Synthesis of Chiral Tertiary α,α-Difluoromethyl Carbinols by Cu-Catalyzed Asymmetric Propargylation

Article abstract of DOI:10.1002/chem.201904543

Chiral α,α-difluoromethyl carbinols are recurring structural motifs in many therapeutic agents. Despite the indubitable interest in the catalytic asymmetric synthesis of such compounds, this research field still remains largely underexplored. Herein, an efficient approach to a range of chiral homopropargylic α,α-difluoromethyl carbinols has been developed, through a Cu-catalyzed enantioselective propargylation of α,α-difluoroketones with (pinacolato)allenylboron. In the presence of a cuprous complex, generated in situ from CuCl and a spiroketal-based diphosphine (SKP) ligand, a variety of aryl-, heteroaryl-, alkyl-, alkynyl, alkenyl, or benzyloxycarbonyl-substituted α,α-difluoromethyl carbinols were obtained in 75–99 % yields with 84–98 % ee values. The catalytic system was further investigated using a combined dynamic NMR spectroscopic, X-ray crystallographic, and non-linear effect studies. The origin of the enantioselectivity was rationalized based on DFT calculations. Finally, several efficient transformations were showcased to highlight the utilities of the protocol in synthesis of complex compounds bearing an α,α-difluoromethyl carbinol moiety.

Full text of DOI:10.1002/chem.201904543

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. 2019, 84, 2012−2021
Schmidt Reaction of ω‑Azido Valeryl Chlorides Followed by
Intermolecular Trapping of the Rearrangement Ions: Synthesis of
Assoanine and Related Pyrrolophenanthridine Alkaloids
Shao-Lei Ding, Yang Ji,† Yan Su, Rui Li, and Peiming Gu*
Department of Chemistry, Ningxia University, Yinchuan 750021, China
S
* Supporting Information
ABSTRACT: The Schmidt reaction of ω-azido valeryl chlorides in
the presence of an additional nucleophile was explored. The arenes,
alcohols, and amines were demonstrated as the intermolecular
trapping reagents for isocyanate ion and N-acyliminium ion from
the Schmidt rearrangement, affording the corresponding products
with moderate to excellent yields. Two 2-oxoindoles from the reaction
were successfully converted into four natural alkaloids, namely,
assoanine, anhydrolycorine, oxoassoanine, and anhydrolycorinone.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
́
The reaction of ω-azido valeryl chloride with benzene was
selected for the initial exploration, and the ω-azido valeryl
chloride was in situ prepared from 5-azidopentanoic acid 1a5
with oxalyl chloride (Table 1). According to our previous
research, generation of isocyanate ion I and N-acyliminium ion
II would be efficient under acidic conditions. It might be very
reasonable to apply the nucleophile after the ω-azido valeryl
chloride was treated with the acid promoter. By doing this, the
competitive Friedel−Crafts acylation of the acyl chloride with
benzene could be avoided. In consideration of the potential
chelation between the nitrogen-containing product and the
acid promoter, generally the reaction was examined with 2.0
equiv of the promoter, and excessive benzene was used to
ensure that the trapping reaction could be efficient.
Several acid promoters including TiCl4, SnCl4, BF3·OEt2,
AlCl3, EtAlCl2, TFA, and TfOH were examined. In screening
the acid promoters, we found that in most cases the ω-azido
acyl chloride was consumed in 15 min when the acid promoter
was applied, so benzene was added after that. The capture
process with 5.0 equiv of benzene seemed to be very slow, and
all of the trapping reactions were kept for 46 h (entries 1−7,
Table 1). TfOH was shown as a good candidate, where the
benzamide 3aa and lactam 4aa were produced in a ratio of
about 1.3/1.0 with a combined yield of 78% (entry 7, Table 1).
Both the 3aa and 4aa were known compounds, and the NMR
data were identified with those reported in the literature.6,7 If
the capture process was shortened to 22 h, formation of 3aa
and 4aa was slightly reduced (entry 8 vs entry 7, Table 1). The
The Schmidt−Aube reaction is involved with the rearrange-
ment of alkyl azides with ketones or aldehydes (Scheme 1),
and it has been used as a powerful strategy for synthesis of
various N-heterocycles.1,2 The analogue reaction of alkyl azides
with acyl chlorides was reported in our group, and it proceeded
through the N-diazonium ion amide intermediate, which was
different from the Schmidt−Aube reaction. Rearrangement of
3
́
the intermediate would produce isocyanate ion and N-
acyliminium ion as the primary products. Therefore, a
nucleophile was preinstalled in the ω-azido acyl chloride for
intramolecular capture of the ions, resulting in electroneutral
products for isolation. In the meantime, Chaturvedi’s group
reported4 that the ω-azido acyl chlorides and arenes reacted
through an intermolecular Friedel−Crafts acylation followed
́
by an intramolecular Schmidt−Aube reaction, producing N-
aryl lactams with good to excellent yields (Scheme 1). The
similar hypothesis for the process had been excluded with the
reaction of aryl substituted ω-azido acyl chlorides in our
previous research,3a where the intramolecular Friedel−Crafts
acylation failed in competition with the intramolecular Schmidt
reaction of alkyl azides with acyl chlorides. It made it confusing
that the intermolecular Friedel−Crafts acylation was preferred
over the intramolecular Schmidt reaction in Chaturvedi’s
research, where only catalytic Lewis acid was employed. To
clarify it, we reported here the Schmidt reaction of ω-azido
valeryl chlorides followed by trapping the rearrangement ions
with several different nucleophiles (arenes, alcohols, and
amines) and application of the conversion in synthesis of
assoanine and related alkaloids.
Received: November 26, 2018
Published: January 14, 2019
© 2019 American Chemical Society
2012
DOI: 10.1021/acs.joc.8b03018
J. Org. Chem. 2019, 84, 2012−2021

The Journal of Organic Chemistry
Article
1), in which the benzamide 3aa and lactam 4aa were isolated
in 51 and 35% yield from the reaction promoted by 2.0 equiv
of TfOH for 46 h. With these two cases, we did not observe
any aromatic ketone from the competitive Friedel−Crafts
acylation.
Scheme 1. Reaction of ω-Azido Acid Chloride with an
Arene
After demonstrating the process, a series of nucleophiles 2
including arenes, alcohols, and amines were examined with the
reaction of 5-azidopentanoic acid 1a (Table 2). Three arenes
were further explored with 1a using the conditions of entry 11
in Table 1. When the p-xylene 2b was used, aryl amide 3ab and
lactam 4ab were produced in a ratio of 35/38 with the
combined yield of 73% (entry 1, Table 2). However, the
trapping reaction with 1,4-dichlorobenzene 2c gave lactam 4ac
as a sole product with 38% yield, indicating only the N-
acyliminium ion is captured (entry 2, Table 2), where the
isocyanate ion might be hydrolyzed into pyrrolidine and lost in
the workup procedure. The reaction with naphthalene 2d was
successful, and the 1-naphthyl amide 3ad and lactam 4ad were
observed with a combined yield of 67% (entry 3, Table 2).
Further, the oxygen nucleophiles and nitrogen nucleophiles
were employed with the rearrangement of 1a (entries 4−7,
Table 2), where the TfOH was applied before these
nucleophiles to avoid the reaction of the acyl chloride with
alcohols and amines. The reaction of 1a and ethanol 2e
afforded the ethyl carbamate 3ae in a yield of 58%, and in the
meantime, 2-pyrrolidinone 4ae was isolated with a yield of
15%. 1-Hexanol 2f was also employed for trapping the reaction
of 1a, and the carbamate 3af and 2-pyrrolidinone 4af were
isolated with 37 and 36% yields, respectively. Only the
carbamides 3ag and 3ah could be isolated when the nitrogen
nucleophiles 2g and 2h were used as the nucleophiles, and they
were both derived from the capture of isocyanate ion.
Table 1. Optimization of the Reaction of 5-Azidopentanoic
Acid 1a and Benzene 2a
a
Then, the 5-azido-2-ethylpentanoic acid 1b and 5-azido-4-
ethylpentanoic acid 1c were investigated (Table 3). 1,2-
Migration of the methine carbon would be preferred over the
methylene carbon;3a,b therefore, an isocyanate ion would be
expected as the major one from the Schmidt reaction of 1b.
The inseparable benzamide 3ba and lactam 4ba in a ratio of 6/
1 were obtained with 72% yield when the benzene 2a was used
as the capture nucleophile for the Schmidt reaction of 1b
(entry 1, Table 3). Only the carbamate 3bf from isocyanate ion
could be separated if the 1-hexanol 2f was applied with the
reaction of 1b (entry 2, Table 3), and similar results were
observed with butanamine 2g and piperidine 2h (entries 3 and
4, Table 3), which indicated that the trapping of N-
acyliminium ion with oxygen nucleophiles and nitrogen
nucleophiles was a bit difficult or the corresponding products
were unstable under the conditions. By contrast, the N-
acyliminium ion intermediate would be mainly participated
from the reaction of 1c, and it could be quenched by benzene
for 46 h with 82% yield (entry 5, Table 3). The capture of the
major N-acyliminium ion and the trace isocyanate ion from the
reaction of 1c could be both achieved with the p-xylene 2b,
where the aryl amide 3cb and lactam 4cb were afforded in a
combined yield of 79% (entry 6, Table 3). The trapping
reaction of 1c with 1,4-dichlorobenzene 2c gave amide 4cc
with only moderate yield (entry 7, Table 3).
b
c
entry acid promoter reaction time (h) 3aa/4aa combined yield (%)
1
2
3
4
5
6
7
8
TiCl4
SnCl4
BF3·OEt2
AlCl3
EtAlCl2
TFA
TfOH
TfOH
TfOH
TfOH
TfOH
46
46
46
46
46
46
46
22
46
46
46
46
-/37
6/19
-/-
-/24
-/-
37
25
0
24
0
-/-
0
44/34
36/26
34/28
43/34
51/35
53/32
78
62
62
77
86
85
d
9
e
10
11
12
f
ef
,
TfOH
a
Treatment of 1a (1.0 mmol) in DCM (1.5 mL) with (COCl)2 (1.4
mmol) at 30 °C for 1.5 h followed with the acid (2.0 equiv) promoter
at 0 °C and then benzene 2a (5.0 mmol) was applied and kept the
b
mixture at refluxing for capture reaction. Time for the capture
c
d
process. Isolated combined yield. Benzene (3.0 equiv) employed.
TfOH (4.0 equiv) employed. Benzene was applied before TfOH.
e
f
Schmidt reaction of the 2-(2-(azidomethyl)phenyl)acetic
acid 1d8 was also explored (Scheme 2). The TfOH-promoted
reaction of 1d was quenched with benzene at refluxing
dichloromethane, and the 1-benzyl-2-oxoindole 4da was
obtained with 96% yield, indicating the exclusive migration
of aryl group in the process of Schmidt reaction. Then, the 1,2-
conversion was dropped if the benzene was cut down (entry 9,
Table 1). Even if more TfOH was employed, the yields for 3aa
and 4aa were not improved (entry 10, Table 1). To our great
surprise, the reaction could be a bit more efficient if the
benzene was employed before TfOH (entries 11 and 12, Table
2013
DOI: 10.1021/acs.joc.8b03018
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Table 2. Schmidt Reaction of 1a Followed by Trapping the
Rearrangement Ions with Nucleophiles
Table 3. Schmidt Reaction of 1b and 1c Followed by
a
a
Trapping the Rearrangement Ions with Nucleophiles
a
Treatment of 1b or 1c (1.0 mmol) in DCM (1.5 mL) with (COCl)2
(1.4 mmol) at 30 °C for 1.5 h followed with TfOH (2.0 mmol) at 0
°C and then the corresponding nucleophile 2 (5.0 mmol) was applied
a
Treatment of 1a (1.0 mmol) in DCM (1.5 mL) with (COCl)2 (1.4
mmol) at 30 °C for 1.5 h followed with TfOH (2.0 mmoL) at 0 °C
and then nucleophile 2 (5.0 mmol) was applied and kept the mixture
b
and kept the mixture at refluxing for capture reaction. Time for the
b
c
at refluxing for capture reaction. Time for the capture process.
capture process. Isolated combined yield and ratio of 3 and 4.
c
d
d
Isolated combined yield and ratio of 3 and 4. TfOH (4.0 equiv)
TfOH (4.0 equiv) employed and the capture reaction at room
employed and the capture reaction at room temperature.
temperature.
dimethoxybenzene 2i, 4-bromo-1,2-dimethoxybenzene 2j, 5-
bromobenzo[d][1,3]dioxole 2k, and 4-iodo-1,2-dimethoxyben-
zene 2l were employed for trapping the promised N-
acyliminium ion, and all gave the corresponding 2-oxoindoles
with good to excellent yields.
To demonstrate the synthetic utility, the 2-oxoindoles 4dj
and 4dk were efficiently reduced by 9-BBN,9 and the crude
reaction mixtures were further treated with NaBH3CN,10
affording the indolines 5dj and 5dk with 88 and 90% yields,
respectively. Then, Harayama’s procedure11 was applied for
the biaryl coupling reaction of the indoline 5dj, and it gave the
pyrrolophenanthridine alkaloid assoanine 6a11,12 in 46% yield
and oxoassoanine 7a13 in 14% yield. Similarly, the Pd-catalyzed
coupling of 5dk furnished the anhydrolycorine 6b14 in 52%
yield and anhydrolycorinone 7b15 in 14% yield. Furthermore,
assoanine 6a and anhydrolycorine 6b could be oxidized with
2014
DOI: 10.1021/acs.joc.8b03018
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Article
4.13 (q, J = 7.2 Hz, 2 H), 3.29 (t, J = 6.4 Hz, 2 H), 2.34 (t, J = 7.2 Hz,
2 H), 1.61−1.73 (m, 4 H), 1.26 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR
(CDCl3, 100 MHz, plus APT) δ (up) 173.0, 60.3, 51.0, 33.6, 28.2,
22.0, δ (down) 14.1. To a stirred solution of the above ethyl 5-
azidopentanoate 9a (5.14 g, 30.0 mmol) in the combined solvent
(THF/H2O = 1/1, 200 mL) was added LiOH·H2O (12.59 g, 300.0
mmol), and the mixture was heated to 80 °C for 24 h. Then, the
reaction mixture was cooled to room temperature and treated with 1
N HCl for adjusting the mixture to pH < 3. The mixture was extracted
by EtOAc (40 mL × 3), washed with brine (10 mL × 3), dried over
Na2SO4, and concentrated, and then, the residue was purified by flash
column chromatography to afford the 5-azidopentanoic acid 1a as a
light yellow oil (4.18 g, 96% yield from 9a). 1a: known compound,16
Rf = 0.57 (EtOAc/PE = 1/5); 1H NMR (CDCl3, 400 MHz) δ 3.31 (t,
J = 6.4 Hz, 2 H), 2.41 (t, J = 7.2 Hz, 2 H), 1.65−1.77 (m, 4 H);
13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 179.8, 51.1,
Scheme 2. Schmidt Reaction of 1d and Synthesis of
Assoanine and Related Alkaloids
a
a
Reaction conditions: (a) (COCl)2, then 2, TfOH, CH2Cl2; (b) 9-
BBN, THF; (c) NaBH3CN, AcOH; (d) Pd(OAc)2, PCy3, K2CO3,
DMF; (e) KMnO4, NaOH, CH2Cl2.
33.5, 28.3, 21.9; IR (film) 2943, 2099, 1709, 1277 cm−1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C5H9N3O2Na 166.0587, found
166.0588.
KMnO4 into oxoassoanine 7a in 63% yield and anhydrolycor-
inone 7b in 61% yield.14b
Ethyl 5-Bromo-2-ethylpentanoate and Ethyl 5-Iodide-2-ethyl-
pentanoate (8b). To a stirred solution of N,N-diisopropylamine
(2.64 g, 26.0 mmol) in dry THF (60 mL) at 0 °C was added a
solution of n-BuLi (15.0 mL, 1.6 M in hexane, 24.0 mmol). The
reaction mixture was kept at 0 °C for 15 min, and then, it was cooled
to −78 °C for 30 min. A solution of ethyl 5-bromopentanoate 8a
(5.02 g, 24 mmol) in THF (10 mL) was added dropwise into the
mixture. The reaction mixture was kept at −78 °C for 45 min, and
then, a solution of iodoethane 10 (3.18 g, 20.0 mmol) in THF (10
mL) was added dropwise. The mixture was slowly warmed to room
temperature and kept stirring for overnight; then, it was quenched
with saturated NH4Cl (60 mL), extracted with EtOAc (40 mL × 3),
washed with brine (20 mL × 3), dried over anhydrous Na2SO4, and
concentrated; then, the residue was purified by flash column
chromatography to afford a mixture of ethyl 5-bromo-2-ethyl-
pentanoate and ethyl 5-iodide-2-ethylpentanoate 8b as a colorless
oil (3.26 g, 61% yield from 8a). Mixture of 8b: Rf = 0.56 (EtOAc/PE
= 1/3); 1H NMR (CDCl3, 400 MHz) (iodide/bromide = about 1/2)
δ 4.14 (q, J = 7.2 Hz, 2 H for bromide and iodide), 3.38−3.42 (m, 2
H for bromide), 3.16−3.19 (m, 2 H for iodide), 2.26−2.30 (m, 1 H
for bromide and iodide), 1.51−1.87 (m, 6 H for bromide and iodide),
1.26 (t, J = 7.2 Hz, 3 H for bromide and iodide), 0.903 (t, J = 7.2 Hz,
3 H for bromide and iodide); 13C{1H} NMR (CDCl3, 100 MHz, plus
APT) δ (up) 175.9 (bromide and iodide), 60.3 (bromide and iodide),
33.5 (bromide), 32.8 (iodide), 31.3 (iodide), 30.6 (bromide), 30.5
(bromide and iodide), 25.6 (bromide), 6.4 (iodide), δ (down) 46.5
(bromide), 46.4 (iodide), 14.5 (bromide and iodide), 11.8 (bromide
and iodide); IR (film) 1732 cm−1; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C9H17BrO2Na 259.0304, found 259.0307.
In summary, the Schmidt reaction of several ω-azido valeryl
chlorides was well demonstrated, and the intermolecular
capture of isocyanate ion and N-acyliminium ion from the
rearrangement with variable arenes, alcohols, and amines was
explored. Generally, the isocyanate ion could be efficiently
captured with oxygen nucleophiles and nitrogen nucleophiles,
and the arenes were excellent nucleophiles for trapping the N-
acyliminium ion. Two lactam products were readily converted
into four alkaloids, and they were assoanine, anhydrolycorine,
oxoassoanine, and anhydrolycorinone, respectitively. The
conversion might be very useful in synthesis of natural
products, and further application was explored in the
laboratory.
EXPERIMENTAL SECTION
■
All reagents were purchased from Titan, Acros, Sigma-Aldrich, Alfa-
Aesar, Aladdin, or Adamas, and they were used as received. All
solvents were distilled using the classic method before use. The
reactions were monitored by thin layer chromatography (TLC) on 3.0
cm × 10 cm, 200−250 μm analytical plates coated with silica gel 60
F254, and the plates were purchased from Qingdao Haiyang
Chemical Co. Ltd. The thin layer chromatography plates were
visualized by exposure to ultraviolet light (UV, 254 nm) or
phosphomolybdic acid. Purification of the synthetic compounds by
flash column chromatography employed neutral silica gel (200−300
mesh or 300−400 mesh), which was purchased from Qingdao
Haiyang Chemical Co. Ltd. The NMR spectra were recorded on a
Bruker 400 MHz spectrometer, and tetramethylsilane (δ = 0 and δ =
5-Azido-2-ethylpentanoic Acid (1b). To a stirred mixture of ethyl
5-bromo-2-ethylpentanoate and ethyl 5-iodide-2-ethylpentanoate 8b
(2.65 g, 10.5 mmol) in DMF (45 mL) was added NaN3 (2.05 g, 31.5
mmol), and the mixture was heated to 80 °C (oil bath) for 11 h.
Then, the mixture was treated with water (10 mL) and extracted by
CH2Cl2 (50 mL × 3). The combined organic phase was washed with
water (20 mL × 3), dried over anhydrous Na2SO4, and concentrated;
then, the residue was purified by flash column chromatography to
afford the ethyl 5-azido-2-ethylpentanoate 9b as a light yellow oil
1
7.26) was used as an internal standard for H NMR (400 MHz) and
CDCl3 (δ = 77.16) for 13C{1H} NMR (100 MHz).
13C{1H} NMR Was Performed with an APT Technique
[Methyl and Methine Were Assigned down; Methylene and
Quaternary Carbon Were Assigned up]. The IR spectra were
recorded on a PerkinElmer spectrometer with a potassium bromide
crystal optic rectangle. High-resolution mass spectra (HRMS) were
measured on a LTQ Orbitrap XL Domain 35A (Thermo Fisher)
spectrometer, and electrospray ionization (ESI) was used as the ion
source. All alkylation reactions and the Schmidt reactions were carried
out in dry reaction vessels or flasks under a positive pressure of
nitrogen or argon.
1
(1.92 g, 92% yield from 8b). 9b: Rf = 0.73 (EtOAc/PE = 1/10); H
NMR (CDCl3, 400 MHz) δ 4.14 (q, J = 7.2 Hz, 2 H), 3.27 (t, J = 6.4
Hz, 2 H), 2.26−2.28 (m, 1 H), 1.50−1.70 (m, 6 H), 1.26 (t, J = 7.2
Hz, 3 H), 0.898 (t, J = 7.6 Hz 3 H); 13C{1H} NMR (CDCl3, 100
MHz, plus APT) δ (up) 175.8, 60.3, 51.3, 29.0, 26.8, 25.6, δ (down)
46.8, 14.4, 11.8. The 5-azido-2-ethylpentanoic acid 1b (1.33 g, 81%
yield from 9b) was prepared from the above ethyl 5-azido-2-
ethylpentanoate 9b (1.92 g, 9.6 mmol) with LiOH·H2O (8.08 g,
193.0 mmol) in the combined solvent (THF/H2O = 1/1, 80 mL) by
the above procedure for preparation of 1a, and the reaction time was
48 h. 1b: Rf = 0.50 (EtOAc/PE = 1/5); 1H NMR (CDCl3, 400 MHz)
δ 3.30 (t, J = 6.4 Hz, 2 H), 2.31−2.35 (m, 1 H), 1.54−1.72 (m, 6 H),
0.956 (t, J = 7.6 Hz, 3 H); 13C{1H} NMR (CDCl3, 100 MHz, plus
5-Azidopentanoic Acid (1a). To a stirred solution of ethyl 5-
bromopentanoate 8a (6.27 g, 30.0 mmol) in the combined solvent
(MeOH/H2O = 1/1, 40 mL) was added NaN3 (2.46 g, 37.8 mmol),
and then, the mixture was heated to 75 °C for 5.5 h. The reaction
mixture was extracted by CH2Cl2 (40 mL × 3), and the combined
organic phase was washed with water (20 mL × 3), dried over
anhydrous Na2SO4, and concentrated to afford the ethyl 5-
azidopentanoate 9a as a colorless oil (5.08 g, 98% yield from 8a).
1
9a: Rf = 0.67 (EtOAc/PE = 1/1); H NMR (CDCl3, 400 MHz) δ
2015
DOI: 10.1021/acs.joc.8b03018
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APT) δ (up) 182.6, 51.3, 28.7, 26.8, 25.3, δ (down) 46.6, 11.7; IR
(film) 2967, 2099, 1706, 1460, 1259 cm−1; HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C7H13N3O2Na 194.0900, found 194.0902.
Diethyl 2-(2-Cyanoethyl)malonate (13). To a stirred solution of
diethyl malonate 11 (5.77 g, 36.0 mmol) in dry THF (80 mL) was
added NaH (60% dispersion in oil, 1.68 g, 42.0 mmol) at room
temperature. After 1 h, a solution of 3-bromopropanenitrile 12 (5.34
g, 40.0 mmol) in dry THF (20 mL) was added dropwise. Then, the
mixture was allowed to vigorously stir for 16 h. The reaction mixture
was quenched by slow addition of saturated NH4Cl (20 mL),
extracted with EtOAc (60 mL × 3), washed with brine (20 mL × 3),
dried over anhydrous Na2SO4, and concentrated; then, the residue
was purified by flash column chromatography to afford the diethyl 2-
(2-cyanoethyl)malonate 13 (6.03 g, 78% yield from 11). 13: known
7.37 (d, J = 8.0 Hz, 2 H), 3.99 (dd, J = 10.0 and 3.6 Hz, 1 H), 3.92
(dd, J = 10.0 and 4.8 Hz, 1 H), 2.46 (s, 3 H), 2.32 (t, J = 6.8 Hz, 2 H),
1.64−1.75 (m, 3 H), 1.32−1.40 (m, 2 H), 0.843 (t, J = 7.2 Hz, 3 H);
13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 145.2, 132.6,
119.3, 70.8, 26.4, 22.9, 14.8, δ (down) 130.1 (2), 127.9 (2), 38.2,
21.7, 10.8; IR (film) 2246, 1176 cm−1; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C14H19NO3SNa 304.0978, found 304.0980.
4-(Azidomethyl)hexanenitrile (18). To a stirred solution of 4-
cyano-2-ethylbutyl 4-methylbenzenesulfonate 17 (3.38 g, 12.0 mmol)
in DMF (70 mL) was added NaN3 (1.56 g, 24.0 mmol), and the
mixture was heated to 50 °C (oil bath) for 10 h. Then, the mixture
was treated with water (10 mL) and extracted by EtOAc (30 mL ×
3). The combined organic phase was washed with water (20 mL × 3)
and brine (20 mL), dried over anhydrous Na2SO4, and concentrated;
then, the residue was purified by flash column chromatography to
afford the 4-(azidomethyl)hexanenitrile 18 as a light yellow oil (1.78
compound,17 Rf = 0.29 (EtOAc/PE = 1/5); H NMR (CDCl3, 400
1
MHz) δ 4.18−4.27 (m, 4 H), 3.48−3.52 (m, 1 H), 2.49−2.52 (m, 2
H), 2.22−2.27 (m, 2 H), 1.28 (t, J = 7.2 Hz, 6 H); 13C{1H} NMR
(CDCl3, 100 MHz, plus APT) δ (up) 168.3 (2), 118.6, 62.1 (2), 24.6,
15.2, δ (down) 50.2, 14.1 (2).
1
g, 97% yield from 17). 18: Rf = 0.63 (EtOAc/PE = 1/1); H NMR
(CDCl3, 400 MHz) δ 3.40 (dd, J = 12.4 and 4.0 Hz, 1 H), 3.31 (dd, J
= 12.4 and 5.2 Hz, 1 H), 2.40 (t, J = 7.2 Hz, 2 H), 1.64−1.76 (m, 3
H), 1.37−1.43 (m, 2 H), 0.941 (t, J = 7.6 Hz, 3 H); 13C{1H} NMR
(CDCl3, 100 MHz, plus APT) δ (up) 119.5, 53.9, 27.3, 23.9, 14.9, δ
(down) 38.7, 10.9; IR (film) 2246, 2099 cm−1; HRMS (ESI-TOF)
m/z [M + Na]+ calcd for C7H12N4Na 175.0954, found 175.0953.
4-(Azidomethyl)hexanoic Acid (1c). The 4-(azidomethyl)-
hexanenitrile 18 (1.78 g, 11.7 mmol) was added into the combined
solvent (EtOH/15% aqueous NaOH = 1/1, 90 mL), and it was
heated to refluxing for 10 h. Then, the reaction mixture was cooled to
room temperature and treated with 1 N HCl for adjusting the mixture
to pH < 3. The mixture was extracted by EtOAc (30 mL × 3), washed
with brine (20 mL × 3), dried over Na2SO4, and concentrated; then,
the residue was purified by flash column chromatography to afford the
4-(azidomethyl)hexanoic acid 1c as a light yellow oil (1.77 g, 89%
Diethyl 2-(2-Cyanoethyl)-2-ethylmalonate (14). The diethyl 2-(2-
cyanoethyl)-2-ethylmalonate 14 (5.42 g, 80% yield from 13) was
prepared from the diethyl 2-(2-cyanoethyl)malonate 13 (6.03 g, 28.3
mmol) with iodoethane 10 (4.80 g, 30.2 mmol) in the presence of
NaH (60% dispersion in oil, 1.17 g, 29.3 mmol) according to the
above procedure for preparation of 13. 14: known compound,18 Rf =
1
0.37 (EtOAc/PE = 1/5); H NMR (CDCl3, 400 MHz) δ 4.18−4.25
(m, 4 H), 2.37−2.41 (m, 2 H), 2.21−2.25 (m, 2 H), 1.95 (q, J = 7.6
Hz, 2 H), 1.26 (t, J = 7.2 Hz, 6 H), 0.861 (t, J = 7.6 Hz, 3 H);
13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 170.5 (2),
119.2, 61.7 (2), 57.1, 28.3, 26.3, 13.0, δ (down) 14.1 (2), 8.5.
Ethyl 4-Cyano-2-ethylbutanoate (15). To a stirred solution of
diethyl 2-(2-cyanoethyl)-2-ethylmalonate 14 (5.43 g, 22.5 mmol) in
DMSO (73 mL) was added LiCl (4.76 g, 112.3 mmol) at room
temperature. Then, the reaction was heated to refluxing (oil bath at
140 °C) for 48 h; the mixture was cooled to room temperature and
quenched by water (20 mL). The mixture was extracted by EtOAc
(60 mL × 3), washed with water (20 mL × 3) and brine (10 mL × 3),
dried over anhydrous Na2SO4, and concentrated to afford the ethyl 4-
cyano-2-ethylbutanoate 15 as a yellow oil (3.62 g, yield 95% from 14).
1
yield from 18). 1c: Rf = 0.42 (EtOAc/PE = 1/5); H NMR (CDCl3,
400 MHz) δ 3.24−3.34 (m, 2 H), 2.39 (t, J = 7.6 Hz, 2 H), 1.67−1.72
(m, 2 H), 1.53−1.59 (m, 1 H), 1.36−1.43 (m, 2 H), 0.92 (t, J = 7.6
Hz, 3 H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 180.2,
54.4, 31.5, 26.3, 24.1, δ (down) 39.0, 10.8; IR (film) 2935, 2100,
1710, 1285 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C7H13N3O2Na 194.0900, found 194.0900.
1
15: Rf = 0.30 (EtOAc/PE = 1/5); H NMR (CDCl3, 400 MHz) δ
Ethyl 2-(2-(Bromomethyl)phenyl)acetate (20). The ethyl 2-(2-
(bromomethyl)phenyl)acetate 20 (17.00 g, 98% yield from 19) was
prepared from the isochroman-3-one 19 (10.00 g, 67.5 mmol)
according to the reported procedure.19 20: known compound,19 Rf =
0.56 (EtOAc/PE = 1/20); 1H NMR (CDCl3, 400 MHz) δ 7.27−7.38
(m, 4 H), 4.60 (s, 2 H), 4.16 (q, J = 7.2 Hz, 2 H), 3.79 (s, 2 H), 1.26
(t, J = 7.2 Hz, 3 H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ
(up) 170.8, 136.2, 133.4, 61.0, 38.2, 31.8, δ (down) 131.1, 130.6,
129.0, 127.8, 14.1.
Ethyl 2-(2-(Azidomethyl)phenyl)acetate (21). The ethyl 2-(2-
(azidomethyl)phenyl)acetate 21 (10.64 g, 97% yield from 20) was
prepared from the ethyl 2-(2-(bromomethyl)phenyl)acetate 20
(12.86 g, 50.0 mmol) according to the reported procedure.8 21:
known compound,8 Rf = 0.41 (EtOAc/PE = 1/20); 1H NMR
(CDCl3, 400 MHz) δ 7.28−7.36 (m, 4 H), 4.42 (s, 2 H), 4.15 (q, J =
7.2 Hz, 2 H), 3.71 (s, 2 H), 1.25 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR
(CDCl3, 100 MHz, plus APT) δ (up) 171.2, 134.0, 133.3, 61.2, 52.9,
38.6, δ (down) 131.3, 130.0, 129.0, 127.8, 14.2.
4.09−4.17 (m, 2 H), 2.27−2.43 (m, 3 H), 1.90−1.99 (m, 1 H), 1.72−
1.84 (m, 1 H), 1.48−1.70 (m, 2 H), 1.23 (t, J = 7.2 Hz, 3 H), 0.87 (t,
J = 6.8 Hz, 3 H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ
(up) 174.5, 119.2, 60.6, 27.1, 25.1, 15.3, δ (down) 45.5, 14.2, 11.3; IR
(film) 2335, 1731 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C9H15NO2Na 192.0995, found 192.0995.
4-Cyano-2-ethylbutyl 4-Methylbenzenesulfonate (17). To a
stirred solution of ethyl 4-cyano-2-ethylbutanoate 15 (3.76 g, 22.2
mmol) in dry THF (100 mL) was added KBH4 (1.43 g, 26.6 mmol)
and LiCl (1.13 g, 26.6 mmol) at room temperature. Then, the
reaction was heated to 75 °C for 22 h, quenched with saturated
NH4Cl (10 mL), and treated with 1 N HCl for adjusting the mixture
to pH ≈ 3−4. The mixture was extracted with CH2Cl2 (40 mL × 3),
washed with brine (20 mL), dried over anhydrous Na2SO4, and
concentrated; then, the residue was purified by flash column
chromatography to afford the 4-(hydroxymethyl)hexanenitrile 16 as
a colorless oil (1.83 g, 64% yield from 15). 16: Rf = 0.45 (EtOAc/PE
= 1/2); 1H NMR (CDCl3, 400 MHz) δ 3.66 (dd, J = 4.8 and 4.8 Hz,
1 H), 3.56 (dd, J = 6.0 and 6.0 Hz, 1 H), 2.39−2.48 (m, 2 H), 1.66−
1.83 (m, 2 H), 1.54−1.63 (m, 1 H), 1.30−1.45 (m, 3 H), 0.933 (t, J =
7.6 Hz, 3 H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up)
120.2, 64.1, 26.8, 23.1, 15.1, δ (down) 40.9, 11.1. To a stirred solution
of the above 4-(hydroxymethyl)hexanenitrile 16 (1.82 g, 14.3 mmol))
in dry DCM (65 mL) was added NEt3 (2.18 g, 21.5 mmol), DMAP
(174.7 mg, 1.43 mmol), and TsCl (5.45 g, 28.6 mmol), and the
reaction mixture was kept for 22 h at room temperature. Then, the
mixture was concentrated and purified by flash column chromatog-
raphy to afford the 4-cyano-2-ethylbutyl 4-methylbenzenesulfonate 17
as a yellow oil (3.38 g, 84% yield from 16). 17: Rf = 0.53 (EtOAc/PE
2-(2-(Azidomethyl)phenyl)acetic Acid (1d). The 2-(2-
(azidomethyl)phenyl)acetic acid 1d (8.94 g, 97% yield from 21)
was prepared from the ethyl 2-(2-(azidomethyl)phenyl)acetate 21
(10.64 g, 48.5 mmol) with LiOH·H2O (10.18 g, 242.5 mmol) in the
combined solvent (THF/H2O = 1/1, 360 mL) by the above
procedure for preparation of 1a, and the reaction was carried out at 70
°C for 19 h. 1d: known compound,8 a white solid, Mp 113.3−115.5
1
°C, Rf = 0.48 (EtOAc/PE = 1/1); H NMR (CDCl3, 400 MHz) δ
7.29−7.37 (m, 4 H), 4.41 (s, 2 H), 3.76 (s, 2 H); 13C{1H} NMR
(CDCl3, 100 MHz, plus APT) δ (up) 177.6, 134.2, 132.4, 52.9, 38.2,
δ (down) 131.4, 130.1, 129.1, 128.2. HRMS (ESI-TOF) m/z [M +
H]+ calcd for C9H9N3O2H 192.0768, found 1942.0778.
1
= 1/2); H NMR (CDCl3, 400 MHz) δ 7.79 (d, J = 8.0 Hz, 2 H),
2016
DOI: 10.1021/acs.joc.8b03018
J. Org. Chem. 2019, 84, 2012−2021

The Journal of Organic Chemistry
Article
Phenyl(pyrrolidin-1-yl)methanone (3aa) and 1-Benzylpyrrolidin-
2-one (4aa). Procedure A. To a stirred solution of 5-azidopentanoic
acid 1a (143.2 mg, 1.0 mmol) in DCM (1.5 mL) was treated with
(COCl)2 (177.7 mg, 1.4 mmol) for 1.5 h at 30 °C; then, the benzene
2a (390.6 mg, 5.0 mmol) was applied. TfOH (300.1 mg, 2.0 mmol)
was slowly added into the reaction mixture at 0 °C, and the mixture
was heated to reflux (oil bath at 60 °C) for 46 h. After that, the
mixture was cooled to room temperature and quenched with 5%
aqueous KOH (4 mL). The mixture was extracted by CH2Cl2 (10 mL
× 4), and the combined organic phase was dried over Na2SO4 and
concentrated; then, the residue was purified by flash column
chromatography to afford the phenyl(pyrrolidin-1-yl)methanone 3aa
(90.0 mg, 51% yield from 1a) and 1-benzylpyrrolidin-2-one 4aa (61.2
mg, 35% yield from 1a). 3aa known compound:6 a light yellow oil, Rf
= 0.59 (EtOAc); 1H NMR (CDCl3, 400 MHz) δ 7.36−7.52 (m, 5 H),
3.64 (t, J = 7.2 Hz, 2 H), 3.42 (t, J = 6.8 Hz, 2 H), 1.92−1.99 (m, 2
H), 1.83−1.89 (m, 2 H); 13C{1H} NMR (CDCl3, 100 MHz, plus
APT) δ (up) 169.7, 137.3, 49.6, 46.2, 26.4, 24.5, δ (down) 129.8,
128.2 (2), 127.1 (2); IR (film) 2971, 2876, 1623, 1575, 700 cm−1;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C11H13NONa 198.0889,
H), 6.95 (s, 1 H), 4.43 (s, 2 H), 3.20 (t, J = 7.2 Hz, 2 H), 2.45 (t, J =
8.0 Hz, 2 H), 2.30 (s, 3 H), 2.25 (s, 3 H), 1.94−2.02 (m, 2 H);
13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 174.5, 135.4,
133.9, 133.3, 46.4, 44.5, 30.8, 17.6, δ (down) 130.3, 129.5, 128.2,
20.8, 18.5; IR (film) 2922, 1685, 1425, 1287, 814 cm−1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C13H17NONa 226.1202, found
226.1203.
1-(2,5-Dichlorobenzyl)pyrrolidin-2-one (4ac). The 4ac (93.6 mg,
38% yield from 1a) was prepared from the Schmidt reaction of 1a
(143.2 mg, 1.0 mmol) with the nucleophile 1,4-dichlorobenzene 2c
(735.0 mg, 5.0 mmol) according to Procedure A for preparation of
3aa and 4aa, and the reaction time for the capture process was 46 h.
1
4ac: a colorless oil, Rf = 0.41 (EtOAc/PE = 1/1); H NMR (CDCl3,
400 MHz) δ 7.18−7.31 (m, 3 H), 4.55 (s, 2 H), 3.33 (t, J = 6.8 Hz, 2
H), 2.46 (t, J = 8.0 Hz, 2 H), 2.02−2.09 (m, 2 H); 13C{1H} NMR
(CDCl3, 100 MHz, plus APT) δ (up) 175.1, 135.7, 132.9, 131.7, 46.9,
43.6, 30.4, 17.7, δ (down) 130.6, 129.1, 128.8; IR (film) 2949, 1689,
1493, 1285, 814 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C11H11Cl2NONa 266.0110, found 266.0108.
Naphthalen-1-yl(pyrrolidin-1-yl)methanone (3ad) and 1-(Naph-
thalen-1-ylmethyl)pyrrolidin-2-one (4ad). The 3ad (61.0 mg, 27%
yield from 1a) and 4ad (89.0 mg, 40% yield from 1a) were prepared
from the Schmidt reaction of 1a (143.2 mg, 1.0 mmol) with the
nucleophile naphthalene 2d (640.9 mg, 5.0 mmol) according to
Procedure A for preparation of 3aa and 4aa, and the reaction time for
the capture process was 46 h. 3ad, known compound,23 a yellow oil,
Rf = 0.56 (EtOAc); 1H NMR (CDCl3, 400 MHz) δ 7.86−7.88 (m, 3
H), 7.45−7.54 (m, 4 H), 3.80 (t, J = 7.2 Hz, 2 H), 3.13 (t, J = 6.8 Hz,
2 H), 1.97−2.04 (m, 2 H), 1.80−1.87 (m, 2 H); 13C{1H} NMR
(CDCl3, 100 MHz, plus APT) δ (up) 169.2, 135.8, 133.5, 129.2, 48.5,
45.6, 26.0, 24.6, δ (down) 129.1, 128.4, 126.9, 126.3, 125.2, 124.9,
123.7; IR (film) 3051, 2974, 2877, 1630, 1439, 800 cm−1; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C15H15NONa 248.1046, found
248.1045. Further elution gave the 4ad: a yellow oil, Rf = 0.41
found 198.0893. Further elution gave the 4aa, known compound,21
a
1
light yellow oil, Rf = 0.31 (EtOAc); H NMR (CDCl3, 400 MHz) δ
7.23−7.35 (m, 5 H), 4.46 (s, 2 H), 3.26 (t, J = 7.2 Hz, 2 H), 2.45 (t, J
= 8.0 Hz, 2 H), 1.96−2.03 (m, 2 H); 13C{1H} NMR (CDCl3, 100
MHz, plus APT) δ (up) 174.9, 136.6, 46.61, 46.58, 31.0, 17.8, δ
(down) 128.7 (2), 128.1 (2), 127.6; IR (film) 2918, 1685, 1495,
1463, 702 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C11H13NONa 198.0889, found 198.0893.
Ethyl Pyrrolidine-1-carboxylate (3ae) and 1-(Ethoxymethyl)-
pyrrolidin-2-one (4ae). Procedure B. To a stirred solution of 5-
azidopentanoic acid 1a (143.2 mg, 1.0 mmol) in DCM (1.5 mL) was
treated with (COCl)2 (177.7 mg, 1.4 mmol) for 1.5 h at 30 °C; then,
the TfOH (600.2 mg, 4.0 mmol) was slowly added into the reaction
mixture at 0 °C. Fifteen min later, ethanol 2e (230.3 mg, 5.0 mmol)
was applied, and the mixture was kept for 4 h at room temperature.
After that, the mixture was quenched with 5% aqueous KOH (4 mL)
and extracted by CH2Cl2 (10 mL × 4), and the combined organic
phase was dried over Na2SO4 and concentrated; then, the residue was
purified by flash column chromatography to afford the ethyl
pyrrolidine-1-carboxylate 3ae (83.3 mg, 58% yield from 1a) and
1
(EtOAc); H NMR (CDCl3, 400 MHz) δ 8.14 (d, J = 8.0 Hz, 1 H),
7.85 (d, J = 8.0 Hz, 1 H), 7.80 (d, J = 8.0 Hz, 1 H), 7.36−7.56 (m, 4
H), 4.89 (s, 2 H), 3.12 (t, J = 7.2 Hz, 2 H), 2.43 (t, J = 8.0 Hz, 2 H),
1.84−1.91 (m, 2 H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ
(up) 174.4, 133.7, 132.0, 131.5, 46.4, 44.8, 31.0, 17.5, δ (down) 128.6,
128.5, 127.3, 126.6, 126.0, 125.1, 123.8; IR (film) 2949, 1680, 1423,
1259, 784 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C15H15NONa 248.1046, found 248.1042.
4ae (21.7 mg, 15% yield from 1a). 3ae known compound:22
a
colorless oil, Rf = 0.62 (MTBE); 1H NMR (CDCl3, 400 MHz) δ 4.12
(q, J = 7.2 Hz, 2 H), 3.34 (m, 4 H), 1.84 (m, 4 H), 1.24 (t, J = 7.2 Hz,
3 H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 155.3,
60.8, 46.1, 45.7, 25.8, 25.0, δ (down) 14.9; IR (film) 2979, 1700,
1423, 1382, 1181 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C7H13NO2H 144.1019, found 144.1015. Further elution gave the 4ae:
Hexyl Pyrrolidine-1-carboxylate (3af) and 1-((Hexyloxy)methyl)-
pyrrolidin-2-one (4af). The 3af (74.0 mg, 37% yield from 1a) and 4af
(70.6 mg, 36% yield from 1a) were prepared from the Schmidt
reaction of 1a (143.2 mg, 1.0 mmol) with the nucleophile 1-hexanol
2f (510.9 mg, 5.0 mmol) according to Procedure B for the
preparation of 3ae and 4ae, and the capture process was carried out at
room temperature for 22 h. 3af: a colorless oil, Rf = 0.57 (EtOAc/
DCM/PE = 1/5/10); 1H NMR (CDCl3, 400 MHz) δ 4.06 (t, J = 6.8
Hz, 2 H), 3.31−3.40 (m, 4 H), 1.85 (m, 4 H), 1.58−1.65 (m, 2 H),
1.25−1.44 (m, 6 H), 0.87−0.90 (m, 3 H); 13C{1H} NMR (CDCl3,
100 MHz, plus APT) δ (up) 155.5, 65.3, 46.0 (2), 31.5, 29.1, 25.7,
25.4 (2), 22.6, δ (down) 14.0; IR (film) 3493, 2956, 1705, 1423,
1105, 770 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C11H21NO2Na 222.1465, found 222.1463. Further elution gave the
4af: a colorless oil, Rf = 0.54 (EtOAc); 1H NMR (CDCl3, 400 MHz)
δ 4.72 (s, 2 H), 3.48 (t, J = 7.2 Hz, 2 H), 3.40 (t, J = 6.8 Hz, 2 H),
2.43 (t, J = 8.0 Hz, 2 H), 2.00−2.08 (m, 2 H), 1.51−1.56 (m, 2 H),
1.25−1.34 (m, 6 H), 0.875 (t, J = 6.8 Hz, 3 H); 13C{1H} NMR
(CDCl3, 100 MHz, plus APT) δ (up) 176.0, 72.6, 68.5, 45.9, 31.6,
31.2, 29.5, 25.8, 22.6, 17.9, δ (down) 14.0; IR (film) 3484, 2932,
2243, 1703, 1422, 1267, 1089, 732 cm−1; HRMS (ESI-TOF) m/z [M
+ Na]+ calcd for C11H21NO2Na 222.1465, found 222.1464.
1
a colorless oil, Rf = 0.30 (MTBE); H NMR (CDCl3, 400 MHz) δ
4.72 (s, 2 H), 3.44−3.50 (m, 4 H), 2.42 (t, J = 8.0 Hz, 2 H), 2.02−
2.08 (m, 2 H), 1.18 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (CDCl3, 100
MHz, plus APT) δ (up) 176.1, 72.5, 63.9, 46.0, 31.3, 18.0, δ (down)
15.1; IR (film) 3473, 2975, 1701, 1423, 1283 cm−1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C7H13NO2Na 166.0839, found
166.0837.
(2,5-Dimethylphenyl)(pyrrolidin-1-yl)methanone (3ab) and 1-
(2,5-Dimethylbenzyl)pyrrolidin-2-one (4ab). The 3ab (70.3 mg, 35%
yield from 1a) and 4ab (78.6 mg, 38% yield from 1a) were prepared
from the Schmidt reaction of 1a (143.2 mg, 1.0 mmol) with the
nucleophile p-xylene 2b (530.8 mg, 5.0 mmol) according to
Procedure A for the preparation of 3aa and 4aa, and the reaction
time for the capture process was 46 h. 3ab: a light yellow oil, Rf = 0.67
1
(EtOAc); H NMR (CDCl3, 400 MHz) δ 7.04−7.09 (m, 2 H), 7.00
(s, 1 H), 3.65 (t, J = 7.2 Hz, 2 H), 3.13 (t, J = 6.4 Hz, 2 H), 2.30 (s, 3
H), 2.25 (s, 3 H), 1.92−1.99 (m, 2 H), 1.82−1.89 (m, 2 H); 13C{1H}
NMR (CDCl3, 100 MHz, plus APT) δ (up) 170.1, 137.8, 135.3,
130.3, 48.2, 45.2, 25.9, 24.6, δ (down) 130.2, 129.4, 126.0, 20.8, 18.4;
IR (film) 2918, 1632, 1435, 814 cm−1; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C13H17NONa 226.1202, found 226.1203. Further
elution gave 4ab: a colorless oil, Rf = 0.52 (EtOAc); 1H NMR
(CDCl3, 400 MHz) δ 7.05 (d, J = 8.0 Hz, 1 H), 7.00 (d, J = 8.0 Hz, 1
N-Butylpyrrolidine-1-carboxamide (3ag). The 3ag (98.7 mg, 58%
yield from 1a) was prepared from the Schmidt reaction of 1a (143.2
mg, 1.0 mmol) with the nucleophile n-butylamine 2g (365.7 mg, 5.0
mmol) according to Procedure B for the preparation of 3ae and 4ae,
and the capture process was carried out at room temperature for 4 h.
3ag, known compound,24 Rf = 0.48 (EtOAc); 1H NMR (CDCl3, 400
2017
DOI: 10.1021/acs.joc.8b03018
J. Org. Chem. 2019, 84, 2012−2021

The Journal of Organic Chemistry
Article
MHz) δ 4.25 (bs, 1 H), 3.14−3.32 (m, 6 H), 1.75−1.85 (m, 4 H),
1.39−1.46 (m, 2 H), 1.24−1.33 (m, 2 H), 0.86 (t, J = 7.2 Hz, 3 H);
13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 156.9, 47.8,
45.3, 40.2, 32.5, 25.43, 25.40, 19.9, δ (down) 13.7; IR (film) 3338,
2956, 2933, 2871, 2225, 2096, 1631, 1538, 733 cm−1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C9H18N2ONa 193.1311, found
193.1311.
1b (171.2 mg, 1.0 mmol) with the nucleophile n-butylamine 2g
(365.7 mg, 5.0 mmol) according to Procedure B for the preparation
of 3ae and 4ae, and the capture process was carried out at room
temperature for 4 h. 3bg: a colorless oil, Rf = 0.57 (EtOAc/PE = 1/1);
1H NMR (CDCl3, 400 MHz) δ 4.12 (m, 1 H), 3.76 (m, 1 H), 3.19−
3.30 (m, 4 H), 1.85−1.94 (m, 3 H), 1.69−1.78 (m, 2 H), 1.45−1.52
(m, 2 H), 1.25−1.39 (m, 3 H), 0.92 (t, J = 7.2 Hz, 3 H), 0.87 (t, J =
7.6 Hz, 3 H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up)
157.0, 45.9, 40.2, 32.6, 29.4, 27.2, 23.7, 20.1, δ (down) 58.5, 13.8,
10.5; IR (film) 3338, 2962, 2097, 1629, 1535, 737 cm−1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C11H22N2ONa 221.1624, found
221.1619.
Piperidin-1-yl(pyrrolidin-1-yl)methanone (3ah). The 3ah (107.9
mg, 59% yield from 1a) was prepared from the Schmidt reaction of 1a
(143.2 mg, 1.0 mmol) with the nucleophile piperidine 2h (425.8 mg,
5.0 mmol) according to Procedure B for the preparation of 3ae and
4ae, and the capture process was carried out at room temperature for
1
4 h. 3ah: a light yellow oil, Rf = 0.31 (EtOAc/PE = 1/5); H NMR
(2-Ethylpyrrolidin-1-yl)(piperidin-1-yl)methanone (3bh). The
3bh (117.7 mg, 56% yield from 1b) was prepared from the Schmidt
reaction of 1b (171.2 mg, 1.0 mmol) with the nucleophile piperidine
2h (425.8 mg, 5.0 mmol) according to Procedure B for the
preparation of 3ae and 4ae, and the capture process was carried out at
room temperature for 4 h. 3bh: a colorless oil, Rf = 0.34 (EtOAc/PE
(CDCl3, 400 MHz) δ 3.33−3.38 (m, 4 H), 3.16−3.21 (m, 4 H),
1.76−1.84 (m, 4 H), 1.54−1.62 (m, 6 H); 13C{1H} NMR (CDCl3,
100 MHz, plus APT) δ (up) 163.2, 48.3 (2), 47.1 (2), 25.8 (2), 25.5
(2), 24.7; IR (film) 3479, 2934, 1639, 1412, 1252 cm−1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C10H18N2ONa 205.1311, found
205.1308.
1
= 1/5); H NMR (CDCl3, 400 MHz) δ 3.96−3.99 (m, 1 H), 3.16−
(2-Ethylpyrrolidin-1-yl)(phenyl)methanone (3ba) and Benzyl-3-
3.33 (m, 6 H), 2.03−2.07 (m, 1 H), 1.29−1.81 (m, 11 H), 0.84 (t, J =
7.6 Hz, 3 H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up)
163.1, 50.7, 47.0 (2), 30.4, 27.3, 25.7 (2), 25.5, 24.7, δ (down) 58.9,
9.7; IR (film) 3478, 2965, 2096, 1631, 1413, 734 cm−1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C12H22N2ONa 233.1624, found
233.1618.
ethylpyrrolidin-2-one (4ba). The mixture of 3ba and 4ba (3ba/4ba
1
= 6/1 from H NMR, 145.5 mg, 72% combined yield from 1b) was
prepared from the Schmidt reaction of 1b (171.2 mg, 1.0 mmol) with
the nucleophile benzene 2a (390.6 mg, 5.0 mmol) according to
Procedure A for the preparation of 3aa and 4aa, and the reaction
time for the capture process was 46 h. The 3ba and 4ba could be
partly separated by careful column chromatography, and the pure
samples were used for further characterization. 3ba: a colorless oil,
1-Benzyl-5-ethylpyrrolidin-2-one (4ca). The 4ca (166.6 mg, 82%
yield from 1c) was prepared from the Schmidt reaction of 1c (171.2
mg, 1.0 mmol) with the nucleophile benzene 2a (390.6 mg, 5.0
mmol) according to Procedure A for the preparation of 3aa and 4aa,
and the reaction time for the capture process was 46 h. 4ca: a
1
mixture of rotamer (3:1 from H NMR), Rf = 0.69 (EtOAc/PE = 1/
1
2); H NMR (CDCl3, 400 MHz) δ 7.35−7.51 (m, 5 H for major
rotamer and minor rotamer), 4.21 (m, 1 H for major rotamer), 3.79
(m, 2 H for minor rotamer), 3.44 (m, 1 H for minor rotamer), 3.40−
3.42 (m, 2 H for major rotamer), 1.86−2.11 (m, 3 H for major
rotamer and 3 H for minor rotamer), 1.65−1.77 (m, 2 H for major
rotamer and 2 H for minor rotamer), 1.48−1.55 (m, 1 H for major
rotamer), 1.23−1.25 (m, 1 H for minor rotamer), 0.95 (t, J = 7.6 Hz,
3 H for major rotamer), 0.62 (m, 3 H for minor rotamer); 13C{1H}
NMR (CDCl3, 100 MHz, plus APT) δ (up) 169.8, 137.6, 50.3, 29.7,
26.3, 25.1, δ (down) 129.7, 128.1 (2), 127.3 (2), 58.5, 10.0; IR (film)
2966, 1627, 1413, 701 cm−1; HRMS (ESI-TOF) m/z [M + Na]+
calcd for C13H17NONa 226.1202, found 226.1204. 4ba: Rf = 0.65
(EtOAc/PE = 1/2); 1H NMR (CDCl3, 400 MHz) δ 7.14−7.26 (m, 5
H), 4.41 (d, J = 14.4 Hz, 1 H), 4.33 (d, J = 14.4 Hz, 1 H), 3.07−3.11
(m, 2 H), 2.31−2.34 (m, 1 H), 2.04−2.10 (m, 1 H), 1.81−1.87 (m, 1
H), 1.54−1.62 (m, 1 H), 1.34−1.41 (m, 1 H), 0.88 (t, J = 6.8 Hz, 3
H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 176.6,
136.7, 46.6, 44.9, 24.3, 24.1, δ (down) 128.6 (2), 128.1 (2), 127.5,
43.3, 11.4; IR (film) 2963, 1687, 1426, 700 cm−1; HRMS (ESI-TOF)
m/z [M + Na]+ calcd for C13H17NONa 226.1202, found 226.1202.
Hexyl 2-Ethylpyrrolidine-1-carboxylate (3bf). The 3bf (141.0 mg,
62% yield from 1b) was prepared from the Schmidt reaction of 1b
(171.2 mg, 1.0 mmol) with the nucleophile 1-hexanol 2f (510.9 mg,
5.0 mmol) according to the Procedure B for preparation of 3ae and
4ae, and the capture process was carried out at room temperature for
22 h. 3bf: a light yellow oil, Rf = 0.58 (EtOAc/PE = 1/10); mixture of
1
colorless oil, Rf = 0.75 (EtOAc); H NMR (CDCl3, 400 MHz) δ
7.22−7.33 (m, 5 H), 4.99 (d, J = 14.8 Hz, 1 H), 3.95 (d, J = 14.8 Hz,
1 H), 3.38−3.40 (m, 1 H), 2.40−2.48 (m, 2 H), 2.04−2.11 (m, 1 H),
1.65−1.74 (m, 2 H), 1.34−1.41 (m, 1 H), 0.82 (t, J = 7.6 Hz, 3 H);
13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 175.2, 136.8,
44.0, 30.3, 25.4, 23.2, δ (down) 128.5 (2), 127.9 (2), 127.3, 57.9, 8.4;
IR (film) 2965, 1689, 1417, 1257, 703 cm−1; HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C13H17NONa 226.1202, found 226.1202.
Dimethylphenyl)(3-ethylpyrrolidin-1-yl)methanone (3cb) and 1-
(2,5-Dimethylbenzyl)-5-ethylpyrrolidin-2-one (4cb). The 3cb and
1
4cb (3cb/4cb = 1/5 from H NMR, 183.7 mg, 79% combined yield
from 1c) were prepared from the Schmidt reaction of 1c (171.2 mg,
1.0 mmol) with the nucleophile p-xylene 2b (530.8 mg, 5.0 mmol)
according to Procedure A for the preparation of 3aa and 4aa, and the
reaction time for the capture process was 46 h. The 3cb and 4cb
could be partly separated by careful column chromatography, and the
pure samples were used for further characterization. 3cb: a light
yellow oil, mixture of rotamer A and rotamer B (1:1 from 1H NMR),
Rf = 0.47 (EtOAc/PE = 1/1); 1H NMR (CDCl3, 400 MHz) δ 7.04−
7.10 (m, 2 H), 6.99 (s, 1 H), 3.86−3.91 (m, 0.5 H), 3.76−3.81 (m,
0.5 H), 3.52−3.59 (m, 0.5 H), 3.09−3.27 (m, 2 H), 2.73−2.78 (m,
0.5 H), 2.30 (s, 3 H), 2.25 (s, 3 H), 1.95−2.12 (m, 2 H), 1.43−1.59
(m, 2 H), 1.31−1.38 (m, 1 H), 0.97 (t, J = 7.2 Hz, 1.5 H), 0.87 (t, J =
7.6 Hz, 1.5 H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up)
170.1, 170.0, 137.7, 137.5, 135.34, 135.32, 130.3, 130.2, 53.5, 50.6,
48.0, 44.9, 31.7, 30.2, 26.2, 25.6, δ (down) 130.2 (2, rotamers), 129.3
(2, rotamers), 126.0 (2, rotamers), 41.0, 39.7, 20.8, 18.4, 12.5, 12.4;
IR (film) 3482, 2960, 1634, 1434, 1192, 813 cm−1; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C15H21NOH 232.1696, found
1
rotamers, (1:1 from 13C{1H} NMR) H NMR (CDCl3, 400 MHz) δ
4.00−4.06 (m, 2 H), 3.69−3.75 (m, 1 H), 3.35−3.44 (m, 2 H), 1.75−
1.89 (m, 3 H), 1.56−1.68 (m, 4 H), 1.25−1.35 (m, 7 H), 0.84−0.94
(m, 6 H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 155.6
(rotamer A and rotamer B), 64.9 (rotamer A and rotamer B), 46.6
(rotamer A), 46.3 (rotamer B), 31.5 (rotamer A and rotamer B), 30.1
(rotamer A), 29.3 (rotamer B), 29.1 (rotamer A and rotamer B), 27.4
(rotamer A), 26.6 (rotamer B), 25.7 (rotamer A and rotamer B), 23.9
(rotamer A), 23.1 (rotamer B), 22.6 (rotamer A and rotamer B), δ
(down) 59.1 (rotamer A), 58.6 (rotamer B), 14.0 (rotamer A and
rotamer B), 10.5 (rotamer A and rotamer B); IR (film) 3497, 2959,
1700, 1462, 1416, 1108, 732 cm−1; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C13H25NO2Na 250.1778, found 250.1773.
1
232.1698. 4cb: a light yellow oil, Rf = 0.45 (EtOAc/PE = 1/1); H
NMR (CDCl3, 400 MHz) δ 7.04 (d, J = 7.6 Hz, 1 H), 6.98 (d, J = 7.6
Hz, 1 H), 6.91 (s, 1 H), 4.97 (d, J = 15.2 Hz, 1 H), 3.92 (d, J = 15.2
Hz, 1 H), 3.33−3.35 (m, 1 H), 2.42−2.48 (m, 2 H), 2.29 (s, 3 H),
2.24 (s, 3 H), 2.06−2.14 (m, 1 H), 1.63−1.74 (m, 2 H), 1.36−1.43
(m, 1 H), 0.83 (t, J = 7.6 Hz, 3 H); 13C{1H} NMR (CDCl3, 100
MHz, plus APT) δ (up) 174.8, 135.5, 134.1, 133.2, 42.1, 30.3, 25.4,
23.1, δ (down) 130.5, 129.0, 128.2, 57.8, 21.1, 18.8, 8.6; IR (film)
2966, 1689, 1496, 1422, 813 cm−1; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C15H21NONa 254.1515, found 254.1510.
N-Butyl-2-ethylpyrrolidine-1-carboxamide (3bg). The 3bg (149.1
mg, 75% yield from 1b) was prepared from the Schmidt reaction of
2018
DOI: 10.1021/acs.joc.8b03018
J. Org. Chem. 2019, 84, 2012−2021

The Journal of Organic Chemistry
Article
1-(2,5-Dichlorobenzyl)-5-ethylpyrrolidin-2-one (4cc). The 4cc
(96.1 mg, 35% yield from 1c) was prepared from the Schmidt
reaction of 1c (171.2 mg, 1.0 mmol) with the nucleophile 1,4-
dichlorobenzene 2c (735.0 mg, 5.0 mmol) according to Procedure A
for the preparation of 3aa and 4aa, and the reaction time for the
capture process was 46 h. 4cc: a colorless oil, Rf = 0.65 (EtOAc/PE =
1/1); 1H NMR (CDCl3, 400 MHz) δ 7.24 (d, J = 8.4 Hz, 1 H), 7.16
(s, 1 H), 7.13 (d, J = 8.4 Hz, 1 H), 4.77 (d, J = 16.0 Hz, 1 H), 4.24 (d,
J = 16.0 Hz, 1 H), 3.38−3.44 (m, 1 H), 2.36−2.50 (m, 2 H), 2.09−
2.19 (m, 1 H), 1.63−1.75 (m, 2 H), 1.30−1.37 (m, 1 H), 0.82 (t, J =
7.2 Hz, 3 H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up)
175.5, 136.3, 133.0, 131.3, 41.4, 30.0, 25.9, 23.5, δ (down) 130.6,
129.0, 128.7, 58.8, 8.7; IR (film) 2966, 1691, 1463, 1421, 1270, 1097,
813 cm−1; HRMS (ESI-TOF) C13H15Cl2NOH m/z [M + H]+ calcd
for 272.0604, found 272.0603.
1-Benzylindolin-2-one (4da). The 4da (215.2 mg, 96% yield from
1d) was prepared from the Schmidt reaction of 1d (191.2 mg, 1.0
mmol) in DCM (2 mL) with the nucleophile benzene 2a (390.6 mg,
5.0 mmol) according to Procedure A for the preparation of 3aa and
4aa, and the in situ formation of acyl chloride was carried out at 45 °C
for 1 h, where the reaction time for the capture process was 23 h. 4da,
known compound,25 Rf = 0.69 (EtOAc/PE = 1/5), 1H NMR (CDCl3,
400 MHz) δ 7.25−7.32 (m, 6 H), 7.17 (t, J = 7.6 Hz, 1 H), 7.01 (t, J
= 7.2 Hz, 1 H), 6.72 (d, J = 7.6 Hz, 1 H), 4.92 (s, 2 H), 3.63 (s, 2 H);
13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 174.9, 144.1,
formation of acyl chloride was carried out at 45 °C for 1 h, where the
capture reaction was promoted with TfOH (300.1 mg, 2.0 mmol) at 0
°C for 6 h. 4dk, known compound,12d Rf = 0.62 (EtOAc/PE = 1/2),
Mp 145.2−145.3 °C; 1H NMR (CDCl3, 400 MHz) δ 7.28 (d, J = 7.2
Hz, 1 H), 7.20 (t, J = 7.8 Hz, 1 H), 7.03−7.06 (m, 2 H), 6.71 (d, J =
8.0 Hz, 1 H), 6.56 (s, 1 H), 5.92 (s, 2 H), 4.93 (s, 2 H), 3.66 (s, 2 H);
13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 175.6, 147.9,
147.8, 143.7, 127.6, 124.3, 113.1, 101.9, 43.6, 35.8, δ (down) 128.0,
124.5, 122.8, 112.7, 109.3, 107.7.
(2-Iodo-4,5-dimethoxybenzyl)indolin-2-one (4dl). The 4dl (335.9
mg, 82% yield from 1d) was prepared from the Schmidt reaction of
1d (191.2 mg, 1.0 mmol) in DCM (2 mL) with the nucleophile 4-
iodo-1,2-dimethoxybenzene 2l (1.32 g, 5.0 mmol) according to
Procedure B for the preparation of 4di, and the in situ formation of
acyl chloride was carried out at 45 °C for 1 h, where the capture
reaction was promoted with TfOH (300.1 mg, 2.0 mmol) at 0 °C for
0.5 h. 4dl: a white solid, Mp 161.5−161.7 °C, Rf = 0.44 (EtOAc/PE =
1
1/1); H NMR (CDCl3, 400 MHz) δ 7.24−7.27 (m, 2 H), 7.17 (t, J
= 7.6 Hz, 1 H), 7.02 (t, J = 7.6 Hz, 1 H), 6.71 (d, J = 7.6 Hz, 1 H),
6.61 (s, 1 H), 4.89 (s, 2 H), 3.84 (s, 3 H), 3.67 (s, 5 H); 13C{1H}
NMR (CDCl3, 100 MHz, plus APT) δ (up) 175.2, 149.7, 148.9,
143.9, 130.0, 124.2, 86.0, 48.4, 35.8, δ (down) 128.0, 124.4, 122.6,
121.4, 110.4, 109.6, 56.1, 55.8; IR (film) 3433, 2938, 1695, 1614,
1508, 1253, 745 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C17H16INO3Na 432.0067 found 432.0070.
1-(2-Bromo-4,5-dimethoxybenzyl)indoline (5dj). To a stirred
solution of 1-(2-bromo-4,5-dimethoxybenzyl)indolin-2-one 4dj
(724.4 mg, 2.0 mmol) in THF (10 mL) was added borane−
dimethylsulfide compex 9-BBN (0.5 M in THF, 8.8 mL, 4.4 mmol);
then, the mixture was kept for 1 h at room temperature. The mixture
was concentrated to afford the crude product, and then, the crude
mixture was dissolved in AcOH (6 mL). NaBH3CN (377.0 mg, 6.0
mmol) was added into the mixture, and it was kept for 2 h at room
temperature. Then, the reaction was treated with 0.5 N KOH for
adjusting the mixture to pH > 7 and the mixture was extracted by
CH2Cl2 (15 mL × 3), dried over Na2SO4, and concentrated; then, the
residue was purified by flash column chromatography to afford the 1-
(2-bromo-4,5-dimethoxybenzyl)indoline 5dj (609.4 mg, 88% yield
from 4dj). 5dj: known compound,11 Rf = 0.36 (EtOAc/PE = 1/10);
1H NMR (CDCl3, 400 MHz) δ 7.14 (d, J = 7.2 Hz, 1 H), 7.07−7.10
(m, 2 H), 7.02 (s, 1 H), 6.72 (t, J = 7.2 Hz, 1 H), 6.52 (d, J = 7.6 Hz,
1 H), 4.26 (s, 2 H), 3.89 (s, 3 H), 3.82 (s, 3 H), 3.39 (t, J = 8.4 Hz, 2
H), 3.03 (t, J = 8.0 Hz, 2 H); 13C{1H} NMR (CDCl3, 100 MHz, plus
APT) δ (up) 152.4, 148.43, 148.41, 129.8, 129.3, 113.2, 54.0, 53.7,
28.5, δ (down) 127.2, 124.4, 117.9, 115.3, 112.0, 107.2, 56.1, 56.0.
1-((6-Bromobenzo[d][1,3]dioxol-5-yl)methyl)indoline (5dk). The
5dk (623.2 mg, 90% yield from 4dk) was prepared from the 4dk
(692.4 mg, 2.0 mmol) with the 9-BBN (0.5 M in THF, 8.8 mL, 4.4
mmol) according to the procedure for preparation of 5dj, and the
reaction time for the reduction process with NaBH3CN (377.0 mg,
6.0 mmol) was 1 h. 5dk: known compound,11 Rf = 0.64 (EtOAc/PE =
135.8, 124.3, 43.5, 35.6, δ (down) 128.6 (2), 127.6, 127.5, 127.2 (2),
124.3, 122.2, 108.9.
1-(3,4-Dimethoxybenzyl)indolin-2-one (4di). The 4di (254.0 mg,
90% yield from 1d) was prepared from the Schmidt reaction of 1d
(191.2 mg, 1.0 mmol) in DCM (2 mL) with the nucleophile 1,2-
dimethoxybenzene 2i (690.8 mg, 5.0 mmol) according to Procedure
B for the preparation of 3aa and 4aa, and the in situ formation of acyl
chloride was carried out at 45 °C for 1 h, where the capture reaction
was promoted with TfOH (300.1 mg, 2.0 mmol) at 0 °C for 6 h. 4di:
Rf = 0.39 (EtOAc/PE = 1/1), Mp 119.7−120.2 °C; 1H NMR
(CDCl3, 400 MHz) δ 7.25 (d, J = 7.6 Hz, 1 H), 7.18 (t, J = 8.0 Hz, 1
H), 7.01 (t, J = 7.2 Hz, 1 H), 6.86−6.88 (m, 2 H), 6.76−6.80 (m, 2
H), 4.85 (s, 2 H), 3.84 (s, 6 H), 3.61 (s, 2 H); 13C{1H} NMR
(CDCl3, 100 MHz, plus APT) δ (up) 174.8, 148.9, 148.2, 144.0,
128.2, 124.2, 43.2, 35.4, δ (down) 127.5, 124.1, 122.1, 119.5, 110.8,
110.5, 108.8, 55.6, 55.5. IR (film) 2950, 2837, 1707, 1616, 1518,
1467, 1142, 749 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C17H17NO3Na 306.1102, found 306.1102.
1-(2-Bromo-4,5-dimethoxybenzyl)indolin-2-one (4dj). Two dif-
ferent capturing conditions were employed for preparation of the 4dj
from the reaction of 1d with 2j,20 and the following were the results:
The 4dj (271.0 mg, 75% yield from 1d) was prepared from the
Schmidt reaction of 1d (191.2 mg, 1.0 mmol) in DCM (2 mL) with
the nucleophile 4-bromo-1,2-dimethoxybenzene 2j (1.09 g, 5.0
mmol) according to Procedure A for the preparation of 4da, and
the in situ formation of acyl chloride was carried out at 45 °C for 1 h,
where the capture reaction was promoted with TfOH (300.1 mg, 2.0
mmol) at 60 °C for 23 h. The 4dj (247.9 mg, 68% yield from 1d) was
prepared from the Schmidt reaction of 1d (191.2 mg, 1.0 mmol) in
DCM (2 mL) with the nucleophile 4-bromo-1,2-dimethoxybenzene
2j (1.09 g, 5.0 mmol) according to Procedure B for the preparation
of 4di, and the in situ formation of acyl chloride was carried out at 45
°C for 1 h, where the capture reaction was promoted with TfOH
(300.1 mg, 2.0 mmol) at 0 °C for 6 h. 4dj, known compound,12d Rf =
0.61 (EtOAc/PE = 1/1), Mp 156.3−158.0 °C; 1H NMR (CDCl3, 400
MHz) δ 7.25 (s, 1 H), 7.19 (t, J = 7.6 Hz, 1 H), 7.03 (t, J = 7.2 Hz, 2
H), 6.90 (d, J = 8.0 Hz, 1 H), 6.70 (s, 1 H), 4.97 (s, 2 H), 3.85 (s, 3
H), 3.70 (s, 3 H), 3.66 (s, 2 H); 13C{1H} NMR (CDCl3, 100 MHz,
plus APT) δ (up) 175.3, 149.0, 148.8, 143.9, 126.8, 124.2, 112.9, 43.3,
35.8, δ (down) 127.9, 124.3, 122.6, 115.3, 111.1, 109.3, 56.1, 56.0.
1-((6-Bromobenzo[d][1,3]dioxol-5-yl)methyl)indolin-2-one
(4dk). The 4dk (251.2 mg, 73% yield from 1d) was prepared from the
Schmidt reaction of 1d (191.2 mg, 1.0 mmol) in DCM (2 mL) with
the nucleophile 5-bromobenzo[d][1,3]dioxole 2k (1.01 g, 5.0 mmol)
according to Procedure B for the preparation of 4di, and the in situ
1
1/10); H NMR (CDCl3, 400 MHz) δ 7.12 (d, J = 7.2 Hz, 1 H),
7.04−7.08 (m, 2 H), 6.97 (s, 1 H), 6.69 (t, J = 7.2 Hz, 1 H), 6.40 (d, J
= 8.0 Hz, 1 H), 5.96 (s, 2 H), 4.22 (s, 2 H), 3.41 (t, J = 8.4 Hz, 2 H),
3.02 (t, J = 8.4 Hz, 2 H); 13C{1H} NMR (CDCl3, 100 MHz, plus
APT) δ (up) 152.3, 147.7, 147.4, 130.9, 129.9, 113.5, 101.8, 54.1,
54.0, 28.7, δ (down) 127.5, 124.6, 117.9, 112.8, 109.3, 107.0.
Assoanine (6a) and Oxoassoanine (7a). To a stirred solution of
1-(2-bromo-4,5-dimethoxybenzyl)indoline 5dj (104.5 mg, 0.3 mmol)
in DMF (8 mL) was added Pd(OAc)2 (6.8 mg, 3% mmol), PCy3
(16.8 mg, 6% mmol), and K2CO3 (82.8 mg, 0.6 mmol), and the
mixture was heated to 125 °C (oil bath) for 1 h. Then, the mixture
was cooled to room temperature, treated with water (2 mL), extracted
by EtOAc (8 mL × 3), washed with water (10 mL × 3) and brine (10
mL × 3), dried over Na2SO4, and concentrated; then, the residue was
purified by flash column chromatography to afford 6a (37.8 mg, 46%
yield from 5dj) and 7a (12.8 mg, 14% yield from 5dj). Assoanine 6a:
known compound,11 Rf = 0.58 (EtOAc/PE = 1/5); 1H NMR (CDCl3,
400 MHz) δ 7.33 (d, J = 8.0 Hz, 1 H), 7.19 (s, 1 H), 7.00 (d, J = 7.2
Hz, 1 H), 6.78 (d, J = 7.6 Hz, 1 H), 6.66 (s, 1 H), 4.11 (s, 2 H), 3.95
2019
DOI: 10.1021/acs.joc.8b03018
J. Org. Chem. 2019, 84, 2012−2021

The Journal of Organic Chemistry
Article
(s, 3 H), 3.90 (s, 3 H), 3.34 (t, J = 8.0 Hz, 2 H), 3.03 (t, J = 8.0 Hz, 2
H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 149.6,
148.7, 148.4, 128.6, 124.8, 124.3, 119.1, 55.5, 53.3, 29.1, δ (down)
123.4, 119.7, 119.4, 110.4, 105.4, 56.1 (2). Oxoassoanine 7a: known
compound,11 Rf = 0.63 (EtOAc); 1H NMR (CDCl3, 400 MHz) δ 7.91
(s, 1 H), 7.90 (d, J = 8.0 Hz, 1 H), 7.51 (s, 1 H), 7.28 (d, J = 7.2 Hz, 1
H), 7.20 (t, J = 7.6 Hz, 1 H), 4.47 (t, J = 8.0 Hz, 2 H), 4.08 (s, 3 H),
4.04 (s, 3 H), 3.42 (t, J = 8.0 Hz, 2 H); 13C{1H} NMR (CDCl3, 100
MHz, plus APT) δ (up) 159.7, 152.9, 149.7, 139.5, 131.0, 128.6,
121.4, 116.8, 46.6, 27.5, δ (down) 123.6, 123.2, 119.3, 108.8, 103.0,
56.3, 56.2, and the sample was found to be congruent (1H NMR) to
the substance previously reported.
Oxoassoanine (7a). The 7a (17.8 mg, 63% yield from 6a) could
also be achieved from the 6a (26.7 mg, 0.1 mmol) via the following
oxidation according to the reported procedure.14b The sample was
found to be congruent (1H, 13C{1H} NMR) to the substance from the
biaryl coupling reaction of 5dj.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (No. 21662027), the Program for
Leading Talents of Ningxia Province (KJT2015002), and the
Natural Science Foundation of Ningxia (NZ17035).
REFERENCES
■
(1) For several selected reviews, see: (a) Wrobleski, A.; Coombs, T.
́
C.; Huh, C. W.; Li, S.-W.; Aube, J. Org. React. 2012, 78, 1−320.
́
(b) Wolff, H. Org. React. 2011, 3 (8), 307−336. (c) Aube, J. In
̈
Organic Azides: Synthesis and Applications; Brase, S., Banert, K., Eds.;
Wiley: Weinheim, Germany, 2010; pp 191−237.
́
(2) For representative research on the Schmidt−Aube reaction, see:
́
(a) Aube, J.; Milligan, G. L. Intramolecular Schmidt Reaction of Alkyl
Azides. J. Am. Chem. Soc. 1991, 113, 8965−8966. (b) Gracias, V.;
́
Milligan, G. L.; Aube, J. Efficient Nitrogen Ring-Expansion Process
Anhydrolycorine (6b) and Anhydrolycorinone (7b). The 6b (39.3
mg, 52% yield from 5dk) and 7b (7.9 mg, 14% yield from 5dk) were
prepared from the 5dk (99.6 mg, 0.3 mmol) with the Pd(OAc)2 (6.8
mg, 3% mmol), PCy3 (16.8 mg, 6% mmol), and K2CO3 (82.8 mg, 0.6
mmol) according to the procedure for preparation of 6a and 7a, and
the reaction time for the process was 1 h. Anhydrolycorine 6b: known
Facilitated by in Situ Hemiketal Formation. An Asymmetric Schmidt
Reaction. J. Am. Chem. Soc. 1995, 117, 8047−8048. (c) Desai, P.;
Schildknegt, K.; Agrios, K.; Mossman, A. C. J.; Milligan, G. L.; Aube,
J. Reactions of Alkyl Azides and Ketones as Mediated by Lewis Acids:
Schmidt and Mannich Reactions Using Azide Precursors. J. Am.
́
compound,11 Rf = 0.60 (EtOAc/PE = 1/5); H NMR (CDCl3, 400
1
́
Chem. Soc. 2000, 122, 7226−7232. (d) Katz, C. E.; Aube, J. Unusual
Tethering Effects in the Schmidt Reaction of Hydroxyalkyl Azides
with Ketones: Cation-π and Steric Stabilization of a Pseudoaxial
Phenyl Group. J. Am. Chem. Soc. 2003, 125, 13948−13949.
(e) Sahasrabudhe, K.; Gracias, V.; Fumess, K.; Sminth, B. T.; Katz,
MHz) δ 7.20 (d, J = 7.2 Hz, 1 H), 7.17 (s, 1 H), 7.02 (d, J = 7.6 Hz, 1
H), 6.76 (t, J = 7.2 Hz, 1 H), 6.64 (s, 1 H), 5.97 (s, 2 H), 4.07 (s, 2
H), 3.32 (t, J = 8.0 Hz, 2 H), 3.02 (t, J = 8.0 Hz, 2 H); 13C{1H} NMR
(CDCl3, 100 MHz, plus APT) δ (up) 149.7, 147.6, 146.8, 128.6,
126.2, 125.8, 119.2, 101.2, 55.5, 53.7, 29.2, δ (down) 123.6, 119.8,
119.7, 107.6, 102.8. Anhydrolycorinone 7b: known compound,11 Rf =
0.60 (EtOAc); 1H NMR (CDCl3, 400 MHz) δ 7.90 (s, 1 H), 7.73 (d,
J = 8.0 Hz, 1 H), 7.52 (s, 1 H), 7.28 (d, J = 7.2 Hz, 1 H), 7.18 (t, J =
7.2 Hz, 1 H), 6.13 (s, 2 H), 4.46 (t, J = 8.0 Hz, 2 H), 3.42 (t, J = 8.0
Hz, 2 H); 13C{1H} NMR (CDCl3, 100 MHz, plus APT) δ (up) 159.5,
151.9, 148.4, 139.4, 130.9, 130.7, 123.1, 116.8, 102.1, 46.6, 27.5, δ
(down) 123.8, 123.3, 119.5, 106.8, 100.9, and the sample was found
to be congruent (1H NMR) to the substance previously reported.
Anhydrolycorinone (7b). The 7b (16.2 mg, 61% yield from 6b)
was prepared from the 6b (25.1 mg, 0.1 mmol) with the aqueous
NaOH (3 mol/L, 1 mL) and KMnO4 (30.0 mg, 0.2 mmol) according
to the above oxidation procedure for the preparation of 7a, and the
reaction time for the process was 2 h. The sample was found to be
congruent (1H, 13C{1H} NMR) to the substance from the biaryl
coupling reaction of 5dk.
́
C. E.; Reddy, D. S.; Aube, J. Asymmetric Schmidt Reaction of
Hydroxyalkyl Azides with Ketones. J. Am. Chem. Soc. 2003, 125,
7914−7922.
(3) (a) Gu, P.; Kang, X.-Y.; Sun, J.; Wang, B.-J.; Yi, M.; Li, X.-Q.;
Xue, P.; Li, R. Intramolecular Schmidt Reaction of Acyl Chlorides
with Alkyl Azides: Rapid Access to Fused Polycyclic Nitrogen-
Containing Heterocycles via a Multistep One-Pot Transformation.
Org. Lett. 2012, 14, 5796−5799. (b) Li, X.-J.; Qiao, J.-B.; Sun, J.; Li,
X.-Q.; Gu, P. Intramolecular Schmidt Reaction of Acyl Chlorides with
Alkyl Azides: Capture of N-Acyliminium Ion Intermediates with
Aromatic Rings. Org. Lett. 2014, 16, 2865−2867. (c) Wang, B.-J.;
Xue, P.; Gu, P. Intramolecular Schmidt Reaction of Acyl Chlorides
with Alkyl Azides: Preparation of Pyrrolizine by Intramolecular
Capture of Intermediates with Alkene or Alkyne. Chem. Commun.
2015, 51, 2277−2279. (d) Li, Q.-F.; Li, R.; Li, X.-Q.; Gu, P.
Preparation of Aryl Fused Pyrrolizidines via Intramolecular Schmidt
Reaction of Acyl Chlorides with Alkyl Azides. Youji Huaxue 2015, 35,
2326−2332. (e) Wang, X.-J.; Su, Y.; Li, R.; Gu, P. Tf2O-Promoted
Intramolecular Schmidt Reaction of the ω-Azido Carboxylic Acids. J.
Org. Chem. 2018, 83, 5816−5824.
ASSOCIATED CONTENT
■
S
* Supporting Information
(4) (a) Chaturvedi, D.; Chaturvedi, A. K.; Mishra, N.; Mishra, V.
Efficient, One-Pot, BF3·OEt2-Mediated Synthesis of Substituted N-
Aryl Lactams. Synlett 2012, 23, 2627−2630. (b) Chaturvedi, D.;
Chaturvedi, A. K.; Mishra, N.; Mishra, V. An Efficient and Novel
Approach for the Synthesis of Substituted N-Aryl Lactams. Org.
Biomol. Chem. 2012, 10, 9148−9151.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b03018.
Copies of NMR spectra for the key compounds (PDF)
AUTHOR INFORMATION
(5) Huang, M.-J.; Deng, Z.-X.; Tian, J.; Liu, T.-G. Synthesis and
Biological Evaluation of Salinomycin Triazole Analogues as
Anticancer Agents. Eur. J. Med. Chem. 2017, 127, 900−908.
(6) Braddock, D. C.; Lickiss, P. D.; Rowley, B. C.; Pugh, D.;
Purnomo, T.; Santhakumar, G.; Fussell, S. J. Tetramethyl
Orthosilicate (TMOS) as a Reagent for Direct Amidation of
Carboxylic Acids. Org. Lett. 2018, 20, 950−953.
■
Corresponding Author
*Phone: +86(951)206-2274. Fax: +86(951)206-2323. E-mail:
gupm@nxu.edu.cn.
ORCID
Peiming Gu: 0000-0002-2812-4019
Present Address
(7) Thai, K.; Wang, L.; Dudding, T.; Bilodeau, F.; Gravel, M. NHC-
Catalyzed Intramolecular Redox Amidation for the Synthesis of
Functionalized Lactams. Org. Lett. 2010, 12, 5708−5711.
†Y.J.: Shanghai Key Laboratory of Green Chemistry and
Chemical Processes, School of Chemistry and Molecular
Engineering, East China Normal University, 3663 N
Zhongshan Road, Shanghai 200062, China.
(8) Andersson, H.; Demaegdt, H.; Vauquelin, G.; Lindeberg, G.;
́
Karlen, A.; Hallberg, M. Ligands to the (IRAP)/AT4 Receptor
Encompassing a 4-Hydroxydiphenylmethane Scaffold Replacing Tyr2.
Bioorg. Med. Chem. 2008, 16, 6924−6935.
Notes
(9) Sharp, L. A.; Zard, S. Z. A Short Total Synthesis of
( )-Aspidospermidine. Org. Lett. 2006, 8, 831−834.
The authors declare no competing financial interest.
2020
DOI: 10.1021/acs.joc.8b03018
J. Org. Chem. 2019, 84, 2012−2021

The Journal of Organic Chemistry
Article
(10) Tsukano, C.; Muto, N.; Enkhtaivan, I.; Takemoto, Y. Synthesis
of Pyrrolophenanthridine Alkaloids Based on C(sp3)-H and C(sp2)-H
Functionalization Reactions. Chem. - Asian J. 2014, 9, 2628−2634.
(11) Harayama, T.; Hori, A.; Abe, H.; Takeuchi, Y. Concise
Synthesis of Pyrrolophenanthridine Alkaloids using A Pd-mediated
Biaryl Coupling Reaction with Regioselective C−H Activation via the
Intramolecular Coordination of the Amine to Pd. Tetrahedron 2004,
60, 1611−1616.
(20) Cui, J.-F.; Chen, C.; Gao, X.; Cai, Z.-W.; Han, J.-W.; Wong, H.-
N. 2, 3, 10, 11-Tetrahydroxytetraphenylene and Its Application in
Molecular Recognition. Helv. Chim. Acta 2012, 95, 2604−2620.
(21) Thai, K.; Wang, L.; Dudding, T.; Bilodeau, F.; Gravel, M.
NHC-Catalyzed Intramolecular Redox Amidation for the Synthesis of
Functionalized Lactams. Org. Lett. 2010, 12, 5708−5711.
(22) Kita, Y.; Haruta, J.; Tagawa, H.; Tamura, Y. Facile and Efficient
Carboalkoxylation and Carboaryloxylation of Amines. J. Org. Chem.
1980, 45, 4519−4522.
(23) Leow, D. Phenazinium Salt-Catalyzed Aerobic Oxidative
Amidation of Aromatic Aldehydes. Org. Lett. 2014, 16, 5812−5815.
(24) Anbazhagan, M.; Deshmukh, A. R. A.; Rajappa, D. S.
Conversion of Carbonimidodithioates into Unsymmetrical Di-and
Tri-substituted Ureas Including Urea Dipeptides. Tetrahedron Lett.
1998, 39, 3609−3612.
(25) Hennessy, E. J.; Buchwald, S. L. Synthesis of Substituted
Oxindoles from α-Chloroacetanilides via Palladium-Catalyzed C−H
Functionalization. J. Am. Chem. Soc. 2003, 125, 12084−12085.
(12) For the synthesis of assoanine, see: (a) Parnes, J. S.; Carter, D.
S.; Kurz, L. J.; Flippin, L. A. Concise Synthesis of Narcissus
Pyrrolophenanthridine Alkaloids: Vasconine, Assoanine and Oxoas-
soanine. J. Org. Chem. 1994, 59, 3497−3499. (b) Xiong, Y.; Moore,
H. W. Ring Expansion of 4-Alkynylcyclobutenones. Synthesis of
Piperidinoquinones, Highly Substituted Dihydrophenanthridines,
Benzophenanthridines, and the Naturally Occurring Pyrrolophenan-
thridine, Assoanine. J. Org. Chem. 1996, 61, 9168−9177. (c) Rosa, A.
́
M.; Lobo, A. M.; Branco, P. S.; Prabhakar, S.; Sa-da-Costa, M. New
Syntheses of the Amaryllidacaea Alkaloids Vasconine Assoanine,
Oxoassoanine, Pratosine and Ismine by Radical Cyclisation.
Tetrahedron 1997, 53, 299−306. (d) De, S.; Ghosh, S.; Bhunia, S.;
Sheikh, J. A.; Bisai, A. Intramolecular Direct Dehydrohalide Coupling
Promoted by KOtBu: Total Synthesis of Amaryllidaceae Alkaloids
Anhydrolycorinone and Oxoassoanine. Org. Lett. 2012, 14, 4466−
4469. (e) Rocaboy, R.; Dailler, D.; Baudoin, O. A Four-Step Synthesis
of ( )-γ-Lycorane via Pd0-Catalyzed Double C (sp2)−H/C (sp3)−H
Arylation. Org. Lett. 2018, 20, 772−775.
(13) For the synthesis of oxoassoanine, see: (a) Meyers, A. I.;
Hutchings, R. H. A Total Synthesis of the Pyrrolophenthridone
Alkaloid Oxoassoanine. Tetrahedron Lett. 1993, 34, 6185−6188.
(b) Ganton, M. D.; Kerr, M. A. A Domino Amidation Route to
Indolines and Indoles: Rapid Syntheses of Anhydrolycorinone,
Hippadine, Oxoassoanine, and Pratosine. Org. Lett. 2005, 7, 4777−
4779. (c) Weinstein, A. B.; Ellman, J. A. Convergent Synthesis of
Diverse Nitrogen Heterocycles via Rh(III)-Catalyzed C−H Con-
jugate Addition/Cyclization Reactions. Org. Lett. 2016, 18, 3294−
3297. (d) See also refs 11, 12a, and 12d.
(14) For the synthesis of anhydrolycorine, see: (a) Hara, H.;
Hoshino, O.; Umezawa, B. Synthesis of Anhydrolycorine and
Dimethylapoerysopine. Tetrahedron Lett. 1972, 13, 5031−5034.
(b) Torres, J. C.; Pinto, A. C.; Garden, S. J. Application of a
Catalytic Palladium Biaryl Synthesis Reaction via C−H Functionaliza-
tion to the Total Synthesis of Amaryllidaceae alkaloids. Tetrahedron
2004, 60, 9889−9900. (c) see also in references 11 and 12d.
(15) For the synthesis of anhydrolycorinone, see: (a) Banwell, M. G.
Trifluoromethanesulfonic Anhydride−4-(N, N-dimethylamino)-
pyridine as a Reagent Combination for Effecting Bischler−Napieraiski
Cyclisation under Mild Conditions: Application to Total Syntheses of
the Amaryllidaceae Alkaloids N-Methylcrinasiadine, Anhydrolycor-
inone, Hippadine and Oxoassoanine. J. Chem. Soc., Chem. Commun.
1995, 2551−2553. (b) Hutchings, R. H.; Meyers, A. I. An Oxazoline-
Mediated Synthesis of the Pyrrolophenanthridine Alkaloids and Some
Novel Derivatives. J. Org. Chem. 1996, 61, 1004−1013. (c) See also
refs 11, 12d, and 13b.
(16) Huang, M.-J.; Deng, Z.-X.; Tian, J.; Liu, T.-G. Synthesis and
Biological Evaluation of Salinomycin Triazole Analogues as
Anticancer Agents. Eur. J. Med. Chem. 2017, 127, 900−908.
(17) Wang, C.; Liu, R.-H.; Tian, M.-Q.; Hu, X.-H.; Loh, T.-P.
Regioselective Copper-Catalyzed Oxidative Coupling of α-Alkylated
Styrenes with Tertiary Alkyl Radicals. Org. Lett. 2018, 20, 4032−4035.
(18) Hsu, S.-W.; Cheng, H.-Y.; Huang, A.-C.; Ho, T.-L.; Hou, D.-R.
Total Synthesis of Quebrachamine through Macrolactamization. Eur.
J. Org. Chem. 2014, 2014, 3109−3115.
́
(19) Philippe, N.; Levacher, V.; Dupas, G.; Queguiner, G.;
Bourguignon, J. Diastereoselective Protonation of Lactam Enolates
Derived from (R)-phenylglycinol. A Novel Asymmetric Route to 4-
phenyl-1, 2, 3, 4-tetrahydroisoquinolines. Org. Lett. 2000, 2, 2185−
2187.
2021
DOI: 10.1021/acs.joc.8b03018
J. Org. Chem. 2019, 84, 2012−2021