Schmidt Reaction of ω-Azido Valeryl Chlorides Followed by Intermolecular Trapping of the Rearrangement Ions: Synthesis of Assoanine and Related Pyrrolophenanthridine Alkaloids

Article abstract of DOI:10.1021/acs.joc.8b03018

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.

Full text of DOI:10.1021/acs.joc.8b03018

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Article
Schmidt Reaction of #-Azido Valeryl Chlorides Followed by
Intermolecular Trapping the Rearrangement Ions: Synthesis
of Ossoanine and Related Pyrrolophenanthridine Alkaloids
Shao-Lei Ding, Yang Ji, Yan Su, Rui Li, and Peiming Gu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03018 • Publication Date (Web): 14 Jan 2019
Downloaded from http://pubs.acs.org on January 14, 2019
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Schmidt Reaction of ω-Azido Valeryl Chlorides Followed by
Intermolecular Trapping the Rearrangement Ions: Synthesis of
Ossoanine and Related Pyrrolophenanthridine Alkaloids
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Shao-Lei Ding, Yang Ji†, Yan Su, Rui Li, Peiming Gu*
Department of Chemistry, Ningxia University, Yinchuan 750021, China
Phone: +86(951)206-2274
Fax: +86(951)206-2323
E-mail: gupm@nxu.edu.cn
Tables of contents
R
R
R
N
R
R
TfOH
N3
NuH
O
N
C
O
N
N
+
+
O
O
Cl
O
Nu
Nu
NuH : arene, alcohol, amine
Synthetic application:
N
N
N
N
O
O
MeO
MeO
O
O
O
O
OMe
assoanine
OMe
oxoassoanine
anhydrolycorinone
anhydrolycorine
ABSTRACT
The Schmidt reaction of ω-azido valeryl chlorides in 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
The Schmidt-Aubé reaction is involved with the rearrangement 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-Aubé reaction.3 Rearrangement of the intermediate would produce isocyanate ion and N-
acyliminium ion as the primary products. Therefore, a nucleophile was pre-installed 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 with an intramolecular Schmidt-Aubé
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 us confusing that
the intermolecular Friedel–Crafts acylation was preferred over the intramolecular Schmidt reaction
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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 with trapping the rearrangement
ions with several different nucleophiles (arenes, alcohols, and amines) and application of the
conversion in synthesis of ossoanine and related alkaloids.
1. Schmidt-Aubé reaction of alkyl azides with ketone
m
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m
N3
R
ALO
m
N
R
N
R
O
N2
O
2. Previous Schmidt reaction of ω-azido acid chloride in our group
(with intramolecular capture of the ion intermediates with a nucleophile )
Nu
Nu
a
N
C
O
N
Nu
O
N
Cl
O
N3
N2
O
isocyanate ion
Nu = Ar
Nu
Nu
b
O
N
N
O
N
Nu
O
Cl
N3
N2
O
N-acyliminium ion
Nu = Ar
R
R
3. the work of Chaturvedi's group:
.
cat. EtAlCl2 or BF3 OEt2
+
O
R
O
N
Cl
N3
O
N3
F-C acylation followed by intramolecular Schmidt rection of alkyl azides with ketones
4. Part work of this research:
R'
R'
R'
O
N
N
TfOH
+
+
R
O
O
Cl
N3
R
R
Schmidt reaction of alkyl azides with acid chlorides followed by arene trapping
Scheme 1. Reaction of ω-azido acid chloride with an arene
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.
Table 1. Optimization of the reaction of 5-azidopentanoic acid 1a and benzene 2aa
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entry
Acid
Reaction
time (h)b
3aa/4aa
Combined
yield (%)c
promoter
6
7
8
9
1
2
TiCl4
SnCl4
46
46
46
46
46
46
46
22
46
46
46
46
-/37
6/19
-/-
37
25
0
.
3
BF3 OEt2
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4
AlCl3
EtAlCl2
TFA
-/24
24
0
5
-/-
6
-/-
0
7
TfOH
44/34
36/26
34/28
43/34
51/35
53/32
78
62
62
77
86
85
8
TfOH
9
TfOHd
TfOHe
TfOHf
TfOHe,f
10
11
12
a) Treatment of 1a (1.0 mmol) in DCM (1.5 mL) with (COCl)2 (1.4 mmol) at 30 ºC for 1.5 h followed with the
acid (2.0 equiv) promoter at 0 ºC, then benzene 2a (5.0 mmol) was applied and kept the mixture at refluxing for
capture reaction; b) time for the capture process; c) isolated combined yield; d) benzene (3.0 equiv) employed; e)
TfOH (4.0 equiv) employed; f) benzene was applied before TfOH.
.
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 mins 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 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 literatures.6,7 If the capture process was shorten to 22 h, formation of 3aa and 4aa
was slightly reduced (entry 8 vs entry 7, Table 1). The 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 emloyed before TfOH (entries 11 and 12, Table 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.
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 being captured (entry 2, Table 2),
where the isocyanate ion might be hydrolyzed into pyrrolidine and lost in the workup procedure.
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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.
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Table 2. Schmidt reaction of 1a followed with trapping the rearrangement ions with nucleophilesa
Time
(h)b
yield
entry
3 and 4
2
(3/4)c
73%
1
46
46
(35/38)
2b
2c
3ab
4ab
38%
2
(-/38)
4ac
67%
3
46
4
(27/40)
2d
2e
3ad
3ae
4ad
4ae
73%
4d
5d
6d
(58/15)
73%
22
4
(37/36)
2f
3af
4af
58%
(58/-)
2g
3ag
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59%
7d
4
(59/-)
2h
3ah
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a) Treatment of 1a (1.0 mmol) in DCM (1.5 mL) with (COCl)2 (1.4 mmol) at 30 ºC for 1.5 h followed with TfOH
(2.0 mmoL) at 0 ºC, then nucleophile 2 (5.0 mmol) was applied and kept the mixture at refluxing for capture reaction;
b) time for the capture process; c) isolated combined yield and ratio of 3 and 4; d) TfOH (4.0 equiv) employed and
the capture reaction at room temperature.
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Table 3. Schmidt reaction of 1b and 1c followed by trapping the rearrangement ions with nucleophilesa
R2
R1
R1
O
R2
1) (COCl)2
R1
O
R2
N
N
+
2) TfOH, NuH 2
OH N3
O
Ar
Ar
4bx or 4cx
1b: R1 = Et, R2 = H;
1c: R1 = H, R2 = Et;
3bx or 3cx
Time
Yield
entry
3 and 4
1
2
(h)b
(3/4)c
72
1
46
2a
(6:1)
3ba
4ba
62
2d
3d
4d
5
22
4
2f
2g
2h
2a
(62/-)
3bf
3bg
3bh
4ca
1b
75
(75/-)
56
4
(56/-)
82
46
(-/82)
79
6
7
46
46
2b
2c
(1:5)
1c
3cb
4cb
35
(-/35)
4cc
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a) Treatment of 1b or 1c (1.0 mmol) in DCM (1.5 mL) with (COCl)2 (1.4 mmol) at 30 ºC for 1.5 h followed
with TfOH (2.0 mmol) at 0 ºC, then the corresponding nucleophile 2 (5.0 mmol) was applied and kept the mixture
at refluxing for capture reaction; b) time for the capture process; c) isolated combined yield and ratio of 3 and 4; d)
TfOH (4.0 equiv) employed and the capture reaction at room temperature.
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,3b 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 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 trace isocyanate ion from 1c
could be 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 with 1,4-dichlorobenzene 2c gave
amide 4cc with only moderate yield (entry 7, Table 3).
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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-dimethoxybenzene 2i, 4-bromo-1,2-
dimethoxybenzene 2j, 5-bromobenzo[d][1,3]dioxole 2k and 4-iodo-1,2-dimethoxybenzene 2l were
employed for trapping the promised N-acyliminium ion, and all gave the corresponding 2-
oxoindoles with good to excellent yields.
Scheme 2. Schmidt reaction of 1d and synthesis of assoanine and related alkaloids.
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.
To demonstrate the synthetic utility, the 2-oxoindoles 4dj and 4dk were efficiently reduced by 9-
BBN9, and the crude reaction mixtures were further treated with NaBH3CN10, 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
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7b15 in 14% yield. Furthermore, assoanine 6a and anhydrolycorine 6b could be oxidized with
KMnO4 into oxoassoanine 7a in 63% yield and anhydrolycorinone 7b in 61% yield.14b
6
7
8
9
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 the
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 exploring in the laboratory.
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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 = 7.26) was used as an
1
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
Perkin Elmer 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.
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),
then the mixture was heated to 75 ºC 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 colourless oil (5.08 g, 98%
yield from 8a). 9a: Rf = 0.67 (EtOAc/PE = 1/1); 1H NMR (CDCl3, 400 MHz) δ 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 ºC for 24 h. Then the reaction mixture was cooled to room temperature
and treated with 1 N HCl for adjusting the mixture with PH<3. The mixture was extracted by EtOAc
(40 mL×3), washed with brine (10 mL×3), dried over Na2SO4 and concentrated, then the residue
was purified by flash column chromatography to afford the 5-azidopentanoic acid 1a as a light
1
yellow oil (4.18 g, 96% yield from 9a). 1a: known compound16, Rf = 0.57 (EtOAc/PE = 1/5); H
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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, 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.
Ethyl 5-bromo-2-ethylpentanoate and ethyl 5-iodide-2-ethylpentanoate (8b). To a stirred
solution of N, N-diisopropylamine (2.64 g, 26.0 mmol) in dry THF (60 mL) at 0 ºC 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 ºC
for 15 min, then it was cooled to -78 ºC 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 ºC for 45 min, 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-ethylpentanoate
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.
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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 ºC (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
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yellow oil (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 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
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mL) was added dropwise. Then the mixture was allowed to vigorous 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 compound17, Rf = 0.29 (EtOAc/PE
= 1/5); 1H NMR (CDCl3, 400 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).
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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 compound18,
Rf = 0.37 (EtOAc/PE = 1/5); 1H 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 ºC) 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). 15: Rf = 0.30 (EtOAc/PE = 1/5); 1H NMR (CDCl3, 400 MHz) δ 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 75ºC for 22 h,
and quenched with saturated NH4Cl (10 mL) and treated with 1 N HCl for adjusting the mixture
with 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 Hz
and 4.8 Hz, 1 H), 3.56 (dd, J = 6.0 Hz 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 chromatography to afford the 4-cyano-2-ethylbutyl 4-methylbenzenesulfonate 17 as a
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yellow oil (3.38 g, 84% yield from 16). 17: Rf = 0.53 ( EtOAc/PE = 1/2 ); H NMR (CDCl3, 400
MHz) δ 7.79 (d, J = 8.0 Hz, 2 H), 7.37 (d, J = 8.0 Hz, 2 H), 3.99 (dd, J = 10.0 Hz and 3.6 Hz, 1 H),
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3.92 (dd, J = 10.0 Hz 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 ºC (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 g, 97% yield from 17). 18: Rf = 0.63 (EtOAc/PE = 1/1); 1H NMR (CDCl3,
400 MHz) δ 3.40 (dd, J = 12.4 Hz and 4.0 Hz, 1 H), 3.31 (dd, J = 12.4 Hz 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 with 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% yield from 18). 1c: Rf = 0.42 (EtOAc/PE = 1/5); 1H 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.
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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)
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according to the reported procedure19. 20: known compound19, Rf = 0.56 (EtOAc/PE = 1/20); H
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 procedure8. 21: known compound8, 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.
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 ºC for 19
h. 1d: known compound8, a white solid, Mp 113.3-115.5 ºC, Rf = 0.48 (EtOAc/PE = 1/1); 1H NMR
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(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.
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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 ºC , 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 ºC, and
the mixture was heated to reflux (oil bath at 60 ºC) 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 compound6: 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 found 198.0893. Further elution gave
the 4aa, known compound21, a light yellow oil, Rf = 0.31 (EtOAc); 1H 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.
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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 wtih (COCl)2 (177.7 mg, 1.4 mmol) for 1.5 h at 30 ºC , then the TfOH (600.2 mg,
4.0 mmol) was slowly added into the reaction mixture at 0 ºC. 15 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), 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 4ae (21.7 mg, 15% yield from 1a). 3ae known compound22: 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: a colorless oil,
Rf = 0.30 (MTBE); 1H 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 the Procedure A for preparation of 3aa
and 4aa, and the reaction time for the capture process was 46 h. 3ab: a light yellow oil, Rf = 0.67
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(EtOAc); 1H 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 the 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 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.
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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 the Procedure A for preparation of 3aa and
4aa, and the reaction time for the capture process was 46 h. 4ac: a colorless oil, Rf = 0.41 (EtOAc/PE
= 1/1); 1H 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-(naphthalen-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 the Procedure A for preparation of
3aa and 4aa, and the reaction time for the capture process was 46 h. 3ad, known compound23, 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 (EtOAc); 1H 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.
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 the Procedure B for 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,
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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.
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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 the Procedure B for preparation of 3ae and 4ae, and the capture process
was carried out at room temperature for 4 h. 3ag, known compound24, Rf = 0.48 (EtOAc); 1H NMR
(CDCl3, 400 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.
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 the Procedure B for preparation of 3ae and 4ae, and the capture
process was carried out at room temperature for 4 h. 3ah: a light yellow oil, Rf = 0.31 (EtOAc/PE
= 1/5); 1H NMR (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.
(2-Ethylpyrrolidin-1-yl)(phenyl)methanone (3ba) and benzyl-3-ethylpyrrolidin-2-one
(4ba).The mixture of 3ba and 4ba (3ba/4ba = 6/1 from 1H NMR, 145.5 mg, 72% combined yield
from 1b) were 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 the Procedure A for 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, mixture of rotamer (3:1 from 1H NMR), Rf = 0.69 (EtOAc/PE = 1/2); 1H 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
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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
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1
= 1/10); mixture of rotamers, (1:1 from 13C{1H} NMR) H NMR (CDCl3, 400 MHz) δ 4.00-4.06
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(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.
N-Butyl-2-ethylpyrrolidine-1-carboxamide (3bg). The 3bg (149.1 mg, 75% yield from 1b) was
prepared from the Schmidt reaction of 1b (171.2 mg, 1.0 mmol) with the nucleophile n-Butylamine
2g (365.7 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 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.
(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 the Procedure B for 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 = 1/5); 1H NMR (CDCl3, 400 MHz) δ 3.96-3.99 (m, 1 H), 3.16-3.33 (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.
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 the Procedure A for preparation of 3aa and 4aa, and the reaction time for
the capture process was 46 h. 4ca: a colorless oil, Rf = 0.75 (EtOAc); 1H 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-
1
ethylpyrrolidin-2-one (4cb). The 3cb and 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
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the nucleophile p-xylene 2b (530.8 mg, 5.0 mmol) according to the Procedure A for 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 232.1698. 4cb: a light yellow oil, Rf = 0.45 (EtOAc/PE = 1/1); 1H
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.
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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 the Procedure A for 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 the Procedure A for preparation of 3aa and 4aa, and the in situ
formation of acyl chloride was carried out at 45 ºC for 1 h, where the reaction time for the capture
1
process was 23 h. 4da, known compound25, Rf = 0.69 (EtOAc/PE = 1/5), H 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,
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 the Procedure B for
preparation of 3aa and 4aa, and the in situ formation of acyl chloride was carried out at 45 ºC for 1
h, where the capture reaction was promoted with TfOH (300.1 mg, 2.0 mmol) at 0 ºC for 6 h. 4di:
Rf = 0.39 (EtOAc/PE = 1/1), Mp 119.7-120.2 ºC ; 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,
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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.
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1-(2-Bromo-4,5-dimethoxybenzyl)indolin-2-one (4dj). Two different capturing conditions
were employed for preparation of the 4dj from the reaction of 1d with 2j, and the followings 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 the Procedure A for preparation of 4da, and the in situ formation
of acyl chloride was carried out at 45 ºC for 1 h, where the capture reaction was promoted with
TfOH (300.1 mg, 2.0 mmol) at 60 ºC 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 the Procedure B for preparation
of 4di, and the in situ formation of acyl chloride was carried out at 45 ºC for 1 h, where the capture
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reaction was promoted with TfOH (300.1 mg, 2.0 mmol) at 0 ºC for 6 h. 4dj, known compound12d
,
Rf = 0.61 (EtOAc/PE = 1/1), Mp 156.3-158.0 ºC; 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 the
Procedure B for preparation of 4di, and the in situ formation of acyl chloride was carried out at 45
ºC for 1 h, where the capture reaction was promoted with TfOH (300.1 mg, 2.0 mmol) at 0 ºC for 6
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h. 4dk, known compound12d, Rf = 0.62 (EtOAc/PE = 1/2), Mp 145.2-145.3 ºC ; H 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 the Procedure B for
preparation of 4di, and the in situ formation of acyl chloride was carried out at 45 ºC for 1 h, where
the capture reaction was promoted with TfOH (300.1 mg, 2.0 mmol) at 0 ºC for 0.5 h. 4dl: a white
1
solid, Mp 161.5-161.7 ºC , Rf = 0.44 (EtOAc/PE = 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
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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 with PH>7, 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
compound11, 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.
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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 compound11, Rf =
0.64 (EtOAc/PE = 1/10); 1H 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), K2CO3 (82.8 mg, 0.6 mmol), and the mixture was heated to
125 ºC (oil bath) for 1 h. Then the mixture was cooled to room temperature and treated with water
(2 mL), and 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 compound11, 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 (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 compound11, 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 (17.8mg, 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 procedure14b. The sample
was found to be congruent (1H, 13C{1H} NMR) to the substance from the biaryl coupling reaction
of 5dj.
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), 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.
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Anhydrolycorine 6b: known compound11,Rf = 0.60 (EtOAc/PE =1/5); 1H NMR (CDCl3, 400 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 compound11,
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.
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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), KMnO4 (30.0 mg, 0.2 mmol) according
to the above oxidation procedure for 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.
AUTHOR INFORMATION
Corresponding Author
*gupm@nxu.edu.cn
Present Addresses
†Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and
Molecular Engineering, East China Normal University, 3663N Zhongshan Road, Shanghai 200062,
China
ACKNOWLEDGMENT
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).
SUPPORTING INFORMATION
The Supporting Information (copies of NMR spectra for the key compounds) is available free of
charge on the ACS Publications website
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