Activation of functional arylzincs prepared from aryl iodides and highly enantioselective addition to aldehydes

Article abstract of DOI:10.1021/ol8008478

(Chemical Equation Presented) An easily available chiral ligand (S)-1 is found to activate the nucleophilic reaction of the arylzincs prepared in situ from the reaction of aryl iodides with Et₂Zn. Both high yields and high enantioselectivity (u

Full text of DOI:10.1021/ol8008478

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2709-2712
Activation of Functional Arylzincs
Prepared from Aryl Iodides and Highly
Enantioselective Addition to Aldehydes
Albert M. DeBerardinis, Mark Turlington, and Lin Pu*
Department of Chemistry, UniVersity of Virginia, CharlottesVille, Virginia 22904-4319
lp6n@Virginia.edu
Received April 13, 2008
ABSTRACT
An easily available chiral ligand (S)-1 is found to activate the nucleophilic reaction of the arylzincs prepared in situ from the reaction of aryl iodides
with Et2Zn. Both high yields and high enantioselectivity (up to >99% ee) for the reaction of these arylzincs with a variety of aldehydes are obtained.
The mild reaction conditions and the good functional group tolerance make this catalytic asymmetric process synthetically useful.
Addition of organozinc reagents to aldehydes to synthesize
secondary alcohols has become a useful method because of
the high functional group tolerance of the organozinc
reagents. Many highly enantioselective catalysts have been
developed for the asymmetric alkylzinc addition to alde-
hydes.1 For the arylzinc additions, most of the reports are
on the use of diphenylzinc because only this diarylzinc
reagent is commercially available.2 Bolm3 and Dahmen4
reported the use of the preprepared arylboronic acids and
arylboranes in combination with Et2Zn to generate various
arylzincs for the catalytic asymmetric addition to aldehydes.
Walsh prepared diarylzincs from the reaction of aryl
bromides with nBuLi at low temperature and conducted the
subsequent enantioselective addition to aldehydes.5 Since the
preparation of arylzincs in this method uses an alkyllithium,
it could potentially limit the type of functional groups on
the resulting diarylzincs.
Recently, Knochel reported a preparation of diarylzincs
from the reaction of aryliodides with a dialkylzinc under very
mild conditions.6 The use of a dialkylzinc in this method
instead of an alkyllithium allows the preparation of a great
variety of functional arylzinc reagents. We tested the reaction
of aldehydes with a few functional arylzincs prepared in situ
with this method but only observed very low yields of the
alcohol products. Scheme 1 shows the reaction of m-
iodoanisole with Et2Zn under Knochel’s conditions, which
presumably produced a diarylzinc complex.6 When this
arylzinc was treated with cyclohexanecarboxaldehyde at
Scheme 1
.
Preparation of a Substituted Arylzinc and Its
Addition to an Aldehyde
(1) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757–824.
(2) (a) Schmidt, F.; Stemmler, R. T.; Rudolph, J.; Bolm, C. Chem. Soc.
ReV. 2006, 35, 454–470. (b) Dosa, P. I.; Ruble, J. C.; Fu, G. C. J. Org.
Chem. 1997, 62, 444–445. (c) Huang, W.-S.; Pu, L. J. Org. Chem. 1999,
64, 4222–4223. (d) Bolm, C.; Mun˜iz, K. Chem. Commun. 1999, 1295–
1296.
(3) Bolm, C.; Rudolph, J. J. Am. Chem. Soc. 2002, 124, 14850–14851.
(4) Dahmen, S.; Lormann, M. Org. Lett. 2005, 7, 4597–4600.
(5) Kim, J. G.; Walsh, P. J. Angew. Chem., Int. Ed. 2006, 45, 4175–
4178.
10.1021/ol8008478 CCC: $40.75
Published on Web 06/04/2008
2008 American Chemical Society

room temperature, the corresponding alcohol was isolated
in only 30% yield after 19 h. Thus, these arylzincs have quite
low nucleophilicity under the reaction conditions and need
to be activated for addition to aldehydes.
Table 1. Addition of the Arylzinc Generated from
m-Iodoanisole to Aldehydes in the Presence of (S)-1
Herein, we report our discovery of a catalytic process that
can not only activate the arylzincs prepared in situ from the
reaction of aryl iodides with Et2Zn for the nucleophilic
addition to aldehydes but can also provide excellent enan-
tioselectivity.
Previously, we found that the chiral 1,1′-binaphthyl
compound (S)-1, prepared in one step from (S)-H8BINOL
(5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-bi-2-naphthol), was highly
enantioselective for the reaction of diphenylzinc with alde-
hydes.7 This compound was tested for the reaction of the
functional arylzincs with aldehydes. We were delighted to
find that in the presence of 10 mol % of (S)-1, the arylzinc
generated in situ from m-iodoanisole reacts with cyclohex-
anecarboxaldehyde to give the desired secondary alcohol not
only in greatly increased yield (94%) but also with very high
enantioselectivity (>99% ee). Thus, (S)-1 not only activates
the nucleophilic arylzinc addition to the aldehyde but also
has excellent stereocontrol.
Table 1 summarizes the reaction of the in situ prepared
(3-MeO-C6H4)2Zn with various aldehydes catalyzed by (S)-
1. In the presence of 10 mol % of (S)-1, the arylzinc additions
to aromatic and aliphatic aldehydes are activated. Without
(S)-1, the reactions are much slower with very low yields of
the alcohol products. For example, almost no product was
obtained for the arylzinc addition to m-nitrobenzaldehyde
in the absence of (S)-1 (entry 4). However, using (S)-1 led
to 93% yield of the desired diarylcarbinol. In addition, high
enantioselectivity (83->99% ee) was achieved for the
arylzinc addition to both aromatic and aliphatic aldehydes.
In entry 8, the addition to a chiral aldehyde generated both
diastereomers in 1:1 ratio, each with over 99% ee.
Following is the general procedure used for the reactions
shown in Table 1. Under nitrogen, to a 10 mL round-bottom
flask (flame dried under vacuum) were added sequentially
Li(acac) (24 mg, 0.23 mmol, 0.25 equiv), 3-iodoanisole (238
µL, 2.0 mmoL, 2.2 equiv), and NMP (1.5 mL). This mixture
was cooled to 0 °C, and Et2Zn (115 µL, 1.1 mmoL, 1.2
equiv) was added dropwise. The mixture was stirred at 0 °C
for 12 h to which a solution of (S)-1 (45 mg, 0.091 mmoL,
10 mol %) in THF (5 mL) was then transferred. This was
stirred at 0 °C for 1 h and then warmed to room temperature.
An aldehyde (0.91 mmoL) was added, and the reaction was
monitored by TLC. Upon completion of the reaction,
ammonium chloride (saturated aqueous) was added to quench
the reaction. CH2Cl2 was used to extract the mixture three
times. The organic fractions were dried over Na2SO4 and
concentrated, and the residue was purified by flash column
a Third step. b The combined yield of both diastereomers.
chromatography on silica gel eluted with hexanes (or
petroleum ether)/ethyl acetate (0-12% ethyl acetate) to give
the alcohol product as either an oil or solid in 85 to 95%
yield. The ee’s were 83->99% determined by using HPLC:
Chiralcel OD-H column (solvent: hexanes/2-propanol). The
absolute configuration for (m-methoxyphenyl)phenylcarbinol
generated from (S)-1 was determined to be R by comparing
its optical rotation with that reported in the literature.8
Using a procedure similar to that described above, we
conducted the reaction of benzaldehyde with the arylzinc
generated in situ from methyl p-iodobenzoate and Et2Zn. As
shown in entry 1 of Table 2, this gave only low yield (47%)
and ee (67%) of the corresponding diarylcarbinol product.
Increasing the time for the arylzinc formation step at room
temperature increased the yield to 63% and the ee to 71%
(entry 2). Using Ph2Zn or Et2Zn to prepare the zinc complex
of (S)-1 as the catalyst increased the yield but decreased the
ee (entries 3,4). Increasing the amount of (S)-1 to 20 mol %
did not improve the enantioselectivity (entry 5). Changing
the solvent in the second step from THF to toluene or Et2O
(6) Kneisel, F. F.; Dochnahl, M.; Knochel, P. Angew. Chem., Int. Ed.
2004, 43, 1017–1021.
(7) Qin, Y.; Pu, L. Angew. Chem., Int. Ed. 2006, 45, 273–277.
(8) Kosaka, M.; Sugito, T.; Kasai, Y.; Kuwahara, S.; Watanabe, M.;
Harada, N.; Job, G. E.; Shvet, A.; Pirkle, W. H. Chirality 2003, 15, 324–
328.
2710
Org. Lett., Vol. 10, No. 13, 2008

Table 2. Conditions for the Reaction of Methyl p-Iodobenzoate with Benzaldehyde in the Presence of Et2Zn and (S)-1a,b
reaction time
first step
(h)
reaction temp
second step
(°C)
reaction temp
third step
(°C)
reaction time
third step
(h)
isolated
yield
(%)
solvent second
step (mL)
entry
(S)-1 (mol %)
ee (%)
1c
2d
3e
4f
5
12
12
18
16
18.5
21
21
18.5
12
17
10
10
10
10
20
10
10
10
10
20
20
THF (5)
THF (5)
THF (5)
THF (5)
THF (5)
toluene (5)
Et2O (5)
CH2Cl2 (5)
CH2Cl2 (10)
CH2Cl2 (5)
CH2Cl2 (20)
rt
rt
rt
rt
0
0
0
0
0
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
27
27
22
27
17.5
23
23
16
9
47
63
75
90
86
quant.
80
88
93
67
71
54
52
65
45
55
79
84
84
94
6g
7
8
9
10
11
0
0
9
17
99
97
18
a Unless otherwise indicated, the following conditions were employed: 2.0 mmol of methyl p-iodobenzoate (2.2 equiv), 0.24 mmol of Li(acac) (0.25
equiv), 1.1 mmol of Et2Zn (1.2 equiv), NMP (1.5 mL), and 0.91 mmol of benzaldehyde. Preparation of the arylzinc in the first step was conducted at 0 °C.
Upon addition of a solution of (S)-1 to the arylzinc solution, the reaction mixture was stirred for 1 h prior to addition of benzaldehyde. b ee’s were measured
on Chiralpak HPLC AD column (2% IPA:98% hexanes, 1 mL/min). c Arylzinc was prepared at 0 °C for 6 h and then at rt for 6 h. d Arylzinc was prepared
at 0 °C for 0.5 h and then at rt for 11.5 h. e (S)-1 was mixed with Ph2Zn (2.0 equiv versus the ligand) at rt for 1 h and then combined with benzaldehyde
before addition to the arylzinc solution. f (S)-1 was mixed with Et2Zn (2.0 equiv versus the ligand) at rt for 1 h and then combined with benzaldehyde before
addition to the arylzinc solution. g 3.2 equiv of aryl iodide was used.
decreased the ee (entries 6 and 7). Using CH2Cl2 as the
solvent in the second step significantly improved both the
yield and ee (entry 8). Increasing the amount of CH2Cl2
further improved the enantioselectivity (entry 9). Finally, by
using 20 mol % of (S)-1 in CH2Cl2 at 0 °C, up to 97% yield
and 94% ee were obtained for this reaction (entry 11).
Table 3. Addition of the Arylzinc Generated from Methyl
p-Iodobenzoate to Aldehydes in the Presence of (S)-1a
The optimized conditions of entry 11 in Table 2 are applied
to the reaction of various aldehydes with the arylzinc
generated in situ from methyl p-iodobenzoate and Et2Zn, and
the results are summarized in Table 3. High yield and
enantioselectivity are observed for a variety of aliphatic,
aromatic, and R,ꢀ-unsaturated aldehydes. Using (S)-1 has
greatly activated the arylzinc addition with high stereocontrol.
For example, without (S)-1, there is little addition of the
arylzinc generated from methyl p-iodobenzoate to cyclohex-
anecarboxaldehyde (4% yield). In the presence of 20 mol %
of (S)-1, the desired product was isolated in 86% yield and
96% ee (entry 1).
We also studied the reaction of benzaldehyde with the
arylzinc generated from m-iodobenzonitrile in the presence
of (S)-1. Table 4 summarizes the conditions for this reaction.
It was found that THF was a better solvent than others such
as CH2Cl2, toluene, and Et2O (entries 1-11). The optimized
conditions involved the use of 40 mol % of (S)-1 and THF
at 0 °C, which gave the product in 87% yield and 84% ee
(entry 14).
a Conditions: 2.0 mmol of methyl p-iodobenzoate (2.2 equiv), 0.23 mmol
of Li(acac) (0.25 equiv), 1.1 mmol of Et2Zn (1.2 equiv), NMP (1.5 mL),
(S)-1 (20 mol %), and 0.91 mmol of aldehyde. Preparation of the arylzinc
in the first step was conducted at 0 °C for 18 h. Upon addition of a CH2Cl2
(20 mL) solution of (S)-1 to the arylzinc solution (second step), the reaction
mixture was stirred at 0 °C for 1 h prior to addition of aldehyde (third
step). b Third step.
The conditions in entry 14 of Table 4 are applied to the
reactions of several aldehydes with the arylzinc generated
in situ from m-iodobenzonitrile and Et2Zn. As shown in Table
5, good yields and enantioselectivity are observed for the
addition to several aromatic and aliphatic aldehydes.
Org. Lett., Vol. 10, No. 13, 2008
2711

Table 4. Conditions for the Reaction of m-Iodobenzonitrile with Benzaldehyde in the Presence of Et2Zn and (S)-1a,b
reaction temp reaction temp
isolated
yield
(%)
m-iodobenzonitrile
solvent second second step
third step
entry (equiv vs PhCHO) (S)-1 (mol%)
step (mL)
(°C)
(°C)
reaction time third step (h)
ee (%)
1c
2.2
2.2
2.2
2.2
2.2
2.2
2.6j
2.6j
2.2
2.2
3.2k
2.2
3.2k
3.2k
10
10
10
10
10
20
20
20
20
20
20
20
40
40
THF (5)
0
0
0
0
0
0
0
0
rt
rt
rt
0
rt
rt
rt
rt
rt
rt
rt
rt
0
0
rt
rt
rt
11-13
0
0
30
20
20
20
20
24
22
22
24
24
36
44
36
48
77
93
87
80
80
61
65
27
70
40
70
50
60
87
66
35
52
25
42
77
52
38
71
73
17
79
88
84
2c, d
3
CH2Cl2 (5)
CH2Cl2 (5)
toluene (5)
Et2O (5)
THF (20)
CH2Cl2 (10)
THF (10)
THF (20)
CH2Cl2 (20)
toluene (20)
THF (20)
THF (25)
THF (25)
4
5e
6
7
8
9f
10f
11f,g
12
13h
14i
a Unless otherwise indicated, the following conditions were employed: Li(acac) (0.25 equiv), Et2Zn (1.2 equiv), NMP (1.5 mL), and 0.91 mmol of
benzaldehyde. Arylzinc preparation proceeded at 0 °C for 18 h. A solution of (S)-1 was added to the arylzinc solution and stirred for 1 h before the addition
of benzaldehyde. b ee’s were measured on a Chiralpak HPLC AD column (solvent: 2-propanol/hexanes). c Arylzinc was prepared at 0 °C for 17 h. d 1.1
mmol of m-iodobenzonitrile and 0.5 mmol of benzaldehyde were used. e (S)-1 was sonicated in Et2O for 45 m. f (S)-1 was mixed with Ph2Zn (2 equiv versus
the ligand) at rt for 1 h and then combined with benzaldehyde before addition to the arylzinc solution. g Arylzinc was prepared at 0 °C for 12 h. h Arylzinc
was prepared at 0 °C for 14 h and then at rt for 4 h. i Arylzinc was prepared at 0 °C for 2 h and then at rt for 34 h. j Li(acac) (0.31 equiv) and Et2Zn (1.4
equiv). k Li(acac) (0.38 equiv) and Et2Zn (1.8 equiv),
In summary, we have discovered that an easily available
chiral ligand (S)-1 can activate the nucleophilic reaction of
the arylzincs prepared in situ from aryliodides and Et2Zn.
Both high yields and high enantioselectivity for the reaction
of the arylzincs with a variety of aldehydes are obtained.
The mild reaction conditions and the good functional group
tolerance make this method synthetically useful. We are
currently working on modifying the structure of the catalyst
in order to further improve this catalytic asymmetric reaction.
Table 5. Addition of the Arylzinc Generated from
m-Iodobenzonitrile to Aldehydes in the Presence of (S)-1a
Acknowledgment. Partial support of this work from the
US National Science Foundation (CHE-0717995) and the
donors of the Petroleum Research Fund, administered by
the American Chemical Society, is gratefully acknowledged.
a Conditions: Li(acac) (0.38 equiv), Et2Zn (1.8 equiv), NMP (1.5 mL),
and 0.91 mmol of aldehyde. Arylzinc preparation proceeded at 0 °C for
2 h and rt for 34 h (first step). A THF (25 mL) solution of (S)-1 (40 mol
%) was added to the arylzinc solution (second step) and stirred at rt for
1 h. It was then cooled to 0 °C for the addition of aldehyde (third step).
b Third step.
Supporting Information Available: Synthesis, charac-
terization and ee determination of the chiral alcohol products
are provided. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL8008478
2712
Org. Lett., Vol. 10, No. 13, 2008