Synthesis and singlet oxygen reactivity of 1,2-diaryloxyethenes and selected sulfur and nitrogen analogs

Article abstract of DOI:10.1111/j.1751-1097.2012.01095.x

1,2-Diaryloxyethene has recently been proposed as a linker in singlet oxygen-mediated drug release. Even though 1,2-diaryloxyethenes look very simple, their synthesis was not an easy task. Previous methods are limited to symmetric molecules, lengthy step and low yield. We report on a facile synthetic method not only for 1,2-diaryloxyethenes but also their sulfur and nitrogen analogs in yields ranging from 40 to 90% with more than 90% purity at the vinylation reaction. Most recently, light-controlled drug release systems were proposed, where singlet oxygen generated from low energy light and a photosensitizer cleaves electron-rich alkenes, e.g. 1,2-diaryloxyethene. However, the synthesis of 1,2-diaryloxyethene was not well established. Herein, we report a facile synthesis of 1,2-diaryloxyethenes and its sulfur and nitrogen analogs. Model compounds were prepared in four steps from 4-phenylphenol via Ullman-type coupling reaction.

Full text of DOI:10.1111/j.1751-1097.2012.01095.x

Photochemistry and Photobiology, 2012, 88: 753–759
Research Note
Synthesis and Singlet Oxygen Reactivity of 1,2-Diaryloxyethenes and
Selected Sulfur and Nitrogen Analogs
Gregory Nkepang1,2, Praveen K. Pogula3, Moses Bio1,2 and Youngjae You*1,2
1Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK
2Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK
3Department of Chemistry and Biochemistry, South Dakota State University, Brookings, SD
Received 17 October 2011, accepted 16 January 2012, DOI: 10.1111/j.1751-1097.2012.01095.x
ethers (20–23), all the synthetic processes are limited only for
symmetric molecules and to procedures that lead to low yield
ABSTRACT
1,2-Diaryloxyethene has recently been proposed as a linker in
singlet oxygen-mediated drug release. Even though 1,2-diaryl-
oxyethenes look very simple, their synthesis was not an easy
task. Previous methods are limited to symmetric molecules,
lengthy step and low yield. We report on a facile synthetic
method not only for 1,2-diaryloxyethenes but also their sulfur
and nitrogen analogs in yields ranging from 40 to 90% with more
than 90% purity at the vinylation reaction.
or nonstereospecificity (mixture of Z and E isomers) (17–19).
Lengthy multiple steps are also required and some of the
processes required harsh reaction conditions. For example,
1,2-diphenoxyethene has been synthesized from ethylene
chlorohydrins in a seven step sequence involving high pressure
and temperature (24). The other method for the same
compound involved chlorination and dehydrochlorination of
1,2-diphenoxyethane (18). This method is limited for the
synthesis of symmetric molecules and yields a mixture of E and
Z products in low yields. The most recent method for the
preparation of 1,2-diphenoxyethene and derivatives involved
bromination followed by stereospecific debromination to give
either E- or Z- product (17). This method is also limited to
symmetric 1,2-diaryloxyethenes using harsh conditions and
providing low yields.
Recently, light-controlled drug release has attracted much
attention for new drug delivery systems (12,15,25,26). How-
ever, the limited synthetic methods for 1,2-diheteroatom-
substituted olefins have been one of the major hurdles. Thus,
versatile, efficient and stereospecific synthetic routes should be
developed for these applications. Herein, we describe the first
facile synthetic approach for E-1,2-diheteroatom-substituted
olefins (R-O[H]C=CX[H]-R¢: X = O, N, or S, Scheme 1). It
is a versatile, efficient and stereospecific method in as few as
four steps from starting materials. We have been able to
demonstrate that the chemistry can be used for preparation of
both symmetrically (R-O[H]C=C[H]O-R) and asymmetrically
diheteroatom-substituted (R-O[H]C=C[H]O-R¢, R-O[H]C=
C[H]S-R¢; R-O[H]C=C[H]N-R¢) olefins from a variety of
common functional groups such as –OH, –NH and SH. The
photooxidation of those olefins that were not tested in our
previous article is also reported.
INTRODUCTION
Electron-rich olefins can be used as reagents in organic
synthesis. Among other things vinyl ethers are reagents for
cycloadditions (1,2), cyclopropanations (3) and polymer syn-
theses (4). Vinyl amines are also used in the preparation of
polymer dyes, and catalysis and ion-exchange resins. Singlet
oxygen being an electrophilic reagent can react with electron-
rich olefins via ene reactions and 1,2-cycloadditions, and with
conjugated dienes via 1,4-cycloadditions. 1,2-Cycloaddition
reactions of singlet oxygen to olefinic bonds form dioxetanes
that spontaneously fragment to generate two carbonyl prod-
ucts (Scheme 2; 5–10). The 1,2-cycloaddition reaction of
singlet oxygen has been proposed for phototriggerable drug
delivery systems in the form of liposomes, cyclodextrin
complexes and prodrugs (11–13). Screening of various 1,2-
substituted olefins resulted in the choice of 1,2-dioxy, 1,2-
dithioxy, 1-oxy and 1-thioxy olefins (vinyl groups activated by
heteroatoms) for the singlet oxygen-cleavable linkers (14). In
particular, 1,2-diaryloxyethene was proposed for site specific
prodrug release and its singlet oxygen-mediated cleavage in
solutions was demonstrated (15).
While considerable efforts have recently been made to
develop synthetic methods for monosubstituted olefins (16),
there have been a number of publications for the syntheses of
1,2-diheteroatom-substituted olefins (17–19). With the excep-
tion of (2-aryloxyvinyl)phenyl sulfanes, which were synthe-
sized by the reaction of benzenesulfenyl chloride with vinylaryl
MATERIALS AND METHODS
All solvents and reagents were used as obtained from Sigma–Aldrich
and Thermo Fisher Scientific unless otherwise stated. All reactions
were monitored by TLC using 5–17 lm silica gel plates with
fluorescent indicators from Sigma–Aldrich. All column chromatogra-
phy was carried out using 40–63 lm silica gel from Sorbent Technol-
ogies. NMR spectra were recorded at 25ꢀC using a 300 or 400 MHz
Spectrometer. NMR solvents with residual solvent signals were used as
*Corresponding author email: youngjae-you@ouhsc.edu (Youngjae You)
ꢁ 2012 Wiley Periodicals, Inc.
Photochemistry and Photobiology ꢁ 2012 The American Society of Photobiology 0031-8655/12
753

754 Gregory Nkepang et al.
Scheme 1. Synthetic route for vinyl diether and its analogs.
internal standards. ESI mass spectrometry was collected at facilities at
South Dakota State University, University of Oklahoma, or Univer-
sity of Buffalo. IR spectra were recorded on a BioRad FT-155FT-IR
spectrometer (using dichloromthane as solvent). Melting points were
determined using a Mel-tempꢂ Electrothermal instrument. Elemental
analyses were performed at Atlantic Microlab, Inc. HPLC analysis was
performed with HP Agilent 1100 (Column: Thermo Fisher Scientific,
Hypersil, BDS 5 lm, C18 column, 5 lm particle size, 250 mm
length · 4.6 mm inner diameter; mobile phase: 90 ⁄ 10 [acetoni-
trile ⁄ water]; flow rate: 1 mL min)1; detection: 254 nm). Photooxida-
tion of olefins were performed using 690 nm diode laser (model #:
MRL-690[FC], Changchun New Industries).
(150 mL · 3). The combine organic phases were dried over anhydrous
magnesium sulfate, filtered and concentrated using the rotary evapo-
rator to give yellowish brown oil. Silica gel (200 g) column chroma-
tography was carried out using hexane as eluent to afford 2 (10.5 g,
85%) as colorless oil that later crystallized to white crystals: mp
52–55ꢀC. 1H NMR (300 MHz, CDCl3): 7.62–7.54 (m, 4H, HAr),
7.48–7.41 (m, 2H, HAr), 7.39–7.32 (m, 1H, HAr), 7.18–7.12 (m, 2H, HAr),
6.00 (s, 1H, HC(Cl)=C(O)) ppm; 13C NMR (75 MHz, CDCl3): 153.3,
140.2, 137.8, 128.8, 128.5, 127.3, 127.0, 117.4, 103.9 ppm; IR (cm)1):
3105, 3031, 1898, 1658, 1630, 1603, 1585, 1543, 1310, 1203, 1184, 1107,
1074, 1008, 996, 915, 863, 840, 641, 547, 511; HRMS (ESI) calculated
for C14H10Cl2O [M-H]) 263.0031; found 263.0030; elemental analysis
calculated for C14H20Cl2O.0.02H2O: C, 63.33; H, 3.81; found: C,
63.34; H, 3.79.
4-(Ethynyloxy)-1,1¢-biphenyl (3). To a two-necked, round-bot-
tomed flask (100 mL) equipped with a nitrogen inlet adapter and rubber
septum was added the vinyl ether 2 (2.0 g, 7.6 mmoL, 1 eq), anhydrous
diethyl ether (30 mL) and TMEDA (23 mmoL, 3.3 mL, 3 eq), and then
cooled at )78ꢀC. 2.5 M n-Butyllithium (9.0 mL, 23 mmoL, 3 eq) was
then added drop-wise to the reaction mixture for over 5 min. The
reaction mixture was then maintained at )78ꢀC and )40ꢀC for 1 h and
40 min respectively, and then cooled to )78ꢀC, whereas 10% ethanol in
pentane (10 mL) was added drop-wise. After 10 min, the reaction
mixture was then diluted with n-pentane (20 mL) and then washed with
saturated solution of ammonium chloride (25 mL). The organic phase
was later washed twice with water (20 mL) and then finally with brine
(20 mL), dried over anhydrous sodium sulfate, filtered and concentrated
to give brown oil. The oil was purified by column chromatography with
4-((1,2-Dichlorovinyl)oxy)-1,1¢-biphenyl (2). To
a two-necked,
round bottom flask (250 mL) equipped with a magnetic stirrer,
pressure equalizing funnel and rubber septum was suspended in oil
free potassium hydride (2.23 g, 55 mmoL, 1.5 eq) in tetrahydrofuran
(THF, 25 mL). 4-Phenylphenol (6.30 g, 37 mmoL, 1 eq) in THF
(50 mL) was then added drop-wise with stirring for over 20 min via the
funnel. After the evolution of hydrogen was complete, the orange-
yellow slurry was cooled to )78ꢀC, and then treated with drop-wise
solution of trichloroethylene (5.8 g, 44 mmoL, 1.2 eq) in THF (25 mL)
for over 10 min. The cooling bath was removed and the reaction
mixture was allowed to warm to room temperature (rt) and then
maintained for overnight (12 h). To the dark brown mixture was
carefully added water (10 mL) using a syringe and then partitioned
between water (200 mL) and ethyl acetate (200 mL). The organic
phase was then washed with brine (200 mL). Extraction of the
combined aqueous layers was carried out using ethyl acetate

Photochemistry and Photobiology, 2012, 88 755
hexane as the eluent to yield 3 as dark brown oil (0.84 g, 70%) that later
crystallized out as brown amorphous solid: mp 48–49ꢀC. The com-
pound was placed in a round bottom flask and flushed with nitrogen
and kept at )78ꢀC to avoid the decomposition if it was not to be used
immediately. 1H NMR (300 MHz, CDCl3): 7.64–7.52 (m, 4H, HAr),
7.48–7.41 (m, 2H, HAr), 7.40–7.34 (m, 3H, HAr), 2.13 (s, 1H,”–H)
ppm; 13C NMR (75 MHz, CDCl3): 155.0, 140.1, 138.0, 128.9, 128.4,
127.4, 127.0, 115.4, 84.5, 33.5 ppm; IR (cm)1): 3317 (”C–H), 3029,
2927, 2174 (C”C), 1606, 1512, 1484, 1208, 1166, 1062, 1008, 941, 838,
641, 548, 450; HRMS (ESI) calculated for C14H10O [M-H]) 193.0654;
found 193.0651; elemental analysis calculated for C14H10O.0.13H2O: C,
85.54; H, 5.26; found: C, 85.54; H, 5.38.
filled with nitrogen and compound 4 (0.32 g, 1 mmoL) added at rt. The
reaction mixture was stirred and heated to the required temperature of
80ꢀC for the 48 h. After cooling to rt, the mixture was diluted with
dichloromethane (20 mL) and filtered through a plug of celite, with the
filter cake being further washed with dichloromethane (10 mL). The
filtrate was washed with saturated NH4Cl (15 mL), and twice with water
(10 mL). The collected aqueous phases were extracted twice with
dichloromethane (10 mL). The organic layers were collected, dried over
MgSO4, filtered, and concentrated in vacuo to yield brown solid. The
crude product was fixed with 6 g silica gel and then purified using silica
gel chromatography (100% hexane) to afford 6 a white solid (0.20 g
65%): mp 59–62ꢀC. 1H NMR (300 MHz, CDCl3) 7.59–7.52 (m, 4H,
HAr), 7.46–7.40 (m, 2H, HAr), 7.38–7.33 (m, 3H, HAr), 7.15–7.09 (d,
2H, J = 8.5 Hz, HAr), 7.02–6.97 (d, 2H, J = 8.6 Hz), 6.91 (s, 2H,
CH=CH), 1.32 (s, 9H, 3 x –CH3) ppm; 13C NMR (75 MHz, CDCl3)
157.2, 155.3, 145.6, 140.6, 135.7, 135.3, 134.2, 128.8, 128.4, 127.0, 126.8,
126.5, 116.0, 115.3, 34.3, 31.5 ppm; IR (cm)1): 3052, 2961, 2931, 2867,
1607, 1512, 1487, 1367, 1298, 1229, 1187, 1127, 1105, 1079, 1006, 839,
723; HRMS(ESI), calculated for C24H24O2 [M+H]+ 345.1854; found
345.1849; elemental analysis calculated for C24H24O2.1.25H2O: C,
78.55; H, 7.01; found: C, 78.55; H, 7.27.
(E)-4-((2-Iodovinyl) oxy)-1,1¢-biphenyl (4). To an oven dried,
two-necked flask (250 mL) under nitrogen and protected from light
was added Cp2ZrCl2 (5.2 g, 20.3 mmoL, 2 eq), dry THF (30 mL) and
1 M lithium triethylborohydride (super hydride) in THF (20 mL,
20 mmoL, 1.9 eq). The mixture was stirred for 1 h where the alkyne 3
(1.97 g, 10.2 mmoL, 1 eq) was added. After 30 min, iodine (2.57 g,
20.3 mmoL, 2 eq) was added and the reaction mixture was stirred for
30–40 min, protected from light. The reaction was quenched by
diluting with ethyl acetate ⁄ hexane (1:1, 50 mL). The diluted mixture
was then washed twice with saturated solution of sodium bicarbonate
(150 mL) and the combined aqueous layers were extracted with ethyl
acetate ⁄ hexane mixture (1:1). Ten percentage aqueous sodium thio-
sulphate (100 mL) was used to wash the combined organic phases
followed by brine (100 mL), dried over sodium sulfate, filtered,
concentrated to yellowish slurry, which was purified by silica gel
column chromatography using 100% hexane as eluent (silica gel was
pretreated with 2.5% vol ⁄ vol triethylamine) to afford 4 as white
(E)-4-[2-(4-Methoxyphenoxy)vinyloxy]biphenyl (7). Compound
7 was prepared according to the general method described for
compound 6 elsewhere, employing 4 (0.2 g, 0.62 mmoL, 1 eq) and 4-
methoxyphenol (0.077 g, 0.62 mmoL,
1 eq), Cs2CO3 (0.50 g,
1.6 mmoL, 2.5 eq), CuI (0.59 g, 0.31 mmoL, 0.5 eq) and L1
(0.057 g, 0.31 mmoL, 0.5 eq) heating the reaction mixture at 80ꢀC
for 48 h to furnish the crude product, which was purified by column
chromatography using hexane as the eluent to afford 7 as white
crystals (40 mg, 40%): mp 112–115ꢀC. 1H NMR (300 MHz, CDCl3):
7.61–7.52 (m, 4H, HAr), 7.47–7.40 (m, 2H, HAr), 7.36–7.30 (m, 1H,
HAr), 7.10 (d, 2H, J = 8.6 Hz), 7.00 (d, 2H, J = 9.0 Hz), 6.91–6.84
(m, 4H, HAr and HC(O) = C(O)H), 3.80 (s, 3H, –CH3) ppm. 13C
NMR (75 MHz, CDCl3): 156.3, 154.3, 150.5, 139.5, 135.6, 135.1,
132.7, 131.4, 129.0, 127.8, 127.3, 125.8, 116.1, 115.0, 113.8, 54.7 ppm;
IR(cm)1): 3059, 1658, 1605, 1517, 1485, 1420, 1319, 1264, 1226, 1173,
1122, 896, 838, 737, 639; HRMS(ESI), calculated for C21H18O3 [M-H])
317.1178; found 317.1158; HPLC analysis: 92% purity.
1
amorphous crystals (1.80 g, 55%): mp 64–66ꢀC. H NMR (300 MHz,
CDCl3): 7.64–7.52 (m, 4H, HAr), 7.49–7.41 (m, 2H), 7.38–7.32 (m, 1H,
HAr), 7.13–7.01 (m, 3H, HAr), 5.74 (s, 1H, CH=CH, J = 12.2 Hz)
ppm; 13C NMR (75 MHz, CDCl3): 155.5, 150.3, 140.3, 137.0, 128.9,
128.4, 127.2, 126.9, 117.5, 57.9 ppm; IR (cm)1): 3316, 3077, 3034,
2960, 2924, 2874, 2174, 1643, 1623, 1601, 1515, 1485, 1330, 1307, 1226,
1186, 1173, 1093, 1008, 919, 854, 837, 697, 579, 549.
General procedure for coupling reactions using 2-pyridin-2yl-1H-
benzoimidazole (L2): (E)-4-((2-(Phenoxy) vinyl) oxy)-1,1¢-biphenyl (5).
An oven dried, three-necked, round-bottomed flask (50 mL) equipped
with a nitrogen inlet, reflux condenser, rubber septum was repeatedly
evacuated and back-filled with dry and pure nitrogen, and was then
charged with CuI (0.074 g, 0.39 mmoL, 0.5 eq), L2 (0.076 g,
0.39 mmoL, 0.5 eq) and Cs2CO3 (0.63 g, 2.0 mmoL, 2.5 eq), followed
by addition of DMF (2 mL). The solution was stirred for 10 min at rt
until reaction turn light green color. The appropriate substrate phenol
(0.073 g, 0.78 mmoL, 1 eq) was added to the reaction mixture and then
stirred for additional 5 min at rt. Compound 4 (0.25 g, 0.78 mmoL,
1eq) was dissolved in minimum amount of solvent and then added into
the reaction mixture. The reaction mixture was then heated from rt to
between 50 and 75ꢀC for 12–36 h depending on the substrate. The
reaction mixture was cooled and then through pad of silica gel using
ethyl acetate and hexane mixture (20:80, 100 mL) and then washed
three times with the same solvent mixture (100 mL). The filtrate was
washed with water (100 mL · 3) followed with brine (200 mL), dried
using anhydrous sodium sulfate and concentrated in vacuo to yield
brown oil. The crude oil was then purified by silica gel column
chromatography using 100% hexane to afford 5 as white crystals.
(0.18 g, 70%): mp 60–63ꢀC. 1H NMR (300 MHz, CDCl3): 7.59–7.54
(m, 4H, HAr), 7.47–7.40 (m, 2H, HAr), 7.37–7.31 (m, 1H, HAr), 7.16–
7.03 (m, 7H), 6.92 (s, 2H, HC=CH); 13C NMR (75 MHz, CDCl3):
157.6, 157.2, 140.4, 135.8, 134.9, 134.6, 129.7, 128.8, 128.4, 127.0,
126.9, 122.7, 116.0, 115.8; IR (cm)1): 3061, 2962, 2870, 1606, 1510,
1485, 1419, 1365, 1230, 1183, 1174, 1124, 1105, 1006, 896, 836, 728;
HRMS (ESI), calculated for C20H16O2 [M-H]) 287.1072; found
287.1053; HPLC analysis: 91% purity.
(E)-(2-([1,1¢-Biphenyl]-4-yloxy)vinyl)(phenyl)sulfane (8). The
compound 8 was prepared according to the general procedure
described for the compound
6 elsewhere employing 4 (0.15g,
0.47 mmoL, 1 eq) and thiophenol (0.051g, 0.05 mL, 0.47 mmoL, 1
eq), Cs2CO3 (0.38 g, 1.2 mmoL, 2.6 eq), CuI (0.044 g, 0.23 mmoL,
0.49 eq) and L1 (0.042 g, 0.23 mmoL, 0.49 eq) heating the reaction
mixture at 60ꢀC for 10 h to give crude product, which was purified
using silica gel column chromatography (100% hexane) to give
compound 8, as white crystals (0.12 g, 90%). (When a mixture of Z
and E-4 [1:9] was used as the starting material under same conditions
at a temperature above 100ꢀC afforded a mixture of Z and E-8 [1:9].
They were distinguished from each other by their coupling constants.
Jcis = 5.7 Hz, whereas Jtrans = 12 Hz (1H-NMR data of these mix-
tures are found elsewhere.) The characterization data below is that of 8
1
obtained from the reaction 4 with thiophenol: mp 92–96ꢀC. H NMR
(300 MHz, CD2Cl2): 7.66–7.54 (m, 4H, HAr), 7.48–7.40 (m, 2H, HAr),
7.37–7.28 (br s, 6H, HAr), 7.20–7.09 (m, 3H, HAr), 6.09–6.10 (d, 2H
CH = CH, J = 12.0 Hz) ppm; 13C NMR (300 MHz, CDCl3): 155.9,
150.6, 140.3, 137.5, 137.1, 128.9, 128.8, 128.5, 127.2, 127.0, 126.9,
125.7, 117.4, 102.1; IR(cm)1): 3054, 2985, 1659, 1624, 1599, 1515, 1485,
1265, 1233, 1185, 1174, 1112, 1086, 1025, 1007, 924, 839, 739, 407;
HRMS (ESI) calculated for C20H16OS[M+H]+ 305.1000; found
305.0998; elemental analysis calculated for C20H16OS. 0.11 H2O: C,
78.40; H, 5.34; found: C, 78.40; H, 5.29.
(E)-1-(2-([1,1¢-Biphenyl]-4-yloxy)vinyl)-1H-indole (9). The com-
pound 9 was prepared following the procedure described for 5 with 4
(0.32 g, 1 mmoL, 1 eq), indole (0.14 g, 1.2 mmoL, 1.2 eq), Cs2CO3
(0.81 g, 2.5 mmoL, 2.5 eq), CuI (0.095 g, 0.5 mmoL, 0.5 eq) and L2
(0.097 g, 0.5 mmoL, 0.5 eq) at 70ꢀC for 12 h to give crude products,
which were purified by silica gel column chromatography using ethyl
acetate-hexane (9:95) to afford compound 9 as white crystals (0.27 g,
87%): mp 140–142ꢀC. 1H NMR (300 MHz, CDCl3): 7.58–7.46 (m, 6H,
HAr), 7.40–7.32 (m, 3H, HAr), 7.25–7.21 (m, 1H, HAr), 7.20–7.14 (m,
2H, HAr), 7.12–7.02 (m, 4H, HAr and H(O)C=(N)CH), 6.55 (d, H,
J = 3.1 Hz, HAr). 13C NMR (75 MHz, CDCl3): 156.8, 140.4, 136.5,
136.4, 128.9, 128.8, 128.5, 127.1, 126.9, 125.7, 125.6, 121.2, 120.5,
General procedure for coupling reactions using trans-N-(2-
pyridylmethylene)aniline (L1): (E)-4-((2-(4-(Tert-butyl)phenoxy)
vinyl)oxy)-1,1¢-biphenyl (6). An oven dried, three-necked, round-
bottomed flask (50 mL) equipped with a nitrogen inlet, reflux con-
denser, rubber septum was repeatedly evacuated and back-filled with
dry and pure nitrogen, and was then charged with CuI (0.095 g,
0.5 mmoL), L1 (0.09 g, 0.5 mmol), tert-butyl phenol (0.18 g 1.2 mmoL)
and Cs2CO3 (0.81 g, 2.5 mmoL), followed by the addition of anhydrous
and degassed acetonitrile (1.2 mL). The flask was evacuated and back-

756 Gregory Nkepang et al.
116.5, 115.2, 109.8, 104.0 ppm; IR (cm)1): 3034, 2358, 2338, 1682,
1606, 1515, 1485, 1475, 1462, 1358, 1333, 1322, 1301, 1232, 1202, 1186,
1174, 1134, 1115, 1088, 1031, 1007, 907, 865, 834; HRMS (ESI),
calculated for C22H17NO [M+H]+ 312.1388; found 312.1381; ele-
mental analysis calculated for C22H17NO.0.25H2O: C, 83.65; H, 5.58;
N, 4.43; found: C, 83.61; H, 5.65; N, 4.01.
Table 1. Copper-catalyzed vinylation of nucleophiles.
I
XR
H
H
10% CuI, 10% Ligand
2 eq. Cs2CO3, 1 eq. HXR
50-80 oC, 10-48 h
H
H
O
(E)-1-[2-(Biphenyl-4-yloxyl)vinyl]-1H pyrrole (10). The com-
pound 10 was prepared following the procedure described for 5 with 4
(0.2 g, 0.62 mmoL, 1 eq), pyrrole (0.062 g, 0.93 mmoL, 1.5 eq), Cs2CO3
(0.40 g, 1.2 mmoL, 2.5 eq), CuI (0.059 g, 0.31 mmoL, 0.5 eq) and L2
(0.060 g, 0.31 mmoL, 0.5 eq) at 70ꢀC for 12 h to give crude products,
which were purified by silica gel column chromatography using ethyl
acetate-hexane (9:95) to afford compound 10 as white crystals (0.14 g,
85%): mp 102–105ꢀC. Olefinic protons coupling on the named com-
pound gave an AB system with a typical roof effect with peaks centered
at 7.04 and 6.99 ppm. 1H NMR (300 MHz, CDCl3): 7.62–7.53 (m, 4H,
HAr), 7.48–7.40(m, 2H, HAr), 7.38–7.31(m, 1H, HAr),7.17–7.09(m, 2H,
HAr), 7.04 (distorted d, 1H, J = 11.1 Hz, (O)-CH=CH(N)), 6.99
(distorted d, 1H, J = 11.1 Hz, (O)-CH=CH(N)), 6.82 (dd, 2H, J1 =
4.2 Hz, J2 = 2.2 Hz, CH=CH of pyrrole), 6.28 (dd, 2H, J1 = 4.2 Hz,
J2 = 2.2 Hz, CH=CH); 13C NMR (75 MHz, CDCl3): 156.8, 140.4,
136.3, 135.0, 128.8, 128.4, 127.1, 126.9, 119.6, 118.3, 116.5, 110.0 ppm; IR
(cm)1): 3086, 3034, 2715, 2682, 1659, 1607, 1587, 1517, 1485, 1360, 1326,
1300, 1239, 1229, 1185, 1173, 1119, 1094, 1072, 1056, 1007, 975, 907, 857,
838, 614; HRMS (ESI) calculated for C18H15NO [M+H]+ 262.1232;
found 262.1233; elemental analysis calculatedfor C18H15NO.0.17H2O: C,
81.77; H 5.85; N, 5.29; found: C, 81.76; H, 5.91; N, 5.03.
General photooxidation procedure. In a NMR tube, an olefin
(0.0048 mmoL) was dissolved in CDCl3 (0.5 mL). The photosensitizer
[5-(4-methoxyphenyl)-10,15,20-triphenyl-21-23-dithiaporphyrin, CMP-
OMe, 3 mg, 0.0048 mmoL] was added to this solution. The reaction
mixture was irradiated for 15 min using a diode laser (690 nm,
200 mW cm)2). The reaction of olefins with singlet oxygen was
monitored by the decrease of olefinic peaks in 1H-NMR spectra. The
formation of photooxidation products were also determined by appear-
ance of the formate (or thioformate) peaks in 1H-NMR spectra.
O
4
5-10
Product
Substrate
(HXR)
Ligand
Yield (%)
[rx. temp (oC), time (h)]
65
70
L1 a (75, 36)
OH
5
6
L2b (75, 16)
OH
L1 (80, 48)
65
OH
7
8
L1 (80, 48)
L1 (60, 10)
40
90
MeO
SH
9
L2 (70, 12)
L2 (65, 12)
87
85
N
H
H
N
10
a L1 = trans-N-(2-pyridylmethylene)aniline.
b L2 = 2-pyridin-2-yl-benzoimidazole.
16–48 h of reaction time and yields were poor–good (40–
70%). Further optimization of reaction conditions for these
low yielding coupling reactions will be pursued. Reaction
with the azole derivatives required low temperatures between
50 and 75ꢀC and shorter reaction time, 12 h. The yields for 9
and 10 were very good (87% and 85% respectively). Our
methodology encountered, however, a limitation in the case
of aniline. Coupling using aniline substrate gave an extremely
low yield that the product could not be isolated. In all of
these reactions, the products gave single isomers (E-1,2-
diheteroatom-substituted olefins) as only the 4 was used for
RESULTS AND DISCUSSION
For the synthesis of the 1,2-diheteroatom-substituted olefins, a
four-step scheme was developed where 4-phenylphenol 1 was
used in one side. First, 4-phenylphenol was vinylated using
1,1,2-trichloroethylene (27) to give the corresponding 4-((1,2-
dichlorovinyl)oxy)-1,1¢-biphenyl 2 with yield of more than
85% (28,29). 4-(ethynyloxy)-1,1¢-biphenyl 3 was prepared by
elimination reaction using n-BuLi in 70% yield (28,29).
Although 1 was used in this article, other types of alcohols
and phenols can also be converted to the alkyne form (28).
Hydrozirconation and iodinolysis of 3 led to 2-iodoenol ether
4 in 55% yield (30,31). Using the copper-catalyzed coupling
reaction, 4 were linked with various substrates bearing the
different functional groups (16,32,33).
The reaction with thiophenol gave the best yield (8: 90%)
and short reaction time followed by reactions with aromatic
amines (9: 87%, 10: 85%) and least yield by the reaction with
phenols (compounds 5, 6 and 7). The trend could be
explained by the relative nucleophilicity of the substracts
(–SH > –NH > –OH; Table 1). Two coupling conditions were
used; either trans-N-(2-pyridylmethylene)aniline as ligand in
acetonitrile as solvent (16,34) or 2-pyridin-2-yl-benzoimidaz-
ole as ligand in DMF as solvent (33). For the compound 5,
slightly better yields were obtained using the latter coupling
condition and the reaction time was reduced to 16 h
compared to the former condition (36 h). To test the
robustness of our method, some selected analogs of the
phenolic and azole derivatives were synthesized. Phenolic
derivatives required high temperatures of 70–80ꢀC for
the coupling (33). This is
a well-known Ullmann-type
coupling reaction, which proceed in stereospecific fashion
(32,33). The stereospecificity of the reaction was also sup-
ported by the fact that a mixture of E ⁄ Z-4 (9:1) at >100ꢀC
gave a mixture of E ⁄ Z-8 at the same ratio of 9:1 (NMR Data
S1, Supporting Information).
Unlike typical coupling constants of 12–18 Hz for protons
at E-olefins and 6–12 Hz at Z-counterparts, the coupling
constants of the hydrogen atoms on 1,2-diheteroatom-substi-
tituted olefins were found to be reduced and in some cases even
to zero. Only a peak was observed from 1,2-diaryloxyalkenes
(5, 6 and 7) where the two olefinic protons are in very similar
environment. On the other hand, whereas 8 showed doublet
peaks, 10 showed distorted doublet peaks (AB system): E-8
(J = 12 Hz), Z-8 (J = 5.3 Hz), E-10 (J = 11.1 Hz). Such
unusual small coupling constants of olefins were also observed
in monohetereoatom-substituted olefins, especially the oxygen-
substituted olefins (16,32,33).
To examine the oxidation rate of these electron-rich alkenes
with singlet oxygen (Scheme 2), we irradiated compounds 6, 8
and 10 in the presence of 5-(4-methoxyphenyl)-10,15,20-
triphenyl-21,23-dithiaporphyrin as a photosensitizer (35). All
experiments were carried out following the standard procedure

Photochemistry and Photobiology, 2012, 88 757
H
S
H
S
H
O
1O2
S
2
X
Control
Ca
Ha
Ha
O
O
O
O
1O2
O
O
Hb
Hb
6b
6a
6
Ha
O
S
O
Ha
O
S
1O2
O
Hb
Hb
8a
8b
8
1O2
Ha
N
uncharacterized products
O
Hb
10
Scheme 2. Possible [2 + 2] addition reaction of electron-rich olefins with singlet oxygen and expected products of control, 6, 8 and 10.
100
Table 2. Time-dependent decrease of the olefins and formation of
photoproducts.
control
80
60
40
20
0
6
Remaining olefins (%)
Observed product (%)
Time
(min) Control
8
6
8
10
Ca (6a + b) ⁄ 2* 8a 8b
10
0
5
10
15
100
38
11
0
100 100 100
0
0
1
2
0
53
87
92
0
0
26
2
29
0
27
0
0
67 32
99 48
99 48
(6a+6b)/2
0
0
8a
8b
*In 1H-NMR, the formate peaks of expected products of 6 (6a and b)
were too close to be distinguished. Thus, two peaks were integrated
together and divided by 2.
0
5
10
15
Reaction Time (min)
(Z)-1,2-Bis(phenylthio)ethylene was used as
a control
Figure 1. Photooxidation of olefins (6, 8 and 10) by the irradiation
a photosensitizer
of 690 nm diode laser at 200 mW cm)2 with
(CMP-OMe) in chloroform-d3.
against which the reaction rates were compared. Analysis of
the data indicated that not much difference exists among these
linkers with respect to their rate of reaction with singlet oxygen
(Fig. 1 and Table 2). Double bond peaks of all four substrates
disappeared within 15 min of the irradiation. The fast reaction
of 6 (1,2-diaryloxyalkene) and 8 (1-aryloxy-2-arythio-alkene) is
consistent with our previous report (14). The cleaved formate
products 6a, b and 8a were formed consistent with the decrease
of the olefins 6 and 8 (Table 2). On the other hand, cleaved
thioformate products 8b was formed much less (about half)
than oxidized olefin 8 presumably due in part to the oxidation
of sulfur atom (14,36) and ⁄ or cleavage of carbon-sulfur bond
(37). In the case of the control, we also detected diphenyl
disulfide after the photooxidation. The fast reaction of 10 (1-
previously set by our group with a slight modification using a
690 nm diode laser source (200 mW cm)2; 14). In our
experiments, the amount of sensitizer used was not catalytic.
Herein, the ratio of olefin and photosensitizer used was 1:1 to
mimic the situation of prodrug where the olefinic linker could
be used for connecting one drug molecule to one photosen-
sitizer molecule (14,15). The reaction solutions were irradiated
for 15 min and monitored every 5 min using olefinic peaks in
1H-NMR each time to monitor the progress of the reactions.
Upon the oxidation by singlet oxygen, the olefinic peaks
decreased.

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In summary, a facile and versatile synthesis of E-1,2-dihetero-
atom-substituted electron-rich alkenes was established. Not
only symmetric vinyl diethers but also unsymmetrically het-
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thiols and N-heterocycles with high stereospecificity. In addi-
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1-aryloxy-2-amino-alkene also react with singlet oxygen.
Acknowledgements—This research was supported by the Department
of Defense (Breast Cancer Research Program) under award number
(W81XWH-09-1-0071). Views and opinions of and endorsements by
the author(s) do not reflect those of the US Army or the
Department of Defense. We thank Dr. Karina Vega-Villa for her
HPLC analysis.
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SUPPORTING INFORMATION
Additional Supporting Information may be found in the online
version of this article:
Data S1. Table of contents.
Please note: Wiley-Blackwell is not responsible for the
content or functionality of any supporting materials supplied
by the authors. Any queries (other than missing mate-
rial) should be directed to the corresponding author for the
article.
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