Reaction of oximes of-diketones with diphosphorous tetraiodide for preparation of oxadiazoles and nitriles

Article abstract of DOI:10.1080/00397911.2011.595035

The utility of diphosphorous tetraiodide as a new, mild, condensing agent for synthesis of oxadiazole is described. These data indicate the simple dehydration of oximes to 1,2,5-oxadiazole as well as the rearrangements of oximes to normal Beckmann product 1,2,4-oxadiazole. However, mono-oxime of benzil undergoes abnormal Beckman rearrangement to benzaldehyde as major product. The described method is simple and important for the synthesis of the oxadiazoles as well as for nitriles.

Full text of DOI:10.1080/00397911.2011.595035

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Reaction of Oximes of α-Diketones
with Diphosphorous Tetraiodide for
Preparation of Oxadiazoles and Nitriles
Vikas N. Telvekar a & Balaram S. Takale a
a Department of Pharmaceutical Sciences and Technology, Institute
of Chemical Technology, Matunga, Mumbai, India
Accepted author version posted online: 01 Feb 2012.Version of
record first published: 18 Oct 2012.
To cite this article: Vikas N. Telvekar & Balaram S. Takale (2013): Reaction of Oximes of α-
Diketones with Diphosphorous Tetraiodide for Preparation of Oxadiazoles and Nitriles, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:2, 221-227
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Synthetic Communications1, 43: 221–227, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.595035
REACTION OF OXIMES OF a-DIKETONES WITH
DIPHOSPHOROUS TETRAIODIDE FOR PREPARATION
OF OXADIAZOLES AND NITRILES
Vikas N. Telvekar and Balaram S. Takale
Department of Pharmaceutical Sciences and Technology, Institute of
Chemical Technology, Matunga, Mumbai, India
GRAPHICAL ABSTRACT
Abstract The utility of diphosphorous tetraiodide as a new, mild, condensing agent for syn-
thesis of oxadiazole is described. These data indicate the simple dehydration of oximes to
1,2,5-oxadiazole as well as the rearrangements of oximes to normal Beckmann product
1,2,4-oxadiazole. However, mono-oxime of benzil undergoes abnormal Beckman rearrange-
ment to benzaldehyde as major product. The described method is simple and important for
the synthesis of the oxadiazoles as well as for nitriles.
Keywords Benzildioxime; benzonitrile; diphosphorus tetraiodide; oxadiazole
INTRODUCTION
Oxadiazoles are important class of heterocycle utilized in variety of bioactive
molecules[1–3] including the metabotropic glutamate subtype 5 (mGlu5) receptor,[4]
and muscarinic receptor (Fig. 1)[5] for the treatment of Alzheimer’s disease.
Various approaches are developed for the preparation of oxadiazoles;[6] how-
ever despite ease of synthesis of dioximes from 1,2-diketone, their utilization for
preparation of 1,2,4 and 1,2,5-oxadiazole has scarcely been reported. Previous
reports for preparation of 1,2,5-oxadiazole from dioximes include use of diisopropyl
azodicarboxylate (DIAD) in combination of triphenyl phospine[7] and crown ether in
the presence of But OK,[8] whereas 1,2,4-oxadiazole is mainly prepared by Beckmann
Received April 23, 2011.
Address correspondence to Vikas N. Telvekar, Department of Pharmaceutical Sciences and
Technology, Institute of Chemical Technology, Matunga, Mumbai, India. E-mail: vikastelvekar@
rediffmail.com
221

222
V. N. TELVEKAR AND B. S. TAKALE
Figure 1. Bioactive molecules with oxadiazoles.
rearrangement using polyphosporic acid and thionyl chloride in liquid sulfur dioxide.[9]
However, both these methods have not been studied on substituted benzil derivative.
Diphosphorus tetraiodide is a bright orange solid reagent of great interest in
synthetic chemistry in several reactions.[10,11] The major driving force for these reac-
=
tions is the formation of a P O bond and the release of energy. It is a unique reagent
able to promote substitution and dehydration as well as reduction reactions.
We previously reported utility of diphosphorus tetraiodide as an agent for dec-
arboxylative bromination and synthesis of nitriles from acids.[12,13] To extend our
previous work on diphosphorus tetraiodide, herein we report its approach to Beck-
mann rearrangement of both mono-oxime and dioxime of a -diketone.
At the beginning, benzildioxime (1 equiv) was used as the starting material to
investigate this reaction. It was found that when P2I4 was used as a reagent in the
presence of CH2Cl2 as a solvent, the normal Beckmann product, 1,2,4-oxadiazole,
could be obtained in 89% yield after the mixture was stirred at room temperature
(Scheme 1).
The rearrangement in this case clearly follows the normal Beckmann path,
where rearrangement occurs at one oximinogroup followed by cyclization to form
the oxadiazole ring.
We also screen various solvents for this reaction. From Table 1, it is clearly
indicated that chlorinated solvents are suitable for this reaction, where dichloro-
methane gives the greatest yield.
RESULTS AND DISCUSSION
Further scope of reaction was explored by using a variety of substituted
1,2-dioximes of a-diketones, and results are summarized in Table 2.
Scheme 1. Synthesis of oxadiazole from benzil dioxime.

REACTION OF OXIMES OF a-DIKETONES
223
Table 1. Effect of various solvents on the reaction of diphosphorus tetraiodide with
dioxime of a-diketone
Entry
Solvent
Yield (%)
1
2
3
4
5
CH2Cl2
CHCl3
CCl4
89
75
72
50
CS2
CH3CN
No reaction
To check further effects of substitution on diketones, we took mono-substituted
benzil for our study and recovered only oxadiazole as a product (Table 2, entry 2).
Heterocyclic substitution on both side of dioxime gives the normal Beckmann product
(Table 2, entry 3). Alkyl substitution on one or both sides of dioxime also results in
formation of 1,2,4-oxadiazole as a product (Table 2, entries 4 and 5). Results clearly
indicate that substitution on both rings of benzil dioxime does not give oxadiazoles
but an abnormal Beckmann rearrangement to nitriles (Table 2, entries 6–8). This
may be due to a steric effect.
The 1,2-cyclohexanedione dioxime does not give a normal Beckmann product
but results in cyclohexano[c]1,2,5-oxadiazole (Table 2, entry 9). As explained by
Tokura and coworkers,[9] Beckmann rearrangement in benzil dioxime is facilitated
by its coplanar structure and participation of the phenyl ring in rearrangement,
whereas cyclohexanedionedioxime prefers dehydration because of steric restriction
to build an azilinium cation. The results obtained for dioximes of other cyclic
a-diketone systems were similar to that of entry 9 (Table 2, entries 10–12).
To check the effect of diphosphorus tetraiodide on Beckmann rearangements
of mono-oxime of a-diketones, we subjected benzil monooxime (1 equiv) with dipho-
sphorus tetraiodide (0.25 equiv), and results are presented in Scheme 2. Previously
benzil monooxime was reported[14] to undergo abnormal Beckmann rearrangement
in the presence of polyphosphoric acid, which resulted in two major products, ben-
zonitrile and benzoic acid. However, we got three products: benzaldehyde, benzoni-
trile, and benzoic acid in the ratio of 40:30:10. Thus, under our reaction conditions
formation of benzaldehyde was quite unexpected.
In conclusion, we have shown that 1,2,4-oxadiazole can be easily synthesized
by corresponding dioximes of a-diketone in good yields whereas dioximes of cyclic
a-diketones resulted in simple dehydration to 1,2,5-oxadiazole because of unfavor-
able conditions for rearrangement. The process is also useful for preparation of
nitriles.
EXPERIMENTAL
Representative Procedure for Synthesis of Oxadiazoles
(Table 2, Entry 1)
Diphosphorus tetraiodide (285 mg, 0.5 mol) in anhydrous CH2Cl2 (10 mL) was
stirred in a round-bottomed flask for 5 min to get a clear solution. Finally dioxime
(240 mg, 1 mol) was added and stirring was continued at room temperature for

224
Entry
1
V. N. TELVEKAR AND B. S. TAKALE
Table 2. Action of diphosphorus tetraiodide on dioxime of a-diketonea
Substrate (a)
Product (b)
Time (h)
Yieldb (%)
3
89
2
3
4
3
3
3
76
80
85
5
6
7
4
2
2
79
90
89
8
2
2
2
85
90
85
9
10
11
12
2
2
87
80
aReaction conditions: Substrate (1 mol) and P2I4 (0.5 mol) in dichloromethane at room temperature.
bIsolated yields after column chromatography and structures were confirmed by comparison of IR and
1H NMR with authentic materials.

REACTION OF OXIMES OF a-DIKETONES
225
Scheme 2. Abnormal Beckmann rearrangement of mono-oxime of a-diketones.
2 h. After completion of the reaction thin-layer chromatography, (TLC), the reaction
mixture was diluted with CH2Cl2(20 mL) and washed successively with 10% aq.
ueous NaHCO3(2 ꢀ 10 mL) and H2O (3 ꢀ 10 mL). The organic layer was dried over
Na2SO4 and concentrated in vacuo. The residue obtained was purified by silica-gel
column chromatography (5% EtOAc–hexane) to afford pure product 1b.
Table 2, Entry 1. Mp 106 ꢁC (lit.[15a] mp 108 ꢁC); 1H NMR (300 MHz,
CDCl3) d 8.10 (d, 2H, J ¼ 7.6 Hz), 8.01–7.97 (m, 2H), 7.74–7.70 (m, 1H),
7.67–7.57 (m, 5H); 13C NMR (75 MHz, CDCl3) d 175.1, 162.5, 130.8, 130.2, 129.3,
1
128.9, 128.1, 127.2, 126.1, 123.3. (mp and H and 13C NMR match with litera-
ture.[15a]
)
Table 2, Entry 2. Mp 143 ꢁC (lit.[15b] mp 145 ꢁC); 1H NMR (300 MHz,
CDCl3): d 9.04 (s, 1H), 8.54–8.56 (m, 1H), 8.47–8.49 (m, 1H), 8.22–8.19 (m, 2H),
7.80–7.76 (m, 1H), 7.59–7.53 (m, 3H); 13C NMR (75 MHz, CDCl3): d 172.2,
167.1, 145.3, 132.2, 130.5, 129.4, 128.9, 127.7, 127.0, 126.3, 123.6, 121.1. (Mp and
1H and 13C NMR match with literature.[15b]
)
1
Table 2, Entry 3. Mp 103 ꢁC; H NMR (300 MHz, CDCl3): d 7.91–7.84 (m,
2H), 7.09–7.16 (m, 2H), 6.72 (m, 2H); 13C NMR (75 MHz, CDCl3): d 165.1,
162.8, 152.2, 147.3, 140.4, 135.1, 115.2, 112.4, 105.6; IR (KBr): 1622, 1520, 1359,
721 cmꢂ1. Anal. calcd. for C10H6N2O3: C, 59.40; H, 2.97; N, 13.86. Found: C,
59.36; H, 2.93; N, 13.82.
Table 2, Entry 4. Mp 37 ꢁC (lit.[15b] mp 38.1 ꢁC); 1H NMR (300 MHz,
CDCl3): d 8.04–7.95 (m, 2H), 7.54–7.50 (m, 3H), 2.62 (s, 3H); 13C NMR (75 MHz,
1
CDCl3): d 175, 165.0, 131.8, 129.6, 127.3, 126.7, 12.4 (Mp and H and 13C NMR
match with literature.[15b]
)
Table 2, Entry 5. Yellowish oil; 1H NMR (300 MHz, CDCl3): d 2.80 (q,
J ¼ 7.8, 2H), 2.60 (q, J ¼ 7.8, 2H), 1.28 (m, 6H); 13C NMR (75 MHz, CDCl3): d
165.2, 159.1, 26.4, 21.2, 12.3, 10.1; IR (liquid film): 2950, 1585, 1530, 1380, 1271,
798 cmꢂ1. Anal. calcd. for C6H10N2O: C, 57.14; H, 7.93; N, 22.22. Found: C,
57.11; H, 7.89; N, 22.18.
Table 2, Entry 9. Mp 27 ꢁC (lit.[15c] mp 26 ꢁC); 1H NMR (300 MHz, CDCl3): d
1
2.7–3.1 (m, 4H), 1.7–2.1 (m, 4H). (Mp and H NMR match with literature.[15c]
)
1
Table 2, Entry 10. Mp 123 ꢁC; H NMR (300 MHz, CDCl3): d 7.9–7.85 (m,
2H), 7.5–7.56 (m, 2H), 2.31 (b, OH); 13C NMR (75 MHz, CDCl3): d 162.2, 147.1,
145.1, 133.2, 130.1, 129.0, 128.8, 123.2; IR (KBr): 3203, 3140, 1628, 1590, 1496,

226
V. N. TELVEKAR AND B. S. TAKALE
1321, 1069 cmꢂ1; Anal. calcd. for C9H5N3O2: C, 57.75; H, 2.67; N, 22.45 Found: C,
57.70; H, 2.63; N, 22.40.
1
Table 2, Entry 12. Mp 189 ꢁC; H NMR (300 MHz, CDCl3): d 8.82 (m, 6H);
13C NMR (75 MHz, CDCl3): d 161.2, 133.1, 132.1, 130.3, 129.7, 127.5, 120.1; IR
(KBr): 1628, 1575, 1488, 1350, 780 cmꢂ1. Anal. calcd. for C14H6N4O5: C, 54.19;
H, 1.93; N, 18.06. Found: C, 54.18; H, 1.89; N, 18.01.
Representative Procedure for Abnormal Beckmann Rearrangement
of Monooxime
Diphosphorus tetraiodide (0.25 mol) in anhydrous CH2Cl2 was stirred in a
round-bottomed flask for 5 min to get a clear solution. Mono-oxime (1 mol) was then
added, and stirring was continued at room temperature for 2 h. The products were
isolated by workup as described.
ACKNOWLEDGMENT
V. N. T. is grateful to the Department of Science and Technology, India, for
financial support under SERC Fast Track Young Scientists Scheme.
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