Asymmetric addition of diethylzinc to ketones promoted by tartaric acid derivatives

Article abstract of DOI:10.1080/00397910802139304

The preparation of new sulfonamide ligands derived from L-tartaric acid and camphor sulfonyl chloride are described. The employment in the titanium tetraisopropoxide-promoted enantioselective addition of diethylzinc to ketones has been studied. The best enantiomeric excess is up to 99% with 7 mol% catalyst loading at room temperature. Copyright Taylor & Francis Group, LLC.

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Asymmetric Addition of
Diethylzinc to Ketones
promoted by Tartaric Acid
Derivatives
Ailing Hui a , Jintang Zhang b & Zhiyong Wang b
a Engineering Research Center of Bio-process, Hefei
University of Techonology, Ministry of Education,
Hefei, China
b Department of Chemistry, University of Science
and Technology of China, Hefei, China
Version of record first published: 11 Jul 2008.
To cite this article: Ailing Hui, Jintang Zhang & Zhiyong Wang (2008): Asymmetric
Addition of Diethylzinc to Ketones promoted by Tartaric Acid Derivatives, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 38:14, 2374-2384
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Synthetic Communications1, 38: 2374–2384, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802139304
Asymmetric Addition of Diethylzinc to Ketones
promoted by Tartaric Acid Derivatives
Ailing Hui,1 Jintang Zhang,2 and Zhiyong Wang2
1Engineering Research Center of Bio-process, Hefei University of Techonology,
Ministry of Education, Hefei, China
2Department of Chemistry, University of Science and Technology of China,
Hefei, China
Abstract: The preparation of new sulfonamide ligands derived from L-tartaric
acid and camphor sulfonyl chloride are described. The employment in the
titanium tetraisopropoxide-promoted enantioselective addition of diethylzinc to
ketones has been studied. The best enantiomeric excess is up to 99% with 7 mol%
catalyst loading at room temperature.
Keywords: Asymmetric addition; Diethylzinc; Ketone; Sulfonamide; Tartaric acid
INTRODUCTION
The synthesis of chiral building blocks containing a quaternary stereo-
genic carbon center[1] is a considerable challenge in organic synthesis,
mainly because of steric factors. The enantioselective addition of organo-
metallic reagents to ketones is probably the most straightforward and
useful method for achieving this goal. Among these organometallics, dia-
lkylzinc reagents are ideal alkyl nucleophile synthons because it is poss-
ible to prepare many different functionalized reagents, due to their low
reactivity.[2] On the other hand, this low reactivity resulted in the dif-
ficulty for the adding dialkylzinc reagents to ketones. Therefore the
new catalyst is crucial for this addition reaction. However, as far as
we know, only a few chiral catalysts have been developed to promote
Received April 19, 2007
Address correspondence to Zhiyong Wang, Department of Chemistry, Univer-
sity of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026,
China. E-mail: zwang3@ustc.edu.cn
2374

Asymmetric Addition of Diethylzinc to Ketones
2375
Figure 1. Typical chiral promoters for the asymmetric addition of alkyls or phe-
nyl to ketones.
the asymmetric addition of diarylzinc or dialkylzinc reagents to ketones.
In 1998, Dosa and Fu[3] reported the first catalytic asymmetric addition
of phenyl groups to ketones. They employed 15 mol% of Noyori’s amino
alcohol ligand 3-exo-(dimethylamino)isoborneol (DAIB) (compound 1 in
Fig. 1) as an effective catalyst, obtaining a new quarternary stereocenter
ꢀ
in good to excellent enantioselectivity. In the same year, Ramon and
Yus[4] reported the first example of enantioselective addition of alkyl
groups to ketones. They employed hydroxysulfonamide ligand (com-
pound 2 in Fig. 1) in combination with titanium tetraisopropoxide to per-
form the asymmetric addition and realized enantioselectivities from 16%
to 89% with good yields. However, the catalyst reactivity was very low;
20 mol% of catalyst loading was required, and the reaction time was
between 4 and 14 days for consumption of the substrate. Afterward,
[5]
Garcıa et al. and Yus et al.[6,7] independently synthesized trans-1,
3 in
´
2-bis-(hydroxyl-camphor-sulfonamide)-cyclohexane (compound
Fig. 1), which was also successfully used in the addition of diphenylzinc
to ketones.[8,9] Recent studies showed the ligands with C2-symmetrical
axes could catalyze this asymmetric addition to efficiently afford quatern-
ary stereogenic carbon center.[5–15] Taking the advantage of the chirality
of L-tartaric acid, we[15] designed and synthesized a sereies of ligands with
C2-symmetrical axes, as shown in Schemes 1 and 2. These ligands were
employed as promoters in the addition of diethylzinc to ketones, and sat-
isfactory yields and ee values were obtained.
RESULTS AND DISCUSSION
The synthesis of these new catalysts is described here. Initially, L-tartaric
acid was reacted with benzyl amine to generate amide 4, which was
reduced in the presence of lithium alumina hydride to obtain diol 5.
The benzyl group in compound 5 was replaced with tert-butoxycarbonyl

2376
A. Hui, J. Zhang, and Z. Wang
Scheme 1. Synthesis of chiral ligand 12 and ligand 13.
group in compound 7 via hydrogenation and the protection. Then the
diol 7 was mesylated with methanesulfonyl chloride in triethyl amine to
furnish the bis(mesylates) 8. Subsequently, double nucleophilic substi-
tution with sodium azide in N, N-dimethyl formamide (DMF) yielded
the bis(azides) 9. After deprotection of the amino group with trifluoroa-
cetic acid and hydrogenation under Pd=C, compound 9 was converted
Scheme 2. Synthesis of chiral ligand 17 and ligand 18.

Asymmetric Addition of Diethylzinc to Ketones
2377
into amine 11.[16] Ligand 12[17] was obtained when compound 11 reacted
with camphor sulfonyl chloride. The same method was used for the syn-
thesis of ligand 17, as shown in Scheme 2.
Our initial experiments in the asymmetric addition of diethylzinc to
p-chloro acetophenone involved the use of ligand 12 and ligand 17.
Under the condition, the reaction was carried out slowly, giving the
desired tertiary alcohol with the enantioselectivity of less than 40%
(entries 1 and 2 in Table 1). These results inspired us to modify the ligand
further. It was assumed that catalytic reactivity could be enhanced by
constraining the geometry of the ligand, which would result in a more
open binding site. Therefore compounds 12 and 17 were reduced with
NaBH4 to generate diastereomers. The major products 13 and 18 were
isolated by chromatography on silica gel.[5] By employing ligand 13 or
18 in the asymmetric addition of diethylzinc to p-chloro acetophenone,
the enantioselectivity was obviously enhanced, giving 80% ee and 73%
ee respectively (entries 3 and 4 in Table 1). These results indicated the
importance of the hydroxyl group in the catalytic process. Next, the reac-
tion was performed in hexane; the reaction yield and the enantiomeric
excess decreased a little (entry 5 vs. entry 3, entry 6 vs. entry 4 in
Table 1. Optimization of the reaction condition
Entry
Lꢀ (mol%)
Solvent
T (ꢁC)
Yield (%)a=Time (h)
Ee (%)b
1
2
3
4
5
6
7
8
12 (5)
17 (5)
13 (5)
18 (5)
13 (5)
18 (5)
13 (10)
18 (10)
13 (15)
13 (7)
13 (7)
13 (7)
13 (7)
Toluene
Toluene
Toluene
Toluene
Hexane
Hexane
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
10
10
10
10
10
10
10
10
10
10
35
60
0
60=48
46=50
72=48
50=60
63=48
48=60
76=48
51=60
75=48
75=48
76=48
65=48
67=60
38
30
80
73
75
63
85
72
84
85
82
74
80
9
10
11
12
13
aIsolated yields.
bThe enantiomeric excess was determined by chiral HPLC using OJ-H column.

2378
A. Hui, J. Zhang, and Z. Wang
Table 1). Increasing the amount of the ligand 13 helped improve the
enantiomeric excess, which was up to 85% (entry 7 vs. entry 3 in Table
1). However, the enantioselectivity decreased a little for ligand 18 (entry
8 vs. entry 4 in Table 1). So, ligand 13 was selected as the model catalyst
(entries 9 and 10 in Table 1). Subsequently, the temperature effect was
also studied. Elevating or reducing temperature was a disadvantage to
the enantioselectivity (entries 11–13 in Table 1). At last, the condition
of entry 10 was selected as the optimal option. To extend the scope of
the reaction substrate, the effect of different ketones on the enantioselec-
tivity was studied. All the experimental results are listed in Table 2.
As shown in Table 2, acetophenone was the best substrate for this
catalyst, which gave excellent enantioselectivity (99% ee, entry 1 in Table
2). Electron-withdrawing substituents at the para-position of acetophe-
none favored both enantioselectivity and reaction yield, with the enantio-
meric excess ranged from 75% to 85% (entries 2, 3, and 4 in Table 2),
while electron-donating substituents at the para-position of acetophenone
Table 2. Asymmetric addition of ethyl groups to ketones
Entry
R
Yield (%)a=Time (h)
Ee (%) (config.)b
1
2
3
4
5
6
7
8
9c
10c
11
12
13
C6H5
4-FC6H4
4-ClC6H4
75=50
81=40
75=48
65=64
45=50
65=30
48=60
35=60
—
99 (S)
83
85
75 (S)
30
54
20
12
—
—
4-BrC6H4
4-MeC6H4
4-PhC6H4
4-MeOC6H4
2-ClC6H4
2-MeC6H4
3-MeC6H4
2-Furan
—
68=70
70=70
83=40
22
36
86
2-Thiophene
2-Naphthyl
aIsolated yields.
bThe enantiomeric excess was determined by chiral HPLC using OD-H or OJ-
H column and the configuration was determined by comparision of specific rota-
tions with literature data.
cNo desired product was detected.

Asymmetric Addition of Diethylzinc to Ketones
2379
did not favor either reaction yield or enantioselectivity (entries 5, 6, and 7
in Table 2). The substituents at the ortho-position or meta-position were
negative to the yield and the enantioselectivity. 2-Chloro acetophenone
gave a lower yield and poor enantioselectivity (entry 8 in Table 2). No
desired product was detected when 2-methyl or 3-methyl acetophenone
were introduced in the addition reaction (entries 9 and 10 in Table 2).
This phenomena was ascribed to the steric repulsion of the substituent
(Cl, Me) located in ortho-position or meta-position and the ethyl group.
As a result, the ethyl nucleophile can hardly approach the carbon atom of
carbonyl. In addition, we also investigated ketones containing heteroaro-
matic groups in the asymmetric addition reaction, such as 2-acetyl furan
and 2-acetyl thiophene, which generated the corresponding products with
low enantioselectivities and moderate yields under the condition (entries
11 and 12 in Table 2). This result may stem from the binding of the het-
eroatom (O, S) in the substrate with the Ti center. In fact, only the coor-
dination of the oxygen atom in carbonyl and the center of titanium were
positive to enantioselectivity. Therefore, the reactivity of the chiral ligand
was weakened to a certain extend. Poor enantioselectivity was obtained
in these substrates (entries 7, 11, and 12 in Table 2). It was noted that
substrate 2-acetyl naphthalene, which has more steric hindrance than
other ketones, gave excellent enantioselectivity in this addition reaction
(entry 13 in Table 2).
CONCLUSIONS
In summary, a new ligand 13 derived from L-tartaric acid was designed
and synthesized, which is efficient to catalyze the asymmetric addition
of diethylzinc to ketones. Moreover, the reaction condition is mild and
the catalyst loading is only 7 mol%. Further modification in the ligand
is currently under investigation.
EXPERIMENTAL
Unless other indicated, all reactions using diethylzinc and titanium tetra-
isopropoxide were carried out in dry glassware under nitrogen. Hexane,
tetrahydrofuran, and toluene were freshly distilled from sodium and ben-
zophenone. Dichloromethane was freshly distilled from CaH2. Titanium
tetraisopropoxide was freshly distilled under reduced pressure. Triethyla-
˚
mine was distilled and stored in 4 A MS. Diethylzinc solution was 1.5 M
in hexane and used directly. Reactions were monitored by thin-layer
chromatography (TLC) analysis. 1H NMR and 13C NMR were recorded
on a Bruker AC-300 FT (1H: 300 MHz, 13C: 75.5 MHz) or AC-400 FT

2380
A. Hui, J. Zhang, and Z. Wang
(1H: 400 MHz, 13C: 100 MHz) using TMS as internal reference. The
chemical shifts (d) and coupling constants (J) were expressed in (parts
per million) and hertz respectively. IR spectra were recorded on a Per-
kin-Elmer 2000 Fourier-transform infrared (FTIR). High-resolution
mass spectra (HRMS) were obtained on GCT-time of flight (TOF)
spectrometer. The optical rotations were measured on WZZ-2 polar-
imeter. Chiral HPLC was performed in an Agilent 1100 series instrument
equipped with a diode array detector. Chiralcel OD-H column and
Chiralcel OJ-H column were purchased from Daicel Chemical Industries
with 0.46 cm U ꢂ 25 cm. Rention times (t) for HPLC are given in minutes.
Preparation and Characterization of Chiral Ligands
The synthesis of chiral ligands was referred from the literature.[16,17]
Spectral and physical data for compound 12: Yellow solid; mp 115–
117 ꢁC; [a]D þ 32.0 (c 1.0, CHCl3); IR (KBr): 3438, 3288, 2961, 1743,
25
1
1147 cmꢃ1; H NMR (400 MHz, CDCl3): d ¼ 0.87 (s, 3H), 0.92 (s, 6H),
1.03 (s, 6H), 1.07 (s, 3H), 1.43–1.46, 1.65–2.04, 2.12–2.42 (3 m, 3H,
12H, 6H respectively), 2.90 (d, J ¼ 14.9 Hz, 1H), 3.00 (d, J ¼ 15.1 Hz,
2H), 3.41–3.43 (m, 2H), 3.48 (d, J ¼ 14.9 Hz, 1H), 3.56 (d, J ¼ 15.1 Hz,
2H), 3.96–3.99 (m, 2H), 4.18–4.20 (m, 2H), 5.82 (d, J ¼ 5.0 Hz, 2H)
ppm; 13C NMR (100 MHz, CDCl3): d ¼ 19.52, 19.70, 19.78, 19.83,
25.21, 25.95, 27.01, 42.72, 42.78, 42.83, 46.74, 48.56, 48.77, 50.11,
50.66, 58.13, 58.41, 58.94, 216.16, 216.44 ppm.
Spectral and physical data for compound 13: White foam solid; mp
125–127ꢁC; [a]D ꢃ52.7 (c 0.5, CHCl3); IR (KBr): 3534, 3280, 2957,
25
1
1142cmꢃ1; H NMR (400MHz, CDCl3): d ¼ 0.85 (s, 9H), 1.07 (s, 9H),
1.10–1.15 1.42–1.48, 1.74–1.80 (3 m, 3H, 3H, 15H respectively), 2.83
(d, J ¼ 12.3 Hz, 1H), 2.97 (d, J ¼ 13.3 Hz, 2H), 2.82–3.00 (br, 3H), 3.30
(br, 2H), 3.44 (d, J ¼ 12.3 Hz, 1H), 3.59 (d, J ¼ 13.4 Hz, 2H), 3.87 (m,
2H,), 4.03–4.08 (m, 5H), 5.75 (d, J ¼ 5.9 Hz, 2H) ppm; 13C NMR
(100MHz, CDCl3): d ¼ 19.99, 20.07, 20.62, 20.71, 27.42, 30.52, 39.56,
39.67, 44.49, 49.03, 49.07, 50.19, 50.42, 50.62, 53.83, 57.55, 76.28,
76.44 ppm; m=z (HPLC-ESI=MS) 748 (M-H)ꢃ . Anal. calcd. for
C34H59N3O9S3: C, 54.45; H, 7.93; N, 5.60. Found: C, 54.53; H, 7.90; N, 5.53.
Spectral and physical data for compound 17: colorless solid; mp 57–
59ꢁC; [a]D þ 11.30 (c 0.5 CHCl3); IR (KBr): 3448, 3299, 2960, 1742,
28
1
1329, 1147 cmꢃ1; H NMR (300 MHz, CDCl3): d ¼ 0.86 (s, 6H), 1.01
(s, 6H), 1.42–1.48, 1.88–2.39 (2 m, 2H and 12H respectively), 2.58 (m,
2H), 2.97 (d, J ¼ 15.2 Hz, 2H), 3.10 (m, 2H), 3.49 (d, J ¼ 15.2 Hz, 2H),
3.64–3.67 (m, 2H), 3.98 (m, 2H), 5.55 (br, 2H), 7.26–7.31 (m, 5H) ppm;
13C NMR (75.5 MHz, CDCl3): d ¼ 19.61, 19.90, 26.38, 27.07, 42.89,

Asymmetric Addition of Diethylzinc to Ketones
2381
42.93, 48.68, 50.46, 58.52, 59.09, 59.72, 59.85, 127.30, 128.43, 128.81,
137.96, 216.31 ppm.
Spectral and physical data for compound 18: yellow foam solid;
28
[a]D
ꢃ44.0 (c 0.5 CHCl3); IR (KBr): 3532, 3276, 2956, 1320,
1143 cmꢃ1; H NMR (400 MHz, CDCl3): d ¼ 0.82 (s, 6H), 1.05 (s, 6H),
1.10–1.13, 1.44–1.49, 1.71–1.80 (3 m, 2H, 2H, 10H respectively), 2.53
(dd, J ¼ 5.4 Hz, 9.9 Hz, 2H), 2.92 (d, J ¼ 13.8 Hz, 2H), 3.04 (dd,
J ¼ 6.8 Hz, 9.9 Hz, 2H), 3.23 (br, 2H), 3.53 (d, J ¼ 13.8 Hz, 2H), 3.63
(m, 2H), 3.87 (m, 2H), 4.06 (m, 2H), 5.13 (d, J ¼ 3.2 Hz, 2H), 7.26–
7.34 (m, 5H) ppm; 13C NMR (100 MHz, CDCl3): d ¼ 19.96, 20.59,
27.41, 30.55, 39.33, 44.48, 48.89, 50.53, 53.44, 58.89, 59.63, 59.79,
76.43, 127.56, 128.55, 128.90, 137.37 ppm. Anal. calcd for C31H49N3O6S2:
C, 59.68; H, 7.92; N, 6.74. Found: C, 59.74; H, 7.93; N, 6.70.
1
General Procedure for Enantioselective Addition of Diethylzinc
to Ketones
Ligand 13 (27 mg, 0.035 mmol, 0.07 equiv.) and Ti(OiPr)4 (175 mg,
0.6 mmol, 1.2 equiv.) were dissolved in toluene (2.5 ml) under nitrogen.
The resulting mixture was stirred for 2 min at room temperature
(10ꢁC). Diethylzinc solution (0.6 ml, 0.9 mmol, 1.8 equiv.) was added
to the flask, and the color of solution became orange-green. After
2 min, the corresponding ketone (0.5 mmol, 1.0 equiv., dissolved in
0.5 ml of toluene or diluted with 0.5 ml of toluene) was added at this
temperature. The reaction was stirred for the appointed time in Table
2 until it was quenched with diluted hydrochloric acid. The resulting
mixture was filtered through silica gel and extracted with ethyl acetate
(3 ꢂ 10 ml), and the organic layer was dried over anhydrous Na2SO4.
The solvent was removed under reduced pressure, and the residue
was purified by flash-chromatography column to afford the
expected tert-alcohol. The enantiomeric excess was determined by
chiral HPLC.
Data
All the spectral data of tert-alcohol were listed in the experiment section
of another article.[15]
2-(2-Chloro-phenlyl)-butan-2-ol (entry 8 in Table 2): colorless oil,
ꢃ0.6 (c 2.0, acetone); IR (film): 3435, 2972, 1162 cmꢃ1
;
1H
25
[a]D
NMR (300 MHz, CDCl3): d ¼ 0.78 (t, J ¼ 7.4 Hz, 3H), 1.69 (s, 3H),
1.92–1.99 (m, 1H), 2.23–2.33 (m, 2H), 7.17–7.36 (m, 3H), 7.66–7.69 (m,
1H) ppm; 13C NMR (75.5 MHz, CDCl3): d ¼ 8.49, 27.61, 33.56, 75.85,

2382
A. Hui, J. Zhang, and Z. Wang
126.85, 128.22, 131.09, 131.39, 143.81 ppm; HRMS calcd. for C10H13ClO
184.0655; found 184.0653. Chiral OD-H column: hexane=
isopropanol ¼ 98:2 (v=v), flow rate ¼ 0.4 ml=min, 260 nm, 25ꢁC,
t1 ¼ 18.2 min, t2 ¼ 20.3 min.
ACKNOWLEDGMENTS
We are grateful to the National Nature Science Foundation of China
(Nos. 20472078 and 30572234) for its support of this study.
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