Synthesis of lactams by isomerization of oxindoles substituted at C-3 by an ω-amino chain

Article abstract of DOI:10.1021/jo501978j

Oxindoles substituted at N-1 by electron-withdrawing groups and at C-3 by ω-amino chains of various lengths undergo mild and easy isomerization to new 5- to 12-membered lactams in good yields (30-96%). As efficient asymmetric syntheses of diversely 3,3-disubstituted oxindoles are currently developed, this isomerization provides a new and valuable access to medium-sized lactams α-substituted with a quaternary asymmetric carbon bearing a 2-aminophenyl residue.

Full text of DOI:10.1021/jo501978j

Article
pubs.acs.org/joc
Synthesis of Lactams by Isomerization of Oxindoles Substituted at
C‑3 by an ω‑Amino Chain
Daad Sarraf, Nicolas Richy, and Joelle Vidal*
̈
́ ́
Chimie et photonique moleculaires, Institut des Sciences Chimiques de Rennes, Universite de Rennes 1, CNRS-UMR 6226, Campus
de Beaulieu, 35042 Rennes Cedex, France
S
* Supporting Information
ABSTRACT: Oxindoles substituted at N-1 by electron-withdrawing groups
and at C-3 by ω-amino chains of various lengths undergo mild and easy
isomerization to new 5- to 12-membered lactams in good yields (30−96%).
As efficient asymmetric syntheses of diversely 3,3-disubstituted oxindoles are
currently developed, this isomerization provides a new and valuable access to
medium-sized lactams α-substituted with a quaternary asymmetric carbon
bearing a 2-aminophenyl residue.
conversion after 18 h at room temperature, neat liquid, Scheme
1). Such an isomerization has occasionally been described5,6
and has complicated the structure determination of the natural
products donoxaridine7 and chimonamidine.7b,8 We also took
advantage of the reported instability of the 2-(2-aminophenyl)-
γ-lactam scaffold in acidic medium that rapidly led to the
protonated form of the starting 2-(3-oxindolyl)ethylamine
(Scheme 1).5d,e,9 To the best of our knowledge, isomerization
of oxindoles substituted at C-3 with longer ω-amino chains has
not been studied. Since ring-closure reactions leading to 7- to
10-membered lactams are generally difficult, this isomerization
may be valuable for the formation of medium-sized lactams that
find widespread use in organic chemistry (key intermediates,
core structures of natural products, or biologically active
compounds).10,11 We reasoned that substituting the oxindole
nitrogen by an electron-withdrawing group (EWG) would
enhance the electrophilicity of the oxindole carbonyl and favor
the isomerization while disfavoring the reverse reaction in
acidic medium due to poor nucleophilicity (Scheme 2).
INTRODUCTION
■
The 3,3-disubstituted oxindole scaffold, which is present in a
large number of natural and synthetic compounds with
significant biological activities, is currently an important target
for the development of very efficient asymmetric synthesis
methods.1 Furthermore, these methods allow the introduction
of a very wide diversity of substituents at C-3. Among the
natural products bearing this scaffold, TMC-95A has attracted
our interest2 because it is a potent proteasome inhibitor
(Scheme 1).3
We showed that linear mimics of TMC-95A, which
contained the 3-hydroxyoxindolyl alanine residue, retained
the proteasome inhibitory activity.4 In the course of their
synthesis, we observed that the 2-(3-oxindolyl)ethylamine core
slowly isomerized to (2-aminophenyl)-2-butyrolactam (25%
Scheme 1. Structures of Some Proteasome Inhibitors and
Isomerization of 3-(2-Aminoethyl)oxindole to 2-(2-
Aminophenyl) γ-Lactam Followed by Acidic Transformation
into Protonated Starting Material
Scheme 2. General Scheme for Isomerization of Oxindole 1
to Lactam 2 and Structures of Precursors 3 or 4
Received: August 27, 2014
© XXXX American Chemical Society
A
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Herein we report the easy formation of 5- to 12-membered
lactams 2 from oxindoles 1 substituted at N-1 by EWG and at
C-3 by ω-amino chains of various lengths (Scheme 2). The
isomerization of two families of oxindoles 1, obtained from
nitro compounds 3 or N-Boc-protected derivatives 4, was
studied (Scheme 2). Lactams 2 proved to be stable in acidic
medium, provided EWG is also stable. Owing to the recent
significant advances in the asymmetric synthesis of the 3,3-
disubstituted oxindole scaffold,1 this isomerization provides a
new access to lactams, substituted with a α-quaternary
asymmetric carbon.10
We then used sodium borohydride in the presence of NiCl2
(entries 3 and 4).12a,i Complete conversion of 3a was observed
after 3 h at room temperature, leading to a 3/2 mixture of 2a
and 7. Adding an excess of sodium borohydride induced further
reduction of 7 and allowed isolation of 2a in 56% yield.
We then examined the substrate scope of different N-EWG-
substituted nitrooxindoles 3a−g using NaBH4/NiCl2 as the
reducing agent (Table 2). Lactams 2a−f (EWG = Ac or Boc)
Table 2. Synthesis of γ-Lactams 2a−g by Reduction of
Oxindoles 3
RESULTS AND DISCUSSION
■
We began our investigation by generating the amino group in 1
from the corresponding nitroethyl derivatives 3, which were
readily prepared by Michael addition of 3-oxindoles 5 to
nitroolefins12 followed by functionalization of 6 by EWG
(Scheme 3).
a
entry
3
2
EWG
R1
R2
yield (%)
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
2a
2b
2c
2d
2e
2f
Ac
Ph
Ph
Me
Ph
Ph
Me
Ph
Ph
H
56
64
58
52
55
57
71
Ac
Scheme 3. Synthesis of Compounds 3
Ac
H
Boc
Boc
Boc
Ms
Ph
H
H
3g
2g
Ph
a
Isolated yield.
were isolated in 52−64% yield (entries 1−6). A higher yield in
2g was obtained from 3g, which was substituted by the better
electron-withdrawing substituent Ms (entry 7).
a
b
EWG-X = Ac-Cl, Boc-OBoc, or Ms-Cl. Compound 6a (dr > 20/
These γ-lactams 2a−g were characterized by 1H NMR
spectroscopy using CD3SOCD3 as solvent rather than CDCl3.
The NH-EWG chemical shifts were in the 9.1−10.2 ppm range.
Noteworthy were the shape of the NH γ-lactam signal which
appeared as a broad singlet instead of a triplet, a feature that has
been generally observed in CD3SOCD3,14 and the unusual
chemical shift (1.24−1.38 ppm) of the N-Ac group in 2a,b.
Fortunately, the single-crystal X-ray structure of lactam 2b was
obtained and allowed interpretation of these apparent
discrepancies (see the Supporting Information).
1)12e was prepared according to the literature. See the formulas of R1,
R2, and EWG in Table 2. Compound 3d12e was prepared according to
the literature. Nonracemic 3e12c and 3f12b have been described.
c
Reduction conditions were optimized using the N-acetyl
compound 3a (Table 1). Catalytic hydrogenation using
Table 1. Reduction of Nitro Derivative 3a
The structure showed the presence of the Ac group in the
magnetic shielding region of the benzene ring at C-3. Lactam
NH−CH dihedral angles were ca. 60°, leading to small vicinal
1
coupling constants in the H NMR. Finally, we noticed the
1
stability of butyrolactams 2 in acidic medium: the H NMR
b
b
2a/7
2a
7
spectrum of 2b (c = 0.05 M, CD3SOCD3) remained unchanged
after 4 days at room temperature in the presence of excess
trifluoracetic acid (3 equiv).
a
entry
conditions
ratio
(%) (%)
1
2
3
H2, Pd/C, MeOH, 18h, rt
1/4
15
74
H2, Pd/C, MeOH/AcOH, 18h, rt
1/4
3/2
In order to study the influence of the ω-amino side chain
length on the isomerization, we prepared Boc-amino precursors
4a−n from 3-hydroxyoxindoles 8 (Table 3).
NaBH4 (16 equiv), NiCl2 (2 equiv), EtOH,
3h, rt
4
NaBH4 (16 equiv), NiCl2 (2 equiv), EtOH,
3h, then NaBH4 (6 equiv), rt
>20/1
56
N-Boc-aminoalkanoic acids (n = 1−5) were efficiently
coupled to hindered 3-hydroxyoxindole 8a using the Steglich
conditions, with DCC resulting in better yields than 1-ethyl-3-
(3-(dimethylamino)propyl)carbodiimide (EDC) (entries 1−
5).15 Compounds substituted by donor or acceptor substituents
on the aromatic ring were synthesized (entries 6−8). Different
EWG groups (Ac, Cbz, and CONMe2) were easily
introduced16 in 3-hydroxy-3-cyanomethyl derivatives 8d−f
(entries 9−12). Reaction of 8d−f with DCC and N-Boc-β-
alanine or N-Boc-aminohexanoic acid worked in good yields to
give 4i−l (entries 9−12). However, addition of DMAP in the
a
Ratio determined by 1H NMR analysis of the crude mixture (solvent
DMSO). Isolated yield.
b
palladium on charcoal was first carried out (entries 1 and
2).12c,13 The crude product contained a 1/4 mixture of γ-lactam
2a and cyclic hydroxamic acid derivative 7, which was isolated
in 74% yield. Compound 7 resulted from the isomerization of
the intermediate hydroxylamine formed from the nitro group.
Adding acetic acid did not favor its further reduction into 2a.
B
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Table 3. Synthesis of Oxindoles 4 Substituted at C-3 by ω-
Boc-amino Side Chains of Varying Lengths
Scheme 5. Synthesis of Lactams 2h−s
a
yield
entry
8
4
EWG
R2
R1
CH3
n
(%)
b
1
8a
8a
8a
8a
8a
8b
8c
8c
8d
8d
8e
8f
4a
4b
4c
4d
4e
4f
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
H
H
H
H
H
F
1
2
3
4
5
2
2
5
2
5
5
5
69
b
2
CH3
95
b
3
CH3
78
b
4
CH3
95
b
5
CH3
97
b
6
CH3
60
b
7
4g
4h
4i
CH3O
CH3O
H
CH3
91
b
8
CH3
78
9
CH2CN
CH2CN
CH2CN
CH2CN
59
98
72
73
10
11
12
4j
H
4k
Cbz
H
4l
CON(CH3)2
H
a
b
Isolated yield. DMAP was added.
synthesis of 4i−l resulted in the formation of unidentified
products. Derivatives 4m−n containing 10-amino or 19-amino
oxyethylene chains were obtained using N-Boc-amino acids 917
(Scheme 4). Boc-amino compound 4o that did not bear an
ester functionality at the quaternary junction was also prepared
in three steps from nitroethyl compound 6d (Scheme 4).
a
b
Isolated yield. Crude product was a 3/2 mixture of 2j and δ-
valerolactam.
give the corresponding 21-membered macrocycle. The
competing attack of the carbonyl of the ester function instead
of the oxindole one was observed only in the case of derivative
4d leading to a 3/2 mixture of the nine-membered lactam 2j
and the six-membered δ-valerolactam. Fortunately, the nine-
membered lactam 2s featuring the cyclic core found in cyclic
peptides that inhibit protein tyrosine phosphatase from
Mycobacterium tuberculosis18 was obtained in a good yield
from 4o. Similarly to γ-lactam 2b, medium-sized lactam 2k
proved to be stable in the presence of trifluoroacetic acid (4
equiv, no change after 6 days at rt).
Scheme 4. Synthesis of Precursors 4m−o
CONCLUSION
■
In summary, we have developed the easy transformation of
oxindole derivatives 3 and 4 substituted at C-3 by an ω-amino
chain of varying length into γ-lactams 2a−g and medium-sized
lactams 2h−s. The reactions are easy to conduct and occur
under mild conditions, and the yields are good. The use of
building blocks 3 or 4 is a new route to lactam synthesis10 and
may allow configuration control of the quaternary carbon α to
the carbonyl, using the asymmetric methods currently
developed for the synthesis of C-3-disubstituted oxindoles.1
As medium-sized lactams 2h−r display unknown depsipeptide
cores, this method may find applications in the discovery of
new macrolactams of therapeutic interest.10a,19
Finally, Boc-amino precursors 4a−o were deprotected using
anhydrous hydrogen chloride (Scheme 5). Integration of the
1H NMR signals of the resulting chlorhydrate (solvent
CD3SOCD3) also showed the formation of up to 40% of the
expected lactam 2, indicating that the isomerization could occur
even in acidic medium. Further treatment overnight by
triethylamine at room temperature led to original 7- to 12-
membered lactams 2h−r, which were isolated in 30−96% yields
(Scheme 5). Unidentified products were obtained from 4a and
4l after prolonged heating at 45 °C. The side chain in 4a was
probably too short to induce a favorable overlap of the amine
HOMO and the carbonyl LUMO. As 4j and 4k successfully
gave 2p and 2q, the failure of 4l to react similarly may indicate
that the electron-withdrawing effect of the carbamoyl group was
not strength enough in order to promote the isomerization.
The basic form of deprotected 4n remained stable, failing to
EXPERIMENTAL SECTION
■
Methods and Materials. Commercially available reagents were
used without further purification. Reagent-grade solvents were used for
extraction and flash chromatography. DCM was stabilized with
amylene. Dry solvents were distilled from the appropriate drying
reagents immediately before use. Yields refer to chromatographically
and spectroscopically homogeneous materials. Reactions were
monitored by thin-layer chromatography carried out on silica gel
C
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aluminum sheets (60F-254) using UV light as a visualizing agent
followed by 15% ethanolic phosphomolybdic acid and heat or 0.2%
ethanolic ninhydrin and heat as developing agent. Column
chromatography was performed on silica gel 60, 0.063−0.200 mm.
1H NMR and 13C NMR spectra were recorded at room temperature
at, respectively, 300 and 75.5 MHz frequencies. Chemical shifts were
reported in ppm (δ units), and residual nondeuterated solvent was
used as internal reference. Assignments of 13C signals were determined
using DEPT experiments. Mass spectrometry accurate mass data
(HRMS) were obtained from a Q-TOF spectrometer using an
electrospray source (ESI). Melting points were determined using a
Griffin melting point apparatus and are uncorrected. Compounds 5a,b
were commercially available.
Procedure for the Synthesis of Compounds 2a−g. To a
mixture of nitro-oxindole 3a (112.4 mg, 0.281 mmol) and NiCl2 (69.1
mg, 0.53 mmol) in absolute ethanol (1 mL) was added sodium
borohydride (170 mg, 4.5 mmol). The black mixture was stirred at
room temperature. The progress of the reaction was monitored by
TLC. Three further portions of sodium borohydride (50 mg, 1.3
mmol) were added after stirring for 3, 5, and 7 h, respectively. After
dilution by CH2Cl2 (30 mL), the mixture was washed by 10% aqueous
ammonium chloride. The organic phase was concentrated in vacuo,
and the residue was purified by chromatography over silica gel (3.5 g,
eluent CH2Cl2) to afford lactam 2a as a white solid (58.5 mg, 56%
yield).
HRMS (ESI-TOF, CH3OH) m/z [M + Na]+ calcd for C13H16N2O2Na
255.1109, found 255.1108; Rf (MeOH/CH2Cl2 1/9) 0.50; mp 160−
165 °C.
tert-Butyl (2-(rel-(3S,4S)-2-oxo-3,4-diphenylpyrrolidin-3-yl)-
phenyl)carbamate (2d): yield 57 mg (52%); crystalline solid; 1H
NMR (300 MHz, DMSO-d6) δ (two rotamers, 57/43 mixture) 1.07
and 1.20 (two s, 9H),3.51 (m, 1H), 3.77 (m, 1H), 4.49 and 4.61 (two
t, J = 4 Hz, 1H), 6.59−7.41 (m, 14 H), 8.04 (d, J = 8 Hz, 0.43 H), 8.57
1
(s, 0.57 H), 8.81 (s, 0.43 H), 9.13 (0.43 H); H NMR (300 MHz,
CDCl3) δ (two rotamers, 57/43 mixture) 1.14 and 1.26 (9H, two s),
3.69 (m, 1H), 3.87 (m, 1H), 4.54 (t, J = 4 Hz, 1H), 6.33 (br s, 0.57
H), 6.70−7.67 (m, 14.43 H), 7.86 (d, J = 7.5 Hz, 0.57 H), 8.77 (s, 0.43
H); 13C NMR (75.5 MHz, CDCl3) δ (two rotamers) 28.0 and 28.1
(CH3), 45.8 and 45.9 (CH2), 50.1 and 50.2 (CH), 61.2 and 61.8 (C),
78.7 and 79.2 (C), 123.0 (CH), 123.4 (CH), 126.3 (CH), 126.7
(CH), 127.0 (CH), 127.4 (CH), 127.5 (CH), 127.70 (CH), 127.75
(CH), 127.8 (CH), 127.9 (CH), 128.1 (CH), 128.2 (CH), 128.3
(CH), 128.8 (CH), 129.2 (CH), 130.0 (CH), 137.2 (C), 137.9 (C),
138.3 (C), 138.5 (C), 138.6 (C), 139.6 (C), 140.5 (C), 152.3 and
152.3 (C), 178.1 and 179.0 (C); HRMS (ESI-TOF, CH3OH) m/z [M
+ Na]+ calcd for C27H28N2O3Na 451.1998, found 451.2000; Rf
(AcOEt/CH2Cl2 1/9) 0.50; mp 189−192 °C.
tert-Butyl (2-(2-oxo-3-phenylpyrrolidin-3-yl)phenyl)carbamate
(2e): yield 60 mg (55%); crystalline solid; 1H NMR (300 MHz,
DMSO-d6) δ 1.13 (s, 9H), 2.23 (m, 1H), 3.06 (m, 1H), 3.23 (m, 1H),
3.38 (m, 1H), 6.99 (d, J = 7.2 Hz, 1H), 7.12−7.42 (m, 7H), 7.64 (d, J
N-(2-(rel-(3S,4S)-2-Oxo-3,4-diphenylpyrrolidin-3-yl)phenyl)-
acetamide (2a): 1H NMR (300 MHz, DMSO-d6) δ 1.24 (s, 3H), 3.52
(dd, J = 10.5, 5 Hz, 1H), 3.81 (dd, J = 10.5, 6.5 Hz, 1H), 4.64 (t, J = 6
Hz, 1H), 6.62 (m, 2H), 6.78−6.82 (m, 2H), 6.87−7.01 (m, 6H),
7.25−7.36 (m, 2H), 7.51 (dd, J = 7.8 Hz, 1.8 Hz, 1H), 8.08 (d, J = 7.8
Hz, 1H), 8.92 (s, 1H), 10.03 (s, 1H); 1H NMR (300 MHz, CDCl3) δ
1.33 (s, 3H), 3.66 (dd, J = 9.9, 5.4 Hz, 1H), 3.86 (dd, J = 9.9, 7.2 Hz,
1H), 4.49 (t, J = 6.2 Hz, 1H), 6.69 (m, 5H), 6.97 (m, 6H), 7.22 (dd, J
= 7.8, 1.5 Hz, 1H), 7.31 (td, J = 7.6, 1.2 Hz, 1H), 7.60 (dd, J = 7.8, 1.5
Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 9.64 (s, 1H); 13C NMR (75.5 MHz,
CDCl3) δ 23.2 (CH3), 45.9 (CH2), 50.0 (CH), 61.9(C), 124.6 (CH),
126.4 (CH), 126.8 (CH), 127.1 (CH), 127.7 (CH), 127.9 (CH),
128.0 (CH), 128.3 (CH), 128.6 (CH), 129.1 (CH), 132.5 (C), 137.80
(C), 137.85 (C), 138.7 (C), 168.1 (C), 179.1 (C); HRMS (ESI-TOF,
MeOH) m/z [M + Na]+ calcd for C24H22N2O2Na 393.1579, found
393.1579; Rf (AcOEt) 0.46; mp 242−246 °C.
1
= 7.6 Hz, 1H), 8.50 (s, 1H), 9.32 (s, 1H); H NMR (300 MHz,
CDCl3) δ 1.14 (s, 9H), 2.41 (m, 1H), 3.03 (m, 1H), 3.34 (m, 1H),
3.46 (m, 1H), 5.81 (br s, 1H), 7.05−7.30 (m, 7H), 7.43 (d, J = 8 Hz,
1H), 7.56 (d, J = 8 Hz, 1H), 8.71 (br s, 1H); 13C NMR (75.5 MHz,
CDCl3) δ 28.1 (CH3), 38.4 (CH2), 39.7 (CH2), 56.6 (C), 79.0 (C),
123.7 (CH), 126.1 (CH), 126.2 (CH), 126.7 (CH), 128.4 (CH),
128.5 (CH), 128.5 (CH), 131.3 (C), 138.1 (C), 143.2 (C), 153.2 (C),
179.4 (C); HRMS (ESI-TOF, CH3OH) m/z [M + Na]+ calcd for
C21H24N2O3Na 375.1685, found 375.1688; Rf (1% Et3N in 1/1
AcOEt/petroleum ether) 0.58; mp 182−185 °C.
tert-Butyl (2-(3-methyl-2-oxopyrrolidin-3-yl)phenyl)carbamate
(2f): yield 59 mg (57%); crystalline solid; 1H NMR (300 MHz,
DMSO-d6) δ 1.44 (s, 12 H), 2.08 (m, 1 H), 2.72 (m, 1H), 3.17−3.30
(m, 2 H), 7.09 (ddd, J = 7.8, 7.8, 1.5 Hz, 1H), 7.24 (ddd, J = 7.8, 7.8,
1.5 Hz, 1H), 7.37 (dd, J = 7.8, 1.5 Hz, 1H), 7.50 (dd, J = 7.8, 1.5 Hz,
1H), 8.11 (s, 1H), 9.86 (s, 1 H); 1H NMR (300 MHz, CDCl3) δ 1.18
(s, 3H), 1.44 (s, 9H), 2.17 (m, 1H), 2.73 (m, 1H), 3.46 (m, 2H), 5.69
(br s, 1H), 7.03 (t, J = 7.6 Hz, 1H), 7.29 (m, 2H), 7.62 (d, J = 8 Hz,
1H), 8.88 (br s, 1H); 13C NMR (75.5 MHz, CDCl3) δ 22.1 (CH3),
28.4 (CH3), 36.6 (CH2), 39.3 (CH2), 47.4 (C), 79.5 (C), 124.5 (CH),
126.1 (CH), 126.7 (CH), 127.9 (CH), 133.4 (C), 137.1 (C), 154.1
(C), 182.1 (C); HRMS (ESI, CH3OH) calcd for C16H22N2O3Na [(M
+ Na)+] 313.1528, found 313.1525; Rf (1/1/0.01 AcOEt/petroleum
ether/Et3N) 0.22; mp 134−138 °C.
N-(2-(2-Oxo-3-phenylpyrrolidin-3-yl)phenyl)acetamide (2b): yield
1
69 mg (64%); crystalline solid; H NMR (300 MHz, DMSO-d6) δ
1.38 (s, 3H), 2.35 (ddd, J = 13.5, 8 Hz, 8 Hz, 1H), 3.13 (ddd, J = 13.5,
6.0, 3 Hz, 1H), 3.29−3.49 (m, 2H), 7.04−7.07 (m, 2H), 7.23−7.41
(m, 5H), 7.58 (dd, J = 7.8, 1 Hz, 1H), 7.73 (dd, J = 7.8, 1 Hz, 1H),
8.60 (s, 1H), 10.19 (s, 1H); NMR signal attribution resulted from
HMBC and HSQC experiments, see the Supporting Information for
atom numbering; 1H NMR (300 MHz, CDCl3) δ 1.43 (s, 3H22), 2.35
(ddd, J = 13, 8, 8 Hz, 1H8), 3.04 (ddd, J = 13, 6, 3 Hz, 1H8), 3.34 (m,
1H9), 3.46 (m, 1H9), 6.92 (br s, 1H10), 7.02−7.04 (m, 2H1,5), 7.12−
7.23 (m, 4H15,3,2,4), 7.29 (ddd, J = 7.8, 7.8, 1.2 Hz, 1H16), 7.47 (d, J =
7.2 Hz, 1H14), 7.62 (dd, J = 7.8, 1.2 Hz, 1H17), 9.82 (s, 1H19); 13C
NMR (75.5 MHz, CDCl3) δ 23.4 (C22), 38.6 (C8), 39.8 (C9), 56.7
(C7), 124.7 (C15), 126.0 (C1,5), 126.2 (C14), 126.8 (C3), 127.5 (C17),
128.6 (C16), 128.7 (C2,4), 131.1 (C13), 137.5 (C18), 143.4 (C6), 168.3
(C20), 179.7 (C11); HRMS (ESI-TOF, CH3OH) m/z [M + Na]+ calcd
for C18H18N2O2Na 317.1266, found 317.1268; Rf (1/1 AcOEt/
CH2Cl2) 0.28; mp 219−222 °C.
N-(2-(rel-(3S,4S)-2-Oxo-3,4-diphenylpyrrolidin-3-yl)phenyl)-
1
methanesulfonamide (2g): yield 45 mg (71%); crystalline solid; H
NMR (300 MHz, DMSO-d6) δ 1.85 (s, 3H), 3.47 (dd, J = 10.8, 2.5
Hz, 1H), 3.81 (dd, J = 10.8, 6.3 Hz, 1H), 4.63 (m, 1H), 6.74−6.75 (m,
2H), 6.81−6.85 (m, 2H), 7.00−7.07 (m, 6H), 7.29 (td, J = 7.8, 1.2 Hz,
1H), 7.39 (td, J = 8.4, 1.2 Hz, 1H), 7.63 (dd, J = 7.8, 1.2 Hz, 1H), 8.13
(d, J = 7.2 Hz, 1H), 9.06 (s, 1H), 10.49(s, 1H); 1H NMR (300 MHz,
CDCl3) δ 1.80 (s, 3H), 3.61 (dd, J = 10.2, 4.2 Hz, 1H), 3.87 (dd, J =
10.2, 6.6 Hz, 1H), 4.42 (dd, J = 6.3, 4.3 Hz, 1H), 6.48 (s, 1H), 6.71−
6.79 (m, 4H), 6.95−6.99 (m, 6H), 7.18 (m, 1H), 7.30 (t, J = 7.5 Hz,
1H), 7.77 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H), 10.08 (s, 1H);
13C NMR (75.5 MHz, CDCl3) δ 38.8 (CH3), 46.2 (CH2), 51.1 (CH),
61.8 (C), 122.3 (CH), 123.8 (CH), 127.0 (CH), 127.1 (CH), 127.2
(CH), 128.0 (CH), 128.2 (CH), 128.5 (CH), 129.2 (CH), 129.3
(CH), 131.0 (C), 137.9 (C), 138.2 (C), 139.4 (C), 178.7 (C); HRMS
(ESI-TOF, CH3OH) m/z [M + Na]+ calcd for C23H22N2O3NaS
429.1249, found 429.1250; Rf (AcOEt/CH2Cl2 1/9) 0.30; mp 195−
198 °C.
N-(2-(3-Methyl-2-oxopyrrolidin-3-yl)phenyl)acetamide (2c): yield
1
54 mg (58%); crystalline solid; H NMR (300 MHz, DMSO-d6) δ
1.45 (s, 3H), 2.03 (s, 3H), 2.09 (m, 1H), 2.63 (m, 1H), 3.22 (m, 1H),
3.29 (m, 1H), 7.14 (td, J = 7.8, 1.2 Hz, 1H), 7.25 (td, J = 7.8, 1.2 Hz,
1H), 7.41 (dd, J = 7.8, 1.2 Hz, 1H), 7.54 (dd, J = 7.8, 1.2 Hz, 1H), 8.09
1
(s, 1H), 10.39 (s, 1H); H NMR (300 MHz, CDCl3) δ 1.60 (s, 3H),
2.18 (m, 4H), 2.87 (m, 1H), 3.45 (m, 2H), 6.02 (broad s, 1H), 7.06 (t,
J = 7.8 Hz, 1H), 7.22−7.27 (m, 2H), 7.83 (d, J = 7.8 Hz, 1H), 10.35
(broad s, 1H); 13C NMR (75.5 MHz, CDCl3) δ 22.4 (CH3), 24.3
(CH3), 36.7 (CH2), 39.3 (CH2), 47.5 (C), 125.1(CH), 126.0 (CH),
126.9 (CH), 128.1 (CH), 132.6 (C), 136.9 (C), 168.8 (C), 182.1 (C);
Procedure for the Synthesis of Compounds 2h−r. To a
solution of Boc derivative 4b (124.5 mg, 0.331 mmol) in AcOEt (0.2
D
dx.doi.org/10.1021/jo501978j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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mL) was added a 3 M solution of anhydrous HCl in AcOEt (0.35 mL,
1.05 mmol). The mixture was stirred at room temperature overnight.
The solvent was removed in vacuo. To the resulting solid were added
CH2Cl2 (0.6 mL) and trietylamine (90 μL, 0.65 mmol). The mixture
was stirred for 8 h at room temperature, diluted with CH2Cl2 (10 mL),
and washed with aqueous 10% citric acid. The organic phase was dried
over sodium sulfate and concentrated in vacuo. Purification by
chromatography over silica gel (6.3 g, eluent 1% MeOH in AcOEt)
afforded lactam 2h as a white solid (87.8 mg, yield 96%).
[M + Na]+ calcd for C17H22N2O4Na 341.1477, found 341.1475; Rf
(AcOEt) 0.23.
N-(4-Fluoro-2-(2-methyl-3,7-dioxo-1,4-oxazepan-2-yl)phenyl)-
acetamide (2l). Starting from Boc derivative 4f (105.7 mg, 0.268
mmol), the general procedure afforded lactam 2l as an amorphous
1
solid (37.86 mg, yield 48%): H NMR (300 MHz, DMSO-d6) δ 1.49
(s, 3H), 1.76 (s, 3H), 2.49−2.53 (m, 2H), 3.13−3.23 (m, 2H), 6.82
(dd, J = 8.4, 4.2 Hz, 1H), 7.06 (ddd, J = 11.1, 8.4, 2.7 Hz, 1H), 7.22
1
(dd, J = 8.1, 2.7 Hz, 1H), 7.91 (t, J = 5.3 Hz, 1H), 10.59 (s, 1H); H
NMR (300 MHz, CDCl3) δ 1.55 (s, 3H), 1.83 (s, 3H), 2.42−2.62 (m,
2H), 3.29−3.49 (m, 2H), 6.28 (t, J = 5.6 Hz, 1H), 6.78 (dd, J = 9.3, 4.2
Hz, 1H), 6.75−6.90 (m, 2H), 8.97 (s, 1H); 13C NMR (75.5 MHz,
CDCl3) δ 23.0 (CH3), 23.2 (CH3), 33.8 (CH2), 35.0 (CH2), 78.2 (d, J
= 2 Hz, C), 110.5 (d, J = 25 Hz, CH), 111.3 (d, J = 8 Hz, CH), 116.1
(d, J = 23 Hz, CH), 130.8 (d, J = 8 Hz, C), 136.3 (d, J = 3 Hz, C),
159.2 (d, J = 242 Hz, C), 170.7 (C), 171.2 (C), 177.2 (C); HRMS
(ESI-TOF, MeOH) m/z [M + Na]+ calcd for C14H15FN2O4Na
317.0914, found 317.0913; Rf (AcOEt) 0.14.
N-(2-(2-Methyl-3,7-dioxo-1,4-oxazepan-2-yl)phenyl)acetamide
1
(2h): H NMR (300 MHz, DMSO-d6) δ 1.48 (s, 3H), 1.76 (s, 3H),
2.47 (m, 2H), 3.14 (m, 2H), 6.83 (d, J = 9 Hz, 1H), 6.96 (t, J = 9 Hz,
1
1H), 7.19−7.23 (m, 2H), 7.90 (br s, 1H), 10.56 (s, 1H); H NMR
(300 MHz, CDCl3, c = 0.24 mol l−1) δ 1.55 (s, 3H), 1.80 (s, 3H),
2.39−2.59 (m, 2H), 3.26−3.48 (m, 2H), 6.34 (br s, 1H), 6.81 (d, J =
7.8 Hz, 1H), 6.96 (t, J = 7.2 Hz, 1H), 7.12−7.20 (m, 2H), 8.93 (s,
1H); 13C NMR (75.5 MHz, CDCl3) δ 23.0 (CH3), 23.2 (CH3), 33.8
(CH2), 34.9 (CH2), 78.1 (C), 110.5 (CH), 122.3 (CH), 122.8 (CH),
129.3 (C), 129.7 (CH), 140.4 (C), 170.6 (C), 171.1 (C), 177.3 (C);
HRMS (ESI-TOF, CH3OH) m/z [M + Na]+ calcd for C14H16N2O4Na
299.1008, found 299.1008; Rf (MeOH/AcOEt 5/95) 0.26; mp 115−
119 °C.
N-(4-Methoxy-2-(2-methyl-3,7-dioxo-1,4-oxazepan-2-yl)phenyl)-
acetamide (2m). Starting from Boc derivative 4g (183.0 mg, 0.450
mmol), the general procedure afforded lactam 2m as an amorphous
solid (56.5 mg, yield 41%): 1H NMR (300 MHz, DMSO-d6) δ 1.47 (s,
3H), 1.76 (s, 3H), 2.47 (m, 2H), 3.18 (m, 2H), 3.71 (s, 3H), 6.73−
N-(2-(2-Methyl-3,8-dioxo-1,4-oxazocan-2-yl)phenyl)acetamide
(2i). Starting from Boc derivative 4c (208.6 mg, 0.534 mmol), the
general procedure afforded lactam 2i as a viscous oil (105 mg, yield
68%): 1H NMR (300 MHz, DMSO-d6) δ 1.48 (s, 3H), 1.55 (m, 2H),
1.77 (s, 3H), 2.32 (t, J = 7.2 Hz 2H), 2.97 (m, 2H), 6.83 (d, J = 7.5
Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 7.20−7.26 (m, 2H), 7.82 (br s, 1H),
1
6.81 (m, 2H), 6.91 (s, 1H), 7.90 (broad s, 1H), 10.36 (s, 1H); H
NMR (300 MHz, CDCl3, c = 0.12 mol l−1) δ 1.55 (s, 3H), 1.82 (s,
3H), 2.39−2.62 (m, 2H), 2.28−2.50 (m, 2H), 3.71 (s, 3H), 6.30
(broad s, 1H), 6.69−6.74 (m, 3H), 8.62 (s, 1H); 13C NMR (75.5
MHz, CDCl3) δ 23.1 (CH3), 23.4 (CH3), 33.9 (CH2), 35.0 (CH2),
55.8 (CH3), 78.5 (C), 109.6 (CH), 111.0 (CH), 114.0 (CH), 130.7
(C), 133.5 (C), 156.1 (C), 170.6 (C), 171.2 (C), 177.2 (C); HRMS
(ESI-TOF, MeOH) m/z [M + Na]+ calcd for C15H18N2O5Na
329.1113, found 329.1112; Rf (1% MeOH in AcOEt) 0.10.
1
10.54 (s, 1H); H NMR (300 MHz, CDCl3, c = 0.14 mol l−1) δ 1.54
(s, 3H), 1.69 (m, 2H), 1.83 (s, 3H), 2.29 (m, 2H), 3.14 (m, 2H), 6.10
(br s, 1H), 6.80 (d, J = 7.8 Hz, 1H), 6.95 (t, J = 7.5 Hz, 1H), 7.10−
7.17 (m, 2H), 8.82 (s, 1H); 13C NMR (75.5 MHz, CDCl3) δ 23.1
(CH3), 23.3 (CH3), 24.3 (CH2), 31.2 (CH2), 38.7 (CH2), 77.8 (C),
110.5 (CH), 122.3 (CH), 122.8 (CH), 129.4 (C), 129.7 (CH), 140.5
(C), 170.8 (C), 171.8 (C), 177.3 (C); HRMS (ESI-TOF, CH3OH)
m/z [M + Na]+ calcd for C15H18N2O4Na 313.1164, found 313.1159;
Rf (AcOEt) 0.15
N-(4-Methoxy-2-(2-methyl-3,10-dioxo-1,4-oxazecan-2-yl)-
phenyl)acetamide (2n). Starting from Boc derivative 4h (181.9 mg,
0.405 mmol), the general procedure afforded lactam 2n as a gum (68.4
1
mg, yield 48%): H NMR (300 MHz, DMSO-d6) δ 1.21−1.47 (m,
9H), 1.77 (s, 3H), 2.30 (m, 2H), 2.97 (m, 2H), 3.70 (s, 3H), 6.73−
1
6.81 (m, 2H), 6.88 (s, 1H), 7.78 (broad s, 1H), 10.36 (s, 1H); H
N-(2-(2-Methyl-3,9-dioxo-1,4-oxazonan-2-yl)phenyl)acetamide
(2j). Starting from Boc derivative 4d (249 mg, 0.616 mmol), the
general procedure afforded a crude product containing a 3/2 mixture
of expected lactam 2j and δ-valerolactam. Purification by chromatog-
raphy over silica gel (8 g, eluent AcOEt) afforded lactam 2j as a
NMR (300 MHz, CDCl3, c = 0.32 mol l−1) δ 1.18−1.55 (m, 9H), 1.87
(s, 3H), 2.20 (m, 2H), 3.12 (m, 2H), 3.69 (s, 3H), 6.28 (broad s, 1H),
6.66−6.71 (m, 3H), 8.99 (broad s, 1H); 13C NMR (75.5 MHz,
CDCl3) δ 23.0 (CH3), 23.4 (CH3), 24.1 (CH2), 25.8 (CH2), 28.7
(CH2), 33.4 (CH2), 39.1 (CH2), 55.7 (CH3), 78.0 (C), 109.5 (CH),
111.0 (CH), 113.8 (CH), 130.9 (C), 133.9 (C), 155.9 (C), 170.8 (C),
171.9 (C), 177.3 (C); HRMS (ESI-TOF, MeOH) m/z [M + Na]+
calcd for C18H24N2O5Na 371.1583, found 371.1583; Rf (MeOH/
AcOEt 5/95) 0.28.
1
viscous oil (56.2 mg, yield 30%): H NMR (300 MHz, DMSO-d6) δ
1.30−1.43 (m, 4H), 1.47 (s 3H), 1.77 (s, 3H), 2.31 (t, J = 6 Hz, 2H),
2.98 (m, 2H), 6.83 (d, J = 8 Hz, 1H), 6.95 (t, J = 7.5 Hz, 1H), 7.20 (m,
2H), 7.79 (broad s, 1H), 10.53 (s, 1H); 1H NMR (300 MHz, CDCl3, c
= 0.26 mol l−1) δ 1.37−1.52 (m, 4H), 1.53 (s, 3H), 1.85 (s, 3H), 2.27
(m, 2H), 3.09 (m, 2H), 6.10 (br s, 1H), 6.79 (d, J = 7.8 Hz, 1H), 6.94
(t, J = 7.2 Hz, 1H), 7.10−7.18 (m, 2H), 8.99 (s, 1H); 13C NMR (75.5
MHz, CDCl3) δ 21.9 (CH2), 23.0 (CH3), 23.2 (CH3), 28.3 (CH2),
33.1 (CH2), 38.9 (CH2), 77.6 (C), 110.5 (CH), 122.1 (CH), 122.6
(CH), 129.4 (CH), 129.5 (C), 140.6 (C), 170.6 (C), 171.8 (C), 177.3
(C); HRMS (ESI-TOF, CH3OH) m/z [M + Na]+ calcd for
C16H20N2O4Na [(M + Na)+] 327.1320, found 327.1321; Rf
(MeOH/AcOEt 1/9) 0.57.
N-(2-(2-(Cyanomethyl)-3,7-dioxo-1,4-oxazepan-2-yl)phenyl)-
acetamide (2o). Starting from Boc derivative 4i (101.8 mg, 0.254
mmol), the general procedure afforded lactam 2o as a white solid (36.7
mg, yield 48%): 1H NMR (300 MHz, DMSO-d6) δ 1.76 (s, 3H), 2.54
(m,2H), 3.17 (m, 2H), 3.29 (s, 2H), 6.89 (d, J = 7.5 Hz, 1H), 7.04 (t, J
= 7.5 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.91
1
(br s, 1H), 10.88 (s, 1H); H NMR (300 MHz, CDCl3) δ 1.84 (s,
3H), 2.54 (m,2H), 2.69, 3.00 (ABq, JAB = 16.8 Hz, 2H), 3.39 (m, 2H),
6.26 (t, J = 6.5 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 7.04 (t, J = 7.5 Hz,
1H), 7.28 (t, J = 7.5 Hz, 1H), 7.38 (d, J = 7.5 Hz, 1H), 9.09 (s, 1H);
13C NMR (75.5 MHz, CDCl3) δ 23.1 (CH3), 26.2 (CH2), 33.7 (CH2),
34.9 (CH2), 75.7 (C), 111.1 (CH), 114.5 (C), 123.5 (CH), 123.6
(CH), 125.0 (C), 131.3 (CH), 140.8 (C), 170.2 (C), 170.9 (C), 173.5
(C); HRMS (ESI-TOF, MeOH) m/z [M + Na]+ calcd for
C15H15N3O4Na 324.0960, found 324.0961; Rf (AcOEt) 0.67; mp
66−70 °C.
N-(2-(2-Methyl-3,10-dioxo-1,4-oxazecan-2-yl)phenyl)acetamide
(2k). Starting from Boc derivative 4e (140.4 mg, 0.335 mmol), the
general procedure afforded lactam 2k as an amorphous solid (67.2 mg,
yield 63%): 1H NMR (300 MHz, DMSO-d6) δ 1.18 (m, 2H), 1.34 (m,
2H), 1.42(m, 2H), 1.47 (s, 3H), 1.78 (s, 3H), 2.29 (t, J = 7.2 Hz, 2H),
2.94, 2.99 (ABq, JAB = 6.7 Hz, 2H), 6.83 (dd, J = 8.1, 1 Hz, 1H), 6.96
(td, J = 8, 1 Hz, 1H), 7.20−7.26 (m, 2H), 7.76 (br s, 1H), 10.53 (s,
1
1H); H NMR (300 MHz, CDCl3, c = 0.31 mol l−1) δ 1.24 (m, 2H),
1.38 (m, 2H), 1.38 (m, 2H), 1.41 (s, 3H), 1.86 (s, 3H), 2.25 (m, 2H),
3.09, 3.14 (ABq, JAB = 6.5 Hz, 2H), 6.20 (br s, 1H), 6.79 (d, J = 7.8 Hz,
1H), 6.93 (t, J = 7.5 Hz, 1H), 7.10−7.17 (m, 2H), 9.03 (s, 1H); 13C
NMR (75.5 MHz, CDCl3) δ 23.1 (CH3), 23.3 (CH3), 24.2 (CH2),
25.8 (CH2), 28.7 (CH2), 33.5 (CH2), 39.1 (CH2), 77.7 (C), 110.6
(CH), 122.2 (CH), 122.6 (CH), 129.6 (C), 129.6 (CH), 140.7 (C),
170.7 (C), 171.9 (C), 177.3 (C); HRMS (ESI-TOF, CH3OH) m/z
N-(2-(2-(Cyanomethyl)-3,10-dioxo-1,4-oxazecan-2-yl)phenyl)-
acetamide (2p). Starting from Boc derivative 4j (197.3 mg, 0.445
mmol), the general procedure afforded lactam 2p as an amorphous
solid (127.6 mg, yield 84%): 1H NMR (300 MHz, DMSO-d6) δ 1.21−
1.47 (m, 6H), 1.77 (s, 3H), 2.35 (m, 2H), 2.98 (m, 2H), 3.28 (s, 2H),
6.90 (d, J = 8 Hz, 1H), 7.06 (t, J = 8 Hz, 1H), 7.30−7.35 (m, 2H), 7.77
(s, 1H), 10.86 (s, 1H); 1H NMR (300 MHz, CDCl3) δ 1.18−1.53 (m,
E
dx.doi.org/10.1021/jo501978j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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6H), 1.89 (s, 3H), 2.30 (m, 2H), 2.64, 2.99 (ABq, JAB = 17.5 Hz, 2H),
3.13 (m, 2H), 6.10 (br s, 1H), 6.86 (d, J = 8 Hz, 1H), 7.01 (t, J = 8 Hz,
1H), 7.24 (t, J = 8 Hz, 1H), 7.37 (d, J = 8 Hz, 1H), 9.38 (s, 1H); 13C
NMR (75.5 MHz, CDCl3) δ 23.1 (CH3), 24.2 (CH2), 25.8 (CH2),
26.2 (CH2), 28.7 (CH2), 33.3 (CH2), 39.2 (CH2), 75.3 (C), 111.1
(CH), 114.8 (C), 123.2 (CH), 123.3 (CH), 125.3 (C), 131.0 (CH),
141.1 (C), 170.9 (C), 171.2 (C), 173.6 (C); HRMS (ESI-TOF,
MeOH) m/z [M + Na]+ calcd for C18H21N3O4Na 366.1430, found
366.1431; Rf (AcOEt) 0.10.
Benzyl (2-(2-(Cyanomethyl)-3,10-dioxo-1,4-oxazecan-2-yl)-
phenyl)carbamate (2q). Starting from Boc derivative 4k (134.7 mg,
0.251 mmol), the general procedure afforded lactam 2q as an
amorphous solid (60 mg, yield 55%): 1H NMR (300 MHz, DMSO-d6)
δ 1.21−1.49 (m, 6H), 2.32 (m, 2H), 2.92 (m, 2H), 3.28 (s, 2H), 5.00
(s, 2H), 6.89 (d, J = 7.8 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 7.23 (t, J =
7.8 Hz, 1H), 7.29−7.38 (m, 7H), 10.86 (s, 1H); 1H NMR (300 MHz,
CDCl3) δ (two rotamers 15/85) 1.18−1.54 (m, 6H), 2.31 (m, 2H),
2.55 (d, J = 16.8 Hz, 1H), 2.97−3.11 (m, 3H), 4.90 (br s, 0.85 H),
5.01−5.07 (br s, 2H), 5.21 (br s, 0.15 H), 6.80 (d, J = 7.8 Hz, 1H),
6.98 (t, J = 7.2 Hz, 1H), 7.19−7.27 (m, 6H), 7.38 (d, J = 7.2 Hz, 1H),
8.70 (s, 0.85 H), 8.82 (s, 0.15 H); 13C NMR (75.5 MHz, CDCl3) δ
24.2 (CH2), 25.8 (CH2), 26.1 (CH2), 29.4 (CH2), 33.3 (CH2), 40.7
(CH2), 66.6 (CH2), 75.2 (C), 111.0 (CH), 114.7 (C), 123.4 (CH),
125.2 (C), 128.1 (CH), 131.1 (CH), 136.6 (C), 140.7 (C), 156.5 (C),
171.1 (C), 173.7 (C); HRMS (ESI-TOF, MeOH) m/z [M + Na]+
calcd for C24H25N3O5Na 458.1692, found 458.1690; Rf (AcOEt/
petroleum ether 2/3) 0.20.
N-(2-(8-Methyl-6,9-dioxo-1,4,7-trioxa-10-azacyclododecan-8-yl)-
phenyl)acetamide (2r). Starting from Boc derivative 4m (82.8 mg,
0.184 mmol), the general procedure afforded lactam 2r as an
amorphous solid (39.3 mg, yield 61%): 1H NMR (300 MHz,
DMSO-d6) δ 1.50 (s, 3H), 1.78 (s, 3H), 3.14 (m, 2H), 3.30−3.49 (m,
6H), 4.17 (s, 2H), 6.86 (d, J = 7.5 Hz, 1H), 6.93 (t, J = 7.5 Hz, 1H),
7.22−7.26 (m, 2H), 7.87 (s, 1H), 10.62 (s, 1H); 1H NMR (300 MHz,
CDCl3) δ 1.57 (s, 3H), 1.78 (s, 3H), 3.28−3.53 (m, 8H), 4.10, 4.13
(ABq, JAB = 16.8 Hz, 2H), 6.45 (br s, 1H), 6.82 (d, J = 7.5 Hz, 1H),
6.96 (t, J = 7.5 Hz, 1H), 7.22−7.26 (m, 2H), 9.03 (s, 1H); 13C NMR
(75.5 MHz, CDCl3) δ 23.0 (CH3), 23.2 (CH3), 39.2 (CH2), 68.0
(CH2), 69.7 (CH2), 69.8 (CH2), 70.9 (CH2), 78.3 (C), 110.7 (CH),
122.4 (CH), 122.7 (CH), 129.0 (C), 129.9 (CH), 140.8 (C), 168.8
(C), 170.8 (C), 176.5 (C); HRMS (ESI, MeOH) m/z [M + Na]+
calcd for C17H22N2O6Na 373.1376, found 373.1379; Rf (AcOEt/
MeOH 9/1) 0.25.
rel-N-(2-((7S,8R)-2,6-Dioxo-7,8-diphenyl-1,5-diazonan-7-yl)-
phenyl)acetamide (2s). To a solution of Boc derivative 4o (32.0 mg,
0.059 mmol) in AcOEt (0.2 mL) was added a 3 M solution of
anhydrous HCl in AcOEt (61 μL, 0.18 mmol). The mixture was
stirred at room temperature for 1 h. The solvent was removed in
vacuo. To the resulting solid were added CH2Cl2 (0.6 mL) and
diisopropylethylamine (20 μL, 0.11 mmol). The mixture was stirred
overnight at room temperature and then diluted with ether (2 mL).
The precipitate was collected on a sintered glass funnel, washed with
ether (1 mL), and chromatographed over silica gel (2.2 g, eluent
AcOEt) to afford compound 2s (19.4 mg, 77% yield) as a white solid:
1H NMR (300 MHz, CDCl3) δ 1.80 (s, 3H), 1.92−2.09 (m, 2H), 3.25,
3-(2-Nitroethyl)-3-phenylindolin-2-one (6b). To a solution of
oxindole 5a (1.00 g, 4.78 mmol) and triethylamine (60 μL, 0.48
mmol) in dry CH2Cl2 (28 mL) at 0 °C and under argon atmosphere
was added using a syringe pump (1.5 mL per hour) a solution of
nitroethylene (0.65 mL, 9.57 mmol) in dry CH2Cl2 (20 mL). The
resulting mixture was stirred overnight at 0 °C and then concentrated
in vacuo. After purification by chromatography over silica gel (54.5 g,
eluent CH2Cl2), the nitro compound 6b was afforded as a beige solid
1
(1.03 g, 82% yield): H NMR (300 MHz, CDCl3) δ 2.82−2.92 (m,
1H), 3.02−3.11 (m, 1H), 4.09−4.30 (m, 2H), 6.92 (d, J = 7.5 Hz,
1H), 7.04 (td, J = 7.5, 1.2 Hz, 1H), 7.12−7.32 (m, 7H), 9.09 (broad s,
1H); 13C NMR (75.5 MHz, CDCl3) δ 33.8 (CH2), 54.6 (C), 71.4
(CH2), 110.8 (CH), 123.3 (CH), 124.8 (CH), 126.5 (CH), 128.0
(CH), 129.0 (CH), 129.1 (CH), 130.8 (C), 138.0 (C), 140.5 (C),
179.7 (C); HRMS (ESI-TOF, MeOH) m/z [M + Na]+ calcd for
C16H14N2O3Na 305.0902, found 305.0899; Rf (AcOEt/petroleum
ether 1/1) 0.67; mp 114−116 °C.
3-Methyl-3-(2-nitroethyl)indolin-2-one (6c). Similarly, compound
6c (192 mg, 85%) was obtained from 5b: 1H NMR (300 MHz,
CDCl3) δ 1.49 (s, 3H), 2.50−2.71 (m, 2H), 4.09−4.18 (m, 1H),
4.26−4.36 (m, 1H), 7.00 (d, J = 7.8 Hz, 1H), 7.11 (t, J = 7.3 Hz, 1H),
7.21−7.31 (m, 2H), 9.15 (broad s, 1H); 13C NMR (75.5 MHz,
CDCl3) δ 23.8 (CH3), 34.5 (CH2), 46.8 (C), 71.5 (CH2), 110.7
(CH), 123.1 (CH), 123.3 (CH), 128.9 (CH), 132.2 (C), 140.2 (C),
181.8 (C); HRMS (ESI-TOF, MeOH) m/z [M + Na]+ calcd for
C11H12N2O3Na 243.0745, found 243.0745; Rf (AcOEt/petroleum
ether 1/1) 0.47; mp 94−98 °C.
rel-(R)-3-((S)-2-Nitro-1-phenylethyl)-3-phenylindolin-2-one (6d).
Compound 6d was obtained according to the literature12e and was
1
recrystallized from a 3/2 2-propanol−water mixture: dr >25/1; H
NMR (300 MHz, CDCl3) δ 4.73−4.78 (m, 2H), 3.02−3.11 (dd, J =
14.1, 12.3 Hz, 1H), 6.66 (d, J = 8.1 Hz, 1H), 7.03−7.19 (m, 7H),
7.28−7.47 (m, 4H), 7.69 (d, J = 6.0 Hz, 2H), 8.86 (s, 1H); 13C NMR
(75.5 MHz, CDCl3) δ 50.2 (CH), 60.5 (C), 75.6 (CH2), 110.1 (CH),
122.8 (CH), 124.8 (CH), 126.6 (CH), 128.07 (CH), 128.10 (CH),
128.15 (CH), 128.5 (CH), 129.0 (CH), 129.6 (CH), 131.6 (C), 133.9
(C), 137.8 (C), 139.4 (C), 179.2 (C); HRMS (ESI-TOF, MeOH/
CH2Cl2) m/z [M + Na]+ calcd for C22H18N2O3Na 381.1215, found
381.1215; Rf (AcOEt/petroleum ether 1/1) 0.64; mp 204−211 °C.
rel-(S)-1-Acetyl-3-((S)-2-nitro-1-phenylethyl)-3-phenylindolin-2-
one (3a). To a solution of oxindole 6a (248 mg, 0.694 mmol), DMAP
(8.5 mg, 0.069 mmol), and triethylamine (110 μL, 0.76 mmol) in dry
CH2Cl2 (1 mL) at 0 °C was added acetyl chloride (54 μL, 0.76 mmol).
The mixture was stirred at room temperature overnight and then
washed with 10% aqueous citric acid. After aqueous workup, the
resulting product was chromatographed over silica gel (8.2 g, eluent
CH2Cl2) to afford nitro compound 3a as a white solid (243 mg, 88%
1
yield): H NMR (300 MHz, CDCl3) δ 2.31 (s, 3H), 4.75−5.04 (m,
3H), 6.80 (d, J = 7.5 Hz, 2H), 7.07−7.21 (m, 3H), 7.39−7.52 (m,
6H), 7.63−7.66 (m, 2H), 8.11 (dd, J = 7.5, 1.8 Hz, 1H); 13C NMR
(75.5 MHz, CDCl3) δ 26.3 (CH3), 50.9 (CH), 60.2 (C), 76.0 (CH2),
117.2 (CH), 125.1 (CH), 125.6 (CH), 126.5 (C), 127.8 (CH), 128.3
(CH), 128.8 (CH), 128.8 (CH), 128.9 (CH), 129.4 (CH), 129.9
(CH), 132.8 (C), 135.3 (C), 141.2 (C), 170.3 (C), 176.6 (C); HRMS
(ESI-TOF, MeOH) m/z [M + Na]+ calcd for C24H20N2O4Na
423.1321, found 423.1320; Rf (CH2Cl2) 0.68; mp 195−200 °C; IR
1746, 1710, 1554 cm−1.
3.29 (ABq, JAB = 6 Hz, 2H), 3.77 (t, J = 6 Hz, 2H), 4.10 (t, J = 7.5 Hz,
1H), 5.56 (t, J = 5.7 Hz, 1H), 6.06 (br s, 1H), 6.56 (d, J = 7.2 Hz, 1H),
6.84−7.04 (m, 7H), 7.13−7.32 (m, 5H), 7.50 (br s 1H), 7.57−7.60
(m, 2H); 13C NMR (75.5 MHz, CD3OD) δ 22.5 (CH3), 36.5 (CH2),
37.0 (CH2), 40.1 (CH2), 52.0 (CH), 62.2 (C), 110.8 (CH), 123.0
(CH), 126.3 (CH), 128.0 (CH), 128.3 (CH), 128.4 (CH), 128.6
(CH), 128.9 (CH), 129.8 (CH), 131.0 (CH), 134.1(C), 138.2 (C),
140.7 (C), 141.9 (C), 173.2 (C), 173.6 (C), 181.5 (C); HRMS (ESI-
TOF, MeOH) m/z [M + Na]+ calcd for C27H27N3O3Na 464.1950,
found 464.1950; Rf (AcOEt/MeOH 9/1) 0.52; mp 191−197 °C.
Procedures for the Synthesis of Compounds 3 and 6.
Nitroethylene,20 and compounds 3d12e,f and 6a (dr >20/1)12e,c were
prepared according to the literature. Nonracemic compounds 3e12c
and 3f12b were previously described.
1-Acetyl-3-(2-nitroethyl)-3-phenylindolin-2-one (3b). To a sol-
ution of oxindole 6b (158.1 mg, 0.560 mmol), DMAP (6.84 mg, 0.056
mmol), and triethylamine (80 μL, 0.62 mmol) in dry CH2Cl2 (0.7
mL) at 0 °C was added a solution of acetyl chloride (80 μL, 1.12
mmol) in dry CH2Cl2 (0.7 mL). The mixture was stirred at room
temperature for 5 h and then washed by 10% aqueous citric acid. After
aqueous workup, the resulting product was dissolved in CH2Cl2 (2
mL) and treated with pentane (5 mL). The filtrate was concentrated in
vacuo to give nitro compound 3b as a white solid (126 mg, 70% yield):
1H NMR (300 MHz, CDCl3) δ 2.59 (s, 3H), 2.82−2.92 (m, 1H),
3.11−3.21 (m, 1H), 4.05−4.25 (m, 2H), 7.18−7.40 (m, 8H), 8.27 (d, J
= 8.1 Hz, 1H). 13C NMR (75.5 MHz, CDCl3) δ 26.6 (CH3), 34.4
(CH2), 54.6 (C), 71.4 (CH2), 117.3 (CH), 124.4 (CH), 125.8 (CH),
F
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126.5 (CH), 128.4 (CH), 128.8 (C), 129.1 (CH), 129.6 (CH), 137.8
(C), 140.0 (C), 170.7 (C), 177.9 (C); HRMS (ESI-TOF, MeOH) m/
z [M + Na]+ calcd for C18H16N2O4Na 347.1008, found 347.1010; Rf
(AcOEt/petroleum ether 1/1) 0.72; mp 147−150 °C.
After filtration through a pad of Celite, concentration in vacuo, and
purification by chromatography over silica gel (2g, eluent 80/20
CH2Cl2/AcOEt), hydroxamic acid 7 (30.0 mg, yield 74%) and lactam
2a (5.80 mg, yield 15%) were afforded as white amorphous solids: 1H
NMR (300 MHz, DMSO-d6) 1.24 (s, 3H), 3.79 (dd, J = 9.9, 4.5 Hz,
1H), 4.11 (dd, J = 9.9, 6.6 Hz, 1H), 4.63 (dd, J = 6 Hz, J = 4.5 Hz,
1H), 6.57 (m, 2H), 6.81−6.84 (m, 2H), 6.96−7.00 (m, 6 H), 7.37 (m,
2 H), 7.51 (dd, J = 7.8, 1.8 Hz, 1H), 8.09 (d, J = 7.5 Hz, 1H), 10.00 (s,
1H),10.64 (br s, 1H); 13C NMR (75.5 MHz, CD3OD) δ 23.1 (CH3),
46.3 (CH), 54.3 (CH2), 62.4 (C), 126.6 (CH), 127.8 (CH), 128.1
(CH), 128.4 (CH), 128.9 (CH), 129.1 (CH), 129.4 (CH), 129.4
(CH), 129.5 (CH), 130.3 (CH), 134.5 (C), 138.5 (C), 139.4 (C),
140.9 (C), 170.5 (C), 173.0 (C); HRMS (ESI-TOF, CH3OH) m/z
[M + Na]+ calcd for C24H22N2O3Na 409.1523, found 409.1521; Rf =
0.08 (AcOEt).
1-Acetyl-3-methyl-3-(2-nitroethyl)indolin-2-one (3c). To a solu-
tion of oxindole 6c (97.2 mg, 0.441 mmol), DMAP (5.66 mg, 0.046
mmol), and triethylamine (72 μL, 0.51 mmol) in dry CH2Cl2 (2 mL)
at 0 °C was added acetyl chloride (35 μL, 0.48 mmol). The mixture
was stirred at room temperature overnight and then diluted with
CH2Cl2, washed with 10% aqueous citric acid, and dried over
magnesium sulfate. After concentration in vacuo and purification by
chromatography over silica gel (10 g, eluent CH2Cl2/petroleum ether
4/1), oxindole 3c was afforded as a white amorphous solid (84.3 mg,
1
73% yield): H NMR (300 MHz, CDCl3) δ 1.48 (s, 3H), 2.46−2.57
(m, 1H), 2.64−2.67 (m, 4H), 4.10−4.29 (m, 2H), 7.23−7.29 (m, 2H),
7.31−7.39 (m, 1H), 8.23 (d, J = 8.1 Hz, 1H); 13C NMR (75.5 MHz,
CDCl3) δ 24.6 (CH3), 26.5 (CH3), 35.0 (CH2), 46.6 (C), 71.0 (CH2),
116.9 (CH), 122.2 (CH), 125.7 (CH), 129.1 (CH), 130.7 (C), 139.1
(C), 170.7 (C), 179.8 (C); HRMS (ESI-TOF, MeOH) m/z [M +
Na]+ calcd for C13H14N2O4Na 285.0851, found 285.0852; Rf
(CH2Cl2) 0.37.
Procedures for the Synthesis of Compounds 8. Compound
8d was prepared according to the literature.16
1-Acetyl-3-hydroxy-3-methylindolin-2-one (8a). Under argon
atmosphere, a 2.5 M solution of methylmagnesium bromide in ether
(2.8 mL, 7 mmol) was added using a syringe pump (0.5 mL per hour)
to a mixture of acetylisatin (1.23 g, 6.53 mmol) and THF (33 mL) at
−60 °C. The resulting mixture was stirred overnight at −60 °C,
quenched with 1 M chlorhydric acid (8 mL) at −60 °C, and then
concentrated in vacuo. The aqueous phase was extracted with AcOEt
(3 × 8 mL). The organic phase was dried over sodium sulfate,
concentrated in vacuo, and purified by chromatography over silica gel
(42 g, eluent CH2Cl2). Hydroxyoxindole 8a was afforded as a pale
yellow solid (0.528 g, 45% yield): 1H NMR (300 MHz, CDCl3) δ 1.67
(s, 3H), 2.70 (s, 3H), 3.15 (broad s, 1H), 7.17 (td, J = 7.5, 1.2 Hz,
1H), 7.29 (td, J = 7.9, 1.5 Hz, 1H), 7.37 (dd, J = 7.5, 1.2 Hz, 1H), 8.11
(d, J = 7.9 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) δ 25.6 (CH3), 26.4
(CH3), 73.6 (C), 116.9 (CH), 123.2 (CH), 125.8 (CH), 130.1 (CH),
130.5 (C), 139.0 (C), 170.9 (C), 179.1 (C); HRMS (ESI-TOF,
MeOH) m/z [M + Na]+ calcd for C11H11NO3Na 228.0636, found
228.0643; Rf (AcOEt) 0.77; mp 119−121 °C (lit.21 mp 102−103 °C).
1-Acetyl-5-fluoro-3-hydroxy-3-methylindolin-2-one (8b). Simi-
larly, compound 8b (0.155 g, 21% yield) was afforded as a light
yellow solid from 1-acetyl-5-fluoroisatin (0.677 g, 3.27 mmol) and 2.5
M MeMgBr in ether (1.7 mL, 4.2 mmol): 1H NMR (300 MHz,
CDCl3) δ 1.65 (s, 3H), 2.66 (s, 3H), 3.15 (s, 1H), 7.08 (td, J = 9, 2.7
Hz, 1H), 7.18 (dd, J = 7.5, 2.7 Hz, 1H), 8.22 (dd, J = 9, 4.5 Hz, 1H);
13C NMR (75.5 MHz, CDCl3) δ 25.7 (CH3), 26.4 (CH3), 73.6 (d, J =
1.7 Hz, C), 110.8 (d, J = 24.4 Hz, CH), 116.6 (d, J = 22.7 Hz, CH),
118.5 (d, J = 7.8 Hz, CH), 132.3 (d, J = 7.9 Hz, C), 134.9 (d, J = 2.6
Hz, C), 160.6 (d, J = 246 Hz, C), 170.6 (C), 178.8 (C); HRMS (ESI-
TOF, MeOH) m/z [M − H]− calcd for C11H9NO3F 222.0572, found
222.0570; Rf (AcOEt/petroleum ether 1/1) 0.56; mp 112−116 °C.
1-Acetyl-3-hydroxy-5-methoxy-3-methylindolin-2-one (8c). Sim-
ilarly, compound 8c (0.345 g, 29% yield) was afforded as a light yellow
solid from 1-acetyl-5-methoxyisatin (1.117 g, 5.09 mmol) and 2.5 M
MeMgBr in ether (2.50 mL, 6.2 mmol): 1H NMR (300 MHz, CDCl3)
δ 1.53 (s, 3H), 2.49 (s, 3H), 3.53 (s, 1H), 3.73 (s, 3H), 6.77 (dd, J =
8.7, 2.7 Hz, 1H), 6.89 (d, J = 2.7 Hz, 1H), 8.00 (d, J = 8.7 Hz, 1H);
13C NMR (75.5 MHz, CDCl3) δ 25.6 (CH3), 26.2 (CH3), 55.6 (CH3),
tert-Butyl 3-(2-Nitroethyl)-2-oxo-3-phenylindoline-1-carboxylate
(3e). To a solution of oxindole 6b (142.2 mg, 0.500 mmol) and
DMAP (5.66 mg, 0.046 mmol) in dry CH2Cl2 (8 mL) at 0 °C was
added tert-butyl pyrocarbonate (120 mg, 0.55 mmol). The mixture was
stirred at room temperature for 2.5 h and then diluted with CH2Cl2,
washed with 10% aqueous citric acid, and dried over magnesium
sulfate. After concentration in vacuo and purification by chromatog-
raphy over silica gel (10 g, eluent 1% triethylamine in CH2Cl2),
1
oxindole 3e was afforded as a white solid (96.3 mg, 53% yield): H
NMR (300 MHz, CDCl3) δ 1.49 (s, 9H), 2.80−2.90 (m, 1H), 3.08−
3.18 (m, 1H), 4.05−4.15 (m, 1H), 4.20−4.30 (m, 1H), 7.19−7.38 (m,
8H), 7.88 (d, J = 8.1 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) δ 28.0
(CH3), 34.6 (CH2), 54.4 (C), 71.4 (CH2), 85.1 (C), 115.7 (CH),
124.6 (CH), 125.1 (CH), 126.7 (CH), 128.3 (CH), 128.7 (C), 129.1
(CH), 129.5 (CH), 138.0 (C), 139.6 (C), 148.9 (C), 175.4 (C);
HRMS (ESI-TOF, MeOH) m/z [M + Na]+ calcd for C21H22N2O5Na
405.1426, found 405.1425; Rf (AcOEt/petroleum ether 1/6) 0.80; mp
56−60 °C.
tert-Butyl 3-Methyl-3-(2-nitroethyl)-2-oxoindoline-1-carboxylate
(3f). Similarly, compound 3f (733 mg, 64% yield) was obtained as a
white solid from 6c: 1H NMR (300 MHz, CDCl3) δ 1.19 (s, 3H), 1.59
(s, 9H), 2.38−2.48 (m, 1H), 2.55−2.64 (m, 1H), 4.00−4.10 (m, 1H),
4.18−4.28 (m, 1H), 7.14−7.20 (m, 2H), 7.28−7.32 (m, 1H), 7.80 (d, J
= 8.1 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) δ 24.3 (CH3), 27.8
(CH3), 34.8 (CH2), 46.3 (C), 70.9 (CH2), 84.6 (C), 115.2 (CH),
122.3 (CH), 124.8 (CH), 128.7 (CH), 130.4 (C), 138. Six (C), 148.7
(C), 177.3 (C); HRMS (ESI-TOF, MeOH) m/z [M + Na]+ calcd for
C16H20N2O5Na 343.1270, found 343.1266; Rf (CH2Cl2) 0.33; mp
106−109 °C.
(S)-1-(Methylsulfonyl)-3-((S)-2-nitro-1-phenylethyl)-3-phenylin-
dolin-2-one (3g). To a solution of oxindole 6a (121.4 mg, 0.339
mmol), DMAP (4.70 mg, 0.038 mmol), and triethylamine (56 μL,
0.40 mmol) in dry CH2Cl2 (2 mL) at 0 °C was added methanesulfonyl
chloride (30 μL, 0.39 mmol). The mixture was stirred at room
temperature overnight. After aqueous workup, the resulting product
was chromatographed over silica gel (22 g, eluent CH2Cl2) to afford
73.7 (C), 109.0 (CH), 114.9 (CH), 118.0 (CH), 131.9 (C), 132.2
(C), 157.7 (C), 170.7 (C), 179.2 (C); HRMS (ESI-TOF, MeOH) m/
z [M + Na]+ calcd for C12H13NO4Na 258.0742, found 258.0741; Rf
(AcOEt/petroleum ether 1/1) 0.63; mp 118−120 °C.
1
nitro compound 3g as a white solid (78 mg, 53% yield): H NMR
(300 MHz, CDCl3) δ 2.54 (s, 3H), 4.73−4.99 (m, 3H), 6.79−6.81 (m,
2H), 7.10−7.21 (m, 3H), 7.40−7.53 (m, 6H), 7.60−7.64 (m, 2H),
7.72 (d, J = 7.5 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) δ 40.1 (CH3),
51.2 (CH), 59.7 (C), 76.3 (CH2), 114.2 (CH), 125.0 (CH), 126.0
(C), 126.4 (CH), 127.6 (CH), 128.5 (CH), 128.8 (CH), 129.1 (CH),
129.4 (CH), 129.5 (CH), 130.3 (CH), 133.4 (C), 134.3 (C), 140.1
(C), 174.4 (C); HRMS (ESI-TOF, MeOH) m/z [M + Na]+ calcd for
C23H20N2O5SNa 459.0991, found 459.0993; Rf (CH2Cl2) 0.74; mp
dec 160 °C.
Benzyl 3-Hydroxy-3-(cyanomethyl)-2-oxoindoline-1-carboxylate
(8e). A mixture of N-benzyloxycarbonyl isatin22 (0.485 g, 1.73 mmol),
cyanoacetic acid (0.170 g, 2.00 mmol), and triethylamine (0.050 mL,
0.10 mmol) in DMF (8.5 mL) was heated at 70 °C for 3 h. DMF was
removed in vacuo. Water was added and extracted three times with
diethyl ether. After drying of the organic phases over sodium sulfate
and concentration in vacuo, purification by chromatography over silica
gel (16 g, eluent DCM) gave product 8e as a beige solid (0.305 g, 54%
1
yield): H NMR (300 MHz, CDCl3) δ 2.65, 2.95 (ABq, JAB = 18 Hz,
Synthesis of Compound 7. A mixture of nitro compound 3a
(42.25 mg, 0.105 mmol) and 10% Pd on C (30.3 mg) in MeOH (2
mL) was stirred at room temperature under an H2 balloon overnight.
2H), 3.59 (br s, 1H), 5.34 (m, 2H), 7.18−7.39 (m, 7H), 7.58 (dd, J =
7.5, 1 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H); 13C NMR (75.5 MHz,
CDCl3) δ 27.9 (CH2), 69.3 (CH2), 72.3 (C), 114.8 (C), 115.8 (CH),
G
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124.2 (CH), 125.9 (CH), 126.3 (C), 128.4 (CH), 128.7 (CH), 128.8
(CH), 131.4 (CH), 134.3 (C), 138.5 (C), 150.1 (C), 173.7 (C);
HRMS (ESI-TOF, acetone) m/z [M + Na]+ calcd for C18H14N2O4Na
345.0851, found 345.0849; Rf (AcOEt/DCM 1/9) 0.42; mp 59−68
°C.
MeOH) m/z [M + Na]+ calcd for C20H26N2O6Na 413.1688, found
413.1689; Rf (AcOEt/CH2Cl2 1/4): 0.71.
1-Acetyl-3-methyl-2-oxoindolin-3-yl 5-((tert-butoxycarbonyl)-
amino)pentanoate (4d). According to the general procedure, 4d
was obtained as a white solid (251 mg, yield: 95%) from 3-
hydroxyoxindole 8a (134.8 mg, 0.656 mmol), Boc-NH-(CH2)4-
COOH (170.9 mg, 0.787 mmol), DCC (148.8 mg, 0.721 mmol),
3-Hydroxy-3-(cyanomethyl)-N,N-dimethyl-2-oxoindoline-1-car-
boxamide (8f). A mixture of N-dimethylcarbamoyl isatin23 (0.472 g,
2.17 mmol), cyanoacetic acid (0.213 g, 2.39 mmol), and triethylamine
(0.060 mL, 0.43 mmol) in DMF (11 mL) was heated at 70 °C for 3 h.
DMF was removed in vacuo. Water was added and extracted three
times with diethyl ether. After drying of the organic phases over
sodium sulfate and concentration in vacuo, purification by
chromatography over silica gel (11 g, eluent DCM) gave product 8f
as a beige solid (0.405 g, 72% yield): 1H NMR (300 MHz, DMSO-d6)
δ 2.98 (s, 3H), 3.05 (s, 3H), 3.20 (s, 2H), 6.97 (s, 1H), 7.09 (d, J = 7.8
Hz, 1H), 7.21 (td, J = 7.8, 1.2 Hz, 1H), 7.40 (td, J = 7.8, 1.2 Hz, 1H),
1
and DMAP (96.1 mg, 0.787 mmol): H NMR (300 MHz, CDCl3) δ
1.36−1.42 (m, 11H), 1.47−1.58 (m, 5H), 2.29 (m, 2H), 2.62 (s, 3H),
3.01 (m, 2H), 4.46 (br s, 1H), 7.11−7.21 (m, 2H), 7.28 (td, J = 7.8,
1.8 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H); 13C NMR (75.5 MHz, CDCl3)
δ 21.8 (CH3), 23.9 (CH2), 26.5 (CH3), 28.4 (CH3), 29.2 (CH2), 33.0
(CH2), 39.9 (CH2), 76.9 (C), 79.2 (C), 116.8 (CH), 121.7 (CH),
125.4 (CH), 128.3 (C), 130.1 (CH), 139.5 (C), 155.9 (C), 170.8 (C),
171.8 (C), 175.6 (C); HRMS (ESI, MeOH) m/z [M + Na]+ calcd for
C21H28N2O6Na 427.1845, found 427.1844; Rf (AcOEt/CH2Cl2 1/4)
0.78; mp 98−102 °C.
1
7.57 (d, J = 7.2 Hz, 1H). H NMR (300 MHz, CDCl3) δ 2.84−3.18
(m, 8H), 3.66 (br s, 1H), 7.16 (d, J = 8.1 Hz, 1H), 7.22 (td, J = 7.8, 1.2
Hz, 1H), 7.40 (td, J = 7.8, 1.2 Hz, 1H), 7.58 (d, J = 8 Hz, 1H); 13C
NMR (75.5 MHz, CDCl3) δ 27.20 (CH2), 36.87 (CH3), 38.41 (CH3),
73.24 (C), 113.28 (CH), 115.05 (C), 123.94 (CH), 124.79 (CH),
127.37 (C), 131.06 (CH), 139.75 (C), 150.89 (C), 173.58 (C);
HRMS (ESI-TOF, MeOH) m/z [M + Na]+ calcd for C13H13N3O3Na
282.0855, found 282.0858; Rf (AcOEt) 0.55; mp 132−139 °C.
General Procedure for the Synthesis of Compounds 4. To a
solution of 3-hydroxyoxindole 8a (205.5 mg, 1.00 mmol) in CH2Cl2
(1 mL) were successively added Boc-β-alanine (227 mg, 1.2 mmol),
DCC (227 mg, 1.1 mmol), and DMAP (147 mg, 1.2 mmol). The
resulting mixture was stirred for 5 h at room temperature and then
diluted with CH2Cl2 (10 mL) and filtered. The filtrate was successively
washed with aqueous 10% citric acid, aqueous 10% sodium carbonate,
and water. After drying over magnesium sulfate and concentration in
vacuo, the residue was chromatographed over silica gel (11 g, eluant:
1% Et3N in CH2Cl2) to yield Boc derivative 4b (359 mg) as an
amorphous solid: yield 95%.
1-Acetyl-3-methyl-2-oxoindolin-3-yl 6-((tert-Butoxycarbonyl)-
amino)hexanoate (4e). According to the general procedure, 4e was
obtained as a solid (406.8 mg, yield: 97%) from 3-hydroxyoxindole 8a
(199.5 mg, 0.972 mmol), Boc-NH-(CH2)5-COOH (269 mg, 1.170
mmol), DCC (221 mg, 1.07 mmol), and DMAP (143 mg, 1.17
1
mmol): H NMR (300 MHz, CDCl3) δ 1.16−1.26 (m, 2H), 1.32−
1.42 (m, 2H), 1.36 (s, 9H), 1.44−1.56 (m, 2H), 1.58 (s, 3H), 2.26 (m,
2H), 2.62 (s, 3H), 3.00 (m, 2H), 4.48 (br s, 1H), 7.11−7.26 (m, 2H),
7.29 (t, J = 7.6 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H); 13C NMR (75.5
MHz, CDCl3) δ 23.8 (CH3), 24.3 (CH2), 26.0 (CH2), 26.5 (CH3),
28.4 (CH3), 29.6 (CH2), 33.9 (CH2), 40.3 (CH2), 76.9 (C), 79.0 (C),
116.8 (CH), 121.6 (CH), 125.4 (CH), 128.3 (C), 130.0 (CH), 139.5
(C), 155.9 (C), 170.7 (C), 171.9 (C), 175.5 (C); HRMS (ESI-TOF,
MeOH) m/z [M + Na]+ calcd for C22H30N2O6Na 441.2001, found
441.1998; Rf (AcOEt/CH2Cl2 1/9) 0.64; mp 67−72 °C.
1-Acetyl-5-fluoro-3-methyl-2-oxoindolin-3-yl 3-((tert-
Butoxycarbonyl)amino)propanoate (4f). According to the general
procedure, compound 4f was obtained as a pale yellow solid (140 mg,
yield: 60%) from 3-hydroxyoxindole 8b (132 mg, 0.595 mmol), Boc-
NH-(CH2)2-COOH (135 mg, 0.714 mmol), DCC (135 mg, 0.655
1-Acetyl-3-methyl-2-oxoindolin-3-yl (tert-Butoxycarbonyl)-
glycinate (4a). According to the general procedure, 4a was obtained
as a viscous liquid (132 mg, yield: 69%) from 3-hydroxyoxindole 8a
(108 mg, 0.526 mmol), Boc-Gly-OH (101.4 mg, 0.579 mmol), DCC
1
mmol), and DMAP (87.2 mg, 0.714 mmol): H NMR (300 MHz,
CDCl3) δ 1.36 (s, 9H), 1.58 (s, 3H), 2.52 (t, J = 6 Hz, 2H), 2.61 (s,
3H), 3.25 (m, 2H), 4.75 (broad s, 1H), 6.92 (dd, J = 7.2, 2.7 Hz, 1H),
7.00 (td, J = 9, 2.7 Hz, 1H), 8.20 (dd, J = 9, 4.8 Hz, 1H); 13C NMR
(75.5 MHz, CD3OD) δ 23.9 (CH3), 26.4 (CH3), 28.7 (CH3), 34.7
(CH2), 37.02(CH2), 78.3 (d, J = 1.7 Hz, C), 80.3 (C), 110.9 (d, J = 25
Hz, CH), 117.2 (d, J = 23 Hz, CH), 119.2 (d, J = 7.8 Hz, CH), 132.0
(d, J = 8.2 Hz, C), 137.1 (d, J = 2.6 Hz, C), 158.2 (C), 161.8 (d, J =
244 Hz, C), 171.9 (C), 171.9 (C), 176.6 (C); HRMS (ESI-TOF,
MeOH) m/z [M + Na]+ calcd for C19H23FN2O6Na 417.1438, found
417.1439; Rf (AcOEt/petroleum ether 1/1) 0.65; mp 118−121 °C.
1-Acetyl-5-methoxy-3-methyl-2-oxoindolin-3-yl 3-((tert-
Butoxycarbonyl)amino)propanoate (4g). According to the general
procedure, 4g was obtained as a solid (195.1 mg, yield: 91%) from
hydroxyoxindole 8c (124.6 mg, 0.529 mmol), Boc-NH-(CH2)2-
COOH (120.2 mg, 0.636 mmol), DCC (120 mg, 0.582 mmol), and
1
(119.5 mg, 0.579 mmol), and DMAP (77.1 mg, 0.631 mmol): H
NMR (300 MHz, CDCl3) δ 1.33 (s, 9H), 1.61 (s, 3H), 2.62 (s, 3H),
3.91 (d, J = 6 Hz, 2H), 4.77 (br s, 1H), 7.20−7.26 (m, 2H), 7.32 (t, J =
6 Hz, 1H), 8.19 (d, J = 6 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) δ
23.8 (CH3), 26.5 (CH3), 28.2 (CH3), 42.0 (CH2), 77.9 (C), 80.1 (C),
116.8 (CH), 122.1 (CH), 125.6 (C), 130.4 (CH), 139.5 (C), 155.3
(C), 168.9 (C), 170. Seven (C), 175.0 (C); HRMS (ESI-TOF,
MeOH) m/z [M + Na]+ calcd for C18H22N2O6Na 385.1376, found
385.1375; Rf (AcOEt/petroleum ether) 0.38.
1-Acetyl-3-methyl-2-oxoindolin-3-yl 3-((tert-butoxycarbonyl)-
1
amino)propanoate (4b): H NMR (300 MHz, CDCl3) δ 1.35 (s,
9H), 1.59 (s, 3H), 2.50 (m, 2H), 2.62 (s, 3H), 3.25 (m, 2H), 4.77 (br
s, 1H), 7.12−7.22 (m, 2H), 7.31 (t, J = 7.8 Hz, 1H), 8.19 (d, J = 8.1
Hz, 1H); 13C NMR (75.5 MHz, CDCl3) δ 23.9 (CH3), 26.5 (CH3),
28.4 (CH3), 34.1 (CH2), 36.0 (CH2), 77.3 (C), 79.5 (C), 116.8 (CH),
121.8 (CH), 125.5 (CH), 128.1 (C), 130.2 (CH), 139.5 (C), 155.7
(C), 170.7 (C), 170. Nine (C), 175.4 (C); HRMS (ESI-TOF, MeOH)
m/z [M + Na]+ calcd for C19H24N2O6Na 399.1532, found 399.1532;
Rf (AcOEt/petroleum ether 1/1) 0.77.
1
DMAP (77 mg, 0.64 mmol): H NMR (300 MHz, CDCl3) δ 1.35 (s,
9H), 1.57 (s, 3H), 2.50 (m, 2H), 2.60 (s, 3H), 3.25 (m, 2H), 3.74 (s,
3H), 4.80 (br s, 1H), 6.74 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 8.7, 2.4
Hz, 1H), 8.13 (d, J = 8.7 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) δ
24.0 (CH3), 26.4 (CH3), 28.3 (CH3), 34.0 (CH2), 36.0 (CH2), 55.6
(CH3), 77.3 (C), 79.5 (C), 108.2 (CH), 114.3 (CH), 117.9 (CH),
129.5 (C), 132.8 (C), 155.7 (C), 157.5 (C), 170.4 (C), 170.9 (C),
175.4 (C); HRMS (ESI-TOF, MeOH) m/z [M + Na]+ calcd for
C20H26N2O7Na 429.1637, found 429.1635; Rf (AcOEt/CH2Cl2 1/9)
0.67; mp 112−114 °C.
1-Acetyl-3-methyl-2-oxoindolin-3-yl 4-((tert-Butoxycarbonyl)-
amino)butanoate (4c). According to the general procedure, 4c was
obtained as a viscous oil (210 mg, yield: 78%) from 3-hydroxyoxindole
8a (142.0 mg, 0.692 mmol), Boc-NH-(CH2)3-COOH (168.6 mg,
0.830 mmol), DCC (157.5 mg, 0.761 mmol), and DMAP (101.2 mg,
1
0.830 mmol): H NMR (300 MHz, CDCl3) δ 1.34 (s, 9H), 1.56 (s,
1-Acetyl-5-methoxy-3-methyl-2-oxoindolin-3-yl 6-((tert-
Butoxycarbonyl)amino)hexanoate (4h). According to the general
procedure, 4h was obtained as a solid (185.68 mg, yield: 78%) from
hydroxyoxindole 8c (125.9 mg, 0.535 mmol), Boc-NH-(CH2)5-
COOH (148.5 mg, 0.642 mmol), DCC (121.4 mg, 0.588 mmol),
3H), 1.62 (m, 2H), 2.29 (m, 2H), 2.58 (s, 3H), 3.00 (m, 2H), 4.75 (br
s, 1H), 7.12 (t, J = 6.8 Hz, 1H), 7.19−7.27 (m, 2H), 8.16 (d, J = 8.4
Hz, 1H); 13C NMR (75.5 MHz, CDCl3) δ 23.7 (CH3), 24.9 (CH2),
26.3 (CH3), 28.2 (CH3), 30.6 (CH2), 39.3 (CH2), 76.8 (C), 78.9 (C),
116.5 (CH), 121.6 (CH), 125.3 (CH), 128.1 (C), 129.9 (CH), 139.3
(C), 155.8 (C), 170.5 (C), 171.4 (C), 175.3 (C); HRMS (ESI-TOF,
1
and DMAP (78.4 mg, 0.642 mmol): H NMR (300 MHz, CDCl3) δ
1.17−1.27 (m, 2H), 1.34−1.43 (m, 11 H), 1.46−1.50 (m, 5H), 2.18−
H
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The Journal of Organic Chemistry
Article
2.37 (m, 2H), 2.59 (s, 3H), 2.98−3.04 (m, 2H), 3.74 (s, 3H), 4.50
(broad s, 1H), 6.73 (d, J = 2.7 Hz, 1H),), 6.79 (dd, J = 9, 2.7 Hz, 1H),
8.12 (d, J = 9 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) δ 23.9 (CH3),
24.3 (CH2), 26.0 (CH3), 26.4 (CH2), 28.4 (CH3), 29.6 (CH2), 33.4
(CH2), 40.3 (CH2), 55.6 (CH3), 77.2 (C), 79.1 (C), 108.2 (CH),
114.1 (CH), 117.9 (CH), 129.8 (C), 132.9 (C), 156.0 (C), 157.4 (C),
170.5 (C), 171.9 (C), 175.6 (C); HRMS (ESI-TOF, MeOH) m/z [M
+ Na]+ calcd for C23H32N2O7Na 471.2107, found 471.2102; Rf
(AcOEt/CH2Cl2 1/9) 0.64; mp 109−112 °C.
1-Acetyl-3-methyl-2-oxoindolin-3-yl 8-(tert-Butoxycarbonyl)-
amino)-3,6-dioxaoctanoate (4m). According to the general proce-
dure, 4m was obtained (59.1 mg, yield: 51%) as a viscous oil from
hydroxyoxindole 8a (53 mg, 0.258 mmol), Boc-NH-(CH2)2O-
(CH2)2OCH2COOH 9a17 (0.284 mmol), DCC (70.8 mg, 0.343
1
mmol), and DMAP (31.5 mg, 0.258 mmol): H NMR (300 MHz,
CDCl3) δ 1.36 (s, 9H), 1.61 (s, 3H), 2.61 (s, 3H), 3.22 (m, 2H), 3.42
(t, J = 5 Hz, 2H), 3.50−3.59 (m, 4H), 4.07, 4.14 (ABq, JAB = 17 Hz,
2H), 4.91 (br s, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H),
7.31 (t, J = 7.8 Hz, 1H), 8.19 (d, J = 8 Hz, 1H); 13C NMR (75.5 MHz,
CDCl3) δ 23.8 (CH3), 26.5 (CH3), 28.4 (CH3), 40.3 (CH2), 68.0
(CH2), 70.2 (CH2), 70.3 (CH2), 70.9 (CH2), 77.5 (C), 79.2 (C),
116.9 (CH), 121.9 (CH), 125.5 (CH), 127.7 (C), 130.3 (CH), 139.6
(C), 155.9 (C), 168.8 (C), 170.7 (C), 175.1 (C); HRMS (ESI-TOF,
MeOH) m/z [M + Na]+ calcd for C22H30N2O8Na 473.1900, found
473.1901; Rf (AcOEt/petroleum ether 1/1) 0.47.
1-Acetyl-3-(cyanomethyl)-2-oxoindolin-3-yl 3-((tert-
Butoxycarbonyl)amino)propanoate (4i). According to the general
procedure, 4i was obtained as a solid (110.5 mg, yield: 59%) from 3-
hydroxyoxindole 8d (108 mg, 0.469 mmol), Boc-NH-(CH2)2-COOH
(106 mg, 0.56 mmol), and DCC (106 mg, 0.516 mmol) after 5 days at
1
40 °C: H NMR (300 MHz, CDCl3) δ 1.35 (s, 9H), 2.57 (m, 2H),
2.62 (s, 3H), 2.74, 3.05 (ABq, JAB = 16.5 Hz, 2H), 4.75 (br s, 1H), 7.23
(t, J = 8 Hz, 1H), 7.39−7.49 (m, 2H), 8.23 (d, J = 8 Hz, 1H); 13C
NMR (75.5 MHz, CDCl3) δ 26.5 (CH3), 26.7 (CH2), 28.3 (CH3),
34.0 (CH2), 35.9 (CH2), 75.1 (C), 79.7 (C), 113.8 (C), 117.2 (CH),
122.8 (CH), 123.7 (C), 126.1 (CH), 131.8 (CH), 140.0 (C), 155.6
(C), 170.2 (C), 172.4 (C); HRMS (ESI-TOF, MeOH) m/z [M +
Na]+ calcd for C20H23N3O6Na 424.1485, found 424.1486; Rf (AcOEt)
0.71; mp 74−77 °C.
Compound 4n. According to the general procedure, 4n was
obtained (123 mg, yield: 66%) as a viscous oil from hydroxyoxindole
8a (64 mg, 0.312 mmol), Boc-[NH-(CH2)2O-(CH2)2OCH2CO]2OH
9b17 (155 mg, 0.374 mmol), DCC (70.8 mg, 0.343 mmol), and
1
DMAP (45.8 mg, 0.374 mmol): H NMR (300 MHz, CDCl3) δ 1.37
(s, 9H), 1.61 (s, 3H), 2.62 (s, 3H), 3.20−3.25 (m, 2H), 3.38−3.60 (m,
14H), 3.90 (s, 2H), 4.06, 4.15 (ABq, JAB = 16.8 Hz, 2H), 5.15 (br s,
1H), 7.11−7.26 (m, 3H), 7.31 (t, J = 7.89 Hz, 1H), 8.19 (d, J = 8.1 Hz,
1H); 13C NMR (75.5 MHz, CDCl3) δ 23.8 (CH3), 26.6 (CH3), 28.4
(CH3), 38.5 (CH2), 40.3 (CH2), 68.0 (CH2), 67.0 (CH2), 70.1 (CH2),
70.4 (CH2), 70.5 (CH2), 70.8, (CH2) 70.9 (CH2), 77.5 (C), 79.2 (C),
116.9 (CH), 121.9 (CH), 125.5 (CH), 127.7 (C), 130.4 (CH), 139.6
(C), 156.0 (C), 168.7 (C), 170.0 (C), 170.7 (C), 175.1 (C); HRMS
(ESI-TOF, CH2Cl2/MeOH 95/5) m/z [M + Na]+ calcd for
C28H41N3O11Na 618.2633, found 618.2633; Rf (AcOEt/MeOH 9/
1): 0.51.
1-Acetyl-3-(cyanomethyl)-2-oxoindolin-3-yl 6-((tert-
Butoxycarbonyl)amino)hexanoate (4j). According to the general
procedure, 4j was obtained (222 mg, yield: 98%) as a vitreous solid
from hydroxyoxindole 8d (117.8 mg, 0.511 mmol), Boc-NH-(CH2)6-
COOH (142 mg, 0.614 mmol), and DCC (116 mg, 0.562 mmol) after
5 days at 40 °C: 1H NMR (300 MHz, CDCl3) δ 1.25 (m, 2H), 1.28−
1.39 (m, 11 H), 1.53 (m, 2H), 2.32 (m, 2H), 2.61 (s, 3H), 2.72 (d, J =
17.5 Hz, 1H), 3.00−3.08 (m, 3H), 4.48 (br s, 1H), 7.23 (t, J = 8 Hz,
1H), 7.39−7.49 (m, 2H), 8.23 (d, J = 8 Hz, 1H); 13C NMR (75.5
MHz, CDCl3) δ 24.2 (CH2), 25.9 (CH2), 26.5 (CH3), 26.7 (CH2),
28.4 (CH3), 29.6 (CH2), 33.2 (CH2), 40.2 (CH2), 74.7 (C), 79.1 (C),
113.9 (C), 117.1 (CH), 122.7 (CH), 124.0 (C), 126.0 (CH), 131.6
(CH), 140.0 (C), 155.9 (C), 170.2 (C), 171.2 (C), 172.6 (C); HRMS
(ESI-TOF, MeOH) m/z [M + Na]+ calcd for C23H29N3O6Na
466.1954, found 466.1953; Rf (AcOEt/petroleum ether 1/1) 0.60.
Benzyl 3-((6-((tert-Butoxycarbonyl)amino)hexanoyl)oxy)-3-(cya-
nomethyl)-2-oxoindoline-1-carboxylate (4k). According to the
general procedure, 4k was obtained (153 mg, yield: 72%) after 3
days at 45 °C as an amorphous solid from hydroxyoxindole 8e (128.6
mg, 0.399 mmol), Boc-NH-(CH2)5-COOH (121.3 mg, 0.520 mmol),
and DCC (92 mg, 0.45 mmol): 1H NMR (300 MHz, CDCl3) δ 1.15−
1.26 (m, 2H), 1.32−1.42 (m, 11H), 1.46−1.56 (m, 2H), 2.31 (m, 2H),
2.63 (d, J = 17.4 Hz, 1H), 2.96−3.08 (m, 3H), 4.48 (br s, 1H), 5.33,
5.39 (ABq, JAB = 12.3 Hz, 2H), 7.19 (t, J = 7.7 Hz, 1H), 7.29−7.43 (m,
7H), 7.92 (d, J = 8.1 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) δ 24.2
(CH2), 25.9 (CH2), 26.6 (CH2), 28.4 (CH3), 29.6 (CH2), 33.2 (CH2),
40.3 (CH2), 69.1 (CH2), 74.5 (C), 79.1 (C), 114.1 (C), 115.9 (CH),
123.0 (CH), 124.0 (C), 125.6 (CH), 128.2 (CH), 128.6 (CH), 128.7
(CH), 131.6 (CH), 134.6 (C), 139.3 (C), 150.1 (C), 156.0 (C), 170.0
(C), 171.1 (C); HRMS (ESI-TOF, MeOH) m/z [M + Na]+ calcd for
C29H33N3O7Na 558.2216, found 558.2221; Rf (AcOEt/CH2Cl2 5/95)
0.53.
1-(Dimethylcarbamoyl)-3-(cyanomethyl)-2-oxoindolin-3-yl 6-
((tert-Butoxycarbonyl)amino)hexanoate (4l). According to the
general procedure, 4l was obtained as an amorphous solid (170 mg,
yield: 73%) after 3 days at 45 °C from hydroxyoxindole 8f (127.1 mg,
0.49 mmol), Boc-NH-(CH2)5-COOH (138 mg, 0.60 mmol) and DCC
(111 mg, 0.539 mmol): 1H NMR (300 MHz, CDCl3) δ 1.18−1.26 (m,
2H), 1.32−1.40 (m, 11H), 1.42−1.55 (m, 2H), 2.31 (m, 2H), 2.6−
3.06 (m, 10H), 4.69 (br s, 1H), 7.08−7.15 (m, 2H), 7.33 (dd, J = 8,
1.5 Hz, 1H), 7.43 (d, J = 7.2 Hz, 1H); 13C NMR (75.5 MHz, CDCl3)
δ 24.00 (CH2), 25.67 (CH2), 26.18 (CH2), 28.17 (CH3), 29.28
(CH2), 33.07 (CH2), 36.62 (CH3), 37.88 (CH3), 39.96 (CH2), 74.77
(C), 78.70 (C), 112.95, 114.16 (C), 122.89, 124.09 (C), 124.29,
131.07, 139.82 (C), 150.31 (C), 155.74 (C), 169.20 (C), 170.92 (C);
HRMS (ESI-TOF, MeOH) m/z [M + Na]+ calcd for C24H32N4O6Na
495.2219, found 495.2221; Rf (AcOEt/petroleum ether 1/1) 0.50.
tert-Butyl rel-(3-(((S)-2-(R-1-Acetyl-2-oxo-3-phenylindolin-3-yl)-2-
phenylethyl)amino)-3-oxopropyl)carbamate (4o). Step 1: To a
mixture of nitro-oxindole 6d (130 mg, 0.364 mmol) and NiCl2 (96
mg, 0.74 mmol) in absolute ethanol (0.7 mL) was added sodium
borohydride (233 mg, 6.16 mmol). The black mixture was stirred at
room temperature. The progress of the reaction was monitored by
TLC. Three further portions of sodium borohydride (50 mg, 1.3
mmol) were added after stirring for 3, 5, and 7 h, respectively. After
dilution with CH2Cl2 (30 mL), the mixture was washed with 10%
aqueous sodium carbonate. The organic phase was dried over sodium
sulfate and then concentrated in vacuo. Step 2: To the resulting
residue in CH2Cl2 (0.7 mL) were added 1-ethyl-3-(3-
(dimethylamino)propyl)carbodiimide (EDC) (64 μL, 0.364 mmol)
and Boc-NH(CH2)2CO2H (69.6 mg, 0.368 mmol). The mixture was
stirred overnight, diluted with CH2Cl2 (20 mL), and washed with 10%
aqueous citric acid and then water. After drying on sodium sulfate and
concentration in vacuo, the residue was chromatographed over silica
gel (5 g, eluent 7/3 CH2Cl2/AcOEt) to afford tert-butyl rel-(3-oxo-3-
(((S)-2-((R)-2-oxo-3-phenylindolin-3-yl)-2-phenylethyl)amino)-
1
propyl)carbamate (100 mg, 55% yield from 6d) as a white solid: H
NMR (300 MHz, CDCl3) δ 1.33 (s, 9H), 1.94−2.05 (m, 2H), 3.13,
3.17 (ABq, JAB = 6 Hz, 2H), 3.73 (t, J = 6 Hz, 2H), 4.13 (t, J = 7.8 Hz,
1H), 4.99 (br s, 1H), 5.74 (t, J = 5.7 Hz, 1H), 6.61 (d, J = 7.5 Hz, 1H),
6.84−7.26 (m, 11H), 7.57 (d, J = 7.5 Hz, 2H), 8.50 (br s, 1H); 13C
NMR (75.5 MHz, CDCl3) δ 28.4 (CH3), 36.1 (CH2), 36.7 (CH2),
38.9 (CH2), 51.4 (CH), 60.2 (C), 79.3 (C), 109.8 (CH), 122.2 (CH),
125.9 (CH), 127.2 (CH), 127.3 (CH), 127.5 (CH), 127.8 (CH),
128.1 (CH), 128.7 (CH), 129.5 (CH), 131.3 (C), 136.7 (C), 138.3
(C), 139.9 (C), 156.1 (C), 171.5 (C), 179.7 (C); HRMS (ESI-TOF,
MeOH) m/z [M + Na]+ calcd for C30H33N3O4Na 522.2369, found
522.2369; Rf (AcOEt/petroleum ether 1/1) 0.18; mp 125−132 °C.
Step 3: To tert-butyl rel-(3-oxo-3-(((S)-2-((R)-2-oxo-3-phenylindolin-
3-yl)-2-phenylethyl)amino)propyl)carbamate (48.5 mg, 0.097 mmol)
in CH2Cl2 (0.2 mL) were added DMAP (14.3 mg, 0.012 mmol), Et3N
(31 μL, 0.21 mmol) and acetyl chloride (16 μL, 0.21 mmol). The
resulting mixture was stirred for 2.5 h at room temperature, diluted by
CH2Cl2, and washed by water. After drying on sodium sulfate,
concentration in vacuo, and chromatography over silica gel (6g, eluent
I
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The Journal of Organic Chemistry
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95/5 CH2Cl2/AcOEt), the expected product 4o (32.9 mg, 63% yield)
was obtained as a white amorphous solid: 1H NMR (300 MHz,
CDCl3, 1/9 mixture of Boc rotamers) δ 1.18, 1.32 (two s, 9H), 2.02 (t,
J = 6 Hz, 2H), 2.64 (s, 3H), 3.13, 3.17 (ABq, JAB = 6 Hz, 2H), 3.65−
3.82 (m, 1H), 3.85−3.94 (m, 1H), 4.12 (dd, J = 11.1, 4.5 Hz, 1H),
4.88 (br s, 1H), 5.32 (br s, 1H), 6.84−6.87 (m, 2H), 6.97−7.11 (m,
5H), 7.15−7.25 (m, 2H), 7.30−7.35 (m, 2H), 7.50−7.54 (m, 2H),
7.85−7.88 (m, 1H); 13C NMR (75.5 MHz, CDCl3) δ 27.0 (CH3),
27.8 (minor CH3), 28.4 (CH3), 36.1 (CH2), 36.5 (CH2), 38.8 (CH2),
51.7 (CH), 60.6 (C), 79.3 (C), 116.3 (CH), 124.7 (CH), 124.9 (CH),
127.1 (CH), 127.8 (CH), 128.1 (CH), 128.4 (CH), 129.1 (CH),
129.2 (CH), 130.6 (C), 135.6 (C), 138.0 (C), 138.8 (C), 155.9 (C),
170.4 (C), 171.6 (C), 178.9 (C); HRMS (ESI-TOF, MeOH) m/z [M
+ Na]+ calcd for C32H35N3O5Na 564.2474, found 564.2470; Rf
(AcOEt/petroleum ether 1/1) 0.40.
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X.-J. Tetrahedron Lett. 2013, 54, 300.
ASSOCIATED CONTENT
(6) For a similar isomerization leading to γ-lactones, see: Liu, Y.-L.;
Wang, B.-L.; Cao, J.-J.; Chen, L.; Zhang, Y.-X.; Wang, C.; Zhou, J. J.
Am. Chem. Soc. 2010, 132, 15176.
(7) (a) Khuzhaev, V. U. Chem. Nat. Compd. 2004, 40, 516. (b) Chen,
W.-B.; Du, X.-L.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Tetrahedron
2010, 66, 1441.
■
S
* Supporting Information
1
X-ray data of 2b and copies of H and 13C spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(8) Takayama, H.; Matsuda, Y.; Masubuchi, K.; Ishida, A.; Kitajima,
M.; Aimi, N. Tetrahedron 2004, 60, 893.
AUTHOR INFORMATION
■
(9) Inoue, M.; Sakazaki, H.; Furuyama, H.; Hirama, M. Angew. Chem.,
Int. Ed. 2003, 42, 2654.
Corresponding Author
*E-mail: joelle.vidal@univ-rennes1.fr.
(10) For reviews on lactam synthesis, see: (a) Natural Lactones and
Lactams: Synthesis, Occurrence and Biological Activity; Janecki, T., Ed.;
Wiley: New York, 2013. (b) Smith, M. B. In Science of Synthesis;
Weinreb, S., Ed.; Georg Thieme Verlag: Stuttgart, 2005; Vol. 21, p
647. (c) Nubbemeyer, U. In Stereoselective Heterocyclic Synthesis III;
Metz, P., Ed.; Topics in Current Chemistry; Springer-Verlag: Berlin,
2001; Vol. 216, p 125.
(11) For difficult medium-sized lactam synthesis, see, for instance:
(a) Ha, K.; Monbaliu, J-C. M.; Williams, B. C.; Pillai, G. G.; Ocampo,
C. E.; Zeller, M.; Stevens, C. V.; Katritzky, A. R. Org. Biomol. Chem.
2012, 10, 8055. (b) Sharma, A.; Appukkuttan, P.; Van der Eycken, E.
Chem. Commun. 2012, 48, 1623. (c) David, O.; Meester, W. J. N.;
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
D.S. thanks the French Ministry of Research for a Ph.D.
fellowship. Thierry Roisnel and Vincent Dorcet (Centre de
́
diffractometrie X, Institut des Sciences Chimiques de Rennes)
are acknowledged for the X-ray structure determination.
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