Rhodium-Catalyzed Vinylic C–H Functionalization of Enol Carbamates with Maleimides

Article abstract of DOI:10.1002/ejoc.201600558

The rhodium(III)-catalyzed direct C–H functionalization of enol carbamates with a range of maleimides is described. With the assistance of the carbamoyl directing group, this reaction provides biologically relevant succinimide compounds by proceeding through a C–Rh addition and subsequent protonation pathway.

Full text of DOI:10.1002/ejoc.201600558

DOI: 10.1002/ejoc.201600558
Full Paper
C–H Activation
Rhodium-Catalyzed Vinylic C–H Functionalization of Enol
Carbamates with Maleimides
Satyasheel Sharma,[a] Sang Hoon Han,[a] Hyeim Jo,[a] Sangil Han,[a] Neeraj Kumar Mishra,[a]
Miji Choi,[a] Taejoo Jeong,[a] Jihye Park,[a] and In Su Kim*[a]
Abstract: The rhodium(III)-catalyzed direct C–H functionaliza- this reaction provides biologically relevant succinimide com-
tion of enol carbamates with a range of maleimides is de- pounds by proceeding through a C–Rh addition and subse-
scribed. With the assistance of the carbamoyl directing group, quent protonation pathway.
Introduction
bonds.[9] In sharp contrast, the conjugate addition of nucleo-
philes to maleimides in organic synthesis has been less ex-
plored.[10] For instance, metal complexes, organocatalysts, and
acids/bases have been used for coupling nucleophiles, such as
arylboronic acids,[10a–10c] ketones,[10d–10g] and hydrazoic ac-
ids,[10h] with maleimides [Scheme 1, Equation (1)].
Cyclic imides have been recognized as crucial structural cores
of a number of organic molecules such as bioactive natural
products, pharmaceuticals, and functional materials.[1] The suc-
cinimide motif is of particular interest because of its prevalence
in natural products such as palasimide[2] and salfredin (Fig-
ure 1).[3] In addition, the succinimide scaffold is the central
functional unit of many drugs such as phensuximide,[4]
thalidomide,[5] and lurasidone[6] as well as new drug candidates
that have interesting bioactivity.[7] Furthermore, synthetic deriv-
atives such as pyrrolidines and γ-lactams, derived from the re-
duction of succinimides, are also found in biologically active
molecules, which makes these derivatives relevant for drug de-
velopment in the pharmaceutical industry.[8]
Figure 1. Natural products and pharmaceuticals that contain succinimide scaf-
folds.
Scheme 1. Coupling reactions using maleimides.
The 1,4-addition reaction of carbon nucleophiles to electron-
With the development of catalytic C–H bond functionaliza-
deficient alkenes such as α,ꢀ-unsaturated ketones is a straight- tions, the C–H olefination reaction has evolved into a powerful
forward strategy for the construction of new carbon–carbon tool for C–C bond formation.[11] Regardless of the versatility
of C–H olefination, however, these transformations are mostly
[a] School of Pharmacy, Sungkyunkwan University,
limited to terminal olefins. Only few examples of C–H olefin-
ations of internal olefins have been reported for the formation
of the corresponding Heck-type products. For instance, Glorius
showed a single example of the Rh-catalyzed oxidative Heck-
type reaction of benzamides with internal olefins to afford ole-
Suwon 440-746, Republic of Korea
E-mail: insukim@skku.edu
http://pharmasyn.skku.edu/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600558.
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finated products.[12a] Antonchick reported the oxidative cou-
pling reaction of quinones and maleic esters with chromones
and flavones under rhodium catalysis.[12b] Recently, Li also de-
scribed the oxidative cross-coupling reaction of benzamides
with quinones by using a RhIII catalyst.[12c] However, maleimides
as internal olefins have rarely been reported in the C–H activa-
tion event. In 2012, Zhu demonstrated the first example of the
C–H olefination of N-benzoylsulfonamides with maleimides fol-
lowed by a cyclization reaction to afford the corresponding
spiro adducts under Rh catalysis.[12d] In addition, Hirano and
Miura developed a synthetic protocol for the formation of spiro-
succinimides from benzamides and maleimides by using a Cu-
mediated 8-aminoquinoline-directed C–H cleavage strategy
[Scheme 1, Equation (2)].[12e] In contrast to Zhu's study, a single
example of a Heck-type product from the reaction of benz-
amides and maleimides under RhIII catalysis was reported by
Hong.[12f] Very recently, Prabhu disclosed the RuII-catalyzed C–H
alkylation of acetophenones[12g] and N-benzoylindoles[12h] with
maleimides by using ketones as directing groups to give aryl-
ated succinimides [Scheme 1, Equation (3)].
Table 1. Selected optimization of reaction conditions.[a]
%
Entry
Catalyst
Additive [equiv.]
Solvent
Yield[b]
AgSbF6 (0.1), Cu(OAc)2
(2)
AgSbF6 (0.1), Cu(OAc)2
(2)
AgSbF6 (0.1), Cu(OAc)2
(2)
AgSbF6 (0.1), Cu(OAc)2
(2)
1
2
3
4
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
DCE
MeOH
THF[c]
44
35
30
tAmOH[c] trace
AgSbF6 (0.1), Cu(OAc)2
(2)
AgSbF6 (0.1), PivOH (2)
AgSbF6 (0.1), Mes-
CO2H[c] (2)
5
6
7
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
dioxane
DCE
17
61
44
DCE
Enol carbamates have been recognized as integral structural
motifs of pharmaceuticals and agrochemicals and have also
served as versatile synthons in organic transformations.[13] How-
ever, the catalytic C–H functionalization of enol carbamates has
rarely been exploited.[14] Our continued efforts on rhodium-cat-
alyzed C–H functionalizations of aromatic compounds[15]
prompted us to explore the reaction of enol carbamates with
maleimides [Scheme 1, Equation (4)].
8
9
10
11[d]
12
13
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[CoCp*(CO)I2]
[Ru(p-Cy)Cl2]2
[RhCp*Cl2]2
AgSbF6 (0.1), AcOH (2)
AgSbF6 (0.1), CsOPiv (2)
AgSbF6 (0.2), PivOH (2)
AgSbF6 (0.2), PivOH (2)
AgSbF6 (0.2), PivOH (2)
AgSbF6 (0.2), PivOH (1)
AgSbF6 (0.2), PivOH
(0.5)
DCE
DCE
DCE
DCE
DCE
DCE
59
trace
80
12
36
[c]
65
14
[RhCp*Cl2]2
DCE
28
15
16
[RhCp*Cl2]2
[RhCp*Cl2]2
–
AgSbF6 (0.2)
PivOH (2)
AgSbF6 (0.2)
DCE
DCE
DCE
DCE
trace
trace
n.r.[c]
78
17
18[d]
[RhCp*(MeCN)3][SbF6]2 AgSbF6 (0.1), PivOH (2)
AgSbF6 (0.2), NaOAc
Results and Discussion
19
20
[RhCp*Cl2]2
(0.5)
–
DCE
DCE
trace
n.r.
–
Our initial study began by investigating the coupling between
1-phenylvinyl N,N-dimethylcarbamate (1a) and N-methyl-
maleimide (2a) under rhodium catalysis (Table 1). Fortunately,
the reaction of 1a and 2a in the presence of 2.5 mol-% of
[RhCp*Cl2]2 (Cp* = pentamethylcyclopentadienyl), 10 mol-% of
AgSbF6, and 2 equiv. of Cu(OAc)2 in 1,2-dichloroethane (DCE)
at 70 °C for 20 h afforded the desired product 3a in 44 % yield
[a] Reagents and conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (2.5 mol-
%), additive (quantity noted above), and solvent (1 mL) under air at 70 °C
for 20 h in pressure tubes. [b] Isolated yield determined after flash column
chromatography. [c] THF = tetrahydrofuran, Am = amyl, Mes = mesityl, p-
Cy = para-cymene, n.r.: no reaction. [d] Catalyst (5 mol-%) was used.
(Table 1, Entry 1). After the further screening of solvents and ficient group on the aromatic ring, successfully participated in
additives, we found either pivalic acid (PivOH) or acetic acid the alkylation process to give the corresponding products 3e–
to be the most effective in the reaction (Table 1, Entries 2–9). 3m. Notably, this transformation showed good tolerance to-
Surprisingly, a change in the loading amount of AgSbF6 to wards alkyl-substituted enol carbamate 1n to provide 3n in
20 mol-% resulted in a remarkable improvement of the catalytic 51 % yield. In addition, trisubstituted enol carbamate 1o and
reactivity to give 3a in 80 % yield (Table 1, Entry 10). Other heteroaryl enol carbamate 1p underwent the coupling reaction
catalysts such as [CoCp*(CO)I2] and [Ru(p-cymene)Cl2]2 were in low to moderate yields. Finally, bis(enol) carbamate 1q af-
found to be less effective (Table 1, Entries 11 and 12). In addi- forded bis(succinimide) 3q in 78 % yield.
tion, decreased amounts of PivOH afforded lower yields of 3a
(Table 1, Entries 13 and 14). Further control experiments re-
vealed that a cationic rhodium complex in the presence of
PivOH is very crucial to promote the coupling of 1a and 2a
(Table 1, Entries 15–20).
To further evaluate the scope of this process, the coupling
of various maleimides 2b–2l with enol carbamate 1a was exam-
ined under the optimal reaction conditions (Scheme 3). Gratify-
ingly, N-alkyl, N-aryl, and unprotected maleimides 2b–2g were
favored in the coupling reaction to afford the desired products
To examine the substrate scope and limitations, a broad 4b–4g in good to high yields. However, N-allylmaleimide 2h
range of enol carbamates were screened in the coupling reac- displayed low reactivity. In addition, N-carbonylated maleimides
tion with 2a (Scheme 2). First, we examined substrates with 2i and 2j were also found to be less reactive. Notably, this reac-
different carbamate groups, which smoothly participated in the tion readily proceeded with maleimide 2k, which was derived
coupling to give 3b–3d in moderate yields. Enol carbamates from its corresponding amino acid, to chemoselectively furnish
1e–1m, which contained either an electron-rich or electron-de- 4k in 83 % yield with a diastereomeric ratio of 1:1. In addition,
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Scheme 3. Scope of maleimides. Reagents and conditions: 1a (0.2 mmol),
2b–2l (0.4 mmol), [RhCp*Cl2]2 (2.5 mol-%), AgSbF6 (20 mol-%), PivOH
(2 equiv.), and DCE (1 mL) under air at 70 °C for 20 h in pressure tubes.
[a] Isolated yield determined after flash column chromatography.
[b] [RhCp*Cl2]2 (5 mol-%) and AgSbF6 (40 mol-%) were used.
Scheme 2. Scope of enol carbamates. Reagents and conditions: 1a–1q
(0.2 mmol), 2a (0.4 mmol), [RhCp*Cl2]2 (2.5 mol-%), AgSbF6 (20 mol-%), PivOH
(2 equiv.), and DCE (1 mL) under air at 70 °C for 20 h in pressure tubes.
[a] Isolated yield determined after flash column chromatography.
[b] [RhCp*Cl2]2 (5 mol-%) and AgSbF6 (40 mol-%) were used. [c] 2a (0.8 mmol,
4 equiv.) was used.
this transformation showed high monoselectivity in the cou-
pling of 2l with 1a to give 4l, the remaining maleimide moiety
of which offers versatile synthetic functionality for further elab-
oration by using other cross-coupling reactions. In contrast,
other substrates such as maleic anhydride, dimethyl maleate,
ethyl (Z)-3-cyanoacrylate, and C-3-substituted maleimides were
unreactive in this transformation.
To determine the site selectivity between aromatic and vin-
ylic C–H bonds, we treated 1r, which has both ketone and carb-
amate directing groups, with 2a under the standard reaction
conditions (Scheme 4). To our delight, the vinylic C–H function-
alization took place to afford 5a in 55 % yield along with 32 %
of the recovered starting material 1r. In addition, this site select-
ivity was observed during the late-stage functionalization of
bioactive estrone derivative 1s, which contains both phenol
and enol carbamates to furnish 5b in 63 % yield with a dia-
stereomeric ratio of 1.2:1.
Scheme 4. Site selectivity and late-stage functionalization.
Scheme 5. Synthetic transformation of coupling product.
To highlight the synthetic utility of succinimide-containing
To gain some insight into the mechanistic, two parallel reac-
enol carbamates, the cleavage of the carbamate group of 3a tions of 1a and deuterio-1a with 2a under the standard reac-
by using trimethylsilyl triflate (TMSOTf) was performed to afford tion conditions were conducted. Experiments showed a kinetic
ketone adduct 6a in 60 % yield (Scheme 5).[16] Further reductive isotope effect (kH/kD) of 1.11 (see Supporting Information for
cleavage of the enol carbamate moiety gave the corresponding details), which suggests that the C–H cleavage might not be
product 6b in 80 % yield.
involved in the rate-determining step (Scheme 6).
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of chemoselectivity as well as with high functional group toler-
ance. Further synthetic transformations reveal that the enol
carbamate group of products can readily be converted into
other useful functionalities.
Experimental Section
Typical Procedure for the Reaction of Enol Carbamates with
Maleimides (3a–3q, 4b–4l, 5a, and 5b): To an oven-dried sealed
tube charged with 1-phenylvinyl N,N-dimethylcarbamate (1a,
38.2 mg, 0.2 mmol, 1 equiv.), [RhCp*Cl2]2 (3.1 mg, 0.005 mmol,
2.5 mol-%), AgSbF6 (13.7 mg, 0.02 mmol, 20 mol-%), and pivalic acid
(40.8 mg, 0.4 mmol, 2 equiv.) were added 1-methyl-(1H)-pyrrole-2,5-
dione (2a, 44.4 mg, 0.4 mmol, 2 equiv.) and DCE (1 mL). The reaction
mixture was allowed to stir at 70 °C for 20 h and then diluted with
EtOAc (3 mL). The resulting mixture was concentrated in vacuo. The
residue was purified by flash column chromatography (n-hexane/
Scheme 6. Kinetic isotope effect (KIE) experiments.
A plausible reaction mechanism is outlined in Scheme 7. The
coordination of a cationic RhIII catalyst and subsequent cleav-
age of the vinylic C–H bond of deuterio-1a affords six-mem- EtOAc, 2:1) to afford 3a (48.4 mg, 80 % yield).
bered rhodacycle intermediate A, which upon coordination of
(Z)-2-(1-Methyl-2,5-dioxopyrrolidin-3-yl)-1-phenylvinyl Dimeth-
ylcarbamate (3a): Light brown sticky oil (48.4 mg, 80 %). H NMR
(400 MHz, CDCl3): δ = 7.42 (dd, J = 8.0, 2.0 Hz, 2 H), 7.35–7.30 (m,
3 H), 5.83 (d, J = 8.0 Hz, 1 H), 3.85–3.80 (m, 1 H), 3.14 (s, 3 H), 3.07
(t, J = 9.6 Hz, 1 H), 3.02 (s, 3 H), 2.96 (s, 3 H), 2.70 (dd, J = 18.4,
5.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.7, 176.1,
153.3, 150.7, 134.5, 128.9, 128.5, 124.7, 112.1, 38.2, 36.8, 36.5, 35.5,
2a and migratory insertion delivers eight-membered rhoda-
cycle species B.[17] Finally, protonation by PivOH takes place to
generate alkylated product 3a, and the active RhIII complex fur-
ther recycles through the catalytic pathway. It should be noted
that the ꢀ-H elimination reaction, which would have led to the
corresponding Heck-type product, was not observed because
of the absence of a syn-planar ꢀ-hydrogen atom relative to the
Rh atom.
1
25.0 ppm. IR (KBr): ν = 3059, 2927, 1777, 1693, 1494, 1434, 1384,
˜
1279, 1157, 1118, 1048, 1028, 955, 862, 754 cm–1. HRMS (quadru-
pole, EI): calcd. for C16H18N2O4 [M]+ 302.1267; found 302.1265.
(Z)-2-(1-Methyl-2,5-dioxopyrrolidin-3-yl)-1-phenylvinyl Diethyl-
carbamate (3b): Brown sticky oil (42.3 mg, 64 %). 1H NMR
(400 MHz, CDCl3): δ = 7.40 (dd, J = 8.4, 2.0 Hz, 2 H), 7.35–7.29 (m,
3 H), 5.83 (d, J = 8.0 Hz, 1 H), 3.83–3.77 (m, 1 H), 3.52–3.44 (m, 2 H),
3.31 (q, J = 7.2 Hz, 2 H), 3.05 (dd, J = 18.4, 9.6 Hz, 1 H), 3.02 (s, 3
H), 2.70 (dd, J = 18.4, 5.6 Hz, 1 H), 1.28 (t, J = 7.2 Hz, 3 H), 1.15 (t,
J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.7, 176.1,
152.7, 150.7, 134.7, 128.8, 128.5, 124.8, 112.1, 42.1, 41.8, 38.2, 35.5,
25.0, 14.4, 13.2 ppm. IR (KBr): ν = 2976, 2931, 1778, 1696, 1473,
˜
1420, 1381, 1279, 1256, 1221, 1152, 1116, 1054, 1002, 960, 752 cm–1
.
HRMS (quadrupole, EI): calcd. for C18H22N2O4 [M]+ 330.1580; found
330.1581.
(Z)-2-(1-Methyl-2,5-dioxopyrrolidin-3-yl)-1-phenylvinyl Pyrrol-
idine-1-carboxylate (3c): Brown solid (34.1 mg, 52 %); m.p. 58.9–
62.8 °C. 1H NMR (400 MHz, CDCl3): δ = 7.42 (dd, J = 8.4, 2.0 Hz, 2
H), 7.34–7.29 (m, 3 H), 5.84 (d, J = 8.0 Hz, 1 H), 3.87–3.82 (m, 1 H),
3.58 (t, J = 7.2 Hz, 2 H), 3.41 (t, J = 6.4 Hz, 2 H), 3.05 (dd, J = 18.4,
9.6 Hz, 1 H), 3.01 (s, 3 H), 2.72 (dd, J = 18.4, 5.6 Hz, 1 H), 2.03–1.89
(m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.8, 176.2, 151.6,
150.5, 134.6, 128.8, 128.5, 124.8, 112.1, 46.6, 46.5, 38.3, 35.5, 25.8,
25.0, 24.9 ppm. IR (KBr): ν = 2924, 2876, 1776, 1694, 1405, 1382,
˜
1278, 1224, 1173, 1117, 1078, 1026, 954, 866, 754 cm–1. HRMS
(quadrupole, EI): calcd. for C18H20N2O4 [M]+ 328.1423; found
328.1424.
Scheme 7. Plausible reaction mechanism.
(Z)-2-(1-Methyl-2,5-dioxopyrrolidin-3-yl)-1-phenylvinyl Morph-
oline-4-carboxylate (3d): Brown sticky oil (35.1 mg, 51 %). 1H NMR
(400 MHz, CDCl3): δ = 7.41–7.33 (m, 5 H), 5.82 (d, J = 8.4 Hz, 1 H),
3.84–3.78 (m, 1 H), 3.74–3.65 (m, 6 H), 3.50 (br. s, 2 H), 3.07 (dd, J =
18.4, 9.6 Hz, 1 H), 3.02 (s, 3 H), 2.70 (dd, J = 18.4, 5.2 Hz, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 177.5, 176.0, 152.2, 150.6, 134.3,
129.1, 128.6, 124.7, 112.4, 66.6, 66.5, 45.0, 44.2, 38.2, 35.5, 25.1 ppm.
Conclusions
In summary, we described the rhodium(III)-catalyzed direct C–
H alkylation reaction of enol carbamates with maleimides to
afford biologically important succinimide-containing enol car-
bamates. These transformations have been applied to a wide
range of substrates, and typically proceed with excellent levels IR (KBr): ν = 3060, 2923, 2855, 1778, 1697, 1495, 1428, 1384, 1360,
˜
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1277, 1220, 1113, 1068, 754 cm–1. HRMS (quadrupole, EI): calcd. for 1H NMR (400 MHz, CDCl3): δ = 7.32 (d, J = 8.8 Hz, 2 H), 6.84 (d, J =
C18H20N2O5 [M]+ 344.1372; found 344.1373.
8.8 Hz, 2 H), 5.70 (d, J = 8.4 Hz, 1 H), 3.83–3.77 (m, 4 H), 3.12 (s, 3
H), 3.04 (dd, J = 18.4, 9.6 Hz, 1 H), 3.01 (s, 3 H), 2.95 (s, 3 H), 2.68
(dd, J = 18.4, 5.2 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
177.9, 176.2, 160.1, 153.4, 150.5, 127.1, 126.2, 113.9, 110.3, 55.2, 38.2,
(Z)-2-(1-Methyl-2,5-dioxopyrrolidin-3-yl)-1-o-tolylvinyl Dimeth-
ylcarbamate (3e): Brown sticky oil (48.7 mg, 77 %). 1H NMR
(400 MHz, CDCl3): δ = 7.34 (d, J = 7.2 Hz, 1 H), 7.21–7.19 (m, 1 H),
7.16–7.13 (m, 2 H), 5.35 (d, J = 8.4 Hz, 1 H), 3.87–3.81 (m, 1 H), 3.08
(dd, J = 18.4, 9.6 Hz, 1 H), 3.01 (d, J = 3.6 Hz, 6 H), 2.86 (s, 3 H), 2.68
(dd, J = 18.4, 5.6 Hz, 1 H), 2.41 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 177.7, 176.2, 153.1, 151.2, 135.9, 135.0, 130.4, 129.1,
128.8, 125.6, 115.3, 38.0, 36.5, 36.3, 35.7, 25.0, 20.1 ppm. IR (KBr):
36.7, 36.4, 35.6, 25.0 ppm. IR (KBr): ν = 2928, 2853, 1777, 1696, 1607,
˜
1511, 1434, 1383, 1280, 1248, 1158, 1115, 1027, 827, 756 cm–1
.
HRMS (quadrupole, EI): calcd. for C17H20N2O5 [M]+ 332.1372; found
332.1375.
(Z)-1-(4-Bromophenyl)-2-(1-methyl-2,5-dioxopyrrolidin-3-
yl)vinyl Dimethylcarbamate (3k): Brown sticky oil (48.0 mg, 63 %).
1H NMR (400 MHz, CDCl3): δ = 7.46 (d, J = 8.4 Hz, 2 H), 7.26 (d, J =
8.8 Hz, 2 H), 5.82 (d, J = 8.0 Hz, 1 H), 3.83–3.77 (m, 1 H), 3.13 (s, 3
H), 3.06 (dd, J = 18.4, 9.2 Hz, 1 H), 2.99 (s, 3 H), 2.95 (s, 3 H), 2.68
(dd, J = 18.4, 5.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
177.5, 176.0, 153.2, 149.9, 133.7, 131.7, 126.4, 123.0, 112.8, 38.2, 36.8,
ν = 2925, 2855, 1778, 1697, 1487, 1433, 1383, 1279, 1221, 1157,
˜
1117, 1036, 754 cm–1. HRMS (quadrupole, EI): calcd. for C17H20N2O4
[M]+ 316.1423; found 316.1426.
(Z)-1-(2-Fluorophenyl)-2-(1-methyl-2,5-dioxopyrrolidin-3-yl)-
vinyl Dimethylcarbamate (3f): Brown sticky oil (34.0 mg, 53 %).
1H NMR (400 MHz, CDCl3): δ = 7.34 (td, J = 8.8, 1.6 Hz, 1 H), 7.28–
7.26 (m, 1 H), 7.13–7.02 (m, 2 H), 5.88 (d, J = 8.4 Hz, 1 H), 3.88–3.83
(m, 1 H), 3.09 (s, 3 H), 3.05–2.96 (m, 4 H), 2.93 (s, 3 H), 2.70 (dd, J =
18.4, 5.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.6, 176.1,
159.5 (d, JC,F = 249.9 Hz), 153.3, 145.8 (d, JC,F = 3.4 Hz), 130.2 (d,
JC,F = 8.7 Hz), 128.1 (d, JC,F = 2.3 Hz), 124.1 (d, JC,F = 3.6 Hz), 122.7,
116.6 (d, JC,F = 8.2 Hz), 116.2 (d, JC,F = 22.5 Hz), 38.2, 36.7, 36.4, 35.5,
36.5, 35.4, 25.1 ppm. IR (KBr): ν = 2924, 2854, 1779, 1696, 1588,
˜
1486, 1434, 1383, 1280, 1157, 1115, 1072, 1007, 812, 754 cm–1
.
HRMS (quadrupole, EI): calcd. for C16H17BrN2O4 [M]+ 380.0372;
found 380.0371.
(Z)-1-(4-Fluorophenyl)-2-(1-methyl-2,5-dioxopyrrolidin-3-
yl)vinyl Dimethylcarbamate (3l): Brown sticky oil (39.7 mg, 62 %).
1H NMR (400 MHz, CDCl3): δ = 7.40–7.37 (m, 2 H), 7.04–6.99 (m, 2
H), 5.75 (d, J = 8.0 Hz, 1 H), 3.83–3.78 (m, 1 H), 3.13 (s, 3 H), 3.06
(dd, J = 18.0, 9.2 Hz, 1 H), 3.01 (s, 3 H), 2.95 (s, 3 H), 2.68 (dd, J =
18.4, 5.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.7, 176.1,
163.0 (d, JC,F = 247.4 Hz), 153.3, 149.9, 130.8 (d, JC,F = 3.3 Hz), 126.7
(d, JC,F = 8.2 Hz), 115.6 (d, JC,F = 21.8 Hz), 112.0, 38.1, 36.8, 36.4,
25.0 ppm. IR (KBr): ν = 2926, 2855, 1779, 1697, 1612, 1488, 1435,
˜
1384, 1280, 1220, 1156, 1117, 1049, 753 cm–1. HRMS (quadrupole,
EI): calcd. for C16H17FN2O4 [M]+ 320.1172; found 320.1169.
(Z)-1-(3-Chlorophenyl)-2-(1-methyl-2,5-dioxopyrrolidin-3-
yl)vinyl Dimethylcarbamate (3g): Brown sticky oil (44.5 mg, 66 %).
1H NMR (400 MHz, CDCl3): δ = 7.36 (s, 1 H), 7.29–7.24 (m, 3 H), 5.82
(d, J = 8.0 Hz, 1 H), 3.83–3.77 (m, 1 H), 3.12 (s, 3 H), 3.04 (dd, J =
18.4, 9.6 Hz, 1 H), 3.0 (s, 3 H), 2.94 (s, 3 H), 2.67 (dd, J = 18.0, 5.6 Hz,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.5, 175.9, 153.2, 149.5,
136.5, 134.6, 129.8, 128.9, 125.0, 122.9, 113.5, 38.2, 36.8, 36.5, 35.3,
35.4, 25.0 ppm. IR (KBr): ν = 3073, 2926, 1779, 1694, 1603, 1508,
˜
1435, 1385, 1281, 1232, 1154, 1119, 829, 756 cm–1. HRMS (quadru-
pole, EI): calcd. for C16H17FN2O4 [M]+ 320.1172; found 320.1175.
(Z)-2-(1-Methyl-2,5-dioxopyrrolidin-3-yl)-1-[4-(trifluoro-
methyl)phenyl]vinyl Dimethylcarbamate (3m): Brown sticky oil
25.0 ppm. IR (KBr): ν = 2928, 2855, 1779, 1697, 1594, 1566, 1434,
˜
1
(42.2 mg, 57 %). H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 8.4 Hz,
1384, 1280, 1221, 1157, 1117, 1048, 865, 754 cm–1. HRMS (quadru-
pole, EI): calcd. for C16H17ClN2O4 [M]+ 336.0877; found 336.0877.
2 H), 7.51 (d, J = 8.4 Hz, 2 H), 5.91 (d, J = 8.0 Hz, 1 H), 3.88–3.82 (m,
1 H), 3.15 (s, 3 H), 3.08 (dd, J = 18.4, 9.6 Hz, 1 H), 3.02 (s, 3 H), 2.96
(s, 3 H), 2.70 (dd, J = 18.4, 5.6 Hz, 1 H) ppm. 13C NMR (100 MHz,
(Z)-1-(3-Methoxyphenyl)-2-(1-methyl-2,5-dioxopyrrolidin-3-
yl)vinyl Dimethylcarbamate (3h): Yellow solid (39.9 mg, 60 %);
m.p. 148.2–149.4 °C. 1H NMR (400 MHz, CDCl3): δ = 7.28 (d, J =
5.6 Hz, 1 H), 7.02 (d, J = 8.0 Hz, 1 H), 6.96 (s, 1 H), 6.87 (d, J = 8.4 Hz,
1 H), 5.86 (d, J = 8.0 Hz, 1 H), 3.87–3.84 (m, 1 H), 3.82 (s, 3 H), 3.17
(s, 3 H), 3.10 (dd, J = 18.4, 9.2 Hz, 1 H), 3.05 (s, 3 H), 2.99 (s, 3 H),
2.73 (dd, J = 18.4, 5.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
177.7, 176.1, 159.6, 153.3, 150.5, 136.0, 129.6, 117.2, 114.3, 112.4,
CDCl3): δ = 177.3, 175.9, 153.1, 149.5, 138.1, 138.0, 130.7 (q, JC,F
32.6 Hz), 127.9, 125.6 (q, JC,F = 3.9 Hz), 125.0, 122.4 (q, JC,F
=
=
270.5 Hz), 114.3, 38.2, 36.8, 36.5, 35.3, 25.1 ppm. IR (KBr): ν = 2923,
˜
2854, 1779, 1697, 1617, 1435, 1387, 1322, 1281, 1159, 1110, 1067,
1013, 955, 823, 755 cm–1. HRMS (quadrupole, EI): calcd. for
C17H17F3N2O4 [M]+ 370.1140; found 370.1142.
(Z)-3,3-Dimethyl-1-(1-methyl-2,5-dioxopyrrolidin-3-yl)but-1-en-
2-yl Dimethylcarbamate (3n): Colorless sticky oil (28.8 mg, 51 %).
1H NMR (400 MHz, CDCl3): δ = 5.22 (d, J = 8.0 Hz, 1 H), 3.56–3.51
(m, 1 H), 3.02 (s, 3 H), 2.99–2.92 (m, 7 H), 2.55 (dd, J = 18.4, 5.6 Hz,
1 H), 1.08 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 178.4, 176.6,
159.3, 153.4, 109.2, 38.3, 36.7, 36.5, 36.3, 35.5, 27.8, 24.9 ppm. IR
110.6, 55.2, 38.2, 36.8, 36.5, 35.5, 25.0 ppm. IR (KBr): ν = 2924, 2854,
˜
2352, 1777, 1696, 1600, 1579, 1487, 1433, 1384, 1281, 1159, 1118,
1038, 955, 877, 755 cm–1. HRMS (quadrupole, EI): calcd. for
C17H20N2O5 [M]+ 332.1372; found 332.1375.
(Z)-2-(1-Methyl-2,5-dioxopyrrolidin-3-yl)-1-(naphthalen-2-
yl)vinyl Dimethylcarbamate (3i): Brown sticky oil (31.0 mg, 44 %).
1H NMR (400 MHz, CDCl3): δ = 7.38–7.79 (m, 4 H), 7.53 (dd, J = 8.8,
2.0 Hz, 1 H), 7.48–7.47 (m, 2 H), 5.96 (d, J = 8.0 Hz, 1 H), 3.91–3.85
(m, 1 H), 3.21 (s, 3 H), 3.09 (dd, J = 18.4, 9.2 Hz, 1 H), 3.04 (s, 3 H),
2.98 (s, 3 H), 2.75 (dd, J = 18.4, 5.6 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 177.7, 176.2, 153.4, 150.8, 133.4, 133.0, 131.9, 128.4,
127.6, 126.5, 126.4, 124.1, 122.5, 112.7, 38.3, 36.8, 36.5, 35.5,
(KBr): ν = 2961, 2934, 2872, 1779, 1696, 1435, 1384, 1279, 1160,
˜
1120, 1055, 955, 756 cm–1. HRMS (quadrupole, EI): calcd. for
C14H22N2O4 [M]+ 282.1580; found 282.1581.
2-(1-Methyl-2,5-dioxopyrrolidin-3-yl)-3,4-dihydronaphthalen-1-
yl Dimethylcarbamate (3o): Yellow sticky solid (17 mg, 26 %). 1H
NMR (400 MHz, CDCl3): δ = 7.18–7.14 (m, 2 H), 7.12–7.10 (m, 1 H),
7.07–7.05 (m, 1 H), 3.97–3.93 (m, 1 H), 3.15 (s, 3 H), 3.07–3.00 (m, 4
H), 2.99 (s, 3 H), 2.89 (t, J = 8.0 Hz, 2 H), 2.70 (dd, J = 18.8, 5.2 Hz,
1 H), 2.31 (t, J = 8.4 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
177.3, 176.5, 153.8, 143.8, 135.6, 130.7, 128.0, 127.3, 126.5, 121.9,
25.1 ppm. IR (KBr): ν = 3056, 2926, 2855, 1778, 1695, 1598, 1433,
˜
1382, 1354, 1279, 1221, 1156, 1127, 1047, 954, 864, 817, 753 cm–1
.
HRMS (quadrupole, EI): calcd. for C20H20N2O4 [M]+ 352.1423; found
352.1425.
121.0, 41.5, 36.8, 36.4, 34.2, 27.5, 25.0 ppm. IR (KBr): ν = 2931, 1776,
˜
(Z)-1-(4-Methoxyphenyl)-2-(1-methyl-2,5-dioxopyrrolidin-3-
yl)vinyl Dimethylcarbamate (3j): Yellow sticky oil (36.5 mg, 55 %).
1698, 1434, 1387, 1278, 1185, 1117, 1074, 767 cm–1. HRMS (quadru-
pole, EI): calcd. for C18H20N2O4 [M]+ 328.1423; found 328.1424.
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(Z)-1-(Benzo[b]thiophen-3-yl)-2-(1-methyl-2,5-dioxopyrrolidin-
3-yl)vinyl Dimethylcarbamate (3p): Yellow sticky solid (30.8 mg,
43 %). H NMR (400 MHz, CDCl3): δ = 7.98 (d, J = 7.2 Hz, 1 H), 7.83
1775, 1699, 1446, 1394, 1342, 1263, 1158, 1052, 755 cm–1. HRMS
(quadrupole, EI): calcd. for C19H24N2O4 [M]+ 344.1736; found
344.1738.
1
(d, J = 7.2 Hz, 1 H), 7.53 (s, 1 H), 7.42–7.33 (m, 2 H), 5.77 (d, J =
8.0 Hz, 1 H), 3.92–3.89 (m, 1 H), 3.15 (dd, J = 17.2, 7.6 Hz, 1 H), 3.10
(s, 3 H), 3.03 (s, 3 H), 2.90 (s, 3 H), 2.75 (dd, J = 18.4, 5.6 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.2, 176.1, 153.3, 146.4,
140.3, 136.4, 131.5, 125.9, 124.6, 122.9, 122.7, 114.6, 38.1, 36.7, 36.5,
(Z)-2-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)-1-phenylvinyl Dimeth-
ylcarbamate (4f): Brown sticky oil (47.4 mg, 65 %). 1H NMR
(400 MHz, CDCl3): δ = 7.50–7.44 (m, 4 H), 7.41–7.37 (m, 1 H), 7.35–
7.30 (m, 5 H), 5.96 (d, J = 7.6 Hz, 1 H), 4.05–3.99 (m, 1 H), 3.24 (dd,
J = 18.4, 9.6 Hz, 1 H), 3.15 (s, 3 H), 2.97 (s, 3 H), 2.90 (dd, J = 18.4,
6.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 176.5, 175.0, 153.4,
150.9, 134.5, 131.8, 129.1, 129.0, 128.6, 126.3, 124.8, 112.0, 38.4, 36.8,
35.6, 25.1 ppm. IR (KBr): ν = 2929, 1776, 1697, 1434, 1385, 1281,
˜
1160, 1126, 1055, 955, 756 cm–1. HRMS (quadrupole, EI): calcd. for
C
18H18N2O4S [M]+ 358.0987; found 358.0984.
36.5, 35.6 ppm. IR (KBr): ν = 3062, 2927, 2855, 1778, 1706, 1597,
˜
1496, 1445, 1382, 1262, 1157, 1051, 862, 756, 697 cm–1. HRMS
(quadrupole, EI): calcd. for C21H20N2O4 [M]+ 364.1423; found
364.1420.
(1Z,1′Z)-1,4-Phenylenebis[2-(1-methyl-2,5-dioxopyrrolidin-3-
yl)ethene-1,1-diyl] Bis(dimethylcarbamate) (3q): Yellow solid
(82.1 mg, 78 %); m.p. 130.2–135.8 °C. 1H NMR (400 MHz, CDCl3): δ =
7.38 (s, 4 H), 5.85 (d, J = 8.4 Hz, 2 H), 3.85–3.79 (m, 2 H), 3.14 (s, 6
H), 3.09–3.03 (m, 2 H), 3.02 (s, 6 H), 2.96 (s, 6 H), 2.70 (dd, J = 18.0,
5.2 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.6, 176.1, 153.2,
150.1, 135.0, 125.0, 112.8, 38.2, 36.8, 36.5, 35.4, 25.1 ppm. IR (KBr):
(Z)-2-(1-Benzyl-2,5-dioxopyrrolidin-3-yl)-1-phenylvinyl Dimeth-
ylcarbamate (4g): Dark brown sticky oil (56.8 mg, 75 %). 1H NMR
(400 MHz, CDCl3): δ = 7.42–7.40 (m, 4 H), 7.33–7.30 (m, 6 H), 5.82
(d, J = 8.0 Hz, 1 H), 4.68 (s, 2 H), 3.86–3.81 (m, 1 H), 3.11 (s, 3 H),
3.07 (dd, J = 18.4, 9.2 Hz, 1 H), 2.95 (s, 3 H), 2.70 (dd, J = 18.4, 5.6 Hz,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.3, 175.7, 153.3, 150.7,
135.6, 134.5, 129.0, 128.9, 128.6, 128.5, 127.9, 124.7, 112.0, 42.6, 38.2,
ν = 2932, 1713, 1701, 1466, 1436, 1389, 1279, 1167, 1118, 755 cm–1
.
˜
HRMS (quadrupole, EI): calcd. for C26H30N4O8 [M]+ 526.2064; found
526.2067.
36.7, 36.4, 35.4 ppm. IR (KBr): ν = 3033, 2925, 2854, 1777, 1699,
˜
(Z)-2-(1-Ethyl-2,5-dioxopyrrolidin-3-yl)-1-phenylvinyl Dimethyl-
carbamate (4b): Yellow sticky oil (47.5 mg, 75 %). 1H NMR
(400 MHz, CDCl3): δ = 7.43–7.38 (m, 2 H), 7.35–7.28 (m, 3 H), 5.83
(d, J = 7.9 Hz, 1 H), 3.84–3.78 (m, 1 H), 3.59 (q, J = 7.2 Hz, 2 H), 3.15
(s, 3 H), 3.04 (dd, J = 18.3, 9.4 Hz, 1 H), 2.96 (s, 3 H), 2.68 (dd, J =
18.3, 5.6 Hz, 1 H), 1.18 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 177.7, 176.1, 153.6, 150.9, 134.8, 129.1, 128.7, 125.0,
1495, 1432, 1394, 1324, 1282, 1162, 1122, 1069, 1014, 754 cm–1
.
HRMS (quadrupole, EI): calcd. for C22H22N2O4 [M]+ 378.1580; found
378.1577.
(Z)-2-(1-Allyl-2,5-dioxopyrrolidin-3-yl)-1-phenylvinyl Dimethyl-
carbamate (4h): Brown sticky oil (25.0 mg, 38 %). 1H NMR
(400 MHz, CDCl3): δ = 7.43–7.40 (m, 2 H), 7.36–7.30 (m, 3 H), 5.85–
5.82 (m, 1 H), 5.81–5.75 (m, 1 H), 5.27–5.22 (m, 1 H), 5.21–5.18 (m,
1 H), 4.14 (d, J = 6.0 Hz, 2 H), 3.88–3.82 (m, 1 H), 3.15 (s, 3 H), 3.08
(dd, J = 18.4, 9.6 Hz, 1 H), 2.97 (s, 3 H), 2.71 (dd, J = 18.4, 5.6 Hz, 1
H) ppm. 13C NMR (175 MHz, CDCl3): δ = 177.1, 175.6, 153.4, 150.8,
134.6, 130.6, 129.0, 128.6, 124.8, 118.6, 112.1, 41.1, 38.2, 36.8, 36.5,
112.4, 38.4, 37.0, 36.7, 35.7, 34.2, 13.2 ppm. IR (KBr): ν = 2977, 2935,
˜
1774, 1696, 1494, 1443, 1398, 1346, 1262, 1223, 1157, 1124, 1048,
753 cm–1. HRMS (quadrupole, EI): calcd. for C17H20N2O4 [M]+
316.1423; found 316.1424.
(Z)-2-(2,5-Dioxopyrrolidin-3-yl)-1-phenylvinyl Dimethylcarb-
amate (4c): Pale yellow solid (35.7 mg, 62 %); m.p. 151.9–154.9 °C.
1H NMR (500 MHz, CDCl3): δ = 8.19 (br. s, 1 H), 7.42 (dd, J = 8.2,
1.8 Hz, 2 H), 7.35–7.29 (m, 3 H), 5.85 (d, J = 8.1 Hz, 1 H), 3.91–3.87
(m, 1 H), 3.15 (s, 3 H), 3.08 (dd, J = 18.5, 9.5 Hz, 1 H), 2.97 (s, 3 H),
2.77 (dd, J = 18.5, 5.9 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
177.8, 176.0, 153.6, 151.1, 134.7, 129.2, 128.8, 125.0, 111.9, 39.8, 37.0,
35.5 ppm. IR (KBr): ν = 2924, 2854, 1775, 1701, 1494, 1391, 1333,
˜
1265, 1160, 757 cm–1. HRMS (quadrupole, EI): calcd. for C18H20N2O4
[M]+ 328.1423; found 328.1419.
Methyl (Z)-3-[2-(Dimethylcarbamoyloxy)-2-phenylvinyl]-2,5-di-
oxopyrrolidine-1-carboxylate (4i): Yellow sticky oil (22.2 mg,
1
32 %). H NMR (400 MHz, CDCl3): δ = 7.42–7.40 (m, 2 H), 7.35–7.33
36.9, 36.7 ppm. IR (KBr): ν = 3214, 3082, 2925, 1783, 1710, 1494,
˜
(m, 3 H), 5.86 (d, J = 8.0 Hz, 1 H), 4.0 (s, 3 H), 3.94–3.88 (m, 1 H),
3.18–3.11 (m, 4 H), 2.96 (s, 3 H), 2.82 (dd, J = 18.4, 6.4 Hz, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 173.0, 171.3, 153.2, 151.4, 148.7,
134.3, 129.2, 128.6, 124.8, 111.0, 55.0, 38.6, 36.8, 36.5, 35.8 ppm. IR
1446, 1395, 1345, 1266, 1165, 758 cm–1. HRMS (quadrupole, EI):
calcd. for C15H16N2O4 [M]+ 288.1110; found 288.1107.
(Z)-2-(1-Cyclohexyl-2,5-dioxopyrrolidin-3-yl)-1-phenylvinyl
Dimethylcarbamate (4d): Yellow oil (64.5 mg, 87 %). 1H NMR
(400 MHz, CDCl3): δ = 7.43–7.40 (m, 2 H), 7.37–7.28 (m, 3 H), 5.82
(d, J = 7.7 Hz, 1 H), 4.03–3.95 (m, 1 H), 3.78–3.73 (m, 1 H), 3.15 (s, 3
H), 3.01 (dd, J = 18.2, 9.4 Hz, 1 H), 3.03–2.94 (m, 4 H), 2.63 (dd, J =
18.2, 5.8 Hz, 1 H), 2.19–2.11 (m, 2 H), 1.83–1.80 (m, 2 H), 1.66–1.57
(m, 3 H), 1.36–1.18 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
177.9, 176.3, 153.6, 150.8, 134.9, 129.0, 128.7, 125.0, 112.8, 52.1, 38.2,
(KBr): ν = 3062, 2925, 2854, 1814, 1768, 1722, 1495, 1439, 1394,
˜
1323, 1254, 1160, 1058, 757 cm–1. HRMS (quadrupole, EI): calcd. for
C17H18N2O6 [M]+ 346.1165; found 346.1166.
Ethyl (Z)-3-[2-(Dimethylcarbamoyloxy)-2-phenylvinyl]-2,5-diox-
opyrrolidine-1-carboxylate (4j): Brown sticky oil (17.3 mg, 24 %).
1H NMR (400 MHz, CDCl3): δ = 7.42–7.40 (m, 2 H), 7.36–7.32 (m, 3
H), 5.86 (d, J = 8.0 Hz, 1 H), 4.44 (q, J = 7.1 Hz, 2 H), 3.93–3.87 (m,
1 H), 3.17–3.10 (m, 4 H), 2.96 (s, 3 H), 2.82 (dd, J = 18.6, 6.6 Hz, 1
H), 1.41 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
173.3, 171.6, 153.4, 151.5, 148.3, 134.5, 129.3, 128.8, 125.0, 111.3,
37.0, 36.7, 35.6, 29.1, 28.8, 26.1, 26.0, 25.2 ppm. IR (KBr): ν = 2929,
˜
2856, 1771, 1696, 1446, 1393, 1371, 1259, 1187, 1157, 1051, 983,
753 cm–1. HRMS (quadrupole, EI): calcd. for C21H26N2O4 [M]+
370.1893; found 370.1895.
65.1, 38.8, 37.0, 36.7, 36.0, 14.1 ppm. IR (KBr): ν = 2925, 2855, 1809,
˜
1765, 1717, 1494, 1394, 1325, 1239, 1153, 1026, 861, 753 cm–1
.
(Z)-2-(1-tert-Butyl-2,5-dioxopyrrolidin-3-yl)-1-phenylvinyl Di-
methylcarbamate (4e): Yellow oil (57.2 mg, 83 %). 1H NMR
(400 MHz, CDCl3): δ = 7.43–7.40 (m, 2 H), 7.36–7.29 (m, 3 H), 5.83
(d, J = 7.7 Hz, 1 H), 3.72–3.66 (m, 1 H), 3.15 (s, 3 H), 2.96–2.89 (m, 4
H), 2.57 (dd, J = 18.0, 6.3 Hz, 1 H), 1.58 (s, 9 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 178.8, 177.2, 153.7, 150.6, 135.0, 129.0, 128.7,
HRMS (quadrupole, EI): calcd. for C18H20N2O6 [M]+ 360.1321; found
360.1320.
Methyl (2S)-2-(3-{(Z)-2-[(Dimethylcarbamoyl)oxy]-2-phenyl-
vinyl}-2,5-dioxopyrrolidin-1-yl)propanoate (4k): Yellow sticky oil
1
(62.1 mg, 83 %, dr 1:1). H NMR (400 MHz, CDCl3): δ = 7.44 (d, J =
125.0, 113.1, 58.8, 38.6, 37.0, 36.7, 36.1, 28.6 ppm. IR (KBr): ν = 2933,
8.0 Hz, 2 H), 7.36–7.31 (m, 3 H), 5.84 (dd, J = 7.9, 3.2 Hz, 1 H), 4.83
˜
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(q, J = 7.2 Hz, 1 H), 3.94–3.87 (m, 1 H), 3.74 (s, 3 H), 3.16 (s, 3 H), 2 H), 3.62 (dd, J = 18.5, 3.5 Hz, 1 H), 3.43 (dd, J = 18.5, 7.5 Hz, 1 H),
3.11 (dq, J = 18.4, 2.8 Hz, 1 H), 2.97 (s, 3 H), 2.74 (dq, J = 18.4, 2.8 Hz,
3.26–3.23 (m, 1 H), 3.04 (s, 3 H), 3.01 (t, J = 9.0 Hz, 1 H), 2.44 (dd,
1 H), 1.58 (d, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
J = 18.0, 5.0 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 196.7,
176.9, 176.8, 175.2, 169.8, 169.7, 153.6, 151.0, 134.7, 129.2, 128.8, 179.7, 176.5, 135.8, 133.7, 128.7, 127.9, 38.9, 35.7, 34.7, 24.9 ppm. IR
125.0, 112.2, 112.1, 53.0, 48.4, 48.4, 38.4, 37.0, 36.7, 35.7, 35.6, 14.7, (KBr): ν = 3062, 2922, 1775, 1682, 1596, 1436, 1384, 1280, 1125,
˜
14.5 ppm. IR (KBr): ν = 2926, 1779, 1708, 1446, 1392, 1261, 1161,
1017, 758 cm–1. HRMS (quadrupole, EI): calcd. for C13H13NO3 [M]+
231.0895; found 231.0894.
˜
1119, 758 cm–1. HRMS (quadrupole, EI): calcd. for C19H22N2O6 [M]+
374.1478; found 374.1483.
Reductive Cleavage of an Enol Carbamate Group: To a stirred
solution of 3a (60.5 mg, 0.2 mmol, 1 equiv.) in MeOH (1 mL) was
added 10 % Pd/C (21.3 mg, 0.02 mmol, 10 mol-%). The reaction
mixture was stirred under a hydrogen balloon for 24 h and then
concentrated in vacuo. The residue was purified by flash column
chromatography (n-hexane/EtOAc, 3:1) to afford 6b (35.0 mg, 80 %
yield).
(Z)-2-{1-[2-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl]-2,5-di-
oxopyrrolidin-3-yl}-1-phenylvinyl Dimethylcarbamate (4l): Light
yellow sticky oil (51.9 mg, 63 %). 1H NMR (400 MHz, CDCl3): δ = 7.43
(d, J = 8.1 Hz, 2 H), 7.36–7.30 (m, 3 H), 6.67 (s, 2 H), 5.82 (d, J =
8.4 Hz, 1 H), 3.83–3.72 (m, 5 H), 3.15 (s, 3 H), 3.04–2.96 (m, 4 H),
2.62 (dd, J = 18.4, 5.4 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
178.0, 176.4, 171.0, 153.6, 150.8, 134.8, 134.4, 129.1, 128.7, 125.0,
112.3, 38.2, 38.1, 37.0, 36.7, 36.1, 35.6 ppm. IR (KBr): ν = 2925, 2855,
˜
2-(1-Methyl-2,5-dioxopyrrolidin-3-yl)-1-phenylethane (6b):
Light yellow oil (35.0 mg, 80 %). 1H NMR (500 MHz, CDCl3): δ =
7.30–7.27 (m, 2 H), 7.21–7.17 (m, 3 H), 2.95 (s, 3 H), 2.83–2.67 (m, 4
H), 2.36 (dd, J = 17.3, 3.8 Hz, 1 H), 2.29–2.22 (m, 1 H), 1.84–1.76 (m,
1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 180.0, 176.6, 140.4, 128.7,
1775, 1700, 1495, 1435, 1393, 1358, 1322, 1150, 1060, 827, 753,
697 cm–1. HRMS (quadrupole, EI): calcd. for C21H21N3O6 [M]+
411.1430; found 411.1433.
(Z)-1-(4-Acetylphenyl)-2-(1-methyl-2,5-dioxopyrrolidin-3-
yl)vinyl Dimethylcarbamate (5a): Colorless sticky solid (37.8 mg,
128.6, 126.5, 39.3, 34.5, 33.2, 33.0, 24.9 ppm. IR (KBr): ν = 2922, 2853,
˜
1774, 1694, 1434, 1381, 1277, 1122, 955 cm–1. HRMS (quadrupole,
EI): calcd. for C13H15NO2 [M]+ 217.1103; found 217.1100.
1
55 %). H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 8.4 Hz, 2 H), 7.49
(d, J = 8.4 Hz, 2 H), 5.96 (d, J = 8.0 Hz, 1 H), 3.88–3.82 (m, 1 H), 3.15
(s, 3 H), 3.07 (dd, J = 18.4, 8.4 Hz, 1 H), 3.02 (s, 3 H), 2.96 (s, 3 H),
2.71 (dd, J = 18.4, 5.6 Hz, 1 H), 2.58 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 197.3, 177.4, 175.9, 153.1, 149.9, 138.9, 137.0, 128.6,
Experimental Procedure and Characterization Data for the
Preparation of Deuterio-1a: To an oven-dried round-bottom flask
charged with sodium hydride (60 % suspension in oil, 400 mg,
10.0 mmol) was added [D6]DMSO (8 mL) at room temperature. The
reaction mixture was stirred at 50 °C for 2 h, and the resulting
mixture was cooled to room temperature. To the reaction mixture
was added dropwise a solution of [D3]acetophenone (0.99 g,
8 mmol) in [D6]DMSO (1 mL) over 10 min, and the resulting mixture
was further stirred at room temperature for 30 min. To this mixture
was added dropwise a solution of dimethylcarbamoyl chloride
(1.08 g, 10.0 mmol) in [D6]DMSO (1 mL) at room temperature over
10 min. The reaction mixture was stirred overnight and then
quenched with D2O (10 mL). The mixture was extracted with EtOAc
(3 × 20 mL). The combined organic layers were washed with water
and brine, dried with MgSO4, and concentrated in vacuo. The resi-
due was purified by flash column chromatography (n-hexane/
EtOAc, 6:1) to afford deuterio-1a (0.485 g, 32 % yield). 1H NMR anal-
ysis showed a mixture of three products d2-1a/(E)-d1-1a/(Z)-d1-1a,
124.8, 114.4, 38.3, 36.8, 36.5, 35.3, 26.6, 25.1 ppm. IR (KBr): ν = 2924,
˜
1779, 1707, 1689, 1435, 1385, 1359, 1266, 1159, 1116, 1047,
756 cm–1. HRMS (quadrupole, EI): calcd. for C18H20N2O5 [M]+
344.1372; found 344.1370.
(8R,9S,13S,14S)-13-Methyl-16-(1-methyl-2,5-dioxopyrrolidin-3-
yl)-7,8,9,11,12,13,14,15-octahydro-6H-cyclopenta[a]phenan-
threne-3,17-diyl Bis(dimethylcarbamate) (5b): Light yellow solid
(66.0 mg, 63 %, dr 1.2:1); m.p. 120.0–125.7 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.20 (d, J = 8.8 Hz, 1 H), 6.84 (d, J = 8.4 Hz, 1 H), 6.80
(s, 1 H), 3.74–3.71 (m, 0.57 H, diastereomeric), 3.65–3.62 (m, 0.43 H,
diastereomeric), 3.07 (s, 3 H), 3.05–2.90 (m, 13 H), 2.86–2.84 (m, 2
H), 2.66–2.57 (m, 1 H), 2.33–2.27 (m, 2 H), 2.16–1.96 (m, 2 H), 1.87–
1.80 (m, 2 H), 1.71–1.69 (m, 2 H), 1.60–1.50 (m, 2 H), 1.43–1.41 (m,
1 H), 0.96 (s, 1.64 H, diastereomeric), 0.89 (s, 1.32 H, diastereo-
meric) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.6, 177.1, 176.7,
157.6, 157.1, 155.1, 153.9, 153.7, 149.2, 137.3, 137.1, 125.7, 121.7,
120.6, 120.5, 118.7, 52.1, 51.8, 45.8, 44.3, 44.2, 39.4, 38.6, 36.8, 36.7,
36.6, 36.4, 36.38, 36.30, 33.9, 33.5, 33.2, 33.1, 29.7, 29.2, 28.5, 26.7,
1
96:2:2; colorless oil. H NMR (500 MHz, CDCl3): δ = 7.49–7.46 (m, 2
H), 7.37–7.28 (m, 3 H), 5.41 (s, 0.02 H), 5.02 (s, 0.02 H), 3.12 (s, 3 H),
2.98 (s, 3 H) ppm.
25.7, 24.8, 15.8, 15.1 ppm. IR (KBr): ν = 2932, 1743, 1701, 1486, 1436,
˜
1389, 1279, 1187, 1065, 759 cm–1. HRMS (quadrupole, EI): calcd. for
C29H37N3O6 [M]+ 523.2682; found 523.2682.
Kinetic Isotope Effect (KIE) Experiments: To an oven-dried sealed
tube charged with 1-phenylvinyl N,N-dimethylcarbamate (1a,
38.2 mg, 0.2 mmol, 1 equiv.), [RhCp*Cl2]2 (2.5 mol-%), AgSbF6
(20 mol-%), and PivOH (2 equiv.) in DCE (1 mL) were added N-
methylmaleimide (2a, 44.4 mg, 0.4 mmol, 2 equiv.) and bromoben-
zene (157.0 mg, 5 equiv.) as an internal standard. In another reac-
tion tube, deuterio-1a (98 % D, 38.6 mg, 0.2 mmol, 1 equiv.) was
used instead of 1a. The two reactions were allowed to stir at 70 °C.
An aliquot of each reaction mixture was removed at 10, 20, 30, 40,
and 50 min intervals. The corresponding yield of product for each
sample was determined by GC analysis (bromobenzene as an inter-
nal standard). A kinetic isotope effect value (kH/kD) of 1.11 was ob-
served.
Cleavage of an Enol Carbamate Group by Using TMSOTf: To an
oven-dried sealed tube charged with 3a (60.5 mg, 0.2 mmol,
1 equiv.) in CH2Cl2 (2 mL) was added TMSOTf (88.9 mg, 0.4 mmol,
2 equiv.) at 0 °C under N2. The reaction mixture was allowed to stir
at room temperature for 3 h. The resulting mixture was quenched
with H2O (10 mL), and the aqueous layer was extracted with EtOAc
(2 × 20 mL). The combined organic layers were washed with H2O
and brine, dried with MgSO4, and concentrated in vacuo. The resi-
due was purified by flash column chromatography (n-hexane/
EtOAc, 5:1) to afford the corresponding ketone 6a (27.5 mg, 60 %
yield).
1
1-Methyl-3-(2-oxo-2-phenylethyl)pyrrolidine-2,5-dione (6a):
Colorless sticky oil (27.5 mg, 60 %). H NMR (500 MHz, CDCl3): δ =
D-3a: Yellow sticky solid. H NMR (400 MHz, CDCl3): δ = 7.42–7.39
1
(m, 1 H), 7.35–7.28 (m, 3 H), 3.84–3.80 (m, 1 H), 3.14 (s, 3 H), 3.09–
7.92 (d, J = 7.0 Hz, 2 H), 7.58 (t, J = 7.5 Hz, 1 H), 7.48 (t, J = 7.5 Hz,
3.02 (m, 4 H), 2.96 (s, 3 H), 2.70 (dd, J = 18.4, 5.6 Hz, 1 H) ppm.
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Acknowledgments
This work was supported by the Korean Government, National
Research Foundation of Korea (NRF) (grant numbers
2015R1A2A1A15053033 and 2015H1D3A1058932).
Keywords: Homogeneous catalysis · Rhodium · C–H
activation · Alkylation · Nitrogen heterocycles · Enols
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Received: May 4, 2016
Published Online: ■
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Full Paper
C–H Activation
S. Sharma, S. H. Han, H. Jo,
S. Han, N. K. Mishra, M. Choi,
T. Jeong, J. Park, I. S. Kim* .............. 1–9
Rhodium-Catalyzed Vinylic C–H
Functionalization of Enol Carbam-
ates with Maleimides
The rhodium(III)-catalyzed direct C–H logically relevant succinimide com-
alkylation of enol carbamates with a pounds by proceeding through a C–Rh
range of maleimides is described. With addition and subsequent protonation
the assistance of the carbamoyl direct- pathway.
ing group, this reaction provides bio-
DOI: 10.1002/ejoc.201600558
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim