Visible-Light-Promoted Polysubstituted Olefins Synthesis Involving Sulfur Ylides as Carbene Trapping Reagents

Article abstract of DOI:10.1021/acs.joc.0c02500

A blue-light-emitting diode (LED) promoted coupling of aryl diazoacetates with sulfur ylides is described. This protocol features mild conditions, good functional group tolerance, and broad substrate scope for both aryl diazoacetates with sulfur ylides. Under optimal reaction conditions, a wide range of trisubstituted olefins is obtained in moderate to good yield, which can be further transferred to other biologically important heterocycles after a two-step simple operation.

Full text of DOI:10.1021/acs.joc.0c02500

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Visible-Light-Promoted Polysubstituted Olefins Synthesis Involving
Sulfur Ylides as Carbene Trapping Reagents
Cong Ye,§ Bao-Gui Cai,§ Juan Lu, Xiao Cheng, Lei Li, Zhong-Wen Pan,* and Jun Xuan*
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ABSTRACT: A blue-light-emitting diode (LED) promoted coupling of aryl diazoacetates with sulfur ylides is described. This
protocol features mild conditions, good functional group tolerance, and broad substrate scope for both aryl diazoacetates with sulfur
ylides. Under optimal reaction conditions, a wide range of trisubstituted olefins is obtained in moderate to good yield, which can be
further transferred to other biologically important heterocycles after a two-step simple operation.
reported approaches utilized high-energy UV light, and
visible-light-promoted sulfur ylides transformation largely
relied on the use of photoredox catalysts (e.g., benzophenone,
[Ir(dF(CF3)ppy)2(dtbbpy)]PF6, fac-Ir(4′-CF3ppy)3, or Ru-
(phen)3Cl2). Thus, continuously expanding the synthetic
potential of sulfur ylides in photochemical transformation
under sole visible light irradiation without an exogenous
photoredox catalyst is still highly desirable.
In the past several decades, carbene generation from diazo
compounds under thermal or transition-metal catalytic
conditions has been well investigated.6 Only recently, since
2018, photolysis of aryl diazoacetates under sole visible light
irradiation has emerged as a promising new and sustainable
approach to initiate free carbene-transfer reactions.7,8 To date,
the strategy has been elegantly applied to X−H insertion,9
cyclopropanation and cyclopropenation,10 and some other
types of reactions.11 In 2018, Zhou, He, and co-workers
developed a blue-light-emitting diode (LED)-promoted cross-
coupling of two distinct diazo compounds, leading to
trisubstituted alkenes in high yields and stereoselectivities.12a
In the same year, Maulide et al. reported a ruthenium-catalyzed
cross-olefination of diazo compounds with sulfoxonium ylides
as metal-carbene trapping reagents.12b Recently, in situ ylides
formation from sulfides and aryl diazoacetates under blue LED
irradiation was also achieved by Xiao,13a Koenigs13b and
INTRODUCTION
■
Since the pioneering work disclosed by Johnson, Corey, and
Chaykovsky, namely the Johnson−Corey−Chaykovsky reac-
tion, sulfur ylides have been witnessed as one of the most
important synthons in synthetic organic chemistry in the past
60 years.1 In most of the reported contributions, sulfur ylides
were always used as nucleophilic 1,1′-dipolar species to
participate in cycloaddition reactions.2 By using this strategy,
a wide range of biologically important carbocycles and
heterocycles can be accessed with high efficiency. Compared
with those well-developed processes, synthetic applications of
sulfur ylides under photochemical reaction conditions are
relatively less exploited.
Generally, the transformation of sulfur ylides under
photochemical reaction conditions can be roughly divided
into the following two categories. The first one utilizes sulfur
ylides as energy acceptors or electron donors. Under
photochemical conditions, sulfur ylides could serve either as
energy acceptors to form carbene species (Scheme 1a, left, ET,
electron transfer)3 or as single-electron reductants to generate
radical cation intermediates (Scheme 1a, right, SET, single-
electron transfer).4 Those strategies have been successfully
applied to the synthesis of many useful molecules, such as
methyl malonate derivatives,3 tetralones,4a 3-acyl oxindoles4b
and indolines.4c The second one utilizes sulfur ylides as
trapping reagents to react with photogenerated reactive species
(Scheme 1b). In 2017, Chen and co-workers reported a visible-
light-promoted indole synthesis using the formal [4 + 1]-
cycloaddition of in situ generated aza-ortho-quinone methides
with sulfur ylides as a key step.5a Shortly after this discovery,
they further extended the strategy to the synthesis of 2,3-
dihydrobenzofuran derivatives.5b However, some of these
Received: October 21, 2020
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© XXXX American Chemical Society
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Scheme 1. Transformation of Sulfur Ylides under Photochemical Reaction Conditions and Our Reaction Design
Gryko.13c Inspired by these contributions, we envision that the
photogenerated free carbene species from aryl diazoacetates
might also be trapped by sulfur ylides. Within the frame of our
continuing interests in visible-light-promoted fine chemical
transformations,14 we herein report the coupling reaction of
aryl diazoacetates with sulfur ylides under blue LED
irradiation, leading to various valuable polysubstituted olefins
in single E configuration.
and 54%, respectively (Table 1, entries 9 and 10). Note that
sulfoxonium ylide 2a′ can also serve as a carbene trapping
reagent to form alkene 3aa, albeit in a low yield (Table 1, entry
11). The control experiment revealed that visible light
irradiation was essential for the product formation (Table 1,
entry 10).
With the optimal reaction conditions in hand, we next
evaluated the substrate scope with respect to both aryl
diazoacetate and sulfur ylide components. It was found that
the reaction showed a broad substrate scope and good
functional group tolerance. As shown in Scheme 2, substrates
1a−e bearing electron-neutral, electron-donating (e.g., −Me,
−OMe), or electron-withdrawing (e.g., −F, −Br) substituents
at the para position were tolerated well, affording trisubstituted
olefins 3aa−ea in moderate to good yield. Incorporation of
ester functional groups proceeded well to afford products 3fa
and 3ga in 68 and 43% yield, respectively. Apart from phenyl
diazoacetate, substrate 1h bearing a 2-naphthyl moiety was also
an amenable substrate, giving the corresponding coupling
product 3ha in 40% yield. It was found that different ester
groups in aryl diazoacetate 1 were well tolerated and the
desired polysubstituted olefin products 3ia−ka were obtained
in 42−55% yields. Note that the relatively low yield in some
cases might be due to the formation of the aryl diazoacetate
homocoupling byproduct under visible light irradiation.
Next, we continued to investigate the generality of the
process by reacting 2-diazo-2-phenylacetate 1a with a
RESULTS AND DISCUSSION
■
We began our investigation by employing methyl 2-diazo-2-
phenylacetate 1a and sulfur ylide 2a as model substrates.
(Table 1). As shown in entry 1, upon irradiating the reaction
mixture with 24 W blue LEDs for 7 h in DCM, the desired
trisubstituted olefin 3aa was obtained in 66% isolated yield as a
single E-isomer. Encouraged by this preliminary result, we
commenced with reaction optimization and investigated the
effect of reaction solvents to further improve the yield.
Replacement of DCM with other commonly used reaction
media, such as CH3CN, THF, EtOAc, and 1,4-dioxane, did not
give better yields (Table 1, entries 2−5). Only a trace amount
of 3aa was observed when the reaction was performed in
dimethyl formamide (DMF) and dimethyl sulfoxide (DMSO)
(Table 1, entries 6 and 7). Further optimization identified
dichloroethene (DCE) to be the best solvent candidate,
affording 3aa in 70% yield (Table 1, entry 8). Changing the
ratio of 1a:2a from 2:1 to 1:2 or 1.5:1 decreased the yield to 41
B
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a
olefin 3qi in 56% yield. Subsequently, the reduction of 3qi
gave 1,4-dicarbonyl 7 in 96% yield upon isolation, which is the
key synthetic intermediate to the target molecule 8.
Table 1. Reaction Optimization
A series of preliminary mechanistic experiments were
conducted in Scheme 4 to gain some insight into the
mechanism. Initially, the UV−vis absorbance spectra of 2-
diazo-2-phenylacetate 1a and sulfur ylide 2a was conducted
and both of the two starting materials presented an absorbance
spectrum in the visible region (Scheme 4a). According to
literature reports, both aryl diazoacetates and sulfur ylides
could serve as carbene precursors under photo-irradia-
tion.3,8−13 Then, we conducted some control experiments to
identify which substrates were activated under our optimal
reaction conditions (Scheme 4b). It was reported that styrene
is an efficient carbene trapping reagent under photochemical
conditions.9a When 1.0 equivalent of styrene was added as a
trapping reagent, the reaction afforded olefin 3aa in 61% yield,
together with 15% yield of cycloaddition adduct 9. Moreover,
we noticed that cyclopropane 10 was not formed even when
the reaction of sulfur ylide 2a with styrene was directly
performed under standard reaction conditions. This result
suggested that under current photochemical reaction con-
ditions, only aryl diazoacetate 1 was selectively activated to
form carbene intermediate, and sulfur ylide 2 did not undergo
photolysis. Moreover, when 1.0 equivalent of radical scavenger
1,4-dinitrobenezene was added under standard conditions, 3aa
could be isolated in 61% yield. The result indicated that the
radical pathway might not be the predominant reaction route
in the current reaction system.
On the basis of the above experimental results and literature
reports,8−13 a plausible reaction mechanism was proposed in
Scheme 4c. Under blue LEDs irradiation, selective photolysis
of aryl diazoacetate yielded free carbene species with the
release of nitrogen gas. Then, the nucleophilic attack of the
negatively polarized carbon atom of sulfur ylide 2 to carbene
intermediate, followed by elimination of dimethyl sulfide, gave
the final trisubstituted olefins.
In summary, we have developed a green and efficient
polysubstituted olefin formation protocol via blue-LED-
promoted coupling of aryl diazoacetates with sulfur ylides.
This reaction takes advantage of aryl diazoacetates as free
carbene precursors and sulfur ylides as carbene trapping
reagents without the need for an exogenous photoredox
catalyst. Simple manipulation of the final olefin products
allowed the facile construction of a wide range of important
heterocycles, including pyrazole, pyrrole, isoxazole, and
pyridazine derivatives. Moreover, the method can be applied
as a key step to the formal synthesis of ETA receptor
radioligand 8. We envision this visible-light-promoted olefin
formation strategy will find further applications in both organic
synthesis and biomolecule studies.
a
Reaction conditions: 1a (0.2 mmol), 2a (0.1 mmol) in the indicated
solvent (1.0 mL), irradiation by 24 W blue LEDs at room temperature
for 7 h under a N2 atmosphere. Isolated yield, E:Z > 19:1.
b
representative set of sulfur ylides 2 under the optimal reaction
conditions (Scheme 2). The results revealed that both the
electronic properties and substitution pattern of the aryl ring in
the sulfur ylide 2 had no obvious effect on the reaction yields.
Both electron-withdrawing (−F, −Cl, −Br, −NO2) and
electron-donating groups (−Me) at para or meta-positions of
the aromatic ring reacted well, providing the trisubstituted
olefin products 3ab−ag in 52−65% yield. It should be pointed
out that the alkyl-acyl-substituted sulfur ylide, such as 2h, was
not suitable, and only a trace amount of 3ah was detected by
gas chromatography−mass spectrometry (GC−MS) analysis.
To further explore the synthetic potential of this blue LED-
promoted trisubstituted olefin synthesis protocol in the
pharmaceutical industry, we introduced some natural isolates
and drug-derived complex molecules, such as estrone, L-
menthol, metronidazole, citronellol, and oleyl alcohol, into the
starting materials of diazoalkane (Scheme 2). To our
satisfaction, all of these diazoalkanes reacted well with 2a,
yielding the corresponding modified complex structures in
moderate to good yields (3la−pa, 35−69% yields).
With the aim of showing the utility of the obtained
trisubstituted olefins, we conducted some synthetic trans-
formations in Scheme 3. It was found that the CC bond in
product 3aa could be easily reduced, which offered us a good
option to transfer the target trisubstituted olefins to a variety of
other important heterocyclic compounds, such as pyridazine
415a and thiophene 5,15b after a two-step simple operation
(Scheme 3a). Treatment of 3aa in BH3. THF solution afforded
diol, which could be transferred to the disubstituted
tetrahydrofuran 6 in 87% yield and 1.4:1 d.r. over two
steps.15c More significantly, a formal synthesis of the ETA
receptor radioligand 8 was achieved using the developed
visible-light-promoted polysubstituted olefins synthesis as a key
step (Scheme 3b).16 Under optimal reaction conditions, the
coupling of diazo compound 1q with sulfur ylide 2i afforded
EXPERIMENTAL SECTION
■
General Information. All reactions involving air- or moisture-
sensitive reagents or intermediates were carried out in preheated
glassware under an argon atmosphere using standard Schlenk
techniques. All solvents and reagents were purified according to
standard procedures or were used as received from chemical suppliers.
The starting materials were synthesized according to literature
procedures. The light employed in this work was bought from
GeAo Chemical: model H106062, 24 W blue LED bulbs, light
intensity, 24 mW/cm2. Analytical thin-layer chromatography was
performed using silica gel plates (Silica gel 60 F254) from Qingdao
Puke Parting Materials Co. Visualization was by ultraviolet
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a b c
, ,
Scheme 2. Reaction Scope
a
Reaction conditions: 1 (0.2 mmol), 2 (0.1 mmol) in DCE (1.0 mL), irradiation by 24 W blue LEDs at room temperature for 7 h under a N2
b
c
atmosphere. Isolated yield, E:Z > 19:1 in all cases. 1.0 mmol scale reaction.
fluorescence (λ = 254 nm) and/or staining with phosphomolybdic
acid or potassium permanganate (KMnO4). Flash column chroma-
tography was performed using 200−300 mesh silica gel. 1H NMR and
13C NMR spectra were recorded on a JEOL JNM ECZ400R at 300 K.
Spectra were calibrated relative to solvent’s residual proton and
carbon chemical shift: CHCl3 (δ = 7.26 for 1H NMR and δ = 77.0 for
13C NMR). Data are reported as follows: chemical shift δ/ppm,
integration (1H only), multiplicity (s = singlet, d = doublet, t = triplet,
q = quartet, dd = doublet of doublets, m = multiplet or combinations
thereof; 13C signals are singlets unless otherwise stated), coupling
constants J in Hz, assignment. Mass spectra were recorded on a
Finnigan MAT 4200S, a Bruker Daltonics Micro Tof, a Waters-
Micromass Quatro LCZ (ESI); peaks are given in m/z (% of basis
peak). UV−vis spectrophotometer: UV−vis absorption spectra were
recorded on an Agilent 8453 spectrophotometer in DCE (0.05 mol·
mL−1) at room temperature. Melting points were determined by
Stuart SMP10 and are uncorrected. All reactions involving heating are
carried out in an oil bath.
General Procedure for the Synthesis of Aryl Diazoacetates.
DBU (1.4 equiv) was added to a mixture of esters (1.0 equiv) and p-
toluenesulfonyl azide (1.2 equiv) in anhydrous acetonitrile (3 mL/
mmol). The reaction mixture was stirred at room temperature
overnight. Upon the complete consumption of the starting materials,
the reaction mixture was diluted with an appropriate amount of water,
D
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Scheme 3. Follow-Up Chemistry
followed by extraction with ethyl acetate. After washing with 10%
NH4Cl solution and brine, the combined organic extracts were dried
over Na2SO4 and concentrated by rotary evaporation. The residue
was purified by flash chromatography (petroleum ether/ethyl acetate
= 60/1 to 30/1) to afford aryldiazoacetates. Aryl diazoacetates 1a−
d,12a 1e,9e 1h,9e 1i−j,12a 1k,17d 1m,17e 1o,17f and 1p11b are known
compounds.
2.19 (m, 3H), 2.07−1.99 (m, 1H), 1.94−1.83 (m, 2H), 1.81−1.73
(m, 2H), 1.68−1.57 (m, 2H), 1.54−1.30 (m, 6H), 0.88 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3, 300 K): δ (ppm) = 166.2, 157.4,
156.7, 138.0, 132.8, 126.3, 125.9, 119.4, 115.2, 114.5, 112.0, 65.2,
64.6, 64.6, 64.2, 51.9, 49.3, 46.1, 43.6, 39.0, 34.2, 30.7, 29.8, 29.3,
27.0, 26.1, 22.3, 14.3; IR (neat, cm−1): 831w, 1057m, 1143m, 1247m,
1429w, 1458w, 1504w, 1516w, 1548w, 1633w, 1654w, 1695w, 1733w,
1776w, 2087s, 2848s, 2925s. HRMS (ESI) exact mass calculated for
C32H39O6: 519.2741 ([M + H-N2]+), found: 519.2747; mp: 87−89
°C.
Methyl 2-(4-(((4-Bromophenyl)sulfonyl)oxy)phenyl)-2-diazoace-
1
tate (1f). H NMR (400 MHz, CDCl3, 300 K): δ (ppm) = 7.68 (s,
4H), 7.45−7.40 (m, 2H), 7.02−6.98 (m, 2H), 3.86 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3, 300 K): δ (ppm) = 165.1, 147.0, 134.2,
132.6, 129.9, 129.7, 125.2, 124.9, 122.8, 52.1; IR (neat, cm−1): 424w,
492w, 570s, 761s, 848s, 935w, 1004m, 1168s, 1369s, 1421m, 1507s,
1577m, 1689s, 1914w, 2114s, 2391w, 2946m, 3015w, 3094m. HRMS
(ESI) exact mass calculated for C15H12BrO5S: 382.9583 ([M + H-
N2]+), found: 382.9586; mp: 167−169 °C.
2-(2-Methyl-5-nitro-1H-imidazol-1-yl)ethyl 2-Diazo-2-phenyla-
1
cetate (1n). H NMR (400 MHz, CDCl3, 300 K): δ (ppm) = 7.97
(s, 1H), 7.47−7.33 (m, 4H), 7.26−7.14 (m, 1H), 4.75−4.52 (m, 4H),
2.46 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, 300 K): δ (ppm) =
164.4, 150.8, 138.4, 133.2, 129.0, 126.3, 124.4, 124.1, 62.7, 45.1, 14.2;
IR (neat, cm−1): 502m, 545m, 675m, 735s, 866w, 987m, 1065s, 1152s,
1238s, 1369s, 1472s, 1585w, 1724s, 2097s, 2964w, 3137m. HRMS
(ESI) exact mass calculated for C14H14N3O4: 288.0979 ([M + H-
N2]+), found: 288.0985; mp: 109−111 °C.
4-(1-Diazo-2-methoxy-2-oxoethyl)phenyl (3R,5R,7R)-Adaman-
1
tane-1-carboxylate (1g). H NMR (400 MHz, CDCl3, 300 K): δ
(ppm) = 7.49−7.43 (m, 2H), 7.09−7.05 (m, 2H), 3.86 (s, 3H),
2.10−2.02 (m, 9H), 1.82−1.73 (m, 6H). 13C{1H} NMR (100 MHz,
CDCl3, 300 K): δ (ppm) = 176.2, 165.6, 149.1, 125.0, 122.6, 122.2,
52.0, 41.0, 38.7, 36.4, 27.9. IR (neat, cm−1): 502m, 553m, 640w, 675s,
774s, 857s, 1047s, 1108w, 1230s, 1291m, 1377s, 1437s, 1524s, 1602w,
1698s, 1724s, 1879w, 2105s, 2686w. HRMS (ESI) exact mass
calculated for C20H23O4: 327.1596 ([M + H-N2]+), found:
327.1585; mp: 134−136 °C.
Methyl 2-Diazo-2-(4-(3-(((13S)-13-methyl-6,7,8,9,11,12,13,
14,15,16-decahydrospiro[cyclopenta[a]phenanthrene-17,2′-[1,3]-
dioxolan]-3-yl)oxy)propoxy)phenyl)acetate (1l). 1H NMR (400
MHz, CDCl3, 300 K): δ (ppm) = 7.36 (d, J = 9.0 Hz, 2H), 7.19
(dd, J = 8.8, 2.8 Hz, 1H), 6.94 (d, J = 9.0 Hz, 2H), 6.73−6.68 (m,
1H), 6.63 (d, J = 2.8 Hz, 1H), 4.18−4.08 (m, 4H), 3.96−3.88 (m,
4H), 3.84 (s, 3H), 2.86−2.78 (m, 2H), 2.34−2.28 (m, 1H), 2.26−
(Z)-Octadec-9-en-1-yl 2-Diazo-2-phenylacetate (1p). 1H NMR
(400 MHz, CDCl3, 300 K): δ (ppm) = 7.50−7.46 (m, 2H), 7.40−
7.35 (m, 2H), 7.20−7.14 (m, 1H), 5.39−5.31 (m, 2H), 4.26 (t, J =
6.7 Hz, 2H), 2.01 (q, J = 7.3, 6.6 Hz, 4H), 1.70 (p, J = 6.7 Hz, 2H),
1.36−1.25 (m, 22H), 0.90−0.86 (m, 3H).; 13C{1H} NMR (100 MHz,
CDCl3, 300 K): δ (ppm) = 165.2, 129.9, 129.7, 128.9, 125.7, 125.6,
123.9, 65.1, 31.9, 29.7, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 28.8, 27.2,
27.2, 25.8, 22.7, 14.1; IR (neat, cm−1): 692m, 744s, 995m, 1160s,
1247s, 1359m, 1594w, 1706s, 2070s, 2842m, 2937s, 3077w. HRMS
(ESI) exact mass calculated for C26H41O2: 385.3107 ([M + H-N2]+),
found: 385.3111.
General Procedure for the Synthesis of Sulfur Ylides.
Dimethyl phenacyl sulfonium bromide (5.0 g, 0.019 mol) was
dissolved in water (30 mL). The colored suspension was filtered, and
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Scheme 4. Mechanism Studies
the clear filtrate was treated with 10% aqueous sodium hydroxide (50
mL, 0.125 mol). The solution was stirred and then extracted several
times with chloroform. The chloroform extract was dried and
evaporated to give an orange oil, which upon cooling immediately
solidified to an orange solid (3.60 g, 100%). The infrared spectrum
and NMR spectrum were identical to that of the previous
phenacylide. Upon recrystallization of the solid, as before, a 95%
yield of product was obtained. Sulfur ylides 2a−c,4c 2d−e,5a and 2g−
h4c are known compounds.
General Procedure for the Synthesis of Polysubstituted
Olefins (GP1). To a 10 mL Schlenk flask equipped with a magnetic
stir bar was added 1a (0.2 mmol), 2a (0.1 mmol), and dry DCE (1.0
mL). The resulting mixture was degassed using the “freeze−pump−
thaw” procedure (3 times). Then, the solution was stirred at a
distance of ∼3 cm from a 24 W blue LED at room temperature for 7
h. The solvent was removed under vacuum, and the crude product
was purified by flash chromatography on silica gel (silica: 200−300;
eluant: petroleum ether/ethyl acetate (20:1 to 5:1)) to obtain the
pure product 3aa as a yellow oil in 70% yield.
Procedure for 1 mmol Reaction. To a 25 mL Schlenk flask
equipped with a magnetic stir bar was added 1a (2.0 mmol), 2a (1.0
mmol), and dry DCE (10.0 mL). The resulting mixture was degassed
using the freeze−pump−thaw procedure (3 times). Then, the
solution was stirred at a distance of ∼3 cm from a 24 W blue LED
at room temperature for 12 h. The solvent was removed under
vacuum, and the crude product was purified by flash chromatography
on silica gel (silica: 200−300; eluant: petroleum ether/ethyl acetate
(20:1 to 5:1)) to obtain the pure product 3aa as a yellow oil in 53%
yield (141.1 mg).
(E)-Methyl 4-Oxo-2,4-diphenylbut-2-enoate (3aa).13a 3aa was
synthesized according to GP1, with 1a (35.2 mg, 0.20 mmol, 2.0
equiv) and 2a (18.0 mg, 0.10 mmol, 1.0 equiv) in 1.0 mL of DCE for
7 h. Purification by silica gel chromatography (eluant: petroleum
ether/ethyl acetate 20:1 to 5:1) afforded the desired 3aa. Yellow oil,
yield: 70% (18.6 mg); 1H NMR (400 MHz, CDCl3, 300 K): δ (ppm)
= 7.86−7.79 (m, 2H), 7.70 (s, 1H), 7.52−7.47 (m, 1H), 7.39−7.34
(m, 2H), 7.24−7.18 (m, 5H), 3.86 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3, 300 K): δ (ppm) = 193.5, 167.0, 140.4, 136.4, 136.2,
133.7, 133.6, 129.4, 128.9, 128.6, 128.5, 127.9, 52.9.
(E)-Methyl 4-Oxo-4-phenyl-2-(p-tolyl)but-2-enoate (3ba).17a 3ba
was synthesized according to GP1, with 1b (38.0 mg, 0.20 mmol, 2.0
equiv) and 2a (18.0 mg, 0.10 mmol, 1.0 equiv) in 1.0 mL of DCE for
7 h. Purification by silica gel chromatography (eluant: petroleum
ether/ethyl acetate 20:1 to 5:1) afforded the desired 3ba. Yellow oil,
yield: 61% (17.1 mg); 1H NMR (400 MHz, CDCl3, 300 K): δ (ppm)
= 7.86−7.80 (m, 2H), 7.67 (s, 1H), 7.52−7.47 (m, 1H), 7.40−7.34
(m, 2H), 7.13−7.08 (m, 2H), 7.02 (d, J = 7.7 Hz, 2H), 3.85 (s, 3H),
2.25 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, 300 K): δ (ppm) =
193.6, 167.2, 140.5, 138.5, 136.3, 135.8, 133.5, 130.7, 129.3, 128.9,
128.7, 128.5, 52.8, 21.2.
(E)-Methyl 2-(4-Methoxyphenyl)-4-oxo-4-phenylbut-2-enoate
(3ca). 3ca was synthesized according to GP1, with 1c (41.2 mg,
0.20 mmol, 2.0 equiv) and 2a (18.0 mg, 0.10 mmol, 1.0 equiv) in 1.0
mL of DCE for 7 h. Purification by silica gel chromatography (eluant:
petroleum ether/ethyl acetate 20:1 to 5:1) afforded the desired 3ca.
1
Yellow oil, yield: 43% (12.7 mg); H NMR (400 MHz, CDCl3, 300
K): δ (ppm) = 7.86−7.80 (m, 2H), 7.61 (s, 1H), 7.51−7.46 (m, 1H),
7.39−7.34 (m, 2H), 7.21−7.12 (m, 2H), 6.80−6.67 (m, 2H), 3.86 (s,
F
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The Journal of Organic Chemistry
pubs.acs.org/joc
Article
3H), 3.72 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, 300 K): δ
(ppm) = 193.9, 167.3, 159.8, 140.0, 136.2, 135.4, 133.5, 130.9, 128.9,
128.5, 125.9, 113.4, 55.1, 52.8; IR (neat, cm−1): 510w, 631w, 718m,
839m, 926w, 1030s, 1178m, 1247s, 1472m, 1515s, 1602m, 1655m,
1724s, 2834w, 2921w, 2964w; HRMS (ESI) exact mass calculated for
C18H17O4: 297.1127 ([M + H]+), found: 297.1118.
petroleum ether/ethyl acetate 20:1 to 5:1) afforded the desired 3ha.
Yellow oil, yield: 40% (12.6 mg); H NMR (400 MHz, CDCl3, 300
1
K): δ (ppm) = 7.85−7.82 (m, 2H), 7.79 (s, 1H), 7.77−7.66 (m, 4H),
7.47−7.40 (m, 3H), 7.35−7.30 (m, 3H), 3.88 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3, 300 K): δ (ppm) = 193.5, 167.1, 140.5, 136.7,
136.2, 133.6, 131.2, 129.1, 128.9, 128.5, 128.2, 127.6, 127.5, 126.8,
126.6, 126.2, 52.9; IR (neat, cm−1): 401w, 440m, 723m, 748m, 954w,
1044w, 1237s, 1456w, 1597m, 1661m, 1713s, 2112w, 2832m, 2909m,
3013w; HRMS (ESI) exact mass calculated for C21H17O3: 317.1178
([M + H]+), found: 317.1175.
(E)-Methyl 2-(4-Fluorophenyl)-4-oxo-4-phenylbut-2-enoate
(3da). 3da was synthesized according to GP1, with 1d (38.8 mg,
0.20 mmol, 2.0 equiv) and 2a (18.0 mg, 0.10 mmol, 1.0 equiv) in 1.0
mL of DCE for 7 h. Purification by silica gel chromatography (eluant:
petroleum ether/ethyl acetate 20:1 to 5:1) afforded the desired 3da.
(E)-Ethyl 4-Oxo-2,4-diphenylbut-2-enoate (3ia). 3ia was synthe-
sized according to GP1, with 1i (38.0 mg, 0.20 mmol, 2.0 equiv) and
2a (18.0 mg, 0.10 mmol, 1.0 equiv) in 1.0 mL of DCE for 7 h.
Purification by silica gel chromatography (eluant: petroleum ether/
ethyl acetate 20:1 to 5:1) afforded the desired 3ia. Yellow oil, yield:
1
Yellow oil, yield: 77% (21.8 mg); H NMR (400 MHz, CDCl3, 300
K): δ (ppm) = 7.85−7.80 (m, 2H), 7.72 (s, 1H), 7.54−7.49 (m, 1H),
7.41−7.36 (m, 2H), 7.22−7.17 (m, 2H), 6.94−6.88 (m, 2H), 3.87 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3, 300 K): δ (ppm) = 193.4,
166.8, 139.4, 136.6, 136.1, 133.8, 131.4 (d, J = 8 Hz), 131.3, 129.6,
128.8 (d, J = 25 Hz), 115.0 (d, J = 21 Hz), 52.9; IR (neat, cm−1):
519w, 640m, 710s, 857s, 961w, 1030m, 1152m, 1247s, 1455m, 1499s,
1568m, 1662s, 1733s, 2851w, 1964m, 3077w; HRMS (ESI) exact
mass calculated for C17H14FO3: 285.0927 ([M + H]+), found:
285.0926.
1
42% (11.8 mg); H NMR (400 MHz, CDCl3, 300 K): δ (ppm) =
7.85−7.79 (m, 2H), 7.67 (s, 1H), 7.51−7.46 (m, 1H), 7.38−7.33 (m,
2H), 7.21 (s, 5H), 4.33 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3, 300 K): δ (ppm) = 193.8, 166.5,
140.7, 136.2, 136.0, 133.8, 133.6, 129.4, 128.9, 128.5, 127.8, 61.9,
14.1; IR (neat, cm−1): 659w, 697m, 774m, 1031m, 1096w, 1173m,
1250s, 1379w, 1443m, 1674m, 171s, 1832w, 1909m, 3063w; HRMS
(ESI) exact mass calculated for C18H17O3: 281.1178 ([M + H]+),
found: 281.1174.
(E)-Methyl 2-(4-Bromophenyl)-4-oxo-4-phenylbut-2-enoate
(3ea). 3ea was synthesized according to GP1, with 1e (50.8 mg,
0.20 mmol, 2.0 equiv) and 2a (18.0 mg, 0.10 mmol, 1.0 equiv) in 1.0
mL DCE for 7 h. Purification by silica gel chromatography (eluant:
petroleum ether/ethyl acetate 20:1 to 5:1) afforded the desired 3ea.
(E)-Isopropyl 4-Oxo-2,4-diphenylbut-2-enoate (3ja). 3ja was
synthesized according to GP1, with 1j (40.8 mg, 0.20 mmol, 2.0
equiv) and 2a (18.0 mg, 0.10 mmol, 1.0 equiv) in 1.0 mL of DCE for
12 h. Purification by silica gel chromatography (eluant: petroleum
ether/ethyl acetate 20:1 to 5:1) afforded the desired 3ja. Yellow oil,
yield: 46% (13.5 mg); 1H NMR (400 MHz, CDCl3, 300 K): δ (ppm)
= 7.84−7.79 (m, 2H), 7.67 (s, 1H), 7.50−7.45 (m, 1H), 7.37−7.33
(m, 2H), 7.22−7.18 (m, 5H), 5.19 (p, J = 6.3 Hz, 1H), 1.32 (d, J =
6.3 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3, 300 K): δ (ppm) =
194.0, 166.0, 141.0, 136.2, 135.7, 133.9, 133.5, 129.5, 129.0, 128.5,
127.8, 69.6, 21.7; IR (neat, cm−1): 530w, 671m, 748m, 838w, 929w,
980m, 1096s, 1237s, 1366m, 1482m, 1661m, 1726s, 2845m, 2898m,
2986m, 3077w; HRMS (ESI) exact mass calculated for C19H19O3:
295.1334 ([M + H]+), found: 295.1328.
(E)-Cyclopentyl 4-Oxo-2,4-diphenylbut-2-enoate (3ka). 3ka was
synthesized according to GP1, with 1k (46.0 mg, 0.20 mmol, 2.0
equiv) and 2a (18.0 mg, 0.10 mmol, 1.0 equiv) in 1.0 mL of DCE for
7 h. Purification by silica gel chromatography (eluant: petroleum
ether/ethyl acetate 20:1 to 5:1) afforded the desired 3ka. Yellow oil,
yield: 55% (17.6 mg); 1H NMR (400 MHz, CDCl3, 300 K): δ (ppm)
= 7.84−7.79 (m, 2H), 7.61 (s, 1H), 7.50−7.45 (m, 1H), 7.38−7.33
(m, 2H), 7.19 (s, 5H), 5.38−5.32 (m, 1H), 1.95−1.87 (m, 2H),
1.80−1.61 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3, 300 K): δ
(ppm) = 194.0, 166.2, 141.1, 136.2, 135.6, 133.9, 133.5, 129.4, 129.0,
128.5, 128.4, 127.8, 78.8, 32.6, 23.7; IR (neat, cm−1): 631w, 675s,
770m, 900w, 944m, 1022m, 1168s, 1238s, 1437m, 1490w, 1602m,
1663s, 1715s, 2868w, 2964s, 3077w; HRMS (ESI) exact mass
calculated for C21H21O3: 321.1491 ([M + H]+), found: 321.1486.
(E)-Methyl 4-Oxo-2-phenyl-4-(p-tolyl)but-2-enoate (3ab).13a 3ab
was synthesized according to GP1, with 1a (35.2 mg, 0.20 mmol, 2.0
equiv) and 2b (19.4 mg, 0.10 mmol, 1.0 equiv) in 1.0 mL of DCE for
7 h. Purification by silica gel chromatography (eluant: petroleum
ether/ethyl acetate 20:1 to 5:1) afforded the desired 3ab. Yellow oil,
yield: 52% (14.6 mg). 1H NMR (400 MHz, CDCl3, 300 K): δ (ppm)
= 7.76−7.71 (m, 2H), 7.70 (s, 1H), 7.23−7.21 (M, 4H), 7.17 (d, J =
7.9 Hz, 2H), 3.86 (s, 3H), 2.36 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3, 300 K): δ (ppm) = 193.1, 167.1, 144.7, 140.0, 136.8, 133.8,
129.3, 129.3, 129.1, 128.5, 127.9, 52.8, 21.7.
1
Yellow oil, yield: 51% (17.5 mg); H NMR (400 MHz, CDCl3, 300
K): δ (ppm) = 7.87−7.82 (m, 2H), 7.77 (s, 1H), 7.56−7.51 (m, 1H),
7.43−7.35 (m, 4H), 7.12−7.06 (m, 2H), 3.87 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3, 300 K): δ (ppm) = 193.0, 166.5, 139.4, 136.8,
136.1, 133.9, 132.6, 131.2, 131.0, 128.9, 128.7, 52.9; IR (neat, cm−1):
626w, 754m, 926m, 1010m, 1071s, 1176s, 1253w, 1314w, 1450m,
1597s, 1666m, 1723s, 2846w, 2918m, 2955w; HRMS (ESI) exact
mass calculated for C17H14BrO3: 345.0126 ([M + H]+), found:
345.0135.
(E)-Methyl 2-(4-(((4-Bromophenyl)sulfonyl)oxy)phenyl)-4-oxo-4-
phenylbut-2-enoate (3fa). 3fa was synthesized according to GP1,
with 1f (82.0 mg, 0.20 mmol, 2.0 equiv) and 2a (18.0 mg, 0.10 mmol,
1.0 equiv) in 1.0 mL of DCE for 7 h. Purification by silica gel
chromatography (eluant: petroleum ether/ethyl acetate 20:1 to 5:1)
1
afforded the desired 3fa. Yellow oil, yield 68% (34.0 mg); H NMR
(400 MHz, CDCl3, 300 K): δ (ppm) = 7.83−7.77 (m, 2H), 7.73 (s,
1H), 7.62−7.52 (m, 5H), 7.44−7.37 (m, 2H), 7.19−7.14 (m, 2H),
6.86−6.81 (m, 2H), 3.87 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3,
300 K): δ (ppm) = 193.1, 166.4, 149.4, 138.8, 137.3, 136.0, 133.9,
133.0, 132.4, 131.0, 129.9, 129.6, 128.9, 128.7, 121.9, 53.0; IR (neat,
cm−1): 530m, 607s, 684w, 761m, 865s, 980m, 1108s, 1147s, 1405s,
1507m, 1661w, 1765m, 1857w, 2961w, 3115w; HRMS (ESI) exact
mass calculated for C23H18BrO6S: 501.0007 ([M + H]+), found:
500.9994.
(3R,5R,7R)-4-((E)-1-Methoxy-1,4-dioxo-4-phenylbut-2-en-2-yl)-
phenyl Adamantane-1-carboxylate (3ga). 3ga was synthesized
according to GP1, with 1g (70.8 mg, 0.20 mmol, 2.0 equiv) and 2a
(18.0 mg, 0.10 mmol, 1.0 equiv) in 1.0 mL of DCE for 7 h.
Purification by silica gel chromatography (eluant: petroleum ether/
ethyl acetate 20:1 to 5:1) afforded the desired 3ga. Yellow oil, yield:
1
43% (19.1 mg); H NMR (400 MHz, CDCl3, 300 K): δ (ppm) =
7.87−7.80 (m, 2H), 7.72 (s, 1H), 7.54−7.50 (m, 1H), 7.41−7.36 (m,
2H), 7.24−7.20 (m, 2H), 6.96−6.91 (m, 2H), 3.85 (s, 3H), 2.07−
1.99 (m, 9H), 1.78−1.73 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3,
300 K): δ (ppm) = 193.3, 175.6, 166.8, 151.2, 139.6, 136.6, 136.1,
133.8, 130.8, 130.5, 128.9, 128.6, 121.0, 52.9, 41.0, 38.7, 36.4, 27.8. IR
(neat, cm−1): 505w, 620w, 723w, 1044s, 1096w, 1147s, 1160s, 1366w,
1418m, 1520m, 1584w, 1774m, 1726s, 2845m, 1922s, 3063w; HRMS
(ESI) exact mass calculated for C28H29O5: 445.2015 ([M + H]+),
found: 445.2012.
(E)-Methyl 2-(Naphthalen-2-yl)-4-oxo-4-phenylbut-2-enoate
(3ha). 3ha was synthesized according to GP1 with 1h (45.2 mg,
0.20 mmol, 2.0 equiv), 2a (18.0 mg, 0.10 mmol, 1.0 equiv) in 1.0 mL
of DCE for 7 h. Purification by silica gel chromatography (eluant:
(E)-Methyl 4-(4-Fluorophenyl)-4-oxo-2-phenylbut-2-enoate
(3ac).17b 3ac was synthesized according to GP1, with 1a (35.2 mg,
0.20 mmol, 2.0 equiv) and 2c (19.8 mg, 0.10 mmol, 1.0 equiv) in 1.0
mL of DCE for 7 h. Purification by silica gel chromatography (eluant:
petroleum ether/ethyl acetate 20:1 to 5:1) afforded the desired 3ac.
1
Yellow oil, yield: 53% (15.1 mg); H NMR (400 MHz, CDCl3, 300
K): δ (ppm) = 7.87−7.79 (m, 2H), 7.64 (s, 1H), 7.25−7.16 (m, 5H),
7.04−6.99 (m, 2H), 3.86 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3,
G
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Article
300 K): δ (ppm) = 192.1, 166.9, 165.9 (d, J = 254.7 Hz), 140.5,
136.0, 133.6, 132.6, 131.6 (d, J = 9.5 Hz), 129.3, 128.7, 128.0, 115.7
(d, J = 25 Hz), 52.9.
510w, 683m, 839m, 952w, 1030s, 1195m, 1213s, 1256m, 1351w,
1515m, 1577m, 1680m, 1741s, 2842m, 2937s, 3059w, 3432s; HRMS
(ESI) exact mass calculated for C40H45O7: 637.3165 ([M + H]+),
found: 637.3169.
(E)-Methyl 4-(4-Chlorophenyl)-4-oxo-2-phenylbut-2-enoate
(3ad).17c 3ad was synthesized according to GP1, with 1a (35.2 mg,
0.20 mmol, 2.0 equiv) and 2d (21.4 mg, 0.10 mmol, 1.0 equiv) in 1.0
mL of DCE for 7 h. Purification by silica gel chromatography (eluant:
petroleum ether/ethyl acetate 20:1 to 5:1) afforded the desired 3ad.
(E)-(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl 4-Oxo-2,4-diphe-
nylbut-2-enoate (3ma). 3ma was synthesized according to GP1,
with 1m (60.0 mg, 0.20 mmol, 2.0 equiv) and 2a (18.0 mg, 0.10
mmol, 1.0 equiv) in 1.0 mL of DCE for 7 h. Purification by silica gel
chromatography (eluant: petroleum ether/ethyl acetate 20:1 to 5:1)
afforded the desired 3ma. Yellow oil, yield: 51% (19.9 mg); 1H NMR
(400 MHz, CDCl3, 300 K): δ (ppm) = 7.84−7.78 (m, 2H), 7.62 (s,
1H), 7.50−7.46 (m, 1H), 7.38−7.33 (m, 2H), 7.20 (s, 5H), 4.81−
4.91 (m, 1H), 2.18−2.10 (m, 1H), 1.92−1.82 (m, 1H), 1.72−1.67
(m, 2H), 1.58−1.50 (m, 1H), 1.46−1.38 (m, 1H), 1.27−1.01 (m,
3H), 0.93 (d, J = 6.6 Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H), 0.80 (d, J =
7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, 300 K): δ (ppm) =
194.0, 166.1, 141.3, 136.3, 135.5, 133.9, 133.5, 129.4, 129.0, 128.5,
128.4, 127.8, 76.1, 46.9, 40.7, 34.1, 31.4, 26.4, 23.5, 22.0, 20.7, 16.4;
IR (neat, cm−1): 545w, 701m, 753m, 909w, 978m, 1108w, 1213s,
1386m, 1446m, 1594s, 1672s, 1733s, 2868m, 2921s, 2946s, 3050w;
HRMS (ESI) exact mass calculated for C26H31O3: 391.2273 ([M +
H]+), found: 391.2269.
1
Yellow oil, yield: 61% (18.3 mg); H NMR (400 MHz, CDCl3, 300
K): δ (ppm) = 7.77−7.71 (m, 2H), 7.63 (s, 1H), 7.34−7.30 (m, 2H),
7.25−7.17 (m, 5H), 3.86 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3,
300 K): δ (ppm) = 192.4, 166.8, 140.8, 140.1, 135.7, 134.5, 133.5,
130.3, 129.3, 128.9, 128.8, 128.0, 52.9.
(E)-Methyl 4-(4-Bromophenyl)-4-oxo-2-phenylbut-2-enoate
(3ae).13a 3ae was synthesized according to GP1, with 1a (35.2 mg,
0.20 mmol, 2.0 equiv) and 2e (25.8 mg, 0.10 mmol, 1.0 equiv) in 1.0
mL of DCE for 7 h. Purification by silica gel chromatography (eluant:
petroleum ether/ethyl acetate 20:1 to 5:1) afforded the desired 3ae.
1
Yellow oil, yield: 65% (22.4 mg); H NMR (400 MHz, CDCl3, 300
K): δ (ppm) = 7.68−7.65 (m, 2H), 7.63 (s, 1H), 7.51−7.47 (m, 2H),
7.25−7.17 (m, 5H), 3.87 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3,
300 K): δ (ppm) = 192.7, 166.8, 140.8, 135.7, 134.9, 133.5, 131.9,
130.4, 129.3, 128.8, 128.0, 52.9.
(E)-2-(2-Methyl-5-nitro-1H-imidazol-1-yl)ethyl 4-Oxo-2,4-diphe-
nylbut-2-enoate (3na). 3na was synthesized according to GP1, with
1n (63.0 mg, 0.20 mmol, 2.0 equiv) and 2a (18.0 mg, 0.10 mmol, 1.0
equiv) in 1.0 mL of DCE for 7 h. Purification by silica gel
chromatography (eluant: petroleum ether/ethyl acetate 20:1 to 5:1)
(E)-Methyl 4-(4-Nitrophenyl)-4-oxo-2-phenylbut-2-enoate (3af).
3af was synthesized according to GP1, with 1a (35.2 mg, 0.20 mmol,
2.0 equiv) and 2f (22.5 mg, 0.10 mmol, 1.0 equiv) in 1.0 mL of DCE
for 7 h. Purification by silica gel chromatography (eluant: petroleum
ether/ethyl acetate 20:1 to 5:1) afforded the desired 3af. Yellow oil,
yield: 54% (16.8 mg); 1H NMR (400 MHz, CDCl3, 300 K): δ (ppm)
= 8.17−8.11 (m, 2H), 7.92−7.87 (m, 2H), 7.62 (s, 1H), 7.23−7.15
(m, 5H), 3.89 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, 300 K): δ
(ppm) = 192.4, 166.5, 150.2, 142.1, 140.6, 134.7, 133.3, 129.8, 129.4,
129.2, 128.1, 123.6, 53.1; IR (neat, cm−1): 492w, 605w, 675m, 692s,
788m, 866m, 926m, 1022m, 1100w, 1264s, 1308m, 1342s, 1542s,
1628m, 1663s, 1698m, 2842w, 2972m, 3077m, 3111w; HRMS (ESI)
exact mass calculated for C17H14NO5: 312.0872 ([M + H]+), found:
312.0865.
1
afforded the desired 3na. Yellow oil, yield: 40% (16.2 mg). H NMR
(400 MHz, CDCl3, 300 K): δ (ppm) = 7.96 (s, 1H), 7.80−7.76 (m,
2H), 7.67 (s, 1H), 7.52−7.48 (m, 1H), 7.39−7.35 (m, 2H), 7.25−
7.19 (m, 3H), 7.09−7.06 (m, 2H), 4.59 (q, J = 2.2 Hz, 4H), 2.04 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3, 300 K): δ (ppm) = 192.9,
166.0, 151.1, 139.5, 137.7, 136.0, 133.8, 133.2, 133.2, 129.1, 128.9,
128.8, 128.6, 128.2, 64.1, 44.8, 13.7; IR (neat, cm−1): 502w, 640w,
710s, 761m, 822m, 1039m, 1179s, 1273s, 1377s, 1429m, 1464s,
1533m, 1594w, 1663m, 1733s, 2834w, 2921w, 3050w, 3137w, 3441s;
HRMS (ESI) exact mass calculated for C22H20N3O5: 406.1403 ([M +
H]+), found: 406.1402.
(E)-Methyl 4-(3-Fluorophenyl)-4-oxo-2-phenylbut-2-enoate
(3ag). 3ag was synthesized according to GP1, with 1a (35.2 mg,
0.20 mmol, 2.0 equiv) and 2g (19.8 mg, 0.10 mmol, 1.0 equiv) in 1.0
mL of DCE for 7 h. Purification by silica gel chromatography (eluant:
petroleum ether/ethyl acetate 20:1 to 5:1) afforded the desired 3ag.
(E)-3,7-Dimethyloct-6-en-1-yl 4-Oxo-2,4-diphenylbut-2-enoate
(3oa). 3oa was synthesized according to GP1, with 1o (60.0 mg,
0.20 mmol, 2.0 equiv) and 2a (18.00 mg, 0.10 mmol, 1.0 equiv) in 1.0
mL of DCE for 7 h. Purification by silica gel chromatography (eluant:
petroleum ether/ethyl acetate 20:1 to 5:1) afforded the desired 3oa.
1
Yellow oil, yield: 63% (17.9 mg); H NMR (400 MHz, CDCl3, 300
K): δ (ppm) = 7.64 (s, 1H), 7.62−7.57 (m, 1H), 7.50−7.45 (m, 1H),
7.36−7.31 (m, 1H), 7.25−7.15 (m, 6H), 3.87 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3, 300 K): δ (ppm) = 192.3, 166.8, 141.1, 138.2,
135.5, 133.5, 130.2 (d, J = 8 Hz), 129.3, 128.8, 128.0, 124.8 (d, J = 3
Hz), 120.6 (d, J = 22 Hz), 115.3 (d, J = 22 Hz), 52.9; IR (neat,
cm−1): 519w, 623w, 692s, 779s, 917m, 969m, 1090w, 1178m, 1256s,
1446m, 1490m, 1602m, 1698m, 1733s, 2851w, 2972m, 3068w; HRMS
(ESI) exact mass calculated for C17H14FO3: 285.0927 ([M + H]+),
found: 285.0920.
(E)-Methyl 2-(4-(3-(((13S)-13-Methyl-6,7,8,9,11,12,13,14,15,16-
decahydrospiro[cyclopenta[a]phenanthrene-17,2′-[1,3]dioxolan]-
3-yl)oxy)propoxy)phenyl)-4-oxo-4-phenylbut-2-enoate (3la). 3la
was synthesized according to GP1, with 1l (109.2 mg, 0.20 mmol,
2.0 equiv) and 2a (18.0 mg, 0.10 mmol, 1.0 equiv) in 1.0 mL of DCE
for 12 h. Purification by silica gel chromatography (eluant: petroleum
ether/ethyl acetate 20:1 to 5:1) afforded the desired 3la. Yellow oil,
yield: 35% (22.3 mg); 1H NMR (400 MHz, CDCl3, 300 K): δ (ppm)
= 7.86−7.80 (m, 2H), 7.60 (s, 1H), 7.51−7.45 (m, 1H), 7.40−7.33
(m, 2H), 7.22−7.10 (m, 3H), 6.77−6.70 (m, 2H), 6.68 (dd, J = 8.6,
2.8 Hz, 1H), 6.61 (d, J = 2.7 Hz, 1H), 4.07 (td, J = 6.1, 4.0 Hz, 4H),
3.97−3.88 (m, 4H), 3.86 (s, 3H), 2.88−2.76 (m, 2H), 2.17 (dd, J =
6.7, 5.5 Hz, 2H), 2.06−1.99 (m, 1H), 1.89−1.75 (m, 3H), 1.62 (q, J =
6.8 Hz, 3H), 1.55−1.29 (m, 6H), 0.88 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3, 300 K): δ (ppm) = 193.9, 167.3, 159.2, 156.6, 140.0,
138.0, 136.3, 135.4, 133.6, 132.8, 130.9, 129.0, 128.5, 126.3, 126.0,
119.4, 114.5, 114.0, 112.0, 65.2, 64.6, 64.4, 64.2, 52.8, 49.3, 46.1, 43.6,
39.0, 34.2, 30.7, 29.8, 29.2, 27.0, 26.1, 22.3, 14.3; IR (neat, cm−1):
1
Yellow oil, yield: 69% (25.9 mg); H NMR (400 MHz, CDCl3, 300
K): δ (ppm) = 7.89−7.76 (m, 2H), 7.67 (s, 1H), 7.51−7.46 (m, 1H),
7.36 (dd, J = 8.4, 7.1 Hz, 2H), 7.20 (s, 5H), 5.12−5.03 (m, 1H),
4.36−4.25 (m, 2H), 2.04−1.90 (m, 2H), 1.77−1.71 (m, 1H), 1.67 (s,
3H), 1.60 (s, 3H), 1.56−1.46 (m, 2H), 1.39−1.31 (m, 1H), 1.24−
1.14 (m, 1H), 0.92 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3, 300 K): δ (ppm) = 193.7, 166.5, 140.8, 136.2, 136.0, 133.8,
133.6, 131.4, 129.4, 128.9, 128.5, 128.5, 127.8, 124.5, 64.5, 36.9, 35.3,
29.5, 25.7, 25.4, 19.4, 17.7; IR (neat, cm−1): 631w, 692m, 770m,
1013m, 1186m, 1247s, 1446m, 1585w, 1663m, 1715s, 2842w, 2921m,
2981m, 3050w; HRMS (ESI) exact mass calculated for C26H31O3:
391.2273 ([M + H]+), found: 391.2271.
(E)-(Z)-octadec-8-en-1-yl 4-Oxo-2,4-diphenylbut-2-enoate (3pa).
3pa was synthesized according to GP1, with 1p (82.5 mg, 0.20 mmol,
2.0 equiv) and 2a (18.0 mg, 0.10 mmol, 1.0 equiv) in 1.0 mL of DCE
for 12 h. Purification by silica gel chromatography (eluant: petroleum
ether/ethyl acetate 20:1 to 5:1) afforded the desired 3pa. Yellow oil,
yield:45% (22.6 mg); 1H NMR (400 MHz, CDCl3, 300 K): δ (ppm)
= 7.84−7.80 (m, 2H), 7.67 (s, 1H), 7.51−7.46 (m, 1H), 7.36 (dd, J =
8.4, 7.1 Hz, 2H), 7.20 (s, 5H), 5.41−5.29 (m, 2H), 4.26 (t, J = 6.7 Hz,
2H), 2.01 (q, J = 6.5 Hz, 4H), 1.70−1.65 (m, 2H), 1.32−1.25 (m,
22H), 0.88 (t, J = 6.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3,
300 K): δ (ppm) = 193.8, 166.5, 140.8, 136.2, 136.0, 133.8, 133.6,
130.0, 129.8, 129.4, 128.9, 128.5, 127.8, 66.0, 31.9, 29.7, 29.7, 29.7,
29.5, 29.4, 29.3, 29.2, 28.5, 27.2, 25.9, 22.7, 14.1; IR (neat, cm−1):
614w, 692s, 761m, 1004m, 1168m, 1247s, 1437m, 1602w, 1663s,
H
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1733s, 2851s, 2912s, 3050w; HRMS (ESI) exact mass calculated for
C34H47O3: 503.3525 ([M + H]+), found: 503.3517.
8.4, 7.4 Hz, 1H), 3.95 (t, J = 8.2 Hz, 1H), 3.53 (p, J = 7.8 Hz, 1H),
2.48 (dt, J = 12.6, 7.7 Hz, 1H), 2.33 (ddd, J = 12.6, 8.3, 5.8 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3, 300 K): δ (ppm) = 42.6, 141.7,
128.6, 128.4, 127.4, 127.2, 126.6, 125.7, 81.8, 75.1, 46.0, 43.7.
Formal Synthesis of ETA Receptor Radioligand 8.16 Step I:
To a 10 mL Schlenk flask equipped with a magnetic stir bar was
added 1q (0.2 mmol), 2i (0.1 mmol), and dry DCE (1.0 mL). The
resulting mixture was degassed using the freeze−pump−thaw
procedure (3 times). Then, the solution was stirred at a distance of
∼3 cm from a 24 W blue LED at room temperature for 7 h. The
solvent was removed by vacuum, and the crude product was purified
by flash chromatography on silica gel (silica: 200−300; eluant:
petroleum ether/ethyl acetate (20:1 to 5:1)) to give the pure product
3qi as a yellow oil in 56% yield. 1H NMR (400 MHz, CDCl3, 300 K):
δ (ppm) = 7.84−7.79 (m, 2H), 7.59 (s, 1H), 6.88−6.84 (m, 2H),
6.74 (d, J = 1.7 Hz, 1H), 6.66 (dd, J = 9.7, 7.9 Hz, 2H), 5.90 (s, 2H),
3.86 (s, 3H), 3.84 (s, 3H).; 13C{1H} NMR (100 MHz, CDCl3, 300
K): δ (ppm) = 192.23, 167.13, 163.98, 147.85, 147.22, 138.87,
136.53, 131.38, 129.25, 127.47, 123.62, 113.85, 109.83, 107.92,
101.14, 55.47, 52.80; IR (neat, cm−1): 588w, 718w, 831m, 944m,
1030m, 1090w, 1168m, 1230s, 1429m, 1481m, 1594m, 1663w, 1724m,
2842w, 2912w, 2955w. HRMS (ESI) exact mass calculated for
C19H17O6: 341.1025 ([M + H]+), found: 341.1039.
Synthesis of Pyridazine (4).15a Step I: A solution of 3aa (0.1
mmol) in ethanol (2 mL) was added to water (80 μL) containing 38
mg of ammonium acetate (0.5 mmol) at room temperature and
stirred vigorously with 3 mg of zinc powder (0.0375 mmol) added in
a period of 15 min. Stirring was continued for a further 4 h
(monitored by TLC). The suspended material was removed by
filtration and washed with ethanol. Then, the filtrate was evaporated
under reduced pressure nearly to dryness and then ice-cold water was
added to the residual material. After filtration, the crude product was
recrystallized from 95% ethanol to give methyl 4-oxo-2,4-diphenylbu-
tanoate in 92% yield (24.6 mg).
Step II: A solution of methyl 4-oxo-2,4-diphenylbutanoate (0.1
mmol) in EtOH (1.0 mL) was taken in an over-dried reaction tube,
and trifluoroacetic acid (100 μL) was added via a syringe. After
stirring at 30 °C for 5 min, hydrazine hydrate (10.0 μL, 0.2 mmol)
was added. The mixture was stirred for 12 h. The reaction mixture
was purified by flash chromatography on silica gel to afford the
desired pyridazine 4. White solid, yield: 91% (22.8 mg, known
1
compound, 84% over two steps); H NMR (400 MHz, CDCl3, 300
K): δ (ppm) = 9.07 (s, 1H), 7.77−7.66 (m, 2H), 7.45−7.38 (m, 3H),
7.38−7.25 (m, 5H), 3.83 (dd, J = 9.2, 7.3 Hz, 1H), 3.35−3.16 (m,
2H); 13C{1H} NMR (100 MHz, CDCl3, 300 K): δ (ppm) = 168.2,
150.9, 137.1, 135.4, 129.9, 129.0, 128.7, 127.8, 125.8, 42.4, 30.5.
Synthesis of Thiophene (5).15b Step I: A solution of 3aa (0.1
mmol) in ethanol (2 mL) was added to water (80 μL) containing 38.0
mg of ammonium acetate (0.5 mmol) at room temperature and
stirred vigorously with 3 mg of zinc powder (0.0375 mmol) added in
a period of 15 min. Stirring was continued for a further 1 h
(monitored by TLC). The suspended material was removed by
filtration and washed with ethanol. The filtrate was evaporated under
reduced pressure nearly to dryness and then ice-cold water was added
to the residual material. After filtration, the crude product was
recrystallized from 95% ethanol to give methyl 4-oxo-2,4-diphenylbu-
tanoate in 92% yield (24.6 mg).
Step II: A solution of 3qi (0.1 mmol) in ethanol (2 mL) was added
to water (80 μL) containing 38 mg of ammonium acetate (0.5 mmol)
at room temperature and stirred vigorously with 3.0 mg of zinc
powder (0.0375 mmol) added in a period of 15 min. Stirring was
continued for a further 4 h (monitored by TLC). The suspended
material was removed by filtration and washed with ethanol. The
filtrate was evaporated under reduced pressure nearly to dryness and
then ice-cold water was added to the residual material. After filtration,
the crude product was recrystallized from 95% ethanol to give 7 in
96% yield (24.6 mg). Note that compound 7 is the key synthetic
1
intermediate to the target ETA Receptor Radioligand 8. H NMR
(400 MHz, CDCl3, 300 K): δ (ppm) = 7.70−7.65 (m, 2H), 7.57−
7.52 (m, 2H), 7.43−7.33 (m, 4H), 7.29−7.26 (m, 1H), 7.25 (s, 1H),
7.25−7.20 (m, 1H), 4.00 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3,
300 K): δ (ppm) = 160.3, 134.5, 129.2, 128.9, 128.4, 126.8, 126.4,
124.8, 122.1, 61.8.
Step II: Lawesson’s reagent (81 mg) was added to a solution of
methyl 4-oxo-2,4-diphenylbutanoate (26.8 g, 0.1 mmol) in toluene (1
mL), and the mixture was stirred at 100 °C for 36 h. After cooling, the
mixture was filtered through Celite, the solvent was evaporated, and
the product was isolated by column chromatography on silica gel
(eluent hexane/AcOEt, 100:1) to give the product 5. White solid, mp
Synthesis of 9. To a 10 mL Schlenk flask equipped with a
magnetic stir bar was added 1a (0.2 mmol), 2a (0.1 mmol), styrene
(0.1 mmol), and dry DCE (2.0 mL).13a The resulting mixture was
degassed using the freeze−pump−thaw procedure (3 times). Then,
the solution was stirred at a distance of ∼3 cm from a 24 W blue LED
at room temperature. Upon the completion of the reaction, monitored
by TLC, the solvent was removed under vacuum. The crude product
was purified by flash chromatography on silica gel (silica: 200−300;
eluant:petroleum ether/ethyl acetate (20:1)) to obtain the pure
product 3aa as a yellow oil in 61% yield (16.2 mg) and 9 as colorless
oil in 15% yield (3.8 mg). 1H NMR of 9 (400 MHz, CDCl3, 300 K): δ
(ppm) = 7.13−7.07 (m, 3H), 7.05−6.99 (m, 5H), 6.78−6.73 (m,
2H), 3.63 (s, 3H), 3.11 (dd, J = 9.4, 7.3 Hz, 1H), 2.12 (dd, J = 9.3, 4.9
Hz, 1H), 1.86 (dd, J = 7.3, 4.9 Hz, 1H). 13C{1H} NMR of 9 (100
MHz, CDCl3, 300 K): δ (ppm) = 174.2, 136.3, 134.7, 131.9, 128.0,
127.6, 127.6, 126.9, 126.2, 52.5, 37.3, 33.0, 20.4.
1
= 92−94 °C, yield: 67% (17.8 mg, 62% over two steps). H NMR
(400 MHz, CDCl3, 300 K): δ (ppm) = 7.70−7.65 (m, 2H), 7.57−
7.52 (m, 2H), 7.43−7.33 (m, 4H), 7.29−7.26 (m, 1H), 7.25 (s, 1H),
7.25−7.20 (m, 1H), 4.00 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3,
300 K): δ (ppm) = 160.3, 134.5, 129.2, 128.9, 128.4, 126.8, 126.4,
124.8, 122.1, 61.8. IR (neat, cm−1): 492m, 580s, 683s, 753s, 926w,
1004m, 1230s, 1499s, 1602m, 1724w, 2841m, 2921m, 3015w. HRMS
(ESI) exact mass calculated for C17H15OS: 267.0838 ([M + H]+),
found: 267.0832.
Synthesis of Tetrahydrofuran (6).15c BH3·THF (1.0 mol/L, 1
mL, 5.0 equiv) was added to a dry Schlenk tube containing 3aa (26.8
mg, 0.1 mmol), and the solution was stirred at 40 °C for 4 h before
being quenched with MeOH carefully. The resulting mixture was
concentrated and dissolved in DCM (2 mL), and then the solution
was treated with BF3·Et2O (25 μL, 2.0 equiv) at room temperature for
2 h. The reaction was quenched with saturated NH4Cl and extracted
with DCM (3 × 5 mL). The combined organic extracts were dried
over anhydrous Na2SO4, filtered, and concentrated. The purification
by preparative TLC (petrol ether/EtOAc = 30:1) gave disubstituted
tetrahydrofuran 6 in 87% yield over two steps (22.4 mg, 1.4:1 d.r.,
known compound). For cis-isomer: 1H NMR (400 MHz, CDCl3, 300
K): δ (ppm) = 7.43−7.21 (m, 10H), 5.07 (dd, J = 10.2, 5.7 Hz, 1H),
4.36 (t, J = 8.2 Hz, 1H), 4.02 (t, J = 8.5 Hz, 1H), 3.64 (dq, J = 10.7,
8.2 Hz, 1H), 2.76 (ddd, J = 12.8, 7.3, 5.8 Hz, 1H), 2.01 (dt, J = 12.4,
10.5 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3, 300 K): δ (ppm) =
142.6, 141.7, 128.6, 128.4, 127.4, 127.2, 126.6, 125.7, 81.8, 75.1, 46.0,
43.7. For trans-isomer: 1H NMR (400 MHz, CDCl3, 300 K): δ (ppm)
= 7.39−7.21 (m, 10H), 5.23 (dd, J = 7.7, 5.8 Hz, 1H), 4.47 (dd, J =
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02500.
■
sı
Mechanism studies, experimental procedures, character-
1
ization data, and H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Zhong-Wen Pan − Anhui Province Key Laboratory of
Chemistry for Inorganic/Organic Hybrid Functionalized
Materials and Key Laboratory of Functional Inorganic
I
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Materials of Anhui Province, College of Chemistry &
Chemical Engineering, Anhui University, Hefei, Anhui
230601, People’s Republic of China; Email: ahpzw@
163.com
Jun Xuan − Anhui Province Key Laboratory of Chemistry for
Inorganic/Organic Hybrid Functionalized Materials and Key
Laboratory of Functional Inorganic Materials of Anhui
Province, College of Chemistry & Chemical Engineering,
Anhui University, Hefei, Anhui 230601, People’s Republic of
China; Key Laboratory of Structure and Functional
Regulation of Hybrid Materials (Anhui University), Ministry
of Education, Hefei 230601, People’s Republic of China;
orcid.org/0000-0003-0578-9330; Email: xuanjun@
ahu.edu.cn
Authors
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Cong Ye − Anhui Province Key Laboratory of Chemistry for
Inorganic/Organic Hybrid Functionalized Materials and Key
Laboratory of Functional Inorganic Materials of Anhui
Province, College of Chemistry & Chemical Engineering,
Anhui University, Hefei, Anhui 230601, People’s Republic of
China
Bao-Gui Cai − Anhui Province Key Laboratory of Chemistry
for Inorganic/Organic Hybrid Functionalized Materials and
Key Laboratory of Functional Inorganic Materials of Anhui
Province, College of Chemistry & Chemical Engineering,
Anhui University, Hefei, Anhui 230601, People’s Republic of
China
Juan Lu − Anhui Province Key Laboratory of Chemistry for
Inorganic/Organic Hybrid Functionalized Materials and Key
Laboratory of Functional Inorganic Materials of Anhui
Province, College of Chemistry & Chemical Engineering,
Anhui University, Hefei, Anhui 230601, People’s Republic of
China
Xiao Cheng − Anhui Province Key Laboratory of Chemistry
for Inorganic/Organic Hybrid Functionalized Materials and
Key Laboratory of Functional Inorganic Materials of Anhui
Province, College of Chemistry & Chemical Engineering,
Anhui University, Hefei, Anhui 230601, People’s Republic of
China
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Lei Li − Anhui Province Key Laboratory of Chemistry for
Inorganic/Organic Hybrid Functionalized Materials and Key
Laboratory of Functional Inorganic Materials of Anhui
Province, College of Chemistry & Chemical Engineering,
Anhui University, Hefei, Anhui 230601, People’s Republic of
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02500
Author Contributions
§C.Y. and B.-G.C. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Nos. 21971001 and 21702001) and the Start-up Grant
from Anhui University for financial support of this work.
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116, 10075−10166. (d) Marzo, L.; Pagire, S. K.; Reiser, O.; Konig, B.
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D.-G.; Zhu, C.-J.; Xiao, W.-J. Visible light-driven organic photo-
chemical synthesis in China. Sci. China: Chem. 2019, 62, 24−57.
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