Asymmetric alkyne addition to aldehydes catalyzed by Schiff bases made from 1,1′-bi-2-naphthol and chiral benzylic amines

Article abstract of DOI:10.1016/j.tetasy.2013.12.013

Several 1,1′-bi-2-naphthol (BINOL)-based Schiff bases were prepared from the condensation of (R)-3,3′-diformyl BINOL with chiral benzylic amine derivatives. These compounds were used to catalyze the reaction of phenylacetylene with aldehydes in the presence of ZnEt₂ with up to 85% ee and 83% yield.

Full text of DOI:10.1016/j.tetasy.2013.12.013

Tetrahedron: Asymmetry 25 (2014) 199–201
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric alkyne addition to aldehydes catalyzed by Schiff bases
made from 1,10-bi-2-naphthol and chiral benzylic amines
b,
Cen Chen a,c, Qingfei Huang a, Sheng Zou a, Lei Wang a,c, Bao Luan a,c, Jin Zhu a, Qiwei Wang a, , Lin Pu
⇑
⇑
a Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
b Department of Chemistry, University of Virginia, Charlottesville, VA 22904-4319, USA
c University of Chinese Academy of Sciences, Beijing 100049, China
a r t i c l e i n f o
a b s t r a c t
Several 1,10-bi-2-naphthol (BINOL)-based Schiff bases were prepared from the condensation of (R)-3,30-
diformyl BINOL with chiral benzylic amine derivatives. These compounds were used to catalyze the reac-
tion of phenylacetylene with aldehydes in the presence of ZnEt2 with up to 85% ee and 83% yield.
Ó 2013 Elsevier Ltd. All rights reserved.
Article history:
Received 28 October 2013
Accepted 18 December 2013
1. Introduction
amine derivatives.6 (R)-3,30-Diformyl-BINOL was prepared accord-
ing to the previously reported procedure from (R)-BINOL.7 Com-
Catalytic asymmetric alkyne addition to aldehydes can generate
chiral propargylic alcohols that are very useful in organic synthesis.
In recent years, significant progress has been made in this area and
pound 6 was previously reported by Brunner and Goldbrunner
for its use in the copper-catalyzed cyclopropanation of styrene
with N2CHCO2Et, although low stereoselectivity was observed.8
The acid catalyst used in the previous synthesis8 of 6 was not nec-
essary as described in our procedure.6
a
number of highly enantioselective catalysts have been
developed.1–3 In our laboratory, we have studied the use of
1,10-bi-2-naphthol (BINOL) and its derivatives to catalyze the al-
kyne addition to aldehydes.4 For example, we found that BINOL
in combination with ZnEt2, Ti(OiPr)4, and Cy2NH (Cy = cyclohexyl)
can catalyze the reaction of a broad range of alkyne and aldehyde
substrates with high enantioselectivity.4c We also found that when
derivatives of BINOL, such as the salen compounds 1 and 2 (Fig. 1)
were used in combination with ZnR2 (R = Et or Me) in the absence
of Ti(OiPr)4 and Cy2NH, high enantioselectivity could still be
achieved.5 However, the analogous salen compounds 3–5 that con-
tain chiral benzylic amine units rather than the cyclohexanedi-
amine unit of 1 or 2 were found to give poor enantioselectivity.5a
For the reaction of phenylacetylene with benzaldehyde in the pres-
ence of ZnEt2, compounds 3–5 gave enantioselectivities of 13%,
<10% and 17% ee respectively. In order to further explore BINOL-
based catalysts for the asymmetric alkyne addition to aldehydes,
we have synthesized several analogues of compounds 3–5 by pre-
paring BINOL-based Schiff bases from chiral benzylic amines.
When such compounds were used to catalyze the reaction of
phenylacetylene with aldehydes, significantly improved enantiose-
lectivity was achieved. Herein, these results are reported.
We first studied the use of compound 6 to catalyze the reaction
of phenylacetylene with benzaldehyde and the results are summa-
rized in Table 1. The reaction was carried out in two steps. In the
first step, phenylacetylene, ZnEt2 (1.0 M in hexane), and 6 were
stirred in a solvent at room temperature for 1 h. Next, the mixture
was cooled to 0 °C and benzaldehyde was added. The reaction was
stopped after 24 h. In entries 1–4, various solvents were examined
for this reaction. It can be seen that the use of nonpolar cyclohex-
ane as the solvent gave the highest enantioselectivity (entry 4).
Increasing the amount of phenylacetylene and ZnEt2 (entry 5)
enhanced both the yield and enantioselectivity to 83% and 85%
ee respectively. The configuration of the propargylic alcohol prod-
uct was determined to be (R) by comparing its specific rotation
with that in the literature.9 Increasing the concentration of the
reaction mixture led to a reduced yield and enantioselectivity (en-
try 6), while decreasing the concentration reduced the ee slightly
(entry 7). We also explored the effect of the reaction temperature
of the second step on this catalytic process. It was found that both
decreasing (entries 10–12) and increasing (entries 13 and 14) the
reaction temperature reduced enantioselectivity. We also found
that addition of a small amount of (R)-BINOL (entry 15) or (S)-BI-
NOL (entry 16) could greatly influence the reaction, giving much
lower or even opposite enantioselectivity. This indicates that BI-
NOL could significantly alter the catalyst structure, probably by
coordination to the Zn center.
2. Results and discussion
As shown in Scheme 1, we obtained Schiff bases 6–9 via con-
densation of (R)-3,30-diformyl-BINOL with several chiral benzylic
Compound 7 is a diastereomer of 6 with the same chiral BINOL
unit, but the opposite chiral amine configuration. When 7 was used
for this reaction, the enantioselectivity was very low (entry 17).
⇑
Corresponding authors.
E-mail addresses: wqw@cioc.ac.cn (Q. Wang), lp6n@virginia.edu (L. Pu).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.12.013

200
C. Chen et al. / Tetrahedron: Asymmetry 25 (2014) 199–201
(R)
(R)
N
N
(R)
(R)
N
N
OH
OH
HO
HO
(S)
(S)
OH
OH
HO
HO
(S)
(S)
N
N
(R)
(R)
1
Ph
2
Ph
Ph
(R)
(R)
Ph
Ph
(S)
Ph
N
N
(S)
(R)
(R)
N
N
N
N
OH
OH
HO
HO
(S)
(S)
OH
OH
HO
HO
OH
OH
HO
HO
(S)
(S)
(S)
(S)
N
N
(R)
Ph
(R)
3
4
Ph
5
Figure 1. BINOL-based chiral salens used for the asymmetric alkyne addition to aldehydes.
(S)
(S)
(S)
(R)
CHO
N
N
N
N
OH
OH
OH
OH
OH
OH
RNH2, MeOH
OH
OH
OH
OH
(R)
(R)
(R)
(R)
(R)
Δ
N
N
N
N
CHO
(S)
(R)
(S)
(S)
97%
96%
98%
97%
8
9
6
7
Scheme 1. Preparation of the BINOL-based Schiff bases 6–9.
Table 1
Results of the use of Schiff bases 6–9 in combination with ZnEt2 for the reaction of phenylacetylene with benzaldehydea
OH
1. chiral Schiff base
rt, 1 h
Ph
ZnEt2
Ph
+
2. PhCHO
Entry
Schiff base (equiv)
Phenylacetylene (equiv)
ZnEt2 (equiv)
Solvent (mL)
Temperature of 2nd step (°C)
Isolated yield (%)
eee (%)
1
2
3
4
5
6
7
8
6 (0.1)
6 (0.1)
6 (0.1)
6 (0.1)
6 (0.1)
6 (0.1)
6 (0.1)
6 (0.2)
6 (0.05)
6 (0.1)
6 (0.1)
6 (0.1)
6 (0.1)
6 (0.1)
6 (0.1)
6 (0.1)
7 (0.1)
8 (0.1)
8 (0.1)
8 (0.1)
9 (0.1)
2
2
2
2
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
2
2
2
2
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
THF (3)
CH2Cl2 (3)
Toluene (3)
0
0
0
0
0
0
0
0
0
ꢀ10
ꢀ20
ꢀ40
10
30
0
0
0
0
0
23
60
71
63
83
39
85
72
62
85
60
52
79
89
62
60
58
74
89
90
77
47
50
55
75
85
78
82
74
17
81
67
63
73
68
27
ꢀ19
27
75
75
75
55
Cyclohexane (3)
Cyclohexane (3)
Cyclohexane (2)
Cyclohexane (4)
Cyclohexane (3)
Cyclohexane (3)
Cyclohexane (3)
Cyclohexane (3)
Cyclohexane (3)
Cyclohexane (3)
Cyclohexane (3)
Cyclohexane (3)
Cyclohexane (3)
Cyclohexane (3)
Cyclohexane (3)
Cyclohexane (3)
Cyclohexane (3)
Cyclohexane (3)
9
10
11
12
13
14
15b
16c
17
18
19c
20c,d
21d
0
0
a
Phenylacetylene (0.5 or 1.0 mmol), ZnEt2 (0.5 or 1.0 mmol, 1.0 M in hexane), and a chiral Schiff base were mixed in a solvent at rt for 1 h. Benzaldehyde (0.25 mmol,
distilled and stored cold) was then added and stirred for 24 h.
b
Add 0.1 equiv (R)-BINOL.
Add 0.1 equiv (S)-BINOL.
Benzaldehyde was freshly distilled and used immediately.
Determined by HPLC equipped with a chiral column.
c
d
e

C. Chen et al. / Tetrahedron: Asymmetry 25 (2014) 199–201
201
3. (a) Trost, B. M.; Weiss, A. H. Adv. Synth. Catal. 2009, 351, 963–983; (b) Gao, G.;
Pu, L. Sci. China Chem. 2010, 53, 21–35.
This demonstrates that there is mismatched chirality between the
BINOL unit and the amino carbon centers in 7. In compound 8, its
conformation around the amino carbon centers is restricted with
the introduction of a cyclic structure. This reduced the enantiose-
lectivity with or without the use of the (S)-BINOL additive or the
freshly distilled benzaldehyde (entries 18–20). In compound 9, a
larger naphthyl substituent at each of the chiral amino carbons
was used to replace the phenyl substituent in 6. This compound
gave a lower enantioselectivity than 6 (entry 21).
Compound 6 contains only half of the structural units of the BI-
NOL-based macrocycle 5, but with the same relative chirality be-
tween the BINOL unit and the amino carbon centers. As shown in
entry 5 of Table 1, compound 6 gave good enantioselectivity for
the reaction of phenylacetylene with benzaldehyde in the presence
of ZnEt2. The greatly enhanced enantioselectivity of 6 over 5 and
the other BINOL-chiral benzylic amine-based Schiff bases 3 and 4
for this reaction prompted us to explore the reaction of other alde-
hydes catalyzed by 6. Figure 2 summarizes the results for the reac-
tion of phenylacetylene with various aromatic aldehydes using the
conditions in entry 5 of Table 1.10 All of these products were iso-
lated and their characterization data matched those previously
reported.4a,11 The configurations of the products were assigned
by analogous with the product of entry 5 of Table 1. The results
in Figure 2 show that various propargylic alcohols could be pre-
pared with encouraging results by using the easily prepared com-
pound 6 as a catalyst. Thus, the BINOL-based Schiff base represents
a promising class of catalyst for asymmetric alkyne addition to
aldehydes.
4. (a) Moore, D.; Pu, L. Org. Lett. 2002, 4, 1855–1857; (b) Gao, G.; Xie, R.-G.; Pu, L.
Proc. Natl. Acad. Sci. 2004, 101, 5417–5420; (c) Turlington, M.; Du, Y.-H.;
Ostrum, S. G.; Santosh, V.; Wren, K.; Lin, T.; Sabat, M.; Pu, L. J. Am. Chem. Soc.
2011, 133, 11780–11794; A review: (d) Turlington, M.; Pu, L. Synlett 2012, 649–
684.
5. (a) Li, Z.-B.; Pu, L. Org. Lett. 2004, 6, 1065–1068; (b) Li, Z.-B.; Liu, T.-D.; Pu, L. J.
Org. Chem. 2007, 72, 4340–4343.
6. Preparation and characterization of 6–9: In a round bottom flask equipped with
a reflux condenser, (R)-3,30-Diformyl-1,10-bi-2-naphthol (100 mg, 0.3 mmol)
was dissolved in MeOH (25 mL), and a chiral primary amine (0.6 mmol) was
then added. The mixture was heated and refluxed for 1–4 h. After the reaction
was completed, the solution was concentrated under vacuum and then filtered.
The solid product was washed with MeOH without further purification.
Compound 6: 97% yield. Mp 132–135 °C. 1H NMR (300 MHz, DMSO) d 13.33 (s,
2H), 8.97 (s, 2H), 8.26 (s, 2H), 7.97–8.00 (d, 2H, J = 8.0 Hz), 7.39–7.42 (m, 4H),
7.23–7.35 (m, 10H), 6.90 (d, 2H, J = 8.1 Hz), 4.74–4.78 (m, 2H), 1.57 (d, 6H,
J = 6.6 Hz). 13C NMR (75 MHz, CDCl3) d = 164.8, 154.3, 143.8, 134.7, 133.5,
129.0, 128.6, 128.3, 127.1, 127.0, 126.4, 124.1, 123.2, 120.7, 116.0, 67.4, 24.4.
½ ꢁ ¼ þ168:3 (c 1.0, CHCl3). HRMS(ESI) calcd for C38H32N2O2+H: 549.2537.
a 2D0
Found for MH+: 549.2522. Compound 7: 97% yield. Mp 134–138 °C. 1H NMR
(300 MHz, CDCl3) d 13.18 (s, 2H), 8.67 (s, 2H), 7.09–7.94 (m, 20H), 4.60 (d,
J = 6.7 Hz, 2H), d1.62 (d, J = 6.7 Hz, 6H). 13C NMR (75 MHz, CDCl3) d 163.6,
154.6, 143.3, 135.3, 133.5, 128.8, 128.6, 128.3, 127.5, 127.3, 126.7, 124.8, 123.3,
121.1, 116.6, 68.9, 24.7. ½ ꢁ ¼ ꢀ20 (c 1.0, CHCl3). HRMS(ESI) calcd for
a 2D0
C
38H32N2O2+H: 549.2537. Found for MH+: 549.2522. Compound 8: 96% yield.
Mp170–172 °C. 1H NMR (300 MHz, DMSO) d 13.20 (s, 2H), 8.98 (s, 2H), 8.25 (s,
2H), 7.97–8.00 (m, 2H), 7.28–7.31 (m, 4H), 7.10–7.15 (m, 8H), 6.91–6.94 (m,
2H), 4.64–4.65 (m, 2H), 1.98–2.03 (m, 2H), 1.87–1.91 (m, 4H), 1.74–1.77 (m,
2H). 13C NMR (75 MHz, CDCl3) d 165.6, 156.0, 137.8, 137.1, 136.3, 134.4, 130.0,
129.8, 128.8, 128.5, 128.0, 126.8, 125.5, 124.0, 123.9, 122.2, 117.6, 67.6, 32.0,
29.8, 20.3. ½a 2D0
¼ þ36:6 (c 1.0, CHCl3). HRMS(ESI) calcd for C42H36N2O2+H:
ꢁ
601.2852. Found for MH+: 601.2852. Compound 9: 98% yield. Mp >184.1 °C. 1
H
NMR (300 MHz, DMSO) d 13.32 (s, 2H), 10.36 (s, 2H), 8.26-8.29 (m, 4H), 7.95–
7.98 (m, 4H), 7.83–7.86 (d, 2H, J = 8.2 Hz), 7.46–7.61 (m, 8H), 7.32–7.35 (m,
4H), 7.02 (s, 2H), 5.60–5.66 (m, 2H), 1.67–1.69 (d, 6H, J = 6.5 Hz). 13C NMR
(75 MHz, CDCl3) d 164.1, 154.7, 138.9, 135.3, 133.9, 133.7, 130.5, 130.0, 129.1,
128.8, 128.4, 127.8, 127.6, 126.2, 125.7, 125.5, 124.8, 124.3, 123.3, 123.0, 121.1,
116.6, 63.8, 24.2. HRMS(ESI) calcd for C46H36N2O2+H: 649.2850. Found for
OH
OH
OH
OH
MH+649.2856. ½a 2D0
¼ þ328:4 (c 1.0, CHCl3).
ꢁ
Ph
Ph
Ph
Ph
7. Deberardinis, A. M.; Turlington, M.; Ko, J.; Sole, L.; Pu, L. J. Org. Chem. 2010, 75,
2836–2850.
(R)
8. Brunner, H.; Goldbrunner, J. Chem. Ber. 1989, 122, 2005–2009.
9. (a) Corey, E. J.; Cimprich, K. A. J. Am. Chem. Soc. 1994, 116, 3151–3152; (b)
Tombo, G. M. R.; Didier, E.; Loubinoux, B. Synlett 1990, 547–548.
10. General procedure for the addition of phenylacetylene to aldehydes catalyzed
77%, 71% ee
79%, 81% ee
76%, 77% ee
83%, 85% ee
OH
CF3
OH
OH
OH
by 6. Under nitrogen, phenylacetylene (1.0 mmol, 110 lL) and 6 (0.025 mmol)
Br
Ph
Ph
Ph
Br
OMe
Ph
were mixed in dry cyclohexane (3 mL) in a 25 mL flask at room temperature.
Next, a solution of diethylzinc (1.0 M in hexane, 1 mL) was added. After the
mixture was stirred at room temperature for 1 h, the yellow solution was
cooled to 0 °C to which was added an aldehyde (0.25 mmol) and stirred for
24 h. The reaction was then quenched with saturated NH4Cl solution and
extracted with ethyl acetate. The organic layer was washed with brine, dried
over Na2SO4, and concentrated under vacuum. The residue was purified by
flash column chromatography on silica gel eluted with EtOAc/petroleum ether
(1:15) to give the product. The enantiomeric excess (ee) was determined by
HPLC analysis using a chiral stationary phase (Daicel Chiralcel OD-H, Daicel
Chiralcel AD-H), eluting with i-PrOH–hexanes or EtOH–hexanes, and using UV
detection at 254 nm.
S
79%, 81% ee
88%, 70% ee
90%, 70% ee
60%, 77% ee*
Figure 2. Propargylic alcohols prepared from the reaction of phenylacetylene with
various aldehydes in the presence of 6 and ZnEt2. ⁄A mixed solvent of cyclohexane/
Et2O (11:1) was used.
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