Halogen effects in Robinson-Gabriel type reaction of cyclopropanecarboxylic acid N′-substituted-hydrazides with PPh3/CX4

Article abstract of DOI:10.1016/j.tetlet.2005.07.048

We found that the reaction of cyclopropanecarboxylic acid N′-substituted-hydrazides with PPh₃/CCl₄ proceeded smoothly to give the corresponding normal Robinson-Gabriel type product 2-cyclopropyl-5-substituted-[1,3,4]-oxadiazoles in good yields. Using CBr ₄ or CI₄ instead of CCl₄ in the above system, the ring opening of cyclopropane occurred after dehydration to give the corresponding 2-(3-halopropyl)-5-substituted-[1,3,4]-oxadiazoles (4 or 5) in good yields.

Full text of DOI:10.1016/j.tetlet.2005.07.048

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6285–6288
Halogen effects in Robinson–Gabriel type reaction
of cyclopropanecarboxylic acid N0-substituted-hydrazides
with PPh3/CX4
Yong-Hua Yang and Min Shi*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
Received 2 June 2005; revised 11 July 2005; accepted 12 July 2005
Available online 28 July 2005
Abstract—We found that the reaction of cyclopropanecarboxylic acid N0-substituted-hydrazides with PPh3/CCl4 proceeded
smoothly to give the corresponding normal Robinson–Gabriel type product 2-cyclopropyl-5-substituted-[1,3,4]-oxadiazoles in good
yields. Using CBr4 or CI4 instead of CCl4 in the above system, the ring opening of cyclopropane occurred after dehydration to give
the corresponding 2-(3-halopropyl)-5-substituted-[1,3,4]-oxadiazoles (4 or 5) in good yields.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Substituted 1,3,4-oxadiazoles have received intensive
interest due to their biological activities and wide use
in medicine and agriculture.1 In addition, these hetero-
cyclic compounds have been used as dye stuffs, UV
absorbing and fluorescent materials, and heat-resistant
polymers.2 1,3,4-Oxadiazoles are generally obtained by
Robinson–Gabriel type reaction, an intramolecular
dehydration, of N,N0-disubstituted hydrazines with
dehydration agents.2d,3
few reports about changing the halogen in the tetrahalo-
methane in the combination with tertiary phosphane
system.1a,6 Herein, we wish to report the halogen effects
in Robinson–Gabriel type reaction of cyclopropane-
carboxylic acid N0-substituted-hydrazides with PPh3/
CX4 (X = Cl, Br, I) as dehydration agents.
At first, we attempted the Robinson–Gabriel type reac-
tion of disubstituted hydrazide 1a with PPh3/CCl4 as a
dehydration agent. We found that the reaction pro-
ceeded smoothly to give the desired oxadiazole product
2a in 90% yield in acetonitrile under reflux with 2 equiv
of PPh3 and 1 equiv of CCl4. The above reaction was
found to be quite general. Other disubstituted hydraz-
ides 1 bearing a variety of substituted phenyl groups
(Table 1, entries 1–3), or a benzyl group (Table 1, entry
4), naphthalen-2-yl group (Table 1, entry 5), and a long
aliphatic alkyl group (Table 1, entry 6) also underwent
the dehydration and cyclization to give the correspond-
ing oxadiazole products 2 in excellent yields under the
similar reaction conditions within 2–10 h.
It is well known that triphenylphosphine in the combi-
nation with a tetrahalomethane provides reagents that
have manifold uses and are finding increasing applica-
tion in preparative chemistry for halogenation, dehydra-
tion, and P–N linking reactions.4 Of more general
importance is tertiary phosphane/tetrachloromethane
system, as chlorinating and dehydrating agent for sensi-
tive substrates to the aggressive and readily hydrolyzed
acid chlorides such as PCl5, P(O)Cl3, thionyl chloride,
and sulfonyl chloride. A great advantage can also be
seen in the ability to the demands made by the various
donor strengths of the substituents chosen for attach-
ment to the phosphorus atom.5 However, there are
Interestingly, we found that when the reaction solution
was refluxed for 2 days, trace amount of ring-opening
product 3a was obtained along with the product 2a
(Table 2, entry 1). Next, we utilized CBr4 to replace
CCl4 for this reaction, the corresponding ring-opening
product 4a was formed in 16% yield along with the for-
mation of the product 2a in 79% yield after refluxing for
Keywords: Halogen effects; Robinson–Gabriel reaction; Cyclopropane;
Ring-opening reaction; 2-(3-Halopropyl)-5-substituted-[1,3,4]-oxa-
diazole; Dehydration.
*
Corresponding author. Fax: +86 21 64166128; e-mail: mshi@
pub.sioc.ac.cn
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.048

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Y.-H. Yang, M. Shi / Tetrahedron Letters 46 (2005) 6285–6288
Table 1. Reaction of cyclopropanecarboxylic acid N0-substituted-
hydrazides 1 with PPh3/CCl4
the presence of PPh3/CBr4. The results are summarized
in Table 3. A series of 2-(3-bromopropyl)-5-substituted-
[1,3,4]oxadiazoles 4 were obtained in good yields for a
variety of substrates 1. The structure of 4a was further
determined by X-ray diffraction. The ORTEP drawing
is shown in Figure 1.7
O
H
O
R
R
N
2 PPh3, CCl4
MeCN, reflux
N
H
O
N
N
2
1
Entry
R
Time/h
Yield/[%]a
Table 3. Reaction of cyclopropanecarboxylic acid N0-substituted-
hydrazides 1 with PPh3/CBr4
2
1
2
3
4
5
6
1a, m,m-Me2C6H3
1b, C6H5
1c, p-BuOC6H4
1d, benzyl
1e, naphthalen-2-yl
1f, tridecyl
2
3
3
10
10
10
2a, 90
2b, 97
2c, 99
2d, 80
2e, 96
2f, 90
O
H
O
2 PPh3, CBr4
MeCN, reflux
R
R
N
Br
N
N N
H
O
4
1
a Isolated yields.
Entry
R
Time/d
Yield/[%]a
4
1
2
3
4
5
6
1a, m,m-Me2C6H3
1b, C6H5
1c, p-BuOC6H4
1d, benzyl
1e, naphthalen-2-yl
1f, tridecyl
3
2
2
2
3
3
4a, 91
4b, 68
4c, 90
4d, 67
4e, 96
4f, 80
2 h in acetonitrile (Table 2, entry 2). When the reaction
solution was refluxed for 2 days, the product 4a was
formed in 91% yield as a sole product (Table 2, entry 3).
Under these optimized reaction conditions, the ring
opening of other substrates was also investigated in
a Isolated yields.
Table 2. Difference in the reaction of 1a with PPh3/CCl4 and PPh3/CBr4
Me
O
+
CX4
N
+
PPh3
Me
MeCN
+
Me
N
H
O
Me
1a
O
O
Me
X
Me
N N
N N
2a
3a (X= Cl) or 4a (X= Br)
Entry
CX4
Temp./[ꢁC]
Time
Yield/[%]a
2a
3a or 4a
1
2
3
CCl4
CBr4
CBr4
Reflux
60
Reflux
2 d
2 h
2 d
95
79
0
Trace
16
91
a Isolated yields.
Figure 1. ORTEP drawing of 4a.

Y.-H. Yang, M. Shi / Tetrahedron Letters 46 (2005) 6285–6288
6287
Table 4. Reaction of cyclopropanecarboxylic acid N0-substituted-
hydrazides 1 with PPh3/Cl4
Formally, the ring-opened products 4 and 5 were the
adducts of HX with the corresponding 2-cyclopro-
pyl-5-substituted-[1,3,4]oxadiazoles 2. However, 1,3,4-
oxadiazole containing cyclopropyl group 2c remained
intact even after reflux for several days with NaI as a
nucleophile (Scheme 1). On the other hand, aqueous
solution of HI (>45%) caused the decomposition of
compound 2c and did not give the ring-opening product
(Scheme 1). This result is similar to the sluggish reaction
of other monoactivated cyclopropane system to a simple
nucleophile.8 At the present stage, we only found that
the reagent of PPh3/CBr4 or PPh3/CI4 can promote this
ring-opening reaction smoothly in MeCN to give the
corresponding ring-opened product in good yield
(Scheme 1).
O
H
O
R
2 PPh3, CI4
R
N
I
N
MeCN, reflux
N N
H
O
5
1
Entry
R
Time/d
Yield/[%]a
5
1
2
3
4
5
6
1a, m,m-Me2C6H3
1b, C6H5
1c, p-BuOC6H4
1d, benzyl
1e, naphthalen-2-yl
1f, tridecyl
2
1
2
1
1
1
5a, 79
5b, 80
5c, 75
5d, 54
5e, 66
5f, 61
a Isolated yields.
Based on the above results and description in the litera-
ture about Robinson–Gabriel reaction,9 a plausible
reaction mechanism is proposed in Scheme 2. At first,
triphenylphosphane reacts with carbon tetrahalide to
give the corresponding dihalogentriphenylphosphorane
6 and dihalogenmethylene ylid 7. Next, the intermediate
A is formed by the reaction of cyclopropanecarboxylic
The ring-opening reaction was also investigated with CI4
instead of CBr4 under the similar conditions. As
expected, the corresponding ring-opened products,
2-(3-iodopropyl)-5-substituted-[1,3,4]oxadiazoles, 5, were
cleanly afforded as sole products for a variety of sub-
strates 1 (Table 4).
BuO
O
NaI
MeCN, r.t. - reflux
5c
N N
2c
HI (>45%)
2c
5c
MeCN, r.t. - reflux
BuO
2 PPh3, CI4
O
2c
I
MeCN, reflux, 2 d, 70%
N N
5c
Scheme 1.
Ph3PX2
Ph3P CX2
+
2 Ph P CX4
+
3
6
7
Ph
Ph
Ph
Ph
P
X
Ph
P
Ph
X
X
- Ph3PCHX2X (8)
O
H
O
N
HN
O
N
HN
O
R
R
A
1
Ph3P O
H
HX
N N
R
O
O
R
8
X
X
N N
N N
R
O
2
4/5
B
Scheme 2. A plausible reaction mechanism of bishydrazides 1 with PPh3/CX4.

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Y.-H. Yang, M. Shi / Tetrahedron Letters 46 (2005) 6285–6288
acid N0-substituted-hydrazides 1 with dihalogentriphen-
ylphosphorane 6 to release a dihalogenmethyltriphenyl-
phosphonium salt 8 as white precipitates, which is
dissolved in MeCN after the solution is heated to re-
flux.4f,g Thus, the corresponding N-substituted formimi-
doyl halogen B is formed along with the generation of
triphenylphosphine oxide. After release of another
HX, the corresponding 1,3,4-oxadiazole product 2 is
given. The dihalogenmethyltriphenylphosphonium salt
8, as a potential donor of HX, makes the subsequent
ring-opening reaction take place and give the corre-
sponding halogen displacement product 4 or 5. As for
Clꢀ, because of its weak nucleophilicity, the ring-open-
ing reaction is difficult to occur and the corresponding
1,3,4-oxadiazole product 2 with a cyclopropyl group is
obtained.
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In conclusion, we succeeded in preparing 1,3,4-oxadiaz-
oles containing cyclopropyl group with most conve-
niently handled PPh3/CCl4 system. In the reaction,
halogen effects were also observed and the correspond-
ing 2-(3-halopropyl)-5-substituted-[1,3,4]oxadiazole pro-
ducts were obtained in good yields when CBr4 or CI4
was used instead of CCl4. Efforts are underway to eluci-
date the mechanistic details and to extend the scope of
this reaction.
Acknowledgments
6. Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, H.;
Uneyama, K. J. Org. Chem. 1993, 58, 32–35.
We thank the State Key Project of Basic Research (Pro-
ject 973) (No. G2000048007), Shanghai Municipal Com-
mittee of Science and Technology, and the National
Natural Science Foundation of China for financial sup-
port (20472096, 203900502, and 20272069).
7. The crystal data of 4a has been deposited in CCDC with
number 264863. Empirical Formula: C11H11N2OBr; For-
mula Weight: 267.13; Crystal size: 0.512 · 0.487 · 0.169;
Crystal Color: Habit: colorless, prismatic; Crystal System:
Monoclinic; Lattice Type: Primitive; Lattice Parameters:
˚
˚
˚
a = 13.511(2) A, b = 10.6087(18) A, c = 8.0276(14) A, a =
3
˚
90ꢁ, b = 104.186(4)ꢁ, c = 90ꢁ, V = 1115.6(3) A ; Space
Supplementary data
group: P2(1)/c; Z = 4; Dcalc = 1.590 g/cm3; F000 = 536;
R1 = 0.0718, wR2 = 0.1824. Diffractometer: Rigaku
AFC7R.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.07.048.
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