A versatile new catalyst for the enantioselective isomerization of allylic alcohols to aldehydes: Scope and mechanistic studies

Article abstract of DOI:10.1021/jo010792v

A new planar-chiral bidentate phosphaferrocene ligand (2) has been synthesized and structurally characterized. The derived rhodium complex, [Rh(cod)(2)]BF₄, serves as an effective catalyst for asymmetric isomerizations of allylic alcohols to aldehydes, furnishing improved yields, scope, and enantioselectivities relative to previously reported methods. The catalyst is air-stable and can be recovered at the end of the reaction. Mechanistic studies establish that the isomerization proceeds via an intramolecular 1,3-hydrogen migration and that the catalyst differentiates between the enantiotopic C1 hydrogens.

Full text of DOI:10.1021/jo010792v

J . Org. Chem. 2001, 66, 8177-8186
8177
A Ver sa tile New Ca ta lyst for th e En a n tioselective Isom er iza tion of
Allylic Alcoh ols to Ald eh yd es: Scop e a n d Mech a n istic Stu d ies
Ken Tanaka and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
gcf@mit.edu
Received August 6, 2001
A new planar-chiral bidentate phosphaferrocene ligand (2) has been synthesized and structurally
characterized. The derived rhodium complex, [Rh(cod)(2)]BF4, serves as an effective catalyst for
asymmetric isomerizations of allylic alcohols to aldehydes, furnishing improved yields, scope, and
enantioselectivities relative to previously reported methods. The catalyst is air-stable and can be
recovered at the end of the reaction. Mechanistic studies establish that the isomerization proceeds
via an intramolecular 1,3-hydrogen migration and that the catalyst differentiates between the
enantiotopic C1 hydrogens.
In tr od u ction
The catalytic enantioselective isomerization of olefins
(e.g., allylic amines,1 allylic ethers,2 and unfunctionalized
alkenes3,4) has been the subject of a number of investiga-
tions. Indeed, one of the landmark accomplishments in
asymmetric catalysis is the industrial-scale application
of a Rh+/BINAP-catalyzed isomerization of geranylamine
to produce (-)-menthol and related terpenes (eq 1).5
In contrast to the remarkable progress that has been
achieved for reactions of allylic amines, comparable
success has not been realized for the corresponding
asymmetric isomerizations of readily available allylic
alcohols (eq 2), due in part to difficulty in effecting
catalysis of even the nonasymmetric reaction.6 At the
time that we initiated our studies of this process, the best
enantioselectivity that had been reported was 53% ee (eq
2; 47% yield).7,8
(1) (a) Kumobayashi, H.; Akutagawa, S.; Otsuka, S. J . Am. Chem.
Soc. 1978, 100, 3949-3950. (b) Tani, K.; Yamagata, T.; Otsuka, S.;
Akutagawa, S.; Kumobayashi, H.; Taketomi, T.; Takaya, H.; Miyashita,
A.; Noyori, R. J . Chem. Soc., Chem. Commun. 1982, 600-601. (c) Tani,
K.; Yamagata, T.; Akutagawa, S.; Kumobayashi, H.; Taketomi, T.;
Takaya, H.; Miyashita, A.; Noyori, R.; Otsuka, S. J . Am. Chem. Soc.
1984, 106, 5208-5217. (d) Tani, K.; Yamagata, T.; Tatsuno, Y.;
Yamagata, Y.; Tomita, K.-I.; Akutagawa, S.; Kumobayashi, H.; Otsuka,
S. Angew. Chem., Int. Ed. Engl. 1985, 24, 217-219. (e) For an overview,
see Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New
York, 1994; Chapter 3. Akutagawa, S.; Tani, K. In Catalytic Asym-
metric Synthesis; Ojima, I., Ed.; Wiley-VCH: New York, 2000; Chapter
3.
(2) (a) Frauenrath, H.; Philipps, T. Angew. Chem., Int. Ed. Engl.
1986, 25, 274. (b) Frauenrath, H.; Kaulard, M. Synlett 1994, 517-
518. (c) Hiroya, K.; Kurihara, Y.; Ogasawara, K. Angew. Chem., Int.
Ed. Engl. 1995, 34, 2287-2289. (d) Hiroya, K.; Ogasawara, K. J . Chem.
Soc., Chem. Commun. 1995, 2205-2206. (e) Kamikubo, T.; Hiroya, K.;
Ogasawara, K. Tetrahedron Lett. 1996, 37, 499-502. (f) Frauenrath,
H.; Reim, S.; Wiesner, A. Tetrahedron: Asymmetry 1998, 9, 1103-
1106. (g) Brunner, H.; Prommesberger, M. Tetrahedron: Asymmetry
1998, 9, 3231-3239. (h) Faitg, T.; Soulie´, J .; Lallemand, J .-Y.; Mercier,
F.; Mathey, F. Tetrahedron 2000, 56, 101-104. (i) Frauenrath, H.;
Brethauer, D.; Reim, S.; Maurer, M.; Raabe, G. Angew. Chem., Int.
Ed. 2001, 40, 177-179.
(3) (a) Carlini, C.; Politi, D.; Ciardelli, F. J . Chem. Soc., Chem.
Commun. 1970, 1260-1261. (b) Giacomelli, G.; Bertero, L.; Lardicci,
L.; Menicagli, R. J . Org. Chem. 1981, 46, 3707-3711. (c) Chen, Z.;
Halterman, R. L. J . Am. Chem. Soc. 1992, 114, 2276-2277. (d)
Halterman, R. L.; Chen, Z.; Khan, M. A. Organometallics 1996, 15,
3957-3967.
(4) For a general review, see: Akutagawa, S. In Comprehensive
Asymmetric Catalysis; J acobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: New York, 1999; Chapter 23.
Several years ago, we decided to pursue the possibility
that, because ligands that are based on planar-chiral
aromatic heterocycles possess novel structural and bond-
ing features9 relative to more conventional ligands such
(6) For a discussion of difficulties encountered in catalyzing the
isomerization of allylic alcohols to aldehydes, see: Bianchini, C.; Meli,
A.; Oberhauser, W. New J . Chem. 2001, 25, 11-12 and references
therein.
(7) (a) Tani, K. Pure Appl. Chem. 1985, 57, 1845-1854. (b) Otsuka,
S.; Tani, K. Synthesis 1991, 665-680.
(8) See also: (a) Botteghi, C.; Giacomelli, G. Gazz. Chim. Ital. 1976,
106, 1131-1134. (b) Kitamura, M.; Manabe, K.; Noyori, R.; Takaya,
H. Tetrahedron Lett. 1987, 28, 4719-4720. (c) Bergens, S. H.; Bosnich,
B. J . Am. Chem. Soc. 1991, 113, 958-967. (d) Reference 2c. (e) Wiles,
J . A.; Lee, C. E.; McDonald, R.; Bergens, S. H. Organometallics 1996,
15, 3782-3784.
(5) Takasago International Corp. manufactures thousands of tons
per year of (-)-menthol and related terpenes through the Rh+/BINAP-
catalyzed enantioselective isomerization of allylic amines: (a) Akuta-
gawa, S. In Chirality in Industry; Collins, A. N., Sheldrake, G. N.,
Crosby, J ., Eds.; Wiley: New York, 1992. (b) Akutagawa, S. In
Comprehensive Asymmetric Catalysis; J acobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: New York, 1999; Chapter 41.4.
10.1021/jo010792v CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/26/2001

8178 J . Org. Chem., Vol. 66, No. 24, 2001
Tanaka and Fu
Ta ble 1. Op tim iza tion of En a n tioselectivity
as tertiary phosphines and amines, they might provide
distinctive reactivity and stereoselection.10-12 As part of
this program, we reported last year that planar-chiral
phosphaferrocene 1 furnishes the highest enantioselec-
tivity described to date for the catalytic asymmetric
isomerization of allylic alcohols to aldehydes (eq 3; 64-
86% ee, 55-91% yield; all Z olefins, with one exception).13
a
Prepared in situ from [Rh(cod)2]BF4, ligand, and H2 (1 atm)
in THF. b Prepared in situ from [Rh(cod)((+)-2)]BF4 and H2 (1 atm)
in THF.
Ca ta lytic En a n tioselective Isom er iza tion s. With
new planar-chiral phosphaferrocene ligand 2 in hand, we
turned our attention to the rhodium-catalyzed asym-
metric isomerization of a representative test substrate,
allylic alcohol 4 (Table 1). As reported earlier, we obtain
aldehyde in 78% ee when we employ ligand 1 in this
process (entry 1).13 We were pleased to discover that,
under the same conditions, di(o-tolyl) phosphine 2 fur-
nishes both improved yield and stereoselection (entry 2).
Until this point, we had been employing Rh/cod (cod
) cyclooctadienyl) complexes as precatalysts, which we
treated with hydrogen to reduce the cod.16 We have
determined that we can simplify this experimental
procedure through the direct use of [Rh(cod)((+)-2)]BF4,
an air-stable crystalline solid, as the catalyst; at 100 °C,
this complex effects isomerization without the need to
hydrogenate the remaining cod. As shown in entry 3 of
Table 1, [Rh(cod)((+)-2)]BF4 is not only more convenient
to use, but also is more enantioselective.17
In this article, we provide the synthesis of a new
planar-chiral phosphaferrocene, di(o-tolyl) phosphine 2,
that is markedly more robust than 1 and that affords
significantly improved scope, enantioselectivity, and yield
in rhodium-catalyzed asymmetric isomerizations of allylic
alcohols. Furthermore, we describe mechanistic studies
that furnish useful insight into the reaction pathway.
Resu lts a n d Discu ssion
Syn th esis of P h osp h a fer r ocen e Liga n d 2. As il-
lustrated in eq 4, it is straightforward to vary the
structure of the tertiary phosphine portion of these
bidentate phosphaferrocene-based ligands. Thus, di(o-
tolyl) phosphine (+)-2 is readily prepared from the
previously reported alcohol (+)-3.13,14 Relative to ligand
1, the more sterically encumbered 2 exhibits significantly
higher stability toward air (e.g., no decomposition during
flash chromatography15).
[Rh(cod)((+)-2)]BF4 has in fact proved to be an effective
catalyst for the asymmetric isomerization of a range of
allylic alcohols.18 Both the yields and the ee’s are higher
for E allylic alcohols (Table 2) than for the Z isomers
(Table 3).19 In contrast, for enantioselective isomeriza-
tions catalyzed by Rh/1, higher stereoselection is observed
for Z allylic alcohols.13
As shown in Table 2, [Rh(cod)((+)-2)]BF4-catalyzed
asymmetric isomerizations of E allylic alcohols proceed
in uniformly good yield. The enantiomeric excess is
dependent on the steric demand of the alkyl substituent;
unbranched groups (entries 1 and 2) furnish lower
selectivities than does a branched group, which provides
excellent ee (entries 3-6). On the other hand, the
stereoselection appears to be independent of the steric
demand (entries 3 and 4), as well as the electronic nature
(entries 3, 5, and 6), of the aromatic substituent.
As for E allylic alcohols (Table 2), the enantioselectivity
for [Rh(cod)((+)-2)]BF4-catalyzed isomerizations of Z
allylic alcohols is dependent on the steric demand of the
alkyl group (Table 3, entries 1-4),20 but not the aromatic
group (entries 3 and 5). However, in contrast to E allylic
alcohols, for Z allylic alcohols the electronic nature of the
aromatic substituent appears to have a modest impact
(9) For leading references, see: (a) Deschamps, B.; Ricard, L.;
Mathey, F. J . Organomet. Chem. 1997, 548, 17-22. (b) Deschamps,
B.; Ricard, L.; Mathey, F. J . Organomet. Chem. 1997, 548, 17-22.
(10) For our studies of phosphorus-based heterocycles, see: (a) Qiao,
S.; Fu, G. C. J . Org. Chem. 1998, 63, 4168-4169. (b) Shintani, R.; Lo,
M. M.-C.; Fu, G. C. Org. Lett. 2000, 2, 3695-3697.
(11) Independently, Ganter has also been exploring applications of
planar-chiral phosphorus heterocycles in asymmetric catalysis: Ganter,
C.; Kaulen, C.; Englert, U. Organometallics 1999, 18, 5444-5446. See
also: Ganter, C.; Glinsbo¨ckel, C.; Ganter, B. Eur. J . Inorg. Chem. 1998,
1163-1168.
(12) For our studies of nitrogen-based heterocycles, see: (a) Dosa,
P. I.; Ruble, J . C.; Fu, G. C. J . Org. Chem. 1997, 62, 444-445. (b) Lo,
M. M.-C.; Fu, G. C. J . Am. Chem. Soc. 1998, 120, 10270-10271. (c)
Rios, R.; Liang, J .; Lo, M. M.-C.; Fu, G. C. Chem. Commun. 2000, 377-
378. (d) Lo, M. M.-C.; Fu, G. C. Tetrahedron 2001, 57, 2621-2634.
(13) Tanaka, K.; Qiao, S.; Tobisu, M.; Lo, M. M.-C.; Fu, G. C. J . Am.
Chem. Soc. 2000, 122, 9870-9871.
(14) Several other diaryl derivatives of 1, prepared similarly, were
less effective than ligand 2 in rhodium-catalyzed asymmetric isomer-
ization reactions (lower yields, lower enantioselectivities).
(15) In contrast, purification of parent diphenyl ligand 1 by flash
chromatography in the air leads to appreciable decomposition.
(16) See footnote 12 of reference 13.
(17) We have not been able to isolate [Rh(cod)((+)-1)]BF4 in pure
form.
(18) Under the same conditions, allylic methyl ethers and homo-
allylic alcohols do not undergo isomerization.
(19) At partial conversion, we see no evidence for E/Z isomerization
of either the E or the Z allylic alcohol.

Catalytic Enantioselective Isomerization
J . Org. Chem., Vol. 66, No. 24, 2001 8179
Ta ble 2. Ca ta lytic En a n tioselective Isom er iza tion of E
An aromatic group is not required to obtain enantio-
selectivity in this catalytic asymmetric isomerization
process. Thus, [Rh(cod)((+)-2)]BF4 cleanly converts the
illustrated cyclohexyl/methyl substituted allylic alcohols
to the desired aldehydes in good ee (eq 5).21,22
Allylic Alcoh ols to Ald eh yd es
P r a ctica l Issu es. For the isomerizations described
above (Table 2, Table 3, and eq 5), we chose to develop a
general protocol, rather than to individually optimize the
reaction conditions for each substrate (e.g., minimizing
the reaction temperature or the catalyst loading). To
demonstrate that the use of a lower catalyst loading is
possible, as well as to provide an example of a prepara-
tive-scale process, we carried out a 1 g isomerization of
allylic alcohol 4 with 1% [Rh(cod)((-)-2)]BF4 (eq 6).
a
Average of two runs (first run, new catalyst; second run,
catalyst recovered from the previous reaction); the values in
b
parentheses are for Rh/1. Isolated yields. c Reaction was carried
out at 150 °C.
It is worth noting that we can reuse the catalyst for
these enantioselective isomerizations. Thus, [Rh(cod)-
((-)-2)]BF4 can be crystallized directly from the reaction
mixture simply by adding pentane. For the isomerization
depicted in eq 6, this process affords 32 mg (68%) of [Rh-
(cod)((-)-2)]BF4,23 which furnishes 91% ee and 96% yield
in a subsequent isomerization of allylic alcohol 4. In fact,
most of the reactions illustrated in Tables 2 and 3 were
run once with recovered catalyst, with no erosion in
enantioselectivity or yield.24
Ta ble 3. Ca ta lytic En a n tioselective Isom er iza tion of Z
Allylic Alcoh ols to Ald eh yd es
Thus, relative to ligand 1, new planar-chiral phospha-
ferrocene ligand 2 provides a substantially more practical
and versatile catalyst for asymmetric isomerizations of
allylic alcohols. From the standpoints of yield and ee, the
advantage is particularly clear for E olefins (see Table
2).
Mech a n istic Stu d ies. With regard to the issue of
mechanism, Takaya and Noyori have proposed that the
Rh+/BINAP-catalyzed isomerizations of allylic amines
proceed through the pathway outlined in eq 7.25 We have
conducted related studies, which afford data that are
consistent with an analogous sequence of steps for the
[Rh(cod)(2)]BF4-catalyzed isomerization of allylic alco-
hols.26
Through the use of a 1,1-dideuterated allylic alcohol,
we have determined that our isomerizations follow a
a
Average of two runs (first run, new catalyst; second run,
catalyst recovered from the previous reaction, except for entry 6).
(21) Use of first-generation phosphaferrocene ligand
isomerization of the E allylic alcohol illustrated in eq 5 furnishes the
aldehyde in 57% ee and 83% yield.
1 for the
b
Isolated yields. c Reaction was carried out at 150 °C.
(22) Under these conditions, geraniol is isomerized in good yield
(91%) and modest enantioselectivity (52% ee). Previous to this work,
the best result that had been reported for geraniol was 37% ee and
70% yield (ref 7).
(23) For isomerizations that are run with 5% catalyst, we typically
recover >80% of the catalyst.
(24) For details, see the Experimental Section.
(25) Inoue, S.-I.; Takaya, H.; Tani, K.; Otsuka, S.; Sato, T.; Noyori,
R. J . Am. Chem. Soc. 1990, 112, In4897-4905.
(26) (a) For a study of rhodium-catalyzed isomerizations of allylic
alcohols to enols, see: ref 8c. (b) For a study of ruthenium-catalyzed
isomerizations of allylic alcohols to aldehydes, see: Trost, B. M.;
Kulawiec, R. J . J . Am. Chem. Soc. 1993, 115, 2027-2036.
on stereoselection (more electron-poor w higher ee;
entries 3, 6, and 7).
(20) New phosphaferrocene ligand 2 is much more effective than
ligand 1 for isomerizations of hindered substrates. For example, for
the allylic alcohol depicted in entry 4 of Table 3, ligand 2 provides an
88% yield of the desired product after 22 h at 100 °C, whereas ligand
1 furnishes a 12% yield after 48 h at 100 °C. Entry 4 of Table 2 affords
an additional example of greatly enhanced reactivity in the presence
of ligand 2, relative to ligand 1.

8180 J . Org. Chem., Vol. 66, No. 24, 2001
Tanaka and Fu
clean 1,3-migration pathway (eq 8).27 Furthermore, we
have established that the migration is an intramolecular
process; thus, treatment of a 1:1 mixture of 1,1-dideu-
terated allylic alcohol 5 and nondeuterated allylic alcohol
7 with [Rh(cod)((+)-2)]BF4 furnishes dideuterated 6 and
nondeuterated 8, with no monodeuterated aldehyde
detectable by high-resolution mass spectrometry (eq 9).
H/D’s during the C-H activation step is an important
element of the catalyst’s stereocontrol. The differing
ratios of D versus H migration for the two enantiomers
of the catalyst (87:13 in eq 12; 94:6 in eq 13) are due to
an H/D isotope effect that diminishes the enantiotopic-
group selectivity of the chiral catalyst in eq 12, but
amplifies it in eq 13.
For the [Rh(cod)(2)]BF4-catalyzed enantioselective
isomerizations depicted in Tables 2 and 3, the R,â-
unsaturated aldehyde, formed through oxidation of the
allylic alcohol, is the major sideproduct (e.g., eq 10). The
pathway outlined in eq 7 readily accounts for the genera-
tion of this compound.
To determine if the unbound R,â-unsaturated aldehyde
is an important intermediate on the route to formation
of the desired saturated aldehyde, we carried out the
reaction illustrated in eq 11. If a significant portion of
the desired product is formed through dissociation/
reassociation of the R,â-unsaturated aldehyde, then
under these conditions a substantial fraction of 9 should
be converted to 11. The small amount of 11 that is
generated, along with its low enantiomeric excess, indi-
cates that the free R,â-unsaturated aldehyde is not a
critical intermediate in our isomerization processes.28
To gain insight into the origin of the stereoselectivity,
we examined the asymmetric isomerization of allylic
alcohol (S)-12 (95% ee) by each enantiomer of the catalyst
(eqs 12 and 13). With (+)-2, the deuterium of (S)-12
migrates preferentially to generate (S)-13 in high ee; with
(-)-2, the hydrogen of (S)-12 migrates predominantly to
furnish (R)-14 with excellent stereoselection. These data
establish that differentiation between the enantiotopic
Con clu sion s
In summary, we have synthesized a new planar-chiral
bidentate phosphaferrocene ligand (2), and we have
applied it to rhodium-catalyzed asymmetric isomeriza-
tions of allylic alcohols to aldehydes. In terms of yield,
scope, and enantioselectivity, this ligand is significantly
more effective than phosphaferrocene 1, which provides
the basis for the only other reasonably general and
stereoselective method for accomplishing this useful
transformation. The isomerization catalyst derived from
ligand 2, [Rh(cod)(2)]BF4, is air-stable and can readily
be recovered from the reaction and reused. Mechanistic
work has established that these asymmetric isomeriza-
tions proceed through an intramolecular 1,3-hydrogen
migration pathway and that the chiral catalyst prefer-
entially activates one of the enantiotopic C1 hydrogens.
Exp er im en ta l Section
(27) The ee of the product (76%) is essentially identical to that
observed for the nondeuterated compound (75% ee; Table 3, entry 1).
(28) The result of the crossover experiment illustrated in eq 9 is
consistent with this conclusion.
Gen er a l. 31P NMR spectra were recorded with complete
proton decoupling on a Varian Mercury 300 spectrometer (121
MHz) at ambient temperature and are referenced to external

Catalytic Enantioselective Isomerization
J . Org. Chem., Vol. 66, No. 24, 2001 8181
85% H3PO4 (δ 0). 19F NMR spectra were recorded on a Varian
Mercury 300 spectrometer (282 MHz) at ambient temperature
and are referenced to external CCl3F (δ 0).
(dt, J ) 1.2 and 6.9 Hz, 1H), 3.96 (dd, J ) 0.6 and 6.9 Hz,
2H), 2.60 (heptet, J ) 6.6 Hz, 1H), 1.04 (d, J ) 6.6 Hz, 6H).
13C NMR (CDCl3) δ: 151.1, 140.3, 128.7, 128.1, 127.0, 123.3,
60.8, 36.0, 21.9. HRMS (EI): calcd for C12H16O (M+), 176.1201;
found, 176.1198.
Analytical chiral GC was performed on either a Chiraldex
G-TA column (20 m × 0.25 mm) or a Chiraldex B-PH column
(20 m × 0.25 mm).
(Z)- a n d (E)-4-Meth yl-3-(4-m eth ylp h en yl)-2-p en ten -1-
ol. These were prepared from 4′-methylisobutyrophenone36 by
the same procedure described for (Z)- and (E)-4-methyl-3-
phenyl-2-penten-1-ol. The configurations of (Z)- and (E)-4-
methyl-3-(4-methylphenyl)-2-penten-1-ol were assigned by
THF and Et2O were distilled from sodium benzophenone
ketyl. CH2Cl2 was distilled from CaH2. Hexanes were distilled
from sodium. Grade V hydrogen (Boc Gases) and 4 Å molecular
sieves (Fluka) were used as received.
[Rh(cod)2]BF4,29 (+)- and (-)-3,30 phosphaferrocene (+)-1,30
and (o-tol)2PH31 were prepared according to literature proce-
dures.
1
analogy with the H NMR spectra of (Z)- and (E)-4-methyl-3-
phenyl-2-penten-1-ol.
Z isomer. Colorless oil. FTIR (neat): 3355, 2959, 1608, 1510,
(Z)- and (E)-3-phenyl-2-buten-1-ol32 were prepared according
to literature procedures, and the olefin configuration was
confirmed by NOE experiments.
1
1464, 1286, 1245, 1178, 1033, 984 cm-1. H NMR (CDCl3) δ:
7.12-7.15 (m, 2H), 6.95-6.99 (m, 2H), 5.63 (dt, J ) 1.2 and
6.9 Hz, 1H), 3.97 (d, J ) 6.9 Hz, 2H), 2.58 (m, 1H), 2.35 (s,
3H), 1.03 (d, J ) 6.9 Hz, 6H). 13C NMR (CDCl3) δ: 151.0, 137.4,
136.7, 128.9, 128.6, 123.2, 60.7, 35.9, 21.8, 21.4. HRMS (EI):
calcd for C13H18O (M+), 190.1358; found, 190.1355.
(Z)- and (E)-phenyl-2-penten-1-ol33 and (E)-3-cyclohexyl-2-
buten-1-ol34 were prepared according to literature procedures.
All reactions were carried out under an atmosphere of
nitrogen or argon in oven-dried glassware with magnetic
stirring, unless otherwise indicated.
E isomer. Colorless oil. FTIR (neat): 3316, 2963, 2927, 2871,
1
2362, 1510, 1456, 1362, 1022, 816 cm-1. H NMR (CDCl3) δ:
(Z)- a n d (E)-4-Meth yl-3-p h en yl-2-p en ten -1-ol. n-BuLi
(31 mL, 50 mmol; 1.6 M in hexane) was added to a stirred
solution of triethylphosphonoacetate (11.2 g, 50.0 mmol) in
hexanes (50 mL) at 0 °C, and the resulting mixture was stirred
for 0.5 h at 0 °C. Isobutyrophenone (7.4 g, 50 mmol) was added,
and the reaction was refluxed for 3 h. The mixture was then
cooled to room temperature, quenched by the addition of
saturated aqueous Na2CO3, and extracted with Et2O. The
organic layer was washed with water, dried over Na2SO4, and
concentrated. The resulting residue was purified by flash
chromatography (hexanes:EtOAc ) 20:1) to give ethyl (E)-4-
methyl-3-phenyl-2-pentenoate35 (first fraction: 3.8 g, 17 mmol,
34%) and ethyl (Z)-4-methyl-3-phenyl-2-pentenoate35 (second
fraction: 2.5 g, 12 mmol, 23%) as colorless oils (not optimized).
Ethyl (E)-4-methyl-3-phenyl-2-pentenoate (200 mg, 0.916
mmol) in Et2O (2 mL) was added to a stirred mixture of LiAlH4
(38 mg, 1.0 mmol) in Et2O (5 mL) at 0 °C. The reaction was
stirred for 10 min at 0 °C and then quenched at 0 °C with
H2O (0.1 mL). After stirring for 10 min at room temperature,
the mixture was dried over MgSO4, filtered through Celite,
and concentrated. The resulting residue was purified by flash
chromatography (hexanes:Et2O ) 5:2) to give (E)-4-methyl-3-
phenyl-2-penten-1-ol (142 mg, 0.806 mmol, 88%) as a colorless
oil. The configuration of (E)-4-methyl-3-phenyl-2-penten-1-ol
was confirmed by an NOE experiment.
FTIR (neat): 3320, 2963, 2929, 2872, 1492, 1464, 1442,
1362, 1087, 1012 cm-1. 1H NMR (CDCl3) δ: 7.17-7.34 (m, 5H),
5.50 (t, J ) 6.9 Hz, 1H), 4.38 (d, J ) 6.9 Hz, 2H), 3.05 (heptet,
J ) 6.9 Hz, 1H), 1.07 (d, J ) 6.9 Hz, 6H). 13C NMR (CDCl3) δ:
150.1, 142.3, 128.5, 127.7, 127.4, 126.7, 59.2, 30.0, 22.3. HRMS
(EI): calcd for C12H16O (M+), 176.1201; found, 176.1197.
Ethyl (Z)-4-methyl-3-phenyl-2-pentenoate (215 mg, 0.985
mmol) was treated with LiAlH4 (40 mg, 1.0 mmol) as described
above to give (Z)-4-methyl-3-phenyl-2-penten-1-ol (147 mg,
0.837 mmol, 85%) as a colorless oil. The configuration of (Z)-
4-methyl-3-phenyl-2-penten-1-ol was confirmed by an NOE
experiment.
7.06-7.12 (m, 4H), 5.48 (t, J ) 6.6 Hz, 1H), 4.36 (d, J ) 6.6
Hz, 2H), 3.03 (heptet, J ) 6.9 Hz, 1H), 2.35 (s, 3H), 1.06 (d, J
) 6.9 Hz, 6H). 13C NMR (CDCl3) δ: 150.1, 139.5, 136.4, 128.6,
128.5, 127.3, 59.2, 30.0, 22.2, 21.3. HRMS (EI): calcd for
C
13H18O (M+), 190.1358; found, 190.1353.
(Z)- a n d (E)-4-Meth yl-3-(4-ch lor op h en yl)-2-p en ten -1-ol.
These were prepared starting from 4′-chloroisobutyrophenone36
by the same procedure described for (Z)- and (E)-4-methyl-3-
phenyl-2-penten-1-ol. The configurations of (Z)- and (E)-4-
methyl-3-(4-chlorophenyl)-2-penten-1-ol were assigned by anal-
ogy with the 1H NMR spectra of (Z)- and (E)-4-methyl-3-
phenyl-2-penten-1-ol.
Z isomer. Colorless oil. FTIR (neat): 3314, 2962, 2872, 1651,
1593, 1489, 1466, 1384, 1361, 1305, 1241, 1090, 1030, 1014,
1
985 cm-1. H NMR (CDCl3) δ: 7.27-7.34 (m, 2H), 7.00-7.05
(m, 2H), 5.67 (dt, J ) 1.2 and 6.9 Hz, 1H), 3.96 (dd, J ) 0.9
and 6.6 Hz, 2H), 2.57 (heptet, J ) 6.9 Hz, 1H), 1.04 (d, J )
6.9 Hz, 6H). 13C NMR (CDCl3) δ: 149.8, 138.6, 132.9, 130.0,
128.3, 123.8, 60.5, 35.9, 21.8. HRMS (EI): calcd for C12H15
-
ClO (M+), 210.0811; found, 210.0814.
E isomer. Colorless oil. FTIR (neat): 3334, 2963, 2362, 1646,
1
1592, 1488, 1464, 1363, 1090, 1015 cm-1. H NMR (CDCl3) δ:
7.25-7.29 (m, 2H), 7.09-7.13 (m, 2H), 5.47 (t, J ) 6.6 Hz, 1H),
4.37 (d, J ) 6.6 Hz, 2H), 3.02 (heptet, J ) 6.9 Hz, 1H), 1.05
(d, J ) 6.9 Hz, 6H). 13C NMR (CDCl3) δ: 148.9, 140.6, 132.7,
129.9, 128.0, 127.9, 59.1, 29.9, 22.2. HRMS (EI): calcd for
C
12H15ClO (M+), 210.0811; found, 210.0816.
(Z)- a n d (E)-4-Meth yl-3-(2-m eth ylp h en yl)-2-p en ten -1-
ol. These were prepared starting from 2′-methylisobutyrophe-
none37 by the same procedure described for (Z)- and (E)-4-
methyl-3-phenyl-2-penten-1-ol. The configurations of (Z)- and
(E)-4-methyl-3-(2-methylphenyl)-2-penten-1-ol were assigned
1
by analogy with the H NMR spectra of (Z)- and (E)-4-methyl-
3-phenyl-2-penten-1-ol.
Z isomer. Colorless oil. FTIR (neat): 3304, 2961, 1460, 1028,
985, 761, 732 cm-1 1H NMR (CDCl3) δ: 7.12-7.20 (m, 3H),
.
6.93-6.96 (m, 1H), 5.69 (dt, J ) 1.5 and 6.6 Hz, 1H), 3.83 (ddd,
J ) 0.9, 3.0, and 6.6 Hz, 2H), 2.45 (m, 1H), 2.19 (s, 3H), 1.09
(d, J ) 6.9 Hz, 3H), 1.05 (d, J ) 6.6 Hz, 3H). 13C NMR (CDCl3)
δ: 149.8, 140.1, 135.5, 130.0, 128.9, 127.0, 125.4, 123.2, 60.9,
35.7, 21.8, 21.5, 19.9. HRMS (EI): calcd for C13H18O (M+),
190.1352; found, 190.1348.
FTIR (neat): 3316, 3055, 2961, 2929, 2871, 1652, 1600,
1
1493, 1465, 1441, 1382, 1360, 1310, 1073, 1024, 985 cm-1. H
NMR (CDCl3) δ: 7.23-7.35 (m, 3H), 7.05-7.09 (m, 2H), 5.64
(29) Schenck, T. G.; Downes, J . M.; Milne, C. R. C.; Mackenzie, P.
B.; Boucher, H.; Whelan, J .; Bosnich, B. Inorg. Chem. 1985, 24, 2334-
2337.
(30) Qiao, S.; Fu, G. C. J . Org. Chem. 1998, 63, 4168-4169.
(31) Casey, C. P.; Paulsen, E. L.; Beuttenmueller, E. W.; Proft, B.
R.; Petrovich, L. M.; Matter, B. A.; Powell, D. R. J . Am. Chem. Soc.
1997, 119, 11817-11825.
(32) Carruthers, W.; Evans, N.; Pooranamoorthy, R. J . Chem. Soc.,
Perkin Trans. 1 1975, 76-79.
(33) Srikrishna, A.; Kumar, P. P. Tetrahedron Lett. 1995, 36, 6313-
6316.
E isomer. Colorless oil. FTIR (neat): 3322, 2962, 2871, 1648,
1
1487, 1461, 1380, 1361, 1101, 1011, 762, 732 cm-1. H NMR
(CDCl3) δ: 7.08-7.21 (m, 3H), 6.99-7.02 (m, 1H), 5.36 (t, J )
6.6 Hz, 1H), 4.39 (d, J ) 6.6 Hz, 2H), 3.03 (heptet, J ) 6.9 Hz,
1H), 2.26 (s, 3H), 1.00 (d, J ) 6.9 Hz, 6H). 13C NMR (CDCl3)
δ: 130.2, 129.4, 127.7, 126.7, 124.7, 59.2, 30.7, 22.1, 20.7.
HRMS (EI): calcd for C13H18O (M+), 190.1352; found, 190.1350.
(34) Bellucci, C.; Gualtieri, F.; Scapecchi, S.; Teodori, E.; Budriesi,
R.; Chiarini, A. Farmaco 1989, 44, 1167-1191.
(35) J alander, L.; Iambolieva, K.; Sundstro¨m, V. Acta Chem. Scand.
1980, B34, 715-720.
(36) Kher, S. M.; Kulkarni, G. H. Indian J . Chem., Sect. B 1989,
28, 675-676.
(37) Budhram, R. S.; Palaniswamy, V. A.; Eisenbraun, E. J . J . Org.
Chem. 1986, 51, 1402-1406.

8182 J . Org. Chem., Vol. 66, No. 24, 2001
Tanaka and Fu
(Z)-4,4-Dim eth yl-3-p h en yl-2-p en ten -1-ol. Ethyl (Z)-4,4-
dimethyl-3-phenyl-2-pentenoate35 (416 mg, 1.79 mmol) in Et2O
(2 mL) was added to a stirred mixture of LiAlH4 (68 mg, 1.8
mmol) in Et2O (10 mL) at 0 °C. The reaction was stirred for
10 min at 0 °C and then quenched at 0 °C with H2O (0.1 mL).
After stirring for 10 min at room temperature, the mixture
was dried over MgSO4, filtered through Celite, and concen-
trated. The resulting residue was purified by flash chroma-
tography (hexanes:Et2O ) 5:2) to give (Z)-4,4-dimethyl-3-
phenyl-2-penten-1-ol (325 mg, 1.71 mmol, 95%) as a colorless
solid.
stirring) at room temperature. The resulting orange suspen-
sion was filtered, and the crystals were dried under vacuum
to give [Rh(cod)((+)-2]BF4 (58 mg, 0.070 mmol, 95%) as orange
crystals.
mp >250 °C. FTIR (neat): 2918, 1451, 1378, 1261, 1055,
1
802, 761 cm-1. H NMR (CD2Cl2) δ: 8.82 (br, 1H), 7.14-7.65
(m, 8H), 6.98 (br, 1H), 5.90 (br, 1H), 5.81 (br, 1H), 4.76 (br,
1H), 3.76 (br, 1H), 3.34 (d, J ) 32.4 Hz, 1H), 2.81-2.95 (m,
2H), 2.36-2.74 (m, 6H), 2.32 (s, 3H), 2.28 (s, 3H), 2.08 (s, 3H),
1.98 (s, 3H), 1.50 (s, 15H). 31P NMR (CD2Cl2) δ: 33.9 (dd, J )
178.2 and 28.7 Hz), 63.2 (dd, J ) 138.5 and 25.0 Hz). 19F NMR
(CD2Cl2) δ: 23.5 (s). HRMS (ESI): calcd for C39H50FeP2Rh
(M+), 739.1787; found, 739.1800. Anal. Calcd for C39H50BF4-
FeP2Rh: C, 56.69; H, 6.10. Found: C, 56.67; H, 6.14.
mp 36-38 °C. FTIR (neat): 3316, 2985, 2905, 2868, 1479,
1482, 1357, 1025, 981, 770, 709 cm-1 1H NMR (CDCl3) δ:
.
7.23-7.34 (m, 3H), 6.99-7.02 (m, 2H), 5.76 (t, J ) 6.6 Hz, 1H),
3.75 (d, J ) 6.6 Hz, 2H), 1.08 (s, 9H). 13C NMR (CDCl3) δ:
153.7, 139.5, 129.5, 127.8, 126.6, 123.3, 61.1, 36.3, 29.7. HRMS
(EI): calcd for C13H18O (M+), 190.1352; found, 190.1337.
(Z)-3-Cycloh exyl-2-bu ten -1-ol.34 Cp2TiCl2 (30 mg, 0.12
mmol) was added to a stirred 0 °C solution of isobutylmagne-
sium bromide (1.4 mL, 2.8 mmol; 2.0 M in Et2O) in Et2O (2
mL), and the resulting mixture was stirred for 5 min at 0 °C.
A solution of 3-cyclohexyl-2-propyn-1-ol38 (163 mg, 1.18 mmol)
in Et2O (2 mL) was added, and the reaction was stirred for 2
h at room temperature. It was then concentrated, and the
residue was dissolved in THF (4 mL). MeI (454 mg, 3.20 mmol)
was added to the 0 °C solution, which was then stirred for 2
h at room temperature. The reaction was quenched (dilute
aqueous HCl) and extracted with Et2O. The organic layer was
washed with saturated aqueous Na2CO3, dried over Na2SO4,
and concentrated. The resulting residue was purified by flash
chromatography (hexanes:Et2O ) 4:1) to give (Z)-3-cyclohexyl-
2-buten-1-ol (108 mg, 0.700 mmol, 59%).
Ta ble 1, En tr y 1. In a N2-filled glovebox, a solution of (+)-1
(6.7 mg, 0.013 mmol) in THF (2 mL) was added dropwise to a
stirred suspension of [Rh(cod)2]BF4 (5.4 mg, 0.013 mmol) in
THF (4 mL), resulting in a bright-red solution. After 5 min,
the reaction mixture was filtered through an acrodisc, which
was washed with THF (1 mL). The filtrate was placed into a
100 mL Schlenk tube, which was removed from the glovebox
and cooled with liquid nitrogen. After three vacuum/H2-refill
cycles, the valve to the Schlenk tube was closed, and the
solution was stirred for 1 h at room temperature, giving a dark-
brown mixture. The mixture was filtered through an acrodisc
in a glovebox, providing a dark-brown solution. The filtrate
was placed into a Schlenk tube and concentrated to dryness.
Then, a solution of (E)-4-methyl-3-phenyl-2-penten-1-ol (47.2
mg, 0.268 mmol) in THF (3 mL) was added to the residue in
the Schlenk tube, and the reaction mixture was stirred for 24
h at 70 °C. The solution was then concentrated, and the
product was purified by silica gel column chromatography
(hexanes:Et2O ) 10:1) to give (R)-4-methyl-3-phenylpentanal
(40.6 mg, 0.231 mmol, 86%; 77% ee; the value in Table 1 is
the average of two runs) as a colorless oil. The enantiomeric
excess of 4-methyl-3-phenylpentanal was analyzed on a Chiral-
dex G-TA column (105 °C; isothermal).
Ta ble 1, En tr y 2. In a N2-filled glovebox, [Rh(cod)((+)-2)]-
BF4 (7.0 mg, 0.0085 mmol) and THF (3 mL) were placed into
a 100 mL Schlenk tube. The Schlenk tube was taken out of
the glovebox and cooled with liquid nitrogen. After three
vacuum/H2-refill cycles, the valve to the Schlenk tube was
closed, and the solution was stirred for 1 h at room temper-
ature, giving a dark-brown mixture. The mixture was filtered
through an acrodisc in a glovebox, providing a dark-brown
solution. The filtrate was placed into a Schlenk tube and
concentrated to dryness. Then, (E)-4-methyl-3-phenyl-2-penten-
1-ol (30.0 mg, 0.170 mmol) in THF (3 mL) was added to the
residue in the Schlenk tube, and the reaction mixture was
stirred for 24 h at 70 °C. The solution was then concentrated,
and the product was purified by silica gel column chromatog-
raphy (pentane:Et2O ) 4:1) to give (R)-4-methyl-3-phenylpen-
tanal (28.6 mg, 0.163 mmol, 95%; 82% ee).
1H NMR (CDCl3) δ: 5.34 (dt, J ) 3.9 and 0.9 Hz, 1H), 4.15
(dq, J ) 7.2 and 0.9 Hz, 2H), 2.39-2.50 (m, 1H), 1.67 (dd, J )
1.5 and 0.9 Hz, 3H), 1.22-1.77 (m, 10H).
Syn th esis of (+)-2 (eq 4). n-BuLi (140 µL, 0.22 mmol; 1.6
M in hexane) was added dropwise to a stirred solution of (+)-3
(74 mg, 0.22 mmol; >99% ee) in THF (7 mL), and the resulting
mixture was stirred for 10 min at room temperature. A solution
of p-toluenesulfonyl chloride (43 mg, 0.23 mmol) in THF (1
mL) was added dropwise, and the reaction mixture was stirred
for 10 min at room temperature. (o-Tol)2PLi, prepared by
mixing (o-tol)2PH (95 mg, 0.44 mmol) in THF (2 mL) with
n-BuLi (277 µL, 0.44 mmol; 1.6 M in hexane), was added
dropwise, and the resulting solution was stirred for 2 h at room
temperature. The reaction was quenched by the addition of
H2O (0.2 mL), dried (MgSO4), and filtered through Celite. The
solvent was evaporated, and the residue was purified by flash
chromatography (hexanes:benzene ) 4:1) to give (+)-2 (45 mg,
0.0852 mmol, 38%) as an amorphous yellow compound.
[R]20 +37.4° (c 0.46, THF; >99% ee). FTIR (neat): 3629,
D
2963, 2911, 1451, 1375, 1231, 1159, 1029, 861, 746 cm-1. H
1
NMR (CD2Cl2) δ: 7.08-7.31 (m, 8H,), 3.18 (d, J ) 35.7 Hz,
1H), 2.76-2.80 (m, 2H), 2.20 (s, 3H), 2.15 (s, 3H), 2.01 (s, 3H),
1.81 (s, 15H), 1.75 (s, 3H). 13C NMR (CD2Cl2) δ: 143.4 (d, J )
25.7 Hz), 142.5 (d, J ) 24.8 Hz), 138.1 (dd, J ) 17.6 Hz), 137.3
(d, J ) 16.1 Hz), 131.9 (d, J ) 2.9 Hz), 131.3, 130.0 (d, J ) 4.3
Hz), 129.7 (d, J ) 4.7 Hz), 128.6, 128.3, 126.1, 126.0, 94.4 (d,
J ) 6.5 Hz), 93.7 (dd, J ) 55.1 and 18.4 Hz), 90.5 (dd, J ) 5.0
and 2.1 Hz), 82.2, 80.9 (dd, J ) 56.9 and 1.4 Hz), 28.4 (dd, J
) 19.7 and 14.6 Hz), 21.6, 21.3, 14.5, 11.0 (d, J ) 3.8 Hz),
10.7. 31P NMR (CD2Cl2) δ: -60.1 (d, 22.0 Hz), -34.2 (d, 22.0
Hz). HRMS (EI): calcd for C31H38FeP2 (M+), 528.1793; found,
528.1827.
Syn th esis of [Rh (cod )((+)-2)]BF 4. In a N2-filled glovebox,
a solution of (+)-2 (41 mg, 0.078 mmol, >99% ee) in THF (2
mL) was added to a stirred suspension of [Rh(cod)2]BF4 (30
mg, 0.074 mmol) in THF (6 mL), and the resulting dark-red
solution was stirred for 10 min at room temperature. The
reaction mixture was filtered through an acrodisc, concen-
trated to 1 mL, and then added dropwise to pentane (15 mL;
Ta ble 1, En tr y 3. In a N2-filled glovebox, [Rh(cod)((+)-2)]-
BF4 (8.2 mg, 0.010 mmol), (E)-4-methyl-3-phenyl-2-penten-1-
ol (35.0 mg, 0.199 mmol), and THF (3 mL) were added to a
Schlenk tube, and the resulting dark-red solution was stirred
for 26 h at 100 °C. The reaction mixture was then cooled to
room temperature and added to pentane (6 mL; stirred). The
resulting slurry was filtered, and the crystals were washed
with pentane, dissolved in THF, and concentrated to furnish
the recovered catalyst, [Rh(cod)((+)-2)]BF4 (7.4 mg, 0.0090
mmol, 90%), as a red solid. The filtrate was concentrated, and
the product was purified by silica gel column chromatography
(pentane:Et2O ) 4:1) to give (R)-4-methyl-3-phenylpentanal
(33.8 mg, 0.192 mmol, 97%; 93% ee).
Ta bles 2 a n d 3: Gen er a l P r oced u r e 1 (With a Glove-
box; Ta ble 2, En tr y 1). In a N2-filled glovebox, [Rh(cod)((+)-
2)]BF4 (9.8 mg, 0.012 mmol), (E)-3-phenyl-2-buten-1-ol (35.0
mg, 0.237 mmol), and THF (3 mL) were added to a Schlenk
tube, and the resulting dark-red solution was stirred for 22 h
at 100 °C. The reaction mixture was then cooled to room
temperature and added to pentane (10 mL). The resulting
slurry was filtered, providing orange crystals. The crystals
were washed with pentane, dissolved in THF, and the solvent
(38) Borne, R. F.; Forrester, M. L.; Waters, I. W. J . Med. Chem. 1977,
20, 771-776.

Catalytic Enantioselective Isomerization
J . Org. Chem., Vol. 66, No. 24, 2001 8183
was removed, affording the recovered catalyst, [Rh(cod)((+)-
2)]BF4 (8.4 mg, 0.010 mmol, 86%), as a red solid. The filtrate
was concentrated, and the product was purified by silica gel
column chromatography (pentane:Et2O ) 4:1) to give (S)-3-
phenylbutanal (31.8 mg, 0.215 mmol, 91%; 74% ee) as a
colorless oil.
(2-methylphenyl)pentanal was obtained in 87% isolated yield
with 92% ee.
(R)-4-Methyl-3-(2-methylphenyl)pentanal. Colorless oil. [R]20
D
-14.2° (c 1.49, CH2Cl2; 91% ee). Chiraldex G-TA column,
retention time ) 20.2 min (105 °C; isothermal).
Ta ble 2, En tr y 5. Procedure 1 was followed, using 7.6 mg
of [Rh(cod)((+)-2)]BF4 and 35.0 mg of (E)-4-methyl-3-(4-meth-
ylphenyl)-2-penten-1-ol. Reaction time: 22 h. (R)-4-Methyl-3-
(4-methylphenyl)pentanal was obtained in 89% isolated yield
with 91% ee.
Ta bles 2 a n d 3: Gen er a l P r oced u r e 2 (With ou t a
Glovebox, With Recycled Ca ta lyst; Ta ble 2, En tr y 6). In
the air, the recovered catalyst, [Rh(cod)((+)-2)]BF4 (5.8 mg,
0.0070 mmol), was placed into a Schlenk tube, which was then
filled with argon. Under a positive pressure of argon, a solution
of (E)-3-(4-chlorophenyl)-4-methyl-2-penten-1-ol (29.5 mg, 0.140
mmol) in THF (3 mL) was added via a Pasteur pipet. The
Schlenk tube was closed, and the dark-red solution was stirred
for 21 h at 100 °C. The reaction mixture was then cooled to
room temperature and added to pentane (10 mL; stirred). The
resulting slurry was filtered, providing orange crystals. The
crystals were washed with pentane, dissolved in THF, and the
solvent was removed, affording the recovered catalyst, [Rh-
(cod)((+)-2)]BF4 (5.3 mg, 0.0064 mmol, 91%), as a red solid.
The filtrate was concentrated and purified by silica gel column
chromatography (pentane:Et2O ) 4:1) to give (R)-3-(4-chlo-
rophenyl)-4-methylpentanal (24.4 mg, 0.116 mmol, 83%; 91%
ee) as a colorless oil.
A second run was carried out according to Procedure 1, using
the recovered catalyst. Reaction time: 21 h. (R)-4-Methyl-3-
(4-methylphenyl)pentanal was obtained in 90% isolated yield
with 91% ee.
(R)-4-Methyl-3-(4-methylphenyl)pentanal. Colorless oil. [R]20
-23.0° (c 0.81, CH2Cl2; 91% ee).
D
The aldehyde was reduced (LiAlH4), acylated (trifluoroacetic
anhydride), and then analyzed on a Chiraldex B-PH column,
retention time ) 13.7 min (90 °C; isothermal).
Ta ble 2, En tr y 6. Procedure 1 was followed, using 6.9 mg
of [Rh(cod)((+)-2)]BF4 and 35.0 mg of (E)-3-(4-chlorophenyl)-
4-methyl-2-penten-1-ol. Reaction time: 22 h. (R)-3-(4-Chlo-
rophenyl)-4-methylpentanal was obtained in 88% isolated yield
with 92% ee.
Although the twice-used catalyst appeared to be pure by
The second run was carried out as described in Procedure
2.
NMR (1H and 31P), an elemental analysis showed a lower than
(R)-3-(4-Chlorophenyl)-4-methylpentanal. Colorless oil. [R]20
-15.3° (c 1.04, CH2Cl2; 92% ee).
expected carbon and hydrogen content. Anal. Calcd for C39H50
BF4FeP2Rh: C, 56.69; H, 6.10. Found: C, 54.01; H, 5.82.
-
D
Ta ble 2, En tr y 1. The first run was carried out as described
in Procedure 1.
The aldehyde was reduced (LiAlH4), acylated (trifluoroacetic
anhydride), and then analyzed on a Chiraldex B-PH column,
retention time ) 47.4 min (90 °C; isothermal).
Ta ble 3, En tr y 1. Procedure 1 was followed, using 9.8 mg
of [Rh(cod)((+)-2)]BF4 and 35.0 mg of (Z)-3-phenyl-2-buten-1-
ol. Reaction time: 22 h. (R)-3-Phenylbutanal was obtained in
79% isolated yield with 58% ee.
A second run was carried out according to Procedure 1, using
the recovered catalyst. Reaction time: 22 h. (S)-3-Phenylbu-
tanal was obtained in 91% isolated yield with 76% ee.
(S)-3-Phenylbutanal.39 Colorless oil. [R]20 +21.3° (c 1.50,
D
CH2Cl2; 74% ee). 1H NMR (CDCl3) δ: 9.71 (t, J ) 2.1 Hz, 1H),
7.19-7.35 (m, 5H), 3.32-3.43 (m, 1H), 2.77 (ddd, J ) 16.8,
6.9, and 2.1 Hz, 1H), 2.66 (ddd, J ) 16.8, 7.5, and 2.1 Hz, 1H),
1.33 (d, J ) 6.9 Hz, 3H). 13C NMR (CDCl3) δ: 202.0, 145.6,
128.9, 127.0, 126.7, 52.1, 34.6, 22.5. Chiraldex G-TA column,
retention time ) 16.1 min (90 °C; isothermal).
A second run was carried out according to Procedure 2, using
the recovered catalyst. Reaction time: 45 h. (R)-3-Phenylbu-
tanal was obtained in 81% isolated yield with 60% ee.
(R)-3-Phenylbutanal.39 Colorless oil. [R]20 -15.5° (c 1.29,
D
CH2Cl2; 58% ee), -12.0° (c 1.20, Et2O; 58% ee) [lit. [R]25D -38.5°
(c 0.2, Et2O; >95% ee)]. Chiraldex G-TA column, retention time
) 17.3 min (90 °C; isothermal).
Ta ble 2, En tr y 2. Procedure 1 was followed, using 8.9 mg
of [Rh(cod)((+)-2)]BF4 and 35.0 mg of (E)-3-phenyl-2-penten-
1-ol. Reaction time: 21 h. (S)-3-Phenylpentanal was obtained
in 97% isolated yield with 76% ee.
Ta ble 3, En tr y 2. Procedure 1 was followed, using 8.9 mg
of [Rh(cod)((+)-2)]BF4 and 35.0 mg of (Z)-3-phenyl-2-penten-
1-ol. Reaction time: 23 h. (R)-3-phenylpentanal was obtained
in 75% isolated yield with 56% ee.
A second run was carried out according to Procedure 2, using
the recovered catalyst. Reaction time: 24 h. (S)-3-Phenylpen-
tanal was obtained in 94% isolated yield with 75% ee.
A second run was carried out according to Procedure 2, using
the recovered catalyst. Reaction time: 24 h. (R)-3-Phenylpen-
tanal was obtained in 80% isolated yield with 58% ee.
(S)-3-Phenylpentanal. Colorless oil. [R]20 +11.8° (c 1.26,
D
benzene; 56% ee). 1H NMR (CDCl3) δ: 9.67 (t, J ) 2.1 Hz,
1H), 7.16-7.34 (m, 5H), 3.04-3.14 (m, 1H), 2.72 (dd, J ) 16.8
and 2.1 Hz, 2H), 1.56-1.79 (m, 2H), 0.81 (t, J ) 7.5 Hz, 3H).
13C NMR (CDCl3) δ: 202.4, 143.9, 128.9, 127.8, 126.8, 50.5,
42.0, 29.7, 12.1. Chiraldex G-TA column, retention time ) 23.8
min (90 °C; isothermal).
(R)-3-Phenylpentanal.40 Colorless oil. [R]20 -18.4° (c 1.56,
D
benzene; 76% ee) [lit. [R]20 -15.9° (c 1.27, benzene; 82% ee)].
D
Chiraldex G-TA column, retention time ) 27.1 min (90 °C;
isothermal).
Ta ble 3, En tr y 3. Procedure 1 was followed, using 8.2 mg
of [Rh(cod)((+)-2)]BF4 and 35.0 mg of (Z)-4-methyl-3-phenyl-
2-penten-1-ol. Reaction time: 46 h. (S)-4-Methyl-3-phenylpen-
tanal was obtained in 81% isolated yield with 83% ee.
A second run was carried out according to Procedure 1, using
the recovered catalyst. Reaction time: 46 h. (S)-4-Methyl-3-
phenylpentanal was obtained in 82% isolated yield with 81%
ee.
Ta ble 2, En tr y 3. Procedure 1 was followed, using 8.2 mg
of [Rh(cod)((+)-2)]BF4 and 35.0 mg of (E)-4-methyl-3-phenyl-
2-penten-1-ol. Reaction time: 26 h. (R)-4-Methyl-3-phenylpen-
tanal was obtained in 97% isolated yield with 93% ee.
A second run was carried out according to Procedure 1, using
the recovered catalyst. Reaction time: 22 h. (R)-4-Methyl-3-
phenylpentanal was obtained in 99% isolated yield with 92%
ee.
(S)-4-Methyl-3-phenylpentanal.40 Colorless oil. [R]20D +14.9°
(c 1.04, CH2Cl2; 83% ee), +24.6° (c 2.26, benzene; 83% ee) [lit.
(R)-4-Methyl-3-phenylpentanal. Colorless oil. [R]20 -17.3°
D
[R]20 +23.1° (c 0.94, benzene; 86% ee)]. 1H NMR (CDCl3) δ:
(c 1.38, CH2Cl2; 93% ee). Chiraldex G-TA column, retention
time ) 14.2 min (105 °C; isothermal).
D
9.71 (t, J ) 2.1 Hz, 1H), 7.24-7.43 (m, 5H), 3.07 (ddd, J )
9.3, 7.5, and 5.7 Hz, 1H), 2.93 (ddd, J ) 16.2, 5.7, and 2.1 Hz,
1H), 2.86 (ddd, J ) 16.2, 9.3, and 2.7 Hz, 1H), 1.99 (d of septet,
J ) 6.6 and 7.5 Hz, 1H), 1.07 (d, J ) 6.6 Hz, 3H), 0.89 (d, J )
6.6 Hz, 3H). 13C NMR (CDCl3) δ: 202.3, 142.5, 128.3, 128.1,
126.4, 47.2, 46.9, 33.5, 20.6, 20.3. Chiraldex G-TA column,
retention time ) 16.2 min (105 °C; isothermal).
Ta ble 2, En tr y 4. Procedure 1 was followed, using 7.6 mg
of [Rh(cod)((+)-2)]BF4 and 35.0 mg of (E)-4-methyl-3-(2-meth-
ylphenyl)-2-penten-1-ol. Reaction time: 24 h. Reaction tem-
perature: 150 °C. (R)-4-Methyl-3-(2-methylphenyl)pentanal
was obtained in 85% isolated yield with 91% ee.
A second run was carried out according to Procedure 2, using
the recovered catalyst. Reaction time: 48 h. (R)-4-Methyl-3-
(40) Ahlbrecht, H.; Enders, D.; Santowski, L.; Zimmermann, G.
Chem. Ber. 1989, 122, 1995-2004.
(39) Lee, T.; J ones, J . B. J . Am. Chem. Soc. 1996, 118, 502-508.

8184 J . Org. Chem., Vol. 66, No. 24, 2001
Tanaka and Fu
Ta ble 3, En tr y 4. Procedure 1 was followed, using 5.8 mg
of [Rh(cod)((+)-2)]BF4 and 26.7 mg of (Z)-4,4-dimethyl-3-
phenyl-2-penten-1-ol. Reaction time: 22 h. (S)-4,4-Dimethyl-
3-phenylpentanal was obtained in 88% isolated yield with 90%
ee.
A second run was carried out according to Procedure 1, using
the recovered catalyst. Reaction time: 51 h. (S)-4,4-Dimethyl-
3-phenylpentanal was obtained in 92% isolated yield with 91%
ee.
The absolute configuration of (+)-4-methyl-3-(4-methylphen-
yl)pentanal was determined to be S by converting it to an
oxazolidine and analyzing the oxazolidine by 13C NMR (ephe-
drine method).40 For the racemic aldehyde and (-)-ephedrine,
13C NMR (CDCl3) δ: 96.8 (C-2, R), 96.0 (C-2, S), 82.0 (C-5, S),
81.6 (C-5, R), 64.6 (C-4, R), 64.4 (C-4, S), 15.6 (4-CH3, R), 15.3
(4-CH3, S).
Ta ble 3, En tr y 7. Procedure 1 was followed, using 6.9 mg
of [Rh(cod)((+)-2)]BF4 and 35.0 mg of (Z)-3-(4-chlorophenyl)-
4-methyl-2-penten-1-ol. Reaction time: 21 h. (S)-3-(4-Chlo-
rophenyl)-4-methylpentanal was obtained in 86% isolated yield
with 84% ee.
(S)-4,4-Dimethyl-3-phenylpentanal.41 Colorless oil. [R]20
D
+44.0° (c 1.29, CH2Cl2; 91% ee). 1H NMR (CDCl3) δ: 9.53 (dd,
J ) 2.7 and 1.8 Hz, 1H), 7.13-7.30 (m, 5H), 3.03 (dd, J ) 7.2
and 5.1 Hz, 1H), 2.88 (ddd, J ) 16.5, 10.2, and 5.1 Hz, 1H),
2.79 (ddd, J ) 16.2, 4.8, and 2.1 Hz, 1H), 0.91 (s, 9H). 13C NMR
(CDCl3) δ: 202.9, 141.3, 129.6, 128.1, 126.8, 50.6, 44.9, 34.1,
28.2. Chiraldex G-TA column, retention time ) 19.0 min (S
isomer) and 21.3 min (R isomer) (105 °C; isothermal).
A second run was carried out according to Procedure 1, using
the recovered catalyst. Reaction time: 20 h. (S)-3-(4-Chlo-
rophenyl)-4-methylpentanal was obtained in 80% isolated yield
with 86% ee.
(S)-3-(4-Chlorophenyl)-4-methylpentanal. Colorless oil. [R]20
D
The absolute configuration of (+)-4,4-dimethyl-3-phenyl-
+12.8° (c 1.20, CH2Cl2; 84% ee). FTIR (neat): 2960, 1725, 1491,
1092, 1013, 819 cm-1 1H NMR (CDCl3) δ: 9.60 (dd, J ) 2.4
.
pentanal was determined to be S by converting it to (S)-4,4-
dimethyl-3-phenylpentanoic acid (CrO3/aqueous H2SO4).42 [R]20
D
and 1.8 Hz, 1H), 7.23-7.28 (m, 2H), 7.06-7.10 (m, 2H), 2.94
(ddd, J ) 9.6, 7.5, and 5.1 Hz, 1H), 2.81 (ddd, J ) 16.5, 5.1,
and 1.8 Hz, 1H), 2.71 (ddd, J ) 16.5, 9.6, and 2.4 Hz, 1H),
1.83 (d of septet, J ) 6.6 and 6.6 Hz, 1H), 0.93 (d, J ) 6.6 Hz,
3H), 0.75 (d, J ) 6.6 Hz, 3H). 13C NMR (CDCl3) δ: 202.0, 141.3,
132.4, 129.8, 128.7, 47.5, 46.5, 33.7, 20.9, 20.5. HRMS (EI):
calcd for C12H15ClO (M+), 210.0811; found, 210.0808.
-20.4° (c 2.2, CHCl3; 91% ee), [R]20D -13.9° (c 1.0, EtOH; 91%
ee) [lit. [R]D -15.8° (c 0.820, EtOH)].
Ta ble 3, En tr y 5. Procedure 1 was followed, using 7.6 mg
of [Rh(cod)((+)-2)]BF4 and 35.0 mg of (Z)-4-methyl-3-(2-meth-
ylphenyl)-2-penten-1-ol. Reaction time: 48 h. Reaction tem-
perature: 150 °C. (S)-4-Methyl-3-(2-methylphenyl)pentanal
was obtained in 63% isolated yield with 83% ee.
A second run was carried out according to Procedure 2, using
the recovered catalyst. Reaction time: 47 h. (S)-4-Methyl-3-
(2-methylphenyl)pentanal was obtained in 58% isolated yield
with 79% ee.
The aldehyde was reduced (LiAlH4), acylated (trifluoroacetic
anhydride), and then analyzed on a Chiraldex B-PH column.
(S)-3-(4-Chlorophenyl)-4-methylpentan-1-ol. Colorless oil.
[R]20D -11.4° (c 0.70, CH2Cl2; 84% ee). FTIR (neat): 3332, 2953,
1489, 1471, 1411, 1386, 1092, 1045, 1014 cm-1 1H NMR
.
(S)-4-Methyl-3-(2-methylphenyl)pentanal. Colorless oil. [R]20
D
(CDCl3) δ: 7.24-7.29 (m, 2H), 7.05-7.10 (m, 2H), 3.45-3.53
(m, 1H), 3.33-3.41 (m, 1H), 2.43 (ddd, J ) 11.7, 7.8, and 3.9
Hz, 1H), 2.03-2.14 (m, 1H), 1.73-1.86 (m, 2H), 0.97 (d, J )
6.6 Hz, 3H), 0.73 (d, J ) 6.6 Hz, 3H). 13C NMR (CDCl3) δ:
142.3, 131.8, 129.8, 128.4, 61.6, 49.0, 36.0, 33.7, 21.2, 20.8.
+13.0° (c 1.11, CH2Cl2; 83% ee). FTIR (neat): 2958, 1724, 1464,
1385, 1035, 758, 730 cm-1 1H NMR (CDCl3) δ: 9.56 (t, J )
.
2.1 Hz, 1H), 7.05-7.19 (m, 4H), 3.23 (ddd, J ) 9.6, 8.1, and
5.4 Hz, 1H), 2.83 (ddd, J ) 16.5, 5.4, and 2.1 Hz, 1H), 2.72
(ddd, J ) 16.5, 9.6, and 2.1 Hz, 1H), 2.37 (s, 3H), 1.88 (m, 1H),
0.99 (d, J ) 6.6 Hz, 3H), 0.80 (d, J ) 6.6 Hz, 3H). 13C NMR
(CDCl3) δ: 202.6, 142.0, 136.4, 130.6, 126.5, 126.4, 126.2, 47.8,
41.7, 34.1, 21.1, 20.58, 20.56. HRMS (EI): calcd for C13H18O2
(M+), 190.1352; found, 190.1356. Chiraldex G-TA column,
retention time ) 21.0 min (105 °C; isothermal).
The absolute configuration of (+)-4-methyl-3-(2-methylphen-
yl)pentanal was determined to be S by converting it to an
oxazolidine and analyzing the oxazolidine by 13C NMR (ephe-
drine method).40 For the racemic aldehyde and (-)-ephedrine,
13C NMR (CDCl3) δ: 97.2 (C-2, R), 96.0 (C-2, S), 81.8 (C-5, S),
81.4 (C-5, R), 64.4 (C-4, R and S), 15.5 (4-CH3, R), 15.2 (4-
CH3, S).
HRMS (EI): calcd for
C
12H15ClO (M+), 212.0968; found,
212.0972. Chiraldex B-PH column, retention time ) 48.7 min
(trifluoroacetate; 90 °C; isothermal).
The absolute configuration of (-)-3-(4-chlorophenyl)-4-
methylpentan-1-ol was determined to be S by converting it to
(S)-4-methyl-3-phenylpentan-1-ol40 (10% Pd/C, 25% aqueous
NaOH, EtOH, 1 atm H2, rt, 3 h). Chiraldex G-TA column,
retention times ) 26.88 min [R isomer, minor], 27.35 min [S
isomer, major] (105 °C; isothermal). An authentic sample of
(S)-4-methyl-3-phenylpentan-1-ol was prepared by reducing
(S)-4-methyl-3-phenylpentanal with LiAlH4.
Equ a tion 5 (Z isom er ). Procedure 1 was followed, using
9.4 mg of [Rh(cod)((+)-2)]BF4 and 35.0 mg of (Z)-3-cyclohexyl-
2-buten-1-ol. Reaction time: 21 h. (R)-3-Cyclohexylbutanal was
obtained in 86% isolated yield with 80% ee.
A second run was carried out according to Procedure 1, using
the recovered catalyst. Reaction time: 19 h. (R)-3-Cyclohexyl-
butanal was obtained in 88% isolated yield with 80% ee.
(R)-3-Cyclohexylbutanal.43 Colorless oil. [R]20D -13.9° (c 0.65,
CH2Cl2; 80% ee). Chiraldex G-TA column, retention time )
42.2 min (70 °C; isothermal).
The aldehyde was reduced (LiAlH4), acylated (trifluoroacetic
anhydride), and then analyzed on a Chiraldex G-TA column,
retention time ) 21.4 min (80 °C; isothermal).
Ta ble 3, En tr y 6. Procedure 1 was followed, using 7.6 mg
of [Rh(cod)((+)-2)]BF4 and 35.0 mg of (Z)-4-methyl-3-(4-meth-
ylphenyl)-2-penten-1-ol. Reaction time: 22 h. (S)-4-Methyl-3-
(2-methylphenyl)pentanal was obtained in 84% isolated yield
with 77% ee.
A second run was carried out according to Procedure 1, using
the recovered catalyst. Reaction time: 21 h. (S)-4-Methyl-3-
(4-methylphenyl)pentanal was obtained in 82% isolated yield
with 77% ee.
(S)-4-Methyl-3-(4-methylphenyl)pentanal. Colorless oil. [R]20
D
+16.1° (c 0.89, CH2Cl2; 77% ee). FTIR (neat): 2960, 1726, 1671,
1514, 1466, 1386, 1036, 810 cm-1 1H NMR (CDCl3) δ: 9.59
.
Equ a tion 5 (E isom er ). Procedure 1 was followed, using
9.4 mg of [Rh(cod)((+)-2)]BF4 and 35.0 mg of (E)-3-cyclohexyl-
2-buten-1-ol. Reaction time: 21 h. (S)-3-Cyclohexylbutanal was
obtained in 91% isolated yield with 74% ee.
(dd, J ) 2.4 and 1.8 Hz, 1H), 7.02-7.11 (m, 4H), 2.93 (ddd, J
) 9.6, 7.5, and 5.4 Hz, 1H), 2.79 (ddd, J ) 16.2, 5.4, and 2.1
Hz, 1H), 2.72 (ddd, J ) 16.2, 9.6, and 2.4 Hz, 1H), 2.32 (s,
3H), 1.84 (d of septet, J ) 6.6 and 6.6 Hz, 1H), 0.94 (d, J ) 6.6
Hz, 3H), 0.78 (d, J ) 6.6 Hz, 3H). 13C NMR (CDCl3) δ: 202.9,
139.6, 136.2, 129.2, 128.3, 47.5, 46.9, 33.8, 21.4, 20.9, 20.6.
HRMS (EI): calcd for C13H18O2 (M+), 190.1352; found, 190.1355.
The aldehyde was reduced (LiAlH4), acylated (trifluoroacetic
anhydride), and then analyzed on a Chiraldex B-PH column,
retention time ) 14.1 min (90 °C; isothermal).
A second run was carried out according to Procedure 1, using
the recovered catalyst. Reaction time: 19 h. (S)-3-Cyclohexyl-
butanal was obtained in 97% isolated yield with 75% ee.
(S)-3-Cyclohexylbutanal.43 Colorless oil. [R]20 +7.4° (c 1.1,
D
CH2Cl2; 75% ee). 1H NMR (CDCl3) δ: 9.75 (dd, J ) 3.0 and
1.8 Hz, 1H), 2.46 (ddd, J ) 15.9, 4.8, and 1.8 Hz, 1H), 2.19
(ddd, J ) 15.9, 9.0, and 3.0 Hz, 1H), 1.89-2.02 (m, 1H), 1.62-
1.78 (m, 5H), 0.83-1.29 (m, 6H), 0.91 (d, J ) 6.9 Hz, 3H). 13C
(41) Meyers, A. I.; Shipman, M. J . Org. Chem. 1991, 56, 7098-7102.
(42) Imajo, S.; Kuritani, H.; Shingu, K.; Nakagawa, M. J . Org. Chem.
1979, 44, 3587-3589.
(43) Ollivier, C.; Renaud, P. Chem. Eur. J . 1999, 5, 1468-1473.

Catalytic Enantioselective Isomerization
J . Org. Chem., Vol. 66, No. 24, 2001 8185
NMR (CDCl3) δ: 203.7, 48.8, 43.1, 33.4, 30.6, 29.5, 26.99, 26.94,
26.89, 17.3. Chiraldex G-TA column, retention time ) 40.9 min
(70 °C; isothermal).
The aldehyde was reduced (LiAlH4), acylated (trifluoroacetic
anhydride), and then analyzed on a Chiraldex G-TA column,
retention time ) 22.4 min (80 °C; isothermal).
a 1:1 mixture of (S)-3-phenylbutanal and (S)-1,3-dideuterium-
3-phenylbutanal as a colorless oil.
The absence of monodeuterated compounds was confirmed
by high-resolution mass spectrometry of the mixture of alco-
hols generated through treatment of the mixture of aldehydes
with LiAlH4.
The absolute configuration of (+)-3-cyclohexylbutanal was
determined to be S by converting (S)-3-phenylbutanal to (S)-
3-phenylbutan-1-ol (LiAlH4) and then to (S)-3-cyclohexylbutan-
1-ol (5% Rh/C, H2, AcOH)44 and comparing it to the product of
the LiAlH4 reduction of (+)-3-cyclohexylbutanal.
Equ a tion 11. In a N2-filled glovebox, [Rh(cod)((-)-2)]BF4
(9.4 mg, 0.11 mmol), (E)-3-phenyl-2-buten-1-ol (30.0 mg, 0.203
mmol), (E)-3-phenyl-2-pentenal (3.5 mg, 0.022 mmol), and THF
(3 mL) were added to a Schlenk tube, and the resulting dark-
red solution was stirred for 24 h at 100 °C. The reaction
mixture was then cooled to room temperature and concen-
trated. The catalyst was removed through passage of the
residue through a pad of silica gel (Et2O as the eluant),
affording a colorless oil. According to GC, the ratio of 3-phen-
ylbutanal:3-phenyl-2-butenal:3-phenyl-2-pentenal:3-phenyl-
pentanal was 89:1.6:9:0.7.
P r ep a r a tive-Sca le Isom er iza tion of (E)-4-Meth yl-3-
p h en yl-2-p en ten -1-ol (eq 6). In the air, [Rh(cod)((-)-2)]BF4
(47.0 mg, 0.057 mmol) was placed into a Schlenk tube, which
was then filled with argon. Under a positive pressure of argon,
a solution of (E)-4-methyl-3-phenyl-2-penten-1-ol (1.00 g, 5.68
mmol) in THF (50 mL) was added via a Pasteur pipet. The
Schlenk tube was closed, and the dark-red solution was stirred
for 67 h at 100 °C. The reaction mixture was then cooled to
room temperature, concentrated to ∼10 mL, and added to
pentane (30 mL; stirred). The resulting slurry was filtered,
providing orange crystals. The crystals were washed with
pentane, dissolved in THF, and the solvent was removed,
affording the recovered catalyst, [Rh(cod)((+)-2)]BF4 (32.0 mg,
0.0387 mmol, 68%), as a red solid.
(E)-1-Deu ter iu m -3-p h en yl-2-bu ten a l.46 A mixture of (E)-
1,1-dideuterium-3-phenyl-2-buten-1-ol (236 mg, 1.57 mmol),
Ag2CO3 (1.73 g, 6.28 mmol), and benzene (25 mL) was stirred
at reflux for 2 h. After cooling to room temperature, the
mixture was filtered through Celite and concentrated. The
resulting residue was purified by flash chromatography (pen-
tane:Et2O ) 4:1) to give (E)-1-deuterium-3-phenyl-2-butenal
(154 mg, 1.05 mmol, 67%; not optimized) as a colorless oil,
along with recovered (E)-1,1-dideuterium-3-phenyl-2-buten-1-
ol (73 mg, 0.487 mmol, 31%).
The filtrate was concentrated and purified by silica gel
column chromatography (pentane:Et2O ) 4:1) to give (S)-4-
methyl-3-phenylpentanal (944 mg, 5.36 mmol, 94%, 90% ee)
as a colorless oil.
1H NMR (CDCl3) δ: 7.54-7.56 (m, 2H), 7.41-7.44 (m, 3H),
6.40 (q, J ) 0.6 Hz, 1H), 2.17 (s, 3H). 2H NMR (CHCl3) δ: 10.25
(s).
(E)-1,1-Did eu ter iu m -3-p h en yl-2-bu ten -1-ol. Ethyl (E)-3-
phenyl-2-butenoate45 (1.00 g, 5.26 mmol) in Et2O (5 mL) was
added to a stirred mixture of LiAlD4 (220 mg, 5.26 mmol) in
Et2O (20 mL) at 0 °C, and the resulting mixture was stirred
for 10 min at 0 °C. H2O (0.1 mL) was added at 0 °C, and the
reaction was stirred for 10 min at room temperature. The
solution was then dried over MgSO4, filtered through Celite,
and concentrated. The resulting residue was purified by flash
chromatography (hexanes:Et2O ) 5:2) to give (E)-1,1-dideu-
terium-3-phenyl-2-buten-1-ol (650 mg, 4.33 mmol, 82%) as a
colorless oil.
(S)-(E)-1-Deu ter iu m -3-p h en yl-2-bu ten -1-ol. To a 0 °C
solution of (E)-1-deuterium-3-phenyl-2-butenal (120 mg, 0.815
mmol) in THF (5 mL) was added (R)-Alpine-Borane (2.0 mL,
1.0 mmol). The resulting reaction mixture was stirred for 14
h at room temperature, and then acetaldehyde (0.023 mL, 0.41
mmol) was added. After 15 min of stirring, the mixture was
concentrated, and the residue was diluted with Et2O (30 mL).
2-Aminoethanol (68 mg, 1.1 mmol) was added, and the
resulting white suspension was filtered. The filtrate was
washed with water, dried over MgSO4, and concentrated. The
residue was purified by flash chromatography (pentane:Et2O
) 4:1 f 2:1) to give (S)-(E)-1-deuterium-3-phenyl-2-buten-1-
ol (100 mg, 0.670 mmol, 82%) as a colorless oil. The enantio-
meric excess of (S)-5 was determined to be 95% by converting
it to the (S)-MTPA ester. The absolute configuration of (S)-5
FTIR (neat): 3316, 2360, 2341, 1494, 1445, 1380, 1263,
1
1147, 1089, 1004, 955, 891, 759, 695 cm-1. H NMR (CDCl3)
δ: 7.26-7.43 (m, 5H), 5.98 (s, 1H), 2.09 (s, 3H). 2H NMR
(CHCl3) δ: 4.31 (s, 2D). HRMS (EI): calcd for C10H10D2O (M+),
150.1008; found, 150.1005.
1
was assigned as S by H NMR analysis (Eu(hfc)3).47
(S)-1,3-Did eu ter iu m -3-p h en ylbu ta n a l (eq 8). In a N2-
filled glovebox, [Rh(cod)((+)-2)]BF4 (5.3 mg, 0.0064 mmol), (E)-
1,1-dideuterium-3-phenyl-2-buten-1-ol (20.0 mg, 0.133 mmol),
and THF (3 mL) were added to a Schlenk tube, and the
resulting dark-red solution was stirred for 24 h at 100 °C. The
reaction mixture was then cooled to room temperature,
concentrated, and purified by silica gel column chromatogra-
phy (pentane:Et2O ) 4:1) to give (S)-1,3-dideuterium-3-phen-
ylbutanal (16.3 mg, 0.109 mmol, 82%; 76% ee) as a colorless
oil.
[R]20 +0.90° (c 3.10, CHCl3; 95% ee). 1H NMR (CDCl3) δ:
D
7.24-7.43 (m, 5H), 5.98 (d, J ) 6.3 Hz, 1H), 4.35 (d, J ) 6.0
2
Hz, 1H), 2.09 (s, 3H). H NMR (CHCl3) δ: 4.40 (s).
(S)-MTPA ester of (S)-(E)-1-deuterium-3-phenyl-2-buten-1-
1
ol. H NMR (CDCl3) δ: 7.30-7.54 (m, 5H), 5.93 (dd, J ) 4.2
and 0.6 Hz, 1H), 5.01 (d, J ) 4.2 Hz, 0.02H), 4.99 (d, J ) 4.2
Hz, 0.98H), 3.58 (d, J ) 0.9 Hz, 3H), 2.13 (d, J ) 0.3 and 0.3
Hz, 3H). 2H NMR (CHCl3) δ: 5.06 (s). The enantiomeric excess
was determined to be 95% by integration of the 1H NMR
resonances at δ 4.99 and 5.01. A mixture of the diastereomeric
(S)-MTPA esters of (()-(E)-1-deuterium-3-phenyl-2-buten-1-
ol was prepared as a reference.
[R]20 +23.9° (c 1.25, CH2Cl2; 76% ee). FTIR (neat): 2962,
D
2069, 1712, 1494, 1447, 1092, 760, 700 cm-1. 1H NMR (CDCl3)
δ: 7.15-7.34 (m, 5H), 2.76 (d, J ) 16.8 Hz, 1H), 2.65 (d, J )
16.8 Hz, 1H), 1.32 (s, 3H). 2H NMR (CDCl3) δ: 9.77 (s, 1D),
3.38 (s, 1D). HRMS (EI): calcd for C10H10D2O (M+), 150.1008;
found, 150.1002. Chiraldex G-TA column, retention times )
15.1 min (S isomer), 16.4 min (R isomer) (90 °C; isothermal).
Cr ossover Exp er im en t (eq 9). In a N2-filled glovebox, [Rh-
(cod)((+)-2)]BF4 (5.3 mg, 0.0064 mmol), (E)-3-phenyl-2-buten-
1-ol (10.7 mg, 0.0723 mmol), (E)-1,1-dideuterium-3-phenyl-2-
buten-1-ol (11.1 mg, 0.0739 mmol), and THF (3 mL) were
added to a Schlenk tube, and the resulting dark-red solution
was stirred for 24 h at 100 °C. The reaction mixture was then
cooled to room temperature, concentrated, and purified by
silica gel column chromatography (pentane:Et2O ) 4:1) to give
Equ a tion 12. In a N2-filled glovebox, [Rh(cod)((+)-2)]BF4
(5.5 mg, 0.0067 mmol), (S)-(E)-1-deuterium-3-phenyl-2-buten-
1-ol (20.0 mg, 0.134 mmol; 95% ee), and THF (2 mL) were
added to a Schlenk tube, and the resulting dark-red solution
was stirred for 24 h at 100 °C. The reaction mixture was then
cooled to room temperature, concentrated, and purified by
silica gel column chromatography (pentane:Et2O ) 4:1) to give
a mixture of 1-deuterium-3-phenylbutanal and 3-deuterium-
3-phenylbutanal (18.7 mg, 0.125 mmol, 93%) as a colorless oil.
According to GC, the ratio of (S)-1-deuterium-3-phenylbu-
tanal:(S)-3-deuterium-3-phenylbutanal:(R)-1-deuterium-3-
phenylbutanal:(R)-3-deuterium-3-phenylbutanal was 2.3:84.2:
(44) Hashimoto, S.-I.; Yamada, S.-I.; Koga, K. Chem. Pharm. Bull.
1979, 27, 771-782.
(45) Sano, S.; Yokoyama, K.; Fukushima, M.; Yagi, T.; Nagao, Y.
Chem. Commun. 1997, 559-560.
(46) Meyers, A. I.; Nabeya, A.; Adickes, H. W.; Fitzpatrick, J . M.;
Malone, G. R.; Politzer, I. R. J . Am. Chem. Soc. 1969, 91, 764-765.
(47) Reich, C. J .; Sullivan, G. R.; Mosher, H. S. Tetrahedron Lett.
1973, 1505-1508.

8186 J . Org. Chem., Vol. 66, No. 24, 2001
Tanaka and Fu
11.1:2.4. Chiraldex G-TA column, retention times ) 48.6 min
((S)-3-deuterium-3-phenylbutanal), 50.1 min ((S)-1-deuterium-
3-phenylbutanal), 53.8 min ((R)-3-deuterium-3-phenylbutanal),
54.7 min ((R)-1-deuterium-3-phenylbutanal) (80 °C; isother-
mal).
Equ a tion 13. In a N2-filled glovebox, [Rh(cod)((-)-2)]BF4
(5.5 mg, 0.0067 mmol), (S)-(E)-1-deuterium-3-phenyl-2-buten-
1-ol (20.0 mg, 0.134 mmol; 95% ee) and THF (2 mL) were added
to a Schlenk tube, and the resulting dark-red solution was
stirred for 24 h at 100 °C. The reaction mixture was then
cooled to room temperature, concentrated, and purified by
silica gel column chromatography (pentane:Et2O ) 4:1) to give
a mixture of 1-deuterium-3-phenylbutanal and 3-deuterium-
3-phenylbutanal (18.6 mg, 0.125 mmol, 93%) as a colorless oil.
According to GC, the ratio of (S)-1-deuterium-3-phenylbu-
tanal:(S)-3-deuterium-3-phenylbutanal:(R)-1-deuterium-3-phenyl-
butanal:(R)-3-deuterium-3-phenylbutanal was 3.5:4.6:90.2:1.7.
Ack n ow led gm en t. We thank Dr. J effrey H. Simp-
son and Mr. Mark C. Wall for assistance with NMR
experiments. Support has been provided by Bristol-
Myers Squibb, Merck, Mitsubishi Chemical (financial
support to K.T.), Novartis, and Pfizer.
Su p p or tin g In for m a tion Ava ila ble: Molecular structure
and numbering schemes for [Rh(cod)((-)-2)]ClO4, as well as
tables describing crystal data and structure refinement,
fractional atomic coordinates, bond distances and angles,
anisotropic displacement parameters, hydrogen coordinates,
and torsional angles. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O010792V