Dinuclear zinc complex catalyzed asymmetric methylation and alkynylation of aromatic aldehydes

Article abstract of DOI:10.1039/c7ob01717k

A general AzePhenol dinuclear zinc catalytic system has been successfully developed and introduced into the asymmetric addition of dimethylzinc and alkynylzinc to aromatic aldehydes. In this system, an azetidine derived chiral ligand has proven to be an effective enantioselective promoter. Under the optimal reaction conditions, a series of chiral 1-hydroxyethyl (up to 99% ee) and secondary propargylic alcohols (up to 96% ee) were generated with good yields and enantioselectivities. Additionally, this novel catalytic system showed good functional group compatibility. Remarkably, the substituent's electronic nature alone is not sufficient to allow for exclusive enantioselectivity, an additional substituent's location also had an effect. We proposed that the formation of a stable and structural rigid transition state by the chelation of ortho substituted benzaldehydes to the zinc atom was responsible for the observed higher enantioselectivity. The possible catalytic cycles of both transformations accounting for the stereoselectivity were described accordingly.

Full text of DOI:10.1039/c7ob01717k

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DOI: 10.1039/C7OB01717K
Organic & Biomolecular Chemistry
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Dinuclear zinc complex catalyzed asymmetric methylation and
alkynylation of aromatic aldehydes
Received 00th January 20xx,
Accepted 00th January 20xx
Shanshan Liu,a Gao-Wei Li,b Xiao-Chao Yang,b De-Yang Zhangb and Min-Can Wang*b
A general AzePhenol dinuclear zinc catalytic system has been successfully developed and introduced into the asymmetric
addition of dimethylzinc and alkynylzinc to aromatic aldehydes. In this system, an azetidine derived chiral ligand has
proven to be effective enantioselective promoter. Under the optimal reaction conditions, a series of chiral 1-hydroxyethyl
(up to 99% ee) and secondary propargylic alcohols (up to 96% ee) were generated with good yields and enantioselectivities.
Additionally, this novel catalytic system showed good functional group compatibility. Remarkably, the substituent’s
electronic nature alone is not sufficient to allow for exclusive enantioselectivity, an additional substituent’s location also
had an effect. We proposed that the formation of a stable and structural rigid transition state by the chelation of ortho
substitued benzaldehydes to the zinc atom was responsible for the observed higher enantioselectivity. The possible
catalytic cycles of both transformations accounted for the stereoselectivity was described accordingly.
catalysts4d were prepared to induce this asymmtric synthesis.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
Among them, the β -amino alcohols generally showed better
performance with excellent level of reactivity and
Asymmetric addition of organometallic reagents to prochiral
carbonyl compounds has emerged as one of the most effective
transformations to construct new C–C bond with a stereogenic
center in one step.1 Organozinc reagents such as alkylzinc and
alkynylzinc serve as attractive alternatives to the
corresponding lithium and magnesium counterparts because
of their easily accessible and well functional group tolerance.2
Dimethylzinc and diethylzinc compounds are commercially
available. The alkynylzinc reagents can be prepared in situ
through the reaction of acidic terminal alkynes and a zinc
reagent.3
enantioselectivity.
Chiral secondary propargylic alcohols are important precursors
of
a
range of natural products and pharmaceutical
compounds.7 Methods of allowing access to this target
molecular are usually based on 1) alkynylation via the lithiated
alkynes and subsequent kinetic resolution; 2) [2,3]- σ -
rearrangement; 3) asymmetric reduction; 4) the catalytic
asymmetric alkyne additions to carbonyl compounds in the
presence of titanium reagents.8 However, the use of lithiated
alkynes always suffers from substrate compatibility. The
limitation of the asymmetric reduction is the unstability of the
ethynyl ─ ketone intermediate, which is prone to undergo
decomposition to form diene ketone. The disadvantage of the
rearrangement is the requirement of chiral substrates
synthesis via kinetic resolution. Alternatively, direct catalytic
asymmetric alkynylation of aldehydes has proven as the most
straightforward approach to access desired alcohols.1b
Catalytic asymmetric methylation of aldehydes with
dimethylzinc reagents generates a tremendous amount of
interest,4 since it allows chemists to synthesis of chiral 1-
hydroxyethyl moiety which is important sub-structure in many
natural products and drug precursors.5 In addition, the
corresponding adducts are also useful intermediates for
further preparation of chiral ligands.6 The relative lower
reactive dimethylzinc compared to the ethyl alternative and
the sensitivity of the reaction to the ligand motivated chemists
to examine the catalytic efficiency of the chiral ligand in the
asymmetric addition of aldehydes. A variety of ligands4, such
as amino alcohols,4a diamines,4b diols,4c and phosphine
Based on the known methods, the asymmetric catalysis
crucially depends on the discovery of remarkable chiral
–
1f,9
ligands.1b
Since Corey and Cimprich reported the first
enantioselective addition of alkynylzinc reagents to aldehydes
using chiral oxazaborolidines,10 the development of efficient
catalysts for alkynylation of aldehydes attracted much
attention. Carreira and co-workers disclosed an addition of
acetylide to aliphatic aldehydes with stoichiometric (+)-N-
methylephedrine, Zn(OTf)2, and triethylamine.11 Furthermore,
1,1’-bi-2-
a. College of Chemistry and Chemical Engineering, Shaanxi University of Science and
Technology, 6 Xuefu Road, Weiyang District, Xi’an, Shaanxi 710021, P. R. China
b. The College of Chemistry and Molecular Engineering, Zhengzhou University, No.
75 Daxue Road, Zhengzhou, Henan 450052, P. R. China. E-mail:
wangmincan@zzu.edu.cn
Electronic Supplementary Information (ESI) available: All chiral HPLC
chromatograms data and spectra for methylation products and alkynylation
products. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 2017
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Organic & Biomolecular Chemistry
Table 1 Identification of the catalyst system and substrate
View Article Online
DOI: 10.10im39/Cth7OylB0 17K
scope for the catalytic asymmetric addition of d e zin17c to
various aromatic aldehydes.a
Scheme 1 Proline (right) and azetidines-derived (left) dinuclear
chiral ligands by Trost and our group respectively.
ee
(%)c
Entry
R
x
Solvent T (°C) Yield (%)b
1
2
3d
4
5
6
7
8
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
2-Cl (1b)
2-Me (1c)
5
5
5
toluene
toluene 30
toluene 30
0
trace (3aa)
81 (3aa)
34 (3aa)
77 (3aa)
trace (3aa)
18 (3aa)
48 (3ba)
92 (3ca)
─
12a–c
naphthol (BINOL) in conjunction with Ti(O-i-Pr)4
and (S)-
43
31
42
─
30
14
27
BINOL in combination with indium12d were found to be
excellent in the alkynylation of aromatic aldehydes. The Wang
group described that sulfoamido alcohols could efficiently
catalyze the asymmetric addition of phenyl acetylene to
aldehydes. Other ligands have been employed in the
asymmetric alkynylzinc additions to aldehydes, including
amino alcohols, hydroxy carboxamides, bifunctional salen
catalysts, phosphine catalyst, as well as nitrogen
heterocycles.13 A few years ago, Trost and co-workers reported
a general alkynylation of aldehydes by using proline-derived
dinuclear zinc catalyst system (Scheme 1, Zn2MeL2) as an
effective promoter in the absence of an additive,14 a variety of
aldehydes and alkynes were employed to give propargylic
alcohols in good yield and enantioselectivity.15
10 toluene 30
5
5
5
5
DCM
THF
toluene 30
toluene 30
toluene 30
30
30
9
2-OMe (1d)
5
99 (3da)
73
10
11
12
3-OMe (1e)
4-OMe (1f)
4-NMe2 (1g)
5
5
5
toluene 30
toluene 30
toluene 30
68 (3ea)
67 (3fa)
78 (3ga)
56
60
79
a
Unless otherwise noted, all reactions were processed using L1 as
chiral ligand under argon in corresponding solvent at 30 oC for
48─72 h. b Isolated yield reported. c The ee values were determined
by HPLC analysis (refer to the experimental part for detail). The
absolute configuration of 3aa was assigned by comparison of
optical rotation and chiral HPLC traces with the literature,16, 22 while
the absolute configurations of products 3ba–3ga were assigned by
In the last decade, our group have successfully developed a
series of chiral azaheterocycle-based ligands for catalytic
d
analogy to 3aa. Trost’s dinuclear zinc-ProPhenol catalyst system
(Zn2MeL2) was introduced instead for comparison.
asymmetric synthesis use.16−21 As expected,
a
highly
enantioselective methylation, ethylation and arylation of
aldehydes were achieved in the presence of catalytic amounts
of azetidino alcohols bearing ferrocenyl or phenyl group on the
nitrogen atom of the heterocycle skeleton16,17. We recently
developed an interesting azetidines-derived dinuclear zinc
catalyst system (Scheme 1,Zn2MeL1 ). This promising catalytic
combination has led to several efficient enantioselective
transformations, including asymmetric domino Michael/
Hemiketalization reaction,18 Friedel–Crafts alkylation,19
enantioselective co-polymerization.20 It was noteworthy that
much higher enantioselectivity was achieved by using our
novel chiral auxiliaries than that of Trost’s dinuclear zinc-
ProPhenol catalyst in the asymmetric co-polymerization of
cyclohexene oxide with carbon dioxide,21 which might
attribute to the lower flexibility azetidine ring skeleton and
appropriate sterically hindered microenvironment compared
with that of pyrrolidine. This more rigid ligand has shown to be
superior for this type of chemistry. Considering further
demonstrating the value of our AzePhenol dinuclear zinc
catalyst system, our studies on the asymmetric addition of
alkynylzinc and dimethylzinc to various aromatic aldehydes
were described herein.
Our initial attempts began with the examination of
temperature on the asymmetric addition of dimethylzinc to
benzaldehyde (1a) in the presence of L1 as potential chiral
ligand. As illustrated, however, only trace amounts of
o
methylated product was obtained at 0 C (Table 1, entry 1).
We found that elevated temperature could greatly promote
desired product formation, affording 1-phenylethan-1-ol (3aa
)
in higher yield and enantioselectivity through the activation of
organozinc reagent (2a, Table 1, entry 2). The catalytic
activities of azetidine ligand L1 and pyrrolindine ligand L2 were
also compared under the identical conditions. As showed in
Table 1, behaving as an effective promoter, azetidine ligand L1
performed more effective than Trost’s pyrrolindine ligand L2
(entries 2 vs 3). Intriguingly, doubling chiral ligand loading did
not yield more product with roughly the same
enantioselectivity (Table 1, entry 4). Solvent screening
revealed that toluene was the choice of reaction medium to
promote transformation in modest enantioselectivity, whereas,
neither DCM nor THF gave acceptable results (Table 1, entries
5 and 6). Notably, the relative reactive carbonyl group was
untouched in DCM medium (Table 1, entry 5). After extensive
reaction optimization, the reaction of benzaldehyde (1a) and
dimethylzinc (2a) was achieved with modest enantioselectivity
Results and discussion
Asymmetric addition of dimethylzinc to aromatic aldehydes
2 | Org. Biomol. Chem., 2017, 00, 1-3
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by using a combination of 2.0 equivelants of Me2Zn and 5 Table 2 Identification of the catalyst system for the asymmetric
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mol% of L1 dissolved in toluene at 30 oC.
addition of alkynylzinc to benzaldehyde.a
DOI: 10.1039/C7OB01717K
The range of arylaldehyde starting materials 1b─1g was further
extended under the optimized reaction conditions as outlined in the
lower part of Table 1. Both electron rich and electron poor
arylaldehydes were carefully investigated with good yields and
modest to good enantioselectivities. These results revealed a
correlation between the catalytic efficiency and the electronic
nature of aromatic substituents. Electron-donating substituents (1c
→ 3ca) generally provided better results than electron-withdrawing
ones (1b → 3ba). For instance, 2-chloro substituted benzaldehyde
(1b) generated product 3ba with only 14% enantiomeric excess (ee),
while a higher ee was achieved when a more electron donating
substituent was employed instead (Table 1, entries 7 vs 8). To our
delight, a methoxy substituent in the ortho position of aldehyde 1d
substrate was found to be beneficial in both yield and
enantioselectivity (Table 1, entry 9). Importantly, this ortho-
methoxy substituted benzaldehyde (1d) afforded slightly better
enantioselectivities than meta- (1e) and para- (1f) positions,
probably due to the formation of a stable and structural rigid
transition state by the chelation of ortho methoxyl benzaldehyde to
the zinc atom. (Table 1, entries 9 vs 10 and 11). In addition, as
expected, an electron rich NMe2 group was found to be more
reactive even located far away from the carbonyl group (1g → 3ga,
Table 1, entry 12). The electron donating substituents led to higher
enantioselectivity because the increasing electron density might
enhance the affinity of aldehyde to the zinc atom, which would
activate the carbonyl group and stablize the transition state in the
asymmetric induction.
T
Yield ee
Entry
x
R2Zn
Additive Solvent
(°C)
0
(%)b
90
99
84
92
85
43
92
58
64
96
(%)c
1
2
3
4
5
6
7
8
9
10
10 Et2Zn
10 Me2Zn
10 Et2Zn
10 Et2Zn
10 Et2Zn
10 Et2Zn
10 Et2Zn
10 Et2Zn
10 Et2Zn
20 Et2Zn
─
─
toluene
toluene
67
70
8
0
Ti(OiPr)4 toluene
DiMPEG toluene
DiMPEG toluene
DiMPEG toluene
DiMPEG DCM
0
0
73
70
68
37
26
16
76
-10
-40
0
DiMPEG THF
0
DiMPEG MeCN
0
DiMPEG toluene
0
a Unless otherwise noted, all reactions were processed under argon
in corresponding solvent at 0 oC for 24 h. b Isolated yield reported. c
The ee values were determined by HPLC analysis (seeing the
experimental part for detail). Absolute configuration was assigned
by comparison of optical rotation and chiral HPLC traces with the
literature.14a DiMPEG = polyethyleneglycol dimethyl ether.
(Table 2, entries 5 and 6). The use of DCM or THF as solvent
resulted in a notable decrease both in reactivity and
enantioselectivity, whereas in CH3CN the optical purity of the
adduct was only 16% (Table 2, entries 7─9). Catalytic
alkynylation of benzaldehyde (1a) proceeded with 96% yield
and 75% ee by the introduction of a combination of
DiMPEG/Et2Zn in toluene at 0 oC (Table 2, entry 10). The
results were comparable with the same transformation in
Trost’s report with the aid of pyrroline-derived dinuclear zinc
catalyst.14
Asymmetric addition of alkynylzinc to aromatic aldehydes
The above achievements promoted us to address other
transformations. Our further studies turned into the
application of this azetidines-derived dinuclear zinc catalyst
system in the asymmetric addition of alkynylzinc to
arylaldehydes (1a
→ 5ab). Extensive screening was carried out
to find suitable reaction conditions. Based on our current
knowledge, the eventually reactive alkynylzinc species was
generated prior to use in situ through the reaction between
dialkylzinc reagent and terminal alkyne. Accordingly, we
examined different dialkylzinc reagents. Compared with
aforementioned methylation, the alkynylation can be
performed under even milder conditions. Comparable
enantioselectivity was observed when dimethylzinc (2a) or
diethylzinc (2b) was employed (Table 2, entries 1 and 2).
Although It has been reported that the titanium complex can
be used to catalyze the alkyne addition to aldehydes with high
enantioselectivity. However, in our case, the product was
obtained in only 8% ee when Ti(OiPr)4 was added.(Table 2,
entry 3). To our delight, the reaction proceeded efficiently with
slightly higher enantiomeric excess when DiMPEG was used as
a Lewis basic additive to facilitate the formation of the
alkynylzinc (Table 2, entry 4). No significant influence of
temperature on the reaction enantioselectivity was observed.
Unfortunately, decreasing the reaction temperature did not
improve any enantioselectivity, whereas yielded less product
We then extensively examined aldehyde coupling partners for this
transformation. Adopting the conditions of table 2, entry 4 as
optimal one, the results of alkynylation of a series of aromatic
aldehydes with phenyl acetylene (4) were documented in Scheme 2.
According to these results, we observed that the enantioselectivity
exhibited a strong dependence of the substrates’ electronic
properties. Starting materials with electron-donating substituents
generated products with better enantioselectivities. Additionally,
the enantioselectivities improved along with the raising of electron-
donating abilities (OMe > Me > Br > Cl), thus the desired chiral
alcohol has been synthesized in enantiopure form from common
precursor. The alkynylation of methoxy substituents 1d─1f with
phenyl acetylene (4) displayed high enantioselectivity, while the
same ring with a chloro group 1b, 1h and 1i was alkynylated with
poor enantioinduction due to its electron-deficient effect. What’s
more, the location of substituents had a significant influence on the
enantioselectivity. Ortho substituted arylaldehydes (1b-1d and 1j)
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Scheme 2 Variation of the aromatic aldehydes and alkynes for the Scheme 3 Ortho substituted effect studies for the asymmetric
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a
asymmetric addition by in situ formed alkynylzinc reagent.a
addition of dimethylzinc reagent to arylaldehDyOdeI:s1.0.1039/C7OB01717K
a
Reaction conditions: 1p─1w (0.5 mmol), 2a (2.0 equiv), L1 (5.0
mol%) in toluene. Unless otherwise noted, all reactions were
o
processed under argon in toluene at 30 C for 48─72 h. Isolated
yield reported. The ee values were determined by HPLC analysis
(refer to the experimental part for detail). The absolute
configurations of products were assigned by analogy to product in
Table 1.
The ortho substituted effect on enantioselectivity
Generally in our study, arylaldehydes with ortho methoxyl
substituents generated desired methylation and alkynylation
products in higher enantioselectivity. Encouraged by these
results, we expanded the substrate scope by using a number of
methoxy substituted arylaldehydes for both methylation and
alkynylation (Scheme 3 and 4). Methylation of 5-Br-2-OMe
benzaldehyde (1t) showed poor enantioselectivity, while 2,5-
dimethoxy substituted starting material 1s restored high
enantioinduction due to its electron density increasing. 3,4-
Dialkyl sunstituted benzaldehyde 1u was methylated with only
58% ee, however, 2,3-dimethoxy 1p, 2,4-dimethoxy 1q, 2,5-
dimethoxy 1r and 2,6-dimethoxy 1s substituents generated
a
Reaction conditions: 1a (0.5 mmol), 4 (2.0 equiv), 2b (2.0 equiv),
L1 (10 mol%), DiMPEG (10 mol%) in toluene. Unless otherwise
noted, all reactions were processed under argon for indicated
reaction time. Isolated yield reported. The ee values were
determined by HPLC analysis (refer to the experimental part for
detail). The absolute configurations of products were assigned by
analogy to product in Table 2.
with appropriate steric bulk provided products with higher
enantioselectivity than meta- (1e, 1h, 1k and 1m) and para- (1f, 1i,
1l and 1n) substitutions that resulted in comparable
enantioselectivities. To our delight, alkynylation of the ortho-
methoxy substituent gave a very promising enantioselectivity (1d →
5db, 95% ee) largely owing to both the electronic effect and the
chelate effect. Interestingly, a similar effect was observed for the
aforementioned asymmetric methylation of aromatic aldehydes
(Table 1, entry 9).
desired methylated products
(
3pa
─
3sa
)
in impressive
enantioselectivity. In a word, very promising ee values were
obtained for the ortho substituted benzaldehyde irrespective
of di- or tri- methoxy substituents (Scheme 3, 1p
1v 1w). Similarly, multiple methoxy substituted benzaldehyde
bearing an ortho substitution led to alkynylated products
1p 1s 5pb 5sb and 1v 1x 5vb 5xb) in satisfied
─1s and
─
(
─
→
─
─
→
─
enantioselectivity which attribute to both the strong electron
donating effect and the chelate effect (Scheme 4). It is
4 | Org. Biomol. Chem., 2017, 00, 1-3
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Scheme 4 Ortho substitution effect studies for the asymmetric Scheme 5 Possible transition state in the asymmetrViciewmAerttichleylOantliionen
addition of alkynylzinc reagent to arylaldehydes.a
DOI: 10.1039/C7OB01717K
with the aid of L1.
methoxy and halogen substitution, we believe the chelate effect
play as the main reason for the observed better enantioselectivity.
In terms of methyl group, there have been no chelate effect, so no
dramatically improved enantioselectivity was observed on ortho
position than that on other positions. The catalytic transition state
of asymmetric methylation of arylaldehydes would involve the
formation of a dinuclear zinc-AzePhenol complex Zn2MeL (TS1),
followed by the coordination of aromatic aldehyde to the other zinc
atom to generate the intermediate TS2 (Scheme 5). In this case, the
ortho substitution such as methoxy and halogen group would
coordinate to the same zinc atom to form a stable six-membered
ring. The transition state would be more stable.and structural rigid,
which is responsible for the largely enhancement of
enantioselectivity. Subsequently, the methyl group attacked the
more sterically accessible face of aldehyde. Finally, the desired
product was released by another dimethylzinc transfer (not shown).
a Reaction conditions: 1p─1s or 1v─1x (0.5 mmol), 4 (2.0 equiv), 2a
(3.0 equiv), L1 (10 mol%) in toluene. Unless otherwise noted, all
Based on Trost’s report,14a the asymmetric alkynylation of aromatic
aldehyde should undergo the generation of a dinuclear zinc-
AzePhenol complex Zn2EtL1 by treatment of the chiral ligand L1
o
reactions were processed under argon in toluene at 0 C for 24 h.
Isolated yield reported. The ee values were determined by HPLC
analysis (refer to the experimental part for detail). The absolute
configurations of products were assigned by analogy to product in
Table 2.
with
2 equivalents of diethylzinc (2b) wherein a dynamic
equilibrium between the (Zn2EtL1)n and Zn2EtL1 existed by our
previous studies.19 Subsequently, coordination of 2 equivalents of
zinc alkynylide formed a complex and followed by the coordination
of aldehyde to the zinc atom from the more sterically accessible site.
Finally, alkyne attacks the aldehyde and followed by the transfer of
another zinc alkynylide to release an alkoxide of the product and
restarts the cycle.
noteworthy that in this asymmetric alkynylation system, no
additive was needed when the dimethlyzinc (2a) was
introduced instead as an activator. Better enantioselectivity of
the ortho substitution was observed not only in the substrates
bearing electron donating groups but also electron-
withdrawing groups. The possible reasons were outlined as
follows: (i) The ortho bromo substituent was more hindered
than other positions to enhance the enantioselectivity, while
the steric effect was not obvious in case of ortho methoxyl,
methyl, or chloro substituents. (ii) An ortho substitution such
as a methoxy or halogen group would coordinate to the metal
center to decrease the structural flexibility of the transition
state in the asymmetric induction, which facilitated the attack
from the more desirable face. (iii) The ortho substituents had
more electronic donating effect than meta and para
substitutions in case of methoxy group, while there should be
more electron withdrawing effect on the ortho position than
that of other positions in terms of a halogen. However, better
results of ortho substitution in both cases indicated that the
electronic factor was not dominant. Therefore in case of
Conclusions
In conclusion, we reported herein an application of dinuclear zinc-
AzePhenol catalyst into the asymmetric addition of organozinc to
aromatic aldehydes. Results showed that an azetidine derived chiral
ligand was quite efficient for the asymmetric addition of both
dimethylzinc and alkynylzinc to prochiral aromatic aldehydes with
good yields and enantioselectivities. The protocol provided an
effective and straightforward access to the chiral 1-hydroxyethyl
and secondary propargylic alcohols. Various arylaldehydes were
tolerated under standard catalytic conditions. We observed that the
enantioselectivity was influenced not only by the electronic nature,
but also by the position of substituents. It was worth noting that the
ortho substituted arylaldehydes generated both methylated and
alkynylated products in promising enantioselectivity. An interesting
effect of ortho substituents on the enatioselectivity was
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Organic & Biomolecular Chemistry
investigated and
accordingly.
a
possible transition state was proposed (300 MHz, CDCl3) δ (major + minor) = 1.48 (d, J = 6.6 Hz, 3H), 1.82 (d,
View Article Online
J = 3.3 Hz, 1H), 4.88 (dq, J = 3.3 Hz, J = 6.6 HzD, 1OHI:)1,07.1.20439–/7C.27O8B(0m1,7117HK),
7.31–7.41 (m, 4H) ppm; 13C NMR (75 MHz, CDCl3) δ = (major +
minor) 22.2, 69.0, 125.2, 126.8, 128.0, 143.6 ppm.
Experimental
(S)-1-(2-Chlorophenyl)ethan-1-ol (3ba): A pale yellow oil, 37,6 mg,
48% yield, 14% ee; HPLC (Chiralcel OB column, hexane/i-PrOH =
15/1, flow rate: 0.5 mL/min, UV detection at 216 nm); Retention
General remarks
All reactions were performed in flame-dried glassware using
conventional Schlenk techniques under a static pressure of argon.
All starting materials, ligands, and racemic products were prepared
according to known procedures. Liquids and solutions were
transferred with (micro)syringes. Solvents were purified and dried
following standard procedures. All aldehydes and alkynes were
purchased from Acros or Fluka. Diethylzinc was prepared from EtI
with Zn and then diluted with toluene to 1.0 mol/L. Technical grade
solvents for extraction and chromatography were distilled prior to
use. Analytical thin-layer chromatography (TLC) and Flash column
chromatography were performed on silica gel using the indicated
solvents. 1H and 13C NMR spectra were recorded in CDCl3 on Bruker
DPX 400/300. Chemical shifts are reported in parts per million (ppm)
downfield from tetramethylsilane and are referenced to the
residual solvent resonance as the internal standard (δ = 7.26 ppm
time: tR(S) = 13.71 min, tR(R) = 10.38 min; 1H NMR (300 MHz, CDCl3)
δ (major + minor) = 1.39 (d, J = 6.4 Hz, 3H), 2.55 (br s, 1H), 5.11 (q, J
= 6.4 Hz, 1H), 7.08 (td, J = 1.9 Hz, J = 7.8 Hz, 1H), 7.15–7.18 (m, 2H),
7.44 (dd, J = 1.9 Hz, J = 8.9 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ
(major + minor) = 23.2, 67.0, 126.2, 126.9, 128.3, 128.9, 131.0,
143.0 ppm.
(S)-1-(o-Tolyl)ethan-1-ol (3ca): A pale yellow oil, 62.6 mg, 92% yield,
27% ee; HPLC (Chiralcel OB column, hexane/i-PrOH = 15/1, flow rate:
0.5 mL/min, UV detection at 216 nm); Retention time: tR(S) = 11.73
min, tR(R) = 16.75 min; 1H NMR (300 MHz, CDCl3) δ (major + minor)
= 1.46 (d, J = 6.5 Hz, 3H), 1.84 (br s, 1H), 2.34 (s, 3H), 4.80–4.89 (m,
1H), 7.03–7.10 (m, 1H), 7.12–7.17 (m, 2H), 7.20–7.28 (m, 1H) ppm;
13C NMR (75 MHz, CDCl3) δ (major + minor) = 18.9, 23.5, 66.1, 124.8,
125.8, 126.5, 130.9, 134.6, 144.2 ppm.
(S)-1-(2-Methoxyphenyl)ethan-1-ol (3da): A pale yellow oil, 75.3
mg, 99% yield, 73% ee; HPLC (Chiralcel OB column, hexane/i-PrOH =
15/1, flow rate: 0.5 mL/min, UV detection at 216 nm); Retention
time: tR(S) = 8.38 min, tR(R) = 14.09 min; 1H NMR (300 MHz, CDCl3) δ
(major + minor) = 1.50 (d, J = 6.4 Hz, 3H), 2.68 (br s, 1H), 3.89 (s, 3H),
5.03–5.12 (m, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.91–6.98 (m, 1H), 7.18–
7.25 (m, 1H), 7.28–7.34 (m, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ
(major + minor) = 21.8, 56.0, 66.3, 109.8, 120.1, 125.2, 127.5, 132.8,
155.9 ppm.
1
for H and δ = 77.16 ppm for 13C). Data are reported as follows:
chemical shift, multiplicity (br s = broad singlet, s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet), coupling constants
(Hz) and integration. Optical rotations were recorded on a Perkin-
Elmer 341 polarimeter. Mass spectra were recorded on VG-FAB
mass spectrometer. The ee value determination was carried out
using chiral HPLC on a Chiralcel OB, OD, or OD-H Column (for all the
columns: 4.6mmφ × 250 mm, Daicel Chemical Ind., LTD, Japan)
combined with a JASCO model PU-1580 intelligent HPLC pump and a
JASCO model UV-1575 intelligent UV-vis detector (216nm).
(S)-1-(3-Methoxyphenyl)ethan-1-ol (3ea): A pale yellow oil, 51.8
mg, 68% yield, 56% ee; HPLC (Chiralcel OB column, hexane/i-PrOH =
15/1, flow rate: 1.0 mL/min, UV detection at 216 nm); Retention
time: tR(S) = 15.36 min, tR(R) = 20.74 min; 1H NMR (300 MHz, CDCl3)
δ (major + minor) = 1.46 (d, J = 6.4 Hz; 3H), 1.71 (br s, 1H), 3.78 (s,
3H), 4.80–4.88 (m, 1H), 6.86 (d, J = 7.6 Hz, 2H), 7.28 (d, J=7.6 Hz, 2H)
ppm; 13C NMR (75 MHz, CDCl3) δ (major + minor) = 25.5, 55.2, 68.9,
111.0, 113.3, 117.6, 131.1, 148.0, 159.8 ppm.
General Procedure for the Catalytic Asymmetric Addition of
Dimethylzinc to Aromatic Aldehydes. In a flame-dried Schlenk tube
equipped with a magnetic stir bar, a solution of dimethylzinc (2a,
0.83 mL, 1.2 mol/L in hexane, 1.0 mmol, 2.0 equiv) is added to a
solution of the chiral ligand L1 (15.3 mg, 0.025 mmol, 5.0 mol%) in
o
dry toluene (1.0 mL, 0.5 M) under nitrogen at 0 C. The mixture is
(S)-1-(4-Methoxyphenyl)ethan-1-ol (3fa): A pale yellow oil, 51.0 mg,
67% yield, 60% ee; HPLC (Chiralcel OD-H column, hexane/i-PrOH =
50/1, flow rate: 1.0 mL/min, UV detection at 216 nm); Retention
time: tR(S) = 31.60 min, tR(R) = 26.53 min; 1H NMR (300 MHz, CDCl3)
δ (major + minor) = 1.49 (d, J = 6.4 Hz, 3H), 1.72 (br s, 1H), 3.78 (s,
stirred at 40 oC for 30 min. Then a newly distilled aromatic aldehyde
(1a─1f or 1p─1w, 0.5 mmol, 1.0 equiv) is added by a micro syringe
o
o
to the mixture at 0 C. The solution is stirred at 30 C for 48–72 h.
After complete consumption of the aldehyde starting material, as
monitored by TLC analysis, the reaction mixture is allowed to cool 3H), 4.80–4.88 (m, 1H), 6.85 (d, J = 7.6 Hz, 2H), 7.27 (d, J = 7.6 Hz,
2H) ppm; 13C NMR (75 MHz, CDCl3) δ (major + minor) = 24.0, 55.3,
to room temperature, quenched with aqueous NH4Cl (5.0 mL), and
69.7, 113.4, 126.2, 137.9, 159.1 ppm.
extracted with diethyl ether (3 × 10 mL). The combined organic
phases are washed with brine (5.0 mL) and dried over anhydrous
Na2SO4. After evaporation of the solvent under reduced pressure,
purification of the residue by column chromatography on silica gel
using mixtures of petroleum ether and ethyl acetate as eluents
affords the analytically pure title compounds. All these products are
known compounds.
(S)-1-(4-(Dimethylamino)phenyl)ethan-1-ol (3ga): A pink solid, 64.4
mg, 78% yield, 79% ee; HPLC (Chiralcel OD column, hexane/i-PrOH =
98/2, flow rate: 0.7 mL/min, UV detection at 216 nm); Retention
time: tR(S) = 45.55 min, tR(R) = 41.70 min; 1H NMR (300 MHz, CDCl3)
δ (major + minor) = 1.47 (d, J = 6.3 Hz, 3H), 1.59 (br s, 1H), 2.98 (s ,
6H), 4.78 (q, J = 6.3 Hz, 1H), 6.66 ( d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4
Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ (major + minor) = 23.5,
39.4, 69.6, 112.0, 125.4, 135.9, 151.8 ppm.
(S)-1-Phenylethan-1-ol (3aa): A pale yellow oil, 49.5 mg, 81% yield,
20
43% ee; [α]D = -10.3 (C = 0.5, CH2Cl2); HPLC (Chiralcel OD column,
(S)-1-(2,3-Dimethoxyphenyl)ethan-1-ol (3pa): A pale yellow oil,
20
hexane/i-PrOH = 95/5, flow rate: 1.0 mL/min, UV detection at 216
1
86.6 mg, 95% yield, 95% ee; [α]D = -16.9 (C = 2.0, CHCl3); HPLC
nm); Retention time: tR(S) = 10.70 min, tR(R) = 8.64 min; H NMR
(Chiralcel OD column, hexane/i-PrOH = 15/1, flow rate: 1.0 mL/min,
6 | Org. Biomol. Chem., 2017, 00, 1-3
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UV detection at 216 nm); Retention time: tR(S) = 10.75 min, tR(R) = 5.01–5.04 (m, 1H), 6.64 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H)
View Article Online
12.08 min; 1H NMR (300 MHz, CDCl3) δ (major + minor) = 1.49 (d, J = ppm.
DOI: 10.1039/C7OB01717K
6.2 Hz, 3H), 2.77 (br s, 1H), 3.90 (s, 3H), 3.93 (s, 3H), 5.15 (q, J = 6.2 (S)-1-(2,4,6-Trimethoxyphenyl)ethan-1-ol (3wa): A white solid,
20
Hz, 1H), 6.81 (dd, J = 2.1 Hz, J = 7.4 Hz, 1H), 7.01 (dd, J = 2.1 Hz, J = 104.8 mg, 99% yield, 99% ee; [α]D = -27 (C = 0.95, CHCl3); HPLC
7.4 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H) ppm.
(Chiralcel OD-H column, hexane/i-PrOH = 25/1, flow rate: 1.0
(S)-1-(2,4-Dimethoxyphenyl)ethan-1-ol (3qa): A white solide, 90.0 mL/min, UV detection at 216 nm); Retention time: tR(S) = 21.13 min,
1
mg, 99% yield, 93% ee; [α]D20 = -36.9 (C = 1.9, CHCl3); HPLC (Chiralcel tR(R) = 22.58 min; H NMR (400 MHz, CDCl3) δ (major + minor) =
OD column, hexane/i-PrOH = 15/1, flow rate: 1.0 mL/min, UV 1.41 (d, J = 6.4 Hz, 3H), 2.50 (br s, 1H), 3.77 (s, 6H), 3.81 (s, 3H),
detection at 216 nm); Retention time: tR(S) = 11.88 min, tR(R) = 4.90–4.97 (m, 1H), 6.12 (s, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ
1
17.89 min; H NMR (300 MHz, CDCl3) δ (major + minor) = 1.49 (d, (major + minor) = 24.8, 55.3, 55.7, 69.2, 91.0, 112.7, 158.5, 160.1
3H), 2.61 (s, 1H), 3.80 (s, 3H), 3.85 (s, 3H), 5.09 (q, J = 6.2 Hz, 1H), ppm.
6.41–6.45 (m, 2H), 7.18–7.22 (m, 1H) ppm; 13C NMR (75 MHz, CDCl3)
General Procedure for the Catalytic Asymmetric Addition of
Alkynylzinc to Aromatic Aldehydes. A flame-dried Schlenk tube
equipped with a magnetic stir bar is successively charged with the
chiral ligand L1 (30.5 mg, 0.05 mmol, 10.0 mol%), DiMPEG (100 mg,
0.10 mmol, 10 mol%), dimethylzinc (2a, 0.83 mL, 1.2 mol/L in
hexane, 1.0 mmol, 2.0 equiv) or diethylzinc (2b, 1.0 mL, 1.0 mol/L in
hexane, 1.0 mmol, 2.0 equiv), alkyne (4, 1.0 mmol, 2.0 equiv), and
δ (major + minor) = 22.2, 54.9, 64.4, 66.8, 97.1, 103.5, 118.8, 131.9,
158.4, 160.1 ppm.
(S)-1-(2,6-Dimethoxyphenyl)ethan-1-ol (3ra): A white solide, 90.1
o
20
mg, 99% yield, 98% ee; m.p. = 95–96 C; [α]D = -15.2 (C = 0.7,
CHCl3); HPLC (Chiralcel OD column, hexane/i-PrOH = 9/1, flow rate:
1.0 mL/min, UV detection at 216 nm); Retention time: tR(S) = 23.38
min, tR(R) = 11.00 min; 1H NMR (300 MHz, CDCl3) δ (major + minor)
= 1.49 (d, J = 6.2 Hz, 3H), 1.52 (br s, 1H), 3.78 (s, 6H), 5.28 (q, J = 6.2
Hz, 1H), 6.51 (d, J = 8.3 Hz, 2H), 7.19 (t, J = 8.3 Hz, 1H) ppm; 13C NMR
(75 MHz, CDCl3) δ (major + minor) = 22.5, 54.2, 62.8, 102.8, 122.7,
126.6, 158.7 ppm.
o
dry toluene (1.0 mL, 0.5 M) under nitrogen at 0 C. The mixture is
o
stirred at 25 C for 2 h. Then a newly distilled aromatic aldehyde
(1a─1f or 1h─1s or 1v─1x, 0.5 mmol, 1.0 equiv) is added by a micro
o
o
syringe to the mixture at 0 C. The solution is stirred at 0 C for 20
or 24 h. After complete consumption of the aldehyde starting
material, as monitored by TLC analysis, the reaction mixture is
allowed to cool to room temperature, quenched with aqueous
NH4Cl (5.0 mL), and extracted with diethyl ether (3 × 10 mL). The
combined organic phases are washed with brine (5.0 mL) and dried
over anhydrous Na2SO4. After evaporation of the solvent under
reduced pressure, purification of the residue by column
chromatography on silica gel using mixtures of petroleum ether and
ethyl acetate as eluents affords the analytically pure title
compounds. All these products are known compounds.
(S)-1-(2,5-Dimethoxyphenyl)ethan-1-ol (3sa): A pale yellow oil, 86.6
20
mg, 95% yield, 82% ee; [α]D = -12 (C = 1.2, CHCl3); HPLC (Chiralcel
OD column, hexane/i-PrOH = 15/1, flow rate: 1.0 mL/min, UV
detection at 216 nm); Retention time: tR(S) = 15.71 min, tR(R) =
28.19 min; 1H NMR (300 MHz, CDCl3) δ (major + minor) = 1.49 (d, J =
6.4 Hz, 3H), 2.58 (d, J = 5.5 Hz, 1H), 3.70 (s, 3H), 3.81 (s, 3H), 5.00 (q,
J = 6.4 Hz, 1H), 6.58 (dd, J = 2.6 Hz, J = 8.6 Hz, 1H), 6.64 (d, J = 8.6 Hz,
1H), 6.99 (d, J = 2.6 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ (major
+ minor) = 22.3, 54.5, 55.1, 64.6, 111.9, 112.2, 112.9, 133.3, 149.7,
154.6 ppm.
(S)-1-(5-Bromo-2-methoxyphenyl)ethan-1-ol (3ta): A pale yellow oil,
108.5 mg, 94% yield, 39% ee; HPLC (Chiralcel OD-H column,
hexane/i-PrOH = 95/5, flow rate: 0.8 mL/min, UV detection at 216
(R)-1,3-Diphenylprop-2-yn-1-ol (5ab): A white solid, 95.7 mg, 92%
20
yield, 73% ee; [α]D = +4.0 (C = 1.0, CH2Cl2); HPLC (Chiralcel OD
1
nm); Retention time: tR(S) = 20.50 min, tR(R) = 18.56 min; H NMR
column, hexane/i-PrOH = 90/10, flow rate: 1.0 mL/min, UV
detection at 254 nm); Retention time: tR(R) = 11.34 min, tR(S) =
21.20 min; 1H NMR (300 MHz, CDCl3) δ (major + minor) = 2.91 (br s,
1H), 5.59 (s, 1H), 7.29–7.41 (m, 6H), 7.43–7.46 (m, 2H), 7.55–7.57
(m, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ (major + minor) = 63.4,
86.5, 88.2, 123.1, 126.8, 128.2, 128.5, 128.7, 128.9, 131.1, 140.8
ppm.
(400 MHz, CDCl3) δ (major + minor) = 1.51 (d, J = 6.4 Hz, 3H), 2.58
(br s, 1H), 3.79 (s, 3H), 5.09 (q, J = 6.2 Hz, 1H), 6.79 (d, J = 8.7 Hz, 1H),
7.34 (dd, J = 2.5 Hz, J = 8.7, 1H), 7.44 (d, J = 2.5 Hz, 1H) ppm; 13C
NMR (100 MHz, CDCl3) δ (major + minor) = 21.9, 55.9, 66.4, 113.0,
113.6, 129.0, 130.7, 138.1, 156.0 ppm.
(S)-1-(Benzo[d][1,3]dioxol-5-yl)ethan-1-ol (3ua): A pale yellow oil,
76.4 mg, 92% yield, 58% ee; HPLC (Chiralcel OD-H column, hexane/i-
PrOH = 50/1, flow rate: 0.5 mL/min, UV detection at 216 nm);
(S)-1-(2-Chlorophenyl)-3-phenylprop-2-yn-1-ol (5bb): A white solid,
111.6 mg, 92% yield, 54% ee; HPLC (Chiralcel OD column, hexane/i-
PrOH = 90/10, flow rate: 0.5 mL/min, UV detection at 254 nm);
1
Retention time: tR(S) = 73.89 min, tR(R) = 66.14 min; H NMR (300
1
MHz, CDCl3) δ (major + minor) = 1.47 (d, J = 6.4 Hz, 3H), 2.35 (br s,
1H), 4.95 (q, J = 6.4 Hz, 1H), 5.85 (s, 2H), 6.77–6.82 (m, 2H), 6.94 (d,
J = 2.1 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ (major + minor) =
25.9, 69.1, 101.6, 108.2, 108.8, 119.6, 141.2, 148.4, 149.1 ppm.
(S)-1-(2,3,4-Trimethoxyphenyl)ethan-1-ol (3va): A pale yellow oil,
Retention time: tR(S) = 10.46 min, tR(R) = 11.56 min; H NMR (300
MHz, CDCl3) δ (major + minor) = 2.55 (d, J = 5.0 Hz, 1H), 6.00 (d, J =
5.0 Hz, 1H), 7.30–7.33 (m, 5H), 7.38 (dd, J = 1.8 Hz, J = 7.4 Hz, 1H),
7.48–7.51 (m, 2H), 7.85 (dd, J = 2.0 Hz, J = 7.4 Hz, 1H) ppm; 13C NMR
(75 MHz, CDCl3) δ (major + minor) = 61.5. 86.0, 87.9, 121.5, 126.4,
128.0, 128.3, 128.4, 129.7, 129.8, 131.1, 132.2, 137.5 ppm.
20
104.9 mg, 99% yield, 94% ee; [α]D = -20.6 (C = 2.1, CHCl3); HPLC
(Chiralcel OD column, hexane/i-PrOH = 9/1, flow rate: 0.2 mL/min,
UV detection at 216 nm); Retention time: tR(S) = 36.80 min, tR(R) =
40.26 min; 1H NMR (300 MHz, CDCl3) δ (major + minor) = 1.47 (d, J =
6.7 Hz, 3H), 2.37 (br s, 1H), 3.82 (s, 3H), 3.84 (s, 3H), 3.91 (s, 3H),
(S)-3-Phenyl-1-(o-tolyl)prop-2-yn-1-ol (5cb): A white solid, 102.1
mg, 92% yield, 73% ee; HPLC (Chiralcel OD column, hexane/i-PrOH =
90/10, flow rate: 1.0 mL/min, UV detection at 254 nm); Retention
time: tR(S) = 10.02 min, tR(R) = 23.36 min; 1H NMR (400 MHz, CDCl3)
δ (major + minor) = 2.29 (d, J = 5.0 Hz, 1H), 2.51 (s, 3H), 5.88 (d, J =
This journal is © The Royal Society of Chemistry 2017
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Organic & Biomolecular Chemistry
4.8 Hz, 1H), 7.16–7.28 (m, 6H), 7.40–7.43 (m, 2H), 7.66–7.70 (m, 1H) MHz, CDCl3) δ (major + minor) = 2.31 (d, J = 6.0 Hz, 1VHie)w, 5A.rt6ic0le(Odn,liJne=
ppm; 13C NMR (100 MHz, CDCl3) δ (major + minor) = 19.4, 62.5, 85.6, 6.0 Hz, 1H), 7.22 (d, J = 7.4 Hz, 1H), 7.23–7.2D8O(mI: 1,02.1H0)3,97/.C471O–B70.41781(7mK ,
88.1, 122.0, 126.0, 126.1, 127.8, 128.0, 128.4, 130.1, 131.2, 135.5, 4H), 7.59 (d, J = 7.4 Hz, 1H), 7.83 (s, 1H) ppm; 13C NMR (75 MHz,
138.2 ppm.
CDCl3) δ (major + minor) = 62.8, 86.3, 87.3, 121.6, 122.6, 124.4,
(S)-1-(2-Methoxyphenyl)-3-phenylprop-2-yn-1-ol (5db):
A
pale 128.3, 128.6, 129.0, 129.8, 131.5, 131.8, 142.9 ppm.
yellow oil, 105.9 mg, 89% yield, 94% ee; HPLC (Chiralcel OD column, (R)-1-(4-Bromophenyl)-3-phenylprop-2-yn-1-ol (5lb): A white solid,
hexane/i-PrOH = 90/10, flow rate: 1.0 mL/min, UV detection at 254 133.5 mg, 93% yield, 68% ee; HPLC (Chiralcel OD column, hexane/i-
1
nm); Retention time: tR(S) = 13.91 min, tR(R) = 17.02 min; H NMR PrOH = 90/10, flow rate: 1.0 mL/min, UV detection at 254 nm);
1
(300 MHz, CDCl3) δ (major + minor) = 3.01 (d, J = 6.1 Hz, 1H), 3.88 (s, Retention time: tR(R) = 9.07 min, tR(S) = 25.05 min; H NMR (300
3H), 5.89 (d, J = 6.0 Hz, 1H), 6.99–7.04 (m, 2H), 7.21–7.28 (m, 4H), MHz, CDCl3) δ (major + minor) = 2.29 (d, J = 6.1 Hz, 1H), 5.66 (d, J =
7.41–7.46 (m, 2H), 7.59–7.62 (m, 1H) ppm; 13C NMR (75 MHz, CDCl3) 6.2 Hz, 1H), 7.28–7.34 (m, 3H), 7.45–7.51 (m, 2H), 7.52–7.58 (m, 4H)
δ (major + minor) = 55.2, 61.0, 86.7, 88.0, 110.1, 121.1, 122.2, 128.1, ppm; 13C NMR (75 MHz, CDCl3) δ (major + minor) = 62.8, 86.1, 88.5,
128.2, 128.5, 128.6, 128.9, 129.2, 157.1 ppm.
121.3, 122.5, 128.2, 128.3, 128.5, 131.8, 131.2, 139.8 ppm.
(S)-1-(3-Methoxyphenyl)-3-phenylprop-2-yn-1-ol (5eb): A white (S)-3-Phenyl-1-(m-tolyl)prop-2-yn-1-ol (5mb): A white solid, 99.9
solid, 100.0 mg, 84% yield, 61% ee; (Chiralcel OD column, hexane/i- mg, 90% yield, 65% ee; HPLC (Chiralcel OD column, hexane/i-PrOH =
PrOH = 90/10, flow rate: 1.0 mL/min, UV detection at 254 nm); 90/10, flow rate: 1.0 mL/min, UV detection at 254 nm); Retention
1
Retention time: tR(S) = 16.49 min, tR(R) = 25.91 min; H NMR (300 time: tR(S) = 9.72 min, tR(R) = 19.41 min; 1H NMR (300 MHz, CDCl3) δ
MHz, CDCl3) δ (major + minor) = 2.99 (d, J = 4.7 Hz, 1H), 3.70 (s, 3H), (major + minor) = 2.41 (s, 3H), 2.82 (s, 1H), 5.68 (s, 1H), 7.08–7.11
5.59 (d, J = 4.7 Hz, 1H), 6.78–6.82 (m, 1H), 7.11–7.15 (m, 2H), 7.18– (m, 1H), 7.26–7.29 (m, 4H), 7.38–7.40 (m, 2H), 7.45–7.47 (m, 2H)
7.23 (m, 4H), 7.35–7.40 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ ppm; 13C NMR (75 MHz, CDCl3) δ (major + minor) = 20.8, 64.2, 86.8,
(major + minor) = 54.9, 65.1, 86.5, 88.6, 112.2, 114.0, 119.2, 122.5, 88.5, 121.6, 123.0, 127.9, 128.1, 128.3, 129.6, 131.5, 138.9, 141.2
128.0, 128.5, 129.6, 131.4, 142.5, 160.6. ppm.
ppm.
(S)-1-(4-Methoxyphenyl)-3-phenylprop-2-yn-1-ol (5fb):
A
white (S)-3-Phenyl-1-(p-tolyl)prop-2-yn-1-ol (5nb): A white solid, 95.5 mg,
solid, 106.0 mg, 89% yield, 58% ee; (Chiralcel OD column, hexane/i- 86% yield, 65% ee; HPLC (Chiralcel OD column, hexane/i-PrOH =
PrOH = 90/10, flow rate: 1.0 mL/min, UV detection at 254 nm); 90/10, flow rate: 1.0 mL/min, UV detection at 254 nm); Retention
1
Retention time: tR(S) = 14.42 min, tR(R) = 31.71 min; H NMR (400 time: tR(S) = 8.85 min, tR(R) = 15.79 min; 1H NMR (300 MHz, CDCl3) δ
MHz, CDCl3) δ (major + minor) = 2.77 (s, 1H), 3.81 (s, 3H), 5.61(s, (major + minor) = 2.42 (s, 3H), 2.45 (d, J = 4.4 Hz, 1H), 5.60 (d, J = 2.8
1H), 6.85–6.88 (m, 2H), 7.22–7.24 (m, 2H), 7.42–7.48 (m, 5H) ppm; Hz, 1H), 7.11 (d, J = 8.0 Hz, 2H), 7.33–7.37 (m, 3H), 7.46–7.48 (m,
13C NMR (100 MHz, CDCl3) δ (major + minor) = 55.1, 64.9, 86.8, 89.2, 2H), 7.52 (d, J = 8.0 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ (major
113.2, 122.0, 128.1, 128.3, 128.4, 131.4, 132.5, 159.9 ppm.
+ minor) = 19.9, 64.2, 86.5, 88.2, 122.0, 126.1, 128.5, 128.9, 129.2,
(R)-1-(3-Chlorophenyl)-3-phenylprop-2-yn-1-ol (5hb): A white solid, 131.5, 137.8, 139.0 ppm.
109.1 mg, 90% yield, 46% ee; HPLC (Chiralcel OD column, hexane/i- (S)-1-(Furan-2-yl)-3-phenylprop-2-yn-1-ol (5ob): A pale brown oil,
PrOH = 90/10, flow rate: 1.0 mL/min, UV detection at 254 nm); 92.1 mg, 93% yield, 85% ee; HPLC (Chiralcel OD column, hexane/i-
1
Retention time: tR(R) = 9.84 min, tR(S) = 38.07 min; H NMR (400 PrOH = 90/10, flow rate: 1.0 mL/min, UV detection at 254 nm);
1
MHz, CDCl3) δ (major + minor) = 2.49 (d, J = 5.4 Hz, 1H), 5.60 (d, J = Retention time: tR(S) = 9.73 min, tR(R) = 18.20 min; H NMR (300
5.0 Hz, 1H), 7.28–7.36 (m, 5H), 7.47–7.52 (m, 3H), 7.61 (s, 1H) ppm.
MHz, CDCl3) δ (major + minor) = 3.00 (br s, 1H), 5.59 (s, 1H), 6.53–
(R)-1-(4-Chlorophenyl)-3-phenylprop-2-yn-1-ol (5ib): A white solid, 6.56 (m, 1H), 7.21–7.26 (m, 3H), 7.46 (dd, J = 2.0 Hz, J = 2.3 Hz, 1H),
109.2 mg, 90% yield, 49% ee; HPLC (Chiralcel OD column, hexane/i- 7.47–7.51 (m, 2H), 7.59–7.62 (m, 1H) ppm; 13C NMR (75 MHz, CDCl3)
PrOH = 90/10, flow rate: 1.0 mL/min, UV detection at 254 nm); δ (major + minor) = 57.5, 85.0, 88.1, 109.2, 122.6, 126.6, 128.3,
1
Retention time: tR(R) = 9.07 min, tR(S) = 30.03 min; H NMR (300 128.8, 132.6, 141.2, 144.9 ppm.
MHz, CDCl3) δ (major + minor) = 3.00 (br s, 1H), 5.58 (s, 1H), 7.21– (S)-1-(2,3-Dimethoxyphenyl)-3-phenylprop-2-yn-1-ol (5pb): A pale
7.27 (m, 5H), 7.35–7.40 (m, 2H), 7.42–7.47 (m, 2H) ppm; 13C NMR yellow oil, 130.0 mg, 97% yield, 96% ee; HPLC (Chiralcel OD column,
(75 MHz, CDCl3) δ (major + minor) = 65.5, 89.2, 89.9, 122.0, 128.1, hexane/i-PrOH = 85/15, flow rate: 1.0 mL/min, UV detection at 254
1
128.3, 128.6, 129.0, 131.7, 134.2, 139.9 ppm.
nm); Retention time: tR(S) = 9.93 min, tR(R) = 12.51 min; H NMR
(S)-1-(2-Bromophenyl)-3-phenylprop-2-yn-1-ol (5jb): A white solid, (300 MHz, CDCl3) δ (major + minor) = 3.14 (s, 1H), 3.92 (s, 3H), 3.98
127.7 mg, 89% yield, 71% ee; HPLC (Chiralcel OD column, hexane/i- (s, 3H), 5.80 (s, 1H), 6.88 (d, J = 8.4 Hz, 1H), 7.05 (t, J = 7.8 Hz, 1H),
PrOH = 90/10, flow rate: 0.5 mL/min, UV detection at 254 nm); 7.22 (d, J = 7.8 Hz, 1H), 7.31–7.34 (m, 3H), 7.49–7.52 (m, 2H) ppm;
1
Retention time: tR(S) = 17.73 min, tR(R) = 20.10 min; H NMR (300 13C NMR (75 MHz, CDCl3) δ (major + minor) = 55.8, 61.5, 62.1, 85.6,
MHz, CDCl3) δ (major + minor) = 2.49 (d, J = 5.9 Hz, 1H), 5.98 (d, J = 89.2, 113.1, 119.5, 123.4, 124.5, 128.5, 128.7, 132.6, 135.7, 147.6,
5.8 Hz, 1H), 7.18–7.26 (m, 2H), 7.36–7.47 (m, 5H), 7.55 (d, J = 7.6 Hz, 154.5 ppm.
1H), 7.88 (d, J = 7.6 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ (major (S)-1-(2,4-Dimethoxyphenyl)-3-phenylprop-2-yn-1-ol (5qb): A pale
20
+ minor) = 63.8, 86.1, 87.1, 122.5, 122.8, 127.1, 127.6, 128.2, 128.4, yellow oil, 123.3 mg, 92% yield, 90% ee; [α]D = +1.6 (C = 0.35,
129.6, 131.7, 132.9, 139.6 ppm.
CHCl3); HPLC (Chiralcel OD column, hexane/i-PrOH = 90/10, flow
(R)-1-(3-Bromophenyl)-3-phenylprop-2-yn-1-ol (5kb): A white solid, rate: 1.0 mL/min, UV detection at 254 nm); Retention time: tR(S) =
1
123.4 mg, 86% yield, 63% ee; HPLC (Chiralcel OD column, hexane/i- 14.88 min, tR(R) = 36.23 min; H NMR (400 MHz, CDCl3) δ (major +
PrOH = 90/10, flow rate: 1.0 mL/min, UV detection at 254 nm); minor) = 2.90 (br s, 1H), 3.81 (s, 6H), 5.59 (d, J = 5.6 Hz, 1H), 6.52 (d,
1
Retention time: tR(R) = 8.96 min, tR(S) = 25.92 min; H NMR (300
8 | Org. Biomol. Chem., 2017, 00, 1-3
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J = 9.9 Hz, 2H), 7.25–7.58 (m, 6H) ppm; MS m/z (ESI): 290.6 (M +
Na)+, 306.5 (M + K)+, 558.1 (2M + Na)+.
Notes and references
View Article Online
1
(a) J.-C. Kizirian, Chem. Rev., 2008, 108,D1O4I0:−102.01053;9(/bC)7EO.BT0y1r7r1e7lKl,
Curr. Org. Chem., 2009, 13, 1540−1552; (c) B. M. Trost, A. H.
Weiss, Adv. Synth. Catal., 2009, 351, 963−983; (d) L. Pu, Acc.
Chem. Res., 2014, 47, 1523−1535; (e) T. Bauer, Coord. Chem.
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(S)-1-(2,6-Dimethoxyphenyl)-3-phenylprop-2-yn-1-ol (5rb): A white
solid, 121.9 mg, 91% yield, 90% ee; m.p. = 98–100 oC; HPLC
(Chiralcel OD column, hexane/i-PrOH = 90/10, flow rate: 1.0 mL/min,
UV detection at 254 nm); Retention time: tR(S) = 24.90 min, tR(R) =
18.69 min; 1H NMR (300 MHz, CDCl3) δ (major + minor) = 2.11 (br s,
1H), 3.90 (s, 6H), 4.04 (d, J = 9.6 Hz, 1H), 6.19 (d, J = 9.6 Hz, 1H), 6.59
(d, J = 8.4 Hz, 2H), 7.24–7.34 (m, 3H), 7.38–7.42 (m, 2H) ppm; 13C
NMR (75 MHz, CDCl3) δ (major + minor) = 55.5, 57.2, 82.3, 90.6,
104.1, 117.4, 123.8, 128.1, 128.3, 129.0, 131.2, 157.9 ppm.
(S)-1-(2,5-Dimethoxyphenyl)-3-phenylprop-2-yn-1-ol (5sb): A white
solid, 129.9 mg, 97% yield, 95% ee; m.p. = 85–87 oC; HPLC (Chiralcel
OD column, hexane/i-PrOH = 90/10, flow rate: 1.0 mL/min, UV
detection at 254 nm); Retention time: tR(S) = 13.39 min, tR(R) =
18.43 min; 1H NMR (300 MHz, CDCl3) δ (major + minor) = 3.19 (d, J =
6.0 Hz,1H), 3.88 (s, 3H), 3.93 (s, 3H), 5.79 (d, J = 5.8 Hz, 1H), 6.85–
6.88 (m, 2H), 7.23–7.28 (m, 3H), 7.49–7.52 (m, 3H) ppm; 13C NMR
(75 MHz, CDCl3) δ (major + minor) = 55.3, 56.1, 62.6, 86.1, 88.4,
112.9, 114.2, 114.3, 122.2, 128.3, 128.5, 130.6, 132.7, 151.7, 154.6
ppm.
2
X.-F. Wu, H. Neumann, Adv. Synth. Catal., 2012, 354,
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3
4
M. Turlington, L. Pu, Synlett, 2012, 23, 649−684.
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C. M. Sprout, M. L. Richmond, C. T. Seto, J. Org. Chem., 2004, 69,
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Marco-Aleixandre, J. R. Pedro, J. Mol. Catal. A-Chem., 2007, 276.
235–243; for an unique example for Me2Zn addition to ketones,
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(S)-3-Phenyl-1-(2,3,4-trimethoxyphenyl)prop-2-yn-1-ol (5vb):
A
pale yellow oil, 140.1 mg, 94% yield, 91% ee; [α]D20 = +5.0 (C = 0.26,
CHCl3); HPLC (Chiralcel OD column, hexane/i-PrOH = 90/10, flow
rate: 1.0 mL/min, UV detection at 254 nm); Retention time: tR(S) =
5
1
13.28 min, tR(R) = 20.11 min; H NMR (400 MHz, CDCl3) δ (major +
minor) = 3.07 (br s, 1H), 3.87 (s, 9H), 5.74 (d, J = 5.5 Hz, 1H), 6.69 (d,
J = 8.6 Hz, 1H), 7.24–7.46 (m, 6H) ppm; MS m/z (ESI): 320.7 (M +
Na)+, 336.6 (M + K)+, 618.9 (2M + Na)+.
6
7
(S)-3-Phenyl-1-(2,4,6-trimethoxyphenyl)prop-2-yn-1-ol (5wb):
A
white solid, 131.1 mg, 88% yield, 84% ee; m.p. = 96-97 oC; [α]D20 = -
15.0 (C = 0.24, CHCl3); HPLC (Chiralcel OD column, hexane/i-PrOH =
90/10, flow rate: 1.0 mL/min, UV detection at 254 nm); Retention
time: tR(S) = 14.51 min, tR(R) = 20.02 min; 1H NMR (400 MHz, CDCl3)
δ (major + minor) = 1.56 (br s, 1H), 3.83 (s, 9H), 5.74 (d, J = 5.5 Hz,
1H), 6.11 (d, J = 11.2 Hz, 2H), 7.24–7.41 (m, 5H) ppm; MS m/z (ESI):
320.7 (M + Na)+, 336.6 (M + K)+, 618.9 (2M + Na)+.
8
(S)-3-Phenyl-1-(2,4,5-trimethoxyphenyl)prop-2-yn-1-ol (5xb):
A
20
white solid, 135.6 mg, 91% yield, 92% ee; [α]D = +22.0 (C = 0.15,
CHCl3); HPLC (Chiralcel OD column, hexane/i-PrOH = 90/10, flow
rate: 1.0 mL/min, UV detection at 254 nm); Retention time: tR(S) =
1
24.48 min, tR(R) = 31.50 min; H NMR (400 MHz, CDCl3) δ (major +
9
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minor) = 2.87 (br s, 1H), 3.88 (s, 9H), 5.92 (d, J = 5.4 Hz, 1H), 6.56 (s,
1H), 7.23–7.48 (m, 6H) ppm; MS m/z (ESI): 320.7 (M + Na)+, 336.6
(M + K)+, 618.1 (2M + Na)+.
Conflicts of interest
There are no conflicts of interest to declare.
Acknowledgements
10 E. J. Corey, K. A. Cimprich, J. Am. Chem. Soc., 1994, 116,
We are grateful to the National Natural Sciences Foundation of
China (NNSFC: 21272216, 20972140), and the Department of
Science and Technology of Henan Province for financial support.
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