Sulfone-mediated syntheses of crocetin derivatives: Regioselectivity of highly functionalized building blocks

Article abstract of DOI:10.1021/jo500478u

New C₅ sulfone building blocks containing a masked polar end group have been devised for the efficient synthesis of carotenoids with polar termini. Chemoselectivity or the regiochemical issue of the highly functionalized units has been carefully addressed depending on the soft or hard nature of electrophiles. These building blocks have been successfully applied to the syntheses of crocetin derivatives, crocetin dial and the novel crocetin dinitrile.

Full text of DOI:10.1021/jo500478u

Note
pubs.acs.org/joc
Sulfone-Mediated Syntheses of Crocetin Derivatives: Regioselectivity
of Highly Functionalized Building Blocks
Eun-Taek Oh,† Young-Hun Kim,‡ Jingquan Jin,§ Liang Su,§ Jung-Ah Seo,† and Sangho Koo*,†,‡,§
†Department of Nano Science and Engineering, ‡Department of Energy and Biotechnology, and §Department of Chemistry, Myong Ji
University, Myongji-Ro 116, Cheoin-Gu, Yongin, Gyeonggi-Do 449-728, Korea
S
* Supporting Information
ABSTRACT: New C5 sulfone building blocks containing a masked polar end group have been devised for the efficient synthesis
of carotenoids with polar termini. Chemoselectivity or the regiochemical issue of the highly functionalized units has been
carefully addressed depending on the soft or hard nature of electrophiles. These building blocks have been successfully applied to
the syntheses of crocetin derivatives, crocetin dial and the novel crocetin dinitrile.
arotenoids are nonpolar hydrocarbons, in which alternat-
ing carbon−carbon double and single bonds bestow a
polyene chain, which makes the synthesis of this carotenoid
more challenging.2 Synthetically, the apocarotenoid, crocetin
dialdehyde (2), has drawn more attention as a useful synthetic
intermediate for further elaboration by the Wittig reaction to
the C40 carotenoids of industrial application such as β-carotene
and lycopene.3
C
radical (or singlet oxygen) quenching ability as well as
characteristic red color.1 Crocetin (1) is an unusual natural
carotene compound, which contains polar carboxyl end groups
instead of the nonpolar cyclohexene ring moieties (Scheme 1).
Contrary to the hydroxyl groups of xanthophylls, the carboxyl
groups of crocetin are directly attached to the conjugated
We have developed sulfone-mediated synthetic methods of
carotenoids, in which various C5 and C10 building blocks have
been devised for the efficient assembly of the conjugated
polyene chain of nonpolar carotenoids.4 A strategy based on
sulfone chemistry afforded several advantages in carotenoid
synthesis in that sulfone intermediates are stable and easy to
crystallize and produce mainly E-alkenes in the elimination.5
Retrosynthesis of crocetin dialdehyde (2) based on the sulfone-
mediated coupling−double elimination strategy intuitively
requires highly functionalized building block 3a, the C5 allylic
sulfone containing a formyl end group, and 2,7-dimethyloct-4-
enedial (4) (Scheme 1).4e Because of the incompatibility of the
functionalities in 3a under basic coupling conditions, a masked
form of the formyl group was required. Several umpolungs of
3a were evaluated for their reactivity: hardness or softness as
well as regioselectivity of the resulting carbanion. We herein
disclose the details of the study described above and delineate
the synthesis of crocetin derivatives by using the new C5
building blocks.
Scheme 1. Building Blocks for Crocetin Dialdehyde (2)
Devised for the Sulfone-Mediated Synthesis
We initially considered hydroxymethyl or ester functionality
(e.g., 3b or 3c) in place of the formyl group in C5 building
Received: February 27, 2014
Published: April 25, 2014
© 2014 American Chemical Society
4712
dx.doi.org/10.1021/jo500478u | J. Org. Chem. 2014, 79, 4712−4717

The Journal of Organic Chemistry
Note
block 3a (Scheme 1). However, the anionic reactivities of the
regioisomeric conjugated hydroxymethyl-sulfone and conju-
gated sulfone-ester have been reported to be unfavorable.6
Because hydroxymethyl-sulfone suffered from low yields due to
the elimination of the hydroxyl group even in the dianionic
form and the wrong regioselectivity has been obtained in
allylation of sulfone-ester, we concentrated on the study of the
protected formyl group.
Scheme 2. Synthesis of Crocetin Dialdehyde (2) Using
Allylic Sulfone 5 with Acetal Protection
Acetal protection of 3a with neopentyl glycol provided highly
stable allylic sulfone 5. However, this crystalline material was
not soluble in most organic solvents, including THF and
MeOH, which did not allow the coupling reaction with dial 4 at
low temperatures. Protection with ethylene glycol or 1,3-
propanediol improved the solubility but did not allow smooth
coupling with dial 4 either. Cleavage of acetals was noticed
under the coupling condition using n-BuLi in THF at −78 °C.
The corresponding allylic sulfide 7 with neopentyl glycol
protection was then prepared to maintain the stability as well as
to circumvent the solubility problem of sulfone. Unfortunately,
the coupling reaction with dial 4 (n-BuLi in THF at −78 °C)
did not proceed either, presumably because of the conversion
of 7a into the more stabilized ring opening alkoxide 7b.7
The solubility problem of C5 building block 5 can be
alleviated at higher temperatures in DMF (e.g., 1 g of 5 per 30
mL of DMF at 25 °C), and bis(chloroallylic)sulfone 6 should
be utilized as a coupling partner to avoid the retro-aldol
reaction, inherent in dial 4 at high temperatures. Thus, a 2-fold
excess of allylic sulfone 5 (over 6) was dissolved in sufficient
DMF at room temperature, and t-BuOK was added to
deprotonate the α-hydrogen. The anionic solution of 5 in
DMF was then cooled to −20 °C and allowed to react with 6 to
produce coupling product 8 in 93% yield (Scheme 2). The
presence of three rigid sulfone functionalities allowed easy
purification of this coupling product just by washing with
MeOH.
the efficient synthesis of a new type of crocetin derivative,
crocetin dinitrile. We thus systematically studied the reactivity
(chemoselectivity) of C5 allylic sulfone 11a and allylic sulfide
11b with hydrazone protection toward the base-promoted
alkylation with hard (acetaldehyde) and soft (iodomethane)
electrophiles. Even though there were some variations in the
yields of the reaction products, different metallic bases
(NaHMDS or t-BuLi) provided a similar trend in the
chemoselectivity of alkylation of the C5 building blocks with
hydrazone protection (Scheme 3).
There is a clear difference between allylic sulfone 11a and
allylic sulfide 11b in the chemoselectivity of alkylation with
acetaldehyde. This hard electrophile reacted at the hard α-
carbon to the hydrazone in allylic sulfide 11b to produce 12b in
up to 70% yield, while γ-alkylation of the hydrazone in allylic
sulfone 11a was observed to produce 13a in only 39% yield.
This was a manifestation of the anion stabilizing effect of
sulfone, which directed α-alkylation (γ to the hydrazone) but
deactivated anionic reactivity. On the other hand, iodomethane
as a soft electrophile reacted only at the soft γ-carbon to the
hydrazone to produce 15a and 15b from allylic sulfone 11a and
allylic sulfide 11b, respectively. It was interesting to note that
no α-alkylation product 14a or 14b was observed in either case.
The utility of novel C5 allylic sulfone 11a with hydrazone
protection was demonstrated in the synthesis of a new crocetin
derivative, crocetin dinitrile (19) (Scheme 4). As was expected
from the previous regioselectivity study, allylic sulfone 11a
matched well with C10 allylic chloride 6 rather than aldehyde 4
for the base-promoted coupling (t-BuOK in DMF) to give
The Ramberg−Backlund reaction of bis-allylic sulfone 8
̈
produced triene 9 in 71% yield. The Ramberg−Backlund
̈
reaction utilizing CCl4 as both a chloronium (Cl+) source and a
solvent should be modified because the reagent has been
banned for environmental reasons.4a,8 Almost the same result
was obtained using only 2 equiv of C2Cl6 over 8 as a halogen
source in CH2Cl2, where the base, t-BuOK, was slowly
generated by the reaction of KOH and t-BuOH.9 Triene 9
containing two rigid sulfone groups was easily purified again
just by washing with MeOH.
A small amount of the Z isomer at C8 (≤20%) was noticed in
the 1H NMR spectrum of 9, but the E/Z mixture was subjected
to the dehydrosulfonation condition under KOMe in a
benzene/cyclohexane mixture at 80 °C to produce the fully
conjugated polyene acetal 10 in 87% crude yield. An analytical
sample was prepared by trituration with diethyl ether to give
all-(E)-10. The crude acetal product 10 was hydrolyzed by 1 M
HCl in THF to give crocetin dial (2) in 46% isolated yield after
silica gel chromatographic separation, which was further
purified by trituration with MeOH. Crocetin dial (2) was
thus synthesized in 26% overall yield (four steps) from C5
acetal building block 5.
Hydrazone protection of 3a with N,N-dimethylhydrazine
provided highly stable C5 building block 11a, in which a very
interesting regiochemical reactivity issue emerged because of
the coexistence of anion-stabilizing sulfone and hydrazone
functionalities. Furthermore, hydrazone is known to be
transformed into nitrile by oxidation,10 which would allow
trisulfone 16 in 72% yield. The Ramberg−Backlund reaction
̈
under the modified condition utilizing C2Cl6 as a halogen
source in CH2Cl2 uneventfully produced triene 17 in 56% yield
1
(3.5:1 E/Z mixture at C8 based on H NMR analysis). Base-
promoted elimination of benzenesulfonyl groups (KOMe at 80
°C) produced fully conjugated polyene 18 with hydrazone in
4713
dx.doi.org/10.1021/jo500478u | J. Org. Chem. 2014, 79, 4712−4717

The Journal of Organic Chemistry
Note
Scheme 3. Regioselectivity of Allylic Sulfone 11a and Allylic Sulfide 11b with Dimethylhydrazone Protection in Base-Promoted
Alkylation with Acetaldehyde and Iodomethane
reaction of urea-hydrogen peroxide (UHP) and phthalic
anhydride in acetonitrile. With novel C5 building block 11a
with hydrazone protection as the starting point, crocetin
dinitrile (19) was synthesized in 21% overall yield (four steps).
In summary, we developed new types of C5 building blocks,
which are amenable to the sulfone-mediated synthesis of
carotenoids with polar end groups. The regiochemical issue of
the highly functionalized C5 building blocks was carefully
addressed, and the utility of them was demonstrated in the
efficient syntheses of crocetin dial (2) and crocetin dinitrile
(19). The carotenoids with nitrile termini are especially
valuable for easy coordination to various metal surfaces.
Scheme 4. Synthesis of Crocetin Dinitrile (19) Using Allylic
Sulfone 11a with Dimethylhydrazone Protection
EXPERIMENTAL SECTION
■
1
General Experimental. H and 13C NMR spectra were recorded
on 400 and 100 MHz NMR spectrometers, respectively, in deuterated
chloroform (CDCl3) with tetramethylsilane (TMS) as an internal
reference. High-resolution mass spectroscopy was performed using a
magnetic sector analyzer. Solvents for extraction and chromatography
were reagent grade and used as received. Column chromatography was
performed by the method of Still with silica gel 60, 70−230 mesh
ASTM supplied by Merck using a gradient mixture of EtOAc and
hexanes. Reactions were performed in a well-dried flask under an
argon atmosphere unless noted otherwise.
(E)-2-Methyl-4-(phenylsulfonyl)but-2-enal (3a). To a stirred
solution of (E)-4-chloro-2-methylbut-2-enal11 (11.10 g, 94.0 mmol) in
MeOH (100 mL) was added p-TsOH (0.50 g 2.80 mmol). The
mixture was stirred at room temperature for 1 h, and NaSO2Ph (15.40
g, 94.0 mmol) was added. The reaction mixture was stirred at room
temperature for 12 h, concentrated under reduced pressure, and then
treated with 1 M HCl (100 mL). The resulting mixture was stirred at
room temperature for 1 h, extracted with CH2Cl2, washed with 1 M
HCl and H2O, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The crude solid product was
purified by being washed with ether to give 3a (10.10 g, 45.0 mmol) in
48% yield as white solid: Rf = 0.07 (1:4 EtOAc/hexane); mp 112−115
°C; 1H NMR δ 1.48 (s, 3H), 4.13 (d, J = 8.0 Hz, 2H), 6.45 (dt, Jd = 1.6
Hz, Jt = 8.0 Hz, 1H), 7.58 (t, J = 8.0 Hz, 2H), 7.70 (t, J = 7.6 Hz, 1H),
7.89 (d, J = 8.4 Hz, 2H), 9.46 (s, 1H); 13C NMR δ 9.2, 56.3, 128.2,
129.4, 134.3, 136.3, 138.3, 145.4, 193.5; IR (KBr) 3071, 2992, 2936,
2848, 1694, 1461, 1312, 1242, 1176, 1144, 1083, 1003, 919, 812, 746,
695, 578 cm−1; HRMS (CI+) calcd for C11H13O3S 225.0585, found
225.0578.
88% crude yield. An analytical sample of 18 was easily prepared
by trituration with MeOH.
Deprotection of the hydrazone was not a trivial task
especially because of the unstable nature of the carotenoid
polyene chain under acidic conditions. However, oxidation of
the tertiary amine in dimethylhydrazone induced smooth
intramolecular oxidative dehydrogenation of the resulting
ammonium oxide to generate nitrile functionality (see the
brackets in Scheme 4).10 Crocetin dinitrile (19) was obtained
in 60% isolated yield from the oxidation of hydrazone 18 by
monoperphthalic acid, which was generated in situ from the
4714
dx.doi.org/10.1021/jo500478u | J. Org. Chem. 2014, 79, 4712−4717

The Journal of Organic Chemistry
Note
(E)-5,5-Dimethyl-2-[4-(phenylsulfonyl)but-2-en-2-yl]-1,3-di-
oxane (5). To a stirred solution of 3a (4.20 g, 18.74 mmol) in toluene
(100 mL) were added neopentyl glycol (9.76 g, 93.73 mmol) and p-
TsOH (0.10 g, 0.56 mmol). The reaction mixture was heated at 120
°C for 8 h in a reflux condenser equipped with a Dean−Stark column.
The resulting mixture was cooled to room temperature and
concentrated under reduced pressure. The crude product was diluted
with CH2Cl2, washed with 1 M NaOH and H2O, dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The crude
product was purified by being washed with ether to give 5 (5.40 g,
17.40 mmol) in 93% yield as white solid: Rf = 0.55 (2:3 EtOAc/
hexane); mp 164−166 °C; 1H NMR δ 0.73 (s, 3H), 1.17 (s, 3H), 1.39
(s, 3H), 3.46 (d, J = 10.8 Hz, 2H), 3.62 (d, J = 10.8 Hz, 2H), 3.85 (d, J
= 8.0 Hz, 2H), 4.67 (s, 1H), 5.70 (t, J = 8.0 Hz, 1H), 7.54 (t, J = 7.6
Hz, 2H), 7.64 (t, J = 7.6 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H); 13C NMR
δ 11.6, 21.8, 22.9, 30.1, 55.5, 77.1, 103.1, 114.6, 128.5, 129.1, 133.7,
138.5, 142.5; IR (KBr) 2965, 2872, 1642, 1478, 1455, 1399, 1315,
1152, 1115, 1092, 1017, 984, 882, 733, 612 cm−1; HRMS (CI+) calcd
for C16H23O4S 311.1317, found 311.1319.
(E)-5,5-Dimethyl-2-[4-(phenylthio)but-2-en-2-yl]-1,3-diox-
ane (7). The mixture of (E)-2-methyl-4-(phenylthio)but-2-enal12
(2.100 g, 10.92 mmol), neopentyl glycol (11.35 g, 0.109 mol), and p-
TsOH (0.55 mmol, 104 mg) in benzene (50 mL) was heated to reflux
in a round-bottomed flask, equipped with a Dean−Stark trap and a
condenser, for 20 h. The mixture was cooled to room temperature,
diluted with ether, washed with a 1 M NaOH solution (3 × 50 mL)
and H2O (50 mL), dried over anhydrous K2CO3, filtered, and
concentrated under reduced pressure. The crude orange oily product
(2.957 g) was purified by SiO2 flash column chromatography to give 7
(1.687 g, 6.06 mmol) as a light yellow oil: Rf = 0.63 (8:2 hexane/
EtOAc); 1H NMR δ 0.72 (s, 3H), 1.20 (s, 3H), 1.70 (s, 3H), 3.47 (d, J
= 10.8 Hz, 2H), 3.58 (d, J = 7.6 Hz, 2H), 3.63 (d, J = 10.8 Hz, 2H),
4.69 (s, 1H), 5.77 (t, J = 7.6 Hz, 1H), 7.15−7.21 (m, 1H), 7.24−7.30
(m, 2H), 7.31−7.36 (m, 2H); 13C NMR δ 11.2, 21.7, 22.8, 30.0, 31.2,
77.0, 77.0, 77.0, 104.0, 124.1, 126.0, 128.7, 129.5, 136.3; IR (KBr)
2961, 2865, 1700, 1600, 1479, 1401, 1241, 1106, 1032, 993, 937, 751,
694 cm−1; HRMS (FAB+) calcd for C16H23O2S 279.1419, found
279.1414.
temperature for 10 min, and pulverized KOH (2.23 g, 39.82 mmol)
was added. The reaction mixture was stirred at room temperature for 2
h, and most of solvent was removed under reduced pressure. The
crude product was diluted with CH2Cl2, washed with a 10% NaHCO3
solution, dried over anhydrous K2CO3, filtered, and concentrated
under reduced pressure. The crude product was purified by being
washed with MeOH to give 9 (2.14 g, 2.84 mmol, a mixture of
diastereomers) in 71% yield as light yellow solid: Rf = 0.35 (2:3
1
EtOAc/hexane); mp 166−169 °C; H NMR δ 0.71 (s, 6H), 1.13 (s,
6H), 1.19 (s, 6H), 1.67 (s, 6H), 2.40 (dd, J = 13.6, 10.8 Hz, 2H), 3.01
(dd, J = 13.6, 2.8 Hz, 2H), 3.40 (d, J = 10.8 Hz, 4H), 3.57 (d, J = 10.8
Hz, 4H), 3.89 (ddd, J = 11.2, 10.0, 2.8 Hz, 2H), 4.58 (s, 2H), 5.41 (d, J
= 10.0 Hz, 2H), 5.82−5.91 (m, 2H), 6.15−6.24 (m, 2H), 7.44−7.55
(m, 4H), 7.57−7.68 (m, 2H), 7.77−7.86 (m, 4H); 13C NMR (peaks
from diastereomers are given in parentheses) δ 11.7 (11.8), 16.8
(16.7), 21.8, 22.8, 30.1, 37.6, 63.0, 63.1, 102.8, 120.6 (120.8), 124.0
(123.5), 127.9 (128.7), 128.8, 129.4 (129.5), 132.8, 133.5 (133.6),
137.4, 141.6; IR (KBr) 2964, 2871, 1724, 1641, 1483, 1460, 1399,
1316, 1153, 1116, 1037, 991, 735, 698, 624 cm−1; HRMS (FAB+)
calcd for C42H57O8S2 753.3495, found 753.3509.
Crocetin Dialdehyde, Neopentyl Diacetal (10). To a stirred
solution of 9 (1.50 g, 1.99 mmol) in benzene (20 mL) and
cyclohexane (30 mL) was added KOMe (4.19 g, 59.76 mmol). The
reaction mixture was heated at 80 °C for 8 h and cooled to room
temperature. The mixture was then filtered through Celite, and the
filtrate was concentrated under reduced pressure. The crude product
was diluted with CH2Cl2, washed with a 10% NaHCO3 solution, dried
over anhydrous K2CO3, filtered, and concentrated under reduced
pressure to give crude 10 (0.86 g, 1.73 mmol) in 87% yield as an
orange solid. An analytical sample was prepared by trituration with
1
diethyl ether: Rf = 0.55 (1:4 EtOAc/hexane); mp 117−120 °C; H
NMR δ 0.75 (s, 6H), 1.23 (s, 6H), 1.89 (s, 6H), 1.94 (s, 6H), 3.51 (d,
J = 10.8 Hz, 4H), 3.67 (d, J = 10.8 Hz, 4H), 4.77 (s, 2H), 6.17−6.26
(m, 2H), 6.29 (d, J = 10.8 Hz, 2H), 6.35 (d, J = 14.8 Hz, 2H), 6.49
(dd, J = 14.8, 10.8 Hz, 2H), 6.55−6.68 (m, 2H); 13C NMR δ 12.1,
12.8, 21.9, 23.0, 30.2, 77.3, 104.6, 123.7, 128.6, 130.1, 132.7, 134.1,
136.2, 138.9; UV (CH2Cl2) λmax (ε) 382 (16408), 402 (25547), 429
nm (25969); IR (KBr) 2934, 2867, 1746, 1470, 1390, 1277, 1190,
1110, 1026, 959, 888, 813, 654 cm−1; HRMS (EI+) calcd for C30H44O4
468.3239, found 468.3242.
2,2′-(2E,2′E,6E,6′E)-8,8′-Sulfonylbis[6-methyl-4-
(phenylsulfonyl)octa-2,6-diene-8,2-diyl]bis(5,5-dimethyl-1,3-
dioxane) (8). To a stirred solution of 5 (5.00 g, 16.12 mmol) in DMF
(150 mL) was added t-BuOK (2.20 g, 19.35 mmol). The mixture was
stirred at room temperature for 30 min and cooled to −20 °C. A
solution of 64c (2.18 g, 8.06 mmol) in DMF (4 mL) was then added.
The resulting mixture was stirred at −20 °C for 2 h, warmed to room
temperature, and stirred for 2 h. The reaction mixture was treated with
H2O (300 mL) and extracted with CH2Cl2. The organic phase was
washed with H2O, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was purified
by being washed with MeOH to give 8 (6.14 g, 7.48 mmol, a mixture
of diastereomers) in 93% yield as white solid: Rf = 0.13 (2:3 EtOAc/
hexane); mp 183−185 °C; 1H NMR δ 0.71 (s, 6H), 1.13 (s, 6H), 1.19
(s, 6H), 1.65 (s, 6H), 2.44 (dd, J = 13.6, 11.2 Hz, 2H), 3.01 (dd, J =
13.6, 2.4 Hz, 2H), 3.38 (d, J = 10.8 Hz, 4H), 3.56 (d, J = 10.8 Hz, 4H),
3.92 (ddd, J = 11.2, 10.8, 2.4 Hz, 2H), 4.54 (s, 2H), 4.56
(diastereomers in 1H NMR) (s, 2H), 5.21 (t, J = 11.2 Hz, 2H),
Crocetin Dialdehyde (2). To a stirred solution of the crude
polyene acetal 10 described above in THF (10 mL) were added 1 M
HCl (20 mL) and oxalic acid (0.33 g, 3.46 mmol). The reaction
mixture was stirred at room temperature for 1 h, extracted with EtOAc,
washed with 1 M HCl, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was purified
by SiO2 flash column chromatography to give 2 (0.23 g, 0.79 mmol) in
46% yield as a red solid. An analytical sample was prepared by
trituration with MeOH: Rf = 0.23 (1:4 EtOAc/hexane); mp 189−192
°C; 1H NMR δ 1.91 (s, 6H), 2.03 (s, 6H), 6.41−6.52 (m, 2H), 6.68−
6.82 (m, 6H), 6.90−7.00 (m, 2H), 9.47 (s, 2H); 13C NMR δ 9.7, 12.8,
123.7, 132.0, 136.7, 137.1, 137.4, 145.4, 148.8, 194.5; UV (CH2Cl2)
λmax (ε) 422 (51422), 446 (78763), 475 nm (77058); IR (KBr) 3044,
2932, 2839, 2726, 1683, 1624, 1570, 1448, 1418, 1330, 1272, 1198,
982, 845, 747, 698, 645 cm−1; HRMS (CI+) calcd for C20H25O2
297.1855, found 297.1852.
(E)-1,1-Dimethyl-2-[(E)-2-methyl-4-(phenylsulfonyl)but-2-
enylidene]hydrazine (11a). To a stirred solution of 3a (2.84 g,
12.66 mmol) in CH2Cl2 (40 mL) were added 1,1-dimethylhydrazine
(1.34 g 13.93 mmol) and Et3N (3.84 g, 37.99 mmol). The reaction
mixture was stirred at room temperature for 3 h, diluted with CH2Cl2,
washed with H2O, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was purified
by silica gel flash column chromatography to give 11a (2.50 g, 8.86
mmol) in 70% yield as a light yellow solid: mp 102−105 °C; Rf = 0.52
(2:3 EtOAc/hexane); 1H NMR δ 1.50 (s, 3H), 2.86 (s, 6H), 3.99 (d, J
= 8.4 Hz, 2H), 5.47 (t, J = 8.4 Hz, 1H), 6.90 (s, 1H), 7.53 (t, J = 7.6
Hz, 2H), 7.64 (t, J = 7.6 Hz, 1H), 7.87 (d, J = 8.0 Hz, 2H); 13C NMR
δ 11.5, 42.6, 56.5, 114.6, 128.4, 129.1, 133.6, 135.5, 138.8, 143.0; IR
(KBr) 2991, 2926, 1637, 1563, 1455, 1310, 1250, 1175, 1142, 1096,
1
5.23 (diastereomers in H NMR) (t, J = 11.6 Hz, 2H), 5.38 (d, J =
10.8 Hz, 2H), 7.48−7.55 (m, 4H), 7.61−7.67 (m, 2H), 7.82−7.86 (m,
4H); 13C NMR (peaks from diastereomers are given in parentheses) δ
11.9 (11.5), 16.9 (16.8), 21.7 (21.3), 22.9, 30.1, 37.3 (37.4), 51.0, 55.4,
62.2, 77.2 (71.7), 102.6 (103.0), 114.5 (114.4), 120.1, 129.1 (128.5),
129.4 (128.9), 133.8 (133.7), 140.4 (136.9), 142.3 (142.5); IR (KBr)
2963, 2869, 1682, 1461, 1405, 1315, 1156, 1113, 1029, 991, 884, 757,
701, 611 cm−1; HRMS (FAB+) calcd for C42H59O10S3 819.3270, found
819.3281.
2,2′-[(2E,6E,8E,10E,14E)-6,11-Dimethyl-4,13-bis-
(phenylsulfonyl)hexadeca-2,6,8,10,14-pentaene-2,15-diyl]bis-
(5,5-dimethyl-1,3-dioxane) (9). To a stirred solution of 8 (3.27 g,
3.98 mmol) in CH2Cl2 (80 mL) were added t-BuOH (32 mL) and
C2Cl6 (1.89 g, 7.96 mmol). The mixture was stirred at room
4715
dx.doi.org/10.1021/jo500478u | J. Org. Chem. 2014, 79, 4712−4717

The Journal of Organic Chemistry
Note
1063, 923, 895, 778, 741, 689, 540 cm−1; HRMS (CI+) calcd for
C13H19N2O2S 267.1167, found 267.1171.
1.08 mmol) in THF (10 mL) at −78 °C was added a 1 M THF
solution of NaHMDS (1.30 mL, 1.30 mmol). The mixture was stirred
for 30 min, and iodomethane (0.77 g, 5.42 mmol) was added. The
resulting mixture was stirred at −78 °C for 30 min, warmed to room
temperature, and stirred for 2.5 h. The reaction mixture was quenched
with a 10% NH4Cl solution (10 mL), extracted with EtOAc, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
The crude product was purified by silica gel flash column
chromatography to give 15a (0.10 g, 0.36 mmol) in 43% yield as a
yellow oil.
The reaction of 11a (0.19g, 0.73 mmol) and iodomethane (0.20 g,
1.46 mmol) in THF (10 mL) at −78 °C for 30 min and then at room
temperature for 2.5 h with t-BuLi (1.7 M hexane solution, 0.52 mL,
0.88 mmol) as a base produced 15a (0.11g, 0.38 mmol) in 52% yield
after purification by silica gel flash column chromatography: Rf = 0.62
(3:2 hexane/EtOAc); 1H NMR δ 1.43 (d, J = 1.2 Hz, 3H), 1.51 (d, J =
6.8 Hz, 3H), 2.85 (s, 6H), 4.08 (dq, Jd = 10.4 Hz, Jq = 6.8 Hz, 1H),
5.29 (d, J = 10.4 Hz, 1H), 6.88 (br s, 1H), 7.48−7.56 (m, 2H), 7.60−
7.65 (m, 1H), 7.81−7.88 (m, 2H); 13C NMR δ 11.7, 14.0, 42.7, 60.1,
122.7, 128.9, 129.0, 133.5, 135.8, 137.7, 141.1; IR (KBr) 2950, 2873,
2797, 1632, 1571, 1456, 1319, 1157, 1095, 1010, 890, 876, 824, 772,
733, 691, 643 cm−1; HRMS (CI+) calcd for C14H21N2O2S 281.1324,
found 281.1324.
(E)-1,1-Dimethyl-2-[(E)-2-methyl-4-(phenylthio)pent-2-
enylidene]hydrazine (15b). To a stirred solution of 11b (0.21 g,
0.90 mmol) in THF (10 mL) at −78 °C was added a 1 M THF
solution of NaHMDS (1.09 mL, 1.09 mmol). The mixture was stirred
for 30 min, and iodomethane (0.64 g, 4.52 mmol) was added. The
reaction mixture was stirred at −78 °C for 2.5 h and quenched with a
10% NH4Cl solution (10 mL). The mixture was extracted with EtOAc,
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The crude product was purified by silica gel flash
column chromatography to give 15b (0.040 g, 0.18 mmol) in 20%
yield as a yellow oil.
(E)-1,1-Dimethyl-2-[(E)-2-methyl-4-(phenylthio)but-2-
enylidene]hydrazine (11b). To a stirred mixture of (E)-2-methyl-4-
(phenylthio)but-2-enal12 (3.30 g, 17.16 mmol) and dimethylhydrazine
hydrochloride salt (2.48 g, 25.75 mmol) in CH2Cl2 (50 mL) was
added Et3N (5.20 g, 51.48 mmol). The mixture was stirred vigorously
at room temperature for 1 day under an argon atmosphere, diluted
with CH2Cl2 (50 mL), and partitioned with a 4% KOH solution (50
mL). The organic layer was separated, dried over anhydrous K2CO3,
filtered, and concentrated under reduced pressure. The crude product
was purified by SiO2 flash column chromatography to give 11b (2.543
g, 10.85 mmol) in 63% yield as a yellow oil: Rf = 0.54 (8:2 hexane/
1
EtOAc); H NMR δ 1.80 (s, 3H), 2.83 (s, 6H), 3.73 (d, J = 8.0 Hz,
2H), 5.63 (t, J = 8.0 Hz, 1H), 6.96 (s, 1H), 7.15−7.22 (m, 1H), 7.24−
7.31 (m, 2H), 7.33−7.38 (m, 2H); 13C NMR δ 11.5, 32.3, 42.8, 42.8,
125.9, 126.1, 128.7, 129.8, 136.2, 137.5, 137.9; IR (KBr) 2970, 2861,
2789, 1699, 1581, 1483, 1448, 1260, 1140, 1089, 1029, 906, 852, 743,
694 cm−1; HRMS (FAB+) calcd for C13H19N2S 235.1269, found
235.1262.
(E)-3-[(E)-(2,2-Dimethylhydrazono)methyl]-3-methyl-5-
(phenylthio)pent-4-en-2-ol (12b). To a stirred solution of 11b
(0.56 g, 2.41 mmol) in THF (15 mL) at −78 °C was added a 1 M
THF solution of NaHMDS (2.89 mL, 2.89 mmol). The mixture was
stirred for 30 min, and acetaldehyde (0.47 g, 10.84 mmol) was added.
The resulting mixture was stirred at −78 °C for 3.5 h, quenched with a
10% NH4Cl solution (10 mL), extracted with EtOAc, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
The crude product was purified by silica gel flash column
chromatography to give 12b (0.58 g, 2.08 mmol) in 70% yield as a
yellow oil.
The reaction of 11b (0.29 g, 1.26 mmol) and acetaldehyde (0.28 g,
6.28 mmol) in THF (10 mL) at −78 °C for 2.5 h with t-BuLi (1.7 M
hexane solution, 0.89 mL, 1.51 mmol) as a base produced 12b (0.17 g,
0.61 mmol) in 48% yield after purification by silica gel flash column
chromatography: Rf = 0.22 (5:1 hexane/EtOAc); 1H NMR δ 1.14 (d, J
= 6.4 Hz, 3H), 1.17 (s, 3H), 2.75 (s, 6H), 4.00 (dq, Jd = 2.0 Hz, Jt =
6.4 Hz, 1H), 4.50 (br s, 1H), 6.14 (d, J = 15.6 Hz, 1H), 6.21 (d, J =
15.6 Hz, 1H), 6.38 (br s, 1H), 7.18−7.25 (m, 1H), 7.27−7.36 (m,
4H); 13C NMR δ 17.3, 21.0, 42.9, 48.6, 72.5, 123.3, 126.3, 128.9,
129.1, 136.0, 138.1, 142.1; IR (KBr) 3430, 2985, 2872, 2798, 1596,
1488, 1451, 1381, 1255, 1128, 1091, 1021, 955, 922, 829, 740, 689,
628 cm−1; HRMS (CI+) calcd for C15H23N2OS 279.1531, found
279.1535.
(4E,6E)-6-(2,2-Dimethylhydrazono)-5-methyl-3-
(phenylsulfonyl)hex-4-en-2-ol (13a). To a stirred solution of 11a
(0.26 g, 0.97 mmol) in THF (10 mL) at −78 °C was added a 1 M
THF solution of NaHMDS (1.16 mL, 1.16 mmol). The mixture was
stirred for 30 min, and acetaldehyde (0.19 g, 4.36 mmol) was added.
The resulting mixture was stirred at −78 °C for 2.5 h, quenched with a
10% NH4Cl solution (10 mL), extracted with EtOAc, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
The crude product was purified by silica gel flash column
chromatography to give 13a (0.09 g, 0.29 mmol) in 30% yield as a
light yellow solid.
The reaction of 11b (0.42 g, 1.78 mmol) and iodomethane (1.26 g,
8.88 mmol) in THF (10 mL) at −78 °C for 30 min and then at room
temperature for 2.5 h with t-BuLi (1.7 M hexane solution, 1.26 mL,
2.14 mmol) as a base produced 15b (0.25 g, 1.01 mmol) in 56% yield
after purification by silica gel flash column chromatography: Rf = 0.67
1
(4:1 hexane/EtOAc); H NMR δ 1.38 (d, J = 6.4 Hz, 3H), 1.65 (s,
3H), 2.82 (s, 6H), 4.19 (dq, Jd = 10.0 Hz, Jq = 6.4 Hz, 1H), 5.44 (d, J =
10.0 Hz, 1H), 6.95 (br s, 1H), 7.22−7.29 (m, 3H), 7.38−7.43 (m,
2H); 13C NMR δ 11.7, 21.3, 42.2, 42.9, 127.3, 128.7, 133.2, 133.7,
134.7, 135.1, 138.4; IR (KBr) 3071, 2974, 2865, 2784, 1571, 1480,
1448, 1380, 1275, 1193, 1120, 1034, 915, 847, 752, 705 cm−1; HRMS
(CI+) calcd for C14H21N2S 249.1425, found 249.1424.
(2E,2′E)-2,2′-{(2E,2′E,6E,6′E)-8,8′-Sulfonylbis[2,6-dimethyl-4-
(phenylsulfonyl)octa-2,6-dien-8-yl-1-ylidene]}bis(1,1-dime-
thylhydrazine) (16). To a stirred solution of 11a (1.50 g, 5.31 mmol)
in DMF (20 mL) at −20 °C was added t-BuOK (0.70 g, 6.37 mmol).
The mixture was stirred at −20 °C for 30 min, and a solution of 6
(0.70 g, 2.66 mmol) in DMF (2 mL) was added. The resulting mixture
was stirred at −20 °C for 2 h, warmed to room temperature, and
stirred for 2 h. The mixture was then quenched with a 10% NH4Cl
solution (10 mL), extracted with CH2Cl2, washed with a 10% NH4Cl
solution, dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was purified by SiO2 flash
column chromatography to give 16 (1.40 g, 1.92 mmol) in 72% yield
as a light yellow solid: Rf = 0.05 (2:3 EtOAc/hexane); mp 144−146
The reaction of 11a (0.17g, 0.65 mmol) and acetaldehyde (0.14 g,
3.27 mmol) in THF (10 mL) at −78 °C for 2.5 h with t-BuLi (1.7 M
hexane solution, 0.46 mL, 0.78 mmol) as a base produced 13a (0.08 g,
0.26 mmol) in 39% yield after purification by silica gel flash column
chromatography: Rf = 0.32 (3:2 hexane/EtOAc); mp 120−123 °C; 1H
NMR δ 1.19 (d, J = 6.4 Hz, 3H), 1.38 (d, J = 1.6 Hz, 3H), 2.86 (s,
6H), 3.13 (d, J = 2.4 Hz, 1H), 3.89 (dd, J = 11.2, 1.6 Hz, 1H), 4.79
(dq, Jd = 1.6 Hz, Jq = 6.4 Hz, 1H), 5.73 (d, J = 11.2 Hz, 1H), 6.97 (br
s, 1H), 7.50−7.56 (m, 2H), 7.62−7.67 (m, 1H), 7.82−7.88 (m, 2H);
13C NMR δ 11.7, 20.6, 42.6, 65.0, 69.6, 115.6, 128.7, 129.0, 133.9,
135.7, 137.9, 144.2; IR (KBr) 3474, 2978, 2937, 1553, 1442, 1363,
1321, 1289, 1257, 1225, 1141, 1099, 1053, 928, 901, 835, 725, 673
cm−1; HRMS (CI+) calcd for C15H23N2O3S 311.1429, found 311.1427.
(E)-1,1-Dimethyl-2-[(E)-2-methyl-4-(phenylsulfonyl)pent-2-
enylidene]hydrazine (15a). To a stirred solution of 11a (0.29 g,
1
°C; H NMR δ 1.33 (d, J = 1.2 Hz, 6H), 1.62 (s, 6H), 2.48 (dd, J =
13.6, 11.2 Hz, 2H), 2.84 (s, 12H), 3.01 (dd, J = 13.6, 3.2 Hz, 2H), 3.48
(d, J = 7.6 Hz, 2H), 4.09 (ddd, J = 11.2, 10.0, 3.2 Hz, 2H), 5.14 (d, J =
10.0 Hz, 2H), 5.27 (t, J = 7.6 Hz, 2H), 6.81 (s, 2H), 7.48−7.55 (m,
4H), 7.60−7.66 (m, 2H), 7.78−7.84 (m, 4H); 13C NMR δ 11.7, 16.7,
37.9, 42.7, 51.3, 63.2, 114.2, 129.8, 129.0, 129.1, 129.3, 133.8, 137.5,
140.8, 142.8; IR (KBr) 2936, 2868, 2791, 1696, 1637, 1565, 1453,
1313, 1155, 1092, 1051, 754, 695, 609 cm−1; HRMS (FAB+) calcd for
C36H51N4O6S3 731.2971, found 731.2975.
(2E,2′E)-2,2′-[(2E,6E,8E,10E,14E)-2,6,11,15-Tetramethyl-4,13-
bis(phenylsulfonyl)hexadeca-2,6,8,10,14-pentaene-1,16-
4716
dx.doi.org/10.1021/jo500478u | J. Org. Chem. 2014, 79, 4712−4717

The Journal of Organic Chemistry
Note
diylidene]bis(1,1-dimethylhydrazine) (17). To a stirred solution
of 16 (0.56 g, 0.76 mmol) in CH2Cl2 (20 mL) were added t-BuOH (5
mL) and C2Cl6 (0.36 g, 1.53 mmol). The mixture was stirred at room
temperature for 10 min, and KOH (0.43 g, 7.66 mmol) was added.
The reaction mixture was stirred at room temperature for 2 h, and
most of solvent was removed under reduced pressure. The crude
product was diluted with CH2Cl2, washed with 10% NaHCO3, dried
over anhydrous K2CO3, filtered, and concentrated under reduced
pressure. The crude product was purified by SiO2 flash column
chromatography to give 17 (0.28 g, 0.42 mmol) in 56% yield as a light
ACKNOWLEDGMENTS
■
This research was supported by the Basic Science Research
Program (Grant 2012R1A2A2A01045344) and by the Priority
Research Centers Program (Grant 2012-0006693) both
through the National Research Foundation of Korea.
REFERENCES
■
(1) Stahl, W.; Nicolai, S.; Briviba, K.; Hanusch, M.; Broszeit, G.;
Peters, M.; Martin, H.-D.; Sies, H. Carcinogenesis 1997, 18, 89−92.
(2) (a) Frederico, D.; Donate, P. M.; Constantino, M. G.; Bronze, E.
S.; Sairre, M. I. J. Org. Chem. 2003, 68, 9126−9128. (b) Gainer, J. L.;
Lanz, M. U.S. Patent 0194973 A1, 2006. (c) Kryshtal, G. V.;
Zhdankina, G. M.; Ignat’ev, N. V.; Schulte, M.; Zlotin, S. G.
Tetrahedron Lett. 2012, 53, 4971−4973.
1
yellow solid: Rf = 0.28 (2:3 EtOAc/hexane); mp 131−134 °C; H
NMR δ 1.35 (s, 6H), 1.66 (s, 6H), 2.44 (dd, J = 12.8, 12.0 Hz, 2H),
2.84 (s, 12H), 3.02 (dd, J = 12.8, 2.8 Hz, 2H), 4.11 (ddd, J = 12.0,
10.4, 2.8 Hz, 2H), 5.24 (d, J = 10.4 Hz, 2H), 5.80−5.92 (m, 2H),
6.14−6.25 (m, 2H), 7.00 (br s, 2H), 7.45−7.58 (m, 4H), 7.56−7.66
(m, 2H), 7.67−7.88 (m, 4H); 13C NMR δ 11.6, 16.6, 37.9, 42.6, 63.8,
121.3, 127.8, 128.9, 129.1, 129.3, 133.1, 133.6, 135.7, 137.8, 142.3; IR
(KBr) 2933, 2866, 2791, 1697, 1453, 1311, 1151, 1088, 1039, 919,
746, 697, 613 cm−1; HRMS (FAB+) calcd for C36H49N4O4S2 665.3195,
found 665.3208.
(3) (a) Isler, O.; Gutmann, H.; Lindlar, H.; Montavon, M.; Ruegg, R.;
̈
Ryser, G.; Zeller, P. Helv. Chim. Acta 1956, 39, 463−473. (b) Pommer,
H. Angew. Chem. 1960, 72, 911−915. (c) Bernhard, K.; Mayer, H. Pure
Appl. Chem. 1991, 63, 35−44. (d) Jackson, H. L.; Nadolski, G. T.;
Braun, C.; Lockwood, S. F. Org. Process Res. Dev. 2005, 9, 830−836.
(4) (a) Choi, H.; Ji, M.; Park, M.; Yun, I.-K.; Oh, S.-S.; Baik, W.; Koo,
S. J. Org. Chem. 1999, 64, 8051−8053. (b) Ji, M.; Choi, H.; Park, M.;
Kee, M.; Jeong, Y. C.; Koo, S. Angew. Chem., Int. Ed. 2001, 40, 3627−
3629. (c) Ji, M.; Choi, H.; Jeong, Y. C.; Jin, J.; Baik, W.; Lee, S.; Kim, J.
S.; Park, M.; Koo, S. Helv. Chim. Acta 2003, 86, 2620−2628.
(d) Jeong, Y. C.; Ji, M.; Lee, J. S.; Yang, J.-D.; Jin, J.; Baik, W.; Koo, S.
Tetrahedron 2004, 60, 10181−10185. (e) Guha, S. K.; Koo, S. J. Org.
Chem. 2005, 70, 9662−9665.
Crocetin Dimethylhydrazone (18). To a stirred solution of 17
(0.44 g, 0.66 mmol) in benzene (12 mL) and cyclohexane (18 mL)
was added KOMe (1.40 g, 19.87 mmol). The reaction mixture was
heated at 80 °C for 8 h and cooled to room temperature. The mixture
was then filtered through Celite, and the filtrate was concentrated
under reduced pressure. The crude product was diluted with CH2Cl2,
washed with a 10% NaHCO3 solution, dried over anhydrous K2CO3,
filtered, and concentrated under reduced pressure to give crude
conjugated polyene hydrazone 18 (0.22 g, 0.58 mmol) in 88% yield as
a red solid. An analytical sample was prepared by trituration with
MeOH: Rf = 0.50 (1:4 EtOAc/hexane); mp 115−118 °C; 1H NMR δ
1.98 (s, 6H), 2.02 (s, 6H), 2.90 (s, 12H), 6.20−6.32 (m, 2H), 6.23 (d,
J = 11.6 Hz, 2H), 6.35 (d, J = 14.8 Hz, 2H), 6.58−6.69 (m, 2H), 6.68
(dd, J = 14.8, 11.6 Hz, 2H), 7.03 (s, 2H); 13C NMR δ 12.1, 12.8, 43.0,
124.9, 130.0, 131.1, 132.6, 135.8, 136.5, 137.1, 138.5; UV (CH2Cl2)
λmax (ε) 443 (167508), 472 (226396), 495 nm (197984); IR (KBr)
2996, 2923, 2788, 1544, 1476, 1404, 1273, 1051, 965, 906, 802 cm−1;
HRMS (FAB+) calcd for C24H36N4 380.2940, found 380.2946.
Crocetin Dinitrile (19). The mixture of urea-hydrogen peroxide
(0.33 g, 3.47 mmol) and phthalic anhydride (0.26 g, 1.73 mmol) in
acetonitrile (10 mL) was stirred vigorously at room temperature for 2
h to give a clear solution. Crude product 18 in CH2Cl2 was added; the
resulting mixture was stirred at room temperature for 2 h, and most of
the solvent was removed under reduced pressure. Crude 18 was
diluted with CHCl3, and the undissolved solid was removed by
filtration. The filtrate was concentrated under reduced pressure, and
the crude product was recrystallized from MeOH to give 19 (0.10 g,
0.35 mmol) in 60% yield as a red solid: Rf = 0.47 (1:4 EtOAc/hexane);
(5) (a) Julia, M.; Arnould, D. Bull. Soc. Chim. Fr. 1973, 743−746.
(b) Julia, M.; Arnould, D. Bull. Soc. Chim. Fr. 1973, 746−750.
(c) Manchand, P. S.; Rosenberger, M.; Saucy, G.; Wehrli, P. A.; Wong,
H.; Chambers, L.; Ferro, M. P.; Jackson, W. Helv. Chim. Acta 1976, 59,
387−396. (d) Otera, J.; Misawa, H.; Onishi, T.; Suzuki, S.; Fujita, Y. J.
Org. Chem. 1986, 51, 3834−3838. (e) Orita, A.; Yamashita, Y.; Toh,
A.; Otera, J. Angew. Chem., Int. Ed. 1997, 36, 779−780.
(6) (a) Lansbury, P. T.; Erwin, R. W.; Jeffrey, D. A. J. Am. Chem. Soc.
1980, 102, 1602−1608. (b) Olson, G. L.; Cheung, H.-C.; Morgan, K.
D.; Neukom, C.; Saucy, G. J. Org. Chem. 1976, 41, 3287−3293.
̀
(7) Xu, L.; Regnier, T.; Lemiegre, L.; Cardinael, P.; Combret, J.-C.;
Bouillon, J.-P.; Blanchet, J.; Rouden, J.; Harrison-Marchand, A.;
Maddaluno, J. Org. Lett. 2008, 10, 729−732.
(8) Meyers, C. Y.; Malte, A. M.; Matthews, W. S. J. Am. Chem. Soc.
1969, 91, 7510−7512.
(9) Choi, S.; Koo, S. J. Org. Chem. 2005, 70, 3328−3331.
(10) (a) Fernan
Vaz
A.; Backhaus, D.; Reinhold, U. Tetrahedron 1995, 51, 10699−10714.
(c) Stankovic, S.; Espenson, J. H. Chem. Commun. 1998, 1579−1580.
́
dez, R.; Gasch, C.; Lassaletta, J.-M.; Llera, J.-M.;
́
quez, J. Tetrahedron Lett. 1993, 34, 141−144. (b) Enders, D.; Plant,
1
́
mp 100−103 °C; H NMR δ 1.97 (s, 6H), 2.01 (s, 6H), 6.35−6.44
(d) Rudler, H.; Denise, B. Chem. Commun. 1998, 2145−2146.
(e) Altamura, A.; D’Accolti, L.; Detomaso, A.; Dinoi, A.; Fiorentino,
M.; Fusco, C.; Curci, R. Tetrahedron Lett. 1998, 39, 2009−2012.
(f) Carmeli, M.; Shefer, N.; Rozen, S. Tetrahedron Lett. 2006, 47,
8969−8972.
(m, 2H), 6.45 (dd, J = 14.8, 10.8 Hz, 2H), 6.55 (d, J = 14.8 Hz, 2H),
6.67−6.77 (m, 2H), 6.81 (d, J = 10.8 Hz, 2H); 13C NMR δ 12.7, 15.3,
106.4, 121.7, 122.0, 131.7, 136.5, 143.9, 144.1; UV (CH2Cl2) λmax (ε)
408 (82824), 430 (128500), 457 nm (128102); IR (KBr) 2992, 2214,
1730, 1686, 1619, 1587, 1453, 1390, 1153, 1063, 974, 916, 732, 656
cm−1; HRMS (FAB+) calcd for C20H22N2 290.1783, found 290.1780.
(11) Eletti-Bianchi, G.; Centini, F.; Re, L. J. Org. Chem. 1976, 41,
1648−1650.
(12) Choi, S.; Yang, J.-D.; Ji, M.; Choi, H.; Kee, M.; Ahn, K.-H.;
Byeon, S.-H.; Baik, W.; Koo, S. J. Org. Chem. 2001, 66, 8192−8198.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of compounds 2, 3a, 5, 7−10, 11a,
11b, 12b, 13a, 15a, 15b, and 16−19. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Phone: +82-31-330-6185. Fax: +82-31-335-7248. E-mail:
sangkoo@mju.ac.kr.
■
Notes
The authors declare no competing financial interest.
4717
dx.doi.org/10.1021/jo500478u | J. Org. Chem. 2014, 79, 4712−4717