Di-p-nitrobenzyl azodicarboxylate (DNAD): An alternative azo-reagent for the Mitsunobu reaction

Article abstract of DOI:10.1016/j.tet.2010.12.036

Di-p-nitrobenzyl azodicarboxylate is prepared in 83.6% yield in two steps as a bright yellow solid, which can be used as an azo-reagent in the Mitsunobu reaction. When a chiral secondary alcohol was used, sufficient configurational inversion of alcohol occurred under Mitsunobu conditions. That the hydrazine produced from DNAD is semisoluble in some solvents such as THF and CH ₂Cl₂ makes it separated easily from the reaction mixture just via filtration. Then the recovered hydrazine compound can be re-exposed to oxidant to produce DNAD. Because DNAD is more stable than DIAD at ambient temperatures and allows easy separation, it is a good alternative azo-reagent for the Mitsunobu reaction.

Full text of DOI:10.1016/j.tet.2010.12.036

Tetrahedron 67 (2011) 1456e1462
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Tetrahedron
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Di-p-nitrobenzyl azodicarboxylate (DNAD): an alternative azo-reagent for the
Mitsunobu reaction
*
Jianhai Yang, Liyan Dai , Xiaozhong Wang, Yingqi Chen
Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Di-p-nitrobenzyl azodicarboxylate is prepared in 83.6% yield in two steps as a bright yellow solid, which
can be used as an azo-reagent in the Mitsunobu reaction. When a chiral secondary alcohol was used,
sufficient configurational inversion of alcohol occurred under Mitsunobu conditions. That the hydrazine
produced from DNAD is semisoluble in some solvents such as THF and CH2Cl2 makes it separated easily
from the reaction mixture just via filtration. Then the recovered hydrazine compound can be re-exposed
to oxidant to produce DNAD. Because DNAD is more stable than DIAD at ambient temperatures and
allows easy separation, it is a good alternative azo-reagent for the Mitsunobu reaction.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 29 September 2010
Received in revised form 8 December 2010
Accepted 14 December 2010
Available online 17 December 2010
Keywords:
DNAD
Mitsunobu reaction
Azo-reagent
Separation-friendly
1. Introduction
modern strategy level separations to simplify the removal of
byproducts.11e21 Even with the development of such dialkyl azodi-
The Mitsunobu reaction, discovered by Mitsunobu in the late
1960s, has been extensively reviewed1e3 and has become one of the
most widely used reactions in organic chemistry.4e6 It is the stan-
dardmethod for the inversion of configuration in secondaryalcohols
and has wide applications in total synthesis, heterocyclic and me-
dicinal chemistry due to its scope, stereoselectivity, and mild re-
action conditions.7e10 Though it is a powerful process in organic
synthesis, a major drawback of this redox-condensation is the re-
quirement of two reagents, a phosphine and a dialkyl azodicarbox-
ylate, which both produce stoichiometric amounts of byproducts.
Traditional azo-reagents such as diethyl azodicarboxylate
(DEAD) and diisopropyl azodicarboxylate (DIAD) are commercially
available and can be used interchangeably in most cases, but they
are sensitive to light, heat and moisture and often be stored below
4 ꢀC in dark and dry area. In addition, diethyl and diisopropyl
hydrazinedicarboxylates arising from DEAD and DIAD are prob-
lematic during the separation of the product and they are difficult
to be recycled. Fine chromatography is usually required to isolate
the pure target product from the unreacted reagents and byprod-
ucts. This situation limits the direct application of the Mitsunobu
reaction in combinatorial library syntheses.
carboxylate ester analogues, DEAD and DIAD are still the major azo-
reagents used in Mitsunobu reactions due tothe availability of them.
Our goal was to find an effective alternative azo-reagent that
should offer the important feature of straightforward separation and
recovery of the hydrazinedicarboxylate arising from the Mitsunobu
reaction. Fortunately, a lot of experimental results in our laboratory
show that di-p-nitrobenzyl azodicarboxylate (DNAD) is such an
ideal reagent that not only facilitates purification of the desired
product but also encourages recycling the hydrazine byproduct. The
triphenylphosphane oxide produced from the triphenylphosphane
can be removed by filtration with a proper solvent due to its low
solubility in some solvents such as cyclohexane. So one-step re-
moval of the two byproducts via filtration was feasible when tri-
phenylphosphane and DNAD were employed. A survey of the
literature shows that there is no report on the application research of
it in the Mitsunobu reaction until now. So this paper describes the
preparation of DNAD by a commercially available process and its
advantages as an azo-reagent in the Mitsunobu reaction.
2. Results and discussion
In order to solve some of these problems, many researches are
focusing on the development of newalternative reagents (Fig.1) and
2.1. Preparation and physical properties of DNAD
Di-p-nitrobenzyl hydrazinedicarboxylate (2) was readily pre-
pared as white solid powder in 88% yield (Scheme 1). Since 2 is not
only a precursor of DNAD but also a co-product in the Mitsunobu
reaction, its properties are of importance for the separation and
* Corresponding author. Tel./fax: þ86 571 8795 2693; e-mail addresses: dai-
liyan@zju.edu.cn, dliyan@olemiss.edu (L. Dai).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.12.036

J. Yang et al. / Tetrahedron 67 (2011) 1456e1462
1457
O
As a matter of fact, DNAD exposed to air for more than six months at
room temperature still works well. Common chromatographic
purification was not needed in either step of this procedure; the
washings reported herein were sufficient to yield clean compounds.
O
N
O
N
O
O
N
O
N
O
O
Diisopropyl azodicarboxylate
(DIAD )
Diethyl azodicarboxylate
(DEAD )
O
O
N
O
N
O
O
N
O
N
2.2. Esterification with inversion
O
Di-t-butyl azodicarboxylate
O
Dimethyl azodicarboxylate
(DMAD )
Asmentioned inIntroduction, thefeature thattheconfiguration of
the stereogenic center in a chiral secondary alcohol can be inverted
under Mitsunobu conditions is valuable. The stereospecificity of the
reaction was studied using common organic solvents and the optical
(þ)-neomenthol, which is a less reactive optically alcohol for steric
hindrance effect but could be converted to the diastereomerically
pure (ꢁ)-menthol ester with picolinic acid (Table 1).
(DBAD )
O
O
N
N
N
CO2Bn
N
N
BnO2C
N
O
1,1'-(Azodicarbonyl)-dipiperidine
O
Dibenzyl azodicarboxylate
(ADDP )
O
O
Me
N
NMe2
N
N
N
N
Me2N
N
O
Me
Table 1
O
N,N,N',N'-Tetramethyl-
Stereospecificity in the reaction of an optically active alcohol with DNAD (or DIAD)
and PPh3
1,6-Dimethyl-1,5,7-hexahydro-
azodicarboxamine (TMAD)
1,4,6,7-tetrazocin-2,5-dione (DHTH)
O
O
O
N
O
N
O
O
N
O
N
DNAD or DIAD
Ph3P, solvent,rt
O
N
N
OH
O
Bis-(2-(1-adamantyl)methyl)
O
Bis-(2-(1-adamantyl)ethyl)
+
O
HO
(+)-neomenthol
azodicarboxylate (BadEAD )
azodicarboxylate (BadMAD)
3
O
O
Cl
Cl
Cl
(97%ee)
(97%ee)
Cl
Cl
Cl
F13C6
N
O
N
O
O
N
O
N
C6 F13
O
O
Fluorous-DEAD
Bis(2,2,2-trichloroethyl0-
azodicarboxylate
O
O
MeOH
Cu(OAc)2
MeOH/rt
N
O
(Ac)2Cu
N
O
CF2CF2CF2CF2CF2CF3
F3CF2CF2CF2CF2CF2C
O
N
O
Bis (1H,1H,2H,2H,3H,3H-perfluoronyl) azodicarboxylate (F-DIAD)
O
N
OH
O
+
O
N
O
O
N
O
HO
(-)-menthol 4
O
Di-2-methoxyethyl azodicarboxylate (DMEAD )
(97%ee)
Fig. 1. Mitsunobu coupling reagents.
Entry
Solvent
Time/h
Yield/%a
DNAD
ee/%b
DIAD
1
2
3
4
Toluene
THF
CH2Cl2
CH3CN
3.5(5.0)c
2.0(4.5)c
1.8(3.0)c
3.0(5.0)c
83
92
94
85
81
85
86
83
97
97
97
97
O
toluene, H2O
NaHCO3
O
Cl
N2H4 H2O
+
NO2
NO2
O
O
O
a
Reactions were carried out with 1.0 equiv of alcohol and 1.2 equiv of all other
reagents.
O
N
H
N
O
O
b
c
Br2, pyridine
Determined by HPLC analysis with a chiral AD-H column.
The Mitsunobu reaction time with DIAD.
H
toluene
NO2
2(88%)
O
In the conventional Mitsunobu reaction, the nucleophiles are
O
N N
believed to undergo an SN2 mechanism.22e24 Therefore, a complete
inversion of stereochemistry at the alcoholic function could be
expected and the results were consistent with the mechanism.
Compared to the esterification reaction under the Mitsunobu
conditions with DIAD/PPh3, that with DNAD/PPh3 gave higher
yields and took less time for completion. Compound 2 precipitated
constantly during the reaction leading to the low concentration of it
in the reaction mixture. As far as chemical reaction kinetics is
concerned, this situation may accelerate the reaction rate. The in-
fluence of different solvents on the reaction was also investigated.
The reactions with THF and CH2Cl2 as solvent gave excellent yields
of the product in comparison of those using toluene or CH3CN as
solvent (Table 1, entries 2 and 3). With the success of the reaction in
hand, we then examined the methanolysis of picolinate ester 3
promoted by copper acetate.25 The methanolysis of picolinate ester
3 with copper acetate in methanol proceeded smoothly and affor-
ded the inverted (ꢁ)-menthol under essentially neutral conditions.
NO2
NO2
1(95%)
Scheme 1. Synthesis of di-p-nitrobenzyl azodicarboxylate.
recycling process. The poor solubilities of 2 (<0.005 g/mL, 25 ꢀC) in
CH2Cl2 and (<0.01 g/mL, 25 ꢀC) in THF make it easy to be separated
from the product and recovered just via filtration after the com-
pletion of the Mitsunobu reaction. For compound 2 is not very
stable at room temperature when it’s exposed to air, it should be
stored under 5 ꢀC or directly used to the next step.
Oxidation was performed by addition of Br2 and pyridine to
a toluene slurry of hydrazine 2 at room temperature, which
transformed the white mixture to orange in color. Finally the pale
yellow solid reagent 1 was obtained after workup. Unlike DIAD, the
former is stable and can be stored indefinitely at room temperature.

1458
J. Yang et al. / Tetrahedron 67 (2011) 1456e1462
2.3. Further study on applicability of DNAD
activated alcohols leading to a poor yield of the desired coupling
product.26 Herein, the purine coupled with 2-chloroethanol or
benzyl alcohol under the optimized Mitsunobu conditions27 and
gave the N-9 selective nonsugar nucleoside in good-to-excellent
yield (entries 3 and 4), but it was still difficult to couple it with
other common alcohols. All the other pronucleophiles except im-
idazole, which is less active in a Mitsunobu-type alkylation for its
low of pKa, could couple with a common primary or secondary al-
cohol smoothly and all these reactions employing DNAD/PPh3 gave
better results than those employing DIAD/PPh3. However, all these
nucleophiles tested in this paper couldn’t react with tertiary alcohol
The pronucleophile used in the Mitsunobu reaction is normally
a relative acid compound containing an OeH, SeH, or an NeH
group with pKaꢂ15. Some common nucleophiles are carboxylic
acids, phenols, imides, purines, thiocarboxylic acids, and thiols. The
performance of DNAD in the reaction was tested for different
combinations of alcohols with some common nucleophiles, in
comparison with that of DIAD, and the results were given in Table 2.
2-Amino-6-chloro-purine has poor solubility in some common
organic solvents such as THF and is not a great nucleophile for
Table 2
Different combinations of the pronucleophile and alcohol
Entry
NueH
Alcohol
Product
DNAD(DIAD)
Time/h
Yield/%a
92(85)b,e
NC
Cl
O
O
OH
OH
1
2
3
1.8(2.5)
0.5(1.2)
8.5(14)
O
Cl
CN
Cl
Cl
Cl
O
O
95(88)b
85(76)c
OH
OH
N
O
Cl
Cl
Cl
N
N
OH
OH
N
N
N
N
N
Cl
N
H
H2N
N
H2N
H2N
N
Cl
Cl
Cl
N
N
4
5
11(18)
83(72)c
93(88)b
N
N
N
H
H2N
N
Ph
O
Cl
Cl
O
O
N
N
N
0.3(1.5)
O
OH
N
H
N
(Boc)2N
N
(Boc)2N
N
Cl
Cl
N
N
OH
OH
N
N
N
N
6
7
1.0(2.4)
90(83)b
0(0)b
(Boc)2N
N
N
H
(Boc)2N
(Boc)2N
N
Cl
N
d
d
N
H
N
O
O
Bn
O
92(89)b
87(83)b
Bn
OH
NH
N
8
9
2.5(4.5)
3.8(5.6)
O
O
O
O
O
OH
N
NH
O
O
OH
55(25)d
N
NH
10
14(24)
N
N
S
OH
SH
11
12
0.3(0.4)
2.2(3.8)
93(86)b
S
S
OH
N
S
88(85)b,e
N
SH
S
S
O
O
O
O
O
O
O
Bn
Bn
OH
13
4.0(6.5)
85(79)d
O

J. Yang et al. / Tetrahedron 67 (2011) 1456e1462
1459
Table 2 (continued )
Entry
NueH
Alcohol
Product
DNAD(DIAD)
Time/h
Yield/%a
O
O
O
O
O
14
15
2.5(4.5)
3.0(5.6)
94(90)d
88(85)b
OH
O
O
O
O
O
O
O
O
OH
O
O
O
NO2
OH
90(86)b
72(65)
O
16
17
1.2(2.0)
2.5(4.0)
OH
O2N
NO2
OH
OH
NO2
d
O
OH
OH
92(85)e
O
O2N
18
d
1.0(2.2)
NO2
a
Isolated yield.
b
These reactions were conducted with alcohol (1.0 equiv), 1.1 equiv of acidic pronucleophile, Ph3P, and azodicarboxylate reagent at rt in CH2Cl2 and isolated yields based on
alcohols.
c
The reactions were conducted with 2-amino-6-chloro-purine (1.0 equiv), 2.0 equiv alcohol, 2.1 equiv of Ph3P, and azodicarboxylate reagent at 70 ꢀC in THF and isolated
yields based on 2-amino-6-chloro-purine.
d
These reactions were conducted with Meldrum’s acid (1.0 equiv), 2.5 equiv of alcohol, Ph3P, and azodicarboxylate reagent at rt in CH2Cl2 and isolated yields based on
Meldrum’s acid.
e
Determined by HPLC analysis with a chiral AD-H column.
such as tert-butanol owing to steric hindrance at the tertiary
carbon.
a Melting Point WRR. Optical rotations were measured on a WZZ-2S
automatic digital polarimeter. Enantiomeric purities were de-
termined by HPLC analysis using a chiral AD-H column. Elementary
analysis was recorded on Flash EA1110 (ThermoFinnigan). Mass
3. Conclusions
spectra were recorded on a Finnigan LCQ DECA XPplus
.
In summary, the di-p-nitrobenzylic azodicarboxylate is very
stable at ambient temperatures and can be conveniently prepared
in good yields. When DNAD and DIAD were used for various Mit-
sunobu couplings, these reactions employing DNAD/PPh3 usually
gave higher isolated yields of products and took less time for
completion than those with DIAD/PPh3. Furthermore, its hydrazine
precursor 2 can be easily separated directly from the reaction
mixture via filtration and then recycled by re-exposure to NBS or
Br2. In addition, the commercially available and cheap raw mate-
rials of preparing DNAD reduce the cost. All of the advantages make
DNAD a very attractive alternative to azo-reagents traditionally
used in the Mitsunobu reactions.
4.2. Preparation of hydrazinedicarboxylate (2)
A solution of p-nitrobenzyl chloroformate (10.78 g, 50 mmol) in
toluene (50 mL) was added to an aqueous solution (water 50 mL) of
NaHCO3 (5 g, 60 mmol) and 80% hydrazine hydrate (1 g, 20 mmol)
at room temperature. The mixture was stirred at room temperature
for 6 h and then precipitated crystals were cropped by filtration,
washed with toulene, and dried in vacuo at 25 ꢀC to give 2 (6.87 g,
88%) as white solid powder. Mp 172e173 ꢀC; IR (NaCl, neat) 3248,
2365, 1755, 1698 cmꢁ1; 1H NMR (500 MHz, DMSO-d6)
7.62 (d, J¼8.2 Hz 4H), 8.25 (d, J¼8.2 Hz, 4H), 9.48 (mix of rotamers,
d 5.25 (s, 4H),
2H total); 13C NMR (500 MHz, DMSO-d6)
d 156.81, 148.09, 128.80,
4. Experimental section
4.1. General
120.99, 65.60; MS (ESI): m/z¼391.3 (MþHþ), 413.4 (MþNaþ). Anal.
Calcd for C16H14N4O8 (390.08): C, 49.24; H, 3.62; N, 14.35. Found: C,
49.18; H, 3.57; N, 14.43.
Chemicals were reagent-grade, purchased from commercial sup-
pliers, and used without further purification. Absolute THF, CH2Cl2,
CH3CN, and toluene used in reactions were prepared by distillation
over a drying agent (THF: Na/benzophenone; CH2Cl2: CaH2; CH3CN:
P2O5; toluene: Na). TLC analyses were performed on Merck Kieselgel
60 F254 plates. Flash chromatography was performed using silica gel
Merck 60 (particle size 0.040e0.063 mm), All anhydrous reactions
were performed under nitrogen in flame-dried glassware using an-
hydrous solvents. 1H NMR and 13C NMR spectra were recorded on
BRUKER AVANCE DX500. Chemical shifts are given in parts per mil-
lion relative to tetramethylsilane (TMS) and the coupling constants J
are given in hertz. The spectra were recorded in CDCl3 or DMSO-d6 as
solvent at room temperature. Melting points were obtained on
4.3. Preparation of di-p-nitrobenzyl azodicarboxylate (1)
Bromine (6.0 mmol) in 10 mL dichloromethane was added
dropwise to a dichloromethane (50 mL) solution of hydrazine 2
(5.0 mmol) and pyridine (10 mmol) cooled to 0 ꢀC under nitrogen.
The reaction mixture turned from colorless to yellow upon addition
and ran at rt. After completion, the mixture was diluted to 100 mL
with dichloromethane, washed with 5% aqueous HCl (2ꢃ50 mL),
saturated aqueous NaHCO3 (50 mL), water (3ꢃ50 mL), and saturated
NaCl (50 mL). The organic phase was then dried over anhydrous
Na2SO4 and concentrated in vacuo to afford the title compound as
pale yellow solid (18.4 g, 95%). Mp 146e147.5 ꢀC; IR (NaCl, neat)
2365, 2338,1761 cmꢁ1; 1H NMR (500 MHz, CDC13)
d 5.39 (s, 4H), 7.37

1460
J. Yang et al. / Tetrahedron 67 (2011) 1456e1462
(d, J¼8.5 Hz, 4H), 8.21 (d, J¼8.5 Hz, 4H); 13C NMR (500 MHz, CDCl3)
a colorless oil (92%). [
a
]
20 þ28.5 (c 1.15, CHCl3); 1H NMR (500 MHz,
D
d
160.10, 147.84, 128.15, 120.46, 69.14; MS (ESI): m/z¼389.3 (MþHþ),
CDCl3)
d
7.99e8.01 (m, 2H), 7.40e7.42 (m, 2H), 4.21 (d, J¼3.5 Hz,
411.3 (MþNaþ). Anal. Calcd for C16H12N4O8 (388.07): C, 49.49; H,
1H), 3.65 (d, J¼5.2 Hz, 2H), 2.68e2.78 (m, 2H); 13C NMR (500 MHz,
3.12; N, 14.43. Found: C, 49.58; H, 3.06; N, 14.38.
CDCl3) d 169.78, 140.21, 131.30, 127.61, 126.30, 118.04, 69.35, 47.83,
21.96. Anal. Calcd for C11H9Cl2NO2 (257.00): C, 51.19; H, 3.51; N,
5.43. Found: C, 51.12; H, 3.46; N, 5.35.
4.4. (1R,2S,5R)-2-Isopropyl-5-methylcyclohexylpicolinate (3)
A 100 mL round bottom flask was charged with picolinic acid
(616 mg, 5.0 mmol), (þ)-neomenthol (390 mg, 2.5 mmol), and tri-
phenylphosphine (1311 mg, 2.5 mmol). The flask was flushed with
nitrogen, and THF (30 mL, freshly distilled from Na) was added, and
the solution cooled to ꢁ20 ꢀC for 10e15 min. A solution of DNAD
(5.0 mmol) in dichloromethane was then added dropwise to the
solution for 10 min. The temperature of the bath was maintained at
ꢁ20 ꢀC for 5 h, and the cold bath was allowed to slowly warm to
ambient temperature and to stir overnight. Filtration of the reaction
mixture afforded the reduced azodicarboxylate 2 as a white pow-
der. The reaction mixture was then concentrated in vacuo, and the
products were purified by flash chromatography (eluted with 1:6
4.6.2. Allyl 4-chlorobenzoate (entry 2). Following the general pro-
cedure: Flash chromatography eluted with hexane to 1:10 EtOAc/
hexane afforded the title compound as a colorless oil (95%). 1H NMR
(500 MHz, CDCl3)
d
7.99 (dd, J1¼6.7 Hz, J2¼1.8 Hz, 2H), 7.42 (dd,
J1¼6.7 Hz, J2¼1.8 Hz, 2H), 6.03 (m, 1H), 5.39e5.43 (dd, J1¼17.2 Hz,
J2¼1.5 Hz, 1H), 5.29e5.31 (dd, J1¼10.5 Hz, J2¼1.25 Hz, 1H), 4.82 (dt,
J1¼5.7 Hz, J2¼1.4 Hz, 2H); 13C NMR (500 MHz, CDCl3)
d 166.04,
139.62, 134.28, 131.15, 129.23, 128.47, 114.19, 68.62. Anal. Calcd for
C10H9ClO2 (196.03): C, 61.08; H, 4.61. Found: C, 61.16; H, 4.46.
4.6.3. 2-Amino-6-chloro-9-(2-bromoethyl)purine (entry 3). White
solid (85%). Mp 182e183 ꢀC; 1H NMR (500 MHz, CDCl3)
d 7.84 (s,
EtOAc/hexane) to afford the title compound as a colorless oil
1H), 5.08 (s, 2H), 4.27 (t, J¼5.7 Hz, 2H), 3.89 (t, J¼5.7 Hz, 2H); 13C
(575 mg, 88%). [
a
]
ꢁ70.5 (c 0.49, CHCl3); 1H NMR (500 MHz,
NMR (500 MHz, CDCl3) d 160.04, 155.57, 150.30, 142.72, 122.20,
20
D
CDCl3)
d
7.96 (d, J¼4.0 Hz, 1H), 7.27 (d, J¼4.0 Hz, 1H), 7.19 (d,
52.21, 40.18. Anal. Calcd for C7H7Cl2N5 (231.01): C, 36.23; H, 3.04; N,
30.18. Found: C, 36.19; H, 3.09; N, 30.21.
J¼7.6 Hz, 1H), 6.88 (d, J¼7.6 Hz, 1H), 4.37 (q, J¼7.1 Hz, 1H), 2.37 (q,
J¼4.4 Hz, 1H), 2.02e2.05 (m, 1H), 1.57e1.67 (m, 3H), 0.80e1.14 (m,
13H); 13C NMR (500 MHz, CDCl3)
d
170.48, 151.52, 151.13, 141.25,
4.6.4. 2-Amino-6-chloro-9-benzylpurine (entry 4). Colorless nee-
131.54, 125.55, 71.74, 50.36, 45.29, 34.79, 31.88, 26.04, 24.02, 21.84,
21.23, 16.32. Anal. Calcd for C16H23NO2 (261.17): C, 73.53; H, 8.87; N,
5.36. Found: C, 73.62; H, 8.76; N, 5.48.
dles (83%). Mp 212.4e213.8 ꢀC; 1H NMR (500 MHz, CDCl3)
d
7.90 (s,
1H), 7.27e7.36 (m, 5H), 5.32 (s, 2H), 5.04 (s, 2H); 13C NMR
(500 MHz, CDCl3) 160.11, 154.98, 151.49, 146.56, 135.98, 130.13,
d
128.70,128.04,120.35, 49.68. Anal. Calcd for C12H10ClN5 (259.06): C,
55.50; H, 3.88; N, 26.97. Found: C, 55.41; H, 3.77; N, 27.11.
4.5. Preparation of (L)-menthol (4)
A 50 mL round bottom flask was charged with CHCl3 (10 mL),
4.6.5. 2-[Bis(tert-butoxycarbonyl)amino]-6-chloro-9-[2-(2,2-dimethyl-
1,3-dioxan-5-yl)ethyl]purine (entry 5). white solid (93%). Mp>280 ꢀC
(dec); IR (KBr) 3117, 2936, 1753, 1694, 1644, 1603, 1567, 1536, 1474,
picolinate ester
3
(653 mg, 2.5 mmol), methanol (890 mL,
20.8 mmol), and Cu(OAc)2 (230 mg, 12.6 mmol). The reaction
mixture was allowed to stir for 6 h at which point it was judged
complete by TLC. The reaction mixture was diluted with hexane
(10 mL) and washed with disodium EDTA (l0 mL of a 0.1 M solu-
tion). The organic layer was dried over anhydrous MgSO4, filtered,
and concentrated to an oil. Flash chromatography (eluted with
hexane then 6:1 hexane/EtOAc) provided the corresponding
1426 cmꢁ1 1H NMR (500 MHz, CDCl3):
; d 8.36 (s, 1H), 4.02 (t,
J¼7.23 Hz, 2H), 3.79 (dd, Heq. J1¼11.57 Hz, J2¼4.46 Hz, 2H), 3.56 (dd,
Hax. J1¼11.57 Hz, J2¼8.77 Hz, 2H), 1.67 (q, J¼7.22 Hz, 2H), 1.53e1.61
(m, 1H), 1.47 (s, 18H), 1.39 (s, 3H), 1.36 (s, 3H); 13C NMR (500 MHz,
CDCl3)
d 154.34, 151.74, 151.49, 151.09, 146.56, 128.04, 104.79, 81.68,
71.52, 50.76, 33.70, 28.58, 26.20, 25.65; MS (ESI): m/z¼512.2 (MþHþ),
534.2 (MþNaþ), 1045.6 (2MþNaþ). Anal. Calcd for C23H34ClN5O6
(511.22): C, 53.95; H, 6.69; N,13.68. Found: C, 53.85; H, 6.57; N, 13.73.
(ꢁ)-menthol (355 mg, 2.28 mmol, 91%) as colorless needles. Mp
20
42e43 ꢀC; [
a
]
D
ꢁ48.5 (c 2, EtOH); 1H NMR (500 MHz, CDCl3)
d
3.38e3.43 (td, J1¼10.4 Hz, J2¼4.2 Hz, 1H), 2.16e2.18 (m, 1H),
1.95e1.98 (m, 1H), 1.59e1.67 (m, 2H), 1.45 (m, 2H), 0.80e1.11 (m,
4.6.6. 2-[Bis(tert-butoxycarbonyl)amino]-6-chloro-9-iso-
propylpurine (entry 6). White solid (90%). Mp 229.5e231.8 ꢀC; IR
(KBr) 3121, 2955, 1771, 1720, 1648, 1598, 1561, 1536, 1495,
13H); 13C NMR (500 MHz, CDCl3)
d
71.74, 50.36, 45.29, 34.79, 31.88,
26.04, 23.38, 22.43, 21.23, 16.32. Anal. Calcd for C10H20O (156.15): C,
76.86; H, 12.90. Found: C, 76.69; H, 12.79.
1478,1456 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d 8.77 (s,1H), 4.12e4.27
(m, 1H), 1.71 (d, J¼6.2 Hz, 6H), 1.47 (s, 18H); 13C NMR (500 MHz,
4.6. General procedure for the Mitsunobu reactions
CDCl3) d 153.65, 151.92, 151.59, 151.29, 145.61, 128.53, 82.69, 52.73,
28.52, 24.55; MS (ESI): m/z¼412.2 (MþHþ), 435.2 (MþNaþ), 845.5
(2MþNaþ). Anal. Calcd for C18H26ClN5O4 (411.17): C, 52.49; H, 6.36;
N, 17.00. Found: C, 52.55; H, 6.27; N, 17.13.
An alcohol (1.0 equiv) was added to a solution of acidic pronu-
cleophile (1.1 equiv) and phosphine reagent (1.1 equiv) in anhydrous
CH2Cl2 or THF under a N2 atmosphere at 0 ꢀC. The resulting sus-
pension/solution was treated with azo-reagent (1.1 equiv) and the
reaction mixture was continued stirring at room temperature up to
completion of the reaction, indicated by TLC monitoring (The re-
action mixture was filtered to recover the reduced azodicarboxylate
2 if DNAD was used as the azo-reagent.). The solvent was evaporated
and the residue dissolved in cyclohexane. The triphenylphosphane
oxide precipitated and was filtered off and then the filtrate evapo-
rated under reduced pressure. The product was purified by column
chromatography on silica gel to afford the pure products.
4.6.7. 2-(2-(Benzyloxy)ethyl)isoindoline-1,3-dione (entry 8). Following
the general procedure: Flash chromatography eluted with hexane to
1:6 EtOAc/hexane afforded the title compound as a beige solid (92%).
Mp 72e73 ꢀC; 1H NMR (500 MHz, DMSO-d6)
d 8.36e8.41 (m, 2H),
8.18e8.23 (m, 2H), 7.28e7.43 (m, 5H), 4.53 (s, 2H), 3.70 (t, J¼4.5 Hz,
2H), 3.54 (t, J¼4.5 Hz, 2H); 13C NMR (500 MHz, DMSO-d6)
d 166.41,
137.56, 131.56, 130.71, 129.08, 128.80, 127.53, 120.99, 72.92, 71.38,
61.29. Anal. Calcd for C17H15NO3 (281.11): C, 72.58; H, 5.37; N, 4.98.
Found: C, 72.44; H, 5.32; N, 4.94.
4.6.1. (R)-3-Chloro-1-cyanopropan-2-yl 4-chlorobenzoate (entry 1).
Following the general procedure: Flash chromatography eluted
with hexane to 1:12 EtOAc/hexane afforded the title compound as
4.6.8. 2-(Pentan-3-yl)isoindoline-1,3-dione (entry 9). Following the
general procedure: Flash chromatography eluted with hexane to
1:9 EtOAc/hexane afforded the title compound as a white solid

J. Yang et al. / Tetrahedron 67 (2011) 1456e1462
1461
(87%). Mp 132.3e134.5 ꢀC; 1H NMR (500 MHz, CDCl3)
d
7.90e7.92
Mp 90.2e91.3 ꢀC; 1H NMR (500 MHz, CDC13)
d
8.00 (d, J¼9.1 Hz,
(m, 2H), 7.64e7.66 (m, 2H), 3.95e4.02 (m, 1H), 1.88e2.01 (m, 4H),
2H), 7.53 (d, J¼9.1 Hz, 2H), 7.28 (m, 2H), 7.28 (m, 2H), 6.87e6.96 (m,
0.94 (t, J¼7.55 Hz, 3H); 13C NMR (500 MHz, CDCl3)
d
169.09, 132.73,
3H); 13C NMR (500 MHz, CDCl3)
d 160.35, 148.48, 147.99, 129.81,
131.36, 123.98, 50.91, 26.48, 11.93. Anal. Calcd for C13H15NO2
(217.11): C, 71.87; H, 6.96; N, 6.45. Found: C, 71.71; H, 6.83; N, 6.41.
127.70, 124.04, 121.73, 114.71, 71.22. Anal. Calcd for C13H11NO3
(229.07): C, 68.11; H, 4.84; N, 6.11. Found: C, 68.19; H, 4.99; N, 6.02.
4.6.9. 1-Benzyl-1H-imidazole (entry 10). Following the general
procedure: Flash chromatography eluted with hexane to 1:6 EtOAc/
hexane afforded the title compound as a yellow solid (55%). Mp
4.6.16. 6-Nitro-3,4-dihydro-1H-isochromene (entry 17). Following
the general procedure: Flash chromatography eluted with 1:6
EtOAc/hexane afforded the title compound as a white solid (72%).
72e73 ꢀC; 1H NMR (500 MHz, CDCl3)
d
7.63 (s, 1H), 7.22e7.31 (m,
Mp: 84.5e85 ꢀC; 1H NMR (500 MHz, CDCl3)
d
7.99 (d, J¼9.1 Hz, 1H),
3H), 7.14 (d, J¼6.5 Hz, 2H), 7.06 (s, 1H), 6.94 (s, 1H), 5.02 (s, 2H); 13C
7.97 (s, 1H), 7.25 (d, J¼9.1 Hz,1H), 4.88 (s, 2H); 4.12 (t, J¼6.0 Hz, 2H);
NMR (500 MHz, CDCl3)
d
137.32, 136.43, 130.91, 130.45, 129.98,
3.08 (t, J¼6.0 Hz, 2H); 13C NMR (500 MHz, CDCl3)
d 150.19, 144.46,
125.82, 120.18, 51.64. Anal. Calcd for C10H10N2 (158.08): C, 75.92; H,
6.37; N, 17.71. Found: C, 75.84; H, 6.32; N, 17.94.
137.88, 127.60, 124.37, 117.68, 71.38, 61.29. Anal. Calcd for C9H9NO3
(179.06): C, 60.33; H, 5.06; N, 7.82. Found: C, 60.25; H, 5.13; N, 7.71.
4.6.10. 2-(Allylthio)benzo[d]thiazole (entry 11). Following the gen-
eral procedure: Flash chromatography eluted with 1:5 EtOAc/hex-
ane afforded the title compound as a colorless oil (93%). 1H NMR
4.6.17. (S)-2-(4-Nitrophenyl)oxirane (entry 18). Following the gen-
eral procedure: Flash chromatography eluted with hexane to 1:8
EtOAc/hexane afforded the title compound as a light yellow solid
(500 MHz, DMSO-d6)
d
7.62 (d, J¼7.8 Hz, 1H), 7.33e7.36 (m, 1H),
(92%). Mp 73.5e75.3 ꢀC; 98% ee; [
(500 MHz, CDCl3)
a
]
D
25 þ37.9 (c 1.21, CHCl3); 1H NMR
7.28 (d, J¼7.8 Hz, 1H), 7.21e7.24 (m, 1H), 6.03 (d, J¼6.7 Hz, 1H), 5.41
d
8.20 (d, J¼8.2 Hz, 2H), 7.38 (d, J¼8.2 Hz, 2H),
(q, J¼6.7 Hz, 1H), 5.29e5.31 (m, 1H), 4.81e4.83 (m, 2H); 13C NMR
3.97 (dd, J1¼4.0 Hz, J2¼2.5 Hz, 1H), 3.25 (dd, J1¼5.5 Hz, J2¼3.9 Hz,
(500 MHz, DMSO-d6) d 190.27,141.71,129.83,128.30, 127.50, 124.60,
1H), 2.69 (dd, J1¼5.5 Hz, J2¼2.5 Hz, 1H); 13C NMR (500 MHz, CDCl3)
122.09, 117.29, 112.86, 47.05. Anal. Calcd for C10H9NS2 (207.02): C,
57.93; H, 4.38; N, 6.76. Found: C, 57.89; H, 4.34; N, 6.79.
d 149.18, 144.73, 128.18, 123.43, 61.29, 49.74. Anal. Calcd for
C8H7NO3 (165.04): C, 58.18; H, 4.27; N, 8.48. Found: C, 58.25; H,
4.35; N, 8.57.
4.6.11. 2-((1S,2S,5R)-2-Isopropyl-5-methylcyclohexylthio)benzo[d]
thiazole (entry 12). Following the general procedure: Flash chro-
matography eluted with 1:8 EtOAc/hexane afforded the title com-
Acknowledgements
pound as a colorless oil (88%). [
(500 MHz, CDCl3)
a
]
35 þ91.5 (c 0.95, CHCl3); 1H NMR
D
We express our appreciation to Sanhe Pharmachem Co, Ltd for
offering financial support to us.
d
7.82 (d, J¼8.25 Hz, 1H), 7.56 (d, J¼7.49 Hz, 1H),
7.23e7.43 (m, 2H), 3.51e3.58 (m, 1H), 2.15e2.17 (m, 1H), 1.95e1.98
(m, 1H), 1.59e1.67 (m, 2H), 1.45 (m, 1H), 1.09e1.11 (m, 1H),
0.86e0.99 (m, 8H), 0.80e0.85 (m, 4H); 13C NMR (500 MHz, CDCl3)
Supplementary data
d
168.09, 154.57, 136.09, 128.04, 123.91, 120.76, 120.04, 50.76, 47.83,
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.12.036. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
41.30, 35.44, 31.74, 27.22, 26.95, 23.48, 20.70, 20.43. Anal. Calcd for
C17H23NS2 (305.13): C, 66.84; H, 7.59; N, 4.58. Found: C, 66.71; H,
7.77; N, 4.49.
4.6.12. 5,5-Dibenzyl-2,2-dimethyl-1,3-dioxane-4,6-dione (entry 13).
Flash chromatography eluted with 1:10 EtOAc/hexane afforded the
title compound as a white solid (85%). Mp 233e234 ꢀC; 1H NMR
References and notes
1. Mitsunobu, O. Synthesis 1981, 1e28.
2. Huges, D. L. In Organic Reactions; Paquette, L. A., Ed.; John Wiley & Sons: New
York, NY, 1992; Vol. 42, pp 335e456.
(500 MHz, CDCl3)
NMR (500 MHz, CDCl3)
d C
7.28e7.38 (m, 10H), 3.56 (s, 4H), 1.12 (s, 6H); 13
d
169.13, 137.71, 129.46, 127.60, 125.22,
3. Huges, D. L. Org. Prep. Proced. Int. 1996, 28, 127e164.
4. Mitsunobu, O.; Yamada, M.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1967, 40,
935e939.
101.97, 63.92, 47.28, 24.46. Anal. Calcd for C20H20O4 (324.14): C,
74.06; H, 6.21. Found: C, 73.93; H, 6.15.
5. Mitsunobu, O.; Eguchi, M. Bull. Chem. Soc. Jpn. 1971, 44, 3427e3430.
6. Wada, M.; Mitsunobu, O. Tetrahedron Lett. 1972, 13, 1279e1282.
7. Yadav, J. S.; Reddy, J. S. S.; Mandal, S. S.; Srihari, P. Synlett 2010, 2636e2638.
8. Fletcher, S.; Shahani, V. M.; Lough, A. J.; Gunning, P. T. Tetrahedron 2010, 66,
4621e4632.
4.6.13. 5,5-Diallyl-2,2-dimethyl-1,3-dioxane-4,6-dione (entry 14).
Flash chromatography eluted with hexane to 1:12 EtOAc/hexane
afforded the title compound as colorless oil (94%). 1H NMR
(500 MHz, CDCl3)
d
5.87e5.97 (m, 2H), 4.92e5.06 (m, 4H), 2.78
9. Navickas, S.; Maier, M. E. Tetrahedron 2010, 66, 94e101.
10. Wang, T.; Zhou, L.; Cao, X. P. Chin. Chem. Lett. 2009, 20, 147e149.
11. Tsunoda, T.; Yamamiya, Y.; Ito, S. Tetrahedron Lett. 1993, 34, 1639e1642.
12. Ito, S.; Tsunoda, T. Pure Appl. Chem. 1999, 71, 1053e1057.
13. Curran, D. P. ChemtractsdOrg. Chem. 1996, 9, 75e87.
14. Curran, D. P. Angew. Chem., Int. Ed. 1998, 37, 1175e1196.
15. Yoshida, J. I.; Itami, K. Chem. Rev. 2002, 102, 3693e3716.
16. Tzschucke, C. C.; Market, C.; Bannwarth, W.; Roller, S.; Hebel, A.; Haag, R. An-
gew. Chem., Int. Ed. 2002, 41, 3964e4000.
(d, J¼7.1 Hz, 4H), 1.52 (s, 6H); 13C NMR (500 MHz, CDCl3)
d 166.01,
140.87, 122.56, 104.13, 64.98, 47.32, 32.07. Anal. Calcd for
C12H16O4 (224.10): C, 64.27; H, 7.19. Found: C, 64.19; H, 7.08.
4.6.14. 5-sec-Butyl-2,2-dimethyl-1,3-dioxane-4,6-dione (entry 15).
Following the general procedure: Flash chromatography eluted
with 1:9 EtOAc/hexane afforded the title compound as white solid
17. Dandapani, S.; Newsome, J. J.; Curran, D. P. Tetrahedron Lett. 2004, 45,
6653e6656.
(88%). Mp 79.3e81.2 ꢀC; 1H NMR (500 MHz, DMSO-d6)
d 3.38 (d,
18. Dandapani, S.; Curran, D. P. Tetrahedron 2002, 58, 3855e3864.
19. Dandapani, S.; Curran, D. P. J. Org. Chem. 2004, 69, 8751e8757.
20. Dobbs, A. P.; McGregor-Johnson, C. Tetrahedron Lett. 2002, 43, 2807e2810.
21. Hagiya, K.; Muramoto, N.; Misaki, T.; Sugimura, T. Tetrahedron 2009, 65,
6109e6114.
22. Crich, D.; Dyker, H.; Harris, R. J. J. Org. Chem. 1989, 54, 257e259.
23. Varasi, M.; Walker, K. A. M.; Maddox, M. L. J. Org. Chem. 1987, 52, 4235e4238.
24. Hughes, D. L.; Reamer, R. A.; Berga, J. J.; Grabowski, E. J. J. J. Am. Chem. Soc. 1988,
110, 6487e6491.
J¼4.1 Hz, 1H), 2.86e2.95 (m, 1H), 1.71 (s, 6H), 1.28e1.36 (m, 2H),
1.02 (d, 3H), 0.82 (t, J¼7.45 Hz, 3H); 13C NMR (500 MHz, DMSO-d6)
d
169.02,106.37, 56.11, 37.17, 27.52, 24.38,17.51,10.90. Anal. Calcd for
C10H16O4 (200.10): C, 59.98; H, 8.05. Found: C, 60.09; H, 7.97.
4.6.15. p-Nitrobenzyl phenyl ether (entry 16). Following the general
procedure: Flash chromatography eluted with hexane to 1:5 EtOAc/
hexane afforded the title compound as a bright yellow solid (90%).
25. Baek, J. Y.; Shin, Y.-J.; Jeon, H. B.; Kim, K. S. Tetrahedron Lett. 2005, 46,
5143e5147.

1462
J. Yang et al. / Tetrahedron 67 (2011) 1456e1462
26. When 2-amino-6-chloro-purin and 2-chloroethanol were reacted at room
temperature under diluted conditions, the coupling product was obtained in
less than 35% isolated yield even after running the reaction for 30 h.
27. The 2-amino-6-chloro-purine (1.0 equiv) was added to a solution of alcohol (1.
0 equiv) and PPh3 (1.05 equiv) in anhydrous THF under a N2 atmosphere. The
resulting suspension/solution was treated with azo-reagent (1.05 equiv) and
the reaction mixture was then stirred at 70 ꢀC for about 6 h. Then the second
portions of alcohol (1.0 equiv), PPh3 (1.05 equiv), and azo-reagent (1.05 equiv)
were added to the reaction mixture sequentially. The mixture was stirred for
about another 6 h at the same temperature. The mixture was cooled and the
hydrazine precursor was separated directly from the reaction mixture via
filtration. Then the mixture was treated with saturated sodium chloride, and
extracted with dichloromethane. The combined organic layer was then
washed with water and dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure. Flash silica gel chromatography gave the
pure product.