Enantioselective intramolecular oxidative aminocarbonylation of alkenylureas catalyzed by palladium-spiro bis(isoxazoline) complexes

Article abstract of DOI:10.1021/jo901778a

(Chemical Equation Presented) An enantioselective synthesis of tetrahydropyrrolo[1,2-c]pyrimidine-1,3-diones via a palladium-catalyzed intramolecular oxidative aminocarbonylation is described. The carbon-carbon double bond of alkenylurea substrates has be

Full text of DOI:10.1021/jo901778a

pubs.acs.org/joc
Enantioselective Intramolecular Oxidative Aminocarbonylation of
Alkenylureas Catalyzed by Palladium-Spiro Bis(isoxazoline) Complexes
Tetsuya Tsujihara,† Toshio Shinohara,‡ Kazuhiro Takenaka,‡ Shinobu Takizawa,‡
Kiyotaka Onitsuka,‡ Minoru Hatanaka,† and Hiroaki Sasai*,‡
‡The Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka 567-0047, Japan and
†Department of Medicinal and Organic Chemistry, School of Pharmacy, Iwate Medical University, Yahaba,
Iwate 028-3694, Japan
sasai@sanken.osaka-u.ac.jp
Received August 20, 2009
An enantioselective synthesis of tetrahydropyrrolo[1,2-c]pyrimidine-1,3-diones via a palladium-catalyzed
intramolecular oxidative aminocarbonylation is described. The carbon-carbon double bond of alkenylur-
ea substrates has been shown to react intramolecularly with a nitrogen nucleophile in the presence of a
palladium catalyst under a carbon monoxide atmosphere. The use of a chiral spiro bis(isoxazoline) ligand
(SPRIX) is essential to obtain the desired products in optically active forms. In comparison with the
coordination ability of other known ligands, this peculiar character of SPRIX originates from two structural
characteristics: low σ-donor ability of the isoxazoline coordination site and rigidity of the spiro skeleton.
Introduction
iodine reagent and SPRIX.4f Enantioselective cyclization
of enyne derivatives catalyzed by the Pd-SPRIX complex
The development of novel chiral ligands is one of the most
important tasks in the area of asymmetric catalysis. The
spirocyclic framework has received considerable attention as
a promising chiral skeleton because ligands containing such a
unique backbone are expected to exhibit unusual reactivity
and selectivity.1,2 In 1999, we developed spiro bis(isoxazoline)
ligands (SPRIXs),3,4 which have a chiral spiro backbone and
isoxazoline units. On the basis of the good affinity of SPRIXs
for PdII salts and the stability of SPRIXs under oxidative
conditions, we demonstrated the first example of the enantio-
selective Wacker-type cyclization of alkenyl alcohols
mediated by the Pd-SPRIX complex and a unique catalytic
asymmetric tandem cyclization of dialkenyl alcohols via
oxypalladation.4b In addition, the Pd-SPRIX catalyst has
been found to be efficient in several enantioselective reactions
such as the cyclization of enyne derivatives to give R-methy-
lene-γ-butyrolactones,4c and the synthesis of polyketones
through alternating copolymerization of CO with styrene
derivatives.4e Recently, the first asymmetric PdII/PdIV cataly-
sis was achieved by employing a combination of a hypervalent
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9274 J. Org. Chem. 2009, 74, 9274–9279
Published on Web 11/19/2009
DOI: 10.1021/jo901778a
r
2009 American Chemical Society

Tsujihara et al.
JOCArticle
SCHEME 1. PdII-Catalyzed Intramolecular Oxidative Ami-
nocarbonylation of Alkenyl Amide Derivatives
the enantioselective intramolecular oxidative aminocarbony-
lation of alkenylureas catalyzed by a Pd-SPRIX complex as
well as the intriguing properties of SPRIXs.
Results and Discussion
Establishment of Reaction Conditions. We previously re-
ported the high utility of SPRIXs 3 for the Pd-catalyzed
enantioselective cyclizations of alkenyl alcohols4b and ami-
nocarbonylation of alkenylamides.8 The alkene moiety of
the substrates was efficiently activated toward intramolecu-
lar attack of the nucleophile through coordination to the
Pd-SPRIX catalyst. It was therefore anticipated that
SPRIXs would also exhibit an acceleration effect in enantio-
selective intramolecular oxidative aminocarbonylation of
alkenylurea 1.9 To our delight, the reaction of N-2,2-di-
methylpent-4-enyl-N0-p-toluenesulfonylurea (1a) proceeded
enantioselectively in the presence of a catalytic amount of (P,
R,R)-i-Pr-SPRIX 3a. Thus, 1a was treated with 10 mol % of
[Pd(MeCN)4](BF4)2, 11 mol % of 3a, and 2 equiv of p-
benzoquinone in MeOH at 0 °C under a carbon monoxide
atmosphere to give 66% ee of the desired cyclic β-amino acid
derivative 2a in 94% yield (Table 1, entry 1).10 When (P,R,
R)-3b and (P,R,R)-3c bearing smaller substituents on the
isoxazoline rings were employed as the chiral ligands, 2a was
obtained quantitatively with 25% ee and 15% ee, respec-
tively (entries 2 and 3). The reaction with (P,R,R)-H-SPRIX
3d also produced 2a in 41% yield, albeit with lower stereo-
selectivity (entry 4).11 Axially chiral bis(isoxazoline) ligand
(R)-4 developed by our group12 turned out to be ineffective
(entry 5). It should be noted that Pd complexes with other
known chiral ligands such as (R)-BINAP, (-)-sparteine,
(S,S)-t-Bu-BOX, and (S,S)-i-Pr-BOXAX did not promote
the aminocarbonylation of 1a at all even at 25 °C (entries
6-9).13 Background reactions were minimal under condi-
tions without ligand, resulting in only a trace amount of 2a
(entry 10). Furthermore, chiral Pd complex 5, which is known to
be an effective catalyst for asymmetric Wacker-type cyclizations
of o-allylphenols,14 did not work in this aminocarbonylation
furnished lactones bearing a bicyclo[3.1.0]hexane skeleton
with high enantioselectivity. Being encouraged by these find-
ings, we envisioned a palladium-catalyzed enantioselective
intramolecular oxidative aminocarbonylation of alkenyl
amides producing optically active cyclic β-amino acid deriva-
tives, in which both the chiral center and the pyrrolidine
framework were constructed in a single step (Scheme 1).5-7
If this reaction could be promoted enantioselectively, it is
expected to be an efficient synthetic method for preparation of
optically active cyclic β-amino acid derivatives. According to
our initial study, the use of SPRIXs was found to be required
for obtaining enantioselectivity in the catalytic cyclization.8
However, despite the unique benefits of the Pd-SPRIX
catalyst, the enantioselectivity of the intramolecular oxidative
aminocarbonylation was moderate. We therefore decided to
reinvestigate the reaction conditions in order to attain highly
enantioselective formation of optically active cyclic β-amino
acid derivatives. Herein we report a detailed investigation of
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(10) The results using other solvents: toluene: trace, 31% ee; CH2Cl2:
24% yield, 12% ee; MeCN: 40% yield, 29% ee; THF: 34% yield, 47% ee;
EtOH: 64% yield, 65% ee. See the Supporting Information.
(6) Tamaru and co-workers extensively studied the corresponding none-
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chemical yield of 2a was diminished. In the reaction, a combination of 10 mol
% of Pd(OCOCF3)2 and 22 mol % of (M,S,S)-3d showed better result. A
61% yield of 2a was obtained with 54% ee when the reaction was conducted
at -20 °C for 7.1 days as reported in ref 8.
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(13) Abbreviations: (R)-BINAP
=
(R)-2,20-bis(diphenylphosphino)-
1,10-binaphthyl; (S,S)-t-Bu-BOX = 2,2-bis[(4S)-4-tert-butyl-2-oxazolin-2-
yl]propane; (S,S)-i-Pr-BOXAX = (S)-2,20-bis[(4S)-4-isopropyl-2-oxazolin-
2-yl]-1,10-binaphthyl.
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TABLE 1. Screening of Catalyst Systems in the Reaction of Alkeny-
lurea 1aa
TABLE 2. Effects of Ligand/Pd Ratio and Reaction Temperaturea
entry
L/Pd ratio
temp (°C)
time (h)
yield (%)
ee (%)b
entry
chiral ligand
(P,R,R)-3a
(P,R,R)-3b
(P,R,R)-3c
(P,R,R)-3d
(R)-4
time (h)
yield (%)
ee (%)b
1
1.1
2.2
3.3
1.1
1.1
1.1
0
0
0
3
4.5
9
36
165
210
94
85
83
98
89
10
66
66
66
75
88
91
1
2
3
4
5
3
1.5
1.5
48
48
24
24
24
24
24
24
94
66
25
15
2c
3d
4e
5f
6f
quant.
quant.
41
trace
NRd
NRd
NRd
NRd
trace
NRd
-20
-40
-50
8
NDc
NDc
NDc
NDc
NDc
6e
7e
8e
9e
10
11e
(R)-BINAP
(-)-sparteine
(S,S)-t-Bu-BOX
(S,S)-i-Pr-BOXAX
none
aAll reactions were carried out in the presence of 10 mol % of
[Pd(MeCN)4](BF4)2, 11 mol % of (P,R,R)-3a, and 2 equiv of p-benzo-
quinone in MeOH (0.1 M for 1a) under a carbon monoxide atmosphere
unless otherwise noted. bDetermined by HPLC analysis (Chiralpak AD-
c
d
H). 22 mol % of (P,R,R)-3a was used. 33 mol % of (P,R,R)-3a was
used. eIn MeOH (0.05 M for 1a). f4 equiv of p-benzoquinone was used in
MeOH (0.02 M for 1a).
5f
NDc
aAll reactions were carried out in the presence of 10 mol % of
[Pd(MeCN)4](BF4)2, 11 mol % of ligand, and 2 equiv of p-benzoquinone
at 0 °C in MeOH (0.1 M for 1a) under a carbon monoxide atmosphere
unless otherwise noted. bDetermined by HPLC analysis (Chiralpak AD-
were necessary due to the low reactivity of 1a and the poor
solubility of p-benzoquinone (entries 4-6). In the reactions
at -20 and -40 °C, 2a was obtained in excellent yields
(98% and 89%) with high enantioselectivities (75% ee and
88% ee), respectively (entries 4 and 5). The selectivity was
further improved to 91% ee at -50 °C, but the chemical
yield of 2a disappointingly dropped to 10% even after
210 h (entry 6).
f
H). cNot determined. dNo reaction. eAt 25 °C. 10 mol % of chiral
complex 5 was used instead of [Pd(MeCN)4](BF4)2.
(entry 11). Pd black and/or insoluble materials were immedi-
ately formed after replacement by CO in entries 5-11, whereas
no such precipitation was observed in the reactions with SPRIX
(entries 1-3). These results clearly demonstrate the high suit-
ability of SPRIXs 3 for the enantioselective intramolecular
oxidative aminocarbonylation of 1a.
Scope and Limitations. Having successfully optimized the
reaction conditions, we explored the scope of this trans-
formation with a variety of alkenylurea substrates 1 (Table
3). The reaction of 1b proceeded sluggishly to give a 48%
yield of 2b with 89% ee after 260 h, presumably due to the
steric bulkiness of the 2-tolyl group (entry 2). X-ray crystal-
lographic analysis of enantiopure 2b unambiguously es-
tablished its S absolute configuration as well as the
desired tetrahydropyrrolo[1,2-c]pyrimidine-1,3-dione skeleton
(see the Supporting Information). Similar to the tosyl
group of 1a, benzenesulfonyl and 4-chlorobenzenesulfonyl
groups were tolerated as protecting groups, leading to the
formation of the corresponding products 2c and 2d in 89%
and 76% yields with 87% ee and 86% ee, respectively
(entries 3 and 4). The chemical yield was considerably
influenced by the substituents R on the homoallylic posi-
tion. Excellent to good yields (97% and 76%) were ob-
served for 2e and 2f based on a cyclohexane and a
cyclopentane backbone (entries 5 and 6). Despite low
chemical yield, the enantioselectivity of 2f was improved
to 72% ee at -40 °C (entry 7). Phenyl-substituted substrate
1g was also tolerated yielding the corresponding product
2g in 80% yield with 30% ee (entry 8). However, the
products 2h (R = CO2Et) and 2i (R = H) were produced
in moderate to low yields (entries 9 and 10).
Being encouraged by the results in Table 1, we performed
further optimization of the reaction conditions in regards to
the ligand/metal ratio and reaction temperature (Table 2).
As the ligand/metal ratio was increased, reaction time was
longer, although 2a was obtained in comparable yields with
the same enantioselectivities. Thus, complete consumption
of 1a was detected at 0 °C after 3 h in the case of 11 mol % of
(P,R,R)-3a, while reactions with 22 and 33 mol % of (P,R,
R)-3a under otherwise identical conditions were complete
in 4.5 and 9 h, respectively (entries 1-3). These results
indicate that an excess amount of (P,R,R)-3a retards the
reaction. The enantiopurity of 2a was successfully im-
proved by lowering the reaction temperature, although a
prolonged reaction time and a dilute concentration of 1a
(15) For recent representative examples on the cyclization of alkenyl
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2005, 127, 11250–11251. (b) Zabawa, T. P.; Chemler, S. R. Org. Lett. 2007, 9,
~
€
ꢀ~
2035–2038. (c) Muniz, K.; Streuff, J.; Hovelmann, C. H.; Nunez, A. Angew.
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3009-3019 and references cited therein.
9276 J. Org. Chem. Vol. 74, No. 24, 2009

Tsujihara et al.
JOCArticle
TABLE 3. Scope and Limitationsa
chemical yield of 9 was improved to 87% when the reaction
was conducted at 0 °C.
time yield
ee
entry
1
R
PG
2
(d) (%) (%)b
We have accomplished the Pd-catalyzed enantioselective
intramolecular oxidative aminocarbonylation of alkenylur-
ea derivatives 1, alkenyl sulfamide 6, and alkenyl tosylamide
8, in which SPRIXs serve as efficient chiral ligands. The
desired cyclic β-amino acid derivatives 2, 7, and 9 were
obtained in high yields with moderate to good enantioselec-
tivities.
1
2
3
4
1a Me
1b Me
1c Me
1d Me
Ts
2a
6.9 89 88
2-MeC6H4SO2 2b 10.8
C6H5SO2 2c 6.9 89 87
4-ClC6H4SO2 2d
48 89 (S)c
6.9 76 86
1.9 97 52
2.0 76 61
7.0 36 72
2.0 80 30
7.0 50 51
7.0 28 61
5d 1e -CH2(CH2)3CH2- Ts
2e
2f
2f
2g
2h
2i
6d 1f -CH2(CH2)2CH2- Ts
7
1f -CH2(CH2)2CH2- Ts
8d 1g Ph
Ts
Ts
Ts
Unique Feature of Spiro Bis(isoxazoline) Ligands. The
results of ligand screening shown in Table 1 clearly indicate
that an isoxazoline coordination site plays an essential role
for this intramolecular oxidative aminocarbonylation. It is
speculated that a low σ-donor ability of isoxazolines keeps
the strong Lewis acidity of the “naked” PdII metal intact,
allowing high activity of the Pd-SPRIX catalysts. To
evaluate the σ-donor ability of isoxazolines, we monitored
the ligand exchange process between SPRIX and BOX by
1H NMR spectroscopy (eq 3). To a solution of Pd(OCO-
CF3)2[(P,R,R)-3a] complex in CD2Cl2 was added an equi-
molar amount of (S,S)-t-Bu-BOX ligand. After 72 h, peaks
corresponding to the original complex completely disap-
peared and new signals assignable to Pd(OCOCF3)2[(S,S)-
t-Bu-BOX] and free (P,R,R)-3a were observed. This result
suggests that the coordination of (P,R,R)-3a to PdII is
weaker than that of (S,S)-t-Bu-BOX, implying the small
σ-donor ability of isoxazolines. Axially chiral ligand (R)-4,
however, does not promote the aminocarbonylation in
spite of its isoxazoline coordination sites (vide supra).
The more flexible 1,10-binaphthyl skeleton of (R)-4 would
be insufficient to fix the conformation of the weakly
coordinating isoxazolines in a chelating fashion, compared
to the spiro[4.4]nonane scaffold. Therefore, a rapid forma-
tion of Pd black was observed in the reaction with (R)-4
(Table 1, entry 5).
9d 1h CO2Et
10d 1i
H
aAll reactions were carried out in the presence of 10 mol % of
[Pd(MeCN)4](BF4)2, 11 mol % of (M,S,S)-3a, and 4 equiv of p-benzo-
quinone at -40 °C in MeOH (0.02 M for 1) under a carbon monoxide
atmosphere unless otherwise noted. bDetermined by HPLC analysis
(Chiralpak AD-H). cDetermined by X-ray analysis. d2 equiv of
p-benzoquinone was used in MeOH (0.05 M for 1) at -20 °C.
Alkenyl sulfamide 615 also participated in this cyclization
to afford bicyclic sulfamide 7 in 86% yield with 33% ee
(eq 1).
It was also feasible to construct a homoproline skeleton in
this cyclization. Thus, a mixture of alkenyl tosylamide 816
and p-benzoquinone in MeOH was stirred at 25 °C for 8 h in
the presence of 10 mol % of [Pd(MeCN)4](BF4)2 and 22 mol
% of (M,S,S)-3a to afford methyl 2-(4,4-dimethyl-1-tosyl-
pyrrolidin-2-yl)acetate (9) in 27% yield with 45% ee (eq 2).
In this reaction, a combination of Pd(OCOCF3)2 and (M,S,
S)-3d displayed higher catalytic activity.8 Accordingly, the
(16) For recent representative examples on the cyclization of alkenyl
tosylamide, see: (a) Fix, S. R.; Brice, J. L.; Stahl, S. S. Angew. Chem., Int. Ed.
2002, 41, 164–166. (b) Sherman, E. S.; Chemler, S. R.; Tan, T. B.; Gerlits, O.
Org. Lett. 2004, 6, 1573–1575. (c) Manzoni, M. R.; Zabawa, T. P.; Kasi, D.;
Chemler, S. R. Organometallics 2004, 23, 5618–5621. (d) Alexanian, E. J.;
Lee, C.; Sorensen, E. J. J. Am. Chem. Soc. 2005, 127, 7690–7691. (e) Rogers,
M. M.; Wendlandt, J. E.; Guzei, I. A.; Stahl, S. S. Org. Lett. 2006, 8, 2257–
2260. (f) Scarborough, C. C.; Stahl, S. S. Org. Lett. 2006, 8, 3251–3254. (g)
Kotov, V.; Scarborough, C. C.; Stahl, S. S. Inorg. Chem. 2007, 46, 1910–1923.
(h) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328–6335. (i) Sherman,
E. S.; Fuller, P. H.; Kasi, D.; Chemler, S. R. J. Org. Chem. 2007, 72, 3896–
To gain insight into the effects of the spiro framework,
achiral bis(isoxazoline) ligand 10 bearing an isopropyli-
dene skeleton was prepared and applied to the intramole-
cular oxidative aminocarbonylation. The reaction of 1a
proceeded at 0 °C to furnish a 57% yield of racemic 2a,
accompanied by the gradual formation of Pd black (eq 4).
Since (P,R,R)-3a promoted the reaction efficiently without
Pd black formation (Table 1, entry 1), it was demonstrated
~
3905. (j) Muniz, K. J. Am. Chem. Soc. 2007, 129, 14542–14543. (k) Zeng, W.;
Chemler, S. R. J. Am. Chem. Soc. 2007, 129, 12948–12949. (l) Zeng, W.;
Chemler, S. R. J. Org. Chem. 2008, 73, 6045–6047. (m) Fuller, P. H.; Kim, J.-
W.; Chemler, S. R. J. Am. Chem. Soc. 2008, 130, 17638–17639. (n) Paderes,
M. C.; Chemler, S. R. Org. Lett. 2009, 11, 1915–1918. (o) Scarborough, C. C.;
Bergant, A.; Sazama, G. T.; Guzei, I. A.; Spencer, L. C.; Stahl, S. S.
Tetrahedron 2009, 65, 5084–5092.
J. Org. Chem. Vol. 74, No. 24, 2009 9277

Tsujihara et al.
JOCArticle
SCHEME 2. Plausible Catalytic Cycle
that the spiro skeleton contributed to the catalyst stability.
Most likely, the highly rigid structure directs the lone pairs
on the isoxazoline nitrogens into the stable bidentate
mode.
acylpalladium intermediate III. Finally, ring closure via
nucleophilic trapping of the acylpalladium by the tethered
tosylamide group proceeds to yield 2 and Pd0, of which the
latter is oxidized by the action of p-benzoquinone to
regenerate the PdII catalyst.
Enantioselectivity is determined in the aminopalladation,
viz. the formation of intermediate II by way of I. Figure 1
depicts the asymmetric environment around Pd based on
the X-ray structure of [Pd{(M*,S*,S*)-3a}2](BF4)2 and the
schematic transition state assembly in the intermediate I. It is
evident that the chiral ligand (M,S,S)-3a creates a C2-sym-
metric environment with isopropyl substituents located in
the second and fourth quadrants (Figure 1a). In the inter-
mediate I, the carbon-carbon double bond of 1 coordinates
to Pd to avoid steric repulsion between the substrate and
isopropyl substituents of (M,S,S)-3a (Figure 1b). Conse-
quently, the activated olefin undergoes intramolecular nucleo-
philic attack of the nitrogen from its re-face to give the bicyclic
β-amino acid products 2 of the observed S configuration.
Reaction Mechanism and Stereochemistry. A plausible
catalytic cycle of the enantioselective intramolecular oxida-
tive aminocarbonylation of alkenylurea derivatives 1 is
illustrated in Scheme 2. On the basis of the results in Table 2,
the catalytically active species is thought to be a 1:1 complex
of Pd and (M,S,S)-3a, which is in equilibrium with an
inert 1:2 [Pd{(M,S,S)-3a}2](BF4)24e complex in the presence
of an excess amount of the ligand. The structure of this
1:2 complex was confirmed by X-ray crystallography
(see the Supporting Information). The production of
bicyclic β-amino acid derivatives 2 seems to be initiated
by the coordination of the olefinic moiety in substrates 1
to the catalytically active species, leading to intermediate I.
The activated alkene is subjected to the nucleophilic
attack of the intramolecular urea group to afford alkylpal-
ladium intermediate II. The subsequent CO insertion gives
FIGURE 1. (a) Quadrant representation for the asymmetric envir-
onment of Pd-(M,S,S)-3a complex stemming from the X-ray
structure of [Pd{(M*,S*,S*)-3a}2](BF4)2 and (b) a plausible stereo-
chemical pathway for the oxidative enantioselective aminocarbo-
nylation of alkenylureas 1 catalyzed by Pd-(M,S,S)-3a.
9278 J. Org. Chem. Vol. 74, No. 24, 2009

Tsujihara et al.
JOCArticle
Conclusion
ethyl acetate. The combined organic layers were dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The
crude product was purified by column chromatography on silica
gel (hexane/acetone = 3/1) to afford bicyclic β-amino acid
derivative 2.
We have developed a catalytic enantioselective intramo-
lecular oxidative aminocarbonylation of alkenylureas 1.
Chiral spiro bis(isoxazoline) ligands, SPRIXs 3, have proven
to be useful for this reaction, affording bicyclic β-amino acid
derivatives 2 with up to 89% ee. Alkenyl sulfamide 6 and
tosylamide 8 are also applicable to the asymmetric catalysis
to give the corresponding products in good yields with
moderate enantioselectivities. The unique acceleration effect
of 3 in these reactions is rationalized by two structural
features. One is the isoxazoline coordination site whose
σ-donor ability is low since the intrinsic Lewis acidity of
the Pd metal is not altered. The other is the rigid spiro
skeleton that provides not only an effective asymmetric
environment but a suitable chelate. Further investigations
into the extension of substrate scope, reaction mechanism
including asymmetric induction, and transformation of pro-
ducts 2 to biologically active molecules are now in progress.
6,6-Dimethyl-2-tosyltetrahydropyrrolo[1,2-c]pyrimidine-1,3-
(2H,4H)-dione (2a): 89% yield; white solid; mp 143.8-145.4 °C
(hexane/EtOAc); HRMS (ESI) calcd for C16H20N2NaO4S m/z
359.1041 ([M þ Na]þ), found m/z 359.1042; [R]25 þ61.4
D
1
(c 0.56, 62% ee, CHCl3); H NMR (500 MHz, CDCl3) δ 1.15
(s, 3H), 1.16 (s, 3H), 1.42 (dd, J = 12.5 Hz, J = 9.9 Hz, 1H), 2.01
(dd, J = 12.5 Hz, J = 6.4 Hz, 1H), 2.35 (dd, J = 17.6 Hz, J =
12.6 Hz, 1H), 2.43(s, 3H), 2.92(dd, J = 17.6 Hz, J = 3.5Hz, 1H),
3.18 (d, J = 11.1 Hz, 1H), 3.41 (d, J = 11.1 Hz, 1H), 4.05-4.11
(m, 1H), 7.33 (d, J = 8.4 Hz, 2H), 8.17 (d, J = 8.4 Hz, 2H); 13
C
NMR (126 MHz, CDCl3) δ 21.7, 26.4, 26.5, 37.5, 41.1, 46.1, 51.1,
58.0, 129.3, 129.3, 135.3, 145.4, 147.8, 167.7; IR (neat) ν (CdO)
1746, 1711, (OdSdO) 1362, 1173 cm-1. The enantiomeric excess
was determined to be 88% ee by HPLC analysis using a chiral
stationary phase column [Chiralpak AD-H, hexane/i-PrOH =
3/1, flow rate = 0.5 mL/min, λ = 227 nm: 21.6 min (major) and
29.1 min (minor)].
Experimental Section
General Procedure for PdII-SPRIX-Catalyzed Enantioselec-
tive Intramolecular Oxidative Aminocarbonylation of Alkenylur-
eas 1. Under an argon atmosphere, a solution of (M,S,S)-3a (11
mol %) and [Pd(MeCN)4](BF4)2 (10 mol %) in MeOH (5.0 mL)
was stirred at 25 °C for 2 h. After addition of p-benzoquinone
(4 equiv), the apparatus was purged with carbon monoxide
by pumping-filling via a three-way stopcock. Alkenylurea 1
(0.10 mmol) was then added to the solution at -40 °C and the
entire mixture was stirred at that temperature for the time
indicated in Table 3. After quenching by the addition of 1 M
aq HCl, the reaction mixture was diluted with ethyl acetate. The
layers were separated and the aqueous layer was extracted with
Acknowledgment. Financial support from the MEXT
(Scientific Research on Priority Areas) is gratefully acknowl-
edged. We are also thankful to the technical staff of the
Material Analysis Center of ISIR for their assistance.
Supporting Information Available: Experimental details
including screening of the reaction conditions, preparation of
substrates, characterization of products, and X-ray crystallo-
graphic data for 2b, (M,S,S)-3a, and [Pd{(M*,S*,S*)-3a}2]-
(BF4)2 in CIF format. This material is available free of charge
via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 24, 2009 9279