C2-symmetrical bipyridyldiols as promising enantioselective catalysts in Nozaki-Hiyama allylation

Article abstract of DOI:10.1002/adsc.201100023

Several new chiral bipyridyldiol ligands that promote the chromium-catalyzed enantioselective addition of allylic halides to aldehydes in up to 99% ee were synthesized. The chromium-catalyzed allylation of aldehydes using ligands 4 and 4a in the presence

Full text of DOI:10.1002/adsc.201100023

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DOI: 10.1002/adsc.201100023
C2-Symmetrical Bipyridyldiols as Promising Enantioselective
Catalysts in Nozaki–Hiyama Allylation
Xin-Ren Huang,a Xin-Hong Pan,a Gene-Hsian Lee,b and Chinpiao Chena,*
a
Department of Chemistry, National Dong Hwa University, Soufeng, Hualien 974, 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: January 11, 2011; Revised: March 18, 2011; Published online: August 10, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100023.
Abstract: Several new chiral bipyridyldiol ligands
that promote the chromium-catalyzed enantioselec-
tive addition of allylic halides to aldehydes in up to
99% ee were synthesized. The chromium-catalyzed
allylation of aldehydes using ligands 4 and 4a in the
pyridyldiol-based chromium catalyst that is effective
in the enantioselective addition of allyl chloride to al-
dehydes.
Our recent study involved chiral bipyridine ligands
from enantioenriched pinene which gave good enan-
tioselectivities in several asymmetric transforma-
tions.[4] The successful application of these ligand sys-
tems motivated us to screen the Nozaki–Hiyama ally-
lation of aromatic aldehydes. Initial evaluation of
symmetrical (4–6) and non-symmetrical bipyridine li-
gands (1–3) in the Cr(II)-catalyzed addition of allyl
halides to benzaldehyde revealed that C2-symmetrical
presence of chromiumACTHNUTRGNEU(GN III) chloride and allyl chlo-
ride provided the highest enantioselectivity.
Keywords: asymmetric catalysis; bipyridyldiol;
chromium catalysis; enantioselectivity; Nozaki–
Hiyama allylation
Table 1. Optimization of chiral bipyridine ligand for the
chromium-catalyzed addition of allyl halide to PhCHO.
The nucleophilic addition of organochromium re-
agents [Nozaki–Hiyama–Kishi (NHK) reaction] to
carbonyl compounds is a versatile carbon-carbon
bond forming reaction that can be used with a wide
range of substrates and has a diverse range of applica-
tion.[1] The synthetic utility of the reaction has been
significantly increased by the development of a cata-
lytic redox process that involves the recycling of
Cr(II) by the reduction of CrACHTNUGRTNEUNG
(III) species.[2] These
preliminary improvements have motivated numerous
efforts to develop an enantioselective version of this
reaction. Many structurally different chiral ligands
were applied as enantioselective catalysts for the ally-
lation of aldehydes, and have resulted in various de-
grees of asymmetric induction.[3] Notably, chiral salen,
quinoline and oxazoline-based chromium complexes
exhibit high enantioselectivities in the asymmetric al-
lylation of aromatic and aliphatic aldehydes. In most
of the catalyst systems, the use of less reactive allylic
chlorides gave lower yields, while the more reactive
allylic iodides worsened the stereochemical outcome
of the reaction. To solve these problems, a new cata-
lyst of the Nozaki–Hiyama allylation is desirable. This
work is the first to describe a new C2-symmetrical bi-
Entry Ligand
X
Yield ee
Configura-
[%][a] [%][b] tion
1
2
3
4
5
6
N
Br 81
Br 79
Cl 70
45
31
75
95
79
69
R
R
R
S
S
S
[a]
[b]
Isolated yield.
HPLC conditions: Chiralcelꢀ OD-H, hexane:i-PrOH 9:1,
flow rate 0.25 mLminÀ1, retention times: 23.30 min (R
isomer) and 24.90 min (S isomer).
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tetradentate ligands offered excellent reactivity and all of the other screened conditions. Also, a 10 mol%
enantioselectivity (Table 1). Ligand 4 with methyl loading of catalyst gave the best yield and enantiose-
groups surprisingly afforded greater reactivity and lectivity. The use of bases other than triethylamine
enantioselectivity than ligands with bulkier groups gave mixed results (see Supporting Information). The
(Table 1, entry 4). Ligands 4–6 have N2O2 binding optimal conditions were therefore 10 mol% of CrCl3,
sites, and so resemble chiral salen ligands. They are an excess of Mn and 10 mol% of 4, in the presence of
readily obtainable from (+)-a-pinene in six steps, triethylamine and THF at room temperature; fol-
which include the stereoselective alkylation of chiral lowed by the successive addition of allyl chloride, al-
bipyridine with ketones as a key step.[4a] To increase dehyde and TMSCl. The final product was isolated
the applicability of the ligand system, the enantiomer following a TBAF work-up.
4a of ligand 4 was synthesized from (À)-b-pinene ac-
The effects of the halide component of the allyl
halide and the chromium(III) halide used in the reac-
cording to the synthetic protocol for ligand
4
ACHTUNGTRENNUNG
(Figure 1). An X-ray crystallographic analysis of tion were explored by adopting various combinations
(+)-6 (Figure 2) verified the general structure of of them, as shown in Table 2. Allyl chloride unexpect-
these tetradentate N2O2 ligands,[5] which have features edly afforded better results than the usually used allyl
that resemble those of the well known Jacobsen salen bromide, independently of the nature of the metal
ligand and TADDOL.
salt employed (Table 1, entries 1 and 4).
Allylation of benzaldehyde using the Cr-4 complex
The extents of enantioselection with various alde-
was optimized by performing the reaction in various hydes using Cr-4 were explored under the optimized
solvents and at various reaction temperatures (see reaction conditions (Table 3). Aryl aldehydes were ex-
Supporting Information). Reactions performed at cellent substrates for the transformation, as revealed
room temperature in THF afforded better results than by the 61–65% yield and the 98% ee of the allylation
of 3-chlorobenzaldehyde (entry 9). The nature and
position of the substituent on the aryl ring only
weakly affects the enantioselective outcome of the re-
action (entries 1–12), although 4-methoxybenzalde-
hyde and 4-cyanobenzaldehyde are unsuitable sub-
strates for the transformations (entries 4 and 12). Ad-
ditionally, good yields were obtained with over 96%
ee using other aryl aldehydes (entries 13–14, 16–17).
An a,b-unsaturated aldehyde was also a good sub-
strate (entry 15). The enantioselection was excellent
when aliphatic aldehydes were used, as revealed by
the 80% yield and >99% ee for the allylation of cy-
clohexanecarboxaldehyde (entry 20).
The synthesis of both enantiomers of a chiral com-
pound usually requires the use of both enantiomers of
Figure 1. Ligand synthesis, a) LDA, R2CO, THF, À508C.
Figure 2. X-ray crystallographic structures of bipyridyldiol 6 (CCDC 757403).
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C2-Symmetrical Bipyridyldiols as Promising Enantioselective Catalysts in Nozaki–Hiyama Allylation
Table 2. Influence of nature of allyl halide and metal halide
a chiral catalyst.[6] Many of the generally used chiral
in the enantioselective allylation of benzaldehyde.
ligands are naturally available in only one enantio-
mer; the other enantiomer often requires a labor-in-
tensive preparation. The importance of enantioselec-
tive catalysis has increased in this regard, as it allows
easy access to both enantiomers of a product without
any complex modification of the structure of the
chiral promoter. In this work, very similar enantiose-
lectivities of both products were obtained, by means
of of ligands 4 and 4a.
The highly enantioselective catalysts were explored
to determine whether any of them showed promise as
an enantioselective catalyst of the Nozaki–Hiyama re-
action. A natural product, (+)-spirolaxine methyl
ether, was synthesized through asymmetric allylation.
Phillips et al. synthesized lactone 28 in 39% yield (4
steps) using (+)-IPC2BOMe as a chiral allylboron re-
Entry CrX3
X
Yield [%][a] ee [%][b] Configuration
1
2
3
4
5
6
Cl
Cl
Cl
Br
Br
Br
Cl 83
Br 62
95
37
73
91
73
23
S
S
S
S
S
S
I
44
Cl 83
Br 79
I
21
[a]
[b]
Isolated yields.
HPLC conditions: Chiralcelꢀ OD-H, hexane:i-PrOH 9:1,
flow rate 0.25 mLminÀ1, retention times: 23.30 min (R
isomer) and 24.90 min (S isomer).
Table 3. Nozaki–Hiyama allylation reactions of aldehydes catalyzed by Cr-4 complexes.
Entry
1
Aldehyde
Catalyst
Product
Yield [%][a]
83
ee [%][b]
Configuration[c]
Cr-4
8
95
S
2
Cr-4
9
89
87
S
3
4
5
Cr-4
Cr-4
Cr-4
10
11
12
75
86
53
91
60
96
S
S
S
6
7
8
Cr-4
Cr-4
Cr-4
13
14
15
44
73
77
90
94
88
S
S
S
9
Cr-4
Cr-4
Cr-4
16
17
18
65
76
70
98
93
92
–
S
–
10
11
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Xin-Ren Huang et al.
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Table 3. (Continued)
Entry
Aldehyde
Catalyst
Product
Yield [%][a]
25
ee [%][b]
Configuration[c]
12
Cr-4
19
65
–
13
Cr-4
20
85
90
S
14
15
Cr-4
Cr-4
21
22
87
90
94
92
S
S
16
17
Cr-4
Cr-4
23
24
87
79
96
92
S
S
18
19
20
Cr-4
Cr-4
Cr-4
25
26
27
85
85
80
92
S
S
S
91
>99[d]
[a]
Isolated yields.
[b]
[c]
[d]
Enantiomeric ratio determined by HPLC equipped with a chiral stationary phase.
Assigned by comparison of the sign of optical rotation with reported value.
Enantiomeric ratio determined by H NMR of Mosherꢂs ester.
agent.[7] Brimble et al. used TiF4, (+)-BINOL and al-
In summary, Cr-bipyridinediol efficiently catalyzed
lyltrimethylsilane as asymmetric allylation reagents to the asymmetric NH allylation reactions of both aro-
produce lactone 28 in 43% yield (4 steps) and matic and aliphatic aldehydes. Excellent enantioselec-
86%ee.[8] Therefore, the asymmetric Nozaki–Hiyama tivities (of up to 99% ee) for the NH allylation reac-
reaction was used as an efficient allylation reaction tion of aldehydes were obtained using both enantio-
using ligand 4a as the enantioselective catalyst, to mers of bipyridyldiols. Moreover, the use of bipyri-
afford the corresponding homoallylic alcohol and si-
ACHTUNGTRENdNGNU inediol in other instances of asymmetric catalysis
multaneously form lactone 28 in a high enantiomeric will be reported upon in due course.
excess (90% ee)[9] and 58% yield (4 steps)
(Scheme 1).
Experimental Section
Synthesis of Bipyridine Ligand 4
To a solution of diisopropylamine (146 mL, 1.04 mmol) in
THF (10 mL) was added n-butyllithium (0.65 mL,
1.04 mmol, 1.6M in hexane) and the misture was stirred at
08C for 30 min. The thus produced LDA solution was
cooled to À508C, and added to a solution of compound 7
(350 mg, 1.02 mmol) in THF (10 mL), and stirred at À508C
for 2 h. A solution of acetone (87 mL, 1.2 mmol) in THF
(2 mL) was added at À508C, after which the reaction tem-
perature was raised to room temperature, and the solution
was stirred for 30 min. The reaction temperature was de-
creased to À508C, and a prepared LDA (1.04 mmol) solu-
tion was added. After stirring at À508C for 4 h, a solution of
acetone (87 mL, 1.2 mmol) in THF (2 mL) was added, and
the mixture was stirred at room temperature overnight until
Scheme 1. Reaction conditions: a) Br2, AcOH; b)
HOCH2CH2OH, p-TSA, benzene; c) n-BuLi, EtOCOCl;
HCl; d) ligand 4a, NH allylation.
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C2-Symmetrical Bipyridyldiols as Promising Enantioselective Catalysts in Nozaki–Hiyama Allylation
the solution turned orange. The reaction was quenched by References
adding water, and the reaction mixture was extracted three
times with ethyl acetate. The combined extracts then were
dried over anhydrous magnesium sulfate. After filtering and
concentration, the residue was purified by flash column
chromatography using silica gel as the stationary phase and
ethyl acetate-hexane (1:49, 1:19) as the mobile phase, thus
producing compound 32 [yield: 310 mg (0.77 mmol 75.5%)],
and compound 4 [yield: 65.0 mg (0.14 mmol, 13.8%)]; [a]2D2:
+41.58 (c 0.8, CH2Cl2). 1H NMR (400 MHz, CDCl3): d=
8.04 (s 2H, OH), 7.94 (d, J=7.8 Hz, 2H, ArH), 7.37 (d, J=
7.9 Hz, 2H, ArH), 2.88–2.76 (m, 2H, -CH-), 3.28 (s, 2H,
-CH-), 2.82–2.79 (t, J=5.6 Hz, 2H, -CH-), 2.65–2.60 (m, 2H,
-CH-), 2.37 (td, J1 =5.9 Hz, J2 =1.7 Hz, 2H, -CH2-), 1.45 (s,
6H, CH3), 1.43 (d, J=7.8 Hz, 2H, -CH-), 1.35 (s, 6H, CH3),
18H), 1.13 (s, 6H, CH3), 0.71 (s, 6H, CH3); 13C NMR
(100.6 MHz, CDCl3): d=158.1, 151.4, 143.3, 134.7, 118.2,
74.5, 52.8, 46.5, 42.5, 42.1, 29.5, 29.0, 27.6, 26.3, 21.0; IR
(KBr): n=3403, 2973, 2940, 2867, 1635, 1558, 1419, 1166,
734, 611 cmÀ1; LR-MS (EI): m/z=460 (M+, 24), 403 (29),
402 (100), 387 (12), 383 (21), 369 (27), 343 (20), 341 (29),
299 (21), 59 (16); HR-MS (EI): m/z=460.3094, calcd. for
C30H40N2O2 [M]+: 460.3090.
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Typical Procedure for Catalytic Enantioselective
Nozaki–Hiyama Allylation
Anhydrous THF (1 mL) was added to CrCl3 (8.0 mg,
50.0 mmol) and Mn (83.0 mg, 1.5 mmol, 325 mesh) in an
inert box, and the mixture was stirred for 1 h at room tem-
perature. After ligand 4 (50.0 mmol) and anhydrous NEt3
(14.0 mL, 10.0 mg, 100 mmol) were added, the suspension
was stirred for 1 h at room temperature. Finally, allyl chlo-
ride (58.0 mL, 750 mmol) was added. After 1 h at room tem-
perature, aldehyde (0.5 mmol) and Me3SiCl (95.0 mL,
750 mmol) were added, and the suspension was stirred at
room temperature for 24 h. Saturated aqueous NaHCO3 was
added. Following filtration and evaporation, the aqueous
phase was extracted with EtOAc. After the combined or-
ganic phases had been evaporated, the residue was dissolved
in THF (2 mL). A TBAF solution (1.5 mL, 1.5 mmol, 1M in
THF) was added and the mixture was stirred until desilyla-
tion was complete (as verified by TLC). Water was added;
the solution was extracted using ethyl acetate, and the com-
bined organic phases were dried over MgSO4. Evaporation
of the solvent and flash chromatography (EtOAc/hexane
1:19) gave the products. The enantiomeric excess was deter-
mined by HPLC analysis using a chiral column (Chiralcel
OD-H or OJ column, flow rate 0.25 mLminÀ1).
Acknowledgements
The authors thank Ms. L. M. Hsu, at the Instruments Center,
National Chung Hsing University, for her help in obtaining
HR-MS, and the National Science Council of the Republic of
China for financially supporting this research under Contract
NSC97-2113M-259-002-MY3.
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[5] The X-ray crystallographic structure of ligand 6 has
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[a]2D4:5: +68.7 (c 0.9, CHCl3), enantiomeric excess 90%
(see Supporting Information).
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Adv. Synth. Catal. 2011, 353, 1949 – 1954