Rhodium-catalyzed asymmetric aqueous Pauson-Khand-type reaction

Article abstract of DOI:10.1002/chem.200401237

An interesting rhodium-catalyzed asymmetric aqueous Pauson-Khand-type reaction was developed. A chiral atropisomeric dipyridyldiphosphane ligand was found to be highly effective in this system. This operationally simple protocol allows both catalyst and r

Full text of DOI:10.1002/chem.200401237

Rhodium-Catalyzed Asymmetric Aqueous Pauson–Khand-Type Reaction
Fuk Yee Kwong,*[a] Yue Ming Li,[a] Wai Har Lam,[a] Liqin Qiu,[a] Hang Wai Lee,[a]
Chi Hung Yeung,[a] Kin Shing Chan,[b] and Albert S. C. Chan*[a]
Abstract: An interesting rhodium-cata-
lyzed asymmetric aqueous Pauson–
Khand-type reaction was developed. A
chiral atropisomeric dipyridyldiphos-
phane ligand was found to be highly ef-
fective in this system. This operational-
ly simple protocol allows both catalyst
and reactants to be handled under air
without precautions. Various enynes
were transformed to the corresponding
bicyclic cyclopentenones in good yield
and enantiomeric excess (up to
95% ee). A study of the electronic ef-
fects of the enyne substrates revealed a
correlation between the electronic
properties of the substrates and the ee
value obtained in the product of the
Pauson–Khand-type reaction. A linear
free-energy relationship was observed
from a Hammett study.
Keywords: asymmetric catalysis
·
cyclization · Pauson–Khand reac-
tions · phosphane ligands · rhodium
Introduction
The first example of the cobalt-catalyzed PKR was report-
ed in 1973 by Pauson, Khand, and co-workers [Eq. (1)].[4]
Several other research groups also attempted to perform
this interesting catalytic reaction in 1980s.[5] In early 1990s, a
successful and practical intramolecular PKR of enynes by
using [Co2(CO)8] with P(OPh)3 ligands was reported by
Jeong et al.[6] Apart from the cobalt-catalyzed PKR,[7] the
use of other transition metals, especially in the correspond-
ing chiral catalysts, for this enantioselective carbonylative
cyclization is currently of high interest. Recent examples
have shown that chiral titanium,[8] rhodium,[9] and iridium[10]
complexes are effective in the asymmetric PKR. Although
major improvements have been shown, the use of highly
toxic gaseous carbon monoxide signifies a drawback to
these procedures. Recently, two independent groups led by
Morimoto/Kakiuchi and Shibata reported notable accom-
plishments in the investigation of aldehydes as CO surro-
gates.[11,12] These findings enable us to use a nontoxic
“carbon monoxide” like reagent for carbonylation reactions.
We envisioned, as a prerequisite, an attractive and con-
venient protocol for a reaction that should be operationally
simple, in particular, a reaction that can be carried out in
less harmful solvents. Recently, tremendous attention has
been given to aqueous transition-metal-catalyzed reac-
tions.[13] However, no catalytic asymmetric systems that
enable the use of water as the only solvent, without a surfac-
tant, in the PKR have been developed yet.[14] To further im-
prove the PKR, the use of an aqueous solvent in this cata-
lytic reaction would be a good direction to take. We herein
describe this approach for a catalytic and enantioselective
Transition-metal-catalyzed/mediated [2+2+1] carbonylative
cycloaddition of an alkene and an alkyne (called the
Pauson–Khand-type reaction or PKR)[1] represents one of
the most versatile methods for the preparation of various
scientifically useful and biologically interesting carbocy-
cles.[2] Conventionally, the PKR requires a stoichiometric
amount of [Co2(CO)8] (obtained by heating a [Co2(CO)6-
(alkyne)] complex with excess alkene). However, the devel-
opment of the catalytic PKR has prospered recently because
of the apparent advantages [Eq. (1)].[3]
[a] Dr. F. Y. Kwong, Dr. Y. M. Li, Dr. W. H. Lam, Dr. L. Qiu, H. W. Lee,
Dr. C. H. Yeung, Prof. Dr. A. S. C. Chan
Open Laboratory of Chirotechnology of the Institute of Molecular
Technology for Drug Discovery and Synthesis
Department of Applied Biology and Chemical Technology
The Hong Kong Polytechnic University, Hung Hom (Hong Kong)
Fax : (+852)23-649-932
E-mail: bcfyk@inet.polyu.edu.hk
bcachan@polyu.edu.hk
[b] Prof. Dr. K. S. Chan
Department of Chemistry
The Chinese University of Hong Kong, Shatin, New Territories
(Hong Kong)
3872
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/chem.200401237
Chem. Eur. J. 2005, 11, 3872 – 3880

FULL PAPER
aqueous Pauson–Khand-type reaction of enynes in the pres-
ence of aldehydes as the source of carbon monoxide. This
attractive protocol uses a catalyst and reactants that can be
handled under air without special precautions.[15]
chemical yields (Table 1, entry 4). Electron-donating p-me-
thoxybenzaldehyde gave a complicated reaction mixture
with poor product yield, while electron-deficient p-chloro-
benzaldehyde furnished the desired product in both good
yield and enantioselectivity (Table 1, entries 11,12). It is par-
ticularly noteworthy that we found the electronic properties
of the aromatic aldehydes were responsible for both the
enantioselectivity and yield of the corresponding substitut-
ed-cyclopentenone products (Table 1, entries 10–12). Addi-
tionally, the aliphatic aldehyde also gave a high ee value in
the product with moderate chemical yield (Table 1,
entry 13). The amount of aldehyde added was further opti-
mized. When we used an equiv-
Results and Discussion
We first examined the reaction of enynes with aldehydes in
conventional organic solvents, such as toluene, dioxane, and
N,N-dimethylformamide (DMF; see Table 1, entries 1–3).
However, moderate chemical yields and ee values were ob-
Table 1. Effects of solvent, ligand, and aldehyde combinations in the enantioselective Pauson–Khand-type re-
action.[a]
alent of aldehyde in these coop-
erative processes (decarbonyla-
tion/Pauson–Khand
cycliza-
tion), it gave a moderate yield
with good enantioselectivity.[19]
To our delight, when the
amount of cinnamylaldehyde
was increased to 1.5 equiva-
lents, optimal yield and enan-
tioselevtivity were both ob-
tained (Table 1, entry 4). Fur-
ther increase of the aldehyde
loading from 1.5 to 10 equiva-
lents had no significant benefi-
cial effect. The effectiveness of
cationic [Rh(cod)2]BF4 and
[Rh(cod)2]OTf complexes as
the metal source was also ex-
amined (Tf=trifluoromethane-
sulfonyl); however, we found
that the neutral complex [{Rh-
(cod)Cl}2] gave the best results.
Entry
Ligand
Aldehyde
Solvent
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
P-Phos
P-Phos
P-Phos
cinnamylaldehyde
cinnamylaldehyde
cinnamylaldehyde
cinnamylaldehyde
cinnamylaldehyde
cinnamylaldehyde
cinnamylaldehyde
cinnamylaldehyde
cinnamylaldehyde
benzaldehyde
toluene
dioxane
DMF
water
water
water
water
water
water
water
water
water
water
65
63
6
82
23
33
5
80
74
0
P-Phos
84
61
79
22
15
30
63
71
80
81
BINAP[17]
tol-BINAP[17]
Et-DuPHOS[17]
PHANEPHOS[17]
FerroTANE[17]
P-Phos
6
9
21
82
19
83
45
10
11
12
13
P-Phos
P-Phos
P-Phos
p-OMe-benzaldehyde
p-Cl-benzaldehyde
n-nonylaldehyde
[a] Reaction conditions: [{Rh(cod)Cl}2] (3 mol%), ligand (6 mol%), enyne (0.3 mmol), and aldehyde
(0.45 mmol) were charged to a screw-cap flask at RT under air. Solvent (0.2 mL; concentration of enyne 1.5m)
was added under nitrogen and the reaction was stirred at 1008C for 36 h. [b] Yield of isolated product.
[c] Average of two runs from chiral HPLC analysis.
tained. To our delight, we observed that an increase in the
concentration of the reaction would give a higher reactivity
in the PKR (data not shown). These significant findings
offer us a good way in which to improve this reaction. An
interesting angle in this direction is the application of the
aqueous micellar concept to the reaction, to increase the ef-
fective concentration of the reactants and thereby accelerate
the reaction.[16] It is noteworthy that when water was used as
the sole solvent in the PKR, the highest activity of the reac-
tion was observed in our case (Table 1, entry 4). These re-
sults prompted us to use water as the prototypical solvent
for further ligand screening. BINAP-class ligands showed
poor conversion with a moderate ee value for the bicyclic
cyclopentenone (Table 1, entries 5,6). Et-DUPHOS, PHA-
NEPHOS, and Et-FerroTANE gave a sluggish reaction rate
during the reaction and a poor yield (Table 1, entries 7–
9).[17] In contrast, the atropisomeric dipyridyldiphosphane
ligand (S)-P-Phos[18] (see Table 2 for formula) was found to
be the best ligand among those screened (Table 1, entries
4–7).
These relatively mild and optimized conditions were ap-
plied to the Pauson–Khand-type cyclization of different
oxygen-tethered substrates. An enyne with a 1,1-disubstitut-
ed alkene reacted smoothly to give high enantioselectivity
(90% ee) in the chiral quaternary-carbon center of the bicy-
clic cyclopentenone (Table 2, entry 2). Alkyl-substituted al-
kynes gave excellent enantioselectivities (95% ee) in the
corresponding products (Table 2, entries 3,4). In order to
further explore this Pauson–Khand-type reaction, we per-
formed an electronic effect investigation. Various new aro-
matic enynes with different electronic properties were pre-
pared and subjected to carbonylative cyclizations. Interest-
ingly, the electronic effect study showed that electron-donat-
ing aromatic enynes provided higher enantioselectivity of
the product, while enynes with electron-withdrawing sub-
stituents afforded relatively lower ee values in the bicyclic
cyclopentenones (Table 2, entries 5–9).
Particularly noteworthy is the fact that this unprecedented
correlation of the product ee value and the electronic prop-
erties of the substrates in Pauson–Khand-type cyclizations
A variety of aldehydes were examined as CO surrogates.
Cinnamylaldehyde gave the best results in both optical and
can be demonstrated from a Hammett Plot (Figure 1).[20]
A
linear free-energy relationship was obeyed for substrates
Chem. Eur. J. 2005, 11, 3872 – 3880
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F. Y. Kwong, A. S. C. Chan et al.
Table 2. Catalytic and enantioselective aqueous Pauson–Khand-type reac-
tions.[a]
(Figure 2). We suggest that, in the stereotransition state, the
electron-rich enyne may coordinate more closely to the rho-
dium center by p interactions;[22] this would result in im-
proved stereochemical communication and would thus give
rise to a higher enantioselectivity (Figure 2, Model A). The
electron-poor enyne may, however, coordinate to the metal
center in a different mode, which is far away from the chiral
environment in the transition state (Figure 2, Model B).[23]
Therefore, a lower ee value is observed in the bicyclic cyclo-
pentenone.
Entry
1
Substrate
Product
Yield[b] [%] ee [%]
82 84
These attractive aqueous PKR conditions were also ex-
plored with other carbon- and nitrogen-tethered enynes. Ex-
cellent isolated yields were obtained for these substrates
with good enantioselectivities (Table 3).
2
71 90
In conclusion, we have demonstrated an interesting cata-
lytic and enantioselective aqueous Pauson–Khand-type cyc-
lization. Although these aqueous reactions required organic
solvents for product purification, this is a good start for the
development of this chemistry with less environmental
impact in the near future. In addition, the unprecedented
electronic effect in the Pauson–Khand-type reaction is nota-
ble. To the best of our knowledge, this is the first example
to show a correlation between enyne electronic properties
and the ee value of the bicyclic cyclopentenones for the
PKR in a Hammett study. Rationalization of these observa-
tions by full investigation of the stereodetermining/rhodacy-
cle-forming step in the aqueous Pauson–Khand-type cycliza-
tion is currently underway.
3
4
82 95
60 95
5
93 93
92 88
90 82
88 81
91 77
49 74
6
7
Experimental Section
8
General considerations: Unless otherwise noted, all reagents were pur-
chased from commercial suppliers and used without purification. All air-
sensitive reactions were performed in Rotaflo (England) resealable
screw-cap Schlenk flasks (approximately 10 mL volume) or screw-cap
vials (approximately 2 mL volume). Toluene and tetrahydrofuran (THF)
were distilled from sodium and sodium benzophenone ketyl, respectively,
under nitrogen,.[24] Allylamine and triethylamine were distilled over
CaH2 prior to use. Aldehydes (liquid form at RT) were distilled under re-
duced pressure and stored in screw-cap vials. NaH (60% in mineral oil)
was washed with dry hexane prior to use. (Caution: This procedure
should be performed in a relatively dry atmosphere with adequate shield-
ing.) [{Rh(cod)Cl}2], as a shiny orange crystalline solid, was purchased
from Strem Chemicals. Water was degassed and stored in a Schlenk flask.
Thin-layer chromatography was performed on Merck precoated silica gel
60 F254 plates. Silica gel (Merck, 230–400 mesh) was used for flash column
chromatography. Melting points were recorded on an uncorrected
Bꢁchi B-545 melting point instrument. 1H NMR spectra were recorded
on a Varian INOVA 500 spectrometer. Spectra were referenced internally
to the residual proton resonance in CDCl3 (d=7.26 ppm) or to tetrame-
thylsilane (TMS; d=0.00 ppm) as the internal standard. Chemical shifts
(d) are reported as parts per million (ppm) on the d scale downfield from
TMS. 13C NMR spectra were recorded on a Varian INOVA 500 spectrom-
eter and referenced to CDCl3 (d=77.0 ppm). 31P NMR spectra were re-
corded on a Varian INOVA 500 spectrometer and referenced externally
to 85% H3PO4 (d=0.0 ppm). Coupling constants (J) are reported in
Hertz (Hz). Mass spectra (EI and FAB) were recorded on a Hewlett–
Packard 5989B mass spectrometer. High-resolution mass spectra
(HRMS) were obtained on a Brꢁker APEX 47e ESI FT-ICR mass spec-
trometer. HPLC analyses were performed on a Waters 600 instrument by
using Chiralcel AS, AS-H, AD, AD-H, OD, and OD-H columns (0.46ꢂ
9
10
11
no reaction
n.d.[c]
[a] Reaction conditions: [{Rh(cod)Cl}2] (3 mol%), (S)-P-Phos (6 mol%),
enyne (0.3 mmol), and aldehyde (0.45 mmol) were charged to a screw-cap
flask at RT under air. Solvent (0.2 mL; concentration of enyne 1.5m) was
added under nitrogen and the reaction was stirred at 1008C for 36 h.
[b] Yield of isolated product. [c] n.d.=not determined.
with para and meta substitutions (Figure 1).[21] However,
sterically congested ortho-substituted enynes gave an ee
value outside the trend (Table 2, entry 10). Presumably, the
steric factor, instead of the electronic effect, plays the domi-
nant role for this particular substrate. A proposed transi-
tion-state model can be used to account for this interesting
electronic effect in asymmetric Pauson–Khand-type reaction
3874
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Chem. Eur. J. 2005, 11, 3872 – 3880

Pauson–Khand-Type Reactions
FULL PAPER
25 cm). Racemic bicyclic cyclopentenone products (for calibration of
chiral HPLC analysis) were obtained from the same PKR representative
procedure except that racemic ligand was used. GC-MS analysis was con-
ducted on a Hewlett-Packard G1800C GCD system by using a HP5MS
column (30 mꢂ0.25 mm).
Preparation of enyne substrates:
3-(Allyloxy)-1-phenyl-1-propyne:[25] General procedure for condensation
of an arylpropargyl alcohol with allyl bromide: NaH (1.44 g, 60 mmol,
freshly prewashed with dry hexane) was added portionwise to a solution
of 3-phenyl-2-propyn-1-ol (5.28 g, 40 mmol) in freshly distilled THF
(80 mL) under a nitrogen atmosphere at 08C. The white suspension was
slowly warmed to room temperature and stirred for 2 h. The reaction
mixture was then cooled to 08C and allyl bromide (6.8 mL, 80 mmol) was
added dropwise. After complete addition, the reaction was warmed to
room temperature and further stirred for 2 h. Water (ꢀ30 mL) was
slowly added and the aqueous layer was extracted with diethyl ether (3ꢂ
ꢀ100 mL). The combined organic layers were washed with water
(ꢀ50 mL) and brine (ꢀ50 mL) and dried over sodium sulfate. Solvent
was removed by rotary evaporation and the light-yellow crude product
was purified by distillation under reduced pressure (b.p.=101–1028C,
5 mmHg) to give the title compound as a colorless liquid (6.53 g, 95%
yield): Rf =0.2 (hexane); 1H NMR (CDCl3, 500 MHz): d=7.30–7.43 (m,
5H), 6.02 (tdd, J=17.0, 10.0, 5.5 Hz, 1H), 5.38 (dd, J=17.0, 2.0 Hz, 1H),
5.27 (dd, J=10.0, 2.0 Hz, 1H), 4.39 (s, 2H), 4.17 ppm (dd, J=5.5, 1.5 Hz,
2H); IR (neat): n˜ =3080, 3019, 2982, 2938, 2849, 2237, 1954, 1881, 1647,
1598, 1571, 1489, 1442, 1424, 1354, 1256, 1124, 1081, 1027, 991, 964, 925,
757, 691, 626, 549, 585, 538, 525 cmꢁ1; MS (EI): m/z (relative intensity):
172 [M]+ (20), 131 (100).
Figure 1. Hammett plot of rhodium-catalyzed asymmetric aqueous
Pauson–Khand-type cyclization.
4-(Allyloxy)-2-butyne:[26] The general procedure for condensation of an
arylpropargyl alcohol with allyl bromide was followed: 2-Butyn-1-ol
(4.0 g, 57.1 mmol), NaH (2.1 g, 87.5 mmol, prewashed with dry hexane),
allyl bromide (9.7 mL, 115 mmol), and freshly distilled THF (200 mL)
were used to obtain the title compound as a colorless liquid (5.5 g, 88%
yield). Purification was conducted by distillation under reduced pressure
(40–428C, 10 mmHg=: Rf =0.2 (hexane); 1H NMR (CDCl3, 500 MHz):
d=5.90 (tdd, J=17.0, 10.0, 5.5 Hz, 1H), 5.28 (dd, J=17.0, 2.0 Hz, 1H),
5.19 (dd, J=10.0, 2.0 Hz, 1H), 4.10 (q, J=2.5 Hz, 2H), 4.04 (d, J=
5.5 Hz, 2H), 1.85 ppm (t, J=2.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz):
d=134.1, 117.5, 82.3, 75.0, 70.4, 57.6, 3.5 ppm; MS (EI): m/z (relative in-
tensity): 110 [M]+ (10), 69 (100).
5-(Allyloxy)-3-pentyne:[26] The general procedure for condensation of an
arylpropargyl alcohol with allyl bromide was followed: 3-Pentyn-1-ol
(4.2 g, 50 mmol), NaH (1.8 g, 75 mmol, prewashed with dry hexane), allyl
bromide (8.5 mL, 100 mmol), and freshly distilled THF (150 mL) were
used to obtain the title compound as a colorless liquid (5.3 g, 85% yield).
Purification was conducted by distillation under reduced pressure (b.p.=
30–338C, 5 mmHg): Rf =0.2 (hexane); 1H NMR (CDCl3, 500 MHz): d=
5.91 (tdd, J=17.0, 10.0, 5.5 Hz, 1H), 5.31 (dd, J=17.0, 2.0 Hz, 1H), 5.20
(dd, J=10.0, 2.0 Hz, 1H), 4.12 (t, J=2.5 Hz, 2H), 4.04 (d, J=5.5 Hz,
2H), 2.21–2.25 (m, 2H), 1.14 ppm (t, J=7.5 Hz, 3H); 13C NMR (CDCl3,
125 MHz): d=133.1, 117.6, 82.5, 75.1, 70.5, 57.7, 11.8, 9.5 ppm; IR (neat):
n˜ =3078, 2978, 2938, 2851, 2289, 2223, 1649, 1454, 1424, 1357, 1316, 1137,
1084, 999, 926, 748, 650, 563 cmꢁ1; MS (EI): m/z (relative intensity): 125
[M]+ (15), 84 (100).
3-[(2-Methyl-2-propenyl)oxy]-1-phenyl-1-propyne:[27] The general proce-
dure for condensation of an arylpropargyl alcohol with allyl bromide was
followed: 3-Phenyl-2-propyn-1-ol (5.28 g, 40 mmol), NaH (1.44 g,
60 mmol, freshly prewashed with dry hexane), 3-bromo-2-methyl-1-pro-
pene (10.8 g, 80 mmol), and freshly distilled THF (100 mL) were used to
obtain the title compound as a colorless liquid (6.8 g, 92% yield). Purifi-
cation was carried out by distillation under reduced pressure (b.p.=125–
1288C, 4 mmHg): Rf =0.2 (hexane); 1H NMR (CDCl3, 500 MHz): d=
7.30–7.43 (m, 5H), 5.38 (d, J=2.0 Hz, 1H), 5.27 (d, J=2.0 Hz, 1H), 4.39
(s, 2H), 4.17 (s, 2H), 1.88 ppm (s, 3H); IR (neat): n˜ =3452, 3078, 2980,
2914, 2842, 2233, 1946, 1885, 1798, 1654, 1593, 1489, 1443, 1356, 1250,
1086, 1034, 903, 757, 691, 594, 523 cmꢁ1; MS (EI): m/z (relative intensity):
186 [M]+ (20), 131 (100).
Figure 2. Suggested transition-state models for electronically controlled
asymmetric aqueous Pauson–Khand-type reactions.
Table 3. Rhodium-catalyzed asymmetric aqueous Pauson–Khand-type re-
action of nitrogen- and carbon-tethered enynes.[a]
Entry
1
Substrate
Product
Yield[b] [%] ee [%]
96
80
2
3
98
91
88
77
[a] Reaction conditions: see Table 2 footnotes. Ts=toluene-4-sulfonyl.
[b] Yield of isolated product.
Chem. Eur. J. 2005, 11, 3872 – 3880
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F. Y. Kwong, A. S. C. Chan et al.
3-(Allyloxy)-1-(4-methoxyphenyl)-1-propyne:[10] General procedure for
Sonogashira coupling of propargyl alcohol with ArI: 4-Iodoanisole
(11.7 g, 50 mmol), [Pd(PPh3)2Cl2] (3 mol%), and CuI (6 mol%) were dis-
solved in freshly distilled toluene (50 mL) under nitrogen at room tem-
perature. Piperidine (8.4 g, 100 mmol) was added and this was followed
by slow addition of the propargyl alcohol (3.07 mL, 52 mmol) by syringe.
(Caution: exothermic reaction when propagyl alcohol is added). The re-
sulting dark brown reaction mixture was stirred at 30–358C for 3 h under
nitrogen. (ArI was completely consumed as judged by GC analysis.) The
reaction was allowed to reach room temperature and the dark-brown
crude product was filtered over a silica pad (5ꢂ5 cm) and rinsed with di-
chloromethane (ꢀ200 mL). Solvent was removed by rotary evaporation
to give a viscous brown liquid, which was purified by flash column chro-
matography on silica gel with dichloromethane as the eluent to afford 3-
(4-methoxyphenyl)-2-propyn-1-ol[28] as a yellow solid (6.07 g, 75% yield):
Rf =0.4 (dichloromethane); 1H NMR (CDCl3, 500 MHz): d=7.37 (d, J=
8.5 Hz, 2H), 6.83 (d, J=8.5 Hz, 2H), 4.47 (d, J=6.0 Hz), 3.81 (s, 2H),
1.75 ppm (t, J=5.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz): d=138.8,
131.3, 128.8, 119.3, 86.5, 85.4, 51.2, 43.6 ppm; MS (EI): m/z (relative in-
tensity): 162 [M]+ (100).
obenzene (11.1 g, 50 mmol), Pd(PPh3)2Cl2 (3 mol%), CuI (6 mol%), pi-
peridine (8.4 g, 100 mmol), propagyl alcohol (3.07 mL, 52 mmol), and
freshly distilled toluene (50 mL) were used to obtain 3-(4-fluorophenyl)-
2-propyn-1-ol[30] (5.85 g, 78% yield) as a light yellow viscous liquid. Puri-
fication was conducted by filtration of the reaction mixture over a silica
pad (5ꢂ5 cm) followed by flash column chromatography on silica gel
with dichloromethane as the eluent: Rf =0.5 (dichloromethane);
1H NMR (CDCl3, 500 MHz): d=7.39 (d, J=8.5 Hz, 2H), 6.97 (d, J=
8.5 Hz, 2H), 4.78 (s, 2H), 2.69 ppm (brs, 1H); 13C NMR (CDCl3,
125 MHz): d=163.5, 161.5, 133.5 (d, JC,F =8.3 Hz), 118.5 (d, JC,F =3.0 Hz),
115.5 (d, JC,F =22.1 Hz), 86.9, 84.5, 51.3 ppm; MS (EI): m/z (relative in-
tensity): 150 [M]+ (100); HRMS: calcd for C9H7FO: 150.04809; found:
150.04820.
The general procedure for condensation of an arylpropargyl alcohol with
allyl bromide was followed: 3-(4-Fluorophenyl)-2-propyn-1-ol[30] (1.5 g,
10 mmol), NaH (360 mg, 15 mmol, prewashed with dry hexane), allyl bro-
mide (1.7 mL, 20 mmol), and freshly distilled THF (30 mL) were used to
obtain the title compound as a colorless liquid (1.42 g, 75% yield). Purifi-
cation was conducted by distillation under reduced pressure (b.p.=89–
908C, 2 mmHg): Rf =0.2 (hexane); 1H NMR (CDCl3, 500 MHz): d=7.41
(d, J=8.5 Hz, 2H), 7.00 (t, J=8.5 Hz), 5.95 (tdd, J=17.0, 10.0, 5.5 Hz,
1H), 5.34 (dd, J=17.0, 1.0 Hz, 1H), 5.24 (dd, J=17.5, 1.0 Hz, 1H), 4.36
(s, 2H), 4.13 ppm (d, J=6.0 Hz); 13C NMR (CDCl3, 125 MHz): d=163.5,
161.6, 134.0, 133.6 (d, JC,F =8.4 Hz), 118.7, (d, JC,F =3.0 Hz), 117.9, 115.5
(d, JC,F =22.0 Hz), 85.1, 84.7, 70.7, 57.8 ppm; IR (neat): n˜ =3073, 3016,
2986, 2934, 2851, 2248, 1885, 1649, 1601, 1506, 1354, 1229, 1156, 1088,
992, 928, 837, 815, 563, 529 cmꢁ1; MS (EI): m/z (relative intensity): 190
[M]+ (10), 149 (100); HRMS: calcd for C12H11FO: 190.07939; found:
190.07923.
The general procedure for condensation of an arylpropargyl alcohol with
allyl bromide was followed: 3-(4-Methoxyphenyl)-2-propyn-1-ol[28] (1.0 g,
6.2 mmol), NaH (223 mg, 9.3 mmol, prewashed with dry hexane), allyl
bromide (1.05 mL, 12.4 mmol), and freshly distilled THF (10 mL) were
used to obtain the title compound as a pale yellow liquid (1.18 g, 95%
yield). Purification of the crude product was conducted by filtration over
a short silica pad followed by flash column chromatography on silica gel
with hexane/ethyl acetate (10:1) as the eluent: Rf =0.5 (hexane/ethyl ace-
tate (10:1)); 1H NMR (CDCl3, 500 MHz): d=7.39 (d, J=8.5 Hz, 2H),
6.84 (d, J=8.5 Hz, 2H), 5.92–5.98 (m, 1H), 5.33 (dd, J=17.0, 1.0 Hz,
1H), 5.23 (dd, J=17.5, 1.0 Hz, 1H), 4.37 (s, 2H), 4.13 (d, J=5.0 Hz, 2H),
3.81 ppm (s, 3H); 13C NMR (CDCl3, 125 MHz): d=159.7, 134.1, 133.2,
117.8, 114.7, 113.9, 86.2, 83.6, 70.6, 57.9, 55.2 ppm; IR (neat): n˜ =3077,
3039, 3006, 2935, 2901, 2839, 2541, 2235, 2049, 1967, 1885, 1648, 1606,
1568, 1509, 1462, 1442, 1354, 1291, 1251, 1175, 1085, 1032, 927, 833, 800,
675, 567, 536, 417 cmꢁ1; MS (EI): m/z (relative intensity): 202 [M]+ (10),
161 (100).
3-(Allyloxy)-1-(3-methoxyphenyl)-1-propyne: The general procedure for
Sonogashira coupling of propagyl alcohol with ArI weas used: 3-Iodoani-
sole (11.7 g, 50 mmol), [Pd(PPh3)2Cl2] (3 mol%), CuI (6 mol%), piperi-
dine (8.4 g, 100 mmol), propagyl alcohol (3.07 mL, 52 mmol), and freshly
distilled toluene (50 mL) were used to afford 3-(3-methoxyphenyl)-2-
propyn-1-ol[31] (5.91 g, 73% yield) as a light-yellow viscous liquid. Purifi-
cation was conducted by filtration of the reaction mixture over a silica
pad (5ꢂ5 cm) followed by flash column chromatography on silica gel
with dichloromethane as the eluent: Rf =0.4 (dichloromethane);
1H NMR (CDCl3, 500 MHz): d=7.22 (t, J=8.0 Hz, 1H), 7.03 (d, J=
7.5 Hz, 1H), 6.97 (m, 1H), 6.89 (m, 1H), 4.50 (d, J=6.5 Hz, 2H), 3.80 (s,
3H), 1.72 ppm (t, J=6.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz): d=
138.9, 131.1, 128.6, 119.6, 86.5, 85.3, 51.2, 44.8 ppm; MS (EI): m/z (rela-
tive intensity): 162 [M]+ (100); HRMS: calcd for C10H10O2: 162.06808;
found: 162.06829.
3-(Allyloxy)-1-(4-methylphenyl)-1-propyne: The general procedure for
Sonogashira coupling of propagyl alcohol with ArI was used: 4-Iodoto-
luene (10.9 g, 50 mmol), [Pd(PPh3)2Cl2] (3 mol%), CuI (6 mol%), piperi-
dine (8.4 g, 100 mmol), propagyl alcohol (3.07 mL, 52 mmol), and freshly
distilled toluene (50 mL) were used to obtain 3-(4-methylphenyl)-2-
propyn-1-ol[29] (5.26 g, 72% yield) as a light-brown solid. Purification was
conducted by filtration of the reaction mixture over a silica pad (5ꢂ
5 cm) followed by flash column chromatography on silica gel with di-
chloromethane as the eluent: Rf =0.5 (dichloromethane); 1H NMR
(CDCl3, 500 MHz): d=7.33 (d, J=8.0 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H),
4.49 (s, 2H), 3.23 (brs, 1H), 2.35 ppm (s, 3H); 13C NMR (CDCl3,
125 MHz): d=138.2, 131.3, 128.6, 119.3, 86.5, 85.3, 51.2, 21.0 ppm; MS
(EI): m/z (relative intensity): 146 [M]+ (100); HRMS: calcd for C10H10O:
146.07316; found: 146.07311.
The general procedure for condensation of an arylpropargyl alcohol with
allyl bromide was followed: 3-(3-Methoxyphenyl)-2-propyn-1-ol[31] (1.0 g,
6.2 mmol), NaH (223 mg, 9.3 mmol, prewashed with dry hexane), allyl
bromide (1.05 mL, 12.4 mmol), and freshly distilled THF (10 mL) were
used to afford the title compound as a light yellow liquid (1.16 g, 94%
yield). Purification of the crude product was conducted by filtration over
a short silica pad followed by flash column chromatography on silica gel
with hexane/ethyl acetate (10:1) as the eluent: Rf =0.5 (hexane/ethyl ace-
tate (10:1)); 1H NMR (CDCl3, 500 MHz): d=7.21 (t, J=8.0 Hz, 1H),
7.02 (d, J=7.5 Hz, 1H), 6.96 (m, 1H), 6.89 (m, 1H), 5.94 (m, 1H), 5.32
(dd, J=17.0, 1.0 Hz, 1H), 5.23 (dd, J=17.5, 1.0 Hz, 1H), 4.37 (s, 2H),
4.13 (d, J=5.0 Hz, 2H), 3.81 ppm (s, 3H); 13C NMR (CDCl3, 125 MHz):
d=159.7, 134.1, 133.2, 117.8, 114.7, 113.9, 86.2, 83.6, 70.6, 57.9, 55.2 ppm;
IR (neat): n˜ =3077, 3004, 2939, 2911, 2840, 2228, 1644, 1600, 1572, 1483,
1419, 1353, 1318, 1289, 1204, 1165, 1124, 1046, 992, 927, 855, 784, 687,
584, 512 cmꢁ1; MS (EI): m/z (relative intensity): 202 [M]+ (10), 161
(100); HRMS: calcd for C13H14O2: 202.09938; found: 202.09923.
The general procedure for condensation of an arylpropargyl alcohol with
allyl bromide was followed: 3-(4-Methylphenyl)-2-propyn-1-ol[29] (1.46 g,
10 mmol), NaH (360 mg, 15 mmol, prewashed with dry hexane), allyl bro-
mide (1.7 mL, 20 mmol), and freshly distilled THF (20 mL) were used to
obtain the title compound as a light yellow liquid (1.78 g, 96% yield). Pu-
rification was conducted by distillation under reduced pressure (b.p.=
130–1338C, 3 mmHg): Rf =0.2 (hexane); 1H NMR (CDCl3, 500 MHz):
d=7.35 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H), 5.92–6.00 (m, 1H),
5.33 (dd, J=17.0, 1.0 Hz, 1H), 5.23 (dd, J=17.5, 1.0 Hz, 1H), 4.38 (s,
2H), 4.13 (d, J=5.0 Hz, 2H), 2.35 ppm (s, 3H); 13C NMR (CDCl3,
125 MHz): d=137.5, 137.4, 132.0, 128.8, 119.3, 115.1, 89.4, 85.5, 72.2, 57.4,
20.1 ppm; IR (neat): n˜ =3080, 3028, 2982, 2921, 2851, 2243, 1910, 1649,
3-(Allyloxy)-1-(4-chlorophenyl)-1-propyne: The general procedure for
Sonogashira coupling of propagyl alcohol with ArI was used: 3-Iodoani-
sole (11.9 g, 50 mmol), [Pd(PPh3)2Cl2] (3 mol%), CuI (6 mol%), piperi-
dine (8.4 g, 100 mmol), propagyl alcohol (3.07 mL, 52 mmol), and freshly
distilled toluene (50 mL) were used to obtain 3-(4-chlorophenyl)-2-
propyn-1-ol[32] (5.91 g, 73% yield) as a light-yellow viscous liquid. Purifi-
cation was conducted by filtration of the reaction mixture over a silica
1509, 1442, 1424, 1354, 1260, 1123, 1080, 991, 926, 817, 666, 558, 526 cmꢁ1
;
MS (EI): m/z (relative intensity): 186 [M]+ (15), 145 (100); HRMS: calcd
for C13H14O: 186.10447; found: 186.10451.
3-(Allyloxy)-1-(4-fluorophenyl)-1-propyne: The general procedure for
Sonogashira coupling of propagyl alcohol with ArI was used: 4-Iodoflur-
3876
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 3872 – 3880

Pauson–Khand-Type Reactions
FULL PAPER
pad (5ꢂ5 cm) followed by flash column chromatography on silica gel
with dichloromethane as the eluent: Rf =0.5 (dichloromethane);
1H NMR (CDCl3, 500 MHz): d=7.36 (d, J=8.0 Hz, 2H), 7.27 (d, J=
8.0 Hz, 2H), 4.45 (s, 2H), 1.98 ppm (brs, 1H); 13C NMR (CDCl3,
125 MHz): d=133.2, 131.3, 128.2, 119.3, 86.5, 85.1, 51.2 ppm; MS (EI): m/
z (relative intensity): 168 [M]+ (30), 166 [M]+ (100); HRMS: calcd for
C9H7ClO: 166.01854; found: 166.01850.
layers were washed with brine and dried over Na2SO4. The crude mixture
was passed through a short silica pad (3ꢂ10 cm). Solvent was removed in
vacuo and the N-allyl-N-(3-phenyl-2-propynyl)amine product was used in
the next step without further purification.
A
dichloromethane solution of p-toluenesulfonyl chloride (967 mg,
5.07 mmol) was added to a mixture of N-allyl-N-(3-phenyl-2-propynyl)a-
mine (crude), triethylamine (0.9 mL), and dichloromethane (5 mL) at
08C. The reaction mixture was slowly warmed to room temperature and
stirred for 2 h. Water (ꢀ50 mL) was added to quench the reaction and
the aqueous phase was extracted with chloroform (2ꢂ ꢀ50 mL). The
combined organic layers were washed with brine and dried over sodium
sulfate. Solvent was removed by rotary evaporation and the crude prod-
uct was purified by column chromatography on silica gel with hexane/di-
chloromethane (2:1!1:1) as the eluent to afford the title compound as a
white solid (1.39 g, 83% yield over two steps): Rf =0.3 (hexane/dichloro-
The general procedure for condensation of an arylpropargyl alcohol with
allyl bromide was followed: 3-(4-Chlorophenyl)-2-propyn-1-ol[32] (1.67 g,
10 mmol), NaH (360 mg, 15 mmol, prewashed with dry hexane), allyl bro-
mide (1.7 mL, 20 mmol), and freshly distilled THF (30 mL) were used to
obtain the title compound as a light yellow liquid (1.84 g, 89% yield). Pu-
rification of the crude product was conducted by filtration over a short
silica pad followed by flash column chromatography on silica gel with
hexane/ethyl acetate (30:1) as the eluent: Rf =0.4 (hexane/ethyl acetate
1
1
(30:1)); H NMR (CDCl3, 500 MHz): d=7.38 (d, J=8.5 Hz, 2H), 7.27 (d,
methane (2:1)); H NMR (CDCl3, 500 MHz): d=7.78 (d, J=8.0 Hz, 2H),
J=8.5 Hz, 2H), 5.94 (tdd, J=17.0, 10.0, 5.5 Hz, 1H), 5.34 (dd, J=17.0,
1.0 Hz, 1H), 5.24 (dd, J=17.5, 1.0 Hz, 1H), 4.36 (s, 2H), 4.12 ppm (d, J=
6.0 Hz); IR (neat): n˜ =3078, 3011, 2980, 2939, 2850, 2243, 1895, 1644,
1583, 1488, 1353, 1260, 1124, 1089, 1015, 991, 927, 828, 753, 526 cmꢁ1; MS
(EI): m/z (relative intensity): 208 [M]+ (10), 206 [M]+ (40), 167 (30), 165
(100); HRMS: calcd for C12H11ClO: 206.04984; found: 206.04989.
7.22–7.28 (m, 5H), 7.06 (d, J=7.0 Hz, 2H), 5.77–5.83 (m, 1H), 5.33 (d,
J=17.5 Hz, 1H), 5.26 (d, J=10.0 Hz, 1H), 4.31 (s, 2H), 3.89 (d, J=
6.0 Hz, 2H), 2.33 ppm (s, 3H); 13C NMR (CDCl3, 125 MHz): d=143.5,
135.9, 132.0, 131.4, 129.5, 128.3, 128.1, 127.7, 122.2, 119.9, 85.6, 81.6, 49.2,
36.7, 21.4 ppm; IR (neat): n˜ =2904, 1460, 1376, 723 cmꢁ1; MS (EI): m/z
(relative intensity): 325 [M]+ (5), 222 (20), 170 (80), 142 (70), 115 (100).
3-(Allyloxy)-1-(2-methylphenyl)-1-propyne: The general procedure for
Sonogashira coupling of propagyl alcohol with ArI was used: 2-Iodoto-
luene (10.9 g, 50 mmol), [Pd(PPh3)2Cl2] (3 mol%), CuI (6 mol%), piperi-
dine (8.4 g, 100 mmol), propagyl alcohol (3.07 mL, 52 mmol), and freshly
distilled toluene (50 mL) were used to obtain 3-(2-methylphenyl)-2-
propyn-1-ol[31] (5.26 g, 72% yield) as a light-brown solid. Purification was
conducted by filtration of the reaction mixture over a silica pad (5ꢂ
5 cm) followed by flash column chromatography on silica gel with di-
chloromethane as the eluent: Rf =0.5 (dichloromethane); 1H NMR
(CDCl3, 500 MHz): d=7.41 (d, J=7.5 Hz, 1H), 7.11–7.24 (m, 3H), 4.54
(d, J=6.0 Hz), 2.43 ppm (s, 3H); 13C NMR (CDCl3, 125 MHz): d=138.2,
131.3, 128.6, 128.1, 119.3, 115.3, 86.5, 85.3, 51.2, 21.2 ppm; MS (EI): m/z
(relative intensity): 146 [M]+ (100); HRMS: calcd for C10H10O:
146.07316; found: 146.07310.
N-Allyl-N-(2-butynyl)-4-tolylsulfonamide:
Allylamine
(15.0 mL,
200 mmol) was charged into a three-necked round-bottomed flask and
freshly distilled diethyl ether (50 mL) was added at room temperature
under nitrogen. 1-Bromo-2-butyne (1.86 mL, 20 mmol) was added drop-
wise at 08C and the reaction mixture was stirred at room temperature for
2 h. The reaction was quenched with water and extracted with ethyl ace-
tate (3ꢂ ꢀ100 mL). The combined organic layers were washed with brine
and dried over Na2SO4. The crude mixture was passed through a short
silica pad (5ꢂ10 cm). Solvent was removed in vacuo and the N-allyl-N-
(2-butynyl)amine product was used in the next step without further puri-
fication.
A dichloromethane solution of p-toluenesulfonyl chloride (4 g, 22 mmol)
was added to a mixture of N-allyl-N-(2-butynyl)amine (crude), triethyl-
amine (4 mL), and dichloromethane (50 mL) at 08C. The reaction mix-
ture was slowly warmed to room temperature and stirred for 2 h. Water
(ꢀ100 mL) was added to quench the reaction and the aqueous phase
was extracted with chloroform (2ꢂ ꢀ100 mL). The combined organic
layers were washed with brine and dried over sodium sulfate. Solvent
was removed by rotary evaporation and the crude product was purified
by column chromatography on silica gel with hexane/dichloromethane
(4:1) as the eleuent to afford the title compound as a colorless liquid
(2.30 g, 44% yield over two steps): Rf =0.2 (hexane/dichloromethane
(4:1)); 1H NMR (CDCl3, 500 MHz): d=7.70 (d, J=7.5 Hz, 2H), 7.27 (d,
J=7.5 Hz, 2H), 5.67–5.73 (m, 1H), 5.25 (d, J=17.0 Hz, 1H), 5.18 (d, J=
10.5 Hz, 1H), 3.98 (d, J=2.0 Hz, 2H), 3.77 (d, J=5.0 Hz, 2H), 2.39 (s,
3H), 1.51 ppm (t, J=6.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz): d=
143.5, 136.4, 132.4, 129.5, 128.1, 119.7, 81.8, 71.9, 49.2, 36.5, 21.7, 3.4 ppm;
IR (neat): n˜ =3073, 3062, 2980, 2914, 2847, 2294, 2223, 1644, 1593, 1491,
1439, 1349, 1255, 1162, 1092, 1055, 899, 814, 735, 663, 572, 545 cmꢁ1; MS
(EI): m/z (relative intensity): 263 [M]+ (5), 248 (10), 184 (40), 155 (60),
108 (100); HRMS: calcd for C14H17NO2S: 263.09800; found: 263.09809.
Diethyl 7-octen-2-yne-5,5-dicarboxylate:[35] Diethyl 1-butene-4,4-dicar-
boxylate (2.0 g, 10 mmol) was charged to a three-necked round-bottomed
flask and dry THF (30 mL) was added under nitrogen at room tempera-
ture. NaH (360 mg, 15 mmol, prewashed with dry hexane) was added por-
tionwise to the reaction mixture at 08C and stirred for 2 h. A white sus-
pension was observed. 1-Bromo-2-butyne (1.86 mL, 20 mmol) was then
added dropwise at 08C and the reaction mixture was slowly warmed to
room temperature with stirring for 3 h. The reaction was quenched by
water (ꢀ50 mL) and the aqueous phase was extracted with diethyl ether
(3ꢂ ꢀ100 mL). The combined organic phase was washed with water and
brine and dried over sodium sulfate. Solvent was removed by rotary
evaporation and the crude mixture was purified by distillation under re-
duced pressure to afford the title compound as a colorless oil (2.31 g,
92% yield): 1H NMR (CDCl3, 500 MHz): d=5.63 (m, 1H), 5.15 (d, J=
17.0 Hz, 1H), 5.09 (d, J=10.0 Hz, 1H), 4.19 (q, J=7.0 Hz, 4H), 2.78 (d,
The general procedure for condensation of an arylpropargyl alcohol with
allyl bromide was followed: 3-(2-Methylphenyl)-2-propyn-1-ol (1.46 g,
10 mmol), NaH (360 mg, 15 mmol, prewashed with dry hexane), allyl bro-
mide (1.7 mL, 20 mmol), and freshly distilled THF (20 mL) were used to
obtain the title compound as a light yellow liquid (1.73 g, 94% yield):
1H NMR (CDCl3, 500 MHz): d=7.43 (d, J=8.0 Hz, 1H), 7.12–7.25 (m,
3H), 5.95–6.01 (m, 1H), 5.36 (dd, J=17.0, 1.0 Hz, 1H), 5.27 (dd, J=17.5,
1.0 Hz, 1H), 4.44 (s, 2H), 4.16 (d, J=6.0 Hz), 2.46 ppm (s, 3H);
13C NMR (CDCl3, 125 MHz): d=137.6, 137.4, 132.0, 128.8, 128.6, 119.6,
119.3, 115.1, 89.4, 85.5, 72.3, 57.4, 20.2 ppm; IR (neat): n˜ =3069, 3020,
2981, 2920, 2850, 2223, 1644, 1603, 1485, 1455, 1425, 1353, 1249, 1117,
1085, 926, 758, 716, 599, 452 cmꢁ1; HRMS: calcd for C13H14O: 186.10447;
found: 186.10453.
N-Allyl-N-(3-phenyl-2-propynyl)-4-tolylsulfonamide:[11, 33] Triphenylphos-
phane (14.4 g, 55 mmol) was dissolved in dichloromethane (250 mL).
Bromine (8.8 g, 2.82 mL, 55 mmol) was then added dropwise at 08C and
the mixture was stirred for 30 min. 3-Phenyl-2-propyn-1-ol was added at
08C and the reaction mixture was left to stir for 1 h. Hexane (ꢀ800 mL)
was added and the white suspension was passed through a short silica
pad (5ꢂ10 cm) and washed with hexane. The crude product was concen-
trated and distilled under reduced pressure (b.p.=88–908C, 1 mmHg) to
afford 3-bromo-1-phenyl-1-propyne[34] (9.01 g, 92% yield) as a light-
yellow liquid: Rf =0.4 (hexane); 1H NMR (CDCl3, 500 MHz): d=7.44–
7.46 (m, 2H), 7.32–7.36 (m, 3H), 4.17 ppm (s, 2H); 13C NMR (CDCl3,
125 MHz): d=132.1, 129.1, 128.6, 122.4, 87.0, 84.5, 15.6 ppm; MS (EI): m/
z (relative intensity): 196 [M]+ (100), 194 [M]+ (100).
Allylamine (4.0 mL, 53 mmol) was charged into a three-necked round-
bottomed flask and freshly distilled diethyl ether (10 mL) was added at
room temperature under nitrogen. 3-Bromo-1-phenyl-1-propyne (1.0 g,
5.13 mmol) was added dropwise at 08C and the reaction mixture was stir-
red at room temperature for 2 h. The reaction was quenched with water
and extracted with ethyl acetate (3ꢂ ꢀ50 mL). The combined organic
Chem. Eur. J. 2005, 11, 3872 – 3880
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3877

F. Y. Kwong, A. S. C. Chan et al.
1
J=7.5 Hz, 2H), 2.72 (q, J=2.5 Hz, 2H), 1.75 (t, J=2.5 Hz, 3H),
1.24 ppm (t, J=7.5 Hz, 6H); 13C NMR (CDCl3, 125 MHz): d=169.9,
131.8, 119.3, 78.6, 73.2, 61.3, 56.8, 36.3, 22.7, 13.9, 3.3 ppm; IR (neat): n˜ =
3646, 3472, 3083, 2982, 2929, 2233, 1739, 1639, 1465, 1441, 1325, 1292,
1218, 1136, 1096, 1036, 912, 855, 661, 574 cmꢁ1; MS (EI): m/z (relative in-
tensity): 252 [M]+ (20), 194 (100).
ethyl acetate (2:1)); H NMR (CDCl3, 500 MHz): d=4.61 (q, J=15.5 Hz,
2H), 4.30–4.34 (m, 1H), 3.19–3.23 (m, 2H), 2.64–2.71 (dd, J=5.5,
18.0 Hz, 1H), 2.19–2.33 (m, 2H), 2.10–2.17 (dd, J=2.5, 18.0 Hz, 1H),
1.12 ppm (t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz): d=208.0,
175.1, 138.6, 71.8, 64.8, 43.2, 38.6, 17.6, 16.3 ppm; MS (EI): m/z (relative
intensity): 152 [M]+, 100), 123 (40), 105 (50).
Catalytic asymmetric Pauson–Khand-type reaction:
2-(4-Methoxyphenyl)-7-oxabicyclo[3.3.0]oct-1-en-3-one
(Table 2,
entry 7):[12a] Purified by column chromatography (1.8ꢂ ꢀ15 cm) on silica
gel with hexane/ethyl acetate (2:1) as the eluent to obtain the title com-
pound as a light-yellow solid (93% yield; 93% ee): HPLC conditions: AS
column, Hex:IPA=9:1, 1.0 mLminꢁ1, 254 nm, Rt =15.9, 25.7 min; Rf =0.2
General procedure for asymmetric Pauson–Khand-type cyclization of
various enynes: [{Rh(cod)Cl}2] (4.4 mg, 9.0 mmol), (S)-P-Phos (11.6 mg,
18.0 mmol), and cinnamylaldehyde (59 mg, 0.45 mmol, 1.5 equiv with re-
spect to the enyne) were charged to a screw-cap vial on the bench top at
room temperature with continuous stirring (magnetic stirrer bar, 2ꢂ
6 mm). Enynes (0.3 mmol) was then added under air. These vials were
evacuated and backfilled with nitrogen (3 cycles) and this was followed
by addition of water (0.2 mL, concentration of enyne 1.5m). The reaction
mixtures were heated to 1008C (ꢂ28C) for 36 h (reaction times were un-
optimized for each substrate). The vials were allowed to cool to room
temperature. Ethyl acetate (ꢀ2 mL) was added and the crude product
was passed through a short plug of Na2SO4. Solvent was removed by
rotary evaporation and the crude mixture was purified by flash column
chromatography on silica gel with hexane/ethyl acetate as the eluent to
afford the chiral bicyclic cyclopentenones. (Alternative workup proce-
dure: dichloromethane (ꢀ2 mL) was added and the reaction mixture
was passed through a short plug of Na2SO4 for initial screening by GC-
MS analysis.) The enantiomeric excess values of the products were deter-
mined by chiral HPLC analysis with Daicel AS, AS-H, and AD-H col-
umns.
1
(hexane/ethyl acetate (2:1)); H NMR (CDCl3, 500 MHz): d=7.48 (d, J=
9.0 Hz, 2H), 6.93 (d, J=9.0 Hz, 1H), 4.89 (d, J=16.0 Hz, 1H), 4.57 (d,
J=16.0 Hz, 1H), 4.35 (t, J=8.0 Hz, 1H), 3.82 (s, 3H), 3.26–3.30 (m, 1H),
3.20 (dd, J=7.5, 11.0 Hz, 1H), 2.81 (dd, J=6.0, 17.5 Hz, 1H), 2.31 ppm
(dd, J=3.0, 17.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz): d=202.3, 175.2,
159.8, 134.1, 129.3, 123.2, 114.0, 71.3, 66.3, 55.2, 43.1, 40.2 ppm; MS (EI):
m/z (relative intensity): 230 [M]+ (100), 201 (10), 189 (30), 172 (60).
2-(4-Methylphenyl)-7-oxabicyclo[3.3.0]oct-1-en-3-one (Table 2, entry 6):
Purified by column chromatography (1.8ꢂ ꢀ15 cm) on silica gel with
hexane/ethyl acetate (3:1) as the eluent to obtain the title compound as a
white solid (92% yield; 87% ee): HPLC conditions: AS-H column,
Hex:IPA=9:1, 1.0 mLminꢁ1
,
254 nm, Rt =13.0, 18.5 min; Rf =0.4
(hexane/ethyl acetate (2:1)); [a]2D5 =+53.78 (c=0.010 in CHCl3);
1H NMR (CDCl3, 500 MHz): d=7.42 (d, J=8.0 Hz, 2H), 7.22 (d, J=
8.0 Hz, 1H), 4.93 (d, J=16.0 Hz, 1H), 4.59 (d, J=16.0 Hz, 1H), 4.37 (t,
J=7.5 Hz, 1H), 3.28–3.32 (m, 1H), 3.23 (dd, J=8.0, 11.5 Hz, 1H), 2.84
(dd, J=6.5, 17.5 Hz, 1H), 2.37 (s, 3H), 2.32 ppm (dd, J=3.5, 18.0 Hz,
1H); 13C NMR (CDCl3, 125 MHz): d=202.3, 175.2, 159.8, 134.1, 129.3,
123.2, 114.0, 71.3, 66.3, 43.1, 40.2, 23.8 ppm; IR (neat): n˜ =3020, 2397,
1747, 1511, 1419, 1215, 1040, 922, 756, 669 cmꢁ1; MS (EI): m/z (relative
intensity): 214 [M]+ (100), 184 (30), 169 (40), 156 (45), 141 (70); HRMS:
calcd for C14H14O2: 214.09938; found: 214.09943.
2-Phenyl-7-oxabicyclo[3.3.0]oct-1-en-3-one (Table 2, entry 1):[9] Purified
by column chromatography (1.8ꢂ ꢀ15 cm) on silica gel with hexane/
ethyl acetate (3:1) as the eluent to obtain the title compound as a light
yellow oil (82% yield; 84% ee (S configuration)): HPLC conditions: AD
column, hexane (Hex):isopropyl alcohol (IPA)=9:1, 1.0 mLminꢁ1
,
254 nm, Rt =12.4, 16.9 min; Rf =0.3 (hexane/ethyl acetate (2:1));
1H NMR (CDCl3, 500 MHz): d=7.52 (d, J=7.5 Hz, 2H), 7.39–7.42 (m,
2H), 7.33–7.37 (m, 1H), 4.93 (d, J=16.5 Hz, 1H), 4.59 (d, J=16.0 Hz,
1H), 4.38 (t, J=8.0 Hz, 1H), 3.30–3.35 (m, 1H), 3.23 (dd, J=8.0 Hz,
11.5 Hz, 1H), 2.85 (dd, J=6.5 Hz, 18.5 Hz, 1H), 2.34 ppm (dd, J=4.0 Hz,
18.0 Hz, 1H); 13C NMR (CDCl3, 125 MHz): d=206.7, 177.3, 134.5, 130.5,
128.6, 128.5, 127.9, 71.2, 66.2, 43.2, 40.2 ppm; MS (EI): m/z (relative in-
tensity): 200 [M]+ (70), 170 (40), 158 (50), 141 (100).
2-Phenyl-5-methyl-7-oxabicyclo[3.3.0]oct-1-en-3-one (Table 2, entry 2):[36]
Purified by column chromatography (1.8ꢂ ꢀ15 cm) on silica gel with
hexane/ethyl acetate (3:1) as the eluent to obtain the title compound as a
light yellow oil (71% yield; 90% ee): HPLC conditions: AS-H column,
Hex:IPA=9:1, 1.0 mLminꢁ1, 254 nm, Rt =9.7, 10.8 min; Rf =0.3 (hexane/
ethyl acetate (2:1)); 1H NMR (CDCl3, 500 MHz): d=7.33–7.51 (m, 5H),
4.98 (d, J=17.0 Hz, 1H), 4.60 (d, J=17.0 Hz, 1H), 4.03 (d, J=8.0 Hz,
1H), 3.43 (d, J=8.0 Hz, 1H), 2.60 (d, J=17.0 Hz, 1H), 2.54 (d, J=
17.0 Hz, 1H), 1.39 ppm (s, 3H); 13C NMR (CDCl3, 125 MHz): d=206.7,
180.6, 133.2, 130.5, 128.7, 128.6, 128.1, 76.5, 65.3, 48.7, 47.8, 24.7 ppm; MS
(EI): m/z (relative intensity): 214 [M]+ (80), 184 (20), 169 (40), 141 (100),
115 (70).
2-(4-Fluorophenyl)-7-oxabicyclo[3.3.0]oct-1-en-3-one (Table 2, entry 7):
Purified by column chromatography (1.8ꢂ ꢀ15 cm) on silica gel with
hexane/ethyl acetate (3:1) as the eluent to obtain the title compound as a
light-yellow oil (90% yield; 82% ee): HPLC conditions: AS-H column,
Hex:IPA=98:2, 1.0 mLminꢁ1
, 254 nm, Rt =29.8, 35.7 min; Rf =0.3
(hexane/ethyl acetate (2:1)); [a]2D5 =+0.78 (c=0.0083 in CHCl3);
1H NMR (CDCl3, 500 MHz): d=7.52 (dd, J=5.5, 8.0 Hz, 2H), 7.09 (t,
J=8.0 Hz, 2H), 4.91 (d, J=16.5 Hz, 1H), 4.56 (d, J=16.5 Hz, 1H), 4.37
(t, J=7.5 Hz, 1H), 3.29–3.33 (m, 1H), 3.24 (dd, J=7.5, 11.0 Hz, 1H),
2.84 (dd, J=6.5, 18.0 Hz, 1H), 2.33 ppm (dd, J=3.5, 17.5 Hz, 1H);
13C NMR (CDCl3, 125 MHz): d=204.1, 177.0, 161.7, 133.6, 129.8 (d,
J
C,F =8.4 Hz), 126.7, 115.6 (d, JC,F =22.0 Hz), 71.3, 66.2, 43.2, 40.1 ppm;
IR (neat): n˜ =3021, 2392, 1701, 1506, 1215, 1029, 758, 669 cmꢁ1; MS (EI):
m/z (relative intensity): 218 [M]+ (70), 188 (50), 176 (50), 159 (100), 146
(60); HRMS: calcd for C13H11FO2: 218.07431; found: 218.07439.
2-(3-Methoxyphenyl)-7-oxabicyclo[3.3.0]oct-1-en-3-one (Table 2, entry 8):
Purified by column chromatography (1.8ꢂ ꢀ15 cm) on silica gel with
hexane/ethyl acetate (3:1) as the eluent to obtain the title compound as a
light-yellow viscous oil (88% yield; 81% ee): HPLC conditions: AS-H
column, Hex:IPA=9:1, 1.0 mLminꢁ1, 254 nm, Rt =20.9, 47.0 min; Rf =0.3
(hexane/ethyl acetate (2:1)); [a]2D5 =+21.48 (c=0.011 in CHCl3);
1H NMR (CDCl3, 500 MHz): d=7.31 (t, J=7.5 Hz, 1H), 7.16 (s, 1H),
7.04 (d, J=8.0 Hz, 1H), 6.90 (dd, J=2.5, 8.0 Hz, 1H), 4.92 (d, J=
16.0 Hz, 1H), 4.59 (d, J=16.0 Hz, 1H), 4.37 (t, J=7.5 Hz, 1H), 3.82 (s,
3H), 3.29–3.33 (m, 1H), 3.23 (dd, J=7.5, 11.5 Hz, 1H), 2.84 (dd, J=6.5,
17.5 Hz, 1H), 2.33 ppm (dd, J=4.0, 17.5 Hz, 1H); 13C NMR (CDCl3,
125 MHz): d=206.7, 177.7, 159.6, 134.5, 131.8, 129.6, 120.5, 114.3, 113.4,
71.3, 66.3, 55.2, 43.3, 40.3 ppm; IR (neat): n˜ =3019, 2386, 1705, 1511,
1413, 1215, 1045, 1024, 922, 758, 669 cmꢁ1; MS (EI): m/z (relative intensi-
ty): 230 [M]+ (100), 213 (5), 199 (10), 185 (20), 171 (20), 159 (30);
HRMS: calcd for C14H14O3: 230.09430; found: 230.09422.
2-Methyl-7-oxabicyclo[3.3.0]oct-1-en-3-one (Table 2, entry 3):[9] Purified
by column chromatography (1.8ꢂ ꢀ15 cm) on silica gel with hexane/
ethyl acetate (3:1) as the eluent to obtain the title compound as a color-
less oil (82% yield; 95% ee): HPLC conditions: AS-H column,
Hex:IPA=9:1, 1.0 mLminꢁ1
,
210 nm, Rt =12.2, 13.7 min; Rf =0.3
1
(hexane/ethyl acetate (2:1)); H NMR (CDCl3, 500 MHz): d=4.54 (q, J=
15.0 Hz, 2H), 4.30–4.32 (m, 1H), 3.19–3.23 (m, 2H), 2.64–2.71 (dd, J=
5.5, 18.0 Hz, 1H), 2.09–2.17 (dd, J=2.0, 18.0 Hz, 1H), 1.77 (s, 3H) ppm;
13C NMR (CDCl3, 125 MHz): d=209.0, 176.1, 132.6, 71.8, 64.7, 43.2, 38.6,
8.9 ppm; MS (EI): m/z (relative intensity): 138 [M]+ (100), 123 (60), 105
(30).
2-Ethyl-7-oxabicyclo[3.3.0]oct-1-en-3-one (Table 2, entry 4):[26] Purified
by column chromatography (1.8ꢂ ꢀ15 cm) on silica gel with hexane/
ethyl acetate (3:1) as the eluent to obtain the title compound as a color-
less oil (60% yield; 95% ee): HPLC conditions: AS-H column,
Hex:IPA=9:1, 1.0 mLminꢁ1, 210 nm, Rt =9.6, 11.7 min; Rf =0.3 (hexane/
2-(4-Chlorophenyl)-7-oxabicyclo[3.3.0]oct-1-en-3-one
(Table 2,
entry 9):[12a] Purified by column chromatography (1.8ꢂ ꢀ15 cm) on silica
gel with hexane/ethyl acetate (3:1) as the eluent to obtain the title com-
pound as a light-yellow oil (91% yield; 77% ee): HPLC conditions: AS-
3878
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 3872 – 3880

Pauson–Khand-Type Reactions
FULL PAPER
H column, Hex:IPA=98:2, 1.0 mLminꢁ1, 254 nm, Rt =26.3, 32.0 min;
Rf =0.3 (hexane/ethyl acetate (2:1)); 1H NMR (CDCl3, 500 MHz): d=
7.48 (d, J=9.0 Hz, 2H), 7.38 (d, J=9.0 Hz, 1H), 4.92 (d, J=16.0 Hz,
1H), 4.57 (d, J=16.0 Hz, 1H), 4.38 (t, J=8.0 Hz, 1H), 3.30–3.37 (m,
1H), 3.25 (dd, J=7.5, 11.0 Hz, 1H), 2.85 (dd, J=6.0, 18.0 Hz, 1H),
2.33 ppm (dd, J=3.5, 18.0 Hz, 1H); 13C NMR (CDCl3, 125 MHz): d=
205.3, 175.1, 159.7, 134.0, 129.3, 123.3, 114.1, 71.1, 66.3, 43.2, 40.2 ppm;
MS (EI): m/z (relative intensity): 236 [M]+ (20), 234 [M]+ (60), 204 (15),
192 (25), 169 (95), 141 (100).
Acknowledgements
We thank the University Grants Committee Areas of Excellence Scheme
in Hong Kong (project no. AoE/P-10/01) and The Hong Kong Polytech-
nic University Area of Strategic Development Fund for financial support
of this study. We are grateful to Prof. Chun Wai Tsang and Mr. Yiu Kwok
Au in The Hong Kong Polytechnic University for performing high-resolu-
tion mass spectrometry analyses.
2-(2-Methylphenyl)-7-oxabicyclo[3.3.0]oct-1-en-3-one (Table 2, entry 10):
Purified by column chromatography (1.8ꢂ ꢀ15 cm) on silica gel with
hexane/ethyl acetate (3:1) as the eluent to obtain the title compound as a
colorless oil (49% yield; 74% ee): HPLC conditions: AD-H column,
[1] For initial development of the PKR, see: a) I. U. Khand, G. R.
Knox, P. L. Pauson, W. E. Watts, J. Chem. Soc. Chem. Commun.
1971, 36. For recent reviews on the PKR, see: b) N. Jeong in Transi-
tion Metals In Organic Synthesis, Vol. 1 (Eds.: M. Beller, C. Bolm),
Wiley-VCH, Weinheim, 1998, p. 560; c) Y. K. Chung, Coord. Chem.
Rev. 1999, 188, 297; d) S. L. Buchwald, F. A. Hicks in Comprehensive
Asymmetric Catalysis II (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yama-
moto), Springer, Heidelberg, 1999, p. 491; e) K. M. Brummond, J. L.
Kent, Tetrahedron 2000, 56, 3263; f) A. J. Fletcher, S. D. R. Christie,
J. Chem. Soc. Perkin Trans. 1 2000, 1657; g) M. R. Rivero, J. Adrio,
J. C. Carretero, Eur. J. Org. Chem. 2002, 2881; h) S. T. Ingate, J.
Marco-Contelle, Org. Prep. Proced. Int. 1998, 30, 121; i) L. V. R.
BoÇaga, M. E. Krafft, Tetrahedron 2004, 60, 9795.
[2] For recent selected examples, see: a) T. F. Jamison, S. Shambayati,
W. E. Crowe, S. L. Schreiber, J. Am. Chem. Soc. 1994, 116, 5505;
b) K. M. Brummond, D. Gao, Org. Lett. 2003, 5, 3491; c) B. Jiang,
M. Xu, Angew. Chem. 2004, 116, 2597; Angew. Chem. Int. Ed. 2004,
43, 2543; d) J. Velcicky, A. Lanver, J. Lex, A. Prokop, T. Wieder, H.-
G. Schmalz, Chem. Eur. J. 2004, 10, 5087. For a recent review, see:
e) J. Blanco-Urgoiti, L. AÇorbe, L. Pꢃrez-Serrano, G. Domꢄnguez, J.
Pꢃrez-Castells, Chem. Soc. Rev. 2004, 33, 32.
[3] For recent reviews on the catalytic PKR, see: a) S. E. Gibson, A.
Stevenazzi, Angew. Chem. 2003, 115, 1844; Angew. Chem. Int. Ed.
2003, 42, 1800; b) B. E. Hanson, Comments Inorg. Chem. 2002, 23,
289.
[4] I. U. Khand, G. R. Knox, P. L. Pauson, W. E. Watts, M. I. Foreman,
J. Chem. Soc. Perkin Trans. 1 1973, 977.
[5] a) D. C. Billington, Tetrahedron Lett. 1983, 24, 2905; b) P. Magnus,
L. M. Principe, M. J. Slater, J. Org. Chem. 1987, 52, 1483; c) V. Rau-
tenstrauch, P. Mꢃgard, J. Conesa, W. Kꢁster, Angew. Chem. 1990,
102, 1441; Angew. Chem. Int. Ed. Engl. 1990, 29, 1413.
[6] N. Jeong, S. H. Hwang, Y. Lee, Y. K. Chung, J. Am. Chem. Soc.
1994, 116, 3159.
[7] For the enantioselective cobalt-catalyzed PKR with CO gas, see:
a) S. J. Sturla, S. L. Buchwald, J. Org. Chem. 1999, 64, 5547; b) S. J.
Sturla, S. L. Buchwald, J. Org. Chem. 2002, 67, 3398; c) K. Hiroi, T.
Watanabe, R. Kawagishi, I. Abe, Tetrahedron Lett. 2000, 41, 891;
d) K. Hiroi, T. Watanabe, R. Kawagishi, I. Abe, Tetrahedron: Asym-
metry 2000, 11, 797; e) X. Verdaguer, M. A. Pericꢅs, A. Riera, M. A.
Maestro, J. Mahꢄa, Organometallics 2003, 22, 1868; f) D. Konya, F.
Robert, Y. Gimbert, A. E. Greene, Tetrahedron Lett. 2004, 45, 6975.
[8] For the enantioselective titanium-catalyzed PKR with CO gas, see:
a) F. A. Hicks, S. L. Buchwald, J. Am. Chem. Soc. 1996, 118, 11688;
b) F. A. Hicks, S. L. Buchwald, J. Am. Chem. Soc. 1999, 121, 7026;
c) S. K. Mandal, S. R. Amin, W. E. Crowe, J. Am. Chem. Soc. 2001,
123, 6457.
[9] For the enantioselective rhodium-catalyzed PKR with CO gas, see:
a) N. Jeong, B. K. Sung, Y. K. Choi, J. Am. Chem. Soc. 2000, 122,
6771; b) N. Jeong, D. H. Kim, J. H. Choi, Chem. Commun. 2004,
1134; c) ref. [14c]. For the most recent reference with molecular
sieves as a CO gas reservoir, see: d) T. M. Schmid, G. Consiglio,
Chem. Commun. 2004, 2318.
Hex:IPA=9:1, 1.0 mLminꢁ1
,
254 nm, Rt =11.8, 12.6 min; Rf =0.4
(hexane/ethyl acetate (2:1)); [a]2D5 =+31.48 (c=0.012 in CHCl3);
1H NMR (CDCl3, 500 MHz): d=7.19–7.29 (m, 3H), 7.10 (d, J=7.5 Hz,
1H), 4.63 (d, J=16.0 Hz, 1H), 4.42 (t, J=7.5 Hz, 1H), 4.36 (d, J=
15.5 Hz, 1H), 3.38–3.42 (m, 1H), 3.34 (dd, J=7.0, 11.0 Hz, 1H), 2.85 (dd,
J=5.5, 17.5 Hz, 1H), 2.35 (dd, J=3.5, 17.5 Hz, 1H); 2.18 ppm (s, 3H);
13C NMR (CDCl3, 125 MHz): d=202.3, 175.2, 159.8, 134.1, 129.3, 128.9,
˜
123.2, 114.0, 111.3, 71.3, 66.3, 43.1, 40.2, 23.8 ppm; IR (neat): n=3021,
2397, 1737, 1510, 1419, 1215, 1043, 922, 758, 669 cmꢁ1; MS (EI): m/z (rela-
tive intensity): 214 [M]+ (100), 199 (5), 183 (40), 169 (50), 154 (30), 141
(70); HRMS: calcd for C14H14O2: 214.09938; found: 214.09946.
2-Phenyl-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[3.3.0]oct-1-en-3-one
(Table 3, entry 1):[37] Purified by column chromatography (2.0ꢂ ꢀ15 cm)
on silica gel with hexane/ethyl acetate (2:1) as the eluent to obtain the
title compound as a light-yellow solid (96% yield; 80% ee): HPLC condi-
tions: AD-H column, Hex:IPA=9:1, 1.0 mLminꢁ1, 254 nm, Rt =43.8,
52.8 min; Rf =0.3 (hexane/ethyl acetate (2:1)); m.p.=159–1608C;
1H NMR (CDCl3, 500 MHz): d=7.71 (d, J=8.0 Hz, 2H), 7.36–7.46 (m,
5H), 7.30 (d, J=8.0 Hz, 2H), 4.63 (dd, J=2.0, 17.0 Hz, 1H), 4.04–4.09
(m, 2H), 3.18–3.23 (m, 1H), 2.78 (dd, J=6.5, 17.5 Hz, 1H), 2.61 (dd, J=
9.0, 10.5 Hz, 1H), 2.40 (s, 3H), 2.25 ppm (dd, J=4.0, 18.0 Hz, 1H);
13C NMR (CDCl3, 125 MHz): d=206.4, 171.9, 144.0, 136.0, 133.6, 130.0,
129.8, 128.9, 128.7, 128.2, 127.4, 52.0, 48.3, 41.8, 40.7, 21.5 ppm; MS (EI):
m/z (relative intensity): 353 [M]+ (20), 198 (100), 171 (50), 141 (60), 128
(45).
2-Methyl-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[3.3.0]oct-1-en-3-one
(Table 3, entry 2):[38] Purified by column chromatography (2.0ꢂ ꢀ15 cm)
on silica gel with hexane/ethyl acetate (2:1) as the eluent to obtain the
title compound as a white solid (98% yield; 88% ee): HPLC conditions:
AD-H column, Hex:IPA=9:1, 1.0 mLminꢁ1, 254 nm, Rt =34.1, 37.1 min;
1
Rf =0.2 (hexane/ethyl acetate (2:1)); m.p.=103–1048C; H NMR (CDCl3,
500 MHz): d=7.73 (d, J=8.5 Hz, 2H), 7.34 (d, J=8.5 Hz, 2H), 4.23 (d,
J=16.0 Hz, 1H), 3.96–4.00 (m, 2H), 2.96–3.06 (m, 1H), 2.54–2.62 (m,
2H), 2.44 (s, 3H), 2.03 (dd, J=3.0, 17.5 Hz, 1H), 1.68 ppm (s, 3H);
13C NMR (CDCl3, 125 MHz): d=205.3, 171.0, 144.0, 134.1, 133.9, 129.9,
127.4, 52.6, 46.7, 41.6, 39.2, 21.5, 8.8 ppm; MS (EI): m/z (relative intensi-
ty): 291 [M]+ (30), 263 (5), 155 (10), 136 (100).
Diethyl 2-methyl-3-oxobicyclo[3.3.0]oct-1-ene-7,7-dicarboxylate (Table 3,
entry 3):[39] Purified by column chromatography (1.8ꢂ ꢀ15 cm) on silica
gel with hexane/ethyl acetate (4:1) as the eluent to obtain the title com-
pound as a light-yellow viscous oil (91% yield; 77% ee (S configura-
tion)): HPLC conditions: AS-H column, Hex:IPA=9:1, 1.0 mLminꢁ1
,
254 nm, Rt =12.5, 15.9 min; Rf =0.3 (hexane/ethyl acetate (4:1));
1H NMR (CDCl3, 500 MHz): d=4.21 (q, J=6.5 Hz, 2H), 4.17 (q, J=
6.5 Hz, 2H), 3.16 (q, J=14.5 Hz, 2H), 2.94 (m, 1H), 2.74 (dd, J=7.0,
12.5 Hz, 1H), 2.60 (dd, J=6.0, 18.0 Hz, 1H), 2.04 (dd, J=3.0, 18.5 Hz,
1H), 1.68 (s, 3H), 1.61 (t, J=13.0 Hz, 3H), 1.24 (t, J=7.0 Hz, 3H),
1.22 ppm (t, J=7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz): d=203.9,
177.7, 171.5, 170.9, 132.8, 61.9, 61.8, 60.8, 42.6, 41.3, 39.0, 33.9, 13.9 (over-
lapped), 8.4 ppm; MS (EI): m/z (relative intensity): 280 [M]+ (40), 235
(20), 206 (80), 178 (30), 133 (100).
[10] For the enantioselective iridium-catalyzed PKR with CO gas, see: T.
Shibata, K. Takagi, J. Am. Chem. Soc. 2000, 122, 9852.
[11] a) T. Morimoto, K. Fuji, K. Tsutsumi, K. Kakiuchi, J. Am. Chem.
Soc. 2002, 124, 3806; b) T. Morimoto, M. Fujioka, K. Fuji, K. Tsutsu-
mi, K. Kakiuchi, Chem. Lett. 2003, 32, 154; c) K. Fuji, T. Morimoto,
K. Tsutsumi, K. Kakiuchi, Angew. Chem. 2003, 115, 2511; Angew.
Chem. Int. Ed. 2003, 42, 2409. For the most recent minireview, see:
Chem. Eur. J. 2005, 11, 3872 – 3880
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3879

F. Y. Kwong, A. S. C. Chan et al.
d) T. Morimoto, K. Kakiuchi, Angew. Chem. 2004, 116, 5698;
Angew. Chem. Int. Ed. 2004, 43, 5580.
Kwong, Q. Yang, T. C. W. Mak, A. S. C. Chan, K. S. Chan, J. Org.
Chem. 2002, 67, 2769.
[12] a) T. Shibata, N. Toshida, K. Takagi, J. Org. Chem. 2002, 67, 7446;
b) T. Shibata, N. Toshida, K. Takagi, Org. Lett. 2002, 4, 1619.
[13] a) C. J. Li, T. H. Chan, Organic Reactions in Aqueous Media, Wiley,
New York, 1997; b) Aqueous-Phase Organometallic Catalysis (Eds.:
B. Cornils, W. A. Herrmann), Wiley-VCH, Weinheim, 1998; c) U. M.
Lindstrçm, Chem. Rev. 2002, 102, 2751; d) P. Tundo, P. T. Anastas,
Green Chemistry: Challenging Perspectives, Oxford University Press,
Oxford, 2000; e) W. M. Nelson, Green Solvents for Chemistry, Per-
spective and Practice, Oxford University Press, Oxford, 2003;
f) Clean Solvents, Alternative Media for Chemical Reactions and
Processing (Eds.: M. A. Abraham, L. Moens), American Chemical
Society Symposium Series 819, American Chemical Society, Wash-
ington, DC, 2002.
[14] For the nonasymmetric Co2CO6-mediated aqueous PKR, which uses
water as a cosolvent and/or with the addition of surfactant (sodium
dodecylsulfate (SDS)), see: a) M. E. Kraff, J. A. Wright, L. V. R.
BoÇaga, Tetrahedron Lett. 2003, 44, 3417; b) S. U. Son, S. I. Lee,
Y. K. Chung, S.-W. Kim, T. Hyeon, Org. Lett. 2002, 4, 277;
c) L. V. R. BoÇaga, J. A. Wright, M. E. Kraff, Chem. Commun. 2004,
1746. For the Rh-catalyzed asymmetric PKR with a water/dioxane
solvent mixture in the presence of surfactant (SDS) with CO gas,
see: d) W. H. Suh, M. Choi, S. I. Lee, Y. K. Chung, Synthesis 2003,
2169. Note added in proof: During the reviewing process of this
manuscript, a close related work on the asymmetric aqueous PKR
appeared: e) K. Fuji, T. Morimoto, K. Tsutsumi, K. Kakiuchi, Tetra-
hedron Lett. 2004, 45, 9163.
[22] For evidences for the role of dp–pp bonding in the rhodium-mediat-
ed reaction, see: a) K. Burgess, W. A. van der Donk, M. B. Jarstfer,
M. J. Ohlmeyer, J. Am. Chem. Soc. 1991, 113, 6139. For models that
assume that the complexation of the alkene/alkyne (p interaction)
to the metal center is the rate stereochemical-determining step of
the reaction, see: b) Homogeneous Transition Metal Catalyzed Reac-
tions (Eds.: W. R. Moser, D. W. Slocum), Advances in Chemistry
Series 230, American Chemical Society, Washington, DC, 1992,
pp. 163. For other mechanistic studies of steric and electronic effects
in the insertion of olefins, see: B. J. Burger, B. D. Santarsiero, M. S.
Trimmer, J. E. Bercaw, J. Am. Chem. Soc. 1988, 110, 3134.
[23] We thank a referee during the manuscript-reviewing process for the
suggestion of other factors that could be responsible for the ob-
served electronic influence, for example, the interaction of the
phenyl p system with the Rh center, which differs in strength and
geometry depending on the substitutent (electron-donating group or
electron-withdrawing group), or an electronically induced shift from
an early to a late transition state.
[24] W. L. F. Armarego, D. D. Perrin, Purification of Laboratory Chemi-
cals, 4th ed., Butterworth-Heinemann, Oxford, 1996.
[25] A. J. Pearson, R. A. Dubbert, J. Chem. Soc. Chem. Commun. 1991,
202.
[26] A. J. Pearson, R. A. Dubbert, Organometallics 1994, 13, 1656.
[27] A. J. Bartlett, T. Laird, W. D. Ollis, J. Chem. Soc. Perkin Trans. 1
1975, 1315.
[28] E. V. Tretyakov, A. V. Tkachev, T. V. Rybalova, Y. V. Gatilov, D. W.
Knight, S. F. Vasilevsky, Tetrahedron 2000, 56, 10075.
[29] A. Godt, J. Org. Chem. 1997, 62, 7471.
[15] Air-stable ligand, enynes, and aldehyde were weighed on the bench
top under air without special precautions.
ˇ
[16] For micelle reviews, see: a) S. Tas¸cioglu, Tetrahedron 1996, 52,
[30] D. H. Wadsworth, S. M. Geer, M. R. Detty, J. Org. Chem. 1987, 52,
3662.
[31] F. Liron, P. Le Garrec, M. Alami, Synlett 1999, 246. (No spectral
data were given.)
[32] N. A. Bumagin, A. B. Ponomarev, I. P. Beletskaya, Synthesis 1984,
728.
[33] T. Kobayahsi, Y. Koga, K. Narasaka, J. Organomet. Chem. 2001,
624, 73.
[34] G. B. Jones, J. M. Wright, G. W. Plourde II, G. Hynd, R. S. Huber,
J. E. Mathews, J. Am. Chem. Soc. 2000, 122, 1937.
[35] a) J.-N. Denis, A. E. Greene, A. A. Serra, M.-J. Luche, J. Org.
Chem. 1986, 51, 46; b) R. B. Grossman, S. L. Buchwald, J. Org.
Chem. 1992, 57, 5803.
11113; b) U. M. Lindstrom, Chem. Rev. 2002, 102, 2751, and referen-
ces therein.
[17] BINAP=2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl, tol-BINAP=
2,2’-bis(di-p-tolylphosphanyl)-1,1’-binaphthyl, (R,R)-Et-DUPHOS=
(ꢁ)-1,2-bis((2R,5R)-2,5-diethylphospholano)benzene; (S)-PHANE-
PHOS=(S)-(+)-4,12-bis(diphenylphosphano)-[2.2]-paracyclophane;
(S,S)-Et-FerroTANE=(ꢁ)-1,1’-bis((2S,4S)-2,4-diethylphospholano)-
ferrocene.
[18] Available from Strem Chemicals 2004 catalogue as CTH-(S)-P-
Phos; A. S. C. Chan, C. C. Pai, US5886182, 1999.
[19] 59% yield, 81% ee (under the same reaction conditions as in
Table 1 except for the aldehyde loading).
[20] For a review of the Hammett study, see: a) C. Hansch, A. Leo,
R. W. Taft, Chem. Rev. 1991, 91, 165; b) A. J. Gordon, R. A. Ford,
The Chemistꢀs Companion, Wiley, New York, 1972.
[21] For recent references on electronic effects in asymmetric catalysis,
see: a) E. N. Jacobsen, W. Zhang, M. L. Gꢁler, J. Am. Chem. Soc.
1991, 113, 6703; b) H. C. Zhang, F. Xue, T. C. W. Mak, K. S. Chan, J.
Org. Chem. 1996, 61, 8002; c) M. M. C. Lo, G. C. Fu, J. Am. Chem.
Soc. 1998, 120, 10270; d) H. Doucet, E. Fernandez, T. P. Layzell,
J. M. Brown, Chem. Eur. J. 1999, 5, 1320; e) W. C. Lo, C. M. Che,
K. F. Cheng, T. C. W. Mak, Chem. Commun. 1997, 1205; f) F. Y.
[36] S. C. Beck, R. B. Grossman, S. L. Buchwald, J. Am. Chem. Soc.
1994, 116, 8593.
[37] a) B. L. Pagenkopf, T. Livinghouse, J. Am. Chem. Soc. 1996, 118,
2285; b) T. Sugihara, M. Yamaguchi, J. Am. Chem. Soc. 1998, 120,
10782.
[38] N. Jeong, S. Lee, B. K. Sung, Organometallics 1998, 17, 3642.
[39] F. A. Hicks, N. M. Kablaoui, S. L. Buchwald, J. Am. Chem. Soc.
1999, 121, 5881.
Received: December 3, 2004
Published online: April 13, 2005
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