Ruthenium-Catalyzed C-H Allylation of Alkenes with Allyl Alcohols via C-H Bond Activation in Aqueous Solution

Article abstract of DOI:10.1021/acs.joc.8b02063

A robust Ru(II)-catalyzed C-H allylation of electron-deficient alkenes with allyl alcohols in aqueous solution is reported. This method provides a straightforward and efficient access to the synthetically useful 1,4-diene skeletons. With the assistance of the N-methoxycarbamoyl directing group, this allylation reaction features a broad substrate scope with good functional group tolerance, excellent regio- and stereoselectivity, absence of metal oxidants, water-tolerant solvents, and mild reaction conditions. The mechanistic studies indicate that the process of the reversible C-H bond ruthenation is assisted by acetate, and the rate-determining step is unlikely to be the step of C-H bond cleavage.

Full text of DOI:10.1021/acs.joc.8b02063

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Article
Ruthenium-Catalyzed C-H Allylation of Alkenes with Allyl
Alcohols via C-H Bond Activation in Aqueous Solution
Xiaowei Wu, and Haitao Ji
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02063 • Publication Date (Web): 13 Sep 2018
Downloaded from http://pubs.acs.org on September 14, 2018
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RutheniumꢀCatalyzed C−H Allylation of Alkenes with Allyl
Alcohols via C−H Bond Activation in Aqueous Solution
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Xiaowei Wu† and Haitao Ji*,†,‡
†Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, 12902
Magnolia Drive, Tampa, Florida 33612ꢀ9416, United States
‡Departments of Oncologic Sciences and Chemistry, University of South Florida, Tampa,
Florida 33612, United States
* To whom correspondence should be addressed:
Haitao Ji, Ph.D.
Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, 12902
Magnolia Drive, MRC room 4047, Tampa, Florida 33612–9416, USA
Phone: 813ꢀ745ꢀ8070
Fax: 813ꢀ745ꢀ4506
Eꢀmail: Haitao.Ji@moffitt.org
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ABSTRACT
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A robust Ru(II)ꢀcatalyzed C−H allylation of electronꢀdeficient alkenes with allyl alcohols in
aqueous solution is reported. This method provides a straightforward and efficient access to the
synthetically useful 1,4ꢀdiene skeletons. With the assistance of the Nꢀmethoxycarbamoyl
directing group, this allylation reaction features a broad substrate scope with good functional
group tolerance, excellent regioꢀ and stereoselectivity, free of metal oxidants, waterꢀtolerant
solvents, and mild reaction conditions. The mechanistic studies indicate that the process of the
reversible C−H bond ruthenation is assisted by acetate, and the rateꢀdetermining step is unlikely
to be the step of C−H bond cleavage.
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INTRODUCTION
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The linear and branched allyl moieties are ubiquitous in biologically active compounds and
natural products, and are the important synthons for the versatile transformation into many useful
functional groups. Allylation is one of the most important reactions in organic synthesis.1–10
Although a variety of methods have been developed to introduce the allyl moiety, such as
nucleophilic substitution, transmetalation of aryl metal compounds to allyl electrophiles, Friedel–
Crafts allylation, and Tsuji−Trost allylation,11–17 these methods usually suffer from the limited
substrate scope, the competing formation of the undesired byꢀproducts, harsh reaction conditions,
and prefunctionalized substrates. Over the past decades, the direct C−H bond functionalization
via transition metalꢀcatalyzed reactions has emerged as a powerful approach for the synthesis of
organic compounds.18–27 In this context, transition metalꢀcatalyzed direct C−H allylation
reactions with varieties of allylation reagents have attracted much attention in consideration of
synthetic efficiency and atom economy.28
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Scheme 1. Transition metalꢀcatalyzed C−H allylation reactions
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In recent years, transition metalꢀcatalyzed direct C−H allylation reactions with diverse allylic
surrogates (such as allyl acetates, allyl carbonates, allyl halides, allyl phosphonates, vinyl
oxiranes, allenes, etc.) have been successfully developed (Scheme 1, eq 1). For instance, Ma and
Cramer separately disclosed the early different examples of Rh(III)ꢀcatalyzed C−H allylation
reactions of Nꢀmethoxybenzamides with polysubstituted allenes.29, 30 Subsequently, Glorius, Loh,
Li, Wang, and other groups reported Rh(III)ꢀcatalyzed C−H allylation with various preactivated
allyl alcohol derivatives (such as allyl acetates, allyl carbonates, etc.). 31–41 Ru(II)ꢀcatalyzed C−H
allylation reactions have been developed by Gooßen, Kim, Kapur, and others.42–49 Direct C−H
allylation reactions with allylation reagents by Cp*Co(III) or Mn(I) catalysis were disclosed by
Glorius, Ackermann, and others.50–56 In addition, Kanai and Matsunaga reported simple allyl
alcohols as allylation reagents for C−H allylation under Cp*Co(III) catalysis, which proceeded
through the βꢀhydroxide elimination pathway (Scheme 1, eq 2).57, 58 Despite remarkable progress
in the area of transition metalꢀcatalyzed C−H allylation, most reactions require preactivated allyl
alcohol derivatives (such as allyl carbonates, allyl acetates, etc.) as the coupling partners, high
reaction temperatures, anhydrous organic solvents, and stoichiometric amounts of metal
oxidants. In this context, the development of robust transition metalꢀcatalyzed C−H
functionalization in waterꢀtolerant medium under metal oxidantꢀfree and mild reaction conditions
is highly desirable. To the best of our knowledge, only two examples of C−H allylation of
(hetero)arenes by Rh(III) and Mn(I) catalysis using allenes and vinyl dioxolanones as the
allylation reagents in aqueous solvent were reported by Ma and Ackermann, respectively.29, 56 In
consideration of the limited examples of utilizing simple allyl alcohols as allylation reagents45, 47,
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49, 57, 58
and the low reactivity of olefins,59, 60 the example of transition metalꢀcatalyzed C−H
allylation of alkenes with unactivated allyl alcohols via CꢀH activation in aqueous solvent
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remains unexplored. Herein, we reported a robust Ru(II)ꢀcatalyzed C−H allylation of
acrylamides with allyl alcohols in aqueous solution. With the assistance of the Nꢀ
methoxycarbamoyl directing group, this transformation features a broad substrate scope with
high functional group tolerance, high regioꢀ and stereoselectivity, metal oxidantsꢀfree, waterꢀ
tolerant solvents, and mild conditions.
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RESULTS AND DISCUSSION
We initiated our studies by choosing the coupling reaction between Nꢀmethoxyꢀ2ꢀ
phenylacrylamide (1a) and allyl alcohol (2a) as the model reaction. First, we investigated a
variety of transition metal catalysts in the presence of NaOAc and dichloromethane (DCM) at 50
oC (entries 1ꢀ4). The results indicated that the reaction did not take place when [Cp*RhCl2]2
[Cp*IrCl2]2, or [Cp*Co(CH3CN)3](SbF6)2 was used as the catalyst. In contrast, the reaction
afforded the skipped diene 3a in 50% yield with excellent stereoselectivity (E/Z > 25:1) when
[RuCl2(pꢀcymene)]2 was employed as the catalyst. The Zꢀconfiguration of one alkene group of
product 3a (labeled as a in Table 1) was determined by the NOESY NMR spectrum (see
Supporting Information). The Eꢀconfiguration of the other alkene group of product 3a (labeled as
b in Table 1) was determined by the coupling constant of its alkene protons. Subsequently,
several solvents were screened (entries 5ꢀ9); we found that the yield was decreased to 33% when
the reaction was conducted in toluene. The reaction did not proceed to provide the desired
product when performed in THF. To our delight, the reaction afforded the desired product in
good yield with excellent stereoselectivity when MeOH or EtOH was employed as the solvent.
Notably, the reaction proceeded smoothly in water. The studies on the different bases concluded
that K2CO3 and Na2CO3 yielded no product (entries 10 and 12). When CsOAc was used as the
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base, the yield of product reached 72% (entry 11). To explore the efficiency of this reaction in
aqueous solution, we performed the coupling reaction in methanolꢀwater (1:1, v/v), which
offered the 1,4ꢀdiene product in good isolated yield with excellent stereoselectivity (entry 13),
demonstrating the robustness of this new synthetic method. When the reaction was conducted at
room temperature, the yield of product was only 29% (entry 14). Additionally, this reaction did
not provide the desired product without the catalyst [RuCl2(pꢀcymene)]2 or the base CsOAc
(entries 15 and 16). Since the similar efficiency was observed when methanol or methanolꢀwater
(1:1, v/v) was used as the solvent, we decided to explore the substrate scope by using the
aqueous solution to develop this method.
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Table 1. Optimization of Reaction Conditiona
Entry
Cat.
Solvent
DCM
DCM
DCM
DCM
Toluene
THF
Base
3a Yield (%)b
E/Z ratioc
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10
[Cp*RhCl2]2
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
K2CO3
0
ꢀ
[RuCl2(pꢀcymene)]2
[Cp*IrCl2]2
50
0
>25:1
ꢀ
[Cp*Co(CH3CN)3](SbF6)2
[RuCl2(pꢀcymene)]2
[RuCl2(pꢀcymene)]2
[RuCl2(pꢀcymene)]2
[RuCl2(pꢀcymene)]2
[RuCl2(pꢀcymene)]2
[RuCl2(pꢀcymene)]2
0
ꢀ
33
0
ꢀ
ꢀ
MeOH
EtOH
H2O
67
61
54
0
>25:1
>25:1
>25:1
ꢀ
MeOH
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[RuCl2(pꢀcymene)]2
[RuCl2(pꢀcymene)]2
[RuCl2(pꢀcymene)]2
[RuCl2(pꢀcymene)]2
ꢀ
MeOH
CsOAc
Na2CO3
CsOAc
CsOAc
CsOAc
ꢀ
72(70)
>25:1
12
MeOH
0
ꢀ
13d
14d,e
15f
16g
MeOH/H2O
MeOH/H2O
MeOH
73(68)
>25:1
29
0
>25:1
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ꢀ
ꢀ
[RuCl2(pꢀcymene)]2
MeOH
0
aReaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (5 mol %), base (1 equiv) in 2 mL
b
solvent at 50 °C, Ar atmosphere. NMR yields were calculated using CH2Br2 as an internal
c
1
standard, and the isolated yields were reported in parentheses. Determined by HꢀNMR using
d
e
the crude reaction mixtures. MeOH/H2O = 1/1, v/v. The reaction was performed at room
temperature. fNo [RuCl2(pꢀcymene)]2. gNo CsOAc. [RuCl2(pꢀcymene)]2. gNo CsOAc.
With the optimized conditions in hand, we began to explore the scope of the reaction. As
shown in Table 2, a variety of acrylamides bearing electronꢀdonating and electronꢀwithdrawing
groups were compatible with the reaction, which provided the corresponding allylation products
smoothly in moderate to good yields with excellent stereoselectivity. For example, when halogen
(such as fluorine and chlorine) and trifluoromethyl groups were introduced to the para position
of benzene ring of acrylamides, the reaction gave the desired products smoothly in moderate to
good yields (3b, 3c, and 3d, respectively). When electronꢀdonating groups, such as methyl,
methoxyl, and tertꢀbutyl groups, were introduced to the Cꢀ4 position of the phenyl group, the
reaction also offered the products in good yields with excellent stereoselectivity (3eꢀ3h). Further,
the desired 1,4ꢀdiene products were obtained smoothly (3iꢀ3l) when α, βꢀdisubstituted
acrylamide substrates (such as cyclic olefins and α, β ꢀdimethyl acrylamide) were used in this
reaction, highlighting the broad scope of alkene substrates. It should be noted that the
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substitution at the α position of acrylamides is essential for the reaction. The βꢀmonosubstituted
or α,βꢀunsubstituted acrylamides did not offer the desired products.
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Table 2. Scope of Alkenes a,b
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O
O
O
Me
O
O
F3C
O
O
HN
HN
HN
Ph
Ph
Ph
3f, 66%
3e, 81%
3d, 70%
aReaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), [RuCl2(pꢀcymene)]2 (5 mol %), CsOAc (1
equiv) in 2 mL MeOH/H2O (1/1, v/v) at 50 °C, Ar atmosphere, 12 h. The E/Z ratios of all
products are >25:1 unless otherwise noted. bIsolated yields are reported.
Next, the scope of allyl alcohols as coupling partners was explored (Table 3). In general, the
coupling reaction with various allyl alcohols or their methyl carbonates afforded the
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corresponding 1,4ꢀdiene derivatives in good to excellent yields (3mꢀ3y). The desired products
were obtained in good yields with excellent stereoselectivity regardless of electronꢀwithdrawing
(such as fluorine, chlorine, bromine, and trifluoromethyl groups) or electronꢀdonating groups
(such as methyl and methoxyl groups) attaching to the benzene ring of allyl alcohols (3mꢀ3r).
The naphthyl or thiophenyl group substituted allyl alcohols also underwent the coupling process
smoothly with satisfactory yields and stereoselectivity (3s and 3t). Unfortunately, the reaction
did not take place with propꢀ2ꢀenꢀ1ꢀol, but the desired product was obtained in good yield when
its methyl carbonate was employed as the coupling partner under the standard reaction
conditions (3u). A similar result was observed when crotyl alcohol was investigated under the
standard reaction conditions (3v). Further, it is worth noting that the use of 2ꢀmethylpropꢀ2ꢀenꢀ1ꢀ
ol (or its methyl carbonate), heptꢀ1ꢀenꢀ3ꢀol (or its methyl carbonate), and cyclohexꢀ2ꢀenꢀ1ꢀol (or
its methyl carbonate) did not provide the desired products under ruthenium catalysis (3wꢀ3y).
However, the corresponding 1,4ꢀdiene products were obtained in good yields when using the
corresponding allylic methyl carbonates as the coupling partners under rhodium catalysis (3wꢀ
3y).
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Table 3. Scope of Allyl Alcohols a,b
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aReaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), [{RuCl2(pꢀcymene)}2] (5 mol %), CsOAc (1
equiv) in 2 mL MeOH/H2O (1/1, v/v) at 50 °C, Ar atmosphere, 12 h. The E/Z ratios of all
b
c
products are > 25:1 unless otherwise noted. Isolated yields are reported. The corresponding
d
allylic methyl carbonate was used. [Cp*RhCl2]2 (5 mol %), CsOAc (1 equiv) in 2 mL MeOH at
50 °C, Ar atmosphere, 12 h.
To further evaluate the efficiency and potential applications of this method, a scaleꢀup
experiment and a product transformation reaction were carried out (Scheme 2). The result of the
gramꢀscale reaction showed that product 3a was obtained in good yield (Scheme 2a). The
epoxidation of the isolated alkene double bond of 3a by 3ꢀchloroperbenzoic acid (mꢀCPBA) and
then the intramolecular epoxide ring opening reaction offered the dihydropyridinone derivative
4a in 63% yield (Scheme 2b).
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Scheme 2. The Gramꢀscale and Transformation Reactions
Deuterium labeling experiments were carried out to gain insight in the mechanism of
this catalytic reaction (Scheme 3). First, we performed the reaction in the presence of
ruthenium catalyst, CsOAc, and the excess amount of methanolꢀd4, but allyl alcohol 2a
.
Approximately 49% deuteration was observed at the ꢀposition of the acrylamide (see
β
Supporting Information). It suggests that the step of the C−H cleavage might be reversible
under the reaction condition. Second, the above reaction was carried out in the absence of
CsOAc, and the result showed that no obvious deuterium incorporated at
acrylamide, indicating that CsOAc plays a critical role in the step of CꢀH cleavage. Third,
performing the reaction with allyl alcohol 2a resulted in no obvious deuteration at the
βꢀposition of the
β
ꢀ
position. These results suggest that the reversible step of ruthenation should be assisted by
acetate ion. This result is consistent with the previous observation on rutheniumꢀcatalyzed
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CꢀH functionalization.61,
Further, we performed the coupling reaction with the
deuterated substrates 1aꢀD and 2aꢀD, respectively. Both reactions afforded the deuterated
1,4ꢀdiene derivatives smoothly. What’s more, the kinetic isotope effect (KIE) experiments
were conducted (Scheme 3b).63 The intermolecular competition reaction of 1a and
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deuteriumꢀlabeled 1aꢀD with allyl alcohol 2a was carried out under standard reaction
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conditions, which resulted in the kinetic isotope effect (kH/kD) of 1.13. The parallel
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reactions led to a KIE value of 1.3. These data indicated that the C−H bond cleavage was
unlikely the rateꢀdetermining step.
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Scheme 3. Mechanism Studies
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A plausible reaction pathway was proposed based on the results of the preliminary
mechanistic experiments and the previous reports45, 57, 58 (Scheme 4). First, the active
ruthenium catalyst was generated through a ligand exchange between the [RuCl2(pꢀcymene)]2
catalyst and cesium acetate. Then, the Nꢀmethoxycarbamoyl group directed C–H activation of
acrylamide 1 by the active catalyst that was formed in situ gave the fiveꢀmembered ruthenacycle
I via acetate assistance. The C−H bond cleavage is probably reversible and not the rateꢀ
determining step. Subsequently, coordination and insertion of olefin 2 afforded intermediate II,
which underwent βꢀhydroxide elimination to generate product 3 and H2O. Finally, the
regeneration of the active catalyst with the assistance of AcOH completed the catalytic cycle.
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Scheme 4. Proposed Catalytic Cycle
CONCLUSION
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In summary, we have developed a robust rutheniumꢀcatalyzed C−H allylation of acrylamides
with the easily available allyl alcohols in aqueous solution. This method provides access to the
synthetically useful, regioꢀ and stereoselective 1,4ꢀdiene derivatives in moderate to good yields.
Additionally, this reaction features a broad substrate scope, free of metal oxidants, good
functionalꢀgroups compatibility, gramꢀscale synthesis, and mild reaction conditions. The
mechanistic studies suggest that the C−H bond cleavage is unlikely involved in the rateꢀ
determining step.
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EXPERIMENTAL SECTION
General Information. Unless otherwise specified, the reagents (chemicals) were purchased
from commercial sources and used without further purification. Analytical thin layer
chromatography (TLC) was HSGF 254 (0.15ꢀ0.2 mm thickness). All products were characterized
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13
by their NMR and MS spectra. H, F, and C NMR spectra were recorded on a 400 MHz or
500 MHz instrument. Chemical shifts were reported as values in parts per million (ppm), and the
1
reference resonance peaks were set at 7.26 ppm for CDCl3 to collect the H NMR spectra and
13
77.16 ppm (CDCl3) to collect the C NMR spectra. Proton coupling patterns are described as
singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), doublet of doublets (dd) and broad
(br). Highꢀresolution mass spectra (HRMS) were measured on Micromass Ultra QꢀTOF
spectrometer. The following substrates were prepared according to the literature methods: Nꢀ
methoxy acrylamides 1 were prepared by the procedure reported in the literature.64, 65 Allyl
alcohols and their derivatives 2a,66 2b,66 2c,67 2d,66 2e,68 2f,66 2g,66 2h,66 2i,69 2k’,70 and 2m71
were also prepared by following the procedures as described in the literatures. 2j, 2k, 2l, and 2n
were commercial materials.
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General Procedure for the Synthesis and Characterization of 3aꢀ3v. Representative
procedure for synthesis of 3a: A reaction tube was charged with Nꢀmethoxyꢀ2ꢀphenylacrylamide
1a (36.0 mg, 0.2 mmol, 1 equiv), allylic alcohol 2a (0.4 mmol, 2 equiv), [RuCl2(pꢀcymene)]2
(0.01 mmol, 0.05 equiv), CsOAc (0.2 mmol, 1 equiv), and 2 mL MeOH/H2O (1/1, v/v). The
mixture was heated at 50 °C for 12 h under Ar atmosphere. The resulting mixture was diluted
with dichloromethane and washed by water. The combined organic layers were dried with
Na2SO4, filtered, concentrated and purified by column chromatography on silica gel
(hexanes/EA = 4/1 ~ 2/1, v/v) to give the desired product 3a (68% yield, 40.5 mg).
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(2Z,5E)ꢀNꢀmethoxyꢀ2,6ꢀdiphenylhexaꢀ2,5ꢀdienamide (3a). Following the general procedure,
1
3a was obtained as colorless oil in 68% yield, 40.5 mg. H NMR (400 MHz, CDCl3) δ 8.27 (br,
1H), 7.41 – 7.29 (m, 9H), 7.25 – 7.19 (m, 1H), 6.48 (d, J = 15.9 Hz, 1H), 6.33 – 6.18 (m, 2H),
13
3.87 (s, 3H), 3.31 (t, J = 6.9 Hz, 2H) ppm. C NMR (126 MHz, CDCl3) δ 166.4, 137.3, 136.7,
135.5, 133.5, 131.7, 128.9, 128.7, 128.4, 127.5, 127.2, 126.6, 126.3, 64.8, 33.4 ppm. HRMS
(ESI) m/z: calculated for C19H20NO2 [M + H]+: 294.1494, found: 294.1491.
+
(2Z,5E)ꢀ2ꢀ(4ꢀFluorophenyl)ꢀNꢀmethoxyꢀ6ꢀphenylhexaꢀ2,5ꢀdienamide (3b). Following the
general procedure, 3b was obtained as colorless oil in 40% yield, 25.0 mg. 1H NMR (500 MHz,
CDCl3) δ 8.29 (br, 1H), 7.40 – 7.28 (m, 6H), 7.24 – 7.20 (m, 1H), 7.05 – 7.00 (m, 2H), 6.48 (d, J
= 15.9 Hz, 1H), 6.26 (dt, J = 15.9, 6.6 Hz, 1H), 6.15 (t, J = 7.8 Hz, 1H), 3.87 (s, 3H), 3.29 (t, J =
13
6.6 Hz, 2H) ppm. C NMR (126 MHz, CDCl3) δ 166.2, 162.9 (d, J = 247.2 Hz), 137.2, 134.6,
133.1, 132.7 (d, J = 3.3 Hz), 131.8, 128.7, 128.3 (d, J = 7.6 Hz), 127.6, 127.0, 126.3, 115.9 (d, J
19
= 21.7 Hz), 64.8, 33.4 ppm. F NMR (471 MHz, CDCl3) δ ꢀ113.34 ppm. HRMS (ESI) m/z:
calculated for C19H19NO2F+ [M + H]+: 312.1400, found: 312.1410.
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(2Z,5E)ꢀ2ꢀ(4ꢀChlorophenyl)ꢀNꢀmethoxyꢀ6ꢀphenylhexaꢀ2,5ꢀdienamide (3c). Following the
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general procedure, 3c was obtained as colorless oil in 63% yield, 42.1 mg. H NMR (500 MHz,
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CDCl3) δ 8.23 (br, 1H), 7.39 – 7.28 (m, 8H), 7.24 – 7.20 (m, 1H), 6.48 (d, J = 15.9 Hz, 1H), 6.29
– 6.18 (m, 2H), 3.87 (s, 3H), 3.29 (t, J = 6.8 Hz, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 166.1,
137.2, 135.0, 134.6, 134.4, 133.5, 131.9, 129.1, 128.7, 127.8, 127.6, 126.8, 126.3, 64.9, 33.5
ppm. HRMS (ESI) m/z: calculated for C19H19NO2Cl+ [M + H]+: 328.1104, found: 328.1093.
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(2Z,5E)ꢀNꢀmethoxyꢀ6ꢀphenylꢀ2ꢀ(4ꢀ(trifluoromethyl)phenyl)hexaꢀ2,5ꢀdienamide
(3d).
1
Following the general procedure, 3d was obtained as colorless oil in 70% yield, 51.0 mg. H
NMR (500 MHz, CDCl3) δ 8.26 (br, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.37
– 7.27 (m, 4H), 7.25 – 7.21 (m, 1H), 6.49 (d, J = 15.9 Hz, 1H), 6.34 – 6.21 (m, 2H), 3.88 (s, 3H),
13
3.32 (t, J = 6.8 Hz, 2H) ppm. C NMR (126 MHz, CDCl3) δ 165.7, 140.0, 137.1, 135.0, 134.7,
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132.1, 128.8, 127.7, 126.8, 126.5, 126.3, 125.9, 125.9, 125.9, 64.9, 33.5 ppm. F NMR (471
MHz, CDCl3) δ ꢀ62.70 ppm. HRMS (ESI) m/z: calculated for C20H19NO2F3 [M + H]+:
+
362.1368, found: 362.1363.
(2Z,5E)ꢀNꢀmethoxyꢀ6ꢀphenylꢀ2ꢀ(pꢀtolyl)hexaꢀ2,5ꢀdienamide (3e). Following the general
procedure, 3e was obtained as colorless oil in 81% yield, 51.2 mg. 1H NMR (500 MHz, CDCl3) δ
8.25 (br, 1H), 7.38 – 7.33 (m, 2H), 7.33 – 7.27 (m, 4H), 7.25 – 7.19 (m, 1H), 7.17 – 7.13 (m,
2H), 6.48 (d, J = 15.8 Hz, 1H), 6.27 (dt, J = 15.8, 6.6 Hz, 1H), 6.17 (t, J = 7.8 Hz, 1H), 3.86 (s,
3H), 3.30 (t, J = 6.6 Hz, 2H), 2.35 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3) δ 166.6, 138.4,
137.4, 135.4, 133.8, 132.6, 131.6, 129.6, 128.7, 127.5, 127.4, 126.5, 126.3, 64.8, 33.4, 21.3 ppm.
+
HRMS (ESI) m/z: calculated for C20H22NO2 [M + H]+: 308.1651, found: 308.1645.
(2Z,5E)ꢀNꢀmethoxyꢀ2ꢀ(4ꢀmethoxyphenyl)ꢀ6ꢀphenylhexaꢀ2,5ꢀdienamide (3f). Following the
general procedure, 3f was obtained as colorless oil in 66% yield, 43.3 mg. 1H NMR (500 MHz,
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CDCl3) δ 8.22 (br, 1H), 7.37 – 7.27 (m, 6H), 7.24 – 7.19 (m, 1H), 6.91 – 6.84 (m, 2H), 6.48 (d, J
= 15.9 Hz, 1H), 6.27 (dt, J = 15.9, 6.5 Hz, 1H), 6.11 (t, J = 7.8 Hz, 1H), 3.87 (s, 3H), 3.81 (s,
3H), 3.29 (t, J = 6.8 Hz, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 166.7, 159.8, 137.4, 135.0,
131.6, 131.5, 129.2, 128.7, 127.9, 127.47, 127.45, 126.3, 114.3, 64.8, 55.5, 33.4 ppm. HRMS
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(ESI) m/z: calculated for C20H22NO3 [M + H]+: 324.1600, found: 324.1591.
(2Z,5E)ꢀNꢀmethoxyꢀ2ꢀ(3ꢀmethoxyphenyl)ꢀ6ꢀphenylhexaꢀ2,5ꢀdienamide (3g). Following the
general procedure, 3g was obtained as colorless oil in 58% yield, 38.0 mg. 1H NMR (500 MHz,
CDCl3) δ 8.28 (br, 1H), 7.37 – 7.34 (m, 2H), 7.33 – 7.26 (m, 3H), 7.24 – 7.19 (m, 1H), 6.98 (d, J
= 7.6 Hz, 1H), 6.94 (br, 1H), 6.88 – 6.80 (m, 1H), 6.48 (d, J = 15.9 Hz, 1H), 6.32 – 6.16 (m, 2H),
3.86 (s, 3H), 3.81 (s, 3H), 3.31 (t, J = 6.8 Hz, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 166.3,
160.0, 138.1, 137.3, 135.3, 133.8, 131.7, 130.0, 128.7, 127.5, 127.1, 126.3, 119.1, 114.0, 112.2,
64.8, 55.5, 33.4 ppm. HRMS (ESI) m/z: calculated for C20H22NO3 [M + H]+: 324.1600, found:
+
324.1595.
(2Z,5E)ꢀ2ꢀ(4ꢀ(tertꢀbutyl)phenyl)ꢀNꢀmethoxyꢀ6ꢀphenylhexaꢀ2,5ꢀdienamide (3h). Following the
general procedure, 3h was obtained as colorless oil in 65% yield, 46.0 mg. 1H NMR (500 MHz,
CDCl3) δ 8.20 (br, 1H), 7.39 – 7.28 (m, 8H), 7.24 – 7.19 (m, 1H), 6.48 (d, J = 15.9 Hz, 1H), 6.28
(dt, J = 15.9, 6.5 Hz, 1H), 6.19 (t, J = 7.8 Hz, 1H), 3.87 (s, 3H), 3.31 (t, J = 6.8 Hz, 2H), 1.32 (s,
9H) ppm. 13C NMR (126 MHz, CDCl3) δ 166.6, 151.6, 137.4, 135.3, 133.8, 132.8, 131.5, 128.7,
127.5, 127.4, 126.4, 126.3, 125.9, 64.8, 34.8, 33.4, 31.4 ppm. HRMS (ESI) m/z: calculated for
C23H28NO2 [M + H]+: 350.2120, found: 350.2111.
+
2ꢀCinnamylꢀNꢀmethoxycyclohexꢀ1ꢀeneꢀ1ꢀcarboxamide (3i). Following the general procedure,
3i was obtained as colorless oil in 71% yield, 40.2 mg. 1H NMR (500 MHz, CDCl3) δ 8.18 (br,
1H), 7.38 – 7.28 (m, 4H), 7.24 – 7.20 (m, 1H), 6.41 (d, J = 15.8 Hz, 1H), 6.21 (dt, J = 15.8, 6.7
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Hz, 1H), 3.81 (s, 3H), 3.03 (d, J = 6.6 Hz, 2H), 2.30 – 2.23 (m, 2H), 2.15 – 2.06 (m, 2H), 1.71 –
1.61 (m, 4H) ppm. 13C NMR (126 MHz, CDCl3) δ 170.0, 137.2, 131.6, 128.7, 127.90, 127.87,
127.5, 126.3, 64.7, 38.6, 29.3, 27.1, 22.4, 22.2 ppm. HRMS (ESI) m/z: calculated for
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+
C17H22NO2 [M + H]+: 272.1651, found: 272.1638.
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2ꢀCinnamylꢀNꢀmethoxycyclopentꢀ1ꢀeneꢀ1ꢀcarboxamide (3j). Following the general
procedure, a mixture of stereoisomers (E/Z = 16:1) was obtained as colorless oil in 60% yield,
31.7 mg. Spectral data for the major isomer (E): 1H NMR (500 MHz, CDCl3) δ 8.12 (br, 1H),
7.36 – 7.33 (m, 2H), 7.31 – 7.27 (m, 2H), 7.23 – 7.18 (m, 1H), 6.46 (d, J = 15.8 Hz, 1H), 6.24
(dt, J = 15.8, 7.0 Hz, 1H), 3.82 (s, 3H), 3.48 (d, J = 6.9 Hz, 2H), 2.60 – 2.48 (m, 4H), 1.93 – 1.85
(m, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 154.1, 137.5, 131.7, 128.7, 127.3, 126.8, 126.3,
+
64.8, 37.7, 33.7, 33.5, 21.9 ppm. HRMS (ESI) m/z: calculated for C16H20NO2 [M + H]+:
258.1494, found: 258.1490.
5ꢀCinnamylꢀNꢀmethoxyꢀ3,4ꢀdihydroꢀ2Hꢀpyranꢀ6ꢀcarboxamide (3k). Following the general
procedure, 3k was obtained as colorless oil in 70% yield, 39.0 mg. 1H NMR (500 MHz, CDCl3) δ
9.01 (br, 1H), 7.38 – 7.32 (m, 2H), 7.30 – 7.26 (m, 2H), 7.22 – 7.11 (m, 1H), 6.44 (d, J = 15.8
Hz, 1H), 6.27 (dt, J = 15.8, 7.1 Hz, 1H), 3.99 – 3.91 (m, 2H), 3.81 (s, 3H), 3.47 (d, J = 7.0 Hz,
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2H), 2.18 (t, J = 6.5 Hz, 2H), 1.90 – 1.77 (m, 2H) ppm. C NMR (126 MHz, CDCl3) δ 161.9,
139.4, 137.8, 131.1, 128.6, 128.4, 127.1, 126.2, 122.6, 65.9, 64.6, 35.6, 26.1, 22.3. HRMS (ESI)
+
m/z: calculated for C16H20NO3 [M + H]+: 274.1443, found: 274.1434.
(2Z,5E)ꢀNꢀmethoxyꢀ2,3ꢀdimethylꢀ6ꢀphenylhexaꢀ2,5ꢀdienamide (3l). Following the general
procedure, 3l was obtained as colorless oil in 56% yield, 28.0 mg. 1H NMR (500 MHz, CDCl3) δ
8.16 (br, 1H), 7.38 – 7.33 (m, 2H), 7.33 – 7.28 (m, 2H), 7.25 – 7.19 (m, 1H), 6.41 (d, J = 15.9
Hz, 1H), 6.21 (dt, J = 15.8, 6.6 Hz, 1H), 3.81 (s, 3H), 3.05 (d, J = 6.5 Hz, 2H), 1.89 – 1.86 (m,
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3H), 1.78 – 1.74 (m, 3H) ppm. 13C NMR (126 MHz, CDCl3) δ 169.9, 137.2, 136.7, 131.7, 128.7,
127.7, 127.5, 126.3, 125.7, 64.7, 39.7, 18.3, 16.4 ppm. HRMS (ESI) m/z: calculated for
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C15H20NO2 [M + H]+: 246.1494, found: 246.1478.
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(2Z,5E)ꢀ6ꢀ(4ꢀFluorophenyl)ꢀNꢀmethoxyꢀ2ꢀphenylhexaꢀ2,5ꢀdienamide (3m). Following the
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general procedure, 3m was obtained as colorless oil in 59% yield, 37.3 mg. H NMR (500 MHz,
CDCl3) δ 8.32 (br, 1H), 7.43 – 7.28 (m, 8H), 7.01 – 6.95 (m, 2H), 6.44 (d, J = 15.9 Hz, 1H), 6.22
– 6.14 (m, 2H), 3.86 (s, 3H), 3.29 (t, J = 6.6 Hz, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 166.4,
162.3 (d, J = 246.4 Hz), 136.6, 135.5, 133.5, 130.5, 128.9, 128.4, 127.7 (d, J = 7.9 Hz), 126.9 (d,
J = 1.7 Hz), 126.6, 115.6 (d, J = 21.6 Hz), 64.8, 33.3 ppm. HRMS (ESI) m/z: calculated for
C19H19NO2F+ [M + H]+: 312.1400, found: 312.1397.
(2Z,5E)ꢀ6ꢀ(4ꢀChlorophenyl)ꢀNꢀmethoxyꢀ2ꢀphenylhexaꢀ2,5ꢀdienamide (3n). Following the
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general procedure, 3n was obtained as colorless oil in 57% yield, 38.0 mg. H NMR (400 MHz,
CDCl3) δ 8.34 (br, 1H), 7.41 – 7.26 (m, 9H), 6.43 (d, J = 15.9 Hz, 1H), 6.28 – 6.16 (m, 2H), 3.85
(s, 3H), 3.30 (t, J = 7.1 Hz, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 166.4, 136.6, 135.8, 135.6,
133.4, 133.1, 130.5, 129.0, 128.8, 128.5, 127.9, 127.5, 126.7, 64.8, 33.4 ppm. HRMS (ESI) m/z:
calculated for C19H19NO2Cl+ [M + H]+: 328.1104, found: 328.1097.
(2Z,5E)ꢀ6ꢀ(4ꢀBromophenyl)ꢀNꢀmethoxyꢀ2ꢀphenylhexaꢀ2,5ꢀdienamide (3o). Following the
1
general procedure, 3o was obtained as colorless oil in 63% yield, 47.6 mg. H NMR (500 MHz,
CDCl3) δ 8.25 (br, 1H), 7.44 – 7.31 (m, 8H), 7.23 – 7.20 (m, 2H), 6.42 (d, J = 15.8 Hz, 1H), 6.26
13
(dt, J = 15.8, 6.6 Hz, 1H), 6.21 – 6.16 (m, 1H), 3.86 (s, 3H), 3.30 (t, J = 6.6 Hz, 2H) ppm. C
NMR (126 MHz, CDCl3) δ 166.4, 136.6, 136.3, 135.6, 133.4, 131.8, 130.6, 129.0, 128.5, 128.0,
127.8, 126.7, 121.2, 64.8, 33.4 ppm. HRMS (ESI) m/z: calculated for C19H19NO2Br+ [M + H]+:
372.0599, found: 372.0601.
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(2Z,5E)ꢀNꢀmethoxyꢀ2ꢀphenylꢀ6ꢀ(4ꢀ(trifluoromethyl)phenyl)hexaꢀ2,5ꢀdienamide
(3p).
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Following the general procedure, 3p was obtained as colorless oil in 62% yield, 45.7 mg. 1H
NMR (500 MHz, CDCl3) δ 8.15 (br, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.42
– 7.28 (m, 5H), 6.52 (d, J = 16.0 Hz, 1H), 6.38 (dt, J = 15.9, 6.5 Hz, 1H), 6.20 (t, J = 7.8 Hz,
1H), 3.87 (s, 3H), 3.37 (t, J = 6.3 Hz, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 162.9, 141.1,
136.9, 136.1, 133.6, 130.7, 130.3, 129.3, 128.8, 127.0, 126.7, 125.9 (q, J = 3.8 Hz), 125.7, 65.1,
33.7 ppm. 19F NMR (471 MHz, CDCl3) δ ꢀ62.48 ppm. HRMS (ESI) m/z: calculated for
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+
C20H19NO2F3 [M + H]+: 362.1368, found: 362.1357.
(2Z,5E)ꢀNꢀmethoxyꢀ2ꢀphenylꢀ6ꢀ(pꢀtolyl)hexaꢀ2,5ꢀdienamide (3q). Following the general
1
procedure, 3q was obtained as colorless oil in 73% yield, 45.5 mg. H NMR (500 MHz, CDCl3)
δ 8.24 (s, 1H), 7.43 – 7.30 (m, 6H), 7.25 – 7.22 (m, 1H), 7.11 (d, J = 7.9 Hz, 2H), 6.45 (d, J =
13
15.9 Hz, 1H), 6.27 – 6.15 (m, 2H), 3.87 (s, 3H), 3.30 (t, J = 6.5 Hz, 2H), 2.33 (s, 3H) ppm. C
NMR (126 MHz, CDCl3) δ 166.5, 137.3, 136.7, 135.4, 134.5, 133.6, 131.5, 129.4, 128.9, 128.4,
+
126.6, 126.2, 126.1, 64.8, 33.4, 21.3 ppm. HRMS (ESI) m/z: calculated for C20H22NO2 [M +
H]+: 308.1651, found: 308.1647.
(2Z,5E)ꢀNꢀmethoxyꢀ6ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀphenylhexaꢀ2,5ꢀdienamide (3r). Following the
1
general procedure, 3r was obtained as colorless oil in 71% yield, 46.4 mg. H NMR (400 MHz,
CDCl3) δ 8.37 (br, 1H), 7.42 – 7.27 (m, 7H), 6.88 – 6.80 (m, 2H), 6.42 (d, J = 15.8 Hz, 1H), 6.24
13
– 6.07 (m, 2H), 3.86 (s, 3H), 3.80 (s, 3H), 3.27 (t, J = 7.1 Hz, 2H) ppm. C NMR (126 MHz,
CDCl3) δ 166.5, 159.2, 136.7, 135.3, 133.6, 131.1, 130.1, 128.9, 128.4, 127.4, 126.6, 124.9,
+
114.1, 64.8, 55.4, 33.4 ppm. HRMS (ESI) m/z: calculated for C20H22NO3 [M + H]+: 324.1600,
found: 324.1608.
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(2Z,5E)ꢀNꢀmethoxyꢀ6ꢀ(naphthalenꢀ2ꢀyl)ꢀ2ꢀphenylhexaꢀ2,5ꢀdienamide (3s). Following the
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6
1
general procedure, 3s was obtained as colorless oil in 90% yield, 63.0 mg. H NMR (500 MHz,
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8
9
CDCl3) δ 8.23 (br, 1H), 7.81 – 7.75 (m, 3H), 7.70 (s, 1H), 7.58 (dd, J = 8.6, 1.7 Hz, 1H), 7.47 –
7.40 (m, 4H), 7.39 – 7.30 (m, 3H), 6.65 (d, J = 15.9 Hz, 1H), 6.41 (dt, J = 15.8, 6.6 Hz, 1H), 6.26
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(t, J = 7.8 Hz, 1H), 3.88 (s, 3H), 3.38 (t, J = 6.7 Hz, 2H) ppm. C NMR (126 MHz, CDCl3) δ
166.5, 136.7, 135.6, 134.8, 133.8, 133.6, 133.0, 131.8, 129.0, 128.5, 128.3, 128.1, 127.8, 127.6,
+
126.7, 126.4, 126.0, 125.9, 123.6, 64.9, 33.5 ppm. HRMS (ESI) m/z: calculated for C23H22NO2
[M + H]+: 344.1651, found: 344.1644.
(2Z,5E)ꢀNꢀmethoxyꢀ2ꢀphenylꢀ6ꢀ(thiophenꢀ2ꢀyl)hexaꢀ2,5ꢀdienamide (3t). Following the
1
general procedure, 3t was obtained as colorless oil in 61% yield, 37.0 mg. H NMR (500 MHz,
CDCl3) δ 8.25 (br, 1H), 7.43 – 7.28 (m, 5H), 7.12 (d, J = 5.0 Hz, 1H), 6.98 – 6.89 (m, 2H), 6.61
(d, J = 15.7 Hz, 1H), 6.18 (t, J = 7.8 Hz, 1H), 6.11 (dt, J = 15.7, 6.6 Hz, 1H), 3.86 (s, 3H), 3.28
(t, J = 6.8 Hz, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 166.3, 142.4, 136.6, 135.6, 133.2, 128.9,
128.5, 127.4, 126.9, 126.7, 125.2, 124.9, 124.0, 64.8, 33.2 ppm. HRMS (ESI) m/z: calculated for
+
C17H18NSO2 [M + H]+: 300.1058, found: 300.1050.
(Z)ꢀNꢀmethoxyꢀ2ꢀphenylhexaꢀ2,5ꢀdienamide (3u). Following the general procedure, 3u was
1
obtained as colorless oil in 80% yield, 35.0 mg. H NMR (500 MHz, CDCl3) δ 8.21 (br, 1H),
7.40 – 7.29 (m, 5H), 6.16 (t, J = 7.8 Hz, 1H), 5.96 – 5.86 (m, 1H), 5.18 – 5.06 (m, 2H), 3.86 (s,
3H), 3.19 – 3.01 (m, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 166.4, 136.7, 135.8, 133.2, 128.9,
+
128.8, 128.4, 126.6, 116.4, 64.8, 34.1 ppm. HRMS (ESI) m/z: calculated for C13H16NO2 [M +
H]+: 218.1181, found: 218.1178.
(Z)ꢀNꢀmethoxyꢀ4ꢀmethylꢀ2ꢀphenylhexaꢀ2,5ꢀdienamide (3v). Following the general procedure,
3v was obtained as colorless oil in 64% yield, 30.2 mg. 1H NMR (500 MHz, CDCl3) δ 8.26 (br,
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1H), 7.41 – 7.37 (m, 2H), 7.36 – 7.27 (m, 3H), 5.95 (d, J = 10.2 Hz, 1H), 5.91 – 5.83 (m, 1H),
5.12 – 5.03 (m, 2H), 3.85 (s, 3H), 3.51 – 3.36 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H) ppm. 13C NMR
(126 MHz, CDCl3) δ 166.5, 141.9, 138.5, 136.6, 133.8, 128.9, 128.3, 126.5, 114.0, 64.7, 38.4,
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+
20.7 ppm. HRMS (ESI) m/z: calculated for C14H18NO2 [M + H]+:232.1338, found:232.1321.
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General Procedure for the Synthesis and Characterization of 3wꢀ3y. Representative
procedure for synthesis of 3w: A reaction tube was charged with Nꢀmethoxyꢀ2ꢀphenylacrylamide
1a (36.0 mg, 0.2 mmol, 1 equiv), allylic alcohol 2l (0.4 mmol, 2 equiv), [Cp*RhCl2]2 (0.01
mmol, 0.05 equiv), CsOAc (0.2 mmol, 1 equiv), and 2 mL MeOH. The mixture was heated at 50
°C for 12 h under Ar atmosphere. The resulting mixture was diluted with dichloromethane and
washed by water. The combined organic layers were dried with Na2SO4, filtered, concentrated
and purified by column chromatography on silica gel (hexanes/EA = 4/1 ~ 2/1, v/v) to give the
desired product 3w (59% yield, 27.9 mg).
(Z)ꢀNꢀmethoxyꢀ5ꢀmethylꢀ2ꢀphenylhexaꢀ2,5ꢀdienamide (3w). Following the general procedure,
3w was obtained as colorless oil in 59% yield, 27.9 mg. 1H NMR (500 MHz, CDCl3) δ 8.25 (br,
1H), 7.42 – 7.39 (m, 2H), 7.36 – 7.29 (m, 3H), 6.21 (t, J = 7.9 Hz, 1H), 4.84 (s, 1H), 4.78 (s,
1H), 3.85 (s, 3H), 3.07 (d, J = 7.8 Hz, 2H), 1.88 – 1.76 (m, 3H). 13C NMR (126 MHz, CDCl3) δ
166.5, 144.4, 136.7, 136.1, 132.9, 128.9, 128.4, 126.5, 111.6, 64.8, 38.0, 23.1 ppm. HRMS (ESI)
+
m/z: calculated for C14H18NO2 [M + H]+: 232.1338, found: 232.1317.
(2Z,5E)ꢀNꢀmethoxyꢀ2ꢀphenylnonaꢀ2,5ꢀdienamide (3x). Following the general procedure, a
mixture of stereoisomers (E/Z = 3:1) was obtained as colorless oil in 85% yield, 45.0 mg.
Spectral data for the major isomer (E): 1H NMR (500 MHz, CDCl3) δ 8.24 (br, 1H), 7.39 – 7.29
(m, 5H), 6.14 (t, J = 7.9 Hz, 1H), 5.54 – 5.47 (m, 2H), 3.86 (s, 3H), 3.11 – 2.98 (m, 2H), 2.03 –
1.96 (m, 2H), 1.43 – 1.35 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H) ppm. 13C NMR (126 MHz, CDCl3) δ
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166.7, 136.8, 135.0, 134.2, 132.7, 129.0, 128.3, 127.2, 126.6, 64.9, 34.9, 29.6, 22.8, 13.9 ppm.
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6
+
HRMS (ESI) m/z: calculated for C16H22NO2 [M + H]+: 260.1651, found: 260.1644.
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(Z)ꢀ3ꢀ(Cyclohexꢀ2ꢀenꢀ1ꢀyl)ꢀNꢀmethoxyꢀ2ꢀphenylacrylamide (3y). Following the general
procedure, 3y was obtained as colorless oil in 67% yield, 35.0 mg. 1H NMR (500 MHz, CDCl3) δ
8.15 (br, 1H), 7.39 – 7.36 (m, 2H), 7.35 – 7.27 (m, 3H), 5.98 (d, J = 10.5 Hz, 1H), 5.83 – 5.78
(m, 1H), 5.57 – 5.52 (m, 1H), 3.86 (s, 3H), 3.39 – 3.30 (m, 1H), 2.09 – 1.98 (m, 2H), 1.96 – 1.87
(m, 1H), 1.83 – 1.75 (m, 1H), 1.69 – 1.59 (m, 1H), 1.52 – 1.45 (m, 1H). 13C NMR (126 MHz,
CDCl3) δ 166.7, 140.0, 136.7, 133.6, 129.0, 128.9, 128.7, 128.2, 126.5, 64.8, 36.5, 29.3, 24.9,
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20.7. HRMS (ESI) m/z: calculated for C16H20NO2 [M + H]+: 258.1494, found: 258.1482.
+
The Gramꢀscale Reaction to Prepare 3a. To a 100 mL roundꢀbottom flask was charged Nꢀ
methoxyꢀ2ꢀphenylacrylamide 1a (1.0 g, 5.64 mmol, 1 equiv), allylic alcohol 2a (1.51 g, 11.29
mmol, 2 equiv), [RuCl2(pꢀcymene)]2 (172.8 mg, 0.28 mmol, 0.05 equiv), CsOAc (1.08 g, 5.64
mmol, 1 equiv) and 50 mL (MeOH/H2O = 1/1, v/v). The mixture was heated at 50 °C for 12 h
under Ar atmosphere. The resulting mixture was diluted with dichloromethane and washed by
water. The combined organic layers were dried with Na2SO4, filtered, concentrated and purified
by column chromatography on silica gel (hexanes/EA = 4/1 ~ 2/1, v/v) to give the desired
product 3a (57% yield, 0.946 g).
Epoxidation and Subsequent Cyclization of 3a. To a solution of 3a (60.0 mg, 1 equiv) in
CH2Cl2 (5 mL) was added 3ꢀchloroperbenzoic acid (52.9 mg, 1.5 equiv), the mixture was
allowed to stirred overnight at room temperature. Then, the resulting mixture was diluted with
dichloromethane and washed by water. The combined organic layers were dried with Na2SO4,
filtered, concentrated and purified by column chromatography on silica gel (hexanes/EA = 4/1 ~
2/1, v/v) to give the product 4a as colorless oil (63% yield, 40.0 mg). 1H NMR (500 MHz,
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CDCl3) δ 9.49 (br, 1H), 7.37 – 7.33 (m, 2H), 7.29 – 7.23 (m, 6H), 7.19 – 7.16 (m, 2H), 6.08 (t, J
= 8.3 Hz, 1H), 3.78 (s, 3H), 3.73 (d, J = 1.7 Hz, 1H), 3.20 – 3.13 (m, 1H), 2.95 – 2.85 (m, 1H),
2.58 – 2.50 (m, 1H) ppm. 13C NMR (126 MHz, CDCl3) δ 165.9, 138.9, 136.5, 136.3, 128.8,
128.69, 128.65, 128.5, 126.7, 126.6, 125.8, 64.6, 61.8, 58.6, 31.8 ppm. HRMS (ESI) m/z:
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calculated for C19H20NO3 [M + H]+: 310.1443, found: 310.1435.
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ASSOCIATED CONTENT
Supporting Information
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The supporting information is available free of charge on the ACS Publications website at DOI:
10.1021/
Procedures for the synthesis of 1 derivatives and deuteriumꢀlabeling experiments, the
NOSEY spectrum for 3a, and the copies of 1H and 13C NMR spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
* H.J.: Phone, (813) 745ꢀ8070; Fax, (813) 745ꢀ4506; Eꢀmail: Haitao.Ji@moffitt.org
ORCID
Haitao Ji: 0000ꢀ0001ꢀ5526ꢀ4503
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The H. Lee Moffitt Cancer Center & Research Institute is a NCIꢀdesignated Comprehensive
Cancer Center, supported under NIH grant P30ꢀCA76292. We thank Cheng Mo for reꢀcollecting
the mass spectrometry data for some compounds.
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