First rhodium/phosphoramidite complex-catalyzed enantioselective isomerization of allylic alcohols into aldehydes

Article abstract of DOI:10.1016/j.tetlet.2006.05.108

Primary allylic alcohols are converted into chiral aldehydes in the presence of a catalytic amount (7 mol %) of a monodentate phosphoramidite rhodium catalyst. The aldehydes are isolated in high yields (84-89%) and moderate to good ee's (38-70%). A preliminary mechanistic study showed that the reaction proceeds through a 1,3-H migration pathway.

Full text of DOI:10.1016/j.tetlet.2006.05.108

Tetrahedron Letters 47 (2006) 5021–5024
First rhodium/phosphoramidite complex-catalyzed
enantioselective isomerization of allylic alcohols into aldehydes
*
´
Fabien Boeda, Paul Mosset and Christophe Crevisy
Sciences Chimiques de Rennes, CNRS UMR 6226, ENSCR, Avenue du Ge´ne´ral Leclerc, 35700 Rennes, France
Received 4 April 2006; revised 10 May 2006; accepted 17 May 2006
Abstract—Primary allylic alcohols are converted into chiral aldehydes in the presence of a catalytic amount (7 mol %) of a mono-
dentate phosphoramidite rhodium catalyst. The aldehydes are isolated in high yields (84–89%) and moderate to good ee’s (38–70%).
A preliminary mechanistic study showed that the reaction proceeds through a 1,3-H migration pathway.
Ó 2006 Elsevier Ltd. All rights reserved.
The double bond enantioselective isomerization of an
allylic amine, allylic ether or allylic alcohol is a powerful
reaction. A very efficient process was developed two dec-
ades ago starting from allylic amines.1 It proved to be
particularly useful as it has been applied at an industrial
scale for the synthesis of (À)-menthol (Scheme 1).1b
Me
Me
P
Fe
P(o-Tol)2
Rh(I)/
OH
Me
Me
Me
Me
R1
R1
H
Me
R2
R2
O
THF, Δ
The version starting from allylic alcohol is very interest-
ing as it is a full atom economy process.2 But, this reac-
tion appears somewhat difficult to achieve efficiently.
Indeed, while the racemic version was extensively stud-
ied,3 the asymmetric version was less studied and the
results obtained in term of reactivity and enantioselectivity
were moderate3,4 until the recent results reported by
Fu.5 Fu reported a very efficient isomerization reaction
of primary allylic alcohols to aldehydes using Rh/phos-
phaferrocene complexes (Scheme 2) and consequently
made an outstanding breakthrough.
57-94% ee
Scheme 2. Enantioselective isomerization of allylic alcohols to alde-
hydes using a Rh/phosphaferrocene complex.
More recently, Ikariya reported a novel asymmetric
isomerization via Cp*Ru(PN) catalyzed kinetic dynamic
resolution of secondary allylic alcohols. Optically active
ketones were isolated with decent ee’s (62–74%).6 Never-
theless, it remains interesting to find alternate readily
accessible, cheap ligands that can perform the reaction
and extend its scope.
Phosphoramidites proved to be particularly efficient in a
wide range of catalyzed reactions such as Rh-catalyzed
hydrogenation of olefins,7 Cu-catalyzed asymmetric
conjugate addition of diorganozinc reagents,8 Pd-cata-
lyzed enantioselective hydrosilylation of alkenes,9 Ir-cata-
lyzed enantioselective allylation of ketone enolates.10
Moreover, these are easily tunable and accessible ligands
and their use in the isomerization of allylic alcohols is at
the present time not described in the literature.
NEt2
H+
Catalytic
CHO
NEt2
[Rh-((S
)-BINAP)]+
> 95%ee
Scheme 1. Enantioselective isomerization of diethylgeranylamine
catalyzed by Rh–BINAP complex.
We started a study to evaluate the efficiency of this class
of ligands in the enantioselective isomerization of allylic
alcohols and we are reporting here that the monodentate
*
Corresponding author. Tel.: +33
23238108; e-mail: crevisy@ensc-rennes.fr
2 0223238074; fax: +33 2
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.108

5022
F. Boeda et al. / Tetrahedron Letters 47 (2006) 5021–5024
ligand L1 (Fig. 1) performs efficiently the reaction.
Indeed, optically active aldehydes are isolated with
decent ee’s.
The optimal conditions for the reaction were first deter-
mined using alcohol 1 or 2 as the substrate and (rac)-L1
or (R)-L1 as the ligand (Scheme 3 and Table 1). Toluene
as the solvent, a temperature of 105 °C and 7 mol % of
Rh proved to be the optimal condition.16 In such condi-
tions, Alcohol 1 was completely converted into aldehyde
6, which was isolated in a very good yield (87%) and an
encouraging (64%) ee (entry 6). The reaction can be com-
pleted with only 3 or 5 mol % of the catalyst (entries 7–9).
Nevertheless, using such an amount of catalyst led to an
increase of the reaction duration. For instance, the reac-
tion was completed after 72 h when 5 mol % was used,
but only 31% and 45% conversions were, respectively,
obtained after 24 and 48 h. For this reason, we decided
to use 7 mol % of the catalyst for further experiments.
Allylic alcohols 1–5 were first synthesized according to
known procedures (Ref. 5 and references cited therein).
Ligands L111 and L212 were synthesized following the
procedure described in the literature. The catalyst was
prepared by adding two equivalents of the monodentate
ligand to commercial Rh(COD)2BF4 followed by hydro-
genation (1 atm) of the solution.13 To the catalyst solu-
tion thus obtained was then added the substrate.
O
O
Various allylic alcohols were then screened to evaluate
the scope of the reaction (Scheme 4 and Table 2). In
each case, a total conversion was obtained after 30 h
and the aldehyde was isolated in high yield. The reactiv-
ity and the ee were not affected by the nature of the sub-
stituents (alkyl–aryl (entries 1, 4 and 5) or alkyl–alkyl
(entry 2)) on the double bond.
P
N
(R)-L1
Ph
N
Ph
N
O
O
O
O
P
P
Aldehydes were isolated with encouraging ee’s starting
from (E) allylic alcohols, while the opposite enantiomer
was obtained with a moderate ee when the (Z) isomer 3
was used (entry 3). This observation is in agreement with
the results obtained by Fu.5
Ph
Ph
(
R,R,R)-L2
(
S,R,R)-L2
Figure 1. Monodentate phosphoramidite ligands L1 and L2.
We then tried to increase the enantioselectivity by using
ligand (R,R,R)-L2 bearing a chiral amine element. It
has indeed been observed that the presence of a chiral
amine can have a dramatic effect on the enantioselectivity
in some metal-phosphoramidite catalyzed reactions.8,9
When allylic alcohol 1 was reacted in the presence of
10 mol % of Rh and (R,R,R)-L2 ligand, a conversion of
only 30% was observed after 96 h at 105 °C. Moreover,
the aldehyde was isolated as an almost racemic mixture
(7% ee). A similar result was obtained with the diastereo-
N
H
*
10
Figure 2. Amine 10.
7 mol%
Rh+/Ligand
Rh+/(rac)-L1
Rh+/(
R)-L1
R2
R2
R2
R2
or
R1
OH
R1
R1
OH
R1
O
O
Toluene, 105 °C
6-7
1-5
6-9
1-2
Scheme 3. Determination of optimal conditions.
Scheme 4. Extension to various aldehydes.
Table 1. Determination of optimal conditions via Scheme 3
Entry R1 R2 Temperature (°C) Rhodium amount (mol %) Duration (h) Conversion (%)a Yield (%)
Ligand Solvent
1
2
3
4
5
6
7
8
9
Ph i-Pr (rac)-L1 THF
Ph i-Pr (rac)-L1 THF
Ph i-Pr (rac)-L1 Dioxane
Ph i-Pr (rac)-L1 Dioxane 105
Ph i-Pr (rac)-L1 Toluene
65
85
25
5
10
10
10
10
7
5
5
3
24
14
24
24
24
30
24
72
72
11
55
0
31
110
105
105
105
105
100
100
31
100
100
Ph i-Pr (R)-L1
Ph i-Pr (R)-L1
Ph i-Pr (R)-L1
Toluene
Toluene
Toluene
Toluene
87
74
68
Cy Me
(R)-L1
a The reaction conversion was obtained from GC analysis on a HP-1 column and 1H NMR.

F. Boeda et al. / Tetrahedron Letters 47 (2006) 5021–5024
Table 2. Extension to various allylic alcohols via Scheme 4
5023
Entry
R1
R2
Alcohol
Ligand
Duration (h)
Conversion (%)
Aldehyde
Isolated yield (%)
ee %
1a
2b
3a
4c
5a
6
Ph
Cy
i-Pr
p-Tol
Ph
i-Pr
Me
Ph
i-Pr
Me
i-Pr
i-Pr
1
2
3
4
5
1
1
(R)-L1
(R)-L1
(R)-L1
(R)-L1
(R)-L1
(R,R,R)-L2
(S,R,R)-L2
30
30
30
30
30
96
96
100
100
100
100
100
30d
30d
6
7
6
8
9
6
6
87
84
85
86
89
—
—
70 (R)
66 (R)
38 (S)
60 (R)
64 (R)
7 (R)
Ph
Ph
7a
6 (R)
a The ee was analyzed on a Lipodex E column (25 m).
b The ee was analyzed on a Chiraldex G-TA column (30 m).
c The ee was analyzed from NMR analysis after conversion of the enantiomeric mixture to the diastereoisomeric mixture of amine 10.17
d 10 mol % of the catalyst was used.
Me
2. Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259–
281.
3. (a) Shakhidayatov, Kh. Russ. Chem. Rev. 1970, 39, 859;
(b) Van der Drift, R. C.; Bouwman, E.; Drent, E.
J. Organomet. Chem. 2002, 650, 1–24; (c) Uma, R.;
Rh+/(
R)-L1
7 mol%
D D
OH
D
Me
Toluene, 105 °C
O
D
11
30h
´
´
12
Crevisy, C.; Gree, R. Chem. Rev. 2003, 103, 27–51.
4. (a) Botteghi, C.; Giacomelli, G. Gazz. Chim. Ital. 1976,
106, 1131–1134; (b) Tani, K. Pure Appl. Chem. 1985, 57,
1845–1854; (c) Otsuka, S.; Tani, K. Synthesis 1991, 665–
680; (d) Chapuis, C.; Barthe, M.; de Saint Laumer, J.-Y.
Helv. Chim. Acta 2001, 84, 230–242.
Scheme 5. Reaction of labelled compound 11.
isomeric (S,R,R)-L2 ligand. This disappointing result
shows that the efficiency of the reaction is dramatically
decreased by a sterically demanding ligand.
5. (a) Tanaka, K.; Qiao, S.; Tobisu, M.; Lo, M. M.-C.; Fu,
G. C. J. Am. Chem. Soc. 2000, 122, 9870–9871; (b)
Tanaka, K.; Fu, G. C. J. Org. Chem. 2001, 66, 8177–8186.
6. Ito, M.; Kitahara, S.; Ikariya, T. J. Am. Chem. Soc. 2005,
127, 6172–6173.
7. See for instance (a) van den Berg, M.; Minnaard, A. J.;
Schudde, E. P.; van Esch, J.; de Vries, A. H. M.; de Vries,
J. G.; Feringa, B. L. J. Am. Chem. Soc. 2000, 122, 11539–
11540; (b) Bernsmann, H.; van den Berg, M.; Hoen, R.;
Minnaard, A. J.; Mehler, G.; Reetz, M. T.; de Vries, J. G.;
Feringa, B. L. J. Org. Chem. 2005, 70, 943–951, and
references cited therein.
Finally, we started preliminary mechanistic studies. The
1,1-dideuterated allylic alcohol 11 was synthesized
according to known procedures.5 Then, it was reacted
with 7% catalyst. A clean formation of aldehyde 12
was observed. Compound 12 bears a deuterium atom
on C-sp2 carbon and more interestingly a second deute-
rium atom on C-3 carbon (Scheme 5).18 This result dem-
onstrates that the reaction proceeds through a 1,3-H
migration pathway.
8. See for instance Duursma, A.; Minnaard, A. J.; Feringa,
B. L. J. Am. Chem. Soc. 2003, 125, 3700–3701.
9. Jensen, J. F.; Svendsen, B. Y.; la Cour, T. V.; Pedersen, H.
L.; Johannsen, M. J. Am. Chem. Soc. 2002, 124, 4558–
4559.
10. Graening, T.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127,
17192–17193.
To conclude, we demonstrate for the first time that
phosphoramidites are valuable ligands for the enantio-
selective Rh-catalyzed isomerization of allylic alcohols to
chiral aldehydes. The isolated yields are high and the
ee’s encouraging. The search for better mono- and bi-
dentate phosphoramidite ligands for this isomerization
reaction is now actively underway.
11. Ma, M. F. P.; Li, K.; Zhou, Z.; Tang, C.; Chan, A. S. C.
Tetrahedron: Asymmetry 1999, 10, 3259–3261.
12. Rimkus, A.; Sewald, N. Org. Lett. 2003, 5, 79–80.
13. The necessity to hydrogenate the mixture of
[Rh(COD)2]BF4 and the ligand has been proved:
[Rh(COD)2]BF4 and 2 equiv of ligand (R)-L1 were mixed
and the allylic alcohol was then added. After 48 h at
105 °C, no trace of aldehyde was detected. The hydro-
genation step perhaps hydrogenates off the COD from the
precatalyst, which can be assumed to be from previous
work, [Rh(COD)L12]BF4.14 Besides, the structure of the
exact active catalytic species, particularly the number of
ligands borne by the metal, has not yet been proved. This
aspect has been discussed in the case of an hydrogenation
reaction catalyzed by a Rh/phosphoramidite catalyst.15
14. (a) Hu, A.-G.; Fu, Y.; Xie, J.-H.; Zhou, H.; Wang, L.-X.;
Zhou, Q.-L. Angew. Chem., Int. Ed. 2002, 41, 2348–2350;
(b) Reetz, M. T.; Ma, J.-A.; Goddard, R. Angew. Chem.,
Int. Ed. 2005, 44, 412–415; (c) Liu, Y.; Ding, K. J. Am.
Chem. Soc. 2005, 127, 10488–10489.
Acknowledgements
We thank the Ministry of Education for the award of
doctoral grant for F.B., Pierre Guenot (CRMPO, Re-
nnes) for performing mass spectroscopy experiments
and Professor Gregory Fu (MIT, Boston) for fruitful
exchanges of information.
References and notes
1. (a) Tani, K.; Yamagata, T.; Akutagawa, S.; Kumoba-
yashi, H.; Taketomi, T.; Takaya, H.; Miyashita, A.;
Noyori, R.; Otsuka, S. J. Am. Chem. Soc. 1984, 106, 5208–
5217; (b) Akutagawa, S. In Chirality in Industry; Collins,
A. N., Sheldrake, G. N., Crosby, J., Eds.; Wiley: New
York, 1992.
15. van den Berg, M.; Minnaard, A. J.; Haak, R. M.; Leeman,
M.; Schudde, E. P.; Meetsma, A.; Feringa, B. L.; de Vries,
A. H. M.; Maljaars, C. E. P.; Willans, C. E.; Hyett, D.;

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F. Boeda et al. / Tetrahedron Letters 47 (2006) 5021–5024
Boogers, J. A. F.; Henderickx, H. J. W.; de Vries, J. G.
Adv. Synth. Catal. 2003, 345, 308–323.
stirred for 30–35 h at 105 °C. The solution was then
concentrated, and the product was purified by silica gel
column chromatography to give the chiral aldehyde.
17. Amine 10 (Fig. 2) was obtained from aldehyde 8 by a
reductive amination process using (S)-a-methylbenzyl-
amine and NaBH(OAc)3.
16. General procedure for the isomerization of allylic alcohols
using rhodium/phosphoramidite complex catalysts: In a
N2-filled glovebox, a solution of monodentate phospho-
ramidite (0.04 mmol) in toluene (2 mL) was added to a
stirred suspension of [Rh(COD)2]BF4 (8 mg, 0.02 mmol)
in toluene (2 mL), and the resulting yellow solution was
stirred for 15 min at room temperature. The catalyst
solution was taken out of the glovebox and after three
vacuum/H2-refill cycles, the solution was stirred for 1 h at
room temperature. Then, under an argon atmosphere,
allylic alcohol (0.285 mmol) in toluene (3 mL) was added
to the catalyst solution and the reaction mixture was
18. Compound 12: 1H NMR (400 MHz, CDCl3): d (ppm) 1.40
(s, 3H, CH3), 2.74 (d, 1H, J = 16 Hz, CH2), 2.85 (d, 1H,
J = 16 Hz, CH2), 7.25–7.82 (m, 7H, HAr); 13C NMR
(100 MHz, CDCl3): d (ppm) 22.5, 34.4 (t, J = 20.0 Hz),
51.8 (t, J = 3.6 Hz), 125.4, 125.8, 126.0, 126.2, 126.5,
128.0, 128.0, 128.8, 132.7, 134.0, 143.2, 202.0 (t,
J = 26.0 Hz); HRMS (EI): calcd for C14H12D2O (M+):
200.1170, found: 200.1159.