Rhenium-catalyzed 1,3-isomerization of allylic alcohols: Scope and chirality transfer

Article abstract of DOI:10.1021/jo061436l

(Chemical Equation Presented) The scope of the triphenylsilyl perrhennate (O₃ReOSiPh₃, 1) catalyzed 1,3-isomerization of allylic alcohols has been thoroughly explored. It was found to be effective for a wide variety of secondary and tertiary allylic alcohol substrates bearing aryl, alkyl, and cyano substituents. Two general reaction types were found which gave high levels of product selectivity: those driven by formation of an extended conjugated system and those driven by selective silylation of a particular isomer. The efficiency of chirality transfer with various substrates was investigated, and conditions were found in which secondary and tertiary allylic alcohols could be formed with high levels of enantioselectivity. Consideration of selectivity trends with respect to the nature of the substituents around the allylic system revealed that this is a reliable and predictable method for allylic alcohol synthesis.

Full text of DOI:10.1021/jo061436l

Rhenium-Catalyzed 1,3-Isomerization of Allylic Alcohols:
Scope and Chirality Transfer
Christie Morrill, Gregory L. Beutner, and Robert H. Grubbs*
Arnold and Mabel Beckman Laboratories of Chemical Synthesis, California Institute of Technology,
1200 East California BouleVard, Pasadena, California 91125
rhg@its.caltech.edu
ReceiVed July 10, 2006
The scope of the triphenylsilyl perrhennate (O3ReOSiPh3, 1) catalyzed 1,3-isomerization of allylic alcohols
has been thoroughly explored. It was found to be effective for a wide variety of secondary and tertiary
allylic alcohol substrates bearing aryl, alkyl, and cyano substituents. Two general reaction types were
found which gave high levels of product selectivity: those driven by formation of an extended conjugated
system and those driven by selective silylation of a particular isomer. The efficiency of chirality transfer
with various substrates was investigated, and conditions were found in which secondary and tertiary
allylic alcohols could be formed with high levels of enantioselectivity. Consideration of selectivity trends
with respect to the nature of the substituents around the allylic system revealed that this is a reliable and
predictable method for allylic alcohol synthesis.
1. Introduction
ment3 of allylic acetates, did not receive considerable attention
until reports appeared of a mild, catalytic version (Scheme 1,
eq 1).4 Although extensive studies have been conducted on these
metal-catalyzed rearrangements, the related isomerization of
allylic alcohols has received much less attention. In this paper,
an extensive investigation of the scope of allylic alcohol
isomerizations promoted by triphenylsilyl perrhennate (O3-
ReOSiPh3, 1), a highly active catalyst originally disclosed by
Osborn and co-workers, is reported (Scheme 1, eq 2).5 Ongoing
studies in our laboratory have revealed that this rhenium(VII)
complex is effective for the isomerization of a wide variety of
secondary and tertiary allylic alcohols.6 In the case of enan-
tioenriched substrates, a high degree of chirality transfer is
observed, generating secondary and tertiary allylic alcohols with
The scope and utility of [3,3]-rearrangements have expanded
greatly since their initial discovery about 100 years ago.1 A wide
variety of methods for promoting Cope and Claisen rearrange-
ments have been reported, including the use of Brønsted acids,
Brønsted bases, Lewis acids, and transition metals. These
developments led to the use of milder reaction conditions and,
therefore, the examination of more complex and synthetically
relevant substrates.2 These methods also enabled new kinds of
[3,3]-rearrangements, distinct from the well-known reactions of
1,5-dienes (Cope) and allyl vinyl ethers (Claisen). Polyhetero-
Cope rearrangements, such as the [1,3]-dioxa-Cope rearrange-
(1) (a) Claisen, B. Chem. Ber. 1912, 45, 3157-3166. (b) Cope, A. C.;
Hardy, E. M. J. Am. Chem. Soc. 1940, 62, 441-444.
(3) For the nomenclature of polyhetero-Cope rearrangements, see:
Widmer, U.; Zsindely, J.; Hansen, H. J.; Schmid, H. HelV. Chim. Acta 1973,
56, 75-105.
(4) (a) Nakamura, H.; Yamamoto, Y. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E. I., Ed.; John Wiley and
Sons: New York, 2002; Chapter IX.2. (b) Overman, L. E. Angew. Chem.,
Int. Ed. 1984, 23, 579-586.
(5) Bellemin-Laponnaz, S.; Gisie, H.; Le Ny, J. P.; Osborn, J. A. Angew.
Chem., Int. Ed. Engl. 1997, 36, 976-978.
(6) Morrill, C.; Grubbs, R. H. J. Am. Chem. Soc. 2005, 127,
2842-2843.
(2) (a) Nubbemeyer, U. Synthesis 2003, 961-1008. (b) Martin Castro,
A. M. Chem. ReV. 2004, 104, 2939-3002. (c) Ito, H.; Taguchi, T. Chem.
Soc. ReV. 1999, 28, 43-50. (d) Enders, D.; Knopp, M.; Schiffers, R.
Tetrahedron: Asymmetry 1996, 7, 1847-1882. (e) Wilson, S. R. Org. React.
1993, 43, 93-250. (f) Blechert, S. Synthesis 1989, 71-82. (g) Ziegler, F.
E. Chem. ReV. 1988, 88, 1423-1452. (h) Lutz, R. P. Chem. ReV. 1984, 84,
205-247. (i) Ziegler, F. E. Acc. Chem. Res. 1977, 10, 227-232. (j) Bennett,
G. B. Synthesis 1977, 589-606. (k) Rhodds, S. J.; Raulins, N. R. Org.
React. 1975, 22, 1-252.
10.1021/jo061436l CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/07/2006
J. Org. Chem. 2006, 71, 7813-7825
7813

Morrill et al.
SCHEME 1. Polyhetero-Cope Rearrangements
FIGURE 1. Mechanism of “cyclization-induced” rearrangements.
SCHEME 2. Late Transition-Metal-Catalyzed
Rearrangement
FIGURE 2. Metal oxo- vs late metal-catalyzed isomerizations.
high levels of enantioselectivity. Consideration of the trends
that correlate substrate structure and selectivity reveals this to
be a reliable and predictable method.
man has classified these transition-metal-catalyzed reactions as
“cyclization-induced” rearrangements, proposing a unique mech-
anism for this class of rearrangements. The key feature of this
mechanism was that the metal acted as an electrophilic catalyst,
binding to the alkene and activating it toward nucleophilic attack
by the pendant carbonyl oxygen to generate a cyclic, organo-
metallic intermediate i (Figure 1).14
2. Background
The rearrangement of allylic esters, or the [1,3]-dioxa-Cope
rearrangement, was originally observed in the gas phase by
Lewis and co-workers in the late 1960s.7 The reaction was
proposed to be a sigmatropic rearrangement, proceeding through
a cyclic transition structure. Unlike the closely related Claisen
rearrangement, this reaction was an equilibrium process, in
which the product distribution was governed by the relative
thermodynamic stabilities of the two allylic isomers. Therefore,
for the [1,3]-dioxa-Cope rearrangement to become synthetically
useful, strategies for obtaining high product selectivity were
required. Brønsted acid catalysts could selectively isomerize
tertiary allylic alcohols into the corresponding primary allylic
acetates through an ionization-recombination mechanism, but
mild reaction conditions were lacking.8
Early studies on a catalytic version of these rearrangements
showed promising results. Overman and co-workers found that
both allylic acetates and carbamates rearranged in the presence
of either mercury(II)9 or palladium(II)10 catalysts with moderate
to high levels of product selectivity (Scheme 2). Under catalysis
by PdCl2(NCCH3)2, high levels of chirality transfer were
observed for enantioenriched allylic acetates. This method has
proven useful in the synthesis of several natural products,
including steroids,11 amino acids,12 and prostaglandins.13 Over-
Although late transition metal catalysis is highly effective
for promoting the [1,3]-dioxa-Cope rearrangements of allylic
esters, the direct isomerization of allylic alcohols cannot be
performed with these catalysts. Such a direct transformation of
allylic alcohols would be similar to that described for allylic
acetates, but it would hold the advantage of occurring in one
synthetic step rather than three (Figure 2). In the late 1960s,
several high oxidation state, early transition metal-oxo catalysts
were reported to directly isomerize allylic alcohols without prior
esterification.15 Binding of a metal-oxo complex to the alcohol
formed the substrate for the [3,3]-rearrangement catalytically.
This novel form of catalysis was originally reported in the patent
literature. Extremely low catalyst loadings of vanadium- or
tungsten-oxo complexes promoted the equilibration of allylic
alcohols at high temperatures.16 These reactions were generally
effective for the isomerization of tertiary alcohols to form
primary alcohols, such as the isomerization of linalool (4) to
form a mixture of geraniol ((E)-5) and nerol ((Z)-5) (Table 1,
entries 1-4). Chabardes and co-workers proposed that these
(12) (a) Kirihata, M.; Kawahara, S.; Ichimoto, I.; Udea, H. Agric. Biol.
Chem. 1990, 54, 753. (b) Kurokawa, N.; Ohfune, Y. Tetrahedron Lett. 1985,
26, 83-84.
(7) (a) Leavell, K. H.; Lewis, E. S. Tetrahedron 1972, 28, 1167-1172.
(b) Lewis, E. S.; Hill, J. T. J. Am. Chem. Soc. 1969, 91, 7458-7462. (c)
Lewis, E. S.; Hill, J. T.; Newmann, E. R. J. Am. Chem. Soc. 1968, 90,
662-668.
(8) (a) Babler, J. H.; Olsen, D. O.; Arnold, W. H. J. Org. Chem. 1974,
39, 1656-1658. (b) Babler, J. H.; Olsen, D. O. Tetrahedron Lett. 1974,
15, 351-354. (c) Kogami, K.; Kumanotani, J. Bull. Chem. Soc. Jpn. 1974,
47, 226-233. (d) Young, W. G.; Webb, I. D. J. Am. Chem. Soc. 1951, 73,
780-782.
(9) (a) Overman, L. E.; Campbell, C. B.; Knoll, F. M. J. Am. Chem.
Soc. 1978, 100, 4822-4834. (b) Overman, L. E.; Campbell, C. B. J. Org.
Chem. 1976, 41, 3338-3340.
(10) (a) Overman, L. E.; Knoll, F. M. Tetrahedron Lett. 1979, 26, 321-
324. (b) Henry, P. M. J. Am. Chem. Soc. 1972, 94, 5200-5206. (c) Sabel,
A.; Smidt, J.; Jira, R.; Prigge, H. Chem. Ber. 1969, 102, 2939-2950.
(11) Takatsuto, S.; Ishiguro, M.; Ikekawa, N. J. Chem. Soc., Chem.
Commun. 1982, 258-260.
(13) (a) Nakazawa, M.; Sakamoto, Y.; Takahashi, T.; Tomooka, K.;
Ishikawa, K.; Nakai, T. Tetrahedron Lett. 1993, 34, 5923-5962. (b)
Mahrwald, R.; Schick, H.; Piunitsky, K. K.; Schwarz, S. J. Prakt. Chem.
1990, 332, 403-413. (c) Grieco, P. A.; Tuthill, P. A.; Sham, H. L. J. Org.
Chem. 1981, 46, 5005-5007. (d) Grieco, P. A.; Takigawa, T.; Bongers, S.
L.; Tanaka, H. J. Am. Chem. Soc. 1980, 102, 7587-7588. (e) Trost, B. M.;
Timko, J. M.; Stanton, J. L. J. Chem. Soc., Chem. Commun. 1978, 436-
438.
(14) (a) Chi, K. W.; Koo, E. C. Bull. Korean Chem. Soc. 1994, 15, 98-
100. (b) Yoo, S. E.; Cha, O. J. Bull. Korean Chem. Soc. 1994, 15, 889-
890.
(15) (a) Bellemin-Laponnaz, S.; Le Ny, J. P. Compt. Rend. Chem. 2002,
5, 217-224. (b) Chabardes, P.; Kuntz, E.; Vargant, J. Tetrahedron 1977,
33, 1775-1783.
(16) Hosogai, T.; Fujita, Y.; Ninagawa, Y.; Nishida, T. Chem. Lett. 1982,
357-360.
7814 J. Org. Chem., Vol. 71, No. 20, 2006

Rhenium-Catalyzed Isomerization of Allylic Alcohols
TABLE 1. Isomerizations with Early Metal-Oxo Complexes
temp time
ratio
entry
catalyst (mol %)
solvent (°C)
(h)
(4/5)
115b
215b
316
416
519
6
OW(OSiPh3)4 (0.003)
OV(OSiPh3)4 (0.007)
OW(OMe)4-pyridine (0.01)
OV(OtBu)4 (0.054)
OV(acac)2-(TMSO)2 (10)
O3ReOSiPh3 (2)
neat
neat
neat
neat
CH2Cl2
Et2O
200
160
200
200
23
3
1.5
3
2.5
12
0.5
0.5
70:30
69:31
61:39
62:38
82:18
62:38
11:89
23
23
7
O3ReOSiPh3/BSA/TMSA (2) Et2O
SCHEME 3. Isomerizations with Early Metal-Oxo
Complexes
FIGURE 3. Proposed mechanism for O3ReOSiPh3-catalyzed isomer-
izations.
SCHEME 4. Rhenium Oxo-Catalyzed Allylic Alcohol
Isomerizations
reactions occurred through a cyclic transition structure similar
to that proposed for the related, thermal [1,3]-dioxa-Cope
rearrangement.
catalysis.21 However, Osborn and co-workers’ study of the
reactions involving O3ReOSiPh3 (1) was the major breakthrough
in this area (Scheme 4, eq 2).5,22 Compared to other metal-
oxo catalysts, 1 rapidly equilibrates an allylic alcohol and its
isomer under neutral conditions with a low catalyst loading
(Table 1, entry 6). The allylic alcohol product is usually obtained
with high levels of E-selectivity. This catalyst has led to some
interest in the synthetic community, as demonstrated by several
recent publications.23
Mechanistic studies performed by Osborn on the isomeriza-
tion of allylic alcohol 12, promoted by rhenium complex 1,
supported a cyclic transition structure similar to that originally
proposed by Chabardes and co-workers. Kinetic analysis
demonstrated that the reaction was first order in both the catalyst
and allylic alcohol. The thermodynamics of the reaction revealed
a large, negative activation entropy for the formation of the
major product, E-13, suggesting a [3,3]-rearrangement through
a highly ordered, polarized, chairlike transition structure iv
(Figure 3). Osborn proposed that the high oxidation state of
the rhenium center generated the polarization in iv. In this
chairlike transition structure, the observed selectivity for E-13
could result from the minimization of diaxial interactions.
Interestingly, this highly ordered transition structure was only
Subsequent investigations with metal-oxo complexes con-
taining molybdenum,17 chromium,18 and vanadium19 revealed
that these reactions could be promoted at ambient temperature.
For example, pyridinium chlorochromate (PCC) isomerized
tertiary allylic alcohols, presumably through the intermediate
ii, with subsequent oxidation to form the isomeric R,â-
unsaturated ketones (Scheme 3, eq 1).18 The use of vanadyl
bisacetoacetate (OdV(acac)2) in combination with a catalytic
amount of bistrimethylsilyl peroxide (TMSOOTMS) also al-
lowed isomerizations to occur at ambient temperature (Table
1, entry 5).19 The first example of chirality transfer with metal-
oxo catalysis was demonstrated in this work with the isomer-
ization of the enantioenriched alcohol 8 (Scheme 3, eq 2).
Further studies revealed that rhenium-oxo complexes also
promoted these isomerizations under mild reaction conditions.
Narasaka and co-workers demonstrated that under acidic condi-
tions tetra-n-butylammonium perrhennate (O3ReONBu4) isomer-
ized a variety of allylic alcohols (Scheme 4, eq 1).20 The use of
methyl trioxorhenium further demonstrated the utility of rhenium
(17) (a) Fronczek, F. R.; Luck, R. L.; Wang, G. Inorg. Chem. Commun.
2002, 5, 384-387. (b) Belgacem, J.; Kress, J.; Osborn, J. A. J. Mol. Catal.
1994, 86, 267-285. (c) Belgacem, J.; Kress, J.; Osborn, J. A. J. Am. Chem.
Soc. 1992, 114, 1501-1502.
(18) Dauben, W. G.; Michno, D. M. J. Org. Chem. 1977, 42, 682-685.
(19) (a) Matsubara, S.; Okazoe, T.; Oshima, K.; Takai, K.; Nozaki, H.
Bull. Chem. Soc. Jpn. 1985, 58, 844-849. (b)Matsubara, S.; Takai, K.;
Nozaki, H. Tetrahedron Lett. 1983, 24, 3741-3744.
(20) (a) Narasaka, K.; Kusama, H.; Hayashi, Y. Tetrahedron 1992, 48,
2059-2068. (b) Narasaka, K.; Kusama, H.; Hayashi, Y. Chem. Lett. 1991,
1413-1416.
(21) (a) Wang, G.; Jimtaisong, A.; Luck, R. L. Organometallics 2004,
23, 4522-4525. (b) Jacob, J.; Espenson, J. H.; Jensen, J. H.; Gordon, M.
S. Organometallics 1998, 17, 1835-1840.
(22) (a) Bellemin-Laponnaz, S.; Le Ny, J. P.; Osborn, J. A. Tetrahedron
Lett. 2000, 41, 1549-1552. (b) Bellemin-Laponnaz, S.; Le Ny, J. P.; Dedieu,
A. Chem.-Eur. J. 1999, 5, 57-64.
(23) (a) Hansen, E. C.; Lee, D. J. Am. Chem. Soc. 2006, 128, 8142-
8143. (b) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2000, 122,
11262-11263.
J. Org. Chem, Vol. 71, No. 20, 2006 7815

Morrill et al.
TABLE 2. Solvent Effects on the O3ReOSiPh3-Catalyzed Isomerization of 14
temp
(°C)
time
(min)
14
15
16
17
entry
solvent
(%)a
(%)a
(%)a
(%)a
1
2
3
4
5
6
7
8
9
CH2Cl2
CH3CN
toluene
THF
23
23
23
23
23
-50
-50
-50
-50
2
0
0
0
0
0
4
28
0
0
15
19
51
38
37
57
72
100
100
55
73
49
38
51
39
0
30
8
0
24
12
0
0
0
0
35
35
35
35
40
40
40
40
Et2O
CH2Cl2
toluene
THF
0
0
Et2O
1
a Determined by H NMR.
TABLE 3. Isomerization of Aryl Secondary Allylic Alcohols
evident in the formation of the major product, E-13. The minor
product, Z-13, appeared to form through a more disordered
process, possibly an ionization-recombination pathway involv-
ing intermediate v, as evidenced by its positive activation
entropy. The formation of only minor amounts of Z-13 indicated
that this less-ordered pathway was kinetically less competent
when compared to the [3,3]-rearrangement pathway.
temp time
(°C) (min)
yield
(%)b
entry
SM (E/Z)a
R1
R2
R3
Despite these studies, allylic alcohol isomerizations catalyzed
by O3ReOSiPh3 still possessed several shortcomings. The scope
of the reaction with respect to substrate structure, general
methods for obtaining high product selectivity, as well as the
degree of chirality transfer inherent to the reactions of O3-
ReOSiPh3 remained unexplored. Therefore, we undertook
studies to delineate the scope and limitations of this method
with respect to allylic alcohol structure as well as to examine
the potential for chirality transfer with O3ReOSiPh3. The first
part of these studies, communicated in 2005,6 described two
methods for obtaining high product selectivity (Table 1, entry
7). The second part of these studies focused primarily on the
chirality transfer and has revealed that this method is useful for
the formation of enantioenriched secondary and tertiary allylic
alcohols. In addition, the activity and selectivity patterns of
related rhenium(VII) imido catalysts were investigated. Con-
sideration of the observed trends with respect to both product
selectivity and chirality transfer supports the mechanism
proposed by Osborn and shows this reaction to be a mechanisti-
cally distinct alternative to the related [1,3]-dioxa-Cope rear-
rangements previously described in the literature. Understanding
how the mechanism of this reaction fits into the continuum of
mechanisms that exist between ionization-recombination and
cyclization-induced rearrangements helps to make predictions
about the performance of this O3ReOSiPh3 catalyst system with
novel substrates.
1
2
3
14 (10:1)
18a (10:1)
n-hex
n-hex
H
NO2
H
H
OMe
H
H
H
H
NO2
OMe
H
H
NO2
CF3
H
-50
23
0
-50
-78
30
30
30
60
98 (15)
98 (19a)
94 (19b)
98 (21)
18b (<1:20) n-hex
4c 20 (>20:1)
n-hex
n-hex
5d 22a (10:1)
120 68 (23a)
120 79 (23b)
6d 22b (>20:1) n-hex
OMe -78
7
8
9
24 (12:1)e
c-C6H11
c-C6H11
H
H
H
H
H
H
H
H
-50
-50
0
23
-50
30
30
30
30
30
95 (25)
93 (25)
98 (27)
98 (29)
65 (31)
24 (1:12)e
26
28
30
10f
11
a Determined by 1H NMR. b E/Z > 20:1 as determined by 1H NMR. c 3
mol % of 1. d 4 mol % of 1. e Determined by GC. Reaction performed in
f
CH2Cl2.
dichloromethane showed rapid consumption of the starting
material. Unfortunately, the desired product 15 was accompanied
by the formation of two other compounds: a mixture of
diastereo- and regioisomeric bisallyl ethers (16, formed by
condensation reactions) and an E/Z-mixture of dienes (17,
formed by elimination reactions). The use of other solvents led
to little improvement in the product distribution (entries 2-5),
but we observed solvent-dependent rate differences among the
competing reaction pathways. Reactions run in dichloromethane
at 23 °C were clearly more rapid than those run in toluene or
in an ethereal solvent at 23 °C. However, we found that only a
combination of low temperatures and ethereal solvents led to
good conversions and selective formation of the desired allylic
alcohol 15 in short reaction times (entries 8 and 9).
3. Results
Using these optimized conditions as a starting point, we
examined the isomerizations of a number of allylic alcohols
(Table 3). In all cases, high E-selectivity was exhibited. Using
only 2-4 mol % of O3ReOSiPh3, we obtained good yields for
substrates bearing either electron-donating or electron-withdraw-
ing substituents on the aryl ring. Substrates bearing electron-
withdrawing substituents exhibited significantly lower reaction
rates. Higher reaction temperatures were required to reach high
conversion in a time comparable to that of the parent compound
3.1. Isomerization of Allylic Alcohols Bearing Conjugating
Substituents. The first strategy identified for obtaining high
levels of product selectivity involved using substrates that would
form an extended conjugated system upon isomerization. We
proposed that the isomerization of 1-aryl-2-alkenol substrates
such as 14 would result in high product selectivity due to the
greater thermodynamic stability of conjugated isomer 15 (Table
2). Initial experiments performed with E-14 at 23 °C in
7816 J. Org. Chem., Vol. 71, No. 20, 2006

Rhenium-Catalyzed Isomerization of Allylic Alcohols
TABLE 4. Isomerization of Heteroaryl Secondary Alcohols
TABLE 5. Isomerization of Cyanohydrins
temp
solvent (°C)
yield
(%)a
yield
(%)
entry SMa
R1
R2
entry
SM
R1
R2
time
1
2
32a 2-furyl
32b 2-furyl
H
n-hex
H
n-hex
H
n-hex
H
THF
Et2O
THF
THF
THF
Et2O
THF
Et2O
-20 ND (33a)
-50 ND (33b)
1
2
3
40a
40b
40c
H
Me
Me
H
H
Me
6 h
6 h
5 min
ND (41a)
ND (41b)
83 (41c)
3
4
5
34a 2-benzofuryl
34b 2-benzofuryl
36a 2-thiophenyl
36b 2-thiophenyl
38a 2-(N-tosyl-indoyl)
-50
-50
-50
-50
-50
-50
98 (35a)
98 (35b)
70 (37a)
92 (37b)
56 (39a)
66 (39b)
6b
7b
8
hydrin acetates and carbonates was precedented.24 We hypoth-
esized that these substrates would exhibit high product selectivity
because the products contain extended conjugated systems in
the form of R,â-unsaturated nitriles. Cyanohydrins 40a,b proved
to be remarkably unreactive substrates (entries 1 and 2).
However, cyanohydrin 40c, which possesses a trisubstituted
alkene, showed a dramatic increase in reactivity (entry 3). The
isomerization of 40c was complete in 5 min at 23 °C, providing
tertiary alcohol 41c in high yield without significant side product
formation. These results reflected the observed correlation
between reaction rate and degree of alkene substitution that was
described previously.
38b 2-(N-tosyl-indoyl) n-hex
a E/Z > 20:1 as determined by 1H NMR. b Reaction run for 10-15 min.
E-14 (entries 2-4). Interestingly, the isomerization of Z-18b
also showed high E-selectivity, despite the change in the initial
alkene geometry (entry 3). Substrates bearing electron-donating
substituents were more reactive. Lower temperatures were
required to suppress the formation of undesired elimination and
condensation products, and higher catalyst loadings were
employed to maintain reasonable reaction rates at these tem-
peratures (entries 5 and 6). Our observation that both the E-
and Z-isomers of a given allylic alcohol isomerize to form the
E-isomer of the product was again demonstrated in the isomer-
izations of E- and Z-24 (entries 7 and 8). In both cases, E-25
was selectively obtained in comparable yields.
A similar trend between the electronic nature of the arene
and its reactivity was observed in the isomerization of the
secondary allylic alcohols 26, 28, and 30 (Table 3, entries
9-11). When compared to the analogous compounds possessing
disubstituted alkenes (entries 1, 2, and 5), these terminal alkene-
containing substrates were noticeably less reactive (compare
entries 1 and 9). Isomerization of electron-deficient substrate
28 only proceeded to high conversion in dichloromethane at
23 °C (compare entries 2 and 10), whereas that of electron-rich
substrate 30 still required the use of an ethereal solvent and a
low temperature (compare entries 5 and 11).
FIGURE 4. Using silylation to control product selectivity.
3.2. Isomerization of Allylic Alcohols without Conjugating
Substituents. Although the results presented thus far established
that conjugating substituents could lead to high product selectiv-
ity, many potential substrates could be envisioned that did not
possess conjugating substituents. Could a method be developed
to induce high product selectivity for this class of substrates as
well? Studies by Osborn and co-workers suggested an interesting
possibility. They observed that the isomerization of allyl silyl
ethers was slow relative to that of allylic alcohols.22a Therefore,
preferential silylation of one of the allylic alcohol isomers during
the course of a reaction would remove it from the equilibrium
(Figure 4). Because the preferential silylation of primary
alcohols in the presence of secondary or tertiary alcohols is
possible, we proposed that high product selectivity, favoring
the primary alcohol isomer, could be obtained for substrates
lacking conjugating substituents.
Allylic alcohols bearing heteroaromatic groups also exhibited
similar electronic trends with respect to their reactivity (Table
4). Highly electron-rich, furyl-substituted substrates 32a,b
rapidly decomposed in the presence of catalyst 1, and thus no
product was obtained from their reactions (entries 1 and 2). The
2-benzofuryl substrates 34a,b provided more promising results
(entries 3 and 4). Thiophenyl substrates 36a,b gave moderate
to high yields under similar conditions (entries 5 and 6). Indoyl
substrates 38a,b which, like the furyl substrates, are relatively
electron rich proved more problematic, again due to rapid
decomposition in the presence of catalyst 1. A strongly electron-
withdrawing N-tosyl substituent was required to obtain reason-
able yields of desired alcohols 39a,b (entries 7 and 8). Other
nitrogen protecting groups, such as an N-2-trimethylsilyl-
ethoxymethyl group, did not lead to formation of the desired
allylic isomer.
The choice of the silylating reagent presented a problem
because it is well-known that most amine bases, which are often
used to promote silylation reactions, form strong complexes with
rhenium-oxo complexes.25 In fact, it was found that tertiary
amines such as diisopropylethylamine and even highly hindered
(24) (a) Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2003,
5, 3021-2024. (b) Huenig, S.; Reichelt, H. Chem. Ber. 1986, 119, 1772-
1800. (c) Mandai, T.; Hashio, S.; Goto, J.; Kawada, M. Tetrahedron Lett.
1981, 22, 2187-2190. (d) Holm, T. Acta Chem. Scand. 1965, 19, 242-
245.
(25) (a) Herrmann, W. A.; Weichselbaumer, G.; Herdtweck, E. J.
Organomet. Chem. 1989, 372, 371-389. (b) Edwards, P.; Wilkinson, G. J.
Chem. Soc., Dalton Trans. 1984, 2695-2702.
To see if nonaryl groups could also serve as conjugating
substituents, the isomerization of allylic cyanohydrins was
investigated (Table 5). The analogous isomerization of cyano-
J. Org. Chem, Vol. 71, No. 20, 2006 7817

Morrill et al.
TABLE 6. Investigations into the Dependence of Isomerization on
the Source of the BSA
TABLE 7. Effect of BSA on the Isomerization of Alkyl Tertiary
Allylic Alcohols
temp time
mol % of 1 (°C) (min)
yield
(%)
entry SM
R
E/Za
equiv of BSA
(source)
additive
(equiv)
conv. yield
entry
(%)a
(%)b
E/Zc
1b
2
3
42a c-C6H11
42a c-C6H11
42b n-C3H7
42c t-Bu
2
2
2
4
0
0
0
0
30
30
30
60
30 (43a)
84 (43a)
93 (43b)
4.7:1
4.6:1
1.9:1
1
2
3
4
5
6
7
8
-
-
-
-
-
-
-
9
6
6
30
89
4.7:1
4.7:1
3.2:1
ND
1.2 (old Aldrich)
1.2 (new Aldrich)
1.2 (distilled)
1.0 (distilled)
1.0 (distilled)
1.0 (distilled)
-
4
82 (43c) >99:1
ND
ND
ND
ND
84
a Determined by GC. b No BSA or TMSA was added.
Ph3SiOH (0.2)
ND
TsOH-H2O (0.2) 58
TMSA (0.2)
TMSA (1.0)
4.6:1
4.6:1
4:1
91
53
TABLE 8. Effect of BSA on the Isomerization of Aryl Tertiary
Allylic Alcohols
42
a Determined by 1H NMR of crude reaction mixtures. b >20:1 43a/42a
as determined by GC. c Determined by GC.
2,4,6-tri-tert-butylpyridine inhibited the isomerization reaction.
The only method that was effective for this reaction employed
N,O-bistrimethylsilyl-acetamide (BSA), a silylating reagent that
does not require the use of an additional base. In the isomer-
ization of tertiary alcohol 42a, conversion to primary alcohol
43a increased from 30% to 89% upon addition of 1.2 equiv of
BSA (Table 6, entries 1 and 2). Under these conditions, a variety
of tertiary alcohols were converted into the corresponding
primary alcohols with high product selectivity.6 However, since
our initial communication, we have found that these results are
dependent upon the source of the BSA. Although older bottles
of BSA provided high product selectivity, freshly opened bottles
did not (Table 6, entries 2 and 3). Our observation that freshly
distilled BSA gave almost no conversion to primary alcohol
43a led us to question the role of BSA as a promoter in these
reactions (entry 4).
Because freshly distilled BSA did not promote high product
selectivity, we suspected that a contaminant in the original bottle
of BSA was vital to these isomerizations. The addition of 0.2
equiv of triphenylsilanol or p-toluenesulfonic acid, meant to
mimic the roles of either trimethylsilanol or trace acid formed
upon hydrolysis of BSA, to freshly distilled BSA did not induce
high product selectivity (Table 6, entries 5 and 6). However,
the addition of 0.2 equiv of N-trimethylsilyl acetamide (TMSA)
did promote high product selectivity (entry 7). TMSA is the
hydrolysis product of BSA, and therefore, it seems likely that
it would be present in older bottles of BSA. Interestingly, the
use of TMSA alone did not induce high product selectivity
(entry 8). Only a combination of BSA and TMSA consistently
reproduced the results that we had obtained with the original
bottle of BSA.
BSA/TMSA temp
yield
(%)
entry SM
R
(equiv)
°C)
time
E/Za
1
44a Me
44a Me
44a Me
44b Et
44b Et
44b Et
0/0
0/0
1.0/0.2
0/0
0/0
-10
-40
-10
-10
-30
-10
30 min 67 (45a) 8.7:1
84 (45a)
30 min 84 (45a)
30 min 25 (45b) 1.2:1
29 h 83 (45b) 1.3:1
30 min 78 (45b) 5.1:1
2b
3
16 h
18:1
19:1
4
5b
6
1.0/0.2
a Determined by GC. b 4 mol % of O3ReOSiPh3.
of tertiary alcohol 44a, the yield improved from 67 to 84%,
and the E/Z selectivity increased from 8.7:1 to 19:1, upon the
addition of BSA and TMSA (entries 1 and 3). Similar results
were observed in the case of alcohol 44b (entries 4 and 6).
Because of the presence of conjugating substituents on 44a,b,
improved yields and selectivities could also be obtained in the
absence of BSA and TMSA, but only by employing a lower
reaction temperature with a higher catalyst loading and signifi-
cantly longer reaction times (entries 2 and 5).
The limitations of this method became clear upon further
attempts to expand the scope of the reaction. The isomerization
of tertiary alcohols 46a,b to form secondary alcohols 47a,b
exhibited only moderate yields, again favoring the E-isomer
(Scheme 5, eqs 1 and 2). The balance of the material existed in
the form of various side products. These yields were still
significant, however, because in the absence of BSA and TMSA
no product could be isolated from these reactions due to rapid
decomposition of 46a,b in the presence of catalyst 1. As we
had observed previously, E-selectivity increased as the steric
demands of the spectator group increased, going from 2.5:1 for
47a to 28:1 for 47b. Unfortunately, the beneficial effect of BSA
and TMSA on product selectivity could not be extended to the
isomerization of nonconjugated secondary allylic alcohols such
as 48 (Scheme 5, eq 3). Although the reaction in the absence
of BSA and TMSA led to an equilibrium mixture of alcohols
(53:47 48/49), the addition of BSA and TMSA led to no reaction
at all, likely due to competitive silylation of 48.
Under these modified reaction conditions, all of the results
reported in our original communication were reproduced with
comparable yields and selectivities. A variety of primary
alcohols were isolated in good yield after hydrolysis of the silyl
ether (Table 7). In most cases, the balance of the material was
unreacted starting material. Varying levels of geometrical
selectivity were observed, again always favoring the E-allylic
alcohol. As the size of the spectator group on the allylic alcohol
substrate increased from n-butyl to cyclohexyl to tert-butyl, so
did the degree of E-selectivity (entries 2-4).
3.3. Chirality Transfer with Enantioenriched Allylic
Alcohols. Having found two different methods for obtaining
high product selectivity, we next examined the efficiency of
chirality transfer with O3ReOSiPh3. If the cyclic transition
structure proposed by Chabardes and Osborn was operative in
these isomerizations, then the enantiopurity of the product should
This method also improved both the product selectivity and
the geometrical selectivity in the isomerization of some tertiary
alcohols bearing conjugating substituents (Table 8). In the case
7818 J. Org. Chem., Vol. 71, No. 20, 2006

Rhenium-Catalyzed Isomerization of Allylic Alcohols
SCHEME 5. Problematic BSA/TMSA-Promoted
Isomerizations
The influence of the electronic nature of the arene ring was
also examined in the context of the chirality transfer. Substrate
(R,E)-22b, possessing an electron-donating methoxy substituent,
exhibited poor chirality transfer. Even at -78 °C, a temperature
at which condensation and elimination pathways are almost
completely suppressed, only racemic product was obtained
(Table 9, entry 3). However, the isomerization of electron-
deficient substrate (R,E)-20 at -50 °C led to the isolation of
highly enantioenriched alcohol (R,E)-21 in good yield (entry
4). Therefore, the degree of chirality transfer increased in the
series 20 > 14 . 22b and tracked well with the electronic nature
of the substrates.
3.3.2. Chirality Transfer to Prepare Enantioenriched
Tertiary Allylic Alcohols. We observed a similar trend in the
isomerization of substrates that generated tertiary allylic alcohols
(Table 10). However, an important difference existed between
these substrates and those shown in Table 9. The additional
methyl substituent in (R,E)-50 dramatically decreased the
efficiency of the chirality transfer compared to (R,E)-14
(compare Table 10, entry 1, to Table 9, entry 1). Substrate (R,E)-
52, bearing a trifluoromethyl substituent, exhibited improved
chirality transfer relative to (R,E)-50, but it was still significantly
less efficient than (R,E)-20 (compare Table 10, entry 2, to Table
9, entry 4). In an effort to further improve the chirality transfer,
we examined substrate (R,Z)-54, bearing two trifluoromethyl
substituents, and found that it indeed exhibited a much higher
degree of chirality transfer (Table 10, entry 3). We also
investigated enantioenriched cyanohydrin (R,E)-56, which bears
a nonaryl, conjugating substituent. Substrate (R,E)-56 was
readily prepared in high levels of enantiopurity by an enzyme-
catalyzed cyanation using the oxynitrilase contained in raw,
commercially available almonds.27 In the isomerization of
cyanohydrin (R,E)-56, high chirality transfer was observed at
ambient temperature, and alcohol (R,E)-57 was obtained in
excellent yield and enantiopurity (Table 10, entry 4).
3.4. Effect of Catalyst Structure on Isomerization Selectiv-
ity. Having thoroughly examined the effect of allylic alcohol
structure on product selectivity and chirality transfer, we then
investigated the effect of catalyst structure by employing a
rhenium(VII) imido catalyst. Imido groups are less electron
withdrawing than oxo groups, partially due to contributions from
the nitrogen lone pair. Rhenium-imido complexes were orig-
inally described by Nugent.28 Early transition-metal-imido
complexes have found only limited applications, including the
stoichiometric isomerization of allylic alcohols to form allylic
amines with tungsten and zirconium-imido complexes.29
Therefore, we wished to ascertain whether rhenium(VII) imido
catalysts would provide any advantages in these isomerizations.
Rhenium-imido complex 58 was synthesized by mixing 10
equiv of N-trimethylsilyl-tert-butylamine with either dirhenium
heptaoxide or tetra-n-butylammonium perrhennate (Scheme 6).
This reaction led to the rapid formation of complex 58, which
was isolated as a moisture-sensitive, yellow solid. As determined
be equal to that of the starting material. Any decrease in
enantiopurity upon isomerization could be attributed to either
the geometrical purity of the starting material (vide infra) or
the involvement of a competitive, acyclic ionized intermediate
analogous to v (Figure 3). The predicted enantiopurity of each
product, accounting for both the geometrical purity and the
enantiopurity of the corresponding starting material, is included
in subsequent tables.
Two classes of enantioenriched secondary benzylic alcohols
were examined, generating secondary and tertiary allylic alco-
hols, respectively, upon isomerization. Both substrate types used
the formation of an extended conjugated system to ensure high
product selectivity. In each case, the isomerization can provide
access to enantioenriched allylic alcohols which may be difficult
to prepare in contrast to their allylic isomers. This is particularly
true in the case of the tertiary allylic alcohols. Relatively few
catalytic, asymmetric methods exist for tertiary allylic alcohol
synthesis. At present, the most general method involves the use
of a zinc reagent and a chiral bissulfonamide catalyst.26
Therefore, a method that can translate the high enantioselectivity
readily attained in secondary alcohol syntheses to that of tertiary
alcohols would represent a novel synthetic approach.
3.3.1. Chirality Transfer to Prepare Enantioenriched
Secondary Allylic Alcohols. Our initial experiments focused
on substrates that generate secondary alcohols. Isomerization
of (R,E)-14 under the optimal conditions identified previously
for its racemic analogue only showed a moderate level of
chirality transfer. Further reducing the temperature to -78 °C
slowed the reaction rate, but it allowed the product (R,E)-15 to
be obtained in good yield and enantiopurity (Table 9, entry 1).
When (R,Z)-14 was examined under similar conditions, the
(S,E)-enantiomer of 15 was formed in good yield and enan-
tiopurity (entry 2). The fact that the E- and Z-isomers of 14 led
to the formation of enantiomeric products is consistent with the
cyclic, chairlike transition structure iv proposed by Osborn and
co-workers.
(27) Deardorff, D. R.; Taniguchi, C. M.; Nelson, A. C.; Pace, A. P.;
Kim, A. J.; Jones, R. A.; Tafti, S. A.; Nguyen, C.; O’Connor, C.; Tang, J.;
Chen, J. Tetrahedron: Asymmetry 2005, 16, 1655-1661.
(28) (a) Schoop, T.; Roesky, H. W.; Noltemeyer, M.; Schmidt, H. G.
Organometallics 1993, 12, 571-574. (b) Toreki, R.; Schrock, R. R.; Davis,
W. M. J. Am. Chem. Soc. 1992, 114, 3367-3380. (c) Danopolous, A. A.;
Longley, C. J.; Wilkinson, G.; Hussain, B.; Hursthouse, M. B. Polyhedron
1989, 8, 2657-2670. (d) Nugent, W. A. Inorg. Chem. 1983, 22, 965-969.
(29) (a) Lalic, G.; Blum, S. A.; Bergman, R. G. J. Am. Chem. Soc. 2005,
127, 16790-16791. (b) Chan, D. M. T.; Nugent, W. A. Inorg. Chem. 1985,
24, 1422-1424.
(26) (a) Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 8355-8361.
(b) Jeon, S. J.; Li, H.; Carcia, C.; LaRochelle, L. K.; Walsh, P. J. J. Org.
Chem. 2005, 70, 448-455. (c) Li, H.; Garcia, C.; Walsh, P. J. Proc. Natl.
Acad. Sci. 2003, 101, 5425-5427. (d) Ramon, D. J.; Yus, M. Tetrahedron
1998, 54, 5651-5666.
J. Org. Chem, Vol. 71, No. 20, 2006 7819

Morrill et al.
TABLE 9. Chirality Transfer to Prepare Enantioenriched Secondary Allylic Alcoholsa
a 0.2 M, ether, 3 mol % of 1.Unless otherwise noted, E/Z was determined by GC, and ee was determined by chiral HPLC. b E/Z > 20:1 (1H NMR).
1
c Absolute configuration determined to be (R). d Absolute configuration determined to be (S). e Determined by H NMR.
TABLE 10. Chirality Transfer to Prepare Enantioenriched Tertiary Allylic Alcoholsa
a 0.2 M, ether, 2 mol % of 1.Unless otherwise noted, E/Z was determined by GC, and ee was determined by chiral HPLC. b E/Z > 20:1 as determined
1
1
by H NMR. c Reaction performed in THF with 4 mol % of 1. d Determined by H NMR. e Absolute configuration determined to be (R).
by ReactIR, this complex could also be generated in situ by a
similar procedure.
product mixture (Table 2, entry 1), this result with catalyst 58
represents an improvement in terms of product selectivity.
However, the chirality transfer with 58 at 23 °C was nearly
identical to that observed with 1 at -78 °C (compare Table 11,
entry 1, to Table 9, entry 1). The chirality transfer observed
with 58 was unaffected by the stoichiometry of the amine (Table
11, compare entries 1 and 2).
Initial experiments conducted with in situ generated imido
complex 58 and allylic alcohol 14 under the optimal reaction
conditions determined previously with oxo complex 1 clearly
demonstrated the lower reactivity of the imido complex. No
conversion to alcohol 15 was observed at -50 °C. Performing
the isomerization at 23 °C, however, led to complete conversion
to 15 after 30 min (Table 11, entry 1). Because the analogous
reaction with oxo complex 1 readily generated a complex
Interestingly, this reaction did not proceed in the presence
of isolated imido complex 58 (Table 11, entry 3). The addition
of triphenylsilanol to the reaction, a substitute for the trimeth-
7820 J. Org. Chem., Vol. 71, No. 20, 2006

Rhenium-Catalyzed Isomerization of Allylic Alcohols
SCHEME 6. Synthesis of Rhenium-Imido Complex 58
ylsilanol formed during the in situ imido group transfer, did
not promote significant isomerization (entry 4). However, the
addition of even small amounts of TMSNHtBu did allow
reactivity to be recovered, generating allylic alcohol (R,E)-15
in good yield and enantiopurity at 23 °C with only 2.5 mol %
of 58 (entry 5).
TABLE 11. Rhenium Imido-Catalyzed Isomerizations
FIGURE 5. Proposed catalytic cycle for O3ReOSiPh3-catalyzed
isomerizations.
catalyst
(mol %)
additive
(mol %)
yield
(%)c
entry
ee
1
2
3
4
5
Re2O7 (1.25)
Re2O7 (1.25)
58 (2.5)
58 (2.5)
58 (2.5)
TMSNHtBu (100)
TMSNHtBu (15)
-
86
89
-
83
81
-
presented. Trends with respect to the electronic nature of the
allylic alcohols and the degree of alkene substitution will be
discussed in the context of both product selectivity and chirality
transfer. The results obtained with imido and oxo catalysts will
be compared, adding further support to the proposed catalytic
cycle. This mechanistic understanding makes it relatively
straightforward to predict the outcome of a given allylic alcohol
isomerization by considering both the structure and the electronic
nature of the substrate.
Ph3SiOH (15)
-
-
TMSNHtBu (15)
76
82
a Determined by GC. b Determined by chiral HPLC. c E/Z > 20:1 as
determined by H NMR.
1
SCHEME 7. Rhenium Imido-Catalyzed Isomerizations of
59
4.1. Proposed Catalytic Cycle for O3ReOSiPh3-Catalyzed
Isomerizations. On the basis of Osborn’s proposed mechanism,
a more detailed catalytic cycle can be drawn for the overall
isomerization process (Figure 5).5,22b The first step forms the
actual [3,3]-rearrangement substrate vi through displacement of
triphenylsilanol from 1. Isomerization then occurs through six-
membered, chairlike transition structure vii, reminiscent of that
involved in the Claisen rearrangement. This structure is sup-
ported by Osborn’s measurement of a large, negative activation
entropy for this reaction. After the isomerization occurs, rhennate
ester viii is formed. Catalyst turnover then occurs by either direct
displacement by allylic alcohol 62 or displacement by triph-
enylsilanol. Although the former seems more likely due to the
high concentration of alcohol relative to that of silanol,
triphenylsilanol may still be involved in the catalyst turnover
step, acting as a proton donor (pKa ) 16.57 (DMSO)30).
Significant polarization exists in transition structure vii due
to the high oxidation state of the rhenium atom and the presence
of three strongly electron-withdrawing oxo ligands. Thus,
carbon-oxygen bond cleavage likely precedes carbon-oxygen
bond formation, leading to a partial positive charge on the allyl
fragment and a partial negative charge on the rhennate fragment.
The strong polarization of the carbon-oxygen bond in vi can
also lead to competitive formation of ion pair intermediate ix.
The involvement of this species is supported by Osborn’s
observation of a second reaction pathway, responsible for
Z-allylic alcohol formation, with a positive activation entropy.
Further support for the involvement of a cationic intermediate
such as ix comes from the fact that trioxorhenium complexes,
The decreased catalytic activity of imido complex 58 was
confirmed by the fact that it did not react with electron-deficient
allylic alcohol 20. On the other hand, exposure of 58 to electron-
rich allylic alcohol 59 promoted a rapid reaction but yielded
none of the desired allylic alcohol isomer. Instead, it generated
a mixture of allylic amines 60 and 61 (Scheme 7). Despite
attempts at optimization, the ratio of these two isomeric amines
could not be affected by changing the solvent or the amine
structure.
4. Discussion
In this paper, the O3ReOSiPh3-catalyzed isomerization of
allylic alcohols has been studied and the scope and limitations
of the method have been examined. In this section, a more in-
depth overview of the isomerization mechanism will be
(30) Bassindale, A. R.; Taylor, P. G. In The Chemistry of Organosilicon
Compounds; Patai, S., Rappoport, Z., Eds.; John Wiley and Sons: New
York, 1989; Chapter 12, Part 1, p 809-838.
J. Org. Chem, Vol. 71, No. 20, 2006 7821

Morrill et al.
SCHEME 8. Consequences of E/Z Isomerism on Selectivity
such as O3ReOSiPh3, are potent catalysts for Beckmann
rearrangements and other dehydration reactions.31 Therefore, we
believe that an ionization-recombination pathway leads to the
observed elimination, condensation, and racemization products
(vide infra).
4.2. Structural Trends with Respect to Reactivity and
Product Selectivity. If highly polarized transition structure vii
is operative in these isomerizations, then electronic variations
in the allylic alcohol should have a strong influence on the
reaction rate. In our studies, a trend with respect to the electronic
nature of the substrate is made clear by examining the reaction
conditions required to suppress elimination and condensation
reactions. In both the racemic and the enantioenriched series,
substrates bearing electron-withdrawing substituents reacted
more cleanly at higher temperatures when compared to their
more electron-rich counterparts. This trend is exemplified in
the reactions of 14, 18a, and 22a (Table 3, entries 1, 2, and 5)
as well as 26, 28, and 30 (Table 3, entries 9-11). We also
observed that substrates bearing electron-donating substituents
generally reacted more rapidly than those with electron-
withdrawing substituents when performed under similar condi-
tions. This trend is echoed in the reactions of the heterocycle-
containing allylic alcohols. Particularly electron-rich substrates,
such as furyl substrates 32a,b, did not give any of the desired
product when exposed to 1, although all of the starting material
was consumed (Table 4, entries 1 and 2). Presumably, these
substrates were so reactive that competing reaction pathways
simply could not be suppressed.
to stabilize the buildup of positive charge in the asynchronous
[3,3]-rearrangement transition structure vii.
4.3. Structural Trends with Respect to Stereoselectivity.
4.3.1. Geometric Selectivity. Beyond the issue of product
selectivity, two issues of stereoselectivity exist in these allylic
alcohol isomerizations. The first is the geometrical selectivity
observed in the formation of allylic alcohol products. In all cases,
we observed moderate to high levels of E-selectivity. Minimiza-
tion of A1,3 interactions in the proposed chairlike transition
structure can account for this observed E-selectivity, similar to
results observed in the palladium(II)-catalyzed rearrangement
of tertiary allylic acetates.32 This explanation is supported by
the results obtained from isomerizations that form trisubstituted
alkenes. In the series 42a-c, the level of E-selectivity increased
with the steric demand of the substituents (Table 7). In addition,
our observation that the E-selectivity in the isomerizations of
44a,b increased upon either lowering the reaction temperature
or adding BSA and TMSA suggests that the E-alkene is the
kinetic product of these reactions (Table 8). Silylation would
effectively remove the initial product from the reaction equi-
librium, preventing further isomerization as well as possible
erosion of E/Z selectivity.
Our observation that electron-withdrawing groups seem to
suppress undesired side processes, as well as decrease the overall
reaction rate, supports the involvement of the two similar
pathways for consumption of the allylic alcohol as suggested
in section 4.1. The pathway leading to the desired products likely
involves an asynchronous [3,3]-rearrangement through polarized
transition structure vii. Electron-withdrawing groups will dis-
favor the buildup of positive charge on the allyl fragment of
vii and thus slow the reaction. The pathway generating the
elimination, condensation, and racemization products, on the
other hand, likely involves an ionized intermediate such as ix.
Electron-donating groups will stabilize this allyl cation, favoring
its formation and therefore increasing the generation of undesired
products. The partitioning of rhennate esters between these two
pathways clearly depends on the electronic nature of the allylic
alcohol.
This analysis, which centers around the proposed chairlike
transition structure vii, also serves to explain why both E- and
Z-alkene-containing allylic alcohols yield the corresponding
E-products after isomerization (Scheme 8). In the transition
structures leading to Z-63 vs E-63, a greater number of diaxial
interactions must always be tolerated in the former. In the case
of E-62, the transition structure leading to E-63 (vii) has no
diaxial interactions, whereas that leading to Z-63 (x) has one.
In the case of Z-62, the transition structure leading to E-63 (xi)
has a single diaxial interaction, whereas that leading to Z-63
(xii) has two.
4.3.2. Chirality Transfer. The use of enantioenriched
substrates in these isomerization reactions allows the efficiency
of chirality transfer with O3ReOSiPh3 to be examined. This is
the second issue of selectivity in these reactions and provides
further insights into the mechanism of the process. In the
A reactivity trend based on the degree of alkene substitution
in the allyl system also exists. In the series 14, 26, and 50, the
reaction temperature required to maintain high product selectiv-
ity decreased as the degree of alkene substitution increased
(Table 3, entries 1 and 9, and Table 10, entry 1). The reaction
of 26 proceeded cleanly at 0 °C, whereas those of more
substituted substrates 14 and 50 required temperatures of -50
°C or lower. The degree of alkene substitution also affected
the reactivity of cyanohydrins 40a-c (Table 5). Although the
reaction of 40c was complete in <5 min at 23 °C, less-
substituted substrates 40a,b did not react at 23 °C. This trend
can be rationalized in a manner similar to that just presented.
As the degree of alkene substitution increases, so does the ability
(31) (a) Ishihara, K.; Furuya, Y.; Yamamoto, H. Angew. Chem., Int. Ed.
2002, 41, 2983-2986. (b) Kusama, H.; Yamashita, Y.; Uchiyama, K.;
Narasaka, K. Bull. Chem. Soc. Jpn. 1997, 70, 965-975. (c) Kusama, H.;
Yamashita, Y.; Narasaka, K. Bull. Chem. Soc. Jpn. 1995, 68, 373-377.
(d) Klass, M. R.; Warwel, S. Fett. Wissen. Technol. 1995, 97, 250-252.
(32) Tamaru, Y.; Yamada, Y.; Ochiai, H.; Nakajo, E.; Yoshida, Z.
Tetrahedron 1984, 40, 1791-1793.
7822 J. Org. Chem., Vol. 71, No. 20, 2006

Rhenium-Catalyzed Isomerization of Allylic Alcohols
SCHEME 9. Pathways for Chirality Transfer and
Racemization
Comparing trifluoromethyl-substituted alcohols (R,E)-20 and
(R,E)-52, we found that significant loss of enantiopurity only
occurred upon isomerization with (R,E)-52 (compare Table 9,
entry 4, and Table 10, entry 2). To obtain comparable levels of
chirality transfer for tertiary and secondary alcohols, more
strongly electron-withdrawing substituents are required on the
former. For example, the addition of a second trifluoromethyl
substituent led to efficient chirality transfer (Table 10, entry
3). This observation is consistent with the idea that electron-
withdrawing substituents disfavor an ionization-recombination
pathway, whereas increased alkene substitution has the opposite
effect.
The direct attachment of an electron-withdrawing substituent
to the allylic system promoted even more efficient chirality
transfer (Table 10, entry 4). This observation is surprising
because a single cyano group (σ ) 0.70) is a less potent electron-
withdrawing substituent when compared to two trifluoromethyl
groups (σtotal ) 1.02). However, the smaller conjugated system
generated upon ionization of (R,E)-56 compared to that of (R,Z)-
54 would be less effective for stabilizing a cationic intermediate.
This result again supports the idea that factors which destabilize
an allyl cation intermediate will positively affect the level of
chirality transfer.
proposed chairlike transition structure, the E- and Z-isomers of
a single enantiomer of an allylic alcohol will generate enantio-
meric, E-alkene-containing products (Scheme 8). Competing
transition structures leading to the Z-alkene-containing products
would generate the epimeric alcohols, but Z-alkene-containing
products are typically not observed in these isomerizations. We
therefore took both the enantiopurity and the geometrical purity
of the starting materials into account when predicting the
enantiopurity of the products (Tables 9 and 10).
Gajewski has pointed out that transfer of chirality in a
rearrangement, such as the Cope or Claisen rearrangement, is a
hallmark of a concerted process.33,34 If the major pathway for
these isomerizations is a cyclic transition structure, then what
is the source of the low level of chirality transfer that we have
observed with some substrates? The formation of elimination
and condensation side products seems to arise from a competi-
tive ionization-recombination mechanism. Ionization and rapid
rotation in the allyl cation prior to recombination could generate
a racemic allylic alcohol (Scheme 9). Racemization through
unselective attack of some oxygen-centered nucleophile, such
as triphenylsilanol or water, on the achiral allylic cation might
also be at play. Therefore, the degree of chirality transfer in
the isomerization of enantioenriched allylic alcohols provides
a unique window into the involvement of ionized intermediates
in these isomerization reactions.
4.4. Effect of Catalyst Structure on Product Selectivity
and Chirality Transfer. The partitioning of rhennate ester
intermediates between an asynchronous [3,3]-rearrangement and
an ionization-recombination pathway accounts for losses in
either type of selectivity: product selectivity or chirality transfer.
Although electron-withdrawing substituents can improve selec-
tivity, a nonsubstrate-dependent method would be preferable.
Because proposed transition structure vii is polarized toward
the rhenium group, increasing the electron density at rhenium
by varying its ligands should decrease this polarization and thus
disfavor the competing ionization-recombination pathway
responsible for the elimination, condensation, and racemization
processes. Therefore, we exchanged less-electron-withdrawing
imido groups for the oxo groups on O3ReOSiPh3 to form imido
complex 58.
Comparison of the isomerizations of 14 with O3ReOSiPh3
and with imido complex 58 confirms this analysis. Similar levels
of product selectivity and chirality transfer could be obtained
with both catalysts but at different temperatures. The reaction
catalyzed by 58 proceeds cleanly at 23 °C with a good level of
chirality transfer (Table 11, entry 1), and the O3ReOSiPh3-
catalyzed reaction only gives comparable results at -78 °C
(Table 9, entry 1). It is important to note that the reactions
involving imido complex 58 must not proceed through a [3,3]-
rearrangement similar to those involving oxo complex 1. Instead,
a less-favorable [1,3]-shift may be occurring, in analogy to that
proposed to be operative in the methyl trioxorhenium (MTO)-
catalyzed isomerization of allylic alcohols.17a,21
The relationship between the efficiency of chirality transfer
and the electronic nature of the enantioenriched allylic alcohol
reflects the same trend that we observed in the context of product
selectivity. For example, in the series of isomerizations leading
to the formation of the secondary allylic alcohols (Table 9),
the degree of chirality transfer increases as the electron-
withdrawing capacity of the aryl substituent increases. This
observation supports the idea that a competing ionization-
recombination pathway is responsible for racemization of the
allylic alcohol. Unfortunately, it appears that lowering the
reaction temperature cannot always completely exclude race-
mization, even though it can completely suppress the elimination
and condensation pathways.
The formation of allylic amine products 60 and 61 also yields
some interesting mechanistic insights (Scheme 7). The favored
isomer is nonconjugated amine 60, which indicates that these
amines were likely not formed through an equilibrium process
in which an imido group was exchanged for an oxo group.
Studies by Osborn and co-workers on the isomerization of allylic
alcohols with mixed oxo/imido-molybdenum complexes have
shown that oxo-oxo transfer is favored over imido-oxo
interchange.17b Therefore, the attack of a free amine on either
the intermediate rhennate ester or an ionized intermediate seems
more reasonable, especially because the nonconjugated isomer
We observed the same electronic trend in reactions that
generated enantioenriched tertiary allylic alcohols (Table 10).
However, in these cases, the higher degree of alkene substitution
counterbalanced the effect of electron-withdrawing groups.
(33) (a) Gajewski, J. J. Acc. Chem. Res. 1980, 13, 142-148. (b) More
O’Ferrall, R. A. J. Chem. Soc. B 1970, 274-277.
(34) As pointed out in ref 33a, if the rate of collapse of the ion pair
within a solvent cage is faster than the rate of bond rotation in the allylic
cation, chirality transfer will be observed just as in the case of the cyclic
transition structure. Therefore, a mechanism involving an extremely short-
lived ion pair intermediate cannot be ruled out.
J. Org. Chem, Vol. 71, No. 20, 2006 7823

Morrill et al.
is favored. Overman has pointed out in his studies of the
palladium(II)-catalyzed rearrangement of allylic acetates that
the observation of such intermolecular trapping products sup-
ports the involvement of ionized intermediates.9a
The exact nature of the active intermediate in the isomeriza-
tions catalyzed by imido complex 58 remains unclear. The use
of isolated imido complex 58 does not yield similar results when
compared to the in situ generated complex. Consideration of
the differences between the reaction conditions with an isolated
vs an in situ generated imido complex reveals two differences:
the presence of silanol and the presence of silylamine. The
addition of triphenylsilanol to an isomerization catalyzed by the
isolated imido complex 58 does not lead to a recovery of
reactivity. However, the addition of TMSNHtBu does, suggest-
ing an important role for this reaction component. Additional
experiments will be required to fully elucidate the exact
mechanism of the reaction with the rhenium-imido complex
58.
4.5. Isomerizations of Nonconjugated Allylic Alcohols in
the Presence of BSA/TMSA. Obtaining high product selectivity
in these equilibrium reactions has been a major goal of this
work from its inception. The formation of an extended
conjugated system proved to be a valid method for obtaining
this goal. Preferential silylation of the less-hindered allylic
alcohol during the isomerization was a complementary method
for substrates devoid of conjugating substituents. Even though
it is established that BSA can silylate tertiary alcohols,35 our
results suggest that it silylates secondary and primary alcohols
faster. These results also suggest that isomerization with O3-
ReOSiPh3 is fast relative to silylation by BSA. Otherwise, we
would have observed lower conversions because silylation
would occur before equilibrium could be established in the
isomerization reaction.
Our observation that BSA alone is not responsible for the
high selectivities observed in these isomerizations does not
change the rationale behind the source of this product selectivity.
Instead, it raises some interesting questions about the nature of
the reactive intermediates. BSA is a nitrogen-centered Lewis
base, much like pyridine or diisopropylethylamine. Therefore,
it seems reasonable that BSA could also bind to O3ReOSiPh3
and inhibit its isomerization activity. The role of TMSA may
then be similar to that of TMSNHtBu in the reactions catalyzed
by rhenium-imido complex 58. The addition of TMSA could
generate the imido complex (CH3CON)3ReOTMS (66). Isomer-
izations with this less Lewis acidic imido complex may not be
inhibited by Lewis bases. Although this analysis seems reason-
able, the inability to prepare 66 through a method analogous to
58, and the fact that 58 in the presence of either BSA or
TMSNHtBu could not give similar results in the isomerization
of nonconjugated allylic alcohols, indicates that further studies
are required to completely understand the role of BSA and
TMSA in these isomerization reactions.
FIGURE 6. Comparison of mechanistically distinct [3,3]-rearrange-
ments.
isomerization of allylic esters or carbamates catalyzed by
palladium(II) or mercury(II). A thorough study of the scope and
limitations of this process has been conducted. High levels of
product selectivity, a significant challenge for these equilibrium
reactions, can be achieved in the formation of conjugated
primary, secondary, and tertiary allylic alcohols. The use of a
BSA/TMSA combination as a silylating reagent promotes high
product selectivity in the formation of nonconjugated primary
and secondary allylic alcohols. Reactions of enantioenriched
allylic alcohols have shown that chirality transfer can be quite
efficient in the formation of conjugated secondary and tertiary
allylic alcohols. Consideration of the trends observed throughout
these studies leads to the conclusion that allylic alcohols bearing
functional groups that are capable of stabilizing a positive charge
(e.g., electron-donating groups, more substituted alkenes) will
be more reactive, but less selective, in this isomerization
reaction.
The relationship of this O3ReOSiPh3-catalyzed 1,3-isomer-
ization of allylic alcohols to other reactions within the family
of [1,3]-dioxa-Cope rearrangements becomes clear when they
are considered in the broader context of a More O’Ferrall-
Jencks Diagram (Figure 6).33 Cyclization-induced rearrange-
ments mediated by palladium(II) and mercury(II) show signifi-
cant carbon-oxygen bond formation prior to carbon-oxygen
bond cleavage and therefore lie in the lower right-hand quadrant
(i). Thermal rearrangements are synchronous processes and lie
in the middle of the diagram (xiii).7b Brønsted acid catalyzed
rearrangements proceed through an ionization-recombination
pathway and show significant carbon-oxygen bond cleavage
prior to carbon-oxygen bond formation. They lie in the upper
left-hand quadrant (xiv). The proposed cyclic transition structure
in this O3ReOSiPh3-catalyzed 1,3-isomerization (vii) occupies
a unique position within this scheme where carbon-oxygen
bond cleavage precedes significant carbon-oxygen bond forma-
tion. However, unlike Brønsted acid catalyzed rearrangements,
ionization is not required for these reactions to proceed.
Therefore, the properties of a synchronous [3,3]-rearrangement
5. Conclusions
The [1,3]-dioxa-Cope rearrangement converts one allylic ester
into its 1,3-isomer in a straightforward manner. The O3-
ReOSiPh3-catalyzed process described in this work promotes
the corresponding isomerization of allylic alcohols, making it
a potentially more atom-economical route relative to the
(35) Sasaki, T.; Nakanishi, A.; Ohno, M. J. Org. Chem. 1982, 47,
3219-3224.
7824 J. Org. Chem., Vol. 71, No. 20, 2006

Rhenium-Catalyzed Isomerization of Allylic Alcohols
added 20 µL of triethylamine, and let it stir until it was warmed to
room temperature. The solution was concentrated in vacuo and
purified directly via silica gel chromatography (8:2 pentane/ether)
process are manifest in this O3ReOSiPh3-catalyzed 1,3-isomer-
ization of allylic alcohols despite its mechanistic differences.
1
to obtain 112.9 mg of 21 as an oil (99% yield). H NMR (300
Experimental Section
MHz, CDCl3, ppm): δ 7.57 (2H, d, J ) 8.4 Hz), 7.47 (2H, d, J )
8.4 Hz), 6.62 (1H, d, J ) 15.9 Hz), 6.33 (1H, dd, J ) 15.9, 6.0
Hz), 4.32 (1H, dt, J ) 6.2, 6.2 Hz), 1.79 (1H, br), 1.65 (2H, m),
1.35 (8H, m), 0.90 (3H, t, J ) 7.1 Hz). 13C NMR (75.4 MHz,
CDCl3, ppm): δ 140.5 (d, J ) 5.4 Hz), 135.5, 129.6 (q, J ) 129
Hz), 128.8, 126.8, 125.7 (q, J ) 15.4 Hz), 124.4 (q, J ) 108.1
Hz), 72.9, 37.6, 32.0, 29.4, 25.6, 22.8, 14.3. HRMS (EI) calcd for
C16H21F3O: 286.1544. Found: 286.1537. Enantiomeric excess
determined to be 95% by chiral HPLC (OD-H column, 1% i-PrOH
in hexanes, 1 mL/min). [R]D ) -7.7 (24 °C, CHCl3, c ) 1.0).
Representative Procedure for Chirality Transfer to Prepare
Enantioenriched Tertiary Allylic Alcohols: (E,R)-4-Hydroxy-
4,8-dimethyl-nona-2,7-diene Nitrile ((R,E)-57). In a glovebox was
added 1 (7 mg, 0.014 mmol) to a 4 mL vial. The solution was
removed from the glovebox, and 3 mL of toluene was added
followed by (R,E)-56 (100 mg, 0.56 mmol). The reaction was
allowed to stir for 10 min at 23 °C prior to addition of 20 µL of
triethylamine. It was concentrated in vacuo and purified directly
via silica gel chromatography (6:4 hexane/ether) to obtain 95 mg
of (R,E)-56 as a clear oil (95% yield). 1H NMR (300 MHz, C6D6,
ppm): δ 5.97 (1H, d, J ) 16.0 Hz), 5.17 (1H, d, J ) 16.0 Hz),
4.99 (1H, m), 1.71 (2H, m), 1.46 (3H, s), 1.12 (2H, m), 0.83 (1H,
s), 0.72 (3H, s). 13C NMR (75.4 MHz, C6D6, ppm): δ 160.45,
132.56, 124.56, 118.04, 98.09, 73.35, 41.82, 27.80, 26.11, 23.04,
18.04. HRMS (EI) calcd for C11H17NO: 179.1307. Found: 179.1310.
IR (thin film): 3468, 2970, 2927, 2225, 1632, 1451, 1376, 1251,
1195, 1124. Enantiomeric excess determined to be 91.8% by chiral
HPLC (OB column, 5% i-PrOH in hexanes, 1 mL/min, 220 nm).
[R]D ) 3.9 (20 °C, EtOH, c ) 1.1).
Experimental procedures and characterization data for novel
compounds are provided in the Supporting Information. Experi-
mental procedures and characterization data for compounds 14, 15,
18a, 19a, 22a, 23a, 24-31, 36b, 37b, 42a-c, and 44a were given
in a previous communication.6
Representative Procedure for Isomerization of Allylic Alco-
hols without Conjugating Substituents: (E)-3-Cyclohexylbut-
2-en-1-ol (43a). In a glovebox, 6.6 mg of 1 (0.0125 mmol) was
added to a two-necked, 25 mL round-bottom flask fitted with a
septum and stopcock adapter. The flask was then removed from
the glovebox, and 20 mg of N-trimethylsilyl-acetamide (0.125
mmol) and 4 mL of Et2O were added to it. The solution was stirred
for 10 min at 0 °C prior to addition of 140 µL of N,O-bis-
(trimethylsilyl)-acetamide36 (0.64 mmol) followed by 100 mg of
42a (0.64 mmol). The reaction quickly turned from yellow to deep
purple, and it was allowed to stir at 0 °C for 30 min prior to addition
of 40 µL of triethylamine. Removed the ice bath and allowed the
solution to stir at room temperature for approximately 10 min before
concentration. The residue was then dissolved in 5 mL of MeOH,
and 220 mg of K2CO3 (0.8 mmol) was added. The suspension was
stirred vigorously for 1 h prior to addition of 10 mL of aqueous
NH4Cl solution, extraction with CH2Cl2 (2 × 25 mL), and drying
over Na2SO4. The residue was purified via silica gel chromatog-
raphy (8:2 hexane/ether) to yield 84 mg of 43a as a clear oil (84%
yield). NMR spectral data agreed with that previously reported in
the literature.2 1H NMR (300 MHz, CDCl3, ppm): δ 5.38 (1H, t, J
) 6.8 Hz), 4.15 (2H, d, J ) 6.6 Hz), 1.7 (7H, m), 1.64 (3H, s), 1.2
(5H, m). 13C NMR (300 MHz, CDCl3, ppm): δ 144.9, 121.7, 59.6,
47.3, 31.9, 26.8, 26.5, 14.8. HRMS (EI) calcd. for C10H18O:
154.1358. Found: 154.1352.
Acknowledgment. The authors thank the National Institutes
of Health for financial support, Prof. Donald R. Deardorff and
Jeffery Cannon at Occidental College for assistance with
oxynitrilase reactions, and Prof. Dan O’Leary of Pomona
College for assistance with NOESY spectra.
Representative Procedure for Chirality Transfer to Prepare
Enantioenriched Secondary Allylic Alcohols: (E)-1-(4-(Trif-
luoromethyl)phenyl)non-1-en-3-ol (21). In a glovebox, added 1
(6 mg, 0.012 mmol) to a 4 mL vial. The solution was removed
from the glovebox. Ether was added (2 mL), and the solution was
placed in a Cryotrol bath set to -50 °C and stirred for ap-
proximately 10 min. 20 (114.3 mg, 0.4 mmol) was added via syringe
and stirred at -50 °C for 1 h. Removed from Cryotrol, immediately
Supporting Information Available: Experimental procedures,
compound characterization data, and 1H and 13C NMR spectra are
provided for new compounds (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
(36) BSA was distilled by a short path at 70 °C/35 mmHg prior to use.
JO061436L
J. Org. Chem, Vol. 71, No. 20, 2006 7825