A chiral bipyridyl alcohol for catalytic enantioselective Nozaki-Hiyama-Kishi allylation of aldehydes and ketones

Article abstract of DOI:10.1002/adsc.201400945

A class of bipyridyl alcohol ligands has been developed. A catalyst synthesized using a chromium(II)-ligand promotes the enantioselective Nozaki-Hiyama-Kishi (NHK) allylation of aldehydes and ketones with allylic halides. The allylation of various aromati

Full text of DOI:10.1002/adsc.201400945

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DOI: 10.1002/adsc.201400945
A Chiral Bipyridyl Alcohol for Catalytic Enantioselective
Nozaki–Hiyama–Kishi Allylation of Aldehydes and Ketones
Rui-Yu Chen,a Attrimuni P. Dhondge,a Gene-Hsian Lee,b and Chinpiao Chena,*
a
Department of Chemistry, National Dong Hwa University, Soufeng, Hualien 97401, Taiwan, Republic of China
Fax : (+886)-3-863-3597; e-mail: chinpiao@mail.ndhu.edu.tw
Instrumentation Center, College of Science, National Taiwan University, Taipei 106, Taiwan, Republic of China
b
Received: September 28, 2014; Revised: December 28, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400945.
Abstract: A class of bipyridyl alcohol ligands has
been developed. A catalyst synthesized using a chro-
mium(II)-ligand promotes the enantioselective
Nozaki–Hiyama–Kishi (NHK) allylation of alde-
hydes and ketones with allylic halides. The allyla-
tion of various aromatic, a,b-unsaturated, and ali-
phatic aldehydes and ketones produces the desired
homoallylic alcohols in satisfactory yields (up to
98%) and high enantioselectivities (up to 99% ee).
The present method can be applied widely and af-
fords an efficient means of obtaining chiral homoal-
lylic alcohols.
extensively because of their potential utility.[3] In addi-
tion, these reactions have been applied to synthesize
several complex natural products because they exhibit
high chemoselectivity and excellent compatibility with
various functional groups.[3] Organochromium re-
agents are easily prepared in situ through the oxida-
tive addition of Cr(II) species to allyl, propargyl, aryl,
vinyl halides and triflates [requiring catalytic amounts
of an Ni(II) salt for sp2 carbon centers] and can be
added to aldehydes to produce the corresponding al-
cohols in satisfactory yields.[3a,b,4] The major drawback
of the original NHK allylation is the requirement for
high stoichiometric amounts of Cr(II) salts for the for-
mation of the organochromium nucleophile.[2,5] Fꢀrst-
ner and Shi[6] developed the original NHK allylation
which requires only catalytic amounts of active Cr(II)
species. Cheap and toxicologically benign Mn is used
as the reducing agent and a trialkylchlorosilane af-
fects the perpetuation of the catalytic cycle.
Keywords: asymmetric catalysis; bipyridyl alcohol;
chromium catalysis; enantioselectivity; Nozaki–
Hiyama–Kishi allylation
These preliminary improvements have motivated
The enantioselective allylation of carbonyl functional numerous efforts to improve the enantioselectivity of
groups for producing homoallylic alcohols has ac- this reaction. Several structurally dissimilar chiral li-
quired considerable attention because of the versatili- gands have been used as enantioselective catalysts for
ty of the products (homoallylic alcohols), which are the allylation of aldehydes, and this has resulted in
major building blocks for synthesizing many natural various degrees of asymmetric induction.[7] Lately, car-
products and pharmaceuticals.[1] The development of bonyl allylation has been extended to ketones.[8] After
asymmetric catalytic processes for obtaining secon- 2009,[8c] to the best of our knowledge, there has been
dary homoallylic alcohols from aldehydes has greatly no report about NHK allylation of ketones. Develop-
enhanced the potential of synthesis. However, the cat- ing new and effective chiral ligands for the NHK ally-
alytic asymmetric allylation of ketones for obtaining lation of ketones is extremely complicated and re-
enantiopure tertiary homoallylic alcohols is more quires a wide screening of chiral ligands.
challenging because of the substantial difference in
Our study on chiral bipyridine ligands obtained
the reactivity between aldehydes and ketones. There- from enantioenriched pinene revealed satisfactory
fore, intensive research has been conducted in this enantioselectivities in several asymmetric transforma-
area in recent years, leading to the development of tions.[9] The successful application of these ligand sys-
a large and diverse array of chiral catalysts for adding tems motivated us to screen the NHK allylation of al-
an allyl transfer reagent to carbonyl functional dehydes and ketones. We posited that manipulating
groups.
a pineno-bipyridyl alcohol framework plays a crucial
À
Cr(II)-mediated C C bond forming reactions origi- role in further improving the catalytic properties, and
nally developed by Nozaki et al.[2] have been studied thus, may afford a promising stereochemical outcome.
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Table 1. Optimization of chiral bipyridyl alcohol ligands for
the chromium-catalyzed addition of allyl bromide to
PhCHO.
Entry
Ligand
Yield [%][a]
ee [%][b]
Configuration
1
2
3
4
5
6
1
2
3
4
5
6
83
88
80
87
70
80
90
89
85
76
72
74
R
R
R
R
R
R
[a]
Isolated yield.
[b]
The ee % was determined on a Chiracel OD-H HPLC
Scheme 1. Ligand synthesis: a) ref.[9]; b) LDA, benzophen-
one, THF, À508C.
column.
ACHTUNGTRENNUNG
(Table 1, entry 1). Ligands 2 and 3, bearing an elec-
Pineno-bipyridyl alcohols are readily obtainable from tron-donating group, gave slightly lower enantioselec-
(+)-a-pinene in six steps, which include the stereose- tivities than did their parent ligand 1. However, li-
lective alkylation of chiral bipyridine with ketones gands 4–6, which contained halogen substituents on
(Scheme 1). X-ray crystallographic analysis of (+)-1 the para-phenyl group, exhibited satisfactory yields
(Figure 1) verified the general structure of these tri- and lower enantioselectivities. The electronic and
dentate N2O ligands.
steric characters of a substituent on the phenyl ring of
Initial evaluation of non-symmetrical bipyridyl al- the ligand had little influence on the enantioselectivi-
cohol ligands (1–6) in the Cr(II)-catalyzed addition of ty of the reaction (Table 1, entries 2–6).
allyl bromide to benzaldehyde revealed that the bi-
The allylation of benzaldehyde in the presence of
pyridyl alcohol ligand 1 afforded a satisfactory yield a Cr-1 catalyst was further optimized with respect to
(83%) and excellent enantioselectivity (90%) the nature of the solvents at various reaction temper-
atures and bases, catalyst loadings, and allyl counter-
parts. Table 2 shows the optimization results. Of all
the solvents used, tetrahydrofuran (THF) was the
most favorable because it afforded superior yields
and enantiomeric excesses (ee) (Table 2, entries 1–5).
The reaction of benzaldehyde at lower temperatures
in the presence of triethylamine (TEA), or after re-
placing TEA with the Hꢀnigꢂs base or K2CO3 did not
furnish any beneficial results (Table 2, entries 6–9).
In addition, the amounts of catalyst and CrCl3 were
studied to improve the enantioselectivity of the NHK
allylation. Reducing the catalyst loading slightly af-
fected the enantioselectivity of the reaction; however,
the yields of the allylation were 31% and 80% by
using 10 mol% and 20 mol% catalyst, respectively
(entries 10 and 11). When CrCl3 and the catalyst load-
ing were reduced to 5 mol% and 10 mol%, respective-
ly, the selectivity and yield of the reaction decreased
(entry 12). Conversely, an increase in the amount of
the Cr-1 catalyst to 40 mol% did not increase the
enantioselectivity (entry 13).
The active role of different allyl halides in the
enantioselective NHK allylation has been investigat-
ed. However, the observed enantioselectivity yielded
by allyl chloride (83%) was not as high as that yielded
Figure 1. X-ray crystallographic structures of bipyridyl alco-
hol 1 (CCDC 995407).[10]
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Table 2. Optimization of reaction conditions for Nozaki–Hiyama–Kishi allylation of benzaldehyde.
Entry Metal Allyl halide
Solvent T [8C] Base
Metal [mol%] Ligand [mol%] Yield [%][a] ee [%][b]
1
2
3
4
5
6
7
8
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
CrBr3
CrBr3
allyl bromide THF
allyl bromide CH2Cl2
allyl bromide DMF
r.t.
r.t.
r.t.
TEA
TEA
TEA
TEA
TEA
TEA
TEA
DIPA
10
10
10
10
10
10
10
10
30
30
30
30
30
30
30
30
30
10
20
10
40
30
30
30
83
27
20
NR
NR
76
83
84
73
31
80
43
77
78
74
80
90
60
84
–
allyl bromide toluene r.t.
allyl bromide ether
allyl bromide THF
allyl bromide THF
allyl bromide THF
allyl bromide THF
allyl bromide THF
allyl bromide THF
allyl bromide THF
allyl bromide THF
r.t.
0
–
84
84
88
89
86
88
86
85
83
80
87
À20
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
9
K2CO3 10
10
11
12
13
14
15
16
TEA
TEA
TEA
TEA
TEA
TEA
TEA
10
10
5
10
10
10
10
allyl chloride
allyl bromide THF
allyl chloride THF
THF
[a]
[b]
Isolated yield.
Enantiomeric ratio determined by HPLC equipped with a chiral stationary phase.
Table 3. Nozaki–Hiyama–Kishi allylation reactions of alde-
hydes catalyzed by Cr(II)-1 complexes.
by allyl bromide (entry 14). We considered that the
Cr source may play a significant role in the NHK ally-
lation. The reactions were induced using allyl bromide
and allyl chloride in the presence of CrBr3; they yield-
ed an appreciable amount of products with an 80% ee
and 87% ee, respectively (entries 15 and 16).
Entry
R
Product Yield ee
[%][a] [%][b]
Config-
uration[c]
Considering the optimized reaction conditions, we
investigated the generality of the NHK allylation by
using various aldehydes. All of the reactions were
completed within 36 h, producing adducts with good
to excellent yields (51–95%) and enantioselectivities
(48–99% ee). The position and electronic property of
a substituent on the aromatic ring exerted a limited
influence on the stereoselectivity of the reaction;
(Table 3, entries 2–12), 4-cyanobenzaldehyde was an
unsuitable substrate for the transformation (entry 12).
Substrates with electron-withdrawing (entries 2–7),
electron-donating (entries 8–12), and neutral (en-
tries 1, 13 and 14) in various substitution patterns
(para, meta and ortho) participated in this reaction ef-
ficiently. Aromatic groups and heteroaromatic groups,
such as furyl and thienyl, could be effectively used to
afford the respective homoallyl alcohol derivatives
with excellent enantioselectivities (entries 15 and 16).
Products with excellent enantioselectivities were ob-
tained when aliphatic aldehydes were used; the allyla-
tion of cyclohexanecarboxaldehyde afforded the cor-
responding homoallyl alcohol with a 51% yield and
>99% ee (entry 18).
1
2
3
4
5
6
7
8
Ph
7
8
9
83
90
R
R
R
R
R
R
R
R
–
R
–
–
R
R
R
R
R
R
2-CH3OC6H4
3-CH3OC6H4
4-CH3OC6H4 10
92 82
80
95
53
78
67
94
86
79
90
55
84
95
90
95
56
51
84
90
92
82
85
69
83
73
76
48
85
80
86
85
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
3-CNC6H4
4-CNC6H4
1-naphthyl
2-naphthyl
2-furyl
11
12
13
14
15
16
17
18
19
20
21
22
23
24
9
10
11
12
13
14
15
16
17
18
2-thienyl
n-pentyl
cyclohexyl
90
>99[d]
[a]
Isolated yields.
Enantiomeric ratio determined by HPLC equipped with
a chiral stationary phase.
[b]
[c]
[d]
Assigned by comparison of the sign of optical rotation
with reported value.[7y]
1
After optimizing the reaction parameters for the al-
lylation, we extended the catalytic enantioselective
Enantiomeric ratio determined by H NMR of Mosherꢂs
ester.
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Table 4. Nozaki–Hiyama–Kishi allylation reactions of ke-
tones catalyzed by Cr(II)-1 complexes.
Experimental Section
Ligand Synthesis: (10,10-Dimethyl-5-pyridin-2-yl-6-
azatricyclo[7.1.1.02,7]-undeca-2(7),3,5-trien-8-yl)-
diphenylmethanol (1)
n-BuLi (3 mL, 4.8 mmol, 1.6M in hexane) was added to a so-
lution of diisopropylamine (728 mL, 5.2 mmol) in THF
(8 mL) at À788C, and the solution was stirred for 30 min to
produce lithium diisopropylamide ( LDA). A solution of bi-
pyridine (1.00 g, 4.0 mmol) in THF (8 mL) was added to the
LDA solution and stirred for 2 h to generate a dark blue so-
lution. A solution of benzophenone (800 mg, 4.4 mmol) in
THF (8 mL) was added to this dark blue solution and the
temperature was slowly raised to room temperature and
maintained there for 8 h. The reaction was quenched by
adding NH4Cl solution and the mixture was then extracted
with EtOAc. The combined organic phase was dried over
anhydrous MgSO4. After concentration, the residue was pu-
rified using flash column chromatography involving silica
gel as the stationary phase and ethyl acetate-hexane (1:9) as
the mobile phase; this procedure produced 1; yield: 1.20 g
Entry
R
Product Yield ee
Config-
[%][a] [%][b] uration[c]
1
2
3
4
5
6
7
8
9
Ph
25
82
96
81
98
81
77
88
92
58
88
91
90
97
91
85
91
67
51
R
–
R
R
–
R
R
R
R
3-CH3OC6H4 26
3-CH3C6H4
3-BrC6H4
3-CNC6H4
27
28
29
3-CF3OC6H4 30
2-naphthyl
PhCH=CH
n-butyl
31
32
33
[a]
Isolated yields.
[b]
Enantiomeric ratio determined by HPLC equipped with
a chiral stationary phase.
1
(2.77 mmol, 70%). [a]2D0: À3888 (c 1.03, CH2Cl2); H NMR
[c]
Assigned by comparison of the sign of optical rotation
with reported value.[8c,j]
(400 MHz, CDCl3): d=9.86 (s, 1H), 8.69–8.68 (d, J=4.0 Hz,
1H), 8.27–8.20 (m, 2H), 7.80–7.75 (td, J1 =16.0 Hz, J2 =
1.3 Hz, 1H), 7.46–7.29 (m, 7H), 7.10 (s, 5H), 4.48 (s, 1H),
2.63–2.57 (m, 2H), 2.11–2.05 (m, 1H), 1.41 (s, 3H), 0.89 (s,
3H), À0.08 to À0.11 (d, J=12.0 Hz, 1H); 13C NMR
(100.6 MHz, CDCl3): d=156.8, 155.3, 151.5, 149.3, 146.9,
145.8, 144.3, 137.2, 135.0, 128.2, 127.9, 127.1, 127.1, 126.5,
123.7, 120.7, 118.8, 81.9, 47.9, 45.8, 43.0, 28.8, 26.4, 21.2; IR
(KBr): n=3861, 3846, 3831, 3743, 3679, 3655, 3622, 3568,
3153, 3057, 2975, 3947, 2872, 2362, 2355, 1558, 1493, 1465,
1435, 1393, 1337, 1292, 1252, 1218, 1184, 1116, 1087, 1024,
993, 965, 940, 904, 860, 788, 762, 742, 699, 630 cmÀ1.
addition of allylchromium to a selection of ketones.
Table 4 shows the results. In all cases, homoallylic al-
cohols with satisfactory enantioselectivities (up to
97% ee) were obtained with aromatic, aliphatic, and
aromatic ketones. Aryl ketones were excellent sub-
strates for the transformation; allylation of 1-(2-bro-
mophenyl)ethanone (Table 4, entry 4) afforded the
corresponding homoallyl alcohol with a 98% yield
and 97% ee. Exceptional functional group tolerance
was observed when halide-containing compounds
were used. The nature of the substituent on the aryl
ring weakly affected the enantioselectivity of the reac-
General Procedure for the Nozaki–Hiyama–Kishi
Reaction
tion (entries 2–6). Moreover, the allylation of 2’-ace- A mixture of CrCl3 (8.0 mg, 0.05 mmol) and Mn (83.0 mg,
1.5 mmol) in THF (1.00 mL) was stirred at room tempera-
ture for 1 h, and ligand 1 (64.8 mg, 0.15 mmol) and TEA
(42.0 mL, 0.30 mmol) were then added to the solution. After
1 h of stirring at room temperature, allyl bromide (65 mL,
0.75 mmol) was added and the solution was stirred for an-
other 1 h. Aldehydes or ketones (0.5 mmol) and trimethyl-
silyl chloride (95 mL, 0.75 mmol) were then added and the
solution was stirred at room temperature for 36 h. The reac-
tion was quenched by adding a saturated NaHCO3 solution
(5 mL), and the solid residue was removed by filtration
tonaphthone afforded the corresponding homoallyl al-
cohol with an 88% yield and 91% ee. The allylation
of a representative conjugated enone exclusively pro-
duced a 1,2-allylation product with a high yield with
decreased enantioselectivity (entry 8). The allylation
of 2-hexanone, an aliphatic ketone, afforded the cor-
responding homoallylic alcohol with a moderate yield
and 51% ee (entry 9).
In conclusion, we demonstrated the high catalytic
enantioselective allylation of aldehydes and ketones through a plug of celite. The filtrate was extracted with
EtOAc (3ꢃ10 mL), and the combined extracts were dried
over MgSO4. After the filtration and concentration of the
organic phase, the residue was dissolved in THF (2 mL).
Tetra-n-butylammonium fluoride (2.0 mL, 2.0 mmol, 1M in
THF) was added slowly, and the solution was stirred for
15 min. The reaction was quenched by adding water (3 mL),
and the aqueous phase was extracted with EtOAc (3ꢃ
5 mL). The combined extracts were dried over MgSO4.
After the filtration and concentration of the organic phase,
the residue was purified through flash column chromatogra-
phy by using silica gel as the stationary phase and ethyl ace-
by using a chiral Cr(II) complex prepared with bipyri-
dine alcohol and CrCl3. Various aldehydes and ke-
tones, including aromatic, heteroaromatic, and ali-
phatic aldehydes and ketones, afforded homoallylic
alcohols with satisfactory yields and excellent enantio-
selectivities (up to 99% ee) for the NHK allylation.
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A Chiral Bipyridyl Alcohol
tate-hexane (1:19) as the mobile phase to obtain the corre-
sponding homoallyl alcohols (7–33). The enantiomeric
excess was determined using high-performance liquid chro-
matography with a chiral column (Chiralcel OD-H or OJ
column, flow rate: 0.25 mL/min).
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Acknowledgements
The authors thank Ms. L. M. Hsu, at the Instruments Center,
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A Chiral Bipyridyl Alcohol for Catalytic Enantioselective
Nozaki–Hiyama–Kishi Allylation of Aldehydes and Ketones
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Rui-Yu Chen, Attrimuni P. Dhondge, Gene-Hsian Lee,
Chinpiao Chen*
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