Synthesis of 5-alkyl-5-aryl-γ-lactams from 1-aryl-substituted nitroalkanes and methyl acrylate via Michael addition and reductive lactamization

Article abstract of DOI:10.1016/j.tet.2014.04.074

A general method for accessing 5-alkyl-5-aryl-γ-lactams has been developed using readily available aryl bromides, nitroalkanes, and methyl acrylate as the starting materials. The palladium-catalyzed arylation of nitroalkanes gave the 1-aryl-substituted nitroalkanes, which underwent the DBU-mediated Michael addition with methyl acrylate at room temperature to afford the methyl 4-aryl-4-nitroalkanoates. The latter were then subjected to the nitro reduction using NaBH₄-NiCl₂·6H₂O in MeOH at 0 °C to furnish, after treatment with aqueous K ₂CO₃ at room temperature, the 5-alkyl-5-aryl-γ- lactams in good to excellent overall yields. Selected examples of N-alkylation of the γ-lactams were also illustrated.

Full text of DOI:10.1016/j.tet.2014.04.074

Accepted Manuscript
Synthesis of 5-alkyl-5-aryl-#-lactams from 1-aryl-substituted nitroalkanes and methyl
acrylate via Michael addition and reductive lactamization
Jingjing Xu, Xingyao Li, Jinlong Wu, Wei-Min Dai
PII:
S0040-4020(14)00608-5
10.1016/j.tet.2014.04.074
TET 25524
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 24 March 2014
Revised Date: 18 April 2014
Accepted Date: 24 April 2014
Please cite this article as: Xu J, Li X, Wu J, Dai W-M, Synthesis of 5-alkyl-5-aryl-#-lactams from 1-
aryl-substituted nitroalkanes and methyl acrylate via Michael addition and reductive lactamization,
Tetrahedron (2014), doi: 10.1016/j.tet.2014.04.074.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Synthesis of 5-alkyl-5-aryl-γ-lactams from 1-aryl-substituted
nitroalkanes and methyl acrylate via Michael addition and
reductive lactamization
Leave this area blank for abstract info.
Jingjing Xu, Xingyao Li, Jinlong Wu,* Wei-Min Dai*
NaBH4
CO Me
2
1
. Pd
Br 2. DBU
CO Me
NiCl
then
CO
2
;
X
X
NO
2
X
R
N
O
R
K
2
3
H
2
+
(
12 examples)
R
NO2
X = 2-Me, 3-Me, 4-Me, 2-MeO, 3-MeO, 4-MeO, 4-Cl, 4-CO Me
2
R = Me, Et
2-(1,3-dioxolan-2-yl), 4-(1,3-dioxolan-2-yl), 3,4-benzo

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of 5-alkyl-5-aryl-γ-lactams from 1-aryl-substituted nitroalkanes and methyl
acrylate via Michael addition and reductive lactamization
a
a
a,
a,b, ,†
Jingjing Xu , Xingyao Li , Jinlong Wu *, Wei-Min Dai
∗
a
Laboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, China
Laboratory of Advanced Catalysis and Synthesis, Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon,
b
Hong Kong SAR, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A general method for accessing 5-alkyl-5-aryl-γ-lactams has been developed using readily
available aryl bromides, nitroalkanes, and methyl acrylate as the starting materials. The
palladium-catalyzed arylation of nitroalkanes gave the 1-aryl-substituted nitroalkanes which
underwent the DBU-mediated Michael addition with methyl acrylate at room temperature to
afford the methyl 4-aryl-4-nitroalkanoates. The latter were then subjected to the nitro reduction
Available online
using NaBH
room temperature, the 5-alkyl-5-aryl-
examples of N-alkylation of the -lactams were also illustrated.
4
–NiCl
2
ꢀ6H
2
O in MeOH at 0 ºC to furnish, after treatment with aqueous K
2 3
CO at
Keywords:
Amidation
Arylation
γ-lactams in good to excellent overall yields. Selected
γ
©
2014 Elsevier Ltd. All rights reserved.
γ-Lactams
Michael addition
Nitroalkanes
Palladium
1
. Introduction
first molecule as a truly specific inhibitor of the proteasome with
enormous potential applications as therapeutic agent.
Salinosporamide A (3) shares the same fused bicyclic core with 4
and was found to be about 35 times more potent than 4 in
inhibiting proteasomal chymotrypsin-like proteolytic activity
against purified 20S proteasome. The compound 3 also possesses
a
The γ-lactam (pyrrolidin-2-one) core is a biologically significant
structural motif and has been found in many natural products.
Figure 1 illustrates some representative structures possessing 5,5-
disubstituted γ-lactams I. Rolapitant (SCH619734, 1) and
oxazolomycin A (2) feature a γ-lactam unit within the
spirobicyclic skeleton while salinosporamide A (3) and clasto-
lactacystin β-lactone (4, also called omuralide, a transformation
product of 5) contain a fused β-lactone ring onto the C4 and C5
positions of the pyrrolidin-2-one core. Lactacystin (5) was
known as a prodrug that delivers its biological activity through
conversion into 4. Moreover, the γ-lactam unit has been found in
the macrocyclic natural products such as ansalactam A (6) and
divergolide D (7). These γ-lactam-containing natural products
exhibit diverse biological activities. Rolapitant (1) was reported
as a selective and orally active neurokinin NK1 receptor1
antagonist with centrally-mediated antiemetic effects.
Oxazolomycin A (2) is the parent member of a family of polyene
lactone-lactam antibiotics with potent antiviral, antibacterial and
cytotoxic activity. Its broad-spectrum activity has been attributed
1
2
cytotoxicity against a number of cancer cell lines with IC /LC
3
50
50
3
values less than 10 nM. Ansalactam A (6) and divergolide D (7)
are the new members of the ansamycin family of polyketide
natural products. The biological activity of ansalactam A (6) is
not available yet but divergolide D (7) was reported to be active
against Mycobacterium vaccae and Stapylococcus aureus and is
4
5
potent against a panel of 40 tumor cell lines with mean IC value
6
50
7
of 2.4 µM. Moreover, the N-substituted γ-lactams, both natural
7
and synthetic origin, have been reported. Some representative
11
examples include the natural products, bisavenanthramide B,
12
13
heliotropamine, and nagelamide U and V (all structures not
shown), and the synthetic libraries prepared by Shaw and other
14
groups.
8
to its protonophoric properties. Lactacystin (5) is known to
transform into omuralide (4) for penetrating cell and forming
9,10
covalent bond conjugate with 20S proteasome. The compound
4b,c
4
—
is also a synthetic intermediate of lactacystin and it is the
——
∗
Corresponding authors. Tel./fax: +86 571 89953128; e-mail addresses: wyz@zju.edu.cn (J. Wu); chdai@zju.edu.cn (W.-M. Dai).
Tel.: +852 23587365; fax: +852 23581594; e-mail address: chdai@ust.hk.
†

2
Tetrahedron
2
. Results and discussion
ACCEPTED MANUSCRIPT
H
R1
R2
Ph
O
N
N
O
N
F C
3
H
The Pd-catalyzed α-arylation of nitroalkanes with both aryl
bromides and chlorides has been reported by Vogl and Buchwald
using Cs CO as the base and DME (dimethoxyethane) as the
solvent. The sterically demanding substrate 14a was not used
for this type of arylation reaction in the previous study. We used
H
O
I:
γ
-lactams
2
3
Me
1
: rolapitant
18
F C
3
O
N
Me
O
1
4a as the substrate for optimization of the reaction conditions
and some representative results are summarized in Table 1. In the
presence of 5 mol % Pd (dba) , 20 mol % of the phosphine ligand
OH
O
Me
O
O
NMe
N
H
HO
Me
2
3
Me Me Me
OH
: oxazolomycin A
O
15a, and 2 equivalents of MeCH NO , three bases were
2 2
2
examined (entries 1–3, Table 1). After heating at 110 ºC for 24 h
in 1,4-dioxane in a closed vial, the desired product 11a was
obtained along with the ketone byproduct 16 and the recovered
14a. The arylation using these three bases gave about 60%
HO
Me
Cl
HO
Me
Me
H
Me
O
Me
O
O
N
conversion of 14a and the milder base K PO provided a better
H
3
4
O
O
O
N
H
O
O
N
S
yield (42%) of 11a with less amount of the ketone 16 in 13%
HO
H
HO
H
H
yield (entry 2, Table 1). In the entries 4–6, the phosphine ligand
Me
CO H
2
18
H
Me
1
5b and the base, K PO , were used to investigate the effect of
3 4
AcHN
the catalyst loading on the product yield. With 5 mol %
3
: salinosporamide A
4: omuralide
5: lactacystin
Pd (dba) , the product 11a was formed in 71% and 67% yields,
2
3
respectively, when 20 and 10 mol % of 15b were used (entries 4
and 5, Table 1). Once the loading of Pd (dba) decreased to 2.5
mol %, a diminished product yield of 50% was obtained with
2% of the recovered 14a (entry 6, Table 1).
Me
HO
Me
HO
2
3
H
OH
Me
O
O
O
2
Me
Me
O
NH
O
N
O
Me
O
Me
O
H
O
Table 1
Me
Me
H
O
Screening of reaction conditions for Pd-catalyzed arylation
Me
HO
Me
Me
Me
Me
: ansalactam A
Figure 1. Structures of -lactam-containing natural products 1–7.
MeCH NO (2 eq)
2 2
Br
Pd (dba) (5 mol %)
ligand (20 mol %), base (1.3 eq)
6
7: divergolide D
2 3
X
γ
O
O
1
,4-dioxane, 110 °C , 24 h
O
O
1
5
R
14a
11a: X = H, NO2
16: X = O
5
-Methyl-5-phenylpyrrolidin-2-one (10, Figure 2), a cyclic
1
5a: R = H
analogue of γ-aminobutyric acid (GABA), was reported to
exhibit powerful anticonvulsive action as the inhibitor of γ-
15b: R = Me
1
5a
P(t-Bu)2
aminobutyric acid–α-ketoglutaric acid transaminase.
It was
also found to act as an inhibitor of mitochondria protein synthesis
and deliver the effect on discrimination learning. Miller and
Goelitz reported a synthesis of 10 from 2-phenylpropionic acid
15b
a
b
b
Entry
Base
Cs CO
PO
KOt-Bu
Ligand
15a
14a (%)
16 (%)
11a (%)
1
2
3
4
2
3
43
20
18
(
8) via a 7-step sequence, involving formation of the urethane 9
16
K
3
4
15a
39
13
42
under thermolysis of the corresponding acyl azide (Figure 2a).
A Pd–Cu-catalyzed oxidative heteroannulation of N-carbamoyl
aminoalkynes was used by Vatéle and coworkers for synthesis of
15a
36
19
38
c
c
K
3
PO
PO
PO
4
4
4
15b
15b
15b
–
–
71
a. Miller and Goelitz
d
c
c
5
K
3
–
–
67
e
c
4
steps
3 steps
NHCO Me
6
K
3
22
–
50
a
N
H
O
O
Recovered substrate after isolation.
CO H
2
Me
10
b
c
d
e
Me
2
Isolated yields. The ketone 16 was formed from 11a via the Nef reaction.
Me
Not determined.
8
9
5
mol % Pd
2
(dba)
3
and 10 mol % of 15b were used. [Pd]/[15b] = 1:1.
and 10 mol % of 15b were used. [Pd]/[15b] = 1:2.
b. current work:
2.5 mol % Pd
2
(dba)
3
CO Me
2
CO Me
2
[
H]
After optimizing the suitable ligand 15b and the base, K PO ,
X
3
4
NO2
R
N
H
the arylation of nitroethane and nitropropane was performed with
a number of aryl bromides 14a–k (Table 2). Presumably due to
steric hindrance, the three ortho-substituted substrates 14a,d,g
entries 1, 4, and 7, Table 2) required a higher palladium loading
while other substrates underwent the arylation with 1 mol %
R
NO2
12
Figure 2. Synthetic approaches toward 5-alkyl-5-aryl-
X
R
X
11
13
γ
-lactams 10 and 13.
,5-dialkyl, 5,5-spiro-, or 4,5-fused pyrrolidin-2-ones. We
(
1
7
5
envisioned a general synthetic route to the 5-alkyl-5-aryl γ-
Pd (dba) and 4 mol % the ligand 15b. After heating in DME at
18
2
3
lactams 13 from the readily available 1-aryl nitroalkanes 11 via
5
0 ºC for 14 h (except for entry 1, Table 2), the products 11b–l
were produced in 74–97% yields. Our results listed in the entries
, 9, 11, and 12 in Table 2 are comparable with those obtained by
19
Michael addition of 11 with methyl acrylate followed by
reductive amidation of the 4-nitrobutyrates 12 (Figure 2b). We
report here the results on synthesis of the γ-lactams 13 and the
3
18
using Cs CO as the base.
2
0–24
2
3
related N-alkylated derivatives.

3
a
ACCEPTED MASc
N
ree
U
nin
S
g
C
of
R
rea
I
ction conditions for the Michael addition of 11f
P
T
Table 2
R2
Results of Pd-catalyzed arylation of nitroalkanes
Me
R1
Me R2
O N
2
CO Me
2
RCH NO (2 eq)
2
2
NO2
17
CO Me
2
Pd (dba) (1 mol %)
R1
2
2
3
base, MeCN, rt
1
5b (4 mol %), K PO (1.3 eq)
Me
Me
3
4
X
11f
1
NO2
12f: R = R = H
X
Me
O
DME, 50 °C , 14 h
Br
R
18: R = H, R = Me
1
2
1
2
1
9: R = Me, R = H
14
11
Me
20
c
Entry
14: X
R
11: Yield (%)
a
1
2
b,c
c
1
14a: 2-(1,3-dioxolan-2-yl)
14b: 4-(1,3-dioxolan-2-yl)
14c: 3,4-Benzo
14d: 2-Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
11a: 71
Entry
R
R
Base (eq)
Et N (2.0)
t (h)
12
1
20 (%)
Yield (%)
12f: trace
12f: 94
12f: 97
12f: 20
18: –
2
3
11b: 82
1
2
3
4
5
H
H
3
–
d,e
11c: 89 (96)
H
H
DBU (1.0)
DBU (0.5)
DBU (0.1)
DBU (1.0)
DBU (1.0)
4
b
4
11d: 87
11e: 90
11f: 78
11g: 91
11h: 97
H
H
2.5
12
4
1
5
6
14e: 3-Me
H
H
10
70
71
14f: 4-Me
H
Me
H
b
7
14g: 2-MeO
6
Me
5
19: –
8
9
14h: 3-MeO
a
Using 2.0 equiv of 17 in MeCN at room temperature.
The Nef reaction product of 11f.
Isolated yields.
b
c
d,e
14i: 4-MeO
11i: 74 (94)
1
1
1
0
1
2
14j: 4-Cl
11j: 84
d
14k: 4-MeO
2
2
C
C
11k: 88 (85)
The Michael addition of the 1-aryl-substituted nitroalkanes
d,f
14k: 4-MeO
11l: 87 (86)
11a–l with methyl acrylate (17a) was found to be general and
efficient in the presence of 0.5 equivalent of DBU in MeCN at
room temperature for 2.5 h (Figure 2). Except for the (1,3-
dioxolan-2-yl)-substituted substrates 11a,b, excellent yields of
94–98% were obtained for the γ-nitrobutyrates 12c–l (Scheme 1
and entries 3–12, Table 4). The yields for the Michael addition of
1a,b are slightly lower (85–88%) and for the ortho-substituted
substrate 11a, 1.0 equiv of DBU and a longer reaction time (21 h)
were required (entries 1 and 2, Table 4).
a
Using 5 mol % Pd
h (taken from entry 4 of Table 1).
Using 5 mol % Pd
Isolated yields.
2 3
(dba) and 20 mol % 15b in 1,4-dioxane at 110 ˚C for 24
b
2 3
(dba) and 10 mol % 15b.
c
d
Data given in the parenthesis are taken from ref. 18 using 4 equiv of the
CO instead of K PO as the base.
(dba) and 6 mol %
nitroalkane and 2.2 equiv of Cs
2
3
3
4
1
e
For the yields given in the parenthesis, 1.5 mol % Pd
2
3
1
5b were used.
f
For the yield given in the parenthesis, the corresponding chloride was used
for the arylation at 60 ºC.
Reduction of aliphatic nitro compounds could be achieved by
a variety of combination of NaBH with another transition metal
4
2
5
26
The Michael addition of nitroalkanes with substituted
acrylates or the equivalent Michael acceptors has been reported
in the literature. With the readily prepared 1-aryl-substituted
nitroalkanes 11 in hand, we investigated the Michael addition
reaction using the nitro compound 11f as the substrate (Table 3).
species, such as NaBH –CoCl , NaBH –NiCl , NaBH4–
4 2 4 2
27 28 29
CuSO4, NaBH –ZrCl , and NaBH –Pd/C. We found that the
4
2
4
19
combination of 5.0 equivalents of NaBH and 1.0 equivalent of
4
NiCl ꢀ6H O could efficiently reduce the nitroalkanes 12 at 0 ºC
2
2
for 1 h in MeOH to form the corresponding amines 21 with
spontaneous formation of the γ-lactams 13 in various ratios under
the reduction conditions (Scheme 1). The reaction mixture of 21
and 13, without separation, was further treated with aqueous
K CO at room temperature for 2 h to afford the γ-lactams 13.
It was found that Et N failed to promote the Michael addition of
3
1
1f with methyl acrylate (17a) at room temperature for 12 h
while the same reaction using DBU as the base afforded 94%
yield of the desired product 12f within 1 h (entry 1 vs. entry 2,
Table 3). p-Tolyl methyl ketone 20 derived from the Nef reaction
of 11f was also isolated from the DBU-mediated reaction in 4%
yield. By lowering the amount of DBU to 0.5 equivalent and with
an extended reaction time to 2 h, the Nef reaction byproduct
could be minimized, giving the desired product 12f in 97% yield
2
3
The yields for 13c–i by the one-pot reductive lactamization are
93–99% (entries 3–9, Table 4) while the yields for 13k,l
possessing a methyl benzoate moiety are 85–86% (entries 11 and
12, Table 4). In the latter cases, hydrolysis of the methyl
benzoate might occur to some extent under the basic conditions.
For the 4-chlorophenyl-substituted nitro compound 12j, although
only 0.3 equivalent of NiCl ꢀ6H O was used, partial reductive
(entry 3, Table 3). However, when only 0.1 equivalent of DBU
was used, the Michael addition became sluggish and, after 12 h,
the product 12f was isolated in 20% yield along with 10% of the
byproduct 20 (entry 4, Table 3). Two other Michael acceptors,
i.e. methyl methacrylate (17b) and methyl crotonate (17c) were
tried using 1.0 equivalent of DBU but the corresponding Michael
adducts 18 and 19 were not obtained. Instead, the Nef product 20
was exclusively generated from 11f in 70 and 71% yields,
respectively (entries 5 and 6, Table 3). These results suggest that
any substituent at the α or β position of the acrylate renders
formation of the nitro-substituted quaternary carbon difficult
presumably due to severe steric interaction among the reactants.
2
2
cleavage of the chloro group was observed to form the byproduct
10 as an inseparable mixture with the desired product 13j in a
11:89 ratio of 10:13j (entry 10, Table 4). It is worthy of
mentioning that a reduced amount of NiCl ꢀ6H O and a shorter
2
2
reaction time were beneficial for the reductive lactamization of
the acetal-containing 12b to furnish 13b in 83% yield (entry 2,
Table 4) as compared to 50% yield under the general reaction
conditions (data not shown). Finally, from the ortho-(1,3-
dioxolan-2-yl)-substituted nitroalkane 12a only 53% yield of the
γ-lactam 13a was formed even though 0.5 equivalent of
NiCl ·6H O was used for the reduction for only 0.5 h (entry 1,
2
2
Table 3

4
Tetrahedron
Table 4), implying that electronic/steric effe
A
ct(
C
s)
C
of
E
th
P
e
T
a
E
ce
D
tal MATa
NUSCRIPT
ble
5
a
moiety should be involved.
Results of N-alkylation of γ-lactam 13f
CO Me
2
NaBH (5 eq)
Me
Me
4
NaH (8 eq), RX (3 eq)
DMF, 15 h
NiCl •6H O (1 eq)
2
2
+
N
O
N
O
N
R
O
R
Me
13f
Me
MeOH
°C , 1 h
R
NH2
X
H
H
X
0
21
13
22a−c
CO Me
2
aq. K CO , rt, 2 h
c
2
3
Entry
RX
T (ºC)
80
Conversion (%)
Yield (%)
22a: 43
22a: 70
22b: 83
b
1
2
3
4
MeI
46
84
100
84
94
NO2
R
X
MeI
70
1
2
N
O
R
X
H
BnBr
70
13
AllylBr
AllylBr
70
22c: complex
22c: 58
Scheme 1.
Table 4
γ-Lactams 13 from reductive lactamization of γ-nitrobutyrates 12.
5
rt
a
Reaction conditions: 13f (0.25 mmol), NaH (2.0 mmol) in DMF (3.0 mL) in
a closed process vial at 60 ºC for 50 min; then RX (0.75 mmol), 15 h at the
indicated temperature.
1.5 equiv each of NaH and MeI were used.
Isolated yields.
a
Synthesis of γ-lactams 13 via Michael addition and reductive lactamization
Entry
X
R
12: Yield
13: Yield
(%)
b
b
b
(%)
c
c
d
1
2
3
4
5
6
7
8
9
2-(1,3-dioxolan-2-yl)
4-(1,3-dioxolan-2-yl)
3,4-Benzo
2-Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
12a: 85
13a: 53
3
. Conclusion
e
12b: 88
12c: 95
12d: 96
12e: 97
12f: 97
12g: 94
12h: 97
12i: 95
12j: 94
12k: 97
12l: 98
13b: 83
In summary, we have established a general and high-yielding
13c: 93
13d: 96
13e: 96
13f: 98
13g: 99
13h: 97
13i: 98
synthesis of 5-alkyl-5-aryl-γ-lactams 13 by Michael addition of
-aryl-substituted nitroalkanes 11 with methyl acrylate followed
1
3-Me
by one-pot reductive lactamization of the adducts 12. Since the
palladium-catalyzed α-arylation of nitroalkanes tolerates a
variety of aryl bromides/chlorides such as 14, the above
described synthetic protocol offers access to the diversely 5,5-
disubstituted γ-lactams 13 from the readily available nitro
compounds 11. The γ-lactams 13 might be used as the candidates
4-Me
18
2-MeO
3-MeO
4-MeO
15
for biological studies or as the building blocks for synthesis of
much more sophisticated molecular entities.
f
1
1
1
0
1
2
4-Cl
13j: 75
4-MeO
2
2
C
C
13k: 86
13l: 85
4
4
. Experimental
4-MeO
.1. General methods
a
Reaction conditions for the Michael addition of 11: 2 equiv methyl acrylate
7a, 0.5 equiv DBU, MeCN, rt, 2.5 h. Reaction conditions for reductive
1
1
13
H and1 C NMR spectra were recorded in CDCl (400 or 500
3
lactamization of 12: 5 equiv NaBH
4
, 1 equiv NiCl
2
ꢀ6H
2
O, MeOH, 0 ºC, 1 h;
13
MHz for H and 100, 125, or 150 MHz for C, respectively). IR
spectra were taken on an FT-IR spectrophotometer. Mass spectra
(MS) were measured by the ESI or EI method. Melting points are
uncorrected. Elemental analyses were performed by Zhejiang
University. Silica gel plates pre-coated on glass were used for
thin-layer chromatography using UV light, or 7% ethanolic
phosphomolybdic acid and heating as the visualizing methods.
Silica gel was used for flash column chromatography. Yields
then aq. K
Isolated yields.
Using1.0 equiv of DBU for 21 h.
Using 0.5 equiv NiCl
Using0.3 equiv NiCl
2
CO
3
, rt, 2 h.
b
c
d
e
2
ꢀ6H
ꢀ6H
2
O, 0.5 h.
2
O, 0.5 h. 50% yield was obtained under the
2
general reaction conditions.
f
2 2
Using 0.3 equiv NiCl ꢀ6H O. An inseparable mixture of 13j with the
dechlorinated byproduct 10 was obtained. 13j:10 = 89:11.
1
refer to chromatographically and spectroscopically ( H NMR)
homogeneous materials. Reagents were obtained commercially
and used as received.
Finally, we attempted to N-functionalization of the γ-lactams
1
3 in order to increase the structural diversity. Unfortunately, the
30
Pd- and Cu-catalyzed arylation of 13f with iodobenzene failed
to give the product presumably due to steric hindrance of the two
substituents at the C5 position. In contrast, N-alkylation of 13f
4
.2. General procedure A for the arylation of nitroalkanes
31
A dried 10-mL process vial was charged with appropriate
proceeded in the presence of NaH as the base. Methylation of
amounts of Pd (dba)3 and 2-(di-tert-butylphosphinyl)-2′-
2
1
1
3f was initially carried out in a closed vial at 80 ºC in DMF with
.5 equivalents each of NaH and MeI to give 22a in 43% yield
methylbiphenyl (15b), and 1.3 equiv of K PO . The vial was
3
4
sealed with as cap containing a silicon septum. The loaded vial
was evacuated and backfilled with nitrogen for three times. Then,
aryl bromide 14 (1.0 mmol), nitroalkane (2.0 mmol), and
degassed DME (5.0 mL) were added sequentially via a syringe.
The resultant mixture was stirred vigorously for 1 min at room
temperature, and then at 50 ºC for 14 h. After cooling to ambient
temperature the reaction mixture was diluted with EtOAc. The
resulting solution was filtered off through a plug of Celite with
washing by EtOAc. The combined filtrate was washed with water
and brine, dried over anhydrous Na SO , filtered, and condensed
with 46% conversion of the substrate (entry 1, Table 5). By
increasing the amounts of NaH (8 equiv) and MeI (3 equiv), the
yield of 22a was improved significantly (70%) with 84%
conversion of 13f (entry 2, Table 5). When benzyl bromide was
used for the reaction at 70 ºC, a higher yield of 83% was obtained
for 22b with 100% conversion of 13f (entry 3, Table 5). The
reaction of allyl bromide with 13f under the same conditions at
7
0 ºC resulted in a complex mixture with only trace product 22c.
Fortunately, allylation of 13f at room temperature afforded the
product 22c in 58% yield (entry 5, Table 5).
2
4

5
2
3
under reduced pressure. The residue was
column chromatography over silica gel to give the product 11.
The results are found in Table 2.
A
pu
C
rif
C
iedEPbyTEfla
D
sh MA4.
N
2.
U
8.
S
1
C
-M
R
e
I
thoxy-3-(1-nitroethyl)benzene (11h).
PT
Prepared according to the general procedure A in 97% yield as
a colorless oil; R =0.40 (9% EtOAc in hexane); H NMR (400
1
f
MHz, CDCl ) δ 7.32 (t, J=8.0 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H),
3
4
(
.2.1. 2-[2-(1-Nitroethyl)phenyl][1,3]dioxolane
11a).
Prepared according to the general procedure A in 71% yield as
a colorless oil; R =0.41 (9% EtOAc in hexane); IR (film): 2894,
6
.99 (t, J=2.0 Hz, 1H), 6.94 (dd, J=8.0, 2.0 Hz, 1H), 5.58 (q,
13
J=6.8 Hz, 1H), 3.82 (s, 3H), 1.88 (d, J=6.8 Hz, 3H); C NMR
100 MHz, CDCl ) δ 159.9, 136.9, 130.0, 119.5, 115.0, 113.0,
(
3
f
–1
1
86.0, 55.3, 19.4.
1
557, 1455, 1385, 1360, 1225, 1087, 1061 cm ; H NMR (400
1
8 , 3 4
MHz, CDCl ) δ 7.60–7.55 (m, 2H), 7.46–7.39 (m, 2H), 6.22 (q,
4.2.9. 1-Methoxy-4-(1-nitroethyl)benzene (11i).
3
J=6.8 Hz, 1H), 6.05 (s, 1H), 4.19–4.01 (m, 4H), 1.89 (d, J=6.8
Prepared according to the general procedure A in 74% yield as
13
1
Hz, 3H); C NMR (125 MHz, CDCl ) δ 135.7, 134.8, 129.9,
3
a colorless oil; R =0.38 (9% EtOAc in hexane); H NMR (400
f
1
29.5, 127.4, 127.0, 102.5, 81.1, 65.4, 65.2, 20.3; HRMS (+EI)
MHz, CDCl ) δ 7.40 (d, J=8.8 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H),
3
+
1
3
calcd for C H O 176.0837 (M –HNO ), found 176.0833.
11
12
2
2
5.57 (q, J=6.8 Hz, 1H), 3.80 (s, 3H), 1.86 (d, J=6.8 Hz, 3H);
C
NMR (100 MHz, CDCl ) δ 160.7, 128.9 (×2), 127.7, 114.3 (×2),
3
4
(
.2.2. 2-[4-(1-Nitroethyl)phenyl][1,3]dioxolane
11b).
Prepared according to the general procedure A in 82% yield as
a colorless oil; R =0.38 (9% EtOAc in hexane); IR (film): 2946,
8
5.8, 55.4, 19.3.
3
2 , 3 4
4.2.10. 1-Chloro-4-(1-nitroethyl)benzene (11j).
f
Prepared according to the general procedure A in 84% yield as
–1
1
1
2
884, 1705, 1552, 1386, 1358, 1085, 1042 cm ; H NMR (400
a colorless oil; R =0.39 (9% EtOAc in hexane); H NMR (400
f
MHz, CDCl ) δ 7.53 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H),
5
J=7.2 Hz, 3H); C NMR (100 MHz, CDCl ) δ 139.8, 136.5,
1
3
MHz, CDCl ) δ 7.42–7.37 (m, 4H), 5.58 (q, J=6.8 Hz, 1H), 1.88
3
13
.82 (s, 1H), 5.62 (q, J=7.2 Hz, 1H), 4.14–4.00 (m, 4H), 1.88 (d,
(
d, J=6.8 Hz, 3H); C NMR (100 MHz, CDCl ) δ 136.1, 134.0,
3
13
3
129.4 (×2), 129.0 (×2), 85.5, 19.5.
.2.11. Methyl 4-(1-nitroethyl)benzoate (11k).
Prepared according to the general procedure A in 88% yield as
27.6 (×2) , 127.1 (×2), 103.1, 85.9, 65.4 (×2), 19.6; HRMS
1
8 , 3 4
+
4
(+EI) calcd for C H O 176.0837 (M –HNO ), found 176.0837.
11 12 2 2
1
8
4
.2.3. 2-(1-Nitroethyl)naphthalene (11c).
Prepared according to the general procedure A in 89% yield as
1
a colorless oil; R =0.44 (17% EtOAc in hexane); H NMR (400
f
MHz, CDCl ) δ 8.04 (d, J=7.2 Hz, 2H), 7.50 (d, J=8.0 Hz, 2H),
3
1
a crystalline solid; R =0.43 (9% EtOAc in hexane); H NMR (400
MHz, CDCl ) δ 7.92–7.85 (m, 4H), 7.57–7.53 (m, 3H), 5.79 (q,
J=6.8, 1H), 1.99 (d, J=6.8 Hz, 3H); C NMR (100 MHz, CDCl3)
δ 133.6, 132.9, 132.8, 128.9, 128.2, 127.6, 127.2, 127.0 126.7,
1
f
5.65 (q, J=6.8, 1H), 3.90 (d, J=0.8 Hz, 3H), 1.88 (dd, J=6.8, 0.8
13
3
Hz, 3H); C NMR (100 MHz, CDCl ) δ 166.3, 140.0, 131.4,
3
13
130.3 (×2), 127.5 (×2), 85.7, 52.4, 19.4.
1
8
4
.2.12. Methyl 4-(1-nitropropyl)benzoate (11l).
Prepared according to the general procedure A in 87% yield as
24.0, 86.2, 19.4.
4
.2.4. 1-Methyl-2-(1-nitroethyl)benzene (11d).
Prepared according to the general procedure A in 87% yield as
1
a colorless oil; R =0.36 (9% EtOAc in hexane); H NMR (400
f
MHz, CDCl ) δ 8.05 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H),
3
a yellow oil; R =0.55 (9% EtOAc in hexane ); IR (film): 3069,
2
NMR (400 MHz, CDCl ) δ 7.44–7.42 (m, 1H), 7.30–7.19 (m,
f
5.40 (dd, J=8.8, 6.8 Hz, 1H), 3.91 (s, 3H), 2.56–2.45 (m, 1H),
–1 1
13
989, 1553, 1494, 1462, 1385, 1359, 1273, 1067, 1046 cm ; H
2
.16–2.05 (m, 1H), 0.97 (t, J=7.2 Hz, 3H); C NMR (100 MHz,
3
CDCl ) δ 166.3, 139.0, 131.6, 130.3 (×2), 127.9 (×2), 92.6, 52.4,
3
3
H), 5.88 (q, J=7.2 Hz, 1H), 2.42 (s, 3H), 1.87 (d, J=6.8 Hz, 3H);
2
7.5, 10.6.
13
C NMR (150 MHz, CDCl ) δ 136.5, 134.1, 130.8, 129.4, 126.7,
3
4
.3. General procedure B for the Michael addition of
1
25.9, 82.1, 19.20, 19.18; HRMS (+EI) calcd for C H 119.0861
9
11
+
nitroalkanes 11 with methyl arylate
(M –NO ), found 119.0858.
2
3
2
4
.2.5. 1-Methyl-3-(1-nitroethyl)benzene (11e).
Prepared according to the general procedure A in 90% yield as
To a solution of 11 (1.0 mmol) and methyl acrylate (2.0
mmol) in MeCN (4.0 mL) at room temperature under a nitrogen
atmosphere was added DBU (0.5 mmol). The resultant mixture
was stirred at room temperature for 2.5 h. The reaction was
1
a colorless oil; R =0.50 (9% EtOAc in hexane); H NMR (400
MHz, CDCl ) δ 7.32–7.21 (m, 4H), 5.58 (q, J=6.8 Hz, 1H), 2.38
s, 3H), 1.88 (d, J=6.8 Hz, 3H); C NMR (100 MHz, CDCl ) δ
f
3
13
quenched with saturated aqueous NH Cl solution (20 mL) and
(
1
4
3
the reaction mixture was extracted with EtOAc (30 mL×3). The
combined organic layer was washed with brine, dried over
anhydrous Na SO , filtered, and condensed under reduced
39.0, 135.6, 130.6, 129.0, 128.1, 124.5, 86.3, 21.5, 19.6.
3
3
4
.2.6. 1-Methyl-4-(1-nitroethyl)benzene (11f).
2
4
Prepared according to the general procedure A in 78% yield as
pressure. The residue was purified by flash column
chromatography over silica gel to afford 12. The results are found
in Table 4.
1
a colorless oil; R =0.56 (9% EtOAc in hexane); H NMR (400
f
MHz, CDCl ) δ 7.37 (d, J=8.0 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H),
3
13
5
.60 (q, J=6.8 Hz, 1H), 2.38 (s, 3H), 1.88 (d, J=6.8 Hz, 3H);
C
4
.3.1. Methyl 4-[2-(1,3-dioxolan-2-yl)phenyl] -4-
NMR (100 MHz, CDCl ) δ 139.9, 132.8, 129.7 (×2), 127.4 (×2),
3
nitropentanoate (12a).
8
6.0, 21.2, 19.4.
Prepared according to the general procedure B with 1 equiv
4
.2.7. 1-Methoxy-2-(1-nitroethyl)benzene (11g).
DBU for 21 h in 85% yield as a colorless oil; R =0.24 (17%
f
Prepared according to the general procedure A in 91% yield as
EtOAc in hexane); IR (film): 2993, 2954, 2886, 1743, 1729,
1549, 1538, 1433, 1208, 1174, 1089, 1060 cm ; H NMR (400
–1
1
a colorless oil; R =0.39 (9% EtOAc in hexane); IR (film): 2943,
f
–1
1
1
603, 1552, 1495, 1463, 1384, 1355, 1250 cm ; H NMR (400
MHz, CDCl ) δ 7.76 (d, J=7.6 Hz, 1H), 7.46–7.35 (m, 3H), 5.68
3
MHz, CDCl ) δ 7.40–7.36 (m, 2H), 7.03–6.99 (m, 1H), 6.94–
(s, 1H), 4.18–4.09 (m, 2H), 4.02–3.93 (m, 2H), 3.65 (s, 3H),
2.87–2.74 (m, 2H), 2.30–2.11 (m, 2H), 2.02 (s, 3H); C NMR
3
1
3
6
.91 (m, 1H), 5.99 (q, J=6.8 Hz, 1H), 3.84 (s, 3H), 1.88 (d, J=6.8
13
Hz, 3H); C NMR (100 MHz, CDCl ) δ 156.9, 130.7, 127.4,
(100 MHz, CDCl ) δ 172.4, 136.5, 136.0, 129.4, 129.2, 128.9,
3
3
1
24.2, 120.7, 110.9, 80.0, 55.5, 18.5; HRMS (+EI) calcd for
126.3, 99.1, 92.4, 65.3 (×2), 51.8, 34.8, 29.5, 27.0; MS (+EI) m/z
+
+
+
C H NO 181.0739 (M ), found 181.0738.
308 (M –H, 1.51), 263 (M –NO , 15), 201 (93), 141 (100);
9
11
3
2

6
Tetrahedron
+
HRMS (+EI) calcd for C H O 262.1205 (MAC–H
C
NO ),
E
P
T
fo
E
u
D
nd MA4.
N
3.
U
7.
S
M
C
e
R
th
I
yl 4-(2-Methoxyphenyl)-4-
P
T
15
18
4
2
2
62.1203.
nitropentanoate (12g)
Prepared according to the general procedure B in 94% yield as
4
.3.2. Methyl 4-[4-(1,3-dioxolan-2-yl)phenyl] -4-
a colorless solid; mp 61–63 ˚C (CH Cl –hexane); R =0.26 (9%
2
2
f
nitropentanoate (12b)
EtOAc in hexane); IR (KBr): 3002, 2951, 1736, 1545, 1491,
Prepared according to the general procedure B in 88% yield as
–1 1
1
348, 1250, 1199, 1174, 1025 cm ; H NMR (400 MHz, CDCl )
3
a colorless oil; R =0.21 (17% EtOAc in hexane); IR (film): 2993,
f
–
δ 7.36 (td, J=8.0, 1.2 Hz, 1H), 7.28 (dd, J=8.0, 1.2 Hz, 1H), 7.00
(t, J=7.2 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 3.76 (s, 3H), 3.62 (s,
H), 2.86–2.79 (m, 1H), 2.72–2.64 (m, 1H), 2.27 (ddd, J=16.4,
2
953, 2888, 1740, 1729, 1548, 1538, 1199, 1174, 1089, 1019 cm
1
1
;
H NMR (400 MHz, CDCl ) δ 7.51 (d, J=8.4 Hz, 2H), 7.38 (d,
3
3
J=8.4 Hz, 2H), 5.81 (s, 1H), 4.12–4.03 (m, 4H), 3.66 (s, 3H),
2
13
10.4, 5.2 Hz, 1H), 2.14 (ddd, J=16.4, 10.8, 6.0 Hz, 1H), 1.91 (s,
.80–2.61 (m, 2H), 2.30–2.26 (m, 2H), 1.95 (s, 3H); C NMR
13
3
1
H); C NMR (100 MHz, CDCl ) δ 172.7, 156.7, 130.3, 127.3,
3
(100 MHz, CDCl ) δ 172.3, 139.5, 138.9, 126.9 (×2), 125.3 (×2),
3
26.8, 120.5, 111.8, 90.5, 55.3, 51.7, 32.3, 29.6, 24.6; MS (+EI)
1
02.7, 92.2, 65.2 (×2), 51.7, 34.4, 29.3, 23.7; MS (+EI) m/z 308
+
+
+
m/z 221 (M –NO
2
, 41), 189 (43), 161 (100). Anal. Calcd for
(
M –H, 0.34), 263 (M –NO , 100); HRMS (+EI) calcd for
2
+
C H17NO : C, 58.42; H, 6.41; N, 5.24. Found: C, 58.86; H, 6.44;
13 5
C H O 262.1205 (M –HNO ), found 262.1198.
15
18
4
2
N, 5.40%.
.3.8. Methyl 4-(3-Methoxyphenyl)-4-
4
.3.3. Methyl 4-(Naphthalene-2-yl)-4-
4
nitropentanoate (12c)
nitropentanoate (12h)
Prepared according to the general procedure B in 95% yield as
Prepared according to the general procedure B in 97% yield as
a colorless oil; R =0.23 (9% EtOAc in hexane); IR (film): 3057,
2
NMR (400 MHz, CDCl ) δ 7.87–7.82 (m, 4H), 7.55–7.50 (m,
2
2
CDCl ) δ 172.5, 135.9, 133.0, 132.7, 128.9, 128.3, 127.5, 127.0,
1
2
f
–1
1
a colorless oil; R
953, 1743, 1729, 1602, 1537, 1346, 1201, 1174, 1045 cm ; H
=0.24 (9% EtOAc in hexane); IR (film): 3000,
f
–1 1
993, 2950, 1738, 1729, 1547, 1534, 1436, 1199, 1172 cm ; H
2
3
NMR (400 MHz, CDCl ) δ 7.33–7.29 (m, 1H), 6.94–6.88 (m,
3
H), 7.43 (dd, J=8.8, 1.6 Hz, 1H), 3.65 (s, 3H), 2.93–2.77 (m,
13
3H), 3.81 (s, 3H), 3.66 (s, 3H), 2.79–2.74 (m, 1H), 2.72–2.62 (m,
H), 2.33 (t, J=8.0 Hz, 2H), 2.07 (s, 3H); C NMR (100 MHz,
13
1
H), 2.29 (t, J=8.0 Hz, 2H), 1.94 (s, 3H); C NMR (100 MHz,
3
CDCl ) δ 172.4, 159.7, 140.2, 129.8, 117.4, 113.7, 111.7, 92.3,
3
26.7, 124.9, 122.6, 92.6, 51.8, 34.4, 29.5, 23.8; MS (+EI) m/z
+
+
55.1, 51.7, 34.4, 29.3, 23.6; MS (+EI) m/z 221 (M –NO
2
, 32),
41 (M –NO , 42), 209 (64), 181 (100); HRMS (+EI) calcd for
2
+
189 (79), 161 (100); HRMS (+EI) calcd for C13 220.1099
H O
16 3
C H NO 287.1158 (M ), found 287.1152.
+
16
17
4
(
M –HNO ), found 220.1093.
2
4
(
.3.4. Methyl 4-(2-Methylphenyl)-4-nitropentanoate
12d)
Prepared according to the general procedure B in 96% yield as
a colorless oil; R =0.31 (9% EtOAc in hexane); IR (film): 2994,
4
.3.9. Methyl 4-(4-Methoxyphenyl)-4-
nitropentanoate (12i)
Prepared according to the general procedure B in 95% yield as
a colorless solid; mp 57–59 ˚C (CH Cl –hexane); R =0.21 (9%
EtOAc in hexane); IR (KBr): 2999, 2954, 1740, 1611, 1538,
f
–1
1
2
2
f
2
953, 1742, 1732, 1547, 1538, 1345, 1201, 1172 cm ; H NMR
(500 MHz, CDCl ) δ 7.32 (dd, J=7.5, 2.0 Hz, 1H), 7.29–7.22 (m,
–1 1
3
1
386, 1344, 1258, 1185 cm ; H NMR (400 MHz, CDCl ) δ 7.33
3
2
2
3
1
H), 7.19 (dd, J=7.0, 1.0 Hz, 1H), 3.63 (s, 3H), 2.76 (t, J=8.0 Hz,
(d, J=8.8 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 3.81 (s, 3H), 3.66 (s,
H), 2.34–2.27 (m, 1H), 2.19 (s, 3H), 2.18–2.11 (m, 1H), 1.96 (s,
13
13
3H), 2.80–2.64 (m, 2H), 2.27 (t, J=8.0 Hz, 2H), 1.94 (s, 3H); C
NMR (100 MHz, CDCl ) δ 172.5, 159.9, 130.5, 126.9 (×2),
114.1 (×2), 91.9, 55.2, 51.8, 34.5, 29.5, 23.5; MS (+EI) m/z 221
(M –NO
H); C NMR (125 MHz, CDCl ) δ 172.4, 136.7, 136.1, 132.8,
3
3
28.8, 126.3, 126.2, 92.6, 51.8, 33.4, 29.6, 26.0, 19.9; MS (+EI)
+
m/z 205 (M –NO , 30), 173 (40), 145 (100); HRMS (+EI) calcd
for C H O 204.1150 (M –HNO ), found 204.1155.
+
2
+
2
, 74), 189 (63), 161 (100). Anal. Calcd for C13
H17NO
5
:
13
16
2
2
C, 58.42; H, 6.41; N, 5.24. Found: C, 58.79; H, 6.41; N, 5.40%.
4
(
.3.5. Methyl 4-(3-Methylphenyl)-4-nitropentanoate
12e)
Prepared according to the general procedure B in 97% yield as
a colorless oil; R =0.32 (9% EtOAc in hexane); IR (film): 2997,
4
.3.10. Methyl 4-(4-Chlorophenyl)-4-
nitropentanoate (12j)
Prepared according to the general procedure B in 94% yield as
a colorless oil; R =0.29 (9% EtOAc in hexane); IR (film): 2997,
953, 1741, 1727, 1547, 1536, 1495, 1346, 1201, 1173, 1100 cm
f
–1
1
f
2
953, 1739, 1541, 1437, 1345, 1201, 1172 cm ; H NMR (400
–
2
MHz, CDCl ) δ 7.29–7.25 (m, 1H), 7.18–7.14 (m, 3H), 3.66 (s,
3
2
1
2
5
1
1
3
;
H NMR (400 MHz, CDCl ) δ 7.37 (d, J=8.4 Hz, 2H), 7.31 (d,
3
H), 2.80–2.73 (m, 1H), 2.69–2.61 (m, 1H), 2.36 (s, 3H), 2.31–
13
J = 8.4 Hz, 2H), 3.66 (s, 3H), 2.80–2.72 (m, 1H), 2.68–2.60 (m,
.27 (m, 2H), 1.94 (s, 3H); C NMR (100 MHz, CDCl ) δ 172.5,
13
3
1
H), 2.28 (t, J=8.0 Hz, 2H), 1.94 (s, 3H); C NMR (100 MHz,
CDCl ) δ 172.3, 137.2, 135.1, 129.0 (×2), 126.9 (×2), 91.9, 51.9,
34.4, 29.3, 23.6; MS (+EI) m/z 225 (M –NO
38.7, 138.6, 129.6, 128.7, 125.8, 122.2, 92.4, 51.8, 34.4, 29.4,
+
+
3
3.7, 21.4; MS (+ESI) m/z 524.8 (2M+Na , 100), 273.8 (M+Na ,
+
+
, 59), 193 (73), 165
2
+
9); HRMS (+EI) calcd for C H O 204.1150 (M –HNO ),
13
16
2
2
(100); HRMS (+EI) calcd for C H O Cl 224.0604 (M –HNO ),
12 13 2 2
found 204.1147.
found 204.0608.
4
(
.3.6. Methyl 4-(4-Methylphenyl)-4-nitropentanoate
12f)
Prepared according to the general procedure B in 97% yield as
a colorless oil; R =0.33 (9% EtOAc in hexane); IR (film): 2997,
4
.3.11. Methyl 4-(3-Methoxycarbonyl-1-methyl-1-
nitropropyl)benzoate (12k)
Prepared according to the general procedure B in 97% yield as
a colorless oil; R =0.11 (9% EtOAc in hexane); IR (film): 2999,
954, 1740, 1727, 1544, 1436, 1284, 1196, 1174, 1115 cm ; H
f
–1
1
f
2
952, 1739, 1541, 1437, 1343, 1197, 1176 cm ; H NMR (400
–1 1
2
MHz, CDCl ) δ 7.26 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H),
3
NMR (400 MHz, CDCl ) δ 8.06 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4
Hz, 2H), 3.93 (s, 3H), 3.66 (s, 3H), 2.83–2.76 (m, 1H), 2.70–2.62
3
3
2
1
.66 (s, 3H), 2.80–2.63 (m, 2H), 2.35 (s, 3H), 2.28 (t, J=8.4, Hz,
13
H), 1.94 (s, 3H); C NMR (125 MHz, CDCl ) δ 172.5, 138.9,
13
3
(m, 1H), 2.30 (dd, J=8.4, 8.0 Hz, 2H), 1.97 (s, 3H); C NMR
35.8, 129.5 (×2), 125.2 (×2), 92.2, 51.8, 34.4, 29.5, 23.6, 20.9;
+
+
(100 MHz, CDCl
125.4 (×2), 92.3, 52.2, 51.9, 34.4, 29.3, 23.9; MS (+EI) m/z 264
3
) δ 172.2, 166.1, 143.4, 130.7, 130.1 (×2),
MS (+ESI) m/z 273.8 (M+Na , 48), 524.8 (2M+Na , 100);
HRMS (+EI) calcd for C H O 204.1150 (M –HNO ), found
2
+
13
16
2
2
+
+
(
M –OCH , 4), 249 (M –NO , 19), 217 (100); HRMS (+EI) calcd
3 2
+
04.1155.
for C H O 248.1049 (M –HNO ), found 248.1047.
14
16
4
2

7
+
4
.3.12. Methyl 4-(1-Ethyl-3-methoxycarbonyl-1-
122.6, 62.1, 37.1, 30.4, 29.4; MS (+EI) m/z 225 (M , 14), 210
ACCEPTED MANUSCRIPT
+
nitropropyl)benzoate (12l)
(M –Me, 100). Anal. Calcd for C H NO: C, 79.97; H, 6.71; N,
15 15
Prepared according to the general procedure B in 98% yield as
6.22. Found: C, 79.81; H, 6.61; N, 6.27%.
a colorless oil; R =0.14 (9% EtOAc in hexane); IR (film): 2985,
f
4
.4.4. 5-Methyl-5-(2-methylphenyl)pyrrolidin-2-one
–1 1
2
954, 1740, 1732, 1544, 1436, 1284, 1192, 1115 cm ; H NMR
(
13d)
Prepared according to the general procedure C in 96% yield as
a colorless solid; mp 119–120 ˚C (CH Cl –hexane); R =0.31
(
400 MHz, CDCl ) δ 8.05 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz,
3
2
H), 3.93 (s, 3H), 3.64 (s, 3H), 2.73 (t, J=8.0 Hz, 2H), 2.55–2.46
2
2
f
(
m, 1H), 2.39–2.29 (m, 1H), 2.25–2.09 (m, 2H), 0.88 (t, J=7.6
13
(50% EtOAc in hexane); IR (KBr): 3178 (br), 3069, 3003, 1694,
1
1H), 7.19–7.16 (m, 3H), 6.73 (br s, 1H), 2.53–2.44 (m, 2H), 2.47
(s, 3H), 2.41–2.33 (m, 2H), 1.69 (s, 3H); C NMR (100 MHz,
CDCl ) δ 177.5, 143.9, 133.8, 132.5, 126.9, 125.9, 124.6, 62.8,
3
Hz, 3H); C NMR (100 MHz, CDCl ) δ 172.2, 166.1, 142.6,
–1 1
3
378, 1248 cm ; H NMR (400 MHz, CDCl ) δ 7.36–7.34 (m,
3
1
8
30.6, 129.9 (×2), 125.9 (×2), 96.3, 52.2, 51.9, 30.3, 29.3, 28.8,
+
+
.2; MS (+EI) m/z 278 (M –OCH , 3), 263 (M –NO , 11), 231
13
3
2
+
(100); HRMS (+EI) calcd for C H O 262.1205 (M –HNO ),
15 18 4 2
3
found 262.1208.
+
+
5.1, 30.2, 29.0, 21.7; MS (+EI) m/z 189 (M , 3), 174 (M –Me,
4
.4. General procedure C for the synthesis of γ-lactams 13
100). Anal. Calcd for C H NO: C, 76.16; H, 7.99; N, 7.40.
12
15
Found: C, 76.30; H, 8.00; N, 7.45%.
To a solution of the nitroalkanes 12 (1.0 mmol) and
4
.4.5. 5-Methyl-5-(3-methylphenyl)pyrrolidin-2-one
NiCl ·6H O (1.0 mmol) in MeOH (10 mL) cooled in an ice–
2
2
(
13e)
Prepared according to the general procedure C in 96% yield as
a colorless oil; R =0.37 (50% EtOAc in hexane); IR (film): 3212
(br), 3066, 2971, 1694, 1455, 1378, 1358, 1212 cm ; H NMR
(500 MHz, CDCl ) δ 7.25 (t, J=7.5 Hz, 1H), 7.16 (s, 1H), 7.15 (d,
J=7.5 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.40 (br s, 1H), 2.49–2.38
water bath (0 ºC) was added NaBH (5.0 mmol) slowly. The
4
resultant mixture was stirred at the same temperature for 1 h. The
reaction was quenched by adding a solution of K CO (4.0 mmol)
2
3
f
–1
1
in H O (5 mL) followed by stirring at room temperature for 2 h.
2
The mixture was extracted with EtOAc (40 mL×3) and the
combined organic layer was washed with brine, dried over
anhydrous Na SO , filtered, and condensed under reduced
3
1
3
(m, 2H), 2.36 (s, 3H), 2.32–2.22 (m, 2H), 1.65 (s, 3H); C NMR
(100 MHz, CDCl ) δ 177.9, 146.5, 138.1, 128.4, 127.7, 125.2,
121.5, 61.9, 37.5, 30.4, 29.6, 21.5; MS (+ESI) m/z 379.1
2
4
pressure. The residue was purified by flash column
chromatography over silica gel to give the γ-lactams 13. The
results are found in Table 4.
3
+
+
(2M+H , 53), 190.2 (M+H , 100); HRMS (+EI) calcd for
+
C H NO 189.1154 (M ), found 189.1159.
12
15
4
.4.1. 5-[2-(1,3-Dioxolan-2-yl)phenyl] -5-
methylpyrrolidin-2-one (13a)
4.4.6. 5-Methyl-5-(4-methylphenyl)pyrrolidin-2-one
13f)
Prepared according to the general procedure C in 98% yield as
a colorless solid; mp 124–126 ˚C (CH Cl –hexane); R =0.32
(50% EtOAc in hexane); IR (KBr): 3180 (br), 3087, 2978, 1691,
(
Prepared according to the general procedure C in 53% yield
using 0.5 equiv NiCl ·6H O and 5 equiv NaBH for 0.5 h at 0 ˚C
2
2
4
followed by addition of aq K CO . A colorless oil; R =0.27 (67%
2
2
f
2
3
f
EtOAc in hexane); IR (film): 3214 (br), 3068, 2968, 1691, 1394,
–1
1
–1 1
1
083, 1062 cm ; H NMR (500 MHz, CDCl ) δ 7.73 (d, J=7.0
1511, 1380, 1363, 1252 cm ; H NMR (400 MHz, CDCl
3
) δ 7.25
3
Hz, 1H), 7.37–7.28 (m, 3H), 7.01 (br s, 1H), 6.21 (s, 1H), 4.21–
.04 (m, 4H), 2.60–2.51 (m, 1H), 2.47–2.40 (m, 2H), 2.37–2.31
(d, J=8.0 Hz, 2H), 7.16 (d, J=8.4 Hz, 2H), 6.97 (br s, 1H), 2.49–
13
4
2.37 (m, 2H), 2.33 (s, 3H), 2.28–2.23 (m, 2H), 1.64 (s, 3H); C
NMR (125 MHz, CDCl ) δ 178.0, 143.6, 136.4, 129.1 (×2),
124.3 (×2), 61.8, 37.3, 30.4, 29.6, 20.7; MS (+ESI) m/z 400.9
13
(
m, 1H), 1.69 (s, 3H); C NMR (100 MHz, CDCl ) δ 177.2,
3
3
1
3
1
44.6, 133.8, 129.1, 127.6, 127.2, 125.4, 100.5, 65.4, 65.2, 62.6,
+ +
+
+
7.6, 31.8, 30.0; MS (+EI) m/z 247 (M , 21), 232 (M –Me, 28),
(2M+Na , 100), 211.8 (M+Na , 9). Anal. Calcd for C12
H15NO: C,
+
89 (100); HRMS (+EI) calcd for C H NO 247.1208 (M ),
76.16; H, 7.99; N, 7.40. Found: C, 76.32; H, 7.97; N, 7.51%.
14
17
3
found 247.1211.
4
.4.7. 5-(2-Methoxyphenyl)-5-methylpyrrolidin-2-
one (13g)
Prepared according to the general procedure C in 99% yield as
a colorless solid; mp 109–111 ˚C (CH Cl –hexane); R =0.30
(50% EtOAc in hexane); IR (KBr): 3179 (br), 3077, 2993, 2963,
4
.4.2. 5-[4-(1,3-Dioxolan-2-yl)phenyl] -5-
methylpyrrolidin-2-one (13b)
Prepared according to the general procedure C in 83% yield
using 0.3 equiv NiCl ·6H O and 5 equiv NaBH for 0.5 h at 0 ˚C
followed by addition of aq K CO . A colorless solid; mp 134–
2
2
f
2
2
4
–
1
1
1695, 1486, 1372, 1246, 1076, 1032 cm ; H NMR (500 MHz,
CDCl ) δ 7.26 (td, J=8.0, 2.0 Hz, 1H), 7.21 (dd, J=8.0, 2.0 Hz,
2
3
1
36 ˚C (CH Cl –hexane); R =0.29 (67% EtOAc in hexane); IR
3
2
2
f
(
KBr): 3171 (br), 3071, 2968, 1716, 1681, 1383, 1363, 1221,
1H), 6.95 (td, J=7.5, 0.5 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.83
–1
1
1
2
3
085 cm ; H NMR (400 MHz, CDCl ) δ 7.47 (d, J=8.0 Hz,
(br s, 1H), 3.87 (s, 3H), 2.63–2.57 (m, 1H), 2.50–2.43 (m, 1H),
3
13
H), 7.37 (d, J=8.0 Hz, 2H), 6.68 (br s, 1H), 5.80 (s, 1H), 4.16–
2.35–2.26 (m, 2H), 1.57 (s, 3H); C NMR (125 MHz, CDCl
3
) δ
13
.99 (m, 4H), 2.46–2.24 (m, 4H), 1.64 (s, 3H); C NMR (125
177.0, 156.2, 133.3, 128.3, 125.1, 120.5, 111.2, 61.2, 55.0, 34.3,
+
+
MHz, CDCl ) δ 177.8, 147.5, 136.7, 126.7 (×2), 124.6 (×2),
1
H, 9), 232 (M –Me, 100); HRMS (+EI) calcd for C H NO
2
29.8, 28.1; MS (+EI) m/z 205 (M , 2), 190 (M –Me, 100). Anal.
Calcd for C12 : C, 70.22; H, 7.37; N, 6.82. Found: C,
70.32; H, 7.37; N, 6.84%.
3
+
03.3, 65.3 (×2), 61.9, 37.5, 30.3, 29.4; MS (+EI) m/z 246 (M –
H15NO
2
+
14
17
3
+
47.1208 (M ), found 247.1203.
4
.4.8. 5-(3-Methoxyphenyl)-5-methylpyrrolidin-2-
one (13h)
Prepared according to the general procedure C in 97% yield as
a colorless oil; R =0.31 (50% EtOAc in hexane); IR (film): 3212
(br), 3075, 2968, 1681, 1602, 1488, 1288, 1258, 1221, 1044 cm
4
.4.3. 5-Methyl-5-(naphthalene-2-yl)pyrrolidin-2-
one (13c)
Prepared according to the general procedure C in 93% yield as
f
–
a colorless solid; mp 142–144 ˚C (CH Cl –hexane); R =0.13
2
2
f
1
1
(50% EtOAc in hexane); IR (KBr): 3179 (br), 3075, 2954, 1694,
; H NMR 400 MHz, CDCl
3
) δ 7.27 (t, J=8.0 Hz, 1H), 7.00 (br s,
–1
1
1
7
2
1
654, 1372, 1312, 1231 cm ; H NMR (400 MHz, CDCl ) δ
1H), 6.93 (d, J=8.0 Hz, 1H), 6.90 (s, 1H), 6.79 (d, J=8.0 Hz, 1H),
3
13
.99–7.96 (m, 1H), 7.85–7.80 (m, 4H), 7.50–7.45 (m, 3H), 2.53–
3.80 (s, 3H), 2.47–2.21 (m, 4H), 1.64 (s, 3H); C NMR (100
MHz, CDCl ) δ 178.1, 159.6, 148.3, 129.5, 116.8, 111.7, 110.7,
62.1, 55.1, 37.2, 30.4, 29.6; MS (+EI) m/z 205 (M , 14), 190
13
.27 (m, 4H), 1.73 (s, 3H); C NMR (100 MHz, CDCl ) δ 178.1,
3
3
+
43.7, 132.9, 132.2, 128.4, 128.0, 127.3, 126.2, 125.8, 123.2,

8
Tetrahedron
+
(
M –Me, 100); HRMS (+EI) calcd for C
A
H
C
NO 2
2
C
E
P
0
T
5.1
E
1
D
03 MAco
NU
m
bin
S
edCRorg
I
anic layer was washed with brine, dried over
P
T
12
15
+
(M ), found 205.1107.
anhydrous Na SO , filtered, and condensed under reduced
2
4
pressure. The residue was purified by flash column
chromatography over silica gel to give the N-alkylated products
4
.4.9. 5-(4-Methoxyphenyl)-5-methylpyrrolidin-2-
one (13i)
2
2a–c. The results are found in Table 5.
Prepared according to the general procedure C in 98% yield as
a colorless solid; mp 136–138 ˚C (CH Cl –hexane); R =0.24
4.5.1. 1,5-Dimethyl-5-(4-methylphenyl)pyrrolidin-
2
2
f
2
-one (22a)
(50% EtOAc in hexane); IR (KBr): 3178 (br), 3072, 2972, 1694,
–1 1
1
514, 1248, 1182, 1027 cm ; H NMR (400 MHz, CDCl ) δ 7.27
Prepared according to the general procedure D in 70% yield as
3
(
d, J=8.4 Hz, 2H), 7.07 (br s, 1H), 6.87 (d, J=8.4 Hz, 2H), 3.78
a colorless oil; R =0.35 (50% EtOAc in hexane); IR (film): 3025,
f
–1 1
13
(s, 3H), 2.46–2.32 (m, 2H), 2.26–2.18 (m, 2H), 1.62 (s, 3H); C
2968, 1691, 1681, 1511, 1417, 1385, 1144 cm ; H NMR (400
NMR (100 MHz, CDCl ) δ 178.0, 158.2, 138.6, 125.5 (×2),
MHz, CDCl ) δ 7.16 (d, J=8.0 Hz, 2H), 7.09 (d, J=8.0 Hz, 2H),
3
3
+
1
5
7
13.7 (×2), 61.6, 55.0, 37.3, 30.4, 29.5; MS (+EI) m/z 205 (M ,
2.65 (s, 3H), 2.44 (t, J=8.0 Hz, 2H), 2.33 (s, 3H), 2.08 (t, J=7.6
+
13
), 190 (M –Me, 100). Anal. Calcd for C H NO : C, 70.22; H,
Hz, 2H), 1.65 (s, 3H); C NMR (100 MHz, CDCl ) δ 174.9,
12
15
2
3
.37; N, 6.82. Found: C, 70.04; H, 7.24; N, 6.86%.
140.9, 136.6, 129.2 (×2), 124.9 (×2), 65.1, 36.5, 29.4, 25.3, 24.1,
+
+
2
(
0.6; MS (+EI) m/z 203 (M , 6), 188 (M –Me, 100); HRMS
4
.4.10. 5-(4-Chlorophenyl)-5-methylpyrrolidin-2-
+
+EI) calcd for C H NO 203.1310 (M ), found 203.1308.
13 17
one (13j) and 5-Methyl-5-phenylpyrrolidin-2-one
1
6
(
10)
Prepared according to the general procedure C using 0.3 equiv
NiCl ·6H O and 5 equiv NaBH for 0.5 h at 0 ˚C followed by
4.5.2. 1-Benzyl-5-methyl-5-(4-
methylphenyl)pyrrolidin-2-one(22b)
2
2
4
Prepared according to the general procedure D in 83% yield as
addition of aq K CO . The product was obtained in 75% yield as
a 89:11 inseparable mixture of 13j with the dechlorinated
a colorless oil; R =0.46 (33% EtOAc in hexane); IR (film): 3029,
2975, 2921, 1691, 1679, 1395, 1171, 1153 cm ; H NMR (500
2
3
f
–1
1
byproduct 10. A colorless oil; R =0.30 (50% EtOAc in hexane);
MHz, CDCl ) δ 7.24–7.17 (m, 7H), 7.10 (d, J=8.0 Hz, 2H), 4.99
f
3
1
H NMR (400 MHz, CDCl ) δ 7.37–7.27 (m, 4.1H), 6.72 (br s,
and 3.67 (ABq, J=15.0 Hz, 2H), 2.58–2.46 (m, 2H), 2.36 (s, 3H),
3
13
0
2
.89H), 6.55 (br s, 0.11H), 2.48–2.37 (m, 2H), 2.28–2.22 (m,
H), 1.66 (s, 0.33H), 1.64 (s, 2.67H).
2.17–2.07 (m, 2H), 1.46 (s, 3H); C NMR (125 MHz, CDCl ) δ
3
175.8, 141.1, 138.7, 137.0, 129.4 (×2), 128.2 (×2), 127.7 (×2),
1
26.8, 125.4 (×2), 66.5, 44.3, 37.1, 29.5, 26.4, 20.8; MS (+EI)
4
.4.11. Methyl 4-(2-Methyl-5-oxo-pyrrolidin-2-
+ +
m/z 279 (M , 37), 264 (M –Me, 23); HRMS (+EI) calcd for
C H NO 279.1623 (M ), found 279.1620.
yl)benzoate (13k)
+
19
21
Prepared according to the general procedure C in 86% yield as
a colorless solid; mp 159–161 ˚C (CH Cl –hexane); R =0.20
4.5.3. 1-Allyl-5-methyl-5-(4-
methylphenyl)pyrrolidin-2-one (22c)
Prepared according to the general procedure D in 58% yield
but by reacting with allyl bromide at room temperature for 15 h
instead of 70 ˚C. A colorless oil; R =0.29 (33% EtOAc in
2
2
f
(
1
50% EtOAc in hexane); IR (KBr): 3184 (br), 3070, 2982, 1725,
–1 1
687, 1433, 1279, 1107 cm ; H NMR (400 MHz, CDCl ) δ 8.03
3
(
d, J=8.4 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 6.59 (br s, 1H), 3.92
13
(s, 3H), 2.50–2.38 (m, 2H), 2.36–2.24 (m, 2H), 1.68 (s, 3H); C
f
NMR (100 MHz, CDCl ) δ 178.1, 166.6, 151.7, 129.8 (×2),
hexane); IR (film): 3024, 2976, 2916, 1693, 1681, 1513, 1393
3
–1 1
1
28.7, 124.5 (×2), 62.2, 52.0, 37.1, 30.3, 29.5; MS (+EI) m/z 233
cm ; H NMR (400 MHz, CDCl ) δ 7.16 (d, J=8.4 Hz, 2H), 7.09
3
+
+
(M , 3), 218 (M –Me, 100). Anal. Calcd for C H NO : C,
(d, J=8.4 Hz, 2H), 5.85–5.75 (m, 1H), 5.07 (dd, J=9.6, 1.6 Hz,
1H), 5.04 (d, J=0.8 Hz, 1H), 4.17 (ddd, J=15.6, 3.2, 1.6 Hz, 1H),
13
15
3
6
6.94; H, 6.48; N, 6.00. Found: C, 67.26; H, 6.38; N, 6.09%.
3
2
1
4
.27 (dd, J=15.6, 6.8 Hz, 1H), 2.51–2.38 (m, 2H), 2.34 (s, 3H),
4
.4.12. Methyl 4-(2-Ethyl-5-oxo-pyrrolidin-2-
13
.18–2.08 (m, 2H), 1.68 (s, 3H); C NMR (125 MHz, CDCl ) δ
3
yl)benzoate (13l)
75.3, 141.6, 137.0, 134.3, 129.4 (×2), 125.4 (×2), 116.5, 66.3,
Prepared according to the general procedure C in 85% yield as
+
3.6, 37.2, 29.5, 26.2, 20.9; MS (+EI) m/z 229 (M , 25), 214
a colorless solid; mp 137–139 ˚C (CH Cl –hexane); R =0.30
+
+
2
2
f
(M –Me, 100); HRMS (+EI) calcd for C H NO 229.1467 (M ),
15 19
(50% EtOAc in hexane); IR (KBr): 3187 (br), 3079, 2975, 1717,
found 229.1461.
–1
1
1
691, 1289, 1113 cm ; H NMR (400 MHz, CDCl ) δ 8.03 (d,
3
J=8.0 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 6.98 (br s, 1H), 3.92 (s,
Acknowledgements
3
3
H), 2.48–2.22 (m, 4H), 2.10–1.89 (m, 2H), 0.79 (t, J=7.2 Hz,
13
The Laboratory of Asymmetric Catalysis and Synthesis is
established under the Cheung Kong Scholars Program of The
Ministry of Education of China. This work is supported in part by
the Zhejiang Natural Science Foundation, Zhejiang, China
H); C NMR (100 MHz, CDCl ) δ 178.6, 166.7, 150.5, 129.8
3
(
×2), 128.7, 125.0 (×2), 66.1, 52.0, 35.5, 35.4, 30.3, 8.6; MS
+ +
(+EI) m/z 248 (M+H , 4), 218 (M –Et, 100). Anal. Calcd for
C H NO : C, 68.00; H, 6.93; N, 5.66. Found: C, 68.16; H, 6.79;
14
17
3
(Grand No. Y207295).
N, 5.77%.
4
.5. General procedure D for the N-alkylation of γ-lactam 13f
Supplementary data
1
13
An oven-dried process vial charged with NaH (60%
H and C NMR spectra for compounds 11–13 are available.
dispersion in mineral oil; 2 mmol) was sealed with a cap
containing a silicon septum. The loaded vial was cooled in an
ice–water bath (0 ºC) under nitrogen atmosphere and a solution
of 13f (0.25 mmol) in dry DMF (3 mL) was added via a syringe.
The resultant mixture was stirred at 0 ˚C for 10 min and at 60 ˚C
for another 50 min. The resultant mixture was cooled to 0 ºC and
a solution of the alkyl halide (0.75 mmol) was added via a
syringe at 0 ˚C followed by heating at 70 ˚C for 15 h. After
cooling to ambient temperature, the reaction mixture was poured
into water (30 mL) and extracted with EtOAc (30 mL×3). The
Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2014.00.000.
References and notes
1
.
For the structure of rolapitant, see: Duffy, R. A.; Morgan, C.;
Naylor, R.; Higgins, G. A.; Varty, G. B.; Lachowicz, J. E.; Parker,
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Synthesis of 5-alkyl-5-aryl-γ-lactams from 1-aryl-substituted nitroalkanes and methyl
acrylate via Michael addition and reductive lactamization
a
a
a,
a,b, ,†
Jingjing Xu , Xingyao Li , Jinlong Wu *, Wei-Min Dai
*
a
Laboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University,
Hangzhou 310027, China
b
Laboratory of Advanced Catalysis and Synthesis, Department of Chemistry, The Hong Kong University of
Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
∗
Corresponding authors. Tel./fax: +86 571 89953128; e-mail addresses: wyz@zju.edu.cn (J. Wu);
chdai@zju.edu.cn (W.-M. Dai)
†
Tel.: +852 23587365; fax: +852 23581594; e-mail address: chdai@ust.hk.
Supporting Information
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Copies of H and C NMR Spectra for Compounds 11a–l, 12a–l, 13a–l, and 22a–c.
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