Highly enantioselective aryl transfer to aldehydes: A remarkable effect of sulfur substitution in amino thioacetate ligands

Article abstract of DOI:10.1021/ol8001249

Chiral amino thioacetate ligands were prepared from the corresponding amino alcohols and used as catalysts for enantioselective aryl transfer reaction. The amino thioacetates were remarkably superior to the corresponding amino alcohols. Low catalyst loadings of only 1-2.5 mol % were sufficient to achieve excellent enantioselectivity as well as high conversion in short reaction time. The results reveal that the thioacetoxy moiety of the amino thioacetates has a surprisingly beneficial effect in enhancing the asymmetric induction.

Full text of DOI:10.1021/ol8001249

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1235-1237
Highly Enantioselective Aryl Transfer to
Aldehydes: A Remarkable Effect of
Sulfur Substitution in Amino Thioacetate
Ligands
Myung-Jong Jin,* Shaheen M. Sarkar, Dong-Hwan Lee, and Huili Qiu
School of Chemical Science and Engineering, Inha UniVersity,
Incheon 402-751, South Korea
mjjin@inha.ac.kr
Received January 18, 2008
ABSTRACT
Chiral amino thioacetate ligands were prepared from the corresponding amino alcohols and used as catalysts for enantioselective aryl transfer
reaction. The amino thioacetates were remarkably superior to the corresponding amino alcohols. Low catalyst loadings of only 1 2.5 mol %
−
were sufficient to achieve excellent enantioselectivity as well as high conversion in short reaction time. The results reveal that the thioacetoxy
moiety of the amino thioacetates has a surprisingly beneficial effect in enhancing the asymmetric induction.
Catalytic enantioselective addition of organozinc to aldehydes
has been widely studied as one of the most important
methods for the synthesis of optically active secondary
alcohols.1 In contrast to the asymmetric alkyl transfer to
aldehydes, the aryl transfer has been the subject of relatively
few reports.2 In 1997, Fu reported chiral ligand 1 for the
addition of diphenylzinc to 4-chlorobenzaldehyde.3 Despite
this modest enantioselectivity, this initial report was the
starting point for the growing field of this asymmetric
catalysis. Soon after, Pu and Bolm developed highly enan-
tioselective catalysts 24 and 35 for the phenyl transfer with
diphenylzinc, respectively (Figure 1). Further, Bolm intro-
* To whom correspondence should be addressed. Tel: 82-32-860-7469.
Fax: 82-32-872-0959.
(1) (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. 1991, 30, 49.
(b) Soai, K.; Niwa, S. Chem. ReV. 1992, 92, 883. (c) Pu, L.; Yu, H.-B.
Chem. ReV. 2001, 101, 757. (d) Walsh, P. J. Acc. Chem. Res. 2003, 36,
739.
(2) (a) Bolm, C.; Hildebrand, J. P.; Muniz, K.; Hermanns, N. Angew.
Figure 1. Asymmetric aryl transfer catalysts.
Chem., Int. Ed. 2001, 40, 3284. (b) Schmidt, F.; Stemmler, R. T.; Rudolph,
J.; Bolm, C. Chem. Soc. ReV. 2006, 35, 454.
(3) Dosa, P. I.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1997, 62, 444.
(4) (a) Huang, W.-S.; Hu, Q.-S.; Pu, L. J. Org. Chem. 1999, 64, 4222.
(b) Huang, W.-S.; Pu, L. Tetrahedron Lett. 2000, 41, 145.
duced the Ph2Zn-Et2Zn mixture6 and the arylboronic acid-
Et2Zn mixture7 as aryl sources to improve the performance
(5) Bolm, C.; Muniz, K. Chem. Commun. 1999, 1295.
of the aryl transfer. Since the discovery, chiral ligands such
10.1021/ol8001249 CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/21/2008

as aminonaphthol,8 piperidinoethanol,9 pyrrolidinylmetha-
nol,10 thiazolidine,11 dialkylnorephedrine,12 and MIB13 have
been emerged along this line. However, high catalyst
loadings of 10-20 mol % were sometimes required to
achieve satisfactory enantioselectivity without additives. Both
accessibility of chiral catalysts and their high efficiency of
asymmetric induction would be necessary for the practical
asymmetric catalysis. Therefore, the search of truly valuable
catalysts is a field of continuous interest for the catalytic
aryl transfer reaction.
Previously, amino thioacetates were found to be highly
enantioselective catalysts for the addition of diethylzinc to
aldehydes.14 We envisioned that amino thioacetates 5 would
be applicable to the aryl transfer to aldehyde. In fact,
outstanding results were obtained in the aryl transfer.
Moreover, the reaction was performed well with low loadings
of the catalysts. Most of the prominent catalysts are based
on protic ligands with hydroxy group. It should be of interest
to explore the catalytic ability of the aprotic ligands 5 in the
aryl transfer. In this context, we report a surprisingly
beneficial effect of the SAc moiety in the amino acetate
ligands on the enantioselectivity in the aryl transfer to
aldehydes.
The (-)-N,N-dialkylamino thioacetates 5a-c were readily
prepared by mesylation of the corresponding (-)-N,N-
dialkylamino alcohols 4a-c with methanesulfonyl chloride
and triethylamine in methylene chloride, followed by sub-
sequent displacement with an excess of potassium thioacetate
in aqueous ethanol, respectively. At first, the phenyl transfer
to 4-chlorobenzaldehyde using phenylboronic acid-Et2Zn
mixture was attempted in the presence of optically active
amino alcohols 4a-c (Table 1). The amino alcohols have
proven to be excellent chiral ligands for the addition of
diethylzinc to aldehydes.15 However, the data in Table 1
reveal that the amino alcohols have very weak enantiocon-
tolling ability in the phenyl transfer (entries 1-7). Although
good chemical yields were obtained, the ee’s were very low
in each case. When the catalyst loading was decreased to 1
mol %, catalysts 4 afforded virtually no asymmetric induction
(entries 2, 3, and 6). Next, we examined the catalytic
behavior of the corresponding amino thioacetates 5 in the
same phenyl transfer reaction. The initial trial with 10 mol
% of 5a gave a remarkable result of 99% ee (entry 8). The
Table 1. Asymmetric Phenyl Transfer to
4-Chlorobenzaldehyde in the Presence of Chiral Ligands
4 and 5a
entry ligand (mol %) time (h) T (°C) yieldb (%) eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
4a (0.05)
4a (0.01)
4a (0.01)
4b (0.05)
4b (0.025)
4b (0.01)
4c (0.05)
5a (0.1)
5a (0.05)
5a (0.05)
5a (0.05)
5a (0.025)
5a (0.01)
5b (0.1)
5b (0.05)
5b (0.05)
5b (0.025)
5b (0.01)
5b (0.005)
5c (0.05)
5c (0.025)
4
6
8
4
6
8
4
3
2
2
4
2
2
2
2
3
3
4
4
2
3
20
20
10
20
10
20
20
10
20
10
0
10
10
10
20
10
10
10
10
10
10
85
76
70
87
83
74
83
95
96
92
83
94
91
97
92
90
91
90
83
94
92
48 (R)
2
3
32 (R)
17
1
29 (R)
99 (R)
96
97
97
96
90
98 (R)
96
98
95
94
91
96 (R)
94
a Reactions were performed with 2 equiv of phenylboronic acid and 6
equiv of Et2Zn in toluene. b Yield of isolated product. c Enantiomeric excess
determined by chiral HPLC on a Chiralcel OB-H column. Absolute
configuration is determined by comparison of the HPLC elution order with
the literature data.7
reaction could be completed within a short time at 10 °C
affording optically pure (R)-product. Unexpectedly, reducing
the catalyst loading to 2.5-5.0 mol % has only a little
influence on the enantioselectivity (entries 9-12). The
catalyst loading could be decreased to 1 mol % to still furnish
a high ee of 90% (entry 13). These results came as a surprise
since the serious effect of catalyst loading has been observed
in most of the previous studies. The reaction gave a slightly
higher ee when the reaction temperature was decreased from
20 to 10 °C. (-)-Norephedrine-derived ligands 5b and 5c
were also examined for the phenyl transfer to 4-chloroben-
zaldehyde (entries 14-21). The reaction proceeded very well
with 91-98% ee in high yields. It is worthy that the phenyl
transfer employing catalyst loading as low as 0.5 mol %
afforded the product in 91% ee (entry 19). Until now, this
level of enantioselectivity has scarcely been achieved without
additives at such low catalyst loadings. The results show that
the amino thioacetates are remarkably superior to the
corresponding amino alcohols.
(6) (a) Bolm, C.; Hermanns, N.; Hildebrand, J. P.; Nuniz, K. Angew.
Chem., Int. Ed. 2000, 39, 3465. (b) Bolm, C.; Kesselgruber, M.; Hermanns,
N.; Hildebrand, J. P. Angew. Chem., Int. Ed. 2001, 39, 1488.
(7) (a) Bolm, C.; Rudolph, J. J. Am. Chem. Soc. 2002, 124, 14850. (b)
Rudolph, J.; Hermanns, N.; C. Bolm, J. Org. Chem. 2004, 69, 3997.
(8) Ji, J.-X.; Wu, J.; Au-Yeung, T. T.-L.; Yip, C.-W.; Haynes, R. K.;
Chan, A. S. J. Org. Chem. 2005, 70, 1093.
(9) (a) Braga, A. L.; Lu¨dtke, D. S.; Vargas, F.; Paixa˜o, M. W. Chem.
Commun. 2005, 2512. (b) Jimeno, C.; Sayalero, S.; Fjermestad, T.; Colet,
G.; Maseras, F.; Perica`s, M. A. Angew. Chem., Int. Ed. 2008, 47, 1098.
(10) Braga, A. L.; Lu¨dtke, D. S.; Schneider, P. H.; Vargas, F.; Schneider,
A.; Wessjohann, L. A.; Paixa˜o, M. W. Tetrahedron Lett. 2005, 46, 7827.
(11) Braga, A. L.; Milani, P.; Vargas, F.; Paixa˜o, M. W.; Sehnem, J. A.
Tetrahedron: Asymmetry 2006, 17, 2793.
(12) Paixa˜o, M. W.; Godoi, M.; Rhoden, C. R. B.; Westermann, B.;
Wessjohann, L.; Lu¨dtke, D. S.; Braga, A. L. J. Mol. Catal. A 2007, 261,
120.
(13) Kim, J. G.; Walsh, P. J. Angew. Chem., Int. Ed. 2006, 45, 4175.
(14) (a) Jin, M.-J.; Ahn, S.-J.; Lee, K.-S. Tetrahedron Lett. 1996, 37,
8767. (b) Wipf, P.; Kendall, C. Chem. Eur. J. 2002, 8, 1779.
(15) Soai, K.; Yokoyama, S.; Hayasaka, T. J. Org. Chem. 1991, 56, 4264.
Encouraged by the high efficiency of the amino thio-
acetates, phenyl transfer to different aromatic aldehydes was
performed in the presence of 2.5 or 5.0 mol % of 5 (Table
2). Amino alcohol 4b gave poor ee’s in the phenyl transfer
to 2-chlorobenzaldehyde and 4-methoxybenzaldehyde (en-
1236
Org. Lett., Vol. 10, No. 6, 2008

Table 2. Asymmetric Phenyl Transfer to Aldehydesa
Table 3. Asymmetric Aryl Transfer to Benzaldehydesa
yieldb (%)
eec (%)
entry
Ar
ligand (mol %)
yieldb (%)
eec (%)
entry
Ar
ligand (mol %)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
5a (0.05)
5a (0.025)
5b (0.05)
5b (0.025)
5c (0.025)
5a (0.05)
5a (0.025)
5b (0.05)
5b (0.025)
5c (0.05)
5c (0.025)
5a (0.025)
5b (0.025)
5b (0.025)
5b (0.025)
93
90
93
86
90
91
92
96
90
92
87
90
90
91
86
92 (S)
90
93
90
93
95 (S)
93
94
92
95
94
92 (S)
90
88 (S)
80 (S)
1
2
3
4
5
6
7
8
9
2-ClC6H4
2-ClC6H4
4-MeOC6H4
2-ClC6H4
2-ClC6H4
2-ClC6H4
4-MeOC6H4
2-MeOC6H4
4-MeC6H4
2-C10H8
4b (0.05)
4b (0.025)
4b (0.025)
5a (0.05)
5b (0.05)
5b (0.025)
5b (0.025)
5b (0.025)
5b (0.025)
5b (0.025)
83
80
85
97
97
93
98
93
94
91
15 (R)
7
8 (R)
98 (R)
98
90
93 (R)
91 (R)
94 (R)
94 (R)
10
4-ClC6H4
a Reactions were performed with 2 equiv of phenylboronic acid and 6
equiv of Et2Zn in toluene. b Yield of isolated product. c Enantiomeric excess
determined by chiral HPLC on a Chiralcel OB-H column. Absolute
configuration is determined by comparison of the HPLC elution order.
4-MeC6H4
4-MeC6H4
3-Cl C6H4
2-Cl C6H4
a Reactions were performed with 2 equiv of arylboronic acid and 6 equiv
of Et2Zn in toluene. b Yield of isolated product. c Enantiomeric excess
determined by chiral HPLC on a Chiralcel OB-H column. Absolute
configuration is determined by comparison of the HPLC elution order.
tries 1-3), whereas amino thioacetates 5a and 5b gave high
ee’s up to 98% regardless of substituent on the aldehydes
(entries 4-10).
In next step, we investigated the aryl transfer to benz-
aldehyde with substituted phenylboronic acids (Table 3). In
cases of 4-substituted phenylboronic acids, very high ee’s
(g90%) were obtained (entries 1-13). In contrast, 3- and
2-chlorophenylboronic acids lowered ee under the same
conditions (entries 14 and 15). All of the ee values were
slightly low compared with those of the phenyl transfer. From
these results, the combination of phenylboronic acid and
substituted benzaldehyde appears to be a better approach for
the preparation of enantioenriched diarylmethanols. Our
results show that replacement of the hydroxy group of the
amino alcohols 4 with thioacetoxy group increases remark-
ably the enantioselectivity. The remarkable efficiency of
ligands 5 may be explained by the fact which sulfur has
stronger affinity toward Zn of arylzinc species16 formed. This
causes an increase in rigidity of the coordination sphere of
the catalyst and leads to higher enantioselectivity.
In conclusion, amino thioacetate ligands 5 turned out to
be highly efficient catalysts for the enantioselective aryl
transfer reaction. The results indicate that the SAc moiety
of the amino thioacetate has a surprisingly beneficial effect
in enhancing the asymmetric induction.
Acknowledgment. This work was supported by Inha
University Research Grant (INHA-2008).
Supporting Information Available: General experimen-
tal procedures, spectral data for 5a-c and chiral HPLC data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(16) (a) Srebnik, M. Tetrahdron Lett. 1991, 32, 2449. (b) Langer, F.;
Schwink, L.; Devasagayaraj, A.; Chavant, P.-Y.; Knochel, P. J. Org. Chem.
1996, 61, 8229. (c) Dahmen, S.; Bra¨se, S. Org. Lett. 2001, 3, 4119.
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