scheme 6. One-pot consecutive synthesis of 4e and the structure obtained by single crystal X-ray analysis.
N=C double bond, followed by five-membered ring according to literature procedures.[34] Other reagents
closure gives unsaturated five-membered ring lactams. were commercially available and used without further
When chlorobutyl-substituted acetylene 1e was used purification.
as a substrate, synthesis of a bicyclic lactam 4e was
achieved by the consecutive radical-mediated [2+2+
1] cyclization and carbonylative 6-endo cyclization.
General Procedure for Radical Mediated [2+2+1]
Cycloaddition Reaction. A magnetic stirring bar, V-40
(18.5 mg, 0.08 mmol), benzene (5 mL), Bu3SnH
(87.3 mg,
0.3 mmol),
1-octyne
(1a,
27.6 mg,
Experimental Section
0.25 mmol), and imine 2c (405.6 mg, 2.5 mmol) were
placed in a 50 mL stainless autoclave. The autoclave
was closed, purged three times with 10 atm carbon
General
The products were purified by flash chromatography monoxide, pressurized with 80 atm of CO and then
°
on silica gel (Kanto Chem. Co.). Silica Gel 60 N heated at 110 C for 6 h. Excess CO was discharged at
(spherical, neutral, 40–50 mm)) and/or a recycling room temperature. The solvent was removed under
preparative HPLC (Japan Analytical Industry Co. Ltd., reduced pressure. The residue was purified by the
LC-918) equipped with GPC columns (JAIGEL-1H+ preparative HPLC to give 3c (39.3 mg, 51% yield).
JAIGEL-2H columns) using CHCl3 as eluent. 1H-NMR
spectra were recorded with a JEOL ECP-500 (500 MHz)
3-Hexyl-5-(4-methoxyphenyl)-1-methyl-1,5-dihy-
spectrometer and referenced to the solvent peak at dro-2H-pyrrol-2-one (3a). Yellow oil. IR (neat): 1683,
1
7.26 ppm for CHCl3. 13C-NMR spectra were recorded 1643, 1601. H-NMR (CDCl3, 500 MHz): 0.85–0.90 (m, 3
with a JEOL ECP-500 (125 MHz) spectrometer and H); 1.29–1.37 (m, 6 H); 1.50–1.59 (m, 2 H); 2.34 (t, J=
referenced to the solvent peak at 77.00 ppm for CDCl3. 7.3, 2 H); 2.80 (s, 3 H); 3.81 (s, 3 H); 4.77 (s, 1 H); 6.56 (d,
Chemical shifts were reported in parts per million (δ). J=1.8, 1 H); 6.67–6.71 (m, 2 H); 7.00–7.10 (m, 2 H).
Splitting patterns are indicated as follows: br., broad; s, 13C-NMR (CDCl3, 125 MHz): 14.20; 22.70; 25.78; 27.22;
singlet; d, doublet; t, triplet; q, quartet; m, multiplet. 27.64; 29.11; 31.73; 55.44; 66.20; 114.52; 127.62; 128.50;
Infrared spectra were recorded on a JASCO FT/IR-4100 139.08; 139.74; 159.81; 171.97. EI-MS: 287 (74, M+), 216
spectrometer; absorptions were reported as wave- (48), 202 (100), 159 (11). HR-EI-MS: 287.1888
number [cmÀ 1]. Conventional and high-resolution (C18H25NO2+; calc. 287.1885).
mass spectra were recorded with a JEOL MS-700
spectrometer. M.p. was measured in capillary using
3-Hexyl-1-methyl-5-phenyl-1,5-dihydro-2H-pyr-
Büchi Melting Point B-540. Imines 2 were prepared rol-2-one (3b). Yellow oil. IR (neat): 1695, 1641, 1601,
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1455, 1494. 1H-NMR (CDCl3, 500 MHz): 0.76–0.88. (m, 3 J=8.7, 2 H); 6.96 (d, J=8.7, 2 H). 13C-NMR (CDCl3,
H); 1.29–1.37 (m, 6 H); 1.53–1.59 (m, 2 H); 2.34 (t, J= 125 MHz): 21.12; 24.28; 25.46; 27.19; 28.43; 40.57;
6.0, 2 H); 2.82 (s, 3 H); 4.82 (s, 1 H); 6.55–6.61 (m, 1 H); 64.40; 66.37; 112.75; 122.38; 128.16; 138.06; 140.50;
7.08–7.13 (m, 2 H); 7.33–7.38 (m, 3 H). 13C-NMR 150.74; 171.29; 171.77. EI-MS: 330 (32, M+), 315 (40),
(CDCl3, 125 MHz): 14.20; 22.72; 25.82; 27.39; 27.64; 210 (100). HR-EI-MS: 330.1940 (C19H26N2O3+; calc.
29.12; 31.75; 66.83; 127.27; 128.59; 129.19; 135.96; 330.1943).
139.24; 139.64; 172.14. EI-MS: 257 (100, M+), 227 (20),
214 (33), 186 (11), 172 (60), 128 (18). HR-EI-MS:
4-{5-[4-(Dimethylamino)phenyl]-1-methyl-2-oxo-
2,5-dihydro-1H-pyrrol-3-yl}butanenitrile (3g). Yel-
low oil. IR (neat): 2939, 1682, 1640, 1612, 1523. 1H-NMR
(CDCl3, 500 MHz): 1.99 (quint., J=6.9, 2 H); 2.40 (t, J=
(C17H23NO+; calc. 257.1780) 257.1773.
5-[4-(Dimethylamino)phenyl]-3-hexyl-1-methyl-
1,5-dihydro-2H-pyrrol-2-one (3c). Yellow oil. IR 7.3, 2 H); 2.52 (t, J=7.8, 2 H); 2.80 (s, 3 H); 2.96 (s, 6 H);
(neat): 1687, 1641, 1613, 1523. 1H-NMR (CDCl3, 4.78 (s, 1 H); 6.67 (d, J=1.8, 1 H); 6.69 (d, J=8.7, 2 H);
500 MHz): 0.86–0.89 (m, 3 H); 1.29–1.37 (m, 6 H); 6.94 (d, J=8.7, 2 H). 13C-NMR (CDCl3, 125 MHz): 16.82;
1.52–1.60 (m, 2 H); 2.30–2.35 (m, 2 H); 2.79 (s, 3 H); 23.72; 25.00; 27.18; 40.53; 66.41; 112.76; 119.45; 121.74;
2.95 (s, 6 H); 4.73 (s, 1 H); 6.56 (d, J=1.8, 1 H); 6.69 (d, 128.08; 136.10; 141.89; 150.79; 171.19. EI-MS: 283 (94,
J=8.7, 2 H); 6.96 (d, J=8.7, 2 H). 13C-NMR (CDCl3, M+), 228 (37), 214 (100), 156 (14). HR-EI-MS: 286.1691
125 MHz): 14.27; 22.72; 25.78; 27.20; 27.69; 29.13; (C17H21N3O+; calc. 283.1685).
31.75; 40.62; 66.34; 112.73; 122.66; 128.23; 138.74;
140.05; 150.69; 172.01. EI-MS: 300 (34, M+), 215 (100),
4-[5-(4-Methoxyphenyl)-1-methyl-2-oxo-2,5-di-
172 (17), 145 (15). HR-EI-MS: 300.2204 (C19H28N2O hydro-1H-pyrrol-3-yl]butyl acetate (3h). Yellow oil.
1
300.2202).
IR (neat) 1735, 1686, 1641, 1610, 1511, 1245. H-NMR
(CDCl3, 500 MHz): 1.63–1.74 (m, 4 H); 2.04 (s, 3 H); 2.38
5-[4-(Dimethylamino)phenyl]-1-methyl-3-(2-phe- (t, J=7.8, 2 H); 2.80 (s, 3 H); 3.81 (s, 3 H); 4.08 (t, J=6.0,
1
nylethyl)-1,5-dihydro-2H-pyrrol-2-one (3d). H-NMR 2 H); 4.79 (s, 1 H); 6.60 (d, J=1.4, 1 H); 6.90 (d, J=8.7, 2
(CDCl3, 500 MHz): 2.66–2.71 (m, 2 H); 2.79 (s, 3 H); H); 7.03 (d, J=8.7, 2 H). 13C-NMR (CDCl3, 125 MHz):
2.90–2.93 (m, 2 H); 2.95 (s, 6 H); 4.71 (s, 1 H); 6.52 (s, 1 21.11; 24.24; 25.46; 27.23; 28.43; 55.44; 64.36; 66.22;
H); 6.65–6.68 (m, 2 H); 6.87–6.90 (m, 2 H); 7.18–7.29 114.57; 127.36; 128.45; 138.40; 140.19; 159.86; 171.27;
(m, 5 H). 13C-NMR (CDCl3, 125 MHz): 27.18; 27.43; 33.76; 171.71. EI-MS: 317 (15, M+), 302 (30), 210 (100). HR-EI-
40.61; 66.35; 112.69; 122.35; 126.05; 128.28; 128.46; MS: 317.1620 (C18H23NO4+; calc. 317.1627).
128.63; 137.61; 140.92; 141.50; 150.72; 171.73. EI-MS:
320 (20, M+), 200 (100), 91 (15). HR-EI-MS: 320.1894
4-[1-Methyl-2-oxo-5-(3,4,5-trimethoxyphenyl)-
(C21H24N2O+; calc. 320.1889).
2,5-dihydro-1H-pyrrol-3-yl]butyl acetate (3i). Yellow
1
oil. H-NMR (CDCl3, 500 MHz): 1.64–1.72 (m, 4 H); 2.04
3-(3-Chloropropyl)-5-[4-(dimethylamino)-
(s, 3 H); 2.39 (t, J=7.4, 2 H); 2.86 (s, 3 H); 3.83 (s, 6 H);
phenyl]-1-methyl-1,5-dihydro-2H-pyrrol-2-one (3e). 3.85 (s, 3 H); 4.08 (t, J=6.4, 2 H); 4.76 (s, 1 H); 6.29 (s, 2
1
Yellow oil. IR (neat): 2924, 1683, 1640, 1612, 1523. H- H); 6.60–6.62 (m, 1 H). 13C-NMR (CDCl3, 125 MHz):
NMR (CDCl3, 500 MHz): 2.07 (quint., J=6.9, 2 H); 2.52 (t, 21.02; 24.03; 25.35; 27.42; 28.30; 56.23; 60.88; 64.25;
J=7.3, 2 H); 2.80 (s, 3 H); 2.96 (s, 6 H); 3.58 (t, J=6.4, 2 67.00; 103.71; 131.08; 137.91; 138.23; 140.16; 153.85;
H); 4.76 (s, 1 H); 6.64 (d, J=1.4, 1 H); 6.69 (d, J=8.7, 2 171.25; 171.89. EI-MS: 377 (15, M+), 262 (25), 210 (100).
H); 6.95 (d, J=8.7, 2 H). 13C-NMR (CDCl3, 125 MHz): HR-EI-MS: 377.1841 (C20H27NO6+; calc. 377.1838).
23.26; 27.20; 30.54; 40.57; 44.46; 66.42; 112.79; 122.12;
128.14;136.84; 141.28; 150.78; 171.51. EI-MS: 292 (58,
3-Hexyl-5-(4-methoxyphenyl)-1,5-dimethyl-1,5-
M+), 229 (36), 215 (100). HR-EI-MS: 292.1348 dihydro-2H-pyrrol-2-one (3k). Yellow oil. IR (neat):
(C16H21N2O+; calc. 292.1342).
1685, 1640. H-NMR (CDCl3, 500 MHz): 0.84–0.90 (m, 3
H); 1.25–1.37 (m, 6 H); 1.52–1.58 (m, 2 H); 1.64 (s, 3 H);
1
4-{5-[4-(Dimethylamino)phenyl]-1-methyl-2-oxo- 2.31 (t, J=7.3, 2 H); 2.69 (s, 3 H); 3.80 (s, 3 H); 6.56 (s, 1
2,5-dihydro-1H-pyrrol-3-yl}butyl acetate (3f). Yellow H); 6.85 (d, J=8.7, 2 H); 7.07 (d, J=8.7, 2 H). 13C-NMR
1
oil. IR (neat): 1737, 1685, 1640, 1612, 1523, 1240. H- (CDCl3, 125 MHz): 14.15; 20.90; 22.65; 24.44; 25.53;
NMR (CDCl3, 500 MHz): 1.65–1.70 (m, 4 H); 2.04 (s, 3 H); 27.59; 29.06; 31.68; 55.37; 66.29; 114.18; 127.26; 130.51;
2.37 (t, J=7.8, 2 H); 2.80 (s, 3 H); 2.96 (s, 6 H); 4.08 (t, 136.61; 146.67; 159.18; 171.37. EI-MS: 301 (39, M+), 230
J=6.4, 2 H); 4.75 (s, 1 H); 6.59 (d, J=1.8, 1 H); 6.69 (d,
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(60), 216 (100). HR-EI-MS: 301.2044 (C19H27NO2+; calc.
301.2042).
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A magnetic stirring bar, V-40 (17.6 mg, 0.07 mmol),
benzene (5 mL), Bu3SnH (104.5 mg, 0.38 mmol), 5-
chloro-1-pentyne (1d, 25.6 mg, 0.25 mmol), and imine
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°
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ylhexahydro-1H-isoindole-1,4(2H)-dione (4e). White
solid. M.p. 139–140 C. 1H-NMR (CDCl3, 500 MHz):
°
1.62–1.68 (m, 1 H); 1.87–1.96 (m, 2 H); 2.22–2.32 (m, 2
H); 2.46–2.50 (m, 1 H); 2.72 (d, J=9.2, 1 H); 2.77 (s, 3
H); 2.95 (s, 6 H); 3.22–3.25 (m, 1 H); 5.09 (s, 1 H); 6.70
(d, J=8.25, 2 H); 7.01 (d, J=8.7, 2 H). 13C-NMR (CDCl3,
125 MHz): 22.21; 23.50; 28.79; 40.66; 40.86; 41.39;
54.49; 61.82; 112.93; 126.09; 126.93; 150.46; 174.09;
208.98. EI-MS: 286 (27, M+), 161 (68), 146 (59), 145 (77),
134 (33), 121 (96), 120 (56), 118 (31), 69 (100). HR-EI-
MS: 286.1680 (C17H22N2O2+; calc. 286.1681).
Acknowledgments
This work was supported by a Grant-in-Aid for
Scientific Research B from the Ministry of Education,
Culture, Sports, and Technology (MEXT), Japan.
Author Contribution Statement
T. O. and N. N. performed the experiments, analyzed
the data. T. F. and I. R. conceived and designed the
experiments and wrote the paper.
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Received July 22, 2019
Accepted August 19, 2019
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