Synthesis of trisubstituted olefins via nickel-catalyzed decarboxylative hydroalkylation of internal alkynes

Article abstract of DOI:10.1016/j.tet.2018.10.037

A novel NiH-catalyzed decarboxylative hydroalkylation of internal alkynes has been developed. Trisubstituted olefins were obtained in moderate to good yields with good regioselectivities. The reaction involves cis addition of NiH to the internal alkyne. The reaction shows good functional-group tolerance.

Full text of DOI:10.1016/j.tet.2018.10.037

Accepted Manuscript
Synthesis of trisubstituted olefins via nickel-catalyzed decarboxylative hydroalkylation
of internal alkynes
Xiao-Yu Lu, Jing-Song Li, Mei-Lan Hong, Jin-Yu Wang, Wen-Jing Ma
PII:
S0040-4020(18)31243-2
10.1016/j.tet.2018.10.037
TET 29870
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 6 July 2018
Revised Date: 8 October 2018
Accepted Date: 15 October 2018
Please cite this article as: Lu X-Y, Li J-S, Hong M-L, Wang J-Y, Ma W-J, Synthesis of trisubstituted
olefins via nickel-catalyzed decarboxylative hydroalkylation of internal alkynes, Tetrahedron (2018), doi:
https://doi.org/10.1016/j.tet.2018.10.037.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Synthesis of Trisubstituted Olefins via Nickel-Catalyzed Decarboxylative Hydroalkylation of
Internal Alkynes
Xiao-Yu Lu, Jing-Song Li, Mei-Lan Hong, Jin-Yu Wang, Wen-Jing Ma
a College of Materials and Chemical Engineering, Chuzhou University, Hui Feng Road 1, Chuzhou 239000, PR
China;
b School of Chemistry and Chemical Engineering, AnHui University, Hefei, 230601, China.

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of Trisubstituted Olefins via Nickel-Catalyzed Decarboxylative
Hydroalkylation of Internal Alkynes
Xiao-Yu Lu, * a,b Jing-Song Li, a Mei-Lan Hong, a Jin-Yu Wang, a Wen-Jing Ma a
a College of Materials and Chemical Engineering, Chuzhou University, Hui Feng Road 1, Chuzhou 239000, PR China;
b School of Chemistry and Chemical Engineering, AnHui University, Hefei, 230601, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel NiH-catalyzed decarboxylative hydroalkylation of internal alkynes has been developed.
Trisubstituted olefins were obtained in moderate to good yields with good regioselectivities. The
reaction involves cis addition of NiH to the internal alkyne. The reaction shows good functional-
group tolerance.
Available online
2018 Elsevier Ltd. All rights reserved
.
Keywords:
Trisubstituted Olefins
Decarboxylative
Hydroalkylation
Internal Alkynes
Nickel-Catalyzed
1. Introduction
Substituted alkenes are important synthetic intermediates, and
are widely present in drug molecules and chemical materials [1-
10]. In the past century, various methods for the synthesis of
substituted olefins have been reported [11-17]. Alkynes are one
of the most important organic synthons [18-23]. Recently,
hydroalkylation reactions of alkynes have been identified as a
convenient method for obtaining substituted alkenes. The use of
different substituted alkynes enables control of the regio- and
stereo-selectivity of the hydroalkylation reaction to produce
different olefins. Lalic’s, Hu’s, Fu’s, and Nishikata’s groups
achieved control of the regioselectivity of the hydroalkylation of
terminal alkynes (Scheme 1a) [24-28]. These methods can be
used to synthesize different disubstituted olefins. Trisubstituted
alkenes are in great demand in organic chemistry. The efficient
synthesis of stereochemically well-defined trisubstituted alkenes
is a significant challenge. In this context, we achieved the first
example of regio- and stereo-selective hydroalkylation of internal
alkynes with alkyl halides (Scheme 1b) [29]. This provides a
highly efficient method for the synthesis of trisubstituted alkenes.
Carboxylic acids are one of the most important classes of
organic compounds, and are found in many drug molecules and
natural products. Recently, the decarboxylation of carboxylic
acids and their derivatives has emerged as a powerful tool for the
construction of C–C bonds. The decarboxylation of carboxylic
acids has been extensively explored by MacMillan’s group [30-
35]. Among carboxylic acid derivatives, redox-active esters
synthesized from aliphatic carboxylic acids and N-
hydroxyphthalimide (NHPI) are efficient electrophiles in cross-
Scheme 1. Hydroalkylation of Alkynes with Alkyl Electrophiles.
coupling reactions [36-37]. For example, Baran’s and Weix’s
group reported a series of Ni-catalyzed cross-coupling reactions
with redox-active esters (NHPI esters) as alkyl electrophiles [38-
41]. Inspired by these results, we have explored the
decarboxylative hydroalkylation reactions of alkynes. Recently,
MacMillan’s group reported
a photoinduced Ni-catalyzed
decarboxylative alkyne hydroalkylation reaction (Scheme 1c)
[32]. The scope of this work included terminal and alkyl–alkyl
internal alkynes. The authors did not report decarboxylative
hydroalkylation of aryl–alkyl acetylenes. The authors suggested
that the reaction proceeds via Ni–alkyl migratory insertion,
therefore the reaction mechanism is different from that in Ni–
silane-catalyzed hydroalkylation of alkynes. Based on our

2
Tetrahedron
ACCEPTED MANUSCRIPT
previous work, we have developed the first example of Ni–
silane-catalyzed regio- and stereo-selective decarboxylative
hydroalkylation of phenyl–alkyl acetylenes (Scheme 1d). This
method does not require sensitive organometallic reagents and
both the alkynes and carboxylic acids are readily available
substrates. This new decarboxylative hydroalkylation reaction
shows good functional-group compatibility and provides a highly
efficient method for synthesizing trisubstituted alkenes from
carboxylic acids and alkynes.
Table 2 Scope of cross-couping.
2. Results and discussion
We chose 1-phenyl-1-propyne (1a) and redox-active NHPI
ester (2a) for the model reaction (Table 1). First, we examined
the use of previously reported conditions for Ni-catalyzed
hydroalkylation of internal alkynes with alkyl halides in our
decarboxylative reaction. However, only 5% yield was obtained
(entry 1). Next, we examined the effects of different bases on the
decarboxylative reaction (entries 2-7). When LiOAc or Ca(OAc)2
was used as the base, the desired product was obtained in
moderate yield (entries 6 and 7). We then used Ca(OAc)2 as a
base and examined the effects of different nitrogen ligands,
namely phenanthroline (L1), pybox (L2), and 4,4'-dimethoxy-
2,2'-bipyridine (L3), on the reaction (entries 8-10). Use of these
ligands did not increase the yield. We then screened a series of
silanes to optimize the reaction conditions (entries 11-14). Use of
(Me2SiH)2O as the hydride donor gave the optimal results (82%
GC yield and 75% isolated yield, entry 13, product ratio
>50:1). When another Ni source, i.e., Ni(PPh3)2Cl2, was used
instead of NiBr2·diglyme, the yield decreased (entry 15). Finally,
no product was detected in the absence of a Ni source (entry 16).
Table 1. Optimization of the reaction conditions.
With the optimized conditions in hand, we explored the
scope of the decarboxylative hydroalkylation reaction. A
variety of aryl–alkyl acetylenes and aliphatic acid NHPI
esters were successfully converted to the desired products in
modest to excellent yields (Table 2). Coupling partners with
different functional groups were satisfactorily converted to
the products. The reaction worked well with cyclic aliphatic
acid esters, and the ring size had no effect on the reaction
conversion (3a-3f). Because of the mild reaction conditions,
the decarboxylative hydroalkylation of internal alkynes
showed good compatibility with many functional groups,
e.g., ether (3d), carbamate (3f), sulfonamide (3h), and amide
En
try
1
2
3
4
5
6
7
8
9
10
11
12
Cat.
Ligand
Base
Silane
Yield %
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
dtbbpy
dtbbpy
dtbbpy
dtbbpy
dtbbpy
dtbbpy
dtbbpy
L1
L2
L3
dtbbpy
dtbbpy
K2CO3
Na2CO3
Cs2CO3
Mg(OAc)2
KOAc
LiOAc
Ca(OAc)2
Ca(OAc)2
Ca(OAc)2
Ca(OAc)2
Ca(OAc)2
Ca(OAc)2
Ca(OAc)2
Ca(OAc)2
Ca(OAc)2
Ca(OAc)2
DEMS
DEMS
DEMS
DEMS
DEMS
DEMS
DEMS
DEMS
DEMS
DEMS
(EtO)3SiH
Ph3SiH
(Me2SiH)2O
PMHS
(Me2SiH)2O
(EtO)3SiH
5
3
trace
10
5
55
61
8
5
46
65
(3i). Some sensitive functional groups such as nitrile (3l),
ketone (3e and 3n), and ester (3n) groups were well
tolerated. Some heterocyclic compounds such as pyrans (3k
and 3l), naphthalene (3o), piperidines (3f, 3h, and 3i), and
pyridine (3p) also survived in the reaction. The internal
alkene group (3g) does not affect the decarboxylative
hydroalkylation of internal alkynes. Aryl–Cl (3m) and aryl–
Br (3q) bonds did not hinder the reaction. In addition to
aryl–alkyl acetylenes, aryl–aryl acetylenes (3q and 3r) were
suitable reaction substrates. Acyclic primary aliphatic acid
esters, e.g., 3s, were also converted to the product. Acyclic
secondary alkyl NHPI ester is also a suitable substrate (3t).
The data in Table 2 show that our protocol gave excellent
regio- and stereo-selectivity (all product ratios >40:1). More
1
13 NiBr2·diglyme dtbbpy
82(75 c)
68
14
15
16
NiBr2·diglyme
Ni(PPh3)2Cl2
-
dtbbpy
dtbbpy
dtbbpy
46
traceb
a
The reactions were conducted on a 0.2 mmol scale. Conditions: 2.5 equiv 1a, 1
equiv 2a, 12 mol% NiBr2·diglyme, 15 mol% dtbbpy, 3 equiv base, 180 ꢀL silane,
1 mL DMAc, 40 oC, 4 h. Yields determined by GC analysis use biphenyl as
internal standard. b Without NiBr2·diglyme. Yield of isolated product. DEMS=
c
diethoxymethylsilane, PMHS= poly-(methylhydrosiloxane).

3
importantly, the regioselectivity of this NiH-catalyzed alkyl
ACCEPTED MANUSCRIPT
addition to internal alkynes is different from that in Wu’s
photoinduced Ni-catalyzed hydroalkylation of aryl–alkyl
acetylenes [42].
To further demonstrate the synthetic value of the
decarboxylative internal alkyne hydroalkylation reaction, we
explored its use in the late-stage modification of active
molecules (Scheme 2). Modification of the NHPI ester of
lithocholic acid with 1-phenyl-1-propyne gave 3ba with
high selectivity and in good yield 65% (Scheme 2a).
Modification of the NHPI ester of dehydrocholic acid, which
has three base-sensitive ketone groups, with 1-phenyl-1-
propyne gave 3ca in moderate yield (Scheme 2b).
Scheme 3 Reaction Mechanism
We investigated the reaction mechanism by adding
2,2,6,6-tetramethylpiperidineoxy (TEMPO; 0.5 equiv). The
reaction was completely inhibited (Scheme 3A, we did not
observe the TEMPO-trapped alkyl radical, and the starting
materials are not detected). Recent reports on
decarboxylative reactions of redox-active esters (NHPI
esters) [43-46] have suggested that the decarboxylative
hydroalkylation reaction proceeds via a radical-type process.
Furthermore, on the basis of recent work on Ni-silane-
catalyzed addition of alkyl radicals to C–C π bonds
[27,29,43,47,48], we propose that the reaction proceeds via
NiH cis addition. Promotion by a base first generates the
Scheme 2a. Modification of lithocholic acid.
Ni(I) hydride intermediate (I). This intermediate then inserts
into the alkyne via cis addition to give (II). Finally,
oxidative addition and reductive elimination give the
product (Scheme 3B). Further studies are on-going
.
3. Conclusion
Carboxylic acids are among the most important feedstock
compounds, and are widely found in drug molecules and natural
products. Carboxylic acids have important applications in organic
chemistry. In summary, we have developed the first example of
NiH-catalyzed decarboxylative hydroalkylation of NHPI esters
with aryl–alkyl acetylenes. The reaction shows good functional-
group tolerance and provides an efficient method for the
synthesis of trisubstituted olefins. This reaction also provides a
direct method for the modification of active organic molecules
containing carboxylic acid groups.
Scheme 2b. Modification of Dehydrocholic acid.
4. Experimental section
4.1 Preparation of redox active esters
The corresponding carboxylic acids (10 mmol, 1 equiv),
N-hydroxyphthalimide (11 mmol, 1.1 equiv), and 4-
dimethylaminopyridine (0.1 mmol, 10 mol%) were mixed in
a flask with a magnetic stirring bar, 30 mL CH2Cl2 was
added. Then a solution of N, N´-dicyclohexylcarbodiimide
(11 mmol, 1.1 equiv) in CH2Cl2 (10 mL) was added slowly
at room temperature. The reaction mixture was maintained
at room temperature with stirring for 5-10h. The white
precipitate was filtered off and the solution was concentrated
on a rotary evaporator. The residue was purified by flash

4
Tetrahedron
column chromatography to give corresponding redox
1174, 1105, 1025, 853, 749, 700. HRMS (APCI) calcd for
ACCEPTED MANUSCRIPT
C13H15O (M+H+): 187.1117; found: 187.1117.
active esters.
4.8 tert-butyl (E)-3-(1-phenylprop-1-en-2-yl)piperidine-1
4.2 general procedure
carboxylate(3f)
In air, NiBr2.diglyme (12 mol%), Ca(OAc)2 (3 equiv.),
dtbbpy (15 mol%) and alkyl NHPI ester (0.2 mmol) were
added to a Schlenk tube equipped with a stir bar. The vessel
was evacuated and filled with argon (three cycles). 1 mL
DMAc was added in turn under argon atmosphere, then
alkyne and (Me2SiH)2O (180 ꢀL) was added. The reaction
was stirred at the 40oC for 4h. Then the reaction was diluted
with EtOAc, filtered through silica gel with copious
washings. The residue was concentrated, and purified by
column chromatography.
1
Pale-yellow solid liquid. H NMR (400 MHz, CDCl3) δ 7.35 –
7.28 (m, 2H), 7.25 – 7.12 (m, 3H), 6.30 (br, 1H), 4.11 (br, 2H),
2.79 – 2.48 (m, 2H), 2.21 – 2.04 (m, 1H), 1.99 – 1.89 (m, 1H),
1.86 (d, J = 1.3 Hz, 3H), 1.53 – 1.46 (m, 12H). 13C NMR (101
MHz, CDCl3) δ 155.04, 140.17, 138.36, 129.05, 128.14, 126.19,
124.97, 79.51, 45.88, 44.71, 29.86, 28.62, 25.56, 24.63, 16.85. IR
(KBr/cm-1) 2975, 2932, 2857, 1693, 1599, 1475, 1420, 1391,
1364, 1288, 1255, 1167, 1149, 1073, 1027, 977, 916, 856, 747,
700. HRMS (APCI) calcd for C19H28NO2 (M+H+): 302.2115;
found: 302.2119.
4.3 (E)-(2-cyclohexylprop-1-en-1-yl)benzene(3a)
1
4.9 (E)-(2-(cyclohex-3-en-1-yl)prop-1-en-1-yl)benzene(3g)
Pale-yellow liquid. H NMR (400 MHz, CDCl3) δ 7.32 – 7.26
1
(m, 2H), 7.22 (dd, J = 5.2, 2.9 Hz, 2H), 7.18 – 7.12 (m, 1H), 6.25
(br, 1H), 2.03 – 1.96 (m, 1H), 1.82 (d, J = 1.3 Hz, 3H), 1.79 (dd,
J = 6.1, 2.9 Hz, 4H), 1.73 – 1.67 (m, 1H), 1.35 – 1.24 (m, 5H).13C
NMR (101 MHz, CDCl3) δ 144.35, 138.97, 129.00, 127.99,
125.72, 123.05, 48.31, 31.96, 26.81, 26.45, 16.21. IR (KBr/cm-1)
3023, 2955, 2926, 2852, 1642,1494, 1448, 1377, 1072, 1029,
745, 698. HRMS (APCI) calcd for C15H21 (M+H+): 201.1638;
found: 201.1635.
Pale-yellow liquid. H NMR (400 MHz, CDCl3) δ 7.33 – 7.28
(m, 2H), 7.26 – 7.21 (m, 2H), 7.20 – 7.13 (m, 1H), 6.31 (br, 1H),
5.79 – 5.65 (m, 2H), 2.38 – 2.27 (m, 1H), 2.20 – 2.03 (m, 4H),
1.89 – 1.80 (m, 4H), 1.66 – 1.46 (m, 1H). 13C NMR (101 MHz,
CDCl3) δ 143.34, 138.85, 129.08, 128.11, 126.95, 126.84,
125.93, 123.74, 43.95, 30.79, 27.70, 25.97, 16.03. IR (KBr/cm-1)
3055, 3021, 2919, 2856, 2836, 1650, 1599, 1494, 1435, 1265,
1185, 1141, 1702, 1020, 916, 750, 737, 663, 640. HRMS (APCI)
calcd for C15H19 (M+H+): 199.1481; found: 199.1480.
4.4 (E)-(2-cyclobutylprop-1-en-1-yl)benzene(3b)
4.10 (E)-4-(1-phenylprop-1-en-2-yl)-1-tosylpiperidine(3h)
1
Pale-yellow liquid. H NMR (400 MHz, CDCl3) δ 7.34 – 7.27
White solid. 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.1 Hz,
2H), 7.40 – 7.08 (m, 7H), 6.24 (br, 1H), 3.90 (d, J = 11.0 Hz,
2H), 2.44 (s, 3H), 2.35 – 2.17 (m, 2H), 1.99 – 1.56 (m, 8H). 13C
NMR (101 MHz, CDCl3) δ 143.55, 141.25, 138.16, 133.29,
129.71, 128.98, 128.14, 127.86, 126.24, 124.59, 46.80, 45.42,
30.25, 21.64, 16.00. HRMS (APCI) calcd for C21H26NO2S
(M+H+): 356.1679; found: 356.1681.
(m, 2H), 7.26 – 7.20 (m, 2H), 7.19 – 7.12 (m, 1H), 6.19 (br, 1H),
3.11 – 2.97 (m, 1H), 2.18 – 2.08 (m, 2H), 2.05 – 1.88 (m, 3H),
1.79 (dd, J = 1.4, 0.7 Hz, 3H), 1.78 – 1.70 (m, 1H). 13C NMR
(101 MHz, CDCl3) δ 142.40, 138.79, 128.97, 128.13, 125.87,
122.37, 44.27, 27.48, 17.75, 15.60. IR (KBr/cm-1) 3085, 3052,
3026, 2970, 2950, 2855, 1711, 1682, 1672, 1650, 1500, 1490,
1440, 918,852, 915, 758, 693. HRMS (APCI) calcd for C13H17
(M+H+): 173.1325; found: 173.1326.
4.11 (E)-phenyl(4-(1-phenylprop-1-en-2-yl)piperidin-1-
yl)methanone(3i)
4.5 (E)-(2-cyclopentylprop-1-en-1-yl)benzene(3c)
1
1
Pale-yellow liquid. H NMR (400 MHz, CDCl3) δ 7.33 – 7.27
Pale-yellow liquid. H NMR (400 MHz, CDCl3) δ 7.44 – 7.38
(m, 2H), 7.26 – 7.20 (m, 2H), 7.19 – 7.14 (m, 1H), 6.31 (br, 1H),
2.62 – 2.51 (m, 1H), 1.88 – 1.77 (m, 5H), 1.70 (ddd, J = 8.7, 4.7,
2.8 Hz, 2H), 1.65 – 1.59 (m, 2H), 1.55 – 1.45 (m, 2H). 13C NMR
(101 MHz, CDCl3) δ 142.20, 138.96, 129.07, 128.09, 125.82,
123.30, 49.97, 31.32, 25.54, 16.21. IR (KBr/cm-1) 3085, 3052,
3026, 2970, 2950, 2855, 1711, 1682, 1672, 1650, 1500, 1490,
1440, 918,852, 915, 758, 693. HRMS (APCI) calcd for C14H19
(M+H+): 187.1481; found: 187.1485.
(m, 5H), 7.32 (t, J = 7.5 Hz, 2H), 7.20 (dd, J = 16.6, 7.6 Hz, 3H),
6.31 (br, 1H), 4.85 (br, 1H), 3.85 (br, 1H), 3.05 (br, 1H), 2.79 (br,
1H), 2.36 – 2.25 (m, 1H), 1.88 (br, 1H), 1.85 (d, J = 1.1 Hz, 3H),
1.77 – 1.54 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 170.43,
141.43, 138.25, 136.39, 129.60, 129.00, 128.54, 128.14, 126.97,
126.20, 124.45, 48.36, 46.32, 42.81, 31.57, 30.71, 16.19. HRMS
(APCI) calcd for C21H24NO (M+H+): 306.1852; found:
306.1850.
4.6 (E)-4-(1-phenylprop-1-en-2-yl)tetrahydro-2H-pyran(3d)
4.12 (E)-(2-cyclohexylbut-1-en-1-yl)benzene(3j)
1
1
Pale-yellow liquid. H NMR (400 MHz, CDCl3) δ 7.35 – 7.27
Pale-yellow liquid. H NMR (400 MHz, CDCl3) δ 7.30 (t, J =
(m, 2H), 7.21 (ddd, J = 14.5, 11.6, 5.0 Hz, 3H), 6.29 (br, 1H),
4.05 (dt, J = 11.0, 3.1 Hz, 2H), 3.52 – 3.38 (m, 2H), 2.26 (dt, J =
15.4, 7.5 Hz, 1H), 1.85 (d, J = 1.3 Hz, 3H), 1.74 – 1.62 (m, 4H).
13C NMR (101 MHz, CDCl3) δ 142.12, 138.54, 129.05, 128.13,
126.10, 123.99, 68.42, 45.17, 31.68, 16.14. IR (KBr/cm-1) 3054,
3022, 2954, 2933, 2856, 1644, 1599, 1466, 1443, 1385, 1236,
1131, 1089, 1019, 980, 917, 864, 748, 699,616. HRMS (APCI)
calcd for C14H19O (M+H+): 203.1430; found: 203.1431.
7.6 Hz, 2H), 7.23 – 7.14 (m, 3H), 6.22 (br, 1H), 2.25 (q, J = 7.5
Hz, 2H), 2.04 – 1.96 (m, 1H), 1.85 – 1.79 (m, 4H), 1.71 (d, J =
11.5Hz, 1H), 1.36 – 1.18 (m, 5H), 1.06 (t, J = 7.5 Hz, 3H). 13C
NMR (101 MHz, CDCl3) δ 150.50, 138.96, 128.57, 128.03,
125.70, 122.61, 44.69, 33.00, 27.04, 26.46, 23.60, 13.71. HRMS
(APCI) calcd for C16H23 (M+H+): 215.1794; found: 215.1796.
4.13 (E)-4-(1-phenylhex-1-en-2-yl)tetrahydro-2H-pyran(3k)
1
Pale-yellow liquid. H NMR (400 MHz, CDCl3) δ 7.35 – 7.26
4.7 (E)-3-(1-phenylprop-1-en-2-yl)cyclobutan-1-one(3e)
(m, 2H), 7.19 (ddd, J = 9.9, 6.2, 4.4 Hz, 3H), 6.27 (br, 1H), 4.11
– 4.00 (m, 2H), 3.46 (td, J = 11.4, 2.8 Hz, 2H), 2.30 – 2.16 (m,
3H), 1.76 – 1.59 (m, 4H), 1.49 – 1.38 (m, 2H), 1.36 – 1.23 (m,
2H), 0.88 (t, J = 7.3 Hz, 3H).13C NMR (101 MHz, CDCl3) δ
147.10, 138.68, 128.74, 128.20, 126.10, 123.98, 68.66, 41.98,
32.72, 31.23, 30.18, 23.10, 14.04. IR (KBr/cm-1) 3004, 2955,
1
Pale-yellow liquid. H NMR (400 MHz, CDCl3) δ 7.38 – 7.31
(m, 2H), 7.28 – 7.17 (m, 3H), 6.42 (br, 1H), 3.29 – 3.08 (m, 5H),
1.93 (d, J = 1.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 206.70,
138.48, 137.76, 128.99, 128.31, 126.55, 125.05, 51.37, 32.30,
15.86. IR (KBr/cm-1) 2923, 2854, 1783, 1665, 1493, 1447, 1380,

5
2927, 2855, 1607, 1509, 1463, 1403, 1300, 1246, 1174, 1037,
838, 821.738. HRMS (APCI) calcd for C17H25O (M+H+):
245.1900; found: 245.1902.
Hz, 2H), 1.75 – 1.62 (m, 2H), 1.40 – 1.29 (m, 1H), 1.27 – 1.15
ACCEPTED MANUSCRIPT
(m, 4H), 0.82 (t, J = 6.8 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ
149.67, 149.06, 147.22, 143.60, 135.85, 133.96, 133.12, 129.72,
127.84, 123.19, 120.73, 77.48, 77.16, 76.84, 46.95, 42.22, 32.03,
31.16, 30.68, 28.67, 22.49, 21.64, 14.08. HRMS (APCI) calcd for
C30H38NO2S (M+H+): 476.2618; found: 476.2615.
4.14 (E)-4-(2-(tetrahydro-2H-pyran-4-yl)oct-1-en-1-
yl)benzonitrile(3l)
Pale-yellow liquid. 1H NMR (400 MHz, CDCl3) δ 7.62 – 7.56
(m, 2H), 7.31 – 7.24 (m, 2H), 6.25 (br, 1H), 4.06 (dd, J = 11.2,
2.9 Hz, 2H), 3.46 (td, J = 11.5, 2.5 Hz, 2H), 2.33 – 2.24 (m, 1H),
2.21 (dd, J = 9.4, 6.7 Hz, 2H), 1.67 (d, J = 15.8 Hz, 4H), 1.36 –
1.20 (m, 8H), 0.87 (t, J = 6.9 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 150.65, 143.61, 132.06, 129.37, 122.72, 119.28,
109.60, 68.50, 42.17, 32.55, 31.66, 30.60, 29.60, 28.83, 22.70,
14.17. IR (KBr/cm-1) 2988, 2945, 2928, 2850, 2225, 1602, 1595,
1558, 1493, 1463, 1445, 1353, 1340, 1308, 1247, 1164, 1142,
1093, 1054, 1019, 931, 859, 819, 757, 725, 706, 669, 650, 593.
HRMS (APCI) calcd for C20H28NO (M+H+): 298.2165; found:
298.2165.
4.19 (Z)-4-(1,2-bis(4-bromophenyl)vinyl)-1-tosylpiperidine(3q)
1
Pale-yellow solid. H NMR (400 MHz, CDCl3) δ 7.63 (d, J =
8.0 Hz, 2H), 7.41 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H),
7.20 (d, J = 8.3 Hz, 2H), 6.89 (d, J = 8.2 Hz, 2H), 6.70 (d, J = 8.3
Hz, 2H), 6.29 (br, 1H), 3.86 (d, J = 11.4 Hz, 2H), 2.43 (s, 3H),
2.32 – 2.11 (m, 3H), 1.80 (d, J = 12.5 Hz, 2H), 1.68 – 1.52 (m,
2H). 13C NMR (101 MHz, CDCl3) δ 145.48, 143.64, 139.01,
135.56, 133.07, 132.05, 131.21, 130.70, 130.51, 129.72, 127.82,
125.10, 121.50, 120.62, 46.72, 44.54, 30.46, 21.65. HRMS
(APCI) calcd for C24H33N2O2S (M+Na+): 413.2257; found:
413.2262.
4.15 (E)-4-(1-(4-chlorophenyl)hept-1-en-2-yl)-1
4.20 (Z)-4-(1,2-diphenylvinyl)tetrahydro-2H-pyran(3r)
tosylpiperidine(3m)
1
Pale-yellow liquid. H NMR (400 MHz, CDCl3) δ 7.35 – 7.26
1
Pale-yellow sticky solid. H NMR (400 MHz, CDCl3) δ 7.69
(m, 3H), 7.13 – 7.08 (m, 2H), 7.08 – 7.01 (m, 3H), 6.91 – 6.83
(m, 2H), 6.39 (br, 1H), 4.06 – 3.97 (m, 2H), 3.43 (td, J = 11.6,
2.4 Hz, 2H), 2.62 – 2.48 (m, 1H), 1.76 – 1.56 (m, 4H). 13C NMR
(101 MHz, CDCl3) δ 146.87, 140.94, 137.34, 129.21, 129.00,
128.69, 127.96, 127.10, 126.41, 125.22, 68.45, 44.60, 32.10.
HRMS (APCI) calcd for C19H21O (M+H+): 265.1587; found:
265.1588.
(d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.30 – 7.24 (m, 2H),
7.10 (d, J = 8.4 Hz, 2H), 6.17 (br, 1H), 3.92 (d, J = 11.5 Hz, 2H),
2.47 (s, 3H), 2.32 – 2.23 (m, 2H), 2.16 – 2.08 (m, 2H), 1.93 –
1.78 (m, 3H), 1.76 – 1.62 (m, 1H), 1.40 – 1.31 (m, 2H), 1.28 –
1.16 (m, 4H), 0.86 (t, J = 6.9 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 147.13, 143.60, 136.74, 133.20, 131.93, 129.98,
129.75, 128.37, 127.89, 123.30, 77.48, 77.16, 76.84, 47.04,
42.24, 32.12, 31.22, 30.62, 28.63, 22.52, 21.68, 14.14. HRMS
(APCI) calcd for C25H33ClNO2S (M+H+): 446.1915; found:
446.1917.
4.21 (E)-(2-methylpent-1-ene-1,5-diyl)dibenzene(3s)
1
Pale-yellow liquid. H NMR (400 MHz, CDCl3) δ 7.34 – 7.25
(m, 4H), 7.25 – 7.11 (m, 6H), 6.28 (br, 1H), 2.70 – 2.61 (m, 2H),
2.26 – 2.16 (m, 2H), 1.92 – 1.78 (m, 5H). 13C NMR (101 MHz,
CDCl3) δ 142.62, 138.87, 138.72, 128.95, 128.60, 128.44,
128.15, 125.97, 125.85, 125.31, 40.38, 35.64, 29.84, 17.87. IR
(KBr/cm-1) 3058, 3024, 2934, 2856, 1716, 1649, 1599, 1495,
1452, 1265, 1179, 1074, 1029, 916, 742, 698. HRMS (APCI)
calcd for C18H21 (M+H+): 237.1638; found: 237.1641.
4.16 ethyl (E)-3-(2-(3-oxocyclobutyl)oct-1-en-1-yl)benzoate(3n)
Pale-yellow liquid. 1H NMR (400 MHz, CDCl3) δ 7.92 (dd, J =
5.7, 1.8 Hz, 2H), 7.43 – 7.36 (m, 2H), 6.41 (br, 1H), 4.39 (q, J =
7.1 Hz, 2H), 3.28 – 3.07 (m, 5H), 2.34 – 2.23 (m, 2H), 1.40 (t, J
= 7.1 Hz, 3H), 1.35 – 1.17 (m, 8H), 0.86 (t, J = 6.9 Hz, 3H). 13C
NMR (101 MHz, CDCl3) δ 206.39, 166.73, 144.97, 138.06,
133.13, 130.65, 129.83, 128.41, 127.73, 123.50, 61.14, 51.87,
31.70, 30.57, 29.74, 29.51, 28.65, 22.71, 14.48, 14.18. IR
(KBr/cm-1) 2955, 2927, 2856, 1787, 1720, 1605, 1464, 1367,
1285, 1199, 1106, 1022, 753. HRMS (APCI) calcd for
C21H29O3 (M+H+): 329.2111; found: 329.2109.
4.22 (E)-(2,3-dimethylpent-1-en-1-yl)benzene(3t)
Pale-yellow liquid. 1H NMR (400 MHz, CDCl3) δ 7.30 (t, J =
7.5 Hz, 2H), 7.287 – 7.20 (m, 2H), 7.18 (t, J = 7.2 Hz, 1H), 6.26
(br, 1H), 2.17 (dd, J = 14.2, 7.0 Hz, 1H), 1.77 (d, J = 1.2 Hz, 2H),
1.53 – 1.33 (m, 3H), 1.09 (d, J = 6.9 Hz, 3H), 0.88 (t, J = 7.4 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 143.22, 138.90, 129.09,
128.10, 125.86, 124.56, 45.53, 27.99, 19.55, 14.19, 12.32. HRMS
(APCI) calcd for C13H19 (M+H+): 175.1481; found: 175.1487.
4.17 (E)-4-(1-(naphthalen-2-yl)oct-1-en-2-yl)-1-
tosylpiperidine(3o)
1
Pale-yellow sticky solid. H NMR (400 MHz, CDCl3) δ 7.81 –
4.23 (3R,8R,9S,10S,13R,14S,17R)-10,13-dimethyl-17-((R,E)-5-
methyl-6-phenylhex-5-en-2-yl)hexadecahydro-1H
cyclopenta[a]phenanthren-3-yl acetate(3ba)
7.73 (m, 3H), 7.68 (d, J = 8.2 Hz, 2H), 7.61 (s, 1H), 7.48 – 7.40
(m, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.30 (dd, J = 8.5, 1.4 Hz, 1H),
6.36 (s, 1H), 3.93 (d, J = 11.5 Hz, 2H), 2.45 (s, 3H), 2.33 – 2.18
(m, 1H), 1.99 – 1.83 (m, 3H), 1.78 – 1.69 (m, 2H), 1.66 – 1.60
(m, 1H), 1.46 – 1.36 (m, 2H), 1.28 – 1.15 (m, 6H), 0.83 (t, J = 6.9
Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 146.86, 143.58, 135.83,
133.48, 133.23, 132.05, 129.74, 127.91, 127.66, 127.42, 127.07,
126.11, 125.62, 124.46, 77.48, 77.16, 76.84, 47.10, 42.39, 31.70,
31.29, 30.78, 29.64, 29.07, 22.72, 21.68, 14.16. HRMS (APCI)
calcd for C30H38NO2S (M+H+): 476.2618; found: 476.2615.
1
Pale-yellow sticky liquid. H NMR (400 MHz, CDCl3) δ 7.34
– 7.28 (m, 2H), 7.25 – 7.14 (m, 3H), 6.26 (br, 1H), 4.78 – 4.66
(m, 1H), 2.12 – 1.96 (m, 5H), 1.92 – 1.78 (m, 6H), 1.73 – 0.91
(m, 31H), 0.65 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 170.77,
139.98, 138.87, 128.90, 128.10, 125.83, 124.66, 74.55, 56.67,
56.34, 42.88, 42.04, 40.57, 40.33, 37.54, 35.94, 35.70, 35.18,
34.72, 34.51, 32.39, 28.49, 27.17, 26.77, 26.48, 24.35, 23.47,
21.60, 20.98, 18.78, 18.03, 12.19. IR (KBr/cm-1) 3054, 3022,
2954, 2933, 2843, 2754, 1713, 1644, 1599, 1493, 1443, 1385,
1352, 1236, 1131, 1089, 1019, 980, 917, 863, 748, 699, 617.
HRMS (APCI) calcd for C34H51O2 (M+H+): 491.3884; found:
491.3887.
4.18 (E)-3-(2-(1-tosylpiperidin-4-yl)hept-1-en-1-yl)pyridine(3p)
1
Pale-yellow sticky solid. H NMR (400 MHz, CDCl3) δ 8.42
(s, 2H), 7.67 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 7.9 Hz, 1H), 7.34
(d, J = 8.1 Hz, 2H), 7.27 – 7.20 (m, 1H), 6.15 (br, 1H), 3.91 (d, J
= 11.5 Hz, 2H), 2.44 (s, 3H), 2.27 (dd, J = 11.7, 10.2 Hz, 2H),
2.18 – 2.09 (m, 2H), 1.92 (d, J = 12.0 Hz, 1H), 1.83 (d, J = 12.8

6
Tetrahedron
ACCEPTED MANUSCRIPT
4.24 (8R,9S,10S,13R,14S,17R)-10,13-dimethyl-17-((R,E)-5-
28.00, 25.31, 22.01, 19.06, 17.97, 11.97. IR (KBr/cm-1) 3200,
methyl-6-4.21 phenylhex-5-en-2-yl)dodecahydro-3H-
cyclopenta[a]phenanthrene-3,7,12(2H,4H)-trione(3ca)
3054, 2942, 2868, 1773, 1751, 1707, 1599, 1491, 1467, 1438,
1385, 1307, 1274, 1247, 1181, 1116, 1090, 1052, 1029, 1006,
742, 712, 699, 647, 549, 524. HRMS (APCI) calcd for
C32H43O3 (M+H+): 475.3207; found: 475.3202.
1
White solid. H NMR (400 MHz, CDCl3) δ 7.42 – 7.08 (m,
5H), 6.26 (br, 1H), 3.02 – 2.79 (m, 3H), 2.49 – 1.93 (m, 15H),
1.85 (s, 3H), 1.76 – 1.53 (m, 2H), 1.40 (s, 3H), 1.36 – 1.21 (m,
4H), 1.08 (s, 3H), 0.97 – 0.80 (m, 3H). 13C NMR (101 MHz,
CDCl3) δ 212.22, 209.26, 208.93, 139.68, 134.38, 128.89,
128.10, 125.86, 124.71, 57.06, 51.94, 49.14, 46.96, 45.91, 45.68,
45.10, 42.90, 38.77, 37.92, 36.59, 36.12, 35.93, 35.38, 33.94,
Acknowledgement
This work was supported by 2017qd11 and Anhui Province
Major
Special
Projects
(16030801108).
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