A Cross-Metathesis/Aza-Michael Reaction Strategy for the Synthesis of Cyclic and Bicyclic Ureas

Article abstract of DOI:10.1021/acs.joc.8b01492

The synthesis of cyclic and bicyclic ureas via a ruthenium-catalyzed cross-metathesis/aza-Michael reaction strategy between protected alkenyl ureas and Michael acceptors is described. The substrates for these reactions are generated in 1-3 steps from comm

Full text of DOI:10.1021/acs.joc.8b01492

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pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
A Cross-Metathesis/Aza-Michael Reaction Strategy for the Synthesis
of Cyclic and Bicyclic Ureas
Elsa M. Hinds and John P. Wolfe*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109-1055, United States
S
* Supporting Information
ABSTRACT: The synthesis of cyclic and bicyclic ureas via a
ruthenium-catalyzed cross-metathesis / aza-Michael reaction strategy
between protected alkenyl ureas and Michael acceptors is described.
The substrates for these reactions are generated in 1−3 steps from
commercially available materials, and products are formed in moderate
yield with up to >20:1 diastereoselectivity.
batzelladine K (4).12 However, the stereochemical outcome
yclic and bicyclic ureas are common subunits that are
Cfound in many biologically active molecules and natural of these reactions is substrate-controlled, and although bicyclic
products, including HIV protease inhibitors,1 5-HT3 receptor
products with a cis-relationship between the angular C4a H
antagonists,2 and NK1 antagonists.3 Chiral imidazolidin-2-ones
atom and the C3 alkyl group are formed in high dr, we have
been unable to access the analogous trans-stereoisomers, which
could serve as precursors to many other biologically active
batzelladine alkaloids,5 in acceptably high yield and selectivity
using the Pd-catalyzed alkene carboamination strategy.13
Herein we describe a new method for the synthesis of
bicyclic and cyclic ureas, via a cross-metathesis/aza Michael
reaction sequence between ureas 5 bearing pendant alkenes
and α,β-unsaturated carbonyl compounds 6, which provides
access to bicyclic urea stereoisomers 7 that cannot be prepared
via the Pd-catalyzed alkene carboamination strategy (eq 1).
The reaction generates the ring, a C−N bond, and a C−C
bond and provides urea products bearing functional groups
that can be further elaborated using standard chemistry.
have also been widely utilized as chiral auxiliaries in organic
synthesis.4 In addition, cyclic or bicyclic ureas have been
utilized as intermediates in the synthesis of cyclic guanidines,5
which are also found in a number of biologically active
compounds and natural products,6 including the Batzelladine
family of alkaloids. Given the significance of cyclic ureas, many
synthetic strategies have been developed to generate these
molecules.7 However, very few of these strategies effect both
formation of the ring and a carbon−carbon bond in a single
one-flask operation.8
Our group has previously described a method for the
synthesis of cyclic and bicyclic ureas via Pd-catalyzed alkene
carboamination reactions9 between N-allylureas and aryl/
alkenyl halides that effects the formation of both the ring
and a C−C bond and generates products with a high level of
diastereoselectivity in most cases (Scheme 1).10−12 The utility
of this method has been demonstrated through its use in the
synthesis of (+)-Merobatzelladine B (3)11 and 9-epi-
Scheme 1. Prior Synthesis of Bicyclic Ureas via Pd-
Catalyzed Alkene Carboamination Reactions
The use of an alkene cross-metathesis/aza-Michael reaction
cascade for the construction of heterocycles was first reported
by Fustero; unsaturated cbz-protected amines were coupled
Received: June 13, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b01492
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The Journal of Organic Chemistry
Note
with α,β-unsaturated ketones to afford N-cbz-pyrrolidine
products in good to excellent yield and moderate stereo-
control.14 Subsequent studies illustrated this approach could
also provide access to cyclic amides15a and that a range of α,β-
unsaturated carbonyl derivatives were viable substrates.15 We
reasoned this strategy could also be applicable to the
construction of cyclic ureas and that this also may provide
access to stereoisomers that were not accessible with the Pd-
catalyzed carboamination method. The major stereoisomer in
the Pd-chemistry derives from syn-aminopalladation of the
alkene through a boat-like transition state (1 → 9 → 2),
whereas it seemed the 1,4-addition of the intermediate
metathesis product 10 would likely proceed through chairlike
transition state 11 to give 7 (Scheme 2).
temperature to 70 °C, and increasing the amount of 6a to 5
equiv, afforded 7a in 70% yield with excellent (>20:1)
diastereoselectivity (entry 2). The CuI cocatalyst was essential,
as efforts to carry out the transformation in the absence of CuI
led to the formation of a 1:1 mixture of 7a:10a in low yield,
along with several unidentified side products (entry 5). This
suggests that the CuI may be acting as a weak Lewis acid in the
Michael addition step, although it was originally included to
facilitate the alkene metathesis.17 An attempt to decrease the
catalyst loading to 5 mol % 8 and 5 mol % CuI also led to a
mixture of 7a and 10a (entry 4). Interestingly, use of the
Grubbs II catalyst in place of 8 produced only 10a (entry 3).
We then explored the scope of this transformation by
varying the substituent on the cyclizing nitrogen atom, along
with the electron-deficient alkene coupling partner (Table 2).
Scheme 2. Bicyclic Urea Stereochemistry
Table 2. Synthesis of Bicyclic Ureas
In order to explore the feasibility of this transformation, we
examined the reaction of urea 5a with methyl vinyl ketone
(MVK) using the Hoveyda−Grubbs II complex 8 as the
catalyst (Table 1), because this catalyst system had provided
good results in the previously reported metathesis/Michael
cascades. An initial run with 1.5 equiv 6a, 10 mol % of catalyst
8, and 10 mol % of CuI at 50 °C afforded the desired product
7a in 47% yield and 5:1 dr (entry 1).16 Increasing the
yield %
c
a
b
entry
R (5)
EWG (6)
conditions
(7) (dr)
1
2
3
4
5
6
7
8
C6H4-p-Cl (5a)
PMP (5b)
PMB (5c)
C6H4-p-NO2 (5d) C(O)Me
C6H4-p-Cl (5a)
PMP(5b)
C(O)Me (6a)
C(O)Me
C(O)Me
A
A
A
B
B
B
B
B
70 (7a) (>20:1)
65 (7b) (>20:1)
60 (7c) (8:1)
40 (7d) (4:1)
38 (7e) (3:1)
24 (7f) (5:1)
43 (7g) (8:1)
29 (7h) (1:1)
CO2Me (6b)
CO2Me
CO2Me
PMB (5c)
C6H4-p-NO2 (5d) CO2Me
a
Table 1. Optimization Studies
a
Conditions A: 1.0 equiv of 5, 5 equiv of 6, 10 mol % CuI, 10 mol % 8
b
DCE, 70 °C, 16 h. Isolated yield (average of two or more
experiments). Conditions B: (1) 1.0 equiv of 5, 5 equiv of 6, 10 mol
% CuI, 10 mol % 8 DCE, 70 °C, 16 h; (2) KOtBu (1.5 equiv), DCE,
70 °C, 16 h. Diastereomeric ratios were determined by H NMR
analysis.
c
1
The one-pot cascade metathesis/Michael reactions proceeded
smoothly for the coupling of 5a−c with MVK to provide 7a−c
in good yield with high diastereoselectivity (entries 1−3).
However, our initially optimized conditions (Table 2,
conditions A) did not afford the bicyclic urea product in the
reaction between p-nitrophenyl urea 5d and MVK. Instead,
only the cross-metathesis product 10 was generated. However,
a two-step sequence (Table 2, conditions B) in which the
cross-metathesis product was isolated, and then treated with
KOtBu at 70 °C, led to the formation of 7d in 40% yield, with
moderate (4:1) diastereoselectivity (entry 4). Use of other
reagents to effect the Michael addition step, such as BF3·OEt2,
Ti(OiPr)4, LiHMDS, or TBAF, failed to provide improved
results in this system, although BF3·OEt2 was subsequently
found to give higher yields in the formation of monocyclic
products (see below). Efforts to employ conditions A in
reactions of 5a−d with methyl acrylate produced only the
b
c
entry
equiv 6a
mol % 8
mol % CuI
7a:10a
yield % (dr)
d
1
2
3
4
5
1.5
5
1.5
5
10
10
10
10
10
10
5
>20:1
>20:1
<1:20
10:1
47 (5:1)
70 (>20:1)
e
e
0
5
5
47 (>20:1)
f
5
0
1:1
20
a
Conditions: 1.0 equiv of 5a, 1.5 or 5 equiv of 6a, 0−10 mol % CuI,
b
5−10 mol % 8 DCE, 70 °C, 16 h. Isolated yield (average of two or
c
1
more experiments). Diastereomeric ratios were determined by H
d
e
NMR analysis. The reaction was conducted at 50 °C. The reaction
was conducted with the Grubbs II catalyst in place of 8. Only the
metathesis product 10a was observed. Several unidentified side
f
products were also formed. The yield in this case was determined by
1H NMR analysis using phenanthrene as an internal standard.
B
DOI: 10.1021/acs.joc.8b01492
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The Journal of Organic Chemistry
Note
cross-metathesis product, but the two-step sequence afforded
the desired products 7e−h in low to moderate yield.
Diasteroselectivities in this latter set of reactions were highly
dependent on the electronic properties of the N-substituent.
Substrates 5a−b bearing a PMP or p-chlorophenyl group on
the cyclizing nitrogen atom provided 7a−b with >20:1 dr, and
the electron-rich PMB-protected substrate 5c was converted to
7g with 8:1 dr. But, in contrast, the p-nitrophenyl derivative 5d
provided 7h with no selectivity (1:1 dr). In this latter case the
lack of selectivity might be due to thermodynamically
controlled, rather than kinetically controlled, selectivity in the
Michael addition step. The origin of the low yield for the
formation of 7h is not entirely clear, as significant amounts of
side products were not detected, but the reaction was
reproducibly low-yielding. Although the cascade cross-meta-
thesis/Michael reactions were effective with MVK and methyl
acrylate, attempts to use other electron-deficient alkenes failed
to afford the desired product in useful yields. Reactions
involving acrylonitrile returned only 5 along with the
metathesis dimer of acrylonitrile, whereas use of crotonalde-
hyde or acrolein provided small amounts of products (ca. 10−
30%) along with complex mixtures of side products, and use of
N-methoxy-N-methylacrylamide gave a complex mixture of
products along with some unreacted starting material.
lectivity was poor (2:1 dr; entries 4−5). Efforts to employ a
substrate related to 12b that contained a methyl group at the
internal alkene carbon failed to afford the desired product.
Instead, only unreacted starting material was observed, which
is consistent with the fact that more highly substituted alkenes
are much less reactive toward alkene metathesis.18
As observed with substrates 5a−d, efforts to use the
standard protocol (conditions A) for reactions of acyclic
ureas 12a−b with methyl acrylate failed to produce acceptable
yields of the desired product, and mixtures of cyclic urea and
acyclic metathesis products were obtained. Moreover, the two-
step procedure used with 5a−d, in which the metathesis
product was treated with KOtBu to effect the Michael addition
(conditions B), was also unsuccessful with 12a−c. However,
we were pleased to find that a modified version of the original
Fustero procedure,15a in which the metathesis was conducted
in one step with the presence of added BF3·OEt2 (conditions
C), provided cyclic ureas 13f−g in moderate yield. In contrast,
electron-poor urea 12c was converted to 13h in one step under
the standard conditions A.
In conclusion, we have developed a new cross-metathesis/
aza-Michael reaction strategy that effects the transformation of
ureas derived from 2-allylpyrrolidine or N-allylbenzylamine
into bicyclic and monocyclic ureas, respectively, with
formation of the ring, a C−N bond, a C−C bond, and
introduction of ketone or ester functionality adjacent to the
ring. Products in reactions that employ MVK are formed in
moderate yield, with moderate to excellent levels of
diastereoselectivity, and similar transformations of methyl
acrylate provide products in low to moderate yield, with
modest diastereoselectivity. The observed high diastereoselec-
tivities likely arise via a kinetically controlled Michael addition
reaction that proceeds through a chairlike transition state,
whereas lower selectivities may result from thermodynamic
control in a reversible Michael addition step.
With reaction conditions in hand for the synthesis of bicyclic
urea products, we sought to expand the scope of this
transformation to the synthesis of monocyclic urea products
from acyclic N-allylurea substrates 12a−e (Table 3). Reactions
Table 3. Synthesis of Monocyclic Ureas
EXPERIMENTAL SECTION
■
General. All reactions were carried out under a nitrogen
atmosphere in flame- or oven-dried glassware. All reagents were
obtained from commercial sources and were used as obtained unless
otherwise noted. The Hoveyda-Grubbs II catalyst and N-Boc-
pyrrolidine were purchased from Sigma-Aldrich Chemical Co. and
used without further purification. 1,2-Dichloroethane (DCE) was
purchased from Acros chemicals and was purified via freeze−pump−
thaw prior to use. tert-Butyl 2-allylpyrrolidine-1-carboxylate,19 N-
benzylprop-2-en-1-amine,10b and N-benzylbut-3-en-2-amine10b were
prepared according to published procedures. Dichloromethane,
toluene, and tetrahydrofuran were purified using a GlassContour
solvent purification system. Boron trifluoride diethyl etherate,
tetramethylethylenediamine, methyl vinyl ketone, and methyl acrylate
were purified by distillation prior to use. Structural and stereochemical
assignments were based on 2-D COSY and NOESY experiments.
Ratios of diastereomers were determined by 1H NMR analysis. Yields
refer to isolated yields of compounds estimated to be ≥95% pure as
a
b
c
entry
R
R1
R2
conditions
yield % (dr)
1
2
3
4
5
6
7
8
C6H4-p-Cl (12a)
PMP (12b)
C6H4-p-NO2 (12c)
PMP (12d)
C6H4-p-NO2 (12e) Me
C6H4-p-Cl (12a)
PMP (12b)
H
H
H
Me
Me
Me
Me
Me
A
A
A
A
A
C
C
A
66 (13a)
57 (13b)
61 (13c)
52 (13d) (2:1)
47 (13e) (2:1)
44 (13f)
Me
H
H
H
OMe
OMe
OMe
41 (13g)
71 (13h)
C6H4-p-NO2 (12c)
a
Conditions A: 1.0 equiv of 5, 5 equiv of 6, 10 mol % CuI, 10 mol % 8
b
DCE, 70 °C, 16 h. Isolated yield (average of two or more
experiments). Conditions C: (1) 1.0 equiv of 5, 5 equiv of 6, 1 equiv
of BF3·OEt2, 10 mol % CuI, 10 mol % 8 DCE, 70 °C, 16 h.
c
1
1
determined by H NMR analysis unless otherwise noted. The yields
Diastereomeric ratios were determined by H NMR analysis.
reported in the experimental section describe the result of a single
experiment, whereas yields reported in Tables 2−3 are averages of two or
more experiments. Thus, the yields reported in the Experimental Section
may differ from those shown in Tables 2−3.
Experimental Procedures and Compound Characterization
Data for Substrates. General Procedure 1. Synthesis of
Pyrrolidinyl Ureas. A flame-dried flask equipped with a stir bar was
cooled under a stream of nitrogen and charged with tert-butyl 2-
allylpyrrolidine-1-carboxylate18 (1 equiv) and dichloromethane (0.2
M). The mixture was cooled to 0 °C, and trifluoroacetic acid (1.0 M)
was added dropwise. The reaction mixture was warmed to rt, stirred
between unsubstituted substrates 12a−c and MVK provided
the desired cyclic urea products 13a−c in moderate yield
(entries 1−3). In contrast to the reactions between 5d and
MVK, the reaction of nitrophenyl urea substrate 12c afforded
the cyclic urea product 13c in one step, without the need for a
subsequent base-mediated transformation. Substrates 12d−e,
which contain a methyl group in the allylic position, were also
converted to cyclic ureas in moderate yield, but diastereose-
C
DOI: 10.1021/acs.joc.8b01492
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The Journal of Organic Chemistry
Note
overnight, and then was basified to pH > 12 with ammonium
hydroxide. The layers were separated, and the aqueous layer was
extracted with dichloromethane. The combined organic layers were
dried over Na2SO4, filtered, and concentrated in vacuo to afford 2-
allylpyrrolidine as a volatile oil that was used without purification.
The crude 2-allylpyrrolidine was dissolved in dichloromethane (0.2
M), and the appropriate isocyanate (1.1 equiv) was added. The
resulting mixture was stirred at rt overnight and then was
concentrated in vacuo. The crude urea product was purified via
flash chromatography on silica gel usig 40% ethyl acetate in hexanes as
the eluent to afford the 2-allylpyrrolidinyl urea, which was stored as a
0.2 M solution in 1,2-dichloroethane.
2-Allyl-N-(4-chlorophenyl)pyrrolidine-1-carboxamide (5a). The
title compound was prepared from tert-butyl 2-allylpyrrolidine-1-
carboxylate (1.20 g, 6 mmol) and para-chlorophenyl isocyanate (1.01
g, 6.66 mmol) according to General Procedure 1. This procedure
afforded 1.04 g (65%) of the title compound as a yellow solid, mp
69−70 °C. 1H NMR (500 MHz, CDCl3) δ 7.38−7.31 (m, 2H),
7.26−7.18 (m, 2H), 6.28 (s, 1H), 5.86−5.73 (m, 1H), 5.16−5.05 (m,
2H), 4.08−4.00 (m, 1H), 3.48−3.37 (m, 2H), 2.54 (ddt, J = 3.0, 5.8,
13.5 Hz, 1H), 2.17 (dt, J = 8.4, 13.6 Hz, 1H), 2.07−1.95 (m, 1H),
1.98−1.88 (m, 2H), 1.81 (ddt, J = 2.5, 6.2, 8.7 Hz, 1H). 13C NMR
(126 MHz, CDCl3) δ 153.7, 137.8, 135.0, 128.7, 127.6, 120.7, 117.6,
57.3, 46.4, 38.6, 29.6, 23.7. IR (film) 3305.2, 1641.1 cm−1. HRMS
(ESI+ TOF) m/z: [M + H]+ calcd for C14H18ClN2O 265.1108; found
265.1106.
benzylamine (1 equiv), dichloromethane (1.0 M), and the appropriate
isocyanate (1.4 equiv). The resulting mixture was stirred at rt
overnight and then was concentrated in vacuo to yield the crude urea
product, which was purified via flash chromatography on silica gel
using 20% ethyl acetate in hexanes as the eluent.
1-Allyl-1-benzyl-3-(4-chlorophenyl)urea (12a). The title com-
pound was prepared from N-benzylprop-2-en-1-amine10a (0.997 g, 6.6
mmol) and 4-chlorophenyl isocyanate (1.44 g, 9.4 mmol) using
General Procedure 2. This procedure afforded 1.68 g (85%) of the
1
title compound as a peach color solid, mp 84−85 °C. H NMR (500
MHz, CDCl3) δ 7.40−7.33 (m, 2H), 7.37−7.27 (m, 3H), 7.27−7.17
(m, 4H), 6.45 (s, 1H), 5.85 (ddt, J = 5.4, 10.5, 17.3 Hz, 1H), 5.35−
5.26 (m, 2H), 4.58 (s, 2H), 3.97 (dt, J = 1.7, 5.6 Hz, 2H). 13C NMR
(126 MHz, CDCl3) δ 155.5, 137.7, 137.4, 133.7, 128.9, 128.8, 127.9,
127.8, 127.5, 120.9, 117.6, 50.6, 50.0. IR (film) 3325.6, 1636.6, cm−1.
HRMS (ESI+ TOF) m/z: [M + H]+ calcd for C17H18ClN2O
301.1108; found 301.1114.
1-Allyl-1-benzyl-3-(4-methoxyphenyl)urea (12b). The title com-
pound was prepared from N-benzylprop-2-en-1-amine10b (0.996 g, 6.6
mmol) and 4-methoxyphenyl isocyanate (1.1 mL, 9.3 mmol) using
General Procedure 2. This procedure afforded 1.53 g (79%) of the
1
title compound as a white-tan solid, mp 88−90 °C. H NMR (500
MHz, CDCl3) δ 7.40−7.26 (m, 5H), 7.23−7.17 (m, 2H), 6.84−6.78
(m, 2H), 6.37 (s, 1H), 5.85 (ddt, J = 5.4, 10.5, 17.2 Hz, 1H), 5.33−
5.23 (m, 2H), 4.57 (s, 2H), 3.96 (dt, J = 1.7, 5.5 Hz, 2H), 3.76 (s,
3H). 13C NMR (126 MHz, CDCl3) δ 156.1, 155.7, 137.7, 133.8,
132.1, 128.8, 127.6, 127.5, 122.0, 117.4, 114.0, 55.5, 50.5, 49.9. IR
(film) 3326.0, 1634.5 cm−1. HRMS (ESI+ TOF) m/z: [M + H]+ calcd
for C18H21N2O2 297.1603; found 297.1604.
2-Allyl-N-(4-methoxyphenyl)pyrrolidine-1-carboxamide (5b).
The title compound was prepared from tert-butyl 2-allylpyrrolidine-
1-carboxylate (1.28 g, 6.06 mmol) and para-methoxyphenyl
isocyanate (0.86 mL, 6.66 mmol) according to General Procedure 1
1-Allyl-1-benzyl-3-(4-nitrophenyl)urea (12c). The title compound
was prepared from N-benzylprop-2-en-1-amine (1.00 g, 6.6 mmol)
and 4-nitrophenyl isocyanate (1.54 g, 9.4 mmol) using General
Procedure 2. This procedure afforded 1.51 g (74%) of the title
1
to afford 1.28 g (81%) of the title compound as a colorless oil. H
NMR (500 MHz, CDCl3) δ 7.32−7.24 (m, 2H), 6.86−6.78 (m, 2H),
6.17 (s, 1H), 5.86−5.73 (m, 1H), 5.13−5.03 (m, 2H), 4.03 (tt, J =
3.5, 7.4 Hz, 1H), 3.76 (s, 3H), 3.44−3.37 (m, 2H), 2.60−2.51 (m,
1H), 2.22−2.11 (m, 1H), 2.04−1.91 (m, 2H), 1.79 (ddt, J = 2.6, 6.1,
8.5 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 155.6, 154.4, 135.2,
132.2, 121.8, 117.4, 114.0, 57.2, 55.5, 46.3, 38.7, 29.5, 23.8. IR (film)
3291.8, 1635.7 cm−1. HRMS (ESI+ TOF) m/z: [M + H]+ calcd for
C15H21N2O2 261.1603; found 261.1602.
1
compound as a pale yellow solid, mp 106−108 °C. H NMR (500
MHz, CDCl3) δ 8.14−8.09 (m, 2H), 7.48−7.42 (m, 2H), 7.41−7.34
(m, 3H), 7.32 (dt, J = 1.7, 6.1 Hz, 2H), 6.88 (s, 1H), 5.87 (ddt, J =
5.4, 10.6, 17.2 Hz, 1H), 5.38−5.30 (m, 2H), 4.60 (s, 2H), 4.00 (dt, J
= 1.7, 5.6 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 154.7, 145.3,
142.4, 136.9, 133.4, 129.0, 128.0, 127.5, 125.0, 118.4, 118.0, 50.8,
50.2. IR (film) 3341.3, 1657.1 cm−1. HRMS (ESI+ TOF) m/z: [M +
H]+ calcd for C17H18N3O3 312.1348; found 312.1351.
2-Allyl-N-(4-methoxybenzyl)pyrrolidine-1-carboxamide (5c).
The title compound was prepared from tert-butyl 2-allylpyrrolidine-
1-carboxylate (2.01 g, 9.5 mmol) and para-methoxybenzyl isocyanate
(1.5 mL, 10.5 mmol) according to General Procedure 1. This
procedure afforded 0.324 g (49%) of the title compound as a colorless
1-Benzyl-1-(but-3-en-2-yl)-3-(4-methoxyphenyl)urea (12d). The
title compound was prepared from N-benzylbut-3-en-2-amine (0.302
g, 1.86 mmol) and 4-methoxyphenyl isocyanate (0.34 mL, 2.61
mmol) using General Procedure 2. This procedure afforded 0.512 g
(88%) of the title compound as an orange-pink solid, mp 87−89 °C.
1H NMR (500 MHz, CDCl3) δ 7.39−7.37 (m, 5H), 7.10−7.03 (m,
2H), 6.81−6.73 (m, 2H), 6.23 (s, 1H), 5.99 (ddd, J = 4.4, 10.6, 17.5
Hz, 1H), 5.31−5.20 (m, 2H), 5.00 (dtt, J = 2.4, 5.3, 7.3 Hz, 1H), 4.53
(d, J = 17.1 Hz, 1H), 4.37 (d, J = 17.1 Hz, 1H), 3.74 (s, 3H), 1.33 (d,
J = 6.9 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 156.1, 155.7, 139.2,
138.0, 132.1, 129.0, 127.7, 126.9, 121.9, 116.2, 114.0, 55.5, 53.2, 47.4,
16.6. IR (film) 3322.7, 1633.5 cm−1 HRMS (ESI+ TOF) m/z: [M +
H]+ calcd for C19H23N2O2 311.1760; found 311.1764.
1
oil. H NMR (500 MHz, CDCl3) δ 7.28−7.21 (m, 2H), 6.90−6.80
(m, 2H), 5.77 (dddd, J = 6.5, 7.7, 10.2, 16.9 Hz, 1H), 5.10−4.99 (m,
2H), 4.45 (s, 1H), 4.36 (q, J = 14.4 Hz, 2H), 3.97 (tt, J = 3.2, 6.9 Hz,
1H), 3.79 (s, 3H), 3.34−3.23 (m, 2H), 2.56−2.47 (m, 1H), 2.13
(dddd, J = 1.2, 8.0, 8.9, 13.7 Hz, 1H), 1.99−1.83 (m, 3H), 1.76 (ddt, J
= 2.6, 6.1, 8.6 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 158.8, 156.6,
135.3, 131.9, 129.1, 117.2, 113.9, 56.9, 55.3, 46.1, 44.1, 38.8, 29.4,
23.6. IR (film) 3321.8, 1624.3, cm−1. HRMS (ESI+ TOF) m/z: [M +
H]+ calcd for C16H23N2O2 275.1760; found 275.1758.
2-Allyl-N-(4-nitrophenyl)pyrrolidine-1-carboxamide (5d). The
title compound was prepared from tert-butyl 2-allylpyrrolidine-1-
carboxylate (0.50 g, 2.4 mmol) and para-nitrophenyl isocyanate (0.43
g, 2.6 mmol) according to General Procedure 1. This procedure
afforded 0.324 g (49%) of the title compound as a yellow solid, mp
99−102 °C. 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J = 9.1 Hz, 2H),
7.61−7.54 (m, 2H), 6.59 (s, 1H), 5.82 (ddt, J = 7.2, 10.3, 17.2 Hz,
1H), 5.18−5.09 (m, 2H), 4.09 (dt, J = 5.0, 10.4 Hz, 1H), 3.53−3.46
(m, 2H), 2.56 (dt, J = 5.5, 12.2 Hz, 1H), 2.27−2.15 (m, 2H), 2.12−
2.01 (m, 1H), 2.04−1.94 (m, 1H), 1.85 (ddq, J = 2.8, 3.6, 6.4, 9.9 Hz,
1H). 13C NMR (126 MHz, CDCl3) δ 152.7, 145.3, 142.3, 134.7,
125.1, 118.0, 57.6, 46.5, 38.5, 29.7, 23.7. IR (film) 3325, 1654.9 cm−1.
HRMS (ESI+ TOF) m/z: [M + H]+ calcd for C14H18N3O3 276.1348;
found 276.1343.
1-Benzyl-1-(but-3-en-2-yl)-3-(4-nitrophenyl)urea (12e). The title
compound was prepared from N-benzylbut-3-en-2-amine (0.135 g,
0.84 mmol) and 4-nitrophenyl isocyanate (0.193 g, 1.2 mmol) using
General Procedure 2. This procedure afforded 0.088 g (32%) of the
1
title compound as a pale yellow oil. H NMR (500 MHz, CDCl3) δ
8.12−8.05 (d, J = 9 Hz, 2H), 7.46−7.39 (m, 2H), 7.39−7.32 (m, 3H),
7.34−7.27 (m, 2H), 6.75 (s, 1H), 6.00 (ddd, J = 4.4, 10.4, 17.6 Hz,
1H), 5.35−5.28 (m, 2H), 4.97 (s, 1H), 4.58 (d, J = 16.9 Hz, 1H),
4.41 (d, J = 16.9 Hz, 1H), 1.37 (d, J = 6.8 Hz, 3H). 13C NMR (126
MHz, CDCl3) δ 154.8, 145.2, 142.4, 138.7, 137.2, 129.3, 128.2, 126.8,
125.0, 118.2, 117.0, 52.8, 47.8, 16.6. IR (film) 3390.6, 1653.2 cm−1.
HRMS (ESI+ TOF) m/z: [M + H]+ calcd for C18H20N3O3 326.1505;
found 326.1501.
General Procedure 2. Synthesis of N-Benzyl-N-allylureas. A
flame-dried round-bottom flask equipped with a stir bar was cooled
under a stream of nitrogen and charged with the appropriate
Experimental Procedures and Compound Characterization
Data for Products of the Metathesis/Michael Reaction
Sequence. General Procedure 3 (Conditions A). A flame-dried
D
DOI: 10.1021/acs.joc.8b01492
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Schlenk tube equipped with a stir bar was cooled under a stream of
nitrogen and charged with the Hoveyda-Grubbs II catalyst (0.02
mmol, 10 mol %) and copper iodide (0.02 mmol, 10 mol %). The
flask was purged with nitrogen and charged with the appropriate urea
substrate (0.2 mmol) in 1,2-dichloroethane (0.2 M), and the resulting
mixture was stirred for 5 min at rt. Methyl vinyl ketone or methyl
acrylate (1.0 mmol) was added, and the reaction mixture was heated
to 70 °C with stirring overnight. The reaction mixture was then
cooled to rt and concentrated in vacuo. The crude product was
purified via flash chromatography on silica gel to afford the desired
product.
General Procedure 4 (Conditions B). The reaction was carried
out according to General Procedure 3. The cross-metathesis product
(10) was purified by flash chromatography on silica gel and then
transferred as a solution in 1,2-dichloroethane (1 mL) to a nitrogen-
filled flame-dried Schlenk tube equipped with a stir bar that had been
charged with potassium tert-butoxide (1.5 equiv). The mixture was
heated to 70 °C with stirring overnight, then was cooled to rt, and
quenched with saturated aqueous ammonium chloride (2 mL). The
aqueous layer was extracted with dichloromethane (3 × 2 mL), and
the combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo. The crude product was purified via flash
chromatography on silica gel to afford the desired product.
General Procedure 5 (Conditions C). A flame-dried Schlenk
tube equipped with a stir bar was cooled under a stream of nitrogen
and charged with the Hoveyda-Grubbs II catalyst (0.02 mmol, 10 mol
%) and copper iodide (0.02 mmol, 10 mol %). The flask was purged
with nitrogen, and the appropriate substrate (0.2 mmol) in 1,2-
dichloroethane (0.2 M) was added. The resulting mixture was stirred
for 5 min at rt, and then methyl acrylate (1.0 mmol) and boron
trifluoride diethyl etherate (0.2 mmol) were added. The reaction
mixture was heated to 70 °C with stirring overnight and then was
cooled to rt, and the reaction was quenched with saturated aqueous
ammonium chloride (2 mL). The aqueous layer was extracted with
dichloromethane (3 × 2 mL), and the combined organic layers were
dried over Na2SO4, filtered, and concentrated in vacuo. The crude
product was purified via flash chromatography on silica gel to afford
the desired product.
( )-(3S*,4aS*)-2-(4-Chlorophenyl)-3-(2-oxopropyl)hexahydro-
pyrrolo[1,2-c]pyrimidin-1(2H)-one (7a). The title compound was
prepared from 2-allyl-N-(4-chlorophenyl) pyrrolidine-1-carboxamide
(52 mg, 0.2 mmol) and methyl vinyl ketone (0.1 mL, 1 mmol) using
General Procedure 3 (chromatography was performed using 50%
ethyl acetate in hexanes →100% ethyl acetate as the eluent). This
procedure afforded 52.7 mg (86%) as a brown solid, mp 110−112 °C.
The compound was obtained as a >20:1 mixture of diastereomers as
judged by 1H NMR analysis. Data are for the major isomer. 1H NMR
(500 MHz, CDCl3) δ 7.29 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.5 Hz,
2H), 4.29 (ddt, J = 3.8, 8.1, 14.9 Hz, 1H), 3.69−3.57 (m, 1H), 3.48
(dd, J = 5.0, 9.4 Hz, 2H), 2.48 (ddt, J = 3.2, 12.6, 28.4 Hz, 2H), 2.33
(ddd, J = 2.8, 8.6, 17.5 Hz, 1H), 2.23−2.10 (m, 1H), 1.96 (s 3H),
1.79 (dddt, J = 3.0, 6.6, 9.6, 12.7 Hz, 2H), 1.56−1.35 (m, 2H). 13C
NMR (126 MHz, CDCl3) δ 206.0, 154.3, 139.2, 132.3, 130.5, 129.0,
54.7, 53.0, 48.5, 45.9, 35.7, 33.5, 30.7, 23.1. IR (film) 3425.6, 1712.6,
1631.3 cm−1. HRMS (ESI+ TOF) m/z: [M + H]+ calcd for
C16H20ClN2O2 307.1213; found 307.1215.
3H), 1.80 (ttd, J = 6.6, 9.3, 12.3 Hz, 2H), 1.56−1.37 (m, 2H). 13C
NMR (126 MHz, CDCl3) δ 206.3, 158.2, 133.3, 130.5, 114.2, 55.4,
54.8, 53.4, 48.6, 46.0, 35.7, 33.6, 30.7, 29.7, 23.2. IR (film) 3412.2,
1713.2, 1635.4 cm−1. HRMS (ESI+ TOF) m/z: [M + H]+ calcd for
C17H23N2O3 303.1709; found 303.1707.
( )-(3S*,4aS*)-2-(4-Methoxybenzyl)-3-(2-oxopropyl)hexahydro-
pyrrolo[1,2-c]pyrimidin-1(2H)-one (7c). The title compound was
prepared from 2-allyl-N-(4-methoxybenzyl) pyrrolidine-1-carboxa-
mide (55 mg, 0.2 mmol) and methyl vinyl ketone (0.1 mL, 1
mmol) using General Procedure 3 (chromatography was performed
using 50% ethyl acetate in hexanes →100:0 ethyl acetate as the
eluent). This procedure afforded 45 mg (71%) of the title compound
as a purple solid, mp 109−112 °C. The compound was obtained as an
8:1 mixture of diastereomers as judged by 1H NMR analysis. Data are
1
for the major isomer. H NMR (500 MHz, CDCl3) δ 7.27−7.13 (m,
2H), 6.88−6.80 (m, 2H), 4.82 (d, J = 15.9 Hz, 1H), 4.29 (d, J = 15.9
Hz, 1H), 3.89−3.84 (m, 1H), 3.78 (s, 3H), 3.80−3.71 (m, 1H),
3.65−3.40 (m, 3H), 2.86 (dd, J = 4.0, 16.9 Hz, 1H), 2.38−2.25 (m,
2H), 2.14−2.02 (m, 1H), 1.99 (s, 2H), 1.93 (dtt, J = 11.8, 7.0, 2.3 Hz,
1H), 1.78 (ttd, J = 6.9, 9.3, 12.4 Hz, 1H), 1.45 (tdd, J = 7.3, 9.8, 11.9
Hz, 1H), 1.36−1.23 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 206.3,
158.5, 156.3, 131.1, 128.4, 113.9, 55.3, 54.2, 50.7, 47.9, 47.2, 46.1,
35.9, 33.7, 30.8, 23.2. IR (film) 3444.4, 1712.3, 1612.6 cm−1. HRMS
(ESI+ TOF) m/z: [M + H]+ calcd for C18H25N2O3 317.1865; found
317.1855.
( )-(3S*,4aS*)-2-(4-Nitrophenyl)-3-(2-oxopropyl)hexahydro-
pyrrolo[1,2-c]pyrimidin-1(2H)-one (7d). The title compound was
prepared from 2-allyl-N-(4-nitrophenyl) pyrrolidine-1-carboxamide
(55 mg, 0.2 mmol) and methyl vinyl ketone (0.1 mL, 1 mmol) using
General Procedure 4. The cross-metathesis step afforded 45 mg
(71%) of ( )-(E)-N-(4-nitrophenyl)-2-(4-oxopent-2-en-1-yl)-
pyrrolidine-1-carboxamide (10d) as a brown oil (chromatography
was performed using 40% ethyl acetate in hexanes →100% ethyl
1
acetate as the eluent). H NMR (500 MHz, CDCl3) 8.17 (d, J = 8.4
Hz, 2H), 7.58 (d, J = 8.8 Hz, 2H), 6.79 (dt, J = 7.3, 15.1 Hz, 1H),
6.56 (s, 1H), 6.13 (d, J = 15.8 Hz, 1H), 4.26 (dq, J = 4.3, 8.3 Hz, 1H),
3.53 (s, 1H), 3.48 (d, J = 7.7 Hz, 1H), 2.76 (dt, J = 5.3, 11.9 Hz, 1H),
2.45−2.34 (m, 1H), 2.25 (s, 3H), 2.04 (dtd, J = 6.8, 11.7, 13.0, 26.1
Hz, 3H), 1.83−1.75 (m, 1H). 13C NMR (126 MHz, CDCl3) δ
198.28, 152.72, 145.05, 143.86, 143.70, 133.29, 124.89, 118.20, 56.83,
46.46, 37.14, 29.57, 27.15, 24.06. IR (film) 3356.4, 2970.5, 1662.6,
1542.5 cm−1. HRMS (ESI+ TOF) m/z: [M + H]+ calcd for
C16H20N3O4 318.1454; found 318.1453.
Treatment of the cross-metathesis product with KOtBu (chroma-
tography was performed using 100% ethyl acetate as the eluent)
afforded 39 mg (65%; 45% over two steps from 5d) of the title
compound as a white-tan solid, mp 143−147 °C. The compound was
1
obtained as a 4:1 mixture of diastereomers as judged by H NMR
analysis. Data are for the major isomer. 1H NMR (500 MHz, CDCl3)
δ 8.19 (dd, J = 7.7, 9.6 Hz, 2H), 7.48−7.41 (d, J = 9 Hz, 2H), 4.68
(dq, J = 2.6, 3.3, 9.5 Hz, 1H), 3.70−3.56 (m, 2H), 3.55−3.47 (m,
1H), 2.78 (dd, J = 9.7, 17.9 Hz, 1H), 2.70−2.61 (m, 1H), 2.28 (ddd, J
= 2.1, 3.7, 13.5 Hz, 1H), 2.23−2.14 (m, 1H), 2.10−1.93 (m, 4H),
1.92−1.75 (m, 2H), 1.61−1.41 (m, 1H). 13C NMR (126 MHz,
CDCl3) δ 205.6, 153.0, 148.0, 144.4, 128.4, 126.4, 124.3, 124.0, 53.1,
46.0, 33.7, 31.5, 30.6, 23.3. IR (film) 2973.4, 1711.9, 1640 cm−1.
HRMS (ESI+ TOF) m/z: [M + H]+ calcd for C16H20N3O4 318.1454;
found 318.1453.
( )-(3S*,4aS*)-2-(4-Methoxyphenyl)-3-(2-oxopropyl)hexahydro-
pyrrolo[1,2-c]pyrimidin-1(2H)-one (7b). The title compound was
prepared from 2-allyl-N-(4-methoxyphenyl) pyrrolidine-1-carboxa-
mide (52 mg, 0.2 mmol) and methyl vinyl ketone (0.1 mL, 1
mmol) using General Procedure 3 (chromatography was performed
using 40% ethyl acetate in hexanes →100% ethyl acetate as the
eluent). This procedure afforded 24.4 mg (75%) of the title
compound as a purple solid, mp 103−106 °C. The compound was
( )-(3S*,4aS*)-Methyl 2-(2-(4-chlorophenyl)-1-oxooctahydro-
pyrrolo[1,2-c]pyrimidin-3-yl)acetate (7e). The title compound was
prepared from 2-allyl-N-(4-chlorophenyl) pyrrolidine-1-carboxamide
(53 mg, 0.2 mmol) and methyl acrylate (0.1 mL, 1 mmol) using
General Procedure 4. The cross-metathesis step afforded 41 mg
(63%) of (E)-4-{1-[(4-chlorophenyl)carbamoyl]pyrrolidin-2-yl]but-
2-enoate (10e) as a purple oil (chromatography was performed using
40% ethyl acetate in hexanes as the eluent). The compound was
1
obtained as a >20:1 mixture of diastereomers as judged by H NMR
analysis. Data are for the major isomer. 1H NMR (500 MHz, CDCl3)
δ 7.13 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 4.27 (ddt, J = 4.0,
8.1, 12.0 Hz, 1H), 3.79 (s, 3H), 3.64 (tt, J = 4.5, 10.3 Hz, 1H), 3.56−
3.47 (m, 2H), 2.57 (dd, J = 4.2, 17.4 Hz, 1H), 2.44 (dt, J = 3.4, 12.7
Hz, 1H), 2.32 (dd, J = 8.4, 17.5 Hz, 1H), 2.20−2.10 (m, 1H), 1.89 (s,
1
obtained as a 4:1 mixture of E/Z isomers as judged by H NMR
analysis. Data are for the major isomer. 1H NMR (500 MHz, CDCl3)
δ 7.38−7.31 (m, 2H), 7.26−7.17 (m, 2H), 6.91 (dt, J = 7.5, 15.3 Hz,
1H), 6.26 (s, 1H), 5.88 (dt, J = 1.4, 15.6 Hz, 1H), 4.17 (dq, J = 3.6,
E
DOI: 10.1021/acs.joc.8b01492
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
10.2 Hz, 1H), 3.72 (s, 3H), 3.49−3.36 (m, 2H), 2.73 (dddd, J = 1.5,
3.6, 6.9, 14.0 Hz, 1H), 2.44−2.33 (m, 1H), 2.06−1.89 (m, 3H),
1.80−1.71 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 166.7, 153.6,
145.2, 137.6, 128.8, 128.5, 123.3, 120.9, 56.6, 51.5, 46.4, 36.7, 29.5,
24.0. IR (film) 3329.9, 1719.5, 1642.9 cm−1. HRMS (ESI+ TOF) m/
z: [M + H]+ calcd for C16H20ClN2O3 323.1162; found 323.1161.
Treatment of the cross-metathesis product with KOtBu (chroma-
tography was performed using 40% ethyl acetate in hexanes →100%
ethyl acetate as the eluent) afforded 25 mg (63%, 38% over two steps
from 5a) of the title compound as a white solid, mp 117−118 °C. The
compound was obtained as a 3:1 mixture of diastereomers as judged
by H NMR analysis. Data are for the major isomer. H NMR (500
MHz, CDCl3) δ 7.38−7.27 (m, 2H), 7.17 (dd, J = 8.6, 1.7 Hz, 2H),
4.23 (ddt, J = 4.1, 8.5, 11.2 Hz, 1H), 3.72−3.60 (m, 1H), 3.56 (s,
3H), 3.53−3.45 (m, 2H), 2.57−2.40 (m, 2H), 2.19−2.12 (m, 2H),
2.05−1.92 (m, 1H), 1.82 (ddt, J = 15.1, 12.0, 4.5 Hz, 1H), 1.60−1.47
(m, 2H). 13C NMR (126 MHz, CDCl3) δ 171.1, 154.2, 139.0, 130.6,
129.1, 54.6, 54.0, 51.7, 45.9, 39.9, 35.6, 33.8, 31.7, 23.1. IR (film)
1733.2, 1639.5 cm−1. HRMS (ESI+ TOF) m/z: [M + H]+ calcd for
C16H20ClN2O3 323.1162; found 323.1163.
1626.1 cm−1. HRMS (ESI+ TOF) m/z: [M + H]+ calcd for
C18H25N2O4 333.1814; found 333.1806.
Treatment of the cross-metathesis product with KOtBu (chroma-
tography was performed using 100% ethyl acetate as the eluent)
afforded 26 mg (54%, 39% over two steps from 5c) of the title
compound as a yellow oil. The compound was obtained as a 8:1
mixture of diastereomers as judged by 1H NMR analysis. Data are for
1
the major isomer. H NMR (500 MHz, CDCl3) δ 7.25−7.14 (m,
2H), 6.84 (d, J = 8.2 Hz, 2H), 5.02 (d, J = 15.9 Hz, 1H), 4.21 (d, J =
15.9 Hz, 1H), 3.78 (s, 2H), 3.64 (d, J = 14.9 Hz, 3H), 3.63−3.40 (m,
3H), 2.77 (dd, J = 3.9, 15.2 Hz, 1H), 2.31−2.20 (m, 2H), 2.11 (qd, J
= 3.8, 7.3 Hz, 1H), 2.05−1.89 (m, 1H), 1.93 (s, 1H), 1.86−1.72 (m,
1H), 1.54−1.35 (m, 2H), 0.39 (s, 1H). 13C NMR (126 MHz, CDCl3)
δ 171.3, 158.6, 156.1, 130.8, 128.5, 113.9, 55.2, 54.1, 51.7, 51.3, 46.7,
46.1, 39.0, 35.5, 33.5, 23.2. IR (film) 1734.0, 1614.3 cm−1. HRMS
(ESI+ TOF) m/z: [M + H]+ calcd for C18H25N2O4 333.1814; found
333.1810.
1
1
Methyl 2[(2-(4-Nitrophenyl)-1-oxooctahydropyrrolo[1,2-c]-
pyrimidin-3-yl]acetate (7h). The title compound was prepared
from 2-allyl-N-(4-nitrophenyl) pyrrolidine-1-carboxamide (55 mg,
0.2 mmol) and methyl acrylate (0.1 mL, 1 mmol) using General
Procedure 4. The cross-metathesis step afforded 36 mg (54%) of (E)-
methyl 4-{1-[(4-nitrophenyl)carbamoyl]pyrrolidin-2-yl}but-2-enoate
(10h) as a brown oil (chromatography was performed using 40%
ethyl acetate in hexanes as the eluent). The compound was obtained
as a 4:1 mixture of E/Z isomers as judged by 1H NMR analysis. Data
( )-(3S*,4aS*)-Methyl 2-[2-(4-methoxyphenyl)-1-oxooctahydro-
pyrrolo[1,2-c]pyrimidin-3-yl]acetate (7f). The title compound was
prepared from 2-allyl-N-(4-methoxyphenyl) pyrrolidine-1-carboxa-
mide (52 mg, 0.2 mmol) and methyl acrylate (0.1 mL, 1 mmol)
using General Procedure 4. The cross-metathesis step afforded 54 mg
(85%) of methyl (E)-4-{1-[(4-methoxyphenyl)carbamoyl]pyrrolidin-
2-yl}but-2-enoate (10f) as a brown/tan oil (chromatography was
performed using 40% ethyl acetate in hexanes as the eluent). The
compound was obtained as a 5:1 mixture of E/Z isomers as judged by
1
are for the major isomer. H NMR (500 MHz, CDCl3) δ 7.39−7.31
(m, 2H), 7.26−7.18 (m, 2H), 6.91 (dt, J = 7.5, 15.3 Hz, 1H), 6.26 (s,
2H), 5.89 (dt, J = 1.5, 15.5 Hz, 1H), 4.18 (dq, J = 3.7, 10.2 Hz, 1H),
3.72 (s, 3H), 3.49−3.36 (m, 2H), 2.73 (dddd, J = 1.4, 3.7, 6.8, 13.7
Hz, 1H), 2.44−2.34 (m, 1H), 2.07−1.95 (m, 2H), 1.75 (tq, J = 3.8,
5.0, 8.5 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 166.6, 152.7, 145.2,
144.8, 142.4, 125.1, 123.6, 118.2, 56.8, 51.6, 46.5, 36.5, 29.5, 24.0. IR
(film) 3357.3, 1718.3, 1654.4 cm−1. HRMS (ESI+ TOF) m/z: [M +
H]+ calcd for C16H20N3O5 334.1403; found 334.1401.
1
1H NMR analysis. Data are for the major isomer. H NMR (500
MHz, CDCl3) δ 7.31−7.24 (m, 2H), 6.97−6.87 (m, 1H), 6.85−6.78
(m, 2H), 6.13 (s, 1H), 5.98−5.84 (m, 1H), 4.20−4.06 (m, 1H), 3.76
(s, 3H), 3.71 (s, 3H), 3.47−3.35 (m, 2H), 2.74 (dddd, J = 1.6, 3.6,
7.0, 14.1 Hz, 1H), 2.38 (dddd, J = 1.4, 8.0, 9.0, 14.2 Hz, 1H), 2.03−
1.96 (m, 3H), 1.74 (ddt, J = 3.4, 5.4, 12.0 Hz, 1H). 13C NMR (126
MHz, CDCl3) δ 166.8, 155.8, 154.3, 145.5, 131.9, 123.2, 122.1, 114.1,
56.5, 55.5, 51.5, 46.3, 36.9, 29.7, 24.0. IR (film) 3322.7, 2950.0,
1719.1, 1639.5 cm−1. HRMS (ESI+ TOF) m/z: [M + H]+ calcd for
C17H23N2O4 319.1658; found 319.1656.
Treatment of the cross-metathesis product with KOtBu (chroma-
tography was performed using 100% ethyl acetate as the eluent)
afforded 19.4 mg (58%, 31% over two steps from 5d) of the title
compound as a yellow solid, mp 99−100 °C. The compound was
Treatment of the cross-metathesis product with KOtBu (chroma-
tography was performed using 100% ethyl acetate as the eluent)
afforded 46 mg (84%, 71% over two steps from 5b) of the title
compound as a yellow solid, mp 107−110 °C. The compound was
1
obtained as a 1:1 mixture of diastereomers as judged by H NMR
1
analysis. Data are for the mixture. H NMR (500 MHz, CDCl3) δ
8.24−8.16 (m, 4H), 7.50−7.42 (m, 4H), 4.61 (dtd, J = 1.9, 5.1, 10.6
Hz, 1H), 4.39 (ddt, J = 4.0, 8.4, 10.7 Hz, 1H), 3.75−3.46 (m, 12H),
2.67−2.43 (m, 4H), 2.34−2.16 (m, 4H), 2.08−1.95 (m, 2H), 1.90−
1.79 (m, 3H), 1.67−1.51 (m, 3H). 13C NMR (126 MHz, CDCl3) δ
170.7, 153.3, 152.9, 148.0, 146.7, 145.5, 144.5, 128.7, 126.7, 124.3,
124.0, 54.5, 53.6, 52.8, 51.9, 46.5, 46.0, 39.7, 37.6, 35.6, 33.7, 33.5,
31.6, 23.3, 23.0. IR (film) 1733.7, 1644.3 cm−1. HRMS (ESI+ TOF)
m/z: [M + H]+ calcd for C16H20N3O5 334.1403; found 334.1403.
1-Benzyl-3-(4-chlorophenyl)-4-(2-oxopropyl)imidazolidin-2-one
(13a). The title compound was prepared from 1-allyl-1-benzyl-3-(4-
chlorophenyl)urea (60 mg, 0.2 mmol) and methyl vinyl ketone (0.1
mL, 1 mmol) using General Procedure 3 (chromatography was
performed using 20% ethyl acetate in hexanes → 40% ethyl acetate in
hexanes as the eluent). This procedure afforded 48 mg (70%) of the
title compound as a brown solid, mp 89−92 °C. 1H NMR (500 MHz,
CDCl3) δ 7.42−7.35 (m, 2H), 7.35−7.18 (m, 5H), 4.59 (dddd, J =
2.8, 4.7, 8.6, 10.0 Hz, 1H), 4.47−4.36 (m, 2H), 3.64 (t, J = 9.1 Hz,
1H), 2.97−2.88 (m, 2H), 2.59 (dd, J = 10.1, 18.3 Hz, 1H), 2.37 (s,
1H), 2.07 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 206.2, 157.3,
137.0, 136.5, 129.1, 128.8, 128.7, 128.3, 127.7, 121.8, 49.1, 48.1, 47.9,
46.1, 30.5. IR (film) 1699.5, 1493.4 cm−1. HRMS (ESI+ TOF) m/z:
[M + H]+ calcd for C19H20ClN2O2 343.1213; found 343.1212.
1-Benzyl-3-(4-methoxyphenyl)-4-(2-oxopropyl)imidazolidin-2-
one (13b). The title compound was prepared from 1-allyl-1-benzyl-3-
(4-methoxyphenyl)urea (60 mg, 0.2 mmol) and methyl vinyl ketone
(0.1 mL, 1 mmol) using General Procedure 3 (chromatography was
performed using 20% ethyl acetate in hexanes → 40% ethyl acetate in
hexanes as the eluent). This procedure afforded 43 mg (63%) of the
1
obtained as a 5:1 mixture of diastereomers as judged by H NMR
analysis. Data are for the major isomer. 1H NMR (500 MHz, CDCl3)
δ 7.12 (d, J = 8.4 Hz, 2H), 6.90−6.84 (m, 2H), 4.23−4.15 (m, 1H),
3.79 (s, 3H), 3.65 (s, 1H), 3.57 (s, 1H), 3.54 (s, 3H), 3.51 (dd, J =
4.9, 9.4 Hz, 2H), 2.45 (td, J = 3.7, 13.7, 14.8 Hz, 2H), 2.18 (dt, J =
7.4, 14.5 Hz, 2H), 2.00−1.93 (m, 1H), 1.81 (s, 1H), 1.55 (s, 1H). 13C
NMR (126 MHz, CDCl3) δ 171.4 158.3, 154.7, 133.2, 130.1, 114.2,
55.4, 54.7, 54.2, 51.6, 46.0, 40.1, 35.6, 33.6, 23.1. IR (film) 1734.2,
1634.1 cm−1. HRMS (ESI+ TOF) m/z: [M + H]+ calcd for
C17H23N2O4 319.1658; found 319.1661.
( )-(3S*,4aS*)-Methyl 2-(2-(4-methoxybenzyl)-1-oxooctahydro-
pyrrolo[1,2-c]pyrimidin-3-yl)acetate (7g). The title compound was
prepared from 2-allyl-N-(4-methoxybenzyl) pyrrolidine-1-carboxa-
mide (55 mg, 0.2 mmol) and methyl acrylate (0.1 mL, 1 mmol)
using General Procedure 4. The cross-metathesis step afforded 48 mg
(72%) of (E)-methyl 4-{1-[(4-methoxybenzyl)carbamoyl]pyrrolidin-
2-yl}but-2-enoate (10g) as a pink-purple oil (chromatography was
performed using 40% ethyl acetate in hexanes as the eluent). The
compound was obtained as a >20:1 mixture of E/Z isomers as judged
1
1
by H NMR analysis. Data are for the major isomer. H NMR (500
MHz, CDCl3) δ 7.31−7.16 (m, 2H), 6.97−6.81 (m, 3H), 5.86 (dt, J =
1.5, 15.6 Hz, 1H), 4.44 (s, 1H), 4.41−4.29 (m, 1H), 4.35 (s, 1H),
4.11 (ddd, J = 3.1, 5.5, 9.8 Hz, 1H), 3.79 (s, 3H), 3.72 (s, 3H), 3.32−
3.19 (m, 2H), 2.70 (dddd, J = 1.5, 3.6, 7.0, 14.0 Hz, 1H), 2.42−2.31
(m, 1H), 1.99−1.85 (m, 2H), 1.75−1.66 (m, 1H). 13C NMR (126
MHz, CDCl3) δ 166.8, 158.9, 156.5, 145.7, 131.7, 129.1, 123.1, 114.0,
56.3, 55.3, 51.5, 46.0, 44.1, 37.1, 29.5, 23.9. IR (film) 3333.9, 1719.5,
1
title compound as a brown solid, mp 110−111 °C. H NMR (500
F
DOI: 10.1021/acs.joc.8b01492
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
MHz, CDCl3) δ 7.38−7.21 (m, 7H), 6.95−6.86 (m, 2H), 4.55−4.42
(m, 2H), 4.38 (d, J = 14.9 Hz, 1H), 3.79 (s, 3H), 3.63 (t, J = 9.0 Hz,
1H), 2.94−2.86 (m, 2H), 2.57 (dd, J = 10.0, 18.2 Hz, 1H), 2.05 (s,
3H). 13C NMR (126 MHz, CDCl3) δ 206.4, 158.2, 156.7, 136.8,
131.2, 128.7, 128.3, 127.6, 124.0, 114.4, 55.5, 50.3, 48.3, 48.1, 46.5,
30.5. IR (film) 1694.4, 1511.5 cm−1. HRMS (ESI+ TOF) m/z: [M +
H]+ calcd for C20H23N2O3 339.1709; found 339.1713.
1-Benzyl-3-(4-nitrophenyl)-4-(2-oxopropyl)imidazolidin-2-one
(13c). The title compound was prepared from 1-allyl-1-benzyl-3-(4-
nitrophenyl)urea (60 mg, 0.2 mmol) and methyl vinyl ketone (0.1
mL, 1 mmol) using General Procedure 3 (chromatography was
performed using 20% ethyl acetate in hexanes → 40% ethyl acetate in
hexanes as the eluent) to afford 44 mg (62%) yellow solid, mp 132−
135 °C. 1H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 9.5 Hz, 2H), 7.62
(d, J = 9.0 Hz, 2H), 7.40−7.25 (m, 5H), 4.76−4.67 (m, 1H), 4.51−
4.37 (m, 2H), 3.67 (t, J = 9.2 Hz, 1H), 3.04−2.94 (m, 2H), 2.69 (dd,
J = 10.3, 18.5 Hz, 1H), 2.13 (s, 3H). 13C NMR (126 MHz, CDCl3) δ
205.9, 156.2, 144.5, 142.2, 135.9, 128.8, 128.3, 128.0, 125.0, 117.8,
48.7, 47.9, 47.8, 45.7, 30.5. IR (film) 3404.4, 2924.0, 1704.3, 1593.4,
1500.5 cm−1. HRMS (ESI+ TOF) m/z: [M + H]+ calcd for
C19H20N3O4 354.1454; found 354.1451.
1732.7, 1703.0, 1594.2 cm−1. HRMS (ESI+ TOF) m/z: [M + H]+
calcd for C19H20ClN2O3 359.1162; found 359.1161.
Methyl 2-[1-Benzyl-3-(4-methoxyphenyl)-2-oxoimidazolidin-4-
yl]acetate (13g). The title compound was prepared from 1-allyl-1-
benzyl-3-(4-methoxyphenyl)urea (60 mg, 0.2 mmol) and methyl
acrylate (0.1 mL, 1 mmol) using General Procedure 5 (chromatog-
raphy was performed using 25% ethyl acetate in hexanes → 40% ethyl
acetate in hexanes as the eluent). This procedure afforded 35 mg
1
(48%) of the title compound as a white-tan solid, mp 64−67 °C. H
NMR (500 MHz, CDCl3) δ 7.38−7.23 (m, 7H), 6.96−6.86 (m, 2H),
4.54−4.43 (m, 2H), 4.39 (d, J = 14.8 Hz, 1H), 3.79 (d, J = 1.3 Hz,
3H), 3.60 (d, J = 1.3 Hz, 3H), 3.07 (ddd, J = 1.2, 5.4, 9.3 Hz, 1H),
2.75 (dt, J = 2.2, 16.3 Hz, 1H), 2.42 (ddd, J = 1.2, 9.8, 16.3 Hz, 1H),
1.25 (s, 1H). 13C NMR (126 MHz, CDCl3) δ 171.0, 158.2, 156.8,
136.8, 128.7, 128.3, 127.6, 124.3, 114.4, 55.5, 51.8, 51.2, 48.1, 47.9,
37.4, 29.7. IR (film) 1733.7, 1699.7, cm−1. HRMS (ESI+ TOF) m/z:
[M + H]+ calcd for C20H23N2O4 355.1658; found 355.1657.
Methyl 2-[1-Benzyl-3-(4-nitrophenyl)-2-oxoimidazolidin-4-yl]-
acetate (13h). The title compound was prepared from 1-allyl-1-
benzyl-3-(4-nitrophenyl)urea (62 mg, 0.2 mmol) and methyl acrylate
(0.1 mL, 1 mmol) using General Procedure 3 (chromatography was
performed using 25% ethyl acetate in hexanes as the eluent). This
procedure afforded 52 mg (70%) of the title compound as a yellow
(4R*,5R*)-1-Benzyl-3-(4-methoxyphenyl)-5-methyl-4-(2-
oxopropyl)imidazolidin-2-one (13d). The title compound was
prepared from 1-benzyl-1-(but-3-en-2-yl)-3-(4-methoxyphenyl)urea
(62 mg, 0.2 mmol) and methyl vinyl ketone (0.1 mL, 1 mmol) using
General Procedure 3 (chromatography was performed using 20%
ethyl acetate in hexanes → 40% ethyl acetate in hexanes as the
eluent). This procedure afforded 40 mg (56%) of the title compound
as a brown oil. The compound was obtained as a 2:1 mixture of
1
solid, mp 130−132 °C. H NMR (500 MHz, CDCl3) δ 8.25−8.18
(m, 2H), 7.77−7.69 (m, 2H), 7.36 (dd, J = 6.4, 7.9 Hz, 2H), 7.34−
7.26 (m, 3H), 4.72−4.63 (m, 1H), 4.51 (d, J = 14.9 Hz, 1H), 4.45 (d,
J = 14.9 Hz, 1H), 3.67 (s, 3H), 3.64 (t, J = 9.0 Hz, 1H), 3.17 (dd, J =
3.2, 9.6 Hz, 1H), 2.84 (dd, J = 2.7, 16.5 Hz, 1H), 2.53 (dd, J = 10.1,
16.4 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 170.4, 156.2, 144.4,
142.4, 135.8, 128.9, 128.3, 128.0, 125.1, 117.9, 52.2, 49.6, 47.9, 47.3,
36.6. IR (film) 1707.8, 1594.1 cm−1. HRMS (ESI+ TOF) m/z: [M +
H]+ calcd for C19H20N3O5 370.1403; found 370.1402.
1
diastereomers as judged by H NMR analysis. Data are for the major
isomer. 1H NMR (500 MHz, CDCl3) δ 7.40−7.19 (m, 5H), 6.89 (dd,
J = 2.6, 9.2 Hz, 2H), 4.86 (d, J = 15.3 Hz, 1H), 4.17 (dt, J = 3.5, 9.2
Hz, 1H), 4.05 (d, J = 15.3 Hz, 1H), 3.79 (s, 3H), 3.84−3.71 (m, 1H),
3.14 (qd, J = 3.8, 6.2 Hz, 1H), 2.82−2.72 (m, 1H), 2.50 (dd, J = 9.2,
17.9 Hz, 1H), 1.98 (s, 3H), 1.29 (d, J = 6.2 Hz, 3H), 1.04 (d, J = 6.5
Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 206.5, 157.1, 156.4, 137.4,
131.3, 128.6, 128.2, 127.5, 123.5, 114.4, 57.6, 55.5, 54.4, 45.9, 45.0,
30.7, 18.2. IR (film) 3362.5, 2932.6, 1693.8, 1511.5 cm−1. HRMS
(ESI+ TOF) m/z: [M + H]+ calcd for C21H25N2O3 353.1865; found
353.1866.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b01492.
■
S
Descriptions of stereochemical assignments and copies
of 1H and 13C NMR spectra for new compounds (PDF)
(4R*,5R*)-1-Benzyl-5-methyl-3-(4-nitrophenyl)-4-(2-oxopropyl)-
imidazolidin-2-one (13e). The title compound was prepared from 1-
benzyl-1-(but-3-en-2-yl)-3-(4-nitrophenyl)urea (40 g, 0.12 mmol)
and methyl vinyl ketone (0.1 mL, 1 mmol) using General Procedure 3
(chromatography was performed using 20% ethyl acetate in hexanes
→25% ethyl acetate in hexanes as the eluent). This procedure
afforded 21 mg (48%) of the title compound as a white-tan solid, mp
155−158 °C. The compound was obtained as a 2:1 mixture of
AUTHOR INFORMATION
Corresponding Author
*E-mail: jpwolfe@umich.edu.
ORCID
John P. Wolfe: 0000-0002-7538-6273
Notes
The authors declare no competing financial interest.
■
1
diastereomers as judged by H NMR analysis. Data are for the major
1
isomer. H NMR (500 MHz, CDCl3) δ 8.24−8.17 (m, 2H), 7.76−
7.68 (m, 2H), 7.36 (dd, J = 6.5, 8.0 Hz, 2H), 7.35−7.26 (m, 3H), 4.93
(d, J = 15.2 Hz, 1H), 4.37−4.27 (m, 1H), 4.03 (d, J = 15.1 Hz, 1H),
3.14 (qd, J = 2.0, 6.3 Hz, 1H), 2.86 (dd, J = 2.3, 18.5 Hz, 1H), 2.56
(dd, J = 10.2, 18.5 Hz, 1H), 2.06 (s, 3H), 1.31 (d, J = 6.3 Hz, 3H).
13C NMR (126 MHz, CDCl3) δ 205.9, 155.2, 144.9, 142.0, 136.6,
128.9, 128.1, 127.9, 125.1, 117.1, 56.1, 54.2, 45.2, 44.9, 30.6, 18.3. IR
(film) 1709.5, 1595.1 cm−1. HRMS (ESI+ TOF) m/z: [M + H]+ calcd
for C20H22N3O4 368.1610; found 368.1608.
ACKNOWLEDGMENTS
■
The authors thank the University of Michigan for financial
support of this work. The authors also thank Dr. Nick Babij for
conducting preliminary experiments in this area.
REFERENCES
■
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G
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Note
Metathesis of Unsaturated Amino Acids. J. Org. Chem. 2016, 81,
8386−8393.
(16) The relative stereochemistry of the cross-metathesis/aza
1
Michael reaction products was assigned by H NMR NOE analysis.
See the Supporting Information for complete descriptions of
stereochemical assignments.
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