Asymmetric Three-Component Coupling Reaction of Alkyne, Enone, and Aldehyde Catalyzed by Chiral Phebox Ruthenium Catalysts

Article abstract of DOI:10.1021/acs.joc.6b00374

Catalytic asymmetric three-component coupling reactions of terminal alkynes, α,β-unsaturated ketones, and aldehydes were studied. The chiral ruthenium complexes containing bis(oxazolinyl)phenyl ligands were found to serve as efficient catalysts for a tandem reaction based on conjugate addition of terminal alkynes to α,β-unsaturated ketones and subsequent aldol reaction with aldehydes, giving β-hydroxyketone derivatives containing α-propargyl groups in high yields with moderate to good enantioselectivities. This method can produce various functional molecules from commercially available substrates in a one-pot procedure. The absolute configuration of the major product was determined by X-ray analysis. The control experiments suggested that a ruthenium enolate species generated in situ by conjugate addition could be involved as an intermediate for the aldol coupling with an aldehyde.

Full text of DOI:10.1021/acs.joc.6b00374

Article
pubs.acs.org/joc
Asymmetric Three-Component Coupling Reaction of Alkyne, Enone,
and Aldehyde Catalyzed by Chiral Phebox Ruthenium Catalysts
Shino Ubukata, Jun-ichi Ito,* Ryota Oguri, and Hisao Nishiyama*
Department of Applied Chemistry, Graduate School of Engineering, Nagoya University, Furo-cho Chikusa-ku, Nagoya 464-8603,
Japan
S
* Supporting Information
ABSTRACT: Catalytic asymmetric three-component coupling
reactions of terminal alkynes, α,β-unsaturated ketones, and
aldehydes were studied. The chiral ruthenium complexes
containing bis(oxazolinyl)phenyl ligands were found to serve
as efficient catalysts for a tandem reaction based on conjugate
addition of terminal alkynes to α,β-unsaturated ketones and subsequent aldol reaction with aldehydes, giving β-hydroxyketone
derivatives containing α-propargyl groups in high yields with moderate to good enantioselectivities. This method can produce
various functional molecules from commercially available substrates in a one-pot procedure. The absolute configuration of the
major product was determined by X-ray analysis. The control experiments suggested that a ruthenium enolate species generated
in situ by conjugate addition could be involved as an intermediate for the aldol coupling with an aldehyde.
aldol coupling reaction with carbonyl compounds can provide
an efficient method for the preparation of complex molecules
with various functional groups (Scheme 1). Despite the
INTRODUCTION
■
Catalytic multicomponent coupling reactions are an effective
synthetic methodology for construction of multifunctional
organic molecules and bioactive compounds from simple and
ubiquitous precursors.1 The advantage of this method is that an
intermediate can be used in the next step without its isolation.
Thus far, successive conjugate addition and aldol reactions have
been widely elucidated as an effective strategy for sequence
bond forming reactions.2 Since Cu-catalyzed enantioselective
conjugate addition of alkylzinc with α,β-unsaturated carbonyl
compounds is a reliable C−C bond formation protocol, the
subsequent aldol reaction with a zinc enolate intermediate
generated in situ accomplishes a tandem coupling reaction.3 In
this context, the seminal study by Feringa and co-workers
showed highly selective Cu catalysts with chiral phosphor-
amidite ligands for asymmetric three-component coupling
reactions of organozinc reagents, α,β-unsaturated carbonyl
compounds, and aldehydes.4 This type of asymmetric tandem
coupling reaction triggered by conjugate addition of alkylzinc
reagents has been expanded to various one-pot processes to
prepare chiral materials.5 Concurrently, Rh-catalyzed conjugate
addition with organoborane reagents has expanded the
substrate variation in transition-metal-catalyzed C−C bond
formation reactions.6 For example, Hayashi and co-workers
reported a sequence of conjugate arylation of an α,β-
unsaturated ketone with an arylborane reagent and aldol
reaction of aldehydes with a Rh enolate species generated in
situ.7 Recently, Krische and co-workers developed an intra-
molecular annulation reaction by using a chiral Rh catalyst.8
Catalytic and direct conjugate addition of terminal alkynes to
α,β-unsaturated carbonyl compounds using transition-metal
catalysts is also a useful and atom-economic C−C bond
forming process.9 Thus, multicomponent coupling via the
direct conjugate addition of a terminal alkyne and successive
Scheme 1. Three-Component Coupling of an Alkyne,
Enone, and Aldehyde
synthetic potential of this process, to our best knowledge, an
efficient process based on direct conjugate alkynylation and
aldol reaction has not been reported. In this process, 1,2-
addition of alkynes to carbonyl compounds, such as aldehydes,
giving propargyl alcohol derivatives is considered to be a major
side reaction.10 In addition, transition metals also catalyze
dimerization and trimerization of alkynes that form byproducts,
namely, enynes and benzene derivatives, respectively.11,12 Thus,
control of chemoselectivity by metal catalysts is a key to obtain
multicomponent coupling products effectively.
Recently, transition-metal complexes with pincer ligands
have been extensively studied as efficient catalysts in various
reactions.13 Their stability and unique reactivity are due to their
structural feature of having two metallacycles. In particular,
chiral NCN pincer complexes have been applied to asymmetric
transformations as efficient catalysts.14 For example, the
bis(oxazolinyl)phenyl (phebox) ligands have recently been
applied to conjugate reduction,15 reductive aldol,16 alkynyla-
tion,17 diborylation,18 and C−H functionalization.19 The
Received: February 21, 2016
© XXXX American Chemical Society
A
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related bis(imidazolinyl)phenyl (phebim) and bis(imida-
zolidine) (phbidine) ligands have also been employed as
efficient chiral NCN ligands for Pt,20 Pd,21 and Rh22 catalysts.
Thus, these pincer metal catalysts have the potential to
promote new catalytic transformations.
Table 1. Enantioselective Three-Component Coupling
Reaction of Phenylacetylene (2a), Methylvinylketone (3a),
and Benzaldehyde (4a) Catalyzed by (phebox)Ru Catalysts
a
yield of
d
5a and 6a
ratio of
% ee
We previously found that the NCN pincer Ru complex
containing the phebox ligand serves as an asymmetric catalyst
in the direct alkynylation of aldehydes and α,β-unsaturated
carbonyl compounds.23,24 These reactions are atom-economic
transformations for the construction of alkyne derivatives. In
the case of conjugate addition, a Ru enolate species could be
formed by insertion of a terminal alkyne into an α,β-
unsaturated carbonyl compound. Thus, trapping of the Ru
enolate intermediate by an electrophile, such as an aldehyde,
could be used to construct various functionalized molecules in a
one-pot procedure. Here, we report the three-component
coupling reaction of aldehydes, alkynes, and enones catalyzed
by the phebox-Ru complex 1.
b
c
entry cat
solvent
THF
(5a:6a)
5a-anti:5a-syn 5a-anti/5a-syn
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
44 (96:4)
34 (87:13)
32 (93:7)
36 (>99:1)
68 (93:7)
77 (93:7)
82 (93:7)
88 (87:13)
90 (>99:1)
84 (>99:1)
85 (>99:1)
83 (>99:1)
92 (>99:1)
1.3:1
1.3:1
3.3:1
2.6:1
1.3:1
3.0:1
2.0:1
1.3:1
2.0:1
1.3:1
1.4:1
1.9:1
0.9:1
47/7
toluene
64/12
69/20
68/22
66/19
70/27
69/25
79/46
53/81
25/60
45/66
32/56
51/46
ethanol
2-propanol
e
f
eg
,
e
e
10
11
12
13
e
e
e
a
RESULTS AND DISCUSSION
Reaction conditions: 1 (0.020 mmol), 2a (1.0 mmol), 3a (4.0 mmol),
■
b
4a (3 mmol), 60 °C, 24 h. The ratio of 5a:6a was determined by 1H
NMR. Determined by H NMR. Determined by HPLC. Use of
ethanol (20 mol %). Use of 2-propanol (20 mol %). Reaction time:
12 h.
First, the catalytic reaction of phenylacetylene (2a), methyl-
vinylketone (3a), and benzaldehyde (4a) was conducted in the
presence of 1a (2 mol %). Heating of a mixture of 2a, 3a, and
4a in a 4:3:1 ratio in THF at 60 °C resulted in the formation of
coupling products 5a and 6a in 44% yield with a high ratio of
94:6 (Table 1, entry 1). In this reaction, the anti-isomer of 5a-
anti was obtained as the major product with an anti/syn
diastereomeric ratio of 1.3:1 and 47% ee of the anti-isomer. A
major byproduct was found to be the γ,δ-alkynyl ketone
PhCC(CH2)2COMe (7), which was formed simply by
c
d
e
1
f
g
Next, the effect of the substituents on the phebox ligands was
examined by using 1b−f (entries 9−13). In the case of 1b with
the isopropyl phebox ligand, the enantioselectivity of 5a-anti
decreased, but the enantioselectivity of 5a-syn was enhanced to
81% (entry 9). Ru catalysts with isobutyl, benzyl, ethyl, and
methyl phebox ligands 1c−f gave good yields and ratios of
5a:6a, but lower enantioselectivity of 5a-anti. Thus, the phenyl
substituent was suitable in terms of product selectivity. We also
examined other Ru catalysts in this coupling reaction. Although
the BINAP-Ru complex [(R)-BINAP]Ru(OAc)2 and the
pybox-Ru complex [(S,S)-pybox-iPr]RuCl2(C2H4) exhibited
catalytic activity, they were less effective than the phebox-Ru
complexes. This result suggested the importance of the NCN-
Ru pincer scaffold. The stereochemistry of 5a was confirmed by
derivatization by hydrogenation to a known compound26 and
X-ray analysis of the related product (vide infra). To the best of
our knowledge, this result is the first example of an asymmetric
three-component coupling involving direct conjugate addition
of a terminal alkyne and aldol reaction with an aldehyde.
Next, the catalytic reaction of other aldehydes and alkynes
was examined by using the phebox-Ru complex 1a (Table 2,
entry 1). Reaction with benzaldehyde derivatives containing
electron-withdrawing groups at the para position proceeded
smoothly to give the desired products 5b−f in 40−82% yields
with dr = 1.3−2.1:1 and 53−78% ee of anti-products (entries
1−5). In the case of a benzaldehyde derivative containing an
electron-donating methoxy group at the para position, the yield
was maintained, but a decrease in enantioselectivity was
observed (entry 6). Reaction with 2-naphthaldehyde showed
1
conjugate addition of 2a with 3a. The H NMR spectrum
indicated that 7 was formed in 37% yield based on the amount
of 3a. In contrast, a propargyl alcohol derivative obtained by
1,2-addition of 2a with 4a was not detected, indicating that
conjugate addition to an enone was more favorable than 1,2-
addition to an aldehyde. The catalytic reaction was affected by
solvents and additives. The use of toluene increased the
enantioselectivity (entry 2). Interestingly, reactions in ethanol
and 2-propanol improved the diastereoselectivity to 2.6−3.3:1
(entries 3 and 4). Furthermore, neat conditions increased the
product yield to 68% (entry 5). In this case, the
diastereoselectivity decreased compared to those of the reaction
in alcohol solutions. This indicated that alcohols influenced the
selectivity of the reaction. When the catalytic reaction was
conducted in the presence of a catalytic amount of alcohol (20
mol %), both the diastereoselectivity and yield were enhanced
without decreasing the enantioselectivity (entries 6 and 7).25 In
these reactions, 7 was also formed as a major byproduct in 59%
and 66% yields based on the amount of 3a. When the reaction
was conducted for 12 h, the enantioselectivity was slightly
improved despite the lower ratio of 5a:6a (entry 8). It is noted
that the catalytic reaction did not proceed in the absence of
NaOAc.
B
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Table 2. Enantioselective Three-Component Coupling Reaction of Alkynes 2, α,β-Unsaturated Ketones 3, and Aldehydes 4
a
Catalyzed by (phebox)Ru Catalyst 1a
b
c
d
entry
R1; R2; R3 (5)
yield of 5 and 6 (5:6)
ratio of 5-anti:5-syn
% ee 5-anti/5-syn
e
1
Ph; Me; 4-BrC6H4 (5b)
Ph; Me; 4-ClC6H4 (5c)
Ph; Me; 4-NO2C6H4 (5d)
Ph; Me; 4-CF3C6H4 (5e)
Ph; Me; 4-MeO2CC6H4 (5f)
Ph; Me; 4-MeOC6H4 (5g)
Ph; Me; 3-BrC6H4 (5h)
Ph; Me; 2-naphthyl (5i)
Ph; Me; 2-thiophenyl (5j)
4-CF3C6H4; Me; Ph (5k)
4-BrC6H4; Me; Ph (5l)
4-MeOC6H4; Me; Ph (5m)
Ph; n-C5H11; Ph (5n)
82 (>99:1)
51 (>99:1)
71 (>99:1)
71 (95:5)
69 (93:7)
52 (86:14)
72 (95:5)
75 (91:9)
68 (>99:1)
87 (>99:1)
51 (>99:1)
40 (95:5)
48 (>99:1)
1.9:1
1.3:1
1.2:1
1.8:1
2.1:1
2.1:1
1.9:1
3.0:1
2.1:1
1.9:1
1.3:1
1.1:1
78/18
61/9
2
3
53/3
e
4
70/10
69/12
39/25
60/8
5
6
7
8
64/16
61/7
9
10
11
12
13
52/12
65/44
52/8
1.6:1
60/13
a
b
Reaction conditions: 1a (0.020 mmol), 2 (1.0 mmol), 3 (4.0 mmol), 4 (3.0 mmol), 60 °C, 24 h. The ratio of 5a:6a was determined by 1H NMR.
c
d
e
1
Determined by H NMR. Determined by HPLC. Reaction time: 12 h.
higher diastereoselectivity than those of other aldehydes (entry
8). A heteroaromatic aldehyde was also used as an electrophile
to give the coupling product in 68% yield (entry 9).
Substituents on the terminal alkynes affected product yields,
with electron-withdrawing groups at an aromatic ring showing
higher yields (entries 10−12). This trend was similar to the
conjugate addition of alkynes to α,β-unsaturated ketones
catalyzed by 1a.24 Thus, efficiency of the conjugate addition
step and stability of the resulting Ru-enolate species are
considered to be significant to obtain products 5 in high yields.
As an enone substrate, oct-1-en-3-one was used in the coupling
reaction to give the corresponding product 5n (entry 13). In
contrast, phenylvinylketone, 2-hydroxypropan-2-ylvinylketone,
and ethyl acrylate were not viable as substrates. Since conjugate
addition with those substrates with phenylacetylene was
catalyzed by the phebox-Ru complexes,24 subsequent aldol
reaction could not occur probably due to first protonation of a
Ru-enolate intermediate prior to the aldol reaction.
Figure 1. Time conversion curves of the catalytic reaction of 2a (4
mmol), 3a (3 mmol), and 4a (1 mmol) with the Ru catalyst 1a (2 mol
%), NaOAc (10 mol %), and EtOH (20 mol %). The vertical scale was
normalized.
The absolute configuration of 5b-anti was determined by X-
ray analysis. The crystals of 5b-anti (93% ee) were obtained by
crystallization twice from a hexane solution. The ORTEP
diagram unambiguously showed the anti-conformation (Figure
S1). The absolute configurations at the C3 and C4 atoms were
determined to be S and R, respectively. The C6−C7 bond
length of 1.201(5) Å is that of a typical triple bond.
in the presence of 1a (2 mol %) and NaOAc (10 mol %) was
heated at 60 °C for 24 h, formation of 4a and 7 in 21% yield
each and recovery of 5a-anti in 58% yield were detected in the
1H NMR spectrum (Scheme 2). This observation indicated the
retro-aldol reaction of 5a-anti. The enantiomeric excess of the
recovered 5a-anti was unchanged, and the formation of 5a-syn
was not detected. Thus, interconversion between 5a-anti and
5a-syn did not proceed under the catalytic conditions.
Simultaneously, this reaction produced unidentified byprod-
ucts, which led to a decrease in material balance. In contrast,
the reaction with 1a in the absence of NaOAc resulted in the
complete recovery of 5a-anti. Furthermore, the use of only
NaOAc gave 4a and 7 in 12% and 23% yields, respectively. We
also confirmed that the reaction in the absence of both 1a and
NaOAc did not proceed. These results clearly indicated that the
retro-aldol reaction of 5 was catalyzed by NaOAc. In this
To obtain insight into the catalytic reaction, we monitored
1
the catalytic reaction by H NMR spectroscopy (Figure 1).
After 12 h, the concentrations of 5a and 4a reached maximum
and minimum values, respectively. At this point, methylvinyl-
ketone 3a was synchronously consumed. After that, the
concentration of 5a gradually decreased and that of 4a
increased. At the same time, the concentration of 6a also
reached a maximum value and then decreased over time. These
results suggested that 5a and 6a underwent a retro-aldol
reaction to give 4a and 7.
The retro-aldol of the product 5 was checked in the presence
and/or absence of the Ru catalyst 1a and NaOAc. When 5a-anti
C
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Article
detected after heating at 60 °C for 24 h [Scheme 3, eq (1)]. To
test the effect of the presence of extra alkyne and enone, the
reaction of 7 and 4a in the presence of 2c and 3a was also
conducted. The NMR spectrum of the crude product showed
the formation of compound 5c, which was formed by coupling
of 2c, 3a, and 4a in 68% yield [Scheme 3, eq (2)]. In this
reaction, the formation of 5a was not detected. Judging from
these results, the phebox Ru catalyst 1 could not catalyze direct
aldol reaction of 7 with 4a to give the coupling product 5a.
Thus, we concluded that the Ru enolate species generated by
conjugate addition of alkynes to α,β-unsaturated carbonyl
compounds is the key to the formation of 5a.
Scheme 2. Retro-Aldol Reaction of 5b-anti
We propose the reaction mechanism shown in Scheme 4.
Reaction of an alkyne 2 with a Ru acetate generates a Ru
acetylide intermediate A (step i). This step is in equilibrium
with the protonation of A, and NaOAc might play a role to
increase the concentration of A. Next, the coordination of 3a
forms the intermediate B, followed by insertion into the Ru−
acetylide bond to give the Ru enolate intermediate C (steps ii
and iii). In this step, alkynylation to an aldehyde is considered
to be much slower than the conjugate addition. Successive
isomerization to a Ru-O-enolate and coordination of an
aldehyde gives intermediate D (step iv), which undergoes C−
C bond formation to afford E (step v). In contrast, protonation
of C results in the formation of the conjugate addition product
7 (step vi), which is the major side reaction. Judging from the
time conversion curve, the ratio of steps iv and vi is estimated
to be ca. 1:3. In the previous report, Rh and Ir enolate
intermediates generated by insertion of an α,β-unsaturated
carbonyl compound into the M−H bond were believed to trap
the aldehyde.28,29 Hayashi and co-workers suggested that the
Rh enolate species generated by insertion of a Rh−Ph bond
into cyclohexenone could undergo the subsequent aldol
reaction.7 We propose that a Ru enolate could be a key
intermediate for the aldol reaction.30 At this stage, the aldol
reaction proceeds without dissociation of 7 due to the lack of
reaction of 7 with the aldehyde catalyzed by 1a. Further
protonation of the resulting intermediate D gives 5,
accompanied by 1 (step vii). At the same time, an undesired
retro-aldol reaction of 5 is independently catalyzed by NaOAc.
The absolute configuration of 5b-anti was determined to be
S(α),R(β). In this sense, the major anti-isomer could be formed
Scheme 3. Aldol Reaction of 4a with 7
regard, the reaction rate of the retro-aldol reaction of 5 and 6
might affect the ratio of 5:6.
Further control experiments for the aldol reaction were also
examined. In the catalytic cycle, the γ-alkynyl ketone 7, which is
produced in situ by the conjugate addition of 2a with 3a, is a
candidate as an intermediate for the aldol reaction with 4a
giving 5a.27 Thus, we monitored the reaction of 7 with 4a in
the presence of 1a (2 mol %) and NaOAc (10 mol %).
However, the formation of the coupling product 5a was not
Scheme 4. Proposed Mechanism
D
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1
(244 mg, 88% yield). 5a-anti: yellowish oil. H NMR (300 MHz,
CDCl3): δ 2.27 (s, 3H), 2.42−2.60 (m, 2H), 2.98 (d, J = 4.8 Hz, 1H),
3.14−3.18 (m, 1H), 4.96 (dd, J = 5.0, 7.7 Hz, 1H), 7.25−7.38 (m,
10H). 13C{1H} NMR (75 MHz, CDCl3): δ 20.0, 32.4, 57.6, 74.8, 82.9,
85.8, 122.9, 126.1, 127.8, 128.0, 128.04, 128.5 131.3, 141.2, 211.4. IR
(KBr): 3448 (νOH), 2235 (νCC), 1703 (νCO) cm−1. [α]D19 = −43.9 (c =
1.0 in CHCl3, 78% ee). HRMS (ESI): m/z calcd for C19H18O2 [M +
Na]+, 301.1204; found, 301.1199. 5a-syn: 1H NMR (300 MHz,
CDCl3): δ 2.20 (s, 3H), 2.68−2.91 (m, 3H), 3.16−3.22 (m, 1H), 5.04
(dd, J = 2.6, 5.3 Hz), 7.25−7.37 (m, 10H); 13C{1H} NMR (75 MHz,
CDCl3): δ 17.6, 32.4, 58.0, 73.3, 82.5, 87.1, 123.0, 125.9, 127.7, 127.8,
128.0, 128.4 131.3, 140.8, 211.1. HPLC (Daicel CHIRALPAK AD-H
× 2, hexane:i-PrOH = 97:3, 0.5 mL/min, 254 nm): 79% ee (anti), 46%
ee (syn), tR = 121.5 (anti, major), 128.2 (syn, major), 132.2 (anti,
minor), 140.7 (syn, minor) min.
by C−C bond formation between the re face of the aldehyde
and the re face of the enolate in a six-membered cyclic
transition state (Scheme 5). At this point, both E- and Z-
Scheme 5. Proposed Transition State
3-[(4-Bromophenyl)(hydroxy)methyl]-6-phenylhex-5-yn-2-one
(5b). Reaction of 2a (408 mg), 3a (210 mg), and 4-bromobenzalde-
hyde 4b (184 mg) for 24 h yielded a mixture of 5b and 6b (264 mg,
88% yield). 5b-anti: yellowish solid, mp: 75 °C. 1H NMR (300 MHz,
CDCl3): δ 2.24 (s, 3H), 2.50 (d, J = 6.6 Hz, 2H), 3.08 (dt, J = 7.5, 6.6
Hz, 1H), 4.92 (d, J = 7.5 Hz, 1H), 7.19−7.33 (m, 7H), 7.44−7.49 (m,
2H). 13C{1H} NMR (75 MHz, CDCl3): δ 19.9, 32.2, 57.4, 74.1, 83.2,
85.4, 121.9, 122.7, 127.8, 127.9, 128.1, 131.3 131.5, 140.3, 211.1. IR
(KBr): 3411 (νOH), 1698 (νCO) cm−1. HRMS (FAB): m/z calcd for
enolate species could be formed. We assume that the E-enolate
is the more favorable pathway to the anti-isomer than the Z-
enolate when the six-membered cyclic transition state is
involved. Although the additive effect of the alcohol is still
unclear, it affects the dissociation step of the product as a
proton donor.
23
C19H17BrO2 [M + Na]+, 379.0310; found, 379.0302. [α]D = +7.0 (c
= 1.0 in CHCl3, 74% ee). 5b-syn: 1H NMR (300 MHz, CDCl3): δ 2.26
(s, 3H), 2.63−2.70 (m, 1H), 2.77 (dd, J = 9.3, 17.1 Hz, 1H), 3.02 (br,
1H), 3.10−3.17 (m, 1H), 5.04 (d, J = 5.1 Hz), 7.23−7.36 (m, 7H),
7.47−7.51 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3): δ 17.3, 32.3,
57.5, 72.5, 82.7, 86.7, 121.6, 122.9, 127.7, 127.8, 128.1, 131.3 131.4,
139.9, 211.0. HPLC (Daicel CHIRALPAK AD-H, hexane:i-PrOH =
97:3, 0.5 mL/min, 254 nm): 78% ee (anti), 18% ee (syn), tR = 79.6
(syn, major), 90.9 (anti, major), 97.1 (anti, minor), 120.2 (syn, minor)
min.
In summary, we described a Ru-catalyzed three-component
coupling between alkyne, α,β-unsaturated ketone, and aldehyde
via direct conjugate alkynylation and successive aldol reaction.
This method provides efficient preparation of a variety of new
β-hydroxyketone derivatives having α-propargyl groups in high
yields and high chemoselectivities. The advantage of this
catalytic system is the commercial availability of the substrates.
While the enantioselectivity is still moderate, this reaction is a
challenging synthetic strategy to construct complex and
functionalized organic molecules from ubiquitous starting
materials in a one-pot procedure. The stereochemistry of the
major anti-product was unambiguously confirmed by X-ray
diffraction studies. Control experiments implied that the Ru-
enolate species, generated by conjugate addition of an alkyne to
an enone, served as a key intermediate for the following aldol
coupling step.
3-((4-Chlorophenyl)(hydroxy)methyl)-6-phenylhex-5-yn-2-one
(5c). Reaction of 2a (408 mg), 3a (210 mg), and 4-chlorobenzalde-
hyde 4c (171 mg) for 24 h yielded a mixture of 5c and 6c (158 mg,
1
51% yield). 5c-anti: yellowish solid; mp: 60 °C. H NMR (300 MHz,
CDCl3): δ 2.20 (s, 3H), 2.44 (m, 2H), 2.94 (br, 1H), 3.04 (q, J = 7.2
Hz, 1H), 4.89 (d, J = 7.8 Hz, 1H), 7.18−7.29 ppm (m, 9H). 13C{1H}
NMR (75 MHz, CDCl3): δ 19.9, 32.2, 57.5, 74.0, 83.1, 85.5, 122.7,
127.5, 127.9, 128.1, 128.4, 131.3, 133.6, 139.8, 211.6. IR (KBr): 3467
(νOH), 1702 (νCO) cm−1. HRMS (FAB): m/z calcd for C19H17ClO2
23
[M + Na]+, 335.0815; found, 335.0814. [α]D = −4.6 (c = 1.0 in
CHCl3, 61% ee). 5c-syn: 1H NMR (300 MHz, CDCl3): δ 2.17 (s, 3H),
2.57−2.76 (m, 2H), 2.92 (br, 1H), 3.04−3.09 (q, J = 7.2 Hz, 1H), 4.96
(d, J = 5.4 Hz, 1H), 7.17−7.31 (m, 9H). 13C{1H} NMR (75 MHz,
CDCl3): δ 17.4, 32.3, 57.7, 72.5, 82.6, 86.8, 122.8, 127.3, 127.8, 128.0,
128.4, 131.2, 133.4, 139.4, 211.0 ppm. HPLC (Daicel CHIRALPAK
AD-H, hexane:i-PrOH = 97:3, 0.5 mL/min, 254 nm): 61% ee (anti),
9% ee (syn), tR = 124.1 (syn, major), 131.5 (anti, major), 139.4 (anti,
minor), 165.6 (syn, minor) min.
EXPERIMENTAL SECTION
■
General Information. 1H and 13C spectra were obtained at 25 °C
1
in CDCl3 on a 300 MHz spectrometer. H NMR chemical shifts are
reported in δ units, in ppm relative to the singlet at 7.26 ppm for
CDCl3. 13C NMR spectra are reported in terms of chemical shifts (δ,
ppm) relative to the triplet at δ = 77.0 ppm for CDCl3. Infrared
spectra were recorded on a Fourier transform IR spectrometer using a
KBr pellet. Mass spectra were recorded on a double-focusing mass
spectrometer (FAB) and hybrid quadrupole-orbitrap mass spectrom-
eter (ESI). Optical rotation measurements were recorded on a
polarimeter in CHCl3. Column chromatography was performed on a
neutral silica gel. The phebox-Ru complexes 1a−b were prepared by
the reported method.23,31
General Procedure of 5. A mixture of 1a (12 mg, 0.020 mmol), 2
(4.0 mmol), 3 (3.0 mmol), 4 (1.0 mmol), NaOAc (8 mg, 0.1 mmol),
and ethanol (8 mg, 0.20 mmol) was stirred at 60 °C for 24 h. After
removal of volatile materials under reduced pressure, the residue was
purified by column chromatography on silica gel with hexane/ethyl
acetate to give 5 and 6 as a diastereomeric mixture. Compounds 5-anti
were separated by a recycle LC.
3-[Hydroxy(4-nitrophenyl)methyl]-6-phenylhex-5-yn-2-one (5d).
Reaction of 2a (408 mg), 3a (210 mg), and 4-nitrobenzaldehyde 4d
(151 mg) for 24 h yielded a mixture of 5d and 6d (228 mg, 71%
yield). 5d-anti: yellowish oil. 1H NMR (300 MHz, CDCl3): δ 2.26 (s,
3H), 2.58 (dd, J = 7.2, 17.2 Hz, 1H), 2.68 (dd, J = 5.9, 17.2 Hz, 1H),
3.15 (m, 1H), 5.16 (d, J = 6.9 Hz, 1H), 7.26−7.38 (m, 5H), 7.58 (d, J
= 8.8 Hz, 2H), 8.23 (d, J = 8.8 Hz, 2H). 13C{1H} NMR (75 MHz,
CDCl3): δ 20.0, 32.0, 57.1, 73.6, 83.7, 84.9, 122.5, 123.7, 127.0, 128.12,
128.15, 131.3, 147.4, 148.6, 210.8. IR (KBr): 3411 (νOH), 1703 (νCO
)
cm−1. HRMS (FAB): m/z calcd for C19H17NO4 [M + Na]+, 346.1055;
found, 346.1047. [α]D18 = −55 (c = 1.0 in CHCl3, 55% ee). 5d-syn: 1H
NMR (300 MHz, CDCl3, 20 °C, TMS): δ 2.35 (s, 3H), 2.61 (dd, J =
5.3, 17.0 Hz, 1H), 2.78 (dd, J = 9.0, 17.0 Hz, 1H), 3.18 (m, 1H), 5.25
(d, J = 4.2 Hz, 1H), 7.24−7.33 (m, 5H), 7.57 (m, 2H), 8.23 (m, 2H).
13C{1H} NMR (75 MHz, CDCl3, 20 °C, TMS): δ 17.3, 32.5, 57.4,
72.3, 83.5, 86.6, 123.0, 123.9, 127.2, 128.4, 128.5, 131.6, 147.6, 148.4,
211.3. HPLC (Daicel CHIRALPAK AD-H, hexane:i-PrOH = 97:3, 0.5
3-[Hydroxy(phenyl)methyl]-6-phenylhex-5-yn-2-one (5a). Reac-
tion of ethynylbenzene 2a (411 mg), but-3-en-2-one 3a (210 mg), and
benzaldehyde 4a (106 mg) for 12 h yielded a mixture of 5a and 6a
E
DOI: 10.1021/acs.joc.6b00374
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
mL/min, 254 nm): 55% ee (anti), 3% ee (syn), tR = 37.1 (syn, major),
40.1 (anti, minor), 42.4 (anti, major), 49.8 (syn, minor) min.
3-{Hydroxyl[4-(trifluoromethyl)phenyl]methyl}-6-phenylhex-5-
yn-2-one (5e). Reaction of 2a (408 mg), 3a (210 mg), and 4-
(trifluoromethyl)benzaldehyde 4e (188 mg) for 12 h yielded a mixture
of 5e and 6e (252 mg, 73% yield). 5e-anti: yellowish solid; mp: 58 °C.
1H NMR (300 MHz, CDCl3): δ 2.27 (s, 3H), 2.55 (d, J = 6.8 Hz, 2H),
J = 4.8 Hz, 1H), 7.18−7.42 (m, 8H), 7.52 (s, 1H). 13C{1H} NMR (75
MHz, CDCl3): δ 17.2, 32.2, 57.4, 72.3, 82.7, 86.7, 122.6, 122.9, 124.6,
127.8, 128.0, 128.9, 129.9, 130.8, 131.3, 143.1, 211.0. HPLC (Daicel
CHIRALCEL OD-H, hexane:i-PrOH = 97:3, 0.5 mL/min, 254 nm):
60% ee (anti), 8% ee (syn), tR = 64.1 (anti, minor), 99.8 (syn, minor),
132.1 (syn, major), 151.0 (anti, major) min.
3-[Hydroxy(naphthalen-2-yl)methyl]-6-phenylhex-5-yn-2-one
(5i). Reaction of 2a (408 mg), 3a (210 mg), and 2-naphthaldehyde 4i
(156 mg) for 24 h yielded a mixture of 5i and 6i (245 mg, 75% yield).
3.71 (q, J = 6.8 Hz, 1H), 3.44 (br, 1H), 5.05 (dd, J = 3.6, 6.8 Hz),
7.24−7.38 (m, 5H), 7.50 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H).
13C{1H} NMR (75 MHz, CDCl3): δ 19.8, 32.1, 57.3, 74.0, 83.3, 85.3,
124.1 (JCF = 220 Hz), 125.3 (JCF = 3.4 Hz), 126.5, 127.9, 128.0, 128.1,
130.0 (JCF = 33 Hz), 131.3, 145.3, 211.0. IR (KBr): 3508 (νOH), 1711
(νCO) cm−1. HRMS (FAB): m/z calcd for C20H17F3O2 [M + Na]+,
1
5i-anti: yellowish solid; mp: 133 °C. H NMR (300 MHz, CDCl3): δ
2.26 (s, 3H), 2.47 (dd, J = 5.1 17.0 Hz, 1H), 2.58 (dd, J = 8.6, 17.0 Hz,
1H), 3.23−3.31 (m, 1H), 5.11 (d, J = 7.8 Hz, 1H), 7.22−7.33 (m,
5H), 7.44−7.49 (m, 3H), 7.78−7.85 (m, 4H). 13C{1H} NMR (75
MHz, CDCl3): δ 20.0, 32.4, 57.5, 75.0, 82.8, 85.9, 122.8, 123.6, 125.3,
125.9, 126.1, 127.4, 127.7, 127.8, 128.0, 128.3, 131.2, 132.8, 132.9,
138.5, 211.3. IR (KBr): 3471 (νOH), 1700 (νCO) cm−1. HRMS (FAB):
21
369.1078; found, 369.1069. [α]D = −45.3 (c = 1.0 in CHCl3, 62%
1
ee). 5e-syn: H NMR (300 MHz, CDCl3): δ 2.26 (s, 3H), 2.53−2.66
(m, 1H), 2.77 (dd, J = 9.0, 17.1 Hz, 1H), 3.10−3.18 (m, 1H), 3.34 (br,
1H), 5.13 (d, J = 4.8 Hz, 1H), 7.21−7.35 (m, 5H), 7.47 (d, J = 8.1 Hz,
2H), 7.60 (d, J = 8.1 Hz, 2H). HPLC (Daicel CHIRALPAK AD-H ×
2, hexane:i-PrOH = 97:3, 0.5 mL/min, 254 nm): 70% ee (anti), 10%
ee (syn), tR = 91.8 (syn, major), 115.7 (anti, minor), 128.0 (anti, major),
138.6 (syn, minor) min.
24
m/z calcd for C23H20O2 [M + Na]+, 351.1361; found, 351.1352. [α]D
1
= −24.6 (c = 1.0 in CHCl3, 64% ee). 5i-syn: H NMR (300 MHz,
CDCl3): δ 2.30 (s, 3H), 2.85 (dd, J = 5.0 16.9 Hz, 1H), 2.94 (dd, J =
9.3, 16.9 Hz, 1H), 3.35−3.42 (m, 1H), 5.29 (d, J = 5.1 Hz, 1H), 7.32−
7.61 (m, 9H), 7.90−7.95 (m, 3H). 13C{1H} NMR (75 MHz, CDCl3):
δ 17.5, 32.3, 57.9, 73.4, 82.5, 87.1, 122.8, 123.6, 125.3, 125.9, 126.1,
127.4, 127.7, 127.8, 128.0, 128.3, 131.2, 132.8, 132.9, 138.5, 211.1.
HPLC (Daicel CHIRALCEL OD-H, hexane:i-PrOH = 95:5, 0.5 mL/
min, 254 nm): 64% ee (anti), 16% ee (syn), tR = 73.4 (anti, minor),
90.3 (syn, minor), 103.6 (anti, major), 115.8 (syn, major) min.
Methyl 4-(2-Acetyl-1-hydroxy-5-phenylpent-4-yn-1-yl)benzoate
(5f). Reaction of 2a (408 mg), 3a (210 mg), and methyl 4-
formylbenzoate 4f (164 mg) for 24 h yielded a mixture of 5f and 6f
1
(234 mg, 69% yield). 5f-anti: yellowish solid; mp: 60 °C. H NMR
(300 MHz, CDCl3): δ 2.24 (s, 3H), 2.57 (d, J = 6.9 Hz, 2H), 3.17 (q, J
= 6.9 Hz, 1H), 3.92 (s, 3H), 5.06 (t, J = 6.2 Hz), 7.26−7.38 (m, 5H),
7.46 (d, J = 8.4 Hz, 2H), 8.02−8.05 (m, 2H). 13C{1H} NMR (75
MHz, CDCl3, rt): δ 19.9, 32.3, 52.3, 57.3, 72.7, 83.3, 85.4, 122.7, 126.1,
127.9, 129.6, 129.7, 131.3, 146.4, 166.3, 211.2. IR (KBr): 3463 (νOH),
1703 (νCO) cm−1. HRMS (FAB): m/z calcd for C21H20O4 [M + Na]+,
3-[Hydroxy(thiophen-2-yl)methyl]-6-phenylhex-5-yn-2-one (5j).
Reaction of 2a (408 mg), 3a (210 mg), and thiophene-2-carbaldehyde
4j (112 mg) for 24 h yielded a mixture of 5j and 6j (224 mg, 79%
1
yield). 5j-anti: yellowish oil. H NMR (300 MHz, CDCl3): δ 2.32 (s,
3H), 2.53−2.56 (m, 2H), 3.17 (m, 1H), 5.20 (d, J = 7.5 Hz, 1H),
6.93−7.00 (m, 2H), 7.22−7.35 (m, 6H). 13C{1H} NMR (75 MHz,
CDCl3): δ 20.0, 32.3, 57.8, 71.0, 83.0, 85.5, 122.8, 124.7, 125.2, 126.6,
26
359.1259; found, 359.1246. [α]D = −39.5 (c = 1.0 in CHCl3, 69%
1
ee). 5f-syn: H NMR (300 MHz, CDCl3): δ 2.27 (s, 3H), 2.58−2.68
127.8, 128.0, 131.3, 145.1, 211.1. IR (KBr): 3486 (νOH), 1706 (νCO
)
(m, 1H), 2.79 (dd, J = 9.6, 17.1 Hz, 1H), 3.92 (s, 3H), 5.14 (dd, J =
2.6, 4.7 Hz, 1H), 7.24−7.37 (m, 5H), 7.45 (d, J = 8.1 Hz, 2H), 8.04 (d,
J = 8.1 Hz, 2H). HPLC (Daicel CHIRALPAK AD-H, hexane:i-PrOH
= 95:5, 0.5 mL/min, 254 nm): 70% ee (anti), 10% ee (syn), tR = 69.6
(anti, major), 75.8 (syn, major), 79.4 (syn, minor), 85.1 (anti, minor)
min.
cm−1. HRMS (FAB): m/z calcd for C17H16O2S [M + Na]+, 307.0769;
26
found, 307.0754. [α]D = −39.3 (c = 1.0 in CHCl3, 61% ee). 5j-syn:
1H NMR (300 MHz, CDCl3): δ 2.21 (s, 3H), 2.79−2.82 (m, 2H),
3.15−3.23 (m, 1H), 5.25−5.27 (m, 1H), 6.93−7.01 (m, 2H), 7.22−
7.35 (m, 6H). HPLC (Daicel CHIRALCEL OD-H, hexane:i-PrOH =
98:2, 0.5 mL/min, 254 nm): 61% ee (anti), 7% ee (syn), tR = 94.0
(anti, minor), 133.5 (syn, major), 180.0 (anti, major), 191.2 (syn,
minor) min.
3-[Hydroxy(phenyl)methyl]-6-[4-(trifluoromethyl)phenyl]hex-5-
yn-2-one (5k). Reaction of 1-ethynyl-4-(trifluoromethyl)benzene 2b
(680 mg), 3a (210 mg), and 4a (106 mg) for 24 h yielded a mixture of
5k and 6k (300 mg, 87% yield). 5k-anti: yellowish solid; mp: 65 °C.
1H NMR (300 MHz, CDCl3): δ 2.16 (s, 3H), 2.31−2.52 (m, 2H),
3-(Hydroxy(4-methoxyphenyl)methyl)-6-phenylhex-5-yn-2-one
(5g). Reaction of 2a (408 mg), 3a (210 mg), and 4-methoxy-
benzaldehyde 4g (136 mg) for 24 h yielded a mixture of 5g and 6g
1
(234 mg, 69% yield). 5g-anti: yellowish solid; mp: 112 °C; H NMR
(300 MHz, CDCl3): δ 2.30 (s, 3H), 2.42 (dd, J = 5.1, 17.1 Hz, 1H),
2.52 (dd, J = 8.4, 17.1 Hz, 1H), 2.86 (br, 1H), 3.14 (dt, J = 5.1, 8.1
Hz), 3.80 (s, 3H), 4.88 (dd, J = 4.2, 8.1 Hz, 1H), 6.87−6.92 (m, 2H),
7.25−7.36 (m, 7H); 13C{1H} NMR (75 MHz, CDCl3): δ 19.9, 32.3,
55.3, 57.8, 74.5, 82.7, 85.9, 113.8, 122.9, 127.3, 127.7, 128.0, 131.2,
133.3, 159.1, 211.4; IR (KBr): 3469 (νOH), 1699 (νCO) cm−1; HRMS
(FAB): m/z calcd for [C20H20O3 + Na+]: 331.1310; found: 331.1315
2.69 (br, 1H), 3.05−3.13 (m, 1H), 4.83 (dd, J = 4.1, 7.7 Hz, 1H),
7.14−7.44 (m, 9H). 13C{1H} NMR (75 MHz, CDCl3): δ 19.8, 32.4,
57.4, 74.9, 81.5, 88.7, 123.7 (JCF = 269 Hz), 125.0 (JCF = 3.5 Hz),
126.1, 126.7, 128.1, 128.5, 129.5 (JCF = 31.9 Hz), 131.5, 141.1, 211.1.
IR (KBr): 3430 (νOH), 2241 (νCC), 1703 (νCO) cm−1. HRMS (FAB):
m/z calcd for C20H17F3O2 [M + Na]+, 369.1078; found, 369.1083.
21
1
[M + Na+]; [α]D = −1.4 (c = 1.0 in CHCl3, 39% ee). 5g-syn: H
NMR (300 MHz, CDCl3): δ 2.14 (s, 3H), 2.75 (d, J = 6.7 Hz, 2H),
2.83 (br, 1H), 3.16 (q, J = 6.7 Hz, 1H), 3.78 (s, 3H), 4.92 (d, J = 6.7
Hz, 1H), 6.85−6.89 (m, 2H), 7.23−7.34 (m, 7H). HPLC (Daicel
CHIRALPAK AY-H, hexane:i-PrOH = 95.5:4.5, 1.0 mL/min, 254
nm): 39% ee (anti), 25% ee (syn), tR = 59.5 (syn, major), 76.2 (anti,
major), 89.1 (syn, minor), 101.6 (anti, minor) min.
25
1
[α]D = −13.6 (c = 1.0 in CHCl3, 52% ee). 5k-syn: H NMR (300
MHz, CDCl3): δ 2.04 (s, 3H), 2.62−2.77 (m, 2H), 2.96−3.06 (m,
1H), 4.85−4.89 (m, 1H), 7.16−7.44 (m, 9H). HPLC (Daicel
CHIRALPAK AD-H × 2, hexane:i-PrOH = 95:5, 0.5 mL/min, 254
nm): 52% ee (anti), 12% ee (syn), tR = 72.1 (anti, major), 76.4 (anti,
minor), 86.2 (syn, major), 103.7 (syn, minor) min.
3-[(3-Bromophenyl)(hydroxy)methyl]-6-phenylhex-5-yn-2-one
(5h). Reaction of 2a (408 mg), 3a (211 mg), and 3-bromo-
benzaldehyde 4h (184 mg) for 24 h yielded a mixture of 5h and 6h
6-(4-Bromophenyl)-3-[hydroxy(phenyl)methyl]hex-5-yn-2-one
(5l). Reaction of 1-bromo-4-ethynylbenzene 2c (724 mg), 3a (210
mg), and 4a (106 mg) for 24 h yielded a mixture of 5l and 6l (278 mg,
78% yield). 5l-anti: yellowish solid; mp: 110 °C. 1H NMR (300 MHz,
CDCl3): δ 2.16 (s, 3H), 2.34 (dd, J = 5.1, 17.0 Hz, 1H), 2.45 (dd, J =
8.3, 17.0 Hz, 1H), 3.06 (m, 1H), 4.84 (d, J = 7.5 Hz, 1H), 7.07−7.32
(m, 9H). 13C{1H} NMR (75 MHz, CDCl3): δ 19.8, 32.3, 57.5, 74.8,
81.7, 87.2, 121.9, 126.0, 128.0, 128.4, 131.2, 132.7, 141.1, 211.1. IR
(KBr): 3388 (νOH), 1708 (νCO) cm−1. HRMS (FAB): m/z calcd for
C19H17BrO2 [M + Na]+, 379.0310; found, 379.0320. [α]D26 = −27.4 (c
= 1.0 in CHCl3, 65% ee). 5l-syn: 1H NMR (300 MHz, CDCl3): δ 2.08
1
(258 mg, 72% yield). 5h-anti: yellowish solid; mp: 88 °C. H NMR
(300 MHz, CDCl3): δ 2.24 (s, 3H), 2.51 (d, J = 6.6 Hz, 2H); 3.03 (br,
1H), 3.10 (q, J = 7.0 Hz, 1H), 4.91 (d, J = 7.5 Hz, 1H), 7.17−7.42 (m,
8H), 7.52 (s, 1H). 13C{1H} NMR (75 MHz, CDCl3): δ 20.0, 32.3,
57.3, 74.0, 83.2, 85.4, 122.65, 122.71, 124.8, 127.9, 128.1, 129.2, 130.0,
131.0, 131.3, 143.6, 211.1. IR (KBr): 3428 (νOH), 1703 (νCO) cm−1.
HRMS (FAB): m/z calcd for C19H17BrO2 [M + Na]+, 379.0310;
found, 379.0315. [α]D24 = −30.9 (c = 1.0 in CHCl3, 60% ee). 5h-syn:
1H NMR (300 MHz, CDCl3): δ 2.26 (s, 3H), 2.62 (dd, J = 4.8, 17.1
Hz, 1H), 2.76 (dd, J = 9.6, 17.1 Hz, 1H), 3.09−3.15 (m, 1H), 5.03 (d,
F
DOI: 10.1021/acs.joc.6b00374
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The Journal of Organic Chemistry
Article
(s, 3H), 2.61 (dd, J = 5.1, 17.0 Hz, 1H), 2.71 (dd, J = 9.3, 17.0 Hz,
1H), 3.08 (m, 1H), 4.93 (d, J = 5.4 Hz, 1H), 7.07−7.33 (m, 9H).
13C{1H} NMR (75 MHz, CDCl3): δ 17.6, 32.2, 58.0, 73.3, 81.4, 88.5,
121.9, 125.9, 127.8, 128.4, 131.3, 132.7, 140.8, 210.7. HPLC (Daicel
CHIRALPAK AD-H × 2, hexane:i-PrOH = 97:3, 0.5 mL/min, 254
nm): 65% ee (anti), 44% ee (syn), tR = 182.8 (anti, major), 194.7 (anti,
minor), 201.7 (syn, major), 249.6 (syn, minor) min.
(s, 1H). 13C{1H} NMR (75 MHz, CDCl3): δ 21.8, 41.9, 68.2, 70.9,
124.3, 126.2, 128.2, 129.0, 131.3, 134.0, 137.7, 141.1, 163.3. Anal.
Calcd for C28H28N2O2: C, 79.22; H, 6.65; N, 6.60. Found: C, 78.92;
H, 6.66; N, 6.60.
[(S,S)-dm-Phebox-Et]H. Reaction of 4,6-dimethylisophthalic acid
(0.98 g, 5.0 mmol) and (S)-2-amino-1-butanol (0.89 g, 10 mmol) gave
1
[(S,S)-dm-Phebox-Et]H in 88% yield (1.32 g, 4.4 mmol). H NMR
(300 MHz, CDCl3): δ 1.00 (t, J = 7.4 Hz, 6H), 1.54−1.81 (m, 4H),
2.58 (s, 6H), 3.96−3.99 (m, 2H), 4.22−4.40 (m, 2H), 4.40−4.43 (m,
2H), 7.10 (s, 1H), 8.21 (s, 1H). 13C{1H} NMR (75 MHz, CDCl3): δ
10.2, 21.7, 28.9, 68.4, 71.2, 124.5, 131.2, 133.9, 140.8, 162.7. Anal.
Calcd for C18H24N2O2: C, 71.97; H, 8.05; N, 9.33. Found: C, 71.67;
H, 8.37; N, 9.28.
3-[Hydroxy(phenyl)methyl]-6-(4-methoxyphenyl)hex-5-yn-2-one
(5m). Reaction of 1-ethynyl-4-methoxybenzene 2d (528 mg), 3a (210
mg), and 4a (106 mg) for 24 h yielded a mixture of 5m and 6m (123
1
mg, 40% yield). 5m-anti: yellowish solid; mp: 60 °C. H NMR (300
MHz, CDCl3): δ 2.17 (s, 3H), 2.36−2.46 (m, 2H), 3.03−3.08 (m,
1H), 3.69 (s, 3H), 4.86 (dd, J = 2.1, 7.5 Hz, 1H), 6.69−6.72 (m, 2H),
7.16−7.27 (m, 7H). 13C{1H} NMR (75 MHz, CDCl3): δ 17.6, 32.3,
55.3, 58.1, 73.4, 82.2, 85.5, 113.7, 115.1, 125.9, 127.7, 128.3, 132.6,
140.9, 158.9, 211.2. IR (KBr): 3412 (νOH), 1702 (νCO) cm−1. HRMS
(FAB): m/z calcd for C20H20O3 [M + Na]+, 331.1310; found,
[(S,S)-dm-Phebox-Me]H. Reaction of 4,6-dimethylisophthalic acid
(1.25 g, 6.4 mmol) and (L)-lalaninol (0.97 g, 13 mmol) gave [(S,S)-
1
dm-Phebox-Me]H in 70% yield (1.22 g, 4.5 mmol). H NMR (300
MHz, CDCl3): δ 1.37 (d, J = 6.3 Hz, 6H), 2.59 (s, 6H), 3.94 (t, J = 7.1
Hz, 2H), 4.39−4.51 (m, 4H), 7.12 (s, 1H), 8.27 (s, 1H). 13C{1H}
NMR (75 MHz, CDCl3): δ 21.7, 21.8, 62.3, 73.2, 124.4, 131.3, 133.9,
140.8, 162.8. Anal. Calcd for C16H20N2O2: C, 70.56; H, 7.40; N, 10.29.
Found: C, 70.46; H, 7.55; N, 10.08.
23
1
331.1302. [α]D = −29.8 (c = 1.0 in CHCl3, 52% ee). 5m-syn: H
NMR (300 MHz, CDCl3): δ 2.10 (s, 3H), 2.60 (dd, J = 5.3, 17.0 Hz,
1H), 2.69 (dd, J = 6.5, 17.0 Hz, 1H), 3.05−3.11 (m, 1H), 3.70 (s, 3H),
4.93 (d, J = 5.1 Hz, 1H), 6.68−6.73 (m, 2H), 7.15−7.29 (m, 7H).
13C{1H} NMR (75 MHz, CDCl3): δ 20.0, 32.4, 55.3, 57.7, 74.8, 82.7,
84.2, 113.7, 115.0, 126.1, 127.9, 128.4, 132.7, 141.3, 159.0, 211.5.
HPLC (Daicel CHIRALPAK AD-H × 2, hexane:i-PrOH = 97:3, 0.5
mL/min, 254 nm): 52% ee (anti), 8% ee (syn), tR = 228.7 (anti,
major), 248.2 (anti, minor), 262.8 (syn, major), 311.3 (syn, minor) min.
4-[Hydroxy(phenyl)methyl]-1-phenyldec-1-yn-5-one (5m). Reac-
tion of 2a (409 mg), oct-1-en-3-one 3b (378 mg), and 4a (106 mg)
for 24 h yielded a mixture of 5n and 6n (334 mg, 48% yield). 5n-anti:
yellowish oil. 1H NMR (300 MHz, CDCl3): δ 0.81 (t, J = 6.8 Hz, 3H),
1.10−1.26 (m, 4H), 1.45−1.56 (m, 2H), 2.32−2.64 (m, 4H), 3.07−
3.19 (m, 2H), 4.93 (dd, J = 5.4, 6.3 Hz, 1H), 7.23−7.35 (m, 10H).
13C{1H} NMR (75 MHz, CDCl3): δ 14.1, 20.3, 22.6, 22.7, 31.3, 45.6,
56.9, 75.0, 82.8, 86.1, 122.9, 125.9, 127.8, 127.9, 128.0, 128.4, 131.3,
141.5, 213.9. IR (KBr): 3467 (νOH), 1712 (νCO) cm−1. HRMS (ESI):
Preparation of Complexes 1c−f.23,31 Complex 1c. A 100 mL
flask was charged with RuCl3·3(H2O) (566 mg, 2.2 mmol), [(S,S)-dm-
Phebox-iBu]H (337 mg, 0.95 mmol), and Zn (337 mg). Under an
argon atmosphere, ethanol (20 mL) and 1,5-cyclooctadiene (0.6 mL)
were added, and the mixture was refluxed for 24 h. After removal of
the solvent under reduced pressure, the residue was extracted with
toluene and the extract was concentrated. The residue was purified by
column chromatography on silica gel with ethyl acetate/hexane (1:3)
to give a yellow solid. 2-Propanol (10 mL) was added to a mixture of
the solid and NaOAc (380 mg, 4.6 mmol). The mixture was stirred at
60 °C for 12 h, and then the solvent was removed under reduced
pressure. The residue was purified by column chromatography on
silica gel (ethyl acetate) to give 1c in 66% yield (340 mg, 0.63 mmol).
1H NMR (300 MHz, CDCl3): δ 0.94 (d, J = 6.6 Hz, 3H), 0.97 (d, J =
6.6 Hz, 3H), 0.99 (d, J = 6.0 Hz, 3H), 1.00 (d, J = 6.6 Hz, 3H), 1.33−
1.42 (m, 2H), 1.54−1.68 (m, 2H), 1.79−2.07 (m, 2H), 1.90 (s, 3H),
2.49 (s, 6H), 3.96−4.16 (m, 2H), 4.27−4.42 (m, 2H), 4.85−4.91 (m,
2H), 6.67 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 19.3, 19.4. 21.8,
22.2, 22.8, 23.4, 23.9, 24.0, 25.5, 25.6, 43.0, 44.6, 60.0, 63.7, 75.7, 76.2,
126.8, 129.3, 129.4, 139.3, 139.5, 173.5, 173.9, 184.9, 193.3, 197.4. IR
(KBr): 1919 (νCO) cm−1; Anal. Calcd for C25H34N2O5Ru: C, 55.24; H,
6.30; N, 5.15. Found: C, 55.35; H, 6.35; N, 5.02.
17
m/z calcd for C23H26O2 [M + Na]+, 357.1825; found, 357.1821. [α]D
1
= −7.7 (c = 0.5 in CHCl3, 60% ee). 5n-syn: H NMR (300 MHz,
CDCl3): δ 0.81 (t, J = 6.8 Hz, 3H), 1.07−1.28 (m, 4H), 1.40−1.56 (m,
2H), 2.25−2.33 (m, 1H), 2.52−2.86 (m, 3H), 2.98 (brs, 1H), 3.13−
3.21 (m, 1H), 4.97 (d, J = 6.0 Hz, 1H), 7.24−7.39 (m, 10H). HPLC
(Daicel CHIRALPAK AD-H × 2, hexane:i-PrOH = 97:3, 0.5 mL/min,
254 nm): 60% ee (anti), 13% ee (syn), tR = 84.5 (anti, major), 101.6
(anti, minor), 105.2 (syn, major), 149.8 (syn, minor) min.
Preparation of Bis(oxazolinyl)benzene.15,31 [(S,S)-dm-Phe-
box-iBu]H. A solution of 4,6-dimethylisophthalic acid (0.97 g, 5.0
mmol) and SOCl2 (3 mL) in toluene (5 mL) was refluxed for 6 h, and
then the solvent was removed under reduced pressure. The residue
was dissolved in THF, and the solution was slowly added to a THF
solution of (L)-leucinol (1.17 g, 10 mmol) and triethylamine (20 mL)
at 0 °C. The mixture was stirred at room temperature for 2 h. Then,
methanesulfonyl chloride (2 mL) was added at 0 °C, and the mixture
was stirred at room temperature for 6 h. Then, aqueous potassium
carbonate (ca. 7 g/50 mL) was added at 0 °C and the mixture was
extracted with ethyl acetate. The organic layer was washed with brine,
dried over magnesium sulfate, and concentrated. The crude product
was purified by column chromatography to give [(S,S)-dm-Phebox-
iBu]H in 29% yield (0.52 g, 1.45 mmol). 1H NMR (300 MHz,
CDCl3): δ 0.95 (d, J = 6.3 Hz, 6H), 0.96 (d, J = 6.6 Hz, 6H), 1.31−
1.40 (m, 2H), 1.62−1.71 (m, 2H), 1.77−1.86 (m, 2H), 2.56 (s, 6H),
3.89 (t, J = 7.2 Hz, 2H), 4.26−4.42 (m, 4H), 7.07 (s, 1H), 8.20 (s,
1H). 13C{1H} NMR (75 MHz, CDCl3): δ 21.8, 22.9, 23.0, 25.7, 45.8,
65.6, 72.2, 124.5, 131.1, 133.9, 140.8, 162.6. Anal. Calcd for
C22H32N2O2: C, 74.12; H, 9.05; N, 7.86. Found: C, 74.03; H, 9.34;
N, 7.88.
Complex 1d. Reaction of RuCl3·3(H2O) (546 mg, 2.1 mmol) and
[(S,S)-dm-Phebox-Bn]H (424 mg, 1.0 mmol) gave 1d in 22% yield
1
(134 mg, 0.22 mmol). H NMR (300 MHz, CDCl3): δ 1.97 (s, 3H),
2.50 (s, 3H), 2.51 (s, 3H), 2.55−2.72 (m, 2H), 3.45−3.66 (m, 2H),
4.20−4.30 (m, 1H), 4.38−4.46 (m, 2H), 4.54−4.71 (m, 3H), 6.61 (s,
1H), 7.20−7.36 (m, 10H). 13C{1H} NMR (75 MHz, CDCl3): δ 19.36,
19.40, 24.2, 40.1, 40.8, 63.3, 66.0, 75.0, 75.1, 126.55, 126.62, 127.0,
128.6, 128.9, 136.9, 137.0, 139.9, 140.0, 174.3, 174.8, 185.4, 193.4,
197.9. IR (KBr): 1920 (νCO) cm−1. Anal. Calcd for C31H30N2O5Ru: C,
60.87; H, 4.94; N, 4.58. Found: C, 60.59; H, 5.32; N, 4.34.
Complex 1e. Reaction of RuCl3·3(H2O) (552 mg, 2.1 mmol) and
[(S,S)-dm-Phebox-Et]H (335 mg, 1.1 mmol) gave 1e in 18% yield (98
mg, 0.20 mmol). 1H NMR (300 MHz, CDCl3): δ 0.91 (t, J = 6.6 Hz,
3H), 1.02 (t, J = 7.5 Hz, 3H), 1.48−1.67 (m, 3H), 1.90 (s, 3H), 1.90−
2.05 (m, 1H), 2.49 (s, 3H), 2.50 (s, 3H), 3.93−4.08 (m, 2H), 4.36 (t, J
= 8.9 Hz, 1H), 4.49 (t, J = 8.1 Hz, 1H), 4.77−4.89 (m, 2H), 6.57 (s,
1H). 13C{1H} NMR (75 MHz, CDCl3): δ 9.7, 9.9, 19.71, 19.74, 24.4,
26.8, 27.6, 63.0, 66.3, 74.95, 75.08, 127.2, 129.59, 129.65, 139.9, 140.0,
174.1, 174.6, 185.4, 193.8, 197.8. Anal. Calcd for C21H26N2O5Ru: C,
51.74; H, 5.38; N, 5.75. Found: C, 51.47; H, 5.23; N, 5.71.
Complex 1f. Reaction of RuCl3·3(H2O) (562 mg, 2.1 mmol) and
[(S,S)-dm-Phebox-Me]H (272 mg, 1.0 mmol) gave 1f in 76% yield
(349 mg, 0.76 mmol). 1H NMR (300 MHz, CDCl3): δ 1.36 (d, J = 6.0
Hz, 3H), 1.36 (d, J = 6.6 Hz, 3H), 1.91 (s, 3H), 2.49 (s, 3H), 2.50 (s,
3H), 4.07−4.40 (m, 4H), 4.86−4.95 (m, 2H), 6.58 (s, 1H). 13C{1H}
NMR (75 MHz, CDCl3): δ 19.28, 19.34, 19.7, 20.6, 24.0, 31.1, 57.4,
60.3, 126.8, 129.3, 129.4, 139.4, 139.6, 173.7, 174.2, 185.0, 193.3,
[(S,S)-dm-Phebox-Bn]H. Reaction of 4,6-dimethylisophthalic acid
(0.93 g, 4.8 mmol) and (L)-phenylalaninol (1.57 g, 10 mmol) gave
1
[(S,S)-dm-Phebox-Bn]H in 61% yield (1.49 g, 3.5 mmol). H NMR
(300 MHz, CDCl3): δ 2.60 (s, 6H), 2.72 (dd, J = 8.6, 13.7 Hz, 2H),
3.21 (dd, J = 5.1, 13.7 Hz, 2H), 4.08 (t, J = 7.8 Hz, 2H), 4.27 (t, J = 9.0
Hz, 2H), 4.55−4.65 (m, 2H), 7.12 (s, 1H), 7.12−7.33 (m, 10H), 8.25
G
DOI: 10.1021/acs.joc.6b00374
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
197.6. IR (KBr): 1917 (νCO) cm−1. Anal. Calcd for C19H22N2O5Ru: C,
49.67; H, 4.83; N, 6.10. Found: C, 49.63; H, 4.78; N, 5.83.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b00374.
E.; Kim, S. Org. Lett. 2001, 3, 2089. (e) Knopfel, T. F.; Carreira, E. M.
̈
J. Am. Chem. Soc. 2003, 125, 6054. (f) Chen, L.; Li, C.-J. Chem.
Crystallographic data for 5-anti (CIF)
Spectral data for all compounds, HPLC charts, and
crystallographic data (PDF)
Commun. 2004, 2362.
(10) (a) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123,
9687. (b) Jiang, B.; Chen, Z.; Xiong, W. Chem. Commun. 2002, 1524.
(c) Chen, Z.; Xiong, W.; Jiang, B. Chem. Commun. 2002, 2098.
(d) Yamashita, M.; Yamada, K.-i.; Tomioka, K. Adv. Synth. Catal. 2005,
347, 1649. (e) Emmerson, D. P. G.; Hems, W. P.; Davis, B. G. Org.
Lett. 2006, 8, 207. (f) Takita, R.; Yakura, K.; Ohshima, T.; Shibasaki,
M. J. Am. Chem. Soc. 2005, 127, 13760. (g) Harada, S.; Takita, R.;
Ohshima, T.; Matsunaga, S.; Shibasaki, M. Chem. Commun. 2007, 948.
(h) Asano, Y.; Hara, K.; Ito, H.; Sawamura, M. Org. Lett. 2007, 9,
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2008, 27, 5984.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: jito@apchem.nagoya-u.ac.jp (J.-i.I.).
*E-mail: hnishi@apchem.nagoya-u.ac.jp (H.N.).
Notes
The authors declare no competing financial interest.
(11) Reviews for trimerization of alkynes: (a) Schore, N. E. Chem.
Rev. 1988, 88, 1081. (b) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100,
2901.
(12) Recent examples for dimerization of alkynes: (a) Pell, C. J.;
Ozerov, O. V. ACS Catal. 2014, 4, 3470. (b) Xu, C.; Du, W.; Zeng, Y.;
ACKNOWLEDGMENTS
■
This research was supported by Grant-in-Aid for Scientific
Research from the Japan Society for the Promotion of Science
(Nos. 26410114, 15H03808). We gratefully acknowledge Prof.
Dr. Takashi Ooi, Dr. Daisuke Uraguchi, Ms. Wakana
Takahashi, and Mr. Ken Yoshioka (Nagoya Univ.) for their
kind support of HRMS.
Dai, B.; Guo, H. Org. Lett. 2014, 16, 948. (c) Alos
Esteruelas, M. A.; Olivan, M.; Onate, E.; Valencia, M. Inorg. Chem.
2014, 53, 1195.
́
, J.; Bolano, T.;
̃
́
̃
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Angew. Chem., Int. Ed. 2001, 40, 3750. (b) van der Boom, M. E.;
Milstein, D. Chem. Rev. 2003, 103, 1759. (c) Choi, J.; MacArthur, A.
H. R.; Brookhart, M.; Goldman, A. S. Chem. Rev. 2011, 111, 1761.
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