Synthesis and application of a novel asymmetric azo reagent: 1-(tert-butyl)-2-(4-chlorobenzyl) azodicarboxylate (tBCAD)

Article abstract of DOI:10.1016/j.tet.2017.07.033

A series of novel asymmetric azo reagents, 1-(tert-butyl)-2-(4-substituted benzyl) azodicarboxylate, were prepared. The synthetic process has the advantage of simpleness, easy operation, mild reaction condition and high yield. The 1-(tert-butyl)-2-(4-chlorobenzyl) azodicarboxylate (tBCAD) was selected for its stability and convenience to handle, and its precursor can be recycled by recrystallization with toluene. The tBCAD and DIAD were applied to a wide variety of Mitsunobu reactions. The experimental results showed that the performance of tBCAD in Mitsunobu reaction was comparable to that of DIAD, while the stability of tBCAD was much better than DIAD. Thus, tBCAD can be a novel, stable, effective azo-reagent for the Mitsunobu reaction.

Full text of DOI:10.1016/j.tet.2017.07.033

Accepted Manuscript
Synthesis and application of a novel asymmetric azo reagent: 1-(tert-butyl)-2-(4-
chlorobenzyl) azodicarboxylate (tBCAD)
Jian Xie, Cai Xu, Qianjin Dai, Xiaozhong Wang, Gang Xu, Yingqi Chen, Liyan Dai
PII:
S0040-4020(17)30768-8
10.1016/j.tet.2017.07.033
TET 28865
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 May 2017
Revised Date: 14 July 2017
Accepted Date: 19 July 2017
Please cite this article as: Xie J, Xu C, Dai Q, Wang X, Xu G, Chen Y, Dai L, Synthesis and application
of a novel asymmetric azo reagent: 1-(tert-butyl)-2-(4-chlorobenzyl) azodicarboxylate (tBCAD),
Tetrahedron (2017), doi: 10.1016/j.tet.2017.07.033.
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Synthesis and application of a novel
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asymmetric azo Reagent: 1-(tert-butyl)-2-(4-
chlorobenzyl) azodicarboxylate (tBCAD)
Jian Xie 1, Cai Xu1, Qianjin Dai1, 2, Xiaozhong Wang1, Gang Xu1, Yingqi Chen1 and Liyan Dai1
1 Zhejiang Provincial Key Laboratory of Advanced Chemical Engineering Manufacture Technology, College of
Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, P. R. China
2 Zhejiang Bestwa EnviTech Co. Ltd.

1
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Tetrahedron
journal homepage: www.elsevier.com
Synthesis and application of a novel asymmetric azo reagent: 1-(tert-butyl)-2-(4-
chlorobenzyl) azodicarboxylate (tBCAD)
Jian Xie1, Cai Xu1, Qianjin Dai1, 2, Xiaozhong Wang1, Gang Xu1, , Yingqi Chen1 and Liyan Dai1,
1 Zhejiang Provincial Key Laboratory of Advanced Chemical Engineering Manufacture Technology, College of Chemical and Biological Engineering, Zhejiang
University, Hangzhou 310027, P. R. China
2 Zhejiang Bestwa EnviTech Co. Ltd.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A
series of novel asymmetric azo reagents, 1-(tert-butyl)-2-(4-substituted benzyl)
azodicarboxylate, were prepared. The synthetic process has the advantange of simpleness, easy
operation, mild reaction condition and high yield. The 1-(tert-butyl)-2-(4-chlorobenzyl)
azodicarboxylate (tBCAD) was selected for its stability and convenience to handle, and its
precursor can be recycled by recrystallization with toluene. The tBCAD and DIAD were applied
to a wide variety of Mitsunobu reactions. The experimental results showed that the performance
of tBCAD in Mitsunobu reaction was comparable to that of DIAD, while the stability of tBCAD
was much better than DIAD. Thus, tBCAD can be a novel, stable, effective azo-reagent for the
Mitsunobu reaction.
Available online
Keywords:
Asymmetric
Synthetic route
tBCAD
Recycle
Mitsunobu reaction
2017 Elsevier Ltd. All rights reserved
.
———
Corresponding author.
Corresponding author.
Tel.: +86-139-5803-0180 (L. Dai); e-mail: xugang_1030@zju.edu.cn (G. Xu), dailiyan@zju.edu.cn (L. Dai).

2
Tetrahedron
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1. Introduction
2. Results and Discussion
2.1. The synthesis methodology and properties of azo reagents
Mitsunobu reaction refers to the reaction of a primary or
secondary alcohol with a nucleophile in the presence of
triarylphosphine or trialkylphosphine and an azo reagent.1,2 Since
its first discovery in 1967 by the Japanese chemist Oyo
Mitsunobu,3,4 the Mitsunobu reaction has found a wide range of
applications due to its stereoselectivity, versatility, effectiveness
and mild reaction condition, especially in the field of
pharmaceutical industry.5-8 The application of Mitsunobu reaction,
initially used for synthesizing esters, was gradually extended to
the domain of ammonias, azides, ethers, thioesters and thioethers,
etc.9 Azo reagents, as an inevitable component of Mitsunobu
reaction have aroused great attention. Traditionally, diethyl
azodicarboxylate (DEAD) or diisopropyl azodicarboxylate
(DIAD) is the appropriate and universal alternative, though other
reagents have been developed and reported with excellent results
(Fig. 1).10-15 Despite the widespread usage of DEAD and DIAD,
conventional azo-reagents can still be problematic: they (a) are
unstable in the absence of solvent, light, heat or even collision, (b)
are difficult to separate hydrazine by-products, (c) are not usually
amenable to recycle and (d) exist explosion hazards.16-19 Research
aimed at solving these drawbacks and discovering better, stable
and non-hazard azo reagents has been a hit since then.
The traditional azo reagents (DEAD, DIAD) are synthesised
by first intermixing alkyl chloroformate with hydrazine. Alkyl
chloroformates are prepared by mixing the alkyl alcohols with
phosgene. However, considering the toxicity of phosgene and
alkyl chloroformate, we selected N, N'-carbonyldiimidazole
(CDI) as a substitute for phosgene.
Scheme 1. The Synthetic route of asymmetric azo reagents
After carefully studying the related literatures on newly
developed azo reagents and phosphine reagents,20-25 we found,
however, that asymmetrical azo reagents were rarely reported.
Only Sivaraman Dandapani and Dennis P. Curran reported F-
DEAD-2, and Daniel P. Furkert’s group synthesized ACCs.14,15
Both F-DEAD-2 and ACCs displayed unique properties
compared to the symmetric ones with similar structure. Therefore,
we designed a new synthetic route to produce a series of
modified novel asymmetric azo reagents to testify our hypothesis.
Among those, the best one is 1-(tert-butyl)-2-(4-chlorobenzyl)
azodicarboxylate (tBCAD), which has similar reactivity to DIAD,
while possessing unique advantages, including easy handling, as
a pure stable solid, facile separation and preeminent recycling
capability. Herein we present a detailed report on the synthesis of
tBCAD.
Table 1. The products, reaction time and corresponding yields of
each synthetic step
N
1
R
product
2a
3a
4a
5a
2b
3b
4b
5b
2c
time/h
yield/%
-
89.1a
86.6
96.0
-
85.7a
80.4
96.8
-
85.1a
86.9
91.8
-
86.9a
84.8
98.5
-
94.4a
84.0
98.6
1
1.5
5
2
Cl
3
4
2
5
1
6
1.5
5
NO2
SO2CH3
H
7
8
2
9
1
10
11
12
13
14
15
16
17
18
19
20
3c
1.5
5
4c
5c
2
2d
3d
4d
5d
2e
1
1.5
5
2
1
3e
1.5
5
Cl
OCH3
O
4e
N
O
O
N
5e
2
O
a The total yield of the first two steps.
Cl
Di-p-chlorobenzyl azodicarboxylate
(DCAD)
The synthetic route used in this article (scheme 1) is safe and
environmentally friendly, while simple to operate with high-yield.
The first step adopted N, N'-carbonyldiimidazole (CDI), which
was solid with low toxicity. The reaction condition was not
rigorous. Room temperature would make it happen. The second
step was ice water bathing, which operated with no difficulty.26-28
The total yield of the two steps was 89.1% (R=Cl). The workup
was simply by washing the reaction solution with pure water.
The yield of the third step was 86.6 % (R=Cl), which was
Fig. 1. Mitsunobu reagents

3
comparable to that of other reported symmetric azo regents.11,12
Similarly, more asymmetric azo reagents can be conveniently
synthesized by introducing different substituents on the side of 3.
Finally, the last step yield was almost quantitative. The detailed
results were given in Table 1.
Since tBCAD was selected according to the stability, we
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afterwards, studied the properties of its precursor 4a. It turned out
that the precursor 4a was a very stable white solid that was
simple and convenient for storage and usage. More importantly,
the solubility of 4a in toluene was very low (<0.008 g/mL).
Therefore, after tBCAD’s employment in the Mitsunobu reaction,
4a can be recovered by recrystallization with toluene, and the
corresponding azo reagent tBCAD was obtained by one more
step of oxidation. Finally, we studied the effect of tBCAD in
Mitsunobu reaction.
The five azo reagents were exposed to the air at room
temperature. Their decomposition was monitored by TLC and 1H
NMR spectroscopy. Except tBCAD 5a, the other four azo
reagents decomposed to various degrees in 9 days while tBCAD
did not disintegrate in 1 month. We also determined the
decomposition temperature of tBCAD, which was 154 by
DSC-TGA. Thus, tBCAD was selected as our desired novel
asymmetric azo reagent, which was stable at room temperature.
2.2. Effect of 1-tert-butyl-2- (4-chlorobenzyl) azodicarboxylate
(tBCAD) in Mitsunobu reaction
The compounds served as nucleophilic precursors in the
Table 2
Comparison of Mitsunobu couplings mediated by DIAD/PPh3 and tBCAD/PPh3
Yield/%a
tBCAD
Entry
1
Nu-H
Alcohol
Product
Time/h
10
DIAD
70[32]
O
69.5c,d
90.6b
76.1b,d
97.9b
80.0c
91.6c
79.7b
89.6b
87.8b
78.3c
90.1c
OH
3
4
88.2b
74.3b
94.9b
75.9c
87.2c
83.1b
88.8b
91.6b
76.4c
89.2c
91.3c
2
3
4
4
OH
5
12
8
O2N
O2N
OH
6
O
N
O
7
3.5
5
NH
O
O
O
O
N
O
( )5
8
NH
O
N
O
9
S
S
SH
3.5
5
S
N
10
11
O
O
6
N
O
N
OH
O
O
O
12
5.5
89.8c
N
OH
O
a Isolated,chromatographically pure material.
b These reactions were conducted with alcohol(1.0 equiv), 1.2 equiv of acidic pronuclephile, PPh3, and azodicarboxylate reagent at rt in
CH2Cl2 and the isolated yields based on alcohols.
c These reactions were conducted with alcohol (1.0 equiv),1.2 equiv of acidic pronuclephile, PPh3,and azodicarboxylate reagent at rt in THF
and the isolated yields based on alcohols.
d Determinded by GC analysis with 10% methyl-β-cyclodextrin chiral column
.

4
Tetrahedron
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Mitsunobu reaction are generally acidic compounds containing
O-H, S-H, or N-H group. These nucleophilic precursors react
with primary alcohols or secondary alcohols forming new C-O
chiral column. Elementary analysis was performed by Vario
MICRO Cube Elemental Analyzer.
4.2 General synthetic procedure for hydrazinecarboxylate (3)
C-S or C-N bond in the reaction.9
1-(tert-butyl)-2- (4-
chlorobenzyl) azodicarboxylate (tBCAD) was adopted as an azo
reagent in the Mitsunobu reaction mixed with triphenylphosphine.
The results were compared with those of DIAD / PPh3. After the
reaction yields were calculated, the results were given in Table 2.
Alcohol 1 (40 mmol) was added in portions to the solid-liquid
mixture of CH2Cl2 (40 mL) and N, N’-carbonyldiimidazole (6.95
g, 42 mmol) at room temperature. The solid-liquid mixture
turned into a yellowish solution, and was stirred at room
temperature for 30 min after feeding. Then the solution was
washed with water (2×40 mL). The organic phase was transferred
to a three-necked flask, and cooled to 0-5 ℃. Hydrazine hydrate
(2.27 g, 44 mmol) was added dropwise and amorphous white
solid produced after a while. The mixture was stirred at room
temperature for 30 min, and then filtered. The white solid was
washed with water. The filtrate was concentrated in vacuo
leading to a white solid and filtered. The white solid was also
washed with water. Both of the white solid was collected and
dried in vacuo to get the product 3.
One of the salient features of the Mitsunobu reaction is that
when the secondary carbon attached to the alcoholic hydroxyl
group having a chiral center, the chirality is completely reversed
via an SN2 mechanism.29-31 That has been widely used in
pharmaceutical industry and becomes a standard method of chiral
flip. 5-7 In this paper, Mitsunobu reaction was carried out using
chiral secondary alcohols (S) - (-) - 1-phenylethyl alcohol with
acetic acid (Table 2, Entry 1) and benzoic acid (Table 2, Entry 3)
to obtain chiral completely inverted products. With tBCAD as the
azo reagent, the reaction yielded a yield of 69.5% (90% ee, Entry
1) for 10 h, and the yield of the reaction with DIAD as azo
reagent was only 70% (91% ee, Entry 1).32 Because of steric
hindrance, the reactivity of the secondary alcohol was worse than
that of the primary alcohol (Table 2, Entry 1-4). The performance
of 1-octanol was better than that of benzyl alcohol when the same
nucleophilic precursors were used in the Mitsunobu reaction
(Table 2, Entry 2, 4, 5, 6, 7, 8, 11, 12). In addition, there was
probably a relationship between the product yields with pKa of
the nucleophilic precursors. From the results of Entry 2, 5, 7, 9
and 11, it was deduced that the lower pKa of the nucleophilic
precursors, the higher the yield probably was. As a whole, in
Mitsunobu reaction, tBCAD served as a good azo reagent with
regard to the yield results, which was comparable with that of
DIAD. Considering the stability and safety, however, tBCAD is
far better than DIAD, and the former is easy to transport and
secure to storage.
4.2.1. 4-chlorobenzyl hydrazinecarboxylate (3a). White solid
(7.15 g, 89.1%). Mp 127.5-127.8℃.
4.2.2. 4-nitrobenzyl hydrazinecarboxylate (3b). White solid (7.24
g, 85.7%). Mp 136.7-137.4℃.
4.2.3. 4-(methylsulfonyl)benzyl hydrazinecarboxylate (3c). White
solid (8.31 g, 85.1%). Mp 104.6-105.3℃.
4.2.4. benzyl hydrazinecarboxylate (3d). White solid (5.78 g,
86.9%). Mp 68.5-69.1℃.
4.2.5. 4-methoxybenzyl hydrazinecarboxylate (3e). White solid
(7.41 g, 94.4%). Mp 77.0-77.5℃.
4.3 General procedure for hydrazinedicarboxylate (4)
Di-tert-butyl dicarbonate (8.02g, 36mmol) dissolved in THF
(10 mL) was added dropwise to the solid-liquid mixture of 3 (30
mmol), TEA (3.64 g, 36 mmol) and THF (15 mL) at 25℃. The
mixture was stirred for 5 h. The resulting clear colorless solution
was concentrated in vacuo, recrystallizing with CH2Cl2 and then
filtered. The white solid was washed with petroleum ether and
water. The filtrate was washed with 1M HCl (20 mL). Then the
organic phase was concentrated and white solid precipitated. The
mixture was filtered and the solid was washed with petroleum
ether and water. Both of the white solid was collected and dried
in vacuo to afford the desired product 4.
3. Conclusion
A series of novel asymmetric azo reagents have been
synthesized and a new synthetic route has been developed. The
route was simple and facile, easy to operate, and the
corresponding yields were high. The required raw materials are
easily accessible with a low price. The tBCAD was selected for
being very stable at room temperature. Furthermore, its precursor
4a can be easily recycled by recrystallization with toluene.
Finally, it was used in various Mitsunobu coupligs. The results
showed that tBCAD's reactivity was comparable with that of
DIAD, while its stability is significantly better. And the solid
state nature of tBCAD makes it more convenient for
transportation, storage and use. Therefore, tBCAD can be used as
a new azo reagent, taking place of DIAD in the industrial scale.
4.3.1. 1-(tert-butyl)-2-(4-chlorobenzyl) hydrazinedicarboxylate
(4a)
White solid (7.79 g, 86.6%). Mp 138.5-139.2℃. 1H NMR (500
MHz, CD3Cl) δ 7.34-7.28 (m, 4H, ArH) 6.47 (s, 1H, NH), 6.28
(s, 1H, NH), 5.14 (s, 2H, CH2), 1.47 (s, 9H, CH3); 13C NMR
(CD3Cl, 500 MHz): δ 156.77, 155.86, 134.51, 134.39, 129.83,
128.98, 82.18, 67.11, 28.35; Anal. Calcd for C13H17ClN2O4
(300.74): C 51.92, H 5.70, N 9.32. Found: C 51.70, H 5.66, N
9.35.
4. Experimental
4.1 General
All the chemicals used were reagent-grade, purchased from
commercial supplier, and used without further purification.
CH2Cl2 used in reactions were prepared by distillation with
anhydrous Na2SO4. THF was dried with molecular sieve. TLC
4.3.2. 1-(tert-butyl)-2-(4-nitrobenzyl) hydrazinedicarboxylate (4b)
White solid (7.51 g, 80.4%). Mp 127.5-128.1℃. 1H NMR (500
MHz, CD3Cl) δ 8.22 (d, J=8.5Hz, 2H), 7.52 (d, J=8.5Hz, 2H),
6.61 (s, 1H, NH), 6.34 (s, 1H, NH), 5.28 (s, 2H,CH2), 1.47 (s,
9H, CH3); Anal. Calcd for C13H17N3O6 (311.29): C 50.16, H 5.50,
N 13.50. Found: C 49.92, H 5.49, N 13.57.
1
analysis was performed on ZF-20D F254 plates. H NMR and 13C
NMR spectra were recorded in CD3Cl or DMSO-d6 using TMS
as an internal standard on a Bruker AVANCE Ⅲ 500 at 500
MHz. Melting points were determined by a WRS-1B digital
melting point apparatus. Enantiomeric purities were determined
by GC analysis (Fuli9790) using a 10% methyl-β-cyclodextrin
4.3.3. 1-(tert-butyl)-2-(4-methylsulfonylbenzyl) hydrazinedicarb-
oxylate (4c)

5
1
White solid (8.97g, 86.9%). Mp 137.0-138.2 . H NMR (500
(264.28): C 59.08, H 6.10, N 10.60. Found: C 58.98, H 6.14, N
10.55.
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MHz, CD3Cl) δ 7.94 (d, J=8.0Hz, 2H), 7.60 (d, J=8.0Hz, 2H),
6.60 (s, 1H, NH), 6.34 (s, 1H, NH), 5.27 (s, 2H,CH2), 3.05 (s,
3H, SO2CH3), 1.47 (s, 9H, CH3); Anal. Calcd for C14H20N2O6S
(344.38): C 48.83, H 5.85, N 8.13. Found: C 48.83, H 5.91, N
8.03.
4.4.5. 1-(tert-butyl)-2-(4-methoxybenzyl) azodicarboxylate (5e)
1
Pale orange solid (1.45 g, 98.6%). Mp 31.2-31.9 . H NMR
(500 MHz, CD3Cl) δ 7.38 (d, J=8.5Hz, 2H), 6.91 (d, J=8.5Hz,
2H), 5.37 (s, 2H, CH2), 3.82 (s, 3H, OCH3), 1.60 (s, 9H, CH3);
13C NMR (500MHz, CD3Cl) δ 160.68, 160.56, 159.18, 131.11,
125.97, 114.36, 87.32, 70.87, 55.51, 27.91; Anal. Calcd for
C14H18N2O5 (294.30): C 57.14, H 6.16, N 9.52. Found: C 56.91,
H 6.08, N 9.57.
4.3.4. 1-(tert-butyl)-2-benzyl hydrazinedicarboxylate (4d)
1
White solid (6.77 g, 84.8%). Mp 75.0-75.5 . H NMR (500
MHz, CD3Cl) δ 7.36-7.32 (m, 5H, ArH), 6.46 (s, 1H, NH), 6.28
(s, 1H, NH), 5.18 (s, 2H,CH2), 1.47 (s, 9H, CH3); Anal. Calcd for
C13H18N2O4 (266.30): C 58.63, H 6.81, N 10.52. Found: C 58.58,
H 6.82, N 10.63.
4.5 General procedure for Mitsunobu reactions
A solution of azo-reagent (1.2 mmol,) in THF or CH2Cl2 (3
mL) was added slowly to the solution of alcohol (1 mmol), acidic
pronucleophile (1.2 mmol) and Ph3P (1.2 mmol) in THF or
CH2Cl2 (5 mL) at 0-5 and the reaction mixture was continued
stirring at room temperature. The reaction was monitored by
TLC. The solution was concentratred and the toluene was added.
The 1-(tert-butyl) 2- (4-chlorobenzyl) hydrazinedicarboxylate
(4a) precipitated and was filtered off. Then the filtrate was
evaporated under reduced pressure. The product was purified by
column chromatography on silica gel to afford the pure products.
4.3.5. 1-(tert-butyl)-2-(4-methoxybenzyl) hydrazinedicarboxylate
(4e)
1
White solid (7.47 g, 84.0%). Mp 87.4-87.8 . H NMR (500
MHz, CD3Cl) δ 7.30 (d, J=7.5Hz, 2H), 6.88 (d, J=7.5Hz, 2H),
6.53 (s, 1H, NH), 6.34 (s, 1H, NH), 5.10 (s, 2H, CH2), 3.80 (s,
3H, OCH3), 1.46 (s, 9H, CH3); Anal. Calcd for C14H20N2O5
(296.32): C 56.75, H 6.80, N 9.45. Found: C 56.66, H 6.78, N
9.52.
4.4 General synthetic procedure for the azodicarboxylate (5)
4.5.1. (R)-1-phenylethyl acetate (Entry 1)
N-bromosuccinimide (1.09 g, 5.5 mmol) was added in portions
to the mixture of 4 (5 mmol), pyridine (0.45 g, 5.5 mmol) and
CH2Cl2 (20 mL) at 0 . The reaction mixture turned to yellow
upon addition, and was stirred at 0 for 30 min after addition.
Then the reaction solution was washed with 5% citric acid
aqueous solution (20 mL×3), 2% NaOH aqueous solution (20
mL×2), water (20 mL). The organic phase was then dried over
anhydrous Na2SO4 and was concentrated in vacuo to afford the
desired product 5.
Following the general procedure: Flash chromatography eluted
with Petroleum ether/ EtOAc=40:1 afforded title compound as
1
colorless oil. H NMR (500 MHz, CDCl3) δ 7.35-7.27 (m, 5H,
ArH), 5.878 (q, J=6.5Hz, 1H, CH), 2.06 (s, 3H, CO2CH3), 1.53
(d, J= 6.5Hz, 3H, CH3); 13C NMR (500MHz, CDCl3) δ 170.50,
141.86, 128.68, 128.05, 126.27, 72.50, 22.41, 21.54.
4.5.2. benzyl benzoate (Entry 2)
Following the general procedure: Flash chromatography eluted
with Petroleum ether/ EtOAc=10:1 afforded title compound as
colorless oil. H NMR (500 MHz, DMSO-d6) δ 8.03-8.01 (m,
4.4.1. 1-(tert-butyl)-2-(chlorobenzyl) azodicarboxylate (5a)
Orange solid (1.43 g, 96.0%). Mp 46.5-47.5 . 1H NMR (500
MHz, CD3Cl) δ 7.39 (s, 4H, ArH), 5.39 (s, 2H, CH2), 1.61 (s, 9H,
CH3); 13C NMR (500 MHz, CD3Cl) δ 160.50, 159.07, 135.42,
132.37, 130.43, 129.24, 87.51, 69.91, 27.92; Anal. Calcd for
C13H15ClN2O4 (298.72): C 52.27, H 5.06, N 9.38. Found: C
52.13, H 5.16, N 9.43.
1
2H), 7.69-7.66 (m, 1H), 7.56-7.53 (m, 2H), 7.50-7.48 (m, 2H),
7.43- 7.40 (m, 2H), 7.38-7.35 (m, 1H), 5.37 (s, 2H, CH2); 13
C
NMR (500MHz, DMSO-d6) δ 165.80, 136.36, 133.66, 129.82,
129.45, 129.04, 128.76, 128.35, 128.21, 66.41.
4.5.3. (R)-1-phenylethyl benzoate (Entry 3)
4.4.2. 1-(tert-butyl)-2-(4-nitrobenzyl) azodicarboxylate (5b)
Following the general procedure: Flash chromatography eluted
with Petroleum ether/ EtOAc=15:1 afforded title compound as
colorless oil. H NMR (500 MHz, DMSO-d6) δ 8.05-8.03 (m,
2H), 7.69-7.66 (m, 1H), 7.56-7.53 (m, 2H), 7.50-7.48 (m, 2H),
7.41- 7.38 (m, 2H), 7.36-7.31 (m, 1H), 6.08 (q, J=6.5Hz, 1H,
CH), 1.62 (d, J=6.5Hz, 3H, CH3); 13C NMR (500MHz, DMSO-
d6) δ 165.40, 142.22, 133.84, 130.33, 129.65, 129.24, 128.97,
128.26, 126.29, 73.01, 22.80.
Orange solid (1.52 g, 96.8%). Mp 43.4-44.1 . 1H NMR (500
MHz, CD3Cl) δ 8.27 (d, J=9.0Hz, 2H), 7.61 (d, J=8.5Hz, 2H),
5.53 (s, 2H, CH2), 1.63 (s, 9H, CH3); 13C NMR (500 MHz,
CD3Cl) δ 160.30, 158.94, 148.42, 140.87, 129.14, 124.22, 87.78,
68.90, 27.92; Anal. Calcd for C13H15N3O6 (309.28): C 50.49, H
4.89, N 13.59. Found: C 50.14, H 4.94, N 13.48.
1
4.4.3. 1-(tert-butyl)-2-(4-methylsulfonylbenzyl) azodicarboxylate
(5c)
4.5.4. 1-octyl benzoate (Entry 4)
1
Orange solid (1.57 g, 91.8%). Mp 88.2-89.5 . H NMR (500
Following the general procedure: Flash chromatography eluted
with Petroleum ether/ EtOAc=10:1 afforded title compound as
colorless oil. H NMR (500 MHz, CDCl3) δ 8.06-8.04 (m, 2H),
7.56-7.53 (m, 1H), 7.45-7.42 (m, 2H), 4.31 (t, J=6.0Hz, 2H,
CH2), 1.80-1.74 (m, 2H, CH2), 1.46-1.28 (m, 10H, (CH2)5), 0.88
(t, J=7.0Hz, 3H, CH3); 13C NMR (500MHz, CDCl3) δ 166.69,
132.78, 130.56, 129.54, 128.32, 65.16, 31.82, 29.28, 29.23,
28.76, 26.08, 22.68, 14.12.
MHz, CD3Cl) 7.99 (d, J=8.5Hz, 2H), 7.65 (d, J=8.5Hz, 2H), 5.52
(s, 2H, CH2), 3.06 (s, 3H, SO2CH3), 1.63 (s, 9H, CH3); 13C NMR
(500 MHz, CD3Cl) δ 160.36, 158.97, 141.38, 139.94, 129.32,
128.21, 87.77, 69.20, 44.70, 27.96; Anal. Calcd for C14H18N2O6S
(342.37): C 49.12, H 5.30, N 8.18. Found: C 49.09, H 5.45, N
8.13.
1
4.4.4. 1-(tert-butyl)-2-benzyl azodicarboxylate (5d)
4.5.5. 1-(benzyloxy)-4-nitrobenzene (Entry 5)
1
Orange oil (1.31 g, 98.5%). H NMR (500 MHz, CD3Cl) δ
7.43-7.38 (m, 5H, ArH), 5.42 (s, 2H, CH2), 1.60 (s, 9H, CH3); 13C
NMR (500 MHz, CD3Cl) δ 160.63, 159.16, 133.89, 129.41,
129.06, 129.02, 87.39, 70.86, 27.94; Anal. Calcd for C13H16N2O4
Following the general procedure: Flash chromatography eluted
with Petroleum ether/ EtOAc=15:1 afforded title compound as
white solid. Mp 106.3-107.1 . 1H NMR (500 MHz, DMSO-d6) δ

6
Tetrahedron
ACCEPTED MANUSCRIPT
8.24-8.21 (m, 2H), 7.48 (d, J=7.5Hz, 2H), 7.42 (t, J=7.5Hz, 2H),
7.38-7.35 (m, 1H), 7.25-7.22 (m, 2H), 5.27 (s, 2H, CH2); 13C
NMR (500MHz, DMSO-d6) δ 164.10, 141.41, 136.43, 129.03,
128.69, 128.40, 126.35, 115.82, 70.64.
pale yellow solid. Mp 34.5-34.9 . 1H NMR (500 MHz, CDCl3) δ
7.85-7.82 (m, 2H), 7.78-7.74 (m, 2H), 4.203 (t, J=7Hz, 2H,
OCH2), 1.82-1.76 (m, 2H, CH2), 1.51-1.45 (m, 2H, CH2), 1.38-
1.25 (m, 8H, (CH2)4), 0.88 (t, J=7Hz, 3H, CH3); 13C NMR
(500MHz, CDCl3) δ 163.84, 134.61, 129.17, 123.64, 78.82, 31.96,
29.47, 29.34, 28.35, 25.74, 22.83, 14.29.
4.5.6. 1-nitro-4-(octyloxy)benzene (Entry 6)
Following the general procedure: Flash chromatography eluted
with Petroleum ether/ EtOAc=5:1 afforded title compound as
yellow oil. H NMR (500 MHz, CDCl3) δ 8.20-8.17 (m, 2H),
Acknowledgments
1
We gratefully acknowledge financial support from the NSFC
(No: 21176213), and Zhejiang Key Innovation Team of Green
Pharmaceutical Technology (No: 2010R50043).
6.95-6.93 (m, 2H), 4.04 (t, J=6.5Hz, 2H, CH2), 1.85-1.79 (m, 2H,
CH2), 1.49-1.29 (m, 10H, (CH2)5), 0.89 (t, J=6.0Hz, 3H, CH3);
13C NMR (500MHz, CDCl3) δ 164.46, 141.46, 126.08, 114.58,
69.10, 31.99, 29.48, 29.41, 29.18, 26.12, 22.86, 14.30.
5. References
4.5.7. N-benzylphthalimide (Entry 7)
1. Swamy KCK, Kumar NNB, Balaraman E, Kumar KVPP. Chem.
Rev. 2009; 109: 2551.
2. But TYS, Toy PH. Chem. Asian J. 2007; 2: 1340.
3. Mitsunobu O, Yamada M. Bull. Chem. Soc. Jpn. 1967; 40: 2380.
4. Mitsunobu O, Yamada M, Mukaiyama T. Bull. Chem. Soc. Jpn.
1967; 40: 935.
5. Wada M, Mitsunobu O. Tetrahedron lett. 1972; 13: 1279.
6. Fletcher S, Shahani VM, Lough AJ, Gunning PT. Tetrahedron.
2010; 66: 4621.
Following the general procedure: Flash chromatography eluted
with Petroleum ether/ EtOAc=10:1 afforded title compound as
1
white solid. Mp 115.5-115.9 . H NMR (500 MHz, CDCl3) δ
8.06-8.04 (m, 2H), 7.56-7.53 (m, 1H), 7.45-7.42 (m, 2H), 4.31 (t,
J=6.0Hz, 2H, CH2), 1.80-1.74 (m, 2H, CH2), 1.46-1.28 (m, 10H,
(CH2)5), 0.88 (t, J=7.0Hz, 3H, CH3); 13C NMR (500MHz, CDCl3)
δ 166.69, 132.78, 130.56, 129.54, 128.32, 65.16, 31.82, 29.28,
29.23, 28.76, 26.08, 22.68, 14.12.
7. Fletcher S. Org. Chem. Front. 2015; 2: 739.
8. Wang T, Zhou L, Cao XP. Chin. Chem. Lett. 2009; 20: 147.
9. Mitsunobu O. Synthesis. 1981; 1: 1.
10. Lanning ME, Fletcher S. Tetrahedron lett. 2013; 54: 4624.
11. Yang JH, Dai LY, Wang XZ, Chen YQ. Chin. Chem. Lett. 2011;
22: 1047.
12. Yang J, Dai L, Wang X, Chen Y. Tetrahedron. 2011; 67: 1456.
13. Lipshutz BH, Chung DW, Rich B, Corral R. Org. Lett. 2006; 8:
5069.
14. Dandapani S, Curran DP. J. Org. Chem. 2004; 69: 8751.
15. Furkert DP, Breitenbach B, Juen L, Sroka I, Pantin M, Brimble
MA. Eur. J. Org. Chem. 2014; 2014: 7806.
4.5.8. N-octylphthalimide (Entry 8)
Following the general procedure: Flash chromatography eluted
with Petroleum ether/ EtOAc=10:1 afforded title compound as
white solid. Mp 50.5-50.9 . 1H NMR (500 MHz, CDCl3) δ 7.85-
7.83 (m, 2H), 7.72-7.70 (m, 2H), 3.68 (t, J=7.5Hz, 2H, CH2),
1.70-1.64 (m, 2H, CH2), 1.33-1.25 (m, 10H, (CH2)5), 0.87 (t,
J=7.0Hz, 3H, CH3); 13C NMR (500MHz, CDCl3) δ 168.43,
133.80, 132.18, 123.12, 38.07, 31.77, 29.16, 29.16, 28.61, 26.87
22.62, 14.08.
4.5.9. 2-((4-methoxybenzyl) thio)benzothiazole (Entry 9)
Following the general procedure: Flash chromatography eluted
with Petroleum ether/ EtOAc=30:1 afforded title compound as
white solid. Mp 69.4-70.1 . 1H NMR (500 MHz, DMSO-d6) δ
7.90 (d, J=8.0Hz, 1H), 7.50 (d, J=7.5Hz, 1H), 7.44-7.41 (m, 1H),
7.37 (d, J=8.5Hz, 2H) 7.31-7.28 (m, 1H), 6.87-6.85 (m, 2H), 4.56
(s, 2H, ArCH2), 3.79 (s, 3H, OCH3); 13C NMR (500MHz,
DMSO-d6) δ 166.48, 158.96, 152.87, 134.88, 130.59, 128.36,
126.60, 124.70, 122.01, 121.40, 114.21, 55.30, 36.51.
16. But TYS, Toy PH. J. Am. Chem. Soc. 2006; 128: 9636.
17. Girardin M, Dolman SJ, Lauzon S, Ouellet SG. Hughes G,
Fernandez P, Zhou G, O’ Shea PD. Org. Process Res. Dev.
2011; 15: 1073.
18. Hagiya K, Muramoto N, Misaki T, Sugimura T. Tetrahedron.
2009; 65: 6109.
19. Hirose D, Gazvoda M, Kosmrlj J, Taniguchi T. Chem. Sci. 2016;
7: 5148.
20. Flynn DL. Med. Res. Rev. 1999; 19: 408.
21. Jackson T, Routledge A. Tetrahedron lett. 2003; 44: 1305.
22. O’Neil IA, Thompson S, Murray CL, Kalindjian SB.
Tetrahedron lett.1998; 39: 7787.
23. Zhang Q, Luo Z, Curran DP. J. Org. Chem. 2000; 65: 8866.
24. Charette AB, Janes MK, Boezio AA. J. Org. Chem. 2001; 66:
2178.
4.5.10. N,N-dibenzyl-4-methylbenzenesulfonamide (Entry 10)
Following the general procedure: Flash chromatography eluted
with Petroleum ether/ EtOAc=7:1 afforded title compound as
white solid. Mp 75.4-76.1 . 1H NMR (500 MHz, DMSO-d6) δ
7.78 (d, J=8.5Hz, 2H), 7.43 (d, J=8Hz, 2H), 7.22-7.20 (m, 5H),
7.08-7.07 (m, 4H), 4.27 (s, 4H, CH2), 2.42 (s, 3H, CH3); 13C
NMR (500MHz, DMSO-d6) δ 143.27, 136.54, 136.17, 129.84,
128.15, 128.12, 127.30, 127.02, 51.18, 20.98.
25. Buonomo JA, Aldrich CC. Angew. Chem. Int. Ed. 2015; 54:
13041.
26. Gao Y, Lam Y. J. Comb. Chem. 2010; 12: 69.
27. Singh R, Kolev JN, Sutera PA, Fasan R. ACS. Catal. 2015; 5:
1685.
28. Kurosu M, Narayanasamy P, Crick DC. Heterocycles. 2007; 73:
169.
29. Crich D, Dyker H, Harris RJ. J. Org Chem. 1989; 54: 257.
30. Varasi M, Walker KAM, Maddox ML. J. Org Chem. 1987 52:
4235.
4.5.11. N-benzyloxyphthalimide (Entry 11)
Following the general procedure: Flash chromatography eluted
with Petroleum ether/ EtOAc=5:1 afforded title compound as
white solid. Mp 143.9-144.7 . 1H NMR (500 MHz, DMSO-d6) δ
7.86 (s, 4H), 7.54-7.52 (m, 2H), 7.44-7.41 (m, 2H), 5.18 (s, 2H,
CH2); 13C NMR (500MHz, DMSO-d6) δ 163.05, 134.75, 134.11,
129.60, 129.05, 128.46, 128.41, 123.20, 79.18.
31. Hughes DL, Reamer RA, Bergan JJ, Grabowski EJJ. J. Am.
Chem. Soc. 1988; 110: 6487.
4.5.12. N-octyloxyphthalimide (Entry 12)
32. Houiene Z, Merabet-Khelassi M, Bouzemi N, Riant O, Aribi-
Zouioueche L. Tetrahedron: Asymmetry. 2013; 24: 290.
Following the general procedure: Flash chromatography eluted
with Petroleum ether/ EtOAc=5:1 afforded title compound as