Palladium-Catalyzed Intermolecular Azidocarbonylation of Alkenes via a Cooperative Strategy

Article abstract of DOI:10.1021/acs.joc.7b01812

A novel intermolecular β-azidocarbonylation reaction of alkenes has been developed in which a combination of iodine(III)-mediated alkene activation and palladium-catalyzed carbonylation was demonstrated as an efficient strategy for the difunctionalization of alkenes. A variety of β-azido carboxylic esters were obtained from mono- and 1,1-disubstituted terminal alkenes with excellent regioselectivities. In addition, the introduced azido group can be reduced to an amine group, providing a facile access to β-amino acid derivatives from simple olefins.

Full text of DOI:10.1021/acs.joc.7b01812

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Featured Article
Palladium-Catalyzed Intermolecular Azidocarbonylation
of Alkenes via a Cooperative Strategy
Ming Li, Feng Yu, Pinhong Chen, and Guosheng Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01812 • Publication Date (Web): 24 Aug 2017
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Palladium-Catalyzed Intermolecular Azidocarbonylation of Alkenes via a
Cooperative Strategy
‡
Ming Li,†,§ Feng Yu,†,§ Pinhong Chen*† and Guosheng Liu*,†,
†State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, University of Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China
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‡Key Laboratory of Functional Molecular Engineering of Guangdong Province, South China
University of Technology, Guangzhou 510640, China
Email: pinhongchen@sioc.ac.cn; gliu@mail.sioc.ac.cn
ABSTRACT: A novel intermolecular βꢀazidocarbonylation reaction of alkenes has been
developed, in which
palladiumꢀcatalyzed carbonylation was demonstrated as an efficient strategy for the
difunctionalization of alkenes. A variety of ꢀazido carboxylic esters were obtained from monoꢀ
a
combination of iodine(III)ꢀmediated alkene activation and
β
and 1,1ꢀdisubstituted terminal alkenes with excellent regioselectivities. In addition, the introduced
azido group can be reduced to amine group, providing a facile access to βꢀamino acid derivatives
from simple olefins.
INTRODUCTION
The carbonylation reaction is one of the most important alkene transformation reactions in
homogeneous catalysis, especially in the chemical industry, and a large variety of valuable bulk
and fine chemicals are produced by this method.1 Despite the tremendous progress in this field,
the reaction types are quite limited to hydrocarbonylation, possibly owing to the high reactivity of
metal hydride complexes involved in these reactions. 2 Particularly, carbonylationꢀbased
difunctionalization reactions of alkenes (DFAs) are synthetically attractive. 3 However, the
pioneering studies were limited to the type of intramolecular reactions,4 and the intermolecular
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counterparts of these DFAs are quite limited.5 Thus, the exploration of new methods to promote
intermolecular DFAs is of high synthetic significance.
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Scheme 1. Cooperative Strategy for Intermolecular Alkene Difunctionalization
βꢀAmino acids have been identified as essential components in bioactive natural products and
broadly utilized for the development of peptideꢀbased pharmaceutical compounds, due to its
biological metabolism property.6 Thus, exploration of the efficient synthesis of βꢀamino acids and
related derivatives has received much attention.7 Recently, we reported a palladiumꢀcatalyzed
intermolecular aminocarbonylation reaction of terminal alkenes and it serves as one of the most
efficient approaches to the synthesis of βꢀamino acids.8 However, the reaction was limited to the
monosubstituted terminal alkenes. In order to address the reactivity of disubstituted alkenes, we
have developed a novel cooperative strategy of iodine (III)ꢀmediated C=C activation and
palladium catalysis for the oxidative oxycarbonylation of alkenes, and various βꢀoxycarboxylic
acids/esters have been synthesized under mild reaction conditions (Scheme 1).9 Notably, this
reaction showed much wider substrate scope, and both terminal and internal alkenes are suitable
for this reaction. We surmised that if an amineꢀbased iodine (III) could be applied to replace
PhI(OAc)2, an intermolecular βꢀaminocarbonylation of alkenes might be expected (Scheme 1).
Considering the utility of azide, we assumed that an azidoꢀbased hypervalent iodine reagent
should be a good choice.10 Herein, we reported a novel palladiumꢀcatalyzed intermolecular
azidocarbonylation of alkenes with Zhdankin I(III) reagents (N3-II) as the azido source and
BF3·OEt2 as the activator.
RESULTS AND DISCUSSION
The initial study was focused on the reaction of terminal alkene 1a, and two azidoꢀbased
iodine(III) reagents11 were employed to test the above hypothesis. As shown in Table 1, when the
azidoꢀbased I(III) reagent N3-I was tested in the palladiumꢀcatalyzed azidocarbonylation reaction
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in the presence of BF3·OEt2, the reaction failed to give the desired product (entry 1). When the
more reactive Zhdankin reagent N3-II was tested, the reaction afforded the desired
βꢀazidocarbonylation products 2a (carboxylic acid) and 2a’ (anhydride) in 78% total yield (entry
2). Solvent screening revealed that acetonitrile is important for the reaction. The reaction in
toluene alone could not afford the target product, however, the yield was slightly dropped in single
acetonitrile (entries 3ꢀ4). Based on our previous oxycarbonylation reaction, BF3·OEt2 as a Lewis
acid is required to activate N3-II, which facilitates alkene activation to form a threeꢀmembered
iodonium ion intermediate. Other Lewis and Brønsted acids were also screened, however, only
strong Lewis and Brønsted acids, such as Mg(ClO4)2, HOTf and H2SO4 gave the desired product
in decreased yields (entries 5ꢀ9). Moreover, the screening of palladium catalysts indicated that the
use of Pd(acac)2 instead of Pd(OAc)2 could further improve the yield to 87% with high efficiency
within 1 hour. The desired product was also formed under the catalysis of Pd(OTFA)2 and PdCl2
but with slightly lower yields. The use of cationic palladium catalyst only provided 15% yield,
which indicated that the nucleophilicity of the palladium species is important for this reaction. No
product was obtained under the catalysis of Pd(PPh3)4 (entries 10ꢀ14). Control experiments
showed that no reaction took place in the absence of neither palladium catalyst nor BF3·OEt2.
Only alkene isomerization has been observed when the reaction was carried out under the
atmosphere of N2 instead of CO (entries 15ꢀ17). For the sake of convenient purification, the crude
product 2a and 2a’ in entry 10 was treated with MeOH followed by TMSCHN2 to give the
corresponding methyl ester 3a in 85% yield. It is worth noting that regioselectivities in all cases
are above 20:1, which is corresponding to addition of the azido and carbonyl groups to the internal
and terminal carbon atoms respectively.
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Table 1. Optimization of Reaction Conditions.a
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Pd cat. (10 mol%)
[N3] reagent (1.5 equiv.)
additive (15 mol %)
N3
O
C
O
PhthN
OR
3
N
Toluene / CH3CN (1:1)
CO (1atm), rt, 12 h
3
2a R = H
O
2a' R = ArCO
Ar =
1a
N3
N3
I
I
I
O
O
N3-I
N3-II
O
O
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2a +2a' Yield (%)b
[N3] reagent
Entry
Pd cat.
additive
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(acac)2
Pd(OTFA)2
PdCl2
N3-I
0
BF3•Et2O
BF3•Et2O
BF3•Et2O
BF3•Et2O
Zn(OTf)2
Mg(ClO4)2
HOAc
2
N3-II
N3-II
N3-II
N3-II
N3-II
N3-II
N3-II
N3-II
N3-II
N3-II
N3-II
78
3c
4d
5
76
0
0
6
22
7
0
8
63
HOTf
9
75
H2SO4
10
11
12
13
14
15
16
17g
87 (85e, 85f)
BF3•Et2O
BF3•Et2O
BF3•Et2O
BF3•Et2O
BF3•Et2O
BF3•Et2O
--
52
62
15
0
Pd(CH3CN)4(BF4)2 N3-II
Pd(PPh3)4
--
N3-II
N3-II
N3-II
N3-II
0
Pd(OAc)2
Pd(OAc)2
0
0
BF3•Et2O
aReaction conditions: all reactions were run at 0.2 mmol scale. b1H NMR Yield with CF3ꢀDMA as
an internal standard, and regioselectivities in all cases are above 20:1. cCH3CN was used as the
solvent alone. dToluene was used as the solvent alone. eYield of ester 3a. f1 h. gThe reaction was
carried out under the atmosphere of N2 instead of CO.
With the optimized reaction conditions in hand, our attention turned to an exploration of the
substrate scope of alkenes. The results (Table 2) show that aliphatic terminal alkenes undergo this
reaction efficiently to yield the corresponding esters 3a–3s in moderate to good yields. A number
of functional groups, including imides, halides, ethers, esters, amides, ketones, aldehydes,
phosphates are survived under the reaction conditions. Free acid group is compatible with this
reaction, which is further methylated to give diester product 3p in 64% yield. Noteworthy,
excellent levels of regioselectivities are observed in all these reactions (>20:1). Also, the reaction
of the tꢀbutyldiphenylsilylꢀprotected allylic alcohol forms 3t in 50% yield with 7:1
diastereoselectivity for the anti isomer. Furthermore, substrates containing heteroarenes are
reactive to deliver the products 3u and 3v in 80% and 84% yields respectively. The reaction of
substrate bearing estrone motif also affords the desired product 3w in 51% yield. Interestingly,
when dienes are used as the substrates, the reactions occur exclusively at the terminal alkene
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Table 2. Substrate Scope of Alkenes.a
1) Pd(acac)2 (10 mol%)
BF3 Et2O (15 mol%)
CO (balloon), r.t.
5
6
7
N3
I
O
N3
R
+
CO
2Me
R
2) MeOH, 40oC
TMSCHN2, r.t.
1
3
O
N3-II
8
9
Monosubstituted unactivated alkenes:
N3
O
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CO2Me
N3
N3
N3
N3
N
( )n
CO2Me
Br
CO2Me
CO2Me
CO
2Me
( )n
O
3a n = 2, 85% (86%, 82%)b
3c 74%
3d n = 4, 86%
3e n = 14, 81%
3f 86%
3g 71%
3b n = 1, 78%
N3
N3
N3
Ts
N
N3
EtO2C
N3
O
CO2Me
( )n
CO2Me
TBDPSO
CO2Me
CO2Me
CO2Me
RO2C
EtO2C
3n 45%c
3h n = 1, 64%
3i n = 2, 84%
3j 80%
3k 80%
3l R = Et, 70%
3m R = Bn, 76%
Ts
N
N3
N3
N3
N3
N3
CO2Me
Bn
CO2Me
R
CO2Me
R
CO2Me
Ph
TBDPSO
CO2Me
( )8
MeO2C
CO2Me
3p R = CO2Me, 64%d
3q R = CHO, 71%
3o 87%
3r R = Ac, 75%
3s R = P(O)(OEt)2, 70%
3t 50% (d.r. 7:1)
3u 80%
O
O
O
N3
N3 N3
H
N3
( )3
CO2Me
MeO2C
CO2Me
N3
( )3
X
H
O
CO2Me
CO2Me
O
3x X = OC(O), 68%
3y X = C(CN)2, 60%
3z 68% e
3v 84%
3w 51%
1,1-Disubstituted unactivated alkenes:
N3
O
N3
N3
N3
O
CO2Me
N3
CO2Me
CO2Me
N
CO2Me
PhO
CO2Me
TsO
O2N
O
O
4a 71%
4b 79%
4c 90%
4d 45%
4e 74%
Monosubstituted activated alkenes:
N3
N3
N3
N3
N3
CO2Me Cl
CO2Me
CO2Me
CO2Me
CO2Me
MeOOC
R
4j 59%
4l 64%d
N3
4m 47%
4k 64%
4f R = H, 73%
4g R = Ph, 62%
4h R = tBu, 69%
4i R = F, 68%
N3
N3
CO2Me
CO2Me
CO2Me
N
Ts
N
Ac
4p 25%
4n 72%
4o 77%
1,2-Disubstituted unactivated alkenes:f
N3 N3
O
N3
1) Pd/C, H2 (1atm)
MeOH
HN
4r
H
H
2) MsCl, NaHCO3
CH3CN
COOH
4s 33% (d.r. > 20:1)
COOH
4q 41% (d.r. > 20:1)
COOH
4r 67% (d.r. > 20:1)
5 38%
aAll reaction conditions: substrate (0.2 mmol, 0.10 M), N3ꢀII (0.3 mmol), Pd(acac)2 (0.02 mmol)
and BF3·Et2O (0.03 mmol) in CH3CN/Toluene (1:1) with CO balloon at room temperature, then
b
esterified with MeOH only, or further with TMSCHN2 (0~1.0 mmol). Yields in 1 mmol and 5
mmol scales respectively. c50% substrate was remained. dAcid is used as the substrate. eN3ꢀII (0.6
mmol). fEꢀalkenes (0.2 mmol, 0.025 M), N3ꢀII (0.5 mmol), Pd(hfacac)2 (0.02 mmol) and BF3·Et2O
(0.04 mmol) in CH3CN/Toluene (9:1) with CO balloon at room temperature.
center to afford 3x and 3y in good yields, probably due to the steric effect. Therefore, the reaction
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of 1,6ꢀheptadiene affords the bisꢀazidocarbonylation product 3z with a increased loading of azido
reagent. It is worth noting that 1,1ꢀdisubstituted alkenes also work well in this reaction, affording
4a-4c in good to excellent yields. The reaction of sterically hindered substrate affords the expected
product 4d as a single product in 45% yield. Exocyclic alkene also serves as a good substrate for
this azidocarbonylation reaction to deliver product 4e in 74% yield. Finally, the reactivity of
styrene derivatives bearing different functional groups on the aryl rings was also surveyed. These
reactions generate the desired products 4f-4l in good yields. While the reaction of
2ꢀvinylnaphthalene shows slightly lower reactivity, affording 4m in only 47% yield. In
comparison, vinylheteroarenes substrates are good for the reaction to deliver products 4n and 4o
in good yields. Unfortunately, 1,1ꢀdisubstituted styrenes exhibited lower efficiency than the
aliphatic 1,1ꢀdisubstituted alkenes (4aꢀ4e), and the reaction provided the desired product 4p in
25% yield. Based on the result of previous oxycarbonylation reaction, we turned our attention to
survey the reactivity of internal alkenes. We were delighted to find that the reaction of
(E)ꢀoctꢀ4ꢀene affords the desired product antiꢀ4r in 67% yield. The reactions of (E)ꢀhexꢀ3ꢀene and
(E)ꢀdecꢀ5ꢀene also proceed well to afford antiꢀ4q and antiꢀ4s in slightly low yields. Even though,
these transformations are important, because these products are difficult to synthesize from other
methods. To our delight, excellent diastereoselectivities were observed in this reaction (d.r. > 20:1).
The stereochemistry, anti addition across the alkenes, is the same as that in oxycarbonylation
reaction,9 which is proved by transferring antiꢀ4r to butyrolactam 5 through hydrogenation and
substitution reactions.12 Importantly, this reaction can be scaled up to 1 mmol and 5 mmol to
provide product 3a in excellent yields (86% and 82% respectively).
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Due to the facile transformation of azido unit to amine group, we believed this reaction would
be an efficient way for the generation of βꢀaminocarboxylic acid products. As shown in eq 1, the
reaction of 4h with either triphenylphosphine/H2O or Pd/C under hydrogen atmosphere generated
the amine product 6h in good yields (70% and 75% repectively). To further prove the convenience
of this reaction, βꢀamino acid 7f can be accessible through sequential reactions from alkenes,
including azidocarbonylation, reduction, and neutralization with hydrochloride through a
easyꢀseparated process (eq 2).
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Based on the mechanism studies of our previous oxycarbonylation reaction,9 we proposed the
similar mechanism for this azidocarbonylation (Scheme 2): First, Zhdankin reagent (N3-II) is
activated by BF3·OEt2 to generate a more electron deficient iodine species A, which reacts with
the alkene to form the threeꢀmembered iodonium ion intermediate B.13 The nucleophilic attack of
an activate palladium catalyst, which is not clear at this stage, affords the alkylꢀPd species C. Then,
CO insertion into alkylꢀPd complex C and nucleophilic attack of azide at hypervalent iodine
center generate the acylꢀPd species D, which is attacked by 2ꢀiodobenzoic acid to give the
anhydride product E. During the workup by water or MeOH, the related carboxylic ester 3 and 4
or carboxylic acid 2 were obtained.
Scheme 2. Proposed Mechanism for Azidocarbonylation Reaction
CONCLUSION
In summary, we have developed a novel transitionꢀmetalꢀcatalyzed and iodine(III)ꢀmediated,
DFAs for βꢀazidocarboxylation. Both monoꢀ and 1,1ꢀdisubstituted terminal alkenes participate.
Some internal alkenes are also feasible to give the antiꢀazidocarboxylation products in excellent
diastereoselectivity in slightly lower reactivity. The reaction, which is conducted under very mild
reaction conditions, has good functionalꢀgroup compatibility, broad substrate scope, and high
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levels of regioselectivity. Due to the easy transformation of azido group, the current methodology
presents a facile synthesis of βꢀamino acid derivatives from simple olefins. Further mechanistic
studies and synthetic application are ongoing in our laboratory.
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EXPERIMENTAL SECTION
General. Pd(OAc)2 Pd(acac)2 and Pd(hfacac)2 was purchased from Strem Chemical, other
commercial reagents with high purity were purchased and used without further purification, unless
otherwise noted. Reactions were monitored by thinꢀlayer chromatography (TLC) carried out on 25
1
mm silica gel plates. H, 19F and 13C NMR spectra were recorded on an agilentꢀ400 MHz
spectrometer. The chemical shifts (δ) are given in parts per million relative to internal standard
TMS (0 ppm for 1H), CDCl3 (77.0 ppm for 13C). Highresolution mass spectra were carried out on
mass spectrometer with Agilent Technologies 6224 TOF LC/MS for positive ions (ESI), Thermo
Fisher Scientific LTQ FTICRꢀMS for negative ions (ESI), and Waters Micromass GCT Premier
for EI. Flash column chromatography was performed on silica gel (particle size 200ꢀ300 mesh,
purchased from Canada) and eluted with petroleum ether/ethyl acetate. Acetonitrile and toluene
were directly obtained from solvent purification system of Innovation Technology Company.
General procedure A for Azidocarbonylation Reaction.
To a suspention of Pd(acac)2 (6.0 mg, 0.02 mmol, 10 mol%), N3-II reagent (86.7 mg, 0.3 mmol,
1.5 equiv) and alkene (0.2 mmol, 1.0 equiv) in toluene/CH3CN (1:1, 2 mL) in a dried 25 mL
Schlenk bottle under CO (1 atm) atmosphere, BF3•Et2O (0.03 mmol, 15 mol%) was added. The
mixture was stirred at room temperature for 1ꢀ6 h. After the alkene was consumed, monitored by
o
TLC, dried MeOH (2.0 mL) was added and the resulting mixture was stirred at 45 C for 10 h. If
the esterification process was not complete, the mixture was filtrated through a short silica gel and
washed with ethyl acetate. The filtration was concentrated in vaccum and the residue was
dissolved in MeOH/CH3CN (1:1, 2 mL), added with TMSCHN2 (1.0 mmol, 0.5 mL, 2.0 M). After
stirring at room temperature for 2 h, the solvent was removed and the residue was purified by
column chromatography on silica gel with a gradient eluent of petroleum ether and ethyl acetate to
afford the products.
General procedure B for Azidocarbonylation Reaction.
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To a suspention of Pd(hfacac)2 (10.4 mg, 0.02 mmol, 10 mol%), N3-II reagent (144.5 mg, 0.5
mmol, 2.5 equiv), and alkene (0.2 mmol, 1.0 equiv) in toluene/CH3CN (1:9, 8 mL) in a dried 100
mL Schlenk bottle under CO (1 atm) atmosphere, BF3•Et2O (0.04 mmol, 20 mol%) was added.
The mixture was stirred at room temperature for 12 h. After the alkene was consumed, monitored
by TLC, the mixture was filtrated through a short silica gel and washed with ethyl acetate. After
removed the solvent, the residue was purified by column chromatography on silica gel with a
gradient eluent of petroleum ether and ethyl acetate to afford the products.
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Methyl 3-azido-6-(1,3-dioxoisoindolin-2-yl)hexanoate (3a). It was prepared according to
procedure A in 0.2 mmol scale, esterified with MeOH and further with TMSCHN2, and purified by
column chromatography on silica gel with petroleum ether/ ethyl acetate (10:1 to 3:1). 53.7 mg
(85%), white solid. mp 71.0 ~ 72.1°C. 1H NMR (400 MHz, CDCl3) δ 7.80 – 7.62 (m, 2H), 7.69 –
7.65 (m, 2H), 3.84 – 3.68 (m, 1H), 3.66 (t, J = 6.8 Hz, 2H), 3.65 (s, 3H), 2.45 (d, J = 6.8 Hz, 2H),
1.88 – 1.79 (m, 1H), 1.77 – 1.68 (m, 1H), 1.59 – 1.50 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3)
δ 170.9, 168.3, 133.9, 131.9, 123.2, 58.7, 51.9, 39.3, 37.3, 31.7, 25.1; HRMS (ESI): m/z calcd for
C15H20N5O4+ [M + NH4]+ 334.1510, found 334.1517.
Methyl 3-azido-5-(1,3-dioxoisoindolin-2-yl)pentanoate (3b). It was prepared according to
procedure A in 0.2 mmol scale, esterified with MeOH and further with TMSCHN2, and purified by
column chromatography on silica gel with petroleum ether/ ethyl acetate (10:1 to 3:1). 47.2 mg
(78%), colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.84 – 7.81 (m, 2H), 7.73 – 7.69 (m, 2H), 3.88
– 3.74 (m, 3H), 3.69 (s, 3H), 2.56 (d, J = 6.8 Hz, 2H), 1.95 – 1.86 (m, 1H), 1.84 – 1.75 (m, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 170.8, 168.2, 134.1, 131.9, 123.3, 56.8, 52.0, 39.3, 34.7, 33.2;
HRMS (ESI): m/z calcd for C14H18N5O4+ [M + NH4]+ 320.1353, found 320.1359.
Methyl 3-azido-4-phenylbutanoate (3c). It was prepared according to procedure A in 0.2 mmol
scale, esterified with MeOH only and purified by column chromatography on silica gel with
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petroleum ether/ ethyl acetate (10:1 to 3:1). 32.4 mg (74%), colorless oil. H NMR (400 MHz,
CDCl3) δ 7.35 ꢀ7.31 (m, 2H), 7.28 – 7.26 (m, 1H), 7.25 – 7.22 (m, 2H), 4.11 – 4.04 (m, 1H), 3.73
(s, 3H), 2.90 (dd, J = 13.6, 7.2 Hz, 1H), 2.84 (dd, J = 13.6, 6.4 Hz, 1H), 2.53 (dd, J = 16.4, 5.2 Hz,
1H), 2.47 (dd, J = 16.0, 8.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.1, 136.7, 129.4,
+
128.7, 127.1, 60.2, 51.9, 40.6, 38.7; HRMS (ESI): m/z calcd for C11H13N3NaO2 [M + Na]+
242.0900, found 242.0906.
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Methyl 3-azidononanoate (3d). It was prepared according to procedure A in 0.2 mmol scale,
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esterified with MeOH only and purified by column chromatography on silica gel with petroleum
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ether/ ethyl acetate (40:1 to 20:1). 36.6 mg (86%), colorless oil. H NMR (400 MHz, CDCl3) δ
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3.82 – 3.75 (m, 1H), 3.72 (s, 3H), 2.48 (d, J = 7.2 Hz, 2H), 1.59 – 1.48 (m, 2H), 1.47 – 1.21 (m,
8H), 0.88 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.3, 59.2, 51.9, 39.4, 34.4,
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31.6, 28.9, 25.9, 22.5, 14.0; HRMS (ESI): m/z calcd for C10H19N3NaO2 [M + Na]+ 236.1369,
found 236.1378.
Methyl 3-azidononadecanoate (3e). It was prepared according to procedure A in 0.2 mmol scale,
esterified with MeOH only and purified by column chromatography on silica gel with petroleum
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ether/ ethyl acetate (40:1 to 20:1). 57.1 mg (81%), colorless oil. H NMR (400 MHz, CDCl3) δ
3.82 – 3.75 (m, 1H), 3.70 (s, 3H), 2.56 – 2.43 (d, J = 6.4 Hz, 2H), 1.58 – 1.48 (m, 2H), 1.47 – 1.05
(m, 28H), 0.87 (t, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.2, 59.1, 51.9, 39.4,
34.3, 31.9, 29.68, 29.67, 29.65, 29.64, 29.63, 29.60, 29.50, 29.44, 29.35, 29.2, 25.9, 22.7, 14.1;
HRMS (ESI): m/z calcd for C20H43N4O2+ [M + NH4]+ 371.3381, found 371.3386.
Methyl 3-azido-4-cyclohexylbutanoate (3f). It was prepared according to procedure A in 0.2
mmol scale, esterified with MeOH only and purified by column chromatography on silica gel with
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petroleum ether/ ethyl acetate (20:1 to 5:1). 38.9 mg (86%), colorless oil. H NMR (400 MHz,
CDCl3) δ 3.91 – 3.81 (m, 1H), 3.71 (s, 3H), 2.48 (d, J = 6.8 Hz, 2H), 1.83 – 1.64 (m, 4H), 1.51 –
1.39 (m, 2H), 1.36 – 1.07 (m, 5H), 1.03 – 0.81 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.2,
56.6, 51.9, 41.9, 39.8, 34.3, 33.6, 32.5, 26.4, 26.2, 26.0; HRMS (ESI): m/z calcd for
C11H19N3NaO2+ [M + Na]+ 248.1369, found 248.1380.
Methyl 3-azido-6-bromohexanoate (3g). It was prepared according to procedure A in 0.2 mmol
scale, esterified with MeOH only and purified by column chromatography on silica gel with
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petroleum ether/ ethyl acetate (20:1 to 10:1). 35.5 mg (71%), colorless oil. H NMR (400 MHz,
CDCl3) δ 3.89 – 3.79 (m, 1H), 3.73 (s, 3H), 3.43 (t, J = 6.4 Hz, 2H), 2.56 (dd, J = 16.0, 7.6 Hz,
1H), 2.51 (dd, J = 16.0, 6.0 Hz, 1H), 2.12 – 1.88 (m, 2H), 1.81 – 1.56 (m, 2H); 13C{1H} NMR
(100 MHz, CDCl3) δ 170.9, 58.4, 52.1, 39.4, 32.9, 32.8, 29.0; HRMS (EI): m/z calcd for
C7H12BrNO2 [M–N2]+ 221.0051, found 221.0054.
Methyl 3-azido-4-phenoxybutanoate (3h). It was prepared according to procedure A in 0.2 mmol
scale, esterified with MeOH and further with TMSCHN2, and purified by column chromatography
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on silica gel with petroleum ether/ ethyl acetate (10:1 to 3:1). 30.1 mg (64%), colorless oil. H
NMR (400 MHz, CDCl3) δ 7.32 – 7.28 (m, 2H), 7.01 – 6.97 (m, 1H), 6.93 – 6.90 (m, 2H), 4.26 –
4.20 (m, 1H), 4.10 (dd, J = 9.6, 4.8 Hz, 1H), 4.06 (dd, J = 9.6, 6.4 Hz, 1H), 3.75 (s, 3H), 2.72 (dd,
J = 16.4, 5.2 Hz, 1H), 2.62 (dd, J = 16.4, 8.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.8,
158.0, 129.6, 121.5, 114.5, 69.6, 57.3, 52.1, 35.8; HRMS (EI): m/z calcd for C11H13N3O3 [M]+
235.0957, found 235.0955.
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Methyl 3-azido-5-phenoxypentanoate (3i). It was prepared according to procedure A in 0.2
mmol scale, esterified with MeOH and further with TMSCHN2, and purified by column
chromatography on silica gel with petroleum ether/ ethyl acetate (10:1 to 3:1). 41.8 mg (84%),
colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.32 ꢀ7.28 (m, 2H), 6.98 – 6.94 (m, 1H), 6.92 – 6.90
(m, 2H), 4.21 – 4.14 (m, 1H), 4.13 – 4.05 (m, 2H), 3.73 (s, 3H), 2.64 (dd, J = 16.4, 5.2 Hz, 1H),
2.59 (dd, J = 14.4, 8.0 HZ, 1H), 2.10 – 2.02 (m, 1H), 1.98 – 1.90 (m, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 171.0, 158.4, 129.5, 121.0, 114.5, 63.9, 56.3, 52.0, 39.5, 34.0; HRMS (ESI): m/z
calcd for C12H19N4O3+ [M + NH4]+ 267.1452, found 267.1458.
Methyl 3-azido-4-((tert-butyldiphenylsilyl)oxy)butanoate (3j). It was prepared according to
procedure A in 0.2 mmol scale, esterified with MeOH only and purified by column
chromatography on silica gel with petroleum ether/ ethyl acetate (20:1 to 10:1). 63.7 mg (80%),
colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 6.9 Hz, 4H), 7.51 – 7.37 (m, 6H), 3.99 –
3.93 (m, 1H), 3.74 (dd, J = 10.8, 4.8 Hz, 1H), 3.71 (dd, J = 10.8, 5.2 Hz, 1H), 3.71 (s, 3H), 2.58
(dd, J = 16.0, 5.2 Hz, 1H), 2.47 (dd, J = 16.0, 8.8 Hz, 1H), 1.10 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3) δ 171.0, 135.6, 132.7, 130.0, 127.9, 66.1, 59.8, 52.0, 35.6, 26.7, 19.2; HRMS (ESI): m/z
calcd for C21H31N4O3Si+ [M + NH4]+ 415.2160, found 415.2169.
Methyl 3-azido-6-(N,4-dimethylphenylsulfonamido)hexanoate (3k). It was prepared according
to procedure A in 0.2 mmol scale, esterified with MeOH and further with TMSCHN2, and purified
by column chromatography on silica gel with petroleum ether/ ethyl acetate (10:1 to 2:1). 56.9 mg
(80%), colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.0 Hz,
2H), 3.87 – 3.76 (m, 1H), 3.71 (s, 3H), 3.07ꢀ2.90 (m, 2H), 2.68 (s, 3H), 2.51 (d, J = 6.8 Hz, 2H),
2.41 (s, 3H), 1.73 – 1.48 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.3, 143.4, 134.2, 129.7,
127.3, 58.7, 52.0, 49.5, 39.4, 34.6, 31.3, 23.9, 21.59; HRMS (ESI): m/z calcd for C15H26N5O4S+
[M + NH4]+ 372.1700, found 372.1706.
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6-Ethyl 1-methyl 3-azidohexanedioate (3l). It was prepared according to procedure A in 0.2
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mmol scale, esterified with MeOH only and purified by column chromatography on silica gel with
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petroleum ether/ ethyl acetate (20:1 to 10:1). 32.1 mg (70%), colorless oil. H NMR (400 MHz,
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CDCl3) δ 4.14 (q, J = 6.8 Hz, 2H), 3.93 – 3.80 (m, 1H), 3.72 (s, 3H), 2.52 (d, J = 6.8 Hz, 2H), 2.44
(m, 2H), 1.96 – 1.84 (m, 1H), 1.81 – 1.71 (m, 1H), 1.25 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 172.6, 170.8, 60.7, 58.4, 52.0, 39.3, 30.6, 29.6, 14.2; HRMS (ESI): m/z calcd for
C9H16N3O4+ [M + H]+ 230.1135, found 230.1142.
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6-Benzyl 1-methyl 3-azidohexanedioate (3m). It was prepared according to procedure A in 0.2
mmol scale, esterified with MeOH and further with TMSCHN2, and purified by column
chromatography on silica gel with petroleum ether/ ethyl acetate (10:1 to 3:1). 44.2 mg (76%),
colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.28 (m, 5H), 5.13 (s, 2H), 3.88 – 3.84 (m, 1H),
3.72 (s, 3H), 2.60 – 2.43 (m, 4H), 1.99 – 1.86 (m, 1H), 1.85 – 1.75 (m, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 172.4, 170.8, 135.7, 128.6, 128.3, 128.3, 66.6, 58.3, 52.0, 39.3, 30.6, 29.5; HRMS
(ESI): m/z calcd for C14H21N4O4+ [M + NH4]+ 309.1557, found 309.1563.
1,1-Diethyl 4-methyl 3-azidobutane-1,1,4-tricarboxylate (3n). It was prepared according to
procedure A in 0.2 mmol scale, esterified with MeOH and further with TMSCHN2, and purified by
column chromatography on silica gel with petroleum ether/ ethyl acetate (20:1 to 5:1). 27.1 mg
(45%), colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.21 (dq, J = 14.4, 7.2 Hz, 4H), 3.93 – 3.84 (m,
1H), 3.72 (s, 3H), 3.57 (dd, J = 9.2, 5.2 Hz, 1H), 2.56 (d, J = 6.8 Hz, 2H), 2.19 – 2.12 (m, 1H),
2.00 – 1.93 (m, 1H), 1.27 (q, J = 7.6 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.6, 168.8,
168.7, 61.84, 61.79, 57.1, 52.1, 48.9, 39.6, 33.5, 14.03, 13.98; HRMS (ESI): m/z calcd for
C12H23N4O6+ [M + NH4]+ 319.1612, found 319.1620.
Trimethyl 2-azido-6-phenylhexane-1,5,5-tricarboxylate (3o). It was prepared according to
procedure A in 0.2 mmol scale, esterified with MeOH and further with TMSCHN2, and purified
by column chromatography on silica gel with petroleum ether/ ethyl acetate (10:1 to 3:1). 65.6 mg
(87%), colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.30 – 7.20 (m, 3H), 7.05 (d, J = 6.4 Hz, 2H),
3.80 – 3.73 (m, 1H), 3.72 (s, 3H), 3.71 (s, 3H), 3.70 (s, 3H), 3.23 (s, 2H), 2.51 (dd, J = 16.0, 7.2
Hz, 1H), 2.47 (dd, J = 18.4, 6.4 Hz, 1H), 2.02 – 1.90 (m, 1H), 1.88 – 1.75 (m, 1H), 1.63 – 1.41 (m,
2H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.3, 171.2, 170.9, 135.5, 129.7, 128.4, 127.2, 58.9,
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58.5, 52.52, 52.50, 52.0, 39.1, 38.6, 29.2, 28.5; HRMS (ESI): m/z calcd for C18H27N4O6 [M +
NH4]+ 395.1925, found 395.1930.
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Dimethyl 3-azidododecanedioate (3p). It was prepared according to procedure A in 0.2 mmol
scale, esterified with MeOH and further with TMSCHN2, and purified by column chromatography
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on silica gel with petroleum ether/ ethyl acetate (20:1 to 10:1). 38.3 mg (64%), colorless oil. H
NMR (400 MHz, CDCl3) δ 3.80 – 3.73 (m, 1H), 3.70 (s, 3H), 3.64 (s, 3H), 2.47 (d, J = 6.4 Hz,
2H), 2.28 (t, J = 7.6 Hz, 2H), 1.64 – 1.55 (m, 2H), 1.56 – 1.22 (m, 12H); 13C{1H} NMR (100 MHz,
CDCl3) δ 174.3, 171.2, 59.1, 51.9, 51.4, 39.4, 34.3, 34.0, 29.18, 29.11, 29.06, 29.02, 25.9, 24.9;
HRMS (ESI): m/z calcd for C14H29N4O4+ [M + NH4]+ 317.2183, found 317.2188.
Methyl 3-azido-12-oxododecanoate (3q). It was prepared according to procedure A in 0.2 mmol
scale, esterified with MeOH and further with TMSCHN2, and purified by column chromatography
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on silica gel with petroleum ether/ ethyl acetate (20:1 to 10:1). 38.2 mg (71%), colorless oil. H
NMR (400 MHz, CDCl3) δ 9.75 (t, J = 1.6 Hz, 1H), 3.81 – 3.74 (m, 1H), 3.71 (s, 3H), 2.48 (d, J =
6.4 Hz, 2H), 2.41 (td, J = 7.2, 1.6 Hz, 2H), 1.65 – 1.58 (m, 2H), 1.56 – 1.47 (m, 2H), 1.47 – 1.22
(m, 10H); 13C{1H} NMR (100 MHz, CDCl3) δ 202.9, 171.3, 59.1, 51.9, 43.9, 39.4, 34.3, 29.2,
29.1, 29.0, 25.9, 22.0; HRMS (ESI): m/z calcd for C13H27N4O3 [M + NH4]+ 287.2083, found
+
287.2083.
Methyl 3-azido-7-oxooctanoate (3r). It was prepared according to procedure A in 0.2 mmol scale,
esterified with MeOH and further with TMSCHN2, and purified by column chromatography on
silica gel with petroleum ether/ ethyl acetate (10:1 to 4:1). 32.0 mg (75%), colorless oil. 1H NMR
(400 MHz, CDCl3) δ 3.76 (q, J = 7.2 Hz, 1H), 3.68 (s, 3H), 2.48 (d, J = 7.2 Hz, 2H), 2.45 (t, J =
7.2 Hz, 2H), 2.11 (s, 3H), 1.78 – 1.54 (m, 2H), 1.54 – 1.42 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 208.0, 171.0, 58.9, 51.9, 42.8, 39.2, 33.6, 29.9, 19.9; HRMS (ESI): m/z calcd for
C9H19N4O3+ [M + NH4]+ 231.1452, found 231.1454.
Methyl 3-azido-6-(diethoxyphosphoryl)hexanoate (3s). It was prepared according to procedure
A in 0.2 mmol scale, esterified with MeOH and further with TMSCHN2, and purified by column
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chromatography on silica gel with DCM/ MeOH (1:0 to 10:1). 43.0 mg (70%), colorless oil. H
NMR (400 MHz, CDCl3) δ 4.15 – 3.99 (m, 4H), 3.82 – 3.75 (m, 1H), 3.70 (s, 3H), 2.49 (d, J = 6.8
Hz, 2H), 1.83 – 1.50 (m, 6H), 1.30 (t, J = 7.2 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.0,
61.6 (d, J = 6.3 Hz), 58.6 (d, J = 1.6 Hz), 52.0, 39.2, 35.0 (d, J = 15.8 Hz), 25.2 (d, J = 141.2 Hz),
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19.1 (d, J = 4.1 Hz), 16.4 (d, J = 6.0 Hz); HRMS (ESI): m/z calcd for C11H23N3O5P+ [M + H]+
308.1370, found 308.1371.
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Methyl 3-azido-4-((tert-butyldiphenylsilyl)oxy)-5-phenylpentanoate (3t). It was prepared
according to procedure A in 0.2 mmol scale, esterified with MeOH only and purified by column
chromatography on silica gel with petroleum ether/ ethyl acetate (1:0 to 10:1). 48.7 mg (50%; d.r.
7:1), colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.79 – 7.72 (m, 2H), 7.63 – 7.56 (m, 2H), 7.53 –
7.35 (m, 6H), 7.21 – 7.11 (m, 3H), 6.83 – 6.76 (m, 2H), 4.05 (ddd, J = 8.0, 5.6, 2.0 Hz, 1H), 3.83
(ddd, J = 8.0, 5.6, 2.0 Hz, 1H), 3.67 (s, 3H), 2.78 (dd, J = 14.0, 5.6 Hz, 1H), 2.69 (dd, J = 14.0, 8.4
Hz, 1H), 2.47 – 2.37 (m, 2H), 1.09 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.4, 137.0,
136.1, 135.9, 133.5, 133.0, 130.0, 129.8, 129.2, 128.5, 127.9, 127.7, 126.6, 76.6, 62.0, 52.0, 39.9,
34.7, 26.9, 19.3; HRMS (ESI): m/z calcd for C28H37N4O3Si+ [M + NH4]+ 505.2629, found
505.2637.
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Methyl 3-azido-6-(1-tosyl-1H-indol-3-yl)hexanoate (3u). It was prepared according to
procedure A in 0.2 mmol scale, esterified with MeOH and further with TMSCHN2, and purified
by column chromatography on silica gel with petroleum ether/ ethyl acetate (1:0 to 20:1). 70.4 mg
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(80%), white solid. mp 94.1 ~ 95.5°C. H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.0 Hz, 1H),
7.74 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 7.6 Hz, 1H), 7.32 (s, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.22 (t, J
= 7.6 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 3.83 (q, J = 6.8 Hz, 1H), 3.71 (s, 3H), 2.69 (t, J = 7.6 Hz,
2H), 2.56 – 2.43 (m, 2H), 2.32 (s, 3H), 1.93 – 1.70 (m, 2H), 1.64 – 1.53 (m, 2H); 13C{1H} NMR
(100 MHz, CDCl3) δ 171.1, 144. 8, 135.4, 135.2, 130.8, 129.8, 126.7, 124.7, 123.1, 122.8, 122.5,
119.4, 113.8, 58.9, 52.0, 39.4, 34.0, 25.2, 24.5, 21.5; HRMS (ESI): m/z calcd for C22H28N5O4S+
[M + NH4]+ 458.1857, found 458.1861.
Methyl 3-azido-6-((2-oxo-2H-chromen-4-yl)oxy)hexanoate (3v). It was prepared according to
procedure A in 0.2 mmol scale, esterified with MeOH and further with TMSCHN2, and purified by
column chromatography on silica gel with petroleum ether/ ethyl acetate (10:1 to 3:1). 55.6 mg
1
(84%), white solid. mp 57.3 ~ 58.8°C. H NMR (400 MHz, CDCl3) δ 7.78 (dd, J = 7.6, 0.9 Hz,
1H), 7.53 (td, J = 7.6, 0.9 Hz, 1H), 7.28 (t, J = 8.8 Hz, 2H), 5.65 (s, 1H), 4.15 (t, J = 6.0 Hz, 2H),
3.97 – 3.85 (m, 1H), 3.71 (s, 3H), 2.61 (dd, J = 16.0, 8.0 Hz, 1H), 2.55 (dd, J = 16.0, 5.6 Hz, 1H),
2.17 – 1.93 (m, 2H), 1..85 – 1.67 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.9, 165.4,
162.9, 153.3, 132.5, 123.9, 122.9, 116.8, 115.5, 90.6, 68.6, 58.6, 52.1, 39.3, 30.9, 25.2; HRMS
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(ESI): m/z calcd for C16H18N3O5+ [M + H]+ 332.1241, found 332.1241.
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Methyl 3-azido-5-(((8R,9S,13S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-
cyclopenta[a]phenanthren-3-yl)oxy)pentanoate (3w). It was prepared according to procedure A
in 0.2 mmol scale, esterified with MeOH and further with TMSCHN2, and purified by column
chromatography on silica gel with petroleum ether/ ethyl acetate (10:1 to 3:1). 43.4 mg (51%),
pale yellow solid. mp 61.5 ~ 62.3°C. 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 8.4 Hz, 1H), 6.72
(dd, J = 8.4, 2.8 Hz, 1H), 6.65 (d, J = 2.4 Hz, 1H), 4.19 – 4.12 (m, 1H), 4.11 – 4.01 (m, 2H), 3.73
(s, 3H), 2.92 – 2.88 (m, 2H), 2.65 (dd, J = 16.0, 4.8 Hz, 1H), 2.56 (dd, J = 16.0, 4.4 Hz, 1H), 2.50
(dd, J = 19.2, 8.8 Hz, 1H), 2.42 – 2.37 (m, 1H), 2.27 – 2.22 (m, 1H), 2.18 – 1.86 (m, 6H), 1.70 –
1.37 (m, 6H), 0.91 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 221.0, 171.0, 156.5, 137.8, 132.4,
126.4, 114.5, 112.1, 63.9, 56.3, 52.0, 50.4, 48.0, 44.0, 39.5, 38.3, 35.9, 34.0, 31.6, 29.7, 26.5, 25.9,
21.6, 13.9; HRMS (ESI): m/z calcd for C24H35N4O4+ [M + NH4]+ 443.2653, found 443.2661.
1-Methyl 6-(3-methylbut-2-en-1-yl) 3-azidohexanedioate (3x). It was prepared according to
procedure A in 0.2 mmol scale, esterified with MeOH only and purified by column
chromatography on silica gel with petroleum ether/ ethyl acetate (20:1 to 5:1). 36.6 mg (68%),
colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.33 (t, J = 6.8 Hz, 1H), 4.58 (d, J = 7.2 Hz, 2H), 3.94
– 3.80 (m, 1H), 3.71 (s, 3H), 2.52 (d, J = 6.8 Hz, 2H), 2.50 – 2.38 (m, 2H), 1.90 (m, 1H), 1.81 –
1.72 (m, 1H), 1.75 (s, 3H), 1.70 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.6, 170.8, 139.4,
118.3, 61.6, 58.4, 52.0, 39.3, 30.6, 29.6, 25.8, 18.0; HRMS (ESI): m/z calcd for C12H23N4O4+ [M +
NH4]+ 287.1714, found 287.1719.
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Methyl 3-azido-6,6-dicyano-9-methyldec-8-enoate (3y). It was prepared according to procedure
A in 0.2 mmol scale, esterified with MeOH and further with TMSCHN2, and purified by column
chromatography on silica gel with petroleum ether/ ethyl acetate (10:1 to 4:1). 34.7 mg (60%),
colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.31 – 5.21 (m, 1H), 3.96 – 3.90 (m, 1H), 3.74 (s, 3H),
2.69 (d, J = 8.0 Hz, 2H), 2.63 (dd, J = 16.4, 8.0 Hz, 1H), 2.57 (dd, J = 16.4, 5.2 Hz, 1H), 2.20 –
2.09 (m, 1H), 2.04 – 1.87 (m, 2H), 1.82 (s, 3H), 1.86 – 1.74 (m, 1H), 1.72 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 170.5, 141.1, 115.3, 115.2, 114.2, 57.9, 52.2, 39.2, 37.5, 36.3, 33.6, 30.6,
26.0, 18.4; HRMS (ESI): m/z calcd for C14H23N6O2+ [M + NH4]+ 307.1877, found 307.1879.
Dimethyl 3,7-diazidononanedioate (3z). It was prepared according to procedure A in 0.2 mmol
scale, esterified with MeOH and further with TMSCHN2, and purified by column chromatography
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on silica gel with petroleum ether/ ethyl acetate (20:1 to 5:1). 40.5 mg (68%), yellow oil.1H NMR
(400 MHz, CDCl3) δ 3.86 – 3.76 (m, 2H), 3.72 (s, 6H), 2.58 – 2.44 (m, 4H), 1.69 – 1.46 (m, 6H);
13C{1H} NMR (100 MHz, CDCl3) δ 171.0, 58.8, 52.0, 39.3, 33.9, 22.4; HRMS (ESI): m/z calcd
for C11H22N7O4+ [M + NH4]+ 316.1728, found 316.1736.
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Methyl 3-azido-3-methyl-5-(tosyloxy)pentanoate (4a). It was prepared according to procedure
A in 0.2 mmol scale, esterified with MeOH and further with TMSCHN2, and purified by column
chromatography on silica gel with petroleum ether/ ethyl acetate (10:1 to 3:1). 48.4 mg (71%),
yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.13
(t, J = 6.4 Hz, 2H), 3.66 (s, 3H), 2.50 (s, 2H), 2.44 (s, 3H), 2.07 – 1.88 (m, 2H), 1.40 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 169.9, 145.0, 132.6, 129.9, 127.9, 66.2, 60.4, 51.9, 43.6, 37.9,
23.7, 21.7; HRMS (ESI): m/z calcd for C14H23N4O5S+ [M + NH4]+ 359.1384, found 359.1388.
Methyl 3-azido-3-methyl-4-(4-nitrophenoxy)butanoate (4b). It was prepared according to
procedure A in 0.2 mmol scale, esterified with MeOH and further with TMSCHN2, and purified
by column chromatography on silica gel with petroleum ether/ ethyl acetate (10:1 to 5:1). 46.4 mg
1
(79%), yellow oil. H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 9.2 Hz, 2H), 6.99 (d, J = 9.2 Hz,
2H), 4.20 (d, J = 9.2 Hz, 1H), 4.12 (d, J = 9.2 Hz, 1H), 3.70 (s, 3H), 2.77 (d, J = 15.2 Hz, 1H),
2.69 (d, J = 15.2 Hz, 1H), 1.54 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.9, 163.0, 141.9,
+
125.9, 114.6, 73.5, 60.7, 52.0, 40.6, 21.0; HRMS (ESI): m/z calcd for C12H18N5O5 [M + NH4]+
312.1302, found 312.1304.
1-Methyl 6-phenyl 3-azido-3-methylhexanedioate (4c). It was prepared according to procedure
A in 0.2 mmol scale, esterified with MeOH and further with TMSCHN2, and purified by column
chromatography on silica gel with petroleum ether/ ethyl acetate (15:1 to 5:1). 52.4 mg (90%),
yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.6 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.43 (t,
J = 7.6 Hz, 2H), 4.52 – 4.39 (m, 2H), 3.66 (s, 3H), 2.65 (d, J = 15.1 Hz, 1H), 2.61 (d, J = 15.1 Hz,
1H), 2.24 – 2.07 (m, 2H), 1.51 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.1, 166.4, 133.0,
+
130.0, 129.5, 128.4, 60.81, 60.79, 51.8, 43.7, 37.7, 23.8; HRMS (ESI): m/z calcd for C14H21N4O4
[M + NH4]+ 309.1557, found 309.1562.
Methyl 3-azido-4-(1,3-dioxoisoindolin-2-yl)-3-methylbutanoate (4d). It was prepared according
to procedure A in 0.2 mmol scale, esterified with MeOH and further with TMSCHN2, and purified
by column chromatography on silica gel with petroleum ether/ ethyl acetate (10:1 to 5:1). 27.1 mg
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(45%), yellow solid. mp 52.8 ~ 54.0°C. 1H NMR (400 MHz, CDCl3) δ 7.90 – 7.84 (m, 2H), 7.77 –
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7.71 (m, 2H), 3.91 (d, J = 14.0 Hz, 1H), 3.86 (d, J = 14.0 Hz, 1H), 3.72 (s, 3H), 2.61 (d, J = 15.6
Hz, 1H), 2.56 (d, J = 15.6 Hz, 1H), 1.52 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.9, 168.4,
+
9
134.3, 131.7, 123.6, 62.1, 51.9, 45.2, 42.0, 21.7; HRMS (ESI): m/z calcd for C1 H18N5O4 [M +
4
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NH4]+ 320.1353, found 320.1360.
Methyl 2-(1-azidocyclohexyl)acetate (4e). It was prepared according to procedure A in 0.2 mmol
scale, esterified with MeOH only and purified by column chromatography on silica gel with
1
petroleum ether/ ethyl acetate (1:0 to 20:1). 29.9 mg (74%), colorless oil. H NMR (400 MHz,
CDCl3) δ 3.71 (s, 3H), 2.54 (s, 2H), 1.80 – 1.76 (m, 2H), 1.62 – 1.50 (m, 7H), 1.31 – 1.21 (m, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 170.4, 62.0, 51.8, 44.7, 34.7, 25.1, 21.9; HRMS (ESI): m/z
calcd for C9H15N3O2Na+ [M + Na]+ 220.1056, found 220.1063.
Methyl 3-azido-3-phenylpropanoate (4f). It was prepared according to procedure A in 0.2 mmol
scale, esterified with MeOH only and purified by column chromatography on silica gel with
1
petroleum ether/ ethyl acetate (1:0 to 10:1). 30.0 mg (73%), colorless oil. H NMR (400 MHz,
CDCl3) δ 7.42 – 7.33 (m, 5H), 4.99 (dd, J = 9.2, 5.2 Hz, 1H), 3.71 (s, 3H), 2.83 (dd, J = 16.0, 9.6
Hz, 1H), 2.70 (dd, J = 16.0, 4.8 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.7, 138.3, 129.0,
128.7, 126. 8, 62.2, 52.1, 41.1; HRMS (EI): m/z calcd for C10H11NO2 [M–N2]+ 177.0790, found
177.0789.
Methyl 3-([1,1'-biphenyl]-4-yl)-3-azidopropanoate (4g). It was prepared according to procedure
A in 0.2 mmol scale, esterified with MeOH only and purified by column chromatography on silica
gel with petroleum ether/ ethyl acetate (1:0 to 10:1). 34.6 mg (62%), white solid. mp 38.5 ~
39.0°C. 1H NMR (400 MHz, CDCl3) δ 7.66 – 7.56 (m, 4H), 7.47 – 7.35 (m, 5H), 5.05 (dd, J = 9.2,
5.2 Hz, 1H), 3.73 (s, 3H), 2.87 (dd, J = 16.0, 9.2 Hz, 1H), 2.75 (dd, J = 16.0, 5.2 Hz, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ 170.6, 141.6, 140.3, 137.2, 128.8, 127.7, 127.6, 127.2, 127.1, 61.9,
52.1, 41.1; HRMS (ESI): m/z calcd for C16H19N4O2+ [M + NH4]+ 299.1503, found 299.1502.
Methyl 3-azido-3-(4-(tert-butyl)phenyl)propanoate (4h). It was prepared according to
procedure A in 0.2 mmol scale, esterified with MeOH only and purified by column
chromatography on silica gel with petroleum ether/ ethyl acetate (1:0 to 20:1). 36.0 mg (69%),
yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.4 Hz, 2H), 7.26 (d, J =8.4 Hz, 2H), 4.97
(dd, J = 9.6, 4.8 Hz, 1H), 3.72 (s, 3H), 2.82 (dd, J = 16.0, 9.6 Hz, 1H), 2.69 (dd, J = 16.0, 4.8 Hz,
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1H), 1.32 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.8, 151.7, 135.3, 126.4, 125.9, 61.9,
52.0, 41.1, 34.6, 31.3; HRMS (ESI): m/z calcd for C14H19N3O2Na+ [M + Na]+ 284.1369, found
284.1373.
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Methyl 3-azido-3-(4-fluorophenyl)propanoate (4i). It was prepared according to procedure A in
0.2 mmol scale, esterified with MeOH only and purified by column chromatography on silica gel
with petroleum ether/ ethyl acetate (1:0 to 10:1). 30.3 mg (68%), colorless oil. 1H NMR (400 MHz,
CDCl3) δ 7.32 (dd, J = 8.8, 5.2 Hz, 2H), 7.08 (t, J = 8.8 Hz, 2H), 4.98 (dd, J = 8.8, 5.6 Hz, 1H),
3.70 (s, 3H), 2.81 (dd, J = 16.0, 8.8 Hz, 1H), 2.67 (dd, J = 16.0, 5.6 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 170.5, 162.7 (d, J = 245.9 Hz), 134.1(d, J = 3.1 Hz), 128.5 (d, J = 8.4 Hz), 115.9
(d, J = 21.2 Hz), 61.5, 52.1, 41.2; HRMS (EI): m/z calcd for C10H10NO2F [M–N2]+ 195.0696,
found 195.0701.
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Methyl 3-azido-3-(3-chlorophenyl)propanoate (4j). It was prepared according to procedure A in
0.2 mmol scale, esterified with MeOH only and purified by column chromatography on silica gel
with petroleum ether/ ethyl acetate (1:0 to 15:1). 28.2 mg (59%), yellow oil. 1H NMR (400 MHz,
CDCl3) δ 7.33 – 7.30 (m, 3H), 7.22 (s, 1H), 4.97 (dd, J = 9.2, 5.2 Hz, 1H), 3.71 (s, 3H), 2.79 (dd, J
= 16.0, 9.2 Hz, 1H), 2.67 (dd, J = 16.0, 5.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.3,
140.5, 134.9, 130.3, 128.9, 126.9, 124.9, 61.6, 52.1, 41.1; HRMS (EI): m/z calcd for C10H10NO2Cl
[M–N2]+ 211.0400, found 211.0402.
Methyl 3-azido-3-(3,4-dimethylphenyl)propanoate (4k). It was prepared according to procedure
A in 0.2 mmol scale, esterified with MeOH only and purified by column chromatography on silica
gel with petroleum ether/ ethyl acetate (1:0 to 10:1). 30.0 mg (64%), colorless oil. 1H NMR (400
MHz, CDCl3) δ 7.18 – 7.02 (m, 3H), 4.92 (dd, J = 9.2, 4.8 Hz, 1H), 3.71 (s, 3H), 2.81 (dd, J =
16.0, 9.6 Hz, 1H), 2.68 (dd, J = 16.0, 5.2 Hz, 1H), 2.28 (s, 3H), 2.26 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 170.8, 137.3, 137.2, 135.6 130.1, 128.0, 124.1, 62.0, 52.0, 41.1, 19.9, 19.5;
HRMS (ESI): m/z calcd for C12H19N4O2+ [M + NH4]+ 251.1503, found 251.1508.
Methyl 3-azido-3-(4-(2-methoxy-2-oxoethyl)phenyl)propanoate (4l). It was prepared according
to procedure A in 0.2 mmol scale, esterified with MeOH and further with TMSCHN2, and purified
by column chromatography on silica gel with petroleum ether/ ethyl acetate (20:1 to 3:1). 35.5 mg
1
(64%), yellow oil. H NMR (400 MHz, CDCl3) δ 7.34 – 7.27 (m, 4H), 4.97 (dd, J = 9.2, 5.2 Hz,
1H), 3.70 (s, 3H), 3.69 (s, 3H), 3.63 (s, 3H), 2.80 (dd, J = 16.0, 9.2 Hz, 1H), 2.67 (dd, J = 16.1, 5.2
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Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.6, 170.5, 137.2, 134.5, 129.9, 126.9, 61.9, 52.0,
52.0, 41.1, 40.7; HRMS (ESI): m/z calcd for C13H19N4O4+ [M + NH4]+ 295.1401, found 295.1403.
Methyl 3-azido-3-(naphthalen-2-yl)propanoate (4m). It was prepared according to procedure A
in 0.2 mmol scale, esterified with MeOH and further with TMSCHN2, and purified by column
chromatography on silica gel with petroleum ether/ ethyl acetate (1:0 to 10:1). 24.0 mg (47%),
colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.92 – 7.79 (m, 4H), 7.54 –7.44 (m, 3H), 5.18 (dd, J =
9.2, 5.6 Hz, 1H), 3.72 (s, 3H), 2.92 (dd, J = 16.0, 9.2 Hz, 1H), 2.79 (dd, J = 16.0, 5.2 Hz, 1H);
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13C{1H} NMR (100 MHz, CDCl3) δ 170.7, 135.6, 133.3, 133.1, 129.1, 128.1, 127.8, 126.6, 126.5,
+
126.2, 124.1, 62.4, 52.1, 41.2; HRMS (ESI): m/z calcd for C1 H17N4O2 [M + NH4]+ 273.1346,
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found 273.1357.
Methyl 3-azido-3-(1-tosyl-1H-pyrrol-3-yl)propanoate (4n). It was prepared according to
procedure A in 0.2 mmol scale, esterified with MeOH and further with TMSCHN2, and purified
by column chromatography on silica gel with petroleum ether/ ethyl acetate (15:1 to 4:1). 53.2 mg
1
(76%), pale yellow solid. mp 74.1 ~ 75.6°C. H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.4 Hz,
2H), 7.29 (d, J = 8.4 Hz, 2H), 7.18 – 7.12 (m, 2H), 6.26 (dd, J = 3.2, 1.6 Hz, 1H), 4.85 (dd, J = 8.8,
5.6 Hz, 1H), 3.68 (s, 3H), 2.74 (dd, J = 16.0, 8.8 Hz, 1H), 2.65 (dd, J = 16.0, 5.6 Hz, 1H), 2.40 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.4, 145.3, 135.6, 130.1, 126.9, 126.0, 121.9, 118.3,
111.9, 55.4, 52.0, 40.2, 21.6; HRMS (ESI): m/z calcd for C1 H20N5O4S+ [M + NH4]+ 366.1231,
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found 366.1239.
Methyl 3-(1-acetyl-1H-indol-5-yl)-3-azidopropanoate (4o). It was prepared according to
procedure A in 0.2 mmol scale, esterified with MeOH and further with TMSCHN2, and purified by
column chromatography on silica gel with petroleum ether/ ethyl acetate (10:1 to 3:1). 44.0 mg
(77%), yellow solid. mp 54.2 ~ 55.2°C. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 8.4 Hz, 1H),
7.54 (d, J = 1.2 Hz, 1H), 7.45 (d, J = 3.6 Hz, 1H), 7.31 (dd, J = 8.8, 1.6 Hz, 1H), 6.65 (d, J = 3.6
Hz, 1H), 5.09 (dd, J = 9.2, 5.2 Hz, 1H), 3.70 (s, 3H), 2.88 (dd, J = 16.0, 9.2 Hz, 1H), 2.74 (dd, J =
16.0, 5.2 Hz, 1H), 2.64 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.7, 168.6, 135.6, 133.7,
130.7, 126.1, 123.8, 119.3, 117.1, 109.1, 62.3, 52.0, 41.4, 23.9; HRMS (ESI): m/z calcd for
C14H18N5O3+ [M + NH4]+ 304.1404, found 304.1411.
Methyl 3-azido-3-phenylbutanoate (4p). It was prepared according to procedure A in 0.2 mmol
scale, esterified with MeOH only and purified by column chromatography on silica gel with
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petroleum ether/ ethyl acetate (1:0 to 10:1). 11.0 mg (25%), yellow oil. H NMR (400 MHz,
CDCl3) δ 7.46 – 7.27 (m, 5H), 3.61 (s, 3H), 2.83 (s, 2H), 1.86 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 169.9, 142.5, 128.6, 127.9, 125.4, 64.4, 51.8, 46.4, 24.9; HRMS (ESI): m/z calcd for
C11H17N4O2+ [M + NH4]+ 237.1346, found 237.1339.
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Anti- 3-azido-2-ethylpentanoic acid (4r). It was prepared according to procedure B in 0.2 mmol
scale and purified by column chromatography on silica gel with petroleum ether/ ethyl acetate
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(10:1 to 3:1). 14.0 mg (41%), colorless oil. H NMR (400 MHz, CDCl3) δ 3.58 ꢀ3.48 (m, 1H),
2.55 – 2.45 (m, 1H), 1.80 – 1.53 (m, 4H), 1.05 (t, J = 6.8 Hz, 3H), 0.98 (t, J = 7.2 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 179.1, 65.0, 51.1, 24.7, 22.0, 11.5, 10.3; HRMS (ESI): m/z calcd for
ꢀ
C7H12N3O2 [MꢀH]ꢀ 170.0935, found 170.0933.
Anti-3-azido-2-propylhexanoic acid (4r). It was prepared according to procedure B in 0.2 mmol
scale and purified by column chromatography on silica gel with petroleum ether/ ethyl acetate
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(10:1 to 3:1). 26.6 mg (67%), colorless oil. H NMR (400 MHz, CDCl3) δ 3.58 ꢀ3.48 (m, 1H),
2.55 – 2.45 (m, 1H), 1.72 – 1.25 (m, 8H), 0.97 (t, J = 7.2 Hz, 3H), 0.94 (t, J = 6.8 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 191.6, 63.7, 37.1, 33.8, 30.9, 20.5, 19.2, 13.9, 13.7; HRMS (ESI): m/z
ꢀ
calcd for C9H16N3O2 [MꢀH]ꢀ 198.1248, found 198.1248.
Anti-3-azido-2-butylheptanoic acid (4s). It was prepared according to procedure B in 0.2 mmol
scale and purified by column chromatography on silica gel with petroleum ether/ ethyl acetate
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(10:1 to 3:1). 15.0 mg (33%), colorless oil. H NMR (400 MHz, CDCl3) δ 3.55 – 3.50 (m, 1H),
2.54 – 2.48 (m, 1H), 1.72 – 1.25 (m, 12H), 0.93 (t, J = 6.8 Hz, 3H), 0.91 (t, J = 5.6 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 178.7, 63.8, 49.9, 31.4, 29.3, 28.5, 28.1, 22.5, 22.4, 13.9, 13.8;
ꢀ
HRMS (ESI): m/z calcd for C11H20N3O2 [MꢀH]ꢀ 226.1561, found 226.1561.
Cis-3,4-dipropylazetidin-2-one (5). 1H NMR (400 MHz, CDCl3) δ 6.06 (m, 1H), 3.29 (dt, J = 6.8,
2.4 Hz, 1H), 2.74 (dt, J = 6.0, 2.7 Hz, 1H), 1.80 – 1.73 (m, 1H), 1.65 – 1.55 (m, 3H), 1.49 – 1.32
(m, 4H), 0.96 (t, J = 7.2 Hz, 3H), 0.94 (t, J = 5.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
171.7, 56.7, 55.2, 37.3, 30.7, 20.6, 19.7, 14.0, 13.9. Known compound.14
Typical procedure for Reduction of Azides.
To a solution of 4h (26.1 mg, 0.1 mmol) in THF (1 mL) was added PPh3 (78.6 mg, 0.3 mmol) and
H2O (18 ꢁL, 1.0 mmol). The reaction solution was stirred at rt overnight. TLC indicated the
completion of the substrate. The solution was concentrated and the residue was purified by
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column chromatography on silica gel with dichloromethane/ methanol (1:0 to 10:1) to afford 6h as
colorless oil. 16.5 mg (70%). 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.8 Hz, 2H), 7.28 (d, J =
8.4 Hz, 2H), 4.41 (t, J = 6.8 Hz, 1H), 3.69 (s, 3H), 2.68 (d, J = 6.8 Hz, 2H), 2.28 (br, 2H), 1.31 (s,
9H). 13C{1H} NMR (100 MHz, CDCl3) δ 172.5, 150.4, 125.8, 125.5, 52.1, 51.7, 43.6, 34.3, 31.3.
Known compound.15
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3-Amino-4-cyclohexylbutanoic acid hydrochloride (7f). It was prepared according to procedure
A in 0.2 mmol scale, after the alkene was consumed monitored by TLC, the reaction mixture was
concentrated and reduced with PPh3 (157 mg, 0.6 mmol) and H2O (36 ꢁL, 2.0 mmol) in THF (2
mL) for 12 h. HCl aq (6N, 1 mL) was then added, and the aquous phase was washed with ethyl
acetate and concentrated to give crude solid. The solid was recrystallised in mixture of EtOH:H2O
to afford 6f as a white solid. 24.3 mg (55%). mp 158 ~ 160°C. 1H NMR (400 MHz, D2O) δ 3.73 –
3.64 (m, 1H), 2.78 (dd, J = 15.6, 4.4 Hz, 1H), 2.63 (dd, J = 15.6, 8.0 Hz, 1H), 1.71 – 1.51 (m, 7H),
1.37 – 1.34 (m, 1H), 1.25 – 1.09 (m, 3H), 0.96 – 0.87 (m, 2H). 13C{1H} NMR (100 MHz, D2O) δ
174.7, 45.9, 39.5, 36.4, 32.8, 32.29, 32.26, 25.7, 25.42, 25.39. Known compound.16
ASSOCIATED CONTENT
Author Contributions
§ M. Li and F. Yu contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for financial support from the National Basic Research Program of China
(973ꢀ2015CB856600), the National Nature Science Foundation of China (Nos. 21532009,
21472217, and 21421091), and the Strategic Priority Research Program of the Chinese Academy
of Sciences (No. XDB20000000). This research was also partially supported by Open Fund of the
Key Laboratory of Functional Molecular Engineering of Guangdong Province, South China
University of Technology (2016kf02).
Supporting Information
1H and 13C NMR spectra of all new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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