Chiral zinc amidate catalyzed additions of diethylzinc to aldehydes

Article abstract of DOI:10.1016/j.tetlet.2019.06.031

A series of bifunctional spiro ligands bearing “carboxamide–phosphine oxide” groups and ethylzinc carboxamidates from these ligands as catalysts for Et₂Zn additions to aldehydes were reported. Excellent yields were obtained with moderate ee′s in Et₂Zn additions to benzaldehyde derivatives, implying effectiveness of our newly designed catalytic structures as well as mediocre stereocontrol by these chiral ligands. Possible transition states were suggested based on the crystal structures of two ligands.

Full text of DOI:10.1016/j.tetlet.2019.06.031

Accepted Manuscript
Chiral Zinc Amidate Catalyzed Additions of Diethylzinc to Aldehydes
Jinxia Zhang, Shasha Li, Xinxin Zheng, Hongjie Li, Peng Jiao
PII:
S0040-4039(19)30582-9
https://doi.org/10.1016/j.tetlet.2019.06.031
TETL 50872
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
16 April 2019
16 June 2019
17 June 2019
Please cite this article as: Zhang, J., Li, S., Zheng, X., Li, H., Jiao, P., Chiral Zinc Amidate Catalyzed Additions of
Diethylzinc to Aldehydes, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.06.031
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Chiral Zinc Amidate Catalyzed Additions of Diethylzinc to
Aldehydes
a
a
a
a
a,
Jinxia Zhang , Shasha Li , Xinxin Zheng , Hongjie Li , and Peng Jiao 
a
Key Laboratory of Radiopharmaceuticals, College of Chemistry, Beijing Normal University, Beijing 100875, P.R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
A series of bifunctional spiro ligands bearing “carboxamide–phosphine
oxide” groups and ethylzinc carboxamidates from these ligands as catalysts
Received in revised form
Accepted
for Et
2
Zn additions to aldehydes were reported. Excellent yields were
Zn additions to benzaldehyde derivatives,
obtained with moderate ee′s in Et
2
Available online
implying effectiveness of our newly designed catalytic structures as well as
mediocre stereocontrol by these chiral ligands. Possible transition states
were suggested based on the crystal structures of two ligands.
Keywords:
asymmetric addition
diethylzinc
2
019 Elsevier Ltd. All rights reserved.
chiral amidate
spiro ligand

Corresponding author. Tel.: +86-10-5880-0316; fax: +86-10-5880-2075; e-mail: pjiao@bnu.edu.cn

type reaction of 1 produced two diastereomers 2 and 2′,10 which
were conveniently separated by recrystallizations (Scheme 1a).
The chiral auxiliary from D-phenylglycinol was removed in
Introduction
Asymmetric additions of organozinc reagents to aldehydes or
ketones may produce chiral secondary or tertiary alcohols, which
are structural motifs in many natural products or bioactive
11
excellent yields by dehydration followed by acidic hydrolysis.
The blocking Br group was removed by hydrogenolysis.
1
compounds. Since Noyori’s pioneering and prominent research
12
Demethylation of 3 and subsequent esterification with PhNTf
2
on dialkylzinc additions to aldehydes catalyzed by (2S)-DAIB
gave 4 in a quantitative yield, which was a key starting material
for the preparation of ligands 5a–h. Introduction of
2
(
Figure 1a), various amino alcohols and other N,O-ligands have
a
2
c, 3
been used in similar reactions. The hydroxy group in an amino
alcohol reacts with dialkylzinc to generate an alkoxy zinc
species, which coordinates to the adjacent tertiary amino group to
form a chiral zinc complex in situ. The coordinatively
unsaturated zinc center in the complex works as a Lewis acid to
activate the aldehyde or ketone substrate. On the other hand, a
Lewis basic O atom of the ligand would coordinate with a
molecule of dialkylzinc, enhancing its nucleophilicity. Such a
diarylphosphinoyl group to 4 was accomplished under Pd
catalyzed C–P coupling conditions established by Morgans and
13
Hayashi (Scheme 1b). A methyl group was installed to generate
5
h from 5a.
OMe
N
OMe
N
O
MeO
i)
(a)
N
Br
Br
+
O
O
O
Ph
Br
OH
OH
Ph
Ph
4
1
2, 48% yield
2', 42% yield
finely elaborated Lewis acid–Lewis base assembly involving
isolate by recrystallization
one catalytic and one reacting zinc species can not only
accelerate the reaction but also realize high enantioselectivities.
Two decades after Noyori’s report, combinations of
O
5a: Ar = Ph
5b: Ar = p-tolyl
5c: Ar = p-MeOC H4
5d: Ar = 3,5-xylyl
OMe
OTf
PAr2
6
ii)-iv)
v), vi)
vii)
(b)
2
5e: Ar = 3,5-(t-Bu)2C6H3
5f: Ar = 3,5-(Ph)2C6H3
5g: Ar = 1-naphthyl
N
H
O
N
O
N
H
O
“
phosphinamide–tertiary
amino”
and
“phenoxy–
H
phosphonamide/phosphonate/phosphine oxide” (Figure 1b), in
substitution for the bifunctional “hydroxy–tertiary amino”
structure, were developed by Ishihara to catalyze asymmetric
3, 84% yield
4, >99% yield
5a-g, 76->99% yields
O
PPh2
viii)
(c) 5a
5
additions of organozinc reagents. High enantioselectivities were
N
O
realized in alkyl zinc additions to ketones.5d Due to the
importance of chiral alcohols for multipurpose applications,
development of a highly effective ligand is still in demand. In the
course of our investigations of a new class of compounds bearing
spiro[indane-1,2′-pyrrolidine] backbone as chiral catalysts or
ligands, we envisioned 7-diarylphosphinoyl-spiro[indane-1,2′-
pyrrolidin]-5′-ones (Figure 1c), which have an amide group
capable of deprotonation by dialkylzinc and a Lewis basic P=O
CH3
h, >99% yield
5
Reagents and conditions: i) AlCl
ii) LiOH·H O (10 equiv), DMSO, 170 °C, 90% total yield; iii) 4 N HCl, THF,
0 °C, 93% yield; iv) H , Pd/C, MeOH, >99% yield; v) BBr (5.0 equiv),
CH Cl , −20 °C, >99% yield; vi) PhNTf (1.5 equiv), Cs CO , DMF, >99%
yield; vii) Ar P(O)H (2.0 equiv), Pd(OAc) , dppb, i-Pr NEt, DMSO, 76–
3
>99% yields; viii) NaH (3.0 equiv), CH I (3.0 equiv), DMF, rt, >99% yield.
3
(3.0 equiv), DCE, −10 °C, 90% total yield;
2
7
2
3
2
2
2
2
3
2
2
2
Scheme 1. Preparation of chiral ligands 5a–h bearing
spiro[indane-1,2′-pyrrolidin]-5′-one backbone.
4
f–j, 5–8
group,
could act as potential ligands for alkyl zinc
additions. Here, we report our results of asymmetric additions of
diethylzinc to aldehydes catalyzed by Zn amidates from these
spiro compounds. To the best of our knowledge, this is the first
example using a carboxamide group to introduce a Lewis acidic
zinc center to a chiral catalyst for alkyl zinc additions. To date,
there has been no research on Zn carboxamidate catalyzed
reactions.
With the ligands 5a–h in hands, the reactivities and
enantioselectivities of their Zn complexes in asymmetric
additions of Et Zn to benzaldehyde were evaluated in toluene
2
(Table 1). At 0 °C and rt, 5a gave the product in high yields and
similarly low ee′s (entries 1, 2). Decreasing the temperature to
−10 °C, the yield decreased to 60% and the ee was at the same
level (entry 3). In Et
(entry 4). Then 5b–g were tested in toluene at 0 °C (entries 5–
0). A para-methyl or methoxy group on the phenyl ring of the
2
O, 36% ee and 68% yield were obtained
O
PR2
1
O
OH
N
HN PAr2
phosphinoyl group did not improve the result. 3,5-Methyl groups
on the phenyl ring slightly improved the ee and the yield (entry
7), indicating a bulkier shielding group was good for enantio
differentiation. When 5e bearing two t-Bu groups on the phenyl
ring was used, 96% yield and 79% ee were obtained (entry 8).
Changing the t-Bu group to phenyl group, lower yield (80%) was
obtained while the ee was almost the same (entry 9). When 5g
bearing di(1-naphthyl)phosphinoyl group was used, only 31%
yield was obtained while the ee was in the same range as when
NMe2
OH
OH
(a)
(b)
PR2
O
(2S)-DAIB
phosphinamide
3,3'-disubstituted BINOL
O
PAr2
acidic proton
Lewis basic site
(c)
N
O
H
5
a–c were used. These results indicated the aryl groups on the P
Figure 1. (a) (2S)-3-exo-(Dimethylamino)isoborneol (DAIB). (b)
Ishihara’s chiral ligands for alkyl or aryl zinc additions. (c) Our
atom influenced the reactivity and the enantioselectivity mainly
through steric effects. Ligand 5e worked as the most promising
one. Using 5e as the ligand, solvents other than toluene, the
new
ligands
bearing
spiro[indane-1,2′-pyrrolidin]-5′-one
backbone.
2
catalyst loading and the amount of Et Zn were examined in the
Results and Discussion
1R)-7-Diarylphosphinoyl-spiro[indane-1,2′-pyrrolidin]-5′-
hope of improving the ee (entries 11–18). In hexanes 5e gave
comparable results as in toluene. In PhCl 24% yield was obtained
(
while in CH
2 2
Cl , THF, or MTBE no product was obtained at all
ones (5a–h) were easily prepared in a cost-effective way from
3R,4S,7aS)-7a-[2-(2-bromo-5-methoxyphenyl)ethyl]-3-
phenyltetrahydropyrrolo[2,1-b]oxazol-5-one (1) (Scheme 1),
which was obtained in quantitative yield from D-
phenylglycinol and
hexanoic acid. AlCl
(
Table 1, entries 12–15). In toluene, 20 mol% 5e gave a
(
quantitative yield and 86% ee in 12 h (entry 16). Further
increasing the amount of 5e did not improve the result (entry 17).
When 1.5 equiv Et
2
a
2
Zn was used, the yield was only 10% though
0 mol% 5e was used (entry 18). Finally, significance of the
6-(2-bromo-5-methoxyphenyl)-4-oxo-
mediated intramolecular Friedel–Crafts
9
3

active proton of the amide group was demonstrated. When the
acidic proton of the amide group in 5e was replaced by a Me
group, the resulting 5h completely lost the function as a ligand
1
2
Ph
24
12
24
12
24
24
24
24
24
12
24
24
12
24
24
24
24
24
24
24
24
24
24
24
5
96
>99
85
>99
>99
>99
>99
92
>99
>99
>99
96
>99
n.r.
n.r.
85
87
80
n.r.
85
43
70
n.r.
45
>99
>99
98
79
89
65
85
78
86
64
82
82
83
84
82
84
n.d.
n.d.
52
72
45
n.d.
2
o-CH
o-CH
o-CH
o-CH
o-ClC H
6 4
3 6 4
m-CH C H
p-CH
p-CH
p-CH
p-ClC
p-BrC
p-CF
m-O NC H
4
3
3
3
3
C
C
C
6
6
6
H
H
H
4
b
3
4
4
c
4
(entry 19), indicating deprotonation of the amide group in 5a–g
5
OC
6
H
4
by Et Zn was involved in the generation of the chiral catalyst.
2
6
7
8
9
Thus, 5e was determined as the optimal “carboxamide–phosphine
oxide” type bifunctional ligand, and 0 °C and toluene were the
optimal conditions.
3 6 4
C H
OC
OC
H
6 4
6 4
H
3
6
H
H
4
1
0d
3
6
4
1
1
1
1
2
3
Table 1. Asymmetric additions of Et
catalyzed by 5a–h.
2
Zn to benzaldehyde
3
C
6
H
4
O
OH
Ligands 5a-h (x mol%)
14
2
6
H
Et2Zn (y equiv)
1
1
1
5
6
7
2 6 4
p-O NC H
1-Naphthyl
2-Naphthyl
2-Furyl
solvent, temperature
Entry Ligand
x
y
Solvent
T
°C)
0
rt
−10
0
0
0
0
0
0
0
0
0
0
0
0
Time Yield
Ee
(%)
30
38
31
36
30
25
52
79
78
32
83
80
n.d.
n.d.
n.d.
86
83
n.d.
n.d.
a
18
(
(h)
12
12
36
36
24
24
24
24
24
24
24
24
24
24
24
12
12
36
36
(%)
95
93
60
68
61
71
83
96
80
31
75
1
2
9
0
Ferrocenyl
1
2
3
4
5
6
7
8
9
5a
5a
5a
5a
5b
5c
5d
5e
5f
10 3.0 toluene
10 3.0 toluene
10 3.0 toluene
(E)-2-Phenylethenyl
(E)-2-Phenylethenyl
2-Phenylethyl
Cyclohexyl
Ph
p-CH
p-ClC
Ph
o-CH
e
2
1
25
34
n.d.
28
8
2
6
3
2
2
2
3
10 3.0
Et
2
O
10 3.0 toluene
10 3.0 toluene
10 3.0 toluene
10 3.0 toluene
10 3.0 toluene
10 3.0 toluene
10 3.0 hexanes
f
2
4
g
2
2
2
2
5
6
7
8
3
OC
6
H
4
g
h
h
6
H
4
5
12
12
3
C
6
H
4
91
1
0
1
2
3
4
5
6
7
8
9
5g
5e
5e
5e
5e
5e
5e
5e
5e
5h
a
Ee was determined by chiral HPLC on a Daicel OB-H, OD-H, AD-H or OJ-
H column. (R)-Enantiomer was the major one. The abs. configuration was
determined by comparison of the HPLC data with literature one
mol% 5e was used. The reaction temperature was rt. 20 mol% 5e was used.
.5 equiv Et
1
1
1
1
1
1
1
1
1
10 3.0
10 3.0 CH
C
6
H
2
5
Cl
Cl
THF
MTBE
24
3
h,5a–c,7b,14 b
. 5
2
n.r.
n.r.
n.r.
>99
>99
10
c
d
10 3.0
10 3.0
20 3.0 toluene
30 3.0 toluene
20 1.5 toluene
10 3.0 toluene
e
f
g
1
2
Zn was used. (n-Bu)
2
Zn was used instead of Et
Zn. EtZnC≡CPh was used instead of Et
2 2
Zn. Ph Zn
h
was used instead of Et
2
2
Zn.
0
0
0
0
To gain some insight into the structures of the chiral zinc
amidates obtained from 5a–g, we tried to get a crystal of the zinc
amidate from 5a and Me Zn but failed. Alternatively, we got the
2
crystal structures of 5a and 5e (Figure 2). For 5a, a single
conformer with the P=O and N–H groups orienting in the same
direction was present in the crystal (Figure 2a). For 5e, two
conformers with the P=O and N–H groups orienting in the same
n.r.
a
Ee was determined by chiral HPLC using a Daicel OB-H column. (R)-
Enantiomer was the major one.
15
2
Then 5e was used to catalyze the additions of Et Zn to several
aldehydes. The results were collected in Table 2. For
benzaldehydes bearing various substituent except nitro group,
(
Figure 2b) or the opposite direction (Figure 2c) were present in
6
4–89% ee′s were obtained with generally high yields (>92%)
the crystal. In both compounds, we believe rotation about the
C7–P bond (Figure 2d) was restricted to a small range due to the
highly constrained spiral structure and the sterically demanding
geminate aryl groups on the P atom. The two observed
conformers in the crystal of 5e represented the extreme ones with
maximum rotation around the C7–P bond. It was due to the
restricted rotation about the C7–P bond that the N atom of the
amide group and the O atom of the P=O group are closely located
and well positioned to await Et Zn, which should facilitate the
2
formation of a stable but unusual “Zn–ligand” complex of a
seven-membered ring structure. It was reasonable to suppose that
a or 5e possess a conformation shown in Figure 2a and 2b,
respectively, in the zinc complex.
(entries 1–12). For other tested aromatic aldehydes except
ferrocenecarboxaldehyde, moderate yields (80–87%) were
obtained with low ee′s (45–72%) (entries 13–16). With 3.0 equiv
Et
phenylpropanal gave the addition product in 34% ee (entries 17,
9). When 1.5 equiv Et Zn was used, cinnamaldehyde gave the
addition product in 25% ee and 43% yield (entry 18). (n-Bu) Zn,
prepared n-BuLi and ZnCl , was reacted with PhCHO. But poor
yield (45%) and ee (28%) were obtained (entry 21).
2
Zn, cinnamaldehyde gave nearly racemic product while 3-
1
2
2
2
2
Additions of Ph Zn or EtZnC≡CPh to aromatic aldehydes as
5
well as Et Zn addition to acetophenone were also tested. Ph Zn,
prepared from PhMgBr and ZnCl , was reacted with p-
CH OC CHO or p-ClC CHO. Nearly racemic products (8%
ee and 2% ee) were obtained in quantitative yields. In the
presence of Et Zn, reactions of phenylacetylene with PhCHO or
o-CH CHO also gave nearly racemic (6% ee and 3% ee)
2
2
2
3
6
H
4
6 4
H
2
3
6 4
C H
products in 98% and 91% yields, respectively, most of which
were possibly generated with no participation of ligand 5e. When
acetophenone was reacted with Et
addition product was observed.
2
Zn in the presence of 5e, no
(a)
(c)
(b)
Figure 2. (a) Single conformer of 5a in the crystal. (b) One
conformer of 5e in the crystal. (c) The other conformer of 5e in
the same crystal. The ellipsoids were drawn at 50% probability.
2
Table 2. Asymmetric additions of Et Zn to aldehydes catalyzed
by 5e.
Ligand 5e (10 mol%)
Et2Zn (3.0 equiv)
O
OH
Based on the crystal structures of 5a and 5e, and the absolute
configurations of the major enantiomers of the addition products,
we proposed the following transition state assemblies for 5e
R
H
R
toluene, 0 °C, 24 h
Entry
R
Time (h)
Yield (%)
Ee (%)a
2 2
catalyzed additions of Et Zn to benzaldehyde. Et Zn

deprotonated the amide group of 5e to generate the ethylzinc
amidate. The zinc amidate was then coordinated with the O atom
of the proximal P=O group, forming the Lewis acid catalyst
precursors, in which several complicated species might be
included. When benzaldehyde was added to the reaction mixture,
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2
3
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2
the ethylzinc amidate, benzaldehyde and the reacting Et Zn might
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3
). For both transition states in Figure 3, the pseudo axial Et
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2
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3
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4
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t-Bu
t-Bu
t-Bu
t-Bu
N
O
N
O
Et
P
Et
Et
P
Et
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t-Bu
Zn
t-Bu
Zn
Zn
O
O
Zn
Re
O
Et
Et
Si
t-Bu
H
H
t-Bu
(a)
(b)
2
000, 122, 6327–6328. (i) Hamashima, Y.; Kanai, M.; Shibasaki,
Figure 3. Proposed transition state assembly of the addition
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2
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In conclusion, we disclosed chiral zinc amidate catalyzed
additions of Et
complexes of a new type of chiral spiro ligands bearing
carboxamide–phosphine oxide” functional groups worked as
2
Zn to aldehydes. The in situ formed Zn
5
443–5445. (f) Hatano, M.; Gouzu, R.; Mizuno, T.; Abe, H.;
“
Yamada, T.; Ishihara, K. Catal. Sci. Technol. 2011, 1, 1149–1158.
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effective catalysts. Excellent yields and moderate ee′s were
obtained for benzaldehyde derivatives. Possible transition states
were proposed according to the crystal structures of two chiral
ligands. Though the ee′s were only moderate, carboxamide acting
as an acidic group to introduce a Lewis acidic Zn center was
demonstrated for the first time, which is conceptually new and
might be of referential value for ligand design.
6
.
2
Chiral phosphonamide ligand in Et Zn addition to aldehydes: (a)
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Zn addition to aldehydes: (a)
Acknowledgments
2
Song, L. J. Org. Chem. 2015, 80, 12614–12619.
For chiral phosphine oxides in asymmetric catalysis, see: (a) Hu,
J.; Hirao, H.; Li, Y.; Zhou, J. Angew. Chem., Int. Ed. 2013, 52,
Financial supports from Beijing Normal University and
National Natural Science Foundation of China (NSFC) are
acknowledged. This work was supported in part by a grant (No.
015BAK45B01) from Ministry of Science and Technology
MOST) of the People’s Republic of China. Prof. Jia-Xin Zhang,
Jin-Ping Qiao at College of Chemistry, Beijing Normal
University are acknowledged for assistance with NMR/HRMS
experiments. We thank Prof. Xiang Hao at Institute of Chemistry,
Chinese Academy of Science (ICCAS) for his help with XRD
analyses.
8
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Supplementary Material
Supplementary data to this article can be found online at
https://doi.org/10.1016.

6

Graphical Abstract
Chiral Zinc Amidate Catalyzed Additions of
Diethylzinc to Aldehydes
Leave this area blank for abstract info.
Jinxia Zhang, Shasha Li, Xinxin Zheng, Hongjie Li, and Peng Jiao*
O
PAr2
(10 mol%)
N
O
H
O
OH
Ar = 3,5-(t-Bu) C H
2
6
3
+
Et Zn
2
R
H
R
toluene, 0 °C

7



Chiral zinc amidate catalyzes additions of Et Zn to aldehydes in high yields and mediocre ee.
2
Carboxamides bearing a phosphine oxide group work as bifunctional ligands.
Spiro[indane-1,2ʹ-pyrrolidin]-5ʹ-one constitutes a rigid backbone for effective chiral ligands.