The first catalytic asymmetric addition of diethylzinc to aldehyde promoted by chiral thiourea

Article abstract of DOI:10.1016/j.cclet.2011.07.015

A series of C₂-symmetric and asymmetric chiral thiourea derivatives were synthesized from commercial l-phenylalanine. All of the new compounds have been fully characterized by IR, ¹H NMR, ¹³C NMR, MS spectra and elemental analyses. The chiral thioureas were used as chiral ligands in the catalytic enantioselective ethylation of aldehydes with diethylzinc, the corresponding sec-alcohols were gained with excellent enantioselectivities (up to 87.1% ee) and high yields (up to 76.7%) after the conditions were optimized.

Full text of DOI:10.1016/j.cclet.2011.07.015

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 1265–1268
www.elsevier.com/locate/cclet
The first catalytic asymmetric addition of diethylzinc to aldehyde
promoted by chiral thiourea
*
Zhi Guo Qiao, Tian Hua Shen, Zhen Fang Fu, Jun Qi Li, Hong Wang, Qing Bao Song
The State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, College of Chemical Engineering and Materials Science,
Zhejiang University of Technology, Hangzhou 310032, China
Received 1 April 2011
Available online 6 September 2011
Abstract
A series of C2-symmetric and asymmetric chiral thiourea derivatives were synthesized from commercial L-phenylalanine. All of
1
the new compounds have been fully characterized by IR, H NMR, 13C NMR, MS spectra and elemental analyses. The chiral
thioureas were used as chiral ligands in the catalytic enantioselective ethylation of aldehydes with diethylzinc, the corresponding
sec-alcohols were gained with excellent enantioselectivities (up to 87.1% ee) and high yields (up to 76.7%) after the conditions were
optimized.
# 2011 Qing Bao Song. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Chiral thiourea; Diethylzinc; Amino alcohol; C2-symmetric; Enantioselective addition
Over the last decade, chiral thioureas have been intensively studied as prominent asymmetric catalyst due to their
strong double hydrogen-bonding interaction with reactants. Since the pioneering work of Jacobson [1], extensive
studies have been carried out in this area. A number of chiral thiourea derivatives have been synthesized and
successfully applied in several types of asymmetric reactions, such as Strecker reactions [2], Henry [3] and aza-Henry
reactions [4], Mannich [5] and nitro-Mannich reactions [6], Michael [7] and nitro-Michael additions [8], Morita-
Baylis-Hillman reactions [9], dynamic kinetic resolution [10], etc. However, to the best of our knowledge, there are no
reports about the enantioselective alkylation of aldehydes by using thiourea [11,12]. To further extend the scope of
applications of thiourea, we firstly report herein the preparation of these easy accessible thiourea ligands and their
applications in the reaction of diethylzinc with aldehyde.
As to the synthetic procedure, thioureas were commonly prepared from the reaction of amine with thiophosgene,
isothiocyanate or dithiocarbamates and related salts [13–15]. But these typical procedures must use isothiocyanate,
thiophosgene and dithiocarbamate, which were not agreement with the principle of environmentally friendly and
large-scale synthesis. So, the thiourea bifunctional compounds were prepared from the reaction of amine with carbon
disulfide or by substitution [16,17] as depicted in Scheme 1. The amino alcohols were gained according to the
literature methods [18], which were derived from L-phenylalanine and converted into the thioureas 3 and 4 with carbon
* Corresponding author.
E-mail address: qbsong@zjut.edu.cn (Q.B. Song).
1001-8417/$ – see front matter # 2011 Qing Bao Song. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.07.015

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Z.G. Qiao et al. / Chinese Chemical Letters 22 (2011) 1265–1268
Scheme 1. Synthesis of asymmetric chiral thiourea organocatalyst.
disulfide in 53–91% yield, 3d was derived from L-(À)-ephedrine. Reaction of 1, 3-diphenylthiourea with (S)-1, 1,
4-triphenyl-1-((trimethylsilyl)-oxy)-butan-2-amine in CH3CN gave 5 in 76% yields [21].
In order to evaluate the catalytic potential of these ligands, our initial experiments in the asymmetric addition of
diethylzinc to 2-naphthaldehyde involve the presence of 10% mol of ligands 3–5 in toluene at room temperature for
24 h, the results were listed in Table 1. The results of 5 and 6 demonstrated that the hydrogen atom of the hydroxy
group play a vital role in the enantioselectivity ethylation of 2-naphthaldehyde, which can not afforded the alkylated
products smoothly after the hydrogen atoms were substituted by -OTMS (Table 1, entries 1–4 vs 5–6). The C2-
symmetric chiral thioureas 3a–3d gave moderate to good yield and enantioselectivity. After verified the effectiveness
of the chiral thioureas 3a–3d with modifying the bulkiness of R1 with H (3a), Ph (3b) to Bn (3c) and 3d, the best results
were achieved by the catalyst 3b with 65.7% ee (R1 = Ph, Table 1, entry 2).
To determine the optimum conditions, 3b was chosen as a model compound for the asymmetric addition of
diethylzinc to 2-naphthaldehyde. The results were listed in Table 1 and depicted that the solvent played an important
Table 1
Asymmetric addition of diethylzinc to 2-naphthaldehyde.
O
OH
Et
Et2Zn (2.4 eqiv), ligand(10mol%)
toluene-hexane (1:1), r.t., 24h
H
.
Entry
Ligand
Ligand (mol%)
Solvent
Temp (8C)
Yield (%)a
Ee (%)b
1
2
3a
3b
3c
3d
4
10
10
10
10
10
10
10
10
10
10
10
10
3
Toluene
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
16.1
50.3
55.5
62.1
n.d.
7.6
Toluene
65.7
46.1
60.7
n.d.
3
Toluene
4
Toluene
5c
6c
7
Toluene
5
Toluene
n.d.
n.d.
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
Toluene:THF = 1:1
Toluene:CH2Cl2 = 1:1
Toluene:Et2O = 1:1
Toluene:hexane = 2:1
Toluene:hexane = 1:1
Toluene:hexane = 1:2
Toluene:hexane = 1:1
Toluene:hexane = 1:1
Toluene:hexane = 1:1
Toluene:hexane = 1:1
36.1
88.7
4.8
14.2
13.1
16.8
54.9
76.7
61.3
13.9
22.0
49.5
85.1
8
9
10
11
12
13
14
15
16
90.5
87.1
70.9
20.1
29.1
97.3
46.9
5
15
10
a
Isolated yield after flash chromatography.
b
c
Values were determined by HPLC with a Chiralcel AD-H or OJ-H column [18–20].
n.d.: not determined.

Z.G. Qiao et al. / Chinese Chemical Letters 22 (2011) 1265–1268
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Table 2
Asymmetric addition of diethylzinc to aldehydes using ligand 3b.
Entry
RCHO
Yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
2-Naphthaldehyde
C6H5CHO
76.7
74.3
64.7
82.1
72.5
42.3
67.2
55.2
87.1
63.7
76.1
71.9
82.3
38.3
31.1
28.9
Furfural
3, 5-(MeO)2C6H3CHO
p-BrC6H4CHO
p-ClC6H4CHO
2-ClC6H4CHO
4-Bromothiophene-2-carboxaldehyde
a
Isolated yield after flash chromatography.
b
Values were determined by HPLC with a chiralcel AD-H or OJ-H column [18–20].
role in the enantioselective process (Table 1, entries 7–12). When the reaction performed in toluene/hexane (1:1, v/v),
the best results with 87.1% yield and 76.7% ee achieved (Table 1, entry 11). Increasing of toluene or combining of
Et2O, THF or CH2Cl2 lowered the ee values of the resulting alcohol (Table 1, entries 7–10). Furthermore, lowered the
reaction temperature and shifted the loading of the catalyst cannot provide better results (Table 1, entries 13–16).
Therefore, the reaction condition of entry 11 was chosen as the optimal conditions for the following reactions.
Under the optimal reaction conditions, the scope of the utility of 3b was extended. A variety of aldehydes were
tested and moderate to excellent enantioselectivity were observed, the results were summarized in Table 2. All of the
alkylated products were affirmed R-configuration by comparison to the known values in the literatures [18–20].
In conclusion, we have prepared a series of chiral thioureas organocatalysts by efficient synthetic routes from
commercial and inexpensive amino acids. We firstly performed these thioureas as ligands to asymmetric addition of
diethylzinc to aldehydes showed a great catalytic potential. Further studies on their applications are in progress in our
laboratories, and the results will be reported in due course.
Acknowledgments
Open-Ended Fund of the State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang
University of Technology is gratefully acknowledged.
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[21] Data of products. 3a: white crystal. Yield 56%. mp 92–95 C. IR (KBr): 3165, 3025, 1528, 1454, 1330, 1268, 1091, 703, 678 cmÀ1. 1H NMR
(500 MHz, CDCl3): d 1.57 (s, 2H, OH), 3.01 (d, 2H, J = 7.5 Hz, PhCH2), 3.35 (m, 2H, J1 = 11.0 Hz, J2 = 4.0 Hz, HOCH2), 3.63 (dd, 2H,
J1 = 11.0 Hz, J2 = 3.5 Hz, HOCH2), 4.46 (p, 2H, J = 7.3 Hz, C*H), 7.08 (s, br, 2H, NH), 7.37–7.21 (m, 10H, PhH). 3b: white crystal. Yield
67%. mp 112–115 8C. IR (KBr): 3335, 3024, 1531, 1199, 749, 702, 678 cmÀ1. 1H NMR (500 MHz, CDCl3): d 1.50 (s, br, 2H, OH), 2.69–2.15
(m, 4H, PhCH2), 4.18 (dd, 1H, J1 = 2.5 Hz, J2 = 10.8 Hz, C*H), 4.84 (dd, 1H, J1 = 3.2 Hz, J2 = 11.6 Hz, C*H), 6.73 (s, br, 2H, NH), 7.65–7.13
(m, 30H, PhH). 13C NMR (125 MHz, CDCl3): d 36.7, 38.9, 58.1, 65.3, 95.5, 125.3, 125.7, 126.0, 126.4, 126.5, 126.7, 127.5, 128.2, 128.4,
128.6, 128.7, 128.8, 129.0, 129.2, 136.1, 138.2, 139.6, 140.9, 144.3, 146.7,187.9. MS (EI): m/z (%) 346 (100.0), 286 (23.0), 269 (24), 194 (63),
91 (15). Anal. calcd. for C43H40N2O2S (648.28): C, 79.60; H, 6.21; N, 4.32. Found: C, 79.54; H, 6.16; N, 4.25. 3c: yellow crystal. Yield 80%.
mp 124–126 8C. IR (KBr): 3161, 3026, 1602, 1521, 1454, 1196, 730, 648 cmÀ1. 1H NMR (500 MHz, CDCl3): d 1.59 (s, 2H, OH), 2.79–2.75
(m, 4H, PhCH2 C*), 2.82 (d, 2H, J = 14.6 Hz, PhCH2 C*), 2.89 (d, 2H, J = 14.2 Hz, PhCH2 C*), 3.11 (d, 2H, J = 14.6 Hz, PhCH2 C*), 3.48 (d,
2H, J = 14.2 Hz, PhCH2 C*), 4.14–4.09 (m, 2H, C*H), 6.46 (s, br, 2H, NH), 7.43–7.07 (m, 30H, PhH). 13C NMR (125 MHz, CDCl3): d 35.1,
39.8, 41.4, 63.0, 92.5, 126.9, 127.1, 127.3, 127.5, 128.4, 128.5, 128.6, 129.2, 130.5, 131.1, 134.2, 134.4, 136.0, 187.9. MS (EI): m/z (%)
373(53), 282(100), 222(17), 205(34), 91(48). Anal. calcd. for C47H48N2O2S (704.34): C, 80.08; H, 6.86; N, 3.97. Found: C, 79.98; H, 6.76; N,
3.85. 3d: white solid. Yield 91%. mp 82–85 8C. IR (KBr): 3193, 3038, 2979, 1523, 1330, 1168, 727, 658 cmÀ1. 1H NMR (500 MHz, CDCl3): d
0.87 (d, 6H, J = 6.6 Hz, CH3), 4.44–4.39 (m, 2H, CH3C*H), 5.95 (d, 2H, J = 8.6 Hz, Ph C*H), 7.43–7.26 (m, 10H, PhH), 7.69 (s, br, 2H, NH).
13C NMR (125 MHz, CDCl3): d 16.6, 56.0, 86.6, 126.2, 128.6, 128.9, 133.6, 189.1. MS (EI): m/z (%) 193 (100.0), 150 (42), 132 (46), 117 (24),
77 (23). Anal. calcd. for C19H24N2O2S (344.16): C, 66.25; H, 7.02; N, 8.13. Found: C, 66.13; H, 6.86; N, 8.02. 4: yellow solid. Yield 53%. mp
68–70 8C. 1H NMR (500 MHz, CDCl3): d 0.99 (t, 6H, J1 = J2 = 7.5 Hz, CH2CH3), 1.09 (t, 6H, J1 = J2 = 7.4 Hz, CH2CH3), 2.04–1.75 (m, 8H,
CH3CH2), 2.88–2.72 (m, 4H, PhCH2), 3.92 (dd, 2H, J1 = 3.4 Hz, J2 = 11.4 Hz, PhCH2 C*H), 6.63 (s, br, 2H, NH), 7.38–7.17 (m, 10H, PhH).
13C NMR (125 MHz, CDCl3): d 7.4, 7.7, 24.9, 29.1, 36.3, 64.4, 94.6, 127.4, 128.7, 129.2, 136.2, 188.1. MS (EI): m/z (%) 249 (70), 158 (100), 98
(63), 91 (64). Anal. calcd. for C33H56N2O2SSi2 (600.36): C, 65.94; H, 9.39; N, 4.66. Found: C, 65.83; H, 9.24; N, 4.48. 5: white solid. Yield
76%. mp 116 8C. IR (KBr): 3229, 3026, 2979, 1603, 1584, 1199, 835, 751, 697 cmÀ1. 1H NMR (500 MHz, CDCl3): d À0.22 (s, 9H, CH3),
1.29–1.23 (m, 2H, PhCH2), 1.62 (s, br, 1H, OH), 2.20 (dd, 1H, J1 = 8.3 Hz, J2 = 14.1 Hz, C*H), 5.89 (s, br, 2H, NH), 7.48–6.87 (m, 20H, PhH).
13C NMR (125 MHz, CDCl3): d 1.7, 37.9, 61.1, 84.2, 126.1, 126.5, 127.4, 127.8, 128.0, 128.6, 130.0, 130.1, 135.4, 138.1, 143.5, 143.7, 180.7.
MS (EI): m/z (%) 328 (20), 255 (100), 120 (46), 91 (11), 73 (35). Anal. calcd. for C31H34N2OSSi (510.22): C, 72.90; H, 6.71; N, 5.48. Found: C,
72.78; H, 6.57; N, 5.39.
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