Synthesis of 3-Ethyl-4-methyl-1,5-dihydro-2H-pyrrol-2-one by Novel Palladium(II)-Catalyzed Cyclization and Ring-Closing Metathesis

Article abstract of DOI:10.1055/s-0034-1379985

Synthesis of 3-ethyl-4-methyl-1,5-dihydro-2H-pyrrol-2-one is described starting from commercially available allylamine and 4-methoxybenzylamine employing palladium-catalyzed cyclization or ring-closing metathesis as the key steps.

Full text of DOI:10.1055/s-0034-1379985

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 955–960
paper
955
S. P. Chavan et al.
Paper
Synthesis
Synthesis of 3-Ethyl-4-methyl-1,5-dihydro-2H-pyrrol-2-one by
Novel Palladium(II)-Catalyzed Cyclization and Ring-Closing
Metathesis
Subhash P. Chavan*
H
Pd-catalyzed
cyclization
PMB
N
PMB
N
Ashok B. Pathak
Kailash P. Pawar
N
RCM
O
O
O
Organic Chemistry Division, CSIR-NCL (National Chemical
Laboratory), Dr. Homi Bhabha Road, Pune 411008,
Maharashtra, India
COOEt
sp.chavan@ncl.res.in
O
Received: 30.09.2014
Accepted after revision: 18.12.2014
Published online: 17.02.2015
DOI: 10.1055/s-0034-1379985; Art ID: ss-2014-z0602-op
NH
Abstract Synthesis of 3-ethyl-4-methyl-1,5-dihydro-2H-pyrrol-2-one
is described starting from commercially available allylamine and
4-methoxybenzylamine employing palladium-catalyzed cyclization or
ring-closing metathesis as the key steps.
3-ethyl-4-methyl-3-pyrrolin-2-one (1)
O
O
N
O
O
S
Key words pyrrolinone, glimepiride, antidiabetic, metabolite, lac-
HN
NH
tams, ring-closing metathesis, cyclization
NH
O
glimepiride (2)
Five- and six-membered lactones and lactams are wide-
ly present as key building blocks in several natural products
showing promising biological activity. 3-Ethyl-4-methyl-
1,5-dihydro-2H-pyrrol-2-one (1) is an important heterocy-
clic building block of antidiabetes drug glimepiride (2)1 and
its derivatives that are sulfonylurea drugs and show potent
activity against diabetic diseases.1b The synthesis of trans-
hydroxyglimepiride, a metabolite of the drug glimepiride
was reported by Gurjar et al.1a Pyrrolinone 1 is also present
as main precursor in bile pigments; the blue protein C-phy-
cocyanin 3 (Figure 1) was isolated from the blue-green alga
Synechococcus sp. 6301.2 Bile pigments take part in photo-
synthesis.
O
N
H
O
HN
NH
CO2R
N
Scrutiny of the literature reveals that several syntheses
of 1 and its derivatives have been reported.1–3 Structurally,
1 is a five-membered α,β-unsaturated lactam bearing sub-
stituents at positions 3 and 4. Though it appears to be a
simple structure, its formation is difficult due to steric
crowding of the substituents present on the olefin and ring
strain. Due to its utility in the field of medicinal chemistry
and biology, devising an efficient and practical route has at-
tracted the attention of synthetic chemists. The literature
reports reveal that there are very few practical synthetic
routes reported for 1. The reported syntheses employ very
CO2R
C-phycocyanin (3)
Figure 1 Structures of 3-ethyl-4-methyl-3-pyrrolin-2-one, glimepiride
and C-phycocyanin
toxic reagents such as sodium cyanide and drastic reaction
conditions like high temperature and pressure with very
poor overall yields in the range of 7–8%.1,2
Palladium plays a very important role in organic syn-
thesis. Palladium in its different oxidation states is a very
useful catalyst in effecting critical C–C, C=C, and C–X bond-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 955–960

956
S. P. Chavan et al.
Paper
Synthesis
PMB
forming reactions and it is utilized in different coupling re-
actions while palladium(II) catalyst finds use in the Wacker
oxidation and in different types of cyclization reactions.4
We have previously described a novel C=C bond-form-
ing annulation strategy as the key step for the synthesis of
six-membered lactams (D ring of camptothecin) under
Wacker oxidation conditions and exploited it for the syn-
thesis of (+)-camptothecin.5 Ring-closing metathesis has
also become a powerful and almost indispensable tool for
the construction of small-to-large rings in various natural
products due to its efficiency and versatility. Our group has
initiated a programme on the utility of ring-closing meta-
thesis in the synthesis of different natural products.6 In
continuation of our ongoing studies, we herein report the
synthesis of 1 by two different methods employing novel
palladium-catalyzed cyclization or ring-closing metathesis
as the key reactions for the formation of the carbon–carbon
double bond.
The synthesis commenced from inexpensive and com-
mercially available allylamine (4), which was converted
into secondary amine 5 in excellent yield (97%) by reductive
amination using p-anisaldehyde and sodium borohydride
(Scheme 1). Amine 5 was treated with ethyl malonyl chlo-
ride using potassium carbonate as the base to furnish am-
ide 6 in 86% yield. When 6 was treated with palladium(II)
chloride (10 mol%) and copper(II) chloride (2.1 equiv) as a
co-oxidant in N,N-dimethylformamide–water (3:1) at 95 °C
for six to eight hours surprisingly the cyclized product 8
was obtained in 62% yield instead of the anticipated ketone
7.7 This observation is consistent with our earlier study of
the formation of six-membered rings.5 Compound 8 under-
went facile Krapcho’s decarboxylation to afford compound
9 in 87% yield.8
N
O
PMB
NH
NH2
PMB
N
c
COOEt
O
O
a
b
7
c
PMB
N
COOEt
4
5
6
O
COOEt
O
8
H
PMB
N
PMB
N
O
O
N
d
e
f
10d
9
1
Scheme 1 Reagents and conditions: (a) (i) p-anisaldehyde (1.1 equiv),
MeOH, 0 °C, 1 h; (ii) NaBH4 (1.0 equiv), MeOH, 0 °C, 1 h, 97%; (b) K2CO3
(1.2 equiv), ethyl malonyl chloride (1.2 equiv), CH2Cl2, 0 °C, 1 h, 86%;
(c) PdCl2 (10 mol%), CuCl2 (2.1 equiv), DMF–H2O (3:1), 95 °C, 6–8 h,
62%; (d) NaCl (4.0 equiv), DMSO–H2O (3:1), 120–130 °C, 12 h, 87%; (e)
NaH (1.2 equiv), EtI (1.2 equiv), anhyd THF, 0 °C to r.t., 3 h, 71%; (f) CAN
(2.5 equiv), MeCN–H2O (5:1), r.t., 2 h, 80%.
PMB
PMB
N
PMB
N
N
O
O
O
PdCl2
CuCl2
OH
OEt
OH
OEt
COOEt
Pd
Cl
H
Cl
PMB
PMB
N
H2O
N
O
cyclization
Cl
O
O
Regioselective ethylation at the α carbon was accom-
plished on α,β-unsaturated lactam 9 using sodium hydride
as the base and ethyl iodide as the electrophile in tetrahy-
drofuran, which resulted in the formation of compound 10d
in good yield (71%).9 PMB deprotection of lactam 10d em-
ploying ammonium cerium(IV) nitrate as the reagent in
acetonitrile–water (5:1) at ambient temperature, furnished
the desired lactam 1 in 80% yield.10 The formation of com-
pound 811 can be explained by the probable mechanism
shown in Scheme 2.
– Cl
H
ClPd
COOEt
PdCl
OEt
PMB
β-hydride
elimination
PMB
N
N
Pd(II)
O
O
– HPdCl
or
Cl–Pd–H
COOEt
COOEt
After the successful synthesis of 1 employing palladi-
um(II)-assisted cyclization (Scheme 1), we felt that 1 could
also be synthesized by employing a ring-closing-metathesis
strategy, which is outlined in Scheme 3. This strategy in-
volved use of commercially available 4-methoxybenzyl-
amine (11) as the starting material which was then alkylat-
ed with methallyl chloride using potassium carbonate as
the base and potassium iodide in catalytic quantities to fur-
nish the secondary amine 12 in 84% yield (based on the re-
covered of starting material 11). N-Acylation of amine 12
2 CuCl2
Pd (0)
PdCl2
H
Pd Cl
2 CuCl
+
– HCl
Scheme 2 Probable mechanism
with ethacryloyl chloride, which in turn was prepared from
butyraldehyde by a reported procedure,12,13 using potassi-
um carbonate as the base afforded tertiary amide 13d in
excellent yield (91%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 955–960

957
S. P. Chavan et al.
Paper
Synthesis
(electron-deficient olefin) does not have a detrimental ef-
fect. The compound 13d was subjected to ring-closing me-
tathesis reactions employing Grubbs’ 2nd generation cata-
lyst (10 mol%) in anhydrous toluene at 80 °C for 24 hours, to
deliver the α,β-unsaturated lactam 10d in 40% yield (90%
yield based on the recovered starting material). The lactam
10d15 was transformed into the desired intermediate 1 as
shown in Scheme 1.
In conclusion, we have described novel synthesis of 3-
ethyl-4-methyl-1,5-dihydro-2H-pyrrol-2-one (1) employ-
ing two metal-catalyzed protocols viz. palladium-catalyzed
cyclization in six steps in 25% overall yield and ring-closing
metathesis in four steps in 55% overall yield that are superi-
or to the reported syntheses.
OMe
a
PMB
N
PMB
NH
PMB
c
b
N
O
O
NH2
11
12
13d
10d
Scheme 3 Reagents and conditions: (a) methallyl chloride (0.33 equiv),
K2CO3 (1.2 equiv), KI (cat.), anhyd CH2Cl2, 0 °C to r.t., 12 h, 84%;
(b) K2CO3 (1.2 equiv), ethacryloyl chloride (1.2 equiv), anhyd CH2Cl2,
0 °C to r.t., 3 h, 91%; (c) Grubbs II catalyst (10 mol%), Ti(Oi-Pr)4 (2.0
equiv), anhyd toluene, 80 °C, 12 h (90% based recovered 13d).
After obtaining the requisite amide 13d, we focused our
attention on the ring-closing metathesis reaction as the key
step. Although a number of syntheses of five- and six-mem-
bered α,β-unsaturated lactones and lactams by ring-closing
metathesis have been reported in the literature,14 very few
reports are available for the construction of five- and six-
membered rings containing tetrasubstituted olefins,15 due
to the difficulties encountered in their formation, which
may be attributed to steric hindrance encountered by the
substituents, electronic features of acrylamide, and ring
strain of the resulting five-membered ring. Hence the con-
struction of tetrasubstituted α,β-unsaturated lactones or
lactams by the ring-closing-metathesis strategy is a chal-
lenging task. In the present study the ring-closing-metathe-
sis reaction was studied and generalized. The substituent
effect was studied by performing ring-closing-metathesis
reactions on differently substituted acrylamides and the re-
sults are given in Table 1.
All reagents and solvents were used as received from the manufactur-
ers. Melting points are recorded using Buchi B-540 melting point ap-
paratus in capillary tubes and are uncorrected. IR spectra were re-
corded on Perkin-Elmer Model 68B or 1615 FT infrared spectropho-
tometer. 1H (200 and 300 MHz) and 13C (50 and 75 MHz) NMR spectra
were recorded on Bruker and Bruker Advance 300 spectrometers,
using CDCl3–CCl4 (2:1) as the solvent with reference to residual CHCl3
(δ = 7.26) for 1H NMR or the central line of CDCl3 (δ = 77.0) for 13C
NMR. In the 13C NMR spectra, the natures of the carbons (C, CH, CH2,
or CH3) were determined by recording the DEPT-135 spectra. The re-
action progress was monitored by the TLC analysis using precoated
with silica gel 60 F254 (Merck) and visualized by fluorescence quench-
ing or I2 or by charring after treatment with p-anisaldehyde and also
2,4-DNP. Merck flash silica gel (230–400 mesh) was used for column
chromatography.
N-(4-Methoxybenzyl)prop-2-en-1-amine (5)
To the stirred solution of allylamine (4, 1.0 g, 1.3 mL, 17.5 mmol) in
dry MeOH (20 mL) was added p-anisaldehyde (2.62 g, 2.34 mL, 19.25
mmol) at 0 °C and the mixture was stirred for 1 h. After disappear-
ance of the starting material (TLC), NaBH4 (0.66 g, 17.5 mmol) was
added portionwise at 0 °C and the mixture was stirred for a further
0.5 h. After completion of the reaction (TLC), the mixture was concen-
trated in vacuo and residue was diluted with H2O (20 mL) and extract-
ed with EtOAc (3 × 15 mL). The combined organic layers were washed
with brine, dried (anhyd Na2SO4), and filtered, and solvent was evapo-
rated on rotary evaporator under reduced pressure. The resultant res-
idue was purified by flash column chromatography (silica gel, EtOAc–
petroleum ether, 4:6) to furnish 5 (3.0 g, 97%) as pale yellow liquid.
Table 1 RCM Reactions of Allyl Acrylamides in Toluene at 80 °C
R1
R1
N
Grubbs II cat. (10 mol%)
Ti(Oi-Pr)4 (2.0 equiv)
toluene, 80 °C, 24 h
N
O
O
R3
R2
R2
10a–g
R3
13a–g
Entry
Substrate R1
R2
R3
Product
Yield (%)
98
IR (CHCl3): 3393, 3019, 1613, 1215, 758 cm–1
.
1
2
3
4
5
6
7
13a16a
13b
PMB
H
H
10a16b,c
1H NMR (200 MHz, CDCl3 + CCl4): δ = 1.94 (s, 1 H), 3.28 (d, J = 4.0 Hz, 2
H), 3.78 (s, 3 H), 4.65 (s, 2 H), 5.14–5.28 (m, 2 H), 5.91 (m, 1 H), 6.87
(d, J = 9.0 Hz, 2 H), 7.26 (d, J = 9.0 Hz, 2 H).
PMB
PMB
PMB
Bn
Me
Me
Me
Me
Me
Me
H
10b (= 9) 45
13c
Me
Et
10c
44
40
45
43
37
13d
10d
10e16e
10f
MS (ESI): m/z = 178 (M + H)+.
13e16d
13f
Me
Et
Anal. Calcd for C11H15NO: C, 74.54; H, 8.53; N, 7.90. Found: C, 74.59;
H, 8.47; N, 7.87.
Bn
13g
Boc
H
10g
Ethyl 3-[Allyl(4-methoxybenzyl)amino]-3-oxopropanoate (6)
To the stirred solution of 5 (1.0 g, 5.6 mmol) in anhyd CH2Cl2 (10 mL)
was added K2CO3 (2.3 g, 16.8 mmol) at 0 °C and the mixture was
stirred for 15 min. Then ethyl malonyl chloride (1.0 g, 0.84 mL, 6.72
mmol) was added dropwise at 0 °C and the mixture was stirred at
From the results in Table 1, it is observed that the sub-
stituent present on the allyl moiety (electron-rich olefin)
has a profound influence on the rate of reaction as well as
the yield while the substituent present on the acrylamide
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S. P. Chavan et al.
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Synthesis
0 °C under N2 atmosphere until completion of reaction (1 h, TLC). The
mixture was filtered and the residue was washed with CH2Cl2 (3 × 15
mL), the filtrate was concentrated in vacuo and the residue obtained
was purified by flash column chromatography (silica gel, EtOAc–pe-
troleum ether, 1:4) to furnish 6 (1.41 g, 86%) as a colorless syrup.
3-Ethyl-1-(4-methoxybenzyl)-4-methyl-1,5-dihydro-2H-pyrrol-2-
one (10d)
To 60% NaH (0.044 g, 1.08 mmol), prewashed with anhyd petroleum
ether (3 × 10 mL), was added 9 (0.2 g, 0.9 mmol) in anhyd THF (10 mL)
slowly at 0 °C. The mixture was stirred for 15 min and the EtI (0.158 g,
0.081 mL, 0.99 mmol) in anhyd THF (5 mL) was added dropwise and
the mixture was stirred for 3 h at this temperature (TLC monitoring).
The reaction was quenched by the addition of sat. NH4Cl solution and
the organic phase was separated and the aqueous phase was extract-
ed with EtOAc (3 × 15 mL). The combined organic layers were washed
with brine, dried (anhyd Na2SO4), and filtered, the solvent was evapo-
rated in vacuo, and the resultant residue was purified by flash column
chromatography (silica gel, EtOAc–petroleum ether, 1:4) to furnish
10d (0.160 g, 71%) as a yellow solid; mp 127–131 °C.
IR (CHCl3): 3458, 2982, 2936, 1735, 1654, 1513, 1248, 1032 cm–1
.
1H NMR (200 MHz, CDCl3 + CCl4): δ = 1.28 (t, J = 7.2 Hz, 3 H), 3.46 (s, 2
H), 3.78 (s, 3 H), 3.75–3.97 (m, 2 H), 4.20 (q, J = 7.2 Hz, 2 H), 4.43–4.50
(m, 2 H), 5.12–5.25 (m, 2 H), 5.59–5.58 (m, 1 H), 6.85 (d, J = 9.0 Hz, 2
H), 7.16 (d, J = 9.0 Hz, 2 H) (mixture of rotamers).
13C NMR (50 MHz, CDCl3 + CCl4): δ = 14.0, 41.0, 41.1, 47.6, 49.25, 50.1,
55.0, 61.1, 113.8, 114.2, 116.95, 117.40, 127.6, 127.8, 128.9, 129.3,
132.3, 158.9, 159.1, 166.0, 166.2, 167.4 (mixture of rotamers).
MS (ESI): m/z = 292 (M)+.
IR (CHCl3): 1671, 1515, 1248, 1212, 757 cm–1
.
Anal. Calcd for C16H21NO4: C, 65.96; H, 7.27; N, 4.81. Found: C, 66.09;
H, 7.19; N, 4.77.
1H NMR (200 MHz, CDCl3 + CCl4): δ = 1.07 (t, J = 7.6 Hz, 3 H), 1.91 (s, 3
H), 2.28 (q, J = 7.6 Hz, 2 H), 3.56 (s, 2 H), 3.77 (s, 3 H), 4.51 (s, 2 H), 6.82
(d, J = 8.8 Hz, 2 H), 7.14 (d, J = 8.8 Hz, 2 H).
Ethyl 1-(4-Methoxybenzyl)-4-methyl-2-oxo-2,5-dihydro-1H-pyr-
role-3-carboxylate (8)
13C NMR (50 MHz, CDCl3 + CCl4): δ = 12.9, 12.95, 18.9, 46.1, 53.2, 54.3,
113.8, 128.1, 128.6, 135.0, 144.95, 158.7, 171.7.
To a stirred solution of olefinic ester 6 (0.2 g, 0.68 mmol) in DMF–H2O
(3:1, 12 mL), PdCl2 (0.011 g, 0.068 mmol), and CuCl2·2 H2O (0.24 g, 1.4
mmol) were added and the resultant solution was heated to 95 °C
(TLC monitoring) for 8 h. The mixture was cooled to r.t. and extracted
with Et2O (3 × 15 mL). The combined organic layers were dried (an-
hyd Na2SO4) and filtered and the solvent was removed on a rotary
evaporator under reduced pressure and the residue obtained was pu-
rified by flash column chromatography (silica gel, EtOAc–petroleum
ether, 2:3) to furnish 8 (0.122 g, 62%) as a pale yellow syrup.
MS (ESI): m/z = 246 (M + H)+, 268 (M + Na)+.
Anal. Calcd for C15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found: C, 73.47;
H, 7.78; N, 5.76.
N-(4-Methoxybenzyl)-2-methylprop-2-en-1-amine (12)
To the stirred solution of 4-methoxybenzylamine (11, 1.0 g, 7.2
mmol) in anhyd CH2Cl2 (10 mL), K2CO3 (3.03 g, 21.6 mmol) was added
at 0 °C and the mixture was stirred for 30 min. A solution of methallyl
chloride (0.217 g, 0.234 mL, 2.37 mmol) in CH2Cl2 (5 mL) was added
dropwise over 10 min at 0 °C followed by cat. KI (0.1 equiv) under N2
atmosphere. The mixture was stirred for 3 h (TLC monitoring). When
the reaction was complete, the mixture was quenched by the addition
of sat. NH4Cl solution and extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were dried (anhyd Na2SO4), filtered, and con-
centrated in vacuo and the residue obtained was purified by flash col-
umn chromatography (silica gel, EtOAc–petroleum ether, 2:3) to fur-
nish 12 (0.384 g, 84%, based on the recovery of starting material) as a
colorless oil; 0.670 g starting material was recovered.
IR (CHCl3): 1721, 1687, 1214, 757 cm–1
.
1H NMR (300 MHz, CDCl3 + CCl4): δ = 1.38 (t, J = 7.1 Hz, 3 H), 2.29 (s, 3
H), 3.74 (s, 2 H), 3.78 (s, 3 H), 4.34 (q, J = 7.1 Hz, 2 H), 4.52 (s, 2 H), 6.82
(d, J = 8.8 Hz, 2 H), 7.15 (d, J = 8.8 Hz, 2 H).
MS (ESI): m/z = 290 (M + H)+, 312 (M + Na)+.
Anal. Calcd for C16H19NO4: C, 66.42; H, 6.62; N, 4.84. Found: C, 66.56;
H, 6.45; N, 4.77.
1-(4-Methoxybenzyl)-4-methyl-1,5-dihydro-2H-pyrrol-2-one (9)
IR (CHCl3): 1611, 1512, 1216, 757 cm–1
.
To a stirred solution of 8 (0.5 g, 1.7 mmol) in DMSO–H2O (3:1, 20 mL),
NaCl (0.4 g, 6.8 mmol) was added and resultant mixture was heated
at 120–130 °C for 12 h. After disappearance of the starting material
(TLC monitoring), the mixture was allowed to cool to r.t., diluted with
water (25 mL), and extracted with CH2Cl2 (3 × 10 mL). The combined
organic layers were washed with brine, dried (anhyd Na2SO4), fil-
tered, and concentrated under reduced pressure. The residue ob-
tained was purified by flash column chromatography (silica gel,
EtOAc–petroleum ether, 4:6) to give 9 (0.326 g, 87%) as a pale yellow
solid; mp 122 °C.
1H NMR (200 MHz, CDCl3 + CCl4): δ = 1.78 (s, 3 H), 1.85 (s, 1 H), 3.18 (s,
2 H), 3.70 (s, 2 H), 3.80 (s, 3 H), 4.86 (s, 1 H), 4.90 (s, 1 H), 6.85 (d, J =
8.7 Hz, 2 H), 7.25 (d, J = 8.7 Hz, 2 H).
13C NMR (50 MHz, CDCl3 + CCl4): δ = 20.5, 52.1, 54.5, 54.6, 110.6,
113.3, 128.9, 132.1, 143.4, 158.3.
MS (ESI): m/z = 192 (M + H)+.
Anal. Calcd for C12H17NO: C, 75.35; H, 8.96; N, 7.32. Found: C, 75.23;
H, 9.07; N, 7.27.
IR (CHCl3): 3347, 1672, 1513, 1247, 1216, 756 cm–1
.
N-(4-Methoxybenzyl)-N-(2-methylallyl)-2-methylenebutanamide
(13d); Typical Procedure
1H NMR (300 MHz, CDCl3 + CCl4): δ = 2.01 (s, 3 H), 3.68 (s, 2 H), 3.78 (s,
3 H), 4.50 (s, 2 H), 5.85 (s, 1 H), 6.82 (d, J = 8.8 Hz, 2 H), 7.14 (d, J = 8.8
Hz, 2 H).
13C NMR (75 MHz, CDCl3 + CCl4): δ = 15.05, 45.05, 54.7, 55.0, 114.0,
122.7, 129.1, 129.5, 154.9, 159.0, 171.6.
To the stirred solution of amine 12 (0.25 g, 1.3 mmol) in anhyd CH2Cl2
(10 mL), K2CO3 (0.545 g, 3.9 mmol) was added at 0 °C under N2 atmo-
sphere followed by dropwise addition of ethacryloyl chloride (0.186
g, 1.56 mmol) at 0 °C and the mixture was stirred for 3 h (TLC moni-
toring). When the reaction was complete, the mixture was filtered
and the residue washed with CH2Cl2 (3 × 10 mL). The filtrate was con-
centrated in vacuo and the residue was purified by flash column chro-
matography (silica gel, EtOAc–petroleum ether, 1:4) to afford 13d
(0.325 g, 91%) as a thick colorless oil.
MS (ESI): m/z = 218 (M + H)+, 240 (M + Na)+.
Anal. Calcd for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.61;
H, 6.98; N, 6.69.
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S. P. Chavan et al.
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Synthesis
IR (CHCl3): 3081, 1970, 1644, 1614, 1512, 1247, 755 cm–1
.
13C NMR (50 MHz, CDCl3 + CCl4): δ = 20.6, 28.1, 49.5, 83.2, 110.1,
128.1, 131.3, 141.0, 153.2, 168.25.
MS (ESI): m/z = 226 (M + H)+.
1H NMR (200 MHz, CDCl3 + CCl4): δ = 1.08 (t, J = 7.5 Hz, 3 H), 1.65 (s, 3
H), 2.33 (q, J = 7.5 Hz, 2 H), 3.77–3.87 (m, 5 H), 4.51 (s, 2 H), 4.67–4.95
(m, 2 H), 5.10 (s, 2 H), 6.82 (d, J = 8.5 Hz, 2 H), 7.17 (d, J = 8.5 Hz, 2 H).
13C NMR (50 MHz, CDCl3 + CCl4): δ = 11.4, 19.65, 26.9, 45.2, 47.6, 49.8,
52.3, 54.6, 111.9, 112.2, 113.3, 113.6, 127.9, 129.1, 139.9, 146.0,
158.65, 172.3 (mixture of rotamers).
3-Ethyl-1-(4-methoxybenzyl)-4-methyl-1,5-dihydro-2H-pyrrol-2-
one (10d); Typical Procedure
To a degassed homogeneous solution of 13d (0.2 g, 0.7 mmol) in an-
hyd toluene (20 mL), Grubbs’ 2nd generation catalyst (0.062 g, 10
mol%) and Ti(Oi-Pr)4 (2 equiv) were added under an argon atmo-
sphere; the resultant mixture was heated at 80 °C for 12 h. When the
reaction was complete (TLC), the solvent was removed on a rotary
evaporator under reduced pressure and residue obtained was purified
by flash column chromatography (silica gel, EtOAc–petroleum ether,
1:4) to provide lactam 10d (0.072 g, 40%) as a yellow solid and 0.11 g
of starting material was recovered; mp 127–131 °C.
MS (ESI): m/z = 274 (M + H)+.
Anal. Calcd for C17H23NO: C, 74.69; H, 8.48; N, 5.12. Found: C, 74.63;
H, 8.37; N, 5.23.
N-(4-Methoxybenzyl)-N-(2-methylallyl)acrylamide (13b)
Yield: 205 mg (80%); colorless liquid.
IR (CHCl3): 2935, 1646, 1612, 1512 cm–1
.
IR (CHCl3): 1671, 1515, 1248, 1212, 757 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.62–1.79 (m, 3 H), 3.64–4.11 (m, 5 H),
4.43–4.65 (m, 2 H), 4.71–5.05 (m, 2 H), 5.61–5.78 (m, 1 H), 6.33–6.70
(m, 2 H), 6.76–6.96 (m, 2 H), 7.03–7.25 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 20.1, 48.0 (49.0), 50.5, (51.8), 55.2,
111.7 (112.4), 113.8 (114.2), 127.6, 127.7, 128.3 (128.5), 128.8, 129.5,
129.7, 139.8 (140.4), 158.9 (159.0), 166.7 (166.9).
1H NMR (200 MHz, CDCl3 + CCl4): δ = 1.07 (t, J = 7.6 Hz, 3 H), 1.91 (s, 3
H), 2.28 (q, J = 7.6 Hz, 2 H), 3.56 (s, 2 H), 3.77 (s, 3 H), 4.51 (s, 2 H), 6.82
(d, J = 8.8 Hz, 2 H), 7.14 (d, J = 8.8 Hz, 2 H).
13C NMR (50 MHz, CDCl3 + CCl4): δ = 12.9, 12.95, 18.9, 46.1, 53.2, 54.3,
113.8, 128.1, 128.6, 135.0, 144.95, 158.7, 171.7.
HRMS (ESI+): m/z calcd for C15H19NO2 [M + H]+: 246.1494; found:
MS (ESI): m/z = 246 (M + H)+, 268 (M + Na)+.
246.1498.
Anal. Calcd for C15H19NO: C, 73.44; H, 7.81; N, 5.71. Found: C, 73.47;
H, 7.78; N, 5.76.
N-(4-Methoxybenzyl)-N-(2-methylallyl)methacrylamide (13c)
Yield: 200 mg (73%); colorless liquid.
IR (CHCl3): 2930, 1648, 1614, 1465 cm–1
1-(4-Methoxybenzyl)-3,4-dimethyl-1H-pyrrol-2(5H)-one (10c)
.
Yield: 39 mg (44%); pale yellowish liquid.
1H NMR (400 MHz, CDCl3): δ = 1.54–1.76 (m, 3 H), 1.98 (br s, 3 H),
3.66–4.02 (m, 5 H), 4.40–4.59 (m, 2 H), 4.63–5.02 (m, 2 H), 5.04–5.34
(m, 2 H), 6.85–6.89 (m, 2 H), 6.99–7.25 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 19.9, 20.6 (20.8), 45.6 (48.0), 50.1
(52.8), 55.1, 112.4, 113.9, 114.7, 114.9, 128.1, 128.5, 129.2 129.5,
139.9 (140.2), 140.5 (140.7), 158.9, 173.0.
IR (CHCl3): 2940, 1666, 1513, 1460 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.84 (s, 3 H), 1.92 (s, 3 H), 3.61 (s, 2 H),
3.81 (s, 3 H), 4.56 (s, 2 H), 6.86 (d, J = 8.80 Hz, 2 H), 7.19 (d, J = 8.56 Hz,
2 H).
13C NMR (100 MHz, CDCl3): δ = 8.7, 12.9, 45.4, 53.5, 55.2, 114.0, 128.6,
129.3, 129.8, 145.7, 158.9, 172.6.
HRMS (ESI+): m/z calcd for C16H21NO2 [M + H]+: 260.1650; found:
260.1650.
HRMS (ESI+): m/z calcd for C14H17NO2 [M + H]+: 232.1337; found:
232.1337.
N-Benzyl-N-(2-methylallyl)-2-methylenebutanamide (13f)
1-Benzyl-3-ethyl-4-methyl-1H-pyrrol-2(5H)-one (10f)
Yield: 303 mg (67%); colorless liquid.
Yield: 38 mg (43%); colorless viscous liquid.
IR (CHCl3): 3020, 1648, 1617, 1421 cm–1
.
IR (CHCl3): 2925, 1671, 1656, 1458 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.03–1.21 (m, 3 H), 1.58–1.80 (m, 3 H),
2.26–2.46 (m, 2 H), 3.69–4.07 (m, 2 H), 4.48–4.67 (m, 2 H), 4.67–5.06
(m, 2 H), 5.14 (s, 2 H), 7.06–7.44 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 11.6, 20.0, 27.1, 46.3 (48.3), 50.7
(52.9), 112.5, 124.5, 126.8, 127.3 (127.4), 128.2, 128.5, 128.7, 136.7
(137.2), 139.9 (140.2), 146.1 (146.3), 173.2.
1H NMR (400 MHz, CDCl3): δ = 1.12 (t, J = 7.5 Hz, 3 H), 1.95 (s, 3 H),
2.34 (q, J = 7.5 Hz, 2 H), 3.63 (s, 2 H), 4.64 (s, 2 H), 7.21–7.42 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 12.8, 13.1, 17.0, 46.0, 53.6, 127.3,
128.0, 128.6, 134.2, 137.7, 145.4, 172.2.
HRMS (ESI+): m/z calcd for C14H17NO [M + H]+: 216.1388; found:
216.1390.
HRMS (ESI+): m/z calcd for C16H21NO [M + H]+: 244.1701; found:
244.1699.
tert-Butyl 4-Methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate
(10g)6e,h
tert-Butyl Acryloyl(2-methylallyl)carbamate (13g)
Yield: 28 mg (37%); thick colorless oil.
Yield: 320 mg (59%); thick colorless oil.
IR (CHCl3): 3364, 2979, 2937, 1734, 1687, 1619, 1404 cm–1
1H NMR (200 MHz, CDCl3 + CCl4): δ = 1.48 (s, 9 H), 1.72 (s, 3 H ), 4.23
(s, 3 H), 4.67–4.80 (2 s, 2 H), 5.69 (dd, J = 10.4, 1.9 Hz, 1 H), 6.32 (dd,
J = 16.8, 1.9 Hz, 1 H), 7.04 (dd, J = 16.8, 10.4 Hz, 1 H).
IR (CHCl3): 3448, 2980, 1778, 1739, 1712, 1643, 1447, 1293, 1164,
.
843, 755 cm–1
.
1H NMR (200 MHz, CDCl3 + CCl4): δ = 1.52 (s, 9 H), 2.07 (s, 3 H), 4.17 (s,
2 H), 5.80 (s, 1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 955–960

960
S. P. Chavan et al.
Paper
Synthesis
13C NMR (50 MHz, CDCl3 + CCl4): δ = 15.3, 27.9, 54.1, 82.1, 122.6,
149.1, 157.8, 169.0.
MS (ESI): m/z = 198 (M + H)+.
(3) (a) Deng, Y.; Zhong, Y. Huaxi Yaoxue Zazhi 2000, 15, 289.
(b) Deng, Y.; Zhong, Y.; Tang, W.; Zhong, Z. Zhongguo Yaowu
Huaxue Zazhi 2000, 10, 134. (c) Coffin, A. R.; Roussell, M. A.;
Tserlin, E.; Pelkey, E. T. J. Org. Chem. 2006, 71, 6678; and refer-
ences cited therein.
Anal. Calcd for C10H15NO3: C, 60.90; H, 7.67; N, 7.10. Found: C, 61.26;
H, 8.06; N, 6.75.
(4) Hayashi, T.; Hegedus, L. S. J. Am. Chem. Soc. 1977, 99, 7093.
(5) Chavan, S. P.; Pathak, A. B.; Kalkote, U. R. Synlett 2007, 2635.
(6) (a) Chavan, S. P.; Pasupathy, K.; Venkatraman, M. S.; Kale, R. R.
Tetrahedron Lett. 2004, 45, 6879. (b) Chavan, S. P.; Praveen, C.
Tetrahedron Lett. 2005, 46, 1939. (c) Chavan, S. P.; Thakkar, M.;
Jogadand, G. F. J. Org. Chem. 2006, 71, 8986. (d) Chavan, S. P.;
Sharma, P. S.; Sivappa, R.; Kalkote, U. R. Tetrahedron Lett. 2006,
47, 9301. (e) Chavan, S. P.; Pathak, A. B.; Dhawane, A. N.;
Kalkote, U. R. Synth. Commun. 2007, 37, 1503. (f) Chavan, S. P.;
Dhawane, A. N.; Kalkote, U. R. Tetrahedron Lett. 2007, 48, 965.
(g) Chavan, S. P.; Pathak, A. B.; Pandey, A.; Kalkote, U. R. Synth.
Commun. 2007, 37, 3143. (h) Li, W.-R.; Lin, S. T.; Hsu, N.-M.;
Chern, M.-S. J. Org. Chem. 2002, 67, 4702.
3-Ethyl-4-methyl-1,5-dihydro-2H-pyrrol-2-one (1)
To a stirred solution of lactam 10d (0.1 g, 0.40 mmol) in MeCN (10
mL) and H2O (2 mL), CAN (0.447 g, 0.80 mmol) was added. The mix-
ture was stirred at r.t. until completion of the reaction (TLC monitor-
ing, 2 h). The solvent was removed on a rotary evaporator under re-
duced pressure, the resultant residue was diluted with H2O (40 mL)
and extracted with EtOAc (3 × 50 mL). The combined organic layers
were washed with brine, dried (anhyd Na2SO4), filtered, and concen-
trated in vacuo and the residue obtained was purified by flash column
chromatography (silica gel, EtOAc–petroleum ether, 1:2) to furnish
target 1 (0.036 g, 80%) as a pale yellow solid; mp 102 °C.
(7) Aggarwal, V. K.; Astle, C. J.; Rogers-Evans, M. Org. Lett. 2004, 6,
1469.
(8) Giles, M.; Hadley, M. S.; Gallagher, T. Chem. Commun. 1990,
1047.
(9) Lee, R. A.; McAndrews, C.; Patel, K. M.; Ruesch, W. Tetrahedron
Lett. 1973, 965.
IR (CHCl3): 3326, 2974, 1681, 1451, 1216 cm–1
1H NMR (200 MHz, CDCl3): δ = 1.02 (t, J = 7.4 Hz, 3 H), 1.95 (s, 3 H),
2.22 (q, J = 7.4 Hz, 2 H), 3.76 (s, 2 H), 8.04 (br s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 12.3, 12.5, 16.0, 49.7, 133.4, 148.2,
175.9.
.
MS (ESI): m/z = 125 (M)+.
(10) Bryans, J. S.; Chessums, E. A. N.; Nathalie, H.; Parsons, A. F.;
Ghelfi, F. Tetrahedron 2003, 59, 6221.
Anal. Calcd for C7H11NO: C, 67.17; H, 8.86; N, 11.19. Found: C, 66.93;
H, 9.11; N, 11.38.
(11) For Pd(II)-mediated isomerization of olefins please see: (a) Sen,
A.; Lai, T.-W. Inorg. Chem. 1981, 20, 4036. (b) Sen, A.; Lai, T.-W.
Inorg. Chem. 1984, 23, 3257. For palladium hydride mediated
isomerization of olefins see: (c) Borszeky, K.; Mallat, T.; Baiker,
A. Catal. Lett. 1999, 59, 95. (d) Crabtree, R. H. The Organometallic
Chemistry of the Transition Metals; Wiley: New York, 1988, 188.
(e) Bartok, M.; Czombos, J.; Felfoldi, K.; Gera, L.; Gondos, G.;
Molnar, A.; Notheisz, F.; Palinko, I.; Wittmann, G.; Zsigmond, A.
G. Stereochemistry of Heterogeneous Metal Catalysis; Wiley: New
York, 1985.
Acknowledgement
A.B.P. and K.P.P. thank CSIR, New Delhi, India, for fellowships. The au-
thors thank Dr. K. Pasupathy, Dr. H. B. Borate, and Dr. U. R. Kalkote for
helpful discussions and Dr. P. R. Rajamohanan for NMR facility, and
CSIR, New Delhi, India, for financial support as part of the XIIth Five
Year plan programme under title ACT (CSC-0301).
(12) Pikh, Z. G.; Fedevich, M. D.; Yatchishin, I. I. Zh. Org. Khim. 1978,
1, 60.
(13) Hon, Y.-S.; Lin, W.-C. Tetrahedron Lett. 1995, 36, 7693.
(14) (a) Furstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.; Nolan, P.
S. J. Org. Chem. 2000, 65, 2204. (b) Rodriguez, S.; Castillo, E.;
Carda, M.; Marco, J. A. Tetrahedron 2002, 58, 1185.
(c) Ackermann, L.; Ftirstner, A.; Weskamp, T.; Kohl, F. J.;
Herrmann, W. A. Tetrahedron Lett. 1999, 40, 4787.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379985.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(15) (a) Andreana, P. R.; McLellan, J. S.; Chen, Y.; Wang, P. G. Org. Lett.
2002, 4, 3875. (b) D’Annibale, A.; Ciaralli, L.; Bassetti, M.;
Pasquini, C. J. Org. Chem. 2007, 72, 6067.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 955–960