Tf2O-Promoted Intramolecular Schmidt Reaction of the ω-Azido Carboxylic Acids

Article abstract of DOI:10.1021/acs.joc.8b00475

A designed Tf₂O-promoted intramolecular Schmidt reaction of 2-substituted ω-azido carboxylic acids was demonstrated. Tf₂O was used as an activation reagent for the carboxylic acid, and ω-azido anhydride was in situ generated, releasing a molecular TfOH, which acted as an acid promoter for the Schmidt process. A series of 2-substituted pyrrolidines was produced and acetylated for better purification. The strategy was also efficient for conversion of a 4-substituted ω-azido carboxylic acid to the tricyclic lactam.

Full text of DOI:10.1021/acs.joc.8b00475

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A Tf2O-promoted Intramolecular Schmidt
Reaction of the #-Azido Carboxylic Acids
Xue-Juan Wang, Yan Su, Rui Li, and Peiming Gu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00475 • Publication Date (Web): 18 Apr 2018
Downloaded from http://pubs.acs.org on April 18, 2018
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A Tf2Oꢀpromoted Intramolecular Schmidt Reaction of the ωꢀAzido
Carboxylic Acids
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XueꢀJuan Wang, Yan Su, Rui Li, Peiming Gu*
Department of Chemistry, Ningxia University, Yinchuan 750021, China
Phone: +86(951)206ꢀ2274
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Fax: +86(951)206ꢀ2323
Eꢀmail: gupm@nxu.edu.cn
Tables of contents
O
H
N
cut
CO2H
N
R
R
R
Ac2O
Tf2O
N
N2
cut
* decarboxylation
* denitrogenation *
* annulation
acetylation of pyrrolidines for better purification
* 9 examples, and 49-80% yield for two steps
ring formed
Abstract
A designed Tf2Oꢀpromoted intramolecular Schmidt reaction of the 2ꢀsubstituted ωꢀazido
carboxylic acids was demonstrated. The Tf2O was used as an activation reagent for the carboxylic
acid, and the ωꢀazido anhydride was in situ generated with releasing a molecular TfOH, acting as
an acid promoter for the Schmidt process. A series of 2ꢀsubstituted pyrrolidines were produced
and acetylated for better purification. The strategy was also efficient for conversion of a
4ꢀsubstituted ωꢀazido carboxylic acid to the tricyclic lactam.
Main Text
The Schmidt reaction is an acidꢀpromoted reaction of an azide with an electrophile, and it
involves the carbonꢀskeleton rearrangement and extrusion of nitrogen gas.1 In the last thirty years,
the alkyl azides were extensively explored for the Schmidt reaction, and they were demonstrated
as the very successful substrates when the carbonyl compounds, ketones3 and aldehydes2, were
used as the electrophiles. The conversion developed by Aubé’s group provides a powerful strategy
for construction of the nitrogenꢀcontaining molecules, especially for the synthesis of the bioactive
nature products. However, the carboxylic acids were more challenging for the analogue reaction of
alkyl azides, which might be due to their low reactivities. An in situ activation strategy of the
carboxylic acids for the Schmidt reaction was reported in our group (Scheme 1), where the oxalyl
chloride was employed as the activator for the carboxyl group, and then an additional acid
promoter was added to facilitate the following rearrangement process.4 In this paper, we report a
designed Tf2Oꢀpromoted intramolecular Schmidt reaction of several ωꢀazido carboxylic acids, and
the addition of an acid promoter is reduced.
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Our Previous work (in situ activation of the carboxyl group by oxalyl chloride)
a) isocyanate ion from the Schmidt reaction captured by an aromatic ring
1) (COCl)2
(1)
(2)
(3)
R
R
R
N
N
2) LA
N3
C
HO
O
O
7
O
8
9
b) N-acyliminium ion from the Schmidt reaction captured by an aromatic ring
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1) (COCl)2
R
R
R
N
N
O
2) TfOH
O
N3 HO
O
O
This work (in situ activation of the carboxyl group by Tf2O)
isocyanate ion from the Schmidt reaction captured by H2O
O
O
H
H2O
Ac2O
Tf2O
C
R
R
N
R
OH
R
N
N
N3
Tf2O as the activator for the carboxyl group and the precursor of the acid promoter
Scheme 1. The in situ activation strategy for Schmidt reaction of the ωꢀazido carboxylic acid
The key point of our previous in situ activation strategy relied on the replacement of the
hydroxyl group of the carboxyl group with a chlorine atom, which might possess a better leaving
aptitude during a nucleophilic addition. This manipulation would enhance a proposed
aminodiazonium ion formation, resulting in the sequent skeleton rearrangement under the acidic
conditions. Similarly, here we envisioned that the rearrangement reaction of the ωꢀazido
carboxylic acid could proceed if the carboxylic acid was modified into a suitable mixed anhydride.
It seems that generation of an organic mixed anhydride could be addressed from a carboxylic acid
and another acid anhydride with releasing an additional acid,5 and the newly generated acid was
just required as an acid promoter for the Schmidt reaction. The TfOH has been identified as a
good promoter for our reported Schmidt reaction of alkyl azides with acyl chlorides.4b Therefore,
the Tf2O might be a reasonable anhydride candidate for realizing this proposal. Certainly, further
conversion of the isocyanate ion4a,4c,4d and/or Nꢀacyliminium ion4b,4c from the rearrangement
process to stable products should be necessary, otherwise they could not be easily isolated and
identified.
To test the above hypothesis, the 2ꢀphenyl ωꢀazido carboxylic acid 1a was selected4d for the
initial exploration (Scheme 2). To our delight, treatment of 1a (0.5 mmol) in dichloromethane (2
mL) with 1.5 equiv of Tf2O at room temperature for 12 h afforded an amine 2a as its triflate. After
the basic workup, the free amine 2a could be isolated as the dominant product with 84ꢀ99% yield
from several different trials, but all the samples were accompanied by some impurities. Therefore,
further protection of 2a with acetic anhydride was applied for better purification of the product.
The amide 3a was obtained with 80% yield for two steps, and the H NMR and 13C NMR of 3a
1
were congruent with those previously reported.6 If more Tf2O (4.0 equiv) was used, the triflamide
4a would be delivered with 64% yield, whose structure was confirmed by Xꢀray analysis. The
triflamide 4a might be generated from the amine 2a with the excessive Tf2O, where the Tf2O
played three important roles of the activator for the substrate, a precursor of the acid promoter, and
the protection reagent for the amine. Furthermore, the tricyclic lactam 5a, a previously reported
product4d from the Schmidt reaction activated by oxalyl chloride, was occasionally observed if the
reaction was carried out in a heavier concentration.
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O
H
N
Tf2O (1.5 eq)
basic workup
Ac2O
N
6
7
8
9
O
3a
(80% for two steps)
2a
O
N
OH
N3
5a
1a
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Tf
N
Tf2O (4.0 eq)
H2O workup
4a (64%)
Scheme 2. The Tf2Oꢀpromoted Schmidt reaction of 1a
Next, the scope of 2ꢀsubstituted ωꢀazido carboxylic acid was explored, and the results were
summarized in Scheme 3. The substrates examined here were prepared according to our
previously reported procedure,4 and they all could be delivered to the amides 3 with acceptable to
good overall yields. Among them, the 2ꢀnaphenylꢀ1ꢀacetylpyrrolidine 3b and the
2ꢀphenylꢀ1ꢀacetylpyrrolidine 3c were obtained in 56% and 70% yields. For these two cases, the
tricyclic lactams 5b and 5c (not shown in Scheme 3), generated from cyclization of the aromatic
rings with the isocyanate ions, were obtained with 26% and 16% yields respectively. For the
ωꢀazido carboxylic acids 1dꢀ1g, the potential tricyclic lactam formation was not preferred, and the
amides 3dꢀ3g was obtained with some better yields. Undoubtedly, the alkyl substituted substrates
1h and 1i were also successfully converted to the corresponding amides.
O
O
Me
H
N
R
R
R
1) Tf2O
2) Ac2O
OH
N3
N
1
3
2
O
O
O
Me
Me
Me
N
N
N
3a (80%)
3b (56%)
3c (70%)
Cl
O
O
Cl
O
Me
Me
Me
N
N
N
3d (67%)
3e (74%)
3f (76%)
O
O
Cl
O
Me
Me
Me
N
N
N
3i (68%)
3g (76%)
3h (49%)
Scheme 3. Schmidt reaction of the 2ꢀsubstituted ωꢀazido carboxylic acids
The Tf2Oꢀpromoted Schmidt reaction of the 2ꢀsubstituted ωꢀazido carboxylic acid mainly
afforded the isocyanate ions as the initial products. As the experimental results, the isocyanate ion
products were mainly hydrolyzed to the corresponding pyrrolidines, and the potential
intramolecular addition of aromatic rings onto the isocyanate ions of the 2ꢀaryl (1a and 1b) and
2ꢀbenzyl (1c) substituted substrates did not dominate the following process. It should be noted that
cyclization of the aromatic ring with the isocyanate ion had been furnished under the previous
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conditions.4a,4c In view of the whole conversion, the 2ꢀsubstituted ωꢀazido carboxylic acids
formally experienced a decarboxylation process, the denitrogenation of the azide, and the
annulation for producing a pyrrolidine ring. The 2ꢀsubstituted pyrrolidines could be found as the
vast substructures in many natural products and pharmaceuticals,7 and lots of synthetic strategies
have been reported.8
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Generally, the Schmidt reaction of alkyl azides is reported to be a stereospecific 1,2ꢀmigration
process. To demonstrate it, an enantiomerically pure (R)ꢀ1c (>99% ee) was prepared9 and
submitted to the above experimental conditions (Scheme 4), affording the optically active amide
(R)ꢀ3c (99% ee) and the tricyclic lactam (R)ꢀ5c (99% ee) with similar yields to that from the
racemic 1c, which indicated that the stereochemistry of the migration group was maintained
during the rearrangement.
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Me
O
O
H
1. Tf2O
2. Ac2O
N
OH
N
N3
(R)-1c (>99% ee)
O
(R)-3c (68%, >99% ee)
(R)-5c (16%, >99% ee)
Scheme 4. Schmidt reaction of the enantiomerically pure (R)ꢀ1c
The above experimental results indicated that the Tf2O could efficiently promote the Schmidt
reaction of the 2ꢀsubstituted ωꢀazido carboxylic acids. A possible mechanism of this conversion
was proposed (Scheme 5). The formation of mixed anhydride I from the ωꢀazido carboxylic acid
and Tf2O with releasing a molecular TfOH was a necessary stage, and it initiated the Schmidt
rearrangement process. An intramolecular attack of the azido group upon the carbonyl group of
the mixed anhydride I resulted in forming the aminodiazonium ion intermediate II. Then a
subsequent TfOHꢀpromoted 1,2ꢀmigration of the more substituted carbon to the nitrogen atom
gave the isocyanate ion III, which would be hydrolyzed to a carbamic acid IV. The unstable
carbamic acid would smoothly decompose into the pyrrolidine 2 with releasing a molecular
carbon dioxide gas. Finally, protection of the pyrrolidine with Ac2O would give the
1ꢀacetylpyrrolidine 3 as the ultimate product.
O
Me
O
H
R
R
N
R
H
N
Tf2O
Ac2O
O
Tf
O
Tf
1
2
3
N3
O
- CO2
O
OH
R
OTf
N
N
R
TfOH
N2
I
IV
- TfO-
H
H
O
- H+
O
O
C
R
R
N2
- N2
N
N
II
III
Scheme 5. The possible mechanism of the reaction of 2ꢀsubstituted ωꢀazido carboxylic acid.
We have reported that the isocyanate ion and the N‑acyliminium ion could be generated from
Schmidt reaction of two different type of acyl chlorides. It could be expected that the 4ꢀsubstituted
ωꢀazido carboxylic acid would proceed through the N‑acyliminium ion under the Tf2O conditions.
Then the 4ꢀbenzyl ωꢀazido carboxylic acid 6 was selected to see if the proposed Schmidt reaction
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and the cyclization of the N‑acyliminium ion with an aromatic ring could both proceed well under
the above conditions. Fortunately, treatment of 6 with Tf2O (4.0 equiv) at room temperature for
48h directly afforded the tricyclic lactam 7 in 64% yield (Scheme 6).
Tf2O
N
64%
N3 HO
O
O
7
6
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Scheme 6. Tf2Oꢀpromoted Schmidt reaction of the 4ꢀbenzyl ωꢀazido carboxylic acid
In summary, we have designed and realized the Tf2Oꢀpromoted Schmidt reaction of the ωꢀazido
carboxylic acids, and the Tf2O was employed as the initial activator for the carboxylic acid and the
precursor of the acid promoter for the Schmidt reaction. A series of 2ꢀsubstituted pyrrolidine were
prepared through the hydrolysis of the isocyanate ions from the Schmidt reaction. One tricyclic
lactam was produced from the 4ꢀbenzyl ωꢀazido carboxylic acid, where a further intramolecular
cyclization of the N‑acyliminium ion with the aromatic ring was addressed.
EXPERIMENTAL SECTION
All the reagents were purchased from Acros, Sigma-Aldrich, Alfa-Aesar, aladdin, Accela or
Adamas, and they were used as received. All the solvents were distilled using the classic method
before use. The reactions were monitored by the thin layer chromatography (TLC) on 2.5*10 cm,
250 ꢁm analytical plates coated with silica gel 60 F254, and they were purchased from Qingdao
Haiyang Chemical Co. Ltd. The thin layer chromatography plates were visualized by exposure to
the ultraviolet light (UV, 254 nm) or Phosphomolybdic acid. Purification of the synthetic
compounds by the flash column chromatography employed the neutral Silica gel (200ꢀ300 mesh
or 300ꢀ400 mesh), which were purchased from Qingdao Haiyang Chemical Co. Ltd. The NMR
spectra were recorded on a Bruker 400 MHz spectrometer, and the tetramethylsilane (δ = 0 and δ
1
= 7.26) was used as an internal standard for H NMR (400MHz) and CDCl3 (δ = 77.16) for 13C
NMR(100 MHz), and the 13C NMR were plus APT [methyl and methine (down), methylene
and quaternary carbon (up)]. The IR spectra were recorded on a Perkein Elmer with potassium
bromide crystal optic rectangle. Highꢀresolution mass spectra (HRMS) were measured on a LTQ
Orbitrap XL Domain 35A (Thermo Fisher) spectrometer, and the electro spray ionization (ESI)
was used as the ion source. All the ωꢀazido carboxylic acids were prepared according to our
previously reported procedure,10 and 1a, 1b and 1c had been previously prepared.4a,4d All the
alkylation reactions and the Schmidt reactions were carried out in dry reaction vessels or flasks
under a positive pressure of nitrogen or argon.
Diethyl 2ꢀphenethylmalonate (9d). To a stirred suspension of NaH (60% in mineral oil, 880
mg, 22.0 mmol) in dry THF (73 mL) at room temperature was added a solution of diethyl
malonate (3.52 g, 22.0 mmol) in THF (7 mL). The reaction mixture was kept for 1 h, then a
solution of bromide 8d (3.70 g, 20.0 mmol) in THF (7 mL) was added dropwise. The reaction
mixture was heated to reflux for 23 h, then the mixture was cooled to room temperature, quenched
with saturated NH4Cl (15 mL), extracted with ethyl acetate (20 mL*3), and washed with brine (20
mL). The organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was
purified by flash chromatography to give 9d as a colorless oil (3.70g, 70%). 9d, known
1
compound11; Rf = 0.57, (EtOAC/PE = 1/5); H NMR (CDCl3, 400 MHz) δ: 7.27ꢀ7.30 (m, 2 H),
7.18ꢀ7.23 (m, 3 H), 4.14ꢀ4.25 (m, 4 H), 3.32ꢀ3.36 (m, 1 H), 2.26 (t, J = 7.8 Hz, 2 H), 2.22 (q, J =
8.0 Hz, 2 H), 1.25ꢀ1.29(m, 6 H); 13C NMR (CDCl3, 100 MHz, plus APT) δ up: 169.4 (2), 140.7,
61.4 (2), 33.3, 30.4, and down: 128.6 (2), 128.5 (2), 126.2, 51.3, 14.1 (2).
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Diethyl 2ꢀ(2ꢀchlorophenethyl)malonate (9e). The malonate 9e (4.30 g) was prepared from
diethyl malonate (3.52 g, 22.0 mmol) and bromide 8e (4.39 g, 20.0 mmol) by the procedure for
preparation of 9d, and the yield was 71%. 9e, Rf = 0.5, (EtOAC/PE = 1/5); 1H NMR (CDCl3, 400
MHz) δ: 7.33 (d, J = 7.6 Hz, 1 H), 7.12ꢀ7.23 (m, 3 H), 4.20 (q, J = 7.2 Hz, 4 H), 3.38 (t, J = 7.4 Hz,
1 H), 2.79 (t, J = 7.8 Hz, 2 H), 2.22 (q, J = 7.6 Hz, 2 H), 1.27 (t, J = 7.0 Hz, 6 H); 13C NMR
(CDCl3, 100 MHz, plus APT) δ up: 169.2 (2), 138.3, 134.0, 61.4 (2), 31.1, 28.6, and down: 130.6,
129.6, 127.8, 126.9, 51.4, 14.1 (2); IR (film) 1749, 1731 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+
calcd for C15H19ClO4Na 321.0864, found 321.0867.
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Diethyl 2ꢀ(3ꢀchlorophenethyl)malonate (9f). The malonate 9f (4.96 g) was prepared from
diethyl malonate (3.52 g, 22.0 mmol) and bromide 8f (4.39 g, 20.0 mmol) by the procedure for
preparation of 9d, and the yield was 83%. 9f, Rf = 0.55, (EtOAC/PE = 1/5); 1H NMR (CDCl3, 400
MHz) δ: 7.17ꢀ7.24 (m, 3 H), 7.07 (d, J = 7.2 Hz, 1 H), 4.20 (q, J = 7.2 Hz, 4 H), 3.33 (t, J = 7.4 Hz,
1 H), 2.64 (t, J = 7.8 Hz, 2 H), 2.20 (q, J = 7.8 Hz, 2 H ), 1.27 (t, J = 7.2 Hz, 6 H); 13C NMR
(CDCl3, 100 MHz, plus APT) δ up: 169.2 (2), 142.7, 134.2, 61.5 (2), 33.0, 30.1, and down: 129.8,
128.7, 126.8, 126.4, 51.1, 14.1 (2); IR (film) 1749, 1732 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+
calcd for C15H19ClO4Na 321.0864, found 321.0861.
Diethyl 2ꢀ(4ꢀchlorophenethyl)malonate (9g). The malonate 9g (5.68 g) was prepared from
diethyl malonate (3.52 g, 22.0 mmol) and bromide 8g (4.39 g, 20.0 mmol) by the procedure for
preparation of 9d, and the yield was 95%. 9g, Rf = 0.47, (EtOAC/PE = 1/5); 1H NMR (CDCl3, 400
MHz) δ: 7.23 (d, J = 8.4 Hz, 2 H), 7.11 (d, J = 8.4 Hz, 2 H), 4.13ꢀ4.25 (m, 4 H), 3.32 (t, J = 7.4 Hz,
1 H), 2.63 (t, J = 7.6 Hz, 2 H), 2.19 (q, J = 7.4 Hz, 2 H), 1.26 (t, J = 7.0 Hz, 6 H); 13C NMR
(CDCl3, 100 MHz, plus APT) δ up: 169.0 (2), 139.1, 131.8, 61.3 (2), 32.5, 30.1, and down: 129.8
(2), 128.4 (2), 50.9, 14.0 (2); IR (film) 1750, 1732 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ calcd
for C15H19ClO4Na 321.0864, found 321.0869.
Diethyl 2ꢀcyclohexylmalonate (9h). The malonate 9h (5.86 g) was prepared according to the
literature: To a stirred suspension of KOtBu (4.03 g, 36.0 mmol) in DMSO (30 mL) was added
diethyl malonate (4.80 g, 30.0 mmol) and iodocyclohexane (9.45g, 45.0 mmol). The mixture was
heated to 80℃for 6 h. Then the mixture was cooled to room temperature and quenched with H2O
(25 mL). The mixture was extracted with EA (10 mL * 3), and the combined organic phase was
washed with brine (10 mL * 5), dried over Na2SO4 and concentrated. The residue was purified by
flash chromatography to give 9h a yellowish oil (5.86 g, 81% yield from the diethyl malonate). 9h,
known compound12; Rf = 0.62, (EtOAC/PE = 1/5); 1H NMR (CDCl3, 400 MHz) δ: 4.15ꢀ4.22 (m, 4
H), 3.14 (d, J = 9.2 Hz, 1 H), 2.04ꢀ2.13 (m, 1 H), 1.64ꢀ1.73 (m, 5 H), 1.01ꢀ1.33 (m, 11 H); 13C
NMR (CDCl3, 100 MHz, plus APT) δ up: 168.9 (2), 61.2 (2), 30.9 (2), 26.2, 26.1 (2), and down:
58.5, 38.0, 14.2 (2).
Diethyl 2ꢀheptylmalonate (9i). The malonate 9i (1.18 g) was prepared from diethyl malonate
(1.76 g, 11.0 mmol) and bromide 8i (2.26 g, 10.0 mmol) by the procedure for preparation of 9d,
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and the yield was 46%. 9i, known compound13; Rf = 0.55, (EtOAC/PE = 1/5); H NMR (CDCl3,
400 MHz) δ: 4.19 (q, J = 7.0 Hz, 4 H), 3.31 (t, J = 7.6 Hz, 1 H), 1.86ꢀ1.91 (m, 2 H), 1.22ꢀ1.43 (m,
16 H), 0.87 (t, J = 6.8 Hz, 3 H); 13C NMR (CDCl3, 100 MHz, plus APT) δ up: 169.8 (2), 61.4 (2),
31.9, 29.3, 29.1, 28.9, 27.5, 22.7, and down: 52.2, 14.2 (3).
Diethyl 2ꢀ(3ꢀchloropropyl)ꢀ2ꢀphenethylmalonate (10d). To a stirred suspension of NaH (60%
in mineral oil, 560 mg, 14.0 mmol) in dry THF (40 mL) at room temperature was added a solution
of malonate 9d (3.70 g, 14.0 mmol) in THF (4 mL). The mixture was kept for 1 h, then a solution
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of 1ꢀchloroꢀ3ꢀiodopropane (2.61 g, 12.7 mmol) in THF (4 mL) was added. The mixture was kept
for 22 h. Then the reaction was quenched by saturated NH4Cl (10 mL), extracted with ethyl
acetate (20 mL*3), and washed with brine (20 mL). The organic phase was dried over anhydrous
Na2SO4 and concentrated. The residue was purified by flash chromatography to give the chloride
10d as a slightly yellow oil (3.45 g, 80% yield from the 1ꢀchloroꢀ3ꢀiodopropane). 10d, Rf = 0.55,
(EtOAC/PE = 1/5); 1H NMR (CDCl3, 400 MHz) δ: 7.26ꢀ7.31 (m, 2 H), 7.17ꢀ7.21 (m, 3 H), 4.20 (q,
J = 7.0 Hz, 4 H), 3.54 (t, J = 6.2 Hz, 2 H), 2.50ꢀ2.55 (m, 2 H), 2.17ꢀ2.39 (m, 2 H), 2.09ꢀ2.13 (m, 2
H), 1.69ꢀ1.77 (m, 2 H), 2.17 (t, J = 7.0 Hz, 6 H); 13C NMR (CDCl3, 100 MHz, plus APT) δ up:
171.3 (2), 141.3, 61.4 (2), 57.1, 44.9, 34.6, 30.6, 30.2, 27.6, and down: 128.5 (2), 128.4 (2), 126.1,
14.2 (2); IR (film) 1729 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ calcd for C18H25ClO4Na
363.1334, found 363.1333.
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Diethyl 2ꢀ(2ꢀchlorophenethyl)ꢀ2ꢀ(3ꢀchloropropyl)malonate (10e). The chloride 10e (3.90 g)
was prepared from malonate 9e (4.30 g, 14.4 mmol) and 1ꢀchloroꢀ3ꢀiodopropane (2.68 g, 13.1
mmol) by the procedure for preparation of 10d, and the yield was 79%. 10e, Rf = 0.51,
(EtOAC/PE = 1/5); 1H NMR (CDCl3, 400 MHz) δ: 7.33 (d, J = 7.2 Hz, 1 H), 7.12ꢀ7.23 (m, 3 H),
4.22 (q, J = 7.2 Hz, 4 H), 3.57 (t, J = 6.4 Hz, 2 H), 2.62ꢀ2.66 (m, 2 H), 2.13ꢀ2.18 (m, 4 H),
1.73ꢀ1.80 (m, 2 H), 1.28 (t, J = 7.2 Hz, 6 H); 13C NMR (CDCl3, 100 MHz, plus APT) δ up: 171.3
(2), 138.9, 133.9, 61.5 (2), 57.1, 44.9, 32.8, 30.0, 28.6, 27.6, and down: 130.6, 129.6, 127.8, 127.0,
14.2 (2); IR (film) 1728 cmꢀ1; IR(film) 1729 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ calcd for
C18H24Cl2O4Na 397.0944, found 397.0950.
Diethyl 2ꢀ(3ꢀchlorophenethyl)ꢀ2ꢀ(3ꢀchloropropyl)malonate (10f). The chloride 10f (4.98 g)
was prepared from malonate 9f (4.96 g, 16.6 mmol) and 1ꢀchloroꢀ3ꢀiodopropane (3.09 g, 15.1
mmol) by the procedure for preparation of 10d, and the yield was 88%. 10f, Rf = 0.52,
(EtOAC/PE = 1/5); 1H NMR (CDCl3, 400 MHz) δ: 7.17ꢀ7.27 (m, 3 H), 7.05 (d, J = 6.8 Hz, 1 H),
4.18ꢀ4.25 (m, 4 H), 3.54 (t, J = 6.4 Hz, 2 H), 2.50ꢀ2.54 (m, 2 H), 2.09ꢀ2.23 (m, 4 H), 1.68ꢀ1.77 (m,
2 H), 1.28 (t, J = 7.2 Hz, 6 H); 13C NMR (CDCl3, 100 MHz, plus APT) δ up: 171.2 (2), 143.4,
134.2, 61.5 (2), 57.0, 44.9, 34.4, 30.4, 30.3, 27.6, and down: 129.8, 128.5, 126.7, 126.4, 14.2 (2);
IR (film) 1728 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ calcd for C18H24Cl2O4Na 397.0944, found
397.0948.
Diethyl 2ꢀ(4ꢀchlorophenethyl)ꢀ2ꢀ(3ꢀchloropropyl)malonate (10g). The chloride 10g (4.66 g)
was prepared from malonate 9g (5.68 g, 19.0 mmol) and 1ꢀchloroꢀ3ꢀiodopropane (3.54 g, 17.0
mmol) by the procedure for preparation of 10d, and the yield was 72%. 10g, Rf = 0.45,
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(EtOAC/PE = 1/5); H NMR (CDCl3, 400 MHz) δ: 7.23ꢀ7.27 (m, 2 H), 7.10ꢀ7.12 (m, 2 H),
4.18ꢀ4.23 (m, 4 H), 3.55 (t, J = 6.4 Hz, 2 H), 2.48ꢀ2.52 (m, 2 H), 2.03ꢀ2.17 (m, 4 H), 1.67ꢀ1.76 (m,
2 H), 1.26ꢀ1.29 (m, 6 H);13C NMR (CDCl3, 100 MHz, plus APT) δ up: 171.2 (2), 139.8, 131.9,
61.5 (2), 57.0, 44.9, 34.6, 30.3, 30.1, 27.6, and down: 129.8 (2), 128.6 (2), 14.2 (2); IR (film) 1729
cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ calcd for C18H24Cl2O4Na 397.0944, found 397.0945.
Diethyl 2ꢀ(3ꢀchloropropyl)ꢀ2ꢀcyclohexylmalonate (10h). The chloride 10h (4.06 g) was
prepared from malonate 9h (5.86 g, 24.2 mmol) and 1ꢀchloroꢀ3ꢀiodopropane (4.50 g, 22.0 mmol)
by the procedure for preparation of 10d, and the yield was 58%. 10h, Rf = 0.65, (EtOAC/PE =
1/5); 1H NMR (CDCl3, 400 MHz) δ: 4.19 (q, J = 7.0 Hz, 4 H), 3.51 (t, J = 6.4 Hz, 2 H), 1.91ꢀ2.06
(m, 3 H), 1.58ꢀ1.78 (m, 8 H), 1.27 (t, J = 7.0 Hz, 6 H), 0.98ꢀ1.18 (m, 4 H); 13C NMR (CDCl3, 100
MHz, plus APT) δ up: 171.0 (2), 61.2, 60.9 (2), 45.2, 31.0, 28.7 (2), 28.2, 27.0 (2), 26.5, and down:
42.7, 14.2 (2); IR (film) 1725 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ calcd for C16H27ClO4Na
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341.1490, found 341.1492.
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Diethyl 2ꢀ(3ꢀchloropropyl)ꢀ2ꢀheptylmalonate (10i). The chloride 10i (332 mg) was prepared
from malonate 9i (714 mg, 2.7 mmol) and 1ꢀchloroꢀ3ꢀiodopropane (511 mg, 2.50 mmol) by the
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procedure for preparation of 10d, and the yield was 39%. 10i, Rf = 0.57, (EtOAC/PE = 1/5); H
NMR (CDCl3, 400 MHz) δ: 4.19 (q, J = 7.0 Hz, 4 H), 3.53 (t, J = 6.2 Hz, 2 H), 1.99ꢀ2.05 (m, 2 H),
1.85ꢀ1.88 (m, 2 H), 1.64ꢀ1.71 (m, 2 H), 1.14ꢀ1.30 (m, 16 H), 0.87 (t, J = 6.8 Hz, 3 H); 13C NMR
(CDCl3, 100 MHz, plus APT) δ up: 171.6 (2), 61.2 (2), 57.1, 44.9, 32.4, 31.8, 29.8 (2), 29.0, 27.6,
23.9, 22.7, and down: 14.1 (3); IR (film) 1731 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ calcd for
C17H31ClO4Na 357.1803, found 357.1801.
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Diethyl 2ꢀ(3ꢀazidopropyl)ꢀ2ꢀphenethylmalonate (11d). To a stirred solution of (3.45 g, 10.1
mmol) in DMF (30 mL) was added NaN3 (1.31 g, 20.3 mmol) at room temperature. The mixture
was kept at 50 oC for 48 h, then the resulting mixture was cooled to room temperature, and it was
partitioned between ethyl acetate (60 mL) and H2O (50 mL). The organic phase was separated and
the aqueous phase was extracted with ethyl acetate (50 mL*3), then the combined extract was
washed by water (15 mL*7), and brine, dried over anhydrous Na2SO4 and concentrated. The
residue was purified by flash chromatography to give azide 11d as a colorless oil (3.35 g, 95%
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yield from chloride 10d). 11d, Rf = 0.55, (EtOAC/PE = 1/5); H NMR (CDCl3, 400 MHz) δ:
7.26ꢀ7.31 (m, 2 H), 7.17ꢀ7.22 (m, 3 H), 4.20 (q, J = 7.0 Hz, 4 H), 3.29 (t, J = 6.6 Hz, 2 H),
2.50ꢀ2.54 (m, 2 H), 2.17ꢀ2.21 (m, 2 H), 2.01ꢀ2.05 (m, 2 H), 1.50ꢀ1.57 (m, 2 H), 1.27 (t, J = 7.2 Hz,
6 H); 13C NMR (CDCl3, 100 MHz, plus APT) δ up: 171.4 (2), 141.4, 61.5 (2), 57.3, 51.5, 34.7,
30.8, 30.1, 24.0, and down: 128.6 (2), 128.5 (2), 126.3, 14.3 (2); IR(film) 2098, 1729 cmꢀ1; IR
(film) 2098, 1724cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ calcd for C18H25N3O4Na 370.1737,
found 370.1732.
Diethyl 2ꢀ(3ꢀazidopropyl)ꢀ2ꢀ(2ꢀchlorophenethyl)malonate (11e). The azide 11e (3.54 g) was
prepared from malonate 10e (3.90 g, 10.4 mmol) and sodium azide (2.03 g, 31.2 mmol) by the
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procedure for preparation of 11d, and the yield was 89%. 11e, Rf = 0.51, (EtOAC/PE = 1/5); H
NMR (CDCl3, 400 MHz) δ: 7.33 (d, J = 7.2 Hz, 1 H), 7.12ꢀ7.21 (m, 3 H), 4.22 (q, J = 7.2 Hz, 4 H),
3.32 (t, J = 6.8 Hz, 2 H), 2.61ꢀ2.66 (m, 2 H), 2.14ꢀ2.21 (m, 2 H), 2.05ꢀ2.09 (m, 2 H), 1.54ꢀ1.62 (m,
2 H), 1.28 (t, J = 7.2 Hz, 6 H); 13C NMR (CDCl3, 100 MHz, plus APT) δ up: 171.1 (2), 138.8,
133.7, 61.4 (2), 57.0, 51.3, 32.7, 29.6, 28.5, 23.8, and down: 130.5, 129.5, 127.7, 126.9, 14.1 (2);
IR(film) 2097, 1728 cmꢀ1; IR (film) 2932, 1724cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ calcd for
C18H24ClN3O4Na 404.1348, found 404.1343.
Diethyl 2ꢀ(3ꢀazidopropyl)ꢀ2ꢀ(3ꢀchlorophenethyl)malonate (11f). The azide 11f (4.06 g) was
prepared from malonate 10f (4.98 g, 13.2 mmol) and sodium azide (2.59 g, 39.8 mmol) by the
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procedure for preparation of 11d, and the yield was 80%. 11f, Rf = 0.52, (EtOAC/PE = 1/5); H
NMR (CDCl3, 400 MHz) δ: 7.17ꢀ7.27 (m, 3 H), 7.05 (d, J = 6.8 Hz, 1 H), 4.21 (q, J = 7.2 Hz, 4 H),
3.32 (t, J = 6.8 Hz, 2 H), 2.49ꢀ2.54 (m, 2 H), 2.15ꢀ2.23 (m, 2 H), 2.00ꢀ2.04 (m, 2 H), 1.50ꢀ1.57 (m,
2 H), 1.27 (t, J = 7.0 Hz, 6 H); 13C NMR (CDCl3, 100 MHz, plus APT) δ up: 171.2 (2), 143.3,
134.2, 61.5 (2), 57.1, 51.4, 34.5, 30.4, 30.1, 23.9, and down: 129.8, 128.5, 126.5, 126.4, 14.2 (2);
IR (film) 2098, 1729 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ calcd for C18H24ClN3O4Na
404.1348, found 404.1347.
Diethyl 2ꢀ(3ꢀazidopropyl)ꢀ2ꢀ(4ꢀchlorophenethyl)malonate (11g). The azide 11g (3.96 g) was
prepared from malonate 10g (4.66 g, 12.4 mmol) and sodium azide (2.42 g, 37.3 mmol) by the
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procedure for preparation of 11d, and the yield was 84%. 11g, Rf = 0.52, (EtOAC/PE = 1/5); H
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NMR (CDCl3, 400 MHz) δ: 7.24 (d, J = 8.4 Hz, 2 H), 7.10 (d, J = 8.4 Hz, 2 H), 4.21 (q, J = 7.0 Hz,
4 H), 3.30 (t, J = 6.4 Hz, 2 H), 2.48ꢀ2.52 (m, 2 H), 2.13ꢀ2.17 (m, 2 H), 2.00ꢀ2.04 (m, 2 H),
1.50ꢀ1.57 (m, 2 H), 1.27 (t, J = 7.0 Hz, 6 H); 13C NMR (CDCl3, 100 MHz, plus APT) δ up: 171.2
(2), 139.8, 131.9, 61.5 (2), 57.1, 51.4, 34.6, 30.1 (2), 23.3, and down: 129.8 (2), 128.6 (2), 14.2 (2);
13C NMR (DMSO, 100 MHz, plus APT) δ, up: 170.7 (2), 140.3, 130.4, 61.2 (2), 56.6, 50.7, 33.9,
29.3, 29.1, 23.3, and down: 130.3 (2), 128.5 (2), 14.0 (2); IR (film) 2099, 1730 cmꢀ1; HRMS
(ESIꢀTOF) m/z: [M + Na]+ calcd for C18H24ClN3O4Na 404.1348, found 404.1343.
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Diethyl 2ꢀ(3ꢀazidopropyl)ꢀ2ꢀcyclohexylmalonate (11h). The azide 11h (1.38 g) was prepared
from malonate 10h (2.03 g, 6.3 mmol) and sodium azide (1.24 g, 19.1 mmol) by the procedure for
preparation of 11d, and the yield was 67%. 11h, Rf = 0.65, (EtOAC/PE = 1/5); 1H NMR (CDCl3,
400 MHz) δ: 4.20 (q, J = 7.0 Hz, 4 H), 3.27 (t, J = 6.6 Hz, 2 H), 1.94 (t, J = 8.4 Hz, 3 H), 1.77 (d,
J = 10.8 Hz, 4 H), 1.67 (d, J = 12.4 Hz, 1 H), 1.50ꢀ1.59 (m, 3 H), 1.27 (t, J = 7.0 Hz, 6 H),
1.02ꢀ1.22 (m, 4 H); 13C NMR (CDCl3, 100 MHz, plus APT) δ up: 170.9 (2), 61.2, 60.8 (2), 51.6,
30.7, 28.6 (2), 26.9 (2), 26.4, 24.4, and down: 42.7, 14.2 (2); IR (film) 2098, 1725 cmꢀ1; HRMS
(ESIꢀTOF) m/z: [M + Na]+ calcd for C16H27N3O4Na 348.1894, found 348.1894.
Diethyl 2ꢀ(3ꢀazidopropyl)ꢀ2ꢀheptylmalonate (11i). The azide 11i (268 mg) was prepared from
malonate 10i (332 mg, 0.57 mmol) and sodium azide (193 mg, 3.0 mmol) by the procedure for
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preparation of 11d, and the yield was 79%. 11i, Rf = 0.53, (EtOAC/PE = 1/5); H NMR (CDCl3,
400 MHz) δ: 4.15 (q, J = 7.2 Hz, 4 H), 3.25 (t, J = 6.6 Hz, 2 H), 1.81ꢀ1.92 (m, 4 H), 1.41ꢀ1.49 (m,
2 H), 1.10ꢀ1.23 (m, 16 H), 0.84 (t, J = 6.8 Hz, 3 H); 13C NMR (CDCl3, 100 MHz, plus APT) δ up:
171.6 (2), 61.2 (2), 57.2, 51.5, 32.5, 31.8, 29.8, 29.6, 29.1, 24.0, 23.9, 22.7, and down: 14.1 (3); IR
(film) 2098, 1731 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ calcd for C17H31N3O4Na 364.2207,
found 364.2200.
5ꢀAzidoꢀ2ꢀphenylpentanoic acid (1a). The ωꢀazido carboxylic acid 1a was previously
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prepared in our laboratory. 1a, Rf = 0.55, (MTBE/1%NaH2PO4/AcOH/PE = 1/0.1/0.01/3); H
NMR (CDCl3, 400 MHz) δ: 11.16 (bs, 1 H), 7.27ꢀ7.36 (m, 5 H), 3.57 (t, J = 7.6 Hz, 1 H), 3.28 (t, J
= 6.6 Hz, 2 H), 2.10ꢀ2.19 (m, 1 H), 1.83ꢀ1.93 (m, 1 H), 1.48ꢀ1.66 (m, 2 H); 13C NMR (CDCl3, 100
MHz, plus APT) δ up: 180.2, 137.9, 51.2, 30.1, 26.9, and down: 129.0 (2), 128.1 (2), 127.9, 51.2.
5ꢀAzidoꢀ2ꢀ(naphthalenꢀ1ꢀyl)pentanoic acid (1b). The ωꢀazido carboxylic acid 1b was
previously prepared in our laboratory. 1b, Rf = 0.53, (MTBE/1%NaH2PO4/AcOH/PE =
1/0.1/0.01/3); 1H NMR (CDCl3, 400 MHz) δ: 11.08 (bs, 1 H), 8.10 (d, J = 8.4 Hz, 1 H), 7.88 (d, J
= 7.6 Hz, 1 H), 7.80 (d, J = 8.0 Hz, 1 H), 7.44ꢀ7.58 (m, 4 H), 4.41 (t, J = 7.4Hz, 1 H), 3.29 (t, J =
6.8 Hz, 2 H), 2.22ꢀ2.37 (m, 1 H), 1.96ꢀ2.08 (m, 1 H), 1.53ꢀ1.75 (m, 2 H); 13C NMR (CDCl3, 100
MHz, plus APT) δ up: 180.4, 134.13, 134.09, 131.6, 51.2, 29.8, 27.1, and down: 129.2, 128.4,
126.7, 125.9, 125.6, 125.1, 123.0, 46.2.
5ꢀAzidoꢀ2ꢀbenzylpentanoic acid (1c). The ωꢀazido carboxylic acid 1c was previously prepared
in our laboratory. 1c, Rf = 0.50, (MTBE/1%NaH2PO4/AcOH/PE = 1/0.1/0.01/3); Daicel Shimadzu
HPLC (Model: LC20AT) for ee determination of enantioꢀenriched (R)ꢀ1c9 [>99% ee, Daicel OJꢀH
0.46*25 cm, nꢀHexane:iꢀPrOH 98:2, 1mL/min, 35°C, 4.4 Mpa, 254 nm, tr (major) 30.2 min, tr
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(minor) 31.8 min; H NMR (CDCl3, 400 MHz) δ: 10.44 (bs, 1 H), 7.27ꢀ7.31(m, 2 H), 7.20ꢀ7.24
(m, 1 H), 7.17ꢀ7.18 (m, 2 H), 3.26 (t, J = 6.2 Hz, 2 H), 2.99ꢀ3.04 (m, 1 H), 2.66ꢀ2.78 (m, 2 H),
1.54ꢀ1.75 (m, 4 H); 13C NMR (CDCl3, 100 MHz, plus APT) δ up: 181.7, 138.6, 51.2, 38.1, 28.6,
26.7, and down: 128.9 (2), 128.6 (2), 126.7, 47.0.
5ꢀAzidoꢀ2ꢀphenethylpentanoic acid (1d). The previous procedure for preparation of 1a was
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employed: To a stirred solution of the azide 11d (3.35 g, 9.65 mmol) in MeOH (44 mL) was added
50% aqueous KOH (44 mL). The mixture was heated to 70 oC for 12 h, then it was cooled to room
temperature, and acidified with aqueous HCl (2.0 M) to PH = 1 ꢀ 2. The mixture was extracted
with CH2Cl2 (30 mL*3). The combined organic phase was dried over Na2SO4, concentrated to
afford the crude dicarboxylic acid as a white solid (3.04 g). The above mixture (1.0 g) was
dissolved in AcOH (14 mL) at room temperature, and kept at 160oC for 12 h. Then the resulting
mixture was cooled, and diluted with H2O (20 mL). The mixture was extracted with DCM (25
mL*3), and the combined organic phase was washed by water (15 mL*5) and brine, dired over
anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography to give
the ωꢀazido carboxylic acid 1d as a colorless oil (580 mg, 70% yield for two steps from azide 11d).
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1d, Rf = 0.50, (MTBE/1%NaH2PO4/AcOH/PE= 1/0.1/0.01/3); H NMR (CDCl3, 400 MHz) δ:
11.38 (bs, 1 H),7.26ꢀ7.31 (m, 2 H), 7.18ꢀ7.21 (m, 3 H), 3.28 (t, J = 6.4 Hz, 2 H), 2.60ꢀ2.74 (m, 2
H), 2.37ꢀ2.47 (m, 1 H), 1.94ꢀ2.07 (m, 1 H), 1.57ꢀ1.85 (m, 5 H); 13C NMR (CDCl3, 100 MHz, plus
APT) δ up: 182.5, 141.3, 51.2, 33.8, 33.5, 29.1, 26.7, and down: 128.53 (2) 128.52 (2), 126.2, 44.5;
IR (film) 2098, 1705 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ calcd for C13H17N3O2Na 270.1213,
found 270.1220.
5ꢀAzidoꢀ2ꢀ(2ꢀchlorophenethyl)pentanoic acid (1e). The previous procedure for preparation of
1a was employed: To a stirred solution of azide 11e (3.54 g, 9.27 mmol) in MeOH (42 mL) was
added 50% aqueous KOH (42 mL). The mixture was heated to 70 oC for 16 h, then it was cooled
to room temperature, and acidified with aqueous HCl (2.0 M) to PH to 1ꢀ2. The mixture was
extracted with CH2Cl2 (30 mL*3). The combined organic phase was dried over Na2SO4,
concentrated to afford the crude dicarboxylic acid as a white solid (2.73g). The crude dicarboxylic
acid (2.73 g) was dissolved in AcOH (45 mL) at room temperature, and kept at 160oC for 12 h.
Then the resulting mixture was cooled, and diluted with H2O (20 mL). The mixture was extracted
with DCM (25 mL*3), and the combined organic phase was washed by water (15 mL*5) and
brine, dired over anhydrous Na2SO4, and concentrated. The residue was purified by flash
chromatography to give the ωꢀazido carboxylic acid 1e as a colorless oil (1.98 g, 76% yield from
alcohol 11e). 1e, Rf = 0.43, (MTBE/1%NaH2PO4/AcOH/PE = 1/0.1/0.01/3); (EtOAC/PE = 1/5);
1H NMR (CDCl3, 400 MHz) δ: 11.67 (bs, 1 H),7.33 (d, J = 6.4 Hz, 1 H), 7.12ꢀ7.26 (m, 3 H), 3.29
(t, J = 6.0 Hz, 2 H), 2.72ꢀ2.87 (m, 2 H), 2.41ꢀ2.51 (m, 1 H), 1.93ꢀ2.04 (m, 1 H), 1.59ꢀ1.90 (m, 5
H); 13C NMR (CDCl3, 100 MHz, plus APT) δ up: 182.1, 138.9, 134.0, 51.3, 32.0, 31.4, 29.1, 26.7,
and down: 130.6, 129.7, 127.8, 127.0, 44.6; IR (film) 2098, 1705 cmꢀ1; HRMS (ESIꢀTOF) m/z:
[M + Na]+ calcd for C13H16ClN3O2Na 304.0823, found 304.0825.
5ꢀAzidoꢀ2ꢀ(3ꢀchlorophenethyl)pentanoic acid (1f). The ωꢀazido carboxylic acid 1f (2.85 g)
was prepared from the azide 11f (4.06 g, 10.6 mmol) by the procedure for preparation of 1e, and
the yield was 95%. 1f, Rf = 0.45, (MTBE/1%NaH2PO4/AcOH/PE= 1/0.1/0.01/3); (EtOAC/PE =
1/5); 1H NMR (CDCl3, 400 MHz) δ: 11.90 (bs, 1 H), 7.09ꢀ7.18 (m, 3 H), 6.99 (d, J = 7.2 Hz, 1 H),
3.22 (t, J = 6.4 Hz, 2 H), 2.50ꢀ2.64 (m, 2 H), 2.30ꢀ2.39 (m, 1 H), 1.87ꢀ1.96 (m, 1 H), 1.50ꢀ1.76 (m,
5 H); 13C NMR (CDCl3, 100 MHz, plus APT) δ up: 181.9, 143.4, 134.4, 51.3, 33.6, 33.3, 29.2,
26.7, and down: 129.8, 128.7, 126.8, 126.5, 44.5; IR(film) 2098, 1705 cmꢀ1; IR (film) 2098, 1704
cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ calcd for C13H16ClN3O2Na 304.0823, found 304.0825.
5ꢀAzidoꢀ2ꢀ(4ꢀchlorophenethyl)pentanoic acid (1g). The ωꢀazido carboxylic acid 1g (1.92 g)
was prepared from the azide 11g (3.96 g, 10.3 mmol) by the procedure for preparation of 1e, and
the yield was 66%. 1g, Rf = 0.44, (MTBE/1%NaH2PO4/AcOH/PE= 1/0.1/0.01/3); 1H NMR
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(CDCl3, 400 MHz) δ: 11.62 (bs, 1 H),7.25 (d, J = 8.0 Hz, 2 H), 7.11 (d, J = 8.4 Hz, 2 H), 3.29 (t, J
= 6.2 Hz, 2 H), 2.57ꢀ2.69 (m, 2 H), 2.39ꢀ2.44 (m, 1 H), 1.96ꢀ2.03 (m, 1 H), 1.56ꢀ1.81 (m, 5 H);
13C NMR (CDCl3, 100 MHz, plus APT) δ up: 182.0, 139.7, 132.0, 51.3, 33.7, 33.0, 29.2, 26.7, and
down: 129.9 (2), 128.7 (2), 44.4; IR(film) 2097, 1704 cmꢀ1; IR (film) 2098, 1704 cmꢀ1; HRMS
(ESIꢀTOF) m/z: [M + Na]+ calcd for C13H16ClN3O2Na 304.0823, found 304.0832.
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5ꢀAzidoꢀ2ꢀcyclohexylpentanoic acid (1h). The ωꢀazido carboxylic acid 1h (1.64 g) was
prepared from the azide 11h (1.38 g, 4.2 mmol) by the procedure for preparation of 1e, and the
yield was 62%. 1h, Rf = 0.51, (MTBE/1%NaH2PO4/AcOH/PE= 1/0.1/0.01/3); (EtOAC/PE = 1/5);
1H NMR (CDCl3, 400 MHz) δ: 11.72 (bs, 1 H),3.29 (t, J = 5.6 Hz, 2 H), 2.16ꢀ2.24 (m, 1 H),
1.54ꢀ1.81 (m, 10 H), 0.95ꢀ1.30 (m, 5 H); 13C NMR (CDCl3, 100 MHz, plus APT) δ up: 182.3, 51.3,
31.0, 30.3 (2), 27.2, 26.3 (2), 26.1, and down: 51.5, 40.0; IR (film) 2097, 1703 cmꢀ1; HRMS
(ESIꢀTOF) m/z: [M + Na]+ calcd for C11H19N3O2Na 248.1369, found 248.1370.
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2ꢀ(3ꢀAzidopropyl)nonanoic acid (1i). The ωꢀazido carboxylic acid 1i (140 mg) was prepared
from the azide 11i (268 mg, 0.70 mmol) by the procedure for preparation of 1e, and the yield was
76%. 1i, Rf = 0.55, (MTBE/1%NaH2PO4/AcOH/PE= 1/0.1/0.01/3); 1H NMR (CDCl3, 400 MHz)
δ: 11.50 (bs, 1 H),3.30 (t, J = 6.0 Hz, 2 H), 2.32ꢀ2.39 (m, 1 H), 1.14ꢀ1.70 (m, 16 H), 0.88 (t, J =
6.2 Hz, 3 H); 13C NMR (CDCl3, 100 MHz, plus APT) δ up: 182.8, 51.3, 32.3, 31.9, 29.6, 29.2,
29.1, 27.3, 26.8, 22.8, and down: 45.1, 14.2; IR (film) 2097, 1706 cmꢀ1; HRMS (ESIꢀTOF) m/z:
[M + Na]+ calcd for C12H23N3O2Na 264.1683, found 264.1687.
1ꢀ(2ꢀPhenylpyrrolidinꢀ1ꢀyl)ethanꢀ1ꢀone (3a). To a stirred solution of 2ꢀphenyl ωꢀazido
carboxylic acid 1a (109 mg, 0.50 mmol) in DCM (2.0 mL) was added Tf2O (126 uL, 0.75 mmol)
at room temperature and kept for 11 h. Then the mixture was concentrated and the crude was
diluted in ethyl acetate (2 mL). Then the mixture was treated with 5% aqueous KOH (2 mL), and
the organic phase was separated. The aqueous phase was extracted with ethyl acetate (2 mL * 3),
and washed with brine (2 mL). The organic phase was dried over anhydrous Na2SO4 and
concentrated to afford the crude product as a pale yellow oil. The crude mixture was dissolved in
DCM (10 mL), and DMAP (73 mg, 0.60 mmol) and Ac2O (151 uL, 3.00 mmol) were added. The
mixture was kept for 6 h at room temperature, then it was washed with aqueous HCl (2.0 M, 2
mL). The organic phase was separated, and the aqueous phase was extracted with DCM (2 mL*2).
The combined organic phase was washed with brine, dired over anhydrous Na2SO4 and
concentrated. The residue was purified by flash chromatography to give 3a as a pale yellow oil (76
mg, 80% yield from 1a). 3a, Rf = 0.20 (EA/PE = 1:1), known compound6, about 1:0.4 rotamer
mixture; 1H NMR (CDCl3, 400 MHz) δ: 7.13ꢀ7.35 (m, 5 H for the major rotamer and 5 H for the
minor rotamer), 5.22 (d, J = 7.6 Hz, 1 H for the minor rotamer), 4.92 (d, J = 8.0 Hz, 1 H for the
major rotamer), 3.58ꢀ3.77 (m, 2 H for the major rotamer and 2 H for the minor rotamer), 2.36ꢀ2.41
(m, 1 H for the major rotamer), 2.22ꢀ2.25 (m, 1 H for the minor rotamer), 2.14 (s, 3 H for the
minor rotamer), 1.83ꢀ1.98 (m, 6 H for the major rotamer and 3 H for the minor rotamer);13C NMR
(CDCl3, 100 MHz, plus APT) δ up: 170.2 (major rotamer), 169.1 (minor rotamer), 143.1 (major
rotamer), 142.8 (minor rotamer), 48.3 (minor rotamer), 46.8 (major rotamer), 36.2 (major rotamer),
34.0 (minor rotamer), 23.5 (minor rotamer), 21.8 (major rotamer), and down: 128.7 (2, major
rotamer), 128.2 (2, minor rotamer), 127.1 (major rotamer), 126.5 (minor rotamer), 125.3 (2, minor
rotamer), 125.2 (2, major rotamer), 62.1 (major rotamer), 60.1 (minor rotamer), 22.7 (minor
rotamer), 22.5 (major rotamer).
1ꢀ(2ꢀ(Naphthalenꢀ1ꢀyl)pyrrolidinꢀ1ꢀyl)ethanꢀ1ꢀone
(3b)
and
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9,10,11,11aꢀtetrahydroꢀ7Hꢀbenzo[g]pyrrolo[2,1ꢀa]isoindolꢀ7ꢀone (5b). The amide 3b (56 mg)
was prepared from the azide 1b (107 mg, 0.4 mmol) by the procedure for preparation of 1a, and
the yield was 56%. The tricyclic lactam 5b (23 mg) was also produced in 26% yield from the
Schmidt reaction. 5b, known compound4d, Rf = 0.32 (EtOAC/PE = 1/1); δ: 8.33 (d, J = 6.8 Hz, 1
H), 7.94 (d, J = 8.4 Hz, 1 H), 7.78 (d, J = 8.4 Hz, 1 H), 7.57 (t, J = 7.6 Hz, 1 H), 7.49 (t, J = 7.86
Hz, 1 H), 7.37 (d, J = 6.8 Hz, 1 H), 5.01ꢀ5.04 (m, 1 H), 3.95ꢀ4.02(m, 1 H), 3.71ꢀ3.80 (m, 1 H),
2.13ꢀ2.27 (m, 1 H), 1.87ꢀ2.10(m, 3 H). 3b, Rf = 0.21 (EA/PE = 1:1), about 1:0.4 rotamer mixture;
1H NMR (CDCl3, 400 MHz) δ: 8.02 ꢀ 7.98 (m, 1 H for the major rotamer and 1 H for the minor
rotamer), 7.90 (d, J = 7.6 Hz, 1 H for the major rotamer), 7.83 (d, J = 8.0 Hz, 1 H for the minor
rotamer), 7.78 (d, J = 8.0 Hz, 1 H for the major rotamer), 7.71 (d, J = 8.0 Hz, 1 H for the minor
rotamer), 7.36ꢀ7.59 (m, 3 H for the major rotamer and 3 H for the minor rotamer), 7.21ꢀ7.26 (m, 1
H for the major rotamer), 7.10 (d, J = 8.0 Hz,1 H for the minor rotamer), 5.98 (d, J = 8.0 Hz, 1 H
for the minor rotamer), 5.66 (d, J = 8.0 Hz, 1 H for the major rotamer), 3.85ꢀ3.93 (m, 1 H for the
major rotamer and 1 H for the minor rotamer), 3.65ꢀ3.76 (m, 1 H for the major rotamer and 1 H
for the minor rotamer), 2.48ꢀ2.58 (m, 1 H for the major rotamer), 2.36ꢀ2.41 (m, 1 H for the minor
rotamer), 2.22 (s, 3 H for the minor rotamer), 1.84ꢀ2.07 (m, 6 H for the major rotamer and 3 H for
the minor rotamer); 13C NMR (CDCl3, 100 MHz, plus APT) δ up: 170.4 (major rotamer), 169.3
(minor rotamer), 137.8 (major rotamer), 137.6 (minor rotamer), 134.2 (minor rotamer), 134.0
(major rotamer), 130.2 (minor rotamer), 129.9 (major rotamer), 48.6 (minor rotamer), 47.1 (major
rotamer), 34.6 (major rotamer), 32.9 (minor rotamer), 23.7 (minor rotamer), 22.1(major rotamer),
and down: 129.2 (major rotamer), 128.9 (minor rotamer), 128.0 (major rotamer), 127.4 (minor
rotamer), 126.4 (major rotamer), 125.9 (major rotamer), 125.8 (minor rotamer), 125.5 (minor
rotamer), 125.4 (major rotamer), 125.2 (minor rotamer), 123.5 (minor rotamer), 122.6 (major
rotamer), 122.4 (major rotamer), 121.4 (minor rotamer), 59.5 (major rotamer), 57.8 (minor
rotamer), 22.9 (minor rotamer), 22.5 (major rotamer); IR (film) 1640 cmꢀ1; HRMS (ESIꢀTOF) m/z:
[M + Na]+ calcd for C16H17NONa 262.1202, found 262.1203.
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1ꢀ(2ꢀBenzylpyrrolidinꢀ1ꢀyl)ethanꢀ1ꢀone
(3c)
and
2,3,10,10aꢀtetrahydropyrrolo[1,2ꢀb]isoquinolinꢀ5(1H)ꢀone (5c). The amide 3c (71 mg) was
prepared from the azide 1c (116 mg, 0.5 mmol) by the procedure for preparation of 1a, and the
yield was 71%. The tricyclic lactam 5c (16 mg) was also produced in 16% yield from the Schmidt
reaction. 5c, known compound4a, Rf = 0.30 (EtOAC/PE = 1/1); Daicel Shimadzu HPLC (Model:
LC20AT) for ee determination of enantioꢀenriched (R)ꢀ3c [99% ee, Daicel ADꢀH 0.46*25 cm,
nꢀHexane:iꢀPrOH 96:4, 1mL/min, 35°C, 3.4 Mpa, 254 nm, tr (major) 16.0 min, tr (minor) 17.3 min;
1H NMR (CDCl3 , 400 MHz) δ: 8.04 (dd, J = 1.2 Hz and 7.6 Hz, 1 H), 7.37ꢀ7.41 (m, 1 H),
7.31ꢀ7.35 (m, 1 H), 7.17 (d, J = 7.6 Hz, 1 H), 3.75ꢀ3.87 (m, 2 H), 3.59ꢀ3.67 (m, 1 H), 3.02 (dd, J =
4.0 Hz and 15.2 Hz, 1 H), 2.82 (t, J = 14.2 Hz, 1 H), 2.24ꢀ2.32 (m, 1 H), 2.09ꢀ2.13 (m, 1 H),
1.67ꢀ1.92 (m, 2 H). 3c, Rf = 0.19 (EA/PE = 1:1), about 1:0.5 rotamer mixture; Daicel Shimadzu
HPLC (Model: LC20AT) for ee determination of enantioꢀenriched (R)ꢀ3c [99% ee, Daicel ADꢀH
0.46*25 cm, nꢀHexane:iꢀPrOH 98:2, 1mL/min, 35°C, 3.2 Mpa, 254 nm, tr (major 1) 29.9 min, tr
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(major 2) 42.3 min, tr (minor 1) 32.0 min, tr (minor 1) 48.6 min; H NMR (CDCl3, 400 MHz) δ:
7.14ꢀ7.32 (m, 5 H for the major rotamer and 5 H for the minor rotamer), 4.29ꢀ4.32 (m, 1 H for the
major rotamer), 3.99ꢀ4.03 (m, 1 H for the minor rotamer), 3.44ꢀ3.57 (m, 2 H for the minor
rotamer), 3.31ꢀ3.41 (m, 2 H for the major rotamer), 3.17 (dd , J = 3.2 Hz and 13.2 Hz , 1 H for the
major rotamer), 2.85 (dd, J = 5.6 Hz and 13.6 Hz, 1 H for the minor rotamer), 2.65 (q, J = 8.8 Hz,
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1 H for the minor rotamer), 2.58 (dd , J = 9.2 Hz and 12.0 Hz, 1 H for the major rotamer), 2.07 (s,
3 H for the major rotamer ), 1.96 (s, 3 H for the minor rotamer), 1.70ꢀ1.91 (m, 4 H for the major
rotamer and 4 H for the minor rotamer); 13C NMR (CDCl3, 100 MHz, plus APT) δ up: 169.1
(major rotamer), 169.0 (minor rotamer), 139.0 (major rotamer), 137.9 (minor rotamer), 47.9
(major rotamer), 45.3 (minor rotamer), 40.7 (minor rotamer), 38.6 (major rotamer), 29.9 (minor
rotamer), 28.2 (major rotamer), 23.5 (major rotamer), 21.6 (minor rotamer), and down: 129.4 (2,
major rotamer), 129.1 (2, minor rotamer), 128.6 (2, minor rotamer), 128.1 (2, major rotamer),
126.6 (minor rotamer), 126.1 (major rotamer), 60.3 (minor rotamer), 58.2 (major rotamer), 23.0
(major rotamer), 21.9 (minor rotamer); IR (film) 1637 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+
calcd for C13H17NONa 226.1202, found 226.1203.
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1ꢀ(2ꢀPhenethylpyrrolidinꢀ1ꢀyl)ethanꢀ1ꢀone (3d). The amide 3d (73 mg) was prepared from
the azide 1d (123 mg, 0.5 mmol) by the procedure for preparation of 1a, and the yield was 67%.
3d, Rf = 0.23 (EA/PE = 1:1), known compound14, about 1:0.5 rotamer mixture; 1H NMR (CDCl3,
400 MHz) δ: 7.05ꢀ7.27 (m, 5 H for the major rotamer and 5 H for the minor rotamer), 4.14 (bs, 1
H for the major rotamer), 3.75 (bs, 1 H for the minor rotamer), 3.37ꢀ3.58 (m, 2 H for the major
rotamer and 2 H for the minor rotamer), 2.51ꢀ2.72 (m, 2 H for the major rotamer and 2 H for the
minor rotamer), 2.13ꢀ2.21 (m, 1 H for the major rotamer and 1 H for the minor rotamer), 1.50ꢀ2.13
(m, 8 H for the major rotamer and 8 H for the minor rotamer); 13C NMR (CDCl3, 100 MHz, plus
APT) δ up: 169.1 (major rotamer), 169.0 (minor rotamer), 141.9 (major rotamer), 140.8 (minor
rotamer), 47.6 (major rotamer), 45.3 (minor rotamer), 36.3 (minor rotamer), 34.8 (major rotamer),
32.68 (major rotamer), 32.65 (minor rotamer), 30.1 (minor rotamer), 29.3 (major rotamer), 24.0
(major rotamer), 22.2 (minor rotamer), and down: 128.5 (2, minor rotamer), 128.27 (2, major
rotamer), 128.25 (2, minor rotamer), 128.23 (2, minor rotamer), 126.2 (minor rotamer), 125.7
(major rotamer), 57.8 (minor rotamer), 56.8 (major rotamer), 23.0 (major rotamer), 21.9 (minor
rotamer).
1ꢀ(2ꢀ(2ꢀChlorophenethyl)pyrrolidinꢀ1ꢀyl)ethanꢀ1ꢀone (3e). The amide 3e (74 mg) was
prepared from the azide 1e (112 mg, 0.4 mmol) by the procedure for preparation of 1a, and the
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yield was 74%. 3e, Rf = 0.25 (EA/PE = 1:1), about 1:0.6 rotamer mixture; H NMR (CDCl3, 400
MHz) δ: 7.19ꢀ7.25 (m, 2 H for the major rotamer and 1 H for the minor rotamer), 6.99ꢀ7.10 (m, 2
H for the major rotamer and 3 H for the minor rotamer), 4.06 (bs, 1 H for the major rotamer), 3.69
(bs, 1 H for the minor rotamer), 3.22ꢀ3.46 (m, 2 H for the major rotamer and 2 H for the minor
rotamer), 2.56ꢀ2.72 (m, 2 H for the major rotamer and 2 H for the minor rotamer), 1.98ꢀ2.09 (m, 1
H for the major rotamer and 1 H for the minor rotamer), 1.44ꢀ1.93 (m, 8 H for the major rotamer
and 8 H for the minor rotamer); 13C NMR (CDCl3, 100 MHz, plus APT) δ up: 168.9 (major
rotamer), 168.7 (minor rotamer), 139.2 (major rotamer), 138.3 (minor rotamer), 133.5 (major
rotamer and minor rotamer), 47.4 (major rotamer), 45.2 (minor rotamer), 34.6 (minor rotamer),
32.9 (major rotamer), 30.4 (minor rotamer), 30.2 (major rotamer), 30.0 (minor rotamer), 29.1
(major rotamer), 23.8 (major rotamer), 22.0 (minor rotamer), and down: 130.11 (minor rotamer),
130.05 (major rotamer), 129.4 (minor rotamer), 129.0 (major rotamer), 127.5 (minor rotamer),
127.0 (major rotamer), 126.8 (minor rotamer), 126.6 (major rotamer), 57.8 (minor rotamer), 56.6
(major rotamer), 22.8 (major rotamer), 21.7 (minor rotamer); IR (film) 1635 cmꢀ1; HRMS
(ESIꢀTOF) m/z: [M + Na]+ calcd for C14H18ClNONa 274.0969, found 274.0969.
1ꢀ(2ꢀ(3ꢀChlorophenethyl)pyrrolidinꢀ1ꢀyl)ethanꢀ1ꢀone (3f). The amide 3f (77 mg) was
prepared from the azide 1f (112 mg, 0.4 mmol) by the procedure for preparation of 1a, and the
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yield was 76%. 3f, Rf = 0.27 (EA/PE = 1:1), about 1:0.5 rotamer mixture; H NMR (CDCl3, 400
MHz) δ: 6.96ꢀ7.16 (m, 4 H for the major rotamer and 4 H for the minor rotamer), 4.04 (bs, 1 H for
the major rotamer), 3.66 (bs, 1 H for the minor rotamer), 3.23ꢀ3.46 (m, 2 H for the major rotamer
and 2 H for the minor rotamer), 2.45ꢀ2.62 (m, 2 H for the major rotamer and 2 H for the minor
rotamer), 2.11 ꢀ 2.02 (m, 1 H for the major rotamer and 1H for the minor rotamer), 1.41ꢀ1.93 (m, 8
H for the major rotamer and 8 H for the minor rotamer); 13C NMR (CDCl3, 100 MHz, plus APT) δ
up: 169.2 (major rotamer), 168.9 (minor rotamer), 143.9 (major rotamer), 142.9 (minor rotamer),
134.2 (minor rotamer), 133.8 (major rotamer), 47.6 (major rotamer), 45.3 (minor rotamer), 36.0
(minor rotamer), 34.6 (major rotamer), 32.32 (major rotamer), 32.28 (minor rotamer), 30.1 (minor
rotamer), 29.3 (major rotamer), 24.0 (major rotamer), 22.1 (minor rotamer), and down: 129.8
(minor rotamer), 129.5 (major rotamer), 128.3 (major rotamer and minor rotamer), 126.5 (major
rotamer), 126.4 (minor rotamer), 126.3 (minor rotamer), 125.8 (major rotamer), 57.7 (minor
rotamer), 56.6 (major rotamer), 22.9 (major rotamer), 21.9 (minor rotamer); IR (film) 1638 cmꢀ1;
HRMS (ESIꢀTOF) m/z: [M + Na]+ calcd for C14H18ClNONa 274.0969, found 274.0968.
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1ꢀ(2ꢀ(4ꢀChlorophenethyl)pyrrolidinꢀ1ꢀyl)ethanꢀ1ꢀone (3g). The amide 3g (77 mg) was
prepared from the azide 1g (112 mg, 0.4 mmol) by the procedure for preparation of 1a, and the
yield was 76%. 3g, Rf = 0.28 (EA/PE = 1:1), about 1:0.5 rotamer mixture; 1H NMR (CDCl3, 400
MHz) δ: 6.99ꢀ7.26 (m, 4 H for the major rotamer and 4 H for the minor rotamer), 4.0 (bs, 1 H for
the major rotamer), 3.64 (bs, 1 H for the minor rotamer), 3.25ꢀ3.44 (m, 2 H for the major rotamer
and 2 H for the minor rotamer), 2.40ꢀ2.59 (m, 2 H for the major rotamer and 2 H for the minor
rotamer), 2.02ꢀ2.09 (m, 1 H for the major rotamer and 1 H for the minor rotamer), 1.39ꢀ1.92 (m, 8
H for the major rotamer and 8 H for the minor rotamer); 13C NMR (CDCl3, 100 MHz, plus APT) δ
up: 169.0 (major rotamer), 168.8 (minor rotamer), 140.2 (major rotamer), 139.2 (minor rotamer),
131.6 (minor rotamer), 131.1 (major rotamer), 47.4 (major rotamer), 45.2 (minor rotamer), 36.0
(minor rotamer), 34.5 (major rotamer), 31.8 (major rotamer and minor rotamer), 29.9 (minor
rotamer), 29.2 (major rotamer), 23.8 (major rotamer), 22.0 (minor rotamer), and down: 129.5 (2,
major rotamer), 129.4 (2, minor rotamer), 128.4 (2, minor rotamer), 128.1 (2, major rotamer), 57.5
(minor rotamer), 56.5 (major rotamer), 22.8 (major rotamer), 21.8 (minor rotamer); IR (film) 1635
cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ calcd for C14H18ClNONa 274.0969, found 274.0970.
1ꢀ(2ꢀCyclohexylpyrrolidinꢀ1ꢀyl)ethanone (3h). The amide 3h (47 mg) was prepared from the
azide 1h (112 mg, 0.5 mmol) by the procedure for preparation of 1a, and the yield was 49%. 3h,
Rf = 0.24 (EA/PE=1:1), about 1:0.5 rotamer mixture; 1H NMR (CDCl3, 400 MHz) δ: 3.5 (bs, 1 H
for the major rotamer), 3.65ꢀ3.70 (m,1 H for the minor rotamer), 3.58 (bs,1 H for the minor
rotamer), 3.27ꢀ3.40 (m, 2 H for the major rotamer ), 3.18 (bs, 1 H for the minor rotamer), 2.02 (s,
3 H for the minor rotamer), 1.98 (s, 3 H for the major rotamer), 1.35ꢀ1.84 (m, 10 H for the major
rotamer and 10 H for the minor rotamer), 0.81ꢀ1.18 (m, 5 H for the major rotamer and 5 H for the
minor rotamer); 13C NMR (CDCl3, 100 MHz, plus APT) δ up: 174.2 (minor rotamer), 169.5
(major rotamer), 48.2 (major rotamer), 45.6 (minor rotamer), 30.3 (minor rotamer), 30.1 (major
rotamer), 28.2 (minor rotamer), 27.8 (major rotamer), 27.5 (minor rotamer), 26.6 (major rotamer),
26.5 (minor rotamer), 26.4 (major rotamer and minor rotamer), 26.3 (minor rotamer), 26.2 (major
rotamer), 26.1 (major rotamer), 24.6 (major rotamer), 22.9 (minor rotamer), and down: 63.5
(minor rotamer), 61.4 (major rotamer), 42.4 (minor rotamer), 40.0 (major rotamer), 23.3 (major
rotamer), 22.4 (minor rotamer); IR (film) 1645 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ calcd for
C12H21NONa 218.1515, found 218.1516.
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1ꢀ(2ꢀHeptylpyrrolidinꢀ1ꢀyl)ethanone (3i). The amide 3i (72 mg) was prepared from the azide
1i (120 mg, 0.5 mmol) by the procedure for preparation of 1a, and the yield was 68%. 3i, Rf = 0.27
(EA/PE = 1:1), about 1:0.7 rotamer mixture; 1H NMR (CDCl3, 400 MHz) δ: 4.04 (bs, 1 H for the
major rotamer), 3.74 (bs, 1 H for the minor rotamer), 3.33ꢀ3.55 (m, 2 H for the major rotamer and
2 H for the minor rotamer), 2.08 (s, 3 H for the minor rotamer), 2.02 (s, 3 H for the major rotamer),
1.68ꢀ1.99 (m, 6 H for the major rotamer and 6 H for the minor rotamer), 1.26 (bs, 10 H for the
major rotamer and 10 H for the minor rotamer), 0.85ꢀ0.89 (m, 3 H for the major rotamer and 3 H
for the minor rotamer); 13C NMR (CDCl3, 100 MHz, plus APT) δ up:168.8 (major rotamer and
minor rotamer), 47.5 (major rotamer), 45.2 (minor rotamer), 34.8 (minor rotamer), 33.1 (major
rotamer), 31.7 (major rotamer), 31.6 (minor rotamer), 30.1 (minor rotamer), 29.5 (major rotamer),
29.4 (minor rotamer), 29.2 (major rotamer), 29.13 (minor rotamer), 29.07 (major rotamer), 26.4
(minor rotamer), 26.3 (major rotamer), 23.9 (major rotamer), 22.53 (major rotamer), 22.50 (minor
rotamer), 22.1 (major rotamer), and down: 58.6 (minor rotamer), 57.0 (major rotamer), 22.9
(major rotamer), 22.0 (minor rotamer), 14.0 (major rotamer and minor rotamer); IR (film) 1646
cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + Na]+ calcd for C13H25NONa 234.1828, found 234.1826.
2ꢀPhenylꢀ1ꢀ((trifluoromethyl)sulfonyl)pyrrolidine (4a). To a stirred solution of 2ꢀphenyl
ωꢀazido carboxylic acid 1a (129 mg, 0.6 mmol) in DCM (2 mL) was added Tf2O (677 mg, 2.4
mmol). The mixture was kept at room temperature for 12 h. Then it was quenched by KOH (50%,
1 mL) and the mixture was kept at room temperature for an additional 1 h. The organic phase was
separated and the aqueous phase was extracted by DCM (10 mL * 4). The combined organic phase
was dried over Na2SO4, and concentrated. The residue was purified by flash chromatography to
afford triflamide 4a as a colorless solid (108 mg, 64% yield from 1a). 4a, known compound15; Rf
= 0.62 (EtOAC/PE = 1/10); 1H NMR (CDCl3, 400 MHz) δ: 7.31ꢀ7.35 (m, 2 H), 7.21ꢀ7.27 (m, 3 H),
5.07ꢀ5.11 (m, 1 H), 3.73ꢀ3.80 (m, 2 H), 2.31ꢀ2.46 (m, 1 H), 1.89ꢀ2.07 (m, 3 H) ; 13C NMR (CDCl3,
100 MHz, plus APT) δ, up: 141.5, 50.3, 35.9, 24.0, and down: 128.6 (2), 127.7, 125.8 (2), 64.8.
5ꢀAzidoꢀ4ꢀbenzylpentanoic acid (6). The ωꢀazido carboxylic acid 6 was previously prepared in
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our laboratory.4b 6, Rf = 0.52, (MTBE/1%NaH2PO4/AcOH/PE= 1/0.1/0.01/3); H NMR (CDCl3,
400 MHz) δ: 10.99 (bs, 1 H), 7.29ꢀ7.32 (m, 2 H), 7.19ꢀ7.24 (m, 1 H), 7.15ꢀ7.17 (m, 2 H), 3.29 (dd,
J = 12.4 Hz and 5.0 Hz, 1 H), 3.22 (dd, J = 12.4 Hz and 5.2 Hz, 1 H), 2.57ꢀ2.72 (m, 2 H),
2.40ꢀ2.45 (m, 2 H), 1.87ꢀ1.97 (m, 1 H), 1.67ꢀ1.82 (m, 2 H); 13C NMR (CDCl3, 100 MHz, plus
APT) δ up: 179.0, 139.3, 53.8, 38.1, 31.5, 26.8, and down: 129.3 (2), 128.7 (2), 126.5, 39.6.
1,5,10,10aꢀTetrahydropyrrolo[1,2ꢀb]isoquinolinꢀ3(2H)ꢀone (7). To a stirred solution of the
4ꢀbenzyl ωꢀazido carboxylic acid 6 (163 mg, 0.7 mmol) in DCM (2 mL) was added Tf2O (789 mg,
2.8 mmol). The mixture was kept at room temperature for 48 h. Then it was quenched by the
addition of water (1 mL) and aqueous KOH (50%, 1 mL), and the mixture was stirred at room
temperature for an additional 1 h. The organic phase was separated and the aqueous phase was
extracted by DCM (10 mL * 4). The combined organic layers were dried over Na2SO4, and
concentrated. The residue was purified by flash chromatography to afford the desired lactams 7 as
a colorless solid (84 mg, 64% yield from 4ꢀbenzyl ωꢀazido carboxylic acid 6). 7, known
1
compound4b; Rf = 0.23 (EtOAC/PE = 2/1); H NMR (CDCl3, 400 MHz) δ: 7.07ꢀ7.25 (m, 4 H),
4.92 (d, J = 17.6 Hz, 1 H), 4.25 (d, J = 17.6 Hz, 1 H), 3.74ꢀ3.90 (m, 1 H), 2.95 (dd, J = 15.6 Hz
and J = 4.0 Hz, 1 H), 2.68 (dd, J = 15.6 Hz and 11.2 Hz, 1 H), 2.33ꢀ2.52 (m, 3 H), 1.75ꢀ1.86 (m, 1
H); 13C NMR (CDCl3, 100 MHz, plus APT) δ up: 174.2, 133.2, 131.7, 42.5, 36.8, 30.1, 25.2, and
down: 129.1, 126.7, 126.60, 126.56, 53.9.
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ACKNOWLEDGMENT
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This work was supported by the National Natural Science Foundation of China (No 21662027),
and the Program for Leading Talents of Ningxia Province (KJT2015002).
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SUPPORTING INFORMATION
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The Supporting Information (copies of NMR spectra for all new compounds and Xꢀray
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crystallographic data for 4a) is available free of charge on the ACS Publications website
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