Dicyclopentyl azodicarboxylate (DCpAD): A new alternative azo-reagent for the Mitsunobu reaction

Article abstract of DOI:10.1016/j.cclet.2011.03.017

Dicyclopentyl azodicarboxylate is introduced as a new azo-reagent which can be conveniently prepared in two steps and be used in the Mitsunobu reaction. Though there are no distinct difference of reactivity between DCpAD and DEAD, the former is a more preferable azo-reagent for its stability.

Full text of DOI:10.1016/j.cclet.2011.03.017

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 1047–1050
www.elsevier.com/locate/cclet
Dicyclopentyl azodicarboxylate (DCpAD): A new alternative
azo-reagent for the Mitsunobu reaction
*
Jian Hai Yang, Li Yan Dai , Xiao Zhong Wang, Ying Qi Chen
Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China
Received 7 December 2010
Available online 25 June 2011
Abstract
Dicyclopentyl azodicarboxylate is introduced as a new azo-reagent which can be conveniently prepared in two steps and be used
in the Mitsunobu reaction. Though there are no distinct difference of reactivity between DCpAD and DEAD, the former is a more
preferable azo-reagent for its stability.
# 2011 Li Yan Dai. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Dicyclopentyl azodicarboxylate; Mitsunobu reaction; Azo-reagent
The Mitsunobu reaction, initiated by Mitsunobu in the late 1960s, has become one of the most widely used reactions
in organic chemistry [1–3]. The Mitsunobu reaction, due to its scope, stereoselectivity, and mild reaction conditions,
has wide applications in total synthesis, heterocyclic, and medicinal chemistry [4–8] and becomes the standard method
for the inversion of configuration in secondary alcohols or the synthesis of aryl ether.
The condensation of an acidic pronucleophile with an alcohol promoted by using the redox couple of a trialkyl or
triaryl phosphine and a dialkyl azodicarboxylate (azo-reagent) is known as the Mitsunobu reaction which has been
extensively reviewed [9–11]. Traditional dialkyl azodicarboxylates are commercially available and they are usually
prepared with hydrazine hydrate [12–14]. Among them DEAD is the commonest one, but it is not stable enough in the
absence of solvent and is sensitive to light and heat. Moreover, it is susceptible to explosion upon strong heating or
impact. Hence, it is preferred to be handled in solution.
We developed a new and efficient azo-reagent which was first used in the Mitsunobu reaction and we found that it
was stable and could be stored indefinitely at room temperature.
1. Results and discussion
Dicyclopentyl hydrazinedicarboxylate 2 was readily prepared in good yields by adding a solution of cyclopentyl
chloroformate in toluene to an aqueous solution of NaHCO3 and 80% hydrazine hydrate in water at room temperature.
Oxidation was performed by addition of Br2 and pyridine to DCM slurry of hydrazine 2 at room temperature, which
transforms the white mixture to orange in color (Scheme 1). Finally the reagent 1 was obtained. The structures of 1 and
* Corresponding author.
E-mail address: dailiyan@zju.edu.cn (L.Y. Dai).
1001-8417/$ – see front matter # 2011 Li Yan Dai. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.03.017

[(Scheme_1)TD$FIG]
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J.H. Yang et al. / Chinese Chemical Letters 22 (2011) 1047–1050
O
O
O
O
O
b
a
O
O
Cl
O
N
H
N
H
O
O
N N
1 (96%)
2 (92%)
.
Scheme 1. Synthesis of dicyclopentyl azodicarboxylate: (a) N2H4 H2O, toluene/H2O, rt.; (b) Br2, pyridine, toluene, rt.
Table 1
The influence of illumination on the stability of compound 1 with time at room temperature.
Exposure time (days)
The purity of compound 1 kept under different preservation condition (%)
Kept in dark place
Kept under natural daylight
Kept under fluorescent light
0
99.37
99.31
99.35
99.41
99.28
99.32
99.37
99.25
99.30
99.28
99.31
99.33
99.37
99.33
99.29
99.37
99.32
99.25
2
4
6
8
10
Table 2
The purity of compound 1 kept under different temperature with time in dark place.
Temperature (8C)
Purity (%)
0 h
24 h
48 h
72 h
96 h
120 h
144 h
168 h
192 h
216 h
240 h
25
40
55
70
85
99.37
99.37
99.37
99.37
99.37
99.31
99.30
99.36
99.27
99.35
99.39
99.39
99.31
99.38
99.27
99.40
99.38
99.35
99.25
99.31
99.29
99.28
99.28
99.31
99.24
99.33
99.33
99.34
99.34
99.32
99.28
99.37
99.39
99.27
99.29
99.35
99.33
99.31
99.24
99.34
99.33
99.35
99.27
99.30
99.26
99.28
99.32
99.33
99.31
99.30
99.36
99.31
99.35
99.30
99.28
1
2 were confirmed by IR, H NMR, 13C NMR, MS, and elemental analysis [15]. The thermal stability of 1 was
evaluated by the decomposition temperature. By thermal gravimetric analysis (TGA) and differencial scanning
calorimetry (DSC), DCpAD was found to decompose at 306 8C, while DEAD was found to decompose at 210 8C. The
higher decomposition temperature indicates more stability at high temperatures.
The influence of illumination and the effect of temperature on the stability of compound 1 were studied and the
results were shown in Tables 1 and 2, respectively. We kept the compound 1 under different conditions within ten days.
Finally we found that the purities of these samples have no obvious difference. So the stability of DCpAD may be
insensitive to these preservation conditions.
The performance of DCpAD in the Mitsunobu reaction was tested for different combinations of alcohols with some
common nucleophiles, in comparison with that of DEAD, and the results were given in Table 3 The pronucleophile
used in the Mitsunobu reaction is normally a relative acid compound containing an O–H, S–H, or an N–H group with
pKa ꢀ 15. Some common nucleophiles are carboxylic acids, phenols, imides, purines, thiocarboxylic acids, and
thiols. Thus, this reaction permits C–O, C–S, C–N, or C–C bonds formed by the condensation of an acidic component
with a primary or a secondary alcohol under Mitsunobu reaction conditions.
When a chiral secondary alcohol is used, configurational inversion of alcohol occurs under mild and neutral
conditions. For the two strong electron withdrawing groups at b-position, (S)-4-chloro-3-hydroxybutanenitrile is an
active optically alcohol which converted to the completely inverted ester with 4-chlorobenzoic acid in good yields
(entry 1). Phthalimide reacted smoothly with a primary or a secondary aliphatic alcohol and gave the corresponding N-
substituted imide (entry 2 and 3). When imidazole which is less active in a Mitsunobu-type alkylation reacted with
benzyl alcohol under the usual Mitsunobu conditions, the N-alkylimidazole was obtained in poor yields and the
reaction did not proceed completely over 24 h (entry 4). A thiol here also tried to couple with a primary alcohol or a
less reactive secondary alcohol and its corresponding thioether was obtained in good yields (entry 5 and 6). The
reaction of Meldrum’s acid with a primary alcohol such as allyl alcohol was investigated. Rewardingly, the

J.H. Yang et al. / Chinese Chemical Letters 22 (2011) 1047–1050
1049
Table 3
Different combinations of the pronucleophile and alcohol.
Entry
Nu–H
Alcohol
Product
Yield (%)a
DCpAD
89b,d
DEAD
85b,d
OH
NC
Cl
O
1
O
[DT$INLE]
Cl
CN
[
OH
[
O
Cl
Cl
2
3
87b
89b
O
OH
O
Bn
O
[DT$INLE]
O
NH
[TD$INLINE]
[DT$INLE]
N
O
O
O
O
88b
86b
OH
[DT$INLE]
[
NH
[
N
O
O
4
5
30b
92b
25b
90b
OH
N
NH
[TD$INLINE]
N
[DT$INLE]
NT
OH
OH
N
[DT$INLE]
N
S
]
SH
[DT$INLE]
S
S
86b
85b
N
6
T
SH
[DT$INLE]
S
N
[DT$INLE]
S
S
O
OH
O
7
8
93c
90c
[DT$INLE]
O
O
O
O
[TD$INLINE]
[DT$INLE]
O
O
O
O
85b
86b
OH
[DT$INLE]
O
O
O
O
[TD$INLINE]
[DT$INLE]
O
O
NO2
OH
OH
NO2
9
–
–
68
65
[DT$INLE]
[DT$INLE]
O
10
87d
85d
OH
O
[DT$INLE]
[DT$INLE]
OH
NO2
NO2
a
Isolated, chromatographically pure material.
b
These reactions were conducted with alcohol (1.0 equiv), 1.1 equiv of acidic pronucleophile, 1.1 equiv of Ph3P, and 1.1 equiv of azodicarbox-
ylate reagent at room temperature in CH2Cl2 and the isolated yields based on alcohols.
c
These reactions were conducted with Meldrum’ acid (1.0 equiv), 2.5 equiv of alcohol, 2.5 equiv of Ph3P, and 2.5 equiv of azodicarboxylate
reagent at room temperature in CH2Cl2 and the isolated yields based on Meldrum’s acid.
d
Determined by HPLC analysis with a chiral AD-H column.
dehydrative alkylations proceeded smoothly and dialkylated Meldrum’s acid was isolateded in good yields. When
Meldrum’s acid reacted with secondary butyl alcohol only the monoalkylated Meldrum’s acid was obtained due to
steric hindrance (entry 7 and 8). Cyclic ether and chiral epoxides were also easily formed under the standard
Mitsunobu conditions (entry 9 and 10). All these common nucleophiles tested in this paper could not react with tertiary
alcohol such as tert-butanol owing to steric hindrance at the tertiary carbon.
In summary, we have developed a novel azo-reagent which can be conveniently prepared in good-to-excellent yield
and purified without resorting to chromatography. It was conveniently used for various Mitsunobu couplings. Though
the results showed that they had no obvious difference of reactivity between DCpAD and DEAD in the Mitsunobu

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J.H. Yang et al. / Chinese Chemical Letters 22 (2011) 1047–1050
reaction, the former is more stable than DEAD and can be stored at ambient temperatures. In addition, the raw
materials for preparation of DCpAD are commercially available and cheap. All of these advantages make DCpAD an
attractive alternative to azo-reagents in the Mitsunobu reactions.
References
[1] O. Mitsunobu, M. Yamada, T. Mukaiyama, Bull. Chem. Soc. Jpn. 40 (1967) 935.
[2] O. Mitsunobu, M. Eguchi, Bull. Chem. Soc. Jpn. 44 (1971) 3427.
[3] M. Wada, O. Mitsunobu, Tetrahedron Lett. 13 (1972) 1279.
[4] J.S. Yadav, J. Shyam Sunder Reddy, S.S. Mandal, et al. Synlett 17 (2010) 2636.
[5] S. Fletcher, V.M. Shahani, A.J. Lough, et al. Tetrahedron 66 (2010) 4621.
[6] T. Wang, L. Zhou, X.P. Cao, Chin. Chem. Lett. 20 (2009) 147.
[7] T.C. Wang, J.Z. Wei, C.S. Guo, et al. Chin. Chem. Lett. 21 (2010) 1407.
[8] R.J. Altenbach, L.A. Black, M.I. Strakhova, et al. J. Med. Chem. 53 (2010) 7869.
[9] K.C. Kumara Swamy, N.N. Bhuvan Kumar, E. Balaraman, et al. Chem. Rev. 109 (2009) 2551.
[10] O. Mitsunobu, Synthesis 1 (1981) 1.
[11] D.L. Huges, Org. Prep. Proced. Int. 28 (1996) 127.
[12] R.D. Little, M.G. Venegas, Org. Synth. 61 (1983) 17.
[13] R.D. Little, M.G. Venegas, Organic Synthesis, Wiley & Sons, New York, 1990, p. 56.
[14] J.T. Starr, G.S. Rai, H. Dang, et al. Synth. Commun. 27 (1997) 3197.
[15] Analytical data for compounds 1, 2. Compound 1: mp 54.3–55.9 8C; IR (NaCl, neat): 2968, 2876, 1770, 1437, 1243 cmÀ1; 1H NMR (500 MHz,
CDC13): d 5.41–5.45 (m, 2H), 1.93–2.00 (m, 8H), 1.64–1.80 (m, 8H); 13C NMR (125 MHz, CDCl3): d 160.85, 80.57, 35.52, 25.32; MS (ESI):
m/z 277.1 (M+Na+); Anal. Calcd. for C12H18N2O4 (254.13): C56.68, H7.13, N11.02. Found: C56.58, H7.06, N11.08. Compound 2: mp 101.9–
103.2 8C; IR (NaCl, neat): 3256, 2965, 2876, 1737, 1687, 1524, 1255 cmÀ1; 1H NMR (500 MHz, CDCl3): d 6.60 (s, 2H), 5.15 (m, 2H), 1.59–
1.88 (m, 16H); 13C NMR (125 MHz, CDCl3): d 156.60, 81.68, 33.70, 25.65; MS (ESI): m/z 257.1 (M+H+), 279.1 (M+Na+), 512.9 (2M+H+),
535.1 (2M+Na+); Anal. Calcd. for C12H20N2O4 (256.14): C56.23, H7.87, N10.93. Found: C56.18, H7.75, N10.83.