A one-pot process for the enantioselective preparation of saturated secondary alcohols from propargyl ketones under hydrogen transfer conditions

Article abstract of DOI:10.1016/j.tetlet.2005.08.008

Propargyl ketones can be directly transformed to enantio-enriched saturated secondary alcohols in a one-pot reaction using chiral RuCl[N-(tosyl)-1,2- diphenylethylenediamine)(p-cymene) and Pd/BaSO₄ as catalysts, under transfer hydrogenation con

Full text of DOI:10.1016/j.tetlet.2005.08.008

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6915–6918
A one-pot process for the enantioselective preparation of
saturated secondary alcohols from propargyl ketones
under hydrogen transfer conditions
Nicolas Bogliotti, Peter I. Dalko and Janine Cossy*
Laboratoire de Chimie Organique, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex05, France
Received 8 June 2005;revised 28 July 2005;accepted 1 August 2005
Abstract—Propargyl ketones can be directly transformed to enantio-enriched saturated secondary alcohols in a one-pot reaction
using chiral RuCl[N-(tosyl)-1,2-diphenylethylenediamine)(p-cymene) and Pd/BaSO4 as catalysts, under transfer hydrogenation
conditions.
Ó 2005 Elsevier Ltd. All rights reserved.
Chiral ruthenium(arene)(L) complexes have emerged as
major tools in the enantioselective reduction of
Ts
ketones.1 Impressive level of enantio-control has been
achieved either under hydrogen transfer conditions or
under hydrogen pressure to reduce aryl and propargyl
ketones, as well as a- and b-dicarbonyl compounds.1,2
The preparative usefulness of these reactions was amply
demonstrated in a number of syntheses of biologically
relevant products.3 While cyclic ketones can be con-
verted to alcohols in high enantiomeric excess without
the presence of stereodirecting groups,1b acyclic sub-
strates require adjacent aryl, alkynyl or ester groups
for the process. These stereodirecting groups are usually
removed or transformed afterwards into other func-
tions. Most commonly, the alkyne function is hydroge-
nated to afford the corresponding saturated
compound. We were interested in examining the enan-
tioselective reduction of propargyl ketones under hydro-
gen transfer conditions, catalyzed by chiral Ru(II)Ln
and by attempting the reduction of the alkyne function
in a one-pot reaction without hydrogen. This strategy
would take advantage of the reductive conditions of
the first reaction, to achieve the hydrogenation of the
alkyne. Ruthenium complexes, which were developed
for the reduction of ketones are, however, poor hydro-
Ph
Ph
N
Ru
N
Cl
H2
(cat.)
HCO2H
Et3N, rt
OH
R2
O
R2
R1
then Pd(X)
R1
Scheme 1. General scheme of transformation.
gen donors toward olefins and alkynes.4,5 This short-
coming can be easily overcome by the addition of
metals such as palladium, iridium or platinum. The
compatibility of the catalysts in a one-pot reaction is
the key factor for the success of this transformation.
The present study is dedicated in finding conditions,
allowing the one-pot reaction using compatible Ru/Pd
catalyst system (Scheme 1).6,7
At first, the reduction of propargyl ketone 1 was studied
in the presence of a catalytic amount (2.5 mol %) of
(R,R)-RuCl[N-(tosyl)-1,2-diphenylethylenediamine)(p-
cymene)], [(R,R)-I], formic acid (10 equiv), and triethyl-
amine (4 equiv) at rt.8 After 2 h, the starting material
was converted to the corresponding alcohol 2 in 94%
yield and in 90% ee (Scheme 2).9 The absolute configu-
ration of 2 was assigned by analogy with the literature
data.10
Keywords: Alcohols;Alkynes;Asymmetric synthesis;Catalysis;
Hydrogenation;Reduction.
*
Corresponding author. Tel.: +33 (0)140794429;fax: +33
(0)140794660;e-mail: janine.cossy@espci.fr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.008

6916
N. Bogliotti et al. / Tetrahedron Letters 46 (2005) 6915–6918
afforded modest yield (44%) and selectivity as the
(R,R)-I
(2.5% mol)
O
OH
desired alcohol 4 and ketone 5 were obtained in a ratio
of 84:16 (Table 1, entry 6).12 The best results were
obtained with Rosemund catalyst (Pd/BaSO4) (Table
1, entry 7). In the presence of this catalyst, the desired
alcohol 4 was obtained accompanied with a small
amount of ketone 5 (ratio 4/5 = 93:7, yield: 80%). What-
ever the reaction conditions used, the enantiomeric
Ph
Ph
HCO2H
Et3N, rt
TMS
TMS
1
2
(94%, ee = 90%)
Scheme 2. The one-pot reduction/hydrogenation of propargylic
ketone 1.
The feasibility of the tandem reduction/hydrogenation
was tested on compound 1. After treatment of 1 for
2 h with formic acid (10 equiv), Et3N (4 equiv) in the
presence of catalyst (R,R)-I (2.5 mol %) and stirring at
rt until complete disappearance of ketone 1, a catalytic
amount of palladium catalyst (10 mol %) was added
and the solution was stirred at rt overnight (15 h). The
results are reported in Table 1.
OH
C7H15
Ph
O
13 (54%, ee=79%)
a then b
Ph
O
C5H11
6
C7H15
13' (16%)
Ph
When Pd(Pb)/CaCO3 was added to the reaction mix-
ture, compound 2 was the only product which was iso-
lated in 59% yield (Table 1, entry 1). Similar results
were obtained in the presence of Pd(PPh3)4 (Table 1, en-
try 2).11 On the contrary, when Pd(OH)2/C (PearlmanÕs
catalyst) was added to the reaction mixture, the satu-
rated alcohol 4 and ketone 5 were obtained in 27% yield
and in a ratio of 52:48 (Table 1, entry 3). Other palla-
dium catalysts, such as Pd(acac)2 (Table 1, entry 4) or
PdCl2 (Table 1, entry 5), afforded similar results as 4
and 5 were isolated in 52% (ratio 55:45) and in 53% (ra-
tio 77:23), respectively. Likewise, the use of Pd/C (10%)
O
OH
a then b
a then b
C4H9
Ph
C4H9
Ph
(87%, ee=87%)
14
7
OH
O
Ph
Ph
8
15
(96%, ee=86%)
O
OH
a then b
C3H6OTBDPS
Ph
C3H6OTBDPS
Ph
Table 1. Reduction/hydrogenation of 1 under hydrogen transfer
conditions
(82%, ee=88%)
16
9
O
a then b
OH
(2.5% mol)
(R,R)-I
C4H9
TBDPSO(CH2)6
C4H9
HCO2H
TBDPSO(CH2)4
O
OH
Et3N, rt
(70%, ee=80%)
17
10
Ph
Ph
then Pd(X)
(10 mol%)
TMS
OH
TMS
3
1
TBDPSO(CH2)6
O
18 (53%, ee=93%)
a then b
Pd(X)
O
O
TBDPSO(CH2)4
TBDPSO(CH2)6
18' (28%)
OH
OH
11
+
TMS
Ph
TMS
Ph
4
5
OBn
OBn
Entry Pd(X)
Ratio
Global yield (%)
TBDPSO(CH2)6
O
2
4
5
OBn
a then b
(74%, ee=75%)
19
1
2
3
4
5
6
7
Pd(Pb)/CaCO3 (5%) 100
Pd(PPh3)4
Pd(OH)2/C (20%)
Pd(acac)2
PdCl2
—
—
52 48
55 45
77 23
84 16
—
—
59
40
27
52
53
44
80
TBDPSO(CH2)4
100
—
—
—
—
—
O
12
TBDPSO(CH2)6
19' (16%)
Pd/C (10%)
Pd/BaSO4 (10%)
93
7
Scheme 3. Generalization of the one-pot reduction/hydrogenation
reaction. Conditions: (a) (R,R)-I (2.5 mol %), HCO2H (10 equiv), Et3N
(4 equiv), rt;(b) Pd/BaSO 4, (10 mol %) rt, 15 h.
Conditions: HCO2H (10 equiv), Et3N (4 equiv), (R,R)-I (2.5 mol %),
rt, 2 h;then Pd(X) (10 mol %), rt, 15 h.

N. Bogliotti et al. / Tetrahedron Letters 46 (2005) 6915–6918
6917
excess of the obtained alcohol 4 is always 75%.13 It is
worth noting that ketone 5 is probably the result of
the isomerization of the intermediate allylic alcohol 3
to the corresponding enol (vide infra).
OH
C4H9
R
(R,R)-I
(2.5% mol)
O
20 (77%, ee>95%)
C4H9
O
HCO2H
Et3N, rt
24 h
Substrates 6–12 were examined and the results are pre-
sented in Scheme 3. For each propargylic ketone, a clean
conversion to the corresponding saturated secondary
alcohol was obtained after 2–15 h of reaction with the
(R,R)-RuCl[N-(tosyl)-1,2-diphenylethylenediamine)(p-
cymene)] complex and Pd/BaSO4 under transfer hydro-
genation conditions at rt. The evolution of the reaction
was monitored by TLC, and the palladium catalyst was
added after consumption of the starting materials 6–12.
After adding the palladium catalyst, and stirring the
mixture overnight at rt the corresponding alcohols 13–
19 were obtained.14 The configuration of 14 was
assigned by comparing the [a]D value with the literature
data.15
R
10
R
C4H9
13' (18%)
OH
R
C4H9
OH
C4H9
H2, Pd/BaSO4
MeOH
13 (91%, ee>95%)
O
R
20
R
C4H9
13' (5%)
(R,R)-I
(2.5% mol)
O
OH
C4H9
For compounds 6, 11, and 19, the formation of ketones
130, 180, and 190 were observed, respectively, as side
products in variable amounts (0–28%). This was proba-
bly due to the isomerization of the allylic alcohol of type
3 to the corresponding ketone. It is worth noting that
this isomerization is suppressed when the C@C bond is
conjugated to an aryl substituent (substrates 7–9).
R
C4H9
13'
R
HCO2H
Et3N, rt
13
( conv=79%, y=74%)
(ee=0%)
6 d
R= TBDPSO(CH2)4-
Scheme 4. Studies concerning the decrease of enantioselectivity in the
one-pot reduction.
The slight erosion of the enantioselectivity, which was
observed in the case of 13 and 19 in the one-pot protocol
compared to the two steps transformation, was intrigu-
ing. In order to check the raison of this decrease of
enantioselectivity, the transformation of 10 to 13 was
realized stepwise.
(R,R)-I
O
(2.5 mol%)
then quinoline (3.4 equiv)
TMS
Pd/BaSO4 (10%)
At first compound 10 was reduced with a catalytic
amount of (R,R)-I under transfer hydrogenation condi-
tions (Scheme 4).1 The reaction afforded, after 24 h, the
desired propargylic alcohol 20 in 77% yield and in ee
>95%.16 The secondary product of this transformation
was ketone 130, isolated in 18% yield. Compound 20
was then hydrogenated over Pd/BaSO4 catalyst under
H2 atmosphere in MeOH at rt. The reaction afforded
13 in 91% yield with no detectable epimerization (ee
>95%), and also a trace amount of ketone 130 (5%). In
a parallel experience, ketone 130 was submitted to reduc-
tion under NoyoriÕs conditions [(R,R)-I, (2.5 mol %),
HCO2H, TEA, rt],1 and transformed to 13 in 74% yield
as a racemic mixture (79% conversion, 6 days). This
experience showed that the non-selective production of
alcohol 13 via the reduction of the ketone byproduct
130 may compromise the overall selectivity of the process
in this one-pot protocol. Noteworthy, only marginal dif-
ference in the ee was observed between the one-pot and
the two steps protocols, when ketone byproducts were
not formed. For example, the stepwise reduction of 8
resulted in the formation of 15 in 88% ee versus 86%
ee in the one-pot reduction.
1
3 h, rt
(66%)
OH
OH
TMS
TMS
+
(E)-3
4
5 : 1
Scheme 5. The selective preparation of (E)-allyl alcohol (E)-3 from
propargyl ketone 1.
the reaction afforded a mixture of (E)-317 and of the sat-
urated compound 4 in a ratio of 5:1. It is worth noting
that the chemoselectivity depends on the reaction condi-
tions, in particular on the reaction time and the amounts
of the quinoline additive used.
In this study, we have established conditions for a
tandem reduction/hydrogenation sequence, which com-
bines the homogeneous chiral RuCl[N-(tosyl)-1,2-
diphenylethylenediamine)(p-cymene)] catalyst mediated
carbonyl reduction and a heterogeneous Pd/BaSO4-
mediated hydrogenation reaction in one pot, under
transfer hydrogenation conditions. This reaction allows
the direct preparation of enantio-enriched saturated sec-
The reaction can be stopped at the allylic alcohol level
by adding an excess of quinoline (3.4 equiv) in comple-
ment with the palladium catalyst (Scheme 5). However,
when compound 1 was reduced under these conditions,

6918
N. Bogliotti et al. / Tetrahedron Letters 46 (2005) 6915–6918
derivative followed by oxidation of the propargyl alcohol
by PCC. Compound 9 was prepared according to Huang,
P.-Q.;Zheng, X.;Deng, X.-M. Tetrahedron Lett. 2001, 42,
9039–9041.
ondary alcohols from propargyl ketones in an experi-
mentally simple procedure, without potentially hazard-
ous gaseous hydrogen. The application of this one-pot
sequence in the synthesis of natural products is under-
way in the laboratory.
9. The enantiomeric purity was determined by chiral HPLC:
Column: Daicel CHIRALCEL OD-H;eluent: n-hexane/2-
propanol: 98:2;flow rate: 0.5 mL/min À1; l = 220 nm;
retention times: 35.8 min (minor), 57.6 min (major).
10. The reduction of propargylic ketones with complex (R,R)-
I affords systematically the corresponding propargylic
alcohols with the (R) absolute configuration according to
Ref. 1b.
11. Prepared from Pd(dba)2 and PPh3 (5 equiv) in CH2Cl2,
stirred for 10 min and added to the mixture via cannula.
12. The low yield observed in these entries is essentially due to
the partial desilylation of 1.
References and notes
1. (a) Kitamura, M.;Tokunaga, M.;Noyori, R.
J. Am.
Chem. Soc. 1993, 115, 144–152;For a review see: (b)
Noyori, R.;Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40,
40–73, See also;(c) Geneˆt, J.-P. Acc. Chem. Res. 2003, 36,
908–918.
2. (a) Cossy, J.;Eustache, F.;Dalko, P. I. Tetrahedron Lett.
2001, 42, 5005–5007;(b) Eustache, F.;Dalko, P. I.;Cossy,
J. Org. Lett. 2002, 4, 1263;(c) Mordant, C.;Du nkelmann,
13. The lower enantioselectivity of the products 4 (75%)
compared to 2 (90%) is probably due to the formation of
5, which was reduced to the corresponding alcohol in low
ee.
¨
P.;Ratovelomanana-Vidal, V.;Gene ˆt, J.-P. Eur. J. Org.
Chem. 2004, 3017–3026;(d) Jung, H.;Koh, J. H.;Kim,
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Papillon, J. P. N.;Harrington, P. E.;Shin, S.;Shireman,
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Eustache, F.;Dalko, P. I.;Cossy, J. J. Org. Chem. 2003,
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4. For ruthenium-mediated tandem olefination/reduction
reactions see: (a) Louie, J.;Bielawski, C. W.;Grubbs, R.
H. J. Am. Chem. Soc. 2001, 123, 11312;(b) Cossy, J.;
Bargiggia, F.;BouzBouz, S. Org. Lett. 2003, 5, 459.
5. For Ru(II)-mediated hydrogenation of C@C double
bonds see: Xue, D.;Chen, Y.-C.;Cui, X.;Wang, Q.-W.;
Zhu, J.;Deng, J.-G. J. Org. Chem. 2005, 70, 3584–3591,
and references cited therein.
14. Typical procedure: To a mixture of propargyl ketone
(0.81 mmol) in formic acid (304 lL, 8.05 mmol, 10 equiv)
and triethylamine (453 lL, 3.22 mmol, 4 equiv) were
added at rt an aliquat amount of the stock solution of
the RuCl[N-(tosyl)-1,2-diphenylethylenediamine)(p-cym-
ene) complex 0.03 M in CH2Cl2 (670 lL, 0.02 mmol,
0.025 equiv), prepared according to Ref. 18. The evolution
of the reaction was monitored by TLC. When the starting
material was totally consumed (2–15 h), the Rosemund
catalyst (Pd on BaSO4, 10%, 85 mg, 0.081 mmol,
0.1 equiv) was added and the mixture was stirred over-
night at rt. Then, the mixture was diluted with CH2Cl2
(3 mL), filtered on a cake of silica gel and the volatile
residues were evaporated under reduced pressure. The
crude product was purified by chromatography on silica
gel using a gradient of solvent (petroleum ether/ethyl
acetate 95:5 to 90:10).
15. Sumida, S.-i.;Ohga, M.;Mitani, J.;Nokami, J.
J. Am.
Chem. Soc. 2000, 122, 1310–1313. (3R)-Phenylheptan-3-ol
lit
(14): [a]D: À12.0 (c 1.0, CHCl3); ½aꢀD: À11.6 (c 3.9,
6. (a) Lee, J. M.;Na, Y.;Han, H.;Chang, S. Chem. Soc. Rev.
2004, 33, 302;(b) Wasilke, J.-C.;Obrey, S. J.;Baker, R.
T.;Bazan, G. C. Chem. Rev. 2005, 105, 1001–1020.
7. For heterogeneous transfer hydrogenation of alkyne and
alkene see: (a) Yu, J.;Spencer, J. B. Chem. Commun. 1998,
1935–1936;(b) Yu, J.;Spencer, J. B. Chem. Eur. J. 1999, 5,
2237–2240.
CHCl3).
16. The alcohol was converted to the corresponding (R)-
MosherÕ ester, and the enantioselectivity of the transfor-
1
mation was established by H NMR.
17. Established by 1H NMR. The kinetic product of the
reaction is the corresponding (Z)-olefin, which is con-
verted slowly to the (E)-product.
8. Starting materials 1, 6–8 and 10–12 were prepared from
the corresponding aldehyde and the lithiated acetylene
18. Uematsu, N.;Fujii, A.;Hashiguchi, S.;Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916–4917.