Stereoselective synthesis of imidazolidin-2-ones via Pd-catalyzed alkene carboamination. Scope and limitations

Article abstract of DOI:10.1016/j.tet.2008.04.015

A method for the synthesis of imidazolidin-2-ones from N-allylureas and aryl or alkenyl bromides via Pd-catalyzed carboamination reactions is described. The N-allylurea precursors are prepared in one step from readily available allylic amines and isocyanates, and the Pd-catalyzed reactions effect the formation of a C-C bond, a C-N bond, and up to two stereocenters in a single step. Good diastereoselectivities are obtained for the conversion of substrates bearing allylic substituents to 4,5-disubstituted imidazolidin-2-ones, and excellent selectivity for the generation of products resulting from syn-addition across the alkene is observed when substrates derived from cyclic alkenes or E-1,2-disubstituted alkenes are employed. A brief discussion of reaction mechanism and product stereochemistry is presented.

Full text of DOI:10.1016/j.tet.2008.04.015

Tetrahedron 64 (2008) 6838–6852
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis of imidazolidin-2-ones via Pd-catalyzed alkene
carboamination. Scope and limitations
*
Jonathan A. Fritz, John P. Wolfe
Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, MI 48109-1055, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A method for the synthesis of imidazolidin-2-ones from N-allylureas and aryl or alkenyl bromides via
Pd-catalyzed carboamination reactions is described. The N-allylurea precursors are prepared in one step
from readily available allylic amines and isocyanates, and the Pd-catalyzed reactions effect the
formation of a C–C bond, a C–N bond, and up to two stereocenters in a single step. Good diastereo-
selectivities are obtained for the conversion of substrates bearing allylic substituents to 4,5-di-
substituted imidazolidin-2-ones, and excellent selectivity for the generation of products resulting from
syn-addition across the alkene is observed when substrates derived from cyclic alkenes or E-1,2-di-
substituted alkenes are employed. A brief discussion of reaction mechanism and product stereo-
chemistry is presented.
Received 15 February 2008
Received in revised form 2 April 2008
Accepted 3 April 2008
Available online 8 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
closure of a simple, readily available acyclic urea derivative, with
formation of both a C–C and a C–N bond in the same step. More-
Substituted imidazolidin-2-ones and other cyclic ureas are of
considerable interest in pharmaceutical and medicinal chemistry,
as many biologically active compounds contain these moieties.
Cyclic ureas have been demonstrated to act as HIV protease in-
hibitors,1 5-HT3 receptor antagonists,2 and NK1 antagonists.3 These
structures have also been employed as monomeric units for
biopolymer scaffolds that exhibit greater stability than typical
peptides.4 In addition, imidazolidin-2-ones have found applications
over, methods that accomplish this are limited in scope. For
example, Pd-catalyzed Wacker-type carbonylation reactions of N-
allylureas are limited to installation of ester functionality in the C–C
bond-forming step.17 Two-step carboamination reactions of N-
allylureas that involve ureidomercuration followed by radical
coupling have been developed, but these methods require stoi-
chiometric amounts of mercury reagents.18 Only one example of
Pd-catalyzed carboamination of an N-propargylurea with acrolein
has been reported, and this transformation does not lead to gen-
eration of new stereocenters.19
in organic synthesis as chiral auxiliaries,5 and as precursors to
amino acids6 and vicinal diamines.7
a-
Due to the utility of imidazolidin-2-ones, a number of methods
have been developed for their construction. The most commonly
employed method for the synthesis of these compounds involves
generation of 1,2-diamines, which are then converted to cyclic
ureas by treatment with phosgene, phosgene equivalents such as
carbonyl diimidazole,8 or through other carbonylation methods.9
However, the preparation of 1,2-diamines frequently requires sev-
eral steps, and is particularly cumbersome when the two amino
groups bear different substituents.10
In order to overcome the limitations of classical methods for the
preparation of imidazolidin-2-ones, several alternative strategies
have been developed for the synthesis of these compounds.11–16
Despite these advances, few existing methods allow for ring-
We recently reported a new strategy for the construction
of imidazolidin-2-ones via Pd-catalyzed carboamination re-
actions20,21 between acyclic N-allylureas (2) and aryl bromides (Eq.
1).22 This method overcomes many limitations of existing ap-
proaches to the synthesis of these compounds. For example, the N-
allylurea substrates (2) are prepared in one step and high yield from
readily available allylic amines and isocyanates. The carboamina-
tion reactions generate two bonds (one C–C and one C–N) and up to
two stereocenters in one step to afford products of general struc-
ture 3 with excellent diastereoselectivity. A number of different
coupling partners can be employed, and preparation of derivatives
bearing different substituents on N1 and N3 is straightforward. In
this article we describe our full studies on the development, scope,
and limitations of this transformation. These studies illustrate that
both aryl and alkenyl halides can be employed as coupling partners
in these reactions, and that the synthesis of imidazolidin-2-ones
that are bicyclic or 4,5-disubstituted can be achieved with good to
excellent levels of diastereoselectivity.
* Corresponding author. Tel.: þ1 734 763 3432; fax: þ1 734 615 3790.
E-mail address: jpwolfe@umich.edu (J.P. Wolfe).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.015

J.A. Fritz, J.P. Wolfe / Tetrahedron 64 (2008) 6838–6852
6839
Table 1
O
O
Optimization studiesa
R3
R2
R–Br
R3
R2
R4
3
N
H
1
1
3
NH
N
R3
R4
R4NCO
N
cat. Pd
N
O
O
ð1Þ
O
NaOtBu
5
4
Br
Ph
Et Ph
+
Et
R1
Ph
Et
N
N
N
N
R = aryl,
R2
3
N
N
H
R1
R1
R
1
2
alkenyl
cat. Pd2(dba)3
cat. ligand
4
5
6
NaOtBu, Toluene
2. Results and discussion
2.1. Optimization
110 °C
Entry
Ligand
NMR ratio 5/6
NMR yield of 5b (%)
In our preliminary studies we examined the Pd-catalyzed re-
action of 1-allyl-3-ethyl-1-phenylurea (4) with 4-bromotoluene.
Related experiments on the conversion of g-aminoalkenes to pyr-
1
2
3
4
5
6
dppb
P(o-tol)3
dppf
dppe
Dpe-phos
Xantphos
1:1
5:1
100:0
2:1
100:0
100:0
24
22
30
24
rolidines suggested that the choice of phosphine ligand would have
a large impact on chemical yield.20 Thus, a series of different phos-
phines were examined for the carboamination of 4. As shown below
(Table 1), treatment of 4 with 4-bromotoluene (1.2 equiv), NaOtBu
(1.2 equiv), and catalytic amounts of Pd2(dba)3 (1 mol % complex,
2 mol % Pd) and phosphine ligand (2–4 mol %) in toluene (0.25 M) at
110 ꢀC provided mixtures of the desired product 5 and oxidative
cyclization product 6. Use of dppb, dppe, or P(o-tol)3 as ligand23
afforded poor product ratios. However, when dppf, Dpe-phos, or
Xantphos were employed as ligands,23 the competing oxidative
cyclization of 4 to 6 was suppressed. Under optimized conditions,
the Pd2(dba)3/Xantphos-catalyzed coupling of 4 with 4-bromoto-
luene provided a 59% isolated yield of the imidazolidin-2-one 5.
Initially, the modest yields obtained in the reactions described
in Table 1 were puzzling, as 1H NMR analysis of the crude reaction
mixtures showed primarily the presence of 5 and 6. To probe the
possibility that volatile side products were generated, the Pd/
Xantphos-catalyzed reaction of 4 with 4-bromotoluene was con-
ducted in an NMR tube and monitored by 1H NMR spectroscopy.
This experiment indicated that significant amounts of N-allylani-
line were generated in this transformation.24 Control experiments
demonstrated that the formation of N-allylaniline was base medi-
ated, as the generation of N-allylaniline from 4 was also observed
when 4 was heated with NaOtBu in the absence of Pd (Eq. 2).25
Although additional optimization failed to improve reactions of 4,
cyclizations of related substrates bearing N3-aryl groups proceed in
much higher yield (see below).
42
50 (59)c
a
Conditions: 1.0 equiv substrate, 1.2 equiv 4-bromotoluene, 1.2 equiv NaOtBu,
1 mol % Pd2(dba)3, 2 mol % ligand (chelating ligands) or 4 mol % ligand (mono-
dentate ligands), toluene (0.25 M), 110 ꢀC.
b
NMR yields were measured against phenanthrene as an internal standard.
Isolated yield is indicated in parentheses.
c
In most cases, moderate yields of the desired imidazolidin-2-
ones were obtained when substrates bearing N3-alkyl groups were
employed due to competing base-mediated side reactions of these
substrates. As noted in Section 2.1, reactions of 4 generated signif-
icant amounts of N-allylaniline. Conversely, transformations of
substrate 7 suffered from the formation of side products resulting
from isomerization of the N-allyl group to a N-(1-propenyl)
group.26
In contrast to results obtained with N3-alkyl urea derivatives,
good to excellent yields were obtained with urea substrates bearing
N3-aryl groups. For example, although the reaction of 1-allyl-3-
ethyl-1-methylurea (7) with 2-bromonaphthalene proceeded in
only 68% yield (entry 5), the analogous coupling of 1-allyl-1-
methyl-3-phenylurea (9) with 2-bromonaphthalene afforded a 97%
yield of the imidazolidin-2-one 17 (entry 8). Of particular note,
substrate 10 bearing an N1-benzyl group and an N3-PMP group
(PMP¼p-methoxyphenyl) was efficiently converted to the differ-
entially protected imidazolidin-2-one products 21–23. The N-ben-
zyl and N-PMP-protecting groups can be removed independently to
afford mono-protected products.27 For example, treatment of 22
with ceric ammonium nitrate effected cleavage of the PMP group to
afford 24 in 75% yield (Eq. 3). Alternatively, selective cleavage of the
N-benzyl group was achieved through reduction with Li/NH3 to
provide 25 in 92% yield (Eq. 4).27a,28,29
O
Ph
Et
Ph
NaOtBu
d8-Toluene
110 °C
N
N
H
NH
ð2Þ
4
20% conversion in 2.5 h
O
Bn
CAN
CH3CN, H2O
75%
N
NH
(3)
(4)
O
2.2. Synthesis of 4-substituted imidazolidin-2-ones
24
Bn
PMP
N
N
With optimized reaction conditions in hand, we proceeded to
examine the scope of N-allylurea carboamination reactions that
afford 4-substituted imidazolidin-2-one products (Table 2). A va-
riety of aryl bromides are effective coupling partners in these
transformations, including derivatives that are o-substituted (en-
tries 4 and 13) or heteroaromatic (entry 9). In addition, a number of
functional groups are tolerated, including nitriles (entry 7), tert-
butyl esters (entry 12), trifluoromethyl groups (entry 10), and
nonenolizable ketones (entry 11). Good yields are generally
obtained with electron-neutral or electron-poor aryl bromides.
However, use of electron-rich aryl bromides led to relatively low
yields of the desired urea products. For example, the Pd-catalyzed
reaction of 7 with 4-bromo-tert-butylbenzene proceeded in 58%
yield (entry 3), but the reaction of 7 with 4-bromoanisole afforded
only 35% yield of 15 (entry 6).
O
22
Li, NH3
THF, –78 °C
92%
PMP
HN
25
N
2.3. Synthesis of 4,4- and 4,5-disubstituted imidazolidin-2-
ones
Having established the feasibility of generating 4-substituted
imidazolidin-2-ones via Pd-catalyzed carboamination reactions of
N-allylureas, we sought to extend the scope of this method to allow
for the construction of more highly substituted products. As shown

6840
J.A. Fritz, J.P. Wolfe / Tetrahedron 64 (2008) 6838–6852
Table 2
Synthesis of N,N-disubstituted-4-benzyl imidazolidin-2-one derivativesa
Entry
Urea
Aryl bromide
Product
Yieldb (%) Entry
Urea
Aryl bromide
Product
Yieldb (%)
Br
O
O
Br
O
O
Ph
Et
Me
Ph
Me
Ph
N
Ph
Et
N
N
N
N
N
H
N
N
1
59
73
8
9
97
H
5
9
4
17
Br
O
O
Br
Ph
Me
Et
Ph
N
N
N
N
2
3
4
9
9
83
92
N
N
18
11
Br
Br
O
O
O
Me
Et
Me
Me
Et
Ph
N
N
H
N
N
N
N
58
63
10
11
19
t-Bu
CF3
12
CF3
Br
t-Bu
7
O
O
Me
Et
N
N
Br
Me
Ph
N
N
4
7
7
9
85
13
20
C(O)Ph
Ph(O)C
Br
Br
O
O
O
Bn
PMP
Me
Et
Bn
PMP
N
N
N
N
N
N
H
5
6
68
35
80
12
13
14
75
71
96
21
14
CO2t-Bu
10
t-BuO2C
O
Br
O
Bn
PMP
N
N
Me
Me
Et
N
Br
N
7
10
22
15
OMe
CN
OMe
Br
Br
O
O
O
Bn
PMP
Me
Bn
Bn
N
N
N
N
N
N
H
7
10
23
16
8
t-Bu
CN
t-Bu
a
Conditions: 1.0 equiv substrate, 1.2 equiv ArBr, 1.2 equiv NaOtBu, 1 mol % Pd2(dba)3, 2 mol % Xantphos, toluene (0.25 M), 110 ꢀC.
Average isolated yields obtained from two or more experiments.
b
in Table 3, N-allylureas bearing allylic substituents were trans-
from base-mediated hydroamination of the substrate.30,31 The
hydroamination side reaction could be minimized by using Cs2CO3
in place of NaOtBu, but this modification resulted in the formation
of other side products derived from oxidative cyclization and/or
Heck arylation32 of the substrate.
The synthesis of 4,4-disubstituted imidazolidin-2-ones was
accomplished via Pd-catalyzed carboamination reactions of N-
allylurea derivatives 32 and 33 bearing 1,1-disubstituted alkenes.
As shown in Table 3 (entries 7–9), these reactions proceed in good
to excellent yield with several different aryl bromides.
formed to trans-4,5-disubstituted imidazolidin-2-ones upon treat-
ment with an aryl bromide in the presence of NaOtBu and the
Pd2(dba)3/Xantphos catalyst. The diastereoselectivity of these
reactions was dependent on the size of the allylic substituent. For
example, the Pd-catalyzed carboamination of methyl-substituted
allylurea 26 provided 34 as an 8:1 mixture of diastereomers; 34 was
obtained in 88% yield and 12:1 dr after chromatographic purifica-
tion (Table 3, entry 1). Urea substrate 27 bearing a relatively large
isopropyl group at the allylic position provided 35 in 83% yield with
>20:1 dr (entry 2). Bicyclic 4,5-disubstituted imidazolidinones
were also prepared in good yield with excellent diastereoselectivity
through carboamination of 2-vinylpiperidine- or 2-vinyl-
pyrrolidine-derived ureas 30 or 31 (entries 5 and 6).
Substrates that were gem-disubstituted or functionalized with
a benzyloxymethyl group at the allylic position were transformed
to the corresponding cyclic ureas in modest yields due to com-
peting side reactions (entries 3 and 4). For example, the conversion
of 28 to 36 proceeded in low yield due to both Pd-catalyzed oxi-
dative cyclization and base-mediated isomerization of the starting
alkene. The carboamination of 29 generated side products resulting
2.4. Imidazolidin-2-ones generated from internal olefins
The Pd-catalyzed carboamination of urea substrates bearing
internal olefins leads to the formation of two new contiguous
stereocenters with excellent stereocontrol. In all cases examined,
these transformations occur with net syn-addition of the nitrogen
atom and the aryl group across the C–C double bond. This stereo-
chemical outcome is identical to that previously observed in related
Pd-catalyzed carboamination reactions between
g-aminoalkenes
and aryl bromides that afford pyrrolidine products.20

J.A. Fritz, J.P. Wolfe / Tetrahedron 64 (2008) 6838–6852
6841
Table 3
Table 4
Synthesis of 4,4- and 4,5-disubstituted imidazolidin-2-onesa
Synthesis of imidazolidin-2-ones generated from internal alkenesa
Entry
Urea
Aryl bromide
Product
drb Yieldc
(%)
Entry
Urea
Aryl bromide
Product
drb
Yieldc (%)
O
Br
O
O
Ph
Ph
O
N
N
Bn
PMP
Bn
PMP
N
Br
12:1
88
N
N
N
N
Ph
Ph
1
H
N
N
(8:1)
47
H
1
>20:1 50
CN
34
CN
Br
26
43
O
O
NCPh2
Br
4:1 E:Z
Ph2CN
Bn
PMP
Bn
iPr
PMP
>20:1
83
N
N
N
H
2
3
O
(>20:1)
Bn
PMP
Ph
iPr
27
N
N
35
O
Bn
PMP
O
O
Br
Br
N
N
H
48
>20:1 74d
Bn
PMP
2
Bn
PMP
N
N
>20:1
21
N
O
N
H
44
(>20:1)
CN
Ph
28
BnO
NC
Bn
49
36
BnO
Bn
O
O
O
PMP
Bn
PMP
PMP
N
N
Br
N
N
N
N
N
4
5
d
30
78
H
Ph
Ph
29
3
4
44
>20:1 65d
37
Ph
Br
O
PMP
PMP
20:1
(11:1)
N
N
N
H
MeO
Br
MeO
O
30
38
O
O
Bn
Ph
Bn
Ph
Ph
N
N
O
N
N
H
>20:1 84
O
Br
PMP
N
N
PMP
>20:1
(>20:1)
N
N
H
50
6
87
77
45
39
CF3
31
O
CF3
Ph
Ph
N
N
O
Br
Ph
O
Br
Et
Ph
N
N
H
5
>20:1 46e
N
N
Et
Ph
N
N
51
7
8
d
H
40
46
CF3
32
CF3
O
a
Conditions: 1.0 equiv substrate, 1.2 equiv ArBr, 1.2 equiv NaOtBu, 1 mol %
Et
Ph
Pd2(dba)3, 2 mol % Xantphos, toluene (0.25 M), 110 ꢀC.
N
N
Br
b
Diastereomeric ratios are for isolated products and were unchanged from
32
d
d
89
97
diastereomeric ratios observed in crude reaction mixtures.
41
c
Average isolated yields obtained from two or more experiments.
Conditions: 1.0 equiv substrate, 1.2 equiv ArBr, 1.2 equiv Cs2CO3, 2 mol %
d
Pd(OAc)2, 2 mol % Xantphos, dioxane (0.25 M), 100 ꢀC.
O
Br
e
O
PEt3$HBF4 (4 mol %) was used in place of Xantphos as ligand.
Bn
PMP
Bn
PMP
N
N
N
N
9
H
42
33
the generation of significant amounts of side products resulting
from base-mediated hydroamination.31 However, this side reaction
could be minimized through use of Cs2CO3 in place of NaOtBu, and
satisfactory yields of 48 and 49 were obtained after other minor
adjustments to the reaction conditions.20g
The Pd-catalyzed carboamination reactions were also effective
with urea substrates derived from cycloalkenes (entries 4 and 5).
For example, cyclopentene-derivative 45 was converted to 50 in
84% yield with >20:1 dr.34 Efforts to couple the analogous cyclo-
hexene derivative 46 with 4-bromotoluene were unsuccessful
when a catalyst composed of Pd2(dba)3/Xantphos was employed.
However, this carboamination reaction could be effected with ex-
cellent diastereoselectivity (albeit moderate yield) when PEt3 was
used in place of Xantphos as ligand. Interestingly, the product
obtained under these conditions (51) was arylated at the 5-position
rather than the expected 4-position.35,36
Conditions: 1.0 equiv substrate, 1.2 equiv ArBr, 1.2 equiv NaOtBu, 1 mol %
Pd2(dba)3, 2 mol % Xantphos, toluene (0.25 M), 110 ꢀC.
Diastereomeric ratios are for isolated products. Diastereomeric ratios in paren-
theses were observed in crude reaction mixtures.
a
b
c
Average isolated yields obtained from two or more experiments.
As shown in Table 4, E-1,2-disubstituted alkene derivatives 43
and 44 were converted to 47–49 in moderate to good yield with
>20:1 dr (entries 1–3). Interestingly, urea 43 was employed as a 4:1
mixture of E/Z alkene isomers, but imidazolidin-2-one 47 was
obtained as a single stereoisomer (50% yield) that derives from syn-
addition across the E-alkene; the unreacted Z-alkene substrate
stereoisomer was observed in the crude reaction mixture.33 Efforts
to employ cinnamyl urea derivative 44 were initially hampered by

6842
J.A. Fritz, J.P. Wolfe / Tetrahedron 64 (2008) 6838–6852
Table 5
O
Synthesis of 4-allyl-imidizolidin-2-onesa
R2
R3
N
N
Entry
Urea
Aryl bromide
Product
drb
Yieldc
(%)
ArBr
LnPd(0)
R1
Ar
O
O
Br
PMP
Bn
Bn
Bn
Bn
Bn
PMP
PMP
PMP
O
N
N
N
N
N
N
N
H
1
d
74
85
R2
R3
Ar
Br
N
N
Ph
52
56
LnPd
10
Ph
Ph
58
R1
PdLn
O
O
Ar
O
PMP
PMP
Br
R3
R2
N
H
2
3
d
N
N
H
O
Ph
R2
33
53
R3
NaOtBu
N
N
O
R1
PdLn
Ar
O
tBuOH
Bn
Br
57
N
N
10:1 (7:1) 91d
N
N
N
H
R1
TMS
26
Scheme 1. Catalytic cycle.
54
TMS
O
O
PMP
Br
PMP
N
N
N
H
O
O
O
O
4
1.6:1 (1.5:1) 87
R2
R2
R2
R2
R3
R3
R3
R3
N
N
N
H
N
N
N
N
N
30
55
or
58
Conditions: 1.0 equiv substrate, 2.0 equiv ArBr, 2.0 equiv NaOtBu, 1 mol %
Pd2(dba)3, 2 mol % Xantphos, toluene (0.25 M), 110 ꢀC.
Diastereomeric ratios are for isolated products. Diastereomeric ratios in paren-
theses were observed in crude reaction mixtures.
a
LnPd
Ar
60
61
59
Ar
PdLn
b
Scheme 2. Formation of oxidative cyclization products.
c
Average isolated yields obtained from two or more experiments.
Nixantphos was used as a ligand in place of Xantphos.
d
provide 59, which could be converted to oxidative cyclization
product 60 or 61 under the reaction conditions (Scheme 2).
The generation of unexpected isomer 51 in the Pd-catalyzed
carboamination of 46 (Table 4, entry 5) also likely results from
hydride elimination after syn-amidopalladation. As shown below
(Scheme 3), -hydride elimination from 63 would provide 64.
2.5. Synthesis of 4-allyl-imidazolidin-2-ones via
carboamination with alkenyl halides
b-
In order to further expand the scope of the Pd-catalyzed car-
boamination reactions of N-allylurea derivatives, we briefly exam-
ined the use of alkenyl bromides as electrophilic coupling partners.
AsshowninTable5, thesetransformations generallyproceed ingood
yield to afford 4-allyl imidazolidin-2-one products. Interestingly,
although the carboamination of 26 with an alkenyl halide proceeded
with similar diastereoselectivity as observed with aryl bromide
coupling partners, the reaction of 30 with E-bromopropene afforded
a 1.5:1 mixture of diastereomers (entry 4). The origin of this
diminished stereoselectivity relative to that obtained when 30 was
coupled with bromobenzene (Table 3, entry 5) is not clear.
b
Reinsertion of the alkene into the Pd–H bond with the opposite
regiochemistry would afford 65, which could undergo reductive
elimination to yield 51. The conversion of 63 to 65 may be facili-
tated by the propensity of the small, electron-rich phosphine PEt3
to slow the rate of C–C bond-forming reductive elimination relative
to b
-hydride elimination.37 It is likely that the conversion of 63 to
65 is also thermodynamically favorable, as the migration of the
metal from C4 to C5 should alleviate a steric interaction between
the metal and the N–Ph substituent.
Ph
Ph
O
Ph
O
N
N
N
N
2.6. Proposed mechanism and origin of side products
LnPd
O
62
N
Ph
N
Ph
LnPd
Ar
H
64
Ar
LnPd
Ar
On the basis of the observed product stereochemistry and the
side products generated in these transformations, it is likely that
the mechanism of Pd-catalyzed carboamination reactions of N-
allylureas is analogous to that previously described for related
63
Ph
Ph
Ph
LnPd
Ar
Ar
N
N
transformations of
g-aminoalkenes that afford pyrrolidine prod-
N
Ph
N
Ph
O
O
51
65
ucts.20 A plausible catalytic cycle that is consistent with the ob-
servations outlined above is illustrated in Scheme 1. Oxidative
addition of the aryl/alkenyl halide to Pd(0) would generate 56,
which could be converted to Pd–amido complex 57 through
reaction with the urea substrate/base combination. syn-Insertion of
the alkene into the Pd–N bond would yield 58, which could
undergo C–C bond-forming reductive elimination to generate the
observed imidazolidin-2-one product with concomitant re-
generation of the Pd(0) catalyst.
Scheme 3. Formation of isomer 51.
2.7. Stereochemistry of imidazolidin-2-one products
On the basis of the mechanism shown in Scheme 1, it appears
likely that the product stereochemistry is set in the alkene insertion
step (57/58). The syn-alkene insertion results in net syn-addition
of the nitrogen atom and the aryl group across the C–C double bond
when cyclic or acyclic internal alkenes are employed as substrates
(Table 4). The syn-addition selectivity is uniformly high (>20:1) in
all examples examined thus far.
Many of the side products observed in these reactions are de-
rived from competing
cases where C–C bond-forming reductive elimination may be rel-
atively slow.37 For example,
-hydride elimination of 58 would
b-hydride elimination of intermediate 58 in
b

J.A. Fritz, J.P. Wolfe / Tetrahedron 64 (2008) 6838–6852
6843
The syn-alkene insertion likely proceeds via an organized, cyclic
transition state in which the allylic substituent is oriented to min-
from Strem Chemical Co. and used without further purification. All
aryl bromides were obtained from commercial sources (Aldrich
Chemical Co. or Acros Chemical Co.) and were used as obtained. N-
Ethyl-2-methylallylamine was purchased from Aldrich Chemical
Co. and used without purification. Toluene, THF, dichloromethane,
and ether were purified using a Glass Contour solvent purification
system. Product regiochemistry was assigned on the basis of 1H
NMR 2D-COSY and HSQC experiments. Product stereochemistry
was assigned on the basis of 1H NMR 2D-NOESY experiments. The
stereochemistry of 47 was assigned on the basis of X-ray crystal-
lographic analysis, and the stereochemistry of 48 and 49 was
assigned based on analogy to 47. Yields refer to isolated yields of
compounds estimated to be ꢁ95% pure as determined by 1H NMR
and either capillary GC or combustion analysis. All transformations
described in this paper have been reproduced in duplicate or
triplicate experiments, and averaged yields of these runs have been
reported in the text and tables of this manuscript. However, since
the yields reported in Section 4 describe the result of a single ex-
periment, whereas the yields reported in Tables 2–5 are average
yields of two or more experiments, the yields reported in Section 4
may differ from those shown in Tables 2–5. Reaction times
described below have not been minimized.
imize unfavorable steric interactions, and the alkene
p-bond is
approximately eclipsed with the Pd–N bond.38 As shown in Scheme
4, cyclization of low energy conformer 66 via transition state 67
would generate the observed trans-4,5-disubstituted imidazolidin-
2-ones 34–36. In contrast, conformer 69 should be higher in energy
due to A(1,3)-strain, and transition state 70 suffers from unfavorable
steric repulsion between R4 and the Pd-bearing methylene group.
As expected, selectivity is observed to improve with increasing size
of R4 (Table 3).
Ar
R2
N
Ar
PdL
Ar
R2
N
R2
N
O
N
O
PdLn
O
N
n
PdLn
34
35
36
3 N
R
R3
R3
R3
R4
R4
67
R4
66
68
favored
O
O
R2
O
R2
R2
R3
R3
N
N
N
N
N
N
PdLn
Ar
PdLn
Ar
PdLn
Ar
R4
70
4
4
71
R
R
69
disfavored
Scheme 4. Stereochemistry of 4,5-disubstituted imidazolidine formation.
4.2. General procedure for the synthesis of N-allylurea
substrates
The selectivity for the conversion of piperidine- and pyrrolidine-
derived ureas 30 and 31 to bicyclic products 38 and 39 (Table 3,
entries 5 and 6) appears to arise from cyclization through transition
state 72 (Scheme 5), in which the 2-vinyl group is oriented in
An oven- or flame-dried round-bottom flask equipped with
a stirbar was cooled under a stream of nitrogen and charged with
the appropriate N-allylamine (1.0 equiv), the appropriate iso-
cyanate (1.0–1.4 equiv), and isopropanol or CH2Cl2 (1.0 M). The re-
action was stirred at room temperature until the starting amine had
been completely consumed as judged by TLC or 1H NMR analysis.
The reaction mixture was then concentrated in vacuo and the crude
product was purified via flash chromatography on silica gel.
a
pseudoequatorial position with its p-bond approximately
eclipsed with the Pd–N bond. The observed major stereoisomer
could also derive from cyclization via the more thermodynamically
stable conformation, in which the alkenyl group is in a pseudoaxial
position to minimize allylic strain interactions with the urea moi-
ety. However, examination of molecular models indicates that the
alkene and the metal are spatially distant in this conformation. The
origin of differences in diastereoselectivity observed, when aryl
halides (>20:1 dr) versus alkenyl halides (1.3:1 dr) are employed in
the carboamination of 30 is unclear.
4.2.1. 1-Allyl-3-ethyl-1-phenylurea (4)
Reaction of 1.57 g (11.8 mmol) of N-allylaniline with 1.17 g
(16.5 mmol) of ethyl isocyanate following the general procedure
afforded 2.22 g (92%) of the title compound as a yellow oil. 1H NMR
Ar
R2
N
Ar
PdLn
Ar
PdLn
R2
N
(500 MHz, CDCl3)
d
7.38 (t, J¼7.0 Hz, 2H), 7.28 (t, J¼7.0 Hz,1H), 7.22–
R2
N
O
N
O
PdLn
O
N
7.18 (m, 2H), 5.92–5.83 (m, 1H), 5.08–5.01 (m, 2H), 4.28–4.24 (m,
38
39
2H), 4.19 (s, 1H), 3.23–3.15 (m, 2H), 1.00 (t, J¼7.0 Hz, 3H); 13C NMR
n( )
n( )
n( )
N
30: n = 1
31: n = 0
72
(100 MHz, CDCl3) d 157.0, 142.1, 134.9, 130.0, 128.7, 127.7, 117.0, 52.4,
favored
35.7, 15.7; IR (film) 3354, 1653 cmꢂ1. Anal. Calcd for C12H16N2O: C,
70.56; H, 7.90; N, 13.71. Found: C, 70.66; H, 8.02; N, 13.69.
Scheme 5. Stereochemistry in the carboamination of 30 and 31.
4.2.2. 1-Allyl-3-ethyl-1-methylurea (7)
3. Summary and conclusion
Reaction of 2.58 g (36.3 mmol) of N-methylallylamine with
3.60 g (50.6 mmol) of ethyl isocyanate following the general pro-
cedure afforded 4.79 g (94%) of the title compound as a clear oil. 1H
In conclusion, we have developed a concise synthesis of
substituted imidazolidin-2-ones from readily available components
(allylic amines, isocyanates, and aryl/alkenyl bromides). These
transformations generate two bonds and up to two stereocenters in
a single step, and afford the desired products in good yield with
good to excellent levels of diastereoselectivity. Further studies are
underway to apply these transformations to the synthesis of
biologically active natural products and to develop catalytic
asymmetric versions of these processes.
NMR (400 MHz, CDCl3)
d 5.81–5.69 (m, 1H), 5.18–5.14, (m, 1H),
5.14–5.08 (m, 1H), 4.33 (s, 1H), 3.84 (d, J¼5.6 Hz, 2H), 3.23 (q,
J¼7.2 Hz, 2H), 2.83 (s, 3H),1.09 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3)
d 158.1, 133.7, 116.1, 50.9, 35.5, 33.8, 15.5; IR (film) 3343,
1629 cmꢂ1. MS (ESI): 143.1178 (143.1184 calcd for C7H14N2O,
MþHþ).
4.2.3. 1-Allyl-3-benzyl-1-methylurea (8)
Reaction of 1.36 g (19.1 mmol) of N-methylallylamine with
2.54 g (19.1 mmol) of benzyl isocyanate following the general
procedure afforded 3.26 g (83%) of the title compound as a white
4. Experimental
4.1. General
solid, mp 60–64 ꢀC. 1H NMR (500 MHz, CDCl3)
d 7.27–7.22 (m, 4H),
7.20–7.17 (m, 1H), 5.76–5.68 (m, 1H), 5.12–5.10 (m, 1H), 5.09–5.08
All reagents were purchased from commercial sources and were
used as obtained unless otherwise noted. Tris(dibenzylideneace-
tone)dipalladium(0) and all phosphine ligands were purchased
(m, 1H), 4.97 (s, 1H), 4.36 (d, J¼5.5 Hz, 2H), 3.83–3.82 (m, 2H), 2.81
(s, 3H); 13C NMR (125 MHz, CDCl3)
d 158.2, 139.8, 133.8,128.5, 127.5,
127.1, 116.4, 51.2, 44.9, 34.1; IR (film) 3336, 1634 cmꢂ1. Anal. Calcd

6844
J.A. Fritz, J.P. Wolfe / Tetrahedron 64 (2008) 6838–6852
for C12H16N2O: C, 70.56; H, 7.90; N, 13.71. Found: C, 70.84; H, 7.96;
N, 13.66.
(400 MHz, CDCl3)
d
6.57 (s, 1H), 5.86–5.74 (m, 1H), 5.25 (d, J¼1.2 Hz,
1H), 5.22 (d, J¼2.0 Hz, 1H), 4.34–4.27 (m, 1H), 2.00–1.87 (m, 1H),
0.99–0.95 (m, 6H). A round-bottom flask was purged with nitrogen
and charged with 2,2,2-trichloro-N-(4-methylpent-1-en-3-yl)acet-
amide (2.97 g, 12.1 mmol), aqueous NaOH (60 mL, 6 M, 360 mmol),
and 60 mL EtOH. The reaction mixture was heated to reflux for 1 h,
then cooled to rt and stirred for 1.5 h. The mixture was then
transferred to a separatory funnel and extracted with ether. The
combined organic extracts were dried over anhydrous Na2SO4 and
decanted into a round-bottom flask. The flask was purged with
nitrogen, cooled to 0 ꢀC, and triethylamine (6.7 mL, 48.4 mmol),
benzoyl chloride (7.0 mL, 60.5 mmol), and 4-dimethylaminopyr-
idine (0.15 g, 1.21 mmol) were added. The reaction mixture was
stirred at rt for 27 h, then was quenched with aqueous NaHCO3 and
transferred to a separatory funnel. The layers were separated, and
the aqueous layer was extracted with EtOAc (3ꢃ150 mL). The
combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo. The crude material was purified by flash
chromatography on silica gel to afford 2.16 g (88%) of N-(4-meth-
ylpent-1-en-3-yl)benzamide as a tan solid. 1H NMR (500 MHz,
4.2.4. 1-Allyl-1-methyl-3-phenylurea (9)
Reaction of 0.829 g (11.7 mmol) of N-methylallylamine with
1.94 g (16.3 mmol) of phenyl isocyanate following the general
procedure afforded 1.82 g (82%) of the title compound as a white
solid, mp 73–76 ꢀC. 1H NMR (400 MHz, CDCl3)
d 7.36–7.32 (m, 2H),
7.29–7.23 (m, 2H), 7.00 (t, J¼7.2 Hz, 1H), 6.38 (br s, 1H), 5.91–5.81
(m, 1H), 5.30–5.21 (m, 2H), 3.98–3.94 (m, 2H), 3.00 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 155.7, 139.3, 133.6, 129.1, 123.1, 119.9, 117.2, 51.8,
34.9; IR (film) 3288, 1636 cmꢂ1. Anal. Calcd for C11H14N2O: C, 69.45;
H, 7.42; N, 14.73. Found: C, 69.80; H, 7.59; N, 14.77.
4.2.5. 1-Allyl-1-benzyl-3-(4-methoxyphenyl)urea (10)
Reaction of 8.1 g (55.0 mmol) of N-allylbenzylamine with 8.2 g
(55.0 mmol) of 4-methoxyphenyl isocyanate following the general
procedure afforded 12.82 g (79%) of the title compound as a white
solid, mp 90–93 ꢀC. 1H NMR (500 MHz, CDCl3)
d 7.36–7.27 (m, 5H),
7.19–7.16 (m, 2H), 6.81–6.78 (m, 2H), 6.26 (s, 1H), 5.87–5.80 (m, 1H),
5.30–5.24 (m, 2H), 4.56 (s, 2H), 3.95 (d, J¼5.0 Hz, 2H), 3.75 (s, 3H);
CDCl3)
d
7.81–7.77 (m, 2H), 7.51 (t, J¼7.0 Hz, 1H), 7.45 (t, J¼7.5 Hz,
13C NMR (125 MHz, CDCl3)
d
156.3, 155.9, 137.8, 134.0, 132.3, 128.9,
2H), 6.03 (d, J¼7.5 Hz, 1H), 5.90–5.81 (m, 1H), 5.26–5.17 (m, 2H),
4.62–4.54 (m, 1H), 2.00–1.89 (m, 1H), 0.99 (d, J¼3.5 Hz, 3H), 0.98 (d,
J¼3.5 Hz, 3H). A flame-dried round-bottom flask equipped with
a stirbar was cooled under a stream of nitrogen and charged with
N-(4-methylpent-1-en-3-yl)benzamide (1.68 g, 8.3 mmol) and
cooled to 0 ꢀC. A solution of LiAlH4 (34 mL, 34 mmol, 1.0 M in THF)
was added and the solution was heated to reflux for 20 h. The re-
action mixture was placed in an ice bath and 1 mL water was slowly
added followed by 1 mL 10 M NaOH, 40 mL ether, and an additional
4 mL water. The solution was filtered through Celite and the Celite
was rinsed with ether. The solvent was removed in vacuo to afford
N-benzyl-4-methylpent-1-en-3-ylamine, which was then treated
with 1.24 g (8.3 mmol) of 4-methoxyphenyl isocyanate for 2.5 h
according to the general procedure to afford 2.36 g (84% over two
steps) of the title compound as a clear oil. 1H NMR (500 MHz,
127.7, 127.6, 122.2, 117.4, 114.1, 55.6, 50.6, 49.9; IR (film) 3322,
1634 cmꢂ1. Anal. Calcd for C18H20N2O2: C, 72.95; H, 6.80; N, 9.45.
Found: C, 72.68; H, 6.80; N, 9.45.
4.2.6. 1-Benzyl-1-(but-3-en-2-yl)-3-(4-methoxyphenyl)urea (26)
Reaction of 1.33 g (8.25 mmol) of N-benzylbut-3-en-2-yl-
amine39,40 with 1.20 g (8.25 mmol) of 4-methoxyphenyl isocyanate
according to the general procedure afforded 2.56 g (88%) of the title
compound as a white solid, mp 95–97 ꢀC. 1H NMR (500 MHz, CDCl3)
d
7.41–7.34 (m, 4H), 7.34–7.29 (m, 1H), 7.07 (d, J¼9.0 Hz, 2H), 6.77
(d, J¼9.0 Hz, 2H), 6.18 (s, 1H), 5.99 (ddd, J¼4.5, 11.0, 17.5 Hz, 1H),
5.29–5.22 (m, 2H), 5.05–4.98 (m, 1H), 4.54 (d, J¼17.0 Hz, 1H), 4.37
(d, J¼17.0 Hz, 1H), 3.75 (s, 3H), 1.34 (d, J¼7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3)
d 156.1, 155.6, 139.3, 138.1, 132.1, 129.0, 127.7,
126.7, 121.8, 116.1, 113.9, 55.5, 52.3, 47.3, 16.5; IR (film) 3338,
1638 cmꢂ1. Anal. Calcd for C19H22N2O2: C, 73.52; H, 7.14; N, 9.03.
Found: C, 73.75; H, 7.11; N, 9.13.
CDCl3)
d
7.41–7.35 (m, 4H), 7.35–7.29 (m, 1H), 7.00 (d, J¼9.0 Hz, 2H),
6.74 (d, J¼9.0 Hz, 2H), 6.06 (s, 1H), 5.86 (ddd, J¼8.0, 10.5, 18.5 Hz,
1H), 5.31 (d, J¼17.5 Hz, 1H), 5.24 (d, J¼10.0 Hz, 1H), 4.56 (d,
J¼17.5 Hz, 1H), 4.44 (d, J¼17.0 Hz, 1H), 4.48–4.39 (m, 1H), 3.73 (s,
3H), 2.09–1.98 (m, 1H), 1.02 (d, J¼7.0 Hz, 3H), 0.97 (d, J¼6.5 Hz, 3H);
4.2.7. 1-Benzyl-3-(4-methoxyphenyl)-1-(4-methylpent-
1-en-3-yl)urea (27)
13C NMR (125 MHz, CDCl3)
d 156.0, 155.5, 137.5, 136.3, 132.0, 128.8,
A flame-dried round-bottom flask equipped with a stirbar was
cooled under a stream of nitrogen and charged with NaH (0.062 g,
1.55 mmol, 60% dispersion in mineral oil). The flask was purged
with nitrogen and a solution of (E)-4-methylpent-2-en-1-ol41
(1.55 g, 15.5 mmol) in ether (2 mL) was added dropwise. The re-
action mixture was cooled to ꢂ5 ꢀC and trichloroacetonitrile
(2.24 g, 15.5 mmol) was added dropwise over 20 min. The reaction
mixture was warmed to rt and stirred for 5 h, and then additional
portions of NaH (0.062 g, 1.55 mmol, 60% dispersion in mineral oil),
trichloroacetonitrile (0.5 mL, 5.0 mmol), and ether (5 mL) were
added. The resulting mixture was stirred at rt for additional 6 h, and
then concentrated in vacuo. The residue was diluted with pentane
(15 mL) and methanol (0.04 mL). The resulting mixture was shaken
vigorously for 1 min and then filtered through Celite. The Celite
was rinsed with 15 mL of pentane and the solvent was removed
in vacuo. The crude (E)-4-methylpent-2-enyl 2,2,2-tri-
chloroacetimidate was transferred to a flame-dried round-bottom
flask charged with a stirbar. Xylenes (100 mL) was added, and the
resulting solution was heated to reflux with stirring for 8 h. The
solution was then cooled to rt and filtered through a plug of silica
gel. The plug was eluted with toluene and the resulting solution
was concentrated in vacuo. The crude product was purified via flash
chromatography to afford 3.05 g (80%) of 2,2,2-trichloro-N-(4-
methylpent-1-en-3-yl)acetamide as an orange solid. 1H NMR
127.6, 126.8, 121.8, 118.5, 113.8, 65.1, 55.3, 48.1, 29.9, 20.2, 19.5; IR
(film) 3337,1640 cmꢂ1. Anal. Calcd for C21H26N2O2: C, 74.52; H, 7.74;
N, 8.28. Found: C, 74.28; H, 7.58; N, 8.16.
4.2.8. 1-Benzyl-1-(1-(benzyloxy)but-3-en-2-yl)-3-(4-
methoxyphenyl)urea (28)
(Z)-4-(Benzyloxy)but-2-en-1-ol42 was converted to the title
compound using a procedure analogous to that employed for the
synthesis of 27. This procedure afforded 1.59 g (20% overall yield)
of the title compound as a clear oil. 1H NMR (400 MHz, CDCl3)
d
7.40–7.24 (m, 10H), 7.20 (s, 1H), 6.95 (d, J¼8.8 Hz, 2H), 6.72 (d,
J¼8.8 Hz, 2H), 5.99–5.86 (m, 1H), 5.32–5.20 (m, 2H), 4.82–4.71 (m,
2H), 4.54–4.40 (m, 3H), 3.74 (s, 3H), 3.77–3.71 (m, 1H), 3.66 (dd,
J¼7.2, 10.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 156.8, 155.3, 138.8,
137.4, 134.4,132.6,128.7, 128.5, 128.1, 128.0,127.4, 127.2, 121.2, 118.2,
113.9, 73.6, 71.3, 58.3, 55.5, 48.7; IR (film) 3334, 1657 cmꢂ1. Anal.
Calcd for C26H28N2O3: C, 74.97; H, 6.78; N, 6.73. Found: C, 75.00; H,
6.80; N, 6.75.
4.2.9. 1-Benzyl-3-(4-methoxyphenyl)-1-(2-methylbut-3-
en-2-yl)urea (29)
A flame-dried round-bottom flask was cooled under a stream of
nitrogen and charged with [Ir(COD)Cl]2 (27 mg, 0.04 mmol),
triphenyl phosphite (42 mL, 0.16 mmol), 2-methylbut-3-en-2-yl

J.A. Fritz, J.P. Wolfe / Tetrahedron 64 (2008) 6838–6852
6845
acetate40 (256 mg, 2.0 mmol), benzylamine (643 mg, 6.0 mmol),
and ethanol (4.4 mL). The resulting solution was heated to reflux
under an atmosphere of nitrogen for 5 h. The solution was then
cooled to rt, diluted with 25 mL of ether, transferred to a separatory
funnel, and washed with 6 M HCl (25 mL). The layers were sepa-
rated, and the aqueous layer was taken to pH 10 through addition of
6 M NaOH (10 mL). The aqueous layer was extracted with ether
(2ꢃ25 mL), and the combined organic layers were dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude
product was purified via flash chromatography on silica gel to
afford 177 mg (51%) of N-benzyl-2-methylbut-3-en-2-ylamine as
rinsed with CH2Cl2 (50 mL), and the resulting solution of 2-vinyl-
pyrrolidine was transferred to a round-bottom flask and cooled to
0 ꢀC. The solution was treated with 4-methoxyphenyl isocyanate
(0.49 g, 0.33 mmol) according to the general procedure to afford
445 mg (55%) of the title compound as a yellow oil. 1H NMR
(400 MHz, CDCl3)
d
7.26 (d, J¼9.2 Hz, 2H), 6.81 (d, J¼8.8 Hz, 2H), 6.36
(s, 1H), 5.90 (ddd, J¼6.8, 10.0, 16.8 Hz, 1H), 5.34 (d, J¼16.8 Hz, 1H),
5.27 (d, J¼10.4 Hz,1H), 4.32–4.23 (m,1H), 3.77 (s, 3H), 3.69–3.58 (m,
1H), 3.57–3.47 (m, 1H), 2.24–2.12 (m, 1H), 1.99–1.77 (m, 3H); 13C
NMR (100 MHz, CDCl3) d 155.1,154.5,139.2,132.2,121.2,115.3,113.6,
59.3, 55.2, 46.4, 32.6, 22.8; IR (film) 3318, 1648 cmꢂ1. MS (ESI):
a yellow oil. 1H NMR (400 MHz, CDCl3)
d
7.37–7.27 (m, 4H), 7.27–
247.1447 (247.1447 calcd for C14H18N2O2, MþHþ).
7.19 (m, 1H), 5.84 (dd, J¼10.8, 17.2 Hz, 1H), 5.14–5.06 (m, 2H), 3.64
(s, 1H), 1.24 (s, 6H), 1.04 (s, 1H). Reaction of N-benzyl-2-methylbut-
3-en-2-ylamine (375 mg, 2.14 mmol) with 4-methoxyphenyl iso-
4.2.12. 1-Ethyl-1-(2-methylallyl)-3-phenylurea (32)
Reaction of 0.99 g (10.0 mmol) of ethyl-(2-methylallyl)amine
with 1.19 g (10.0 mmol) of phenyl isocyanate following the general
procedure afforded 2.16 g (99%) of the title compound as a yellow
cyanate (278
afforded 574 mg (83%) of the title compound as a white solid, mp
81–85 ꢀC. 1H NMR (500 MHz, CDCl3)
7.39–7.34 (m, 4H), 7.30–7.24
mL, 2.14 mmol) according to the general procedure
d
oil. 1H NMR (400 MHz, CDCl3)
d 7.33–7.30 (m, 2H), 7.26–7.22 (m,
(m, 1H), 7.16 (d, J¼9.0 Hz, 2H), 6.79 (d, J¼9.0 Hz, 2H), 6.76 (s, 1H),
6.24 (dd, J¼10.5, 18.0 Hz, 1H), 5.27 (d, J¼17.5 Hz, 1H), 5.18 (d,
J¼11.0 Hz, 1H), 4.71 (s, 2H), 3.75 (s, 3H), 1.54 (s, 6H); 13C NMR
2H), 7.00–6.96 (m, 1H), 6.45 (s, 1H), 5.012 (s, 1H), 5.009 (s, 1H), 3.82
(s, 2H), 3.41 (q, J¼7.6 Hz, 2H), 1.77 (s, 3H), 1.18 (t, J¼6.8 Hz, 3H); 13
C
(125 MHz, CDCl3) d 155.6,142.1,139.4,128.9,122.9,119.7,112.3, 53.2,
(100 MHz, CDCl3)
d
157.0, 155.5, 147.1, 140.2, 132.3, 128.8, 127.0,
42.8, 20.0, 13.6; IR (film) 3331, 1626 cmꢂ1. MS (EI): 218.1411
(218.1419 calcd for C13H18N2O).
126.3, 121.5, 114.0, 112.3, 59.8, 55.5, 48.5, 26.5; IR (film) 3403,
1659 cmꢂ1. MS (ESI): 347.1741 (347.1735 calcd for C20H24N2O2,
MþNaþ).
4.2.13. 1-Benzyl-3-(4-methoxyphenyl)-1-(2-methylallyl)urea (33)
Reaction of 1.61 g (10 mmol) of N-benzyl-2-methylprop-2-en-1-
amine45 with 1.49 g (10 mmol) of 4-methoxyphenyl isocyanate for
1 h according to the general procedure afforded 2.56 g (83%) of the
4.2.10. N-(4-Methoxyphenyl)-2-vinylpiperidine-1-carb-
oxamide (30)
A flame-dried round-bottom flask equipped with a stirbar was
cooled under a stream of nitrogen and charged with N-(tert-
butoxycarbonyl)-2-vinylpiperidine43 (2.11 g, 10 mmol) and CH2Cl2
(100 mL). The solution was cooled to 0 ꢀC and trifluoroacetic acid
(15 mL, 202 mmol) was added. The reaction mixture was warmed
to rt and stirred for 1 h, at which point the reaction was judged
complete by TLC analysis. The reaction was quenched with 100 mL
saturated aqueous NaHCO3 and the resulting mixture was trans-
ferred to a separatory funnel. The layers were separated and the
aqueous layer was extracted with CH2Cl2 (3ꢃ150 mL). The com-
bined organic extracts were dried over anhydrous Na2SO4 and
decanted into a round-bottom flask equipped with a stirbar. The
solution was cooled to 0 ꢀC, 4-methoxyphenyl isocyanate (1.3 mL,
1.49 g, 10 mmol) was added, and the reaction was stirred at rt for
1.5 h. The reaction mixture was concentrated in vacuo and the
crude product was purified by flash chromatography on silica gel to
afford 2.04 g (78%) of the title compound as a white solid, mp 101–
title compound as a clear oil. 1H NMR (500 MHz, CDCl3)
d 7.39–7.27
(m, 5H), 7.21 (d, J¼8.5 Hz, 2H), 6.82 (d, J¼9.0 Hz, 2H), 6.37 (s, 1H),
5.02 (s,1H), 5.01 (s,1H), 4.59 (s, 2H), 3.86 (s, 2H), 3.77 (s, 3H),1.75 (s,
3H); 13C NMR (100 MHz, CDCl3)
d
156.3, 155.7, 141.5, 137.7, 132.2,
128.7, 127.6, 127.5, 121.8, 114.0, 112.3, 55.5, 53.0, 50.6, 19.8; IR (film)
3332, 1640 cmꢂ1
C
. MS (ESI): 333.1573 (333.1579 calcd for
19H22N2O2, MþNaþ).
4.2.14. (E)-1-(But-2-enyl)-1,3-diphenylurea (43)
Reaction of 0.973 g (6.61 mmol) of (E)-N-(but-2-enyl)aniline46
(4:1 mixture of E/Z isomers) with 0.867 g, (7.27 mmol) of phenyl
isocyanate according to the general procedure afforded 1.70 g (97%)
of the title compound as a white solid, mp 61–65 ꢀC. This material
was obtained as a 4:1 mixture of E/Z isomers as judged by 1H NMR
analysis. Data are reported for the major isomer. 1H NMR (400 MHz,
CDCl3)
d
7.45 (t, J¼7.2 Hz, 3H), 7.36 (t, J¼7.2 Hz, 2H), 7.32–7.17 (m,
4H), 6.96 (t, J¼7.2 Hz, 1H), 6.12 (s, 1H), 5.63–5.48 (m, 2H), 4.25 (d,
103 ꢀC. 1H NMR (400 MHz, CDCl3)
d
7.23 (d, J¼9.2 Hz, 2H), 6.80 (d,
J¼5.6 Hz, 2H), 1.64 (d, J¼6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
J¼8.8 Hz, 2H), 6.43 (br s, 1H), 5.82 (ddd, J¼4.0, 10.8, 17.6 Hz, 1H),
5.26 (d, J¼10.4 Hz, 1H), 5.16 (d, J¼17.2 Hz, 1H), 4.71 (br s, 1H), 3.97
(d, J¼13.6 Hz, 1H), 3.76 (s, 3H), 2.97 (dt, J¼3.2, 12.0 Hz, 1H), 1.84–
1.71 (m, 2H), 1.70–1.59 (m, 2H), 1.57–1.42 (m, 2H); 13C NMR
d 154.1, 141.6, 139.0, 130.3, 129.0, 128.9, 128.8, 128.2, 126.9, 122.9,
119.3, 51.7,17.9; IR (film) 3323,1675 cmꢂ1. Anal. Calcd for C17H18N2O:
C, 76.66; H, 6.81; N, 10.52. Found: C, 76.58; H, 6.94; N, 10.52.
(100 MHz, CDCl3)
d
155.9, 155.5, 136.5, 132.3, 122.1, 116.2, 113.9,
4.2.15. (E)-1-Benzyl-1-cinnamyl-3-(4-methoxyphenyl)urea (44)
Reaction of 1.21 g (5.4 mmol) of (E)-N-benzylcinnamylamine47
with 0.81 g (5.4 mmol) of 4-methoxyphenyl isocyanate for 36 h
according to the general procedure afforded 1.41 g (70%) of the title
compound as a white solid, mp 127–130 ꢀC. 1H NMR (500 MHz,
55.4, 53.1, 39.8, 29.2, 25.2, 19.2; IR (film) 3316, 1630 cmꢂ1. MS (ESI):
283.1418 (283.1422 calcd for C15H20N2O2, MþNaþ).
4.2.11. N-(4-Methoxyphenyl)-2-vinylpyrrolidine-1-carb-
oxamide (31)
CDCl3)
d
7.44–7.23 (m, 10H), 7.17 (d, J¼9.0 Hz, 2H), 6.79 (d, J¼9.0 Hz,
A flame-dried round-bottom flask equipped with a stirbar was
cooled under a stream of nitrogen and charged with N-(tert-butoxy-
carbonyl)-2-vinylpyrrolidine44 (0.647 g, 3.3 mmol) and CH2Cl2
(33 mL). The solution was cooled to 0 ꢀC and trifluoroacetic acid
(6 mL, 80.8 mmol) was added. The reaction mixture was warmed to
rt and stirred for 4 h, at which point the reaction was judged com-
plete by TLC analysis. The solvent was removed in vacuo, and the
residue was redissolved in CH2Cl2 (20 mL). Solid K2CO3 (10 g) was
added to the solution and the resulting suspension was stirred for
30 min and then filtered through a fritted funnel. The solids were
2H), 6.57 (d, J¼16.0 Hz,1H), 6.35 (s, 1H), 6.21 (dt, J¼5.5, 15.5 Hz, 1H),
4.62 (s, 2H), 4.14 (d, J¼5.0 Hz, 2H), 3.75 (s, 3H); 13C NMR (100 MHz,
CDCl3)
d 156.2, 155.8, 137.6, 136.1, 132.5, 132.0, 128.9, 128.7, 128.0,
127.7, 127.4, 126.4, 125.0, 122.0, 114.1, 55.5, 50.5, 49.5; IR (film) 3328,
1638 cmꢂ1. MS (ESI): 373.1927 (373.1916 calcd for C24H24N2O2,
MþNaþ).
4.2.16. 1-Benzyl-1-(cyclopent-2-enyl)-3-phenyl-urea (45)
N-Benzylcyclopent-2-enylamine was prepared from benzyl-
amine (4.91 g, 45.8 mmol) and cyclopentadiene (6.04 g, 91.6 mmol)

6846
J.A. Fritz, J.P. Wolfe / Tetrahedron 64 (2008) 6838–6852
using Hartwig’s procedure for hydroamination of cyclo-
pentadiene.48 This procedure generated 1.94 g (25%) of N-benzyl-
cyclopent-2-enylamine as a colorless oil. 1H NMR (400 MHz, CDCl3)
(m, 2H), 3.43 (dd, J¼6.4, 9.2 Hz, 1H), 3.25–3.11 (m, 2H), 2.59 (dd,
J¼9.6, 13.6 Hz, 1H), 2.33 (s, 3H), 1.20 (t, J¼7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3)
d 157.4, 140.7, 136.7, 133.4, 129.7, 129.1, 128.8,
d
7.34–7.26 (m, 4H), 7.24–7.20 (m, 1H), 5.87–5.83 (m, 1H), 5.82–5.80
122.2, 117.3, 53.0, 47.9, 38.7, 36.4, 21.2, 13.1; IR (film) 1704 cmꢂ1
.
(m, 1H), 3.90–3.86 (m, 1H), 3.83–3.77 (m, 2H), 2.43–2.40 (m, 1H),
2.28–2.16 (m, 2H), 1.62–1.55 (m, 1H), 1.28 (br s, 1H). Reaction of
1.94 g (11.2 mmol) of N-benzylcyclopent-2-enylamine with 1.33 g
(11.2 mmol) of phenyl isocyanate following the general procedure
afforded 3.0 g (92%) of the title compound as a white solid, mp 95–
Anal. Calcd for C19H22N2O: C, 77.52; H, 7.53; N, 9.52. Found: C,
77.81; H, 7.68; N, 9.50.
4.3.1.1. 3-Ethyl-4-methyl-1-phenyl-1,3-dihydroimidazol-2-one (6).
This material was isolated as a side product in the Pd-catalyzed
coupling of 1-allyl-3-ethyl-1-phenylurea with 4-bromotoluene as
described in Table 1 and was characterized by 1H NMR analysis. 1H
97 ꢀC. 1H NMR (400 MHz, CDCl3)
d 7.39–7.27 (m, 5H), 7.20 (m, 4H),
6.98–6.94 (m, 1H), 6.48 (s, 1H), 6.03–6.00 (m, 1H), 5.75–5.73 (m,
1H), 5.38–5.36 (m, 1H), 4.46 (q, J¼10.8, 16.8 Hz, 2H), 2.49–2.39 (m,
1H), 2.37–2.29 (m, 2H), 1.75–1.68 (m, 1H); 13C NMR (100 MHz,
NMR (400 MHz, CDCl3)
d
7.60 (d, J¼8.0 Hz, 2H), 7.39 (t, J¼7.2 Hz,
2H), 7.19 (t, J¼7.2 Hz, 1H), 6.31 (s, 1H), 3.73 (q, J¼7.6, 14.8 Hz, 2H),
2.12 (d, J¼1.6 Hz, 3H), 1.28 (t, J¼7.2 Hz, 3H).
CDCl3)
d 155.9, 139.3, 138.4, 135.6, 131.6, 129.1, 128.9, 127.7, 126.9,
122.9, 119.7, 62.9, 48.1, 31.6, 28.6; IR (film) 3336, 1651 cmꢂ1. Anal.
Calcd for C19H20N2O: C, 78.05; H, 6.89; N, 9.58. Found: C, 78.25; H,
6.93; N, 9.50.
4.3.2. 3-Ethyl-4-(naphthalen-2-ylmethyl)-1-phenylimidazolidin-2-
one (11)
Reaction of 102 mg (0.5 mmol) of 1-allyl-3-ethyl-1-phenylurea
with 124 mg (0.6 mmol) of 2-bromonaphthalene for 2 h according to
thegeneralprocedure afforded 121 mg(73%) of the title compound as
4.2.17. 1-(Cyclohex-2-enyl)-1,3-diphenylurea (46)
N-(Cyclohex-2-enyl)aniline was prepared from aniline (1.17 mL,
12.82 mmol) and 1,3-cyclohexadiene (4.11 g, 51.3 mmol) using
Hartwig’s procedure for hydroamination of 1,3-cyclohexadiene.49
This procedure generated 2.0 g (90%) of N-(cyclohex-2-enyl)aniline
a lime green solid, mp 132–135 ꢀC. 1H NMR (400 MHz, CDCl3)
d 7.86–
7.77 (m, 3H), 7.66 (s, 1H), 7.52–7.43 (m, 4H), 7.32 (dd, J¼2.0, 10.5 Hz,
1H), 7.30–7.23 (m, 2H), 6.97 (t, J¼7.6 Hz,1H), 4.12–4.03 (m,1H), 3.76–
3.61 (m, 2H), 3.49 (dd, J¼6.0, 9.2 Hz,1H), 3.38 (dd, J¼4.0,13.6 Hz,1H),
3.28–3.18 (m, 1H), 2.78 (dd, J¼9.6,13.2 Hz,1H), 1.23 (t, J¼6.8 Hz, 3H);
as a colorless oil. 1H NMR (400 MHz, CDCl3)
d
7.15 (t, J¼7.2 Hz, 2H),
6.67 (t, J¼4.4 Hz, 1H), 6.61 (d, J¼8.0 Hz, 2H), 5.86–5.81 (m, 1H),
5.75–5.72 (m, 1H), 3.98 (br s, 1H), 3.67 (br s, 1H), 2.10–1.94 (m, 2H),
1.93–1.84 (m, 1H), 1.76–1.54 (m, 3H). Reaction of 1.96 g (11.0 mmol)
of N-(cyclohex-2-enyl)aniline with 1.31 g (11.0 mmol) of phenyl
isocyanate following the general procedure afforded 3.0 g (93%) of
the title compound as a white solid, mp 122–125 ꢀC. 1H NMR
13C NMR (125 MHz, CDCl3)
d 157.4, 140.6, 134.1, 133.7, 132.6, 128.9,
128.8, 128.0, 127.9, 127.7, 127.3, 126.6, 126.1, 122.3, 117.4, 53.0, 48.0,
39.4, 36.5, 13.2; IR (film) 1703 cmꢂ1. Anal. Calcd for C22H22N2O: C,
79.97; H, 6.71; N, 8.48. Found: C, 80.00; H, 6.77; N, 8.32.
(400 MHz, CDCl3)
d
7.47–7.38 (m, 3H), 7.28–7.17 (m, 6H), 6.95 (t,
4.3.3. 4-(4-tert-Butylbenzyl)-3-ethyl-1-methylimidazolidin-
2-one (12)
J¼7.0 Hz, 1H), 5.93 (s, 1H), 5.75–5.68 (m, 2H), 5.35–5.28 (m, 1H),
1.99–1.75 (m, 3H), 1.68–1.52 (m, 2H), 1.46–1.37 (m, 1H); 13C NMR
Reaction of 71 mg (0.5 mmol) of 1-allyl-3-ethyl-1-methylurea
with 128 mg (0.6 mmol) of 1-bromo-4-tert-butylbenzene for 3 h
according to the general procedure afforded 94 mg (69%) of the title
(125 MHz, CDCl3)
d 154.5, 139.2, 138.6, 131.0, 130.2, 130.0, 129.6,
128.9, 128.8, 122.9, 119.4, 52.5, 28.4, 24.6, 21.6; IR (film) 3326,
1672 cmꢂ1. Anal. Calcd for C19H20N2O: C, 78.05; H, 6.89; N, 9.58.
Found: C, 77.73; H, 6.89; N, 9.46.
compound as a pale yellow oil. 1H NMR (400 MHz, CDCl3)
d 7.31 (d,
J¼8.0 Hz, 2H), 7.08 (d, J¼8.0 Hz, 2H), 3.80–3.71 (m,1H), 3.60–3.49 (m,
1H), 3.18–3.03 (m, 3H), 2.91 (dd, J¼7.2, 8.8 Hz, 1H), 2.70 (s, 3H), 2.52
(dd, J¼10.0, 13.6 Hz, 1H), 1.29 (s, 9H), 1.11 (t, J¼7.2 Hz, 3H); 13C NMR
4.3. General procedure for Pd-catalyzed synthesis
of imidazolidin-2-ones
(125 MHz, CDCl3)
d 161.3, 149.8, 133.9, 128.9, 125.7, 53.9, 51.0, 38.3,
36.5, 34.6, 31.5, 31.4, 13.0; IR (film) 1704 cmꢂ1. Anal. Calcd for
C17H26N2O:C,74.41;H, 9.55;N,10.21. Found:C,74.20;H, 9.61;N,10.08.
An oven- or flame-dried Schlenk tube equipped with a stirbar
was cooled under a stream of nitrogen and charged with Pd2(dba)3
(1 mol % complex, 2 mol % Pd), Xantphos (2 mol %), NaOtBu
(1.2 equiv), the N-allylurea substrate (1.0 equiv), and the aryl bro-
mide (1.2 equiv). The tube was purged with nitrogen, and undecane
(0.125 equiv, internal standard) and toluene (4 mL/mmol urea
substrate) were then added. If the acyclic urea and/or the aryl
bromide were oils they were added at the same time as the toluene.
The Schlenk tube was then heated to 110 ꢀC with stirring until the
starting material had been consumed as judged by GC or 1H NMR
analysis of aliquots removed from the reaction mixture. The mix-
ture was then cooled to rt, saturated aqueous NH4Cl (4–6 mL/mmol
substrate) was added, and the mixture was extracted with meth-
ylene chloride or ethyl acetate (3ꢃ7 mL). The combined organic
extracts were dried over Na2SO4, filtered, and concentrated in
vacuo. The crude product was then purified by flash chromatog-
raphy on silica gel.
4.3.4. 3-Ethyl-1-methyl-4-(naphthalen-1-ylmethyl)imidazolidin-2-
one (13)
Reaction of 71 mg (0.5 mmol) of 1-allyl-3-ethyl-1-methylurea
with 124 mg (0.6 mmol) of 1-bromonaphthalene for 4 h according
to the general procedure afforded 91 mg (68%) of the title com-
pound as a yellow oil. 1H NMR (500 MHz, CDCl3)
d
7.98 (d, J¼8.5 Hz,
1H), 7.89–7.85 (m, 1H), 7.77 (d, J¼8.0 Hz, 1H), 7.57–7.48 (m, 2H),
7.43–7.38 (m, 1H), 7.32 (d, J¼6.5 Hz, 1H), 4.02–3.94 (m, 1H), 3.72–
3.59 (m, 2H), 3.24–3.16 (m, 1H), 3.03–2.96 (m, 2H), 2.92 (dd, J¼10.0,
14.0 Hz,1H), 2.72 (s, 3H),1.20 (t, J¼13.5 Hz, 3H); 13C NMR (100 MHz,
CDCl3)
d 161.3, 134.1, 133.1, 132.0, 129.2, 127.8, 127.4, 126.5, 125.9,
125.6, 123.2, 52.9, 51.0, 36.7, 35.9, 31.4, 13.4; IR (film) 1699 cmꢂ1
.
Anal. Calcd for C17H20N2O: C, 76.09; H, 7.51; N, 10.44. Found: C,
75.97; H, 7.54; N, 10.37.
4.3.5. 3-Ethyl-1-methyl-4-(naphthalen-2-ylmethyl)imidazolidin-2-
one (14)
4.3.1. 3-Ethyl-4-(4-methylbenzyl)-1-phenylimidazolidin-2-one (5)
Reaction of 102 mg (0.5 mmol) of 1-allyl-3-ethyl-1-phenylurea
with 103 mg (0.6 mmol) of 4-bromotoluene for 1 h according to the
general procedure afforded 91 mg (62%) of the title compound as
Reaction of 71 mg (0.5 mmol) of 1-allyl-3-ethyl-1-methylurea
with 124 mg (0.6 mmol) of 2-bromonaphthalene for 4 h according
to the general procedure afforded 91 mg (68%) of the title com-
a yellow solid, mp 93–95 ꢀC. 1H NMR (400 MHz, CDCl3)
d
7.47 (d,
pound as a pale yellow oil. 1H NMR (400 MHz, CDCl3)
d 7.84–7.75
J¼7.6 Hz, 2H), 7.27 (t, J¼7.2 Hz, 2H), 7.13 (d, J¼8.0 Hz, 2H), 7.08 (d,
(m, 3H), 7.62 (s, 1H), 7.51–7.41 (m, 2H), 7.28 (dd, J¼1.6, 8.4 Hz, 1H),
J¼7.6 Hz, 2H), 6.98 (t, J¼7.2 Hz, 1H), 3.98–3.88 (m, 1H), 3.73–3.60
3.93–3.84 (m, 1H), 3.64–3.53 (m, 1H), 3.29 (dd, J¼4.4, 13.2 Hz, 1H),

J.A. Fritz, J.P. Wolfe / Tetrahedron 64 (2008) 6838–6852
6847
3.19–3.08 (m, 2H), 2.96 (dd, J¼7.2, 8.8 Hz, 1H), 2.72 (dd, J¼9.6,
13.2 Hz, 1H), 2.71 (s, 3H), 1.15 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz,
according to the general procedure afforded 158 mg (95%) of the
title compound as a yellow oil. 1H NMR (400 MHz, CDCl3)
7.52–
d
CDCl3)
d
161.3, 134.5, 133.6, 132.4, 128.5, 127.8, 127.7, 127.6, 127.3,
7.49 (m, 4H), 7.37 (t, J¼7.6 Hz, 2H), 7.24 (t, J¼4.0 Hz, 2H), 7.10 (t,
126.4,125.9, 53.8, 50.9, 39.1, 36.5, 31.3, 13.0; IR (film) 1699 cmꢂ1. MS
J¼7.6 Hz, 1H), 4.53–4.45 (m, 1H), 3.38 (t, J¼8.8 Hz, 1H), 3.18–3.09
(ESI): 291.1474 (291.1473 calcd for C17H20N2O2, MþNaþ).
(m, 2H), 2.84–2.75 (m, 4H); 13C NMR (100 MHz, CDCl3)
d 158.0,
140.5, 138.6, 129.5, 129.1 (q, J¼32.3 Hz), 129.0, 125.5 (q, J¼3.7 Hz),
124.0 (q, J¼270.3), 123.6, 120.8, 53.8, 48.9, 37.7, 30.9; IR (film)
1706 cmꢂ1. Anal. Calcd for C18H17F3N2O: C, 64.66; H, 5.13; N, 8.38.
Found: C, 64.79; H, 5.13; N, 8.29.
4.3.6. 3-Ethyl-4-(4-methoxybenzyl)-1-methylimidazolidin-2-
one (15)
Reaction of 71 mg (0.5 mmol) of 1-allyl-3-ethyl-1-methylurea
with 112 mg (0.6 mmol) of 4-bromoanisole for 4 h according to the
general procedure afforded 48 mg (39%) of the title compound as
4.3.11. 4-(4-Benzoylbenzyl)-1-methyl-3-phenylimidazolidin-2-
one (20)
Reaction of 95 mg (0.5 mmol) of 1-allyl-1-methyl-3-phenyl-
urea with 157 mg (0.6 mmol) of 4-bromobenzophenone for 5 h
according to the general procedure afforded 152 mg (82%) of the
title compound as a white solid, mp 44–50 ꢀC. 1H NMR (500 MHz,
a yellow oil. 1H NMR (400 MHz, CDCl3)
d
7.07 (d, J¼8.4 Hz, 2H), 6.83
(d, J¼8.8 Hz, 2H), 3.87 (s, 3H), 3.84–3.68 (m, 1H), 3.60–3.43 (m, 1H),
3.16–3.00 (m, 3H), 2.89 (dd, J¼7.2, 8.8 Hz, 1H), 2.70 (s, 3H), 2.50 (dd,
J¼9.6, 13.6 Hz, 1H), 1.10 (t, J¼7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d
158.6, 155.9, 127.5, 126.2, 111.5, 52.7, 51.2, 48.1, 35.3, 33.8, 28.6,
10.3; IR (film) 1699 cmꢂ1. MS (ESI): 271.1408 (271.1422 calcd for
CDCl3)
d
7.78–7.72 (m, 4H), 7.58 (t, J¼7.5 Hz, 1H), 7.55–7.50 (m,
C
14H20N2O2, MþNaþ).
2H), 7.47 (t, J¼8.0 Hz, 2H), 7.37 (t, J¼7.5 Hz, 2H), 7.27–7.22 (m,
2H), 7.10 (t, J¼7.0 Hz, 1H), 4.56–4.49 (m, 1H), 3.41 (t, J¼8.5 Hz,
1H), 3.21–3.14 (m, 2H), 2.82 (dd, J¼9.5, 14.0 Hz, 1H), 2.80 (s, 3H);
4.3.7. 4-(3-Benzyl-1-methyl-2-oxo-imidazolidin-4-ylmethyl)-
benzonitrile (16)
13C NMR (100 MHz, CDCl3)
d 196.3, 158.2, 141.5, 138.8, 137.6,
Reaction of 110 mg (0.54 mmol) of 1-allyl-3-benzyl-1-methyl-
urea with 118 mg (0.65 mmol) of 4-bromobenzonitrile for 8 h
according to the general procedure afforded 131 mg (80%) of the
title compound as a white solid, mp 114–118 ꢀC. 1H NMR (400 MHz,
136.3, 132.6, 130.5, 130.0, 129.3, 129.1, 128.4, 123.7, 120.9, 54.0,
49.2, 38.1, 31.1; IR (film) 1704, 1656 cmꢂ1
Anal. Calcd for
24H22N2O2: C, 77.81; H, 5.99; N, 7.56. Found: C, 77.58; H, 6.11;
N, 7.43.
.
C
CDCl3)
d
7.54 (d, J¼8.4 Hz, 2H), 7.34–7.23 (m, 5H), 7.12 (d, J¼8.0 Hz,
2H), 4.83 (d, J¼15.2 Hz, 1H), 4.07 (d, J¼15.2 Hz, 1H), 3.61–3.54 (m,
4.3.12. 4-[1-Benzyl-3-(4-methoxyphenyl)-2-oxoimidazolidin-1-
ylmethyl]benzoic acid tert-butylester (21)
1H), 3.16–3.06 (m, 2H), 2.90–2.86 (m, 1H), 2.75 (s, 3H), 2.65–2.60
(m, 1H); 13C NMR (125 MHz, CDCl3)
d
161.2,142.6,137.2,132.6,130.1,
Reaction of 148 mg (0.5 mmol) of 1-allyl-1-benzyl-3-(4-
methoxyphenyl)urea with 154 mg (0.6 mmol) of 4-bromo-tert-
butylbenzoate for 8 h according to the general procedure afforded
176 mg (75%) of the title compound as a yellow solid, mp 78–82 ꢀC.
128.9, 128.3, 127.8, 118.8, 111.1, 53.4, 50.6, 46.4, 39.0, 31.4; IR (film)
2226, 1693 cmꢂ1. Anal. Calcd for C19H19N3O: C, 74.73; H, 6.27; N,
13.76. Found: C, 74.69; H, 6.26; N, 13.70.
1H NMR (500 MHz, CDCl3)
d
7.84 (d, J¼8.5 Hz, 2H), 7.43
4.3.8. 1-Methyl-4-(naphthalen-2-ylmethyl)-3-phenylimidazolidin-
2-one (17)
Reaction of 95 mg (0.5 mmol) of 1-allyl-1-methyl-3-phenylurea
with 124 mg (0.6 mmol) of 2-bromonaphthalene for 1 h according
to the general procedure afforded 153 mg (97%) of the title com-
pound as an off-white solid, mp 122–126 ꢀC. 1H NMR (400 MHz,
(d, J¼9.0 Hz, 2H), 7.29–7.24 (m, 3H), 7.12 (d, J¼6.5 Hz, 2H), 7.04
(d, J¼8.0 Hz, 2H), 6.94 (d, J¼8.5 Hz, 2H), 4.39–4.28 (m, 3H), 3.78
(s, 3H), 3.21 (t, J¼9.0 Hz, 1H), 3.01–2.97 (m, 2H), 2.74 (dd, J¼5.0,
14.0 Hz, 1H), 1.57 (s, 9H); 13C NMR (125 MHz, CDCl3)
d 165.6, 158.3,
156.6, 141.2, 137.0, 131.7, 130.8, 129.8, 129.3, 128.7, 128.2, 127.6,
123.7, 114.6, 81.1, 55.6, 54.9, 48.1, 46.2, 38.1, 28.3; IR (film)
1700 cmꢂ1. Anal. Calcd for C29H32N2O4: C, 73.70; H, 6.83; N, 5.93.
Found: C, 73.40; H, 6.90; N, 5.81.
CDCl3) d 7.83–7.76 (m, 3H), 7.61–7.56 (m, 3H), 7.51–7.37 (m, 4H), 7.27
(dd, J¼1.6, 8.4 Hz,1H), 7.11 (t, J¼7.2 Hz,1H), 4.60–4.51 (m,1H), 3.37–
3.26 (m, 2H), 3.26–3.21 (m,1H), 2.83 (dd, J¼10.0,14.0 Hz,1H), 2.79 (s,
3H); 13C NMR (125 MHz, CDCl3)
d
158.5, 139.1, 134.3, 133.6, 132.5,
4.3.13. 1-Benzyl-3-(4-methoxyphenyl)-4-(2-methylbenzyl)-
imidazolidin-2-one (22)
Reaction of 148 mg (0.5 mmol) of 1-allyl-1-benzyl-3-(4-
methoxyphenyl)urea with 103 mg (0.6 mmol) of 2-bromotoluene
for 8 h according to the general procedure afforded 138 mg (71%) of
the title compound as a white solid, mp 83–85 ꢀC. 1H NMR
129.3, 128.6, 128.0, 127.9, 127.6, 127.4, 126.5, 126.0, 123.8, 121.1, 54.5,
49.4, 38.3, 31.3; IR (film) 1704 cmꢂ1. Anal. Calcd for C21H20N2O: C,
79.72; H, 6.37; N, 8.85. Found: C, 79.36; H, 6.38; N, 8.60.
4.3.9. 1-Methyl-3-phenyl-4-(pyridin-3-ylmethyl)imidazolidin-2-
one (18)
(400 MHz, CDCl3)
d 7.42–7.40 (m, 2H), 7.33–7.19 (m, 5H), 7.09–7.03
Reaction of 95 mg (0.5 mmol) of 1-allyl-1-methyl-3-phenylurea
with 95 mg (0.6 mmol) of 3-bromopyridine for 30 min according to
the general procedure afforded 120 mg (90%) of the title compound
as a pale green solid, mp 150–151 ꢀC. 1H NMR (500 MHz, CDCl3)
(m, 3H), 6.93–6.91 (m, 3H), 4.41 (s, 2H), 4.32–4.29 (m, 1H), 3.80 (s,
3H), 3.20 (t, J¼8.8 Hz, 1H), 3.08–3.00 (m, 2H), 2.56 (dd, J¼3.6,
14.0 Hz, 1H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 158.5, 156.6,
137.1, 136.4, 134.9, 131.7, 130.6, 129.7, 128.7, 128.3, 127.5, 126.9, 126.1,
d
8.48 (d, J¼4.0 Hz,1H), 8.41 (s,1H), 7.53–7.48 (m, 2H), 7.43–7.40 (m,
124.1, 114.4, 55.5, 54.6, 48.1, 46.6, 35.5, 19.5; IR (film) 1699 cmꢂ1
.
1H), 7.39–7.34 (m, 2H), 7.24–7.19 (m, 1H), 7.12–7.07 (m, 1H), 4.53–
4.46 (m, 1H), 3.41 (t, J¼9.0 Hz, 1H), 3.14 (dd, J¼5.0, 9.0 Hz, 1H), 3.02
(dd, J¼3.0, 14.0 Hz, 1H), 2.80 (dd, J¼8.5, 14.0 Hz, 1H), 2.75 (s, 3H);
Anal. Calcd for C25H26N2O2: C, 77.69: H, 6.78; N, 7.25. Found: C,
77.80; H, 6.85; N, 7.33.
13C NMR (125 MHz, CDCl3)
d
158.2, 150.4, 148.5, 138.7, 137.1, 132.2,
4.3.14. 1-Benzyl-4-(4-tert-butylbenzyl)-3-(4-methoxyphenyl)-
imidazolidin-2-one (23)
129.3, 124.0, 123.8, 121.0, 53.8, 49.1, 35.3, 31.1; IR (film) 1684 cmꢂ1
.
Anal. Calcd for C16H17N3O: C, 71.89; H, 6.41; N, 15.72. Found: C,
71.97; H, 6.37; N, 15.36.
Reaction of 148 mg (0.5 mmol) of 1-allyl-1-benzyl-3-(4-meth-
oxyphenyl)urea with 128 mg (0.6 mmol) of 1-bromo-4-tert-butyl-
benzene for 30 min according to the general procedure afforded
206 mg (97%) of the title compound as an orange oil. 1H NMR
4.3.10. 1-Methyl-3-phenyl-4-[4-(trifluoromethyl)benzyl]imid-
azolidin-2-one (19)
Reaction of 95 mg (0.5 mmol) of 1-allyl-1-methyl-3-phenylurea
with 135 mg (0.6 mmol) of 4-bromobenzotrifluoride for 1 h
(400 MHz, CDCl3)
d
7.44 (d, J¼9.2 Hz, 2H), 7.35–7.20 (m, 7H), 6.99–
6.92 (m, 4H), 4.48–4.29 (m, 3H), 3.82 (s, 3H), 3.26 (t, J¼8.8 Hz, 1H),
3.08 (dd, J¼5.2, 8.8 Hz, 1H), 3.00 (dd, J¼3.2, 13.6 Hz, 1H), 2.62 (dd,

6848
J.A. Fritz, J.P. Wolfe / Tetrahedron 64 (2008) 6838–6852
J¼9.2, 13.6 Hz, 1H), 1.29 (s, 9H); 13C NMR (100 MHz, CDCl3)
d
158.3,
4.3.18. 3-Benzyl-5-(biphenyl-4-ylmethyl)-1-(4-methoxyphenyl)-
4,4-dimethylimidazolidin-2-one (37)
Reaction of 162 mg (0.5 mmol) of 1-benzyl-3-(4-methoxy-
phenyl)-1-(2-methylbut-3-en-2-yl)urea with 140 mg (0.6 mmol) of
4-bromobiphenyl for 4.5 h according to the general procedure
afforded 79 mg (33%) of the title compound as a clear oil. 1H NMR
156.1,149.4,136.9,133.2,131.6,128.7,128.4,127.9,127.2,125.3,123.3,
114.2, 55.3, 55.1, 47.8, 46.4, 37.5, 34.2, 31.2; IR (film) 1701 cmꢂ1. MS
(ESI): 429.2523 (429.2542 calcd for C28H32N2O2, MþHþ).
4.3.15. (ꢄ)-(4R,5R)-4-[1-Benzyl-3-(4-methoxyphenyl)-5-methyl-2-
oxoimidazolidin-4-ylmethyl]benzonitrile (34)
(400 MHz, CDCl3)
d
7.53 (d, J¼6.8 Hz, 2H), 7.46–7.37 (m, 4H), 7.36–
7.24 (m, 7H), 7.24–7.17 (m, 1H), 7.15 (d, J¼8.0 Hz, 2H), 6.87 (d,
J¼8.8 Hz, 2H), 4.50 (d, J¼15.6 Hz, 1H), 4.28 (d, J¼15.6 Hz, 1H), 4.13
(dd, J¼4.4, 9.2 Hz, 1H), 3.75 (s, 3H), 3.03 (dd, J¼4.4, 14.8 Hz, 1H),
2.80 (dd, J¼9.2, 14.8 Hz, 1H), 1.20 (s, 3H), 0.99 (s, 3H); 13C NMR
Reaction of 155 mg (0.5 mmol) of 1-benzyl-1-(but-3-en-2-yl)-3-
(4-methoxyphenyl)urea with 109 mg (0.6 mmol) of 4-bromo-
benzonitrile for 1 h according to the general procedure afforded
181 mg (88%) of the title compound as a clear oil. This compound
was isolated as a 12:1 mixture of diastereomers as judged by 1H
NMR analysis. The crude reaction mixture contained an 8:1 mixture
of diastereomers. Data are for the major diastereomer. 1H NMR
(100 MHz, CDCl3)
d 158.6, 156.9, 140.6, 139.9, 139.1, 136.9, 131.8,
129.3, 128.7, 128.3, 127.6, 127.2, 127.0, 126.9, 126.8, 125.6, 114.1, 67.0,
59.8, 55.4, 43.1, 34.1, 26.7, 20.1; IR (film) 1698 cmꢂ1. MS (ESI):
477.2533 (477.2542 calcd for C32H32N2O2, MþHþ).
(400 MHz, CDCl3)
d
7.46 (d, J¼8.0 Hz, 2H), 7.42 (d, J¼8.8 Hz, 2H),
7.33–7.28 (m, 3H), 7.24–7.10 (m, 2H), 6.98 (d, J¼8.4 Hz, 2H), 6.94
(d, J¼9.2 Hz, 2H), 4.82 (d, J¼15.2 Hz, 1H), 4.00–3.95 (m, 1H), 3.95 (d,
J¼15.2 Hz, 1H), 3.83 (s, 3H), 3.18 (dt, J¼6.4, 11.2 Hz, 1H), 2.89 (dd,
J¼4.0,14.0 Hz,1H), 2.80 (dd, J¼7.2 Hz,14.0 Hz,1H),1.08 (d, J¼6.4 Hz,
4.3.19. (ꢄ)-(1R,8aR)-1-Benzyl-2-(4-methoxyphenyl)hexahydro-
imidazo[1,5-a]pyridin-3(5H)-one (38)
Reaction of 130 mg (0.5 mmol) of N-(4-methoxyphenyl)-2-
vinylpiperidine-1-carboxamide with 94 mg (0.6 mmol) of bromo-
benzene for 1 h according to the general procedure afforded
137 mg (81%) of the title compound as a brown oil. This compound
was isolated as a 20:1 mixture of diastereomers as judged by 1H
NMR analysis. The crude reaction mixture contained an 11:1 mix-
ture of diastereomers. Data are for the major diastereomer. 1H NMR
3H); 13C NMR (100 MHz, CDCl3)
d 157.0, 156.2, 141.6, 136.7, 132.0,
131.3, 130.1, 128.5, 127.9, 127.3, 123.2, 118.5, 114.3, 110.5, 61.8, 55.3,
51.0, 44.7, 37.2, 18.5; IR (film) 2227, 1697 cmꢂ1. MS (ESI): 412.2013
(412.2025 calcd for C26H25N3O2, MþHþ).
4.3.16. (ꢄ)-(4R,5R)-1-Benzyl-5-isopropyl-3-(4-methoxyphenyl)-4-
(4-methylbenzyl)imidazolidin-2-one (35)
(500 MHz, CDCl3)
d
7.38 (d, J¼9.0 Hz, 2H), 7.32–7.27 (m, 2H), 7.25–
7.21 (m, 1H), 7.13 (d, J¼7.0 Hz, 2H), 6.93 (d, J¼9.0 Hz, 2H), 4.00–3.90
(m, 2H), 3.81 (s, 3H), 3.27–3.19 (m, 1H), 3.07 (dd, J¼4.0, 14.0 Hz, 1H),
2.74–2.61 (m, 2H), 1.78–1.70 (m, 1H), 1.62–1.54 (m, 1H), 1.44–1.16
Reaction of 169 mg (0.5 mmol) of 1-benzyl-3-(4-methoxy-
phenyl)-1-(4-methylpent-1-en-3-yl)urea with 103 mg (0.6 mmol)
of 4-bromotoluene for 1 h according to the general procedure
afforded 171 mg (85%) of the title compound as a yellow oil. This
compound was isolated as a >20:1 mixture of diastereomers as
judged by 1H NMR analysis. The crude reaction mixture contained
a >20:1 mixture of diastereomers. Data are for the major dia-
(m, 4H); 13C NMR (100 MHz, CDCl3)
d 156.8, 156.2, 136.6, 131.7,
129.1, 128.5, 126.6, 123.7, 114.2, 62.2, 57.1, 55.3, 40.8, 37.7, 30.9, 24.6,
23.2; IR (film) 1702 cmꢂ1. MS (ESI): 359.1738 (359.1735 calcd for
C
21H24N2O2, MþNaþ).
stereomer. 1H NMR (500 MHz, CDCl3)
d
7.56 (d, J¼9.0 Hz, 2H), 7.35–
4.3.20. (ꢄ)-(1R,7aR)-2-(4-Methoxyphenyl)-1-(3-(trifluoromethyl)-
benzyl)tetrahydro-1H-pyrrolo[1,2-c]imidazol-3(2H)-one (39)
7.27 (m, 3H), 7.17–7.12 (m, 2H), 7.00 (d, J¼8.0 Hz, 2H), 6.95 (d,
J¼9.0 Hz, 2H), 6.73 (d, J¼8.0 Hz, 2H), 4.99 (d, J¼15.5 Hz, 1H), 3.99
(dt, J¼3.0, 8.5, 1H), 3.88 (d, J¼15.5 Hz, 1H), 3.82 (s, 3H), 3.09 (dd,
J¼2.5, 3.5 Hz, 1H), 2.80 (dd, J¼3.0, 13.5 Hz, 1H), 2.51 (dd, J¼8.5,
13.5 Hz, 1H), 2.29 (s, 3H), 1.90–1.80 (m, 1H), 0.76 (d, J¼7.0 Hz, 3H),
Reaction of 62 mg (0.25 mmol) of N-(4-methoxyphenyl)-2-
vinylpyrrolidine-1-carboxamide with 68 mg (0.3 mmol) of 3-bro-
mobenzotrifluoride for 1 h according to the general procedure
afforded 86 mg (88%) of the title compound as a yellow oil. This
compound was isolated as a >20:1 mixture of diastereomers as
judged by 1H NMR analysis. The crude reaction mixture contained
a 20:1 mixture of diastereomers. Data are for the major di-
0.46 (d, J¼6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 157.0, 155.6,
137.2, 136.0, 132.8, 131.9, 129.5, 129.0, 128.5, 128.0, 127.2, 122.0,
114.3, 58.6, 55.9, 55.4, 44.9, 37.9, 27.7, 21.0, 17.1, 15.0; IR (film)
1695 cmꢂ1. MS (ESI): 451.2374 (451.2361 calcd for C28H32N2O2,
MþNaþ).
astereomer. 1H NMR (400 MHz, CDCl3)
d
7.50 (d, J¼7.6 Hz, 1H), 7.42
(t, J¼7.6 Hz,1H), 7.39–7.31 (m, 4H), 6.92 (d, J¼9.2 Hz, 2H), 4.29 (ddd,
J¼2.4, 4.0, 9.6 Hz, 1H), 3.81 (s, 3H), 3.76–3.66 (m, 1H), 3.50–3.41 (m,
1H), 3.14 (dd, J¼3.6, 13.6 Hz, 1H), 3.14–3.03 (m, 1H), 2.85 (dd, J¼9.2,
14.0 Hz, 1H), 2.02–1.88 (m, 1H), 1.88–1.68 (m, 2H), 1.46–1.29 (m,
4.3.17. (ꢄ)-(4R,5R)-1-Benzyl-5-(benzyloxymethyl)-3-(4-
methoxyphenyl)-4-(4-methylbenzyl)imidazolidin-2-one (36)
Reaction of 208 mg (0.5 mmol) of 1-benzyl-1-(1-(benzyl-
1H); 13C NMR (100 MHz, CDCl3)
d 161.1, 156.3, 137.7, 132.6, 131.0,
oxy)but-3-en-2-yl)-3-(4-methoxyphenyl)urea
with
103 mg
130.8 (q, J¼32.2 Hz), 129.0, 125.8 (q, J¼3.6 Hz), 123.9 (q,
J¼270.3 Hz), 123.6 (q, J¼3.7 Hz), 123.4, 114.4, 60.8, 60.8, 55.4, 45.1,
38.4, 30.8, 24.6; IR (film) 1702 cmꢂ1. MS (ESI): 391.1634 (391.1633
calcd for C21H21F3N2O2, MþHþ).
(0.6 mmol) of 4-bromotoluene for 5 h according to the general
procedure afforded 78 mg (31%) of the title compound as a yellow
oil. This compound was isolated as a 20:1 mixture of diastereomers
as judged by 1H NMR analysis. The crude reaction mixture con-
tained a 20:1 mixture of diastereomers. Data are for the major di-
4.3.21. 1-Ethyl-4-methyl-3-phenyl-4-(3-trifluoromethylbenzyl)-
imidazolidin-2-one (40)
astereomer. 1H NMR (500 MHz, CDCl3)
d
7.47 (d, J¼9.0 Hz, 2H),
7.34–7.24 (m, 6H), 7.17–7.09 (m, 4H), 6.99 (d, J¼8.0 Hz, 2H), 6.93 (d,
J¼9.0 Hz, 2H), 6.77 (d, J¼7.5 Hz, 2H), 4.78 (d, J¼15.0 Hz, 1H), 4.27 (s,
2H), 4.17 (m, 1H), 4.05 (d, J¼15.5 Hz, 1H), 3.81 (s, 3H), 3.37 (dd,
J¼5.0, 9.0 Hz, 1H), 3.27 (dd, J¼5.0, 10.0 Hz, 1H), 3.21 (dd, J¼5.0,
10.0 Hz, 1H), 2.89 (dd, J¼3.0, 13.5 Hz, 1H), 2.57 (dd, J¼8.5, 14.0 Hz,
Reaction of 109 mg (0.5 mmol) of 1-ethyl-1-(2-methylallyl)-3-
phenylurea with 135 mg (0.6 mmol) of 3-bromobenzotrifluoride
according to a slight modification of the general procedure in which
urea was added to the reaction mixture as a 0.25 M solution in tol-
uene afforded 154 mg (81%) of the title compound as a yellow oil. 1H
1H), 2.29 (s, 3H); 13C NMR (125 MHz, CDCl3)
d
157.4, 156.0, 137.7,
NMR (500 MHz, CDCl3)
d
7.50 (d, J¼8.0 Hz, 1H), 7.42–7.38 (m, 3H),
137.4,136.1,132.7,131.9,129.3,129.2,128.4,128.3,128.0,127.6,127.5,
127.2, 123.1, 114.3, 72.9, 69.8, 58.1, 55.4, 55.0, 45.8, 37.3, 21.0;
IR (film) 1698 cmꢂ1. MS (ESI): 529.2458 (529.2467 calcd for
7.35–7.27 (m, 5H), 3.41(d, J¼9.0 Hz,1H), 3.37–3.31 (m,1H), 3.23–3.15
(m, 1H), 3.09 (d, J¼16.0 Hz, 1H), 2.92 (d, J¼9.0 Hz, 1H), 2.76 (d,
J¼13.5 Hz,1H),1.29 (s, 3H),1.07 (t, J¼7.0 Hz, 3H); 13C NMR (100 MHz,
C
33H34N2O3, MþNaþ).
CDCl3)
d
159.1, 137.6, 136.9, 133.7, 130.8 (q, J¼32.2 Hz), 129.4, 129.2,

J.A. Fritz, J.P. Wolfe / Tetrahedron 64 (2008) 6838–6852
6849
129.0, 127.2, 127.0 (q, J¼3.7 Hz), 124.2 (q, J¼271 Hz), 123.9 (q,
J¼3.7 Hz), 60.5, 53.0, 44.4, 38.4, 24.7, 12.8; IR (film) 1701 cmꢂ1. MS
(ESI): 385.1501 (385.1504 calcd for C20H21F3N2O MþNaþ).
136.4, 132.0, 131.4, 129.1, 128.6, 128.4, 127.7, 127.3, 127.2, 124.3,118.4,
114.0, 110.3, 56.2, 55.3, 52.9, 47.6, 45.2 (one carbon signal is absent
due to incidental equivalence); IR (film) 2227, 1698 cmꢂ1. MS (ESI):
474.2181 (474.2182 calcd for C31H27N3O2, MþNaþ).
4.3.22. 1-Ethyl-4-methyl-4-(2-methylbenzyl)-3-phenylimid-
azolidin-2-one (41)
4.3.26. (ꢄ)-(10S,4R)-1-Benzyl-4-[6-methoxynaphthalen-2-
Reaction of 109 mg (0.5 mmol) of 1-ethyl-1-(2-methylallyl)-3-
phenylurea with 103 mg (0.6 mmol) of 2-bromotoluene for 5 h
according to the general procedure afforded 135 mg (88%) of the
yl(phenyl)methyl]-3-(4-methoxyphenyl)imidazolidin-2-one (49)
Reaction of 93 mg (0.25 mmol) of 1-benzyl-1-cinnamyl-3-(4-
methoxyphenyl)urea with 71 mg (0.3 mmol) of 2-bromo-6-
methoxynaphthalene for 14 h according to a modified general
procedure where Pd(OAc)2 was used as the Pd source, Cs2CO3 was
the base, dioxane was the solvent, and 100 ꢀC was the reaction
temperature afforded 97 mg (73%) of the title compound as an off-
white solid, mp 86–92 ꢀC. Analysis of the crude reaction mixture by
1H NMR indicated that the desired product had formed with >20:1
title compound as a clear oil. 1H NMR (500 MHz, CDCl3)
d 7.41 (t,
J¼8.0 Hz, 2H), 7.34–7.28 (m, 3H), 7.19–7.08 (m, 4H), 3.44–3.34 (m,
2H), 3.32–3.22 (m, 1H), 3.05 (d, J¼13.5 Hz, 1H), 2.92 (d, J¼8.5 Hz,
1H), 2.79 (d, J¼14.0 Hz, 1H), 2.25 (s, 3H), 1.33 (s, 3H), 1.13 (t,
J¼7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 159.2,137.0,136.8,134.8,
130.6, 130.6, 129.3, 128.8, 126.8, 126.7, 125.7, 61.4, 53.1, 39.8, 38.5,
24.7, 20.0, 12.6; IR (film) 1698 cmꢂ1. Anal. Calcd for C20H24N2O: C,
77.89; H, 7.84; N, 9.08. Found: C, 77.54; H, 7.91; N, 9.01.
dr. 1H NMR (400 MHz, CDCl3)
d
7.60 (dd, J¼8.8, 16.4 Hz, 2H), 7.40 (d,
J¼8.8 Hz, 3H), 7.26–7.17 (m, 6H), 7.13 (dd, J¼2.4, 8.8 Hz, 1H), 7.09–
7.04 (m, 2H), 7.01–6.95 (m, 2H), 6.94–6.89 (m, 2H), 6.83 (d,
J¼9.2 Hz, 2H), 5.14 (dt, J¼4.0, 9.6 Hz,1H), 4.62 (d, J¼3.6 Hz,1H), 4.20
(q, J¼15.2 Hz, 2H), 3.88 (s, 3H), 3.73 (s, 3H), 3.63 (t, J¼9.2 Hz, 1H),
4.3.23. 1-Benzyl-3-(4-methoxyphenyl)-4-methyl-4-(4-methyl-
benzyl)imidazolidin-2-one (42)
Reaction of 155 mg (0.5 mmol) of 1-benzyl-3-(4-methoxy-
phenyl)-1-(2-methylallyl)urea with 103 mg (0.6 mmol) of 4-bro-
motoluene for 7.5 h according to the general procedure afforded
195 mg (97%) of the title compound as a yellow oil. 1H NMR
3.38 (dd, J¼4.4, 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 157.8,
157.6, 155.8, 139.2, 136.6, 135.8, 133.2, 131.7, 129.4, 129.1, 128.5,
128.4, 128.3, 127.8, 127.7, 127.2, 127.1, 126.9, 126.1, 123.1, 119.0, 114.2,
105.5, 55.8, 55.4, 55.3, 50.5, 47.7, 44.6; IR (film) 1698 cmꢂ1. MS (ESI):
529.2497 (529.2491 calcd for C35H32N2O3, MþHþ).
(500 MHz, CDCl3)
d 7.38–7.33 (m, 2H), 7.32–7.28 (m, 3H), 7.23 (d,
J¼9.0 Hz, 2H), 6.99 (d, J¼7.5 Hz, 2H), 6.95 (d, J¼9.0 Hz, 2H), 6.81 (d,
J¼8.0 Hz, 2H), 4.54 (d, J¼15.0 Hz, 1H), 4.34 (d, J¼15.0 Hz, 1H), 3.84
(s, 3H), 3.32 (d, J¼9.5 Hz, 1H), 2.88 (d, J¼13.0 Hz, 1H), 2.75 (d,
J¼9.0 Hz, 1H), 2.64 (d, J¼13.0 Hz, 1H), 2.28 (s, 3H), 1.19 (s, 3H); 13C
4.3.27. (ꢄ)-(3aS,4R,6aR)-1-Benzyl-3-phenyl-4-(p-tolyl)hexa-
hydrocyclopentaimidazol-2-one (50)
Reaction of 150 mg (0.51 mmol) of 1-benzyl-1-cyclopent-2-
enyl-3-phenylurea with 105 mg (0.62 mmol) of 4-bromotoluene for
8 h according to the general procedure afforded 172 mg (88%) of the
title compound as a white solid, mp 170–174 ꢀC. Analysis of the
crude reaction mixture by 1H NMR indicated that the desired
product had formed with >20:1 dr. 1H NMR (500 MHz, CDCl3)
NMR (125 MHz, CDCl3) d 159.4,158.5,137.3, 136.1, 133.1,131.0, 130.0,
129.1,128.8,128.4,128.2,127.3,114.1, 60.6, 55.3, 52.7, 47.9, 43.7, 24.0,
20.8; IR (film) 1699 cmꢂ1. MS (ESI): 423.2042 (423.2048 calcd for
C
26H28N2O2, MþNaþ).
4.3.24. (ꢄ)-(10S,4R)-4-10-[(4-Benzhydrylideneamino)phenyl]ethyl-
1,3-diphenylimidazolidin-2-one (47)
d
7.34–7.31 (m, 4H), 7.30–7.24 (m, 1H), 7.06 (d, J¼8.5 Hz, 1H), 6.94–
6.91 (m, 5H), 6.75–6.70 (m, 3H), 4.90 (d, J¼15.5 Hz, 1H), 4.78 (t,
J¼7.5 Hz, 1H), 4.15 (d, J¼15.0 Hz, 1H), 4.10–4.07 (m, 1H), 3.21–3.16
Reaction of 133 mg (0.50 mmol) of (E)-1-(but-2-enyl)-1,3-
diphenylurea (4:1 mixture of E/Z isomers) with 202 mg (0.6 mmol)
of benzhydrilidene-(4-bromophenyl)amine50 for 8 h according to
the general procedure afforded 132 mg (51%) of the title compound
as a yellow solid, mp 190–194 ꢀC. Analysis of the crude reaction
mixture by 1H NMR indicated that the desired product had formed
(m, 1H), 2.15–2.06 (m, 5H), 1.94–1.89 (m, 1H), 1.67–1.59 (m, 1H); 13
C
NMR (100 MHz, CDCl3)
d 158.7, 140.0, 137.3, 136.2, 135.2, 129.2,
128.8, 128.63, 128.60, 127.9, 127.7, 122.1, 120.2, 61.1, 58.5, 51.4, 45.9.
29.9, 29.3, 21.0; IR (film) 1699 cmꢂ1. MS (ESI): 405.1957 (405.1943
calculated for C26H26N2O, MþNaþ).
with >20:1 dr. 1H NMR (400 MHz, CDCl3)
d 7.74–7.72 (m, 2H), 7.57–
7.52 (m, 4H), 7.48–7.38 (m, 5H), 7.35 7.31 (m, 2H), 7.29–7.22 (m, 3H),
7.19–7.02 (m, 6H), 6.71 (d, J¼8.4 Hz, 2H), 4.63–4.59 (m, 1H), 3.52–
3.45 (m, 2H), 3.36–3.33 (m, 1H), 1.11 (d, J¼7.2 Hz, 3H); 13C NMR
4.3.28. (ꢄ)-(3aS,5R,7aR)-1,3-Diphenyl-5-(p-tolyl)octahydro-
benzimidazol-2-one (51)
Reaction of 50 mg (0.17 mmol) of 1-(cyclohex-2-enyl)-1,3-
diphenylurea with 35 mg (0.21 mmol) of 4-bromotoluene for 8 h
according to the general procedure using PEt3$HBF4 (4 mol %) in
place of Xantphos afforded 33 mg (50%) of the title compound as
a gray solid, mp 195–198 ꢀC. Analysis of the crude reaction mixture
by 1H NMR indicated that the desired product had formed with
(100 MHz, CDCl3)d168.9,155.5,150.4,140.2,139.7,138.0,136.5,135.7,
131.1, 129.8,129.5,129.3,129.0,128.8,128.5, 128.1, 127.7, 124.7,123.0,
122.5,121.6,118.0, 57.3, 42.8, 37.3,10.5; IR (film) 1707,1597 cmꢂ1. MS
(ESI): 522.2546 (522.2545 calcd for C36H31N3O, MþHþ).
4.3.25. (ꢄ)-(10S,4R)-4-{[1-Benzyl-3-(4-methoxyphenyl)-2-
>20:1 dr. 1H NMR (400 MHz, CDCl3)
d 7.64–7.62 (m, 2H), 7.44–7.40
(m, 2H), 7.33–7.21 (m, 5H), 7.08–7.00 (m, 5H), 4.46–4.40 (m, 1H),
4.32–4.29 (m, 1H), 2.55–2.49 (m, 1H), 2.36–2.29 (m, 1H), 2.28–2.23
(m, 1H), 2.26 (s, 3H), 1.82–1.59 (m, 4H); 13C (125 MHz, CDCl3)
oxoimidazolidin-4-yl](phenyl)methyl}benzonitrile (48)
Reaction of 186 mg (0.5 mmol) of 1-benzyl-1-cinnamyl-3-(4-
methoxyphenyl)urea with 109 mg (0.6 mmol) of 4-bromobenzo-
nitrile for 26 h according to a modified general procedure where
Pd(OAc)2 was used as the Pd source, Cs2CO3 was used as the base,
dioxane was used as solvent, and a reaction temperature of 100 ꢀC
afforded 179 mg (76%) of the title compound as a yellow oil. Anal-
ysis of the crude reaction mixture by 1H NMR indicated that the
desired product had formed with >20:1 dr. 1H NMR (400 MHz,
d
157.3, 142.6, 139.1, 138.1, 136.2, 129.4, 129.2, 126.7, 126.0, 125.3,
123.4, 119.9, 55.4, 53.6, 40.0, 35.6, 28.0, 25.4, 21.2 (one carbon signal
is absent due to incidental equivalence); IR (film) 1702 cmꢂ1. MS
(ESI): 405.1960 (405.1943 calcd for C26H26N2O, MþNaþ).
4.3.29. (E)-1-Benzyl-4-cinnamyl-3-(4-methoxyphenyl)imid-
azolidin-2-one (52)
CDCl3)
d
7.44 (d, J¼8.4 Hz, 2H), 7.30–7.22 (m, 6H), 7.19 (d, J¼8.8 Hz,
2H), 7.15 (d, J¼8.0 Hz, 2H), 7.07–7.01 (m, 2H), 7.00–6.94 (m, 2H),
6.78 (d, J¼9.2 Hz, 2H), 4.99 (p, J¼5.2 Hz, 1H), 4.40 (d, J¼6.0 Hz, 1H),
4.26 (s, 2H), 3.78 (s, 3H), 3.52 (t, J¼9.2 Hz, 1H), 3.20 (dd, J¼4.4,
Reaction of 148 mg (0.5 mmol) of 1-allyl-1-benzyl-3-(4-
methoxyphenyl)urea with 183 mg (1.0 mmol) of
for 3 h according to the general procedure afforded 147 mg (74%) of
the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3)
7.38
b-bromostyrene
9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
157.9, 156.3, 146.3, 138.3,
d

6850
J.A. Fritz, J.P. Wolfe / Tetrahedron 64 (2008) 6838–6852
(d, J¼9.2 Hz, 2H), 7.34–7.19 (m, 10H), 6.93 (d, J¼8.8 Hz, 2H), 6.33 (d,
J¼15.6 Hz, 1H), 6.01 (dt, J¼7.2, 15.6 Hz, 1H), 4.47 (d, J¼14.8 Hz, 1H),
4.41 (d, J¼14.8 Hz, 1H), 4.33–4.24 (m, 1H), 3.81 (s, 3H), 3.42 (t,
J¼9.2 Hz, 1H), 3.13, (dd, J¼5.6, 9.2 Hz, 1H), 2.55–2.38 (m, 2H); 13C
(77 mg, 0.2 mmol) and CH3CN (2 mL). The resulting solution was
cooled to 0 ꢀC, and a solution of ceric ammonium nitrate (329 mg,
0.6 mmol) in water (3 mL) was slowly added over 3 min. The re-
action mixture was warmed to rt and stirred for 2 h. The reaction
mixture was then transferred to a separatory funnel and extracted
with EtOAc (3ꢃ5 mL). The combined organic layers were washed
with saturated aqueous Na2SO3 (15 mL), saturated aqueous NaHCO3
(15 mL), and brine (15 mL). The organic layer was then dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude
product was purified via flash chromatography on silica gel to afford
41 mg (73%) of the title compound as a yellow solid, mp 91–96 ꢀC.1H
NMR (100 MHz, CDCl3)
d 158.3, 156.4, 136.9, 136.7, 133.7, 131.4,
128.5, 128.4, 128.0, 127.4, 127.3, 126.0, 123.9, 123.3, 114.2, 55.4, 53.6,
48.0, 46.4, 35.7; IR (film) 1698 cmꢂ1. MS (ESI): 399.2075 (399.2073
calcd for C26H26N2O2, MþHþ).
4.3.30. (E)-1-Benzyl-4-cinnamyl-3-(4-methoxyphenyl)-4-
methylimidazolidin-2-one (53)
Reaction of 155 mg (0.5 mmol) of 1-benzyl-3-(4-methoxy-
NMR (400 MHz, CDCl3) d 7.38–7.31 (m, 2H), 7.31–7.24 (m, 3H), 7.17–
phenyl)-1-(2-methylallyl)urea with 183 mg (1.0 mmol) of
b
-bro-
7.09 (m, 3H), 7.08–7.02 (m, 1H), 4.62 (s, 1H), 4.38 (s, 2H), 3.92–3.80
mostyrene for 1.5 h according to the general procedure afforded
(m, 1H), 3.38 (t, J¼8.4 Hz, 1H), 3.03 (dd, J¼6.0, 8.8 Hz, 1H), 2.79 (d,
177 mg (86%) of the title compound as a yellow oil. 1H NMR
J¼7.2 Hz, 2H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 161.4, 137.0,
(400 MHz, CDCl3)
d
7.34–7.18 (m, 12H), 6.93 (d, J¼9.2 Hz, 2H), 6.32
136.2, 135.2, 130.6, 129.6, 128.6, 128.0, 127.4, 126.9, 126.2, 49.9, 49.7,
47.4, 39.0, 19.5; IR (film) 3242, 1697 cmꢂ1. MS (ESI): 303.1461
(303.1473 calcd for C18H20N2O, MþNaþ).
(d, J¼16 Hz, 1H), 6.16–6.05 (m, 1H), 4.55 (d, J¼15.2 Hz, 1H), 4.34 (d,
J¼15.2 Hz, 1H), 3.83 (s, 3H), 3.31 (d, J¼8.8 Hz, 1H), 2.99 (d, J¼8.8 Hz,
1H), 2.51 (ddd, J¼1.2, 6.8, 14.4 Hz, 1H), 2.25 (ddd, J¼0.8, 7.6, 14.0 Hz,
1H), 1.29 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 159.4, 158.5, 137.1,
4.4.2. 1-(4-Methoxyphenyl)-5-(2-methylbenzyl)imidazolidin-2-
one (25)
136.8, 134.0, 130.8, 128.9, 128.4, 128.4, 128.0, 127.4, 127.2, 126.0,
123.9, 114.1, 59.7, 55.3, 53.2, 47.9, 42.3, 25.6; IR (film) 1698 cmꢂ1. MS
(ESI): 435.2047 (435.2048 calcd for C27H28N2O2, MþNaþ).
A three-necked round bottom flask was flame-dried then was
cooled under a stream of argon and equipped with a dry ice/ace-
tone cold finger. The flask was cooled to ꢂ78 ꢀC and charged with
liquid ammonia (30 mL). Li wire (20 mg, 3 mmol) was added and
the solution turned blue. The solution was stirred at ꢂ78 ꢀC for
5 min and then a solution of 1-benzyl-3-(4-methoxyphenyl)-4-(2-
methylbenzyl)imidazolidin-2-one (22) (116 mg, 0.3 mmol) in THF
(10 mL) was added. The resulting mixture was stirred at ꢂ78 ꢀC for
4.3.31. (ꢄ)-(E)-(4R,5R)-1-Benzyl-3-(4-methoxyphenyl)-5-methyl-
4-[3-(trimethylsilyl)allyl]imidazolidin-2-one (54)
Reaction of 155 mg (0.5 mmol) of 1-benzyl-1-(but-3-en-2-yl)-3-
(4-methoxyphenyl)urea with 179 mg (1.0 mmol) of 2-bromovinyl-
trimethylsilane for 1 h according to the general procedure using
Nixantphos in place of Xantphos afforded 187 mg (92%) of the title
compound as a clear oil. This compound was isolated as a 10:1
mixture of diastereomers as judged by 1H NMR analysis. The crude
reaction mixture contained a 7:1 mixture of diastereomers. Data
40 min, then a solution of diphenyl ether (320 mL, 6 mmol) in THF
(20 mL) was added and the mixture immediately turned clear. The
solution was warmed to rt and 1 mL of water was added. The
resulting mixture was concentrated in vacuo, and the crude prod-
uct was purified by flash chromatography on silica gel to afford
82 mg (92%) of the title compound as a white solid, mp 126–131 ꢀC.
are for the major diastereomer. 1H NMR (500 MHz, CDCl3)
d 7.38–
7.27 (m, 7H), 6.90 (d, J¼9.0 Hz, 2H), 5.77 (dt, J¼6.5,18.5 Hz,1H), 5.54
(d, J¼18.5 Hz, 1H), 4.83 (d, J¼15.5 Hz, 1H), 4.13 (d, J¼15.0 Hz, 1H),
3.80 (s, 3H), 3.76–3.70 (m, 1H), 3.33–3.25 (m, 1H), 2.44–2.37 (m,
1H), 2.32–2.23 (m, 1H), 1.19 (d, J¼6.5, 3H), ꢂ0.03 (s, 9H); 13C NMR
1H NMR (400 MHz, CDCl3)
d
7.36 (d, J¼9.2 Hz, 2H), 7.19–7.10 (m,
3H), 7.10–7.04 (m, 1H), 6.94 (d, J¼8.8 Hz, 2H), 4.99 (s, 1H), 4.50–4.37
(m, 1H), 3.82 (s, 3H), 3.44 (t, J¼8.4 Hz, 1H), 3.27 (dd, J¼5.6, 8.0 Hz,
1H), 3.09 (dd, J¼3.6, 14.0 Hz, 1H), 2.70 (dd, J¼10.4, 14.0 Hz, 1H),
(125 MHz, CDCl3)
d 157.9, 156.4, 139.9, 137.3, 135.3, 131.6, 128.5,
2.24 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 160.9, 157.0, 136.3, 134.9,
128.0, 127.2, 124.2, 114.1, 61.3, 55.3, 52.4, 45.2, 38.8, 18.6, ꢂ1.5; IR
(film) 1699 cmꢂ1. Anal. Calcd for C24H32N2O2Si: C, 70.55; H, 7.89; N,
6.86. Found: C, 70.66; H, 7.95; N, 6.81.
130.9, 130.5, 129.6, 126.8, 126.0, 125.1, 114.4, 57.6, 55.4, 43.0, 35.6,
19.4; IR (film) 3247, 1704 cmꢂ1. MS (ESI): 319.1412 (319.1422 calcd
for C18H20N2O2, MþNaþ).
4.3.32. (ꢄ)-(E)-(1R,8aR)-1-(But-2-enyl)-2-(4-methoxyphenyl)-
hexahydroimidazo[1,5-a]pyridin-3-(5H)-one (55)
4.5. Assignment of product stereochemistry
Reaction of 130 mg (0.5 mmol) of N-(4-methoxyphenyl)-2-
vinylpiperidine-1-carboxamide with 121 mg (1.0 mmol) of 1-
bromo-1-propene for 40 min according to the general procedure
afforded 130 mg (87%) of the title compound as a brown oil. The
crude reaction mixture contained a 1.5:1 mixture of diastereomers
as judged by 1H NMR analysis. Upon purification, the compound
was obtained as a 1.6:1 mixture of diastereomers. Data are for the
4.5.1. Stereochemistry of 34–36 and 54
The stereochemistry of 34 was assigned by 1H NMR NOE
experiments as shown below.
mixture. 1H NMR (400 MHz, CDCl3)
d 7.32–7.24 (m, 2H), 6.88 (d,
O
Bn
PMP
J¼9.2 Hz, 2H), 5.64–5.42 (m, 1H), 5.36–5.24 (m, 1H), 3.99 (d,
J¼12.0 Hz, 1H), 3.79 (s, 3H), 3.76–3.65 (m, 1H), 3.28–3.16 (m, 1H),
2.74 (dt, J¼3.2, 13.2 Hz, 1H), 2.41–2.14 (m, 2H), 1.94–1.86 (m, 1H),
1.82–1.74 (m, 1H), 1.67–1.52 (m, 4H), 1.50–1.31 (m, 3H); 13C NMR
N
N
H
H3C
CN
H
H
(100 MHz, CDCl3)
d
157.0, 156.1, 131.8, 129.0, 125.0, 123.8, 114.1, 60.7,
34
56.9, 55.4, 40.8, 34.5, 31.0, 24.7, 23.4, 18.0; IR (film) 1699 cmꢂ1. MS
(ESI): 323.1729 (323.1735 calcd for C18H24N2O2, MþNaþ).
The stereochemistry of 35, 36, and 54 was assigned based on
analogy to 34.
4.4. Selective deprotection of 22
4.4.1. 1-Benzyl-4-(2-methylbenzyl)imidazolidin-2-one (24)
4.5.2. Stereochemistry of 38 and 55
A
round-bottom flask was charged with 1-benzyl-3-
The stereochemistry of 38 was assigned by 1H NMR NOE
experiments as shown below.
(4-methoxyphenyl)-4-(2-methylbenzyl)imidazolidin-2-one (22)

J.A. Fritz, J.P. Wolfe / Tetrahedron 64 (2008) 6838–6852
6851
O
Acknowledgements
PMP
N
N
The authors thank the NIH-NIGMS (GM 071650) for generous
financial support of this work. Additional support was provided by
the Camille and Henry Dreyfus Foundation (New Faculty Award,
Camille Dreyfus Teacher Scholar Award), Research Corporation
(Innovation Award), Eli Lilly, Amgen, GlaxoSmithKline, and 3M.
H
H
H
H
38
The stereochemistry of 55 was assigned based on analogy to 38.
References and notes
4.5.3. Stereochemistry of 39
The stereochemistry of 39 was assigned by 1H NMR NOE ex-
periments as shown below.
1. (a) De Lucca, G. V.; Lam, P. Y. S. Drugs Future 1998, 23, 987–994; (b) Salituro, F.
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Wright, L. L. Bioorg. Med. Chem. Lett. 2000, 10, 1159–1162; (d) De Clerq, E. Bio-
chim. Biophys. Acta 2002, 1587, 258–275; (e) Kazmierski, W. M.; Furfine, E.;
Gray-Nunez, Y.; Spaltenstein, A.; Wright, L. Bioorg. Med. Chem. Lett. 2004, 14,
5685–5687.
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3. (a) Reichard, G. A.; Stengone, C.; Paliwal, S.; Mergelsberg, I.; Majmundar, S.;
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A.; Varty, G. B.; Shih, N.-Y. Bioorg. Med. Chem. Lett. 2006, 16, 1065–1069.
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5309–5312.
5. (a) Cardillo, G.; D’Amico, A.; Orena, M.; Sandri, S. J. Org. Chem. 1988, 53, 2354–
2356; (b) Davies, S. G.; Mortlock, A. A. Tetrahedron Lett. 1991, 32, 4791–4794; (c)
Sankhavasi, W.; Yamamoto, M.; Kohmoto, S.; Yamada, K. Bull. Chem. Soc. Jpn.
1991, 64, 1425–1427; (d) Taguchi, T.; Shibuya, A.; Sasaki, H.; Endo, J.-i.; Mor-
ikawa, T.; Shiro, M. Tetrahedron: Asymmetry 1994, 5, 1423–1426; (e) Davies, S.
G.; Evans, G. B.; Mortlock, A. A. Tetrahedron: Asymmetry 1994, 5, 585–606; (f)
Kubota, H.; Kubo, A.; Takahashi, M.; Shimizu, R.; Da-te, T.; Okamura, K.; Nu-
nami, K.-i J. Org. Chem. 1995, 60, 6776–6784; (g) Palomo, C.; Oiarbide, M.;
Gonzalez, A.; Garcia, J. M.; Berree, F. Tetrahedron Lett. 1996, 37, 4565–4568; (h)
Guillena, G.; Najera, C. Tetrahedron: Asymmetry 1998, 9, 1125–1129; (i) Wulff,
W. D. Organometallics 1998, 17, 3116–3134; (j) Parisi, M.; Solo, A.; Wulff, W. D.;
Guzei, I. A.; Rheingold, A. L. Organometallics 1998, 17, 3696–3700; (k) Kise, N.;
Ueda, T.; Kumada, K.; Terao, Y.; Ueda, N. J. Org. Chem. 2000, 65, 464–468.
O
PMP
N
N
H
H
H
CF3
39
4.5.4. Stereochemistry of 47–49
The stereochemistry of 47 was assigned by single crystal X-ray
analysis as shown below.
O
Ph
N
Ph
N
H
Me
Ph
H
Ph
N
47
´
6. (a) Guillena, G.; Najera, C. J. Org. Chem. 2000, 65, 7310–7322; (b) Cardillo, G.;
Orena, M.; Penna, M.; Sandri, S.; Tomasini, C. Tetrahedron 1991, 47, 2263–2272.
7. Trost, B. M.; Fandrick, D. R. J. Am. Chem. Soc. 2003, 125, 11836–11837.
8. Sartori, G.; Maggi, R. Science of Synthesis (Houben-Weyl Methods of Molecular
Transformations); Ley, S. V., Knight, J. G., Eds.; Thieme: Stuttgart, 2005; Vol. 18,
pp 665–758.
9. (a) Qian, F.; McCusker, J. E.; Zhang, Y.; Main, A. D.; Chlebowski, M.; Kokka, M.;
McElwee-White, L. J. Org. Chem. 2002, 67, 4086–4092; (b) Gabriele, B.; Salerno,
G.; Mancuso, R.; Costa, M. J. Org. Chem. 2004, 69, 4741–4750.
The stereochemistry of 48 and 49 was assigned based on anal-
ogy to 47.
10. Lucet, D.; Gall, T. L.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2580–2627.
11. For synthesis of imidazolidin-2-ones via ring expansion reactions of aziridines,
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4.5.5. Stereochemistry of 50
The stereochemistry of 50 was assigned by 1H NMR NOE ex-
periments as shown below.
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Bn
H
N
O
N
H
p-tolyl
Ph
H
50
4.5.6. Stereochemistry of 51
The stereochemistry of 51 was assigned by 1H NMR NOE
experiments as shown below.
Bn
H
N
O
p-tolyl
N
Ph
H
H
51
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Nakhla, J. S.; Wolfe, J. P. Org. Lett. 2006, 8, 2531–2534.
23. dppb¼1,4-bis(diphenylphosphino)butane; dppe¼1,2-bis(diphenylphosphino)-
ethane; dppf¼1,10-bis(diphenylphosphino)ferrocene; Xantphos¼9,9-dimethyl-
4,5-bis(diphenylphosphino)xanthene; Nixantphos¼4,6-bis(diphenyl-
phosphino)phenoxazine.
33. The relative stereochemistry of 47 was assigned via X-ray crystallographic
analysis. Crystallographic data (excluding structure factors) for the structures
in this paper have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC 604846. Copies of the data
can be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK, (fax: þ44 (0)1223 336033) or e-mail: deposit@ccdc.
cam.ac.uk).
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identified products.
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