Further Studies on the Direct Synthesis of α,β-Unsaturated Ketimines and α,β-Enones by Chemoselective Dehydrative Addition of Functionalized Alkenes to Secondary Amides

Article abstract of DOI:10.1002/cjoc.201600700

Described in this paper are the results of an investigation on the extension of the C-H alkyliminylation and acylation of alkenes with secondary amides. The nucleophilic partner has been extended to cover a series of functionalized alkenes bearing functional groups including ester, α,β-unsaturated ester, uncongested ketone groups, as well as enol derivatives of acetaldehyde such as enol ether and enamides. The electrophilic partner has been extended from N-(2,6-dimethylphenyl) and N-methyl amides to N-n-butyl, and N-cyclohexyl amides. The results demonstrated that the method can be used to synthesize a number of functionalized α,β-unsaturated ketimines and α,β-enones in an efficient, high yielding, and one-pot manner. The method was applied to a concise synthesis of (E)-6-styryltetrahydro-2H-pyran-2-one (5), an immediate intermediate in the syntheses of a series of styryllactone natural products including (±)-goniothalamine (6), (±)-goniothalamine oxide (7), (±)-goniodiol (8), (±)-leiocarpin A (9), (±)-9-deoxygoniopypyrone (10), and (±)-7-epi-goniodiol (11).

Full text of DOI:10.1002/cjoc.201600700

FULL PAPER
DOI: 10.1002/cjoc.201600700
Further Studies on the Direct Synthesis of α,β-Unsaturated
Ketimines and α,β-Enones by Chemoselective Dehydrative
Addition of Functionalized Alkenes to Secondary Amides
Pei-Qiang Huang* and Ying-Hong Huang
Department of Chemistry, Fujian Provincial Key Laboratory of Chemical Biology, iChEM (Collaborative
Innovation Center of Chemistry for Energy Materials), College of Chemistry and Chemical Engineering,
Xiamen University, Xiamen, Fujian 361005, China
Described in this paper are the results of an investigation on the extension of the C－H alkyliminylation and ac-
ylation of alkenes with secondary amides. The nucleophilic partner has been extended to cover a series of function-
alized alkenes bearing functional groups including ester, α,β-unsaturated ester, uncongested ketone groups, as well
as enol derivatives of acetaldehyde such as enol ether and enamides. The electrophilic partner has been extended
from N-(2,6-dimethylphenyl) and N-methyl amides to N-n-butyl, and N-cyclohexyl amides. The results demon-
strated that the method can be used to synthesize a number of functionalized α,β-unsaturated ketimines and
α,β-enones in an efficient, high yielding, and one-pot manner. The method was applied to a concise synthesis of
(E)-6-styryltetrahydro-2H-pyran-2-one (5), an immediate intermediate in the syntheses of a series of styryllactone
natural products including (±)-goniothalamine (6), (±)-goniothalamine oxide (7), (±)-goniodiol (8), (±)-leio-
carpin A (9), (±)-9-deoxygoniopypyrone (10), and (±)-7-epi-goniodiol (11).
Keywords enimines, one-pot reaction, dehydrative coupling, chemoselectivity, amide transformation, metal-free
amide activation
Introduction
lamin (6) and its derivatives, the cytotoxic and antiproli-
ferative activity against inhibitory effect on the growth
of several human cancer cell lines has attracted a great
deal of attention.[8] Interestingly, the unnatural (S)-enan-
tiomer disclosed high activity with IC50 values of 4
nmol/L on kidney and breast cancer cells, while IC50
values of naturally occurring goniothalamine were only
moderate.[8e] Moreover, racemic GTN has revealed to
exhibit antinociceptive and anti-inflammatory activi-
ties.[8a,8e] The results of this investigation is reported
herein.
Amide is a versatile functional group being widely
used in organic synthesis.[1] As a consequence of the
high stability, the subsequent transformation of amide
into other class of compounds requires harsh conditions.
In recent years, chemoselective transformation of amide
has attracted considerable attention which cumulated in
many valuable synthetic methods.[2-4] As a part of our
efforts to develop mild methods for the direct transfor-
mation of amides,[4] lately, we have reported a highly
chemoselective intermolecular cross-coupling between
secondary amides and alkenes to yield α,β-unsaturated
ketimines (enimines) and enones (Scheme 1).[4a] In view
of the mildness of the method and versatility of the re-
sulting α,β-unsaturated ketimines[5] and enones[6] in or-
ganic synthesis, the investigation was pursuit to further
extend both the substrate scope and functional group
tolerance of the reaction. Moreover, the method was
applied to the formal racemic synthesis of goniothala-
mine (6). (R)-Goniothalamine (GTN, 6) belongs to the
styryl lactone natural products isolated from various
species of the genus Goniothalamus.[7] Among the broad
spectrum of biological activities exhibited by goniotha-
Scheme 1 Chemoselective intermolecular addition of function-
alized alkenes to secondary amides
one-pot
X
R3
O
R3
Y
H
metal-free
R'
+
R
Y
R
N
R1
Tf2O/2-F-Pyr.
R1
H
1
2
3 X = NR'
4 X = O
Experimental
For general methods and general procedures I and II,
*
E-mail: pqhuang@xmu.edu.cn; Tel.: 0086-0592-2182240; Fax: 0086-0592-2189959
Received October 21, 2016; accepted November 7, 2016; published online XXXX, 2017.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201600700.
Dedicated to the Memory of Professor Enze Min.
Chin. J. Chem. 2017, XX, 1—8
© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Huang and Huang
FULL PAPER
see reference 4a.
769, 728 cm1. HRMS (ESI) calcd for [C29H24N]＋
(M＋H＋): 386.1903; found 386.1896.
2,6-Dimethyl-N-[(E)-3-(naphthalen-1-yl)-1-phenyl
allylidene]aniline (3a) Following the general proce-
dure I, the reaction of amide 1a (113 mg, 0.5 mmol)
with 1-vinylnaphthalene gave, after FC (eluent: EtOAc/
n-hexane＝1∶50), α,β-unsaturated imine 3a (164 mg,
yield: 91%) as a 10∶1 inseparable mixture of E/Z iso-
mers. Yellow oil. 1H NMR (400 MHz, CDCl3, data of
the major isomer read from the spectrum of the two
geometric isomers) δ: 2.15 (s, 6H), 6.70 (d, J＝16.2 Hz,
1H), 6.93－6.98 (m, 1H), 7.08 (d, J＝7.5 Hz, 2H), 7.35
－7.41 (m, 1H), 7.42－7.48 (m, 3H), 7.53－7.58 (m,
3H), 7.70 (d, J＝16.2 Hz, 1H), 7.72－7.83 (m, 3H),
7.89－7.94 (m, 2H); 13C NMR (100 MHz, CDCl3, data
of the major isomer read from the spectrum of the two
geometric isomers) δ: 18.2 (2C), 121.1, 123.1, 123.3,
126.1 (2C), 126.6, 126.9, 127.7, 127.9 (2C), 128.2,
128.4 (2C), 128.5, 129.0 (2C), 129.7, 133.1, 133.2,
133.8, 139.0, 141.8, 148.5, 167.1; IR (film) νmax: 3059,
2913, 2847, 1619, 1586, 1569, 1196, 798, 773, 698 cm1.
HRMS (ESI) calcd for [C27H24N]＋ (M＋H＋): 362.1903;
found 362.1907.
2,6-Dimethyl-N-[(E)-1-phenylbut-2-en-1-ylidene]-
aniline (3d) Following the general procedure I, the
reaction of amide 1a (113 mg, 0.5 mmol) with 1-vinyl-
naphthalene gave, after FC (eluent: EtOAc/ n-hexane＝
1∶50), α,β-unsaturated imine 3d (99 mg, yield: 80%)
as a 10∶1 inseparable mixture of E/Z isomers. Brown
1
oil. H NMR (400 MHz, CDCl3, data of the major iso-
mer read from the spectrum of the two geometric iso-
mers) δ: 1.74 (dd, J＝6.7, 1.5 Hz, 3H), 2.07 (s, 6H),
5.98 (dq, J＝15.8, 1.5 Hz, 1H), 6.17 (dq, J＝15.8, 6.7
Hz, 1H), 6.89－6.94 (m, 1H), 7.02－7.06 (m, 2H), 7.42
－7.47 (m, 3H), 7.65－7.70 (m, 2H); 13C NMR (100
MHz, CDCl3, data of the major isomer read from the
spectrum of the two geometric isomers) δ: 18.0 (2C),
18.6, 122.7, 125.2, 126.0 (2C), 127.7 (2C), 128.1 (2C),
128.7 (2C), 129.4, 139.2, 141.2, 148.5, 166.9; IR (film)
νmax: 3059, 3025, 2967, 2913, 2847, 1640, 1590, 1574,
1470, 1441, 1196, 761, 699 cm1. HRMS (ESI) calcd for
[C18H20N]＋ (M＋H＋): 250.1590; found 250.1589.
N-[(E)-3-Ethoxy-1-phenylallylidene]-2,6-dimethyl
aniline (3e) Following the general procedure I, the
reaction of amide 1a (113 mg, 0.5 mmol) with ethyl
vinyl ether gave, after FC (eluent: EtOAc/n-hexane＝
1∶50), α,β-unsaturated imine 3e (113 mg, yield: 81%)
as a 7∶1 inseparable mixture of E/Z isomers. Brown
2,6-Dimethyl-N-[(E)-1-(naphthalen-1-yl)-3-phenyl
allylidene]aniline (3b) Following the general proce-
dure I, the reaction of amide 1b (138 mg, 0.5 mmol)
with styrene gave, after FC (eluent: EtOAc/n-hexane＝
1∶50), α,β-unsaturated imine 3b (161 mg, yield: 89%)
as a 15∶1 inseparable mixture of E/Z isomers. Yellow
1
solid, m.p. 178－179 ℃; H NMR (400 MHz, CDCl3,
1
oil. H NMR (400 MHz, CDCl3, data of the major iso-
data of the major isomer read from the spectrum of the
two geometric isomers) δ: 1.19 (t, J＝7.1 Hz, 3H), 2.09
(s, 6H), 3.68 (t, J＝7.1 Hz, 2H), 5.42 (d, J＝12.9 Hz,
1H), 6.83 (d, J＝12.9 Hz, 1H), 6.86－6.91 (m, 1H),
7.00－7.05 (m, 2H), 7.42－7.46 (m, 3H), 7.64－7.68
(m, 2H); 13C NMR (100 MHz, CDCl3, data of the major
isomer read from the spectrum of the two geometric
isomers) δ: 14.4, 18.0 (2C), 66.6, 101.1, 122.6, 126.3
(2C), 127.8 (2C), 128.2 (2C), 128.6 (2C), 129.3, 139.6,
148.7, 160.2, 165.9; IR (film) νmax: 3050, 3029, 2967,
2913, 2847, 1611, 1586, 1499, 1379, 1179, 765, 703
cm1. HRMS (ESI) calcd for [C19H22NO]＋ (M＋H＋):
280.1696; found 280.1695.
mer read from the spectrum of the two geometric iso-
mers) δ: 2.28 (s, 6H), 6.60 (d, J＝16.2 Hz, 1H), 6.81 (d,
J＝16.2 Hz, 1H), 6.98－7.03 (m, 1H), 7.11－7.17 (m,
4H), 7.19－7.25 (m, 3H), 7.46－7.54 (m, 2H), 7.58－
7.64 (m, 1H), 7.66－7.70 (m, 1H), 7.92－7.99 (m, 2H),
8.04－8.08 (m, 1H); 13C NMR (100 MHz, CDCl3, data
of the major isomer read from the spectrum of the two
geometric isomers) δ: 18.6 (2C), 121.4, 123.2, 125.3,
125.8, 125.9, 126.1 (2C), 126.4, 126.6, 127.6 (2C),
128.0 (2C), 128.4, 128.6 (2C), 129.0, 129.6, 131.4,
133.6, 135.3, 137.2, 142.8, 148.1, 168.1; IR (film) νmax
:
3059, 3029, 2918, 2851, 1619, 1586, 1470, 1192, 806,
777, 761 cm1. HRMS (ESI) calcd for [C27H24N]＋
(M＋H＋): 362.1903; found 362.1904.
N-{(1E)-3-[(2,6-Dimethylphenyl)imino]-3-phenyl-
prop-1-en-1-yl}acetamide (3f) Following the general
procedure I, the reaction of amide 1a (113 mg, 0.5
mmol) with N-vinylacetamide gave, after FC (eluent:
EtOAc/n-hexane ＝1 ∶50), α,β-unsaturated imine 3f
(111 mg, yield: 76%) as a 1.9∶1 inseparable mixture of
N-[2-(9H-Fluoren-9-ylidene)-1-phenylethylidene]-
2,6-dimethylaniline (3c) Following the procedure I,
the reaction of amide 1a (113 mg, 0.5 mmol) with sty-
rene gave, after FC (eluent: EtOAc/n-hexane＝1∶50),
α,β-unsaturated imine 3c (146 mg, yield: 76%) as a sin-
1
E/Z isomers. White solid, m.p. 143－146 ℃; H NMR
1
gle isomer. Yellow solid, m.p. 165－167 ℃; H NMR
(400 MHz, CDCl3) δ: 1.87 (s, 1.1H), 2.02 (s, 3.9H),
2.04 (s, 2.1H), 2.07 (s, 1.9H), 5.50－5.63 (m, 1H),
6.78－7.68 (m, 9H), 8.53 (d, J＝10.6 Hz, 0.35H), 12.38
(br s, 0.65H); 13C NMR (100 MHz, CDCl3) δ: 18.0, 18.6,
22.9, 23.6, 104.7, 104.9, 122.7, 123.2, 126.3, 126.6 (2C),
126.8 (2C), 127.8 (2C), 127.9 (2C), 128.4, 128.5, 129.1,
129.6, 132.6, 135.5, 138.3, 138.6, 147.6, 166.8, 167.4,
168.2, 169.2; IR (film) νmax: 3266, 3071, 3025, 2913,
2851, 1690, 1628, 1516, 1271, 1105 cm1. HRMS (ESI)
calcd for [C19H20N2NaO]＋ (M＋Na＋): 315.1468; found
(400 MHz, CDCl3) δ: 2.06 (s, 6H), 6.81 (s, 1H), 6.82－
6.92 (m, 2H), 6.94－6.98 (m, 2H), 7.04－7.08 (m, 1H),
7.16－7.23 (m, 2H), 7.29－7.34 (m, 1H), 7.36－7.47
(m, 4H), 7.56－7.62 (m, 2H), 8.08－8.12 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ: 18.2 (2C), 119.6, 119.9,
120.8, 123.2, 125.6 (2C), 126.7, 126.9, 127.1, 127.9
(2C), 128.4 (2C), 128.7 (2C), 129.1, 129.2, 131.0, 134.9,
137.4, 138.1, 139.9, 140.3, 141.6, 149.0, 165.5; IR (film)
νmax: 3059, 3025, 2926, 2851, 1607, 1586, 1570, 1449,
2
www.cjc.wiley-vch.de
© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2017, XX, 1—8

Direct Synthesis of α,β-Unsaturated Ketimines and α,β-Enones
315.1467.
129.5, 130.2, 138.8, 148.3, 166.7, 171.4; IR (film) νmax:
1-{(1E)-3-[(2,6-Dimethylphenyl)imino]-3-phenyl-
3069, 3025, 2984, 2918, 2847, 1731, 1632, 1453, 1254,
1159, 1030, 761, 699 cm1. HRMS (ESI) calcd for
[C26H30NO2]＋ (M＋ H＋): 388.2271; found 388.2272.
4-{2-[(2,6-Dimethylphenyl)imino]-2-phenylethyli-
dene}cyclohexanone (3j) Following the general pro-
cedure I, the reaction of amide 1a (113 mg, 0.5 mmol)
with 4-methylenecyclohexanone gave, after FC (eluent:
EtOAc/n-hexane ＝1 ∶50), α,β-unsaturated imine 3j
(141 mg, yield: 89%) as a 10∶1 inseparable mixture of
prop-1-en-1-yl}azepan-2-one (3g)
Following the
general procedure I, the reaction of amide 1a (113 mg,
0.5 mmol) with N-vinylcaprolactam gave, after FC (el-
uent: EtOAc/n-hexane＝1∶50), α,β-unsaturated imine
3g (140 mg, yield: 81%) as a 9∶1 inseparable mixture
1
of E/Z isomers. Yellow wax. H NMR (400 MHz,
CDCl3, data of the major isomer read from the spectrum
of the two geometric isomers) δ: 1.41－1.53 (m, 2H),
1.63－1.69 (m, 3H), 2.08 (s, 6H), 2.57－2.67 (m, 3H),
3.30－3.56 (m, 2H), 5.46 (d, J＝15.0 Hz, 1H), 6.20－
7.21 (m, 4H), 7.40－7.52 (m, 3H), 7.64－7.72 (m, 2H),
1
E/Z isomers. Yellow oil. H NMR (400 MHz, CDCl3,
data of the major isomer read from the spectrum of the
two geometric isomers) δ: 2.06 (s, 6H), 2.14－2.21 (m,
2H), 2.30 (t, J＝6.9 Hz, 2H), 2.67－2.75 (m, 2H),
3.25－3.34 (m, 2H), 5.27－5.33 (m, 1H), 6.92 (t, J＝7.5
Hz, 1H), 7.05 (d, J＝7.5 Hz, 2H), 7.43－7.50 (m, 3H),
7.93－8.00 (m, 2H); 13C NMR (100 MHz, CDCl3, data
of the major isomer read from the spectrum of the two
geometric isomers) δ: 18.1 (2C), 29.1, 38.0, 38.3, 39.5,
122.0, 123.0, 125.8 (2C), 127.6 (2C), 128.0 (2C), 128.4
(2C), 130.4, 133.7, 138.5, 148.1, 166.2, 209.4; IR (film)
νmax: 3059, 3025, 2918, 2847, 1711, 1628, 1445, 1196,
769, 690 cm1. HRMS (ESI) calcd for [C22H24NO]＋
(M＋H＋): 318.1852; found 318.1859.
13
7.78 (d, J＝15.0 Hz, 1H); C NMR (100 MHz, CDCl3,
data of the major isomer read from the spectrum of the
two geometric isomers) δ: 17.9 (2C), 23.2, 26.8, 28.8,
36.9, 44.8, 102.7, 122.6, 126.1 (2C), 127.7 (2C), 128.3
(2C), 128.6 (2C), 129.5, 138.4, 139.1, 148.6, 166.7,
174.6; IR (film) νmax: 3069, 2930, 2851, 1686, 1611,
1586, 1445, 1391, 1176, 1080, 972, 769, 699 cm1.
HRMS (ESI) calcd for [C23H27N2O] ＋ (M ＋ H ＋ ):
347.2118; found 347.2116.
Ethyl
2-{4-{2-[(2,6-dimethylphenyl)imino]-2-
phenylethylidene}cyclohexyl}acetate (3h) Following
the general procedure I, the reaction of amide 1a (113
mg, 0.5 mmol) with ethyl 2-(4-methylenecyclohexyl)-
acetate (110 mg, 0.6 mmol, 1.2 equiv) gave, after FC
(eluent: EtOAc/n-hexane ＝ 1 ∶ 10), α,β-unsaturated
imine 3h (189 mg, yield: 97%) as a 1∶1 inseparable
2,6-Dimethyl-N-[1-phenyl-2-(1,4-dioxaspiro[4.5]-
decan-8-ylidene)ethylidene]aniline (3k) Following
the general procedure I, the reaction of amide 1a (113
mg, 0.5 mmol) with 8-methylene-1,4-dioxaspiro[4.5]-
decane gave, after FC (eluent: EtOAc/n-hexane＝1∶
50), α,β-unsaturated imine 3j (100 mg, yield: 63%) as a
10∶1 inseparable mixture of E/Z isomers and 3k (42
mg, yield: 23%) as a 10∶1 inseparable mixture of E/Z
1
mixture of E/Z (olefin) isomers. Yellow oil. H NMR
(400 MHz, CDCl3) δ: 1.08－1.18 (m, 1H), 1.22 (t, J＝
7.1 Hz, 3H), 1.19－1.29 (m, 1H), 1.54－1.93 (m, 5H),
2.05 (s, 3H), 2.06 (s, 3H), 2.09－2.14 (m, 2H), 3.12－
3.18 (m, 2H), 4.08 (q, J＝7.1 Hz, 2H), 5.16－5.24 (m,
1H), 6.87－6.92 (m, 1H), 7.00－7.04 (m, 2H), 7.38－
7.50 (m, 3H), 7.91－7.99 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ: 14.2, 18.1, 18.1, 28.4, 28.5, 30.0, 31.3, 38.7,
40.4, 60.1, 122.7, 123.9, 125.9 (2C), 127.6 (2C), 127.8
(2C), 128.2 (2C), 130.1, 132.6, 138.9, 148.3, 167.2,
172.8; IR (film) νmax: 3067, 2988, 2918, 2843, 1731,
1632, 1453, 1200, 1163, 757 cm1. HRMS (ESI) calcd for
[C26H32NO2]＋ (M＋H＋): 390.2428; found 390.2421.
(E)-Ethyl-2-{(E)-4-{(Z)-2-[(2,6-dimethylphenyl)-
imino]-2-phenylethylidene}cyclohexylidene}acetate
(3i) Following the general procedure I, the reaction of
amide 1a (113 mg, 0.5 mmol) with 2-(4-methylene-
cyclohexylidene)acetate (90 mg, 0.6 mmol, 1.2 equiv.
gave, after FC (eluent: EtOAc/n-hexane＝1/50), α,β-un-
aturated imine 3i (180 mg, yield: 93%) as a 1∶1 insep-
1
isomers. 3k: Yellow oil. H NMR (400 MHz, CDCl3,
data of the major isomer read from the spectrum of the
two geometric isomers) δ: 1.58 (t, J＝6.5 Hz, 2H), 1.90
－1.97 (m, 2H), 2.05 (s, 6H), 2.08－2.14 (m, 2H), 3.19
－3.24 (m, 2H), 3.86－3.93 (m, 4H), 5.09－5.16 (m,
1H), 6.89 (t, J＝7.5 Hz, 1H), 7.02 (d, J＝7.5 Hz, 2H),
7.40－7.49 (m, 3H), 7.94－8.04 (m, 2H); 13C NMR
(100 MHz, CDCl3, data of the major isomer read from
the spectrum of the two geometric isomers) δ: 18.1 (2C),
28.2, 31.0, 35.6, 38.2, 64.3 (2C), 107.5, 122.5, 122.8,
125.9 (2C), 127.7 (2C), 127.8 (2C), 128.3 (2C), 130.2,
132.5, 138.9, 148.3, 166.9; IR (film) νmax: 3063, 3021,
2959, 2922, 2851, 1628, 1474, 1458, 1200, 1109, 1059,
765, 694 cm1. HRMS (ESI) calcd for [C24H27NNaO2]＋
(M＋ Na＋): 384.1934; found 384.1923.
4-{(1E,3E)-3-[(2,6-Dimethylphenyl)imino]-3-(2-
nitrophenyl)prop-1-en-1-yl}phenol (3l)
Following
1
arable mixture of E/Z (olefin) isomers. Yellow oil. H
the general procedure I, the reaction of amide 1c (135
mg, 0.5 mmol) with 4-vinylphenol (72 mg, 0.6 mmol)
gave, after FC (eluent: EtOAc/n-hexane ＝ 1 ∶ 2),
α,β-unsaturated imine 3l (151 mg, yield: 81%). Yellow
NMR (400 MHz, CDCl3) δ: 1.22 (t, J＝7.1 Hz, 3H),
2.05 (s, 6H), 2.38－2.46 (m, 2H), 2.50－2.58 (m, 2H),
2.89 (br s, 2H), 3.17 (br s, 2H), 4.10 (q, J＝7.1 Hz, 2H),
5.17－5.22 (m, 1H), 5.40－5.45 (m, 1H), 6.86－6.92
(m, 1H), 6.99－7.05 (m, 2H), 7.39－7.49 (m, 3H), 7.95
－8.02 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: 14.2,
18.1, 29.9, 30.6, 38.0, 42.6, 60.5, 122.0, 122.4, 122.8,
125.8 (2C), 127.6 (2C), 127.8 (2C), 128.1 (2C), 128.3,
1
solid, m.p. 193－195 ℃; H NMR (500 MHz, Metha-
nol-d4) δ: 2.22 (s, 6H), 6.50 (d, J＝16.2 Hz, 1H), 6.60 (d,
J＝16.2 Hz, 1H), 6.67－6.73 (m, 2H), 7.01－7.10 (m,
3H), 7.12－7.17 (m, 2H), 7.76－7.84 (m, 2H), 7.90－
7.96 (m, 1H), 8.21－8.26 (m, 1H); 13C NMR (125 MHz,
Chin. J. Chem. 2017, XX, 1—8
© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
3

Huang and Huang
FULL PAPER
Methanol-d4) δ: 19.3 (2C), 117.7 (2C), 119.4, 126.2,
126.5 (2C), 128.3, 129.5, 130.1 (2C), 131.5 (2C), 132.5,
133.3, 135.9, 136.2, 144.4, 148.6, 150.6, 162.0, 169.3;
IR (film) νmax: 3375, 3068, 3014, 2917, 1569, 1524,
1345, 1274, 1175 cm1. HRMS (ESI) calcd for
[C23H21N2O3]＋ (M＋H＋): 373.1547; found 373.1546.
2,6-Dimethyl-N-[(E)-3-phenyl-1-(thiophen-2-yl)-
allylidene]aniline (3m) Following the general proce-
dure I, the reaction of amide 1d (116 mg, 0.5 mmol)
with styrene gave, after FC (eluent: EtOAc/n-hexane＝
1∶50), α,β-unsaturated imine 3m (141 mg, yield: 89%)
as a 15∶1 inseparable mixture of E/Z isomers. Yellow
oil. 1H NMR (400 MHz, CDCl3, data of the major iso-
mer read from the spectrum of the two geometric iso-
mers) δ: 2.08 (s, 6H), 6.59 (d, J＝16.4 Hz, 1H), 6.89－
6.95 (m, 1H), 7.03 (d, J＝7.4 Hz, 2H), 7.13－7.17 (m,
1H), 7.20 (d, J＝16.4 Hz, 1H), 7.26－7.32 (m, 5H),
7.48－7.52 (m, 1H), 7.53－7.56 (m, 1H); 13C NMR
(100 MHz, CDCl3, data of the major isomer read from
the spectrum of the two geometric isomers) δ: 18.2 (2C),
121.0, 123.2, 126.2 (2C), 127.3, 127.4 (2C), 127.8 (2C),
128.8 (2C), 129.3, 129.4, 135.5, 139.8, 143.8, 148.0,
159.5; IR (film) νmax: 3063, 3021, 2922, 2855, 1624,
1578, 1424, 1292, 1191, 757, 707, 690 cm1. HRMS
(ESI) calcd for [C21H20NS]＋ (M＋H＋ ): 318.1311;
found 318.1313.
(S)-5-{(1E,2E)-1-[(2,6-Dimethylphenyl)imino]-3-
phenylallyl}dihydrofuran-2(3H)-one (3n) Following
the procedure I, the reaction of amide 1e (117 mg, 0.5
mmol) with styrene gave, after FC (eluent: EtOAc/
n-hexane＝1∶3), α,β-unsaturated imine 3n (124 mg,
yield: 78%) as a single isomers. Yellow solid, m.p. 104
－105 ℃; []2D0 ＋149.5 (c 1.0, CHCl3); 1H NMR (400
MHz, CDCl3) δ: 1.97 (s, 3H), 1.98 (s, 3H), 2.49－2.68
(m, 2H), 2.77－2.88 (m, 1H), 2.89－2.98 (m, 1H), 5.74
(dd, J＝7.5, 4.3 Hz, 1H), 6.38 (d, J＝16.8 Hz, 1H), 6.91
－6.99 (m, 1H), 7.01－7.08 (m, 2H), 7.25 (d, J＝16.8
Hz, 1H), 7.27－7.33 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ: 17.9, 18.0, 25.1, 27.9, 78.0, 118.4, 123.5,
125.4, 125.6, 127.7 (2C), 127.9, 128.1, 128.8 (2C),
53.7, 122.0, 124.0, 125.0, 125.1, 125.5, 126.1, 126.2,
126.4, 126.5, 127.1, 128.2, 128.4, 130.4, 133.3, 135.6,
136.8, 144.1, 149.6, 165.1; IR (film) νmax: 3056, 2955,
2927, 2858, 1637, 1587, 1556, 1461, 1350, 1247, 1184,
797, 756 cm1; MS (ESI) m/z: 326 (M＋H＋, 100%);
HRMS (ESI) calcd for [C24H24N]＋ (M＋H＋): 326.1909;
found: 326.1908.
1-(1H-Inden-2-yl)pentan-1-one (4a)
Following
the procedure II, the reaction of amide 1g (115.2 mg,
1.0 mmol) with 1H-indene gave, after FC (eluent:
EtOAc/n-hexane＝1∶10), ketone 2m (141 mg, 70%).
1
Pale yellow oil. H NMR (400 MHz, CDCl3) δ: 0.95 (t,
J＝7.4 Hz, 3H), 1.40 (qt, J＝7.5, 7.5 Hz, 2H), 1.70 (tt,
J＝7.5, 7.5 Hz, 2H), 2.83 (t, J＝7.5 Hz, 2H), 3.67 (s,
2H), 7.30－7.37 (m, 2H), 7.48－7.57 (m, 2H), 7.63 (s,
1H) ; 13C NMR (100 MHz, CDCl3) δ: 13.9, 22.5, 27.0,
37.5, 38.6, 123.7, 124.5, 126.9, 127.9, 140.0, 142.9,
144.9, 146.1, 198.3; IR (film) νmax: 3064, 2951, 2922,
2847, 1658, 1600, 1478, 1384, 749, 716 cm1; MS (ESI)
m/z: 223 (M＋Na＋, 100%). HRMS (ESI) calcd for
[C14H16NaO]＋ (M＋Na＋): 223.1099; found 223.1098.
1-(1H-Inden-2-yl)pentan-1-one (4b)
Following
the general procedure II, the reaction of amide 1h (113
mg, 0.5 mmol) with styrene gave, after FC (eluent:
EtOAc/n-hexane＝1∶50), the known α,β-unsaturated
ketone 4b[9] (108 mg, yield: 98%). White solid, m.p.
1
70－71 ℃ (lit., 68.4－69.3 ℃); H NMR (400 MHz,
CDCl3) δ: 3.88 (s, 2H), 7.32－7.39 (m, 2H), 7.46－7.59
(m, 6H), 7.81－7.85 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ: 38.5, 123.9, 124.5, 127.0, 128.1, 128.3 (2C),
128.8 (2C), 131.8, 138.9, 143.0, 143.6, 145.0, 145.1,
192.9; IR (film) νmax: 3063, 3017, 2951, 2918, 2855,
1632, 1549, 1354, 1250, 1213, 1118, 753, 703 cm1; MS
(ESI) m/z: 243 (M＋Na＋, 100%).
(E)-6-Styryltetrahydro-2H-pyran-2-one (5) To a
cooled (0 ℃) solution of α,β-unsaturated ketone 4c
(116 mg, 0.5 mmol) and CeCl3•7H2O (223 mg, 0.6
mmol) in MeOH (10 mL), was added NaBH4 (39 mg,
1.0 mmol) in three portions. After being stirred for 2 h
at room temperature, the mixture was re-cooled to 0 ℃,
and 3 mol/L HCl (5 mL) was added, the aqueous phase
was extracted with CH2Cl2 (10 mL×3). The combined
organic layers were dried over anhydrous Na2SO4, fil-
tered, and concentrated under reduced pressure to give
crude product as a colorless oil, which was used in the
next step without further purification. The crude alcohol
was dissolved in 10 mL THF and cooled to 0 ℃. 0.2
mol/L aqueous LiOH (7.5 mL, 1.5 mmol) solution was
added. The solution was stirred for 1 h before it was
transferred into an emulsion of 20 mL 1 mol/L HCl in
20 mL EtOAc. The acidic aqueous layer was extracted
three times with EtOAc, the combined organic layers
were dried over Na2SO4 and the solvents were removed
under reduced pressure. A solution of the residue in 10
mL CH2Cl2 at 0 ℃ was treated with DMAP (30 mg,
0.25 mmol) followed by 1-[(3-dimethylamino)propyl]-
3-ethylcarbodiimide hydrochloride (EDC•HCl) (115 mg,
0.6 mmol). The mixture was stirred for 3 h at room
129.9, 135.2, 139.6, 147.0, 162.7, 177.0; IR (film) νmax
:
3065, 3023, 2953, 2914, 2850, 1777, 1627, 1165 cm1.
HRMS (ESI) calcd for [C21H21NO2Na]＋ (M＋Na＋):
342.1465; found 342.1472. Conditions for the chiral
HPLC analysis: Chiralpak OD-H＋G (n-hexane/ethanol,
85∶15), flow rate＝1.0 mL•min1, tR＝8.363 min, re-
spectively. The enantiomeric excess was determined to
be 88%.
N-((1H-Inden-2-yl)(naphthalen-2-yl)methylene)-
butan-1-amine (3o) Following the procedure I, the
reaction of amide 1f (114 mg, 0.5 mmol) with
1H-indene gave, after FC (eluent: EtOAc/n-hexane＝
1∶10), α,β-unsaturated imine 3o (120 mg, yield: 74%).
1
Yellow oil. H NMR (400 MHz, CDCl3) δ: 0.80 (t, J＝
7.3 Hz, 3H), 1.25 (qt, J＝7.5, 7.5 Hz, 2H), 1.60 (tt, J＝
7.4, 7.4 Hz, 2H), 3.08－3.26 (m, 2H), 3.98 (s, 2H), 6.40
(s, 1H), 7.14－7.640 (m, 9H), 7.90 (d, J＝8.4 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ: 13.9, 20.6, 33.3, 38.3,
4
www.cjc.wiley-vch.de
© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2017, XX, 1—8

Direct Synthesis of α,β-Unsaturated Ketimines and α,β-Enones
temperature, diluted with Et2O (10 mL) and subjected to
a filtration over silica gel. The filtrate was concentrated
under reduced pressure, and the residue purified by FC
(eluent: EtOAc/n-hexane＝1∶3) affording the known
lactone 5[10c] (85 mg, yield: 84% over 3 steps). Colorless
oil. 1H NMR (400 MHz, CDCl3) δ: 1.70－1.81 (m, 1H),
1.85－2.11 (m, 3H), 2.47－2.57 (m, 1H), 2.59－2.68 (m,
1H), 4.96－5.03 (m, 1H), 6.20 (dd, J＝16.0, 6.0 Hz,
1H), 6.67 (d, J＝16.0 Hz, 1H), 7.23－7.41 (m, 5H); 13C
NMR (100 MHz, CDCl3) δ: 18.2, 28.4, 29.5, 80.3, 126.6
(2C), 127.0, 128.1, 128.6 (2C), 132.0, 135.9, 171.1; IR
(film) νmax: 3058, 3026, 2953, 2924, 2850, 1729, 1236,
1041 cm1; MS (ESI) m/z: 225 (M＋Na＋, 100%).
unsaturated ketimines and β-amido-α,β-unsaturated ke-
timines could serve as versatile building blocks, howev-
er, to date, no practical synthesis has been reported.[11]
Next, the functional group compatibility of the reac-
tion was further examined. Methylenecyclohexane, a
2,2-dialkylalkene bearing an ester group (2h) reacted
smoothly with 1a to give 3h in 97% yield (ratio＝1∶1)
(Entry 8). A similar result was obtained using 2i, an al-
kene bearing an α,β-unsaturated ester moiety, which
produced chemoselectively 3i in 93% yield (ratio＝1∶
1) (Entry 9). These results showed that alkyl substituted
alkenes are effective nucleophiles in the coupling with
amides, while those bearing an electron-withdrawing
group failed to react. Furthermore, the reaction of keto
amide 2j, an alkene bearing an unprotected aliphatic
ketone group, was undertaken. To our delight, its reac-
tion with benzamide 1a proceeded chemoselectively at
the amido group to give keto-enimine 3j in 89% yield
(Entry 10). The observed good functional group com-
patibility is noteworthy because C－C bond-forming
reaction with substrates bearing either an aliphatic ester
or an aliphatic ketone is rare. The fact that under ordi-
nary reaction conditions, the reaction took place chemo-
selectively at the least reactive amido carbonyl group
and the more reactive ketone and ester carbonyl groups
remained intact is remarkable. Interestingly, the reaction
of the corresponding acetal 2k afforded the same ketone
enamine 3j in 63% yield, along with the acetal enamine
3k in 23% yield (Entry 11). This result implicates that
the reaction medium is acidic, which cleaves the acetal
protecting group before, during, and/or after the cou-
pling reaction. The C－C bond-forming reaction with
concomitant de-acetalization might be used as an ad-
vantageous procedure-economical method[12] for the
synthesis of natural products or medicinal agents. To
extend this tactic, the reaction of THP protected phenol
2l was examined. Following the general procedure, 2l
coupled smoothly with o-nitrobenzamide 1c which
yielded concomitantly O-deprotected product 3l in 91%
yield (Entry 12).
Results and Discussion
The reaction of 1-vinylnaphthelene (2a) was first
examined by following our previously established con-
ditions.[4a] Thus N-(2,6-dimethylphenyl)benzamide (1a)
was treated with triflic anhydride (Tf2O, 1.1 equiv.) and
2-fluoropyridine (2-F-Pyr., 1.2 equiv.) in CH2Cl2 at 0 ℃
for 10 min., and the resultant activated intermediate was
allowed reacting with 1-vinylnaphthelene (2a) at r.t. for
2 h. The desired enimine 3a was produced in 91% yield
with good geometric (E/Zimine) selectivity (ratio＝10∶1)
(Table 1, Entry 1). To demonstrate the flexibility of the
method, an alternative reductive coupling of N-(2,6-di-
methylphenyl)-1-naphthamide 1b with styrene was un-
dertaken, which yielded enimine 3b as an α,γ-substitu-
ents exchanged isomer of 3a in 89% yield as a 15∶1
geometric mixture (Entry 2). Employing 9-methylene-
9H-fluorene (2c) as a special 1,1-disubstituted alkene to
couple with benzamide 1a, (Z)-3c was obtained in 81%
yield as single geometric isomer (Entry 3). The reduc-
tive coupling of allyltrimethylsilane with amide 1a
yielded, instead of the expected β,γ-enimine, α,β-eni-
mine 3d as the only observable product in 80% yield
(geometric ratioimine＝10∶1) (Entry 4). It can be as-
sumed that β,γ-enamine was the primary adduct, and the
double bond migrated during the reaction and/or purifi-
cation procedure to yield the more stable α,β-unsatu-
rated ketimine. To further extend the scope of alkene
substrates, the reactions of functionalized alkenes 2e－
2g were undertaken. Although these compounds are
derivatives of acetaldehyde, they are also -nucleo-
philes, which can be viewed as a special class of func-
tionalized electron-rich olefins. Their reactions with
amides would provide an easy access to hetero-substi-
tuted enimines. Indeed, addition of ethyl vinyl ether 2e
to Tf2O-activated amide 1a produced β-ethoxy-α,β-un-
saturated ketimine 3e in 85% yield (imine geometric
ratio＝7∶1) (Entry 5). Reacting N-vinyl acetamide (2f)
with activated amide 1a afforded β-acetylamino-α,β-un-
saturated ketimine 3f in 76% yield with low imine E/Z
selectivity (ratio＝1.9∶1) (Entry 6). The reaction of
N-vinyl lactam 2g produced functionalized enimine 3g
in 81% yield with excellent geometric selectivity (ratio
＝9∶1) (Entry 7). It is worth noting that β-ethoxy-α,β-
To investigate the suitability of hetero-aromatic am-
ides in coupling with alkenes, the reaction of N-(2,6-di-
methyphenyl)thiophene-2-carboxamide (1d) was exam-
ined. As expected, 1d reacted with styrene to give,
without incidence, 3m in 87% yield (geometric ratio＝
6∶1) (Entry 13).
In our previous report,[4a] we have demonstrated that
the reductive coupling of styrene with an N-methyl am-
ide analogue of (S)-1e, readily available from L-glutamic
acid,[13] proceeded free of racemization. In the case of
lactone N-(2,6-dimethylphenyl)amide (S)-1e, its reduc-
tive coupling with styrene also proceeded smoothly to
furnish lactone-enimine derivative (S,E)-3n as a single
geometric isomer in 78% yield (Entry 14). This synthe-
sis allowed determining unambiguously the stereo-
chemistry of 3n as Eimine by single-crystal X-ray diffrac-
tion analysis[14] (Figure 1).
Chin. J. Chem. 2017, XX, 1—8
© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
5

Huang and Huang
FULL PAPER
Continued
Product
Regarding the N-substituents of amide substrates, in
our previous report,[4a] only N-(2,6-dimethylphenyl)-
amides and four N-methyl amides have been employed
in the reaction with styrene. Thus the reactions of
N-methyl, N-(n-butyl), and N-cyclohexyl, aliphatic or
aromatic amides with indene (2m) were investigated.
Indene (2m) can be viewed as a special 1,2-disubsti-
tuted alkene, whose coupling with N-n-butyl 2-naph-
thamide (1f) furnished enimine 3o in 74% yield (Entry
15). The coupling of indene (2m) with N-n-butyl ali-
phatic amide 1g afforded, after acidic hydrolysis with 3
mol/L HCl in ethanol, enone 4a in 70% yield (Entry 16).
Similarly, the reaction of indene with N-cyclohexyl
benzamide 1h yielded, after acidic hydrolysis, enone 4b
in 65% yield (Entry 17).
R1
H
Amide
R/R' (1)
(yieldb/%)
2
Entry
7
(E/Z)d
R2
R3
O
Ph/Ar (1a)
2g
3g (81f, 9∶1)
N
(97c, 1 1e)
8
9
Ph/Ar (1a)
Ph/Ar (1a)
3h
∶
2h
2i
3i (93c, 1∶1e)
10 Ph/Ar (1a)
11 Ph/Ar (1a)
3j (89c, 10∶1)
3j (62c, 10∶1)
2j
O
It is worth mentioning that attempted reactions of
benzamide 1a with cyclohexene (Entry 18), and forma-
mide 1i with styrene (Entry 19) were unsuccessful,
while that of (S)-2-methoxy-2-phenylacetamide 1j with
styrene led only to the recovery of starting material (En-
try 20).
O
2k
2l
＋
3k (23c, 10∶1)
O
2-NO2C6H4/Ar
(1c)
12
3l (91c)
THPO
13 2-Thienyl/Ar (1d)
3m (87f, 6∶1)
3n (78c, E)
2b
2b
Table 1 Direct addition of functionalized alkenes to Tf2O-acti-
vated secondary amidesa
14
1e
2-Naphthyl/n-Bu
15
3o (74c, 6∶1)
4a (70)c,g
2m
2m
2m
(1f)
16 n-Bu/Me (1g)
17 Ph/c-hex (1h)
4b (65)c,g
18 Ph/Ar (1a)
19 H/Ar (1i)
Ndh
Nd
2n
2b
Product
Amide
R/R' (1)
Entry
(yieldb/%)
2
20
Recovered SM
2b
(E/Z)d
1j
a Reaction conditions: Amide (1.0 equiv.), 2-F-Pyr. (1.2 equiv.),
1
2
3
Ph/Ar (1a)
3a (91c, 10∶1)
3b (89c, 15∶1)
3c (81f, Z)
2a
2b
2c
CH2Cl2 (0.25 mol/L), then 0 ℃, Tf2O (1.1 equiv.), 10 min. Al-
c
kene (1.2 equiv), 2 h. b Isolated yield. Reaction ran at room tem-
1
perature (r.t.). d The E/Zimine ratio determined by H NMR. e The
1-Naphthyl/Ar
1
E/Z ratio of alkene determined by H NMR; f Reaction ran at
(1b)
40 ℃. g Hydrolysis conditions: EtOH and 3 mol/L HCl, reflux.
h No desired product isolated.
Ph/Ar (1a)
4
5
Ph/Ar (1a)
Ph/Ar (1a)
3d (80c, 10∶1)
3e (85f, 7∶1)
2d
2e
N
S
O
Ph
O
6
6
Ph/Ar (1a)
3f (76f, 1.9∶1)
2f
(E)-3n
Figure 1 Single-crystal X-ray diffraction analysis of (E)-3n.
www.cjc.wiley-vch.de
© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2017, XX, 1—8

Direct Synthesis of α,β-Unsaturated Ketimines and α,β-Enones
As a demonstration of the synthetic utility of the
chemoselective reaction, the synthesis of (E)-6-styryl-
tetrahydro-2H-pyran-2-one (5), an immediate interme-
diate for the syntheses of a series of styryl lactone natu-
ral products[8b,8d,10] including ( ± )-goniothalamine
(6),[10c-10e] ( ± )-goniothalamine oxide (7),[10a,15b]
groups including acetal, ester, α,β-unsaturated ester, and
ketone, as well as enol ether and enamides provides a
straightforward access to functionalized enimines in
good to excellent yields. In the case of p-OTHP-styrene,
concomitantly O-deprotected product was obtained in
high yield constituting a direct introduction of (4-hy-
droxyphenyl)vinyl group. On the other hand, the amide
partner has been extended to N-n-butyl and N-cyclo-
hexyl amides as well as to heteroaromatic amide. The
one-step access to β-ethoxy-α,β-unsaturated ketimines
and β-amido-α,β-unsaturated ketimines from easily
available starting materials is remarkable, because to
date, no practical synthesis of these multi-functionalized
compounds has been reported. Possessing multiple
functionalities and ambident reactivities, the enimines
thus obtained constitute a class of versatile building
blocks, which will find applications in both organic
synthesis and medicinal chemistry.[17]
( ± )-goniodiol (8),[10a,10f,15c] ( ± )-leiocarpin
A
(9),[10a,10b,15d] ( ± )-9-deoxygoniopypyrone (10),[10f,15c]
and (±)-7-epi-goniodiol (11)[10f,15a] (Scheme 2), was
undertaken. Our synthesis of 5 started from the aminol-
ysis of commercially available glutaric anhydride 12,
which gave the amido ester 1k in 98% yield. Chemose-
lective reductive coupling of amido ester 1k furnished
enone-ester 4c in 97% yield. Chemoselective Luche
reduction[16] followed by saponification and lactoniza-
tion yielded δ-styryl-δ-lactone (5).
Scheme 2 Synthesis of (±)-styryl-δ-lactone (5), a key interme-
diate in the synthesis of styryl lactone natural products 6－11
one-pot
2,6-dimethylaniline
CHCl3, r.t. 0.5 h;
Acknowledgment
O
O
O
O
The authors are grateful to the National Natural Sci-
ence Foundation of China (21332007) and to the Pro-
gram for Changjiang Scholars and Innovative Research
Team in University of Ministry of Education, China, for
financial support.
MeO
N
H
SOCl2, MeOH, r.t. 2 h
98%
O
1k
12
one-pot
97%
Tf2O, 2-F-Pyr. CH2Cl2, 0 °C
Styrene, 40 °C
(1) CeCl3 7H2O, NaBH4
MeOH, 15 C, 1 h
O
O
O
References
(2) LiOH, THF/H2O, r.t.
MeO
Ph
[1] (a) Tan, P. W.; Seayad, J.; Dixon, D. J. Angew. Chem., Int. Ed. 2016,
55, 13436; (b) He, L.; Gu, M.-D.; Wang, D.-X.; Zhao, L.; Wang,
M.-X. Acta Chim. Sin. 2015, 73, 1018; (c) Sun, Y.-N.; Wang, C.-L.;
Zhang, N.; Wang, Z.; Liu, Z.-L.; Liu, J.-L. Chem. Lett. 2014, 25,
1503; (d) Shi, X.-Y.; Dong, X.-F.; Fan, J.; Liu, K.-Y.; Wei, J.-F.; Li,
C.-J. Sci. China Chem. 2015, 58, 1286; (e) Shi, Z.-J. Sci. China
Chem. 2015, 58, 1243; (f) He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza,
B. N.; Spangler, J. E.; Homs, A.; Yu, J.-Q. Science 2014, 343, 1216;
(g) Medley, J. W.; Movassaghi, M. Angew. Chem., Int. Ed. 2012, 51,
4572; (h) Smith, K.; El-Hiti, G. A.; Alshammari, M. B. J. Org. Chem.
2012, 77, 11210; (i) Chen, Z.-H.; Chen, Z.-M.; Zhang, Y.-Q.; Tu,
Y.-Q.; Zhang, F.-M. J. Org. Chem. 2011, 76, 10173; (j) Jakubec, P.;
Kyle, A. F.; Calleja, J.; Dixon, D. J. Tetrahedron Lett. 2011, 52, 6094;
(k) Paetzold, J.; Bäckvall, J. E. J. Am. Chem. Soc. 2005, 127, 17620.
[2] For recent reviews, (a) Sato, T.; Chida, N. J. Syn. Org. Chem. Jap.
2016, 74, 599; (b) Kaiser, D.; Maulide, N. J. Org. Chem. 2016, 81,
4421; (c) Pace, V.; Holzer, W.; Olofsson, B. Adv. Synth. Catal. 2014,
356, 3697; (d) Sato, T.; Chida, N. Org. Biomol. Chem. 2014, 12,
3147; (e) Pace, V.; Holzer, W. Aust. J. Chem. 2013, 66, 507.
[3] For direct transformation of tert-amides with C－C bond formation,
see: (a) Nakajima, M.; Sato, T.; Chida, N. Org. Lett. 2015, 17, 1696;
(b) Romanens, A.; Bélanger, G. Org. Lett. 2015, 17, 322; (c) Gregory,
A. W.; Chambers, A.; Hawkins, A.; Jakubec, P.; Dixon, D. J. Chem.
Eur. J. 2015, 21, 111; (d) Nakajima, M.; Oda, Y.; Wada, T.;
Minamikawa, R.; Shirokane, K.; Sato, T.; Chida, N. Chem. Eur. J.
2014, 20, 17565; (e) Yoritate, M.; Meguro, T.; Matsuo, N.;
Shirokane, K.; Sato, T.; Chida, N. Chem. Eur. J. 2014, 20, 8210; (f)
Peng, B.; Geerdink, D.; Farès, C.; Maulide, N. Angew. Chem., Int.
Ed. 2014, 53, 5462; (g) Shirokane, K.; Wada, T.; Yoritate, M.;
Minamikawa, R.; Takayama, N.; Sato, T.; Chida, N. Angew. Chem.,
Int. Ed. 2014, 53, 512; (h) Peng, B.; Geerdink, D.; Maulide, N. J.
Am. Chem. Soc. 2013, 135, 14968; (i) Valerio, V.; Petkova, D.; Mad-
elaine, C.; Maulide, N. Chem. Eur. J. 2013, 19, 2606; (j) Yanagita, Y.;
4c
(3) DMAP, EDC HCl
CH2Cl2. r.t. 4 h
84% over three steps
O
one-pot
LDA, THF, 15 °C;
O
O
Cl
S
Ph
Ph
t-Bu
Ph
N
( )-5
( )-goniothalamine (6)
ref. 10c
63%
O
H
O
H O
OH
O
O
Ph
O
O
Ph
Ph
HO
H
O
OH
( )-goniothalamine oxide
(7) (one step from 6)
ref. 10a
( )-goniodiol (8)
( )-leiocarpin A (9)
(one step from 6)
(two steps from 6)
ref. 10a
ref. 10b
O
H
H O
Ph
OH
O
O
Ph
O
HO
H
OH
( )-9-deoxygoniopypyrone (10) ( )-7-epi-goniodiol (11)
(one step from 6)
(one step from 6)
ref. 10f
ref. 10f
Conclusions
In summary, the Tf2O-mediated direct dehydrative
addition reaction of secondary amides with alkenes has
been extended in terms of versatility. The use of func-
tionalized alkenes incorporating a series of functional
Chin. J. Chem. 2017, XX, 1—8
© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
7

Huang and Huang
FULL PAPER
Nakamura, H.; Shirokane, K.; Kurosaki, Y.; Sato, T.; Chida, N.
Chem. Eur. J. 2013, 19, 678; (k) Peng, B.; O'Donovan, D. H.;
Jurberg, I. D.; Maulide, N. Chem. Eur. J. 2012, 18, 16292; (l) Shiro-
kane, K.; Kurosaki, Y.; Sato, T.; Chida, N. Angew. Chem., Int. Ed.
2010, 49, 6369; For chemoselective transformations of sec-amides
with C－C bond formations, see: (m) Oda, Y.; Sato, T.; Chida, N.
Org. Lett. 2012, 14, 950; (n) Bechara, W. S.; Pelletier, G.; Charette,
A. B. Nat. Chem. 2012, 4, 228; (o) Xiao, K.-J.; Huang, Y.-H.; Huang,
P.-Q. Acta Chim. Sin. 2012, 70, 1917; (p) Movassaghi, M.; Hill, M.
D. Org. Lett. 2008, 10, 3485; (q) Cui, S.-L.; Wang, J.; Wang, Y.-G. J.
Am. Chem. Soc. 2008, 130, 13526; (r) Dong, Q.-L.; Liu, G.-S.; Zhou,
H.-B.; Chen, L.; Yao, Z.-J. Tetrahedron Lett. 2008, 49, 1636; (s)
Movassaghi, M.; Hill, M. D.; Ahmad, O. K. J. Am. Chem. Soc. 2007,
129, 10096; (t) Movassaghi, M.; Hill, M. D. J. Am. Chem. Soc. 2006,
128, 4592; (u) Marquart, A. L.; Podlogar, B. L.; Huber, E. W.; De-
meter, D. A.; Peet, N. P.; Weintraub, H. J. R.; Angelastro, M. R. J.
Org. Chem. 1994, 59, 2092; (v) Gawley, R. E.; Chemburkar, S. Tet-
rahedron Lett. 1986, 27, 2071.
Y.-L.; Chang, Y.-L.; Lee, S.-J.; Wu, Y.-C. J. Nat. Prod. 2003, 66,
487.
[8] For bioactivities, see: (a) Vendramini-Costa, D. B.; Spindola, H. M.;
de Mello, G. C.; Antunes, E.; Pilli, R. A.; de Carvalho, J. E. Life Sci.
2015, 139, 83; (b) Mohideen, M.; Zulkepli, S.; Nik-Salleh, N.-S.;
Zulkefeli, M.; Weber, J.-F. F. A.; Rahman, A. F. M. M. Arch. Pharm.
Res. 2013, 36, 812; (c) Wach, J.-Y.; Güttinger, S.; Kutay, U.;
Gademann, K. Bioorg. Med. Chem. Lett. 2010, 20, 2843; (d)
Vendramini-Costa, D. B.; de Castro, I. B. D.; Ruiz, A. L. T. G.;
Marquissolo, C.; Pilli, R. A.; de Carvalho, J. E. Bioorg. Med. Chem.
2010, 18, 6742; (e) de Fátima, Â.; Kohn, L. K.; de Carvalho, J. E.;
Pilli, R. A. Bioorg. Med. Chem. 2006, 14, 622; (f) Ali, A. M.;
Mackeen, M. M.; Hamid, M.; Aun, Q. B.; Zauyah, H.; Azimathol, H.
L. P.; Kawazu, K. Planta Med. 1997, 63, 81.
[9] Tu, S.; Sha, Y.; Xu, L.; Xiao, Z.; Ye, L.; Fang, J. J. Chem. Res. 2010,
34, 254.
[10] For selected synthesis, see: (a) Ramesh, P.; Rao, T. P. J. Nat. Prod.
2016, 79, 2060; (b) Meruva, S. B.; Rao, K. R.; Mohammed, A.; Da-
hanukar, V. H.; Kumar, U. K. S.; Dubey, P. K. Syn. Commun. 2016,
46, 187; (c) Fischer, T.; Pietruszka, J. Adv. Synth. Catal. 2012, 354,
2521; (d) Das, B.; Nagendra, S.; Reddy, C. R. Tetrahedron:
Asymmetry 2011, 22, 1249; (e) Bressy, C.; Bargiggia, F.; Guyonnet,
M.; Arseniyadis, S.; Cossy, J. Synlett 2009, 565; (f) Chen, J.; Lin,
G.-Q.; Wang, Z.-M.; Liu, H.-Q. Synlett 2002, 1265.
[11] (a) Barluenga, J.; Tomás, M.; Suárez-Sobrino, A.; Gotor, V.
Tetrahedron Lett. 1988, 29, 4855; (b) Nishio, T.; Omote, Y. J. Chem.
Soc., Perkin Trans. 1 1984, 239.
[12] For recent examples, see: (a) Huang, P.-Q.; Wang, Y.; Luo, S.-P.;
Geng, H.; Ruan, Y.-P.; Wang, A.-E Tetrahedron Lett. 2015, 56, 1255;
(b) Luo, S.-P.; Peng, Q.-L.; Xu, C.-P.; Wang, A.-E; Huang, P.-Q.
Chin. J. Org. Chem. 2014, 32, 757.
[4] For the direct transformations of secondary amides, see: (a) Huang,
P.-Q.; Huang, Y.-H.; Geng, H.; Ye, J.-L. Sci. Rep. 2016, 6, 28801; (b)
Huang, P.-Q.; Huang, Y.-H.; Xiao, K.-J.; Wang, Y.; Xia, X.-E. J. Org.
Chem. 2015, 80, 2861; (c) Huang, P.-Q.; Ou, W.; Ye, J.-L. Org.
Chem. Front. 2015, 2, 1094; (d) Wang, A.-E; Chang, Z.; Liu, Y.-P.;
Huang, P.-Q. Chin. Chem. Lett. 2015, 26, 1055; (e) Zheng, J.-F.;
Qian, X.-Y.; Huang, P.-Q. Org. Chem. Front. 2015, 2, 927; (f) Zheng,
J.-F.; Xie, Z.-Q.; Chen, X.-J.; Huang, P.-Q. Acta Chim. Sin. 2015, 73,
705; For the direct transformations of secondary amides, see: (g)
Huang, P.-Q.; Wang, Y.; Xiao, K.-J.; Huang, Y.-H. Tetrahedron 2015,
71, 4248; (h) Geng, H.; Huang, P.-Q. Tetrahedron 2015, 71, 3795; (i)
Huang, P.-Q.; Geng, H.; Tian, Y.-S.; Peng, Q.-R.; Xiao, K.-J. Sci.
China Chem. 2015, 58, 478; (j) Mao, Z.-Y.; Huang, S.-Y.; Gao,
L.-H.; Wang, A.-E; Huang, P.-Q. Sci. China Chem. 2014, 57, 252.
[5] For recent reviews, see: (a) Neely, J. M.; Rovis, T. Org. Chem. Front.
2014, 1, 1010; (b) Monbaliu, J.-C. M.; Masschelein, K. G. R.; Ste-
vens, C. V. Chem. Soc. Rev. 2011, 40, 4708; For selected recent ex-
amples, see: (c) Braunstein, H.; Langevin, S.; Khim, M.; Adamson,
J.; Hovenkotter, K.; Kotlarz, L.; Mansker, B.; Beng, T. K. Org. Bio-
mol. Chem. 2016, 14, 8864; (d) Fallon, B. J.; Garsi, J.-B.; Derat, E.;
Amatore, M.; Aubert, C.; Petit, M. ACS Catal. 2015, 5, 7493; (e)
Yamakawa, T.; Yoshikai, N. Org. Lett. 2013, 15, 196; (f) Duttwyler,
S.; Lu, C.; Rheingold, A. L.; Bergman, R. G.; Ellman, J. A. J. Am.
Chem. Soc. 2012, 134, 4064; (g) Stokes, S.; Bekkam, M.; Rupp, M.;
Mead, K. T. Synlett 2012, 23, 389.
[13] Ruan, Y.-P.; Wei, B.-G.; Xu, X.-Q.; Liu, G.; Yu, D.-S.; Liu, L.-X.;
Huang, P.-Q. Chirality 2005, 17, 595.
[14] CCDC 1510907 (3n) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif or pm application to CCDC,
12 Union Road, Cambridge CB2 1 EZ, UK [fax: ＋44-1223/
336-033; email: deposit@ccdc.cam.ac.uk].
[15] (a) Mu, Q.; Tang, W.; Li, C.; Lu, Y.; Sun, H.; Zheng, H.; Hao, X.;
Zheng, Q.; Wu, N.; Lou, L.; Xu, B. Heterocycles 1999, 51, 2969; (b)
Mu, Q.; Li, C. M.; Zhang, H. J.; Wu, Y.; Sun, H. D. Chin. Chem. Lett.
1996, 7, 617; (c) Fang, X. P.; Anderson, J. E.; Chang, C. J.;
McLaughlin, J. L.; Fanwick, P. E. J. Nat. Prod. 1991, 54, 1034; (d)
Sam, T. W.; Chew, S. Y.; Sabirin, M.; Gan, E. K.; Dzulkifli, R.;
Abdul, L. M. Tetrahedron Lett. 1987, 28, 2541.
[6] (a) Thebtaranonth, C.; Thebtaranonth, Y. The Chemistry of Enones,
vol. 29, Eds.: Patai. S.; Rappoport, Z. Wiley, New York, 1989, p. 199;
(b) Foster, C. E.; Mackie, P. R. In Comprehensive Organic Func-
tional Group Transformations II, Vol. 3, chapter 3.05, Eds.: Taylor,
R. J. K.; Katritzky, A. R., Elsevier, Oxford, 2005, p. 215.
[16] Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226.
[17] For the latest progress of the current reaction, see: Huang, P.-Q.;
Huang, Y.-H.; Wang, S.-R. Org. Chem. Front. 2017, 4, DOI:
10.1039/c6qo00720a.
[7] For isolation, see: (a) Hlubucek, J. R.; Robertson, A. V. Aust. J.
Chem. 1967, 20, 2199; (b) Lan, Y.-H.; Chang, F.-R.; Yu, J.-H.; Yang,
(Pan, B.; Qin, X.)
8
www.cjc.wiley-vch.de
© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2017, XX, 1—8