Application of tridentate bis(oxazoline) ligands in catalytic asymmetric Nozaki-Hiyama allylation and crotylation: An example of high enantioselection with a non-symmetric bis(oxazoline) ligand

Article abstract of DOI:10.1002/adsc.200505332

A series of both symmetric and non-symmetric bis(oxazoline) ligands was applied in the Nozaki-Hiyama allylation and crotylation of benzaldehyde. It was found that both the magnitude and sense of the asymmetric induction depended strongly on the nature and

Full text of DOI:10.1002/adsc.200505332

FULL PAPERS
DOI: 10.1002/adsc.200505332
Application of Tridentate Bis(oxazoline) Ligands in Catalytic
Asymmetric Nozaki–Hiyama Allylation and Crotylation: An
Example of High Enantioselection with a Non-Symmetric
Bis(oxazoline) Ligand
Helen A. McManus,a Pier Giorgio Cozzi,b Patrick J. Guirya,*
a
Centre for Synthesis and Chemical Biology, Conway Institute of Biomolecular and Biomedical Research,
School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
Fax: (þ353)-1-716-2501, e-mail: p.guiry@ucd.ie
b
`
Dipartimento di Chimica “G. Ciamician”, Universita di Bologna, Via Selmi 2, 40126 Bologna, Italy
Received: August 8, 2005; Revised: January 6, 2006; Accepted: January 12, 2006
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A series of both symmetric and non-sym- and was applied successfully in the allylation and cro-
metric bis(oxazoline) ligands was applied in the Noza- tylation of a range of aryl and aliphatic aldehydes.
ki–Hiyama allylation and crotylation of benzalde- The enantioselectivities obtained in allylation were
hyde. It was found that both the magnitude and sense up to 91% ee and in crotylation up to 92% with typ-
of the asymmetric induction depended strongly on the ical syn:anti ratios of up to 80:20.
nature and combination of the oxazoline substituents.
For both reactions, the non-symmetric tert-butyl/ben- Keywords: allylation; asymmetric catalysis; ligand de-
zyl-substituted ligand proved to be the optimal ligand sign; N ligands; tridentate ligands
Introduction
triles in both reaction partners; (v) distinct stereochem-
ical preferences particularly in reactions with crotyl-
À
The Nozaki–Hiyama Kishi reaction, first reported by chromium reagents; (vi) excellent reliability even
Nozaki and Hiyama, is an important and versatile car- when applied to sensitive and polyfunctional com-
bon-carbon bond forming transformation involving the pounds; (vii) high preference for the formation of allyl-
nucleophilic addition to carbonyl compounds (in partic- chromium reagents in the presence of alkyl and alkenyl
ular aldehydes) of intermediate organochromium(III) halides. As a consequence, this reaction has been utiliz-
reagents, which are generated in situ from the insertion ed effectively in numerous total syntheses of complex
of chromium(II) species into allyl, alkenyl, alkynyl, natural products.[3]
propargyl and aryl halides/sulfonates.[1] This methodol-
The synthetic utility of the reaction was significantly
ogy was enhanced by independent reports from Nozaki increased by the development by Fürstner of a catalytic
and Kishi that theaddition of trace amounts ofnickel(II) redox process in which chromium(II) is recycled from
salts accelerated the formation of organochromium(III) chromium(III), thus allowing the use of much reduced
intermediates especially with less reactive substrates quantities of toxic chromium salts and therefore making
such as alkenyl and aryl halides/triflates.[2] Following the reaction more environmentally benign.[4] Chromi-
these reports, extensive research in this transformation um(III) chloride is preferred because, in contrast to
revealed a number of unique and important features: chromium(II) chloride, it is cheap, relatively insensitive
(i) applicability of a broad range of substrates to the in- to oxygen and moisture and much easier to manipulate.
À
sertion of chromium(II) under mild conditions; (ii) pro- Other catalytic versions of the Nozaki–Hiyama Kishi
nounced chemoselectivity of the organochromium(III) reaction employing an organic reducing agent [tetra-
reagents for reactions with aldehydes in the presence kis(dimethylamino)ethylene][5] or electrochemical driv-
of ketones; (iii) a strong driving force for the nucleophil- ing forces have also been reported.[6]
ic addition due to the formation of highly stable
O Cr(III) bonds; (iv) an unprecedented compatibility Hiyama Kishi reaction was highly desirable, but due
with numerous functional groups such as esters or ni- to difficulties such as ligand coordination and specificity
The development of an enantioselective Nozaki–
À
À
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Helen A. McManus et al.
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and the tendency of chromium(II) to form dimers or
clusters with polydentate ligands, relatively few reports
relating to the enantioselective variant have been pub-
lished. As a consequence, only a selection of ligands
has been reported to give good enantiocontrol and
high reactivity, mainly in the allylation of aldehydes.
The first somewhat successful reactions relied on over
stoichiometric amounts (up to 400%) of specially de-
signed chiral ligands and afforded only moderate yields.
The best of these ligands were the chiral bipyridine li-
gand 1 developed by Kishi,[7] which gave poor to good
enantioselectivities (28–74% ee) for the allylation and
alkenylation of benzaldehyde and the N-benzoylproli-
nol derivative 2 which gave up to 98% ee for the reaction
of allyl bromide with different aldehydes.[8]
Cozzi developed the first catalytic enantioselective
À
Nozaki–Hiyama Kishi reaction using chromium(II)
complexes (10 mol %) of the commercially available
chiral salen ligand 3.[9] High levels of enantiodiscrimina-
tion were afforded for both the allylation (77–90% ee)
and crotylation (78–90% ee) of a range of aldehydes us-
ing allyl chloride and crotyl bromide, respectively.[10]
However, only moderate yields of product were ob-
tained (41–67%) due to the formation of a considerable
quantity of the corresponding pinacol side product. Ber-
kessel employed the salen derivative [(S,S)-DIA-
NANE] 4 and obtained higher enantiodiscrimination
in the reaction of benzaldehyde with allyl bromide
(90% ee) than with allyl chloride (79% ee).[11]
Oxazoline-containing ligands have also been used dition to non-symmetric analogues. Here we define
with some success in the enantioselective Nozaki–Hiya- ꢁsymmetricꢂ as those with identical substituents at the
À
ma Kishi reaction. The chromium(III)/sulfonamide- oxazoline chiral centre and ꢁnon–symmetricꢂ as those
oxazoline ligand complex 5 gave good enantioselectivi- with different substituents. The similarity of our triden-
ties for the Ni/Cr-mediated alkenylation and the Co/Cr- tate bis(oxazoline) ligands 8 to the bis(oxazolinyl)carba-
mediated alkylation of aliphatic aldehydes and was thus zole ligands 6 and 7 prompted us to probe their enantio-
À
applied by Kishi in the synthesis of the C14 –C26 segment differentiating ability in the Nozaki–Hiyama Kishi al-
of halichondrins.[12] Nakada developed the tridentate bis- lylation and crotylation of benzaldehyde. Chiral triden-
(oxazolinyl)carbazole ligand 6 and it induced good tate bis(oxazoline) ligands of this type are thought to be
enantioselectivities (up to 73% ee) in the asymmetric al- good candidates for this reaction as stabilisation of the
lylation of benzaldehyde.[13] The introduction of phenyl allylchromium(III)/ligand complex by three bonds, a
substituents at the 3 and 6 positions of the carbazole s-bond with the central nitrogen atom and two coordi-
backbone provided a highly effective ligand 7, which af- nation bonds with the oxazoline nitrogen atoms, would
forded very high levels of enantioselection (86–96% ee) prevent any significant dissociation. We now report
for the allylation and methallylation of various aromatic our results on the application of these ligands in the
and aliphatic aldehydes.[14] Crotylation of benzaldehyde asymmetric Nozaki–Hiyama allylation and crotylation
using this ligand was less successful affording the anti of aldehydes.
product preferentially (anti:syn¼73:27) in 38% yield
and 75% ee. The chromium complex of ligand 6 was wa-
ter-tolerant and amenable to catalyst recycling with lit- Results and Discussion
tle change in the enantiodiscrimination.
We have recently reported the preparation of a similar Ligands 8a–j were first investigated in the chromi-
class of bis(oxazoline) ligands 8, in which an N-phenyl- um(II)-mediated reaction of benzaldehyde 9a with allyl
aniline unit links the two chiral oxazoline rings, by em- bromide 10a (Table 1). An optimization of reaction con-
ploying a palladium-catalyzed Hartwig–Buchwald- ditions revealed THF/acetonitrile (7:1) and N,N-diiso-
type aryl amination as the key synthetic step.[15] This ap- propylethylamine (DIPEA) as the best solvent and
proach, unlike a more recent synthesis by Xu and Du,[16] base in terms of easy reduction of chromium(III), yield
allowed for the preparation of symmetric ligands in ad- and enantioselectivity. In all cases, the reactions pro-
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Catalytic Asymmetric Nozaki–Hiyama Allylation and Crotylation
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asymmetric induction were highly dependent on the na-
ture and combination of the substituents on the oxazo-
line rings and that small changes in the substituents
translated into large variation in enantiodiscrimination.
This was particularly evident from the similar levels of
enantioselection (69 and 71% ee) but opposite absolute
configuration of product afforded by the diisopropyl-
substituted ligand 8b and the tert-butyl/isopropyl-substi-
tuted ligand 8g (Table 1, entries 2 and 9).
Using the optimal ligand, the tert-butyl/benzyl-substi-
tuted derivative 8f, the chromium(II)-catalysed reaction
of benzaldehyde with other allyl halides was examined
(Table 1, entries 7 and 8). Although the reaction with all-
yl iodide showed a similar reactivity profile (98% con-
ceeded with excellent conversions after 16 h at room version after 16 h) to that of allyl bromide, the reaction
temperature with no evidence of any by-products. Of with allyl chloride was sluggish giving only 19% conver-
the four symmetric ligands 8a–d, only the diisopropyl- sion over the same time period. In terms of enantiodis-
and diphenyl-substituted ligands 8b and 8c afforded 1- crimination, both reactions were less enantioselective
phenylbut-3-en-1-ol 11 with significant levels of enan- than that with allyl bromide, giving the homoallylic alco-
tioselectivity [69% ee (S) and 44% ee (S)], respectively) hol 11a in 74 and 80% ee with allyl chloride and allyl io-
(Table 1, entries 1–4). Although the majority of the dide, respectively.
non-symmetric ligands 8e–j gave poor enantioselectiv-
The enantiodiscriminating ability of ligand 8f in the
ities (up to 18% ee) (Table 1, entries 5–12), notable ex- chromium(II)-catalysed reaction of allyl bromide with
ceptions include the tert-butyl/benzyl-substituted ligand a range of aldehydes was also investigated (Table 2).
8f and the tert-butyl/isopropyl-substituted ligand 8g, In all cases, complete consumption of the aldehyde,
which provided (R)-11a in 87 and 71% ee, respectively good to excellent isolated yields and high enantioselec-
(Table 1, entries 6 and 9). Interestingly, the results fur- tivities (86–91% ee) were obtained. Reactions with 4-
nished by both the symmetric and non-symmetric li- methoxybenzaldehyde 9b and 4-chlorobenzaldehyde
gands revealed that both the extent and sense of the 9c proceeded with a similar level of enantioselectivity
Table 1. Catalytic asymmetric Nozaki–Hiyama allylation of benzaldehyde using ligands 1a–j.
Entry
Ligand
R1
R2
X
Yield.[a] (Conv.[c]) [%]
ee[b] [%] (Conf.[d]
)
1
2
3
4
5
6
7
8
9
8a
8b
8c
8d
8e
8f
8f
8f
8g
8h
8i
Bn
i-Pr
Ph
t-Bu
Ph
t-Bu
t-Bu
t-Bu
t-Bu
i-Pr
t-Bu
Bn
Bn
i-Pr
Ph
t-Bu
Bn
Bn
Bn
Bn
i-Pr
Ph
Br
Br
Br
Br
Br
Br
Cl
I
Br
Br
Br
Br
75 (99)
78 (96)
60 (99)
63 (88)
78 (98)
87 (100)
10 (19)
88 (98)
97 (100)
90 (100)
65 (100)
75 (100)
10 (R)
69 (S)
44 (S)
11 (S)
3 (S)
87 (R)
74 (R)
80 (R)
71 (R)
18 (R)
Rac
10
11
12
Ph
i-Pr
8j
8 (R)
[a]
Yields of the isolated homallylic alcohol.
[b]
Determined by chiral GC analysis of the alcohol product 11a on a Supelco b-Dex 120 column [30 m, 0.25 mm (diam.),
0.25 mm].
[c]
[d]
1
Determined from the 300 MHz H NMR spectrum of the crude silylated product.
Determined by comparison of the chiral GC retention times with literature values.[10b]
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(88 and 86% ee, respectively) compared to benzalde- tion of an a,b-unsaturated aldehyde, trans-cinnamalde-
hyde 9a (87% ee) indicating that the presence of elec- hyde 9g, was also successful furnishing the correspond-
tron-donating and electron-withdrawing substituents ing homoallylic alcohol 11g in 89% ee (Table 2, entry 7).
did not have a profound effect on the asymmetric induc-
The chiral bis(oxazoline) ligands 8 were also investi-
tion (Table 2, entries 1–3). Aliphatic compounds were gated in asymmetric Nozaki–Hiyama crotylation. All
also found to be good substrates for this reaction with ten ligands were examined for their stereocontrolling
both cyclic 9d and linear (9e and 9f) aldehydes providing ability in the reaction of benzaldehyde 9a with crotyl
enantioselectivities (¼90% ee) slightly higher than the bromide 12 and some interesting results were obtained
aromatic substrates (Table 2, entries 4–6). The allyla- (Table 3).[18] All reactions again proceeded with high
Table 2. Catalytic asymmetric Nozaki–Hiyama allylation of aldehydes 9a–g using ligand 8f.
Entry
1
Aldehyde
Yield[a] (Conv.[c]) [%]
87 (100)
ee[b] [%] (Conf.[d]
)
87 (R)
2
93 (100)
98 (100)
64 (100)
88 (R)
86 (R)
90 (R)
3
4[e]
5[f]
69 (100)
82 (100)
91 (S)
90 (S)
6
7
84 (100)
89 (R)
[a]
Isolated yields of the homallylic alcohol.
Determined by chiral GC analysis on a Supelco b-Dex 120 column or chiral HPLC analysis on a Daicel Chiralcel OD or
[b]
OD-H column.
[c]
[d]
[e]
[f]
1
Determined from the 300 MHz H NMR spectrum of the crude silylated product.
Determined by comparison of the chiral GC/HPLC retention times with literature values.[10b,12d,14b,17]
ee determined by HPLC analysis of the 3,5-dinitrobenzoate ester.
Configuration determined by analogy with alcohol 11f.
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Catalytic Asymmetric Nozaki–Hiyama Allylation and Crotylation
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Table 3. Catalytic asymmetric Nozaki–Hiyama crotylation of benzaldehyde using ligands 8a–j.
Entry
Ligand
Yield.[a] (Conv.[d]) [%]
anti:syn[b]
ee[b] [%] (Conf.)[c]
anti
syn
1
2
3
4
5
6
7
8
9
8a
8b
8c
8d
8e
8f
8g
8h
8i
70 (92)
86 (100)
74 (98)
50 (78)
62 (84)
77 (94)
79 (100)
68 (96)
80 (88)
68 (87)
77: 23
77: 23
87: 13
87: 13
78: 22
77: 23
77: 23
81: 19
88: 12
77: 23
10 (1S,2S)
65 (1S,2S)
64 (1S,2S)
Rac.
11 (1S,2S)
82 (1R,2R)
56 (1R,2R)
2 (1S,2S)
4 (1R,2R)
5 (1S,2S)
31 (1R,2S)
56 (1S,2R)
7 (1S,2R)
5 (1S,2R).
10 (1R,2S)
90 (1R,2S)
66 (1R,2S)
43 (1R,2S)
48 (1R,2S)
27 (1R,2S)
10
8j
[a]
Isolated yields of alcohols 13a.
[b]
[c]
[d]
Determined by chiral GC analysis of the corresponding methyl ether derivative on a Supelco b-Dex 120 column.
Determined by comparison of the chiral GC retention times with literature values.[12d]
1
Determined from the 300 MHz H NMR spectrum of the crude silylated product.
conversions with no evidence of any by-products and selectivity of the major anti-product was opposite to that
were anti-selective with the tert-butyl/phenyl-substitut- obtained in allylation.
ed ligand 8i affording the highest anti:syn selectivity of
The ligand of choice 8f was then applied in the asym-
88:12 (Table 3, entry 9). As for the reactions with allyl metric crotylation of a range of aldehydes (Table 4). In
bromide, both the magnitude and sense of asymmetric all cases, excellent conversions (94–100%), good isolat-
induction depended strongly on the combination of ox- ed yields (60–87%) and moderate diastereoselectivity
azoline substituents. The highest level of enantiodiscri- (up to 80:20 anti:syn) were obtained. In addition, the
mination was again achieved using the non-symmetric enantioselectivity of the syn-diastereomer was greater
tert-butyl/benzyl-substituted ligand 8f, which afforded than that of the anti-diastereomer for the majority of
82% ee (1R,2R) for anti-2-methyl-1-phenylbut-3-en-1- substrates. 4-Methoxybenzaldehyde 9b, 4-chlorobenzal-
ol 13a and 90% ee (1R,2S) for the syn-diastereomer (Ta- dehyde 9c and the aliphatic aldehydes 9e and 9f all pro-
ble 3, entry 6). The tert-butyl/isopropyl-substituted li- vided good levels of enantiodiscrimination for both the
gand 8g and the tert-butyl/phenyl-substituted ligand 8i anti- and syn-products (71–92% and 80–91% ee, re-
also afforded the same anti- and syn-diastereomers but spectively) (Table 4, entries 2–5). However, the reac-
with lower enantioselectivities (Table 3, entries 7 and tion with the a,b-substituted benzaldehyde, trans-cinna-
9). All three ligands induced a higher level of asymmet- maldehyde 9g, was considerably less enantioselective af-
ric induction in the formation of the minor syn-product fording anti-and syn-14g in 38 and 52% ee, respectively
than that of the major anti-product. As in the allylation (Table 4, entry 6).
reactions, ligands 8f and 8g favoured a different enantio-
meric product (for both the anti- and syn-diastereomers)
compared to the symmetric ligands 8b and 8c (Table 2, Conclusion
entries 2 and 3). Ligands 8b, 8c, 8f, 8g and 8i induced
the same enantiofacial selectivity of benzaldehyde for In conclusion, both symmetric (8a–d) and non-symmet-
both the anti- and syn-products which was the same as ric (8e–j) bis(oxazoline) ligands were applied in the No-
that observed in Nozaki–Hiyama allylation. In contrast zaki–Hiyama allylation and crotylation of benzalde-
to this finding, ligands 8a, 8e, 8h and 8j promoted differ- hyde. It was found that both the magnitude and sense
ent enantiofacial selectivity of benzaldehyde on reac- of the asymmetric induction depended strongly on the
tion with crotyl bromide (for both the anti- and syn- nature and combination of the oxazoline substituents.
products), albeit with low to moderate enantioselectivi- A similar trend but to a lesser extent was also noticed
ty (Table 3, entries 1, 5, 8 and 10). In addition, the facial by Nakada on the application of his bis(oxazolinyl)car-
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Helen A. McManus et al.
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Table 4. Catalytic asymmetric Nozaki–Hiyama crotylation of aldehydes 2 using ligand 1f.
[a]
Entry
1
Aldehyde
Yield (Conv.[d]) [%]
anti/syn[b]
ee[b] [%] (Conf.[c]
)
anti
syn
77 (94)
77: 23
82 (1R,2R)
90 (1R,2S)
2[e]
87 (97)
79: 21
78: 22
92 (1R,2R)
71 (1R,2R)
91 (1R,2S)
80 (1R,2S)
3[e]
76 (100)
4
5
60 (95)
65 (96)
74: 26
77: 23
83 (3R,4S)
84 (3S,4R)
90 (3S,4S)
90 (3S,4S)
6
64 (100)
80: 20
38 (3R,4R)
52 (3R,4S)
[a]
Isolated yields of alcohols 14.
[b]
Determined by chiral GC analysis on a Supelco b-Dex 120 column or chiral HPLC analysis on a Daicel Chiralcel OD col-
umn.
[c]
[d]
[e]
Determined by comparison of the chiral GC/HPLC retention times with literature values.[12d,19]
1
Determined from the 300 MHz H NMR spectrum of the crude silylated product.
Configuration determined by analogy with alcohols 14a.
bazole ligands in asymmetric Nozaki–Hiyama propar- Studies are currently underway to elucidate the struc-
gylation.[14b] For both reactions, the non-symmetric tures of the chromium-ligand complexes in an effort to
tert-butyl/benzyl-substituted ligand 8f proved to be the determine the mechanism of the reaction and to fully ex-
optimal ligand and was applied successfully in the allyla- plain the effect of the oxazoline substituents on the
tion and crotylation of a range of aryl and aliphatic alde- asymmetric induction.
hydes. The enantioselectivities obtained in allylation
were up to 91% ee and in crotylation up to 92% with typ-
ical syn:anti ratios of up to 80:20. The results obtained
Experimental Section
compare favourably and in some cases improve upon
the best results reported to date. These results also rep-
resent one of the few examples in the literature[20] where
non-symmetric bis(oxazoline) ligands are utilized to in-
General
1H NMR (300 MHz) spectra were recorded on a Varian Oxford
duce high enantioselectivity in asymmetric catalysis. 300 spectrometer at room temperature in CDCl3 using tetra-
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Catalytic Asymmetric Nozaki–Hiyama Allylation and Crotylation
FULL PAPERS
methylsilane (TMS) as an internal standard. Chemical shifts
(d) are givenin parts per million andcoupling constants are giv-
en as absolute values expressed in Hertz. All reactions were
carried out under a nitrogen atmosphere in flame-dried
Schlenk tubes. Thin layer chromatography (TLC) was carried
out on plastic sheets pre-coated with silica gel 60 F254 (Merck).
Column chromatography separations were performed using
Merck Kieselgel 60 (0.040–0.063 mm). GC analysis was per-
formed using a Shimadzu GC-17A gas chromatograph equip-
ped with a Shimadzu C-R3A chromatopac integrator and a Su-
pelco b-Dex 120 chiral capillary column [30 m, 0.25 mm (di-
am.)ꢀ0.25 mm] with helium as a carrier gas at 1.0 mL/min
and a flame-ionizing detector. HPLC analysis was performed
using a Shimadzu LC-2010A liquid chromatograph equipped
with a Daicel Chiralcel OD or OD-H column (0.46 cm I. D.ꢀ
25 cm). HPLC grade hexane and isopropyl alcohol were used
as the eluting solvents. THF was distilled from sodium/benzo-
phenoneketyl. Acetonitrile was distilledfrom calcium hydride.
DIPEAwas distilled and stored over KOH under nitrogen. All
aldehydes were distilled prior to use. Allyl bromide and crotyl
bromide were purchased from Aldrich and distilled before use.
Chlorotrimethylsilane was purchased from Aldrich and flush-
edthrougha small column of basicalumina (Brockmann, grade
1) immediately prior to use. All other reagents were purchased
from Aldrich and were used as received.
complete desilylation. The solvent was removed under vacuum
and the resulting aqueous phase was extracted with Et2O
(3ꢀ2 mL). The organic layers were combined, dried over an-
hydrous Na2SO4 and concentrated under vacuum to give a yel-
low oil. This was then purified by flash column chromatogra-
phy on silica gel (1ꢀ15 cm) using pentane/AcOEt (9:1) as
the eluent to give the required product as a pale yellow oil.
Further experimental information and chromatographic
data can be obtained in the Supporting Information.
Acknowledgements
We thank Enterprise Ireland for the award of a Research Schol-
arship (BR/99/239) and UCD for a Research Demonstratorship
to H.McM. We acknowledge financial support from the Centre
for Synthesis and Chemical Biology (CSCB), which was funded
by the Higher Education Authorityꢀs Programme for Research
in Third-level Institutions (PRTLI).
References and Notes
[1] a) Y. Okude, S. Hirano, T. Hiyama, H. Nozaki, J. Am.
Chem. Soc. 1977, 99, 3179–3181; b) T. Hiyama, K. Ki-
mura, H. Nozaki, Tetrahedron Lett. 1981, 22, 1037–
1040; c) T. Hiyama, Y. Okude, K. Kimura, H. Nozaki,
Bull. Chem. Soc. Jpn. 1982, 55, 561–568; d) K. Takai,
K. Kimura, T. Kuroda, T. Hiyama, H. Nozaki, Tetrahe-
dron Lett. 1983, 24, 5281–5284.
General Procedure for Catalytic Asymmetric Nozaki–
Hiyama Allylation and Crotylation
A flame-dried Schlenk tube was charged with dry THF (1 mL)
and dry ACN (150 mL). Anhydrous chromium(III) chloride
(4.0 mg, 25.3 mmol) and manganese (41.7 mg, 0.76 mmol)
were added together to the solvent mixture. The resulting sus-
pension was allowed to stand at room temperature for approx.
10 min and was then stirred vigorously under an atmosphere of
nitrogen for 1 h. This resulted in the disappearance of the char-
acteristic purple colour of the chromium(III) salt and the for-
mation of a white/grey suspension with a pale green superna-
tant. DIPEA (13 mL, 75.9 mmol) was then added followed by
the bis(oxazoline) ligand 8 (30.4 mmol) resulting in an immedi-
ate deep green catalyst mixture. This was then stirred at room
temperature for 1 h prior to the addition of the halide
(0.51 mmol) with the resulting chromium(III)-allyl solution
being stirred for a further 1 h. The reaction was then initiated
by the addition of aldehyde (0.25 mmol) and chlorotrimethyl-
silane (64 mL, 0.51 mmol) and stirred under an atmosphere of
nitrogen at room temperature for 16 h. The resulting green/
brown suspension was quenched with saturated aqueous
NaHCO3 (1 mL) and extracted with Et2O (3ꢀ1 mL). The
combined organic layers were then concentrated under vac-
uum to give a green residue. This was flushed through a small
silica gel column (1.5ꢀ5 cm, pentane/AcOEt, 9:1) to remove
the catalyst and after evaporation of the solvent, the reaction
products were isolated as a yellow oil. The % conversion of
[2] a) H. Jin, J.-I. Uenishi, W. J. Christ, Y. Kishi, J. Am.
Chem. Soc. 1986, 108, 5644; b) K. Takai, M. Tagashira,
T. Kuroda, K. Oshima, K. Utimoto, H. Nozaki, J. Am.
Chem. Soc. 1986, 108, 6048.
[3] Recent reviews: a) A. Fürstner, Chem. Rev. 1999, 99,
991–1045; b) L. A. Wessjohann, G. Scheid, Synthesis
1999, 1–36; c) M. Avalos, R. Babiano, P. Cintas, J. L. Ji-
´
menez, J. C. Palacios, Chem. Soc. Rev. 1999, 28, 169–177;
S. E. Denmark, J. Fu, Chem. Rev. 2003, 103, 2763–2793.
[4] a) A. Fürstner, N. Shi, J. Am. Chem. Soc. 1996, 118,
2533–2534; b) A. Fürstner, N. Shi, J. Am. Chem. Soc.
1996, 118, 12349–12357.
[5] a) M. Kuroboshi, K. Goto, M. Mochizuki, H. Tanaka,
Synlett, 1999, 1930–1932; b) M. Kuroboshi, M. Tanaka,
S. Kishimoto, K. Goto, M. Mochizuki, H. Tanaka, Tetra-
hedron Lett. 2000, 41, 81–84.
[6] R. Grigg, B. Putnikovic, C. J. Urch, Tetrahedron Lett.
1997, 38, 6307–6308.
[7] C. Chen, K. Tagami, Y. Kishi, J. Org. Chem. 1995, 60,
5386–5387.
[8] K. Sugimoto, S. Aoyagi, C. Kibayashi, J. Org. Chem.
1997, 62, 2322–2323.
[9] a) M. Bandini, P. G. Cozzi, P. Melchiorre, A. Umani-
Ronchi, Angew. Chem. 1999, 111, 3558–3561; Angew.
Chem. Int. Ed. 1999, 38, 3357–3359; b) M. Bandini,
P. G. Cozzi, A. Umani-Ronchi, Polyhedron 2000, 19,
537–539.
[10] a) M. Bandini, P. G. Cozzi, A. Umani-Ronchi, Angew.
Chem. 2000, 112, 2417–2420; Angew. Chem. Int. Ed.
2000, 39, 2327–2330; b) M. Bandini, P. G. Cozzi, A.
1
the reaction was determined at this stage from the H NMR
spectrum of the crude product (generally a mixture of silylated
and free alcohol) by measuring the ratio of aldehyde to product
and assuming that all aldehyde consumed went to product. The
yellow oil was then dissolved in THF (1 mL), a few drops of
aqueous 1 M HCl were added, and the resulting solution was
stirred for 5 min when TLC (pentane/AcOEt, 9:1) showed
Adv. Synth. Catal. 2006, 348, 551 – 558
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
557

Helen A. McManus et al.
FULL PAPERS
Umani-Ronchi, Tetrahedron 2001, 57, 835–843; c) M.
Bandini, P. G. Cozzi, P. Melchiorre, S. Morganti, A.
Umani-Ronchi, Org. Lett. 2001, 3, 1153–1155; d) M.
Bandini, P. G. Cozzi, P. Melchiorre, R. Tino, A. Umani-
Ronchi, Tetrahedron: Asymmetry 2001, 12, 1063–1069;
e) M. Lombardo, S. Licciulli, S. Morganti, C. Trombini,
Chem. Commun. 2003, 1762–1763; f) M. Bandini, P. G.
Cozzi, S. Licciulli, A. Umani-Ronchi, Synthesis 2004,
409–414.
[13] T. Suzuki, A. Kinoshita, H. Kawada, M. Nakada, Synlett
2003, 570–572.
[14] a) M. Inoue, T. Suzuki, M. Nakada, J. Am. Chem. Soc.
2003, 125, 1140–1141; b) M. Inoue, M. Nakada, Org.
Lett. 2004, 6, 2977–2980.
[15] H. A. McManus, P. J. Guiry, J. Org. Chem. 2002, 67,
8566–8573.
[16] S.-F. Lu, D.-M. Du, S.-W. Zhang, J. Xu, Tetrahedron:
Asymmetry 2004, 15, 3433–3441.
[11] a) A. Berkessel, D. Menche, C. A. Sklorz, M. Schrçder, I.
Paterson, Angew. Chem. 2003, 115, Angew. Chem. Int.
Ed. 2003, 42, 1032–1035; b) A. Berkessel, M. Schrçder,
C. A. Sklorz, S. Tabanella, N. Vogl, J. Lex, J. M. Neu-
dçrfl, J. Org. Chem. 2004, 69, 3050–3056.
[12] a) Z.-K. Wan, H. Choi, F.-A. Kang, K. Nakajima, D. De-
meke, Y. Kishi, Org. Lett. 2002, 4, 4431–4434; b) H.
Choi, K. Nakajima, D. Demeke, F.-A. Kang, H.-S. Jun,
Z.-K. Wan, Y. Kishi, Org. Lett. 2002, 4, 4435–4438;
c) M. Kurosu, M.-H. Lin, Y. Kishi, J. Am. Chem. Soc.
2004, 126, 12248–12249; d) J.-Y. Lee, J. J. Miller, S. S.
Hamilton, M. S. Sigman, Org. Lett. 2005, 7, 1837–1839.
[17] a) T. R. Wu, L. Shen, J. M. Chong, Org. Lett. 2004, 6,
´
2701–2704; b) A. V. Malkov, L. Dufkova, L. Farrugia,
P. Kocovsky, Angew. Chem. 2003, 115, Angew. Chem.
Int. Ed. 2003, 42, 3674–3677.
[18] Commercially available crotyl bromide (85% tech.) was
used.
[19] a) J. A. Marshall, M. R. Palovich, J. Org. Chem. 1998, 63,
4381–4384; b) B. M. Hackman, P. J. Lombardi, J. L.
Leighton, Org. Lett. 2004, 6, 4375–4377.
[20] H. Nishiyama, N. Soeda, T. Naito, Y. Motoyama, Tetrahe-
dron: Asymmetry 1998, 9, 2865–2869.
558
asc.wiley-vch.de
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 551 – 558