Enantioselective synthesis of chiral propargylic alcohols catalyzed by bifunctional zinc-based complexes

Article abstract of DOI:10.1080/00397911.2010.531367

This work demonstrates an efficient way to prepare chiral propargylic alcohols by asymmetric addition of terminal Zn-acetylide to aldehydes catalyzed by bifunctional zinc-based complexes. The corresponding products with moderate to good yields and enantio

Full text of DOI:10.1080/00397911.2010.531367

This article was downloaded by: [University of New Hampshire]
On: 12 March 2013, At: 09:43
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Enantioselective Synthesis of Chiral
Propargylic Alcohols Catalyzed by
Bifunctional Zinc-Based Complexes
Xinhua Lu a , Guanlei Xie a , Tingyi Li a , Xiaoming Qu a & Jincheng
Mao a
a Key Laboratory of Organic Synthesis of Jiangsu Province, College
of Chemistry, Chemical Engineering and Materials Science, Soochow
University, Suzhou, P. R. China
Accepted author version posted online: 24 Aug 2011.Version of
record first published: 11 Nov 2011.
To cite this article: Xinhua Lu , Guanlei Xie , Tingyi Li , Xiaoming Qu & Jincheng Mao (2012):
Enantioselective Synthesis of Chiral Propargylic Alcohols Catalyzed by Bifunctional Zinc-Based
Complexes, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 42:6, 775-783
To link to this article: http://dx.doi.org/10.1080/00397911.2010.531367
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Synthetic Communications1, 42: 775–783, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.531367
ENANTIOSELECTIVE SYNTHESIS OF CHIRAL
PROPARGYLIC ALCOHOLS CATALYZED BY
BIFUNCTIONAL ZINC-BASED COMPLEXES
Xinhua Lu, Guanlei Xie, Tingyi Li, Xiaoming Qu, and
Jincheng Mao
Key Laboratory of Organic Synthesis of Jiangsu Province, College of
Chemistry, Chemical Engineering and Materials Science, Soochow
University, Suzhou, P. R. China
GRAPHICAL ABSTRACT
Abstract This work demonstrates an efficient way to prepare chiral propargylic alcohols by
asymmetric addition of terminal Zn-acetylide to aldehydes catalyzed by bifunctional
zinc-based complexes. The corresponding products with moderate to good yields and
enantioselectivities were obtained in the absence of moisture-sensitive Ti(OiPr)4.
Keywords Alkyne; asymmetric addition; bifunctional complexes; enantioselectivities
INTRODUCTION
Chiral secondary propargylic alcohols were important and useful building
blocks in the synthesis of many natural products and pharmaceuticals.[1,2] However,
the most effective and straightforward way is asymmetric alkynylation of aldehydes,
which can simultaneously form a new C-C bond and a stereogenic center in one
step.[3–6] In past decades, various excellent chiral ligands in combination with differ-
ent central metals have been developed for such an enantioselective transformation
process, such as alkyl zinc–catalyzed asymmetric alkynylation of aldehydes,[7]
titanium-catalyzed enantioselective alkynylide addition to aldehydes,[8] Zn(OTf)2-
meditated enantioselective additions,[9] InBr3-catalyzed alkynylation of aldehydes,[10]
vanadium-mediated asymmetric additions,[11] and copper-promoted enantioselective
addition of terminal alkynes to aldehydes.[12] Among them, alkylzinc-mediated
Received November 17, 2009.
Address correspondence to Jincheng Mao, Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University,
Suzhou 215123, P. R. China. E-mail: jcmao@suda.edu.cn
775

776
X. LU ET AL.
Figure 1. Design of possible bifunctional zinc-based catalysts for asymmetric alkynylation reaction.
Figure 2. Chiral ligands evaluated in this research.
asymmetric addition of phenylacetylene to aldehydes is most attractive.[13] Although
great effort has been made in this field, development of novel readily available chiral
catalysts is still desirable. Based on our interest in such catalytic reactions,[14–19] here
we report our recent findings in this asymmetric transformation using the bifunc-
tional zinc-based catalysts (Fig. 1).
We know that bifunctional catalysts have been developed for various asymmet-
ric transformation processes.[20–22] However, this concept for the design of catalysts
has not been extensively applied in asymmetric addition reactions.[23] When this
bifunctional catalyst was employed in this reaction, the Lewis-acid part could
activate the electrophilic substrate, such as aldehyde, and the Lewis-base part could
activate the nuclephilic substrate, such as metal acetylide. In this way, double activa-
tions could make this catalyst efficient for the asymmetric alkynylation of aldehydes.
RESULTS AND DISCUSSION
Based on commercially available chiral amino alcohols, ligands A–H were
easily prepared in one-step reaction with good yields. Then, we applied these stable

BIFUNCTIONAL COMPLEX FOR ALKYNYLATION
777
ligands to the asymmetric addition of Zn-phenylacetylide to benzaldehyde as the
model reaction, and the related results are listed in Table 1. Using toluene as the sol-
vent, ligand C gave the best enantioselectivity (48% ee) (entries 1–8, Table 1). At the
same time, additional Lewis acid Ti(OiPr)4 was employed in the reaction. However,
less than 5% ee was obtained, although the yield of the desired product was very high
(91%) (entry 9, Table 1). After screening different solvents (entries 10–12, Table 1),
we found that hexane afforded the greatest enantioselectivity (entry 11, Table 1).
When 1 equiv. of 1,2-dimethoxyethane (DME) and hexamethylphosphoramide
(HMPA) were employed as the additives, we did not get the enhanced ee values
Table 1. Asymmetric addition of Zn-phenylacetylide to benzaldehyde using various chiral ligandsa
Entry Ligand (mol%) Solvent PhCCH (equiv) R2Zn (equiv) Yield (%)b Ee (%)c Config.
1
2
3
4
5
6
7
8
9d
A (10)
B (10)
C (10)
D (10)
E (10)
F (10)
G (10)
H (10)
C (10)
C (10)
C (10)
C (10)
C (10)
C (10)
C (10)
C (10)
C (10)
C (10)
C (20)
C (40)
C (5)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCM
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
3.0
4.0
1.4
2.0
2.0
2.0
2.0
2.0
Me (2.0)
Me (2.0)
Me (2.0)
Me (2.0)
Me (2.0)
Me (2.0)
Me (2.0)
Me (2.0)
Me (2.0)
Me (2.0)
Me (2.0)
Me (2.0)
Me (2.0)
Me (2.0)
Et (2.0)
Et (3.0)
Et (4.0)
Et (1.4)
Et (2.0)
Et (2.0)
Et (2.0)
Et (2.0)
Et (2.0)
26
29
34
25
33
17
15
13
91
82
26
17
89
30
83
80
85
67
84
75
76
62
47
18
31
48
40
43
21
35
32
<5
15
53
20
9
R
R
R
R
S
S
R
S
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
10
11
Hexane
THF
12
13e
14f
15
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
52
60
40
44
51
59
61
28
26
0
16
17
18
19
20
21
22g
23h
C (10)
C (10)
aAll the reactions were performed under argon at room temperature for 24 h. Alkyne=Me2Zn=
benzaldehyde=ligand 1:1:0.5:0.05.
bIsolated yield.
cThe enantiomeric excess was determined by chiral HPLC analysis of the corresponding products on a
Chiralcel OD-H column.
d0.2 mmol Ti(OiPr)4 was used.
e1 mmol HMPA was added.
f1 mmol DME was added.
gReaction was carried out at 0 ꢀC.
hReaction was carried out at 60 ꢀC.

778
X. LU ET AL.
Table 2. Results for asymmetric alkynylzinc additions to various aldehydes catalyzed by ligand Ca
Entry
1
Substrate
Product
Yield (%)b
Ee (%)c
Config.
83
60
R
2
3
64
72
39
43
R
R
4
63
41
R
5
6
7
76
73
72
52
32
48
R
R
R
8
9
67
70
47
56
R
R
(Continued )

BIFUNCTIONAL COMPLEX FOR ALKYNYLATION
779
Config.
R
Table 2. Continued
Entry
10
Substrate
Product
Yield (%)b
Ee (%)c
76
60 [90]d
11
12
51
56
50
50
R
R
aAll the reactions were performed under argon at room temperature for 24 h. Alkyne=Et2Zn=
benzaldehyde=C 1:1:0.5:0.05.
bIsolated yield.
cThe enantiomeric excess was determined by chiral HPLC analysis of the corresponding products on a
Chiralcel OD-H column.
dThe ee in parentheses was determined after simple recrystallization.
(entries 13 and 14, Table 1). Replacement of Me2Zn with Et2Zn led to better yield
(83%) and better enantioselectivity (60% ee) (entry 15, Table 1). Varying the amount
of phenylacetylene and diethyl zinc did not improve results (entries 16–18, Table 1).
To our surprise, higher or lower loading of ligand C did not afford better results
(entries 19–21, Table 1). Changing reaction temperatures did not lead to enhanced
enantioselectivities (entries 22 and 23, Table 1).
The influence of various aromatic aldehyde substrates on the reactivity and
enantioselectivity was studied under the standard conditions. As shown by the results
summarized in Table 2, moderate yields and enantioselectivities were achieved for the
addition of Zn-phenylacetylide to aromatic aldehydes (entries 1–11, Table 2). Substitu-
ents of aromatic aldehydes containing an electron-withdrawing group at the ortho- or
para-position have little effect on the enantiomeric excess. It is noteworthy that for
b-naphthaldehyde, the desired product was obtained with good enantioselectivity
(90%) after simple recrystallization (entry 10, Table 2). In addition, promising enan-
tioselectivity (50%) can also be obtained with aliphatic aldehyde (entry 12, Table 2).
In addition, we performed different asymmetric reactions using C as the ligand
to test its possible catalytic performances. One selected reaction is copper-catalyzed
asymmetric Henry reaction of 4-nitrobenzaldehyde and nitromethane. In air, the
desired product was obtained in good yield and enantioselectivity in the presence
of Cu(OAc)2 ꢁ H2O using C as the ligand (Scheme 1). The other reaction is
copper-catalyzed asymmetric Michael addition reaction of 40-methylchalcone and
nitromethane. The promising result was acquired using Cu(OAc)2 ꢁ H2O=C catalytic
system as shown in Scheme 2. Thus, it shows that our catalytic system may be
efficient in various enantioseletive catalytic processes.

780
X. LU ET AL.
Scheme 1. Copper-catalyzed asymmetric Henry reaction in the presence of ligand C.
Scheme 2. Copper-catalyzed asymmetric Michael addition reaction in the presence of ligand C.
CONCLUSIONS
In summary, we have developed a bifunctional zinc-based complex for the
enantioselective reaction of phenylacetylene with various aldehydes for the synthesis
of optically active propargylic alcohols. Using 10 mol% of easily prepared amino
alcohol derivative C as the chiral ligand, the desired products were obtained in mod-
erate to good yields and enantioselectivities. Thus, the easily available catalyst made
this catalytic process potentially practical and useful. Further studies on highly effec-
tive asymmetric addition reactions using novel catalysts are in progress in our
laboratory.
EXPERIMENTAL
All manipulations were carried out under an argon atmosphere in dried and
degassed solvents. All solvents were dried and degassed by the standard methods
and all aldehydes, dimethyl zinc, and diethyl zinc were commercially available. Melt-
ing points were determined using a standard melting-point apparatus and are uncor-
rected. The reactions were monitored by thin-layer chromatography (TLC). NMR
spectra were measured in CDCl3 on a Varian-Inova 400 NMR spectrometer
(400 MHz) with tetramethylsilane (TMS) as an internal reference. Optical rotations
were measured with a HORIBA SEPA-200 highly sensitive polarimeter. Enantio-
meric excess (ee) determination was carried out using a chiral OD-H column (sol-
vent, hexane=isopropanol; flow rate, 1 cm3 minꢂ1; UV detection, 254 nm). High-
resolution mass spectra (HRMS) were measured with electron impact (EI).
General Procedure for the Addition of Zinc-Phenylacethylene to
Aldehydes
All manipulations were carried out under an argon atmosphere using dried and
degassed solvent. The ligand C (0.05 mmol) was suspended in dry hexane (2.0 mL) at

BIFUNCTIONAL COMPLEX FOR ALKYNYLATION
781
room temperature. Then, a solution of diethyl zinc (1.0 M in hexane, 1.0 mL,
1.0 mmol) was added. After the mixture was stirred at room temperature for 1.5 h,
phenylacetylene (1.0 mmol) was added, and the stirring continued for another
1.5 h. The yellow solution was cooled to 0 ꢀC and treated with benzaldehyde
(50 mL, 0.5 mmol); then the resultant mixture was allowed to warm up to room tem-
perature naturally and stirred for 20 h. After the reaction was completed, it was
cooled to 0 ꢀC again and quenched by 5% aqueous HCl (2 mL). The mixture was
extracted with ethyl acetate (EtOAc) (2 ꢃ 10 mL). The organic layer was dried over
Na2SO4 and concentrated under vacuum. The residue was purified by flash column
chromatography (silica gel H, EtOAc–petroleum ether ¼ 1:6) to give the pure pro-
1
duct. H NMR (400 MHz, CDCl3): d 7.62 (d, J ¼ 7.2 Hz, 2H), 7.48–7.25 (m, 8H),
5.69 (s, 1H), 2.36 (s, 1H); 13C NMR (100 MHz, CDCl3): d 141.1, 132.2, 129.2,
129.1, 128.9, 128.8, 127.2, 122.9, 89.1, 87.2, 65.6.
Chiral HPLC Chromatography Data
1,3-Diphenylprop-2-yn-1-ol. Yield 83%; 60% ee determined by HPLC analy-
sis (Chiralcel OD-H column, IPA–hexane 20:80). Retention time: tminor ¼ 9.53 min,
tmajor ¼ 6.42 min.
1-(2-Fluorophenyl)-3-phenylprop-2-yn-1-ol. Yield 64%; 39% ee determined
by HPLC analysis (Chiralcel OD-H column, IPA–hexane 20:80). Retention time:
tminor ¼ 7.02 min, tmajor ¼ 5.77 min.
1-(4-Fluorophenyl)-3-phenylprop-2-yn-1-ol. Yield 72%; 43% ee determined
by HPLC analysis (Chiralcel OD-H column, IPA–hexane 20:80). Retention time:
tminor ¼ 11.58 min, tmajor ¼ 5.91 min.
1-(4-Bromophenyl)-3-phenylprop-2-yn-1-ol. Yield 63%; 41% ee determined
by HPLC analysis (Chiralcel OD-H column, IPA–hexane 20:80). Retention time:
tminor ¼ 13.49 min, tmajor ¼ 6.25 min.
1-(4-Chlorophenyl)-3-phenylprop-2-yn-1-ol. Yield 76%; 52% ee determined
by HPLC analysis (Chiralcel OD-H column, IPA–hexane 20:80). Retention time:
tminor ¼ 12.62 min, tmajor ¼ 6.03 min.
1-(Naphthalen-4-yl)-3-phenylprop-2-yn-1-ol. Yield70%;56%eedetermined
by HPLC analysis (Chiralcel OD-H column, IPA–hexane 20:80). Retention time:
tminor ¼ 15.21 min, tmajor ¼ 9.04 min.
1-(2-Chlorophenyl)-3-phenylprop-2-yn-1-ol. Yield 73%; 32% ee determined
by HPLC analysis (Chiralcel OD-H column, IPA–hexane 20:80). Retention time:
tminor ¼ 6.22 min, tmajor ¼ 5.77 min.
3-Phenyl-1-p-tolylprop-2-yn-1-ol. Yield 72%; 48% ee determined by HPLC
analysis (Chiralcel OD-H column, IPA–hexane 20:80). Retention time: tminor
¼
9.22 min, tmajor ¼ 5.62 min.
3-Phenyl-1-o-tolylprop-2-yn-1-ol. Yield 67%; 47% ee determined by HPLC
analysis (Chiralcel OD-H column, IPA–hexane 20:80). Retention time: tminor
9.16 min, tmajor ¼ 5.49 min.
¼

782
X. LU ET AL.
1,4-Diphenylbut-3-yn-2-ol. Yield 56%; 50% ee determined by HPLC analy-
sis (Chiralcel OD-H column, IPA–hexane 20:80). Retention time: tminor ¼ 9.15 min,
tmajor ¼ 5.53 min.
1-(Naphthalen-3-yl)-3-phenylprop-2-yn-1-ol. Yield76%;60%eedetermined
by HPLC analysis (Chiralcel OD-H column, IPA–hexane 20:80). Retention time:
tminor ¼ 7.74 min, tmajor ¼ 5.57 min.
3-Phenyl-1-(thiophen-2-yl)prop-2-yn-1-ol. Yield 51%; 50% ee determined
by HPLC analysis (Chiralcel OD-H column, IPA–hexane 20:80). Retention time:
tminor ¼ 9.46 min, tmajor ¼ 6.16 min.
ACKNOWLEDGMENTS
We are grateful to the grants from the National Natural Science Foundation of
China (No. 20802046), International S&T Cooperation Program of Jiangsu Province
(BZ2010048), the Priority Academic Program Development of Jiangsu Higher
Education Institutions, and the Key Laboratory of Organic Synthesis of Jiangsu
Province for financial support.
REFERENCES
1. Barouh, V.; Dall, H.; Patel, D.; Hite, G. Stereochemical aspects of antihistamine action, 4:
Absolute configuration of carbinoxamine antipodes. J. Med. Chem. 1971, 14, 834.
2. Trost, B. M.; Krische, M. J. Palladium-catalyzed enyne cycloisomerization reaction in an
asymmetric approach to the picrotoxane sesquiterpenes, 2: Second-generation total synth-
eses of corianin, picrotoxinin, picrotin, and methyl picrotoxate. J. Am. Chem. Soc. 1999,
121, 6131.
3. Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Acetylenes in catalysis: Enantioselective
additions to carbonyl groups and imines and applications beyond. Eur. J. Org. Chem.
2004, 4095.
4. Lu, G.; Li, Y. M.; Li, X. S.; Chan, A. S. C. Synthesis and application of new chiral cat-
alysts for asymmetric alkynylation reactions. Coord. Chem. Rev. 2005, 249, 1736.
5. Pu, L. Asymmetric alkynylzinc additions to aldehydes and ketones. Tetradedron 2003, 59,
9873.
6. Trost, B. M.; Weiss, A. H. The enantioselective addition of alkyne nucleophiles to
carbonyl groups. Adv. Synth. Catal. 2009, 351, 963.
7. Mao, J. C.; Xie, G. L. Novel chiral catalysts for asymmetric addition of terminal alkynes
to aldehydes. Curr. Org. Chem. 2009, 13, 1553.
8. Li, X.; Lu, G.; Kwok, W. H.; Chan, A. S. C. Highly enantioselective alkynylzinc addition
to aromatic aldehydes catalyzed by self-assembled titanium catalysts. J. Am. Chem. Soc.
2002, 124, 12636.
9. Tyrrell, E. Asymmetric alkynylation reactions of aldehydes using a Zn(OTf)2-chiral
ligand-base system. Curr. Org. Chem. 2009, 13, 1540.
10. Takita, R.; Yakura, K.; Ohshima, T.; Shibasaki, M. Asymmetric alkynylation of alde-
hydes catalyzed by an In(III)=BINOL complex. J. Am. Chem. Soc. 2005, 127, 13760.
11. Hsieh, S. S.; Gau, H. M. Asymmetric alkynyl additions to aldehydes catalyzed by tunable
oxovanadium(V) complexes of Schiff bases of b-amino alcohols. Synlett. 2006, 1871.
12. Asano, Y.; Hara, K.; Ito, H.; Sawamura, M. Enantioselective addition of terminal alkynes
to aldehydes catalyzed by a Cu(I)-TRAP complex. Org. Lett. 2007, 9, 3901–3904.

BIFUNCTIONAL COMPLEX FOR ALKYNYLATION
783
13. Li, Z. B.; Liu, T. D.; Pu, L. Chiral macrocycle-catalyzed highly enantioselective phenyla-
cetylene addition to aliphatic and vinyl aldehydes. J. Org. Chem. 2007, 72, 4340.
14. Xu, Z.; Mao, J.; Zhang, Y. Highly enantioselective alkynylation of aldehydes catalyzed by
a new oxazolidine–titanium complex. Org. Biomol. Chem. 2008, 6, 1288.
15. Mao, J.; Wan, B.; Wu, F.; Lu, S. Readily available sulfamide-amine alcohols for enantio-
selective phenylacetylene addition to aldehydes in the absence of Ti(OiPr)4. Chirality 2005,
17, 245.
16. Xu, Z.; Wu, N.; Ding, Z.; Wang, T.; Mao, J.; Zhang, Y. L-Proline-derived teriary amino
alcohol as a new chiral ligand for enantioselective alkynylation of aldehydes. Tetrahedron
Lett. 2009, 50, 926.
17. Mao, J.; Guo, Jun. Enantioselective addition of methyl propilate to aldehydes catalyzed
by oxazolidine-titantium complex. Synlett. 2009, 2295.
18. Mao, J.; Bao, Z.; Guo, J.; Ji, S. Enantioselective alkynylation of aromatic and heteroaro-
matic aldehydes catalyzed by resin-supported oxazolidine–titanium complexes. Tetra-
hedron 2008, 64, 9901.
19. Xu, Z.; Mao, J.; Zhang, Y. (1S, 2R)-2-Amino-1,2-diphenylethanol as a new chiral ligand
for enantioselective alkynylation of aldehydes. Catal. Commun. 2008, 10, 113.
20. Shibasaki, M.; Kanai, M. Multifunctional asymmetric catalysis. Chem. Pharm. Bull. 2001,
49, 511.
21. Gro¨ger, H. The development of new monometallic bifunctional catalysts with Lewis acid
and Lewis base properties, and their application in asymmetric cyanation reactions. Chem.
Eur. J. 2001, 7, 5246.
22. Shibasaki, M.; Kanai, M.; Funabashi, K. Recent progress in asymmetric two-center
catalysis. Chem. Commun. 2002, 1989.
23. Kang, Y. F.; Liu, L.; Wang, R.; Yan, W.; Zhou, Y. F. The use of bifunctional catalyst
systems in the asymmetric addition of alkynylzinc to aldehydes. Tetrahedron: Asymmetry
2004, 15, 3155.