Highly enantioselective addition of linear alkyl alkynes to linear aldehydes

Article abstract of DOI:10.1016/j.tetlet.2010.07.082

It is discovered that the use of biscyclohexylamine (Cy₂NH) as an additive can greatly enhance the enantioselectivity for the reaction of linear alkyl alkynes with linear aldehydes. The combination of (S)-BINOL (20 mol %), Cy₂NH (5 mol %), ZnEt₂ (2 equiv), and Ti(OiPr) ₄ (0.5 equiv) catalyzes the reaction at room temperature in diethyl ether solution with 81-89% ee and 57-77% yield.

Full text of DOI:10.1016/j.tetlet.2010.07.082

Tetrahedron Letters 51 (2010) 5024–5027
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly enantioselective addition of linear alkyl alkynes to linear aldehydes
b,
Yuhao Du a,b, Mark Turlington b, Xiang Zhou a, , Lin Pu
*
*
a College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, China
b Department of Chemistry, University of Virginia, Charlottesville, VA 22904-4319, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
It is discovered that the use of biscyclohexylamine (Cy2NH) as an additive can greatly enhance the enanti-
oselectivity for the reaction of linear alkyl alkynes with linear aldehydes. The combination of (S)-BINOL
(20 mol %), Cy2NH (5 mol %), ZnEt2 (2 equiv), and Ti(OiPr)4 (0.5 equiv) catalyzes the reaction at room tem-
perature in diethyl ether solution with 81–89% ee and 57–77% yield.
Received 7 June 2010
Revised 14 July 2010
Accepted 15 July 2010
Available online 9 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
BINOL
Chiral propargylic alcohols
Asymmetric catalysis
Alkynes
Aldehydes
In recent years, the catalytic asymmetric alkyne addition to
aldehydes has been demonstrated as a very efficient method to
generate the synthetically versatile chiral propargylic alcohols.1–3
A number of highly enantioselective catalyst systems for a range
of substrates have been developed. In spite of the significant pro-
gress in this area, however, almost no efficient catalyst was found
to carry out the highly enantioselective reaction of linear alde-
hydes with terminal alkynes of linear alkyl substituents. This could
be attributed to the less steric bias of linear alkyl groups on the
substrates versus the branched alkyl and aryl groups as well as
the susceptibility of linear aldehydes toward aldol addition in the
presence of both acid and base catalysts. In an example reported
by Carreira, the catalytic asymmetric reaction of 4-phenyl-1-bu-
tyne, a b-aryl substituted alkyne, with a linear aldehyde n-octanal
was observed with high enantioselectivity, but the yield was low,
and heating and slow addition of the aldehyde were needed.2b In
two other examples of linear alkyne addition to linear aldehydes,
the use of stoichiometric amount of chiral amino alcohols was
required.4
Earlier, we reported the use of 1,10-bi-2-naphthol (BINOL) in
combination with ZnEt2 and Ti(OiPr)4 to catalyze the alkyne addi-
tion to aryl, alkyl, and vinyl aldehydes with high enantioselectivi-
ty.3a,b We further found that using HMPA as a Lewis base
additive allows the reaction to be conducted entirely at room tem-
perature and expands the substrates’ scope to include various
functional alkynes.3c,d Later, You and coworkers reported that
N-methyl imidazole (NMI) can be used as a Lewis base additive
in place of HMPA to increase the efficiency of the BINOL–ZnEt2–
Ti(OiPr)4 catalyst system.5 We have tested the use of NMI in
combination with (S)-BINOL, Ti(OiPr)4, and ZnEt2 to catalyze the
HO
2. Ti(OiPr)4
CHO
1. (S)-BINOL (40 mol%)
3.
(1 equiv)
NMI (5 mol%)
3
N
N
3
OH
OH
ZnEt2 (2 equiv)
rt, 24 h
3
rt, 2 h
3
CH2Cl2
rt, 24 h
36% yield
64% ee
(2 equiv)
NMI
Scheme 1. A linear alkyne addition to a linear aldehyde in the presence of (S)-BINOL and NMI.
(S)-BINOL
* Corresponding authors. Tel.: +1 434 924 6953; fax: +1 434 924 3710.
E-mail address: lp6n@virginia.edu (L. Pu).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.082

Y. Du et al. / Tetrahedron Letters 51 (2010) 5024–5027
5025
Table 1
1-Hexyne addition to valeraldehyde in the presence of various Lewis base additives
Entry
Base
Base (mol %)
Solvent
CH2Cl2
Isolated yielda (%)
36
eea (%)
N
N
1
1
5
64
62
66
NMI
N
2
3
5
5
CH2Cl2
CH2Cl2
92
25
2
N
H
N
3
N
Ph
N
N
4
5
CH2Cl2
44
70
4
5
6
5
10
2.5
CH2Cl2
CH2Cl2
34
52
76
70
CN
N
N
7
8
CH2Cl2
CH2Cl2
30
49
75
71
5
O
N
N
5
6
7
O
Ph
9
N
N
5
5
CH2Cl2
CH2Cl2
56
49
72
61
O
10
N
N
8
N
11
12
5
5
CH2Cl2
CH2Cl2
50
75
72
60
9
N
N
10
N
13
14
5
5
THF
Toluene
95
56
55
56
CN
N
N
15
16
17
5
5
5
Et2O
Et2O
Et2O
83
91
40
77
64
79
5
CH3NH(CH2)3NH2 (11)
12
N
H
Ph
N
H
Ph 13
18
5
Et2O
76
77
14
Cy2NH
19
20
5
5
Et2O
Et2O
59
56
84
74
N
H
Et3N (15)
21
22
5
5
Et2O
Et2O
51
44
78
77
N
16
N(n-C4H9)4Br (17)
a
Determined by using the 1H NMR spectra of their esters prepared with (R)-PhCH(OAc)CO2H.
reaction of a linear alkyne 1-hexyne with a linear aldehyde valer-
aldehyde at room temperature, but observed only 36% yield and
64% ee (Scheme 1). We have attempted to modify the structure
of NMI and also examined various other nitrogen-based Lewis base
additives for this reaction. Herein, we wish to report the discovery
of greatly enhanced enantioselectivity for the asymmetric linear al-
kyne addition to linear aldehydes.
Table 1 lists the experiments we have conducted for the reac-
tion of 1-hexyne with valeraldehyde in the presence of various Le-
wis base additives under the same conditions as those shown in

5026
Y. Du et al. / Tetrahedron Letters 51 (2010) 5024–5027
Table 2
Reaction conditions for 1-hexyne addition to valeraldehyde in the presence of Cy2NH
HO
3
chiral ligand
Cy2NH (5 mol%)
1.
CHO
Ti(OiPr)
rt, 2 h
3.
2.
4
3
ZnR2 (2 equiv)
rt, 24 h
3
3
Et2O (3 mL)
rt, 24 h
(2 equiv)
Entry
Ligand (mol %)
Ti(OiPr)4/BINOL
ZnR2
Isolated yield (%)
eea (%)
1
(S)-BINOL (40)
(S)-BINOL (40)
(S)-BINOL (40)
(S)-BINOL (30)
(S)-BINOL (20)
(S)-BINOL (10)
(S)-BINOL (20)
(S)-BINOL (20)
(S)-BINOL (20)
(S)-BINOL (20)
(S)-H8BINOL (40)
1.5
3.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnMe2
ZnEt2
ZnEt2
ZnEt2
ZnEt2
59
41
88
49
73
63
44
25
32
51
68
81
81
82
81
81
55
83
73
52
80
78
2
3b
4
5
6
7
8c
9d
10e
11
a
b
c
Determined by using the 1H NMR spectra of their esters prepared with (R)-PhCH(OAc)COOH.
4 equiv ZnEt2 and 4 equiv hexyne were used.
(S)-BINOL, Cy2NH, hexyne, and Et2Zn in Et2O were stirred for 2 h, then Ti(OiPr)4 was added.
After valeraldehyde was added, the reaction solution was stirred at 0 °C for 24 h.
d
e
Cy2NH, (S)-BINOL, and Et2Zn in Et2O were stirred for 6 h, and then hexyne was added. 18 h later, Ti(OiPr)4 was added.
Scheme 1 unless noted otherwise. We first modified the structure
of NMI by introducing additional alkyl substituents to increase the
basicity and steric bulkiness of NMI. As shown in entry 2, when
compound 2 was used in place of NMI used in entry 1, the yield
of the reaction was greatly increased but the enantioselectivity
was reduced slightly. Removal of the N-methyl group of 2 dimin-
ished the yield (entry 3). The use of the N-benzyl group in 4 to re-
place the N-methyl group in 2 improved the enantioselectivity but
decreased the yield (entry 4). Using compound 5 containing a polar
N-alkyl group further improved the enantioselectivity (entry 5).
Increasing the amount of 5 increased the yield but reduced the
ee (entry 6). Decreasing the amount of 5 could not improve the
reaction (entry 7). The use of N-acyl imidazole derivatives 6, 7,
and 8 gave lower enantioselectivity than 5 (entries 8–10). Using
other types of N-heterocycles such as 9 and 10 improved the yields
but not the enantioselectivity (entries 11 and 12). We have studied
the effect of solvent on the reaction carried out in the presence of 5.
When CH2Cl2 was replaced with THF in entry 13, the yield was
greatly increased over entry 5 but the enantioselectivity was re-
duced. No improvement was observed by changing THF to toluene
(entry 14). However, when Et2O was used, the yield was improved
without sacrificing the ee in comparison with entry 5 (entry 15).
This demonstrates that Et2O is a superior solvent over CH2Cl2 for
this reaction. We also screened various alkyl amines for this reac-
tion in Et2O. The use of the primary amine 11 gave an excellent
yield but the ee was low (entry 16). Using the secondary amine
12 gave a higher enantioselectivity but the yield was low (entry
17). N-Benzyl aniline (13) gave a better yield and a slightly reduced
ee (entry 18). When the secondary amine Cy2NH (14) was used,
high enantioselectivity was observed also with much better yield
than the initial NMI (entry 19). The tertiary amines 15 and 16 gave
lower enantioselectivity than the secondary amine Cy2NH (entries
20 and 21). Interestingly, the quaternary ammonium salt 17 gave a
higher enantioselectivity than NMI (entry 22). This indicates that
Brꢀ can also act as a Lewis base to promote this reaction.
ity for the reaction of 1-hexyne with valeraldehyde. We have fur-
ther explored the reaction conditions for the use of Cy2NH and
the experiments are listed in Table 2. When the amount of Ti(OiPr)4
was decreased, a slight reduction of the ee was observed (entry 1).
Increasing the amount of Ti(OiPr)4 decreased the yield (entry 2).
When the amounts of ZnEt2 and 1-hexyne were doubled (4 equiv),
a high yield was obtained but there was no gain in ee (entry 3).
Varying the amount of (S)-BINOL in entries 4–6 showed that
20 mol % of (S)-BINOL gave good yield and good ee (entry 5). Using
ZnMe2 in place of ZnEt2 significantly decreased the yield (entry 7).
Decreasing the reaction time in the first step from 24 h to 2 h gave
a diminished yield, indicating insufficient formation of the nucleo-
philic alkynylzinc reagent (entry 8). Conducting the reaction at 0 °C
in the third step decreased both the yield and ee (entry 9). Mixing
(S)-BINOL, Cy2NH, and ZnEt2 in Et2O for 6 h followed by the addi-
tion of 1-hexyne in the first step (entry 11) gave a lower yield than
that in entry 5. When (S)-BINOL was replaced with the partially
hydrogenated (S)-H8BINOL (40 mol %), lower enantioselectivity
was observed (entry 11).
OH
OH
(S)-H8BINOL
Because entry 5 in Table 2 gives the reduced usage of the chiral
ligand and the higher reaction yield and ee, its conditions are ap-
plied to catalyze the reactions of other linear alkynes and alde-
hydes, and the results are summarized in Table 3. As shown in
the table, high enantioselectivity and moderate to good yields have
been achieved for the reactions of linear alkynes with a variety of
linear aldehydes. The absolute configurations of the products are
assigned to be R in analogous to the previously reported reac-
The result in entry 19 of Table 1 demonstrates that Cy2NH is a
much better base additive than NMI, giving a high enantioselectiv-

Y. Du et al. / Tetrahedron Letters 51 (2010) 5024–5027
5027
Table 3
was added an aldehyde (0.25 mmol). After 24 h, the reaction was
quenched with saturated aqueous ammonium chloride (5 mL).
The reaction mixture was extracted three times with CH2Cl2 and
the organic phase was dried with sodium sulfate and concentrated
by rotary evaporation. The residue was purified by flash column
chromatography on silica gel eluted with hexanes/Et2O (10:1) to
give the product as an oil. The ee was determined by using the
1H NMR spectra of their esters prepared with (R)-PhCH(OAc)CO2H.
Reactions of various linear alkynes with linear aldehydes in the presence of (S)-BINOL,
Cy2NH, ZnEt2, and Ti(OiPr)4
a
Entry Alkyne
Aldehyde
Isolated yield
(%)
eeb
(%)
O
O
n-C4H9
1
2
73
61
77
76
67
70
63
59
60
57
81
87
88
85
85
89
87
83
88
77
n-C6H13
H
H
3
Cl
O
n-C4H9
4
Acknowledgments
n-C6H13
5
H
6
Cl
Partial supports of this work from the US National Science
Foundation (CHE-0717995 and ECCS-0708923), and the Program
of Introducing Talents of Discipline to Universities of China (111
project, 111-2-10) are gratefully acknowledged.
n-C4H9
7
n-C6H13
8
9
Cl
O
n-C6H13
10
Cl
Supplementary data
11
61
83
Cl
H
Ph
O
n-C4H9
n-C6H13
12
13
14
71
74
65
83
84
89
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.07.082.
H
Cl
References and notes
a
Reagents used: (S)-BINOL/ZnEt2/alkyne/Cy2NH/Ti(OiPr)4/aldehyde = 0.2:2:2:
0.05:0.5:1.
1. (a) Frantz, D. E.; Fässler, R.; Tomooka, C. S.; Carreira, E. M. Acc. Chem. Res. 2000,
33, 373–381; (b) Pu, L. Tetrahedron 2003, 59, 9873–9886; (c) Cozzi, P. G.; Hilgraf,
R.; Zimmermann, N. Eur. J. Org. Chem. 2004, 4095–4105; (d) Lu, G.; Li, Y.-M.; Li,
X.-S.; Chan, A. S. C. Coord. Chem. Rev. 2005, 249, 1736–1744.
b
Determined by using the 1H NMR spectra of their esters prepared with (R)-
PhCH(OAc)CO2H.
2. (a) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122, 1806–
1807; (b) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687–9688; (c)
Li, X. S.; Lu, G.; Kwok, W. H.; Chan, A. S. C. J. Am. Chem. Soc. 2002, 124, 12636–
12637; (d) Trost, B. M.; Weiss, A. H.; von Wangelin, A. J. J. Am. Chem. Soc. 2006,
128, 8–9; (e) Xu, Z.; Wang, R.; Xu, J.; Da, C.; Yan, W.; Chen, C. Angew. Chem., Int.
Ed. 2003, 42, 5747–5749; (f) Wolf, C.; Liu, S. J. Am. Chem. Soc. 2006, 128, 10996–
10997; (g) Takita, R.; Yakura, K.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc.
2005, 127, 13760–13761; (h) Trost, B. M.; Chan, V. S.; Yamamoto, D. J. Am. Chem.
Soc. 2010, 132, 5186–5192.
3. (a) Moore, D.; Pu, L. Org. Lett. 2002, 4, 1855–1857; (b) Gao, G.; Moore, D.; Xie, R.
G.; Pu, L. Org. Lett. 2002, 4, 4143–4146; (c) Gao, G.; Xie, R. G.; Pu, L. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5417–5420; (d) Gao, G.; Wang, Q.; Yu, X. Q.; Xie, R. G.;
Pu, L. Angew. Chem., Int. Ed. 2006, 45, 122–125.
tions.3,5 It is interesting to notice that 5-chloro-1-pentyne consis-
tently gave better enantioselectivity than the other linear alkynes
when reacted with various aldehydes. The results in Table 3 dem-
onstrate that the readily available BINOL–Cy2NH–ZnEt2–Ti(OiPr)4
catalyst system is useful for the synthesis of chiral propargylic
alcohols from linear alkynes and aldehydes.
A general procedure for the reactions in Table 3 is given below.
Under nitrogen, (S)-BINOL (14.3 mg, 0.05 mmol) was dissolved in
Et2O (3 mL) in a flame-dried flask. ZnEt2 (53
kyne (0.5 mmol), and Cy2NH (2.4 L, 0.0125 mmol) were added
sequentially and the resulting mixture was stirred at room temper-
ature for 24 h. Ti(OiPr)4 (37
L, 0.125 mmol) was then added and
the reaction mixture was stirred for 2 h. To the resulting solution
lL, 0.5 mmol), an al-
l
4. (a) Smith, A. B., III; Kim, D.-S. Org. Lett. 2004, 6, 1493–1495; (b) Jiang, B.; Chen, Z.;
Xiong, W. Chem. Commun. 2002, 1524–1525.
5. Yang, F.; Xi, P.; Yang, L.; Lan, J.; Xie, R.; You, J. J. Org. Chem. 2007, 72, 5457–5460.
l