A triazine core for a new class of Sharpless asymmetric dihydroxylation ligands

Article abstract of DOI:10.1016/j.tetlet.2004.09.098

Sharpless asymmetric dihydroxylation ligands were synthesized using a triazine spacer group in two, high yielding steps and gave good enantioselectivities in the asymmetric dihydroxylation of alkenes. Sharpless asymmetric dihydroxylation ligands were synthesized using a triazine spacer group in two, high yielding steps from cheap, readily available starting materials. The ligands, gave good enantioselectivities in the asymmetric dihydroxylation of alkenes and may provide a very economic alternative to current systems.

Full text of DOI:10.1016/j.tetlet.2004.09.098

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8527–8529
A triazine core for a new class of Sharpless asymmetric
dihydroxylation ligands
a
Catherine Anne McNamara, Frank King and Mark Bradley
b
a,
*
a
Department of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK
Johnson Matthey Research and Technology, PO Box 1, Belasis Avenue, Billingham, Cleveland TS23 1LB, UK
b
Received 22 July 2004; revised 3 September 2004; accepted 13 September 2004
Available online 1 October 2004
Abstract—Sharpless asymmetric dihydroxylation ligands were synthesized using a triazine spacer group in two, high yielding steps
from cheap, readily available starting materials. The ligands, gave good enantioselectivities in the asymmetric dihydroxylation of
alkenes and may provide a very economic alternative to current systems.
ꢀ
2004 Elsevier Ltd. All rights reserved.
The catalytic asymmetric dihydroxylation of alkenes
with osmium tetroxide in the presence of bis-cinchona
alkaloid derivatives (1–3, Fig. 1) has provided a remark-
able tool by which a range of optically pure diols can be
easily obtained in high yields and with excellent enantio-
selectivities. The synthesis of a range of analogues,
using a number of heterocyclic spacer groups between
the two chiral moieties (four different possible alkaloid
moieties are used: quinine 4 and its pseudoenantiomer
quinidine 6 and their dihydro analogues hydroquinine
R1
N N
*Alk
Alk*
Alk* =
N
O R
O
1
,2
1
phthalazine spacer
N
N N
*Alk
Alk*
R = heterocyclic spacer
1
4; R = CHCH
= Quinine (QN)
2
2
1
5
capable of performing the transformation across a
and hydroquinidine 7), has afforded a set of ligands
pyridazine spacer
5; R = CH CH = Hydroquinine (HQN)
2
3
R1
2
–4
or
broad range of alkene substrates (Fig. 1).
N
O R
Herein, the synthesis of a new ligand with a triazine
spacer group between the two chiral moieties (9,
Scheme 1) is reported. Compound 9 was synthesized in
two, high yielding steps from inexpensive, readily
available starting materials; 4-bromoaniline, cyanuric
*
Alk
Alk*
O
N
N
N
R = heterocyclic spacer
5
chloride and quinine as shown in Scheme 1. Such
1
6
7
; R = CHCH = Quinidine (QD)
2
construction allows for broad diversification of the
ligand, with the availability of many aniline and amine
derivatives for the first reaction. Thus 4-bromoaniline
was dissolved in acetone/water (1:1) and added to a
suspension of cyanuric chloride in a crushed ice/acetone
mixture (1:1) to give 8. Following drying under vacuum,
the mono-substituted triazine was dissolved in dry THF
3
1
; R = CH CH = Hydroquinidine (HQD)
pyrimidine spacer
2
3
Figure 1. Range of ligands with different heterocyclic spacer groups
used in the asymmetric dihydroxylation of alkenes.
and added to the anion of quinine, generated in situ with
NaH to afford 9 in 98% isolated overall yield.
Results for the asymmetric dihydroxylation of several
alkenes, using K Fe(CN) as a secondary oxidant are
shown in Table 1 with the results obtained for SharplessÕ
Keywords: Triazine; Sharpless; Dihydroxylation.
*
Corresponding author. Tel.: +44 23 80593598; fax: +44 23
0596766; e-mail: mb14@soton.ac.uk
3
6
8
0
040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.098

8528
C. A. McNamara et al. / Tetrahedron Letters 45 (2004) 8527–8529
Table 2. Enantioselective dihydroxylation of alkenes catalyzed by the
triazine catalysts with different alkaloid moieties attached
NH2
Cl
+
N
Cl acetone/water (1:1)
Cl
N
Cl
Alkene
2-(4-Bromophenyl(amino))-1,3,5-triazine
core ee (%)
N
N
N
N
0
°C, 2 h
Cl
quant
NH
Br
QN
HQN
HQD
QD
Br
9
3
94
86
92
8
N
64
64
24
64
29
74
22
N
O
N
O
2
.1 eq quinine, NaH
O
O
N
N
2
6
THF, reflux, 18 h
8%
NH
N
N
9
Br
9
and 2), while for other alkene geometries, lower eeÕs
were observed, similar to the pyrimidine ligand (3, Fig.
4
1
) where the ee achieved for a-methyl styrene and ind-
Scheme 1. Synthesizes of tri-substituted triazine 9.
ene were only 69% and 35% (Table 1, entries 4 and 5),
respectively, suggesting that the 1,3 and 1,4 relationship
between the chiral moieties is important (Fig. 1).
In order to ascertain if any differences in ee would occur
as a result of the incorporation of the different chiral lig-
ands (HQN, QD, HQD), the synthesis of the three ana-
logues of 9 was undertaken in a manner similar to that
shown in Scheme 1.
Table 1. Enantioselective dihydroxylation of alkenes mediated with
triazine 9
1
0 mol% 9, OsO4,
R
K
3
FeCN /K CO , MeSO
6
2
3
NH ,
2 2
HO
R
t
R
BuOH/H O (1:1), 0 °C, 14 h
R
OH
2
a
b
Table 2 shows the eeÕs achieved by catalysis with the dif-
ferent alkaloid moieties with conditions similar to those
described in Table 1. Overall no significant differences in
ee for the different ligands were observed, suggesting
that diols of both configurations are achievable.
Alkene
Yield (%)
ee (%)
Sharpless
1
2
75
>99
>99
CO Me
Since the triazine moiety contains three sites, which can
be substituted it was considered interesting to investigate
the catalytic activity of the C-3 symmetric ligand, which
was synthesized in a manner similar to that for 9, in 66%
yield from cyanuric chloride and 3.1equiv of quinine.
This had a disastrous result on the catalytic activity;
eeÕs dropped from 94% to 76%, 64% to 42% and 24%
to 2% for b-methyl styrene, a-methyl styrene and ind-
2
c
97
Quant
>99
3
4
78
85
93
64
97
94
6
ene, respectively. This supports previous observations
that the presence of a binding pocket for the alkene is
crucial for high enantioselectivities. It appears that the
aniline moiety is necessary for the construction of such
a pocket, hence the function of the third component is
not merely as a steric block.
5
90
26
42
Experimental conditions: 0.6mmol alkene, 9lmol OsO
FeCN , 1.8mmol K CO , 0.6mmol MeSO NH and 0.06mmol
chiral triazine catalyst.
4
, 1.8mmol
K
3
6
2
3
2
2
a
ee was determined by RP-HPLC on a Chiralpak AD-RH column,
using 20% MeCN/H
In summary a novel Sharpless-type asymmetric dihydr-
oxylation ligand with a triazine core was synthesized
in two, easy, high yielding steps from readily available
starting materials, and may offer an economic alterna-
tive to current systems. The catalyst was found to be ac-
tive in the asymmetric dihydroxylation of alkenes,
especially those of trans-geometry. As cyanuric chloride
can be easily and selectively reacted with a variety of
nucleophiles including thiols, phenols and Grignard rea-
2
O as solvent with a flow rate of 0.5mL/min.
b
c
See Ref. 1b.
Value reported for the ethyl ester.
phthalazine ligand (1, Fig. 1), added for comparison. It
was immediately evident that the catalyst was most
selective for trans-substituted alkenes, which all gave
greater than 90% ee (unoptimized). For two alkenes
the catalyst was found to be comparable to those re-
ported for the Sharpless derivative (Table 1, entries 1
7
gents, it could therefore serve as an extremely useful
spacer group to further extend the scope of the asym-
metric dihydroxylation reaction.

C. A. McNamara et al. / Tetrahedron Letters 45 (2004) 8527–8529
8529
Acknowledgements
100mL) was added dropwise with vigorous stirring. After
stirring for 2h at 0ꢁC the resulting yellow suspension was
filtered, washed with cold water (20mL) and dried under
vacuum to yield the title compound as a pale yellow solid
We thank the EPSRC and Johnson Matthey for a
CASE award.
(
17.1g, 3.9mmol).
Synthesis of 9: Compound 8 (17.1g, 53.9mmol) was
dissolved in dry THF (50mL) and added to a stirred
suspension of quinine (36.4g, 54mmol) and NaH (60%
dispersion in mineral oil) (6.5g, 0.17mol) in THF (200mL).
The reaction mixture was refluxed overnight, then
References and notes
1
2
3
. (a) Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schroder,
G.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968; (b)
Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483.
. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G.
A.; Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.;
Wang, Z. M.; Xu, D. Q.; Zhang, X. L. J. Org. Chem. 1992,
8, 2768.
. (a) Lohray, B. B.; Bhusan, V. Tetrahedron Lett. 1992, 33,
113; (b) Corey, E. J.; Noe, M. C.; Sarshar, S. J. Am. Chem.
4
quenched by transfer into saturated NH Cl (100mL). The
phases were separated, the product extracted into ethyl
acetate (3 · 200mL) and the solvent removed in vacuo to
afford a yellow solid, which was chromatographed in ethyl
acetate on base activated alumina to give the title product
as a white slurry, 4-bromoanaline (47.3g, 53mmol, 98%).
6. (a) Becker, H.; Ho, P. T.; Kolb, H. C.; Loren, S.; Norrby,
P.-O.; Sharpless, K. B. Tetrahedron Lett. 1994, 35, 7315; (b)
Kolb, H. C.; Anderson, P. G.; Sharpless, K. B. J. Am.
Chem. Soc. 1994, 116, 1278; (c) Lohray, B. B.; Bhusan, B.;
Nandanan, E. Indian J. Chem. Sec. B: Org. Chem. Inc.
Med. Chem. 1996, 35B, 1119; (d) Corey, E. J.; Noe, M. C. J.
Am. Chem. Soc. 1996, 118, 319.
5
5
Soc. 1993, 115, 3828.
4
. Crispino, G. A.; Jeong, K.-S.; Kolb, H. C.; Wang, Z.-M.;
Xu, D.; Sharpless, K. B. J. Org. Chem. 1993, 58, 3785.
. Synthesis of 8: A solution of cyanuric chloride (10.0g,
4mmol) in acetone (100mL) was heated to 50ꢁC and
added to stirred crushed ice/water (200mL). To the
resulting fine white slurry 4-bromoaniline (18.7g,
5
5
7. (a) Delia, T. J.; Nagarajan, A. J. Heterocycl. Chem. 1998,
35, 269; (b) Menicagli, R.; Samaritani, S.; Zucchelli, V.
Tetrahedron 2000, 56, 9705.
1
0.8mmol), dissolved in an acetone/water mixture (1:1,