Asymmetric reformatsky reaction of aldehydes catalyzed by novel β -amino alcohols and zinc complexes

Article abstract of DOI:10.1080/00397911.2013.879898

A series of β-amino alcohols derived from (1R, 2S)-2-amino-1,2- diphenylethanol and substituted salicylaldehydes as novel chiral tridentate ligands has been applied to an asymmetric Reformatsky reaction of aldehydes with ethyl iodoacetate in the presence

Full text of DOI:10.1080/00397911.2013.879898

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Asymmetric Reformatsky Reaction of
Aldehydes Catalyzed by Novel β-Amino
Alcohols and Zinc Complexes
Yan Li a & Bin He b c
a School of Basic Medical Science , Guiyang Medical College ,
Guiyang , Guizhou , China
b School of Pharmacy , Guiyang Medical College , Guiyang ,
Guizhou , China
c Engineering Research Center for the Development and Application
of Ethnic Medicine and TCM (Ministry of Education) , Guiyang
Medical College , Guiyang , Guizhou , China
Accepted author version posted online: 18 Mar 2014.Published
online: 29 May 2014.
To cite this article: Yan Li & Bin He (2014) Asymmetric Reformatsky Reaction of Aldehydes Catalyzed
by Novel β-Amino Alcohols and Zinc Complexes, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 44:13, 1938-1943, DOI:
10.1080/00397911.2013.879898
To link to this article: http://dx.doi.org/10.1080/00397911.2013.879898
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Synthetic Communications1, 44: 1938–1943, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.879898
ASYMMETRIC REFORMATSKY REACTION OF
ALDEHYDES CATALYZED BY NOVEL b-AMINO
ALCOHOLS AND ZINC COMPLEXES
Yan Li1 and Bin He2,3
1School of Basic Medical Science, Guiyang Medical College, Guiyang,
Guizhou, China
2School of Pharmacy, Guiyang Medical College, Guiyang, Guizhou, China
3Engineering Research Center for the Development and Application of Ethnic
Medicine and TCM (Ministry of Education), Guiyang Medical College,
Guiyang, Guizhou, China
GRAPHICAL ABSTRACT
Abstract A series of b-amino alcohols derived from (1R, 2S)-2-amino-1,2-diphenylethanol
and substituted salicylaldehydes as novel chiral tridentate ligands has been applied to an
asymmetric Reformatsky reaction of aldehydes with ethyl iodoacetate in the presence of
ZnMe2. This novel catalytic system produced the desired -hydroxyl esters with moderate
to good enantioselectivities (up to 81% ee) and yields for many aldehydes, including
aromatic, heteroaromatic, conjugated, and aliphatic aldehydes.
Keywords b-Amino alcohols; aldehydes; asymmetric Reformatsky; chiral tridentate
ligands
Received November 20, 2013.
Address correspondence to Bin He, School of Pharmacy, Guiyang Medical College, Guiyang
550004, Guizhou, China. E-mail: binhe@gmc.edu.cn
1938

ASYMMETRIC REFORMATSKY REACTION
1939
INTRODUCTION
The Reformatsky reaction is a classical carbon–carbon bond-forming reaction
that was introduced for the first time in 1887.[1] The Reformatsky reaction involves
the zinc-induced formation of b-hydroxyesters by the reaction of a-halo esters with
aldehydes or ketones.[2,3] Because of the importance of the Reformatsky products,
b-hydroxy esters, as versatile intermediates for the synthesis of such natural products
as macrolides[4] and polyether antibiotics,[5] there has been continuous effort to con-
duct these reactions with asymmetric versions. Many existing chiral auxiliaries[6–9]
and catalysts[10–14] can induce useful levels of diastereoselectivity or enantioselectiv-
ity. A recent review summarized the results of work showing that by using a large var-
iety of chiral auxiliaries,[15] the diastereoselective Reformatsky reactions have
excellent diastereochemical control with regard to the synthesis of specific cyclic
and acyclic chiral moieties and have been successfully applied to the total synthesis
of natural products.[15] Conversely, the improved homogeneous asymmetric versions
by chiral ligands have also been reported in recent years. The first catalytic enantio-
selective Reformatsky reaction of ethyl iodoacetate was reported in 2006 using
20 mol% of a chiral manganese salen catalyst and dimethylzinc to homogeneously
generate the zinc reagent.[16,17] The catalytic enantioselective Reformatsky reactions
of a-halogenated esters with aldehydes and ketones have subsequently been promoted
by BINOL derivatives,[18] chiral aminoalcohols,[19,20] a chiral Schiff base,[21] and a
chiral bisoxazolidine.[22] Despite the abovementioned progress in this field, efforts
to seek novel effective chiral ligands for the asymmetric catalysis of this practical
carbon–carbon bond-forming reaction are ongoing.
Previously, we reported that novel b-amino alcohols as chiral tridentate ligands
can efficiently catalyze the enantioselective cyanosilylation of aldehydes.[23] Because
most ligands for asymmetric Reformatsky reaction are bidentate ligands, there are
few reports of tridentate ligands. To extend the applications of these novel b-amino
alcohols, we tested whether they could be good chiral tridentate ligands for an
asymmetric Reformatsky reaction.
In this study, we report that these b-amino alcohols as novel chiral tridentate
ligands can indeed catalyze the asymmetric Reformatsky reaction of aldehydes with
moderate to good enantioselectivities and yields.
RESULTS AND DISCUSSION
From previous studies, we know that the steric effect of the ligand has a greater
contribution than the electronic effect to enhance the entioselectivity.[23] On the other
hand, based on the pioneering works of Refs. 16–18 and 22, it was established that
the Reformatsky reaction can be carried out with high conversion and excellent che-
moselectivity by using ZnMe2 and ethyl iodoacetate with air in an hour. Therefore,
under these optimum conditions, by using benzaldehyde as standard substrate, we
first evaluated the effects of ligands 1a–1e with different sized substituents of R1
or R2 on the asymmetric Reformatsky reaction (Figure 1 and Table 1).
We performed the asymmetric Reformatsky reaction by using 20 mol% ligand,
2.25 equiv ZnMe2, and 2 equiv ethyl iodoacetate. After 1 h of reaction, we isolated the
desired product 3a, and no 1, 2-addition product of ZnMe2 to benzaldehyde was

1940
Y. LI AND B. HE
Figure 1. Structures of chiral amino alcohol ligands 1a–1e.
detected by LC-MS. Therefore, it is confirmed that the conditions described can
provide excellent chemoselectivity in the Reformatsky reaction. In support of our
original hypothesis, the results indicated that the enantioselectivity was highly
influenced by the structures of the ligands (Table 1). The reaction catalyzed by ligand
1d (R1 ¼ tert-butyl, R2 ¼ tert-butyl) gave the greatest enantioselectivity (63% ee)
(entry 4, Table 1). More or less bulky substitutes all led to less enantioselectivity
(entries 1–5, Table 1). The most bulky R1, adamantanyl, was detrimental for both
the enantioselectivity and reactivity. Lower temperature can facilitate an increase
in the enantioselectivity in many cases of asymmetric catalysis. Therefore, we inves-
tigated the temperature effect on this reaction. Lower temperature, which caused dra-
matic decreases in both the enantioselectivity and the yield, actually disadvantaged
this reaction (entry 4 vs. entries 9 and 10, Table 1). Additionally, we investigated the
loading amount of the ligand 1d. By lowering the ligand to 10 mol% 1d, the reaction
Table 1. Screening of different ligands 1a–1e for asymmetric Reformatskya
Entry
Ligand (Lꢀ)
Lꢀ (mol%)
Temp. (ꢁC)
Yield (%)b
Ee (%)c
1
2
1a
1b
1c
1d
1e
1d
1d
1d
1d
1d
20
20
20
20
20
10
30
50
20
20
RT
RT
RT
RT
RT
RT
RT
RT
0
54
63
34
50
61
63
54
56
59
53
28
nde
3
72
68
4
5
23
53
6
7
68
65
8
9
10
18
Traced
ꢂ10
aAll reactions were carried out using 2 equiv ethyl iodoacetate and 2.25 equiv ZnMe2 in Et2O at RT for
1 hour with air.
bIsolated yield.
cThe enantiomeric excess was determined by chiral HPLC analysis using a Chiralcel OD column.
dDetermined by LC-MS.
end, not determined.

ASYMMETRIC REFORMATSKY REACTION
1941
Table 2. Asymmetric Reformatsky reaction of aldehydes catalyzed by 1d=ZnMe2 with ethyl iodoacetatea
Entry
Aldehydes
Yield (%)b
ee (%)c
Config.d
1
2
Benzaldehyde (2a)
4-Chlorobenzaldehyde (2b)
4-Bromobenzaldehyde (2c)
4-Methylbenzaldehyde (2d)
4-Methoxybenzaldehyde (2e)
1-Naphthaldehyde (2f)
2-Naphthaldehyde (2g)
2-Furaldehyde (2h)
68
63
60
60
60
65
68
45
58
62
52
56
63
61
60
60
60
81
80
53
63
33
25
45
R
R
R
R
R
3
4
5
6
7
8
R
9
2-Thienylaldehyde (2i)
10
11
12
(E)-Cinnamaldehyde (2j)
Phenylpropyl aldehyde (2k)
Isopropyl aldehyde (2l)
aAll reactions were carried out using 10 mol% 1d, 2 equiv ethyl iodoacetate, and 2.25 equiv ZnMe2 in
Et2O at RT for 1 h with air.
bIsolated yield.
cThe enantiomeric excess was determined by chiral HPLC analysis using Chiralcel OD column and
Chiralpak AS column, or by chiral GC analysis using Chiralsil Dex CB column.
dThe absolute configuration of the product was assigned by comparison of HPLC retention time with
values in the literature.[18,22]
showed lower enantioselectivity, whereas there was little enhancement of enantioselec-
tivity with 30 mol% or 50 mol% 1d (entry 4 vs. entries 6–8, Table 1).
Encouraged by the results obtained from these model reactions, the scope of this
novel catalytic system was examined with different aldehydes, including aromatic,
heteroaromatic, conjugated, and aliphatic aldehydes (Table 2). Aldehydes with sub-
stituents on the aromatic ring gave similar ee values as benzaldehyde (entries 1–5,
Table 2). Heteroaromatic aldehydes also gave similar ee values with benzaldehyde
(entries 8 and 9, Table 2). Among all tested aldehydes, 1-naphthaldehyde and
2-naphthaldedyde gave the best enantioselectivities, with 81% and 80% ee, respect-
ively (entries 6 and 7, Table 2). a, b-Unsaturated aldehyde and aliphatic aldehydes
gave relatively lower enantioselectivities, from 25% to 45% ee (entries 10–12, Table 2).
EXPERIMENTAL
General Procedure for Preparation of Chiral Amino-Alcohol
Ligands 1a–1e
According to our previous report,[23] it is easy to synthesize the chiral amino
alcohol ligands 1a–1e (Fig. 1). A typical procedure for the synthesis of ligand 1d
was shown as following: A mixture of 2,5-di-tertbutylsalicylaldehyde (1 mmol) and

1942
Y. LI AND B. HE
chiral (1R,2S)-2-amino-1,2-diphenylethanol (1 mmol) in absolute EtOH was stirred
for 24 h. Then NaBH4 (114 mg, 3 mmol) was directly added in it. After the mixture
was stirred for an additional 4 h, it was quenched by water. The resulting mixture
was extracted with CH2Cl2, and the organic layer was washed with brine. After drying
over anhydrous sodium sulfate, the solvent was removed and the residue was purified
by silica-gel column chromatography to afford the title ligand 1d.[23]
1
Yield: 85%. H NMR (400 MHz, CDCl3): d 7.18–7.36 (m, 11H), 6.65 (s, 1H),
4.92 (d, J ¼ 6.0 Hz, 1H), 3.88 (d, J ¼ 6.4 Hz, 1H), 3.78 (d, J ¼ 13.2 Hz, 1H), 3.56
(d, J ¼ 13.2 Hz, 1H), 1.41 (s, 9H), 1.21 (s, 9H); 13C NMR (100 MHz, CDCl3): d
154.3, 140.5, 137.8, 135.9, 128.6, 128.4, 128.2, 128.1, 126.8, 123.3, 122.9, 122.0,
68.3, 51.1, 34.9, 34.1, 31.6, 29.6.
General Procedure for Asymmetric Reformatsky Reaction
In a two-neck 100-mL flame-dried flask equipped with a CaCl2 tube, Et2O
(5 mL), ligand 1d (0.05 mmol, 20 mol%) and ethyl iodoacetate (0.5 mmol, 2 equiv)
were added at room temperature. ZnMe2 (0.5 mmol, 2 equiv, 2 M solution in toluene)
was added and immediately followed by the addition over 10 min of a solution
of aldehyde (0.25 mmol) in Et2O (1 mL). In the meantime, additional ZnMe2
(0.25 mmol, 0.25 equiv, 2 M solution in toluene) was added. The resulting solution
was stirred for 1 h and quenched with aqueous HCl (1 M). The organic phase was
separated, and the aqueous phase was extracted with Et2O (20 mL). The product
was purified by flash chromatography. The enantiomeric excess of product was
analyzed by chiral high-performance liquid chromatography (HPLC) or gas chroma-
tography (GC). Absolute configurations were determined by comparison of the
known order of elution of the two enatiomers or the sign of optical rotation with
literature data.[18,22]
CONCLUSIONS
In summary, this report describes the first attempt to use b-amino alcohols as
novel chiral tridentate ligands for asymmetric Reformatsky reaction of aldehydes.
The asymmetric Reformatsky reaction of aldehydes was achieved by the catalysis
of 20 mol%, chiral b-amino alcohol, and ZnMe2 with moderate to good enantioselec-
tivities (up to 81% ee) and yields.
FUNDING
We are grateful for financial support from National Natural Science Foun-
dation of China (No. 21302027) and the Special Support in Guizhou Province for
Research and Development of Modern Science and Technology Industrialization
in TCM (QKHGZ[2013] 4001).
SUPPORTING INFORMATION
1
Full experimental details and H and 13C NMR, HPLC, and GC data for this
article can be accessed on the publisher’s website.

ASYMMETRIC REFORMATSKY REACTION
1943
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