Lithium binaphtholate-catalyzed enantioselective enyne addition to ketones: Access to enynylated tertiary alcohols

Article abstract of DOI:10.1021/jo5005839

A new catalytic enantioselective enyne addition to ketones has been developed. In the presence of chiral lithium binaphtholate, the addition reaction proceeded smoothly to produce a series of enynylated tertiary alcohols in up to 96% yield and 94% enantiomeric excess. Convenient transformation of the adduct via Pauson-Khand cycloaddition reaction afforded the bicyclic product without detectable loss of enantioselectivity. Furthermore, catalytic asymmetric enyne addition to trifluoromethylketone was applied in the synthesis of the Efavirenz analogue.

Full text of DOI:10.1021/jo5005839

Article
pubs.acs.org/joc
Lithium Binaphtholate-Catalyzed Enantioselective Enyne Addition to
Ketones: Access to Enynylated Tertiary Alcohols
Hua Cai, Jing Nie, Yan Zheng, and Jun-An Ma*
Department of Chemistry, Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, and Collaborative
Innovation Centre of Chemical Science and Engineering (Tianjin), Tianjin 300072, China
S
* Supporting Information
ABSTRACT: A new catalytic enantioselective enyne addition to ketones has been developed. In the presence of chiral lithium
binaphtholate, the addition reaction proceeded smoothly to produce a series of enynylated tertiary alcohols in up to 96% yield
and 94% enantiomeric excess. Convenient transformation of the adduct via Pauson−Khand cycloaddition reaction afforded the
bicyclic product without detectable loss of enantioselectivity. Furthermore, catalytic asymmetric enyne addition to
trifluoromethylketone was applied in the synthesis of the Efavirenz analogue.
Scheme 1. Catalytic Enantioselective Addition of
Conjugated Enynes to Carbonyl Compounds
INTRODUCTION
■
Optically active propargylic alcohols are important structural
subunits that can be found in a wide range of natural products
and biologically active compounds.1 Catalytic enantioselective
addition of alkynylating reagents to carbonyl compounds,
which can construct a carbon skeleton with concomitant
creation of a stereogenic center, represents one of the most
direct and efficient methods for synthesis of optically active
propargylic alcohols.2 In this context, the catalytic enantiose-
lective alkynylation of aldehydes and ketones has been
extensively studied in the past decade, and many addition
reactions have been successfully used in the efficient synthesis
of natural products and bioactive compounds.3 However, nearly
all such studies have focused on the utility of alkynes and
diynes, and little attention has been paid to exploring
conjugated enynes as viable nucleophilic substrates in catalytic
enantioselective addition to carbonyl compounds. Recently,
Koide and co-workers4a provided an example of enantiose-
lective enynylation of acetaldehyde by using a stoichiometric
amount of chiral zinc complex (Scheme 1a), whereas Yu, Pu,
and co-workers4b described titanium-catalyzed enantioselective
addition of enynes to aldehydes (Scheme 1b). In contrast, the
use of ketones as electrophilic acceptors for the catalytic
enantioselective addition of enynes still remains a formidable
challenge, and there has been no report in the literature to date
of such a potentially useful transformation. Herein, we report
our efforts in developing a new lithium binaphtholate-catalyzed
enantioselective addition of conjugated enynes to ketones
(Scheme 1c). This rapid approach would set the stereocenter of
the tertiary alcohol and introduce the enyne moiety in a single
chemical operation.
Received: March 12, 2014
© XXXX American Chemical Society
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Scheme 2. Synthesis of Aromatic and Aliphatic Enynes
Table 1. Effect of Ligand, Solvent, and Other Reaction
Conditions on Addition Reaction
RESULTS AND DISCUSSION
■
a
Preparation of Enynes. Aryl- and alkyl-substituted enynes
were synthesized according to the procedures shown in Scheme
2. In the presence of Pd(OAc)2/PPh3, CuBr, and LiBr, the
cross-coupling reaction of 2-aryl-1-bromoethenes with 2-
methylbut-3-yn-2-ol proceeded smoothly to give the coupling
intermediates, which were refluxed with KOH in toluene to
afford the corresponding aryl-substituted enynes 2a−j in 42−
64% yields (Scheme 2a).5 The aliphatic enyne 2l was
synthesized according to known methods in the literature.6
The Wittig olefination of cyclopropanecarbaldehyde with
trimethylsilyl-protected prop-2-yn-1-ylide gave the correspond-
ing (E)-enynyltrimethylsilane (enyne-TMS) in 62% yield.
Subsequent desilylation afforded (E)-but-1-en-3-yn-1-ylcyclo-
propane 2l in essentially quantitative yield (Scheme 2b).
Optimization of Reaction Conditions. We recently
developed both catalytic enantioselective alkynylation and
diynylation of ketones in the presence of titanium and copper
complexes by using zinc acetylides.7 On the basis of these two
precedents, we first examined the model reaction of
acetophenone 1a with enyne 2a under otherwise identical
reaction conditions. However, low reactivity and/or low
enantioselectivity were observed. Inspired by the success with
lithium acetylides in enantioselective alkynylations,8 we
subsequently investigated the use of lithium binaphtholate
based on 3,3′-functionalization of (1,1′-binaphthalene)-2,2′-
diol (BINOL). The results are listed in Table 1. In the presence
of n-butyllithium, the simplest ligand BINOL (L1) catalyzed
this enynlation reaction in tetrahydrofuran (THF) at −78 °C
for 24 h to give adduct 3a in 30% yield with 26% enantiomeric
excess (ee) (entry 1). Next, a series of BINOL-type ligands
containing various groups at the 3,3′-positions of the
binaphthol backbone were tested for the model reaction
(entries 2−12). The 4-biphenyl-substituted ligand L10 proved
to be optimal, delivering product 3a in 80% yield with high
enantioselectivity (86% ee), whereas all the other ligands
resulted in a substantial decrease in the yield and/or
enantioselectivity (entries 2−9, 11, and 12 versus entry 10).
Subsequent screening of solvents revealed that this asymmetric
addition is highly sensitive to the solvent used (entries 13−15),
and THF was found to be the best solvent for this reaction. In
addition, this reaction was carried out in higher yield and
enantioselectivity with prolonged reaction time and/or by
increasing the amount of ligand L10 (entries 16−18). Finally,
the addition reaction was run at 0 or 25 °C, and the desired
adduct 3a was also obtained in respectrable yields and
enantioselectivities (entries 19 and 20).
b
c
entry chiral ligand (mol %)
solvent
time, days yield,
%
ee, %
1
L1 (10)
L2 (10)
L3 (10)
L4 (10)
L5 (10)
L6 (10)
L7 (10)
L8 (10)
L9 (10)
L10 (10)
L11 (10)
L12 (10)
L10 (10)
L10 (10)
L10 (10)
L10 (10)
L10 (20)
L10 (40)
L10 (20)
L10 (20)
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
toluene
CH2Cl2
Et2O
THF
THF
THF
THF
THF
1
30
26
80
67
71
85
0
2
1
80
42
70
62
62
60
46
50
80
40
80
52
48
45
90
92
93
86
88
3
1
4
1
5
1
6
1
7
1
10
37
3
8
1
9
1
10
11
12
13
14
15
16
17
18
19
20
1
86
25
81
33
5
1
1
1
1
1
0
2
86
91
91
86
85
5
5
d
e
0.5
0.5
a
Reactions were conducted with 1 equiv of 1a, 2 equiv of 2a, 2 equiv
of n-BuLi (2.5 M in hexane), and the ligand in solvent at −78 °C.
Yield of isolated products. The ee values were determined by HPLC
b
c
d
analysis on a chiral stationary phase. Reaction temperature was 0 °C.
e
Reaction temperature was 25 °C.
ynes, the position and electronic properties of the substituents
on the phenyl ring have a limited effect on enantioselectivity of
the addition. Regardless of whether there were electron-neutral,
-donating, or -withdrawing groups on the phenyl ring, the
addition reactions proceeded smoothly to give the desired
adducts 3a−g in good to high yields (80−96%) with high
enantioselectivities (88−94% ee). 2-Naphthyl-, 1-naphthyl-,
and 3-thiophenyl-substituted enynes were also good substrates,
affording products 3h−j in 81−90% yields with 90−92% ee.
Three alkyl-substituted enynes were subjected to this addition
reaction under the same conditions, and the desired products
3k−m were obtained in 80−90% yields with good to high
enantioselectivities.
Scope of Enynylation Addition. Under these conditions,
we examined the scope of lithium binaphtholate-catalyzed
enantioselective addition of various enynes and ketones
(Scheme 3). For a series of phenyl-substituted but-3-en-1-
B
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a b
,
Scheme 3. Enantioselective 1,2-Addition of Various Enynes 2 to Acetophenone 1a
a
b
Yield of isolated products. The ee values were determined by HPLC analysis on a chiral stationary phase.
ab
,
Scheme 4. Enantioselective 1,2-Addition of Enyne 2a to a Series of Ketones 1
a
b
Yield of isolated products. The ee values were determined by HPLC analysis on a chiral stationary phase.
C
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Scheme 5. Scaled-up Version of Addition Reaction and Further Synthetic Transformation of Adduct 3a
Scheme 6. Preparation of Analogue 8 of Anti-HIV Drug Efavirenz
Next, this protocol was extended to the use of various
ketones (Scheme 4). The results showed that addition reactions
took place to afford the adducts 3n−z in yields of 80−92% with
81−94% ee for aromatic- and heteroaromatic-substituted
methylketones. One of the enynylated tertiary alcohols (3u)
was crystallized from CH2Cl2−petroleum ether, and its absolute
configuration was determined to be R from the X-ray structural
analysis.9 Interestingly, two acetophenones bearing 4-cyano and
ester groups on the phenyl ring participated in the addition
reaction, affording the desired products 3v and 3w with
exceptional chemoselectivity. To further define the scope of our
methodology, the addition reactions of different alkyl-
substituted phenylketones were also tested. The corresponding
products 3a′−3c′ were also obtained in high yields and
enantioselectivities. In addition, we investigated the addition
reaction with alkyl-substituted ketones. These substrates were
found to give good yields and ee values. For example, in the
presence of ligand L10, 1-cyclohexylethanone and 3-methyl-
butan-2-one provided the adducts 3d′ and 3e′ in good yields
with 70% ee.
Further Synthetic Transformation of Enynylation
Adduct. To evaluate this catalytic system on a large scale, 5
mmol of acetophenone 1a was used to perform the enynylation
reaction, and adduct 3a was obtained in 91% yield and 91% ee
(Scheme 5). Treatment of 3a with sodium hydride and allyl
bromide in N,N-dimethylformamide (DMF) led to formation
of optically active dienyne 4 in 95% yield. Then we tested the
Pauson−Khand cycloaddition reaction of dienyne 4 by using a
Co2(CO)8 catalyst and CO at atmospheric pressure. Bicyclic
adduct 5 was obtained in 68% yield without detectable loss of
enantioselectivity. Simple recrystallization provided the single
stereoisomer 5 with excellent optical purity. Furthermore, X-ray
structure analysis revealed the syn relationship between the
methyl group and the newly formed bridgehead hydrogen.9
Efavirenz Analogue Synthesis. Subsequently, a short
synthesis of the Efavirenz10 analogue was also conducted
(Scheme 6). Trifluoromethylketone 6 was synthesized in two
steps in high yield.10c The enantioselective catalytic addition of
(E)-but-1-en-3-yn-1-ylcyclopropane to trifluoromethylketone 6
provided the desired adduct 7 in 80% yield, albeit with 10% ee.
Apparently, the electron-withdrawing substituents at the phenyl
ring and the trifluoromethyl group could influence the
stereoselectivity of this reaction. Reduction of 7 in the presence
of iron powder and acetic acid in THF/MeOH gave the
corresponding amine, which was then converted in good overall
yield to 1H-benzo[d][1,3]oxazin-2(4H)-one 8, an analogue of
the anti-HIV drug Efavirenz. Further investigation will be
necessary to improve the enantioselectivity of this reaction and
to assess the biological activity of this intriguing compound.
CONCLUSION
■
In summary, we have successfully developed the first catalytic
enantioselective 1,2-addition of enynes to ketones. In the
presence of chiral lithium binaphtholate, the addition reaction
proceeded smoothly to give a broad variety of tertiary
propargylic alcohols in 80−96% yields with 70−94% ee.
Synthetic transformation of the adduct via Pauson−Khand
cycloaddition reaction afforded the bicyclic product without
detectable loss of enantioselectivity. Furthermore, catalytic
asymmetric enyne addition to trifluoromethylketone was
applied in synthesis of the Efavirenz analogue. Further
extension of this enynylation addition to other substrates and
investigation of the biological activity of the relative derivatives
are ongoing in our laboratory, and the results will be reported
in due course.
EXPERIMENTAL SECTION
■
General Information. Solvents were distilled following standard
procedures before use. Analytical thin-layer chromatography (TLC)
was performed on 0.20 mm silica gel plates. Silica gel (200−300 mesh)
was used for flash chromatography. 1H, 13C, and 19F NMR were
recorded at 400 or 600 MHz (1H NMR), 100 or 150 MHz (13C
NMR), and 376 or 565 MHz (19F NMR). Chemical shifts were
reported in parts per million (ppm) downfield from internal Me4Si and
external CCl3F, respectively. High-resolution mass spectra (HRMS)
were recorded by using the following ion sources: time-of-flight
(TOF) QII or Fourier transform mass spectrometer with electrospray
ionization (FTMS-ESI) or with matrix-assisted laser desorption
ionization (FTMS-MALDI).
Materials. Tetrahydrofuran (THF), diethyl ether, and toluene were
distilled from sodium/benzophenone prior to use; CH2Cl2 (dichloro-
methane, DCM) were distilled from CaH2. All purchased reagents
D
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were used without further purification. Aliphatic enyne 2m6 and 3,3′-
disubstituted (S)-BINOLs L2−L1211 are known compounds and
could be prepared according to inatiliterature methods.
CDCl3) δ −112.01∼−112.06 (m, 1F); HRMS (ESI) found m/z
147.0605 [M + H]+, calcd for C10H7F + H 147.0610; IR (KBr) ν 3271,
2962, 1585, 1499, 1402, 1034, 937, 824, 656, 560 cm−1.
General Procedure for Preparation of Aryl-Substituted
Enynes 2a−2j.5a Under a nitrogen atmosphere, 2-aryl-1-bromoe-
thene (27.3 mmol), Pd(OAc)2 (18.2 mg, 0.082 mmol), CuBr (52.1
mg, 0.36 mmol), and PPh3 (143.2 mg, 0.55 mmol) were mixed and
stirred for a few minutes at ambient temperature. Piperidine (80 mL,
distilled from CaH2) and 2-methyl-3-butyn-1-ol (2.73 g, 32.8 mmol)
were added to this mixture, and it was stirred at 50 °C for 30 min.
Then LiBr (166.0 mg, 1.9 mmol) was added and the mixture was
further stirred for 1.5 h. The reaction was quenched with water, and
the mixture was extracted with ether (30 mL × 3). The organic layer
was combined, washed twice with 2 N HCl solution, and dried over
Na2SO4. The solvent was distilled under vacuum, and the residue was
purified by flash column chromatography to give the corresponding
enynol for the next step.
(E)-1-(But-1-en-3-ynyl)-4-chlorobenzene (2g). White solid; mp
39−40 °C; 1096.2 mg, 63% yield; 1H NMR (600 MHz, CDCl3) δ 7.31
(s, 4H), 6.98 (d, J = 16.3 Hz, 1H), 6.10 (dd, J = 16.3, 2.3 Hz, 1H), 3.07
(d, J = 2.2 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 141.9, 134.8,
134.5, 129.1, 127.7, 107.9, 82.7, 80.0; HRMS (ESI) found m/z
163.0313 [M + H]+, calcd for C10H7Cl + H 163.0315; IR (KBr) ν
3272, 2918, 1591, 1496, 1403, 1089, 1010, 954, 804, 614, 515 cm−1.
(E)-2-(But-1-en-3-ynyl)naphthalene (2h). White solid; mp 77−78
°C; 1068.0 mg, 56% yield; 1H NMR (600 MHz, CDCl3) δ 7.72−7.66
(m, 3H), 7.62 (s, 1H), 7.45 (dd, J = 8.6, 1.5 Hz, 1H), 7.41−7.37 (m,
2H), 7.12 (d, J = 16.3 Hz, 1H), 6.18 (dd, J = 16.3, 2.1 Hz, 1H), 3.07
(d, J = 2.3 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 143.3, 133.7,
133.5, 133.4, 128.6, 128.4, 127.8, 127.3, 126.6, 122.8, 107.4, 83.3, 79.8;
HRMS (ESI) found m/z 179.0863 [M + H]+, calcd for C14H10 + H
179.0861; IR (KBr) ν 3287, 3053, 2922, 1688, 1597, 1505, 1360, 1264,
1170, 956, 858, 813, 747, 645 cm−1.
(E)-1-(But-1-en-3-ynyl)naphthalene (2i). White solid; mp 54−55
°C; 1144.3 mg, 60% yield; 1H NMR (600 MHz, CDCl3) δ 8.12 (d, J =
8.3 Hz, 1H), 7.86 (d, J = 16.0 Hz, 3H), 7.64 (d, J = 7.2 Hz, 1H), 7.53
(dd, J = 13.0, 7.5 Hz, 2H), 7.46 (t, J = 7.7 Hz, 1H), 6.21 (dd, J = 16.1,
2.2 Hz, 1H), 3.12 (d, J = 1.6 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ
140.5, 133.8, 133.5, 131.0, 129.5, 128.8, 126.7, 126.2, 125.7, 123.8,
123.6, 109.9, 83.3, 79.2; HRMS (ESI) found m/z 179.0861 [M + H]+,
calcd for C14H10 + H 179.0861; IR (KBr) ν 3287, 3050, 1594, 1510,
1430, 1375, 1252, 1189, 951, 773, 628 cm−1.
To a solution of enynol (10.7 mmol) in toluene (200 mL) was
added powdered potassium hydroxide (1.2 g, 21.4 mmol). The
mixture was refluxed for 1 h under an argon atomsphere. After
completion of the reaction (monitored by TLC), the reaction mixture
was filtered and solvent was removed under reduced pressure. The
residue was purified by column chromatography to give the
corresponding aryl-substituted enynes 2a−2j.
(E)-1-(But-1-en-3-ynyl)benzene (2a). Liquid; 864.0 mg, 63% yield;
1H NMR (600 MHz, CDCl3) δ 7.36 (d, J = 7.3 Hz, 2H), 7.33−7.27
(m, 3H), 7.03 (d, J = 16.3 Hz, 1H), 6.12 (dd, J = 16.3, 1.8 Hz, 1H),
3.05 (d, J = 1.4 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 143.2, 136.0,
129.0, 128.8, 126.5, 107.2; HRMS (ESI) found m/z 129.0703 [M +
H]+, calcd for C10H8 + H 129.0704; IR (KBr) ν 3298, 3055, 2935,
1601, 1509, 1446, 1223, 987, 706, 695, 622, 520 cm−1.
(E)-2-(But-1-en-3-ynyl)thiophene (2j). Liquid; 818.5 mg, 57%
yield; 1H NMR (600 MHz, CDCl3) δ 7.22 (d, J = 5.0 Hz, 1H),
7.15 (d, J = 16.1 Hz, 1H), 7.05 (d, J = 3.4 Hz, 1H), 7.00 (dd, J = 4.9,
3.7 Hz, 1H), 5.96 (dd, J = 16.0, 1.8 Hz, 1H), 3.09 (d, J = 1.8 Hz, 1H);
13C NMR (150 MHz, CDCl3) δ 141.0, 136.0, 127.9, 127.6, 125.9,
(E)-1-(But-1-en-3-ynyl)-2-methoxybenzene (2b). Liquid; 846.4
1
mg, 50% yield; H NMR (600 MHz, CDCl3) δ 7.42 (dd, J = 14.3,
106.3, 82.8, 79.8; HRMS (ESI) found m/z 135.0263 [M + Na]+, calcd
for C8H6S + H 135.0268; IR (KBr) ν 3301, 3038, 2971, 1627, 1532,
1469, 1226, 991, 812, 723, 629, 523 cm−1.
5.6 Hz, 2H), 7.30 (t, J = 7.8 Hz, 1H), 6.97 (t, J = 7.3 Hz, 1H), 6.90 (d,
J = 8.3 Hz, 1H), 6.28 (dd, J = 16.5, 2.3 Hz, 1H), 3.86 (s, 3H), 3.10 (d,
J = 2.2 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 157.1, 138.6, 130.0,
127.0, 124.9, 120.7, 111.1, 107.6, 83.8, 78.8, 55.45; HRMS (ESI) found
m/z 159.0812 [M + H]+, calcd for C11H10O + H 159.0810; IR (KBr) ν
3312, 3066, 3011, 2975, 2865, 1605, 1501, 1482, 1261, 1130, 1058,
982, 752, 626, 505 cm−1.
(E)-1-(But-1-en-3-ynyl)-3-methoxybenzene (2c). Liquid; 711.0 mg,
42% yield; 1H NMR (600 MHz, CDCl3) δ 7.54−7.04 (m, 3H), 6.98−
6.73 (m, 2H), 6.65 (s, 1H), 5.98 (d, J = 15.6 Hz, 1H), 3.71 (s, 3H),
3.00 (d, J = 34.8 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 159.1,
141.8, 136.5, 133.9, 116.4, 114.6, 111.7, 110.1, 82.6, 80.5, 55.7; HRMS
(ESI) found m/z 159.0812 [M + H]+, calcd for C11H10O + H
159.0810; IR (KBr) ν 3308, 3030, 2980, 1619, 1483, 1298, 1251, 1187,
1054, 981, 804, 625, 498 cm−1
General Procedure for Enantioselective Addition of Enynes
to Ketones. A solution of (E)-but-1-en-3-yn-1-ylbenzene (2a) (51.2
mg, 0.4 mmol) and ligand L10 (23.6 mg, 0.04 mmol) in THF (1 mL)
was stirred at −78 °C for 20 min under Ar2. n-BuLi (2.5 M in hexane,
0.16 mL, 0.4 mmol) was slowly dropped into the above solution via
syringe and the homogeneous solution was stirred for 20 min, and
then acetophenone (23.5 μL, 0.2 mmol) was added. The mixture was
allowed to stir at −78 °C for 5 days. After completion of the reaction
(monitored by TLC), the reaction was quenched with saturated
NH4Cl solution. The mixture was extracted by ether (5 mL × 3). The
organic layer was washed with NaHCO3 and brine, dried over Na2SO4,
and concentrated under reduced pressure. The residue was purified via
flash column chromatography (silica gel) with 5% ethyl acetate in
petroleum ether as eluent to give the addition product 3a. The
enantiomeric excess was determined by HPLC analysis on a Chiralcel
column. Other adducts 3b−k, 3m−z, and 3a′−e′ were obtained
through similar procedures.
(E)-1-(But-1-en-3-ynyl)-4-methoxybenzene (2d). White solid; mp
46−47 °C; 1083.4 mg, 64% yield; 1H NMR (600 MHz, CDCl3) δ 7.33
(d, J = 8.7 Hz, 2H), 6.99 (d, J = 16.3 Hz, 1H), 6.87 (d, J = 8.7 Hz,
2H), 5.99 (dd, J = 16.3, 2.3 Hz, 1H), 3.82 (s, 3H), 3.01 (d, J = 2.3 Hz,
1H); 13C NMR (150 MHz, CDCl3) δ 160.5, 142.9, 128.9, 127.9,
114.4, 104.7, 83.5, 78.6, 55.51; HRMS (ESI) found m/z 159.0810 [M
+ H]+, calcd for C11H10O + H 159.0810; IR (KBr) ν 3278, 2988, 2955,
1602, 1512, 1274, 1258, 1176, 1029, 964, 851, 814, 687, 534 cm−1.
(E)-1-(But-1-en-3-ynyl)-4-methylbenzene (2e). Liquid; 882.5 mg,
(R,E)-2,6-Diphenylhex-5-en-3-yn-2-ol (3a). Liquid; 45.6 mg, 92%
20
1
yield; 91% ee; [α]D = +21.2 (c 1.0, CH2Cl2); H NMR (600 MHz,
CDCl3) δ 7.71 (d, J = 7.5 Hz, 2H), 7.40 (dd, J = 7.2, 4.8 Hz, 4H),
7.36−7.29 (m, 4H), 7.01 (d, J = 16.3 Hz, 1H), 6.25 (d, J = 16.3 Hz,
1H), 2.50 (s, 1H), 1.85 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
145.8, 142.0, 136.3, 128.9, 128.5, 127.9, 126.5, 125.1, 107.6, 94.8, 84.3,
70.6, 33.4; HRMS (ESI) found m/z 271.1100 [M + Na]+, calcd for
C18H16O + Na 271.1099; IR (KBr) ν 3481, 3031, 2992, 2933, 2836,
1600, 1510, 1489, 1250, 1170, 1021, 956, 823, 760, 701, 530 cm−1;
HPLC (Daicel Chiralpak IC, n-hexane/i-PrOH = 90/10, 1.0 mL/min,
254 nm) tR (major) = 6.3 min, tR (minor) = 7.0 min.
1
58% yield; H NMR (600 MHz, CDCl3) δ 7.30 (d, J = 8.0 Hz, 2H),
7.16 (d, J = 7.9 Hz, 2H), 7.04 (d, J = 16.3 Hz, 1H), 6.11 (dd, J = 16.3,
2.2 Hz, 1H), 3.06 (d, J = 2.2 Hz, 1H), 2.37 (s, 3H); 13C NMR (150
MHz, CDCl3) δ 143.3, 139.2, 133.3, 129.6, 126.4, 106.0, 79.0, 21.5;
HRMS (ESI) found m/z 143.0860 [M + H]+, calcd for C11H10 + H
143.0861; IR (KBr) ν 3283, 3028, 2920, 1607, 1512, 1449, 1412, 1211,
1181, 959, 800, 522 cm−1.
(E)-1-(But-1-en-3-ynyl)-4-fluorobenzene (2f). White solid; mp 29−
(R,E)-6-(2-Methoxyphenyl)-2-phenylhex-5-en-3-yn-2-ol (3b).
1
20
30 °C; 875.8 mg, 56% yield; H NMR (600 MHz, CDCl3) δ 7.38−
Liquid; 48.9 mg, 88% yield; 94% ee; [α]D = +17.6 (c 1.0,
1
7.33 (m, 2H), 7.02 (dd, J = 20.9, 12.4 Hz, 3H), 6.05 (d, J = 16.3 Hz,
1H), 3.06 (d, J = 1.9 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 163.2
(d, J = 247.7 Hz), 142.0, 132.2, 128.2 (d, J = 8.1 Hz), 116.0 (d, J =
10.1 Hz), 107.0 (d, J = 2.4 Hz), 82.9, 79.4; 19F NMR (565 MHz,
CH2Cl2); H NMR (600 MHz, CDCl3) δ 7.69 (d, J = 7.8 Hz, 2H),
7.37 (dd, J = 14.8, 7.4 Hz, 3H), 7.30 (dd, J = 15.1, 6.6 Hz, 2H), 7.26−
7.22 (m, 1H), 6.91 (t, J = 7.5 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 6.31
(d, J = 16.4 Hz, 1H), 3.83 (s, 3H), 2.55 (s, 1H), 1.82 (s, 3H); 13C
E
dx.doi.org/10.1021/jo5005839 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
NMR (150 MHz, CDCl3) δ 157.1, 145.9, 137.4, 129.9, 128.5, 127.8,
127.1, 125.3, 125.2, 120.9, 111.2, 108.2, 94.2, 85.0, 70.6, 55.6, 33.4;
HRMS (ESI) found m/z 301.1199 [M + Na]+, calcd for C19H18O2 +
Na 301.1205; IR (KBr) ν 3396, 3057, 2983, 2837, 1597, 1488, 1463,
1247, 1163, 1027, 959, 924, 752, 700, 598, 579 cm−1; HPLC (Daicel
Chiralpak IA, n-hexane/i-PrOH = 90/10, 1.0 mL/min, 254 nm) tR
(major) = 7.4 min, tR (minor) = 8.2 min.
(R,E)-6-(Naphthalen-2-yl)-2-phenylhex-5-en-3-yn-2-ol (3h).
20
White solid; mp 78−79 °C; 53.1 mg, 89% yield; 90% ee; [α]D
=
+21.6 (c 1.0, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ 7.86−7.79 (m,
3H), 7.78−7.70 (m, 3H), 7.59 (d, J = 8.4 Hz, 1H), 7.51−7.47 (m,
2H), 7.42 (t, J = 7.5 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H), 7.18 (d, J = 16.2
Hz, 1H), 6.38 (d, J = 16.2 Hz, 1H), 2.52 (s, 1H), 1.88 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 145.8, 142.1, 133.8, 133.7, 133.6, 128.7,
128.5, 128.4, 127.9, 127.9, 127.2, 126.7, 126.6, 125.2, 122.9, 107.9,
95.1, 84.4, 70.7, 33.4; HRMS (ESI) found m/z 321.1256 [M + Na]+,
calcd for C22H18O + Na 321.1256; IR (KBr) ν 3382, 3056, 2983, 2929,
2860, 1598, 1492, 1447, 1263, 1235, 1097, 1067, 1028, 954, 810, 529
cm−1; HPLC (Daicel Chiralpak IA, n-hexane/i-PrOH = 90/10, 1.0
mL/min, 254 nm) tR (minor) = 13.2 min, tR (major) = 16.6 min.
(R,E)-6-(Naphthalen-1-yl)-2-phenylhex-5-en-3-yn-2-ol (3i).
(R,E)-6-(3-Methoxyphenyl)-2-phenylhex-5-en-3-yn-2-ol (3c).
20
Liquid; 44.5 mg, 80% yield; 91% ee; [α]D = +10.8 (c 1.0,
1
CH2Cl2); H NMR (600 MHz, CDCl3) δ 7.73 (d, J = 7.4 Hz, 2H),
7.42 (t, J = 7.1 Hz, 2H), 7.35 (d, J = 7.0 Hz, 1H), 7.28 (t, J = 7.7 Hz,
1H), 7.06−6.97 (m, 2H), 6.95 (s, 1H), 6.88 (d, J = 7.8 Hz, 1H), 6.26
(d, J = 16.2 Hz, 1H), 3.84 (s, 3H), 2.59 (s, 1H), 1.87 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 160.0, 145.8, 141.9, 137.7, 129.9, 128.5,
127.9, 125.1, 119.2, 114.5, 111.8, 108.0, 94.9, 84.2, 70.6, 55.4, 33.4;
HRMS (ESI) found m/z 301.1197 [M + Na]+, calcd for C19H18O2 +
Na 301.1205; IR (KBr) ν 3414, 3028, 2928, 2851, 2836, 1578, 1490,
1450, 1289, 1242, 1155, 1042, 953, 765, 700, 510 cm−1; HPLC (Daicel
Chiralpak IB, n-hexane/i-PrOH = 92.5/7.5, 1.0 mL/min, 254 nm) tR
(major) = 15.9 min, tR (minor) = 43.5 min.
20
Liquid; 48.3 mg, 81% yield; 90% ee; [α]D = +7.0 (c 1.0, CH2Cl2);
1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.2 Hz, 1H), 7.85 (dd, J =
13.3, 7.5 Hz, 3H), 7.79−7.74 (m, 2H), 7.64 (d, J = 7.2 Hz, 1H), 7.53
(t, J = 6.6 Hz, 2H), 7.44 (dd, J = 14.4, 7.4 Hz, 3H), 7.35 (d, J = 7.2 Hz,
1H), 6.32 (d, J = 16.0 Hz, 1H), 2.55 (s, 1H), 1.90 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 145.8, 139.2, 133.9, 133.8, 131.1, 129.3, 128.8,
128.6, 128.0, 126.6, 126.2, 125.7, 125.2, 123.7, 123.7, 110.4, 94.7, 84.5,
70.7, 33.4; HRMS (ESI) found m/z 321.1251 [M + Na]+, calcd for
C22H18O + Na 321.1256; IR (KBr) ν 3298, 3057, 2958, 2927, 2857,
1509, 1447, 1260, 1097, 1088, 1027, 949, 795, 774, 699 cm−1; HPLC
(Daicel Chiralpak IB, n-hexane/i-PrOH = 90/10, 1.0 mL/min, 254
nm) tR (major) = 14.5 min, tR (minor) = 27.3 min.
(R,E)-6-(4-Methoxyphenyl)-2-phenylhex-5-en-3-yn-2-ol (3d).
20
Liquid; 53.3 mg, 96% yield; 93% ee; [α]D = +24.3 (c 1.0,
1
CH2Cl2); H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 7.5 Hz, 2H),
7.42 (t, J = 7.5 Hz, 2H), 7.34 (dd, J = 11.1, 8.1 Hz, 3H), 6.98 (d, J =
16.3 Hz, 1H), 6.89 (d, J = 8.6 Hz, 2H), 6.12 (d, J = 16.3 Hz, 1H), 3.84
(s, 3H), 2.58 (s, 1H), 1.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
160.3, 146.0, 141.6, 129.2, 128.5, 127.8, 125.2, 114.4, 105.2, 94.1, 84.6,
70.6, 55.5, 33.4; HRMS (ESI) found m/z 301.1201 [M + Na]+, calcd
for C19H18O2 + Na 301.1205; IR (KBr) ν 3420, 3031, 2983, 2932,
2837, 1604, 1511, 1448, 1250, 1175, 1097, 1030, 956, 926, 813, 764,
700, 533 cm−1; HPLC (Daicel Chiralpak IA, n-hexane/i-PrOH = 90/
10, 1.0 mL/min, 254 nm) tR (minor) = 15.0 min, tR (major) = 20.4
min.
(R,E)-2-Phenyl-6-(thiophen-2-yl)hex-5-en-3-yn-2-ol (3j). Liquid;
20
1
50.8 mg, 90% yield; 92% ee; [α]D = +12.0 (c 1.0, CH2Cl2); H
NMR (600 MHz, CDCl3) δ 7.68 (d, J = 7.1 Hz, 2H), 7.39 (t, J = 6.7
Hz, 2H), 7.32 (d, J = 6.8 Hz, 1H), 7.21 (d, J = 3.6 Hz, 1H), 7.10 (d, J
= 15.9 Hz, 1H), 7.01 (d, J = 21.4 Hz, 2H), 6.05 (d, J = 15.9 Hz, 1H),
2.42 (s, 1H), 1.82 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 145.7,
141.3, 134.8, 128.5, 127.9, 127.4, 125.8, 125.1, 106.7, 95.0, 84.0, 70.6,
33.4; HRMS (ESI) found m/z 277.0663 [M + Na]+, calcd for
C16H14OS + Na 277.0663; IR (KBr) ν 3399, 3031, 2954, 2861, 1597,
1492, 1445, 1264, 1075, 1027, 968, 809, 761, 700, 511 cm−1; HPLC
(Daicel Chiralpak IA, n-hexane/i-PrOH = 90/10, 1.0 mL/min, 254
nm) tR (minor) = 11.5 min, tR (major) = 12.8 min.
(R,E)-2-Phenyl-6-(p-tolyl)hex-5-en-3-yn-2-ol (3e). Liquid; 44.6 mg,
20
1
85% yield; 89% ee; [α]D = +16.5 (c 1.0, CH2Cl2); H NMR (600
MHz, CDCl3) δ 7.73 (d, J = 7.5 Hz, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.35
(d, J = 7.2 Hz, 1H), 7.31 (d, J = 7.9 Hz, 2H), 7.17 (d, J = 7.7 Hz, 2H),
7.00 (d, J = 16.3 Hz, 1H), 6.21 (d, J = 16.3 Hz, 1H), 2.65 (s, 1H), 2.38
(s, 3H), 1.86 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 145.9, 142.0,
139.0, 133.5, 129.6, 128.5, 127.8, 126.40, 125.1, 106.5, 94.4, 84.5, 70.6,
33.4, 21.5; HRMS (ESI) found m/z 285.1252 [M + Na]+, calcd for
C19H18O + Na 285.1256; IR (KBr) ν 3299, 3026, 2961, 2929, 2871,
1601, 1513, 1448, 1261, 1182, 1074, 1027, 940, 800, 700, 521 cm−1;
HPLC (Daicel Chiralpak IC, n-hexane/i-PrOH = 90/10, 1.0 mL/min,
254 nm) tR (major) = 6.2 min, tR (minor) = 6.7 min.
(R)-5-Methyl-2-phenylhex-5-en-3-yn-2-ol (3k). Liquid; 33.5 mg,
20
1
90% yield; 94% ee; [α]D = −0.5 (c 1.0, CH2Cl2); H NMR (600
MHz, CDCl3) δ 7.67 (d, J = 7.6 Hz, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.31
(t, J = 7.2 Hz, 1H), 5.33 (d, J = 49.9 Hz, 2H), 2.63 (d, J = 12.9 Hz,
1H), 1.95 (s, 3H), 1.80 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
145.8, 128.4, 127.8, 126.4, 125.1, 122.5, 91.5, 86.2, 70.4, 33.40, 23.6;
HRMS (ESI) found m/z 209.0937 [M + Na]+, calcd for C13H14O +
Na 209.0943; IR (KBr) ν 3427, 3035, 2984, 2931, 2833, 1604, 1511,
1490, 1253, 1178, 1028, 951, 813, 767, 699, 523 cm−1; HPLC (Daicel
Chiralpak AD-H, n-hexane/i-PrOH = 95/5, 0.8 mL/min, 254 nm) tR
(minor) = 12.2 min, tR (major) = 12.7 min.
(R,E)-6-(4-Fluorophenyl)-2-phenylhex-5-en-3-yn-2-ol (3f). Liquid;
51.1 mg, 96% yield; 91% ee; [α]D20 = +6.7 (c 1.0, CH2Cl2); 1H NMR
(400 MHz, CDCl3) δ 7.70 (d, J = 7.5 Hz, 2H), 7.41−7.30 (m, 5H),
7.03 (t, J = 8.6 Hz, 2H), 6.96 (d, J = 16.3 Hz, 1H), 6.15 (d, J = 16.3
Hz, 1H), 2.55 (s, 1H), 1.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
163.2 (q, J = 247.4 Hz), 145.8, 140.7, 132.5, 128.5, 128.1(q, J = 8.1
Hz), 127.9, 125.1, 115.9 (q, J = 21.7 Hz), 107.4, 94.8, 84.0, 70.6, 33.4;
19F NMR (377 MHz, CDCl3) δ −112.27; HRMS (ESI) found m/z
289.1002 [M + Na]+, calcd for C18H15FO + Na 289.1005; IR (KBr) ν
3419, 3037, 2983, 2931, 2839, 1600, 1508, 1234, 1158, 1096, 1070,
1028, 814, 764, 700, 526 cm−1; HPLC (Daicel Chiralpak IC, n-
hexane/i-PrOH = 90/10, 1.0 mL/min, 254 nm) tR (major) = 6.5 min,
tR (minor) = 7.4 min.
(R,E)-2,8-Diphenyloct-5-en-3-yn-2-ol (3m). Liquid; 47.0 mg, 85%
20
1
yield; 88% ee; [α]D = +1.8 (c 1.0, CH2Cl2); H NMR (600 MHz,
CDCl3) δ 7.64 (d, J = 7.5 Hz, 2H), 7.36 (t, J = 7.2 Hz, 2H), 7.29 (t, J =
6.5 Hz, 3H), 7.23−7.16 (m, 3H), 6.31−6.08 (m, 1H), 5.59 (d, J = 15.9
Hz, 1H), 2.71 (t, J = 7.6 Hz, 2H), 2.44 (dd, J = 13.7, 5.3 Hz, 3H), 1.77
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 146.0, 144.3, 141.3, 128.6,
128.5, 128.4, 127.8, 126.2, 125.1, 109.8, 91.5, 70.5, 35.2, 34.9, 33.4;
HRMS (ESI) found m/z 299.1407 [M + Na]+, calcd for C20H20O +
Na 299.1412; IR (KBr) ν 3345, 3061, 3027, 2982, 2929, 2860, 1601,
1494, 1450, 1260, 1179, 1028, 801, 764, 699, 583 cm−1; HPLC (Daicel
Chiralpak IB, n-hexane/i-PrOH = 92/8, 1.0 mL/min, 254 nm) tR
(major) = 6.2 min, tR (minor) = 6.5 min.
(R,E)-6-(4-Chlorophenyl)-2-phenylhex-5-en-3-yn-2-ol (3g).
20
Liquid; 50.8 mg, 90% yield; 88% ee; [α]D = +8.5 (c 1.0, CH2Cl2);
1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 5.7 Hz, 2H), 7.41 (t, J =
5.9 Hz, 2H), 7.37−7.28 (m, 5H), 6.96 (d, J = 16.3 Hz, 1H), 6.22 (d, J
= 16.3 Hz, 1H), 2.58 (s, 1H), 1.86 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 145.7, 140.6, 134.8, 134.6, 129.1, 128.5, 127.9, 127.6, 125.1,
108.3, 95.4, 83.9, 70.6, 33.3; HRMS (ESI) found m/z 305.0705 [M +
Na]+, calcd for C18H15ClO + Na 305.0709; IR (KBr) ν 3131, 2960,
2927, 2866, 1592, 1489, 1401, 1261, 1091, 1019, 800, 698, 522 cm−1,
HPLC (Daicel Chiralpak IC, n-hexane/i-PrOH = 90/10, 1.0 mL/min,
254 nm) tR (major) = 6.3 min, tR (minor) = 6.9 min.
(R,E)-2-(3-Methoxyphenyl)-6-(4-methoxyphenyl)hex-5-en-3-yn-2-
20
ol (3n). Liquid; 56.13 mg, 91% yield; 94% ee; [α]D = +17.9 (c 1.0,
CH2Cl2); 1H NMR (600 MHz, CDCl3) δ 7.32−7.25 (m, 5H), 6.92 (d,
J = 16.2 Hz, 1H), 6.84 (t, J = 8.7 Hz, 3H), 6.07 (d, J = 16.2 Hz, 1H),
3.82 (s, 3H), 3.80 (s, 3H), 2.57 (s, 1H), 1.81 (s, 3H); 13C NMR (150
MHz, CDCl3) δ 160.3, 159.7, 147.7, 141.6, 129.5, 129.1, 127.8, 117.6,
114.3, 113.2, 111.1, 105.1, 93.9, 84.5, 70.5, 55.5, 33.4; HRMS (ESI)
found m/z 331.1305 [M + Na]+, calcd for C20H20O3 + Na 331.1310;
IR (KBr) ν 3446, 3032, 2982, 2960, 2934, 2836, 1603, 1510, 1252,
F
dx.doi.org/10.1021/jo5005839 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1175, 1034, 957, 812, 701, 530 cm−1; HPLC (Daicel Chiralpak IA, n-
hexane/i-PrOH = 92/8, 1.0 mL/min, 254 nm) tR (minor) = 24.4 min,
tR (major) = 32.5 min.
7.30 (t, J = 10.0 Hz, 3H), 7.16 (t, J = 7.5 Hz, 1H), 7.09 (dd, J = 11.7,
8.3 Hz, 1H), 6.93 (d, J = 16.3 Hz, 1H), 6.86 (d, J = 8.7 Hz, 2H), 6.06
(d, J = 16.3 Hz, 1H), 3.80 (s, 3H), 2.92 (s, 1H), 1.96 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 160.3 (q, J = 246.5 Hz), 160.3, 141.7,
132.3 (q, J = 10.5 Hz), 129.6 (q, J = 8.4 Hz), 129.1, 127.8, 126.9 (q, J
= 3.2 Hz), 124.1 (q, J = 3.3 Hz), 116.4 (q, J = 22.2 Hz), 114.3, 105.1,
93.0, 84.0, 68.3, 55.4, 30.7 (q, J = 2.4 Hz); 19F NMR (377 MHz,
CDCl3) δ −112.77; HRMS (ESI) found m/z 319.1107 [M + Na]+,
calcd for C19H17FO2 + Na 319.1111; IR (KBr) ν 3435, 3034, 2985,
2960, 2935, 2837, 1604, 1511, 1486, 1250, 1175, 1084, 1031, 956, 811,
760, 529 cm−1; HPLC (Daicel Chiralpak IA, n-hexane/i-PrOH = 90/
10, 1.0 mL/min, 254 nm) tR (minor) = 17.5 min, tR (major) = 29.0
min.
(R,E)-6-(4-Methoxyphenyl)-2-[4-(trifluoromethyl)phenyl]hex-5-
en-3-yn-2-ol (3u). White solid; mp 84−86 °C; 58.8 mg,; 85% yield;
85% ee; [α]D20 = +22.1 (c 1.0, CH2Cl2); 1H NMR (600 MHz, CDCl3)
δ 7.81 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.8
Hz, 2H), 6.95 (d, J = 16.3 Hz, 1H), 6.87 (d, J = 8.8 Hz, 2H), 6.07 (d, J
= 16.3 Hz, 1H), 3.81 (s, 3H), 2.78 (s, 1H), 1.83 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 160.4, 149.9, 142.1, 130.0 (q, J = 32.1 Hz),
129.0, 127.9, 125.6, 125.5 (q, J = 3.8 Hz), 124.3 (q, J = 270.5 Hz),
114.4, 104.7, 93.1, 85.1, 70.3, 55.5, 33.6; 19F NMR (376 MHz, CDCl3)
δ −62.40; HRMS (ESI) found m/z 369.1076 [M + Na]+, calcd for
C20H17F3O2 + Na 369.1079; IR (KBr) ν 3400, 3034, 2986, 2935, 2839,
1755, 1605, 1511, 1410, 1327, 1251, 1174, 1125, 1033, 845, 532 cm−1;
HPLC (Daicel Chiralpak IA, n-hexane/i-PrOH = 90/10, 1.0 mL/min,
254 nm) tR (minor) = 14.4 min, tR (major) = 19.9 min.
(R,E)-6-(4-Methoxyphenyl)-2-(p-tolyl)hex-5-en-3-yn-2-ol (3o).
20
White solid; mp 72−74 °C; 52.6 mg, 90% yield; 92% ee; [α]D
=
+15.4 (c 1.0, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ 7.59 (d, J = 7.8
Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 7.7 Hz, 2H), 6.95 (d, J
= 16.2 Hz, 1H), 6.87 (d, J = 8.4 Hz, 2H), 6.10 (d, J = 16.2 Hz, 1H),
3.82 (s, 3H), 2.48 (s, 1H), 2.37 (s, 3H), 1.83 (s, 3H); 13C NMR (150
MHz, CDCl3) δ 160.3, 143.1, 141.5, 137.5, 129.1, 127.8, 125.1, 114.4,
105.3, 94.2, 84.4, 70.5, 55.5, 33.3, 21.2; HRMS (ESI) found m/z
315.1357 [M + Na]+, calcd for C20H20O2 + Na 315.1361; IR (KBr) ν
3432, 3031, 2983, 2932, 2837, 1605, 1511, 1251, 1175, 1032, 957, 817,
533 cm−1; HPLC (Daicel Chiralpak IA, n-hexane/i-PrOH = 90/10, 1.0
mL/min, 254 nm) tR (minor) = 21.2 min, tR (major) = 23.6 min.
(S,E)-2-(2-Chlorophenyl)-6-(4-methoxyphenyl)hex-5-en-3-yn-2-ol
20
(3p). Liquid; 53.1 mg, 85% yield; 91% ee; [α]D = +10.8 (c 1.0,
1
CH2Cl2); H NMR (600 MHz, CDCl3) δ 7.72 (d, J = 7.6 Hz, 1H),
7.32 (d, J = 7.6 Hz, 1H), 7.21 (t, J = 9.4 Hz, 3H), 7.17−7.14 (m, 1H),
6.82 (d, J = 16.2 Hz, 1H), 6.76 (d, J = 8.4 Hz, 2H), 5.96 (d, J = 16.2
Hz, 1H), 3.71 (s, 3H), 3.04 (s, 1H), 1.90 (s, 3H); 13C NMR (150
MHz, CDCl3) δ 160.3, 141.7, 141.6, 132.1, 131.5, 129.2, 129.1, 127.8,
127.1, 126.9, 114.3, 105.2, 93.0, 84.3, 69.5, 55.5, 29.9; HRMS (ESI)
found m/z 335.0812 [M + Na]+, calcd for C19H17ClO2 + Na 335.0815;
IR (KBr) ν 3446, 3032, 3002, 2959, 2933, 2837, 1604, 1510, 1250,
1177, 1077, 1035, 955, 813, 759, 71, 533 cm−1; HPLC (Daicel
Chiralpak IA, n-hexane/i-PrOH = 90/10, 1.0 mL/min, 254 nm) tR
(minor) = 20.4 min, tR (major) = 37.2 min.
(E)-4-(2-Hydroxy-6-(4-methoxyphenyl)hex-5-en-3-yn-2-yl)-
benzonitrile (3v). White solid; mp 118−119 °C; 50 mg, 83% yield;
81% ee; [α]D20 = +22.8 (c 1.0, CH2Cl2); 1H NMR (600 MHz, CDCl3)
δ 7.79 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.6
Hz, 2H), 6.93 (d, J = 16.3 Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H), 6.04 (d, J
= 16.3 Hz, 1H), 3.80 (s, 3H), 2.84 (s, 1H), 1.80 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 160.4, 151.1, 142.2, 132.3, 128.8, 127.9, 126.0,
118.9, 114.4, 111.5, 104.56, 92.6, 85.4, 70.4, 55.5, 33.6; HRMS (ESI)
found m/z 304.1337 [M + H]+, calcd for C20H17NO2 + H 304.1338;
IR (KBr) ν 3520, 2988, 2954, 2932, 2834, 2223, 1604, 1509, 1454,
1439, 1340, 1310, 1249, 1178, 1095, 1030, 977, 839, 822, 592, 571,
532 cm−1; HPLC (Daicel Chiralpak IC, n-hexane/i-PrOH = 90/10, 1.0
mL/min, 254 nm) tR (minor) = 25.5 min, tR (major) = 21.6 min.
Methyl (E)-4-[2-Hydroxy-6-(4-methoxyphenyl)hex-5-en-3-yn-2-
yl]benzoate (3w). White solid; mp 119−120 °C; 60 mg, 89% yield;
89% ee; [α]D20 = +14 (c 1.0, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ
8.02 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H), 7.31 (s, 2H), 6.92
(d, J = 16.3 Hz, 1H), 6.85 (d, J = 8.5 Hz, 2H), 6.05 (d, J = 16.3 Hz,
1H), 3.90 (s, 3H), 3.79 (s, 3H), 2.95 (s, 1H), 1.81 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 167.0, 160.3, 151.0, 141.8, 129.8, 129.5, 129.0,
127.8, 125.2, 114.3, 104.8, 93.3, 84.9, 70.3, 55.4, 52.3, 33.5; HRMS
(ESI) found m/z 337.1438 [M + H]+, calcd for C21H20O4 + H
337.1440; IR (KBr) ν 3483, 2992, 2952, 2937, 2842, 1700, 1604, 1512,
1433, 1313, 1289, 1247, 1176, 1121, 1033, 1017, 976, 855, 813, 774,
705, 543 cm−1; HPLC (Daicel Chiralpak IA, n-hexane/i-PrOH = 90/
10, 1.0 mL/min, 254 nm) tR (minor) = 31.0 min, tR (major) = 38.7
min.
(R,E)-2-(3-Chlorophenyl)-6-(4-methoxyphenyl)hex-5-en-3-yn-2-ol
20
(3q). Liquid; 53.7 mg, 86% yield; 90% ee; [α]D = +28.2 (c 1.0,
CH2Cl2); 1H NMR (600 MHz, CDCl3) δ 7.59 (s, 1H), 7.47 (d, J = 7.4
Hz, 1H), 7.23 (d, J = 8.7 Hz, 2H), 7.21−7.15 (m, 2H), 6.85 (d, J =
16.3 Hz, 1H), 6.77 (d, J = 8.6 Hz, 2H), 5.98 (d, J = 16.3 Hz, 1H), 3.71
(s, 3H), 2.58 (s, 1H), 1.71 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
160.4, 148.1, 141.9, 134.4, 129.8, 129.0, 127.9, 127.9, 125.6, 123.4,
114.4, 104.9, 93.2, 85.0, 70.2, 55.5, 33.5; HRMS (ESI) found m/z
335.0814 [M + Na]+, calcd for C19H17ClO2 + Na 335.0815; IR (KBr)
ν 3401, 3033, 2984, 2932, 2837, 1604, 1511, 1468, 1420, 1250, 1175,
1032, 956, 812, 735, 696, 529 cm−1; HPLC (Daicel Chiralpak IA, n-
hexane/i-PrOH = 90/10, 1.0 mL/min, 254 nm) tR (minor) = 15.9
min, tR (major) = 24.7 min.
(R,E)-2-(4-Chlorophenyl)-6-(4-methoxyphenyl)hex-5-en-3-yn-2-ol
20
(3r). Liquid; 55.0 mg, 88% yield; 89% ee; [α]D = +8.0 (c 1.0,
1
CH2Cl2); H NMR (600 MHz, CDCl3) δ 7.62 (d, J = 8.4 Hz, 2H),
7.36−7.31 (m, 4H), 6.94 (d, J = 16.3 Hz, 1H), 6.87 (d, J = 8.6 Hz,
2H), 6.07 (d, J = 16.3 Hz, 1H), 3.81 (s, 3H), 2.68 (s, 1H), 1.80 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 160.4, 144.5, 141.8, 133.6,
129.0, 128.5, 127.8, 126.7, 114.4, 104.9, 93.5, 84.9, 70.2, 55.5, 33.5;
HRMS (ESI) found m/z 335.0815 [M + Na]+, calcd for C19H17ClO2 +
Na 335.0815; IR (KBr) ν 3406, 3033, 2984, 2837, 1604, 1511, 1488,
1250, 1175, 1091, 1032, 956, 829, 720, 534 cm−1; HPLC (Daicel
Chiralpak IA, n-hexane/i-PrOH = 90/10, 1.0 mL/min, 254 nm) tR
(minor) = 18.0 min, tR (major) = 23.3 min.
(R,E)-2-(4-Fluorophenyl)-6-(4-methoxyphenyl)hex-5-en-3-yn-2-ol
20
(3s). White solid; mp 79−81 °C; 53.3 mg, 90% yield; 89% ee; [α]D
=
(R,E)-2-[(1,1′-Biphenyl)-4-yl]-6-(4-methoxyphenyl)hex-5-en-3-yn-
+10.8 (c 1.0, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ 7.62−7.58 (m,
2H), 7.27 (d, J = 8.7 Hz, 2H), 7.01−6.97 (m, 2H), 6.88 (d, J = 16.3
Hz, 1H), 6.82−6.80 (m, 2H), 6.02 (d, J = 16.3 Hz, 1H), 3.75 (s, 3H),
2.53 (s, 1H), 1.75 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 162.4 (q, J
= 244.5 Hz), 160.4, 141.8, 129.0, 127.8, 127.0 (q, J = 8.1 Hz), 115.2
(q, J = 21.2 Hz), 114.4, 105.0, 93.7, 84.8, 70.2, 55.5, 33.6; 19F NMR
(377 MHz, CDCl3) δ −115.20; HRMS (ESI) found m/z 319.1103 [M
+ Na]+, calcd for C19H17FO2 + Na 319.1111; IR (KBr) ν 3417, 3034,
2984, 2838, 1602, 1505, 1462, 1250, 1175, 1031, 956, 920, 837, 653,
573, 533 cm−1; HPLC (Daicel Chiralpak IA, n-hexane/i-PrOH = 90/
10, 1.0 mL/min, 254 nm) tR (minor) = 15.9 min, tR (major) = 22.0
min.
2-ol (3x). White solid; mp 78−80 °C; 57.4 mg, 81% yield; 92% ee;
20
1
[α]D = +11.4 (c 1.0, CH2Cl2); H NMR (600 MHz, CDCl3) δ 7.77
(d, J = 8.2 Hz, 2H), 7.62 (dd, J = 7.7, 3.1 Hz, 4H), 7.46 (t, J = 7.6 Hz,
2H), 7.36 (dd, J = 16.4, 8.1 Hz, 3H), 6.98 (d, J = 16.3 Hz, 1H), 6.88
(d, J = 8.6 Hz, 2H), 6.12 (d, J = 16.2 Hz, 1H), 3.82 (s, 3H), 2.54 (s,
1H), 1.89 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 160.3, 145.0,
141.7, 140.9, 140.8, 129.1, 129.0, 127.8, 127.5, 127.3, 127.3, 125.7,
114.4, 105.1, 93.9, 84.7, 70.5, 55.5, 33.4; HRMS (ESI) found m/z
377.1512 [M + Na]+, calcd for C25H22O2 + Na 377.1518; IR (KBr) ν
3301, 3030, 2987, 2957, 2931, 2836, 1604, 1510, 1250, 1175, 1091,
1031, 957, 812, 531 cm−1; HPLC (Daicel Chiralpak IA, n-hexane/i-
PrOH = 90/10, 1.0 mL/min, 254 nm) tR (minor) = 27.0 min, tR
(major) = 34.7 min.
(S,E)-2-(2-Fluorophenyl)-6-(4-methoxyphenyl)hex-5-en-3-yn-2-ol
20
(3t). Liquid; 54.5 mg, 92% yield; 88% ee; [α]D = +11.8 (c 1.0,
(R,E)-6-(4-Methoxyphenyl)-2-(naphthalen-2-yl)hex-5-en-3-yn-2-
ol (3y). White solid; mp 68−70 °C; 52.5 mg, 80% yield; 89% ee;
1
CH2Cl2); H NMR (600 MHz, CDCl3) δ 7.72 (t, J = 8.0 Hz, 1H),
G
dx.doi.org/10.1021/jo5005839 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
[α]D20 = +36.0 (c 1.0, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ 8.17
(s, 1H), 7.90−7.85 (m, 3H), 7.80 (d, J = 8.5 Hz, 1H), 7.52−7.49 (m,
2H), 7.34 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 16.3 Hz, 1H), 6.88 (d, J =
8.5 Hz, 2H), 6.13 (d, J = 16.2 Hz, 1H), 3.82 (s, 3H), 2.67 (s, 1H), 1.93
(s, 3H); 13C NMR (150 MHz, CDCl3) δ 160.3, 143.2, 141.7, 133.2,
133.0, 129.1, 128.5, 128.3, 127.8, 127.7, 126.4, 126.2, 123.8, 123.5,
114.4, 105.1, 94.0, 84.8, 70.7, 55.5, 33.3; HRMS (ESI) found m/z
351.1361 [M + Na]+, calcd for C23H20O2 + Na 351.1361; IR (KBr) ν
3408, 3032, 2932, 2836, 1604, 1510, 1462, 1251, 1175, 1032, 955, 816,
533 cm−1; HPLC (Daicel Chiralpak IA, n-hexane/i-PrOH = 90/10, 1.0
mL/min, 254 nm) tR (minor) = 29.2 min, tR (major) = 34.6 min.
(S,E)-6-(4-Methoxyphenyl)-2-(thiophen-2-yl)hex-5-en-3-yn-2-ol
Hz, 2H), 1.69 (d, J = 12.2 Hz, 1H), 1.49 (s, 3H), 1.29−1.22 (m, 2H),
1.22−1.10 (m, 3H); 13C NMR (150 MHz, CDCl3) δ 160.1, 140.9,
129.2, 127.7, 114.3, 105.5, 94.2, 83.6, 71.8, 55.4, 49.1, 28.0, 27.6, 27.5,
26.5, 26.4; HRMS (ESI) found m/z 307.1673 [M + Na]+, calcd for
C19H24O2 + Na 307.1674; IR (KBr) ν 3440, 3032, 2931, 2853, 1605,
1511, 1451, 1251, 1175, 1033, 955, 813, 531 cm−1; HPLC (Daicel
Chiralpak IA, n-hexane/i-PrOH = 90/10, 1.0 mL/min, 254 nm) tR
(minor) = 11.7 min, tR (major) = 17.5 min.
(R,E)-7-(4-Methoxyphenyl)-2,3-dimethylhept-6-en-4-yn-3-ol
20
(3e′). White solid; mp 28−30 °C; 39.1 mg, 80% yield; 70% ee; [α]D
1
= +0.5 (c 1.0, CH2Cl2); H NMR (600 MHz, CDCl3) δ 7.30 (d, J =
8.5 Hz, 2H), 6.86 (t, J = 13.1 Hz, 3H), 6.03 (d, J = 16.2 Hz, 1H), 3.80
(s, 3H), 2.08 (d, J = 7.0 Hz, 1H), 1.86 (dt, J = 13.4, 6.7 Hz, 1H), 1.50
(s, 3H), 1.08 (d, J = 6.7 Hz, 3H), 1.04 (d, J = 6.8 Hz, 3H); 13C NMR
(150 MHz, CDCl3) δ 160.2, 141.0, 129.2, 127.7, 114.3, 105.5, 93.7,
83.6, 72.3, 55.4, 39.3, 27.4, 18.1, 17.7; HRMS (ESI) found m/z
267.1358 [M + Na]+, calcd for C16H20O2 + Na 267.1361; IR (KBr) ν
3408, 3032, 2932, 2836, 1604, 1510, 1462, 1251, 1175, 1032, 955, 816,
533 cm−1; HPLC (Daicel Chiralpak IA, n-hexane/i-PrOH = 90/10, 1.0
mL/min, 254 nm) tR (minor) = 12.0 min, tR (major) = 14.8 min.
Syntheses of Aliphatic Enyne 2l6 and Their Direct
Application to Enantioselective Addition to Ketone. To a
solution of triphenyl[3-(trimethylsilyl)prop-2-yn-1-yl]phosphonium
bromide (22.6 g, 50 mmol) in THF was added potassium t-butoxide
(7.3 g, 65 mmol) at 0 °C. The mixture was warmed to 25 °C, stirred
for 1 h, and cooled to 0 °C again. Cyclopropanecarbaldehyde (3.5 g,
50 mmol) was added via syringe. After 15 min, the reaction was
warmed to room temperature. The aqueous layer was extracted three
times with Et2O (90 mL). The combined organic layers were washed
with brine, dried with Na2SO4, filtered, and concentrated in vacuo.
Purification by flash chromatography afforded (E)-(4-cyclopropylbut-
3-en-1-yn-1-yl)trimethylsilane (enyne-TMS).
(E)-(4-Cyclopropylbut-3-en-1-yn-1-yl)trimethylsilane (Enyne-
TMS). Liquid; 5.10 g, 62% yield; 1H NMR (600 MHz, CDCl3) δ
5.69 (dd, J = 15.7, 9.3 Hz, 1H), 5.55 (d, J = 15.8 Hz, 1H), 1.48−1.45
(m, 1H), 0.80 (d, J = 7.4 Hz, 2H), 0.47 (d, J = 4.5 Hz, 2H), 0.16 (s,
9H); 13C NMR (150 MHz, CDCl3) δ = 150.2, 106.8, 104.5, 92.7, 14.9,
7.9, 0.2; HRMS (ESI) found m/z 187.0915 [M + Na]+, calcd for
C10H16Si + Na 187.0919; IR (KBr) ν 3085, 3009, 2960 2899, 1626,
1456, 1409, 1249, 1076, 949, 843, 759, 698, 649 cm−1.
Then tetra-n-butylammonium fluoride (TBAF) (125.4 mg, 0.48
mmol, 1.0 M solution in Et2O) was added to the cooled (0 °C)
solution of (E)-(4-cyclopropylbut-3-en-1-yn-1-yl)trimethylsilane (66
mg, 0.4 mmol) in Et2O. The reaction was stirred for half an hour,
quenched with saturated aqueous NH4Cl, and extracted twice with
Et2O (20 mL). The organic layer was combined, dried with Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by flash
column chromatography with hexane as eluent to give the
corresponding enyne 2l for the next step.
The above-obtained enyne 2l and ligand L10 (23.6 mg, 0.04 mmol)
in THF were stirred at −78 °C for 20 min under Ar2. n-BuLi (2.5 M in
hexane, 0.16 mL, 0.4 mmol) was slowly dropped into the mixture and
stirred for 20 min. Acetophenone (23.5 μL, 0.2 mmol) was added, and
the mixture was stirred for 5 days at −78 °C. After completion of the
reaction (monitored by TLC), the reaction was quenched with
saturated NH4Cl solution. The mixture was extracted by ether (5 mL
× 3). The organic layer was washed with NaHCO3 and brine, dried
with Na2SO4, and concentrated under reduced pressure. The residue
was purified via flash column chromatography (silica gel) with 5%
ethyl acetate in petroleum ether as eluent to give adduct 3l. The
enantiomeric excess was determined by HPLC analysis on a Chiralcel
column.
(R,E)-6-Cyclopropyl-2-phenylhex-5-en-3-yn-2-ol (3l). Liquid; 34.0
mg, 80% yield; 80% ee; [α]D20 = +9.0 (c 1.0, CH2Cl2); 1H NMR (600
MHz, CDCl3) δ 7.66 (d, J = 7.2 Hz, 2H), 7.36 (t, J = 6.7 Hz, 2H), 7.30
(d, J = 6.6 Hz, 1H), 5.66 (dt, J = 29.5, 12.5 Hz, 2H), 2.64 (s, 1H), 1.78
(s, 3H), 1.50 (s, 1H), 0.83 (d, J = 6.5 Hz, 2H), 0.50 (s, 2H); 13C NMR
(150 MHz, CDCl3) δ 149.5, 146.0, 128.3, 127.7, 125.1, 106.0, 91.1,
83.9, 70.4, 33.4, 14.9, 7.8; HRMS (ESI) found m/z 235.1094 [M +
Na]+, calcd for C15H16O + Na 235.1099; IR (KBr) ν 3518, 3058, 3026,
20
(3z). Liquid; 51.7 mg, 91% yield; 90% ee; [α]D = +12.8 (c 1.0,
CH2Cl2); 1H NMR (600 MHz, CDCl3) δ 7.32 (s, 1H), 7.19 (d, J = 8.6
Hz, 3H), 7.14 (d, J = 4.5 Hz, 1H), 6.81 (d, J = 16.3 Hz, 1H), 6.74 (d, J
= 8.4 Hz, 2H), 5.95 (d, J = 16.3 Hz, 1H), 3.67 (s, 3H), 2.89 (s, 1H),
1.74 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 160.1, 147.4, 141.5,
128.9, 127.7, 126.3, 125.8, 120.9, 114.2, 104.9, 93.7, 83.6, 67.8, 55.4,
32.2; HRMS (ESI) found m/z 285.0953 [M + H]+, calcd for
C17H16O2S + H 285.0950; IR (KBr) ν 3523, 3056, 2959, 2933, 2907,
2836, 1600, 1510, 1251, 1144, 1029, 960, 817, 532 cm−1; HPLC
(Daicel Chiralpak IA, n-hexane/i-PrOH = 90/10, 1.0 mL/min, 254
nm) tR (minor) = 18.8 min, tR (major) = 24.7 min.
(R,E)-7-(4-Methoxyphenyl)-3-phenylhept-6-en-4-yn-3-ol (3a′).
20
Liquid; 53.2 mg, 91% yield; 84% ee; [α]D = +16.7 (c 1.0,
1
CH2Cl2); H NMR (600 MHz, CDCl3) δ 7.67 (d, J = 7.4 Hz, 2H),
7.39 (t, J = 7.6 Hz, 2H), 7.35−7.29 (m, 3H), 6.97 (d, J = 16.3 Hz, 1H),
6.88 (d, J = 8.7 Hz, 2H), 6.12 (d, J = 16.3 Hz, 1H), 3.82 (s, 3H), 2.54
(s, 1H), 2.06 (dq, J = 14.6, 7.3 Hz, 1H), 1.98 (dq, J = 14.6, 7.4 Hz,
1H), 1.01 (t, J = 7.4 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 160.3,
144.8, 141.5, 129.1, 128.3, 127.8, 127.8, 125.8, 114.4, 105.2, 92.9, 85.7,
74.6, 55.5, 38.6, 9.3; HRMS (ESI) found m/z 315.1358 [M + Na]+,
calcd for C20H20O2 + Na 315.1361; IR (KBr) ν 3450, 3031, 2968,
2935, 2837, 1603, 1511, 1448, 1251, 1174, 1031, 958, 813, 759, 700,
533 cm−1; HPLC (Daicel Chiralpak IA, n-hexane/i-PrOH = 90/10, 1.0
mL/min, 254 nm) tR (minor) = 17.0 min, tR (major) = 24.9 min.
(R,E)-8-(4-Methoxyphenyl)-4-phenyloct-7-en-5-yn-4-ol (3b′).
20
Liquid; 54.0 mg, 88% yield; 86% ee; [α]D = +27.6 (c 1.0,
1
CH2Cl2); H NMR (600 MHz, CDCl3) δ 7.67 (d, J = 7.6 Hz, 2H),
7.38 (t, J = 7.5 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 7.30 (t, J = 7.2 Hz,
1H), 6.96 (d, J = 16.2 Hz, 1H), 6.87 (d, J = 8.5 Hz, 2H), 6.12 (d, J =
16.2 Hz, 1H), 3.82 (s, 3H), 2.46 (s, 1H), 1.99 (td, J = 12.8, 4.6 Hz,
1H), 1.95−1.87 (m, 1H), 1.54 (dt, J = 12.2, 7.1 Hz, 1H), 1.45−1.40
(m, 1H), 0.92 (t, J = 7.4 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ
160.3, 145.2, 141.5, 129.2, 128.3, 127.8, 127.8, 125.7, 114.46, 105.3,
93.2, 85.7, 74.0, 55.5, 47.9, 18.3, 14.2; HRMS (ESI) found m/z
329.1515 [M + Na]+, calcd for C21H22O2 + Na 329.1518; IR (KBr) ν
3447, 3031, 2959, 2933, 2872, 2832, 1604, 1511, 1250, 1175, 1031,
956, 813, 767, 701, 533 cm−1; HPLC (Daicel Chiralpak IA, n-hexane/
i-PrOH = 90/10, 1.0 mL/min, 254 nm) tR (minor) = 16.0 min, tR
(major) = 21.0 min.
(R,E)-1-(4-Methoxyphenyl)-5-phenyldec-1-en-3-yn-5-ol (3c′).
20
Liquid; 62.8 mg, 94% yield; 89% ee; [α]D = +23.9 (c 1.0,
1
CH2Cl2); H NMR (600 MHz, CDCl3) δ 7.68 (d, J = 7.5 Hz, 2H),
7.39 (t, J = 7.4 Hz, 2H), 7.36−7.27 (m, 3H), 6.96 (d, J = 16.2 Hz, 1H),
6.88 (d, J = 8.5 Hz, 2H), 6.13 (d, J = 16.2 Hz, 1H), 3.81 (s, 3H), 2.58
(s, 1H), 2.07−1.99 (m, 1H), 1.98−1.89 (m, 1H), 1.53 (s, 1H), 1.44−
1.38 (m, 1H), 1.31 (s, 4H), 0.89 (d, J = 6.7 Hz, 3H); 13C NMR (150
MHz, CDCl3) δ 160.3, 145.2, 141.5, 129.1, 128.3, 127.8, 127.7, 125.7,
114.3, 105.3, 93.3, 85.6, 74.0, 55.4, 45.6, 31.9, 24.6, 22.7, 14.2; HRMS
(ESI) found m/z 357.1829 [M + Na]+, calcd for C23H26O2 + Na
357.1831; IR (KBr) ν 3437, 3031, 2954, 2861, 1604, 1511, 1448, 1250,
1175, 1032, 955, 813, 767, 701, 533 cm−1; HPLC (Daicel Chiralpak
IA, n-hexane/i-PrOH = 90/10, 1.0 mL/min, 254 nm) tR (minor) =
13.6 min, tR (major) = 20.5 min.
(R,E)-2-Cyclohexyl-6-(4-methoxyphenyl)hex-5-en-3-yn-2-ol (3d′).
20
Liquid; 46.6 mg, 82% yield; 70% ee; [α]D = +12.0 (c 1.0, CH2Cl2);
1H NMR (600 MHz, CDCl3) δ 7.30 (d, J = 8.5 Hz, 2H), 6.86 (t, J =
12.7 Hz, 3H), 6.03 (d, J = 16.2 Hz, 1H), 3.80 (s, 3H), 2.12 (s, 1H),
2.01 (d, J = 11.9 Hz, 1H), 1.90 (d, J = 12.2 Hz, 1H), 1.82 (d, J = 9.1
H
dx.doi.org/10.1021/jo5005839 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2984, 2962, 2927, 2855, 1625, 1601, 1495, 1427, 1236, 1170, 1095,
1027, 949, 764, 699, 812, 500 cm−1; HPLC (Daicel Chiralpak IB, n-
hexane/i-PrOH = 90/10, 1.0 mL/min, 254 nm) tR (major) = 4.9 min,
tR (minor) = 5.4 min.
MnO2 (20.30 g, 234.0 mmol) was added to the solution of 1-(5-
chloro-2-nitrophenyl)- 2,2,2-trifluoroethan-1-ol (3.00 g, 11.7 mmol) in
CH2Cl2 (60 mL). The mixture was stirred for 16 h at 38 °C. After
filtration and removal of CH2Cl2 in vacuo, the residue was purified by
column chromatography (petroleum ether/ethyl acetate 50/1) to give
6 as a yellow solid.
Procedure for Allylation of Adduct 4. To a cooled suspension
(0 °C) of NaH (57% dispersion in oil, 17.5 mg, 0.416 mmol) in
anhydrous THF (4 mL) under argon atmosphere was added a solution
of 3a (99.3 mg, 0.4 mmol) in anhydrous THF (1 mL). The resulting
gray suspension was stirred for 20 min, and allyl bromide (136 μL,
1.58 mmol) was added. The mixture was stirred for 30 min at 0 °C,
and then the ice bath was removed and the mixture was stirred at
room temperature overnight. The mixture was cooled to 0 °C and
quenched with water (15 mL). The solution was warmed to 25 °C and
extracted with ether (3 × 10 mL). The combined organic layer was
washed with brine, dried over MgSO4, and concentrated under
reduced pressure. The crude oil was purified by flash column
chromatography (petroleum ether) to yield the allylation product 4.
(R,E)-[5-(Allyloxy)hex-1-en-3-yne-1,5-diyl]dibenzene (4). Faint
1-(5-Chloro-2-nitrophenyl)-2,2,2-trifluoroethanone (6). Yellow
solid; 2.80 g, 94% yield; mp 38−39 °C; 1H NMR (600 MHz,
CDCl3) δ 8.26 (d, J = 8.8 Hz, 1H), 7.76 (dd, J = 8.8, 2.2 Hz, 1H), 7.50
(d, J = 2.2 Hz, 1H) ;13C NMR (150 MHz, CDCl3) δ 182.7 (q, J = 39.2
Hz), 144.6, 142.7, 132.9, 131.9, 128.8, 126.1, 115.5 (q, J = 288.6 Hz);
19F NMR (565 MHz, CDCl3) δ −75.74; HRMS (ESI) found m/z
253.9830 [M + H]+, calcd for C8H3ClF3NO3 + H 253.9832; IR (KBr)
ν 3107, 1754, 1657, 1604, 1533, 1345, 1193, 966, 852, 801, 727, 690,
538 cm−1.
Enantioselective Addition of (E)-But-1-en-3-yn-1-ylcyclopro-
pane to Trifluoromethylketones (6). A solution of (E)-but-1-en-3-
yn-1-ylcyclopropane (37.0 mg, 0.4 mmol) and ligand L10 (23.6 mg,
0.04 mmol) in THF (1 mL) was stirred at −78 °C for 20 min under
Ar2. n-BuLi (2.5 M in hexane, 0.16 mL, 0.4 mmol) was slowly dropped
into the above solution via syringe and the homogeneous solution was
stirred for 20 min, and then trifluoromethylketone 6 (50.6 mg, 0.2
mmol) in THF (1 mL) was added. The mixture was allowed to stir at
−78 °C for 5 days. After completion of the reaction (monitored by
TLC), the reaction was quenched with saturated NH4Cl solution. The
mixture was extracted by ether (5 mL × 3). The organic layer was
washed with NaHCO3 and brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified via
flash column chromatography (silica gel) with 5% ethyl acetate in
petroleum ether as eluent to give addition product 7.
(E)-2-(5-Chloro-2-nitrophenyl)-6-cyclopropyl-1,1,1-trifluorohex-5-
en-3-yn-2-ol (7). Liquid; 55.3 mg, 80% yield; E/Z 8/1; 1H NMR (600
MHz, CDCl3) δ 7.81 (s, 1H), 7.47 (dd, J = 23.1, 8.0 Hz, 2H), 5.81
(dd, J = 15.6, 9.7 Hz, 1H), 5.55 (d, J = 15.8 Hz, 1H), 3.81 (s, 1H), 1.51
(d, 1H), 0.87 (d, J = 6.4 Hz, 2H), 0.54 (s, 2H); 13C NMR (150 MHz,
CDCl3) δ 153.9, 148.7, 137.2, 130.8, 130.3, 129.8, 125.8, 122.9 (q, J =
285.2 Hz), 104.0, 89.0, 80.5, 72.6 (q, J = 33.6 Hz), 15.3, 8.3; 19F NMR
(565 MHz, CDCl3) δ −78.09, −78.16; HRMS (ESI) found m/z
368.0282 [M + Na]+, calcd for C15H11ClF3NO3 + Na 368.0277; IR
(KBr) ν 3476, 3010, 1627, 1542, 1478, 1366, 1179, 1117, 942, 852,
750, 580 cm−1.
Preparation of Efavirenz Analogue 8. Fe (532.0 mg, 9.5 mmol)
and CH3CO2H (0.48 mL) were added into a solution of 7 (200.0 mg,
0.58 mmol) in THF/MeOH (2/1, 6.5 mL) at room temperature
under nitrogen atmosphere. After the reaction mixture was stirred for
one night, the resulting mixture was filtrated through Celite, and
washed with AcOEt (5 mL). The filtrate was evaporated under
reduced pressure, and the residue was dissolved in AcOEt (30 mL).
The organic layer was washed with saturated aqueous solution of
NaHCO3 (5 mL) and brine (5 mL), dried over Na2SO4, and
concentrated under reduced pressure to give the corresponding amino
alcohol for the next step.
To a solution of the corresponding amino alcohol and KHCO3 (87
mg, 0.87 mmol) in MTBE/H2O (1/2, 1.2 mL) was added 4-
nitrophenyl chloroformate (122.8 mg, 0.61 mmol), and the reaction
mixture was stirred for 1 h at ambient temperature. Then the pH of
the reaction mixture was adjusted to 12 by addition of 2 N KOH
aqueous until the carbamate dissolved. The resulting mixture was
neutralized by addition of saturated aqueous solution NH4Cl. The
whole mixture was extracted with AcOEt (10 mL × 3), and the
combined organic layers was washed with brine, dried over Na2SO4,
and concentrated under reduced pressure. The residue was purified by
a single recrystallization (petroleum ether/CH2Cl2) to give the
product 8.
20
1
yellow oil; 110 mg, 95% yield; [α]D = +3.0 (c 1.0, CH2Cl2); H
NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.4 Hz, 2H), 7.52−7.36 (m,
8H), 7.15 (d, J = 16.3 Hz, 1H), 6.40 (d, J = 16.3 Hz, 1H), 6.08 (ddt, J
= 16.0, 10.6, 5.5 Hz, 1H), 5.43 (d, J = 17.2 Hz, 1H), 5.27 (d, J = 10.3
Hz, 1H), 4.29 (dd, J = 12.2, 5.4 Hz, 1H), 3.84 (dd, J = 12.2, 5.5 Hz,
1H), 1.93 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 141.4, 140.0,
134.3, 133.2, 126.9, 126.9, 126.5, 125.9, 124.5, 124.1, 114.6, 105.7,
89.8, 84.8, 74.7, 64.5, 31.1; HRMS (ESI) found m/z 311.1411 [M +
Na]+, calcd for C21H20O + Na 311.1412; IR (KBr) ν 3649, 3060, 2986,
2930, 2859, 1647, 1599, 1491, 1446, 1233, 1082, 953, 898, 748, 699,
519 cm−1.
Procedure for Pauson−Khand Cycloaddition of 5. Co2(CO)8
(208.7 mg, 0.61 mmol) was added to a solution of 4 (80 mg, 0.28
mmol) in CH2Cl2 (4 mL) at room temperature under strict exclusion
of light, and the stirring was maintained for 2 h under an atmosphere
of CO. Then N-methylmorpholine-N-oxide (NMO) (519 mg, 4.43
mmol) was added. After the mixture was stirred for another 2 h, TLC
monitoring indicated the reaction was complete. The solvent was
removed in vacuo, and the crude product was subjected to column
chromatography on silica gel to afford cyclopentenone 5.
(1R,3aS)-1-Methyl-1-phenyl-6-[(E)-styryl]-3a,4-dihydro-1H-
cyclopenta[c]furan-5(3H)-one (5). Pale yellow powder; 59.6 mg, 68%
yield; mp 132−133 °C; [α]D20 +124.0 (c 1.0, CH2Cl2); 1H NMR (600
MHz, CDCl3) δ 7.78 (d, J = 16.3 Hz, 1H), 7.51 (d, J = 7.5 Hz, 2H),
7.46 (d, J = 7.5 Hz, 2H), 7.41 (t, J = 7.6 Hz, 2H), 7.35 (dd, J = 16.6,
8.9 Hz, 3H), 7.29 (t, J = 7.2 Hz, 1H), 6.95 (d, J = 16.2 Hz, 1H), 4.42
(t, J = 8.0 Hz, 1H), 3.56 (dd, J = 10.5, 8.3 Hz, 1H), 3.37 (d, J = 6.8 Hz,
1H), 2.73 (dd, J = 17.6, 6.5 Hz, 1H), 2.31 (dd, J = 17.6, 3.7 Hz, 1H),
1.91 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 208.0, 180.2, 143.6,
137.3, 135.4, 131.3, 129.0, 128.8, 128.5, 128.1, 126.9, 125.3, 116.3,
83.0, 70.3, 43.8, 40.2, 26.3; HRMS (ESI) found m/z 317.1542 [M +
H]+, calcd for C22H20O2 + H 317.1537; IR (KBr) ν 3649, 3025, 2977,
2931, 2854, 1598, 1493, 1446, 1267, 1175, 1091, 1031, 957, 812, 531
cm−1; HPLC (Daicel Chiralpak AD-H, n-hexane/i-PrOH = 90/10, 1.0
mL/min, 254 nm) tR (minor) = 9.2 min, tR (major) = 10.0 min.
Synthetic Procedure for 1-(5-Chloro-2-nitrophenyl)-2,2,2-
trifluoroethanone (6). To a solution of 5-chloro-2-nitrobenzalde-
hyde (3.00 g, 20.6 mmol) in dry CH2Cl2/PhMe (2:1) (100 mL)
cooled to −20 °C were added CF3Si(CH3)3 (10.0 mL, 61.8 mmol)
and tetra-n-butylammonium bromide (TBAB) [10 mL, 1.0 M in dry
CH2Cl2/PhMe (2:1)]. After the mixture was stirred for 2 h, CsF (31.9
mg, 0.2 mmol) was added and the mixture was stirred for another 6 h.
Aqueous 2 N HCl was added and the mixture was stirred for 15 min,
and then TBAF (33 mL, 1.0 M in dry THF) was added and the
mixture was stirred for one night. The reaction was quenched with
water (50 mL), the organic layer was separated, and the aqueous layer
was extracted with EtOAc (3 × 50 mL). The combined organic phases
were washed with water and brine and dried over anhydrous Na2SO4.
Filtration and removal of the solvent in vacuo gave the residue 1-(5-
chloro-2-nitrophenyl)-2,2,2-trifluoroethan-1-ol, which was used for the
next step without further purification.
(E)-6-Chloro-4-(4-cyclopropylbut-3-en-1-yn-1-yl)-4-(trifluoro-
methyl)-1H-benzo[d][1,3]oxazin-2(4H)-one (8). White solid; mp
1
177−178 °C; 158.2 mg, 80% yield; H NMR (600 MHz, CDCl3) δ
9.06 (s, 1H), 7.49 (s, 1H), 7.35 (d, J = 6.8 Hz, 1H), 6.90 (d, J = 7.6
Hz, 1H), 5.88 (dd, J = 14.4, 10.2 Hz, 1H), 5.63 (d, J = 15.6 Hz, 1H),
1.54 (s, 1H), 0.90 (d, J = 4.6 Hz, 2H), 0.57 (s, 2H); 13C NMR (150
I
dx.doi.org/10.1021/jo5005839 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
MHz, CDCl3) δ 154.6, 149.6, 133.6, 132.0, 129.4, 127.9, 122.4 (q, J =
286.5 Hz), 116.7, 115.2, 104.0, 90.3, 79.7 (q, J = 35.0 Hz), 77.9, 15.4,
8.5; 19F NMR (565 MHz, CDCl3) δ −80.67; HRMS (ESI) found m/z
364.0327 [M + Na]+, calcd for C16H11ClF3NO2 + Na 364.0328; IR
(KBr) ν 3151, 2962, 1735, 1599, 1496, 1402, 1340, 1255, 1192, 1034,
937, 867, 824, 743, 692, 656, 560 cm−1.
(4) (a) Albert, B. J.; Sivaramakrishnan, A.; Naka, T.; Koide, K. J. Am.
Chem. Soc. 2006, 128, 2792. (b) Chen, W.; Tay, J.-H.; Ying, J.; Yu, X.-
Q.; Pu, L. J. Org. Chem. 2013, 78, 2256.
(5) (a) Mizukoshi, K.; Okada, S.; Kimura, T.; Shimada, S.; Matsuda,
H. Bull. Chem. Soc. Jpn. 2008, 81, 1028. (b) Patil, N. T.; Singh, V.
Chem. Commun. 2011, 47, 11116.
(6) (a) Corey, E. J.; Ruden, R. A. Tetrahedron Lett. 1973, 14, 1495.
(b) Evans, P. A.; Murthy, V. S.; Roseman, J. D.; Rheingold, A. L.
Angew. Chem., Int. Ed. 1999, 38, 3175. (c) Marko, I. E.; Giard, T.;
Sumida, S.; Gies, A. E. Tetrahedron Lett. 2002, 43, 2317.
(7) (a) Zhang, G.-W.; Meng, W.; Ma, H.; Nie, J.; Zhang, W.-Q.; Ma,
J.-A. Angew. Chem., Int. Ed. 2011, 50, 3538. (b) Liu, T.-L.; Ma, H.;
Zhang, F.-G.; Zheng, Y.; Nie, J.; Ma, J.-A. Chem. Commun. 2011, 47,
12873.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR spectra, 13C NMR spectra, and/or HPLC analytic
results for 2a−j, 3a−z, 3a′−e′, and 4−8 (PDF), as well as
crystallographic data for compounds 3u and 5 (CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
(8) (a) Kauffman, G. S.; Harris, G. D.; Dorow, R. L.; Stone, B. R. P.;
Parsons, J. R. L.; Pesti, J. A.; Magnus, N. A.; Fortunak, J. M.;
Confalone, P. N.; Nugent, W. A. Org. Lett. 2000, 2, 3119. (b) Corbett,
J. W.; Ko, S. S.; Rodgers, J. D.; Gearhart, L. A.; Magnus, N. A.;
Bacheler, L. T.; Diamond, S.; Jeffrey, S.; Klabe, R. M.; Cordova, B. C.;
Garber, S.; Logue, K.; Trainor, G. L.; Anderson, P. S.; Erickson-
Viitanen, S. K. J. Med. Chem. 2000, 43, 2019. (c) Cozzi, P. G.; Alesi, S.
Chem. Commun. 2004, 2448. (d) Tanaka, K.; Kukita, K.; Ichibakase,
T.; Kotanib, S.; Nakajima, M. Chem. Commun. 2011, 47, 5614.
(9) CCDC 983025 and 983026 contain the supplementary
crystallographic data for 3u and 5. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
(10) (a) Young, S. D. Perspect. Drug Discovery Des. 1993, 1, 181.
(b) Thompson, A. S.; Corley, E. G.; Huntington, M. F.; Grabowski, E.
J. J. Tetrahedron Lett. 1995, 36, 8937. (c) Thompson, A. S.; Corley, E.
G.; Huntington, M. F.; Grabowski, E. J. J.; Remenar, J. F.; Collum, D.
B. J. Am. Chem. Soc. 1998, 120, 2028. (d) Tan, L.; Chen, C.; Tillyer, R.
D.; Grabowski, E. J. J.; Reider, P. J. Angew. Chem., Int. Ed. 1999, 38,
711.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail majun_an68@tju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported financially by the National Natural
Science Foundation of China (21172170 and 21225208) and
the National Basic Research Program of China (973 Program,
2014CB745100).
REFERENCES
■
(1) Selected reviews: (a) Christoffers, J., Baro, A., Eds. Quaternary
Stereocenters: Challenges and Solutions for Organic Synthesis; Wiley−
VCH: Weinheim, Germany, 2005. (b) Garcia, C.; Martin, V. S. Curr.
Org. Chem. 2006, 10, 1849. (c) Riant, O.; Hannedouche, J. Org.
Biomol. Chem. 2007, 5, 873. (d) Shibasaki, M.; Kanai, M. Chem. Rev.
2008, 108, 2853. (e) Das, J. P.; Marek, I. Chem. Commun. 2011, 47,
4593.
(2) For selected reviews, see (a) Pu, L. Tetrahedron 2003, 59, 9873.
(b) Lu, G.; Li, Y.-M.; Li, X.-S.; Chan, A. S. C. Coord. Chem. Rev. 2005,
249, 1736. (c) Lin, L.; Wang, R. Curr. Org. Chem. 2009, 13, 1565.
(d) Trost, B. M.; Weiss, A. H. Adv. Synth. Catal. 2009, 351, 963.
(3) For selected examples, see (a) Jiang, B.; Chen, Z.; Tang, X. Org.
Lett. 2002, 4, 3451. (b) Cozzi, P. G. Angew. Chem., Int. Ed. 2003, 42,
(11) (a) Ishihara, K.; Kurihara, H.; Matsumoto, M.; Yamamoto, H. J.
Am. Chem. Soc. 1998, 120, 6920. (b) Simonsen, K. B.; Gothelf, K. V.;
Jørgensen, K. A. J. Org. Chem. 1998, 63, 7536. (c) Akiyama, T.; Itoh, J.;
Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43, 1566.
(d) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356.
(e) Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am. Chem. Soc.
2007, 129, 6756. (f) Cheng, X.; Goddard, R.; Buth, G.; List, B. Angew.
Chem., Int. Ed. 2008, 47, 5079. (g) Terada, M.; Soga, K.; Momiyama,
́
́ ́
dez-Ibanez, M. A.;
̃
N. Angew. Chem., Int. Ed. 2008, 47, 4122. (h) Fernan
Macia, B.; Minnaard, A. J.; Feringa, B. L. Org. Lett. 2008, 10, 4041.
́
(i) Evans, C. G.; Gestwicki, J. E. Org. Lett. 2009, 11, 2957. (j) Rueping,
M.; Nachtsheim, B. J.; Koenigs, R. M.; Ieawsuwan, W. Chem.Eur. J.
2010, 16, 13116. (k) Kano, T.; Yurino, T.; Asakawa, D.; Maruoka, K.
Angew. Chem., Int. Ed. 2013, 52, 5532.
2895. (c) Reber, S.; Knopfel, T. F.; Carreira, E. M. Tetrahedron 2003,
̈
59, 6813. (d) Lu, G.; Li, X.; Jia, X.; Chan, W. L.; Chan, A. S. C. Angew.
Chem., Int. Ed. 2003, 42, 5057. (e) Saito, B.; Katsuki, T. Synlett 2004,
1557. (f) Cozzi, P. G.; Alesi, S. Chem. Commun. 2004, 2448. (g) Zhou,
Y.; Wang, R.; Xu, Z.; Yan, W.; Liu, L.; Kang, Y.; Han, Z. Org. Lett.
́
2004, 6, 4147. (h) Forrat, V. J.; Ramon, D. J.; Yus, M. Tetrahedron:
Asymmetry 2005, 16, 3341. (i) Lu, G.; Li, X.; Li, Y.-M.; Kwong, F. Y.;
Chan, A. S. C. Adv. Synth. Catal. 2006, 348, 1926. (j) Liu, L.; Wang, R.;
Kang, Y.-F.; Cai, H.-Q.; Chen, C. Synlett 2006, 1245. (k) Chen, C.;
Hong, L.; Xu, Z.-Q.; Liu, L.; Wang, R. Org. Lett. 2006, 8, 2277.
(l) Forrat, V. J.; Prieto, O.; Ramon
́
, D. J.; Yus, M. Chem.Eur. J. 2006,
12, 4431. (m) Wang, Q.; Zhang, B.; Hu, G.; Chen, C.; Zhao, Q.;
Wang, R. Org. Biomol. Chem. 2007, 5, 1161. (n) Chen, C.; Hong, L.;
Zhang, B.; Wang, R. Tetrahedron: Asymmetry 2008, 19, 191.
(o) Motoki, R.; Kanai, M.; Shibasaki, M. Org. Lett. 2007, 9, 2997.
(p) Trost, B. M.; Chan, V. S.; Yamamoto, D. J. Am. Chem. Soc. 2010,
132, 5186. (q) Aikawa, K.; Hioki, Y.; Mikami, K. Org. Lett. 2010, 12,
5716. (r) Turlington, M.; Du, Y.; Ostrum, S. G.; Santosh, V.; Wren, K.;
Lin, T.; Sabat, M.; Pu, L. J. Am. Chem. Soc. 2011, 133, 11780.
(s) Graham, E. R.; Tykwinski, R. R. J. Org. Chem. 2011, 76, 6574.
(t) Ohshima, T.; Kawabata, T.; Takeuchi, Y.; Kakinuma, T.; Iwasaki,
T.; Yonezawa, T.; Murakami, H.; Nishiyama, H.; Mashima, K. Angew.
Chem., Int. Ed. 2011, 50, 6296.
J
dx.doi.org/10.1021/jo5005839 | J. Org. Chem. XXXX, XXX, XXX−XXX