Asymmetric meso-epoxide ring-opening with trimethylsilyl cyanide promoted by chiral binuclear complexes of titanium. Dichotomy of C-C versus C-N bond formation

Article abstract of DOI:10.1002/adsc.200900523

In the presence of chiral catalysts derived from the same chiral hexadentate ligand and aluminium, zinc or titanium ions, the reaction between cyclohexene oxide and trimethylsilyl cyanide can be controlled to give predominantly either the nitrile (up to 99% ee) or the isonitrile product (up to 94% ee). The metal ion, ligand stereochemistry and base concentration all play a role in determining the product ratio.

Full text of DOI:10.1002/adsc.200900523

FULL PAPERS
DOI: 10.1002/adsc.200900523
Asymmetric meso-Epoxide Ring-Opening with Trimethylsilyl
Cyanide Promoted by Chiral Binuclear Complexes of Titanium.
À
À
Dichotomy of C C versus C N Bond Formation
Yuri N. Belokon,a,* Denis Chusov,a Alexander S. Peregudov,a Lidia V. Yashkina,a
Galina I. Timofeeva,a Victor I. Maleev,a Michael North,b and Henri B. Kaganc
a
A.N. Nesmeyanov Institute of Organo-Element Compounds Russian Academy of Sciences, Vavilov 28, 119991 Moscow,
Russian Federation
Fax : (+7)-499-135-5085; e-mail: yubel@ineos.ac.ru
School of Chemistry and University Research Centre in Catalysis and Intensified Processing, Newcastle University,
b
Bedson Building, Newcastle upon Tyne, NE1 7RU, U.K.
Laboratoire de Catalyse Molꢀculaire, Institut de Chimie Molꢀculaire et des Matꢀriaux d’Orsay, UMR 8182, Universitꢀ
c
Paris-Sud, 91405 Orsay, France
Received: July 28, 2009; Revised: October 28, 2009; Published online: December 2, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900523.
Abstract: In the presence of chiral catalysts derived concentration all play a role in determining the prod-
from the same chiral hexadentate ligand and alumi- uct ratio.
nium, zinc or titanium ions, the reaction between cy-
clohexene oxide and trimethylsilyl cyanide can be
controlled to give predominantly either the nitrile Keywords: asymmetric ring-opening; binuclear cata-
(up to 99% ee) or the isonitrile product (up to 94% lysts; meso-epoxides; N/C dichotomy; trimethylsilyl
ee). The metal ion, ligand stereochemistry and base cyanide
Introduction
tate ligands (RaSS)-1 and (SaSS)-2 (Figure 1) as cata-
lysts.[12] These complexes catalyzed the asymmetric
Epoxides are widely utilized as versatile synthetic in- addition of TMSCN to aldehydes under mild reaction
termediates.[1] Their reactions generally involve the
cleavage of the strained three-membered ring by a
wide range of nucleophiles to give b-substituted alco-
hols. In particular, the asymmetric ring opening
(ARO) of epoxides is a rational and effective way to
form two or even three contiguous stereogenic cen-
ters.[2]
Catalytic ARO is of particular interest because it is
an efficient method to convert readily available chem-
icals into non-racemic products.[3] meso-Epoxides
have been successfully employed in ARO reactions
with a large variety of heteroatom-based nucleophiles
such as azides,[4] alcohols,[5] water,[6] thiols,[7] selenols,[8]
amines,[9] and halides.[10] In contrast, only five papers
describe asymmetric ring opening of meso-epoxides
by trimethylsilyl cyanide (TMSCN) as a C-nucleo-
ACHTUNGTRENNUNG
synthesis and ARO of meso-epoxides using TMSCN
promoted by new titanium complexes of the hexaden- Figure 1. Hexadentate and tridentate ligands.
Adv. Synth. Catal. 2009, 351, 3157 – 3167
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3157

Yuri N. Belokon et al.
FULL PAPERS
Scheme 1. Asymmetric ring-opening of cyclohexene oxide
with TMSCN.
conditions furnishing cyanohydrins in excellent chemi-
cal yields and in higher enantiomeric purity, as com-
pared with the complex derived from a tridentate
ligand 3.[12] According to preliminary data, ARO of
meso-cyclohexene oxide with TMSCN (Scheme 1)
was also catalyzed by the complexes, leading predom-
inantly to b-trimethylsilyloxy cyanide (89% ee). How-
Figure 2. Structures of titanium and vanadium complexes.
ever, the rate of the reaction was very slow and there instead of a simple set of signals reflecting C2 symme-
were some unidentified products formed.[12]
try. Estimation of the molecular weight of the com-
In this work we studied the ARO reaction of meso- plex in dichloromethane by the ultracentrifugation
cyclohexene oxide with TMSCN in more mechanistic method[12b] gave a value of 1430Æ70 which was, evi-
detail in order to improve both the stereoselectivity dently, much greater than that expected for the
of the reaction and its rate. In addition, as ARO is an simple dinuclear complex of (RaSS)-1 and 2 equiva-
irreversible reaction, both hydroxy isonitrile (4) and lents of titanium tetraisopropoxide (MW 840).
hydroxy nitrile (5) formation could be expected, de-
The IR spectra of the mixture did not contain
pending on the hardness/softness of the catalyst metal strong absorptions in the region of 800–690 cmÀ1
ions.[14] It was of significant interest to test if the ni- which is typical for Ti O Ti bridges. Attempts to pro-
trile/isonitrile ratio could also be varied by changing duce a crystal suitable for X-ray structure determina-
the structure of the ligands rather than that of the tion failed. However, a Schiff base analogue derived
À À
metal.
from (Ra)-2,2’-dihydroxy-3,3’-diformyl-1,1’-binaphtha-
lene and (S)-valine surprisingly produced a dimeric
coordinatively saturated complex, containing two Ti
ions per two hexadentate ligands instead of the ex-
pected four Ti atoms (the X-ray stucture was pub-
Results and Discussion
The synthesis of ligands (RaSS)-1 and (SaSS)-2 lished earlier[12b]). The four phenolate oxygen atoms
(Figure 1) was described earlier.[12] All the complexes of the complex were well situated to function as che-
derived from 1 and 2 were prepared in situ in di- late donor atoms. Possibly, the predominant solution
chloromethane. The zinc complexes were prepared by structure of 8 contained a coordinatively saturated
the interaction of 2 equivalents of diethylzinc with 1, core with two titanium atoms and two other titanium
the aluminium precatalysts were synthesized by the tetraisopropoxide moieties associated with the phe-
reaction of the ligands with 2 equivalents of alumini- nolic oxygen atoms of the core (Figure 3). This would
um triisopropoxide and titanium-based precatalysts give a molecular weight for 8 equal to 1680. An ad-
were obtained from 2 equivalents of titanium tetraiso- mixture of this complex with the simple monomeric
propoxide. Other precatalysts 6 and 7 (Figure 2) were complex with a 1:TiACHTNUGTRENUNG(O-i-Pr)4 ratio of 1:2 would ac-
previously shown to be highly efficient at promoting count for the molecular weight data. The structure of
asymmetric TMSCN addition to aldehydes.[15] The 8 was easily modified in the presence of strong donor
structure of the titanium complex 8 derived from solvents such as methanol, producing a dimeric com-
ligand (RaSS)-1 is rather complicated. Its 1H NMR plex with the expected two titanium atoms for each
spectrum in CD2Cl2 showed several sets of resonances ligand (see the Supporting Information).
3158
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 3157 – 3167

Asymmetric meso-Epoxide Ring-Opening with Trimethylsilyl Cyanide
FULL PAPERS
from the data, the soft zinc(II) complex promoted the
formation of only racemic isonitrile 4 (Table 1, run 1),
whereas the use of the aluminiumACTHNUTRGNEUNG(III) complex led to
the exclusive formation of racemic nitrile 5 (Table 1,
run 2).
Both titanium complexes derived from (RaSS)-1
and (SaSS)-2 were much less active than those of zinc
and aluminium (Table 1, runs 3 and 4). (1S,2R)-2-Cya-
nocyclohexan-1-ol derivative 5 was formed predomi-
nantly in the case of the 1-Ti2 complex with 89% ee
(determined by chiral GC, Table 1, run 3) and in the
case of 2-Ti2 the (1R,2S)-nitrile (ee 30%) was formed
(Table 1, run 4). The configuration of 5 was assigned
according to the sign of its optical rotation (see Ex-
perimental Section). A sizable amount of b-trimethyl-
silyloxy isonitrile 4, apparently resulting from N-nu-
cleophilic ARO by cyanide, was also found in the re-
1
action mixture after detailed analysis by H, 13C NMR
and IR-spectroscopy (Table 1, runs 3 and 4).[14,16] The
absolute configuration of 4 was assigned according to
the sign of the optical rotation of the 2-amino alcohol
derived from 4 by hydrolysis[17] (see Experimental
Section) and its ee was determined by chiral GC of
the amino alcohol.[18]
titanium
trile with 40% ee (Table 1, run 5). Vanadium oxo-
(salen) chloride complex 7 gave no detectable amount
of any products of ARO with TMSCN (Table 1,
A
reaction catalyzed by
AHCTUNGTRENNG(UN salen) complex 6 was slow and gave only ni-
Figure 3. Possible predominant structure of tetranuclear tita-
nium complex 8 derived from (RaSS)-1 in CH2Cl2.
AHCTUNGTRENNUNG
The chosen model reaction was that of cyclohexene run 6). A mononuclear catalyst derived from 3 gave
oxide ring opening with TMSCN (Scheme 1) in DCM only racemic nitrile 5 in low yield (Table 1, run 7).
at 258C (or À208C). No spontaneous reaction was ob-
The results of runs 1, 2, 3, and 5 seemed to be
served under the experimental conditions. The chemi- easily rationalized by the hard/soft theory, as the soft
cal yields of the products after 24 h reaction, their zinc complex generated isonitrile, whereas aluminium
enantiomeric purities and percentage of nitrile vs. iso- and titanium complexes produced predominantly ni-
nitrile are summarized in Table 1. As can be seen triles.[2,11,13,14] Unexpectedly however, there was a sig-
Table 1. ARO of meso-cyclohexene oxide (Scheme 1) with TMSCN in DCM.[a]
Run
Precatalyst
Conversion [%][b]
Nitrile:isonitrile[b]
ee of nitrile [%]
ee of isonitrile [%][d]
(configuration)
(configuration)[c]
1
1+2 equiv. of ZnEt2
>99
only isonitrile[f]
–
0
2
3
4
1+2 equiv. of Al
1+2 equiv. of Ti(O-i-Pr)4
(O-i-Pr)4
(O-i-Pr)3
>99
60
83
>99:1
12:1
2:1
0
–
G
89 (1S,2R)
30 (1R,2S)
86 (1S,2S)
27 (1R,2R)
2+2 equiv. of Ti
G
5
6
7
56
>99:1
–
>99:1
40 (1R,2S)
–
0
–
–
–
6[e]
7
no reaction
20
3+1 equiv. of Ti
G
[a]
The ligand (10.0 mg, 19.5 mmol), metal precursor (39 mmol) [in case of 3 it was 0.2 equiv. of the ligand and 0.2 equiv of
Ti(O-i-Pr)4 with respect to cyclohexene oxide], TMSCN (40 mL, 298 mmol) with respect to cyclohexene oxide (20 mL,
ACHTUNGTRENNUNG
200 mmol) under Ar, stirring for 24 h in DCM (0.55 mL).
Determined by H NMR spectroscopy.
Determined by chiral GC on a b-DM column.
[b]
[c]
[d]
1
The isonitrile was hydrolyzed to give the b-hydroxy amine which was reacted with trifluoroacetic anhydride. The enantio-
meric excess of the trifluoroacetate derivative was determined by chiral GC analysis.[18]
[e]
[f]
1
No product of ARO with TMSCN was found by H NMR spectroscopy.
No traces of nitrile were found in the proton NMR spectrum which means that there is less than 0.5% of nitrile in the
mixture.
Adv. Synth. Catal. 2009, 351, 3157 – 3167
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3159

Yuri N. Belokon et al.
FULL PAPERS
Figure 4. The rate of the ARO of meso-cyclohexene oxide with TMSCN promoted by titanium-catalysts generated from
(RaSS)-1 and Ti(O-i-Pr)4 with different quantities of Hunigꢂs base and/or Ph3PO added (equivalents relative to cyclohexene
oxide), as monitored by H NMR spectroscopy in CD2Cl2 (600 MHz).
ACHTUNGTRENNUNG
1
Table 2. ARO of cyclohexene oxide promoted by dinuclear
nificant difference in the ratio of nitrile/isonitrile
formed when reaction was promoted by the two dia-
stereoisomeric complexes of titanium with ligands
(RaSS)-1 (entry 3) and (SaSS)-2 (entry 4). Thus, there
are three observations that had to be rationalized:
1) The relatively low activity of the titanium-based
catalytic systems derived from 1 and 2, as compared
with the corresponding zinc- and aluminium-based
systems (Table 1, runs 1, 2 and 3, 4). The accepted
Lewis acidity order of the ions is opposite to the ob-
served activity of the complexes.
2) It appeared that alteration of the steric arrange-
ment of the ligand could result in a six-fold change in
the nitrile/isonitrile ratio (Table 1, runs 3 and 4).
Clearly, this was not accounted for by the hard/soft
metal centre theory.
3) The nitrile and isonitrile formed under 1-Ti2 cat-
alysis had the same stereochemistry (Table 1, entries 3
and 4). The difference in absolute configuration at C-
2 is simply due to the differences in priorities in the
Cahn–Ingold–Prelog priority rules.
In order to rationalize these observations, kinetic
studies were undertaken. The consumption of the ep-
oxide was monitored by following the disappearance
of the resonances at 3.1 ppm. The appearance of the
products was followed by the increase of the resonan-
ces at 2.4 ppm (nitrile) and 3.3 ppm (isonitrile).
The addition of bases and, in particular, Hunigꢂs
titanium complexes derived from ligand (RaSS)-1 or (SaSS)-
2 at room temperature in DCM.[a]
Entry DIPEA Nitrile-isonitrile[b] ee 5 [%][c] ee 4 [%][d]
1
0
12:1
89 (1S,2R) nd
2
3
4
0.2 equiv. 6.1:1
0.4 equiv. 5.2:1
2.0 equiv. 4.0:1
0.2 equiv. 3.3:1
0.2 equiv. 2.1:1
2.0 equiv. 1.2:1
2.0 equiv. 0.8:1
91 (1S,2R) nd
91 (1S,2R) nd
91 (1S,2R) nd
96 (1S,2R) nd
93 (1S,2R) 90 (1S,2S)
13 (1R,2S) nd
42 (1R,2S) 24 (1R,2R)
5[e]
6[f]
7[g]
8[e,g]
[a]
0.1 equiv of ligand (10.0 mg, 19.5 mmol), 0.2 equiv of
Ti(O-i-Pr)4 (11.4 mL, 39 mmol), 1.5 equiv. of TMSCN
AHCTUNGTRENNUNG
(40 mL, 298 mmol) with respect to cyclohexene oxide
(20 mL, 200 mmol) in 0.55 mL of DCM.
Determined by NMR spectroscopy.
[b]
[c]
[d]
Enantiomeric excesses were determined by chiral GC.
The isonitrile was hydrolyzed to give the b-hydroxy
amine which was reacted with trifluoroacetic anhydride.
The enantiomeric excess of the trifluoroacetamide deriv-
ative was determined by chiral GC analysis.[18]
The reaction was carried out at À208C.
[e]
[f]
3.0 equiv. (80 mL, 596 mmol) of TMSCN were used.
Ligand (SaSS)-2 was used instead of ligand 1.
[g]
Some s-donors, such as Ph3PO, DMF and others,
base (N,N-diisopropylethylamine, DIPEA) to the re- also accelerated the reaction, but after adding one
action mixture accelerated the reaction promoted by equivalent of the donor relative to each titanium
1-Ti2 (Figure 4) and the increase in the rate was pro- atom, no further increase in the rate was observed. In
portional to the amount of the base added (Figure 4). addition, both the base and the donor operated in
The enantioselectivity of the process increased to concert, increasing the rate of the reaction (Figure 4)
91% when the ratio between the Hunigꢂs base and ti- to a greater extent than each of them separately. Evi-
tanium atoms reached 1:1. Addition of more base did dently, the mechanisms of their action are different.
not lead to a change in enantioselectivity, but unex-
pectedly, led to an increased amount of isonitrile to the titanium ions in the complex, leading to the dis-
product (see Table 2). sociation of the initial inactive tetrameric structure
The function of the donor might be to coordinate
3160
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 3157 – 3167

Asymmetric meso-Epoxide Ring-Opening with Trimethylsilyl Cyanide
FULL PAPERS
1
Figure 5. Reaction was monitored by H NMR (600 MHz). Method A: 0.1 equiv. of ligand (10.0 mg, 19.5 mmol), 0.2 equiv. of
Ti
cyclohexene oxide (200 mmol) with respect to the epoxide were added sequentially in CD2Cl2. Method B: the same as
Method A but without DIPEA added. Method C: the same amount of the ligand and Ti(O-i-Pr)4 were dissolved in CD2Cl2,
ACHTUNGTRENNUNG(O-i-Pr)4 (11.4 mL, 39 mmol), 0.2 equiv. of DIPEA (6.8 mL, 39 mmol), 1.5 equiv. of TMSCN (40 mL, 298 mmol), 1 equiv. of
AHCTUNGTRENNUNG
the solvent was evaporated and the residue redissolved in CD2Cl2, 0.2 equiv. of DIPEA (6.8 mL, 39 mmol), 1.5 equiv. of
TMSCN (40 mL, 298 mmol), and 1 equiv. of cyclohexene oxide were added sequentially in CD2Cl2.
(Figure 3) into more active monomeric units. One DIPEA, cyclohexene oxide, and TMSCN were added
possibility was that DIPEA neutralized the HCN sequentially to the residue. In this case, the rate of
evolved by the reaction of liberated i-PrOH with the reaction dropped significantly and was similar to
TMSCN, producing reactive cyanide ions. The pro- that of the reaction without any DIPEA added
pensity of cyanide ions to activate silicon derivatives (Method B). The ee of the product (58%) was also
via supravalent complex formation is documented.[19]
low, compared to the 91% ee obtained in experiments
This concept was supported by several experiments without i-PrOH removal.
the results of which are presented graphically in
The rate of formation of the reaction product
Figure 5. Method A corresponds to an experiment under the standard reaction conditions with cyclohex-
where DIPEA was added to the reaction mixture with ene oxide added last (see the legend to Figure 5) was
a combination of (RaSS)-1 and Ti
present. Method C corresponds to the experiment of the only 1:1.5 ratio of the reagents (epoxide and
where a mixture of (RaSS)-1 and Ti(O-i-Pr)4 in di- TMSCN).
chloromethane was evaporated under vacuum to There was a decrease in the rate of product forma-
ACHTUNGTERN(NUNG O-i-Pr)4 already best described by a first order rate equation in spite
AHCTUNGTRENNUNG
remove the liberated i-PrOH. Then, dichloromethane, tion if the amount of cyclohexene oxide was increased
Figure 6. The dependence of reaction rate on the concentration of epoxide and TMSCN (in CD2Cl2). In all cases catalyst de-
rived from (RaSS)-1 and DIPEA was added.
Adv. Synth. Catal. 2009, 351, 3157 – 3167
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3161

Yuri N. Belokon et al.
FULL PAPERS
Scheme 2. Proposed mechanism for the epoxide ring-opening.
twofold (Figure 6). This can be rationalized by possi- In addition, it explains the apparent contradiction –
ble saturation of coordination positions of the titani- poor catalysis by a strong Lewis acid (titanium ion),
um ions by the substrate. At the same time, a two- as compared to good catalysis by a weak Lewis acid
fold increase in the concentration of TMSCN led to a (zinc ion), as documented in Table 1. Evidently, the
two-fold acceleration of the reaction (Figure 6). A regeneration of the catalyst from the intermediate,
mechanistic scheme that may account for the ob- strongly held by two titanium cations, makes the total
served data is shown in Scheme 2. Accordingly, the reaction rate slow in comparison with the zinc- or alu-
first stage of the reaction is the interaction of the ini- minium-based catalysts.
tial complex with TMSCN, producing a catalytic cya-
nide complex.
Additional support for the mechanism comes from
1H NMR monitoring of the reaction mixture in
The next stage is cyclohexene oxide complexation, CD2Cl2 (Figure 7). The reaction was conducted with
which is a fast step. The intramolecular attack of cya- TMSCN added first to complex 8 and 0.2 equivalents
nide on the complexed substrate is also fast and facili- of DIPEA followed by cyclohexene oxide. The forma-
tated by the charge compensating breaking of the tion of the silylated product in the solution was moni-
oxygen bridge. As a result, a new complex is formed tored, following the appearance of resonances at
with the intermediate alkoxide strongly held by the 0.18 ppm (resonances of the Me3SiO group of silylat-
two titanium ions. The slow step is regeneration of ed hydroxy nitrile and silylated hydroxy isonitrile).
the catalytic species with formation of the final silylat- The relative amount of coordinated alkoxide was cal-
ed hydroxy nitrile. Such a scheme explains why there culated from the difference of the total amount of the
is almost no dependence of the reaction rate on the nitrile formed (silylated and non-silylated), assessed
concentration of the substrate and the observed first by resonances at 2.4 ppm, and that of the silylated
order dependence on the concentration of TMSCN. products (Figure 7). As can be seen from the data, an
3162
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 3157 – 3167

Asymmetric meso-Epoxide Ring-Opening with Trimethylsilyl Cyanide
FULL PAPERS
Figure 7. The variation of the silylated product and product on the catalyst (oxynitrile on the catalyst) with time during the
ARO of meso-cyclohexene oxide with TMSCN promoted by (RaSS)-1 and Ti(O-i-Pr)4 in DCM. Order of addition: 1)
AHCTUNGTRENNUNG
5 mol% of 8, 2) 20 mol% of DIPEA, 3) 150 mol% of TMSCN, 4) 100 mol% (195 mmol) of epoxide.
unsilylated product was accumulated at the beginning mixture accelerated the reaction promoted by the ti-
of the reaction. After 25 min (Figure 7, the maximum tanium complex generated from 1.
on the triangle marked curve) the complex was recov-
The enantioselectivity of the process increased to
ered by precipitation with hexane. Treatment of the 91% when the ratio between the base and titanium
precipitate with TMSCl furnished approximately one atoms reached 1:1 (Table 2, entry 2). Addition of
equivalent of silylated hydroxy nitrile for each titani- more base did not lead to a change in enantioselectiv-
um atom and the product had >99% ee [(1S,2R)-con- ity (Table 2, entries 3 and 4) but, unexpectedly, led to
figuration]. No traces of isonitrile were found in the an increased amount of isonitrile product (Table 2,
1
product, according to H NMR analysis.
entries 1–4). The ratio of nitrile/isonitrile changed
All these findings corroborate the early stage of the from 12/1 (Table 2, entry 1) to 6/1 (Table 2, entry 2)
reaction, according to Scheme 2. At the beginning of with the addition of 0.2 equivalents of DIPEA.
the reaction, when most of the complex was convert-
An additional increase in the amount of base to 0.4
ed to its CN form, the formation of coordinated alk- and 2.0 equivalents at room temperature gave nitrile/
oxide occurred very rapidly. The next step, silylation isonitrile ratios of 5/1 and 4/1, respectively (Table 2,
of the alkoxide and the regeneration of the catalytic entries 3 and 4). Lowering of the reaction tempera-
species, was slow.
ture to À208C with 0.2 equivalents of base further in-
However, the accumulation of the product in solu- creased the proportion of isonitrile, furnishing a 2/1
tion (Figure 7, curve with square markers) had no in- ratio of nitrile/isonitrile (Table 2, run 5). As expected,
duction period, as would have been expected had the the titanium complex generated from (SaSS)-2 gave
rapidly formed complex with two coordinated alkox- an even greater ratio of nitrile/isonitrile equal to 0.8/1
ides been the real catalytic intermediate.
with 2.0 equivalents of base at À208C (Table 2,
Evidently, the intermediate was just a side product entry 8).
and not a catalytic intermediate. No accumulation of
It appeared that both nitrile and isonitrile forma-
such an intermediate complex was observed if the tion occurred within the same chiral coordination
order of addition of the reagents was changed to first sphere of the titanium complexes, as both products
adding the epoxide. This suggests that the real catalyt- had almost the same (90%) ee values (Table 2,
ically active species had a very low concentration in entry 6). In addition, the stereochemistry of the isoni-
the reaction mixture and most likely had only one trile formed was the same as that of the nitrile in the
alkoxide coordinated to both titanium atoms case of both Ti-2 and Ti-1 precatalysts (Table 2, en-
(Scheme 2).
tries 6 and 8). This suggests that there is no difference
This experiment also seemed to indicate that the in- in the orientation of the coordinated substrate within
tramolecular attack of coordinated cyanide on the ep- the coordination sphere of the Ti complex relative to
oxide resulted in the exclusive formation of hydroxy the attacking nucleophile in the transition states lead-
nitrile. This raises the question as to how the isonitrile ing to nitrile- and isonitrile-containing products.
was formed. Furthermore, as detailed in Table 2 and
Undoubtedly, the hard/soft metal center principle
Figure 5, the addition of Hunigꢂs base to the reaction had to be modified to account for the observations
Adv. Synth. Catal. 2009, 351, 3157 – 3167
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3163

Yuri N. Belokon et al.
FULL PAPERS
dinated epoxide activated by the two titanium ions
À
(Scheme 2). The result is C C bond formation to give
the nitrile, as predicted by the hard/soft principle. A
parallel reaction pathway was assumed to involve the
direct attack of TMSCN (or cyanide ion pair [HDI-
PEA]+CNÀ) at the coordinated epoxide. As TMSCN
À
exists predominantly as the NC TMS isomer, this re-
sults in C N bond formation to give isontrile. The
À
positive effect of the addition of Hunigꢂs base can be
explained by an increase in the amount of cyanide ion
generated from the base and HCN (formed from
TMSCN and isopropyl alcohol). Thus, the overall in-
crease in the reaction rate is partly due to the rate of
direct TMSCN addition which results in a greater pro-
Figure 8. Rationalization of the nitrile/isonitrile dichotomy.
and a mechanistic model devised to rationalize the portion of isonitrile being formed.
unusual effect of the reaction conditions on the 5/4
ratio.
The great difference in the stereoselectivities of
ARO in cases of (RaSS)-1 and (SaSS)-2 catalysis
A mechanism to explain these results is shown in (Table 1, runs 3 and 4, Table 2, runs 6 and 8) could be
Figure 8. This is based on the fact that nitrile forma- rationalized by a simple stereochemical model of the
tion followed an intramolecular reaction pathway transition state (see the Supporting Information).
À
with the cyanide coordinated by its nitrogen atom to
The amount of catalytic Ti NC species in solution
titanium ion (hard acid/hard base), attacking the coor- should be constant and independent of the TMSCN
Table 3. ARO of different epoxides promoted by dinuclear complexes generated from (RaSS)-1 or 2.[a]
Entry
Ligand
Epoxide
Conversion [%]
Nitrile/isonitrile
ee (nitrile) [%]
ee (isonitrile) [%]
1[a]
1
2
1
2
1
2
1
2
1
2
1
1
1
1
9
9
98
70
81
93
>99
78
>99
70
4:1
1.3:1
4:1
1.6:1
4:1
1.6:1
5:1
1.2:1
3:1
2.5:1
–
5:1
only nitrile
only nitrile
94
93
À25
nd
nd
94
nd
nd
nd
nd
nd
–
2[a]
À7
3[a]
10
10
10
10
11
11
11
11
12
13
13
14
90
4[b]
À26
94
5[a]
6[a]
À26
7[a]
96
8[a]
À18
91
9[b]
65
79
10[b]
11[a]
12[a]
13[c]
14[d]
À12
no reaction
–
54
10
37
91
>99
75
nd
–
–
[a]
The order of addition: 1) 10 mol% of the catalyst, 2) 200 mol% DIPEA, 3) 100 mol% of the epoxide, 4) 200 mol% of
TMSCN, 118 h, À158C, CH2Cl2.
[b]
[c]
[d]
1) 10 mol% of the catalyst, 2) 20 mol% of the co-catalyst, 3) 100 mol% of the epoxide, 4) 150 mol% of TMSCN, 24 h,
room temperature, CH2Cl2.
1) 10 mol% of the catalyst, 2) 20 mol% DIPEA, 3) 100 mol% of the epoxide, 4) 300 mol% of TMSCN, 72 h, À208C,
CH2Cl2.
1) 10 mol% of the catalyst, 2) 20 mol% of the co-catalyst, 3) 200 mol% of the epoxide, 4) 100 mol% of TMSCN, 24 h,
room temperature, CH2Cl2, the attack occurred at the least hindered end of the epoxide.
3164
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 3157 – 3167

Asymmetric meso-Epoxide Ring-Opening with Trimethylsilyl Cyanide
FULL PAPERS
nal standard. Data are reported as s=singlet, d=doublet,
dd=double doublet, t=triplet, q=quartet, m=multiplet,
b=broad; coupling constant(s) in Hertz, integration.
Proton-decoupled 13C NMR spectra were recorded on a
Bruker Avance 300 (75.5 MHz) spectrometer and are re-
ported in parts per million using the solvent as internal stan-
dard.
concentration. Therefore, the relative rate of forma-
tion of nitrile had also to be independent of this
factor. On the other hand, the rate of formation of
isonitrile should increase as the concentration of
TMSCN increased. This was found to be the case and
a three-fold increase in the amount of isonitrile
formed was observed when the concentration of
TMSCN was doubled (Table 2, entries 2 and 6).
Some other epoxides were also tested in the same
reaction. As expected, in the case of epoxides 9–11
the catalyst derived from (RaSS)-1 with DIPEA was
more active and stereoselective than the catalyst de-
rived from (SaSS)-2 with DIPEA (Table 3, entries 1–
10). However, a catalyst based on ligand (SaSS)-2
gave more isonitrile product (Table 3, entries 1, 3, 5, 7
vs. 2, 4, 6, 8). In the case of epoxides having smaller
rings than cyclooctene oxide, the catalysts are active
and highly enantioselective with ees of both nitrile
and isonitrile of 93–96%. For the reaction of cyclooc-
tene oxide with TMSCN, the catalysts are completely
inactive (Table 3, entry 11), but if cyclooctene oxide is
changed to cyclooctadiene oxide, the reaction pro-
ceeds with moderate yield but very high ee. In all
cases nitrile and isonitrile can by easily separated (see
the Supporting Information).
Dichloromethane (or CD2Cl2) was distilled under argon
from P2O5 and dried over 3 ꢃ molecular sieves (1 g sieves
per 1 mL dichloromethane). All reagents were purchased
from Aldrich or Acros, and used without purification unless
otherwise stated.
Ligands 1, 2, 3, and complexes 7 and 8 were available
from our previous work.[12,15]
Asymmetric Ring-Opening of Epoxides with TMSCN
(General Procedure).
TiACTHUNTRGNE(UGN O-i-Pr)4 (11.4 mL, 39 mmol) was added to a solution of
the ligand 1 (or 2) (10 mg, 19.5 mmol) in DCM (0.5 mL). If
an additive was present it was added next. Epoxide (195
mmol) was added to the reaction mixture. After 2 min
TMSCN (40 mL, 298 mmol) was added. Reaction time de-
pends on the additive. The solvent was evaporated and
hexane (or petroleum ether) (3 mL) was added, The precipi-
tated complex was filtered off and the solution was evapo-
rated under vacuum and analyzed by GC to determine the
enantiomeric excess of the nitrile. To asses the enantiomeric
purity of the isonitrile (2-isocyanocyclohexyloxy)trimethylsi-
lane, 4 was converted into the amino alcohol by refluxing
the reaction mixture with 6M HCl in methanol for 16 h.
The reaction mixture was evaporated and washed with
chloroform. The residue was reacted with TFAA to produce
the derivative for GLC analysis. GLC analysis: b-DM
column T(column) =1208C, T(evaporator) =T(detector) =2308C; pres-
sure of the He=15 psi; TR =19.1 min (1R,2R)-isomer, TR =
21.3 min (1S,2S)-isomer.
Run 14 clearly indicates a potential of the catalyst
to resolve racemic epoxides. The reaction could gen-
erate different regio- and stereoisomers, but for pro-
pylene oxide at room temperature, only one 2-hy-
droxy nitrile product was found in the reaction mix-
ture with 75% ee and in 37% chemical yield (max.
50% yield).
Conclusions
Recovery of Trimethylsilyl Derivative of (1S,2R)-2-
Cyanocyclohexan-1-ol and Establishment of its
Configuration
In conclusion, we have elaborated a highly efficient
Ti-based dinuclear catalytic system for the ARO of
epoxides with TMSCN. The unprecedented dichoto-
my of C C versus N C bond formation in the reac-
tion was traced to intra- versus intermolecular catalyt-
ic reactions observed in this dinuclear system. Studies
on the further application of this catalytic system are
in progress and will be reported in due course.
Ligand 1 (10.0 mg, 19.5 mmol) was dissolved in DCM
(0.55 mL). TiACHTNUGTRENUNG(O-i-Pr)4 (11.4 mL, 39 mmol) was then added.
À
À
The solution changed color from orange to orange-red.
Then, DIPEA (Hunigꢂs base, N,N-diisopropylethylamine)
(6.8 mL, 39 mmol) and TMSCN (40 mL, 298 mmol) were
added followed by cyclohexene oxide (20 mL, 195 mmol).
After 25–30 min the reaction was stopped by adding hexane
(3 mL) to precipitate the titanium complex, which was fil-
tered, and treated with 4 equivalents of TMSCl in CH2Cl2 to
Experimental Section
À
recover the nitrile. The formed Cl Ti complex was filtered,
and washed with hexane. The filtrate and washings were
combined and evaporated to give the silylated hydroxy ni-
trile with ee >99%, according to chiral GLC. The product
did not contain any trace of isonitrile. 1H NMR (CDCl3):
d=0.17 (s, 9H), 1.25–1.33 (m, 3H), 1.55–1.75 (m, 3H), 1.90–
2.07 (m, 1H), 2.08–2.11 (m, 1H), 2.38–2.44 (m, 1H), 3.64–
3.70 (m, 1H); 13C NMR (CDCl3): d=0.18, 23.3, 23.9, 28.2,
Specific rotations were measured on a Perkin–Elmer 241 po-
larimeter and are reported as follows: [a]Tl : [a]T (concentra-
l
tion in g/100 mL, solvent). Enantiomeric excesses were de-
termined by GLC. Analytical ultracentrifugation was con-
ducted using a MOM 3180 (Hungary) ultracentrifuge with
differential Philpot-Svenssonꢂs optics.[12a]
1H NMR spectra were recorded on Bruker Avance 300
(300 MHz) and Avance 600 (600 MHz) spectrometers and
are reported in parts per million using the solvent as inter-
34.7, 37.7, 71.1, 121.6. ACTHUNGTERNNU(G 1S,2R)-Isomer of 2-cyanocyclohexan-
1-ol derivative [or (1R,2S)-2-trimethylsilyloxycyclohexane-1-
carbonitrile]; [a]D25: +45.0 (c 0.42, DCM) for 99% ee {lit.[2]
Adv. Synth. Catal. 2009, 351, 3157 – 3167
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3165

Yuri N. Belokon et al.
FULL PAPERS
[a]2D7: À38.5 (c 4.52, DCM) for
(1R,2S)-isomer of 2-cyanocy- References
N
clohexan-1-ol derivative of 91% ee (or 1S,2R)-2-trimethyl-
A
[1] C. Schneider, Synthesis 2006, 3919–3944.
[2] S. E. Schaus, E. N. Jacobsen, Org. Lett. 2000, 2, 1001–
1004.
[3] a) I. M. Pastor, M. Yus, Current Organic Chemistry,
2005, 9, 1–29; b) M. Pineschi, Eur. J. Org. Chem. 2006,
4979–4988.
Absolute Configuration of 4
(2-Isocyanocyclohexyloxy)trimethylsilane
4:
1H NMR
(CDCl3): d=0.2 (s, 9H), 1.25–1.33 (m, 3H), 1.55–1.75 (m,
3H), 1.90–2.07 (m, 1H), 2.08–2.11 (m, 1H), 3.30–3.35 (m,
1H), 3.60–3.65 (m, 1H); 13CNMR (CDCl3): d=0.27, 23.0,
23.2, 31.3, 33.4, 58.7, 72.9 155.1.
[4] a) H. Yamashita, Bull. Chem. Soc. Jpn. 1988, 61, 1213–
1220; b) M. Hayashi, K. Kohmura, N. Oguni, Synlett
1991, 774–776; c) W. A. Nugent, J. Am. Chem. Soc.
1992, 114, 2768–2769; d) B. W. McCleland, W. A.
Nugent, M. G. Finn, J. Org. Chem. 1998, 63, 6656–
6666; e) L. E. Martinez, J. L. Leighton, D. H. Carsten,
E. N. Jacobsen, J. Am. Chem. Soc. 1995, 117, 5897–
5898; f) K. B. Hansen, J. L. Leighton, E. N. Jacobsen, J.
Am. Chem. Soc. 1996, 118, 10924–10925; g) R. G.
Konsler, J. Karl, E. N. Jacobsen, J. Am. Chem. Soc.
1998, 120, 10780–10781; h) H. Adolfsson, C. Moberg,
Tetrahedron: Asymmetry 1995, 6, 2023–2031; i) J. L.
Leighton, E. N. Jacobsen, J. Org. Chem. 1996, 61, 389–
390; j) J. F. Larrow, S. E. Schaus, E. N. Jacobsen, J. Am.
Chem. Soc. 1996, 118, 7420–7421.
[5] a) S. Matsunaga, J. Das, J. Roels, E. M. Vogl, N. Yama-
moto, T. Iida, K. Yamaguchi, M. Shibasaki, J. Am.
Chem. Soc. 2000, 122, 2252–2260; b) C. Schneider,
A. R. Sreekanth, E. Mai, Angew. Chem. 2004, 116,
5809–5812; Angew. Chem. Int. Ed. 2004, 43, 5691–
5694.
[6] a) C. A. G. M. Weijers, Tetrahedron: Asymmetry 1997,
8, 639–647; b) L. Zhao, B. Han, Z. Huang, M. Miller,
H. Huang, D. S. Malashock, Z. Zhu, A. Milan, D. E.
Robertson, D. P. Weiner, M. J. Burk, J. Am. Chem. Soc.
2004, 126, 11156–11157; c) J. M. Ready, E. N. Jacobsen,
J. Am. Chem. Soc. 2001, 123, 2687–2688.
After hydrolysis of 4 the corresponding hydrochloride was
converted to its free base as follows: To a solution of 0.5M
NaOMe in MeOH (0.5 mL) was added 2-aminocyclohexan-
1-ol hydrochloride (36.5 mg, 0.24 mmol). The mixture was
stirred for 1 h at room emperature. The precipitated NaCl
was removed by filtration through Celite and washed with
MeOH (5 mL). The solvent was removed under reduced
pressure. The absolute configuration of the initial isonitrile
was assumed to be the same as the amino alcohol and, con-
sequently, it was determined by measuring the optical rota-
tion of the amino alcohol and comparing the data with that
ACTHNUTRGNEUNG
in the literature.[17] (1R,2R)-2-Aminocyclohexanol, [a]2D7:
À15.4 (c 0.2 MeOH) for 27% ee {lit.[17] [a]D25: +48.8 (c 0.19
MeOH) (1S,2S)-isomer}.
General Method for meso-Epoxide Synthesis
Cyclooctadiene oxide: A solution of alkene (94 mmol) in
DCM was cooled in an ice bath. m-CPBA (70%, 23 g,
93 mmol) was added over 3 h. The reaction mixture was
stirred for 72 h at room temperature, then washed with a sa-
turated aqueous solution of sodium bicarbonate (100 mL),
water (100 mL) and dried with anhydrous magnesium sul-
fate. Solvent was evaporated under vacuum and the crude
1
product was distilled under vacuum; yield: 64%. H NMR
[7] a) H. Yamashita, T. Mukaiyama, Chem. Lett. 1985, 14,
1643–1646; b) T. Iida, N. Yamamoto, H. Sasai, M. Shi-
basaki, J. Am. Chem. Soc. 1997, 119, 4783–4784;
c) M. H. Wu, E. N. Jacobsen, J. Org. Chem, 1998, 63,
5252–5254; d) J. Wu, X. L. Hou, L. X. Dai, L. J. Xia,
M. H. Tang, Tetrahedron: Asymmetry 1998, 9, 3431–
3436; e) Y.-J. Chen, C. Chen, Tetrahedron: Asymmetry
2007, 18, 1313–1319.
(300 MHz, CDCl3): d=1.95–2.22 (m, 6H); 2.35–2.52 (m, 2H);
2.97–3.08 (m, 2H); 5.50–5.63 (m, 2H).
Cyclohexadiene oxide:
A solution of cyclohexadiene
(5 mL, 52 mmol) in DCM (300 mL) was cooled in an ice
bath. m-CPBA (70%, 13 g, 52 mmol) was added over 0.5 h.
The reaction mixture was stirred for 24 h at room tempera-
ture, then purified by flash chromatography on basic Al2O3
(eluent CH2Cl2). The product was then distilled under
vacuum; yield: 4.0 g (85%). 1H NMR (300 MHz, CDCl3):
d=2.30–2.70 (m, 4H); 3.10–3.40 (m, 2H); 5.40–5.50 (m,
2H).
[8] M. Yang, C. Zhu, F. Yuan, Y. Huang, Y. Pan, Org. Lett.
2005, 7, 1927–1930.
[9] a) K. Arai, M. M. Salter, Y. Yamashita, S. Kobayashi,
Angew. Chem. 2007, 119, 973–975; Angew. Chem. Int.
Ed. 2007, 46, 955–957; b) R. I. Kureshy, S. Singh, N. H.
Khan, S. H. R. Abdi, E. Suresh, R. V. Jasra, Eur. J. Org.
Chem. 2006, 1303–1309; c) F. Carree, R. Gil, J. Collin,
Org. Lett. 2005, 7, 1023–1026; d) X. L. Hou, J. Wu,
L. X. Dai, L. J. Xia, M. H. Tang, Tetrahedron: Asymme-
try 1998, 9, 1747–1752; e) S. Sagawa, H. Abe, Y. Hase,
T. Inaba, J. Org. Chem. 1999, 64, 4962–4965; f) A.
Sekine, T. Ohshima, M. Shibasaki, Tetrahedron 2002,
58, 75–82; g) S. Azoulay, K. Manabe, S. Kobayashi,
Org. Lett. 2005, 7, 4593–4595; h) C. Ogawa, S. Azoulay,
S. Kobayashi, Heterocycles 2005, 66, 201–206; i) F.
Carree, R. Gil, J. Collin, Tetrahedron Lett. 2004, 45,
7749–7751; j) R. I. Kureshy, S. Singh, N. Khan, S. H. R.
Abdi, S. Agrawal, V. J. Mayani, R. V. Jasra, Tetrahedron
Lett. 2006, 47, 5277–5279.
Cycloheptene oxide: A solution of cycloheptene (2 mL,
17.1 mmol) in DCM (150 mL) was cooled in an ice bath. m-
CPBA (70%, 4.4 g, 18 mmol) was added over 0.5 h. The re-
action mixture was stirred for 24 h at room temperature,
then purified by flash chromatography on basic Al2O3
(eluent CH2Cl2). The product was then distilled under
1
vacuum; yield: 1.64 g (84%). H NMR (300 MHz, CDCl3):
d=1.10–1.70 (m, 6H); 1.80–2.05 (m, 4H); 3.05–3.12 (m,
2H).
Acknowledgements
We thank INTAS (05-1000008-7822) for financial support.
3166
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 3157 – 3167

Asymmetric meso-Epoxide Ring-Opening with Trimethylsilyl Cyanide
FULL PAPERS
[10] a) W. A. Nugent, J. Am. Chem. Soc. 1998, 120, 7139–
7140; b) S. E. Denmark, P. A. Barsanti, K. T. Wong,
R. A. Stavenger, J. Org. Chem. 1998, 63, 2428–2429;
c) B. Tao, M. M .C. Lo, G. C. Fu, J. Am. Chem. Soc.
2001, 123, 353–354; d) C. E. Garrett, G. C. Fu, J. Org.
Chem. 1997, 62, 4534–4535; e) M. Nakaijama, M.
Saito, M. Uemura, S. Hashimoto, Tetrahedron Lett.
2002, 43, 8827–8829; f) E. Tokuoka, S. Kotani, H. Mat-
sunaga, T. Ishizuka, S. Hashimoto, M. Nakaijama, Tet-
rahedron: Asymmetry 2005, 16, 2391–2392; g) S. Bruns,
G. Haufe, J. Fluorine Chem. 2000, 104, 247–254; h) G.
Haufe, S. Bruns, Adv. Synth. Catal. 2002, 344, 165–171.
[11] a) B. M. Cole, K. D. Shimizu, C. A. Krueger, J. P. A.
Harrity, M. L. Snapper, A. H. Hoveyda, Angew. Chem.
1996, 108, 1776–1779; Angew. Chem. Int. Ed. Engl.
1996, 35, 15, 1668–1671; b) K. D. Shimizu, B. M. Cole,
C. A. Krueger, K. W. Kuntz, M. L. Snapper, A. H. Hov-
eyda, Angew. Chem. 1997, 109, 1782–1785; Angew.
Chem. Int. Ed. Engl. 1997, 36, 1704–1707, 1703–1707.
[12] a) Y. N. Belokon, D. Chusov, D. A. Borkin, L. V. Yash-
kina, A. V. Dmitriev, D. Katayev, M. North, Tetrahe-
dron: Asymmetry 2006, 17, 2328–2333; b) Y. N. Belo-
kon, D. Chusov, T. V. Skrupskaya, D. A. Borkin, L. A.
Yashkina, K. A. Lysenko, M. M. Ilyin, T. V. Strelkova,
G. I. Timofeeva, A. S. Peregudov, M. North, Russ.
Chem. Bull. 2008, 57, 1981–1988.
[13] B. Saha, M.-H. Lin, T. V. RajanBabu, J. Org. Chem.
2007, 72, 8648–8655.
[14] K. Imi, N. Yanagihara, K. Utimoto, J. Org. Chem. 1987,
52, 1013–1016.
[15] a) Y. N. Belokon, S. Caveda-Cepas, B. Green, N. S.
Ikonnikov, V. N. Khrustalev, V. S. Larichev, M. A. Mo-
scalenko, M. North, C. Orizu, V. I. Tararov, M. Tasinaz-
zo, G. I. Timofeeva, L. V. Yashkina, J. Am. Chem. Soc.
1999, 121, 3968–3973; b) Y. N. Belokon, V. I. Maleev,
M. North, D. L. Usanov, Chem. Commun. 2006, 4614–
4616;c) Y. N. Belokon, W. Clegg, R. W. Harrington,
V. I. Maleev, M. North, M. O. Pujol, D. L. Usanov, C.
Young, Chem. Eur. J. 2009, 15, 2148–2165.
[16] P. G. Gassman, T. L. Guggenheim, J. Am. Chem. Soc.
1982, 104, 5849–5850.
[17] F. G. Glansdorp, G. L. Thomas, J. K. Lee, J. M. Dutton,
G. P. C. Salmond, M. Welch, D. R. Spring, Org. Biomol.
Chem. 2004, 2, 3329–3336; A. Chaterjee, M. Sasiku-
mar, N. N. Joshi, Synth. Commun. 2007, 37, 1727–1733;
A. Nishida, F. Shirato, M. Nakagawa, Tetrahedron:
Asymmetry 2000, 11, 3789–3805.
[18] a) C. Zhu, F. Yuan, W. Gu, Y. Pan, Chem. Commun.
2003, 692–693; b) F. Yuan, C. Zhu, J. Sun, Y. Liu, Y.
Pan, J. Organomet. Chem. 2003, 682, 102–107.
[19] Y. Belokon, E. Ishibashi, H. Nomura, M. North, Chem.
Commun. 2006, 1775–1777.
Adv. Synth. Catal. 2009, 351, 3157 – 3167
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3167