New homochiral phosphine ligands having a hexahydro-1H-pyrrolo[1,2-c]imidazolone backbone: Preparation and use for palladium-catalyzed asymmetric alkylation of cycloalkenyl carbonates

Article abstract of DOI:10.1016/S0957-4166(02)00467-6

New chiral ligands having a pyrrolo[1,2-c]imidazolone backbone were prepared by condensation of anilides of homochiral cyclic amino acids with 2-(diphenylphosphino)benzaldehyde. Of these ligands, (3R,9aS)-(3-(2-diphenylphosphino)phenyl-2-phenyl)tetrahydro-1H-imidazo [1,5-a]indole-1-one was found to be effective for palladium-catalyzed asymmetric allylic alkylation of cycloalkenyl carbonates with dimethyl malonate to give the corresponding dimethyl cycloalkenylmalonates with e.e. of up to 89%.

Full text of DOI:10.1016/S0957-4166(02)00467-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1769–1772
New homochiral phosphine ligands having a
hexahydro-1H-pyrrolo[1,2-c]imidazolone backbone: preparation
and use for palladium-catalyzed asymmetric alkylation of
cycloalkenyl carbonates
Kazutaka Shibatomi and Yasuhiro Uozumi*
Institute for Molecular Science, Nishi-Gonaka 38, Myodaiji, Okazaki 444-8585, Japan
Received 3 July 2002; accepted 29 July 2002
Abstract—New chiral ligands having a pyrrolo[1,2-c]imidazolone backbone were prepared by condensation of anilides of
homochiral cyclic amino acids with 2-(diphenylphosphino)benzaldehyde. Of these ligands, (3R,9aS)-(3-(2-diphenylphos-
phino)phenyl-2-phenyl)tetrahydro-1H-imidazo[1,5-a]indole-1-one was found to be effective for palladium-catalyzed asymmetric
allylic alkylation of cycloalkenyl carbonates with dimethyl malonate to give the corresponding dimethyl cycloalkenylmalonates
with e.e. of up to 89%. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
The development of new ligands for use in asymmetric
catalysis continues to undergo very rapid growth.
Organophosphorus compounds having a homochiral
backbone are recognized as one of the most versatile
and successful classes of ligands in transition metal-cat-
alyzed asymmetric reactions. We have recently designed
and prepared a library of bicyclic tertiary amines bear-
3
ing an sp -bridgehead nitrogen with a view to using it
1
for screening enantioselective amine reagents. Highly
functionalized bicyclic amines having a hexahydro-1H-
pyrrolo[1,2-c]imidazolone framework were identified
through library-based screening as effective chiral
amine agents. These results prompted us to prepare
triarylphosphines having a pyrrolo[1,2-c]imidazolone
skeleton as new basic chiral units for transition metal-
2
catalyzed asymmetric reactions (Fig. 1). Herein, we
wish to report the development of (3R,9aS)-3-[2-
(
diphenylphosphino)phenyl] - 2 - phenyltetrahydro - 1H-
imidazo[1,5-a]indole-1-one (b-3) as a new chiral ligand
and its use for palladium-catalyzed asymmetric alkyla-
tion of cyclic allyl esters with dimethyl malonate where
high stereoselectivity of up to 89% e.e. was achieved.
Figure 1. Homochiral phosphine ligands having a pyrroloimi-
*
0
Corresponding author. Fax: +81-564-55-5245; e-mail: uo@ims.ac.jp
dazole backbone.
957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00467-6

1
770
K. Shibatomi, Y. Uozumi / Tetrahedron: Asymmetry 13 (2002) 1769–1772
2
. Results and discussion
The triarylphosphine ligands 1, 2 and 3 having a
homochiral pyrroloimidazolone backbone were pre-
pared from the corresponding anilides 5, 6 and 7,
respectively (Scheme 1). Thus, reaction of 2-
(
6
4
diphenylphosphino)benzaldehyde with anilides 5 and
, which were readily prepared from proline and trans-
3
-hydroxyproline,
in refluxing methanol gave
(
pyrroloimidazolone)phosphine 1 and its 6-hydroxyl
derivative 2 both in 90% yield. The phosphine ligand 3
having an imidazoindole unit was obtained as a mixture
of diastereomers a-3 (27%) and b-3 (48%) from the
anilide of (S)-indoline-2-carboxylic acid 7 by a similar
procedure. Condensation of the tetrahydroisoquinoline
carboxamide 8 with 2-(diphenylphosphino)benzalde-
hyde in DMF at 150°C gave imidazoisoquinoline 4 in
2
0% yield.
The enantiocontrolling abilities of the chiral phosphine
ligands 1, 2, a-3, b-3 and 4 were examined for palla-
dium-catalyzed asymmetric allylic alkylation of cyclic
allyl esters (Scheme 2). Although the palladium-cata-
lyzed asymmetric allylic alkylation of acyclic substrates
is one of the most thoroughly investigated car-
bonꢀcarbon bond forming reactions using a variety of
chiral ligands, the corresponding substitution of
Scheme 2.
chiral phosphine–palladium complexes to give the
dimethyl (cyclohexen-2-yl)malonate 10. The enan-
tiomeric purity of the alkylated product 10 was deter-
mined by GC analysis using a chiral stationary phase
capilliary column (Cyclodex CB). The results, summa-
rized in Table 1 (entries 1–5), revealed that the most
stereoselective ligand is (3R,9aS)-3-[(2-diphenylphos-
phino)phenyl]-2-phenyltetrahydro-1H-imidazo[1,5-a]-
indole-1-one (b-3). Thus, the allylic alkylation of 9 with
dimethyl malonate in the presence of 2.5 mol% of a
palladium complex generated in situ by mixing
4
cycloalkenyl esters is still a major challenge. Reaction
of the cyclohexenyl methyl carbonate 9 with the sodium
salt of dimethyl malonate in THF was catalyzed by
3
3
the bis(m-chloro)bis(h -allyl)dipalladium(II) ([PdCl(h -
C H )] ) and 1.5 equiv. (versus palladium) of the (imi-
3
5 2
dazoindole)phosphine ligand b-3 was carried out at
2
8
5°C for 3 h to give compound 10 with 82% e.e. (S) in
6% yield (Table 1, entry 4). Palladium complexes of
the pyrroloimidazolones 1 or 2, which lack fused ben-
zene rings, were significantly less enantioselective to
give 10 with 14 and 7% e.e., respectively (entries 1 and
2
). A palladium complex coordinated with the imida-
Scheme 1.
zoindole ligand a-3 showed slightly higher catalytic
a
Table 1. Asymmetric allylic alkylation of cycloalkenyl carbonates with dimethyl malonate
Yield (%)b
E.e.% (config.)
c
d
Entry
Allyl ester
Ligand
Product
1
2
3
9
9
9
9
9
11
13
15
1
2
10
10
10
10
10
12
14
16
84
84
100
86
100
86
100
100
14 (S)
7 (S)
b
a-3
b-3
4
b-3
b-3
b-3
47 (S)
82 (S)
46 (S)
82 (S)
88 (S)
89 (S)
4
5
6
b
7
8
a
All reactions were carried out in THF in the presence of 2.5 mol% Pd of Pd–L* complex generated in situ. A ratio of allyl ester/NaCH-
COOMe) /Pd/L*=1.0/2.0/0.025/0.038.
Isolated yield.
Determined by GC analysis using chiral stationary capillary column (Cyclodex CB).
Determined by comparing the specific rotation with the literature value (Ref. 4e (Supporting Information)).
(
2
b
c
d

K. Shibatomi, Y. Uozumi / Tetrahedron: Asymmetry 13 (2002) 1769–1772
1771
performance than its diastereomeric isomer b-3 to
give a quantitative yield of the alkylation product 10
within 1 h of reaction time, whereas the enantiomeric
purity of 10 was much lower (entry 3). The allylic
alkylation with (imidazoisoquinoline)phosphine ligand
mmol) and the reaction mixture was stirred at room
temperature for 1 h. To this mixture was added 2-
(diphenylphosphino)benzaldehyde (580 mg, 2.0 mmol)
and the reaction mixture was heated at 80°C in a
sealed tube for 3 h. After being cooled to room tem-
perature, the reaction mixture was extracted with
4
also showed low enantioselectivity to give 10 with
6% e.e. (entry 5).
4
chloroform, dried over Na SO4 and concentrated in
2
vacuo. The resulting residue was chromatographed on
To explore the generality of this enantioselective reac-
tion, we carried out the alkylation of the cycloalkenyl
carbonates 11, 13 and 15 under otherwise similar con-
ditions. The cyclopentenyl carbonate 11 underwent
alkylation with dimethyl malonate to give an 86%
yield of 12 with 82% e.e. (entry 6). The alkylation of
the racemic cis-5-carbomethoxy-2-cyclohexenyl methyl
carbonate 13 gave 88% e.e. of 14 in a quantitative
yield as a single diastereoisomer having the cis-
configuration, demonstrating that the allylic alkyla-
tion proceeded through the generally accepted double
silica gel (eluent: ethyl acetate/hexane=1/3) to give 1
1
9
as a white solid (416 mg, 90%): [h] =+44 (c 1.4,
D
+
1
chloroform); EI MS (m/z): 462 (M ); H NMR (chlo-
roform-d): l 1.42–1.56 (m, 1H), 1.65–1.76 (m, 1H),
1.97–2.15 (m, 2H), 2.63–2.70 (m, 1H), 3.09–3.14 (m,
1H), 3.92 (dd, J=4.4, 9.0 Hz, 1H), 6.53 (d, J=6.1,
1H), 6.99–7.07 (m, 2H), 7.14–7.39 (m, 15H), 7.44 (d,
31
1
J=8.1 Hz, 2H); P{ H} NMR (chloroform-d): l
−18.0 (s). Anal calcd for C H N OP: C, 77.90; H,
30
27
2
5.88; N, 6.06. Found: C, 77.73; H, 5.98; N, 5.93%.
5
inversion pathway (entry 7). The highest enantiose-
4
.3. (3R,7aS)-3-[2-(Diphenylphosphino)phenyl]-6-
hydroxy-2-phenylhexahydro-1H-pyrrolo[1,2-c]imidazol-
-one, 2
lectivity was observed in the reaction of the cyclohep-
tenyl carbonate 15 to give a quantitative yield of 16
with 89% enantioselectivity (entry 8).
1
The same procedure as employed for the preparation
of 1 was followed with (2S,4R)-2-anilinocarbonyl-4-
3. Conclusion
3
hydroxy-1-trifluoroacetylpyrrolidine
(302 mg, 1.0
mmol). The resulting crude product was chro-
matographed on silica gel (eluent: ethyl acetate/hex-
ane=2/1) to give 2 as a white solid (430 mg, 90%):
In summary, we have developed new homochiral
phosphine ligands having a pyrrolo[1,2-c]imidazolone
backbone, of which (3R,9aS)-3-[(2-diphenylphos-
phino)phenyl]-2-phenyltetrahydro-1H-imidazo[1,5-a]-
indole-1-one was found to exhibit high enantioselec-
tivity ranging from 82 to 89% e.e. in a palladium-cata-
lyzed allylic alkylation of cycloalkenyl substrates.
19
+
[
h] =+9 (c 1.6, chloroform); EI MS (m/z): 478 (M );
D
1
H NMR (chloroform-d): l 1.94–2.00 (m, 1H), 2.32–
.38 (m, 1H), 2.67 (dd, J=3.6, 10 Hz, 1H), 3.13 (d,
J=10 Hz, 1H), 3.82 (dd, J=4.5, 9.6 Hz, 1H), 4.10
br s, 1H), 6.58 (d, J=5.9 Hz, 1H), 7.05–7.13 (m,
2
(
2
H), 7.19–7.38 (m, 15H), 7.57 (d, J=7.8 Hz, 2H);
P{ H} NMR (chloroform-d): l −18.4 (s). Anal calcd
31
1
4. Experimental
for C H N O P: C, 75.30; H, 5.69; N, 5.85. Found:
30 27 2 2
C, 75.24; H, 5.82; N, 5.62%.
4.1. General
4
.4. (3S,9aS)-3-[2-(Diphenylphosphino)phenyl]-2-
All manipulations were carried out under a nitrogen
atmosphere. Nitrogen gas was dried by passage
phenyltetrahydro-1H-imidazo[1,5-a]indole-1-one, a-3
and (3R,9aS)-3-[2-(diphenylphosphino)phenyl]-2-
phenyltetrahydro-1H-imidazo[1,5-a]indole-1-one, b-3
through P O (Merck, Sicapent). NMR spectra were
2
5
recorded on a Jeol JNM-AL400 spectrometer (400
1
MHz for H NMR), or Jeol JNM LA500 spectrome-
The same procedure as employed for the preparation
1
31
ter (500 MHz for H and 202 MHz for P). Chemi-
of 1 was followed with (S)-2-anilinocarbonylindoline
cal shifts are reported in l ppm referenced to an
6
7
(338 mg, 1.0 mmol). The resulting crude product
1
internal SiMe4 standard for H NMR, and to an
was chromatographed on silica gel (eluent: acetone/
3
1
1
external 85% H PO standard for P NMR. H and
3
4
hexane=1/2) to give b-3 (245 mg, 48%) and a-3 (138
3
1
P NMR spectra were recorded in CDCl at 25°C.
25
3
mg, 27%) as white solids: a-3: [h] =+135 (c 1.0,
D
1
GC analysis was performed on Hewlett Packard HP
890 and HP 4890 series with a chiral stationary
+
chloroform); EI MS (m/z): 510 (M ); H NMR (chlo-
roform-d): l 3.38 (dd, J=11.0, 16.5 Hz, 1H), 3.69
6
phase capillary column, Cyclodex CB (50 m). Optical
rotations were measured on a Jasco DIP-370 polar-
imeter.
(
dd, J=4.2, 16.5 Hz, 1H), 4.72 (dd, J=4.2, 11.0 Hz,
H), 5.23 (d, J=8.1 Hz, 1H), 6.56–7.64 (m, 23H);
1
31
1
P{ H} NMR (chloroform-d): l −20.0 (s). Anal calcd
for C H N OP: C, 80.00; H, 5.33; N, 5.49. Found:
34
27
2
1
9
4
.2. (3R,7aS)-3-[2-(Diphenylphosphino)phenyl]-2-phenyl-
C, 80.04; H, 5.48; N, 5.26%. b-3: [h] =+127 (c 0.7,
D
+ 1
hexahydro-1H-pyrrolo[1,2-c]imidazol-1-one, 1
chloroform); EI MS (m/z): 510 (M ); H NMR (chlo-
roform-d): l 3.12 (dd, J=10, 16 Hz, 1H), 3.54 (d,
J=16 Hz, 1H), 4.39 (dd, J=1.6, 10 Hz, 1H), 6.90–
To a solution of (S)-2-anilinocarbonyl-1-trifluoro-
3
31
1
acetylpyrrolidine (286 mg, 1.0 mmol) in methanol (3
7.63 (m, 24H); P{ H} NMR (chloroform-d): l −20.0
(s).
mL) was added anhydrous K CO (276 mg, 2.0
2
3

1
772
K. Shibatomi, Y. Uozumi / Tetrahedron: Asymmetry 13 (2002) 1769–1772
4
.5. (3R,10aS)-3-[2-(Diphenylphosphino)phenyl]-2-
Creative Scientific Research (No. 13GS0024), the Min-
istry of Education and Science, Japan, Uehara Memorial
Life Science Foundation, Toray Science Foundation,
Asahi Glass Foundation and the Sumitomo Foundation.
phenytetrahydro-1H,5H-imidazo[1,5-b]isoquinoline-1-
one, 4
7
(
S)-3-Anilinocarbonylisoquinoline 8 (100 mg, 0.4 mmol)
and 2-(diphenylphosphino)benzaldehyde (232 mg, 0.8
mmol) were dissolved in DMF (5 mL). The reaction
mixture was heated to 150°C in a sealed tube for 12 h.
After cooling to room temperature, the reaction mixture
References
1. (a) Uozumi, Y.; Mizutani, K.; Nagai, S.-I. Tetrahedron
Lett. 2001, 42, 407; (b) Uozumi, Y.; Yasoshima, K.;
Miyachi, T.; Nagai, S.-I. Tetrahedron Lett. 2001, 42, 411.
. We have reported the immobilization of this class of
chiral ligands on an amphiphilic polymer resin and their
use for asymmetric catalysis in water, where up to 98%
e.e. of asymmetric allylic alkylation of cycloalkenyl esters
was achieved. See: Uozumi, Y.; Shibatomi, K. J. Am.
Chem. Soc. 2001, 123, 2919.
wasextractedwithchloroformanddriedoverNa SO and
2
4
concentrated in vacuo. The resulting residue was chro-
matographed on silica gel (eluent: acetone/hexane=1/5)
2
2
5
to give 4 as a white solid (42 mg, 20%): [h] =+6 (c 0.5,
D
+
1
chloroform); EI MS (m/z): 524 (M ); H NMR (chloro-
form-d): l 3.06 (dd, J=6.6, 15.4 Hz, 1H), 3.14 (dd, J=6.6,
1
5.4 Hz, 1H), 3.50 (d, J=14.9 Hz, 1H), 3.67 (d, J=14.9
Hz, 1H), 4.17 (br s, 1H), 6.66 (d, J=7.6 Hz, 1H), 6.80
31
1
(
(
d, J=7.3 Hz, 1H), 7.00–7.41 (m, 22H); P{ H} NMR
chloroform-d): l −20.0 (s).
3
. Mori, M.; Uozumi, Y.; Kimura, M.; Ban, Y. Tetra-
hedron 1986, 42, 3793.
4
. For examples of palladium-catalyzed asymmetric allylic
alkylation of cycloalkenyl substrates, see: (a) Trost, B.
M.; Bunt, R. C. J. Am. Chem. Soc. 1994, 116, 4089; (b)
Kn u¨ hl, G.; Sennhenn, P.; Helmchen, G. J. Chem. Soc.,
Chem. Commun. 1995, 1845; (c) Nishimata, T.; Mori, M.
J. Org. Chem. 1998, 63, 7586; (d) Kudis, S.; Helmchen,
G. Angew. Chem. Int. Ed. 1998, 37, 3047; (e) Gilbertson,
S.; Xie, D. Angew. Chem. Int. Ed. 1999, 38, 2750; (f)
Evans, D. A.; Campos, K. R.; Tedrow, J. S.; Michael,
F. E.; Gagn e´ , M. R. J. Am. Chem. Soc. 2000, 122, 7905;
4
.6. Catalytic asymmetric alkylation of cycloalkenyl
carbonates with dimethyl malonate
A typical procedure was given for the reaction of 9 with
dimethyl malonate (Table 1, entry 4). To a suspension
of NaH in THF (1 mL) was added a solution of dimethyl
malonate (105.7 mg, 0.8 mmol) at 0°C. To a solution of
3
[
(h -C H )PdCl] (1.8 mg, 0.005 mmol), ligand b-3 (7.7
3
5
2
mg, 0.015 mmol) and cyclic allyl substrate 9 (68 mg, 0.4
mmol) in THF (2 mL) was added a THF solution of
sodium salt of malonate and the reaction mixture was
stirred at 25°C for 3 h. The reaction mixture was quenched
(
g) Saitoh, A.; Achiwa, K.; Tanaka, K.; Morimoto, T. J.
Org. Chem. 2000, 65, 4227; (h) Hou, D.-R.; Reibenspies,
J. H.; Burgess, K. J. Org. Chem. 2001, 66, 206; (i)
Hamada, Y.; Sakaguchi, K.; Hara, O. Tetrahedron Lett.
with a small portion of saturated NH Cl solution, and
extracted with Et O. The organic phase was dried over
Na SO and concentrated in vacuo. The residue was
chromatographed on silica gel (eluent: n-hexane/ethyl
acetate 5/1) to give 10 as a colorless oil (86.8 mg, 96%).
4
2
2001, 42, 1297; (j) Xiao, L.; Weissensteiner, W.; Mere-
2
4
iter, K.; Widhalm, M. J. Org. Chem. 2002, 67, 2206.
Also see Ref. 3.
5. Hayashi, T.; Yamamoto, A.; Hagihara, T.; Ito, Y. Tet-
rahedron Lett. 1986, 27, 191.
Acknowledgements
6. Roloff, A.; Gschwend, H. W. Eur. Pat. Appl., 1986.
7. Weir, E. C.; Niopas, I.; Samil, G. A. Chem. Chrom.
This work was partially supported by a Grant-in-Aid for
1989, 18, 3.