Pd-Catalyzed Remote Site-Selective and Stereoselective C(Alkenyl)-H Alkenylation of Unactivated Cycloalkenes

Article abstract of DOI:10.1021/acs.joc.9b02797

A palladium-catalyzed alkenylation involving remote δ-position C(alkenyl)-H activation of cycloalkenes reacting with electron-deficient alkenes is described. This method features excellent site selectivity and stereoselectivity to efficiently afford only E-selective highly substituted 1,3-diene derivatives with extra-ligand-free and good functional group tolerance including estrone and free N-H tryptamine under weakly alkaline conditions. Mechanistic studies suggest that picolinamide as a bidentate directing group enables the formation of unique alkenyl palladacycle intermediates.

Full text of DOI:10.1021/acs.joc.9b02797

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Article
Pd-Catalyzed remote site- and stereo-selective
C(alkenyl)–H alkenylation of unactivated cycloalkenes
Chun-Li Mao, Sheng Zhao, Zhong-Lin Zang, Lin Xiao, Cheng-He Zhou, Yun He, and Gui-Xin Cai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02797 • Publication Date (Web): 12 Dec 2019
Downloaded from pubs.acs.org on December 12, 2019
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Page 1 of 36
The Journal of Organic Chemistry
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Pd-Catalyzed remote site- and stereo-selective C(alkenyl)–H
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alkenylation of unactivated cycloalkenes
Chun-Li Mao,† Sheng Zhao,‡ Zhong-Lin Zang,† Lin Xiao,† Cheng-He Zhou,† Yun He,‡, * and Gui-Xin Cai†, *
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†Key Laboratory of Luminescent and Real-Time Analytical Chemistry, Ministry of Education, Institute of Bioorganic
& Medicinal Chemistry, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715,
P. R. China
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‡Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences,
Chongqing University, Chongqing, 401331, P. R. China
* E-mails of corresponding author: gxcai@swu.edu.cn; yun.he@cqu.edu.cn.
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Keywords: C–C coupling; C(alkenyl)–H activation; palladium catalysis; alkenylation; site- and stereo-selectivity
Remote site- and stereo-selective C(alkenyl) H activation
cat.
Pd
H
N
H
NHPA
EWG
EWG
N
O
NHPA
n = 1-4
n
n
H
only E-selectivity
general 2 h reaction time
external ligand free
removable directing group
Abstract: A palladium-catalyzed alkenylation involving remote δ position C(alkenyl)–H activation of cycloalkenes
reacting with electron-deficient alkenes is described. This method features excellent site- and stereoselectivity to
efficiently afford only E-selective highly substituted 1,3-diene derivatives, extra-ligand-free and good functional group
tolerance including estrone and free N–H tryptamine under weakly alkaline conditions. Mechanistic studies suggest
that picolinamide as a bidentate directing group enables the formation of unique alkenyl palladacycle intermediates.
Introduction
Conjugated dienes are extremely valuable molecular skeletons in organic synthesis and represent essential
structural motifs in a large class of natural products and bio-active compounds.1 Strategies for the synthesis of
these diene molecules can be generally divided into three categories. First, the reactions of carbonyl alkenylation
are classical routes.2 Second, C–C cross-coupling reactions of activated substrates include Heck reaction,3 Stille
coupling4 and Negishi coupling.5 Third, a more direct strategy involving double C(alkenyl)–H bonds activation
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has attracted considerable attention from the scientific community.6 Although the challenges have changed from
extra pre-activated steps for starting materials, low atom economy to subsequent issues of adjusting the steric and
electronic properties of the alkenes to avoid the homo-coupling reaction, the synthesis of diene is still confronted
with two of major challenges — site-selectivity and the low Z/E-selectivity. A novel and highly stereoselective
strategy for dealing with site-selective C(alkenyl)–H activation is the introduction of directing groups (DGs).7,8
This strategy provides easy access to the desired site-selectivity and stereoselectivity via electronic effects and /
or chelation and convenience of further functionalization.9 Ishii,10a Glorius,10b Nakamura,10c and Loh,10d etc. have
described the strategies for proximal C(alkenyl)–H activation of aliphatic olefins in the presence of monodentate
DGs via metal catalysts.10
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In contrast, fewer examples regarding stereoselective remote directed C(alkenyl)–H activation are reported.11
Loh12a,12b and Li12c have demonstrated δ or γ-C(alkenyl)–H activation and functionalization (Scheme 1 A). Loh13
and Bi14 respectively reported alkylation of γ-C(alkenyl)–H, and Engle recently published elegant alkenylation of
β or γ-C(alkenyl)–H utilizing different bidentate auxiliaries (Scheme 1 A).15 Notably, picolinamide (PA) as a
removable directing group facilitated remote site-selective functionalization16 of C(alkenyl)–H bond such as
arylation at γ-position, alkenylation and iodination at δ-position at a distance of three methylenes from PA, as
well as acetoxylation at δ-position (Scheme 1 B).17-19 However, only E-selective δ-C(alkenyl)–H alkenylation of
aminoethyl cycloalkenes with PA as a remote bidentate directing group has not been documented. Thus, inspired
by the above literature and previous work,19,20 we report an efficient method for the synthesis of cycle-containing
dienes starting from cycloalkenes bearing PA and electron-deficient alkenes to generate corresponding only
E-products (Scheme 1 C).
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The Journal of Organic Chemistry
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Scheme 1. Remote directed C(alkenyl)–H activation and functionalization.
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A. Previously reported C(alkenyl)-H activation via remote directing group
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6
HO
TIPSO
O

NH
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9
S


H
Ar
H
O
H
Alkenylation, Loh 2012/2017
Alkenylation, Li 2013
O
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O
R5
N
R2
H



H
H
N
H
N
X
N
H
H
N
R4 R6
N
O
R1 R3
R7
Alkylation, Loh 2019
Alkylation, Bi 2018
Alkenylation, Engle 2018
(X = C/O)
B. Picolinamide remote directed C(alkenyl)-H activation
O
O
O
H

H

N
N
N

H
H
H
N
N
H
N
R8
Alkenylation, Engle 2018
Iodination, Carreira 2019
Acetoxylation, He 2016
Arylation, Babu 2017
C. This work
H
H
EWG
NHPA
N
[Pd]
N

H
n = 1, 2, 3, 4
O
n
n
EWG
NHPA
 only E-selectivity
 general 2 h reaction time
 external ligand free
 removable directing group
Results and Discussion
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We set out to research olefination of δ-C(alkenyl)–H bond of cyclic olefins in Table 1. The model
reaction conditions have been established by using 1a and 2a as substrates after much trial and error
(entry 1). Notably, palladium catalyst is a crucial factor and this reaction did not occur in the absence of
Pd(OAc)2 (entry 2). And copper-free conditions led to the moderate yield (entry 3), which demonstrated
that Cu(OAc)2·H2O as an oxidant can effectively regenerate Pd(II) catalyst from Pd(0). Moreover,
PhI(OAc)2 serving as an oxidant in the Pd(II)/Pd(IV) catalytic cycle great reduced the yield (entry 4),
which demonstrated that this reaction differentiating from previous research19 could prefer a Pd(0)/Pd(II)
catalytic cycle. Additionally, removal of base or using acids such as HOAc and PivOH which can boost
the palladium catalysis15,20a showed unsatisfactory results (entries 5-7). Polar solvent DMSO almost
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completely suppressed the desired transformation (entry 8). Further screening reaction conditions
including palladium catalysts, oxidants, bases and solvents, as well as reaction temperature has been
shown in Supporting Information (SI) Table S1 for more details.
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Table 1. Optimization of the reaction conditionsa
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Pd(OAc)2 (10 mol%)
NHPA
NHPA
OEt
O
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OEt
Cu(OAc)2•H2O (0.5 equiv)
O
KHCO3 (2.5 equiv)
H
t-AmylOH (0.4 M)
130 °C, 2 h, air
" standard conditions "
1a
2a
3aa
Entry
1
Variation from standard conditions
None
Yieldb (%)
80
2
3
4
0
Without Pd(OAc)2
Without Cu(OAc)2∙H2O
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PhI(OAc)2 instead of Cu(OAc)2∙H2O
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7
Without KHCO3
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HOAc instead of KHCO3
PivOH instead of KHCO3
8
DMSO instead of t-AmylOH
Trace
a
1a (0.2 mmol), 2a (0.4 mmol), Pd(OAc)2 (0.02 mmol), Cu(OAc)2∙H2O (0.1 mmol), KHCO3 (0.5 mmol),
t-AmylOH (0.4 M) in a sealed tube under air at 130 °C for 2 h. b Isolated yield.
To examine the scope of alkenes, we made 1a as the coupling partner under the optimal conditions (Scheme 2).
Various acrylates can afford the corresponding products (3aa-3al) with excellent site-selectivity and
stereoselectivity in moderate to good yields. These experimental results showed that the chain length and steric
hindrance of ester groups had less effect on the yields of desired products (3aa-3ak), and 3aa was characterized
by X-ray crystallography21. Owing to the transesterification, t-AmylOH was substituted with toluene when 1a
reacted with phenyl acrylate to produce 3al with 63% isolated yield. Other acrylate derivatives can smoothly
transform into corresponding products (3am-3an). In addition, the results of 3ao and 3ap illustrated that the
reaction can be seriously affected by the steric hindrance of double bonds. Unfortunately, the desired products
(3aq-3ar) cannot be obtained in the treatment of styrene or electron-deficient derivative.
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The Journal of Organic Chemistry
Scheme 2. Scope of alkenesa
1
2
3
NHPA
4
5
6
7
R2
NHPA
" standard conditions "
R2
H
FG
H
R1
FG
R1
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9
1a
2
3
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NHPA
NHPA
O
O
O
O
3aa
3ac
3ab
3ae
, 80 %
, 76 %
3aa
X-ray structure of
NHPA
NHPA
NHPA
O
O
O
O
O
3
5
O
3ad
3ag
, 72 %
, 70 %
, 75 %
NHPA
NHPA
NHPA
O
O
O
O
O
CF3
OH
O
3af
3ai
3al
3ah
, 75 %
, 64 %
, 48 %
NHPA
NHPA
O
NHPA
OBn
O
O
O
O
OMe
O
3aj
3ak
3an
, 70 %
, 70 %
, 73 %
NHPHA
OPh
O
NHPA
NMe2
O
NHPA
OEt
P
OEt
O
b
3am
, 57 %
, 32 %
, 63 %
NHPA
NHPA
NHPA
O
O
O
X
c
X = H, 3aq
, NP
O
c
c
3ao
, Trace
3ap
, NP
F, 3ar
, NP
a 1a (0.2 mmol), 2 (0.4 mmol), Pd(OAc)2 (0.02 mmol), Cu(OAc)2∙H2O (0.1 mmol), KHCO3 (0.5 mmol),
t-AmylOH (0.4 M) in a sealed tube under air at 130 °C for 2 h with isolated yields. b Using toluene as the
solvent. c No desired product.
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We also explored various cyclic olefins with picolinamide (PA) directing group reacting with 2a under the
optimal conditions with excellent chemoselectivity for relatively stable C(alkenyl)–H of olefins when compared
with activated C(allylic)–H of olefins (Scheme 3). It was observed that the ring size of olefins (5-, 7-,
8-membered) has less influence on the reaction to afford corresponding cross-coupling products (3ba-3da) In
addition, reactions of the substituent groups (such as methyl, dimethyl and tert-butyl groups) on the ring of
cyclohexene gave corresponding products (3ea-3ga) in moderate and good yields meaning the inapparent steric
effect, while desired products (3ha-3ia) in lower yields implied a degree of electronic effect. Additionally, the
product 3ja was obtained in 52% yield.
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Scheme 3. Scope of olefins with PA directing group a
NHPA
NHPA
CO2Et
" standard conditions "
n = 1-4
CO2Et
n
H
n
1
2a
3
NHPA
CO2Et
, 65 %
NHPA
NHPA
CO2Et
CO2Et
, 54 %
3ba
3ca
3fa
3da
3ga
, 65 %
NHPA
CO2Et
NHPA
NHPA
CO2Et
CO2Et
, 70 %
tBu
3ea
, 56 %
, 57 %
NHPA
CO2Et
NHPA
CO2Et
OMe
NHPA
F
F
Ph
CO2Et
, 52 %
3ha
3ia
3ja
, 47 %
, 49 %
a
1 (0.2 mmol), 2a (0.4 mmol), Pd(OAc)2 (0.02 mmol), Cu(OAc)2∙H2O (0.1 mmol), KHCO3 (0.5 mmol),
t-AmylOH (0.4 M) in a sealed tube under air at 130 °C for 2 h with isolated yields.
To elucidate the reaction mechanism, relative control experiments were conducted (Schemes 4-7). The addition
of TEMPO into the reaction mixture cannot suppress the desired procedure and only led to a slight decline in the
yield of 3aa, which suggested that this reaction do not involve a radical process (Scheme 4).
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The Journal of Organic Chemistry
Scheme 4. Control experiment of radical inhibitor
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2
3
4
5
6
7
8
9
10
2a
NHPA
NHPA
CO2Et
TEMPO (1 equiv)
H
" standard conditions "
The isolated yield: 61%
1a
3aa
, 0.2 mmol
We have conducted a series of control experiments to explore the effect of picolinamide directing group, and
experimental results showed that the removal of free N–H bond, the substrate without PA, changing the position
of nitrogen on pyridinyl substituent or replacing pyridinyl group with phenyl substituent had negative effects on
the reaction outcome (Scheme 5, eq. 1-5). According to above experimental results, we proposed that this
transformation could involve palladacycle 4.
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Scheme 5. Effect of picolinamide directing group
Ph
N
N
Ph
N
2a
O
eq. 1
N
" standard conditions "
O
CO2Et
, NP
H
1k
, 0.2 mmol
3ka
NH2
NH2
CO2Bn
2k
eq. 2
H
CO2Bn
" standard conditions "
1l
3lk
, NP
, 0.2 mmol
H
N
N
H
N
2a
N
N
O
eq. 3
" standard conditions "
O
H
CO2Et
, <10%
1m
, 0.2 mmol
3ma
N
H
N
H
N
2a
O
eq. 4
O
" standard conditions "
H
CO2Et
, Trace
1n
, 0.2 mmol
3na
H
N
H
N
2a
O
eq.5
O
" standard conditions "
H
CO2Et
, NP
O
N
1o
, 0.2 mmol
3oa
Pd
L
N

4
Palladacycle
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The treatment of 1p led to a poor performance indicating a highly unstable double 5-membered palladacycle 5
in this system (Scheme 6, eq. 1). Moreover, using acyclic aliphatic olefin 1q provided the trace amount of product
3qa, which demonstrated that the rigidity skeleton of cycloalkenes facilitated the formation of palladacycle
intermediate 4 in contrast with the palladacycle 6 (Scheme 6, eq. 2).
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4
5
6
7
8
9
Scheme 6. Effect of palladacycles
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2a
NHPA
NHPA
eq. 1
" standard conditions "
O
CO2Et
, Trace
H
3pa
1p
, 0.2 mmol
N
Pd
N
OAc
5
Palladacycle
2a
NHPA
, 0.2 mmol
EtO2C
eq. 2
H
NHPA
" standard conditions "
3qa
, Trace
1q
O
N
Pd
N
OAc
6
Palladacycle
The reaction of 1a without 2a was treated with D2O (10 equiv) and selective deuterium incorporation at the
δ-C(alkenyl)–H of 1a was observed (30% D), which confirmed reversible formation of palladacycle 4 (Scheme 7,
eq. 1). Research on the initial rate constant for the intermolecular competition alkenylation of 1a and 1a-D5,
provided a kH/kD value of 2.08 (Scheme 7, eq. 2), showing that alkenyl sp2 C–H cleavage could involve the
turnover-limiting step of the reaction and supported a Concerted Metallation Deprotonation (CMD)
mechanism.22b
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The Journal of Organic Chemistry
Scheme 7. Deuterium labelling experiments
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2
3
4
5
Deuterium incorporation
( eq. 1)
NHPA
NHPA
10 equiv D2O
6
7
8
9
" standard conditions "
D
1a
1a
-D1
30 % D
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23
Kinetic deuterium isotope effect
X X X X
D D D D
NHPA
OEt
2a
, 0.5 h
NHPA
NHPA
( eq. 2)
" standard conditions "
kH/kD = 2.08
H
D
O
1a
1a
3aa 3aa
, 0.1 mmol
-D5, 0.1 mmol
27.62% D
/
-D4
X = H/D
A plausible cycle is illustrated in Scheme 8.15,
Initially, following substrate 1a coordination to give a
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π-alkene palladium complex A, δ C(alkenyl)–H activation occurs to produce the six-membered palladacycle B.
Ligand exchange of the electron-deficient alkene to generate the intermediate C, followed by migratory insertion
and coordination to afford the intermediate D, syn β-H elimination of D and reductive elimination of palladium
hydride species E to release the product 3aa and oxidation of Pd(0) by Cu(OAc)2·H2O to regenerate Pd(II)
catalyst, then closes the Pd(0)/Pd(II) cycle.
Scheme 8. The proposed mechanism
air
CuI
1a
+ base
PdII(OAc)2
CuII
Pd0L
O
AcO-
3aa
base+H+
N
PdII
N
O
L
A
base+H+
N
PdII
N
O
H
E
CO2Et
N
PdII
N
O
B
L
N
PdII
L
CO2Et
N
2a
O
N
D
L
PdII
N
L
CO2Et
C
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The facile removal of PA made it fairly easy to be utilized as a useful protecting group of terminal NH2 for
further functionalization. For example, 3ha followed a two-step sequence of PA removal and Cbz protection in
one pot (Scheme 9, eq. 1).16d Natural product estrone derivative 2s reacted with 1a to give the corresponding
alkenylated product 8 in 51% isolated yield (Scheme 9, eq. 2). In addition, the one-pot tandem reaction of
norbornene can be achieved to afford norbornene derivative 9 with the 43% isolated yield (Scheme 9, eq. 3). Free
N–H alkenylated tryptamine derivative 10 was obtained in 25% isolated yield (Scheme 9, eq. 4), while product 11
was not observed (Scheme 9, eq. 5).
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Scheme 9. Synthetic applications
The removal of picolinamide directing group
1. Zn, aq. HCl
NHCbz
CO2Et
NHPA
THF/H2O, rt, 1.5 h
( eq. 1)
2. CbzCl, NaHCO3
THF/H2O, rt, 3 h, 38%
(two steps in one pot)
Ph
Ph
CO2Et
3ha
7
O
Functionalization of estrone and tryptamine derivatives
O
H
H
O
H
H
1a
, 0.2 mmol
( eq. 2)
( eq. 3)
( eq. 4)
O
O
H
H
" standard conditions "
O
NHPA
t-AmylOH (0.2 M)
2s
8
, 0.4 mmol
, 51 %
NHPA
1a
2.
(0.2 mmol)
1. BF3O(C2H5)2
80 C, 0.5 h
OH
O
" standard conditions "
2 h
O
O
9
0.54 mmol
0.5 mmol
NHPA
, 43 %
NHPA
CO2Et
2a
" standard conditions "
16 h
N
H
N
H
10
, 25%
1r
, 0.2 mmol
NH2
NH2
CO2Et
2a
( eq. 5)
N
H
N
H
" standard conditions "
11
, NP
1s
, 0.2 mmol
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1
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Conclusion
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In summary, we have developed a palladium-catalyzed E-selective cross-coupling of unactivated cycloalkenes
and electron-deficient alkenes under weakly alkaline conditions. The picolinamide auxiliary as a remote bidentate
directing group enabled highly selective alkenylation of δ C(alkenyl)–H bond via a six-membered palladacycle
intermediate involving a Pd(II)/Pd(0) catalytical cycle. Gratifyingly, natural product estrone and free N–H
tryptamine derivatives can be tolerated, which can enrich the functional toolkit of natural products.
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EXPERIMENTAL SECTION
General Information
Reagents and solvents were purchased from commercial sources (Energy Chemical and J&K) and were used
without further purification. All reactions were monitored by TLC with silica gel coated plates. 1H NMR and 13C
NMR spectra were recorded on a BrukerAvance 600 spectrometer. The chemical shift was given in dimensionless
1
13
δ values and was frequency referenced relative to TMS in H and C NMR spectroscopy. Chemical shifts were
1
13
reported relative to CDCl3 (δ = 7.26 ppm) for H NMR and relative to CDCl3 (δ = 77 ppm) for C NMR. Peak
multiplicities were recorded as follows: s = singlet, d = doublet, t = triplet, m = multiplet or unresolved, and br =
broad singlet or a combination of them, J-values were in Hz. And high-resolution mass spectra were obtained
from Q-TOF instrument by electrospray ionization (ESI). Melting points were measured on a GongyiYuhua
Instrument X-5 digital display micro melting point apparatus and were uncorrected. 1j and 1k were directly
obtained from He’s group.23, 24
Synthetic Procedures and Characterization Data.
General Procedure I for preparation of general primary amines (GP I)23.
Step1: The solution of ketone (1.0 equiv), cyanoacetic acid (1.0 equiv), ammonium acetate (2.0 equiv) in toluene
was refluxed at 160 °C (oil bath temperature) for 3h. The mixture was cooled to room temperature, concentrated
and monitored by TLC (ethyl acetate: petroleum ether = 1:3). Corresponding nitrile was obtained after
purification by flash silica column chromatography.
Step2: An appropriate and dried flask was added LiAlH4 (170 mg, 4.5 mmol) and dry diethyl ether (7 mL) was
slowly added. The solution was stirred at 0 °C and then AlCl3 (600 mg, 4.5 mmol) was placed in batches to the
solution of LiAlH4 in ether. After stirring 10 min, the solution of prepared nitrile in diethyl ether (2 mL) was
dropped at 0 °C to the mixture of LiAlH4 /AlCl3/ether and stirred for 1.5-2 h at room temperature. The reaction
was quenched by saturated NaHCO3, adjusted to alkaline until no longer bubbling phenomenon. The filtrate
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extracted by ethyl acetate (EA) was dried with anhydrous Na2SO4 and concentrated to afford corresponding
primary amines. And prepared primary amines were used in the next step without further purification.
General Procedure II for preparation of PA substrates 1 (GP II)24.
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The
DCM
solution
of
primary
amine
(1.0
equiv),
picolinic
acid
(1.1
1.1
equiv),
equiv),
[dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium
(HATU,
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N,N-Diisopropyl-ethylamine (DIPEA, 3.0 equiv) was stirred overnight at room temperature in nitrogen
atmosphere. The reaction was monitored by TLC and quenched with water and stirred at ice-bath for 10 min,
extracted twice with DCM, then dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure.
The concentrate was purified by flash silica column chromatography to afford compounds 1.
N-(2-(cyclohex-1-en-1-yl) ethyl) picolinamide (1a)24. 1a was synthesized following GP II. A reaction vessel
was charged with 2-(1-cyclohexenyl)ethylamine (1.50 g, 12.0 mmol, 1.0 equiv), 2-picolinic acid (1.62g, 13.2
mmol, 1.1 equiv), HATU (5.011 g, 13.2 mmol, 1.1 equiv), DIPEA (5.9 mL, 35.9 mmol, 3.0 equiv) and DCM (30
mL) to produce 1a (3.68 g, yield 80%) as colorless oil via the purification by flash silica column chromatography
(ethyl acetate: petroleum ether = 1:5). 1H NMR (600 MHz, CDCl3) δ 8.54 (d, J = 4.4 Hz, 1H), 8.19 (d, J = 7.8 Hz,
1H), 8.05 (s, 1H), 7.85 – 7.82 (m, 1H), 7.42 – 7.38 (m, 1H), 5.54 (s, 1H), 3.55 (q, J = 6.9 Hz, 2H), 2.26 (t, J = 7.0
Hz, 2H), 2.02 – 1.97 (m, 4H), 1.66 – 1.61 (m, 2H), 1.59 – 1.54 (m, 2H).
N-(2-(cyclopent-1-en-1-yl) ethyl) picolinamide (1b) 24. 1b was synthesized following GP II. A reaction vessel
was charged with 2-(cyclopent-1-en-1-yl) ethan-1-amine (186 mg, 1.67 mmol, 1.0 equiv), 2-picolinic acid (209
mg, 1.7 mmol, 1.1 equiv), HATU (646 mg, 1.7 mmol, 1.1 equiv), DIPEA (843 µL, 5.1 mmol, 3.0 equiv) and
DCM (5 mL) to produce 1b (90 mg, yield 42%) as colorless oil via the purification by flash silica column
chromatography (ethyl acetate: petroleum ether = 1:8~1:6). 1H NMR (600 MHz, CDCl3) δ 8.54 (d, J = 4.3 Hz,
1H), 8.20 (d, J = 7.7 Hz, 1H), 8.07 (s, 1H), 7.86 – 7.82 (m, 1H), 7.42 – 7.36 (m, 1H), 5.49 (s, 1H), 3.61 (q, J = 6.9
Hz, 2H), 2.42 (t, J = 6.7 Hz, 2H), 2.32 (dt, J = 15.2, 7.0 Hz, 4H), 1.88 (p, J = 7.5 Hz, 2H).
N-(2-(cyclohept-1-en-1-yl) ethyl) picolinamide (1c) 24. 1c was synthesized following GP II. A reaction vessel
was charged with 2-(cyclohept-1-en-1-yl)ethan-1-amine (162 mg, 1.2 mmol, 1.0 equiv), 2-picolinic acid (160 mg,
1.3 mmol, 1.1 equiv), HATU (494 mg, 1.3 mmol, 1.1 equiv), DIPEA (579 µL, 3.5 mmol, 3.0 equiv) and DCM (3
mL) to produce 1c (113 mg, yield 46%) as colorless oil via the purification by flash silica column
1
chromatography (ethyl acetate: petroleum ether = 1:6~1:5). H NMR (600 MHz, CDCl3) δ 8.54 (d, J = 4.6 Hz,
1H), 8.19 (d, J = 7.8 Hz, 1H), 8.09 (s, 1H), 7.83 (td, J = 7.7, 1.2 Hz, 1H), 7.41 (dd, J = 7.2, 5.0 Hz, 1H), 5.70 (t, J
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= 6.4 Hz, 1H), 3.53 (q, J = 6.8 Hz, 2H), 2.30 (t, J = 6.9 Hz, 2H), 2.19 – 2.17 (m, 2H), 2.10 (dd, J = 10.9, 6.2 Hz,
2H), 1.74 (dt, J = 11.8, 6.0 Hz, 2H), 1.53 – 1.46 (m, 4H).
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2
3
4
5
1
(E)-N-(2-(cyclooct-1-en-1-yl) ethyl) picolinamide (1d)24. 1d was directly obtained from He’s group. H NMR
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(600 MHz, CDCl3) δ 8.53 (d, J = 4.7 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H), 8.09 (s, 1H), 7.83 (td, J = 7.7, 1.5 Hz,
1H), 7.42 – 7.37 (m, 1H), 5.49 (t, J = 8.1 Hz, 1H), 3.57 (q, 6.9 Hz, 2H), 2.32 (t, J = 7.0 Hz, 2H), 2.23 – 2.18 (m,
2H), 2.11 (d, J = 7.6 Hz, 2H), 1.54 – 1.46 (m, 8H).
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N-(2-(4-methylcyclohex-1-en-1-yl) ethyl) picolinamide (1e). (1) 4-methylcyclohexanone (801 µL, 7.1 mmol,
1.2 equiv), cyanoacetic acid (510 mg, 6 mmol, 1.0 equiv), NH4OAc (930 mg, 12 mmol, 2.0 equiv) and toluene
(10 mL) were added in a dry 25 mL round bottom flask through the condition of GP I ( Step 1) to obtain the
corresponding the nitrile (585 mg, yield 72%, yellow liquid, ethyl acetate: petroleum ether = 1:3, Rf = 0.82) via
the purification by flash silica column chromatography (ethyl acetate: petroleum ether = 1:6). And then the
purified nitrile was disposed according to the way GP I ( Step 2 ) for 1.5 h to afford the amine (283 mg, yellow
liquid). (2) According to GP II, a reaction vessel was charged with corresponding amine (283 mg, 2.0 mmol, 1.0
equiv), 2-picolinic acid (270 mg, 2.2 mmol, 1.1 equiv), HATU (837 mg, 2.2 mmol, 1.1 equiv), DIPEA (745 µL,
6.0 mmol, 3.0 equiv) and DCM (5 mL) to produce 1e via the purification by flash silica column chromatography
(ethyl acetate: petroleum ether = 1:6): 211 mg; yield 43%; pale-yellow solid; m.p. 43-44 °C, Rf = 0.38 (ethyl
acetate: petroleum ether = 1:3); 1H NMR (600 MHz, CDCl3) δ 8.54 (d, J = 4.7 Hz, 1H), 8.19 (d, J = 7.9 Hz, 1H),
8.06 (s, 1H), 7.83 (td, J = 7.6, 1.8 Hz, 1H), 7.41 (dd, J = 7.7, 4.7 Hz, 1H), 5.50 (s, 1H), 3.55 (q, J = 6.6 Hz, 2H),
2.27 (t, J = 7.1 Hz, 2H), 2.13 – 1.97 (m, 3H), 1.67 (dd, J = 52.1, 10.3 Hz, 3H), 1.29 – 1.20 (m, 1H), 0.94 (d, J =
5.7 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 164.1, 150.2, 148.0, 137.2, 134.2, 125.9, 123.0, 122.1, 37.6,
37.4, 33.8, 31.0, 28.2, 28.1, 21.6; HRMS (ESI/TOF) m/z: [M + H]+ Calcd for C15H21N2O 245.1648; Found
245.1649.
N-(2-(4,4-dimethylcyclohex-1-en-1-yl) ethyl) picolinamide (1f). (1) 4,4-dimethylcyclohexanone (500 mg, 4
mmol, 1.0 equiv), cyanoacetic acid (340 mg, 4 mmol, 1.0 equiv), NH4OAc (616 mg, 8 mmol, 2.0 equiv) and
toluene (8 mL) were added in a dry 25 mL round bottom flask through the condition of GP I ( Step 1) to obtain
the corresponding nitrile (330 mg, yield 55%, yellow liquid, ethyl acetate: petroleum ether = 1:3, Rf = 0.56) via
the purification by flash silica column chromatography (ethyl acetate: petroleum ether = 1:6). And then the
purified nitrile was disposed according to the way GP I ( Step 2 ) for 1.5 h to afford the amine (215 mg, colorless
liquid). (2) According to GP II, a reaction vessel was charged with corresponding amine (215 mg, 1.4 mmol, 1.0
equiv), 2-picolinic acid (190 mg, 1.54 mmol, 1.1 equiv), HATU (586 mg, 1.54 mmol, 1.1 equiv), DIPEA (695 µL,
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4.62 mmol, 3.0 equiv) and DCM (4 mL) to produce 1f via the purification by flash silica column chromatography
(ethyl acetate: petroleum ether = 1:7~1:6): 185 mg, yield 51%; pale-yellow solid; m.p. 50-51 °C; Rf = 0.36 (ethyl
acetate: petroleum ether = 1:3); 1H NMR (600 MHz, CDCl3) δ 8.53 (d, J = 4.7 Hz, 1H), 8.19 (d, J = 7.9 Hz, 1H),
8.05 (s, 1H), 7.83 (td, J = 7.7, 1.8 Hz, 1H), 7.40 (dd, J = 6.9, 5.4 Hz, 1H), 5.46 (s, 1H), 3.56 (q, J = 6.6 Hz, 2H),
2.29 (t, J = 7.1 Hz, 2H), 2.01 (d, J = 6.8 Hz, 2H), 1.80 (dt, J = 4.2, 2.2 Hz, 2H), 1.38 (t, J = 6.4 Hz, 2H), 0.89 (s,
6H); 13C{1H} NMR (151 MHz, CDCl3) δ 164.1, 150.1, 148.0, 137.2, 133.1, 125.9, 122.7, 122.1, 39.3, 37.5, 37.2,
35.6, 28.4, 28.1, 25.9; HRMS (ESI/TOF) m/z: [M + H]+ Calcd for C16H23N2O 259.1805; Found 259.1806.
N-(2-(4-(tert-butyl)cyclohex-1-en-1-yl) ethyl) picolinamide (1g). (1) 4-tert-butylcyclohexanone (1036 µL, 6
mmol, 1.0 equiv), cyanoacetic acid (510 mg, 6 mmol, 1.0 equiv), NH4OAc (925 mg, 12 mmol, 2.0 equiv) and
toluene (10 mL) were added in a dry 25 mL round bottom flask through the condition of GP I ( Step 1) to obtain
the corresponding nitrile (766 mg, yield 72%, yellow liquid, ethyl acetate: petroleum ether = 1:3, Rf = 0.72) via
the purification by flash silica column chromatography (ethyl acetate: petroleum ether = 1:6). And then the
purified nitrile was disposed according to the way GP I ( Step 2 ) for 2 h to afford the amine (517 mg, pale
yellow liquid). (2) According to GP II, a reaction vessel was charged with corresponding amine (517 mg, 2.9
mmol, 1.0 equiv), 2-picolinic acid (393 mg, 3.2 mmol, 1.1 equiv), HATU (1213 mg, 3.2 mmol, 1.1 equiv),
DIPEA (1438 µL, 8.7 mmol, 3.0 equiv) and DCM (8 mL) to produce 1g via the purification by flash silica
column chromatography (ethyl acetate: petroleum ether = 1:7~1:6): 141 mg; yield 17%; yellow solid; m.p. 57-58
°C, Rf = 0.42 (ethyl acetate: petroleum ether = 1:3); 1H NMR (600 MHz, CDCl3) δ 8.54 (d, J = 4.8 Hz, 1H), 8.20
(d, J = 7.7 Hz, 1H), 8.07 (s, 1H), 7.86 – 7.79 (m, 1H), 7.41 (dd, J = 7.7, 4.5 Hz 1H), 5.54 (s, 1H), 3.55 (q, J = 6.7
Hz, 2H), 2.28 (t, J = 7.1 Hz, 2H), 2.06 – 2.00 (m, 3H), 1.86 – 1.75 (m, 2H), 1.27 – 1.14 (m, 2H), 0.86 (s, 9H);
13C{1H} NMR (151 MHz, CDCl3) δ 164.1, 150.2, 148.0, 137.2, 134.4, 125. 9, 123.7, 122.1, 44.0, 37.7, 37.2, 32.2,
29.6, 27.2, 26.9, 24.2; HRMS (ESI/TOF) m/z: [M + H]+ Calcd for C18H27N2O 287.2118; Found 287.2121.
N-(2-(1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-yl) ethyl) picolinamide (1h). (1) 4-phenylcyclohexanone (1045 mg,
6 mmol, 1.0 equiv), cyanoacetic acid (510 mg, 6 mmol, 1.0 equiv), NH4OAc (925 mg, 12 mmol, 2.0 equiv) and
toluene (10 mL) were added in a dry 25 mL round bottom flask through the condition of GP I ( Step 1) to
produce the corresponding nitrile (964 mg, yield 82%, yellow brown liquid, ethyl acetate: petroleum ether = 1:3,
Rf = 0.35) via the purification by flash silica column chromatography (ethyl acetate: petroleum ether = 1:3). And
then the purified nitrile was disposed according to the way GP I ( Step 2 ) for 1.5 h to afford the amine (547 mg,
yellow liquid). (2) According to GP II, a reaction vessel was charged with corresponding amine (547 mg, 2.7
mmol, 1.0 equiv), 2-picolinic acid (366 mg, 2.97 mmol, 1.1 equiv), HATU (1129 mg, 2.97 mmol, 1.1 equiv),
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DIPEA (1340 µL, 8.1 mmol, 3.0 equiv) and DCM (7 mL) to obtain 1h via the purification by flash silica column
1
2
3
chromatography (ethyl acetate: petroleum ether = 1:7~1:6): 378 mg; yield 46%; white solid; m.p. 73-74 °C; Rf =
4
5
1
0.26 (ethyl acetate: petroleum ether = 1:3); H NMR (600 MHz, CDCl3) δ 8.55 (d, J = 4.3 Hz, 1H), 8.21 (d, J =
6
7
8
9
7.8 Hz, 1H), 8.10 (s, 1H), 7.84 (td, J = 7.7, 1.7 Hz 1H), 7.41 (dd, J = 7.6, 4.8 Hz 1H), 7.28 (t, J = 7.6 Hz, 2H),
7.25 – 7.20 (m, 2H), 7.22 – 7.15 (m, 1H), 5.63 (s, 1H), 3.59 (p, J = 6.5 Hz, 2H), 2.80 – 2.73 (m, 1H), 2.36 – 2.27
(m, 3H), 2.26 – 2.13 (m, 2H), 2.10 (d, J = 16.5 Hz, 1H), 1.95 (dq, J = 10.3, 2.6 Hz, 1H), 1.83 – 1.75 (m, 1H);
13C{1H} NMR (151 MHz, CDCl3) δ 164.2, 150.2, 148.1, 147.0, 137.3, 134.6, 128.3, 126.9, 126.0, 126.0, 123.1,
122.2, 39.9, 37.6, 37.4, 33.4, 30.0, 28.7; HRMS (ESI/TOF) m/z: [M + H]+ Calcd for C20H23N2O 307.1805; Found
307.1804.
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N-(2-(4,4-difluorocyclohex-1-en-1-yl) ethyl) picolinamide (1i) 25a. (1) 4,4-difluorocyclohexan-1-one (706 µL, 4
mmol, 1.0 equiv), cyanoacetic acid (340 mg, 4 mmol, 1.0 equiv), NH4OAc (618 mg, 8 mmol, 2.0 equiv) and
toluene (8 mL) were added in a dry 25 mL round bottom flask through the condition of GP I ( Step 1) to obtain
the corresponding nitrile (526 mg, yield 84%, colorless liquid, ethyl acetate: petroleum ether = 1:3, Rf = 0.34) via
the purification by silica flash column chromatography (ethyl acetate: petroleum ether = 1:3). And then the
purified nitrile was disposed according to the way GP I ( Step 2 ) for 1.5 h to afford the amine (208 mg, yellow
liquid). (2) According to GP II, a reaction vessel was charged with corresponding amine (208 mg, 1.3 mmol, 1.0
equiv), 2-picolinic acid (176 mg, 1.43 mmol, 1.1 equiv), HATU (543 mg, 1.43 mmol, 1.1 equiv), DIPEA (643 µL,
3.90 mmol, 3.0 equiv) and DCM (4 mL) to obtain 1i via the purification by flash silica column chromatography
(ethyl acetate: petroleum ether = 1:5): 207 mg; yield 60%; white solid; m.p. 66-67 °C; Rf = 0.3 (ethyl acetate:
petroleum ether = 1:2); 1H NMR (600 MHz, CDCl3) δ 8.54 (d, J = 4.8 Hz, 1H), 8.19 (d, J = 7.7 Hz, 1H), 8.09 (s,
1H), 7.84 (t, J = 7.1 Hz, 1H), 7.42 (dd, J = 6.2, 5.2 Hz, 1H), 5.39 (s, 1H), 3.58 (q, J = 6.7 Hz, 2H), 2.50 (t, J =
14.2 Hz, 2H), 2.33 (dd, J = 18.1, 11.3 Hz, 4H), 2.08 – 1.98 (m, 2H); 19F NMR (565 MHz, CDCl3) δ -96.78;
13C{1H} NMR (151 MHz, CDCl3) δ 164.2, 149.9, 148.0, 137.2, 134.3, 126.0, 122.8 (t, JC-F = 239.7 Hz), 122.0,
118.1(t, JC-F = 5.2 Hz), 37.4, 36.6, 34.5 (t, JC-F = 26.4 Hz), 30.3 (t, JC-F = 24.3 Hz), 26.4 (t, JC-F = 5.4 Hz); HRMS
(ESI/TOF) m/z: [M + H]+ Calcd for C14H17F2N2O 267.1303; Found 267.1309.
N-(2-(cyclohex-1-en-1-yl) ethyl) nicotinamide (1m)24. 1m was synthesized following GP II. A reaction vessel
was charged with 2-(1-cyclohexenyl)ethylamine (280 µL, 2 mmol, 1.0 equiv) and nicotinic acid (271 mg, 2.2
mmol, 1.1 equiv), HATU (836 mg, 2.2 mmol, 1.1 equiv), DIPEA (1034 µL, 6.0 mmol, 3.0 equiv) and DCM (6
mL) in N2 to produce 1m (385 mg, yield 84%) as colorless oil via the purification by flash silica column
chromatography (ethyl acetate: petroleum ether = 1:1). 1H NMR (600 MHz, CDCl3) δ 8.95 (s, 1H), 8.71 (s, 1H),
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8.11 (d, J = 7.1 Hz, 1H), 7.39 (s, 1H), 6.55 (s, 1H), 5.53 (s, 1H), 3.56 – 3.48 (m, 2H), 2.28 – 2.22 (m, 2H), 2.03 –
1.93 (m, 4H), 1.69 – 1.53 (m, 4H).
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N-(2-(cyclohex-1-en-1-yl) ethyl) isonicotinamide (1n)24. 1n was synthesized following GP II. A reaction vessel
was charged with 2-(1-cyclohexenyl)ethylamine (140 µL, 1 mmol, 1.0 equiv ) and isonicotinic acid (136 mg, 1.1
mmol, 1.1 equiv), HATU (418 mg, 1.1 mmol, 1.1 equiv), DIPEA (517 µL, 3.0 mmol, 3.0 equiv) and DCM (3
mL) in N2 to obtain 1n (177 mg, yield 77%) as colorless oil via the purification by flash silica column
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chromatography (ethyl acetate: petroleum ether = 1:4~1:2). H NMR (600 MHz, CDCl3) δ 8.74 (d, J = 4.5 Hz,
2H), 7.56 (d, J = 4.6 Hz, 2H), 6.20 (s, 1H), 5.55 (s, 1H), 3.54 (q, J = 6.5 Hz, 2H), 2.26 (t, J = 6.4 Hz, 2H), 2.06 –
2.01 (m, 2H), 2.00 – 1.95 (m, 2H), 1.67 – 1.63 (m, 2H), 1.58 (dt, J = 9.0, 5.7 Hz, 2H).
N-(2-(cyclohex-1-en-1-yl) ethyl) benzamide (1o). 1o was synthesized following GP II. A reaction vessel was
charged with 2-(1-cyclohexenyl)ethylamine (140 µL, 1 mmol, 1.0 equiv) and benzoic acid (134 mg, 1.1 mmol,
1.1 equiv), HATU (418 mg, 1.1 mmol, 1.1 equiv), DIPEA (517 µL, 3.0 mmol, 3.0 equiv) and DCM (3 mL) in N2
to obtain 1o (58 mg, yield 35%) as colorless oil via the purification by flash silica column chromatography (ethyl
acetate: petroleum ether = 1:6). 1H NMR (600 MHz, CDCl3) δ 7.73 (d, J = 7.2 Hz, 2H), 7.49 (t, J = 7.2 Hz, 1H),
7.43 (t, J = 7.4 Hz, 2H), 6.12 (s, 1H), 5.55 (s, 1H), 3.53 (q, J = 6.5 Hz, 2H), 2.25 (t, J = 5.9 Hz, 2H), 2.00 (d, J =
27.9 Hz, 4H), 1.66 – 1.55 (m, 4H). 1H NMR of 1o is consistent with the previous report.25b
N-(cyclohex-1-en-1-yl methyl) picolinamide (1p). (1) To a 15 mL tube was added cyclohexanone (207 µL, 2
mmol), ethylenediamine (7 µL, 0.1 mmol), nitromethane (1.5 mL) and the resulting was refluxed in a preheated
oil bath at 110 °C for 7 h, using TLC to monitor the reaction (ethyl acetate: petroleum ether = 1:3). The reaction
was cooled to room temperature and evaporated under reduced pressure to get the crude compound
1-(2-nitroethyl)cyclohex-1-ene without further purification. Then 1-(2-nitroethyl)cyclohex-1-ene was treated with
zinc powder (0.7 g) and acetic acid (2 mL) at room temperature for 1-3 h, and the mixture was filtered with
diatomaceous earth, adjusted pH value by saturated NaHCO3 solution and extracted with EA to afford
cyclohex-1-en-1-ylmethanamine (116 mg, the crude product) without further purification. (2) According to the
GP II, the prepared cyclohex-1-en-1-ylmethanamine (116 mg, 1 mmol, 1 equiv), 2-picolinic acid (135 mg, 1.1
mmol, 1.1 equiv), HATU (418 mg, 1.1 mmol, 1.1 equiv), DIPEA (517 µL, 3.1 mmol, 3.0 equiv) and DCM (3
mL) were added in the 25 mL reaction flask in N2 to obtain 1p (23 mg, yield 11%, as yellow oil) via the
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purification by flash silica column chromatography (ethyl acetate: petroleum ether =1:7~ 1:6). H NMR (600
MHz, CDCl3) δ 8.55 (d, J = 4.6 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H), 8.09 (s, 1H), 7.85 (td, J = 7.7, 1.6 Hz, 1H), 7.45
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– 7.39 (m, 1H), 5.66 (s, 1H), 3.97 (d, J = 6.0 Hz, 2H), 2.04 – 1.99 (m, 4H), 1.67 – 1.61 (m, 2H), 1.58 (td, J = 5.8,
3.5 Hz, 2H). 1H NMR of 1p is consistent with the previous report.24
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N-(but-3-en-1-yl)picolinamide (1q)26. (1) To the solution of 4-bromo-1-buten (1015 μL, 10 mmol), Potassium
phtalimide (2315 mg, 12.5 mmol), TBAB (160 mg, 0.5 mmol) in MeCN (16 mL) was refluxed in a preheated oil
bath at 90 °C for 5h. The mixture was filtered to remove an excess of potassium salts and MeCN was evaporated
under reduced pressure. And then it was extracted by Et2O and brine twice (4 mL × 2), dried over K2CO3 and
concentrated to afford N-(3-butenyl) phthalimide (1.939 g, yield 96 %). (2) N-(3-butenyl) phthalimide was
dissolved in EtOH (32 mL) and hydrazine hydrate (972 μL) was added. The mixture was refluxed in a preheated
oil bath at for 1 h (90 °C). Next, 2N NaOH (50 mL) was put into the system and evaporated the solution,
extracted by EA twice. The organic phase was dried over anhydrous Na2SO4 and concentrated to give
but-3-en-1-amine (558 mg, yield 80%) without further purification. (3) The mixture of but-3-en-1-amine (558
mg), triethylamine (1648 µL, 11.85 mmol) and DMAP (96 mg, 0.79 mmol) was charged into a 50 mL flask
containing 20 mL DCM. Sequentially, picolinoyl chloride which is synthesized via 2-picolinic acid (1476 mg, 12
mmol, 1.0 equiv), oxalyl chloride (1270 µL, 15 mmol, 1.25 equiv), DMF (1.5 mL) and DCM (30 mL) in the
reaction flask (100 mL) for 24 h at room temperature was added dropwise under the ice bath. The reaction was
room temperature and stirred for 28 h. When the system was finished, it was quenched with water, extracted by
DCM, washed with brine and purified by flash silica column chromatography (ethyl acetate: petroleum ether =
1:8) to get 1q (34 mg, yield 3%, yellow oil). 1H NMR (600 MHz, CDCl3) δ 8.54 (d, J = 4.0 Hz, 1H), 8.20 (d, J =
7.8 Hz, 1H), 8.10 (s, 1H), 7.84 (td, J = 7.7, 1.6 Hz, 1H), 7.41 (dd, J = 6.4, 4.8 Hz, 1H), 5.86 (ddt, J = 13.6, 10.1,
6.8 Hz, 1H), 5.16 (dd, J = 17.1, 1.4 Hz, 1H), 5.11 (d, J = 10.2 Hz, 1H), 3.56 (q, J = 6.7 Hz, 2H), 2.40 (q, J = 6.8
Hz, 2H). 1H NMR of 1q is consistent with the previous report27.
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N-(2-(1H-indol-3-yl) ethyl) picolinamide (1r). 1r was synthesized following GP II. A reaction vessel was
charged with tryptamine (160 mg, 1.0 mmol, 1.0 equiv), 2-picolinic acid (136 mg, 1.1 mmol, 1.1 equiv), HATU
(418 mg, 1.1 mmol, 1.1 equiv), DIPEA (517 µL, 3.0 mmol, 3.0 equiv) and DCM (3 mL) in N2 to obtain 1r (179
mg, yield 68%) as white solid via the purification by flash silica column chromatography (ethyl acetate:
petroleum ether = 1:1). 1H NMR (600 MHz, CDCl3) δ 8.49 (d, J = 4.7 Hz, 1H), 8.21 (d, J = 7.9 Hz, 2H), 8.13 (s,
1H), 7.83 (t, J = 7.8 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.44 – 7.36 (m, 2H), 7.21 (t, J = 7.6 Hz, 1H), 7.17 – 7.07
(m, 2H), 3.83 (q, J = 6.8 Hz, 2H), 3.11 (t, J = 7.0 Hz, 2H). 1H NMR of 1r is consistent with the previous report28.
(8R,9S,13S,14S)- 13-Methyl- 17-oxo- 7,8,9,11,12,13,14,15, 16,17-decahydro-6H-cyclopenta [a]
phenanthren-3-yl acrylate (2s)29. Estrone (1352 mg, 5 mmol), acrylic acid (340 µL, 5 mmol), DCC (1288 mg,
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6.25 mmol) were dissolved by DCM (20 mL). Next, DMAP (60 mg, 0.5 mmol) was added and stirred at RT for
24 h under an atmosphere of argon, filtered to remove of excess of estrone and the filtrate was evaporated under
reduced pressure and purified by flash silica column chromatography (ethyl acetate: petroleum ether = 1:6) to get
the desired product 2s (334 mg, yield 21%, white solid). 1H NMR (600 MHz, CDCl3) δ 7.30 (d, J = 8.4 Hz, 1H),
6.93 – 6.82 (m, 2H), 6.59 (d, J = 17.3 Hz, 1H), 6.31 (dd, J = 17.3, 10.5 Hz, 1H), 6.00 (d, J = 10.4 Hz, 1H), 2.97 –
2.87 (m, 2H), 2.51 (dd, J = 19.0, 8.7 Hz, 1H), 2.44 – 2.38 (m, 1H), 2.30 (t, J = 8.8 Hz, 1H), 2.19 – 1.94 (m, 4H),
1.64 – 1.46 (m, 6H), 0.91 (s, 3H). 1H NMR of 2s is consistent with the previous report30a.
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General Procedure of Synthesis of Products 3. (Note: All the non-solid PA substrates are dissolved in the
solvent and then added to the reaction system.)
Ethyl (E)-3-(2-(2-(picolinamido)ethyl)cyclohex-1-en-1-yl) acrylate (3aa). The reaction was carried out using
N-(2-(cyclohex-1-en-1-yl)ethyl)picolinamide 1a (46 mg, 0.2 mmol) and ethyl acrylate 2a (44 μL, 0.4 mmol) in
the presence of Pd(OAc)2 (5 mg, 0.02 mmol), KHCO3 (50 mg, 0.5 mmol), Cu(OAc)2∙H2O (20 mg, 0.1 mmol) in
2-methyl-2-butanol (t-AmylOH, 0.4 M) in a sealed tube (25 mL) under air atmosphere at 130 °C via a heating
mantle with magnetic stirrer for 2 h. And the reaction was monitored by TLC and cooled to room temperature.
Then the solvent was evaporated. The crude product was purified by flash silica column chromatography (ethyl
acetate: petroleum ether = 1:4~1:3) to afford 3aa (53 mg, yield 80%, pale yellow solid, m.p. 82-83 oC). 1H NMR
(600 MHz, CDCl3) δ 8.51 (d, J = 4.6 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.14 (s, 1H), 7.83 (dd, J = 7.7, 1.5 Hz,
1H), 7.80 (d, J = 15.8 Hz, 1H), 7.44 – 7.34 (m, 1H), 5.77 (d, J = 15.6 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.57 (q, J
= 6.8 Hz, 2H), 2.62 (t, J = 7.3 Hz, 2H), 2.30 – 2.25 (m, 2H), 2.20 – 2.13 (m, 2H), 1.72 – 1.57 (m, 4H), 1.27 (t, J =
7.1 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 167.7, 164.2, 149.9, 147.9, 143.5, 141.9, 137.2, 129.5, 125.9,
122.1, 115.8, 60.0, 38.4, 33.7, 31.6, 25.4, 22.4, 22.3, 14.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C19H25N2O3 329.1860; Found 329.1859.
Methyl (E)-3-(2-(2-(picolinamido)ethyl)cyclohex-1-en -1-yl)acrylate (3ab). The reaction was carried out using
N-(2-(cyclohex-1-en-1-yl)ethyl)picolinamide 1a (46 mg, 0.2 mmol) and methyl acrylate 2b (36 μL, 0.4 mmol) in
the presence of Pd(OAc)2 (5 mg, 0.02 mmol), KHCO3 (50 mg, 0.5 mmol), Cu(OAc)2∙H2O (20 mg, 0.1 mmol) in
2-methyl-2-butanol (t-AmylOH, 0.4 M) in a sealed tube (25 mL) under air atmosphere at 130 °C via a heating
mantle with magnetic stirrer for 2 h. And the reaction was monitored by TLC and cooled to room temperature.
Then the solvent was evaporated. The crude product was purified by flash silica column chromatography (ethyl
acetate: petroleum ether = 1:4) to afford 3ab (48 mg, yield 76%, pale yellow oil). 1H NMR (600 MHz, CDCl3) δ
8.50 (d, J = 3.7 Hz, 1H), 8.18 (d, J = 7.7 Hz, 1H), 8.14 (s, 1H), 7.85 – 7.81 (m, 1H), 7.79 (d, J = 15.6 Hz, 1H),
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7.42 – 7.38 (m, 1H), 5.77 (d, J = 15.6 Hz, 1H), 3.68 (s, 3H), 3.57 (q, J = 6.8 Hz, 2H), 2.62 (t, J = 7.0 Hz, 2H),
2.31 – 2.24 (m, 2H), 2.18 – 2.13 (m, 2H), 1.70 – 1.62 (m, 4H); 13C{1H} NMR (151 MHz, CDCl3) δ 168.1, 164.3,
149.9, 148.0, 143.8, 142.2, 137.2, 129.5, 126.0, 122.1, 115.3, 51.31, 38.4, 33.8, 31.7, 25.4, 22.5, 22.3; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C18H23N2O3 315.1703; Found 315.1701.
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Butyl (E)-3-(2-(2-(picolinamido)ethyl)cyclohex-1-en-1-yl) acrylate (3ac). The reaction was carried out using
N-(2-(cyclohex-1-en-1-yl)ethyl)picolinamide 1a (46 mg, 0.2 mmol) and butyl acrylate 2c (57 μL, 0.4 mmol) in
the presence of Pd(OAc)2 (5 mg, 0.02 mmol), KHCO3 (50 mg, 0.5 mmol), Cu(OAc)2∙H2O (20 mg, 0.1 mmol) in
2-methyl-2-butanol (t-AmylOH, 0.4 M) in a sealed tube (25 mL) under air atmosphere at 130 °C via a heating
mantle with magnetic stirrer for 2 h. And the reaction was monitored by TLC and cooled to room temperature.
Then the solvent was evaporated. The crude product was purified by flash silica column chromatography (ethyl
acetate: petroleum ether = 1:4) to afford 3ac (53 mg, yield 75%, pale yellow solid, m.p. 83-84 oC). 1H NMR (600
MHz, CDCl3) δ 8.50 (d, J = 4.1 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.13 (s, 1H), 7.83 (dd, J = 7.7, 1.6 Hz, 1H),
7.80 (d, J = 15.7 Hz, 1H), 7.42 – 7.38 (m, 1H), 5.78 (d, J = 15.6 Hz, 1H), 4.09 (t, J = 6.7 Hz, 2H), 3.57 (q, J = 6.7
Hz, 2H), 2.62 (t, J = 7.3 Hz, 2H), 2.31 – 2.24 (m, 2H), 2.21 – 2.14 (m, 2H), 1.69 – 1.59 (m, 6H), 1.43 – 1.34 (m,
2H), 0.94 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 167.8, 164.2, 149.9, 148.0, 143.5, 141.9, 137.2,
129.5, 126.0, 122.1, 115.8, 64.0, 38.4, 33.8, 31.6, 30.8, 25.4, 22.5, 22.3, 19.2, 13.7; HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C21H29N2O3 357.2173; Found 357.2171.
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Hexyl (E)-3-(2-(2-(picolinamido)ethyl)cyclohex-1-en-1-yl) acrylate (3ad). The reaction was carried out using
N-(2-(cyclohex-1-en-1-yl)ethyl)picolinamide 1a (46 mg, 0.2 mmol) and hexyl acrylate 2d (70 μL, 0.4 mmol) in
the presence of Pd(OAc)2 (5 mg, 0.02 mmol), KHCO3 (50 mg, 0.5 mmol), Cu(OAc)2∙H2O (20 mg, 0.1 mmol) in
2-methyl-2-butanol (t-AmylOH, 0.4 M) in a sealed tube (25 mL) under air atmosphere at 130 °C via a heating
mantle with magnetic stirrer for 2 h. And the reaction was monitored by TLC and cooled to room temperature.
Then the solvent was evaporated. The crude product was purified by flash silica column chromatography (ethyl
acetate: petroleum ether = 1:5) to afford 3ad (55 mg, yield 72%, pale yellow solid, m.p. 84-85 oC). 1H NMR (600
MHz, CDCl3) δ 8.50 (d, J = 4.6 Hz, 1H), 8.17 (d, J = 7.7 Hz, 1H), 8.13 (s, 1H), 7.83 (d, J = 7.3 Hz, 1H), 7.80 (d, J
= 15.5 Hz, 1H), 7.40 (dd, J = 7.4, 4.8 Hz, 1H), 5.78 (d, J = 15.5 Hz, 1H), 4.08 (t, J = 6.8 Hz, 2H), 3.57 (q, J = 6.8
Hz, 2H), 2.62 (t, J = 7.3 Hz, 2H), 2.28 (t, J = 5.8 Hz, 2H), 2.17 (d, J = 5.6 Hz, 2H), 1.66 – 1.62 (m, 4H), 1.40 –
1.24 (m, 8H), 0.89 (t, J = 6.7 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 167.8, 164.2, 149.9, 148.0, 143.5,
141.9, 137.2, 129.5, 126.0, 122.1, 115.8, 64.3, 38.5, 33.8, 31.7, 31.5, 28.7, 25.6, 25.4, 22.5, 22.5, 22.3, 14.0;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C23H33N2O3 385.2486; Found 385.2486.
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tert-Butyl (E)-3-(2-(2-(picolinamido)ethyl)cyclohex-1-en-1-yl)acrylate (3ae). The reaction was carried out
using N-(2-(cyclohex-1-en-1-yl)ethyl)picolinamide 1a (46 mg, 0.2 mmol) and tert-butyl acrylate 2e (58 μL, 0.4
mmol) in the presence of Pd(OAc)2 (5 mg, 0.02 mmol), KHCO3 (50 mg, 0.5 mmol), Cu(OAc)2∙H2O (20 mg, 0.1
mmol) in 2-methyl-2-butanol (t-AmylOH, 0.4 M) in a sealed tube (25 mL) under air atmosphere at 130 °C via a
heating mantle with magnetic stirrer for 2 h. And the reaction was monitored by TLC and cooled to room
temperature. Then the solvent was evaporated. The crude product was purified by flash silica column
chromatography (ethyl acetate: petroleum ether = 1:5) to afford 3ae (50 mg, yield 70%, pale yellow solid, m.p.
94-95 oC). 1H NMR (600 MHz, CDCl3) δ 8.52 (d, J = 4.2 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.14 (s, 1H), 7.84 –
7.81 (m, 1H), 7.73 (d, J = 15.5 Hz, 1H), 7.42 – 7.38 (m, 1H), 5.72 (d, J = 15.5 Hz, 1H), 3.56 (q, J = 6.8 Hz, 2H),
2.61 (t, J = 7.3 Hz, 2H), 2.27 (t, J = 5.0 Hz, 2H), 2.17 – 2.13 (m, 2H), 1.68 – 1.61 (m, 4H), 1.46 (s, 9H); 13C{1H}
NMR (151 MHz, CDCl3) δ 167.2, 164.2, 149.9, 148.0, 142.8, 141.0, 137.2, 129.5, 126.0, 122.1, 117.6, 79.9, 38.5,
33.7, 31.6, 28.2, 25.5, 22.5, 22.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H29N2O3 357.2173; Found
357.2176.
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Cyclohexyl (E)-3-(2-(2-(picolinamido)ethyl)cyclohex-1-en-1-yl)acrylate (3af). The reaction was carried out
using N-(2-(cyclohex-1-en-1-yl)ethyl)picolinamide 1a (46 mg, 0.2 mmol) and cyclohexyl acrylate 2f (63 μL, 0.4
mmol) in the presence of Pd(OAc)2 (5 mg, 0.02 mmol), KHCO3 (50 mg, 0.5 mmol), Cu(OAc)2∙H2O (20 mg, 0.1
mmol) in 2-methyl-2-butanol (t-AmylOH, 0.4 M) in a sealed tube (25 mL) under air atmosphere at 130 °C via a
heating mantle with magnetic stirrer for 2 h. And the reaction was monitored by TLC and cooled to room
temperature. Then the solvent was evaporated. The crude product was purified by flash silica column
chromatography (ethyl acetate: petroleum ether = 1:5) to afford 3af (57 mg, yield 75%, yellow solid, m.p. 70-71
oC). 1H NMR (600 MHz, CDCl3) δ 8.51 (d, J = 4.3 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.13 (s, 1H), 7.83 (d, J = 7.7
Hz, 1H), 7.80 (d, J = 15.7 Hz, 1H), 7.43 – 7.38 (m, 1H), 5.78 (d, J = 15.5 Hz, 1H), 4.78 (td, J = 8.8, 4.2 Hz, 1H),
3.57 (q, J = 6.9 Hz, 2H), 2.62 (t, J = 7.3 Hz, 2H), 2.29 – 2.26 (m, 2H), 2.19 – 2.15 (m, 2H), 1.87 – 1.60 (m, 10H),
1.45 – 1.34 (m, 4H); 13C{1H} NMR (151 MHz, CDCl3) δ 167.2, 164.2, 149.9, 148.0, 143.3, 141.6, 137.2, 129.6,
126.0, 122.1, 116.4, 72.2, 38.5, 33.7, 31.7, 31.6, 25.5, 23.8, 22.5, 22.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C23H31N2O3 383.2329; Found 383.2335.
2,2,2-Trifluoroethyl (E)-3-(2-(2-(picolinamido)ethyl) cyclohex-1-en-1-yl)acrylate (3ag). The reaction was
carried out using N-(2-(cyclohex-1-en-1-yl)ethyl)picolinamide 1a (46 mg, 0.2 mmol) and 2,2,2-trifluoroethyl
acrylate 2g (51 μL, 0.4 mmol) in the presence of Pd(OAc)2 (5 mg, 0.02 mmol), KHCO3 (50 mg, 0.5 mmol),
Cu(OAc)2∙H2O (20 mg, 0.1 mmol) in 2-methyl-2-butanol (t-AmylOH, 0.4 M) in a sealed tube (25 mL) under air
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atmosphere at 130 °C via a heating mantle with magnetic stirrer for 2 h. And the reaction was monitored by TLC
and cooled to room temperature. Then the solvent was evaporated. The crude product was purified by flash silica
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6.5 Hz, 2H), 2.63 (t, J = 6.4 Hz, 2H), 2.33 – 2.27 (m, 2H), 2.19 – 2.13 (m, 2H), 1.70 – 1.61 (m, 4H); F NMR
(565 MHz, CDCl3) δ -73.72. 13C{1H} NMR (151 MHz, CDCl3) δ 165.9, 164.3, 149.9, 147.9, 145.8, 144.4, 137.2,
129.5, 126.0, 123.2 (q, JC-F = 277.3 Hz), 122.1, 113.2, 60.1 (q, JC-F = 36.4 Hz), 38.4, 33.9, 31.8, 25.4, 22.4, 22.2;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H22F3N2O3 383.1577; Found 383.1580.
2-Hydroxyethyl (E)-3-(2-(2-(picolinamido)ethyl) cyclohex-1-en-1-yl)acrylate (3ah). The reaction was carried
out using N-(2-(cyclohex-1-en-1-yl)ethyl)picolinamide 1a (46 mg, 0.2 mmol) and 2-hydroxyethyl acrylate 2h (42
μL, 0.4 mmol) in the presence of Pd(OAc)2 (5 mg, 0.02 mmol), KHCO3 (50 mg, 0.5 mmol), Cu(OAc)2∙H2O (20
mg, 0.1 mmol) in 2-methyl-2-butanol (t-AmylOH, 0.4 M) in a sealed tube (25 mL) under air atmosphere at 130
°C via a heating mantle with magnetic stirrer for 2 h. And the reaction was monitored by TLC and cooled to room
temperature. Then the solvent was evaporated. The crude product was purified by flash silica column
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chromatography (ethyl acetate: petroleum ether = 1:1) to afford 3ah (33 mg, yield 48%, yellow oil). H NMR
(600 MHz, CDCl3) δ 8.52 (d, J = 4.0 Hz, 1H), 8.35 (s, 1H), 8.23 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 15.6 Hz, 1H),
7.86 (t, J = 7.6 Hz, 1H), 7.45 – 7.39 (m, 1H), 5.77 (d, J = 15.6 Hz, 1H), 4.76 (s, 1H), 4.28 – 4.24 (m, 2H), 3.93 (s,
2H), 3.48 (q, J = 6.9 Hz, 2H), 2.66 – 2.58 (m, 2H), 2.28 – 2.22 (m, 2H), 2.19 – 2.14 (m, 2H), 1.71 – 1.60 (m, 4H);
13C{1H} NMR (151 MHz, CDCl3) δ 167.7, 165.3, 149.5, 148.1, 143.2, 142.6, 137.5, 129.9, 126.3, 122.3, 115.6,
66.6, 61.0, 39.4, 33.9, 32.0, 25.0, 22.5, 22.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H25N2O4 345.1809;
Found 345.1812.
2-Methoxyethyl (E)-3-(2-(2-(picolinamido)ethyl) cyclohex-1-en-1-yl)acrylate (3ai). The reaction was carried
out using N-(2-(cyclohex-1-en-1-yl)ethyl)picolinamide 1a (46 mg, 0.2 mmol) and 2-methoxyethyl acrylate 2i (52
μL, 0.4 mmol) in the presence of Pd(OAc)2 (5 mg, 0.02 mmol), KHCO3 (50 mg, 0.5 mmol), Cu(OAc)2∙H2O (20
mg, 0.1 mmol) in 2-methyl-2-butanol (t-AmylOH, 0.4 M) in a sealed tube (25 mL) under air atmosphere at 130
°C via a heating mantle with magnetic stirrer for 2 h. And the reaction was monitored by TLC and cooled to room
temperature. Then the solvent was evaporated. The crude product was purified by flash silica column
chromatography (ethyl acetate: petroleum ether = 1:2) to afford 3ai (50 mg, yield 70%, yellow oil). 1H NMR (600
MHz, CDCl3) δ 8.51 (d, J = 3.7 Hz, 1H), 8.20 – 8.10 (m, 2H), 7.87 – 7.79 (m, 2H), 7.40 (dd, J = 7.7, 4.6 Hz, 1H),
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5.84 (d, J = 15.5 Hz, 1H), 4.26 (t, J = 4.8 Hz, 2H), 3.62 (t, J = 4.8 Hz, 2H), 3.56 (q, J = 7.0 Hz, 2H), 3.40 (s, 3H),
2.62 (t, J = 7.4 Hz, 2H), 2.30 – 2.25 (m, 2H), 2.17 – 2.13 (m, 2H), 1.68 – 1.60 (m, 4H); 13C{1H} NMR (151 MHz,
CDCl3) δ 167.7, 164.2, 149.9, 148.0, 143.9, 142.4, 137.2, 129.5, 126.0, 122.1, 115.3, 70.6, 63.2, 59.0, 38.5, 33.8,
31.7, 25.4, 22.4, 22.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H27N2O4 359.1965; Found 359.1968.
(Tetrahydrofuran-2-yl) methyl (E)-3-(2-(2-(picolinamido) ethyl)cyclohex-1-en-1-yl)acrylate (3aj). The
reaction was carried out using N-(2-(cyclohex-1-en-1-yl)ethyl)picolinamide 1a (46 mg, 0.2 mmol) and
(tetrahydrofuran-2-yl)methyl acrylate 2j (59 μL, 0.4 mmol) in the presence of Pd(OAc)2 (5 mg, 0.02 mmol),
KHCO3 (50 mg, 0.5 mmol), Cu(OAc)2∙H2O (20 mg, 0.1 mmol) in 2-methyl-2-butanol (t-AmylOH, 0.4 M) in a
sealed tube (25 mL) under air atmosphere at 130 °C via a heating mantle with magnetic stirrer for 2 h. And the
reaction was monitored by TLC and cooled to room temperature. Then the solvent was evaporated. The crude
product was purified by flash silica column chromatography (ethyl acetate: petroleum ether = 1:1) to afford 3aj
(54 mg, yield 70%, yellow solid, m.p. 64-65 oC). 1H NMR (600 MHz, CDCl3) δ 8.51 (d, J = 4.9 Hz, 1H), 8.19 –
8.11 (m, 2H), 7.87 – 7.77 (m, 2H), 7.40 (t, d, J = 5.9 Hz, 1H), 5.84 (d, J = 15.5 Hz, 1H), 4.20 – 4.12 (m, 2H), 4.04
(dd, J = 10.9, 6.4 Hz, 1H), 3.90 (dd, J = 7.0, 6.3 Hz, 1H), 3.80 (q, J = 7.2, Hz, 1H), 3.58 – 3.53 (m, 2H), 2.61 (t, J
= 6.6 Hz, 2H), 2.31 – 2.24 (m, 2H), 2.18 – 2.12 (m, 2H), 2.00 (p, J = 6.4 Hz, 1H), 1.94 – 1.87 (m, 2H), 1.64 (t, J =
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7.0 Hz, 5H); C{1H} NMR (151 MHz, CDCl3) δ 167.6, 164.2, 149.8, 148.0, 143.9, 142.4, 137.2, 129.5, 126.0,
122.1, 115.4, 76.6, 68.4, 66.2, 38.5, 33.7, 31.6, 28.0, 25.7, 25.4, 22.4, 22.3; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C22H29N2O4 385.2122; Found 385.2123.
Benzyl (E)-3-(2-(2-(picolinamido)ethyl) cyclohex-1-en-1-yl)acrylate (3ak). The reaction was carried out using
N-(2-(cyclohex-1-en-1-yl)ethyl)picolinamide 1a (46 mg, 0.2 mmol) and benzyl acrylate 2k (60 μL, 0.4 mmol) in
the presence of Pd(OAc)2 (5 mg, 0.02 mmol), KHCO3 (50 mg, 0.5 mmol), Cu(OAc)2∙H2O (20 mg, 0.1 mmol) in
2-methyl-2-butanol (t-AmylOH, 0.4 M) in a sealed tube (25 mL) under air atmosphere at 130 °C via a heating
mantle with magnetic stirrer for 2 h. And the reaction was monitored by TLC and cooled to room temperature.
Then the solvent was evaporated. The crude product was purified by flash silica column chromatography (ethyl
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acetate: petroleum ether = 1:4) to afford 3ak (57 mg, yield 73%, yellow solid, m.p. 92-93 C). H NMR (600
MHz, CDCl3) δ 8.46 (d, J = 4.2 Hz, 1H), 8.15 (d, J = 7.8 Hz, 1H), 8.13 (s, 1H), 7.86 (d, J = 15.6 Hz, 1H), 7.80 (td,
J = 7.7, 1.6 Hz, 1H), 7.39 – 7.34 (m, 5H), 7.33 – 7.30 (m, 1H), 5.82 (d, J = 15.5 Hz, 1H), 5.15 (s, 2H), 3.56 (q, J =
6.7 Hz, 2H), 2.62 (t, J = 7.3 Hz, 2H), 2.31 – 2.26 (m, 2H), 2.18 – 2.12 (m, 2H), 1.67 – 1.62 (m, 4H); 13C{1H}
NMR (151 MHz, CDCl3) δ 167.5, 164.3, 149.9, 148.0, 144.1, 142.5, 137.2, 136.4, 129.6, 128.5, 128.1, 128.0,
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126.0, 122.1, 115.3, 65.9, 38.4, 33.8, 31.7, 25.4, 22.4, 22.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C24H27N2O3 391.2016; Found 391.2017.
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Phenyl (E)-3-(2-(2-(picolinamido)ethyl) cyclohex-1-en-1-yl)acrylate (3al). The reaction was carried out using
N-(2-(cyclohex-1-en-1-yl)ethyl)picolinamide 1a (46 mg, 0.2 mmol) and phenyl acrylate 2l (55 μL, 0.4 mmol) in
the presence of Pd(OAc)2 (5 mg, 0.02 mmol), KHCO3 (50 mg, 0.5 mmol), Cu(OAc)2∙H2O (20 mg, 0.1 mmol) in
toluene (0.4 M) in a sealed tube (25 mL) under air atmosphere at 130 °C via a heating mantle with magnetic
stirrer for 2 h. And the reaction was monitored by TLC and cooled to room temperature. Then the solvent was
evaporated. The crude product was purified by flash silica column chromatography (ethyl acetate: petroleum
ether = 1:4) to afford 3al (47 mg, yield 63%, yellow solid, m.p. 90-91 oC). 1H NMR (600 MHz, CDCl3) δ 8.50 (d,
J = 4.4 Hz, 1H), 8.16 (d, J = 7.8 Hz, 2H), 7.98 (d, J = 15.5 Hz, 1H), 7.80 (td, J = 7.7, 1.5 Hz, 1H), 7.41 – 7.34 (m,
3H), 7.21 (t, J = 7.4 Hz, 1H), 7.09 – 7.06 (m, 2H), 5.95 (d, J = 15.5 Hz, 1H), 3.59 (q, J = 6.8 Hz, 2H), 2.65 (t, J =
7.2 Hz, 2H), 2.32 (t, J = 5.5 Hz, 2H), 2.26 – 2.20 (m, 2H), 1.73 – 1.63 (m, 4H); 13C{1H} NMR (151 MHz, CDCl3)
δ 166.1, 164.3, 151.0, 149.8, 148.0, 145.1, 143.8, 137.3, 129.7, 129.2, 126.1, 125.5, 122.2, 121.6, 114.8, 38.5,
33.9, 31.8, 25.4, 22.4, 22.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C23H25N2O3 377.1860; Found 377.1861.
Diethyl (E)-(2-(2-(2-(picolinamido)ethyl) cyclohex-1-en-1-yl)vinyl)phosphonate (3am). The reaction was
carried out using N-(2-(cyclohex-1-en-1-yl)ethyl) picolinamide 1a (46 mg, 0.2 mmol) and diethyl
vinylphosphonate 2m (61 μL, 0.4 mmol) in the presence of Pd(OAc)2 (5 mg, 0.02 mmol), KHCO3 (50 mg, 0.5
mmol), Cu(OAc)2∙H2O (20 mg, 0.1 mmol) in 2-methyl-2-butanol (t-AmylOH, 0.4 M) in a sealed tube (25 mL)
under air atmosphere at 130 °C via a heating mantle with magnetic stirrer for 2 h. And the reaction was monitored
by TLC and cooled to room temperature. Then the solvent was evaporated. The crude product was purified by
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flash silica column chromatography (ethyl acetate) to afford 3am (45 mg, yield 57%, yellow oil). H NMR (600
MHz, CDCl3) δ 8.54 (d, J = 4.8 Hz, 1H), 8.18 (d, J = 8.9 Hz, 2H), 7.84 (t, J = 7.8 Hz, 1H), 7.63 (dd, J = 22.8, 17.3
Hz, 1H), 7.41 (t, J = 6.1 Hz, 1H), 5.59 (t, J = 18.1 Hz, 1H), 4.12 – 3.95 (m, 4H), 3.56 (q, J = 7.1 Hz, 2H), 2.62 (t,
J = 7.7 Hz, 2H), 2.30 – 2.26 (m, 2H), 2.17 – 2.13 (m, 2H), 1.69 – 1.60 (m, 4H), 1.31 (t, J = 7.1 Hz, 6H); 13C{1H}
NMR (151 MHz, CDCl3) δ 164.1, 149.7, 147.9, 145.5 (d, JC-P = 7.2 Hz), 142.7, 137.1, 129.5 (d, JC-P = 22.6 Hz),
125.9, 121.9, 110.9 (d, JC-P = 191.9 Hz), 61.4 (d, JC-P = 5.5 Hz), 38.3, 33.4, 31.3, 25.0, 22.3, 22.2, 16.2 (d, JC-P
=
6.2 Hz); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H30N2O4P 393.1938; Found 393.1939.
(E)-N-(2-(2-(3-(dimethylamino)-3-oxoprop-1-en-1-yl) cyclohex-1-en-1-yl)ethyl)picolinamide (3an). The
reaction was carried out using N-(2-(cyclohex-1-en-1-yl)ethyl) picolinamide 1a (46 mg, 0.2 mmol) and
N,N-dimethylacrylamide 2n (41 μL, 0.4 mmol) in the presence of Pd(OAc)2 (5 mg, 0.02 mmol), KHCO3 (50 mg,
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0.5 mmol), Cu(OAc)2∙H2O (20 mg, 0.1 mmol) in 2-methyl-2-butanol (t-AmylOH, 0.4 M) in a sealed tube (25 mL)
under air atmosphere at 130 °C via a heating mantle with magnetic stirrer for 2 h. And the reaction was monitored
by TLC and cooled to room temperature. Then the solvent was evaporated. The crude product was purified by
flash silica column chromatography (ethyl acetate: petroleum ether = 1:1) to afford 3an (21 mg, yield 32%,
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yellow oil). H NMR (600 MHz, CDCl3) δ 8.52 (d, J = 4.2 Hz, 1H), 8.21 – 8.15 (m, 2H), 7.86 – 7.81 (m, 1H),
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7.79 (d, J = 15.5 Hz, 1H), 7.42 – 7.38 (m, 1H), 6.22 (d, J = 15.0 Hz, 1H), 3.55 (q, J = 7.0 Hz, 2H), 3.06 (s, 3H),
3.02 (s, 3H), 2.63 (t, J = 7.6 Hz, 2H), 2.30 – 2.26 (m, 2H), 2.23 –2.17 (m, 2H), 1.71 – 1.60 (m, 4H); 13C{1H}
NMR (151 MHz, CDCl3) δ 167.7, 164.2, 150.0, 148.0, 141.9, 139.8, 137.1, 129.4, 125.9, 122.1, 114.7, 38.7, 37.3,
35.8, 33.8, 31.6, 25.7, 22.6, 22.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H26N3O2 328.2020; Found
328.2018.
Ethyl (E)-3-(2-(2-(picolinamido)ethyl)cyclopent-1-en-1-yl) acrylate (3ba). The reaction was carried out using
N-(2-(cyclopent-1-en-1-yl)ethyl)picolinamide 1b (43 mg, 0.2 mmol) and ethyl acrylate 2a (44 μL, 0.4 mmol) in
the presence of Pd(OAc)2 (5 mg, 0.02 mmol), KHCO3 (50 mg, 0.5 mmol), Cu(OAc)2∙H2O (20 mg, 0.1 mmol) in
2-methyl-2-butanol (t-AmylOH, 0.4 M) in a sealed tube (25 mL) under air atmosphere at 130 °C via a heating
mantle with magnetic stirrer for 2 h. And the reaction was monitored by TLC and cooled to room temperature.
Then the solvent was evaporated. The crude product was purified by flash silica column chromatography (ethyl
acetate: petroleum ether = 1:4~1:3) to afford 3ba (41 mg, yield 65%, pale yellow solid, m.p. 71-72 oC). 1H NMR
(600 MHz, CDCl3) δ 8.51 (d, J = 4.2 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.09 (s, 1H), 7.83 (t, J = 7.6 Hz, 1H), 7.58
(d, J = 15.5 Hz, 1H), 7.42 – 7.38 (m, 1H), 5.71 (d, J = 15.5 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.60 (q, J = 6.8 Hz,
2H), 2.68 (t, J = 7.0 Hz, 2H), 2.59 (t, J = 7.1 Hz, 2H), 2.50 (t, J = 7.1 Hz, 2H), 1.94 – 1.87 (m, 2H), 1.27 (t, J = 7.1
Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 167.5, 164.2, 149.9, 149.0, 148.0, 137.5, 137.2, 135.3, 126.0, 122.1,
118.0, 60.1, 37.8, 37.5, 32.6, 29.2, 21.6, 14.3; HRMS (ESI-TOF) m/z: Calcd for [M + Na]+ C18H22N2O3Na
337.1523; Found 337.1522.
Ethyl (E)-3-(2-(2-(picolinamido)ethyl)cyclohept-1-en-1-yl) acrylate (3ca). The reaction was carried out using
N-(2-(cyclohept-1-en-1-yl)ethyl)picolinamide 1c (49 mg, 0.2 mmol) and ethyl acrylate 2a (44 μL, 0.4 mmol) in
the presence of Pd(OAc)2 (5 mg, 0.02 mmol), KHCO3 (50 mg, 0.5 mmol), Cu(OAc)2∙H2O (20 mg, 0.1 mmol) in
2-methyl-2-butanol (t-AmylOH, 0.4 M) in a sealed tube (25 mL) under air atmosphere at 130 °C via a heating
mantle with magnetic stirrer for 2 h. And the reaction was monitored by TLC and cooled to room temperature.
Then the solvent was evaporated. The crude product was purified by flash silica column chromatography (ethyl
acetate: petroleum ether = 1:4~1:3) to afford 3ca (37 mg, yield 54%, pale yellow solid, m.p. 76-77 oC). 1H NMR
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(600 MHz, CDCl3) δ 8.50 (d, J = 4.1 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.12 (s, 1H), 7.82 (t, J = 7.7 Hz, 1H), 7.75
(d, J = 15.5 Hz, 1H), 7.43 – 7.36 (m, 1H), 5.83 (d, J = 15.5 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.57 (q, J = 6.9 Hz,
2H), 2.67 (t, J = 7.2 Hz, 2H), 2.47 – 2.44 (m, 2H), 2.41 – 2.36 (m, 2H), 1.80 – 1.76 (m, 2H), 1.56 – 1.51 (m, 2H),
1.49 – 1.42 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 167.8, 164.2, 149.9, 148.9,
148.0, 142.3, 137.2, 136.7, 126.0, 122.0, 116.1, 60.1, 37.9, 35.6, 35.0, 32.0, 28.5, 26.1, 25.9, 14.3; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C20H27N2O3 343.2016; Found 343.2018.
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Ethyl (E)-3-((Z)-2-(2-(picolinamido)ethyl) cyclooct-1-en-1-yl)acrylate (3da). The reaction was carried out
using (E)-N-(2-(cyclooct-1-en-1-yl)ethyl)picolinamide 1d (52 mg, 0.2 mmol) and ethyl acrylate 2a (44 μL, 0.4
mmol) in the presence of Pd(OAc)2 (5 mg, 0.02 mmol), KHCO3 (50 mg, 0.5 mmol), Cu(OAc)2∙H2O (20 mg, 0.1
mmol) in 2-methyl-2-butanol (t-AmylOH, 0.4 M) in a sealed tube (25 mL) under air atmosphere at 130 °C via a
heating mantle with magnetic stirrer for 2 h. And the reaction was monitored by TLC and cooled to room
temperature. Then the solvent was evaporated. The crude product was purified by flash silica column
chromatography (ethyl acetate: petroleum ether = 1:4~1:3) to afford 3da (46 mg, yield 65%, pale yellow solid,
m.p. 86-87 oC). 1H NMR (600 MHz, CDCl3) δ 8.51 (d, J = 4.7 Hz, 1H), 8.18 (d, J = 7.9 Hz, 2H), 7.83 (t, J = 7.7
Hz, 1H), 7.74 (d, J = 15.6 Hz, 1H), 7.40 (dd, J = 7.7, 4.7 Hz, 1H), 5.86 (d, J = 15.6 Hz, 1H), 4.15 (q, J =7.1 Hz,
2H), 3.58 (q, J = 6.8 Hz, 2H), 2.67 (t, J = 7.4 Hz, 2H), 2.45 (dt, J = 28.4, 6.2 Hz 4H), 1.65 (p, J = 6.0 Hz, 2H),
1.59 – 1.52 (m, 2H), 1.50 – 1.38 (m, 4H), 1.27 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 167.8,
164.2, 149.9, 148.0, 146.7, 141.4, 137.2, 133.1, 126.0, 122.1, 116.6, 60.1, 38.5, 33.5, 33.1, 29.7, 28.9, 26.9, 26.5,
26.4, 14.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H29N2O3 357.2173; Found 357.2174.
Ethyl (E)-3-(5-methyl-2-(2-(picolinamido)ethyl) cyclohex-1-en-1-yl)acrylate (3ea). The reaction was carried
out using N-(2-(4-methylcyclohex-1-en-1-yl)ethyl) picolinamide 1e (49 mg, 0.2 mmol) and ethyl acrylate 2a (44
μL, 0.4 mmol) in the presence of Pd(OAc)2 (5 mg, 0.02 mmol), KHCO3 (50 mg, 0.5 mmol), Cu(OAc)2∙H2O (20
mg, 0.1 mmol) in 2-methyl-2-butanol (t-AmylOH, 0.4 M) in a sealed tube (25 mL) under air atmosphere at 130
°C via a heating mantle with magnetic stirrer for 2 h. And the reaction was monitored by TLC and cooled to room
temperature. Then the solvent was evaporated. The crude product was purified by flash silica column
chromatography (ethyl acetate: petroleum ether = 1:4~1:3) to afford 3ea (38 mg, yield 56%, pale yellow solid,
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m.p. 70-71 C). H NMR (600 MHz, CDCl3) δ 8.50 (d, J = 4.2 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.13 (s, 1H),
7.83 (td, J = 7.7, 1.4 Hz, 1H), 7.79 (d, J = 15.6 Hz, 1H), 7.43 – 7.38 (m, 1H), 5.79 (d, J = 15.5 Hz, 1H), 4.14 (q, J
= 7.0 Hz, 2H), 3.63 – 3.50 (m, 2H), 2.70 – 2.54 (m, 2H), 2.35 – 2.25 (m, 3H), 1.81 – 1.58 (m, 4H), 1.26 (t, J = 7.1
13
Hz, 3H), 1.00 (d, J = 6.3 Hz, 3H); C{1H} NMR (151 MHz, CDCl3) δ 167.7, 164.2, 149.9, 147.9, 143.1, 141.8,
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137.1, 129.1, 125.9, 122.0, 115.8, 60.0, 38.4, 34.0, 33.4, 31.7, 30.5, 28.3, 21.7, 14.3; HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C20H27N2O3 343.2022; Found 343.2027.
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Ethyl (E)-3-(5,5-dimethyl-2-(2-(picolinamido)ethyl) cyclohex-1-en-1-yl)acrylate (3fa). The reaction was
carried out using N-(2-(4,4-dimethylcyclohex-1-en-1-yl)ethyl) picolinamide 1f (52 mg, 0.2 mmol) and ethyl
acrylate 2a (44 μL, 0.4 mmol) in the presence of Pd(OAc)2 (5 mg, 0.02 mmol), KHCO3 (50 mg, 0.5 mmol),
Cu(OAc)2∙H2O (20 mg, 0.1 mmol) in 2-methyl-2-butanol (t-AmylOH, 0.4 M) in a sealed tube (25 mL) under air
atmosphere at 130 °C via a heating mantle with magnetic stirrer for 2 h. And the reaction was monitored by TLC
and cooled to room temperature. Then the solvent was evaporated. The crude product was purified by flash silica
column chromatography (ethyl acetate: petroleum ether = 1:5~1:4) to afford 3fa (50 mg, yield 70%, pale yellow
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solid, m.p. 79-80 C). H NMR (600 MHz, CDCl3) δ 8.50 (d, J = 4.0 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.13 (s,
1H), 7.82 (td, J = 9.2, 4.7 Hz, 2H), 7.42 – 7.36 (m, 1H), 5.79 (d, J = 15.6 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.58
(q, J = 6.8 Hz,, 2H), 2.64 (t, J = 7.1 Hz, 2H), 2.31 (t, J = 6.5 Hz, 2H), 1.94 (s, 2H), 1.41 (t, J = 6.4 Hz, 2H), 1.27
(t, J = 7.1 Hz, 3H), 0.92 (s, 6H); 13C{1H} NMR (151 MHz, CDCl3) δ 167.6, 164.1, 149.8, 147.9, 142.0, 142.0,
137.1, 128.5, 125.9, 122.0, 115.8, 60.0, 39.3, 38.4, 34.9, 33.2, 29.4, 28.6, 28.1, 14.2; HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C21H29N2O3 357.2173; Found 357.2172.
Ethyl (E)-3-(5-(tert-butyl)-2-(2-(picolinamido)ethyl) cyclohex-1-en-1-yl)acrylate (3ga). The reaction was
carried out using N-(2-(4-(tert-butyl)cyclohex-1-en-1-yl)ethyl) picolinamide 1g (57 mg, 0.2 mmol) and ethyl
acrylate 2a (44 μL, 0.4 mmol) in the presence of Pd(OAc)2 (5 mg, 0.02 mmol), KHCO3 (50 mg, 0.5 mmol),
Cu(OAc)2∙H2O (20 mg, 0.1 mmol) in 2-methyl-2-butanol (t-AmylOH, 0.4 M) in a sealed tube (25 mL) under air
atmosphere at 130 °C via a heating mantle with magnetic stirrer for 2 h. And the reaction was monitored by TLC
and cooled to room temperature. Then the solvent was evaporated. The crude product was purified by flash silica
column chromatography (ethyl acetate: petroleum ether = 1:5~1:4) to afford 3ga (44 mg, yield 57%, pale yellow
1
oil). H NMR (600 MHz, CDCl3) δ 8.51 (d, J = 4.7 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H), 8.13 (s, 1H), 7.85 – 7.77
(m, 2H), 7.40 (dd, J = 7.5, 4.7 Hz, 1H), 5.82 (d, J = 15.4 Hz, 1H), 4.21 – 4.12 (m, 2H), 3.65 – 3.49 (m, 2H), 2.72
– 2.55 (m, 2H), 2.41 – 2.20 (m, 3H), 1.94 – 1.79 (m, 3H), 1.27 (d, J = 7.0 Hz, 3H), 1.15 (qd, J = 12.2, 5.1 Hz,
1H), 0.91 (s, 9H); 13C{1H} NMR (151 MHz, CDCl3) δ 167.7, 164.2, 149.9, 148.0, 143.5, 142.1, 137.2, 129.6,
126.0, 122.1, 115.6, 60.1, 43.9, 38.4, 33.4, 33.1, 32.3, 27.2, 27.1, 23.8, 14.3; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C23H33N2O3 385.2486; Found 385.2485.
Ethyl (E)-3-(4-(2-(picolinamido)ethyl)-1,2,5,6-tetrahydro-[1,1'-biphenyl]-3-yl) acrylate (3ha). The reaction
was carried out using N-(2-(1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-yl)ethyl)picolinamide 1h (61 mg, 0.2 mmol) and
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The Journal of Organic Chemistry
ethyl acrylate 2a (44 μL, 0.4 mmol) in the presence of Pd(OAc)2 (5 mg, 0.02 mmol), KHCO3 (50 mg, 0.5 mmol),
Cu(OAc)2∙H2O (20 mg, 0.1 mmol) in 2-methyl-2-butanol (t-AmylOH, 0.4 M) in a sealed tube (25 mL) under air
atmosphere at 130 °C via a heating mantle with magnetic stirrer for 2 h. And the reaction was monitored by TLC
and cooled to room temperature. Then the solvent was evaporated. The crude product was purified by flash silica
column chromatography (ethyl acetate: petroleum ether = 1:5~1:4) to afford 3ha (38 mg, yield 47%, pale yellow
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solid, m.p. 100-101 C). H NMR (600 MHz, CDCl3) δ 8.51 (d, J = 4.0 Hz, 1H), 8.19 (d, J = 7.8 Hz, 2H), 7.82
(dd, J = 11.7, 3.7 Hz, 2H), 7.42 – 7.38 (m, 1H), 7.31 (t, J = 7.5 Hz, 2H), 7.22 (dd, J = 13.5, 7.1 Hz, 3H), 5.77 (d, J
= 15.6 Hz, 1H), 4.13 (q, J = 7.0 Hz, 2H), 3.61 (ddq, J = 34.0, 13.6, 6.8 Hz, 2H), 2.83 (d, J = 10.2 Hz, 1H), 2.77 –
2.70 (m, 1H), 2.67 – 2.59 (m, 1H), 2.55 – 2.44 (m, 3H), 2.32 – 2.19 (m, 1H), 2.00 (d, J = 12.1 Hz, 1H), 1.79 (qd,
J = 12.1, 5.7 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H); C{1H} NMR (151 MHz, CDCl3) δ 167.5, 164.2, 149.9, 148.0,
13
146.1, 143.0, 141.4, 137.2, 129.3, 128.4, 126.8, 126.2, 126.0, 122.1, 116.2, 60.0, 39.7, 38.4, 33.7, 33.5, 32.0,
29.2, 14.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C25H29N2O3 405.2173; Found 405.2172.
Ethyl (E)-3-(5,5-difluoro-2-(2-(picolinamido)ethyl) cyclohex-1-en-1-yl)acrylate (3ia). The reaction was
carried out using N-(2-(4,4-difluorocyclohex-1-en-1-yl)ethyl)picolinamide 1i (53 mg, 0.2 mmol) and ethyl
acrylate 2a (44 μL, 0.4 mmol) in the presence of Pd(OAc)2 (5 mg, 0.02 mmol), KHCO3 (50 mg, 0.5 mmol),
Cu(OAc)2∙H2O (20 mg, 0.1 mmol) in 2-methyl-2-butanol (t-AmylOH, 0.4 M) in a sealed tube (25 mL) under air
atmosphere at 130 °C via a heating mantle with magnetic stirrer for 2 h. And the reaction was monitored by TLC
and cooled to room temperature. Then the solvent was evaporated. The crude product was purified by flash silica
column chromatography (ethyl acetate: petroleum ether = 1:8~1:2) to afford 3ia (36 mg, yield 49%, pale yellow
oil). 1H NMR (600 MHz, CDCl3) δ 8.50 (d, J = 4.3 Hz, 1H), 8.16 (d, J = 7.8 Hz, 2H), 7.86 – 7.80 (m, 1H), 7.73
(d, J = 15.6 Hz, 1H), 7.41 (dd, J = 6.9, 5.3 Hz, 1H), 5.70 (d, J = 15.6 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.59 (q, J
19
= 6.8 Hz, 2H), 2.68 – 2.61 (m, 4H), 2.57 (t, J = 6.0 Hz, 2H), 2.13 – 2.04 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H); F
NMR (565 MHz, CDCl3) δ -95.81; 13C{1H} NMR (151 MHz, CDCl3) δ 167.0, 164.4, 149.7, 148.0, 141.6, 140.3,
137.3, 126.1, 125.4 (t, JC-F = 5.3 Hz), 122.5 (t, JC-F = 239.0 Hz), 122.1, 117.1, 60.3, 38.1, 34.9 (t, JC-F = 27.5 Hz),
33.1, 30.1 (t, JC-F = 24.3 Hz), 29.6(t, JC-F = 5.4 Hz), 14.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C19H23F2N2O3 365.1671; Found 365.1671.
Ethyl (E)-3-(2-(2-(3-methoxyphenyl)-2-(picolinamido) ethyl)cyclohex-1-en-1-yl)acrylate (3ja). The reaction
was carried out using N-(2-(cyclohex-1-en-1-yl)-1-(3-methoxyphenyl)ethyl)picolinamide 1j (67 mg, 0.2 mmol)
and ethyl acrylate 2a (44 μL, 0.4 mmol) in the presence of Pd(OAc)2 (5 mg, 0.02 mmol), KHCO3 (50 mg, 0.5
mmol), Cu(OAc)2∙H2O (20 mg, 0.1 mmol) in 2-methyl-2-butanol (t-AmylOH, 0.4 M) in a sealed tube (25 mL)
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under air atmosphere at 130 °C via a heating mantle with magnetic stirrer for 2 h. And the reaction was monitored
by TLC and cooled to room temperature. Then the solvent was evaporated. The crude product was purified by
flash silica column chromatography (ethyl acetate: petroleum ether = 1:5~1:4) to afford 3ja (45 mg, yield 52%,
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pale yellow solid, m.p. 99-100 C). H NMR (600 MHz, CDCl3) δ 8.50 (d, J = 4.8 Hz, 1H), 8.45 (d, J = 8.6 Hz,
1H), 8.14 (d, J = 7.8 Hz, 1H), 7.86 – 7.74 (m, 2H), 7.39 (dd, J = 7.6,4.7 Hz 1H), 7.29 – 7.20 (m, 1H), 6.97 (d, J =
7.7 Hz, 1H), 6.90 (s, 1H), 6.78 (dd, J = 8.2, 2.6 Hz, 1H), 5.67 (d, J = 15.5 Hz, 1H), 5.28 (q, J = 7.8 Hz, 1H), 4.23
– 4.16 (m, 2H), 3.80 (s, 3H), 3.02 (dd, J = 13.5, 8.1 Hz, 1H), 2.75 (dd, J = 13.6, 6.9 Hz, 1H), 2.19 (t, J =5.4 Hz,
2H), 2.07 (s, 2H), 1.60 – 1.54 (m, 4H), 1.31 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 167.7, 163.5,
159.9, 149.8, 148.0, 143.1, 142.4, 142.0, 137.2, 130.3, 129.7, 126.0, 122.1, 118.8, 115.7, 112.9, 112.4, 60.0, 55.2,
52.9, 40.9, 31.9, 25.5, 22.4, 22.2, 14.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C26H31N2O4 435.2278; Found
435.2281.
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General
procedure
of
facile
removal
of
PA
group
to
generate
ethyl
(E)-3-(4-(2-(((benzyloxy)carbonyl)amino)ethyl)-1,2,5,6-tetrahydro-[1,1'-biphenyl]-3-yl)acrylate (7). Ethyl
(E)-3-(4-(2-(picolinamido) ethyl) -1,2,5,6-tetrahydro-[1,1'-biphenyl]-3-yl) acrylate (3ha) (40 mg, 0.1 mmol) was
dissolved in THF/H2O (2:1, 1.5 mL), and aq. HCl (245 μL, 12 N) was added into a 10 mL reaction bottle. Then
Zinc powder (98 mg, 1.5 mmol) was added in batches and the mixture was stirred at RT for 1.5 h. Afterward,
NaHCO3 was added to adjust the pH to 7~8 and CbzCl (22 μL, 0.15 mmol) were added and the resulting mixture
was stirred at RT for another 3 hours and quenched with water. The mixture was extracted with DCM (2 x 10
mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in
vacuo. The crude product was purified by flash silica column chromatography (ethyl acetate: petroleum ether =
1:12~1:11)
to
afford
ethyl
(E)-3-(4-(2-(((benzyloxy)carbonyl)amino)ethyl)-
o
1
1,2,5,6-tetrahydro-[1,1'-biphenyl]-3-yl)acrylate 7 (17 mg, yield 38%, white solid, m.p. 94-95 C). H NMR (600
MHz, CDCl3) δ 7.80 (d, J = 15.6 Hz, 1H), 7.36 – 7.28 (m, 7H), 7.21 (d, J = 7.8 Hz, 3H), 5.82 (d, J = 15.5 Hz,
1H), 5.09 (s, 2H), 4.88 (s, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.38 – 3.28 (m, 2H), 2.79 (s, 1H), 2.59 (dt, J = 12.9, 6.6
Hz, 1H), 2.54 – 2.46 (m, 2H), 2.36 (t, J = 20.9 Hz, 2H), 2.25 – 2.18 (m, 1H), 1.97 (d, J = 10.6 Hz, 1H), 1.75 (ddd,
J = 16.5, 11.9, 5.6 Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) 13C NMR (151 MHz,
CDCl3) δ 167.8, 156.3, 146.1, 143.0, 141.5, 136.6, 129.4, 128.5, 128.1, 126.8, 126.3, 116.3, 66.7, 60.2, 39.9,
39.7, 33.8, 31.9, 29.2, 14.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C27H32NO4 434.2326; Found 434.2326.
Synthesis of (8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]
phenanthren-3-yl (E)-3-(2-(2-(picolinamido)ethyl)cyclohex-1-en-1-yl) acrylate (8). The reaction was carried
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The Journal of Organic Chemistry
out
using
N-(2-(cyclohex-1-en-1-yl)ethyl)picolinamide
1a
(46
mg,
0.2
mmol)
and
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(8R,9S,13S,14S)-13-Methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl
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acrylate 2s (127 mg, 0.4 mmol) in the presence of Pd(OAc)2 (5 mg, 0.02 mmol), KHCO3 (50 mg, 0.5 mmol),
Cu(OAc)2∙H2O (20 mg, 0.1 mmol) in 2-methyl-2-butanol (t-AmylOH, 0.2 M) in a sealed tube (25 mL) under air
atmosphere at 130 °C via a heating mantle with magnetic stirrer for 2 h. And the reaction was monitored by TLC
and cooled to room temperature. Then the solvent was evaporated. The crude product was purified by flash silica
column chromatography (ethyl acetate: petroleum ether = 1:8~1:2) to afford 8 (56 mg, yield 51%, pale yellow
solid, m.p. 198-199 oC). 1H NMR (600 MHz, CDCl3) δ 8.51 (d, J = 4.0 Hz, 1H), 8.19 – 8.11 (m, 2H), 7.96 (d, J =
15.5 Hz, 1H), 7.85 – 7.80 (m, 1H), 7.40 (dd, J = 6.5, 4.9 Hz, 1H), 7.27 (d, J = 9.6 Hz, 1H), 6.87 – 6.83 (m, 1H),
6.80 (s, 1H), 5.95 (d, J = 15.5 Hz, 1H), 3.59 (q, J = 6.8 Hz, 2H), 2.94 – 2.88 (m, 2H), 2.65 (t, J = 7.0 Hz, 2H),
2.51 (dd, J = 19.0, 8.7 Hz, 1H), 2.43 – 2.37 (m, 1H), 2.32 – 2.28 (m, 2H), 2.25 – 2.21 (m, 2H), 2.19 – 1.94 (m,
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5H), 1.70 – 1.45 (m, 10H), 0.92 (s, 3H); C{1H} NMR (151 MHz, CDCl3) δ 220.6, 166.3, 164.2, 149.8, 148.8,
148.0, 145.0, 143.6, 137.7, 137.2, 137.0, 129.6, 126.2, 126.0, 122.1, 121.6, 118.8, 114.9, 50.5, 47.9, 44.1, 38.4,
38.0, 35.8, 33.8, 31.7, 31.6, 29.4, 26.4, 25.7, 25.4, 22.4, 22.3, 21.6, 13.8; HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C35H40N2O4Na, 575.2880; Found 575.2881.
Synthesis of (1S,4R)-bicyclo[2.2.1]heptan-2-yl (E)-3-(2-(2-(picolinamido)ethyl)cyclohex-1-en-1-yl)acrylate
(9) (two steps in one pot): The acrylate system was synthesized following the reference30b. (1) A mixture of
norbornene (51 mg, 0.54 mmol), acrylic acid (34 µL, 0.5 mmol) and BF3·O(C2H5)2 (2 µL, 0.016 mmol) was
o
heated at 80 C for 0.5 h in a sealed tube (25 mL) and then cooled down to room temperature, quenched by two
drops of water to give the acrylate system. (2) And then N-(2-(cyclohex-1-en-1-yl)ethyl)picolinamide 1a (46 mg,
0.2 mmol), Pd(OAc)2 (5 mg, 0.02 mmol), KHCO3 (50 mg, 0.5 mmol), Cu(OAc)2∙H2O (20 mg, 0.1 mmol) and
2-methyl-2-butanol (t-AmylOH, 0.5 mL) were added the acrylate system. The mixture was heated under air
atmosphere at 130 °C via a heating mantle with magnetic stirrer for 2 h. And the reaction was monitored by TLC
and cooled to RT. Then the solvent was evaporated. The crude product was purified by flash silica column
chromatography (ethyl acetate: petroleum ether = 1:3) to afford 9 (34 mg, yield 43%, white solid, m.p. 110-111
oC). 1H NMR (600 MHz, CDCl3) δ 8.50 (d, J = 4.8 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.12 (s, 1H), 7.83 (t, J = 7.7
Hz, 1H), 7.77 (d, J = 15.5 Hz, 1H), 7.40 (dd, J = 7.5, 4.8 Hz, 1H), 5.75 (d, J = 15.5 Hz, 1H), 4.61 (d, J = 7.0 Hz,
1H), 3.56 (q, J = 7.0 Hz, 2H), 2.61 (t, J = 7.3 Hz, 2H), 2.28 (q, J = 5.4, 4.9 Hz, 4H), 2.16 (d, J = 5.5 Hz, 2H), 1.76
– 1.70 (m, 2H), 1.64 (t, J = 6.6 Hz, 3H), 1.55 – 1.49 (m, 2H), 1.46 – 1.40 (m, 2H), 1.16 – 1.08 (m, 3H); 13C{1H}
NMR (151 MHz, CDCl3) δ 167.4, 164.2, 149.9, 148.0, 143.3, 141.6, 137.2, 129.5, 126.0, 122.1, 116.3, 77.3, 41.5,
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