Novel chiral biheteroaromatic diphosphine oxides for Lewis base activation of Lewis acids in enantioselective allylation and epoxide opening

Article abstract of DOI:10.1002/adsc.200700564

Enantiomerically pure biheteroaromatic diphosphine oxides were synthesised and tested as organocatalysts in two different reactions involving trichlorosilyl compounds. The allylation of aldehydes with allyl(trichloro) silane afforded homoallylic alcohols

Full text of DOI:10.1002/adsc.200700564

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DOI: 10.1002/adsc.200700564
Novel Chiral Biheteroaromatic Diphosphine Oxides for Lewis
Base Activation of Lewis Acids in Enantioselective Allylation
and Epoxide Opening
a
a,
b,
Valentina Simonini, Maurizio Benaglia, * and Tiziana Benincori *
a
Dipartimento di Chimica Organica e Industriale – Universitaꢀ degli Studi di Milano, via Golgi 19, 20133 Milano, Italy
Fax : (+39)-025-031-4159; e-mail: maurizio.benaglia@unimi.it
Dipartimento di Scienze Chimiche ed Ambientali dell’Università dell’Insubria, Via Valleggio 11, 22100 Como, Italy
b
Received: December 3, 2007; Published online: February 26, 2008
Abstract: Enantiomerically pure biheteroaromatic
diphosphine oxides were synthesised and tested as
organocatalysts in two different reactions involving
trichlorosilyl compounds. The allylation of alde-
hydes with allyl(trichloro)silane afforded homoallyl-
ic alcohols in fair to good yields and up to 95% ee.
Preliminary experiments showed that this new class
of metal-free catalysts was able also to promote the
stilbene oxide opening by addition of tetrachlorosi-
lane with enantioselectivity higher than 80%. The
interesting results in terms of chemical and stereo-
chemical efficiency open the way to further studies
towards the development of new chiral heteroaro-
matic Lewis bases as efficient metal-free catalysts.
classes of compounds which have been employed as
[
4]
chiral Lewis bases to catalyze the reaction, chiral
[
5]
[6]
phosphoramides and pyridine N-oxides have been
widely employed with excellent results. Even if sys-
[
7]
tems with relatively easy syntheses were developed,
[
8]
including chiral bispyridine N,N’-dioxides, or simple
pyridine N-oxides that are easily assembled from in-
expensive amino acids, the search for new, readily
available, efficient chiral organocatalysts for the reac-
tion of trichlorosilyl compounds is still a true necessi-
ty.
[
9]
Quite surprisingly diphosphine oxides, which are
also able to coordinate trichlorosilyl derivatives and
generate hypervalent silicates, have been scarcely
considered as Lewis bases in such organocatalysed re-
[
10]
Keywords: allylation; biheteroaromatic diphosphine
oxides; chiral Lewis bases; organic catalysts
actions. So far, only BINAPO 1a, the corresponding
bis-phosphine oxide of the very popular diphosphine
ligand BINAP, was employed by Nakajima’s group in
the allylation of aldehydes and the aldol reaction of
[
11]
trichlorosilyl enol ethers. However, modest results
were obtained in the addition of allyl(trichloro)silane
The chemistry of penta- and/or hexavalent silicon to aldehydes (<44% ee) and only when working with
compounds has recently attracted much attention be- additives and substitued allylsilanes were the enantio-
cause it offers the possibility to develop organocata- selectivties improved to a typical range of 50–70%
[
11]
lyzed enantioselective reactions which employ cheap, ee.
low toxic and environmental friendly compounds.
[
1]
Since in the past years a wide and homogeneous
The hypervalent silicon species involved in syntheti- series of electronically tunable C symmetric diphos-
2
cally useful processes are generally formed in situ by phines characterized by a biheteroaromatic atropiso-
[
12]
reaction between a four-coordinated silicon atom and meric backbone has been synthesized by us, we de-
a Lewis base in what is often called the “activation cided to test the corresponding diphosphine oxides as
[2]
step”. The so formed five- or six-coordinated silicon organic catalysts in the reaction of trichlorosilyl com-
species is able to promote the desired reaction in a pounds. The advantages offered by the biheteroaryldi-
catalytic process where the base dissociates from sili- phosphine oxides, with respect to carbocyclic aromatic
con after the product is formed and can start a new derivatives, reside in their greater synthetic accessibil-
catalytic cycle.
ity and in the possibility of testing a series of catalysts
In this context, the enantioselective addition of al- displaying different electronic properties. The influ-
lyl(trichloro)silane to aldehydes represents a clear ex- ence of not only the electronic availability of the het-
ample of how metal-based enantioselective catalysts erocyclic system but also the position of the phospho-
may be effectively replaced with simple organic mole- rus atoms on the latter on the kinetics and stereose-
cules while maintaining high levels of chemical and lection has been demonstrated for the biheteroaro-
[
3]
[13a]
stereochemical efficiency.
Among the different matic diphosphines.
Since similar effects could be
Adv. Synth. Catal. 2008, 350, 561 – 564
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561

Valentina Simonini et al.
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observed also in the case of the corresponding diphos- Table 1. Enantioselective addition of allyltrichlorosilane to
[
a]
[
13b]
benzaldehyde.
phine oxides, we selected tetraMe-BITIOPO 2
N-Me-2-BINPO 3,
and
which are based on electron-
rich 3-thiophenyl and 3-indolyl scaffolds, and the elec-
[
13a]
[b]
[c]
Entry Catalyst T [8C] Solvent Yield [%]
ee [%]
[
13c]
[11]
tron-poorer BITIANPO 4
where the sulfur atom
1
2
3
4
5
6
7
8
9
1a
2
3
4
1b
2
2
2
2
25
0
0
0
0
DCM
79
37
93
81
n.d.
51
87
n.d.
93
exerts electron-withdrawing effects on the adjacent
phosphorus function. These diphosphine oxides can
be easily resolved through fractional crystallization of
the diastereomeric adducts with optically active acids
and recovered in an enantiopure state after alkaline
decomplexation.
CH CN 85
3
CH CN 83
3
CH CN <5
3
CH CN 55
3
0
DCM
67
À20
CH CN <5
3
[d]
[e]
0
CH CN 65
3
For sake of comparison also p-Tol-BINAPO (S)-1b,
obtained by oxidation of (S)-Tol-BINAP, was tested
0
CH CN 83
77
3
[a]
Typical experimental conditions: 0.1 mol equiv. of cata-
lyst, 1.2 mol equiv. of allyl(trichloro)silane, and 3 mol
equiv. of DIPEA, 40 h reaction time.
(
Figure 1).
The catalytic activity of the phosphine oxides was
established using the allylation of benzaldehyde to
afford homoallylic alcohol 5a as the model reaction
Scheme 1). A typical experiment involved the use of
.1 mol equiv. of catalyst, 1.2 mol equiv. of allyl(tri-
chloro)silane, and 3 mol equiv. of DIPEA in acetoni-
trile for 48 h at 08C. Isolated yields and ees, as deter-
mined by HPLC, are collected in Table 1; the absolute
[b]
Yields of isolated products.
[c]
As determined by HPLC on a chiral stationary phase;
yields and ee are average of duplicate experiments.
Reaction run in the presence of 1 mol equivof SiCl 4.
Reaction run with 0.05 mol equivof catalyst.
(
0
[
[
d]
e]
configuration was assigned to the predominant isomer ferently as organocatalysts for the allylation of ben-
of 5a by comparison of its optical rotation. zaldehyde. The most electron-deficient diphosphine
From the preliminary experiments it was immedi- oxide 4 was not able to promote the reaction in ap-
ately clear that the compounds 1–4 behaved very dif- preciable yields, while the electron-rich compounds 2
and 3 showed a significant catalytic activity, promot-
ing the addition of allyl(trichloro)silane at 08C in
85% and 83% yield, respectively. Interestingly, the re-
action catalysed by the medium electron-rich diphos-
phine oxide 1b afforded the product in 55% yield, an
intermediate value between those obtained with 2
and 4. (entries 2–5 of Table 1). Biheteroaromatic di-
phosphine oxides showed not only a high chemical ac-
tivity but also an extraordinary ability in determining
the stereochemical outcome of the reaction. With (S)-
N-Me-2-BINPO 3 the homoallylic alcohol was isolat-
ed in 81% ee, a result clearly higher than 51% of
enantioselectivity obtained with catalyst 1b. It is
worth mentioning that BINAPO was shown to pro-
mote the reaction at 258C in only 37% ee (entry 1,
[
11]
Table 1).
raMe-BITIOPO 2 which catalysed the allylation in
3% ee, a very high level of enantioselectivity, compa-
rable to those obtained with the best known cata-
Best results were obtained with (S)-tet-
9
[
4,7]
lysts.
A few experimental parameters of the reaction pro-
moted by (S)-2 were investigated; among the differ-
ent solvents tested in the reaction, such as toluene,
tetrahydrouran, hexane and dichloromethane, only
the last one led to good reasults and it allowed to us
obtain the product in 87% ee even if in lower yield
Figure 1. Structures of chiral diphosphine oxides.
(
entry 6 vs. entry 2, Table 1). Upon further lowering
the reaction temperature the product was not isolated
in an appreciable yield, while it was possible to de-
Scheme 1. Addition of allyl(trichloro)silane to benzalde- crease the catalyst loading amount: by running the re-
hyde. action with 5% of the catalyst it was still possible to
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Novel Chiral Biheteroaromatic Diphosphine Oxides for Lewis Base Activation
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Scheme 3. Addition of (Z)-crotyltrichlorosilane to benzalde-
hyde promoted by catalysts 2.
Scheme 2. Addition of allyl(trichloro)silane to different al-
dehydes.
Table 2. Addition of allyltrichlorosilane to different alde-
[a]
hydes promoted by catalyst 2.
[b]
[c]
Entry
R group
Product
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
Ph
4-NO C H
4-ClC H4
4-OMeC H
2-OMeC H
3-OMeC H
1-naphthyl
Ph-CH=CH
5a
5b
5c
5d
5e
5f
5g
5h
5i
85
51
55
95
95
83
98
55
98
93
93
95
91
83
87
81
55
Scheme 4. Enantioselective opening of cis-stilbene oxide.
2
6
4
6
6
4
4
4
allylation of cinnamaldehyde and 3-phenylpropanal
was also attempted. While the former gave adduct 5h
in fair yield (55%) and ee (55%), surprisingly the
latter proved to be highly reactive, even if the product
5i was isolated in low enantioselectivity (98% yield,
6
6
Ph-CH CH
23[d]
2
2
[
15]
[
a]
23% ee, entry 9).
Typical experimental conditions: 0.1 mol equiv. of cata-
lyst, 1.2 mol equiv. of allyl(trichloro)silane, and 3 mol
equivof DIPEA, 40 h reaction time at 0 8C in CH CN.
Yields of isolated products.
As determined by HPLC on a chiral stationary phase; diastereoisomeric alcohols anti and syn in 83/17 ratio
yields and ee are average of duplicate experiments.
The enantiomer with opposite configuration was ob-
tained.
The use of catalyst 2 was extended to the reaction
of benzaldehyde with an 80:20 mixture of (E)- and
(Z)-crotyltrichlorosilane (Scheme 3). A mixture of
3
[
[
b]
c]
was obtained in 47% yield, the anti isomer having
[
d]
85% ee. The fact that the anti:syn diastereoisomeric
ratio reflected the (E):(Z) ratio of the starting silane,
is generally considered a strong indication that a six-
membered cyclic chair-like transition structure is in-
obtain 5a in 83% yield, even if with decreased enan- volved in the allylation.
tioselectivity (entry 8 vs. entry 2, Table 1). Yields were
(S)-TetraMe-BITIOPO 2 efficiently promoted also
not improved by using some additives, such as tetra- the ring opening of cis-stilbene oxide by addition of
[
16]
chlorosilane, but the enantioselectivity was not influ- tetrachlorosilane in DCM. (Scheme 4) By perform-
enced either (entry 9 vs. entry 2, Table 1)
ing the reaction a À788C (0.1 mol equiv. of 2, 12 h,
[
17]
Having thus identified (S)-tetraMe-BITIOPO 2 as 1.2 mol equiv. of DIPEA, À788C, DCM) the corre-
the more efficient catalyst, its use was extended to sponding chlorohydrin 7 was isolated in quantitative
the allylation of other aromatic aldehydes to afford yield and 81% ee, which favourably compares with
[
18]
alcohols 5b–g (Scheme 2 and Table 2).
the 82% ee obtained with catalyst 1b.
The reported data show that ees equal to or greater
In conclusion, the biheteroaromatic diphosphine
than 80% could be obtained, with a maximum value oxide tetraMe-BITIOPO easily available in both the
of 95% ee observed in the case of the 4-chlorophenyl- enantiomerically pure forms in large amounts, being
substituted alcohol 5c (entry 3). Catalyst (S)-2 effi- the precursor of the industrially produced tetra-Me-
[
19]
ciently promoted the addition of allyltrichlorosilane BITIOP, was shown to be a really chemically and
both to aromatic aldehydes bearing electron-with- stereochemically efficient catalyst for the reaction of
drawing groups (entries 2 and 3) as well as electron- trichlorosilyl compounds. In particular the allylation
donating groups (entry 4) always with enantioselectiv- of aldehydes afforded the products in very high yields
ities higher than 90%. Interestingly the chemical yield and ees up to 95%, providing novel insights in the
seems to depend on the electronic nature of the aryl design and synthesis of new chiral Lewis bases as eff-
substituents in the aldehydes. Electron-poor alde- cient organocatalysts.
hydes react slower than electron-rich aldehydes which
give the product constantly in yields higher than 90%
[
14]
(
entries 4, 5, 7 vs. entries 2 and 3). The 2-catalyzed
Adv. Synth. Catal. 2008, 350, 561 – 564
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
563

Valentina Simonini et al.
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Experimental Section
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2
003, 103, 2763.
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ˇ
´
[
[
6] A. V. Malkov, P. Kocovsky, Eur. J. Org. Chem. 2007, 29.
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ACHTREUNG
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dropwise by means of a syringe. After 48 h stirring at 08C
the reaction was quenched by the addition of a saturated
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3
lowed to warm up to room temperature and water (2 mL)
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2
4
[2]
under vacuum at room temperature to afford the crude
products. These were purified by flash chromatography with
different hexane:AcOEt mixtures as eluant. Yield and ee for
each reaction are indicated in the Tables.
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Acknowledgements
This work was supported by MIUR (Nuovi metodi catalitici
stereoselettivi e sintesi stereoselettiva di molecole funzionali).
T.B. thanks the Dipartimento di Chimica Organica e Indus-
triale for hospitality.
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[
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[4,6]
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Adv. Synth. Catal. 2008, 350, 561 – 564