Cobalt-catalyzed asymmetric addition of silylacetylenes to 1,1-disubstituted allenes

Article abstract of DOI:10.1021/jo401604n

The asymmetric addition of silylacetylenes to 1,1-disubstituted allenes proceeded in the presence of a cobalt/chiral bisphosphine ligand to give the corresponding enynes with high enantioselectivity. The results of deuterium-labeling experiments indicated

Full text of DOI:10.1021/jo401604n

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Cobalt-Catalyzed Asymmetric Addition of Silylacetylenes to 1,1-
Disubstituted Allenes
Takahiro Sawano,† Keiyu Ou,† Takahiro Nishimura,*,† and Tamio Hayashi‡,§
†Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
‡Institute of Materials Research and Engineering, A*STAR, 3 Research Link, Singapore 117602
§Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543
S
* Supporting Information
ABSTRACT: The asymmetric addition of silylacetylenes to
1,1-disubstituted allenes proceeded in the presence of a
cobalt/chiral bisphosphine ligand to give the corresponding
enynes with high enantioselectivity. The results of deuterium-
labeling experiments indicated that a hydrogen atom at the
chiral center is originated from the terminal alkyne, and they
were in good agreement with the proposed catalytic cycle where enantioselectivity is determined by the reaction of the proposed
π-allylcobalt intermediate with the terminal alkyne.
Scheme 1. Rh-Catalyzed Asymmetric Addition of Terminal
Alkynes to Diphenylphosphinylallenes
INTRODUCTION
■
A recent report of the transition-metal-catalyzed asymmetric
alkynylation using terminal alkynes provides one of the most
efficient ways of preparing chiral internal alkynes in view of
high atom efficiency.1,2 There have been many successful
reports on the asymmetric alkynylation of polar unsaturated
bonds, such as aldehydes, ketones, and imines.2a,3 On the other
hand, several reports have recently appeared that describe the
asymmetric addition of terminal alkynes to less polar C−C
double bonds such as α,β-unsaturated carbonyl compounds and
related compounds or strained double bonds catalyzed by Cu,4
Rh,5 Ir,6 Ni,7 and Pd complexes.8 In this context, we recently
reported that cobalt complexes catalyze the asymmetric
alkynylation of α,β-unsaturated ketones,9 oxa- and azabenzo-
norbornadienes,10 and α,β,γ,δ-unsaturated carbonyl com-
pounds.11,12
that a cobalt/bisphosphine catalytic system displays high
catalytic activity in the addition of a silylacetylene to a 1,1-
disubstituted allene with high regio- and stereoselectivity. Here
we report the asymmetric addition of terminal alkynes to 1,1-
disubstituted allenes having a variety of substituents, which is
realized by use of a chiral cobalt catalyst.
Conjugated enynes are important building blocks found in a
variety of biologically active compounds,13 and the addition of
terminal alkynes to alkynes or allenes represents a powerful
method for the synthesis of conjugated enynes.14 There have
been several reports on the alkynylation of allenes leading to
enynes by use of Pd,15 Rh,16 and Ru catalysts.17 The first
asymmetric hydroalkynylation of allenes was reported in the
addition of terminal alkynes to 1,1-disubsituted diarylphosphi-
nylallenes in the presence of a chiral rhodium(I) catalyst and an
acid, where the enantioselective protonation of a π-
allylrhodium(I) intermediate generated by the alkynylation of
a central carbon of the allene gives the enantioenriched enynes
with high exo-selectivity (Scheme 1).18 Unfortunately, however,
applicable substrates have been limited to allenes substituted
with a phosphinyl group.
RESULTS AND DISCUSSION
■
Treatment of 1-(2,3-butadien-2-yl)-4-methoxybenzene (1a)
with (triisopropylsilyl)acetylene (2m) (2.0 equiv) in the
presence of Co(OAc)2·4H2O (5 mol %), dppe (5 mol %),
and zinc powder (50 mol %) in dimethyl sulfoxide (DMSO) at
80 °C for 3 h, which is one of the standard reaction conditions
of the cobalt-catalyzed alkynylations,9 gave a mixture of the
addition products in 89% yield, exo-enyne 3am as a major
product and its isomer endo-enyne 4am (3am/4am = 90/10,
E/Z of 4am = 97/3, Table 1, entry 1). The catalytic system
based on the cobalt complex displaying high exo-selectivity was
promising for the development of asymmetric variant of the
reaction. Of several commercially available chiral bisphosphine
ligands, (S,S)-chiraphos,21 (S,S)-bdpp,22 (R,R)-QuinoxP*,23
(S,S)-Me-Duphos,24 and (R,Sp)-Josiphos25 (entries 2−6),
The cobalt-catalyzed reaction has been recently developed as
one of the useful tools of carbon−carbon bond formation with
the unique reactivity and selectivity.19,20 During our ongoing
investigation into cobalt-catalyzed alkynylation, it was found
Received: July 30, 2013
© XXXX American Chemical Society
A
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amount of the silylacetylene (1.5 equiv) and zinc powder (10
mol %, entry 11). Anhydrous Co(OAc)2 can also be used as a
catalyst precursor giving the addition product with essentially
the same yield and ee as that with Co(OAc)2·4H2O (entry 12).
The reaction without zinc gave only a very low yield (1%) of
the addition products (entry 13). The absolute configuration of
3am obtained with (R,Sp)-L4 was assigned to be S-(+) by X-ray
crystallographic analysis of compound 8, which was derived
from 3am in two steps (vide infra).
Table 1. Cobalt-Catalyzed Asymmetric Alkynylation of
Allene 1a
a
The results obtained for the cobalt-catalyzed addition of
silylacetylenes to 1,1-disubstituted allenes are summarized in
Table 2. The reaction of 1,2-butadienes substituted with p-, m-,
Table 2. Cobalt-Catalyzed Asymmetric Addition of
a
Silylacetylenes 2 to Allenes 1
b
c
entry
ligand
yield (%)
ee (%)
1
2
dppe
89 (90/10)
89 (76/24)
67 (85/15)
75 (92/8)
35 (90/10)
91 (99/1)
91 (87/13)
10 (30/70)
95 (>99/1)
83 (98/2)
89 (97/3)
82 (96/4)
1 (>99/1)
b
c
entry
Ar
R
product
yield (%)
ee (%)
(S,S)-chiraphos
(S,S)-bdpp
(R,R)-QuinoxP*
(S,S)-Me-Duphos
(R,Sp)-Josiphos
(R,Sp)-L1
25 (R)
18 (R)
71 (S)
50 (S)
82 (S)
43 (S)
1
2
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
4-FC6H4
Me (1a)
Me (1b)
Me (1c)
Me (1d)
Me (1e)
Me (1f)
Me (1g)
Et (1h)
3am
3bm
3cm
3dm
3em
3fm
3gm
3hm
3im
3jm
3an
89 (97/3)
87 (95/5)
74 (85/15)
82 (96/4)
81 (95/5)
94 (98/2)
88 (89/11)
77 (89/11)
81 (98/2)
70 (96/4)
74 (95/5)
99
98
3
4
d
3
96
5
4
98
6
5
4-ClC6H4
Ph
>99.5
98
7
6
d
8
(R,Sp)-L2
−
7
1-naphthyl
4-MeOC6H4
4-MeOC6H4
Ph
99
9
(R,Sp)-L3
89 (S)
99 (S)
99 (S)
98 (S)
8
97
10
(R,Sp)-L4
e
9
Bu (1i)
96
e
11
(R,Sp)-L4
e
10
11
MeOCH2 (1j)
Me (1a)
96
e,f
12
13
(R,Sp)-L4
e
4-MeOC6H4
92
g
d
(R,Sp)-L4
−
a
Reaction conditions: allene 1 (0.20 mmol), alkyne 2 (0.30 mmol),
Co(OAc)2·4H2O (5 mol %), (R,Sp)-L4 (5 mol %), Zn (10 mol %),
DMSO (0.3 mL) at 80 °C for 3 h. Yield of isomers. The value in
a
Reaction conditions: allene 1a (0.20 mmol), (triisopropylsilyl)-
acetylene (2m) (0.40 mmol), Co(OAc)2·4H2O (5 mol %), ligand (5
mol %), Zn (50 mol %), DMSO (0.3 mL) at 80 °C for 3 h. Yield of
isomers. The value in parentheses is the ratio of isomers (3am/4am).
The ee of 3am was determined by chiral HPLC analysis of the
desilylated product of 3am. Not determined. Alkyne (0.30 mmol),
Zn (10 mol %). Co(OAc)2 was used instead of Co(OAc)2·4H2O.
Alkyne (0.30 mmol) without Zn. Cy = cyclohexyl. dppe =1,2-
b
b
c
parentheses is the ratio of isomers (3/4). Determined by chiral HPLC
d
e
analysis of the desilylated products of 3. For 10 h. Determined by
chiral HPLC analysis of 3.
c
d
e
f
g
and o-methoxyphenyl groups (1a−c) gave the corresponding
enynes 3am−cm in good yields with high enantioselectivity
(96−99% ee, entries 1−3). Allenes having electron-deficient
aryl groups (1d and 1e), phenyl (1f), and 1-naphthyl (1g) are
also good substrates to give the corresponding enynes 3dm−
gm with high enantioselectivity (entries 4−7). The alkynylation
of allenes substituted with not only methyl on R (1a, entry 1)
but also ethyl (1h), butyl (1i), and methoxymethyl (1j)
proceeded to give the corresponding addition products 3hm−
jm in good yields with high enantioselectivity (entries 8−10).
The present cobalt-catalyzed alkynylation can introduce bulky
silylacetylene 2n with high enantioselectivity (92% ee, entry
11), but phenylacetylene and 1-octyne were not applicable due
to the alkyne oligomerization.
The reactions of allenes substituted with cyclohexyl (1k) and
dimethylphenylsilyl (1l) with alkyne 2m in the presence of the
Co/dppe catalytic system proceeded well to give the
corresponding enynes 3km and 3lm in high yields with high
exo-selectivity (eq 1). However, the asymmetric alkynylation of
1k by use of (R,Sp)-L4 resulted in a 6% yield with 31%
conversion of 1k (eq 2). A less bulky ligand (R,Sp)-Josiphos
displayed higher catalytic activity in the reaction of 1k to give
3km in 88% yield, although the ee was modest (58% ee).
bis(diphenylphosphino)ethane.
(R,Sp)-Josiphos displayed both high catalytic activity and
enantioselectivity to give 3am with 82% ee (entry 6). The
substituents on two phosphorus atoms of the Josiphos-type
ligands have significant influences on both the yield and
enantioselectivity. Thus, the use of (R,Sp)-L1,26 which has
phosphorus groups replacing each other in the Josiphos ligand,
displayed low enantioselectivity (43% ee, entry 7). The ligand
(R,Sp)-L225 bearing bulky tert-butyl groups (R1) gave a low
yield of the addition products (entry 8). The ligand L326
substituted with bulkier aromatic rings than those of the
Josiphos ligand, 3,5-dimethyl-4-methoxyphenyl groups on the
ferrocenylphosphino group (R2), increased the enantioselectiv-
ity (89% ee, entry 9). Based on these results, we prepared L4
bearing a bis(3,5-di-tert-butyl-4-methoxyphenyl)-
phosphinoferrocenyl moiety, and it was found that the use of
(R,Sp)-L4 displays a very high enantioselectivity (99% ee) to
give 83% yield of the addition products with high exo-selectivity
(3am/4am = 98/2, entry 10). The yield and enantioselectivity
of 3am were kept high (89% yield, 3am/4am = 97/3, E/Z of
4am = 22/78, 99% ee of 3am) in the reaction with a reduced
B
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π-allylcobalt(I) complex and the enantioselective protonation
of the π-allylcobalt(I) takes place to give the enantioenriched
enyne in the present reaction (vide infra).
Further experiments to gain some mechanistic insight were
carried out using allene 1f and dppe as a ligand (eqs 4−6). A
The enyne 3am obtained here with high enantioselectivity
can be converted into several chiral compounds without loss of
the enantiomeric purity (Scheme 2). Thus, removal of a silyl
Scheme 2. Transformations of 3am*
*
Key: (a) Bu4NF, MeOH, THF, rt; (b) N-mesyl-2-iodoaniline, cat.
Pd(PPh3)4, cat. CuI, 1,8-diazabicyclo[5.4.0]undec-7-ene, EtOH, reflux;
(c) 1,4-diphenylbutadiyne, cat. Pd(PPh3)4, THF, reflux; (d) 1-azido-4-
chlorobenzene, cat. CuSO4·5H2O, Na-(+)-ascorbate, PhCO2H,
31
monovalent tetrahedral cobalt(I) complex CoCl(PPh3)3 can
a
tBuOH, H2O, rt. Including other isomers (<4%).
be applied as a catalyst precursor without use of zinc, and the
reaction in the presence of dppe and KOAc even in a short
reaction time of 30 min gave the addition products in 49% yield
(eq 4), where both dppe and KOAc were required for the
formation of the addition products. As shown in Table 1 (entry
11 vs 13), the use of Zn is essential for the reaction starting
with Co(OAc)2. These results indicate that the active catalytic
species in the present reaction is a monovalent cobalt in situ
generated by reduction of cobalt(II) acetate with zinc.31a The
formation of a cobalt(I) species by reduction of a cobalt(II)
complex with zinc has been proposed in the cobalt-catalyzed
reactions using cobalt(II) halides as catalyst precursors with
zinc.20
Equations 5 and 6 demonstrate that the hydrogen atom at
the chiral center of the product is directly derived from the
terminal alkyne not from other possible proton source such as
in situ generated acetic acid. Treatment of 1f with 2m (2 equiv)
in the presence of acetic acid-d (2 equiv), Co(OAc)2 (20 mol
%), dppe (20 mol %), and zinc powder (40 mol %) at 80 °C for
30 min gave 3fm in 56% yield, which contains 6% of deuterium
at the chiral center (eq 5). On the other hand, the reaction of 1f
with the deuterated alkyne 2m-d in the presence of acetic acid
gave 12% yield of 3fm with 79% D (eq 6). The partial H−D
scrambling is probably due to the H−D exchange of the
terminal alkyne with acetic acid, which was observed in the
reaction of 2m with acetic acid-d under the same reaction
conditions except in the absence of 1f (38% D in the recovered
2m). The H−D exchange may proceed by way of an
alkynylcobalt(I) intermediate, whose formation was also
group of 3am by treatment with tetrabutylammonium fluoride
gave 5 in 84% yield (Scheme 2a), which was transformed into
indole 6 by the reaction with N-mesyl-2-iodoaniline in the
presence of a palladium and a copper catalyst (Scheme 2b).27
The palladium-catalyzed benzannulation28 of 5 with 1,4-
diphenylbutadiyne gave chiral diarylethane 7 in 91% yield
(Scheme 2c). The copper-catalyzed cycloaddition29 of 5 with 1-
azido-4-chlorobenzene proceeded to give triazole 8 in 92%
yield (Scheme 2d), and its absolute configuration was
determined to be S by X-ray crystallographic analysis with the
Flack parameter (−0.02).30
The reaction of allene 1a with the deuterated alkyne 2m-d in
place of 2m gave the addition product 3am-d, where the chiral
center was selectively deuterated (eq 3). The endo-enyne 4am
also contained deuterium at the methyl group originated from
the allene terminal carbon. These results imply that both the
exo-enyne and the endo-enyne are formed via a protonation of a
C
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quintet; m, multiplet. DMSO was distilled over CaH2 under N2.
Co(OAc)2·4H2O, CoCl(PPh3)3, and zinc powder were purchased and
used as received. Co(OAc)2 was dried under reduced pressure before
use. Allenes35 1a (CAS no. 87959-49-7), 1b (CAS no. 57532-79-3), 1d
(CAS no. 221312-24-9), 1e (CAS no. 1037048-15-9), 1f (CAS no.
22433-39-2), 1g (CAS no. 1115021-07-2), 1h (CAS no. 1041791-80-
3), 1i (CAS no. 1020255-02-0), 1j (CAS no. 343951-53-1), 1k (CAS
no. 59409-49-3), 1l (CAS no. 252639-93-3), and deuterated alkyne
2m-d (CAS no. 1115020-74-0)10 were prepared according or
analogous to the reported procedures.
proposed in our previous studies on the cobalt-catalyzed
alkynylation of oxabenzonorbornadienes under similar reaction
conditions. The different reactivity between 2m and 2m-d is
demonstrated by the intermolecular competition experiment
(eq 7). A positive kinetic isotope effect (kH/kD = 2.4) was
observed in the reaction of 1f with 2m and 2m-d.
On the basis of the results described above in eqs 3−7, the
catalytic cycle proposed for the present hydroalkynylation of
allene 1a is illustrated in Scheme 3. The catalytic reaction is
1-(Buta-2,3-dien-2-yl)-2-methoxybenzene (1c). To a solution
of 1-(2,2-dibromo-1-methylcyclopropyl)-2-methoxybenzene (CAS no.
1064001-03-1)36 (1.80 g, 5.63 mmol) in Et2O (5 mL) was added
dropwise MeLi (1.12 M Et2O solution, 6.0 mL, 6.8 mmol) at −40 °C.
After the solution was stirred at the same temperature for 1.5 h, water
was added. The mixture was extracted with Et2O, and the combined
organic extracts were washed with water until the aqueous layer
became neutral, dried (Na2SO4), filtered, and concentrated on a rotary
evaporator. After evaporation of the solvent, the residue was subjected
to flash column chromatography (silica gel, hexane) to give compound
1c as a pale yellow oil (664 mg, 4.15 mmol, 74%): 1H NMR (CDCl3)
δ 2.09 (t, J = 3.2 Hz, 3H), 3.84 (s, 3H), 4.79 (q, J = 3.2 Hz, 2H), 6.88
(d, J = 8.0 Hz, 1H), 6.93 (td, J = 8.0, 1.0 Hz, 1H), 7.20−7.25 (m, 2H);
13C NMR (CDCl3) δ 19.2, 55.5, 73.5, 97.8, 111.3, 120.6, 127.3, 128.2,
129.2, 156.9, 209.3; HRMS (ESI-TOF) calcd for C11H12NaO (M +
Na)+ 183.0780, found 183.0779.
Scheme 3. Proposed Catalytic Cycle
(R,Sp)-L4. Reported procedures37 were modified and used for the
preparation of (R,Sp)-L4. To a solution of N,N-diethylphosphor-
amidous dichloride (CAS no. 1069−08−5)38 (1.9 mL, 13 mmol) in
THF (13 mL) was added dropwise 3,5-di(tert-butyl)-4-methoxyphe-
nylmagnesium bromide (1.0 M in THF solution, 39 mL, 39 mmol),
prepared from 1-bromo-3,5-di(tert-butyl)-4-methoxybenzene and
magnesium turnings, at 0 °C, and then the mixture was warmed to
room temperature. After being stirred overnight, the mixture was
filtered through a pad of Celite with pentane as eluent and the filtrate
was concentrated under reduced pressure. The residue was dissolved
in pentane and filtered through a pad of Celite. After removal of the
solvent under reduced pressure, the residue was dissolved in hexane
(65 mL). To the solution was added HCl solution (1 M in Et2O, 26
mL, 26 mmol) at 0 °C, and the mixture was stirred at 0 °C for 2 h.
The mixture was filtered through a pad of Celite with hexane as eluent,
and the filtrate was concentrated under reduced pressure to give
chlorobis(3,5-di-tert-butyl-4-methoxyphenyl)phosphane (s1), which
was used without further purification. To a solution of (R)-N,N-
dimethyl-1-ferrocenylethylamine (CAS no. 31886-58-5)39 (2.3 g, 9.0
mmol) in Et2O (13 mL) was added dropwise BuLi (1.64 M in hexane
solution, 6.6 mL, 11 mmol) at 0 °C. The mixture was stirred for 1.5 h,
and then the solution of s1 (13 mmol) in Et2O (8 mL) was added at 0
°C. After being stirred for 1 h, the mixture was warmed to room
temperature and aqueous NaHCO3 was added. The mixture was
extracted with Et2O, and the combined organic extracts were dried
(MgSO4), filtered, and concentrated under reduced pressure. The
residue was subjected to column chromatography (alumina, hexane/
Et2O = 5/1) to give (R,Sp)-2-bis(3,5-di-tert-butyl-4-methoxyphenyl)-
phosphino-1-(1′-N,N-dimethylaminoethyl)ferrocene (s2) with some
initiated by the reduction of cobalt(II) to cobalt(I) by zinc
powder giving cobalt(I) acetate A, which undergoes the
reaction with alkyne 2m to form alkynylcobalt(I)32 B and
acetic acid. The insertion of allene 1a into the alkynyl cobalt
bond results in the formation of π-allylcobalt(I)33 C.
Protonation of C at the more substituted carbon with the
terminal alkyne 2m leads to enyne 3am and regenerates
alkynylcobalt(I) B. Provided that the protonation of the π-
allylcobalt(I) intermediate C by the terminal alkyne takes place
from the same side of cobalt via an oxidative addition/reductive
elimination or a σ-bond metathesis pathway, the C-1 and C-2
structures are favorable leading to (S)-3am.34
CONCLUSION
■
In summary, the catalytic asymmetric addition of silylacetylenes
to 1,1-disubstituted allenes was realized by use of a chiral cobalt
catalyst, giving the corresponding enynes with high enantiose-
lectivity. The results of deuterium-labeling experiments were in
good agreement with the proposed catalytic cycle, where
enantioselectivity is determined by the reaction of the proposed
π-allylcobalt intermediate with the terminal alkyne.
1
impurities (950 mg, 1.3 mmol, 15% yield): H NMR (CDCl3) δ 1.26
(d, J = 6.7 Hz, 3H), 1.32 (s, 18H), 1.41 (s, 18H), 1.71 (s, 6H), 3.58 (s,
3H), 3.71 (s, 3H), 3.79−3.82 (m, 1H), 3.94 (s, 5H), 4.12 (qd, J = 6.7
Hz, JP−H = 2.5 Hz, 1H), 4.22 (t, J = 2.1 Hz, 1H), 4.29−4.34 (m, 1H),
7.21 (d, JP−H = 8.4 Hz, 2H), 7.50 (d, JP−H = 7.8 Hz, 2H); 31P NMR
(CDCl3) δ −25.3; HRMS (ESI-TOF) calcd for C44H64FeNO2P (M)+
725.4019, found 725.4020. A mixture of s2 (950 mg, 1.3 mmol) and
dicyclohexylphosphine (0.29 mL, 1.4 mmol) in acetic acid (11 mL)
was stirred at 80 °C overnight. After removal of the solvent under
reduced pressure, the residue was subjected to column chromatog-
raphy (alumina, hexane/Et2O = 20/1) to give (R,Sp)-L4 as a yellow
EXPERIMENTAL SECTION
General Methods. All anaerobic and moisture-sensitive manipu-
lations were carried out with standard Schlenk techniques under
predried nitrogen or glovebox techniques under argon. NMR spectra
■
1
were recorded on a NMR spectrometer (500 MHz for H, 125 MHz
for 13C, and 202 MHz for 31P). Chemical shifts are reported in δ
(ppm) referenced to the residual peaks of CDCl3 (δ 7.26) or C6D6 (δ
7.16) for 1H NMR, CDCl3 (δ 77.00) or C6D6 (δ 128.00) for 13C NMR
and an external H3PO4 standard for 31P NMR. The following
abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; quint,
solid (1.0 g, 1.2 mmol, 89% yield): mp 82−84 °C; [α]20 −199 (c
D
0.46, CHCl3); 1H NMR (C6D6) δ 1.10−1.43 (m, 12H), 1.45 (s, 18H),
1.47 (s, 18H), 1.55−1.92 (m, 10H), 1.64 (dd, J = 7.2 Hz, JP−H = 4.7
Hz, 3H), 3.39 (s, 3H), 3.44 (s, 3H), 3.66 (qd, J = 7.2 Hz, JP−H = 3.7
D
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Hz, 1H), 3.96 (s, 5H), 4.23 (t, J = 2.4 Hz, 1H), 4.23−4.26 (m, 1H),
4.30−4.35 (m, 1H), 7.63 (d, JP−H = 7.6 Hz, 2H), 7.88 (d, JP−H = 8.1
Hz, 2H); 13C NMR (C6D6) δ 16.9 (1C), 26.9−31.8 (m, 11 C), 27.2
(dd, JP−C = 25, 10 Hz, 1C), 32.3 (6C), 32.4 (6C), 33.4 (dd, JP−C = 22,
3 Hz, 1C), 35.98 (2C), 36.03 (2C), 64.2 (2C), 68.6 (1C), 68.8 (dd,
JP−C = 4, 3 Hz, 1C), 69.7 (5C), 71.5 (d, JP−C = 5 Hz, 1C), 77.1 (dd,
JP−C = 13, 3 Hz, 1C), 102.2 (dd, JP−C = 27, 20 Hz, 1C), 132.3 (d, JP−C
= 20 Hz, 2C), 133.9 (dd, JP−C = 8, 2 Hz, 2C), 134.7 (d, JP−C = 24 Hz,
2C), 135.2 (dd, JP−C = 5, 1 Hz, 2C), 142.5 (d, JP−C = 11 Hz, 1C),
143.0 (d, JP−C = 13 Hz, 1C), 159.7 (1C), 160.8 (1C); 31P NMR
(C6D6) δ −27.8 (d, J = 31 Hz), 14.8 (d, J = 31 Hz); IR (thin film) ν
1410, 1220, 1115, 1011, 810 cm−1; HRMS (ESI-TOF) calcd for
C54H80FeO2P2 (M)+ 878.4977, found 878.4976.
111.6, 113.5, 119.9, 122.3, 129.2, 135.1, 145.3, 159.6; HRMS (ESI-
TOF) calcd for C13H14NaO (M + Na)+ 209.0937, found 209.0940.
Table 2, entry 3 ((R)-3cm): colorless oil, 74% yield (50.7 mg, 3cm/
4cm = 85/15); [α]20D +23 (c 0.82, CHCl3) for 96% ee (R); 1H NMR
(CDCl3) δ 0.98−1.05 (m, 21H), 1.42 (d, J = 7.1 Hz, 3H), 3.81 (s,
3H), 4.08 (q, J = 7.1 Hz, 1H), 5.29−5.32 (m, 1H), 5.42−5.44 (m,
1H), 6.83 (dd, J = 7.8, 1.0 Hz, 1H), 6.90 (td, J = 7.8, 1.0 Hz, 1H), 7.16
(td, J = 7.8, 1.6 Hz, 1H), 7.31 (dd, J = 7.8, 1.6 Hz, 1H); 13C NMR
(CDCl3) δ 11.3, 18.6, 19.2, 37.9, 55.4, 90.9, 107.2, 110.4, 120.4, 120.9,
127.2, 127.7, 132.5, 136.0, 156.8; IR (neat) ν 2942, 2864, 1492, 1462,
1243, 883, 750, 675 cm−1; HRMS (ESI-TOF) calcd for C22H34NaOSi
(M + Na)+ 365.2271, found 365.2268. (R)-3cm′: colorless oil (3cm′/
4cm′ = 94/6); the ee was measured by HPLC (Chiralcel OD-H
column, flow 0.5 mL/min, hexane, 224 nm, t1 = 24.8 min (R), t2 = 29.9
General Procedure for Table 2. A mixture of Co(OAc)2·4H2O
(2.5 mg, 0.010 mmol), (R,Sp)-L4 (8.8 mg, 0.010 mmol), and Zn
powder (1.3 mg, 0.020 mmol) in DMSO (0.3 mL) was stirred at 80
°C for 15 min under N2. To the mixture were added allene 1 (0.20
mmol) and (triisopropylsilyl)acetylene (2m) (68 μL, 0.30 mmol) at
room temperature, and it was stirred at 80 °C for 3 h. The mixture was
passed through a short column of silica gel with Et2O as eluent. After
removal of the solvent on a rotary evaporator, the residue was
subjected to preparative TLC (silica gel, hexane/ethyl acetate = 50/1).
Characterization of the Products. Data for major products 3 are
shown below. For endo-enyne 4am, the structure was determined by
NOE experiments and the data of 1H NMR are shown below. The ee
values of compounds 3am−hm were determined by chiral HPLC
analysis of their desilylated products 5 and 3′ (including a small
amount of their isomer) of them by tetrabutylammonium fluoride
(80−99% yields).
min (S)); [α]20 +4 (c 0.47, CHCl3) for 96% ee (R). 1H NMR
D
(CDCl3) δ 1.42 (d, J = 7.2 Hz, 3H), 2.84 (s, 1H), 3.82 (s, 3H), 4.07
(q, J = 7.2 Hz, 1H), 5.33−5.36 (m, 1H), 5.49−5.51 (m, 1H), 6.86 (dd,
J = 7.8, 1.0 Hz, 1H), 6.94 (td, J = 7.8, 1.0 Hz, 1H), 7.21 (td, J = 7.8, 1.7
Hz, 1H), 7.27 (dd, J = 7.8, 1.7 Hz, 1H); 13C NMR (CDCl3) δ 19.0,
37.8, 55.5, 77.4, 83.9, 110.6, 120.5, 122.2, 127.4, 127.5, 132.0, 134.7,
156.9; HRMS (ESI-TOF) calcd for C13H14NaO (M + Na)+ 209.0937,
found 209.0939.
Table 2, entry 4 ((S)-3dm): colorless oil, 82% yield (53.9 mg, 3dm/
1
4dm = 96/4); [α]20 +9 (c 0.81, CHCl3) for 98% ee (S); H NMR
D
(CDCl3) δ 0.98−1.02 (m, 21H), 1.46 (d, J = 7.1 Hz, 3H), 3.57 (q, J =
7.1 Hz, 1H), 5.30−5.32 (m, 1H), 5.41−5.44 (m, 1H), 6.92−6.99 (m,
2H), 7.21−7.26 (m, 2H); 13C NMR (CDCl3) δ 11.2, 18.5, 19.9, 45.3,
92.0, 106.3, 114.8 (d, JF−C = 21 Hz), 120.9, 128.9 (d, JF−C = 8 Hz),
136.4, 139.7 (d, JF−C = 3 Hz), 161.6 (d, JF−C = 244 Hz); IR (neat) ν
2943, 2865, 1509, 1226, 882, 836, 675 cm−1; HRMS (ESI-TOF) calcd
for C21H31FNaSi (M + Na)+ 353.2071, found 353.2074. (S)-3dm′:
colorless oil (3dm′/4dm′ = 97/3); the ee was measured by HPLC
(Chiralcel OJ-H column, flow 0.5 mL/min, hexane, 224 nm, t1 = 26.3
min (R), t2 = 27.6 min (S)); [α]20D +3 (c 0.47, CHCl3) for 98% ee (S).
1H NMR (CDCl3) δ 1.46 (d, J = 7.2 Hz, 3H), 2.86 (s, 1H), 3.58 (q, J
= 7.2 Hz, 1H), 5.36−5.38 (m, 1H), 5.49−5.51 (m, 1H), 6.96−7.02 (m,
2H), 7.20−7.26 (m, 2H); 13C NMR (CDCl3) δ 19.8, 45.0, 78.3, 83.1,
115.0 (d, JF−C = 21 Hz), 122.2, 128.9 (d, JF−C = 8 Hz), 135.2, 139.2 (d,
JF−C = 4 Hz), 161.6 (d, JF−C = 244 Hz); HRMS (APCI-TOF) calcd for
C12H11F (M)+ 174.0839, found 174.0839.
Table 2, entry 1 ((S)-3am): colorless oil; 89% yield (60.8 mg, 3am/
1
4am = 97/3); [α]20 +9 (c 0.87, CHCl3) for 99% ee (S); H NMR
D
(CDCl3) δ 1.00−1.05 (m, 21H), 1.46 (d, J = 7.0 Hz, 3H), 3.54 (q, J =
7.0 Hz, 1H), 3.78 (s, 3H), 5.27−5.29 (m, 1H), 5.39−5.41 (m, 1H),
6.82 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 8.7 Hz, 2H); 13C NMR (CDCl3)
δ 11.2, 18.6, 19.9, 45.2, 55.3, 91.6, 106.7, 113.6, 120.6, 128.4, 136.2,
137.0, 158.2; IR (neat) ν 2943, 2865, 1511, 1462, 1246, 1178, 1037,
882, 830, 676 cm−1; HRMS (ESI-TOF) calcd for C22H34NaOSi (M +
1
Na)+ 365.2271, found 365.2268. 4am: (E)-4am, H NMR (CDCl3) δ
1.00−1.05 (m, 21H, overlapped with peaks of 3am), 1.82 (q, J = 1.5
Hz, 3H, CH3), 2.28 (q, J = 1.5 Hz, 3H, Ar(CH3)C), 3.82 (s, 3H,
OCH3), 6.88 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H); (Z)-4am,
1H NMR (CDCl3) δ 1.00−1.05 (m, 21H, overlapped with peaks of
3am), 1.99 (q, J = 1.0 Hz, 3H, Ar(CH3)C), 2.06 (q, J = 1.0 Hz, 3H,
CH3), 3.81 (s, 3H, OCH3), 6.85 (d, J = 8.7 Hz, 2H), 7.35 (d, J = 8.7
Hz, 2H). (S)-5. Colorless oil (5/5′ = 98/2): the ee was measured by
HPLC (Chiralpak AD-H column, flow 0.5 mL/min, hexane, 224 nm,
Table 2, entry 5 ((S)-3em): colorless oil, 81% yield (56.4 mg, 3em/
4em = 95/5); [α]20D +8 (c 0.66, CHCl3) for >99.5% ee (S); 1H NMR
(CDCl3) δ 0.99−1.03 (m, 21H), 1.46 (d, J = 7.1 Hz, 3H), 3.56 (q, J =
7.1 Hz, 1H), 5.31−5.33 (m, 1H), 5.42−5.44 (m, 1H), 7.21 (d, J = 8.7
Hz, 2H), 7.24 (d, J = 8.7 Hz, 2H); 13C NMR (CDCl3) δ 11.2, 18.5,
19.7, 45.4, 92.1, 106.2, 121.1, 128.3, 128.9, 132.1, 136.1, 142.5; IR
(neat) ν 2942, 2865, 1493, 1462, 1092, 1014, 881, 830, 674 cm−1;
HRMS (ESI-TOF) calcd for C21H31ClNaSi (M + Na)+ 369.1776,
found 369.1780. (S)-3em′: colorless oil (3em′/4em′ = 94/6); the ee
was measured by HPLC (Chiralcel OD-H column, flow 0.5 mL/min,
t1 = 17.9 min (R), t2 = 18.8 min (S)); [α]20 −6 (c 0.31, CHCl3) for
D
1
99% ee (S); H NMR (CDCl3) δ 1.46 (d, J = 7.1 Hz, 3H), 2.85 (s,
1H), 3.55 (q, J = 7.1 Hz, 1H), 3.79 (s, 3H), 5.34−5.36 (m, 1H), 5.47−
5.49 (m, 1H), 6.85 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H); 13C
NMR (CDCl3) δ 19.8, 44.9, 55.2, 78.0, 83.4, 113.7, 121.9, 128.4,
135.68, 135.69, 158.2; HRMS (ESI-TOF) calcd for C13H14NaO (M +
Na)+ 209.0937, found 209.0942.
hexane, 224 nm, t1 = 13.3 min (S), t2 = 14.2 min (R)); [α]20 +1 (c
D
0.60, CHCl3) for >99.5% ee (S). 1H NMR (CDCl3) δ 1.45 (d, J = 7.1
Hz, 3H), 2.85 (s, 1H), 3.57 (q, J = 7.1 Hz, 1H), 5.37−5.39 (m, 1H),
5.50−5.52 (m, 1H), 7.21 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H);
13C NMR (CDCl3) δ 19.6, 45.1, 78.4, 83.0, 122.4, 128.4, 128.8, 132.3,
134.8, 142.1; HRMS (APCI-TOF) calcd for C12H11Cl (M)+ 190.0544,
found 190.0543.
Table 2, entry 2 ((S)-3bm): colorless oil, 87% yield (59.6 mg, 3bm/
1
4bm = 95/5); [α]20 +5 (c 0.51, CHCl3) for 98% ee (S); H NMR
D
(CDCl3) δ 0.98−1.04 (m, 21H), 1.48 (d, J = 7.1 Hz, 3H), 3.55 (q, J =
7.1 Hz, 1H), 3.79 (s, 3H), 5.30−5.32 (m, 1H), 5.42−5.44 (m, 1H),
6.74 (dd, J = 8.1, 2.2 Hz, 1H), 6.83 (t, J = 2.2 Hz, 1H), 6.87−6.91 (m,
1H), 7.19 (t, J = 8.1 Hz, 1H); 13C NMR (CDCl3) δ 11.2, 18.6, 19.8,
46.0, 55.1, 91.7, 106.6, 111.6, 113.5, 120.0, 121.0, 129.1, 136.4, 145.6,
159.5; IR (neat) ν 2941, 2865, 1601, 1463, 1248, 1178, 1046, 882, 674
cm−1; HRMS (ESI-TOF) calcd for C22H34NaOSi (M + Na)+
365.2271, found 365.2261. (S)-3bm′: colorless oil (3bm′/4bm′ =
93/7); the ee was measured by HPLC (Chiralpak AD-H column ×2,
flow 0.5 mL/min, hexane, 224 nm, t1 = 48.7 min (S), t2 = 50.4 min
(R)); [α]20D +0.8 (c 0.33, CHCl3) for 98% ee (S); 1H NMR (CDCl3)
δ 1.47 (d, J = 7.2 Hz, 3H), 2.87 (s, 1H), 3.57 (q, J = 7.2 Hz, 1H), 3.80
(s, 3H), 5.37−5.39 (m, 1H), 5.50−5.52 (m, 1H), 6.77 (ddd, J = 8.1,
2.4, 0.9 Hz, 1H), 6.84 (t, J = 2.4 Hz, 1H), 6.86−6.89 (m, 1H), 7.23 (t,
J = 8.1 Hz, 1H); 13C NMR (CDCl3) δ 19.7, 45.7, 55.1, 78.1, 83.3,
Table 2, entry 6 ((S)-3fm): colorless oil, 94% yield (58.8 mg, 3fm/
1
4fm = 98/2); [α]20 −0.9 (c 0.54, CHCl3) for 98% ee (S); H NMR
D
(CDCl3) δ 0.99−1.04 (m, 21H), 1.49 (d, J = 7.1 Hz, 3H), 3.58 (q, J =
7.1 Hz, 1H), 5.30−5.32 (m, 1H), 5.42−5.44 (m, 1H), 7.16−7.21 (m,
1H), 7.24−7.31 (m, 4H); 13C NMR (CDCl3) δ 11.3, 18.6, 19.8, 46.0,
91.7, 106.6, 120.9, 126.3, 127.5, 128.2, 136.6, 144.0; IR (neat) ν 2942,
2865, 1462, 997, 881, 698, 675 cm−1; HRMS (ESI-TOF) calcd for
C21H32NaSi (M + Na)+ 335.2165, found 335.2159. (S)-3fm′: colorless
oil (3fm′/4fm′ = 98/2); the ee was measured by HPLC (Chiralcel OJ-
H column, flow 0.5 mL/min, hexane, 224 nm, t1 = 44.9 min (S), t2 =
1
49.2 min (R)); [α]20 −4 (c 0.75, CHCl3) for 98% ee (S); H NMR
D
(CDCl3) δ 1.48 (d, J = 7.1 Hz, 3H), 2.86 (s, 1H), 3.60 (q, J = 7.1 Hz,
1H), 5.36−5.39 (m, 1H), 5.49−5.52 (m, 1H), 7.20−7.25 (m, 1H),
E
dx.doi.org/10.1021/jo401604n | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
7.25−7.34 (m, 4H); 13C NMR (CDCl3) δ 19.7, 45.7, 78.1, 83.3, 122.2,
126.5, 127.5, 128.3, 135.3, 143.6; HRMS (APCI-TOF) calcd for
C12H13 (M + H)+ 157.1012, found 157.1012.
(d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 7.5 Hz, 6H),
7.40 (tt, J = 7.5, 1.5 Hz, 3H), 7.55 (dd, J = 7.5, 1.5 Hz, 6H); 13C NMR
(CDCl3) δ 19.9, 45.1, 55.2, 90.0, 109.5, 113.7, 122.0, 127.9, 128.5,
129.8, 133.6, 135.5, 135.8, 136.5, 158.2; IR (neat) ν 2943, 2867, 1510,
1428, 1246, 1178, 1112, 1032, 830, 696 cm−1; HRMS (ESI-TOF)
calcd for C31H28NaOSi (M + Na)+ 467.1802, found 467.1803.
Equation 2 ((S)-3km): colorless oil, 88% yield (56.0 mg, 3km/4km
= 99/1); the ee obtained with (R,Sp)-Josiphos was determined by
chiral HPLC analysis of (S)-1-chloro-4-(4-cyclohexyl-3-methylene-
Table 2, entry 7 ((R)-3gm): colorless oil, 88% yield (63.6 mg, 3gm/
4gm = 89/11); [α]20D +28 (c 0.92, CHCl3) for 99% ee (R); 1H NMR
(CDCl3) δ 0.95−1.02 (m, 21H), 1.65 (d, J = 7.0 Hz, 3H), 4.41 (q, J =
7.0 Hz, 1H), 5.27−5.30 (m, 1H), 5.47−5.50 (m, 1H), 7.38−7.54 (m,
4H), 7.72 (d, J = 8.2 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.4
Hz, 1H); 13C NMR (CDCl3) δ 11.2, 18.5, 20.1, 41.1, 91.5, 107.1,
121.5, 123.5, 124.4, 125.2, 125.4, 125.7, 127.0, 128.8, 131.7, 133.9,
136.4, 139.7; IR (neat) ν 2941, 2863, 1462, 881, 775, 664 cm−1;
HRMS (ESI-TOF) calcd for C25H34NaSi (M + Na)+ 385.2322, found
385.2324. (R)-3gm′: colorless oil (3gm′/4gm′ = 99/1); the ee was
measured by HPLC (Chiralcel OJ-H column, flow 0.5 mL/min,
pent-1-yn-1-yl)benzene (3km′) derived from 3km; [α]20 +4 (c 0.70,
D
1
CHCl3) for 58% ee (S); H NMR (CDCl3) δ 0.80−0.92 (m, 2H),
0.98−1.28 (m, 27H), 1.35−1.45 (m, 1H), 1.58−1.85 (m, 5H), 1.95
(quint, J = 7.2 Hz, 1H), 5.18 (d, J = 1.8 Hz, 1H), 5.32 (d, J = 1.8 Hz,
1H); 13C NMR (CDCl3) δ 11.3, 17.1, 18.6, 26.5, 26.58, 26.61, 30.1,
31.6, 41.1, 47.1, 90.9, 106.5, 120.9, 137.0; IR (neat) ν 2922, 2864,
1462, 996, 882, 675 cm−1; HRMS (APCI-TOF) calcd for C21H38Si
(M)+ 318.2737, found 318.2736. (S)-3km′. To a solution of 3km
(42.1 mg, 0.132 mmol, 3km/4km = >99/1) in THF (1.3 mL) were
added MeOH (11 μL, 0.26 mmol) and tetrabutylammonium fluoride
(1.0 M solution in THF, 0.40 mL, 0.40 mmol) at room temperature,
and the mixture was stirred for 2 h. To the mixture were added 1-
chloro-4-iodobenzene (37.3 mg, 0.158 mmol), Pd(PPh3)4 (7.6 mg,
0.0066 mmol), CuI (1.3 mg, 0.0066 mmol), and triethylamine (37 μL,
0.26 mmol) at room temperature, and the mixture was stirred for 10 h.
The mixture was passed through a short column of silica gel with Et2O
as eluent. After evaporation of the solvent, the residue was subjected to
preparative TLC (silica gel, hexane) to give 3km′ as a colorless oil
(30.4 mg, 0.111 mmol, 84% yield): the ee was measured by HPLC
(Chiralcel OJ-H column × 2, flow 0.5 mL/min, hexane, 224 nm, t1 =
19.0 min (R), t2 = 20.3 min (S)); [α]20D +12 (c 0.59, CHCl3) for 58%
ee (S); 1H NMR (CDCl3) δ 0.85−0.98 (m, 2H), 1.05−1.30 (m, 6H),
1.33−1.45 (m, 1H), 1.60−1.87 (m, 5H), 2.06 (quint, J = 7.3 Hz, 1H),
5.26 (d, J = 1.9 Hz, 1H), 5.40 (d, J = 1.9 Hz, 1H), 7.29 (d, J = 8.4 Hz,
2H), 7.36 (d, J = 8.4 Hz, 2H); 13C NMR (CDCl3) δ 17.1, 26.47, 26.54,
26.6, 30.1, 31.6, 41.1, 47.0, 88.8, 89.9, 121.1, 122.1, 128.6, 132.8, 134.0,
136.3; HRMS (APCI-TOF) calcd for C18H22Cl (M + H)+ 273.1405,
found 273.1406.
hexane, 224 nm, t1 = 45.1 min (R), t2 = 51.1 min (S)); [α]20 +7 (c
D
0.30, CHCl3) for 99% ee (R); 1H NMR (CDCl3) δ 1.63 (d, J = 7.1 Hz,
3H), 2.86 (s, 1H), 4.41 (q, J = 7.1 Hz, 1H), 5.30 (s, 1H), 5.56 (s, 1H),
7.42−7.54 (m, 4H), 7.75 (d, J = 7.9 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H),
8.08 (d, J = 8.5 Hz, 1H); 13C NMR (CDCl3) δ 19.9, 40.8, 77.8, 83.9,
122.9, 123.5, 124.2, 125.35, 125.42, 125.9, 127.3, 128.9, 131.6, 133.9,
135.1, 139.2; HRMS (ESI-TOF) calcd for C16H14Na (M + Na)+
229.0988, found 229.0995.
Table 2, entry 8 ((S)-3hm): colorless oil, 77% yield (55.1 mg, 3hm/
4hm = 89/11); [α]20D +25 (c 0.72, CHCl3) for 97% ee (S); 1H NMR
(CDCl3) δ 0.89 (t, J = 7.4 Hz, 3H), 1.03−1.07 (m, 21H), 1.70−1.83
(m, 1H), 1.94−2.07 (m, 1H), 3.19 (t, J = 7.6 Hz, 1H), 3.78 (s, 3H),
5.30−5.34 (m, 1H), 5.39−5.41 (m, 1H), 6.81 (d, J = 8.8 Hz, 2H), 7.22
(d, J = 8.8 Hz, 2H); 13C NMR (CDCl3) δ 11.3, 12.4, 18.6, 26.6, 53.4,
55.2, 91.8, 106.4, 113.6, 121.7, 128.7, 135.4, 135.8, 158.2; IR (neat) ν
2942, 2864, 1510, 1463, 1248, 1178, 1038, 881, 825, 675 cm−1; HRMS
(ESI-TOF) calcd for C23H36NaOSi (M + Na)+ 379.2428, found
379.2421. (S)-3hm′: colorless oil (3hm′/4hm′ = 98/2); the ee was
measured by HPLC (Chiralpak AD-H column, flow 0.3 mL/min,
hexane, 224 nm, t1 = 27.8 min (R), t2 = 29.4 min (S)); [α]20 −2 (c
D
0.66, CHCl3) for 97% ee (S); 1H NMR (CDCl3) δ 0.89 (t, J = 7.3 Hz,
3H), 1.73−1.83 (m, 1H), 1.93−2.03 (m, 1H), 2.87 (s, 1H), 3.21 (t, J =
7.7 Hz, 1H), 3.79 (s, 3H), 5.37−5.40 (m, 1H), 5.47−5.48 (m, 1H),
6.85 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.8 Hz, 2H); 13C NMR (CDCl3)
δ 12.3, 26.3, 53.1, 55.2, 78.1, 83.1, 113.7, 122.7, 128.7, 134.5, 134.7,
158.2; HRMS (ESI-TOF) calcd for C14H16NaO (M + Na)+ 223.1093,
found 223.1094.
Equation 1 (3lm): colorless oil, 93% yield (69.2 mg, 3lm/4lm = 95/
1
5); H NMR (CDCl3) δ 0.35 (s, 3H), 0.36 (s, 3H), 1.00−1.13 (m,
21H), 1.15 (d, J = 7.4 Hz, 3H), 1.98 (q, J = 7.4 Hz, 1H), 4.98 (s, 1H),
5.29 (s, 1H), 7.30−7.38 (m, 3H), 7.47−7.55 (m, 2H); 13C NMR
(CDCl3) δ −5.3, −3.8, 11.4, 14.3, 18.7, 30.3, 90.6, 108.2, 119.4, 127.6,
129.0, 134.0, 134.8, 137.8; IR (neat) ν 2944, 2865, 1252, 1119, 1061,
882, 830, 699, 675 cm−1; HRMS (APCI-TOF) calcd for C23H39Si2 (M
+ H)+ 371.2585, found 371.2589.
Table 2, entry 9 ((S)-3im): colorless oil, 81% yield (62.6 mg, 3im/
4im = 98/2). the ee was measured by HPLC (Chiralcel OD-H
column, flow 0.5 mL/min, hexane, 224 nm, t1 = 15.2 min (R), t2 = 17.8
1
min (S)); [α]20 +18 (c 0.78, CHCl3) for 96% ee (S); H NMR
D
(CDCl3) δ 0.88 (t, J = 7.2 Hz, 3H), 0.97−1.15 (m, 21H), 1.15−1.38
(m, 4H), 1.67−1.79 (m, 1H), 1.95−2.05 (m, 1H), 3.28 (t, J = 7.6 Hz,
1H), 3.78 (s, 3H), 5.29−5.32 (m, 1H), 5.37−5.40 (m, 1H), 6.81 (d, J
= 8.6 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H); 13C NMR (CDCl3) δ 11.3,
14.0, 18.6, 22.6, 29.9, 33.4, 51.5, 55.2, 91.8, 106.4, 113.6, 121.5, 128.6,
135.6, 136.0, 158.1; IR (neat) ν 2942, 2865, 1511, 1463, 1247, 1177,
1036, 882, 830, 676 cm−1; HRMS (ESI-TOF) calcd for C25H40NaOSi
(M + Na)+ 407.2741, found 407.2742.
Procedure for Scheme 2a. To a solution of a mixture of 3am and
4am (115 mg, 0.337 mmol, 3am/4am = 97/3) in THF (1.7 mL) were
added MeOH (27 μL, 0.67 mmol) and tetrabutylammonium fluoride
(1.0 M solution in THF, 1.0 mL, 1.0 mmol) at room temperature. The
mixture was stirred for 1.5 h, and then it was passed through a short
column of silica gel with Et2O as eluent. After evaporation of the
solvent, the residue was subjected to preparative TLC (silica gel,
hexane/ethyl acetate = 50/1) to give a mixture of 5 and 5′ as a
colorless oil (52.6 mg, 0.282 mmol, 84% yield, 5/5′ = 97/3, 99% ee of
5).
Table 2, entry 10 ((S)-3jm): colorless oil, 70% yield (47.8 mg, 3jm/
4jm = 96/4); the ee was measured by HPLC (Chiralcel OD-H
column, flow 0.5 mL/min, hexane, 224 nm, t1 = 16.2 min (R), t2 = 17.4
Procedure for Scheme 2b.27 To a mixture of N-mesyl-2-
iodoaniline (CAS no. 116547−92−3)39 (29.7 mg, 0.100 mmol), CuI
(3.8 mg, 0.020 mmol), Pd(PPh3)4 (2.3 mg, 0.0020 mmol), and DBU
(75 μL, 0.50 mmol) in EtOH (0.4 mL) was added a mixture of 5 and
5′ (22.4 mg, 0.120 mmol, 5/5′ = 97/3, 99% ee of 5) at room
temperature. After the mixture was stirred under reflux for 2 h, water
was added, and the mixture was extracted with ethyl acetate. After the
organic extracts were concentrated on a rotary evaporator, the residue
was subjected to preparative TLC (hexane/ethyl acetate = 5/1) to give
a mixture of 6 and 6′ as a yellow oil (31.8 mg, 0.0895 mmol, 89% yield,
6/6′ = 98/2). (S)-6: the ee was measured by HPLC (Chiralpak AD-H
column, flow 0.5 mL/min, hexane/2-propanol = 98/2, 224 nm, t1 =
24.9 min (R), t2 = 29.8 min (S)); [α]20D −6 (c 1.24, CHCl3) for 99%
1
min (S)); [α]20 +21 (c 0.51, CHCl3) for 96% ee (S); H NMR
D
(CDCl3) δ 0.97−1.10 (m, 21H), 3.38 (s, 3H), 3.68−3.77 (m, 2H),
3.88−3.96 (m, 1H), 5.39−5.41 (m, 1H), 5.52−5.54 (m, 1H), 7.22 (t, J
= 7.4 Hz, 1H), 7.28 (t, J = 7.4 Hz, 2H), 7.34 (d, J = 7.4 Hz, 2H); 13C
NMR (CDCl3) δ 11.3, 18.6, 52.1, 58.9, 74.6, 92.4, 105.9, 123.5, 126.9,
127.9, 128.3, 132.7, 140.1; IR (neat) ν 2943, 2865, 1512, 1463, 1248,
997, 882, 699, 676 cm−1; HRMS (ESI-TOF) calcd for C22H34NaOSi
(M + Na)+ 365.2271, found 365.2269.
Table 2, entry 11 ((S)-3an): colorless oil, 70% yield (65.5 mg, 3an/
4an = 95/5); the ee was measured by HPLC (Chiralcel OD-H
column, flow 0.5 mL/min, hexane/2-propanol = 500/1, 224 nm, t1 =
24.4 min (R), t2 = 25.3 min (S)); [α]20 +1 (c 0.44, CHCl3) for 92%
D
ee (S); 1H NMR (CDCl3) δ 1.49 (d, J = 7.0 Hz, 3H), 3.62 (q, J = 7.0
Hz, 1H), 3.79 (s, 3H), 5.42−5.44 (m, 1H), 5.55−5.57 (m, 1H), 6.81
ee (S); H NMR (CDCl3) δ 1.44 (d, J = 7.1 Hz, 3H), 2.72 (s, 3H),
1
3.76 (s, 3H), 4.08 (q, J = 7.1 Hz, 1H), 5.29−5.31 (m, 1H), 5.31−5.33
F
dx.doi.org/10.1021/jo401604n | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
(m, 1H), 6.32 (s, 1H), 6.78 (d, J = 8.7 Hz, 2H), 7.15 (d, J = 8.7 Hz,
2H), 7.26 (td, J = 7.3, 0.8 Hz, 1H), 7.31 (td, J = 8.0, 1.3 Hz, 1H), 7.44
(d, J = 7.3 Hz, 1H), 8.03 (dd, J = 8.0, 0.8 Hz, 1H); 13C NMR (CDCl3)
δ 20.5, 38.8, 44.5, 55.2, 112.5, 113.6, 115.3, 116.0, 121.0, 124.3, 124.9,
128.8, 130.4, 136.2, 137.6, 142.7, 147.6, 158.0; IR (neat) ν 1509, 1363,
1245, 1169, 1032, 957, 830, 769, 747 cm−1; HRMS (ESI-TOF) calcd
for C20H21NNaO3S (M + Na)+ 378.1134, found 378.1133.
= 1.7 Hz, 1H), 5.40 (d, J = 1.7 Hz, 1H), 6.82 (d, J = 8.6 Hz, 2H), 7.20
(d, J = 8.6 Hz, 2H).
Procedure for Equation 4. A mixture of CoCl(PPh3)3 (8.8 mg,
0.010 mmol), dppe (4.0 mg, 0.010 mmol), and KOAc (2.0 mg, 0.020
mmol) in DMSO (0.3 mL) was stirred at room temperature for 15
min. To the mixture were added allene 1f (26.0 mg, 0.200 mmol) and
alkyne 2m (67 μL, 0.30 mmol), and it was stirred at 80 °C for 30 min.
The mixture was passed through a short column of silica gel with Et2O
as eluent and concentrated on a rotary evaporator. The yields of 3fm
and 4fm were determined by 1H NMR using nitromethane as an
internal standard.
Procedure for Scheme 2c.28 To a solution of Pd(PPh3)4 (5.8 mg,
0.0050 mmol) in THF (0.4 mL) were added a mixture of 5 and 5′
(18.6 mg, 0.100 mmol, 5/5′ = 97/3, 99% ee of 5) and 1,4-
diphenylbutadiyne (20.2 mg, 0.100 mmol) at room temperature. The
mixture was stirred under reflux for 24 h, and then it was passed
through a short column of silica gel with Et2O as eluent. After removal
of the solvent on a rotary evaporator, the residue was subjected to
preparative TLC (silica gel, hexane/ethyl acetate = 40/1) to give
compound 7 as a yellow oil (35.5 mg, 0.914 mmol, 91% yield). (S)-7:
the ee was measured by HPLC (Chiralcel OD-H column, flow 0.5
Procedure for Equation 5. A mixture of Co(OAc)2 (3.5 mg,
0.020 mmol), dppe (8.0 mg, 0.020 mmol), and Zn powder (2.6 mg,
0.040 mmol) in DMSO (0.3 mL) was stirred at 80 °C for 15 min
under N2. To the mixture were added allene 1f (13.0 mg, 0.100
mmol), alkyne 2m (36.5 mg, 0.200 mmol), and acetic acid-d (12.2 mg,
0.200 mmol, 99.9% D) at room temperature, and it was stirred at 80
°C for 30 min. The mixture was passed through a short column of
silica gel with Et2O as eluent and concentrated on a rotary evaporator.
mL/min, hexane/2-propanol = 100/1, 224 nm, t1 = 21.8 min (S), t2 =
1
24.2 min (R)); [α]20 +9 (c 1.42, CHCl3) for 99% ee (S); H NMR
D
1
(CDCl3) δ 1.65 (d, J = 7.2 Hz, 3H), 3.79 (s, 3H), 4.16 (q, J = 7.2 Hz,
1H), 6.85 (d, J = 8.6 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 7.14−7.20 (m,
1H), 7.23−7.34 (m, 6H), 7.38 (t, J = 7.8 Hz, 1H), 7.44 (t, J = 7.8 Hz,
2H), 7.55 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 7.8 Hz, 2H); 13C NMR
(CDCl3) δ 21.9, 43.9, 55.2, 89.5, 91.7, 113.8, 119.2, 123.6, 126.3,
127.4, 127.8, 127.9, 128.2, 128.5, 128.7, 129.4, 131.3, 132.9, 137.9,
140.7, 143.9, 147.4, 158.0; IR (neat) ν 1509, 1244, 1176, 1033, 829,
754, 690 cm−1; HRMS (ESI-TOF) calcd for C29H24NaO (M + Na)+
411.1719, found 411.1714.
The yield of 3fm was determined by H NMR using nitromethane as
an internal standard. The deuterium content of 3fm was determined
by 1H NMR (6% D) after isolation of the mixture of 3fm and 4fm by
preparative TLC (silica gel, hexane).
Procedures for Equation 6. A mixture of Co(OAc)2 (3.5 mg,
0.020 mmol), dppe (8.0 mg, 0.020 mmol), and Zn powder (2.6 mg,
0.040 mmol) in DMSO (0.3 mL) was stirred at 80 °C for 15 min
under N2. To the mixture were added allene 1f (13.0 mg, 0.100
mmol), deuterated alkyne 2m-d (36.7 mg, 0.200 mmol, 98% D), and
acetic acid (11.8 mg, 0.200 mmol) at room temperature, and it was
stirred at 80 °C for 30 min. The mixture was passed through a short
column of silica gel with Et2O as eluent and concentrated on a rotary
evaporator. The yield of 3fm was determined by 1H NMR using
nitromethane as an internal standard. The deuterium content of 3fm
was determined by 1H NMR (79% D) after isolation of the mixture of
3fm and 4fm by preparative TLC (silica gel, hexane).
Procedure for Equation 7. A mixture of Co(OAc)2 (1.8 mg,
0.010 mmol), dppe (4.0 mg, 0.010 mmol), and Zn powder (1.3 mg,
0.020 mmol) in DMSO (0.3 mL) was stirred at 80 °C for 15 min
under N2. To the mixture were added allene 1f (26.0 mg, 0.200
mmol), alkyne 2m (36.5 mg, 0.200 mmol), and deuterated alkyne 2m-
d (36.7 mg, 0.200 mmol, 98% D) at room temperature, and it was
stirred at 80 °C for 10 min. The mixture was passed through a short
column of silica gel with Et2O as eluent and concentrated on a rotary
evaporator. The yield of 3fm was determined by 1H NMR using
nitromethane as an internal standard. The deuterium content of 3fm
was determined by 1H NMR (29% D) after isolation of the mixture of
3fm and 4fm by preparative TLC (silica gel, hexane).
Procedure for Scheme 2d.29b To a mixture of CuSO4·5H2O (2.5
mg, 0.010 mmol), Na-(+)-ascorbate (4.0 mg, 0.020 mmol), and
benzoic acid (12.2 mg, 0.10 mmol) in t-BuOH (0.2 mL) and H2O (0.4
mL) were added a mixture of 5 and 5′ (18.6 mg, 0.100 mmol, 5/5′ =
97/3, 99% ee of 5) and 1-azido-4-chlorobenzene (CAS no. 3296-05-
7)41 (16.9 mg, 0.110 mmol) at room temperature. After being stirred
for 18 h, the mixture was extracted with dichloromethane and the
combined organic extracts were concentrated on a rotary evaporator.
The residue was subjected to preparative TLC (silica gel, hexane/
dichloromethane = 1/1) to give a mixture of 8 and 8′ as a white solid
(31.3 mg, 0.0921 mmol, 92% yield, 8/8′ = 99/1). (S)-8: the ee was
measured by HPLC (Chiralpak IB column, flow 0.5 mL/min, hexane/
chloroform/ethanol = 90/30/1, 254 nm, t1 = 11.3 min (R), t2 = 12.0
min (S)); [α]20D +2 (c 1.57, CHCl3) for 99% ee (S); mp 156−158 °C;
1H NMR (CDCl3) δ 1.52 (d, J = 6.9 Hz, 3H), 3.77 (s, 3H), 4.02 (q, J
= 6.9 Hz, 1H), 5.35−5.38 (m, 1H), 6.07−6.10 (m, 1H), 6.83 (d, J =
8.7 Hz, 2H), 7.23 (d, J = 8.7 Hz, 2H), 7.44 (d, J = 9.0 Hz, 2H), 7.50 (s,
1H), 7.56 (d, J = 9.0 Hz, 2H); 13C NMR (CDCl3) δ 21.3, 42.4, 55.2,
113.0, 114.0, 118.0, 121.5, 128.4, 129.8, 134.2, 135.5, 136.6, 141.3,
149.0, 158.1; IR (thin film) ν 1499, 1246, 1176, 1034, 913, 823 cm−1;
HRMS (ESI-TOF) calcd for C19H18ClN3NaO (M + Na)+ 362.1031,
found 362.1030. Colorless crystals of 8 suitable for X-ray crystallo-
graphic analysis were obtained by recrystallization from hexane/ethyl
acetate. The crystal structure has been deposited at the Cambridge
Crystallographic Centre (deposition number: CCDC 922867). The
data can be obtained free of charge via www.ccdc.cam.ac.uk/data_
request/cif.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of all new compounds, chiral HPLC
charts, and crystallographic data (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
Procedure for Equation 3. A mixture of Co(OAc)2 (1.8 mg,
0.010 mmol), (R,Sp)-L4 (8.8 mg, 0.010 mmol), and Zn powder (1.3
mg, 0.020 mmol) in DMSO (0.3 mL) was stirred at 80 °C for 15 min
under N2. To the mixture were added allene 1a (32.0 mg, 0.200
mmol) and deuterated alkyne 2m-d (55.0 mg, 0.300 mmol, 98% D) at
room temperature, and it was stirred at 80 °C for 3 h. The mixture was
passed through a short column of silica gel with Et2O as eluent. After
removal of the solvent on a rotary evaporator, the residue was
subjected to preparative TLC (silica gel, hexane/ethyl acetate = 50/1)
to give a mixture of 3am-d and 4am-d as a colorless oil (61.1 mg,
0.178 mmol, 89% yield, 3am-d/4am-d = 93/7). The deuterium
contents were determined by 1H NMR (89% D for 3am-d, 81% D for
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tnishi@kuchem.kyoto-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work has been supported by a Grant-in-Aid for Scientific
Research from the MEXT, Japan. T.S. thanks the JSPS for a
research Fellowship for Young Scientists.
1
(Z)-4am and 89% D for (E)-4am-d). Compound 3am-d: H NMR
(CDCl3) δ 0.98−1.05 (m, 21H), 1.46 (s, 3H), 3.78 (s, 3H), 5.28 (d, J
G
dx.doi.org/10.1021/jo401604n | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
Asymmetry 1993, 4, 1977. (c) Hilt, G.; Luers, S. Synthesis 2003, 1784.
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