Enantioselective addition of organozinc reagents to ketones catalyzed by grafted isoborneolsulfonamide polymers and titanium isopropoxide

Article abstract of DOI:10.1016/j.tetasy.2009.01.011

The catalytic enantioselective addition of different organozinc reagents, such as diethylzinc, or in situ generated phenylzinc derivatives to simple aryl methyl ketones was accomplished using titanium tetraisopropoxide and a polymeric ligand grafted with

Full text of DOI:10.1016/j.tetasy.2009.01.011

Tetrahedron: Asymmetry 20 (2009) 65–67
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Tetrahedron: Asymmetry
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Enantioselective addition of organozinc reagents to ketones catalyzed
by grafted isoborneolsulfonamide polymers and titanium isopropoxide
*
*
Vicente J. Forrat, Diego J. Ramón , Miguel Yus
Instituto de Síntesis Orgánica (ISO) and Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, E-03080-Alicante, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The catalytic enantioselective addition of different organozinc reagents, such as diethylzinc, or in situ
generated phenylzinc derivatives to simple aryl methyl ketones was accomplished using titanium tetra-
isopropoxide and a polymeric ligand grafted with trans-1-phenylsulfonylamino-2-isoborneolsulfonylam-
idocyclohexane, to give the corresponding tertiary alcohols with enantioselectivities of up to >99% ee.
Whereas the highest enantioselectivities were obtained in the ethylation process, the highest chemical
yields were obtained in the phenylation process. The ligand could be re-used at least three times without
any significant loss of activity.
Received 7 January 2009
Accepted 20 January 2009
Available online 11 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Although isoborneolsulfonamide ligands can be isolated from
the reaction crude by flash chromatography, its complete recovery
Nowadays, the catalytic enantioselective generation of com-
pounds with stereogenic tertiary carbon atoms can be easily
achieved in most cases.1 However, the related approach to
compounds bearing quaternary stereocenters is still an enormous
challenge for synthetic organic chemistry. Thus, every new enan-
tioselective procedure for the construction of a fully substituted
carbon center is of great value,2 with the simplest approach for
the preparation of chiral tertiary alcohols being the enantioselec-
tive 1,2-addition of organometallic reagents3 to ketones.4
remains difficult. In general, to facilitate the separation of the
homogeneous ligands or catalysts from the reaction mixture, they
are usually immobilized on solid supports.12 There are two main
methods to immobilize a chiral ligand on a support: (a) the grafting
of the desired ligand onto a preformed support containing reactive
groups, and (b) the copolymerization of the suitable functionalized
ligand with polymerizable monomers and cross-linkers. While the
latter offers many possibilities for generating and controlling a
specific environment around the ligand within the polymer matrix
(needing more synthetic efforts), the former is often preferred
since many suitable polymeric supports are commercially
available.
The usual pathway of grafting a chiral molecule on a previously
formed polymer is via the formation of a carbon–oxygen bond as
ether or ester functionality. The functionalization of polymers via
free-radical addition of mercaptans13 has been less studied, even
this protocol having the advantage of its high tolerance to different
functionalities. This strategy has been only used in the grafting of
chiral salen subunits to silica and single-wall carbon nanotubes,14
as well as of a chiral styryl–proline derivative to a mercaptomethyl
functionalized polystyrene.15
Recently, we introduced the isoborneolsulfonamide5 1 as the
first chiral ligand6 that has the ability to promote the catalytic
enantioselective addition of dialkylzinc reagents to simple ke-
tones7 in the presence of titanium tetraisopropoxide,8 other bisiso-
borneolsulfonamides having improved the initial results.9 Among
all tested ligands, trans-1-arylsulfonylamino-2-isobornylcyclohex-
ane derivatives 2 gave the best results,10 not only for alkylation
but also for arylation process.11
X
OH
Herein, we report for the first time the preparation and use as
heterogeneous chiral ligands of a mercaptomethyl functionalized
polystyrene polymer grafting trans-1-phenylsulfanylamino-2-iso-
bornylamino-cyclohexane moieties.
S
O2
NH
O2S
SO2
NH HN
OH
2a: X = Me
2. Results and discussion
2b: X = MeO
1
Styryl derivative 3 was prepared in 41% overall yield starting
from commercially available sodium 4-vinylbenzenesulfonate. Its
reaction with thionyl chloride16 gave the expected sulfonyl
* Corresponding authors. Tel.: +35 965 90 35 48; fax: +35 965 90 35 49 (D.J.R.).
E-mail addresses: djramon@ua.es (D.J. Ramón), yus@ua.es (M. Yus).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.01.011

66
V. J. Forrat et al. / Tetrahedron: Asymmetry 20 (2009) 65–67
Table 1
Ethylation of methyl ketones
chloride derivative, which was trapped by reaction with (1R,2R)-
trans-1,2-diaminocyclohexane under classical biphasic conditions.
The final standard coupling reaction of the above prepared amine
with (1S)-(+)-10-camphorsulfonyl chloride17 yielded the corre-
sponding ketone, which was diastereoselectively reduced to com-
pound 3, and easily isolated in pure form (>99%) by column
chromatography.18 The grafting of commercially available mercap-
tomethyl functionalized polystyrene polymer 4 (100–200 mesh,
cross-linked with 1% divinylbenzene and functionalized in
2 mmol/g) was accomplished by a standard radical addition proto-
col19 rendering the expected polymer 5, after being washed with
several portions of methanol and ethyl ether, with incorporations
of the chiral subunit between 16% and 28%, according to the micro-
analysis data (Scheme 1).
Ti(OPri)4 (110 mol %)
O
OH
+ Et2Zn
Ar
Ar
Polymer 5 (0.8 mol %)
PhMe, 25 ºC
6
7
8
Entry
Time (d)
No.
Ar
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
6
8a
8a
8b
8c
8d
8d
8d
Ph
Ph
36
40
29
42
94
85
90
>99 (S)
>99 (S)
96 (À)
94 (À)
>99 (+)
>99 (+)
>99 (+)
5c
17
17
5
4-MeC4H5
4-FC4H5
PhC„C
PhC„C
PhC„C
5d
5e
a
Isolated yields after bulb-to-bulb distillation.
Determined by GLC using a b-CD column. In parentheses, the absolute config-
b
uration or the obtained sign of the specific rotation.
c
Reaction performed using 2 mol % of polymer.
Reaction performed after one use of the polymer.
Reaction performed after two uses of the polymer.
d
e
+
O2S
NH HN
SO2
HS
OH
3
reactivity. The idea was to improve the reactivity of the zinc re-
agent in order to increase the chemical yield. Recently, the prepa-
ration of ethyl phenyl zinc reagent by transmetallation of
diethylzinc with triphenylboron has been described;20 this inter-
mediate showed a higher reactivity and enantioselectivity in com-
parison to the related diethyl or diphenylzinc reagents.21 The
corresponding ethyl phenyl zinc intermediate was obtained start-
ing from commercially available triphenyl boron 9 and diethylzinc
7 by heating in toluene at 70 °C. This intermediate was reacted
in situ with para-bromoacetophenone in the presence of substoi-
chiometric amounts of polymeric ligand 5 and a small excess of
titanium tetraisopropoxide, giving the expected diaryl ethanol
derivative 10a with good chemical yield, but unfortunately with
moderate enantioselectivity (Table 2, entry 1). This behavior has
previously been described in the case of using aldehydes as elec-
trophiles and using a homogeneous ligand.22 The reaction gave
similar enantioselectivities for other methyl aryl ketones, practi-
cally independent of the electronic character of aryl substituents
(Table 2, entries 2–4).
4
AIBN (0.3 equiv)
THF, 70 ºC, 2 d
NH HN
O2S
SO2
OH
S
5 (16-28 %)
Scheme 1. Synthesis of grafted polymer 5.
The polymeric ligand 5 was first tested in the enantioselective
addition of commercially available diethylzinc 7 to acetophenone
in the presence of Ti(OPri)4. The reaction gave the expected tertiary
alcohol 8a at room temperature. Although the reaction rate was
slow, the enantioselectivity was excellent, the minor (R)-enantio-
mer could not be detected by chiral column GC-analysis (Table 1,
entry 1). An increase in the amount of polymeric ligand did not im-
prove the moderate chemical yield previously obtained (compare
entries 1 and 2 in Table 1). Next, we studied the influence of the
electronic character of para-substituted groups, finding that both,
electron-donating or electron-withdrawing groups, seemed to
have a small negative impact on the results (entries 3 and 4 in Ta-
ble 1). After these results, we changed the initial aryl methyl ke-
Table 2
Phenylation of methyl ketones
OH
i, PhMe, 70 ºC, 16 h
BPh3
+ Et2Zn
Ar
Ph
ii, Polymer 5 (0.8 mol %),
Ti(OPri)4 (110 mol %),
9
7
10
6
ArCOMe ( ), 25 ºC
Entry
Time (d)
No.
Ar
Yielda (%)
eeb (%)
1
2
3
4
5
6
6
6
10a
10b
10c
10d
4-BrC6H4
4-ClC6H4
4-MeC6H4
3-MeC6H4
92
98
38
90
60 (+)
61 (+)
66 (À)
28 (À)
a
tone to another
a,b-unsaturated ketone with the results being
Isolated yields after column chromatography.
Determined by HPLC using Chiracel columns. In parentheses, sign of the optical
b
excellent with regards to enantioselectivity concerns as well as
chemical yield. The recyclability of polymer 5 was studied using
this ketone (Table 1, entries 5–7). After performing and quenching
the reaction with methanol, the polymeric ligand was successively
washed with water and ether, then dried under high vacuum and
re-used in a new reaction. The obtained results were concordant
in all cases, rendering only one enantiomer with yields higher than
85%.
rotation.
3. Conclusion
In conclusion, we have described an easy and simple grafting of
a sulfanyl-containing polymer bearing chiral trans-1-phenylsulfo-
nylamino-2-isoborneolsulfonylaminocyclohexane moiety. This li-
After the partial success found for the enantioselective ethyla-
tion of simple ketones, we turned our attention to the zinc reagent
gand has been shown to be
a
good promoter for

V. J. Forrat et al. / Tetrahedron: Asymmetry 20 (2009) 65–67
67
9. For recent results from our group, see: (a) Yus, M.; Ramón, D. J.; Prieto, O.
Tetrahedron: Asymmetry 2002, 13, 2291–2293; (b) Yus, M.; Ramón, D. J.; Prieto,
O. Tetrahedron: Asymmetry 2003, 14, 1103–1114; (c) Prieto, O.; Ramón, D. J.;
Yus, M. Tetrahedron: Asymmetry 2003, 14, 1955–1957; (d) Yus, M.; Ramón, D. J.;
Prieto, O. Eur. J. Org. Chem. 2003, 2745–2748.
10. (a) Forrat, V. J.; Ramón, D. J.; Yus, M. Tetrahedron: Asymmetry 2005, 16, 3341–
3344; (b) Forrat, V.; Prieto, O.; Ramón, D. J.; Yus, M. Chem. Eur. J. 2006, 12,
4431–4445 (corrigendum: Chem. Eur. J. 2006, 12, 6727); (c) Forrat, V. J.; Ramón,
D. J.; Yus, M. Tetrahedron: Asymmetry 2007, 18, 400–405.
the heterogeneous catalytic enantioselective alkylation and aryla-
tion of simple ketones, as well as its recovery and re-use.
Acknowledgments
This work was generously supported by the Dirección General
de Universidades of the Spanish Ministerio de Ciencia e Innovación
(Consolider Ingenio 2010/CSD2007-00006 and CTQ2007-65218/
BQU) and University of Alicante (UA). V.J.F. thanks the UA for a fel-
lowship. We also thank MEDALCHEMY SL for the gift of some
chemicals.
11. For
a review on enantioselective arylation processes, see: Schmidt, F.;
Stemmler, R. T.; Rudolph, J.; Bolm, C. Chem. Soc. Rev. 2006, 35, 454–470.
12. For reviews, see: (a) Gladysz, J. A. Chem. Rev. 2002, 102, 3215–3216 (thematic
issue on recoverable catalysts and reagents); (b) Corma, A.; García, H. Chem.
Rev. 2003, 103, 4307–4365; (c) Dai, L.-X. Angew. Chem., Int. Ed. 2004, 43, 5726–
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13. Justynska, J.; Hordyjewicz, Z.; Schlaad, H. Polymer 2005, 46, 12057–12064 and
literature quoted therein.
14. Baleizão, C.; Gigante, B.; García, H.; Corma, A. Tetrahedron 2004, 60, 10461–
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