Tandem metal- and organocatalysis in sequential hydroformylation and enantioselective aldol reactions

Article abstract of DOI:10.1002/adsc.200700160

Metal-catalysed hydroformylation is successfully combined with organocatalysed stereoselective aldol addition into a tandem reaction sequence. This novel type of "tandem catalysis" allows access to complex molecular systems with high levels of enantioselectivity, using simple starting materials and an amino acid as the chiral catalyst.

Full text of DOI:10.1002/adsc.200700160

FULL PAPERS
DOI: 10.1002/adsc.200700160
Tandem Metal- and Organocatalysis in Sequential
Hydroformylation and Enantioselective Aldol Reactions
Serghei Cherchejaa and Peter Eilbrachta,*
a
Fachbereich Chemie, Organische Chemie I, Universität Dortmund, Otto-Hahn-Str. 6, 44227 Dortmund, Germany
Fax : (+49)-231-755-5363; e-mail: peter.eilbracht@udo.edu
Received: March 29, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Metal-catalysed hydroformylation is suc- enantioselectivity, using simple starting materials and
cessfully combined with organocatalysed stereoselec- an amino acid as the chiral catalyst.
tive aldol addition into a tandem reaction sequence.
This novel type of “tandem catalysis” allows access Keywords: aldol reaction; hydroformylation; organo-
to complex molecular systems with high levels of catalysis; tandem catalysis
Introduction
excess of phosphorus ligand. l-Proline was employed
as the organocatalyst since, according to previous in-
Control of stereochemistry during aldol addition reac- vestigations,[6] it exhibits excellent catalytic activity in
tions has attracted considerable interest over the last enantioselective aldol reactions. Based on earlier find-
decades, as the aldol reaction is one of the most pow- ings that high pressure efficiently promotes l-proline-
erful and versatile methods in modern carbonyl catalysed asymmetric aldol reactions in low-boiling
chemistry.[1] Simple chiral organic molecules have solvents,[7] acetone was chosen both as a ketone com-
been found to catalyse the direct aldol addition of un- ponent and a solvent.
modified ketones to aldehydes with high chemical
In control experiments possible negative interac-
and stereochemical efficiency.[2] On the other hand, tions between Rh catalyst and organocatalyst were
hydroformylation of olefins, one of the largest indus- tested in he hydroformylation of cyclopentene and 4-
trially applied homogeneously catalysed processes, chlorostyrene in the presence of l-proline (Table 1).
provides the synthetically useful aldehyde function
As shown in Table 1, hydroformylation of olefins
for further transformations, e.g., aldol addition. Fol- with triphenyl phosphite-modified rhodium catalyst
lowing a general trend in organic chemistry to com- both in the presence and in the absence of l-proline
bine several individual reaction steps to a single syn- takes place with excellent conversions and yields (>
thetic procedure,[3] we have developed hydroformyla- 99%), no self-aldolisation of the aldehydes 1 and 2a,
tion/aldol reaction sequences[4] and here now report b is observed (Table 1, entries 3, 4, 7 and 8). The un-
an enantioselective version with chiral organocata- modified Rh catalyst under the same conditions gives
lysts.
full conversion of cyclopentene but incomplete con-
version of 4-chlorostyrene (Table 1, entries 1, 2, 5, and
6). According to GC and HNMR analyses of crude
1
Results and Discussion
mixtures during the hydroformylation reaction only
aldehydes are formed. Under the conditions given in
The conversion of cyclopentene and acetone to an Table 1, aldehyde 2a is generated with excellent regio-
aldol product under hydroformylation conditions in selectivities (up to 99:1 branched/linear ratio), but
the presence of Rh catalyst and l-proline was selected shows no optical activity, thus l-proline does not in-
as a first model reaction in order to avoid the regiose- fluence the stereochemistry of the hydroformylation
lectivity problems of hydroformylation and aldol reac- step.
tions. As an additional advantage the hydroformyla-
Next we investigated whether rhodium catalysts are
tion of this alkene can be performed under mild con- compatible with organocatalysed enantioselective
ditions.[5] The active catalyst for the hydroformylation aldol reactions, and performed test aldol reactions
was prepared in situ from [Rh(acac)(CO)2] and an with preformed aldehyde 1 both under atmospheric
G
Adv. Synth. Catal. 2007, 349, 1897 – 1905
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Serghei Chercheja and Peter Eilbracht
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Table 1. Hydroformylation reactions both in the presence and in the absence of l-proline.
Entry Conditions[a]
Substrate
Conversion [%][b] Aldehyde yield [%][b] b:l ratio[b]
1
2
3
4
5
6
7
8
Rh
Rh(acac)(CO)2, acetone
Rh(acac)(CO)2, P(OPh)3, acetone
Rh(acac)(CO)2, P(OPh)3, acetone
Rh(acac)(CO)2, l-proline, CH2Cl2
Rh(acac)(CO)2, l-proline, CH2Cl2
Rh(acac)(CO)2, P(OPh)3, l-proline, CH2Cl2 cyclopentene
Rh(acac)(CO)2, P(OPh)3, l-proline, CH2Cl2 4-chlorostyrene >99
C
cyclopentene
4-chlorostyrene 49
cyclopentene
4-chlorostyrene >99
cyclopentene
4-chlorostyrene 75
>99
>99
>99
49
>99
>99
>99
75
-
97:3
-
98:2
-
97:3
-
99:1
>99
>99
>99
>99
[a]
[b]
20/20 bar CO/H2, 408C, 72 h.
Determined by GC using an internal standard.
Table 2. Aldol reactions in the presence of Rh catalysts both under atmospheric pressure and under hydroformylation condi-
tions.
Entry Conditions[a]
Temperature Time Aldehyde conversion Yield
ee [%][d]
of 3
[8C]
[h]
(%)[b]
[%][c]
3
4
1
2
3
4
l-proline, acetone
25
25
25
25
24
24
24
24
87
93
88
41
30 5
27 3
38 12 78
80
71
Rh
Rh
ACHTREUNG
A
N
20/20 bar CO/H2, Rh
U
E
19 <1 81
proline, acetone
5
6
7
20/20 bar CO/H2, Rh
proline, acetone
A
G
40
40
40
24
48
72
88
96
97
62 <1 81
65 <1 79
63 <1 78
20/20 bar CO/H2, Rh
N
proline, acetone
20/20 bar CO/H2, Rh
C
proline, acetone
[a]
[b]
[c]
[d]
20/20 bar CO/H2, 408C, 72 h.
Based on isolated unreacted aldehyde.
Based on isolated product.
Determined by chiral HPLC.
pressure and under hydroformylation conditions plexes only marginally affects the conversion of alde-
(Table 2). For the determination of results direct GC hyde 1 (Table 2, entries 2 and 3). In contrast, at room
analysis was impossible. After injection of a crude re- temperature under hydroformylation conditions, a de-
action mixture aldol product 3 partially self-decom- crease of aldehyde conversion and suppression of the
posed with generation of aldehyde 1, therefore deter- elimination to product 4 are observed (Table 2,
mination of the aldehyde conversion was based on entry 4). Under hydroformylation conditions at 408C
isolated unreacted aldehyde.
aldehyde 1 is almost fully converted to aldol product
As shown in Table 2, under atmospheric pressure at 3 within 48 h (Table 2, entry 6). Enantioselectivity is
room temperature the presence of rhodium com- not affected by the pressure and presence of rhodium
1898
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Sequential Hydroformylation and Enantioselective Aldol Reactions
FULL PAPERS
(Table 3, entry 2). Diphosphine ligands lowered the
activity of the corresponding Rh catalysts. As a result
the olefin is not converted with XANTPHOS, and
poor conversion is observed with dppb and dppf li-
gands under the given conditions (vide supra), al-
though good stereoselectivities (65–72% ee) of the
aldol product 3 were obtained (Table 3, entries 3, 4
and 5).
Triphenyl phosphite and BIPHEPHOS show a sig-
nificant advantage over all other phosphorus ligands
tested. After 72 h the olefin is fully converted under
hydroformylation conditions and the aldol product 3
is formed with good enantioselectivities (Table 3, en-
tries 6 and 7). Usually phosphites give more active
catalysts than phosphines. This is mainly based on
electronic factors. The phosphite ligands as a stronger
electron p-acceptor induce faster replacement of a
carbonyl ligand by the alkene substrate, resulting in
higher reaction rates.[5a,9]
Figure 1. Phosphorus ligands tested.
catalysts. The absolute stereochemistry of the b-hy-
As hydroformylation and aldol reactions are ex-
droxy group of the aldol adduct 3 being (R) was de- tremely sensitive to the reaction conditions, various
termined by Mosherꢁs method.[8]
CO and H2 partial pressures were studied to ascertain
For effective tandem catalysis a range of phospho- pressure effects on tandem hydroformylation/enantio-
rus ligands (Figure 1) was tested for sequential hydro- selective aldol reactions. The reactions of cyclopen-
formylation and enantioselective aldol reactions of cy- tene and acetone were performed at 10/10, 20/20, 30/
clopentene and acetone. The results are summarised 30, 40/40 and 70/10 bar pressures of CO/H2 (Table 4).
in Table 3.
Reactions at 10/10, 20/20, 30/30 and 40/40 bar gas
Surprisingly, the catalytic system with unmodified pressures provided medium to good yields (48–76%)
rhodium catalyst gave no conversion of the olefin of the desired compound 3 (Table 4, entries 1, 2, 3
(Table 3, entry 1). The steric and electronic properties and 4). In contrast with 6a, b (vide infra), at 70/10 bar
of ligands drastically influence the rate of the hydro- CO/H2, a drastic decrease in yields of the aldol prod-
formylation reaction sequence. Rh catalyst modified uct 3 (23%) was observed. Noteworthy, varying the
with non-bulky PPh3 ligand gave good conversion total pressure from 20 to 80 bar has only small effects
(89%) of the olefin after three days of reaction on the enantioselectivities (73–81% ee).
Table 3. Phosphorus ligand screening for the sequential hydroformylation/enantioselective aldol reactions.
Entry
Ligand
Reaction time [h]
Alkene conversion [%][b]
Isolated yield [%][c]
ee (%)[d] of 3
3
1
1
2
3
4
5
6
7
8
9
none
PPh3
XANTPHOS
dppb
dppf
72
72
72
72
72
72
72
48
24
none
89
none
10
-
46
-
3
7
72
76
70
18
-
8
-
nd
3
7
6
8
15
-
74
-
65
72
82
75
81
80
17
BIPHEPHOS
>99
>99
95
P
P
P
C
54
[a]
0.5 mol% Rh(acac)(CO)2, 2 mol% phosphorus ligand, 30 mol% l-proline, 20/20 bar CO/H2, 408C, acetone.
Determined by GC using an internal standard.
Based on isolated product.
A
[b]
[c]
[d]
Determined by chiral HPLC; nd=not determined.
Adv. Synth. Catal. 2007, 349, 1897 – 1905
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Serghei Chercheja and Peter Eilbracht
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Table 4. Influence of CO and H2 partial pressures on sequential hydroformylation/enantioselective aldol reactions.
Entry
PCO [bar]
PH [bar]
Alkene conversion [%][b]
Isolated yield [%]
ee [%][c] of 3
2
3
1
1
2
3
4
5
10
20
30
40
70
10
20
30
40
10
>99
>99
>99
>99
>99
51
76
70
48
23
8
6
9
3
5
74
75
73
81
78
[a]
0.5 mol% Rh
Determined by GC using an internal standard.
Determined by chiral HPLC.
N
A
[b]
[c]
Using similar conditions cycloheptene on conver- formed using 40 and 80 bar total gas pressures
sion by sequential hydroformylation and enantioselec- (Table 5). The absolute stereochemistry of the b-hy-
tive aldol reactions, gives the aldol product 5 in 47% droxy group of the aldol adduct 6a was determined
yield with 89% ee (Scheme 1). The absolute configu- by Mosherꢁs method.[8] The relative configurations of
ration of compound 5 was assigned by analogy with compunds 6a, b were assigned by analogy with the
compound 3.
known racemic compounds 7a, b[10] (vide infra).
Up to now, olefins and ketones explored in the se-
As shown in Table 5, here, no significant influence
quential hydroformylation and enantioselective aldol of pressure on yields, enantio- and diastereoselectivi-
reactions were not prochiral. For further studies pro- ties was observed. The two major stereoisomers ob-
chiral olefins and/or prochiral ketones were consid- tained have the same configuration at the carbon
ered since additional stereogenic centres are formed bonded to the hydroxy group and opposite configura-
(Scheme 2).
tions at the carbons bearing the methyl group. Here
At first, for the reaction between prochiral 4-chloro- diastereoselectivities are not expected to be high
styrene and acetone, pressure experiments were per- since the hydroformylation step gives a racemate
even in the presence of l-proline (see Table 1, en-
tries 6 and 8), whereas the organocatalyst stereoselec-
tively catalyses the aldol step towards the same con-
figuration at the b-hydroxy group of both diastereo-
isomers.
Despite the findings that the best enantioselectivi-
ties were obtained at 80 bar total pressure, 20/20 bar
Scheme 1. Sequential
aldol reactions of cycloheptene and acetone.
CO/H2, 0.5 mol% Rh(acac)(CO)2, 2 mol% P
mol% L-proline, 408C, 72 h, acetone. Determined by GC
using an internal standard.
hydroformylation/enantioselective
[a]
CO/H2 was selected as the milder reaction conditions
for all further studies with styrene and 2,5-dihydrofur-
an as prochiral olefins, and cyclopentanone as a pro-
chiral ketone (Table 6).
20/20 bar
(OPh)3, 30
G
ACHTREUNG
[b]
Styrene, as another prochiral olefin, gave identical
results as compared to 4-chlorostyrene. In the reac-
tion of prochiral 2,5-dihydrofuran acetone enantiose-
lectivities of 71% were observed, but no diastereose-
lectivity. On the other hand, with non-prochiral cyclic
alkenes and prochiral cyclopentanone very good
yields and enantioselectivities, but again only low dia-
stereoselectivities were obtained (Table 6, entries 3
and 4).
In order to determine the relative and absolute
configurations of compounds 9a, b and 10a, b a con-
trol room temperature experiment was performed
with cyclohexanecarbaldehyde and cyclopentanone in
the presence of l-proline. (Scheme 3). The assignment
Scheme 2. Origin of stereogenic centres in sequential hydro-
formylation/enantioselective aldol reactions.
1900
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Sequential Hydroformylation and Enantioselective Aldol Reactions
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Table 5. Influence of CO and H2 partial pressures on sequential hydroformylation/enantioselective aldol reactions.
Entry
PCO [bar]
PH [bar]
Alkene conversion [%][b]
Yield [%][c] 6a+6b
dr[d] (syn:anti)
ee [%][e]
2
6a
6b
1
2
3
20
40
70
20
40
10
>99
>99
>99
89
85
89
1.5 : 1
1.5 : 1
1.5 : 1
72
76
77
>99
>99
>99
[a]
0.5 mol% Rh
Determined by GC using an internal standard.
Based on isolated product.
Determined by HNMR analyses.
Determined by chiral HPLC.
A
G
[b]
[c]
[d]
[e]
1
Table 6. Sequential hydroformylation/enantioselective aldol reactions of alkenes with P
ACHTREUNG
Entry Substrate Ketone=solvent Product
Olefin conversion
[%][b]
Yield
[%][c]
72 (for syn);>99 (for
anti)
1
>99
83
1.5 : 1
71 (for syn); 71 (for
anti)
2
3
>99
>99
71
59
1 : 1
95[f] (for syn); 96 (for
anti)
1 : 2.7
83 (for syn); 85 (for
anti)
4
>99
76
1 : 1.9
[a]
0.5 mol% Rh
Determined by GC using an internal standard.
Based on isolated product.
Determined by HNMR analyses.
Determined by chiral HPLC.
A
G
[b]
[c]
[d]
[e]
[f]
1
Determined by Mosherꢁs method.
was based on the comparison of spectral data known surprising sensitivity of the diastereoselectivity to-
for racemic compounds 12a, b[11] and the results ob- wards substrate structure and reaction conditions.
tained in the reaction of cyclohexanone with benzal- Thus, for further investigations of syn:anti diastereo-
dehyde.[12]
selectivities various parameters have to be explored.
In all cases the absolute configuration at the b-hy-
droxy group is not identical for the syn/anti diastereo-
mers (Table 6, entries 3 and 4, and Scheme 3). Note- Conclusions
worthy, with cyclohexanecarbaldehyde (Scheme 3) the
syn:anti ratio is reversed as compared to the tandem In conclusion, we successfully combined a metal-cata-
reactions with cyclic olefins and cyclopentanone de- lysed (hydroformylation) reaction with an organocata-
scribed above (Table 6, entries 3 and 4). This shows a lysed (stereoselective aldol) reaction in a tandem re-
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Serghei Chercheja and Peter Eilbracht
FULL PAPERS
ence (dH =7.26 ppm for CDCl3 and dH =7.15 ppm for C6D6).
13C NMR spectra were recorded on the same spectrometers
and referenced to solvent signals (dC =77 ppm for CDCl3
and dC =128.02 ppm for C6D6). Chemical shifts (d) are given
in parts per million (ppm) and coupling constants (J) are
given in Hertz (Hz). The proton spectra are reported as fol-
lows d/ppm (multiplicity, number of protons, coupling con-
stant J/Hz). DEPT135 and two dimensional (COSY,
HMQC, HMBC) NMR spectroscopy were used where ap-
propriate, to aid the assignment of signals in the 1Hand
13C NMR spectra. IR spectra were recorded on an Impact
400 spectrometer and are reported in terms of frequency of
absorption (cmÀ1). Mass spectra were obtained from the
University of Dortmund Mass Spectral facility. Elemental
analyses were carried out in the Laboratory of Elemental
Analyses at the University of Dortmund. Optical rotations
were measured on a Perkin–Elmer 341 polarimeter. Semi-
preparative HPLC was performed using a SUPELCOSILTM
LC-SI 5 mm (25 cm”21.2 mm) column. Analytical HPLC
was performed on a Hewlett–Packard 1050 Series chromato-
graphs using a CHIRALCEL OD (250”4.6 mm), CHIRAL-
CEL OJ (250”4.6 mm) and CHRALPAK AD (250”
4.6 mm) columns as noted.
Scheme 3. l-Proline-catalysed asymmetric aldol reaction of
cyclohexanecarbaldehyde and cyclopentanone
action sequence. It could be demonstrated that orga-
nocatalysis of aldol reactions even under hydroformy-
lation conditions occur with high enantioselectivities,
although the usually observed[11] diastereoselectivities
are still to be optimised. This novel type of “tandem
catalysis”[13] is expected to be applicable to a variety
of olefins and ketones, affording complex molecular
systems with high levels of enantioselectivity, using
simple starting materials and an amino acid as the
chiral catalyst. We are currently investigating a com-
bination of enantioselective hydroformylation and
enantioselective aldol reactions in a tandem reaction
sequence, with more complex starting materials, in-
cluding combinations of both prochiral olefins and
prochiral ketones.
Hydroformylation Reactions in the Presence of l-
Proline (Table 1, entries 7 and 8)
To
0.005 equivs.) in 5 mL of CH2Cl2 in a vial, was added
(OPh)3 (24 mg, 0.078 mmol, 0.02 equivs.). The solution was
a
solution of Rh
A
P
ACHTREUNG
stirred with a magnetic stirrer for 5 min and then charged
with olefin (3.9 mmol, 1 equiv.), dodecane (199 mg,
1.17 mmol, 0.3 equivs.) and l-proline (135 mg, 1.17 mmol,
0.3 equivs.). The vial was transferred to the autoclave, pres-
surised to 20/20 bar CO/H2 and heated to 408C. After the
reaction was completed, the autoclave was cooled down to
room temperature, depressurised, flushed with argon and
opened to obtain a sample for GC analysis. Cyclopentene
products: carrier gas 40 kPa He, temperature program of
308C for 10 min, then 158C/min to 2608C; retention times:
4.57 min for cyclopentene, 17.60 min for cyclopentanecarbal-
dehyde, 21.23 min for dodecane. 4-Chlorostyrene products:
carrier gas 65 kPa He, temperature program of 358C for
10 min, then 108C/min to 2608C; retention times: 21.63 min
for 4-chlorostyrene, 22.27 min for dodecane, 26.47 min for
aldehyde 2a (branched regioisomer), 27.86 min for aldehyde
2b (linear regioisomer).
Experimental Section
General Remarks
Hydroformylation experiments were carried out in a Ber-
ghof HR-200 high pressure reactor with magnetic stirring
and electrical heating. The inside part of the cover was
made from Teflonꢂ to protect the solution from direct con-
tact with the stainless steel. All reactions were carried out in
freshly distilled solvents. Dichloromethane and triethyl-
amine were distilled from calcium hydride. All phosphorus
ligands, except BIPHEPHOS, are commercially available.
BIPHEPHOS was synthesised according to the literature
procedure.[14] Commercial reagents were used as received.
Organic solutions were concentrated under reduced pressure
on a rotary evaporator. Column chromatography was car-
ried out using MN Kieselgel 60 (0.063–0.2 mm/70–230
mesh). TLC was performed on Merck Silica gel 60 F254
plates. Visualisation of the developed chromatograms was
performed by ultraviolet irradiation (254 nm) or by anisal-
dehyde stain. Melting points were performed on a Büchiꢂ
melting point apparatus, and are uncorrected. For gas chro-
matographic analyses, a Carlo Erba HRGC Mega2 Series
MFC 800 chromatograph with a Carlo Erba EL 580 flame-
ionisation detector (FID) was used. Separations were per-
formed on the column CHROMPACK DB-1701 (25 m”
0.32 mm”1.0 mm). 1HNMR spectra were recorded on
Bruker 400 and Bruker 500 spectrometers, with residual
proton signal of the deuterated solvent as the internal refer-
Aldol Reaction in the Presence of Rh Catalyst under
Atmospheric Pressure (Table 2, entry 3)
To
0.005 equivs.) in 5 mL of acetone in a flask, was added
(OPh)3 (24 mg, 0.076 mmol, 0.02 equivs.). The solution was
a
solution of Rh(acac)(CO)2 (5 mg, 0.019 mmol,
A
P
ACHTREUNG
stirred with a magnetic stirrer for 5 min and then charged
with cyclopentanecarbaldehyde (373 mg, 3.8 mmol, 1 equiv.)
and l-proline (131 mg, 1.14 mmol, 0.3 equivs.). The resulting
mixture was stirred at room temperature for 24 h. Then, the
reaction mixture was filtered through a column filled with
silica gel. Additionally the column was washed with 50 mL
of diethyl ether. The filtrate was concentrated under
vacuum (compounds 1 and 4 are volatile, it is not recom-
1902
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Sequential Hydroformylation and Enantioselective Aldol Reactions
FULL PAPERS
mended to use pressure less than 200 mbar at 408C) and the
crude product was purified by column chromatography
(MTBE/cyclohexane, 1:4) to give unreacted cyclopentane-
carbaldehyde (yield: 36 mg, 12%), (Z)-4-cyclopentylbut-3-
en-2-one 4 (Rf =0.68) as a pale yellow oil (yield: 51 mg,
12%) and (R)-4-cyclopentyl-4-hydroxybutan-2-one 3 (Rf =
0.34) as a pale yellow oil (yield: 178 mg, 38%). HPLC:
(35 mg, 26 mL, 0.14 mmol), CH2Cl2 (300 mL) and the sub-
strate aldol (0.10 mmol). After 24 h of stirring, the mixture
was diluted with diethyl ether, washed (cold dilute HCl,
cold saturated NaHCO3 and brine), dried (MgSO4) and con-
centrated under reduced pressure to afford a colourless oil,
which was further purified by column chromatography.
CHIRALPAK
AD,
n-heptane/i-PrOH,
98.2:1.8,
1.0 mLminÀ1, 280 nm, ee=78%: tR (major)=19.0 min; tR
(minor)=20.5 min.
l-Proline-Catalysed Asymmetric Aldol Reaction of
Cyclohexanecarbaldehyde and Cyclopentanone
(Scheme 3)
Aldol Reaction in the Presence of Rh-catalyst under
Hydroformylation Conditions (Table 2, entry 6)
To a stirred suspension of l-proline (126 mg, 1 mmol,
0.3 equivs.) in 5 mL of cyclopentanone was added cyclohex-
anecarbaldehyde (300 mg, 3.65 mmol, 1 equiv.). The result-
ing mixture was stirred at room temperature for 72 h. Then,
the reaction mixture was filtered through a column filled
with silica gel. Additionally the column was washed with
50 mL of diethyl ether. The filtrate was concentrated under
vacuum and the crude product was purified by column chro-
matography (EtOAc/cyclohexane, 1:4) to afford compounds
13,[15] 12a[15] and 12b.
(E)-2-(Cyclohexylmethylene)cyclopentanone (13): Rf =
0.50 (yield: 43 mg, 9%). 1HNMR (400 MHz, CDCl 3): d=
6.37 (td, 1H, J=6.0, 2.5 Hz), 2.58 (dt, 2H, J=7.2, 2.5 Hz),
2.30 (t, 2H, J=7.8 Hz), 2.19–2.10 (m, 1H), 1.94–1.89 (m,
2H), 1.75–1.61 (m, 5H), 1.32–1.10 (m, 5H); 13C NMR
(100 MHz, CDCl3): d=19.8, 25.4, 25.7, 26.5, 31.6, 38.5, 38.7,
135.2, 140.9, 207.9, in accord with the literature data.[15]
To
0.005 equivs.) in 5mL of acetone in a vial, was added
(OPh)3 (24mg, 0.076mmol, 0.02 equivs.). The solution was
a
solution of Rh(acac)(CO)2 (5mg, 0.019mmol,
A
P
ACHTREUNG
stirred with a magnetic stirrer for 5min and then charged
with cyclopentanecarbaldehyde (373mg, 3.8mmol, 1 equiv.)
and l-proline (131mg, 1.14mmol, 0.3 equivs.). The vial was
transferred to the autoclave, pressurised to 20/20 bar CO/H2
and heated to 408C. After the reaction was completed, the
autoclave was cooled down to room temperature, depressur-
ised, flushed with argon and opened. The reaction mixture
was filtered through a column filled with silica gel. Addi-
tionally the column was washed with 50mL of diethyl ether.
The filtrate was concentrated under vacuum (compounds 1
and 4 are volatile, it is not recommended to use pressure
less than 200mbar at 408C) and the crude product was puri-
fied by column chromatography (MTBE/cyclohexane, 1:4)
to give unreacted cyclopentanecarbaldehyde (yield: 12mg,
4%) and (R)-4-cyclopentyl-4-hydroxybutan-2-one 3 (Rf =
0.34) as a pale yellow oil (yield: 396mg, 65%). HPLC:
(S)-2-[(R)-Cyclohexyl(hydroxy)methyl]cyclopentanone
R
(12a): Rf =0.31 (yield: 225 mg, 43%). 1HNMR (400 MHz,
CDCl3): d=3.98 (br. s, 1H), 3.51 (dd, 1H, J=9.0, 1.9 Hz),
2.40–1.10 (m, 18H); 13C NMR (100 MHz, CDCl3): d=20.6,
25.0, 26.4, 26.6, 30.0, 38.4, 40.9, 51.3, 76.0, 224.9, in accord
with the literature data.[15] 1HNMR (400 MHz, C 6D6): d=
4.29 (br. s, 1H), 3.37 (dd, 1H, J=9.1, 2.5 Hz), 1.88–0.80 (m,
18H); 13C NMR (100 MHz, C6D6): d=20.5, 25.2, 26.3, 26.8,
26.9, 27.1, 30.5, 38.1, 41.3, 51.1, 76.1, 223.6; [a]2D0: À112.8 (c
1.00, n-heptane); HPLC: CHIRALPAK AD, n-heptane/i-
PrOH, 95:5, 1.0 mLminÀ1, 280 nm, ee=86%: tR (major)=
11.1 min; tR (minor)=9.7 min.
CHIRALPAK
AD,
n-heptane/i-PrOH,
98.2:1.8,
1.0mLminÀ1, 280 nm, ee=79%: tR (major)=19.0min; tR
(minor)=20.5min.
Sequential Hydroformylation and Enantioselective
Aldol Reactions
To
a
solution of Rh(acac)(CO)2 (5 mg, 0.019 mmol,
A
(S)-2-[(S)-Cyclohexyl(hydroxy)methyl]cyclopentanone
N
0.005 equivs.) in 5 mL of ketone in a vial, was added a phos-
phorus ligand (0.076 mmol, 0.02 equivs.). The solution was
stirred with a magnetic stirrer for 5 min and then charged
with alkene (3.8 mmol, 1 equiv.) and l-proline (131 mg,
1.14 mmol, 0.3 equivs.). The vial was transferred to the auto-
clave, pressurised and heated to 408C. After the reaction
was completed, the autoclave was cooled down to room
temperature, depressurised, flushed with argon and opened
to obtained a sample for GC analysis. Then the reaction
mixture was filtered through a column filled with silica gel.
Additionally the column was washed with 50 mL of diethyl
ether. The filtrate was concentrated under vacuum and the
crude product was purified by column chromatography.
1
(12b): Rf =0.13 (yield: 120 mg, 23%). HNMR (400 MHz,
CDCl3): d=3.79 (dd, 1H, J=9.0, 2.4 Hz), 2.33–0.82 (m,
18H); 13C NMR (100 MHz, CDCl3): d=20.6, 22.4, 25.7, 26.0,
26.2, 29.0, 29.5, 39.0, 41.2, 52.1, 73.9, 222.3; 1HNMR
(400 MHz, C6D6): d=3.80 (dd, 1H, J=8.8, 1.8 Hz), 2.06–
0.66 (m, 18H); 13C NMR (100 MHz, C6D6): d=20.8, 22.6,
26.2, 26.4, 26.7, 29.3, 29.7, 38.9, 41.8, 52.0, 74.0, 220.2; [a]2D0:
+115.5 (c 1.00, n-heptane); HPLC: CHIRALCEL OD-H,
n-heptane/i-PrOH, 98:2, 1.0 mLminÀ1, 280 nm, ee=79%: tR
(major)=12.3 min; tR (minor)=9.6 min.
(R)-4-Cyclopentyl-4-hydroxybutan-2-one (3) (Table 4,
entry 4): Purified using column chromatography (EtOAc/cy-
clohexane, 1:4) to afford the title compound as a colourless
1
oil (yield: 293 mg, 48%). HNMR (400 MHz, CDCl 3): d=
Preparation of MTPA Derivatives (Mosherꢀs
Method)
3.84–3.79 (m, 1H), 2.96 (d, 1H, J=3.2 Hz), 2.64 (dd, 1H,
J=17.6, 2.0 Hz), 2.52 (dd, 1H, J=17.6, 9.6 Hz), 2.17 (s, 3H),
1.90–1.75 (m, 2H), 1.67–1.49 (m, 5H), 1.42–1.34 (m, 1H),
1.19–1.13 (m, 1H); 13C NMR (100 MHz, CDCl3): d=25.4,
25.6, 28.7, 28.9, 30.7, 45.2, 49.0, 71.5, 210.2; HR-MS (FAB+):
exact mass calculated for [M+H]+ (C9H17O2) requires m/z=
157.1229, found: m/z=157.1155; elemental analysis (%),
The reaction was carried out in a dry Schlenk tube fitted
with a rubber septum. The reagents were injected via sy-
ringe into the tube in the following order: Et3N (300 mL,
220 mg), DMAP (1 mg, 0.01 mmol), S-(+)-MTPA-Cl
(MTPA=a-methoxy-a-trifluoromethylphenylacetic
acid)
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ꢀ 2007 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
asc.wiley-vch.de
1903

Serghei Chercheja and Peter Eilbracht
FULL PAPERS
calculated for C9H16O2: C 69.19, H10.32; found: C 68.96, H
the mixture of syn/anti diastereomers (1.5:1) of the title
compound as a colourless oil (yield: 615 mg, 83%). Diaste-
10.60. IR (filM): nmax =3435, 2952, 2868, 1709, 1360 cmÀ1
;
[a]2D0: +45.7 (c 1.00, n-heptane); HPLC: CHIRALPAK AD,
n-heptane/i-PrOH, 98.2:1.8, 1.0 mLminÀ1, 280 nm, ee=81%:
tR (major)=19.1 min; tR (minor)=20.7 min.
reomers were separated on
column (EtOAc/cyclohexane, 1:6).
(4R,5R)-4-Hydroxy-5-phenylhexan-2-one (7a): 1HNMR
a semi-preparative HPLC
AHCTREUNG
1
(Z)-4-Cyclopentylbut-3-en-2-one (4): HNMR (400 MHz,
(500 MHz, CDCl3): d=7.32–7.29 (m, 2H), 7.24–7.16 (m,
3H), 4.09 (ddd, 1H, J=7.9, 5.8, 5.8 Hz), 2.74 (qd, 1H, J=
7.9, 7.0 Hz), 2.42–2.40 (m, 2H), 2.07 (s, 3H), 1.36 (d, 3H,
J=7.0 Hz); 13C NMR (100 MHz, CDCl3): d=17.6, 30.7, 45.4,
47.9, 72.1, 126.6, 127.6, 128.6, 143.8, 210.1, in accord with the
literature data;[17] HR-MS (FAB+): exact mass calculated
for [M+H]+ (C12H17O2) requires m/z=193.1229, found:
m/z=193.1236; elemental analysis (%), calculated for
C12H16O2: C 74.97, H8.39; found: C 74.48, H8.50; IR
(film): nmax =3461, 2965, 1708, 1493, 1452, 1361, 1164, 702
cmÀ1; [a]2D0: +13.8 (c 1.23, n-heptane); HPLC: CHIRAL-
PAK AD, n-heptane/i-PrOH, 98:2, 1.0 mLminÀ1, 254 nm,
ee=72%: tR (major)=14.9 min; tR (minor)=15.8 min.
CDCl3): d=6.76 (dd, 1H, J=16.0, 8.0 Hz), 6.03 (d, 1H, J=
16.0 Hz), 2.61–2.54 (m, 1H), 2.30 (s, 3H), 1.89–1.21 (m, 8H),
in accord with the literature data.[16]
(R)-4-Cycloheptyl-4-hydroxybutan-2-one (5): Purified
using column chromatography (EtOAc/cyclohexane, 1:4) to
afford the title compound as a colourless oil (yield: 337 mg,
1
47%). HNMR (400 MHz, CDCl 3): d=3.91–3.87 (m, 1H),
2.92 (d, 1H, J=2.8 Hz), 2.60–2.48 (m, 2H), 2.16 (s, 3H),
1.86–1.17 (m, 13H); 13C NMR (100 MHz, CDCl3): d=26.7,
26.9, 28.2, 29.2, 29.8, 30.8, 44.1, 46.6, 71.8, 210.5; HR-MS
(FAB+): exact mass calculated for [M+H]+ (C11H21O2) re-
quires m/z=185.1542, found: m/z=185.1565; elemental
analysis (%), calculated for C11H20O2: C 71.70, H10.94;
found: C 71.46, H11.10; IR (film) nmax =3435, 2921, 2854,
1709, 1358 cmÀ1; [a]D20: +50.8 (c 1.00, n-heptane); HPLC:
CHIRALPAK AD, n-heptane/i-PrOH, 98:2, 1.0 mLminÀ1,
280 nm, ee=89%: tR (major)=15.7 min; tR (minor)=
18.9 min.
(4R,5S)-4-Hydroxy-5-phenylhexan-2-one (7b): 1HNMR
(500 MHz, CDCl3): d=7.34–7.31 (m, 2H), 7.26–7.22 (m,
3H), 4.20 (ddd, 1H, J=9.3, 6.1, 2.6 Hz), 2.82 (qd, J=7.0,
6.1 Hz), 2.58 (dd, 1H, J=17.2, 2.6 Hz), 2.47 (dd, 1H, J=
17.2, 9.3 Hz), 2.14 (s, 3H), 1.31 (d, 3H, J=7.0 Hz);
13C NMR (125 MHz, CDCl3): d=17.0, 30.8, 45.0, 47.3, 71.7,
126.6, 128.1, 128.4, 142.8, 209.4, in accord with the literature
data;[17] HR-MS (FAB+): exact mass calculated for [M+
H]+ (C12H17O2) requires m/z=193.1229, found: m/z=
193.1236; elemental analysis (%), calculated for C12H16O2: C
74.97, H8.39; found: C 74.62, H8.60; IR (film): nmax =3461,
2965, 1708, 1493, 1452, 1361, 1164, 702 cmÀ1; [a]D20: +32.7 (c
1.97, n-heptane); HPLC: CHIRALCEL OJ, n-heptane/i-
PrOH, 90:10, 1.0 mLminÀ1, 254 nm, ee >99%: tR =13.4 min.
5-(4-Chlorophenyl)-4-hydroxyhexan-2-one
(6a,
b)
(Table 5, entry 1): Purified using column chromatography
(EtOAc/cyclohexane, 1:4) to afford the mixture of syn/anti
diastereomers (1.5:1) of the title compound as a colourless
oil (yield: 0.786 g, 89%). The diastereomers were separated
on a semi-preparative HPLC column (EtOAc/cyclohexane,
1:6).
A
1HNMR (500 MHz, CDCl 3): d=7.29–7.26 (m, 2H), 7.21–
7.11 (m, 2H), 4.06 (dddd, 1H, J=7.8, 5.8, 5.8, 3.8 Hz), 3.13
(d, 1H, J=3.8 Hz), 2.73 (qd, 1H, J=7.8, 7.0 Hz), 2.41–2.39
(m, 2H), 2.08 (s, 3H), 1.33 (d, 3H, J=7.0 Hz); 13C NMR
(100 MHz, CDCl3): d=17.3, 30.8, 44.3, 47.4, 71.4, 128.4,
129.5, 132.3, 141.4, 209.4; HR-MS (FAB+): exact mass cal-
culated for [M+H]+ (C12H16ClO2) requires m/z=227.0839,
found: m/z=227.0822; elemental analysis (%), calculated
for C12H15ClO2: C 63.58, H6.67; found: C 63.39, H6.90; IR
(film): nmax =3464, 2964, 2927, 1711, 1492, 1411, 1360, 1091,
1012, 828 cmÀ1; [a]2D0: +17.8 (c 1.60, n-heptane); HPLC:
CHIRALPAK AD, n-heptane/i-PrOH, 98:2, 1.0 mLminÀ1,
230 nm, ee=72%: tR (major)=16.0 min; tR (minor)=
17.3 min.
C
A
(6b):
1HNMR (500 MHz, CDCl 3): d=7.30–7.26 (m, 2H), 7.21–
7.18 (m, 2H), 4.17 (ddd, 1H, J=9.2, 6.00, 2.8 Hz), 2.78 (qd,
1H, J=7.2, 6.0 Hz), 2.58 (dd, 1H, J=17.3, 2.8 Hz), 2.43 (dd,
1H, J=17.3, 9.2 Hz), 2.14 (s, 3H), 1.29 (d, 3H, J=7.2 Hz);
13C NMR (125 MHz, CDCl3): d=17.3, 30.8, 44.3, 47.4, 71.4,
128.4, 129.5, 132.3, 141.4, 209.4; HR-MS (FAB+): exact
mass calculated for [M+H]+ (C12H16ClO2) requires m/z=
227.0839, found: m/z=227.0822; elemental analysis (%),
calculated for C12H15ClO2: C 63.58, H6.67; found: C 63.45,
H6.90; IR (film): nmax =3464, 2964, 2927, 1711, 1492, 1411,
1360, 1091, 1012, 828 cmÀ1; [a]2D0: +45.4 (c 1.00, n-heptane);
HPLC: CHIRALCEL OJ, n-heptane/i-PrOH, 97:3,
0.5 mLminÀ1, 230 nm, ee >99%: tR =16.0 min.
4-Hydroxy-5-phenylhexan-2-one (7a,b): Purified using
column chromatography (EtOAc/cyclohexane, 1:4) to afford
1904
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ꢀ 2007 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 1897 – 1905

Sequential Hydroformylation and Enantioselective Aldol Reactions
FULL PAPERS
10.10; IR (film): nmax =3496, 2952, 2867, 1720, 1405, 1159 References
cmÀ1; [a]2D0: À119.0 (c 1.00, n-heptane).
(S)-2-[(S)-Cyclopentyl
(9b): Purified using column chromatography (EtOAc/cyclo-
hexane, 1:4, Rf =0.25) to afford the title compound as a col-
A
[1] For recent reviews, see: a) C. Palomo, M. Oiarbide,
J. M. Garcia, Chem. Soc. Rev. 2004, 33, 65; b) Modern
Aldol Reactions, (Ed.: R. Mahrwald), Wiley-VCH
Verlag, Weinheim, 2004; c) Modern Carbonyl Chemis-
try, (Ed.: J. Otera), Wiley-VCH, Weinheim, 2000.
[2] a) A. Berkessel, H. Groeger, Asymmetric Organocatal-
ysis, Wiley-VCH, Weinheim, 2005; b) K. Sakthivel, W.
Notz, T. Bui, C. F. Barbas III, J. Am. Chem. Soc. 2001,
123, 5260; c) E. R. Jarvo, S. J. Miller, Tetrahedron 2002,
58, 2481; d) A. Cordova, W. Zou, I. Ibrahem, E. Reyes,
M. Engqvist, W.-W. Liao, Chem. Commun. 2005, 3586.
[3] a) T. L. Ho, Tandem Organic Reactions; Wiley, New
York, 1992; b) L. F. Tietze, Chem. Rev. 1996, 96, 115;
c) R. A. Bunce, Tetrahedron 1997, 53, 9477; d) L. F.
Tietze, G. Brasche, K. Gericke, Domino reactions in
Organic Synthesis, Wiley-VCH, Weinheim, 2006.
[4] a) C. Hollmann, P. Eilbracht, Tetrahedron Lett. 1999,
40, 4313; b) C. Hollmann, P. Eilbracht, Tetrahedron
2000, 56, 1685; c) P. Eilbracht, L. Barfacker, C. Buss, C.
Hallman, B. E. Kitsos-Rzychon, C. L. Kranemann, T.
Rische, R. Roggenbuck, A. Schmidt, Chem. Rev. 1999,
99, 3329; d) M. D. Keränen, K. Kot, C. Hollmann, P.
Eilbracht, Org. Biomol. Chem. 2004, 2, 3379; e) M. D.
Keränen, P. Eilbracht, Org. Biomol. Chem. 2004, 2,
1688.
ourless oil (yield: 302 mg, 43%). HNMR (400 MHz, C 6D6):
d=3.88 (dd, 1H, J=9.2, 2.0 Hz), 2.02–0.86 (m, 16H);
13C NMR (100 MHz, CDCl3): d=20.6, 22.4, 25.4, 29.1, 29.9,
39.0, 44.2, 53.7, 74.0, 221.6; HR-MS (FAB+): exact mass
calculated for [M+H]+ (C11H19O2) requires m/z=183.1385,
found: m/z=183.1351; elemental analysis (%), calculated
for C11H18O2: C 72.49, H9.95; found: C 72.21, H10.20; IR
(film): nmax =3451, 2953, 2869, 1732, 1156 cmÀ1; [a]D20: +152.0
(c 1.00, n-heptane); HPLC: CHIRALCEL OD, n-heptane/i-
PrOH, 90:10, 1.0 mLminÀ1, 280 nm, ee=96%: tR (major)=
5.4 min; tR (minor)=4.7 min.
(S)-2-[(R)-Cycloheptyl(hydroxy)methyl]cyclopentanone
(10a): Purified using column chromatography (EtOAc/cyclo-
hexane, 1:4, Rf =0.62) to afford the title compound as a col-
ourless oil (yield: 211 mg, 26%). HNMR (400 MHz, C 6D6):
d=3.45 (dd, 1H, J=9.2, 2.0 Hz), 1.90–1.10 (m, 18H), 1.10–
0.97 (m, 1H), 0.90–0.79 (m, 1H); 13C NMR (100 MHz,
C6D6): d=20.4, 26.4, 26.6, 27.4, 27.9, 28.9, 32.9, 38.0, 42.8,
51.6, 77.7, 223.6; HR-MS (FAB+): exact mass calculated
for [M+H]+ (C13H23O2) requires m/z=211.1698, found: m/
z=211.1675; elemental analysis (%), calculated for
C13H22O2: C 74.24, H10.54; found: C 73.96, H10.80; IR
(film): nmax =3498, 2923, 1712 cmÀ1; [a]D20: À90.3 (c 1.00, n-
[5] a) A. M. Trezeciak, J. J. Ziolkowski, J. Organomet.
Chem. 1994, 479, 213; b) M. P. Doyle, M. S. Shanklin,
M. V. Zlokazov, Synlett 1994, 615.
[6] a) B. List, R. A. Lerner, C. F. Barbas III, J. Am. Chem.
Soc. 2000, 122, 2395; b) B. List, Tetrahedron 2002, 58,
5573.
[7] Y. Sekiguchi, A. Sasaoka, A. Shimamoto, S. Fujioka, H.
Kotsuki, Synlett 2003, 1655.
[8] J. A. Dale, H. S. Mosher, J. Am. Chem. Soc. 1973, 95,
512.
heptane);
HPLC:
0.5 mLminÀ1, 280 nm, ee=83%: tR (major)=19.4 min; tR
(minor)=21.1 min.
(S)-2-[(S)-Cycloheptyl(hydroxy)methyl]cyclopentanone
R
(10b): Purified using column chromatography (EtOAc/cyclo-
hexane, 1:4, Rf =0.40) to afford the title compound as col-
ourless crystals (yield: 406 mg, 50%); mp 72–748C.
1HNMR (400 MHz,
C 6D6): d=3.87 (dd, 1H, J=8.2,
1.8 Hz), 2.01–1.15 (m, 19H), 0.98–0.89 (m, 1H); 13C NMR
(100 MHz, C6D6): d=20.8, 22.9, 26.6, 26.8, 28.8, 29.3, 29.6,
30.7, 38.8, 43.4, 52.3, 73.3, 219.8; HR-MS (FAB+): exact
mass calculated for [M+H]+ (C13H23O2) requires m/z=
211.1698, found: m/z=211.1724; elemental analysis (%),
calculated for C13H22O2: C 74.24, H10.54; found: C 74.05, H
10.70; IR (KBr): nmax =3441, 2912, 1724 cmÀ1; [a]D20: +157.4
(c 1.00, n-heptane); HPLC: CHIRALPAK AD, n-heptane/i-
PrOH, 98:2, 1.0 mLminÀ1, 280 nm, ee=85%: tR (major)=
28.5 min; tR (minor)=26.8 min.
[9] W. N. M. P. van Leeuwen, C. Claver, Rhodium Cata-
lyzed Hydroformylation, Kluwer Academic Publisher,
Dordrecht, 2000.
[10] C. H. Heathcock, L. A. Flippin, J. Am. Chem. Soc.
1983, 105, 1667.
[11] E. J. Enholm, P. E. Whitley, Y. Xie, J. Org. Chem. 1996,
61, 5384.
[12] B. List, P. Pojarliev, C. Castello, Org. Lett. 2001, 3, 573.
[13] a) J. C. Wasilke, S. J. Obrey, R. T. Baker, G. C. Bazan,
Chem. Rev. 2005, 105, 1001; b) J. M. Lee, Y. Na, H.
Han, Chem. Soc. Rev. 2004, 33, 302; c) D. E. Fogg,
E. N. Santos, Coordin. Chem. Rev. 2004, 248, 2365.
[14] G. D. Cuny, S. L. Buchwald, J. Am. Chem. Soc. 1993,
115, 2066.
Acknowledgements
We would like to thank PD Dr. Bernd Plietker for the help
with the chiral HPLC experiments and Prof. Dr. Burkhard
Costisella for the help with NMR experiments.
[15] H. Bhandal, A. R. Howwel, V. F. Patel, D. Pattenden, J.
Chem. Soc., Perkin Trans. 1 1990, 2709.
Adv. Synth. Catal. 2007, 349, 1897 – 1905
ꢀ 2007 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
asc.wiley-vch.de
1905