The application of bis(oxazoline) ligands in the catalytic enantioselective methallylation of aldehydes

Article abstract of DOI:10.1039/b618516a

The application of symmetric and non-symmetric bis(oxazoline) ligands in the asymmetric methallylation of a range of aromatic and aliphatic aldehydes was investigated. Catalytic asymmetric methallylation of benzaldehyde was performed, using acetonitrile l

Full text of DOI:10.1039/b618516a

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The application of bis(oxazoline) ligands in the catalytic enantioselective
methallylation of aldehydes
a
a
b
a
Gr a´ inne C. Hargaden, Helen A. McManus, Pier Giorgio Cozzi and Patrick J. Guiry*
Received 19th December 2006, Accepted 15th January 2007
First published as an Advance Article on the web 26th January 2007
DOI: 10.1039/b618516a
A series of symmetric and non-symmetric bis(oxazoline)
ligands were applied in the Nozaki–Hiyama–Kishi methallyl-
ation of a range of aromatic and aliphatic aldehydes. A
non-symmetrical ligand with tert-butyl/benzyl-substituted
oxazolines provided the highest enantioselectivity of 99.5%
for the methallylation of benzaldehyde.
The Nozaki–Hiyama–Kishi reaction was first reported in the late
1
970’s and has proven to be a highly versatile procedure for the
formation of C–C bonds involving the nucleophilic addition to car-
bonyl compounds of intermediate organochromium(III) reagents,
which are generated in situ from the insertion of chromium(II)
species into allyl, alkenyl, alkynyl, propargyl and aryl halides or
1
sulfonates. A number of unique and important features including
pronounced chemoselectivity for reactions with aldehydes in the
presence of ketones and an unprecedented compatibility with
numerous functional groups in both reaction partners have led to
the reaction being utilised in the synthesis of many complex natural
products, two examples being the total synthesis of palytoxin and
halichondrin B which both involved extensive use of chromium
provided enantioselectivities of up to 73% ee in the asymmetric
8
allylation of benzaldehyde, whilst Kishi’s ligand 5 afforded
9
enantioselectivities of up to 94%. Sigman recently reported the
2
additions. The development of a catalytic redox process by
development of proline-oxazoline ligand 6, which achieved 94% ee
10
F u¨ rstner in 1996 significantly enhanced the synthetic utility of
in the allylation of benzaldehyde. The reaction scope has recently
been extended by Nakada to include allenylation and methally-
lation of benzaldehyde employing ligand class 4, with optimum
3
the reaction. However, the presence of relatively few examples
in the literature of successful enantioselective Nozaki–Hiyama–
Kishi reactions highlights the significant difficulties encountered
due to poor ligand coordination and specificity, in addition
to the tendency of chromium(II) to form dimers or clusters
with polydentate ligands. The most successful enantioselective
reactions relied on over stoichiometric amounts (up to 400%) of
chiral ligands. Examples of these ligands include bipyridine ligand
8,11
enantioselectivities of 95% and 83% respectively. We recently
12
13
reported the synthesis and application of bis(oxazoline) ligands
7 in the catalytic asymmetric chromium-catalysed allylation and
crotylation of a variety of aromatic and aliphatic aldehydes.
The convergent synthesis, which utilises a Buchwald–Hartwig
aryl amination as the key step, allowed for the preparation
of both the symmetric 7a–c and non-symmetric 7d–g series of
ligands. There are few other examples of the application of C1-
symmetric bis(oxazoline) ligands in asymmetric catalysis apart
1
, which afforded 28–74% ee for the allylation and alkenylation
4
of benzaldehyde, and the N-benzoylprolinol ligand 2, which gave
up to 98% ee for the reaction of allyl bromide with a range of
5
14
15
aldehydes.
from the groups of Nishiyama and Bolm. We now report the
application of a range of these ligands in the catalytic asymmetric
methallylation of aldehydes. This is an important asymmetric
transformation as, in addition to creating a secondary alcohol
chiral centre, the 2,2-disubstituted olefin is a useful functional
handle for further manipulation. Such potential has previously
been realised in the synthesis of a key intermediate of calcitriol
In 1999 Cozzi and co-workers developed the first catalytic
enantioselective Nozaki–Hiyama–Kishi (NHK) reaction using
6
chromium(II) complexes of chiral salen 3. High levels of enan-
tioselectivity were obtained for the allylation (77–90% ee) and
7
crotylation (78–90% ee) of a range of aldehydes. There have since
been numerous applications of a range of ligands, particularly
those containing a chiral oxazoline ring in the catalytic asymmet-
ric NHK reaction. Nakada’s bis(oxazolinyl)carbazole ligand 4a
16
lactones.
a
Centre for Synthesis and Chemical Biology, Conway Institute of Biomole-
cular and Biomedical Research, School of Chemistry and Chemical Biology,
University College Dublin, Belfield, Dublin 4, Ireland. E-mail: p.guiry@
ucd.ie; Fax: +353-1-7162501
b
Dipartimento di Chimica “G. Ciamician”, Universit a` di Bologna, Via Selmi
2
, 40126, Bologna, Italy
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Ligands 7a–g were initially investigated in the chromium(II)-
mediated reaction of benzaldehyde 8a with methallyl bromide
acetonitrile (7 : 1) as the solvent and N,N-diisopropylethylamine
as the base. The methallylations proceeded cleanly using these con-
ditions, with high conversions after 16 hours at room temperature.
The best symmetrical ligand was the bis(isopropyl)-substituted
9
(Table 1).† Our previous studies have shown that the optimal
reaction conditions for allylation and crotylation employ THF–
Table 1 Catalytic asymmetric methallylation of benzaldehyde using ligands 7a–g
1
2
a
b
c
Entry
Ligand
R
R
Conv. (%)
Yield (%)
ee (%) (conf.)
1
2
3
4
5
6
7
7a
7b
7c
7d
7e
7f
Bn
Bn
80
90
70
78
86
75
78
70
75
58
65
64
60
60
7 (R)
58 (S)
5 (S)
19 (R)
95 (R)
35 (R)
16 (S)
i-Pr
t-Bu
Ph
t-Bu
t-Bu
i-Pr
i-Pr
t-Bu
Bn
Bn
i-Pr
Bn
7g
a
1
b
c
Determined from the 300 MHz H NMR spectrum of the crude silylated product. Isolated yields of the allylic alcohol 10a. Determined by chiral
d
HPLC analysis of the alcohol product 10a using a Daicel Chiralcel OD column (see general procedure†). Determined by comparison of the chiral HPLC
retention times with literature values.
17
Table 2 Catalytic asymmetric Nozaki–Hiyama–Kishi methallylation of aldehydes using ligand 7e
a
b
c
d
Entry
1
Aldehyde
Conv. (%)
Yield (%)
ee (%) (conf. )
86
100
50
64
95 (R)
e
2
92
41
50 (R)
59 (R)
3
f
4
90
58
78
48
65 (R)
33 (R)
g
5
f,g
6
70
75
57
60
89 (S)
55 (S)
7
a
c
1
b
Determined from the 300 MHz H NMR spectrum of the crude silylated product (except entry 2). Isolated yields of the homallylic alcohol 10a–f.
d
Determined by chiral HPLC analysis on a Daicel Chiralcel OD or AD column (see general procedure†). Determined by comparison of the chiral
16,17
e
18 f
HPLC retention times with literature values.
3
ZrCp
2
Cl
2
used in place of TMSCl. Enantiomeric excess determined by HPLC analysis of the
g
,5-dinitrobenzoate ester. Configuration determined by analogy with alcohol 10e.
7
64 | Org. Biomol. Chem., 2007, 5, 763–766
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Scheme 1 Catalytic asymmetric Nozaki–Hiyama–Kishi methallylation of benzaldehyde using methallyl chloride.
ligand 7b, which afforded alcohol 10a with a moderate enantio-
selectivity of 58% (S) (Table 1, entry 2). Both the bis(benzyl) ligand
a and the bis(tert-butyl) ligand 7c afforded poor enantioselectiv-
Acknowledgements
We thank the Irish Research Council for Science, Engineering and
Technology for the award of a postgraduate scholarship to GH
7
ities of 7% (R) and 5% (S), respectively. Of the unsymmetrical
ligands, the tert-butyl/isopropyl ligand 7f provided a disappoint-
ing enantioselectivity of 35% (R). The optimal enantioselectivity
of 95% (R) was obtained using the tert-butyl/benzyl-substituted
ligand 7e (Table 1, entry 5). A small change in ligand structure
to the isopropyl/benzyl-substituted oxazoline ligand 7g led to a
reversal and lowering of enantioselectivity to 16% (S). These are
similar trends to those we observed in the allylation and crotylation
of benzaldehyde using ligands 7a–g, with ligand 7e again affording
the best enantioselectivity.
(RS/2003/36). We acknowledge financial support from the Centre
for Synthesis and Chemical Biology (CSCB), which was funded
by the Higher Education Authority’s Programme for Research
in Third-Level Institutions (PRTLI). A research visit by GH to
Bologna was supported by LigBank, a European Union Sixth
Framework Programme (FP6-505267-1).
Notes and references
†
General procedure: A flame-dried Schlenk tube was charged with dry
We then proceeded to examine the enantiodiscriminating ability
of ligand 7e in the reaction of methallyl bromide 9 with a range of
aromatic and aliphatic aldehydes 8a–f (Table 2).
THF (1 mL) and dry acetonitrile (150 lL). Anhydrous chromium(III)
chloride (4.0 mg, 25.3 lmol) and manganese (41.7 mg, 0.76 mmol) were
added simultaneously to the solvent mixture. The resulting suspension was
allowed to stand at room temperature for approximately 30 min until the
characteristic purple colour of the chromium(III) salt disappeared. The
mixture was stirred vigorously under an atmosphere of nitrogen for 1 h,
resulting in a green reaction mixture. DIPEA (13 lL, 75.9 lmol) was added
followed by the bis(oxazoline) ligand 7 (30.4 lmol), immediately resulting
in a deep green catalyst mixture. This was 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
initiated by the addition of aldehyde (0.25 mmol) and chlorotrimethylsilane
In an effort to increase the yield of homoallylic alcohol 10a, we
changed our dissociating agent from TMSCl to ZrCp
2
2
Cl (Table 2,
18
entry 2). While we observed complete conversion after 16 hours
at room temperature and a yield of 92%, there was a significant
decrease in enantioselectivity to 50% (R). We also wished to
examine the effect of having electron-donating and electron-
withdrawing groups on the aromatic aldehyde, and thus studied
para-methoxybenzaldehyde 8b and para-chlorobenzaldehyde 8c as
substrates. The enantioselectivities obtained were moderate, 59%
(
64 lL, 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 NaHCO (1 mL) and extracted with
3
(
R) and 65% (R) respectively, with the yield obtained for 8b (41%)
Et O (3 × 1 mL). The combined organic layers were concentrated in vacuo
2
being significantly lower than that obtained with 8c (78%) (Table 2,
entries 3 and 4). Asymmetric nucleophilic addition to aliphatic
aldehydes is a less developed process, and we were pleased to find
that aldehydes 8d–f were successful substrates, and, in the case of
heptaldehyde 8e, an ee of 89% (S) was obtained.
to give a green residue. This was flushed through a small silica gel column
(
1.5 × 5 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 percentage conversion of the reaction was determined at this stage
from the H NMR spectrum of the crude product (generally a mixture of
1
silylated and free alcohol) by measuring the ratio of aldehyde to product
and assuming that all aldehyde consumed was converted to product. The
yellow oil was dissolved in THF (1 mL), a few drops of aqueous 1 M
HCl were added, and the resulting solution was stirred for 10 min, at
which point TLC (9 : 1 pentane–AcOEt) showed complete desilylation.
The solvent was removed in vacuo and the resulting aqueous phase was
Replacing methallyl bromide 9a with the less reactive methallyl
chloride 9b (Scheme 1) gave both low conversion (40%) and yield
(
24%) with an excellent enantioselectivity of 99.5% (R). To the
best of our knowledge, this is the best enantioselectivity achieved
to date for the methallylation of benzaldehyde. As a comparison
extracted with Et
over anhydrous Na
2
O (3 × 2 mL). The organic layers were combined, dried
2
SO and concentrated in vacuo to give a yellow oil. This
4
16
with literature values, ligand 4c afforded enantiomeric excesses
was purified by flash column chromatography on silica gel (1 × 15 cm) using
10
5 : 1 cyclohexane–AcOEt as the eluent to give the required product as a
of up to 95% whereas ligand 6 gave an ee of 91%.
pale yellow oil. Enantioselectivity was determined by HPLC as follows:
In summary, we have applied both symmetric (7a–c) and
non-symmetric (7d–g) bis(oxazoline) ligands in the asymmetric
methallylation of a range of aromatic and aliphatic aldehydes.
The best ligand was found to be the tert-butyl/benzyl-substituted
ligand 7e, which provided enantioselectivities of 95% and 99.5% in
the reaction of benzaldehyde with methallyl bromide and methallyl
chloride, respectively. Our results again highlight the significant
effect the substituents on the oxazoline rings have on both the
magnitude and sense of asymmetric induction. Efforts are ongoing
to elucidate the structures of the chromium–ligand complexes to
determine the mechanism of the reaction and explain these effects.
The results of such investigations will form the basis of future
publications from these laboratories.
0a: Chiralcel OD, hexane–isopropanol, 98 : 2, flow rate 1.0 mL min− ):
1
1
(
R) = 14.1 min, (S) = 16.9 min; 10b: Chiralcel, OD, hexane–isopropanol,
−1
99 : 1 to 90 : 10 over 30 min, flow rate 0.5 mL min ): (R) = 22.7 min,
(
S) = 23.9 min; 10c (3,5-dinitrobenzoate ester): Chiralcel AD, hexane–
−
1
isopropanol, 99 : 1 to 90 : 10 over 20 min, flow rate 0.5 mL min ): (S) =
2
2.8 min, (R) = 28.2 min; 10d (3,5-dinitrobenzoate ester): Chiralcel OD,
−1
hexane–isopropanol, 95 : 5, flow rate 0.2 mL min : (R) = 35.5 min,
(S) = 37.9 min; 10e (3,5-dinitrobenzoate ester): Chiralcel OD, hexane–
−
1
isopropanol, 99 : 1, flow rate 0.2 mL min : (R) = 29.5 min, (S) = 34.4 min;
0f: Chiralcel OD, hexane–isopropanol, 90 : 10, flow rate 0.2 mL min−
1
:
1
(
R) = 26.5 min, (S) = 32.9 min.
1
(a) Y. Okude, S. Hirano, T. Hiyama and H. Nozaki, J. Am. Chem. Soc.,
1
977, 99, 3179–3181; (b) T. Hiyama, K. Kimura and H. Nozaki, Tetra-
hedron Lett., 1981, 22, 1037–1040; (c) T. Hiyama, Y. Okude, K. Kimura
and H. Nozaki, Bull. Chem. Soc. Jpn., 1982, 55, 561–568; (d) K. Takai,
This journal is © The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 763–766 | 765

View Article Online
K. Kimura, T. Kuroda, T. Hiyama and H. Nozaki, Tetrahedron Lett.,
983, 24, 5281–5284.
2001, 3, 1153–1155; (d) M. Bandini, P. G. Cozzi, P. Melchiorre, R. Tino
and A. Umani-Ronchi, Tetrahedron: Asymmetry, 2001, 12, 1063–1069;
(e) M. Lombardo, S. Licciulli, S. Morganti and C. Trombini, Chem.
Commun., 2003, 1762–1763; (f) M. Bandini, P. G. Cozzi, S. Licciulli
and A. Umani-Ronchi, Synthesis, 2004, 409–414.
8 T. Suzuki, A. Kinoshita, H. Kawada and M. Nakada, Synlett, 2003,
570–572.
1
2
3
(a) R. W. Armstrong, J.-M. Beau, S. H. Cheon, W. J. Christ, H. Fujioka,
W.-H. Ham, L. D. Hawkins, H. Jin, S. H. Kang, Y. Kishi, M. J.
Martinelli, W. W. McWhorter, Jr, M. Mizuno, M. Nakata, A. E. Stutz,
F. X. Talamas, M. Taniguchi, J. A. Tino, K. Ueda, J. Uenishi, J. B.
White and M. Yonaga, J. Am. Chem. Soc., 1989, 111, 7530; (b) T. D.
Aicher, K. R. Buszek, F. G. Fang, C. J. Forsyth, S. H. Jung, Y. Kishi,
M. C. Matelich, P. M. Scola, D. M. Spero and S. K. Yoon, J. Am. Chem.
Soc., 1992, 114, 3162.
9 M. Kurosu, M.-H. Lin and Y. Kishi, J. Am. Chem. Soc., 2004, 126,
12248–12249.
10 J. Y. Lee, J. J. Miller, S. S. Hamilton and M. S. Sigman, Org. Lett., 2005,
7(9), 1837–1839.
11 M. Inoue and M. Nakada, Angew. Chem., Int. Ed., 2006, 45, 252–255.
12 H. A. McManus and P. J. Guiry, J. Org. Chem., 2002, 67, 8566–8573.
13 H. A. McManus, P. G. Cozzi and P. J. Guiry, Adv. Synth. Catal., 2006,
348, 551–558.
(a) A. F u¨ rstner and N. Shi, J. Am. Chem. Soc., 1996, 118, 2533–2534;
(
b) A. F u¨ rstner and N. Shi, J. Am. Chem. Soc., 1996, 118, 12349–12357.
4
5
C. Chen, K. Tagami and Y. Kishi, J. Org. Chem., 1995, 60, 5386–5387.
K. Sugimoto, S. Aoyagi and C. Kibayashi, J. Org. Chem., 1997, 62,
2
322–2323.
6
7
(a) M. Bandini, P. G. Cozzi, P. Melchiorre and A. Umani-Ronchi,
Angew. Chem., 1999, 111, 3558–3561; M. Bandini, P. G. Cozzi, P.
Melchiorre and A. Umani-Ronchi, Angew. Chem., Int. Ed., 1999,
14 H. Nishiyama, N. Soeda, T. Naito and Y. Motovama, Tetrahedron:
Asymmetry, 1998, 9, 2865–2869.
15 I. Atodiresei, I. Schiffers and C. Bolm, Tetrahedron: Asymmetry, 2006,
17, 620–633.
3
8, 3357–3359; (b) M. Bandini, P. G. Cozzi and A. Umani-Ronchi,
Polyhedron, 2000, 19, 537–539.
16 M. Inoue, T. Suzuki and M. Nakada, J. Am. Chem. Soc., 2003, 125,
(a) M. Bandini, P. G. Cozzi and A. Umani-Ronchi, Angew. Chem., 2000,
1140–1140.
1
12, 2417–2420; M. Bandini, P. G. Cozzi and A. Umani-Ronchi, Angew.
17 K. Iseki, S. Mizuno, Y. Kuroki and Y. Kobayashi, Tetrahedron, 1999,
55, 977–988.
18 K. Namba, S. Cui, J. Wang and Y. Kishi, Org. Lett., 2005, 7(24), 5417–
5419.
Chem., Int. Ed., 2000, 39, 2327–2330; (b) M. Bandini, P. G. Cozzi and A.
Umani-Ronchi, Tetrahedron, 2001, 57, 835–843; (c) M. Bandini, P. G.
Cozzi, P. Melchiorre, S. Morganti and A. Umani-Ronchi, Org. Lett.,
7
66 | Org. Biomol. Chem., 2007, 5, 763–766
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