Highly Enantioselective Addition of Phenylacetylene to Aldehydes Catalyzed by a β-Sulfonamide Alcohol-Titanium Complex

Article abstract of DOI:10.1002/anie.200352572

Three simple steps were required to prepare the β-sulfonamide alcohol ligand (L*) from L-phenylalanine. Its titanium complex efficiently catalyzes the asymmetric addition of phenylacetylene (2) to aromatic aldehydes 1 to form enantiomerically pure proparg

Full text of DOI:10.1002/anie.200352572

Angewandte
Chemie
Asymmetric Additions
Highly Enantioselective Addition of
Phenylacetylene to Aldehydes Catalyzed by a
b-Sulfonamide Alcohol–Titanium Complex**
Zhaoqing Xu, Rui Wang,* Jiangke Xu, Chao-shan Da,
Wen-jin Yan, and Chao Chen
The enantioselective formation of CÀC bonds is an area of
[
1,2]
intense research.
The asymmetric addition of alkynyl
reagents to aldehydes is very useful for the synthesis of
chiral secondary propargyl alcohols, which are important
[
3]
building blocks for many chiral organic compounds. Several
studies into the alkynylation of aldehydes with amino alcohol
ligands have led to methods that give moderate to good yields
[
4]
and enantioselectivities. Carreira and co-workers reported
the addition of terminal acetylenes to aliphatic aldehydes in
the presence of stoichiometric or catalytic amounts of amino
alcohol 1 to give the desired products in high yields and
enantioselectivities. However, this method was not suitable
for the addition reaction to aromatic aldehydes because of
[
5]
significant competition from the Cannizzaro reaction.
Recently, Chan and co-workers reported that binol (2) can
catalyze the addition of alkynyl zinc reagents to aromatic
aldehydes with high ee values. However, the reaction also
requires 1 equivalent of a sulfonamide ligand and must be run
[
6]
at 08C for 1–2 days. Pu and co-workers reported that a
[*] Prof. R. Wang
Department of Biochemistry and Molecular Biology
School of Life Science, Lanzhou University
and
State Key Laboratory for Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics
Chinese Academy of Sciences
Lanzhou 730000 (China)
Fax: (+86)931-891-2561
E-mail: wangrui@lzu.edu.cn
Dr. Z. Xu, J. Xu, C.-s. Da, W.-j. Yan, C. Chen
Department of Biochemistry and Molecular Biology
School of Life Science, Lanzhou University
Lanzhou 730000 (China)
[
**] This work was supported by the National Natural Science
Foundation of China, the Ministry of Science and Technology of
China, the Teaching and Research Award Program for Outstanding
Young Teachers, the Specialized Research Fund for the Doctoral
Program in Higher Education Institutions, and the Key Research
Program of Science and Technology of the Ministry of Education of
China.
Angew. Chem. Int. Ed. 2003, 42, 5747 –5749
DOI: 10.1002/anie.200352572
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5747

Communications
binol–Ti complex can also catalyze this reaction, but this
method requires a separate step for the preparation of the
Table 1: Asymmetric addition of phenylacetylene to benzaldehyde with
[
a]
6
a or 6b as ligands.
[
7]
alkynyl zinc reagent at high temperatures for 5 h. Thus there
is a growing need to find an inexpensive and novel catalyst for
the asymmetric addition of terminal acetylenes to aromatic
aldehydes; the reaction should be fast, occur in a single step
under mild and convenient conditions, and should also lead to
has ee values.
[
b]
[c]
Entry Ligand [mol%] Ligand/Ti(OiPr)4
Solvent
T
ee [%]
1
2
3
4
5
6
7
8
9
10
6a
6b
6b
6b
6b
6b
6b
6b
6b
6b
6b
10
10
10
10
10
10
10
10
15
20
20
1:3
1:3
1:1
1:2
1:4
1:5
1:3
1:3
1:3
1:3
1:3
toluene RT
toluene RT
toluene RT
toluene RT
toluene RT
toluene RT
10
90
11
88
85
78
4
The N-H group of sulfonamides is acidic owing to the
highly electron-withdrawing nature of the sulfonyl group.
Therefore, unlike traditional metal amides (M-NR ), the
2
sulfonamide nitrogen atom is a poor electron donor and
CH Cl
RT
RT
2
2
[
8]
sulfonamide–Ti complexes are Lewis acids. Aminoalcohols
derived from natural amino acids are among the best and
THF
6
toluene RT
toluene RT
toluene 08C
93
95
95
[
9]
most economical ligands available. We therefore decided to
prepare a few b-sulfonamide alcohols 6 (Scheme 1). As a
result of the acidic N-H and O-H groups, a titanium complex
11
[
a] Phenylacetylene/Et Zn/benzaldehyde=3:3:1.
freshly distilled. [c] The enantiomeric excess was determined by HPLC
analysis of the corresponding products on a Chiralcel OJ-H column.
[b] Ti(OiPr)4
was
2
is readily formed when combined with Ti(OiPr) under basic
4
[
10]
conditions. These complexes behave similarly to binol–Ti
complexes, and we therefore applied them in the enantio-
selective addition of phenylacetylene to aldehydes.
Table 2: Asymmetric addition phenylacetylene to aromatic aldehydes
[
a]
Three simple steps were required to prepare 6a and 6b
from l-phenylalanine in overall yields of 67% and 62%,
respectively (Scheme 1). The two ligands were initially tested
promoted by ligand 6b.
[b]
Entry
Aldehyde
t [h]
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
benzaldehyde
3-tolualdehyde
4-tolualdehyde
3-anisaldehyde
12
12
12
12
14
12
12
18
18
92
89
90
88
91
80
87
70
71
95
92
93
90
92
98
93
90
95
4-anisaldehyde
4-chlorobenzaldehyde
4-fluorohenzaldehyde
a-naphthaldehyde
b-naphthaldehyde
[
a] Et Zn/phenylacetylene/aldehyde/Ti(OiPr) /6b=3:3:1:0.6:0.2. All the
2
4
Scheme 1. Preparation of sulfonamide from l-phenylalanine. a) NaOH
reactions were processed under argon and at room temperature.
Ti(OiPr) was fresh distilled before use. [d] The ee values were
determined by chiral HPLC on a Chiracel OJ-H column.
(
(
(
2 equiv), H O, TsCl (1 equiv), Et O, room temperature, 24 h; b) SOCl
2
1.2 equiv), MeOH, À308C, 30 min; then reflux, 2 h; c) RMgBr
5 equiv), THF, room temperature, 24 h. Ts=p-toluenesulfonyl.
4
2
2
In conclusion, we successfully prepared two b-sulfon-
amide alcohol ligands from natural l-phenylalanine in three
steps in good yields. Ligand 6b exhibits excellent catalytic
activity in the enantioselective addition of phenylacetylene to
aromatic aldehydes under very mild conditions.
in the asymmetric addition of phenylacetylene to benzalde-
hyde in the presence of diethylzinc (Table 1). Interestingly,
6
a, which has the bulkier, less-flexible phenyl substituents at
the hydroxy-bearing carbon atom, resulted in a lower
enantioselectivity (Table 1, entry 1) than 6b, which has the
more-flexible ethyl substituents (Table 1, entry 2). We varied
the amount of Ti(OiPr)4 and found that the best ee are Experimental Section
obtained when the 6b/Ti(OiPr)4 ratio is 1:3 (Table 1,
entries 2–6). We also found that this reaction was strongly
influenced by the solvent: Low enantioselectivities were
found in CH Cl and THF (Table 1, entries 7 and 8). When
the amount of ligand increased from 10% to 15 and 20%, the
ee values improved slightly (Table 1, entries 9 and 10). No
significant changes in ee values were observed when the
temperature of the reaction was decreased from room
temperature to 08C (Table 1, entry 11).
All manipulations were carried out under an argon atmosphere in
dried and degassed solvent. b-Sulfonamide alcohols 6a and 6b were
[
12]
synthesized according to literature procedures.
S)-6a. White needles (67% yield); m.p. 122–1238C; [a]D = + 105
2
0
(
2
2
(
1
c = 0.121 in CHCl ); IR (KBr): n˜ = 3528, 3303, 3066, 3028, 2926, 1660,
3
À1
598, 1493, 1448, 1324, 1153, 1087, 968, 908, 811, 740, 700 cm
;
1
H NMR (200 MHz, CDCl , TMS): d = 2.37 (s, 3H; CH ), 2.53 ( s, 1H;
3
3
3
2
OH), 2.86 (dd, J(H-H) = 6.0, J(H-H) = 14.2 Hz, 1H; PhCH H ),
3.27 (dd, J(H-H) = 3.6 Hz, J(H-H) = 14.2 Hz, 1H; PhCH H ), 4.69
A
B
3
2
A B
3
(m, 1H; CHN), 4.86 (d, J(H-H) = 8.2 Hz, 1H; NH), 6.96–7.52 ppm
À
(m, 19H; 4 ” Ph-H); MS(E SI ): m/z: 456[M À H] .
Under these optimized reaction conditions, ligand 6b was
employed to induce the enantioselective addition of phenyl-
2
D
0
(
S)-6b. White needles (62% yield); m.p. 95–968C; [a] = À 39
(c = 0.102 in CHCl ); IR(KBr): n˜ = 3512, 3287, 3066, 3028, 2969, 2882,
3
[
11]
acetylene to a number of aromatic aldehydes, all of which
gave rise to products with high enantioselectivity (up to
À1
1
648, 1599, 1457, 1321, 1152, 1086, 960, 908, 812, 736, 698 cm
;
1
H NMR (200 MHz, CDCl , TMS): d = 0.84–0.95 (m, 6H; CH ), 1.43–
3
3
9
8% ee; Table 2).
1.75 (m, 4H; CH Me), 2.01 (s, 1H; OH), 2.37 (s, 3H; PhCH ), 2.48
2
3
5
748
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Angew. Chem. Int. Ed. 2003, 42, 5747 –5749

Angewandte
Chemie
3
2
(
dd, J(H-H) = 9.2 Hz, J(H-H) = 14.2 Hz, 1H; PhCH H ), 2.94 (dd,
A B
3
2
J(H-H) = 6.2 Hz, J(H-H) = 14.2 Hz, 1H; PhCH H ), 4.65 (m, 1H;
A
B
CHN), 4.75 (s, 1H; NH), 6.93–7.40 ppm (m, 9H; 2 ” Ph-H); MS(ESI):
À
m/z: 360 [M À H] .
General addition procedure: Under argon, the ligand 6b (18 mg,
0
.05 mmol) and Ti(OiPr) (41.2 mL, 0.15 mmol) were mixed in dry
4
toluene at room temperature. A solution of Et Zn (1.0m in toluene,
2
0
.75 mL) was then added. After the mixture was stirred at the room
temperature for 2 h, phenylacetylene (82.4 mL, 0.75 mmol) was added
and the stirring continued for 1 h. The orange solution was cooled to
0
8C and treated with aldehyde (0.25 mmol). The resulting mixture
was allowed to warm to room temperature and stirred for 12–18 h.
After the reaction was complete (monitoring with TLC), it was cooled
to 08C and quenched with aqueous HCl (5%). The mixture was
extracted with diethyl ether. The organic layer was washed with brine,
dried over Na SO , and concentrated under vacuum. The residue was
2
4
purified by flash column chromatography (silica gel, 12.5% EtOAc in
hexane) to give the product.
Received: August 5, 2003 [Z52572]
Keywords: addition · aldehydes · alkynes · asymmetric catalysis ·
.
sulfonamides
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[
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phenylacetylene to two aliphatic aldehydes: isobutylaldehyde
and cyclohexanecarboxaldehyde. The enantioselectivities were
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Angew. Chem. Int. Ed. 2003, 42, 5747 –5749
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ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5749