Exceptionally active yttrium-salen complexes for the catalyzed ring opening of epoxides by TMSCN and TMSN3

Article abstract of DOI:10.1021/jo071076h

(Chemical Equation Presented) Halide or alkoxide free yttrium-salen complexes are excellent catalysts for the ring opening of epoxides mediated by TMSCN and TMSN₃. Substrate to catalyst ratios up to 10000 have been realized in these potentially

Full text of DOI:10.1021/jo071076h

Exceptionally Active Yttrium-Salen Complexes for the Catalyzed
Ring Opening of Epoxides by TMSCN and TMSN3
Biswajit Saha, Mei-Huey Lin, and T. V. RajanBabu*
Department of Chemistry, 100 West 18th AVenue, The Ohio State UniVersity, Columbus, Ohio 43210
rajanbabu.1@osu.edu
ReceiVed May 24, 2007
Halide or alkoxide free yttrium-salen complexes are excellent catalysts for the ring opening of epoxides
mediated by TMSCN and TMSN . Substrate to catalyst ratios up to 10000 have been realized in these
3
potentially useful reactions, which can be run under solvent-free conditions. Even though the
enantioselectivities for the TMSCN-mediated reaction remains modest (best 77% ee), these studies with
a highly tunable ligand system may provide further impetus for work in this important area of catalysis.
Even though attempts to isolate a Y-cyanide complex, which was detected by in situ IR spectroscopy,
failed, a related dimeric hydroxide complex was isolated. A kinetic study using in situ IR spectroscopy
did not provide conclusive data to assign an order with respect to Y in this reaction.
Introduction
(substrate/catalyst ) 10000) seen for the addition of TMSCN
eq 2) prompted us to examine the scope and limitations of this
reaction.
(
1
In previous publications, we disclosed that Y(III)-alkoxides
and salen complexes are excellent catalysts for acylation of
secondary alcohols using enol esters. In selected cases, the
Y-salen catalysts afford moderate enantioselectivity in kinetic
resolution of secondary alcohols (for example, kf/ks ) 4.81 for
1-indanol, eq 1). Based on the solid-state structure of the catalyst
complex, we proposed a novel mechanism in which the yttrium
center acts as a Lewis acid, activating the electrophile (the enol
acetate) and the nucleophile (the putative alkoxide). We have
been searching for other applications of such coordination
catalysis and now find that Y-salen complexes serve as
excellent catalysts for ring opening of epoxides by trialkylsilyl
2
nitriles and azides. The unusually high turnover efficiency
(
1) Lin. M. -H.; RajanBabu, T. V. Org. Lett. 2000, 2, 997. (b) Lin, M.
H.; RajanBabu, T. V. Org. Lett. 2002, 4, 1607.
2) The initial results on the yttrium-catalyzed opening of epoxycyclo-
-
(
hexane and epoxycyclopentane are extracted from: Lin, M.-H. Yttrium-
Catalyzed Reactions: Transacylation, Secondary Alcohol Resolution,
Cyanosilylation of Ketones and Epoxides. Ph.D. Dissertation, The Ohio
State University, 2002.
Desymmetrization of meso-epoxides and aziridines by carbon
nucleophiles such as cyanides or organometallic reagents is a
reaction of great synthetic potential, and considerable effort has
10.1021/jo071076h CCC: $37.00 © 2007 American Chemical Society
8
648
J. Org. Chem. 2007, 72, 8648-8655
Published on Web 10/12/2007

Catalyzed Ring Opening of Epoxides by TMSCN and TMSN
3
been invested in this reaction.3,4 The best results in this area
are represented by the works of Hoveyda, who used a combi-
natorial approach to discover Ti-imine complexes3 to achieve
modest to good enantioselectivities for this reaction, and of
Jacobsen, who added TMSCN to meso-epoxides under catalysis
by Yb(III)-pybox complexes.3b The major limitation of both
of these methods is the relatively large amount of the catalyst
needed to complete the reaction. In order to obtain even modest
yields (60-70%) in the Ti-catalyzed reaction, one needs to use
a,5
1
0-20 mol % of a high-molecular weight catalyst. The yields
in the Yb-catalyzed reactions are better, yet it still requires 10
mol % of catalyst (4 days at - 45 °C for 90% yield and 91%
ee for epoxycyclohexane). The need for such large quantities
of the catalyst in the [imine]Ti-mediated reaction is understand-
able in light of the large number of Lewis basic centers in the
ligand, which could reduce the effective Lewis acidity of the
metal. In the case of the Yb-catalyzed reaction there are two
possible reasons why excessive catalyst is needed. This could
be due to the residual chloride ions that are present which
compete with the electrophilic activation of the epoxide and/or
due to the termolecular nature of the reaction, in which the metal
FIGURE 1. Prototypical salen ligands.
TABLE 1. Opening of Epoxycyclohexane with TMSCN in the
Presence of Y Complexes of L1-L7a
(
Yb) serves dual roles, one, for activation of the epoxide and,
b
entry
ligand
solvent
time (h)
% ee (config)
3b,6
two, for activation of the nitrile. We reasoned that a catalyst
devoid of extraneous Lewis basic centers (either on the ligand
1
2
3
4
5
6
7
8
9
L1
L1
L1
L1
L2
CH2Cl2
PhCH3
THF
11
11
10
10
10
8.5
20
10
10
10
14
16
20
20
23
16 (1S,2R)
13 (1S,2R)
8 (1R,2S)
7 (1S,2R)
16 (1R,2S)
15 (1R,2S)
77 (1R,2S)
<5
7
3a
or present as free halide or alkoxide ions during the catalyst
generation) should be more effective in achieving this reaction.
In addition, if the role of catalyst can be limited to that of a
Lewis acid alone (i. e., unimolecular in the metal), significant
kinetic advantages could be derived. We conjectured that the
square-pyramidal yttrium-salen complex (eq 1) with Y in a low-
hexane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
c
L3
L4
L5
L6
L7
L4
L4
L4
L4
L4
<5
<5
1
1
0
1
8
coordinate environment might be a suitable candidate to test
72 (1R,2S)
56 (1R,2S)
62 (1R,2S)
64 (1R,2S)
15 (1R,2S)
these ideas.
12
PhCH3
hexane
13
14
15
t
BuOMe
CH3CN
(3) For leading references, see, for TMSCN: (a) Cole, B. M.; Shimizu,
K. D.; Krueger, C. A.; Harrity, J. P. A.; Snapper, M. L.; Hoveyda, A. H.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1668. (b) Schaus, S. E.; Jacobsen,
E. N. Org. Lett. 2000, 2, 1001. (c) Addition of TMSCN to aziridines: Mita,
T.; Fujimori, I.; Wada, R.; Wen, J.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2005, 127, 11252. For other notable results: (d) addition of an
enolate: Crotti, P.; Di Bussolo, V.; Favero, L.; Macchia, F.; Pineschi, M.
Gazz. Chim Acta 1997, 127, 273. (e) Addition of PhLi: Oguni, N.; Miyagi,
Y.; Itoh, K. Tetrahedron Lett. 1998, 39, 9023. (f) Addition of alkynyllithium
reagents: Zhu, C.; Yang, M.; Sun, J.; Zhu, Y.; Pan, Y. Synlett 2004, 465.
a
1
:1 epoxide/TMSCN 1 M; 2 mol % of catalyst; rt, 100% conversion
except in entry 6. Determined by GC analysis. c 88% conversion.
b
Results
Our investigations started with an examination of the reaction
between epoxycyclohexane with TMSCN in the presence of
salen complexes (Figure 1) of yttrium, and the results are shown
in Table 1. The catalytically active complexes were prepared
(
g) Addition of TMSCN with ephedrine Ga and In complexes gives
isonitriles: Yuan, F.; Zhu, C.; Sun, J.; Liu, Y.; Pan, Y. J. Organomet. Chem.
2
003, 682, 102. (h) For a report of TMSCN-mediated ring opening of R,â-
9
epoxy carboxamides catalyzed by Sm(III), see: Tosaki, S.; Tsuji, R.;
by the silylamide route (eq 3), and the reaction was run with
Oshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 2147.
1-2 mol % of the catalyst in a 1 M solution of the epoxide
and TMSCN in a molar ratio of 1:1. The reaction was followed
by TLC or GC until all starting materials disappeared. The
reaction mixture was quenched by the addition of water, and
the product was isolated and analyzed by GC and NMR.
Separation of the enantiomers was accomplished on a Cyclodex
B or Chiraldex B-Ph column, which showed baseline separation
of the two enantiomers (GC traces of the crude material are
included in the Supporting Information).
(4) For a review of asymmetric ring opening reactions of epoxides, see:
Jacobsen, E. Acc. Chem. Res. 2000, 33, 421. For a compilation of more
recent references, see: Schneider, C.; Sreekanth, A. R.; Mai, E. Angew.
Chem., Int. Ed. 2004, 43, 5691.
(
5) Shimizu, K. D.; Cole, M. B.; Krueger, C. A.; Kuntz, K. W.; Snapper,
M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1997, 36, 1704.
6) Evidence for such dual activation by metal, and the attendant kinetic
(
consequences have been documented in additions of TMSN3 to epoxycy-
clohexane. (a) See: Jacobsen, E. Acc. Chem. Res. 2000, 33, 421 and
references cited therein. (b) Konsler, R. G.; Karl, J.; Jacobsen, E. N. J. Am.
Chem. Soc. 1998, 120, 10780. Footnote 7 of this paper is especially relevant
to the present discussion.
(7) Anecdotal evidence for such inhibition by chloride ion can be found
+ligand: (L-H2]
in the early experiments of Utimoto who showed that lanthanide chlorides
are poor catalysts for the reaction between epoxycyclohexane and TMSCN.
See: Matsubara, S.; Onishi, H.; Utimoto, K. Tetrahedron Lett. 1990, 31,
Y[N(SiMe H) ] ‚2THF
8 LY[N(SiMe H) ]
2 2
2HN(SiHMe2)2
2
2 3
-
[THF] (3)
6
209.
8) For a discussion of low coordinate Y-complexes, see: Schuetz, S.
(
A.; Silvernail, C. M.; Incarvito, C. D.; Rheingold, A. L.; Clark, J. L.; Day,
V. W.; Belot, J. A. Inorg. Chem. 2004, 23, 6203.
(9) Runte, O.; Priermeier, T.; Anwander, R. J. Chem. Soc., Chem.
Commun. 1996, 1385.
J. Org. Chem, Vol. 72, No. 23, 2007 8649

Saha et al.
TABLE 2. Effect of the Metal on the Opening of
TABLE 4. Epoxide Opening Reactions Catalyzed by
[L4]Y(THF)(dms)a
a
Epoxycyclohexane with TMSCN
metal
time (h)
conv (%)
% ee
entry
TMSX
epoxide
S/C ratio
time (h)
% ee (config)
Y
20
72
5
47
72
72
120
120
100
>98
100
100
0
0
18
35
77
28
33
1
2
3
4
5
6
7
TMSCN
TMSCN
TMSCN
TMSCN
TMSN3
TMSN3
TMSN3
2
2
3
4
1
1
2
10000
100
100
50
10000
100
50
44
20
40
- -
Yb
La
Pr
Sc
Al
Ti
Zr
54 (1R,2S)
<5
b
47
62
<5
c
NA
NA
12
38
24
72
29 (1R,2S)
32 (1R,2S)
12 (1R,2S)
35
a
See eq 4. b For 100% conversion except for entry 4. c With no solvent.
a
Catalyst generated as shown in eq 3 using ligand L4; 1 mol % of
catalyst, CH2Cl2, rt.
reactions conditions, and nonselective catalysis by adventitious
Y or any other species is most likely not involved in the reaction.
As the concentration of the catalyst is decreased to 0.05 mol %
(0.0005 M in catalyst, S/C ) 2000), there is a noticeable
decrease in the enantioselectivity. Surprisingly the reaction can
be carried to completion even with 0.01 mol % of catalyst
TABLE 3. Effect of the Catalyst Concentrationa
entry
[Y] (mol %)
solvent
T (°C)
time (h)
% ee
1
2
3
4
5
6
2.0
1.5
1.0
0.5
0.1
0.05
0.01
CH2Cl2
hex
hex
hex
hex
25
-15
-15
-15
-15
25
2
3
3
3
3
4
4
77b
72
73
74
73
56
56
(0.0001 M in catalyst, S/C 10000), even though under these
conditions, the enantioselectivity is significantly lower. Note
also that this highly catalytic reaction is carried out with
stoichiometric amounts of the epoxide and TMSCN with no
solVent added. We also noted that addition of molecular sieves
improve the reproducibility of these reactions.
no solvent
no solvent
b
7
25
a
Catalyst generated as shown in eq 3 using ligand L4. See text for
b
experimental procedure. With 4 Å molecular sieves.
In early experiments, we identified CH2Cl2 as the best solvent
for the reaction (entries 1-4, 7, 11-15 in Table 1). Among
the ligands examined,1
b,10
salen derivatives from vicinal di-
amines (L1-L3) and 2,2′-diamino-1,1′-binaphthyl (L4-L7)
showed the most activity. For BINAP(NH2)2-derived ligands,
t
in order to achieve high selectivity both the 3- and 5- Bu
substituents on the salicylaldehyde from which these are derived
are essential (entries 7-10). Thus, all BINAP ligands (L4-
t
L7) gave nearly quantitative yields, but only ligand L4 (3,5- -
Bu) showed good enantioselectivity (entries 7, 11-14). Others
yielded nearly racemic products (entries 8-10). As with L1,
the best solvent for the reactions catalyzed by complex from
L4 appears to be CH2Cl2 (entry 7).
Having identified L4 as a suitable ligand, the effect of the
metal was briefly examined and the results are shown in Table
Other Epoxide Opening Reactions. Encouraged by the high
turnovers in the reactions of epoxycyclohexane, we briefly
examined other related reactions, and the results are shown in
Table 4. Thus, the Y catalyst prepared from L4 effects
quantitative ring-opening reactions of epoxycyclopentane, ep-
oxycyclooct-5-ene, and epoxy[4-bis(methoxycarbonyl)]cyclo-
pentane, even though the enantioselectivities of these reactions
are not satisfactory for preparative purposes. Note that reactions
of epoxycyclohexane with both TMSCN and TMSN3 can be
run under exceptionally low catalyst loading (S/C ) 10000)
2
. In each case, the catalyst was prepared as described in eq 3
1
1
from the corresponding metal dimethylsilylamide (dms) salts
and the ligand L4. Yttrium and lanthanides (lanthanum,
praseodymium, and ytterbium) were viable metals for the ring
opening reaction, with the yttrium giving by far the best results.
Surprisingly, Sc, Al, Ti, and Zr showed only low reactivity.
The efficacy of the catalyst derived from ligand L4 was tested
by examining the effect of its concentration on the reaction.
The results are shown in Table 3. As shown in entries 1-5, a
1
2
under solvent-free conditions. A similar reaction of epoxy-
cyclopentane with TMSCN is reported in entry 1. Substrates
with medium-size rings and those carrying Lewis basic centers
(e.g., -CO2Me groups in 4) react considerably slower than
2
0-fold decrease in the catalyst has very little effect on the
epoxycyclohexane and epoxycyclopentane (entries 3 and 4).
Geometry of the Y-Salen Complexes and Possible Rel-
evance to High Efficiency of the Catalyst. We have determined
structures of two yttrium complexes (5 and 6) that may be
enantioselectivity, suggesting that there are few deleterious side
reactions including uncatalyzed background reaction. When the
enantiomeric excess of the product was measured as a function
of the conversion it was observed that, even for the slower
reactions, the ee remains constant until the end of the reaction.
This clearly suggests that the catalyst is robust under these
1
3
relevant to this highly catalytic reaction. They are shown in
Figures 2 and 3. In connection with our work on the trans-
acylation of secondary alcohols using enol acetates (eq 1), we
had previously reported on the solid-state structure of the
(10) For full experimental details, including the preparation and use of
the ligands listed in Figure 1, see the Supporting Information. Details of
the spectroscopic and chromatographic identification of compounds are also
included there.
(12) Jacobsen has reported that 1 mol % of a monomeric (salen)Cr-N3
complex is needed effect the opening of epoxycyclopentane with TMS-N3
under these conditions (see ref 6).
(11) For the synthesis of the amides, see: Anwander, R.; Runte, O.;
Eppinger, J.; Gerstberger, G.; Herdtweck, E.; Spiegler, M. J. Chem. Soc.,
Dalton Trans. 1998, 847.
(13) Crystallographic details for 6 and a figure representing thermal
ellipsoids are included in the Supporting Information.
8650 J. Org. Chem., Vol. 72, No. 23, 2007

Catalyzed Ring Opening of Epoxides by TMSCN and TMSN
3
salen-Cr catalyst (24 h) is needed to complete the reaction.6
In this better-understood TMS-N3 reaction, it is known that the
reactive nucleophile (LCr-N3) is generated from initially formed
HN3, which when used separately, can also initiate the reaction.
We believe that the cyanide-opening reactions catalyzed by Y
are mechanistically different. For example, in an early experi-
ment we saw that no trace of the ring-opening product was
formed when HCN was used in place of TMSCN. Also running
the reaction with 5 fold excess (with respect to the catalyst) of
a desiccant Cp2Zr(Me)2 or activated molecular sieve has no
effect on the reaction. A set of parallel reactions with either
TMSCN or TMSN3 with epoxycyclohexane proceed with the
same rate and selectiVity, whether 5 equiV of Cp2Zr(Me)2 is
present or not.
FIGURE 2. Monomeric and dimeric Y-salen complexes.
An examination of a possible nonlinear effect using catalyst
[
L4]Y[N(dms)2][THF] of varying enantiomeric excess showed
yttrium-salen complex [L1]Y[THF][N(dms)2] (Figure 2).1b
Here, we report the structure of the complex [(L4)Y(µ-OH)]2
that there is no such effect operating in the Y-salen-mediated
TMSCN opening of epoxides. Thus, between 0 and 100% ee
of the catalyst, a plot of % ee of the ligand vs % ee of the
product showed a nearly perfect linear fit (R ) 0.9758).
With the structural information on the Y catalysts, and the
early evidence suggesting an exceptionally fast reaction (Table
(
[
Figure 3).14 The former incorporates one anionic ligand
-N(SiHMe2)2] and one neutral ligand (THF), while the latter
2
10
appears to be an adventitious hydrolysis product of a similar
complex from BINAP(NH2)2-derived salen. This complex has
a dimeric structure carrying a bridging OH ion. The structure
of [L1]Y[THF][N(dms)2] (eq 1) has distorted trigonal prismatic
geometry while the latter (Figure 3) has a distorted octahedral
geometry. The structure of L1-derived complex 5 also reveals
an unusual agostic interaction between one of the Si atoms and
Y, presumably brought about by the highly Lewis acidic nature
of Y and the particular geometry of the backbone. In a related
3
), we wondered whether the dual-activation mechanism sug-
gested by Jacobsen is plausible in such a highly efficient catalyst.
We sought to clarify the mechanism of the TMSCN-mediated
reaction by studying its kinetics by in situ IR spectroscopy. Four
factors make this an almost ideal reaction for the use of this
technique: (i) the total absence of any other side reactions
1
5
(
including the formation of the isonitrile adduct, νNC ) 2140
salen complex prepared from 1,2-ethylenediamine, this interac-
-
1
tion is absent.14b In 5, the large yttrium atom is placed 0.95 Å
cm ); (ii) the distinct and clearly resolved IR signatures of
-1
TMSCN (νCN ) 2192 cm ) of and of the product cyanohydrin
above the N2O2 plane. From a mechanistic perspective, such a
structure would permit activation of either the epoxide (ligand
substitution of THF) or of the cyanide (substitution of the
silylamide ligand). A comparison of structures 6 and 7, a dimer
-
1
TMS ether (νCN ) 2246 cm ); (iii) moderate and easily
measurable reaction rates under near stoichiometric conditions
of the reagents, using 0.10-0.50 mol % of catalyst at temper-
atures between -20 and +25 °C; and (iv) the fact that there is
no deterioration of selectivity as a function of conversion, clearly
suggesting that the catalyst is quite robust under these reaction
conditions.
prepared by Morken14a from L1 and yttrium isopropoxide, seems
to suggest that L1 is a sterically less demanding ligand (vis- a` -
vis L4) since the dimer 7 contains an additional acetone moiety
coordinated to each of the Y atoms. Such an additional ligand
is not seen in 6, prepared from L4. Thus, a tightly controlled
ligand field in complexes of L4 might account for the improved
selectivity of catalysts derived from BINAP(NH2)2.
An Attempt To Determine the Order of the Reaction in
the Metal. The moderate enantioselectivity in the epoxycyclo-
hexane opening (77% ee vs the best published result, 91%)
notwithstanding, the Y-catalyzed reaction, which can be run
under solvent-free conditions with 0.0001 equiv of the catalyst,
is truly remarkable in its efficiency. Most relevant is the
comparison to the Jacobsen protocol which uses an YbCl3-
In initial blank experiments, it was observed that the addition
of epoxide to a stoichiometric amount of the Y catalyst brought
about very little change in either the IR (hexane) or NMR spectra
(toluene-d8) for 22 h. The characteristic peaks due to the
1
coordinated epoxide [ H NMR in tol-d8: broad doublet δ 2.93
1
3
and 3.01; C NMR δ 53.84 (m), 24.46 (s) and 24.38(s)] are
retained at least up to 22 h after mixing a stoichiometric amount
of the catalyst [L4]Y[N(dms)2][THF] and epoxycyclohexane.
However, upon addition of an equivalent amount of cyanide,
significant changes ensue, the most important being an immedi-
ate (<1 min) replacement in the IR of the peak due to TMSCN
(pybox) complex, where, through kinetic studies, he has
-1
-1
(νCN ) 2192 cm ) by a strong signal at 2077 cm , tentatively
provided tentative evidence for the possible involvement of a
bimetallic activation.3b In a corresponding solvent-free TMSN3
opening, Jacobsen reports that 0.01 equiv of a monomeric
(15) In the ring-opening reaction of epoxycyclohexane by TMSCN,
selective formation of a nitrile or an isonitrile product can be achieved by
the choice of Lewis acids. Thus, Zn, Pd, Sn, In, and Ga salts give the
isonitrile, whereas Ca, Mg, Zn, Y, Ti, and most lanthanide salts give the
nitrile. Isonitrile: (a) Gassman, P. G.; Guggenheim, T. L. J. Am. Chem.
Soc. 1982, 104, 5849. (b) Spessard, G. O.; Ritter, A. R.; Johnson, D. M.;
Montgomery, A. M. Tetrahedron Lett. 1983, 24, 655. (c) Imi, K.;
Yanagihara, N.; Utimoto, K. J. Org. Chem. 1987, 52, 1013. (d) Zhu, C.;
Yuan, F.; Gu, W.; Pan, Y. Chem. Commun. 2003, 692. Nitrile: (e) Lidy,
W.; Sundermeyer, W. Tetrahedron Lett. 1973, 1449. (f) Mullis, J. C.; Weber,
W. P. J. Org. Chem. 1982, 47, 2873. (g) Hayashi, M.; Tamura, M.; Oguni,
N. Synlett 1982, 663. (h) Sugita, K.; Ohta, A.; Onaka, M.; Izumi, Y. Chem.
Lett. 1990, 481. (i) Matsubara, S.; Onishi, H.; Utimoto, K. Tetrahedron
Lett. 1990, 31, 6209. See also refs 3a,b,g.
(
14) For recent examples of related structures of other salen metal
complexes, see, Y: (a) Y(L1)(µ-OH)]2: Mascarenhas, C. M.; Miller, S.
P.; White, P. S.; Morken, J. P. Angew. Chem., Int. Ed. 2001, 40, 601. (b)
Runte, O.; Priermeier, T.; Anwander, R. J. Chem. Soc., Chem. Commun.
996, 1385. (c) Herrmann, W. A.; Anwander, R.; Munck, F. C.; Scherer,
W.; Dufaud, V.; Huber, N. W.; Artus, G. R. J. Z. Naturforsch., B 1994, 49,
789. (d) Evans, W. J.; Fujimoto, C. H.; Ziller, J. W. J. Chem. Soc., Chem.
Commun. 1999, 311. (e) An alkoxide bridged dimer: Ovitt, T. M.; Coates,
G. W. J. Am. Chem. Soc. 2002, 124, 1316. Al: (f) Al(L4)X: Evans, D. A.;
Janey, J. M.; Magomedov, N.; Tedrow, J. S. Angew. Chem., Int. Ed. 2001,
1
1
4
0, 1884.
J. Org. Chem, Vol. 72, No. 23, 2007 8651

Saha et al.
FIGURE 3. Solid-state structure of {[L
4 2
]Y[µ-OH]} (6). Hydrogens omitted for clarity.
FIGURE 4. Typical kinetic run. Stacked IR spectra showing disappearance of TMSCN (2192 cm-1) and appearance of the product (2246 cm-1).
assigned as arising from a bridged Y-isonitrile intermediate.16,17
In the NMR, peaks due to the epoxide disappear. Even though
the resulting NMR spectra are inscrutable, upon workup, the
only product seen is the expected cyanohydrin trimethylsilyl
ether.
A typical kinetic experiment was run as follows with TMSCN
as the limiting reagent with excess of the epoxide. To a mixture
of the epoxide (0.250 g, 0.257 mL, 2.5 mmol) and the catalyst
for TMSCN (2192 cm ) and the product cyanohydrin-TMS
-1
-
1
ether (2246 cm ), is shown in Figure 4. The concentration
profile of TMSCN and the product as a function of time is
shown in Figure 5. Individual spectra at t ) 1, 53, and 85 min
and at the end of the reaction are shown in Figure 6.
Kinetic runs were carried out with different concentrations
of the catalyst, in a 10 fold range, between 0.1 and 1 mol %,
with respect to TMSCN. Plots of ln[(a )/(a - x)] versus time
0
0
[L4]Y[N(dms)2][THF] (0.005 g, 0.005 mmol) in 0.5 mL of
0
0
hexane, under nitrogen, was added 5 µL (0.038 mmol) of
TMSCN, and the mixture was stirred for 30 min. The ReactIR
probe was introduced, and the mixture was cooled to 0 °C in
an ice bath where the temperature was rigorously maintained
(min), where (a ) is the initial absorbance of (TMSCN) and (a
-
x) is the absorbance of remaining TMSCN as measured by
the absorbance at time t] gives straight lines (Figure 1,
Supporting Information), indicting a first-order reaction under
these conditions. The relative values of kobs were derived from
the slope of these lines. A plot of kobs vs [cat.] and kobs vs
cat.] (Figure 2, Supporting Information) gave inconclusive
((0.1 °C) through out the experiment. After equilibration,
TMSCN (0.05 g, 0.067 mL, 0.5 mmol) was added and the
spectra were collected at 1 min intervals.
2
[
A typical stack of spectra obtained (0.1 mol % of catalyst, 1
M in substrate, 0.001 M in catalyst), showing the relevant peaks
2
results, with R values of 0.995 for the former and 0.961 for
the latter. We believe that this distinction is ambiguous even
2
though very similar data (R ) 0.997 and 0.967, respectively)
(16) For IR spectroscopy of bridged nitrile/isonitrile complexes, see: (a)
Sheng, T.; H. Vahrenkamp, H. Inorg. Chim. Acta 2004, 357, 1739. (b)
Dixon, D. A.; Hertler, W. R.; Chase, D. B.; Farnham, W. B.; Davidson, F.
Inorg. Chem. 1988, 27, 4012.
3b
was used by Jacobsen to argue in favor of a bimetallic
activation process in the (pybox)YbCl3-mediated epoxide open-
ing by TMSCN.
(17) Plecnik, C. E.; Liu, S.; Shore, S. S. Acc. Chem. Res. 2003, 36, 499.
8652 J. Org. Chem., Vol. 72, No. 23, 2007

Catalyzed Ring Opening of Epoxides by TMSCN and TMSN
3
FIGURE 5. Profiles of absorbances for TMSCN and the cyanohydrin-TMS ether product as a function of time (conditions: 1 M TMSCN and
epoxycyclohexane (1:1) in hexane, 0.1 mol % (0.001 M in catalyst) [L ]Y[N(dms) ][THF]).
4
2
FIGURE 6. Individual spectra at t ) 1 min (a), 53 min (b), and 85 min (c) using 0.1 mol % of catalyst at 0 °C and at the end of the reaction (d).
Discussion
Y-catalyzed reaction. Indeed, attempting to carry out the
reaction with HCN (2 M solution of HCN in toluene, see the
Supporting Information for details of the experiment) instead
of TMSCN yielded no product. These reactions were done with
rigorous exclusion of moisture in a drybox. Besides, addition
of activated 4 Å molecular sieves or Cp2ZrMe2 to remove
residual water has no effect on the ring-opening reaction with
TMSCN (or TMSN3). Indeed, highly reproducible reactions at
the lowest concentrations of the catalyst (0.01 mol %) were
carried out with molecular sieves present in the reaction medium.
In a stoichiometric reaction with the catalyst, epoxide, and
TMSCN in molar ratio of 1:1:1, the only isolated product is
the product cyanohydrin-TMS ether.
The key features that distinguish the Y-catalyzed TMSCN-
mediated opening from the well-studied Cr-catalyzed TMSN3
opening are the following:
(i) There appears to be no induction period observed in the
TMSCN-mediated reactions once the bulk of the TMSCN is
added. However, since the addition of ∼5 µL of TMSCN at
the beginning of the reaction before equilibration helps repro-
ducibility of the runs, formation of an exceedingly reactive
catalyst at this stage cannot be totally discounted. Obviously,
if that is the case, no induction period would be observed.
(
ii) We have not observed any nonlinear effects in the
asymmetric induction process.
iii) While the TMS-N3 reaction is known to proceed through
At this stage, one can only speculate about the origin of the
remarkable efficiency of the Y(III)-catalyzed reaction vis- a` -vis
the Yb(III)- or Ti(IV)-catalyzed reactions. One clear difference
between these reactions is the absence of chloride or alkoxide
(
the initial generation of HN3, and thus through a chromium
azide, there is no indication that HCN is involved in the
J. Org. Chem, Vol. 72, No. 23, 2007 8653

Saha et al.
ions in solution in the (salen)Y[N(dms)2]-catalyzed reactions.
The instantaneous disappearance of absorbance of TMSCN
Preparation of Pr[N(SiMe
(7 mL) of PrCl
(SiMe H) (0.23 g, 1.66 mmol), and the mixture was stirred for 12
2 2
2
H)]
3
‚2THF. To a hexane solution
3
‚2THF (0.25 g, 0.64 mmol) was added LiN-
-
1
(2192 cm ) upon mixing with stoichiometric amounts of the
h at room temperature. The white precipitate of the reaction mixture
was allowed settle, and the solution was filtered through a pad of
Celite to get a clear solution. The residual solid was washed two
times with hexanes (5 mL) and filtered as mentioned above. The
solvent was removed under vacuum to give a pale yellowish solid
which was crystallized from pentane (0.21 g) and directly used for
chiral complex preparation.
catalyst (vide supra) suggests the rapid formation of the reactive
nucleophilic species. Likewise, activation of the epoxide
involves a simple ligand displacement of neutral THF by the
epoxide, which could be expected to be a more facile process
than the corresponding one in the LYbCl3 or LnTi (OR)m
mediated reactions since Cl- or RO- ligands are harder to
displace.
IV
Preparation of La[N(SiMe H)] ‚3THF. A three-neck, round-
2
3
2 2
bottom flask was charged with LiN(SiMe H) (0.21 g, 1.52 mmol)
and fitted with rubber septum, stopper, and solid addition funnel
containing La(OTf) (0.3 g, 0.51 mmol). The flask was removed
from the glovebox and connected to N line, and THF (11 mL)
hexanes (5.5 mL) were introduced subsequently to the reaction flask.
The glass stopper was replaced by a reflux condenser and connected
Conclusions
3
In this paper, we report a highly efficient halide- or alkoxide-
free yttrium complex that catalyzes the ring opening of epoxides
mediated by TMSCN and TMSN3. Substrate to catalyst ratios
up to 10000 has been realized in these potentially useful
reactions, which can be run under solvent-free conditions.
2
to N
point, La(OTf)
2
, and then the septum was replaced by a glass stopper; at this
3
was added to the reaction mixture under stirring
conditions. The reaction was refluxed for 14 h, cooled to room
temperature, and taken inside the drybox, and the solvent was
removed under vacuum to get a white solid. To that solid was added
Experimental Section
1
0 mL of pentane. The mixture was stirred for 15 min, and the
See the Supporting Information for general descriptions of
procedures, separations, and characterization of compounds. Details
of the kinetic experiments are also reported there.
A Typical Procedure for Ring Opening of Epoxycyclohexane
with TMSCN using Chiral Yttrium Complexes (Table 1):
solvent was decanted and evaporated under vacuum to get a white
1
solid (0.18 g). H NMR (C
H, -SiHMe , 3.68 (m, 12 H, THF), 1.36 (m, 12 H, THF), 0.38 (d,
SiHMe ).
Synthesis of Chiral Lanthanide Complexes. To a mixture of
chiral ligand L (0.043 mmol) in THF (0.25 mL) was added La-
‚nTHF [La ) Yb, Pr, La] (0.043 mmol) in hexanes
0.25 mL). The reaction mixture was stirred for 4 days at room
6 6
D , 250 MHz NMR): δ 5.01 (sept, 6
2
-
2
(
1R,2S)-2-Trimethylsilyloxycyclohexane-1-carbonitrile. To a CH
Cl solution (0.5 mL) of Y complex was added epoxide (0.049 g,
.5 mmol), the yellow colored solution was stirred at room
2
-
4
2
2 2 3
[N(SiMe H) ]
0
(
temperature for 10 min, and TMSCN (neat) (0.050 g, 0.50 mmol)
was added slowly and dropwise to the stirred solution of epoxide
and catalyst. The reaction was monitored by GC. After completion
of the reaction, the mixture was passed through a short silica gel
column, and evaporation of the solvent gave clean product nearly
in quantitative yield in almost every case. Spectroscopic data were
identical with what has been reported in the literature.3b Enantiomer
separation: chiral GC analysis (Cyclodex-B column, 110 °C
temperature, and finally, the solvent was removed under high
vacuum to obtain a solid which was directly used for catalytic
reactions without further purification.
Reaction of Epoxycyclohexane in the Absence of a Catalyst.
A mixture of the epoxide (0.049 g, 0.5 mmol) and TMSCN (0.050
mg, 0.5 mmol) in 0.5 mL of hexane was stirred for 20 h, following
the reaction by GC. No trace of the product was detected under
these conditions.
isothermal for 50 min, t
1.63 min [R] ) +25 (c 1, CH
-38.5 (c 4.52 CH Cl , 91% ee]. See the Supporting Information
for chromatograms.
‚2.7THF.1 Ytterbium trichloride (YbCl
) (0.2 g, 0.72
3
R
(minor) ) 30.70 min, t
R
(major,1R,2S) )
Reaction of Epoxycyclohexane with TMSCN in the Presence
of the Salen Ligand Only. A mixture of the epoxide (0.049 g, 0.5
mmol), TMSCN (0.050 g, 0.5 mmol), and the ligand L (0.02 equiv)
4
3
)
D
2
Cl
2
), 77% ee [lit.3b (1S2R): [R]
D
2
2
in 0.5 mL of hexane was stirred for 18 h, following the reaction
by GC. No trace of the product was detected under these conditions.
Reaction of Epoxycyclohexane with TMSCN in the Presence
of Y-Amide Only. A mixture of epoxycyclohexane (0. 049 g,
8
YbCl
3
mmol) in THF (4.2 mL) was charged in a 25 mL two-necked flask
under an inert atmosphere and heated to reflux for 1.5 h. The
mixture was cooled to room temperature and evaporated to dryness
0
.5 mmol), TMSCN (0.05 g, 0.5 mmol), and Y[N(SiMe
2 2 3
H) ] ‚2THF
to give a white solid (0.34 g). By weight difference between YbCl
and the white THF adduct, the composition of the product was
calculated as YbCl ‚2.7THF.
Preparation of Yb[N(SiMe
7 mL) of YbCl ‚2.7THF (0.3 g, 0.63 mmol) was added LiN-
SiMe H) (0.23 g, 1.64 mmol), and the mixture was stirred for 12
3
(0.01 equiv) in CH Cl (0.5 mL) was stirred, and the reaction was
2
2
followed by GC. No trace of the expected product was detected up
to 3 h.
Reaction of Epoxycyclohexane with TMSCN in the Presence
of Stoichiometric Amount of the Catalyst. An NMR Study. In
3
2 2 3
H) ] ‚2.7THF. To a hexane solution
(
(
3
2
2
a nitrogen-filled drybox, the catalyst (L
g, 0.03 mmol) was dissolved in 1 mL of toluene-d
4
)Y[(N(dms)
2
](THF) (0.030
. Both H and
h at room temperature. The white precipitate of the reaction mixture
was allowed settle down, and the solution was filtered through a
pad of Celite to get clear solution. The residual solid was washed
two times with hexanes (5 mL) and filtered as mentioned above.
The solvent was removed under vacuum to give pale yellowish
solid that was crystallized from pentane (352 mg) and directly used
for chiral complex preparation.
1
8
13
C NMR spectra of this sample were recorded. Among the most
discernible lines are three sets of Si-Me’s (three doublets between
δ 0.06 and 0. 0.16, J ) 3 Hz in the proton NMR and three singlets
at δ 0.17, 3.22, and 3.28 in the carbon NMR) and a broad doublet
2
between δ 3.40 and 3.70, which has been assigned to the CH O
protons of the coordinated THF. The Si-H protons appear as three
PrCl
3
‚2THF.18 Praseodymium chloride (PrCl
3
) (0.5 g, 2.02
distinct multiplets at δ 4.66, 4.79, and 4.93 in a ratio of 0.09:0.35:
mmol) in THF (12 mL) was charged in a 50 mL two-necked flask
under an inert atmosphere and heated to reflux for 1.5 h. The
mixture was cooled to room temperature and was evaporated to
dryness to give white solid (0.78 g). By weight difference between
0.05, clearly suggesting that several geometric isomers maybe
8
present in solution. The residual protons of toluene-d appearing
at δ 2.09 were used to calibrate the changes in intensities of the
other protons. After 10 min, epoxycyclohexane (0.003 g, 0.03 mmol,
PrCl
PrCl
3
and the white THF adduct, the product was estimated to be
‚2THF.
1
equiv) was added, and the NMR was recorded again after 10
3
min and 22 h. The spectra remain unchanged over this period of
1
time. A new broad doublet in the H NMR that appears at δ 2.93
1
3
(18) Rossmanith, K.; Auer-Welsbach, C. Monatsch. Chem. 1965, 96, 602.
and 3.01 is most likely from the epoxycyclohexane. In the
C
8654 J. Org. Chem., Vol. 72, No. 23, 2007

Catalyzed Ring Opening of Epoxides by TMSCN and TMSN
3
spectrum new peaks appear at δ 24.39, 24.46, and 53.84, and these
are assigned to the epoxide. The Si-Me signals show some
dispersion; now each of the three doublets appear at δ 0.103, 0.219,
and 0.277. The corresponding 13C signals appear at δ 0.57, 3.95,
and 4.11. Careful examination of the spectra revealed no changes
in any of the major absorptions over the 22 h between the two
recordings. The absence of any significant new peaks between δ 3
and 4 suggests that the coordinated amide most likely does not
open the epoxide. Further GC analysis indicated no new products
are formed under these conditions. Finally, the presence of unreacted
epoxide in the mixture was confirmed by addition to the above
solution of 1 equiv (0.003 g) of TMSCN. The broad signals at δ
mmol) was added slowly and dropwise to the stirred solution of
epoxide and catalyst. The reaction was monitored by GC. After
completion of the reaction, the mixture was passed through a short
silica gel column, and evaporation of the solvent gave clean product
in nearly quantitative yield in almost every case.
(1R,2S)-2-Trimethylsilyloxycyclopentane-1-carbonitrile (from
Epoxide 2). Spectroscopic data were identical with the literature
value.3b Enantiomer separation: chiral GC analysis (Cyclodex-B
column, 90 °C for 25 min, 1 °C/min, t
(major) ) 35.51 min.
R
R
(minor) ) 34.54 min, t -
Yttrium-Catalyzed Reaction of Epoxycyclohexane with 2 M
HCN in Toluene. To a toluene solution of epoxycyclohexane
2.905 and 2.975 gradually disappear, and new TMS peaks appear
4 2
(0.049 g, 0.5 mmol) and [L ]Y[N(dms) ][THF] (0.005 g, 0.005
13
19
at δ 0.58 and -2.54 in the C NMR spectrum. Workup of the
reaction and isolation of the major product confirms the structure
of the product as the expected cyanohydrin-TMS ether by GC
and NMR.
mmol) was added 2 M HCN in toluene (0.28 mL, 0.56 mmol)
slowly, in a dropwise manner, and the reaction mixture was stirred
at room temperature. A small amount of the reaction sample was
analyzed by GC periodically in every 2 h interval to determine the
conversion of the reaction until 8 h. No ring opening of the epoxide
with HCN was observed. The reaction mixture was stirred for
another 10 h, and final analysis of the crude reaction mixture using
GC and proton NMR also showed no ring opening with HCN.
Procedures for Yttrium-Catalyzed Reactions of Epoxycyclo-
A Typical Procedure for Ring Opening of Epoxycyclohexane
with TMSCN Using Lanthanide Complexes (Table 2). To a CH
2
-
Cl solution (0.5 mL) of catalyst was added epoxide (0.049 g, 0.5
2
mmol), the solution was stirred at room temperature for 5 min,
and TMSCN (0.05 g, 0.5 mmol) (neat) was added slowly and
dropwise to the stirred solution of epoxide and catalyst. The reaction
was monitored by GC and the stirring continued until completion
hexane with TMSCN and TMSN
To a CH Cl solution (0.5 mL) of epoxycyclohexane (0.05 g, 0.5
mmol) and TMSCN [or TMSN (0.5 mmol)] was added Cp ZrMe
(0.01 mmol). The reaction mixture was stirred at rt for 10 min,
yttrium complex [L ]Y[N(dms) ][THF] (0.0085 mg, 0.01 mmol)
3 2 2
in the Presence of Cp ZrMe .
2
2
(see Table 2 for the exact times). After completion of the reaction,
3
2
2
the mixture was passed through a short silica column, and
evaporation of the solvent gave clean product.
1
2
A Typical Procedure for Solvent-Free Ring Opening of
was added, and stirring was continued until the complete consump-
tion of epoxide (based on GC analysis). No inhibition of the reaction
was observed under these conditions.
Probing the Nonlinear Effect. For this experiment the two
4 4
enantiomerically pure ligands L and ent-L were mixed in the
Epoxycyclohexane with TMSCN Using [L
4
]Y[N(SiMe
THF] (Table 3). In a 10 mL vial was dissolved [L ]Y[N(SiMe
THF] (2.5 mg, 0.0025 mmol) in epoxycyclohexane (∼5 mmol,
00 mg), the yellow solution was stirred for 5 min, and 50 mg of
2
H)
2
]-
[
[
5
4
2 2
H) ]-
this mixture (∼0.00025 mmol catalyst + 0.5 mmol epoxycyclo-
hexane) was transferred to an another vial. To this was added 200
mg (2 mmol) more of epoxycyclohexane (epoxide/catalyst 10000).
To a 50 mg sample of this solution (0.5 mmol of epoxide and
appropriate ratios, and the catalysts were prepared as described
earlier. The reaction was run under standard conditions using 1
mol % of catalyst. After all the starting material was consumed,
the product was isolated and analyzed by gas chromatography to
ascertain the enantiomeric excess. The ee of the product is plotted
against the ee of the starting ligand (see the Supporting Information
0.00005 mmol of catalyst) was added TMSCN (50 mg, 0.5 mmol)
slowly and dropwise at rt. The reaction mixture was stirred for 4
h to get complete conversion of epoxide to the desired product.
The crude mixture was passed through a short silica gel column,
and evaporation of the solvent gave the clean product in nearly
quantitative yield (enantioselectivity 56%).
2
for the graph). A linear relationship (R ) 0.989) between the two
ee’s indicates the absence of nonlinear effects in this reaction.
Acknowledgment. Financial assistance for this research by
the National Science Foundation (CHE-0526864, CHE-060349)
and the Petroleum Research Fund of the American Chemical
Society (42964-AC1) is gratefully acknowledged. We thank Dr.
Judith C. Gallucci for the X-ray crystallographic analysis of 6.
A Typical Procedure for Solvent-Free Ring Opening of
Epoxycyclohexane with TMSN
Table 4). To another 50 mg sample of epoxycyclohexane and the
catalyst (0.5 mmol of epoxide and 0.00005 mmol of catalyst) from
the above experiment was added TMSN (58 mg, 0.5 mmol) slowly
3 4 2 2
Using [L ]Y[N(HSiMe ) ][THF]
(
3
Supporting Information Available: Full experimental proce-
dures, ORTEP representation of 6 with details of the X-ray analysis,
and chromatographic data for enantiomeric mixtures listed. Details
of the kinetic measurements and the graphical representations of
data including the plots of kobs vs [cat. concn] and kobs vs [cat.
and dropwise at rt. The reaction mixture was stirred for 38 h to get
complete conversion of epoxide to the desired product. The crude
mixture was passed through a short silica gel column, and
evaporation of the solvent gave the clean product in nearly
quantitative yield (enantioselectivity 29%).
2
concn] . This material is available free of charge via the Internet
General Procedure for Ring-Opening of meso-Epoxides (2-
at http://pubs.acs.org.
4
) with TMSCN Using Chiral Yttrium Complex [L
4
]Y-
[
N(SiMe H) ][THF] (Table 4). To a CH Cl solution (0.5 mL) of
2 2 2 2
JO071076H
catalyst was added epoxide (0.5 mmol), the yellow solution was
stirred at room temperature for 10 min, and TMSCN (neat) (0.50
(19) Saha, B.; RajanBabu, T. V. Org. Lett. 2006, 8, 4657.
J. Org. Chem, Vol. 72, No. 23, 2007 8655