A novel one-pot synthesis of α-keto-1,3,4-oxadiazole derivatives based on isocyanide-Nef reaction

Article abstract of DOI:10.1016/j.tetlet.2011.08.086

Various α-keto-1,3,4-oxadiazole derivatives were synthesized through a sequential intermolecular dehydrochlorination/intramolecular aza-Wittig reaction of carboxylic acids and imidoyl chloride intermediates, which were generated by isocyanide-Nef reaction

Full text of DOI:10.1016/j.tetlet.2011.08.086

Tetrahedron Letters 52 (2011) 5530–5533
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A novel one-pot synthesis of
isocyanide-Nef reaction
a-keto-1,3,4-oxadiazole derivatives based on
⇑
Liren Cui, Qiong Liu, Jingxun Yu, Chongzhi Ni, Hui Yu
Department of Chemistry, Tongji University, Shanghai 200092, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 May 2011
Revised 27 July 2011
Accepted 16 August 2011
Available online 22 August 2011
Various a-keto-1,3,4-oxadiazole derivatives were synthesized through a sequential intermolecular dehy-
drochlorination/intramolecular aza-Wittig reaction of carboxylic acids and imidoyl chloride intermedi-
ates, which were generated by isocyanide-Nef reaction of acyl chlorides and (N-isocyanimine)
triphenylphosphorane (1) in CH2Cl2 at room temperature.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
1,3,4,-Oxadiazole
Isocyanide-Nef reaction
Dehydrochlorination
Aza-Wittig condensation
Introduction
N
N
PPh3
O
R1COCl
+
CN-N=PPh3
1,3,4-Oxadiazoles are important classes of molecules and het-
erocyclic scaffolds in biologically active compounds. As surrogates
of peptide bonds in medicinal chemistry, 1,3,4-oxadiazoles have
attracted much attention due to their increased hydrolytic and
metabolic stability of the oxadiazole ring.1 Several methods have
been developed for the synthesis of 1,3,4-oxadiazole derivatives.2
Among these methods, the most commonly used route is the cyc-
lodehydration of diacylhydrazines, which always requires highly
toxic and corrosive reagents, such as sulfuric acid, phosphorous
oxychloride, and thionyl chloride.3 Therefore, more facile routes
to 1,3,4-oxadiazoles under milder conditions are still needed.
In recent years, (N-isocyanimine) triphenylphosphorane (1) has
been found to be a versatile reagent for the construction of nitro-
gen-containing heterocyclic scaffolds.4 Ali et al have reported some
new reactions to prepare substituted 1,3,4-oxadiazoles using 1 as
the starting material via intramolecular aza-Wittig condensation.5
To the best of our knowledge, there is no report about the effective
R1
Cl
1
2
N
N
N
O
N
PPh3
O
R2COOH
-HCl
- Ph3PO
R1
R2
O
4
R1
O
O
3
R
Scheme 1. Proposed one-pot synthesis of a-keto-1,3,4-oxadiazoles.
1 has also been proved to react with acyl chloride smoothly to give
imidoyl chloride 2, which was converted into diazoketones by
treating with 4-toluene sulfonyl chloride, and Et3N.8 We envisaged
that this intermediate 2 could also be trapped by a carboxylic acid,
and then 1,3,4-oxadiazole 4 would be obtained through an inter-
molecular dehydrochlorination/intramolecular aza-Wittig conden-
sation sequence (Scheme 1).
With this idea in mind, we initially investigated the preparation
of 4a from benzoyl chloride, 1, and benzoic acid. Thus, a mixture of
benzoyl chloride and 1 was stirred in CH2Cl2 at room temperature
for 2 h until the complete consumption of benzoyl chloride as
monitored by TLC. To the resulted solution benzoic acid was added,
and 4a was isolated in 10% yield after 12 h. The presence of base
could promote the reaction and Et3N provided the highest yield
(Table 1, entry 6). The reaction was carried out in various solvents,
and CH2Cl2 remained as the best one. Some solvents, such as
toluene, TMBE, and EtOAc were not suitable for the reaction due
to their low solubilities to 1. In most cases, even the reaction was
run in dry CH2Cl2 in the presence of 4A molecular sieves, a byprod-
synthesis of a
-keto-1,3,4-oxadiazole derivatives.6
Results and discussion
Acyl chloride–isocyanide condensation (isocyanide-Nef reac-
tion) is an efficient way for the formation of active a-keto imidoyl
chloride, which can be trapped by different nucleophiles to form
various cyclic adducts.7 Besides aliphatic and aromatic isocyanides,
⇑
Corresponding author.
E-mail address: yuhui@mail.tongji.edu.cn (H. Yu).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.086

L. Cui et al. / Tetrahedron Letters 52 (2011) 5530–5533
5531
Table 1
Effect of solvents and bases in the synthesis of
a-keto-1,3,4-oxadiazoles
N
N
N
N
PPh3
CN-N=PPh3(1)
O
PhCOOH, Et3N
CH2Cl2, rt, 12 h
Ph
PhCOCl
Ph
O
4a
CH2Cl2, rt, 2 h
Ph
Cl
2a
O
Entry
Base
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
9
10
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
Toluene
TMBE
–
10
12
18
20
K2CO3
DBU
DIPEA
Pyridine
Et3N
Et3N
Et3N
Et3N
Et3N
34
37 (54)b
33
17
10
10
EtOAc
a
Isolated yield.
b
Yield in bracket corresponds to 2 equiv PhCOOH and 2 equiv Et3N.
Table 2
One-pot synthesis of
a
-keto-1,3,4-oxadiazoles
R2COOH, Et3N
CH2Cl2, rt, 8 h
N N
N N
Cl
CN-N=PPh3
O
R1
R1COCl
PPh3
R2
R1
O
4
CH2Cl2, rt, 2 h
O
2
Entry
1
R1
R2
Compound
Yielda (%)
54
N
N
N
N
N
N
N
N
N
C6H5
C6H5
O
O
O
O
4a
NO2
N
2
3
C6H5
2-NO2C6H4
4-MeC6H4
56
50
O
4b
N
C6H5
O
4c
Br
N
4
5
6
7
8
C6H5
C6H5
C6H5
C6H5
C6H5
2-BrC6H4
2-Furyl
Vinyl
47
60
51
69
51
O
4d
O
O
O
O
O
N
O
O
4e
N
O
4f
N
Isopropenyl
CH3
O
4g
N
O
4h
Cl
N
N
9
4-ClC6H4
C6H5
54
O
4i
O
(continued on next page)

5532
L. Cui et al. / Tetrahedron Letters 52 (2011) 5530–5533
Table 2 (continued)
Entry
R1
R2
Compound
Yielda (%)
40
N
N
N
10
4-MeC6H4
C6H5
O
4j
O
N
11
12
C6H5CH2
C6H5
36
38
Ph
O
O
4k
N
N
O
i-BuO
4-MeC6H4
O
4l
O
a
Isolated yield.
N
N
X = S
Ph
Ph
5 40%
S
N
N
PPh3
O
O
PhCOXH, Et3N
CH2Cl2, rt, 8 h
CN-N=PPh3 (1)
PhCOCl
N
N
CH2Cl2, rt, 2 h
Ph
Cl
2a
X = NH
Ph
Ph
6 40%
N
H
O
Scheme 2. One-pot synthesis of 1,3,4-thiadiazole and 1,2,4-triazole.
uct was isolated and finally characterized as N-unsubstituted
-keto hydrazidoyl chlorides, which suggested the slow hydrolysis
Acknowledgment
a
of intermediate 2a during long reaction period. To suppress the
hydrolysis of 2a, 2 equiv benzoic acid and 2 equiv Et3N were
employed, and then the yield was improved to 54% after 8 h
(Table 1, entry 6).
This work was supported by National Science Foundation of
China (No. 20802053).
Supplementary data
Under the optimized condition,9 the substrate scope of this
domino process was examined by employing a range of acyl chlo-
rides and carboxylic acids, as shown in Table 2. Electron-
withdrawing or electron-donating groups on the phenyl ring of
benzoic acid did not affect the reaction significantly (Table 2, en-
tries 2–4), and other heterocycle such as 2-Furyl acid gave the yield
similar to benzoic acid (Table 2, entry 5). To our delight, the reac-
tion could be expanded to vinyl and aliphatic acids, and in the case
of methylacrylic acid the yield reached 69% (Table 2, entries 6–8).
As expected, substituted benzoyl chlorides were also reactive sub-
strates for the reaction (Table 2, entries 9–10). For phenylacetyl
chloride and isobutyl chlorocarbonate, the products were isolated
with a little lower yield (Table 2, entries 11–12). Unfortunately,
acetyl chloride and acryloyl chloride did not give the desired prod-
ucts. Although imidoyl chloride intermediates could be formed
favorably, the reactions only led to complex mixtures after stirring
with benzoic acid. As to 4-toluene sulfonyl chloride, no products
were found and all the starting materials remained.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.08.086.
References and notes
1. (a) Bhatia, S.; Gupta, M. J. Chem. Pharm. Res. 2011, 3, 137; (b) Holla, B. S.;
Gonsalves, R.; Shenoy, S. Eur. J. Med. Chem. 2000, 35, 267; (c) Somani, R. R.;
Shirodkar, P. Y. Der Pharm. Chem. 2009, 1, 130; (d) Hassan Khan, M. T.;
Choudhary, M. I.; Mohammed Khan, K.; Rani, M.; Rahman, A. Bioorg. Med. Chem.
2005, 13, 3385; (e) Cui, Z.; Yang, L.; Li, X.; Wang, Z.; Yang, X. Chin. J. Org. Chem.
2006, 26, 1647. in chinese; (f) Borg, S.; Estenne-Bouhtou, G.; Luthman, K.;
Csoregh, I.; Hesselink, W.; Hacksell, U. J. Org. Chem. 1995, 60, 3112.
2. For review of synthesis of 1,3,4-oxadiazoles, see: Jakopin, Z.; Dolenc, M. S. Curr.
Org. Chem. 2008, 12, 850.
3. (a) Katritzky, A. R.; Mohapatra, P. P.; Huang, L. ARKIVOC 2008, 62; (b) Bentiss, F.;
Lagrenée, M. J. Heterocycl. Chem. 1999, 36, 1029.
4. (a) Souldozi, A.; Ramazani, A.; Bouslimani, N.; Richard Welterb, R. Tetrahedron
Lett. 2007, 48, 2617; (b) Adib, M.; Ansari, S.; Fatemi, S.; Bijanzadeh, H. R.; Zhu, L.
Tetrahedron 2010, 66, 2723; (c) Stolzenberg, H.; Weinberger, B.; Fehlhammer,
W. P.; Puhlhofer, F. G.; Weiss, R. Eur. J. Inorg. Chem. 2005, 4263; (d) Adib, M.;
Ansari, S.; Feizi, S.; Bijanzadeh, H. R. Synlett 2010, 921.
5. (a) Ramazani, A.; Rezaei, A. Org. Lett. 2010, 12, 2852; (b) Souldozi, A.; Ramazani,
A. Tetrahedron Lett. 2007, 48, 1549; (c) Ramazani, A.; Souldozi, A. ARKIVOC 2008,
235; (d) Ramazani, A.; Ahmadi, Y.; Rouhani, M.; Shajari, N.; Souldozi, A.
Heteroat. Chem. 2010, 21, 368; (e) Adib, M.; Kesheh, M. R.; Ansari, S.;
Bijanzadeh, H. R. Synlett 2009, 1575.
By such a strategy, we were pleased to find that
a-keto-1,3,4-
thiadiazole10 and -keto-1,2,4-triazole11 could also be obtained
a
when thiobenzoic acid and benzoic amide were subjected to this
procedure instead of benzoic acid, respectively (Scheme 2).
6. Mostafa, M. A.; Sallam, M. A.; Abd El-Wahed, E. S. Egyptian J. Chem. 2003, 45,
1133.
Conclusion
7. (a) Ugi, I.; Fetzer, U. Chem. Ber. 1961, 94, 1116; (b) Lee, C. H.; Westling, M.;
Livinghouse, T.; Williams, A. C. J. Am. Chem. Soc. 1992, 114, 4089; (c) dos Santos,
A.; El Kaim, L.; Grimaud, L.; Ronsseray, C. Chem. Commun. 2009, 3907; (d)
Coffinier, D.; El Kaim, L.; Grimaud, L. Org. Lett. 2009, 11, 3799; (e) El Kaim, L.;
Grimaud, L.; Patil, P. Org. Lett. 2011, 13, 1261.
In summary, we have developed a concise method for the
synthesis of
animine) triphenylphosphorane, and carboxylic acid. Various
-keto-1,3,4-oxadiazoles have been synthesized and the method
could also be applied to the synthesis of -keto-1,3,4-thiadiazoles
and -keto-1,2,4-triazoles.
a-keto-1,3,4-oxadiazole using acyl chloride, (N-isocy-
8. (a) Aller, E.; Molina, P.; Lorenzo, A. Synlett 2000, 526; (b) Bio, M. M.; Javadi, G.;
Song, Z. J. Synthesis 2005, 19.
a
9. Typical experimental procedure for synthesis of
a-keto-1,3,4-oxadiazoles: A mixture
a
of acetyl chloride (1 mmol) and (N-isocyanimine) triphenylphosphorane
a

L. Cui et al. / Tetrahedron Letters 52 (2011) 5530–5533
5533
(1 mmol) was stirred in 5 mL dry CH2Cl2 at room temperature for 2 h, then
carboxylic acid (2 mmol) was added before a solution of Et3N (2 mmol) in 2 mL
CH2Cl2 was added dropwise. The solution was stirred for an additional 8 h, and
then washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated on
rotary evaporator. The residue was purified by flash column chromatography
(petroleum ether/ethyl acetate, 8:1 v/v) to give the product. Compound 4a:
orange solid, mp 134–136 °C, 1H NMR (400 MHz, CDCl3): d 8.58 (d, J = 7.2 Hz, 2H),
8.23 (d, J = 7.2 Hz, 2H), 7.72 (t, J = 7.2 Hz, 1H), 7.63–7.55 (m, 5H); 13C NMR
(100 MHz, CDCl3): d 177.6 165.9, 160.9, 134.8, 132.8, 130.9, 129.2, 128.8, 128.3,
2H), 8.18–8.16 (m, 1H), 8.01–7.99 (m, 1H), 7.87–7.83 (m, 2H), 7.74 (t, J = 7.2 Hz,
1H), 7.59 (t, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 177.3, 162.9, 161.4,
148.3, 135.1, 134.0, 133.4, 133.2, 132.1, 131.0, 128.9, 125.0, 118.2; IR(KBr): 2357,
1652, 1382, 1280, 1065, 911, 843 cmÀ1. HRMS-ESI calcd for C15H9N3O4 [M+H]+:
296.0671, found 296.0666. Compound 4c: orange solid, mp 139–141 °C, 1H
NMR(400 MHz, CDCl3) d 8.58 (d, J = 8.0 Hz, 2H), 8.11(d, J = 8.0 Hz, 2H), 7.64–7.57
(m, 5H), 2.46 (s, 3H); 13C NMR (100 MHz, CDCl3): d 177.6, 166.2, 160.8, 134.8,
132.8, 130.9, 129.9, 128.7, 127.8, 122.8, 120.0, 21.7; IR(KBr) m 2366, 1662, 1385,
1172, 1105, 914, 723 cmÀ1. HRMS-ESI calcd for C16H12N2O2 [M+Na]+: 287.0796,
found 287.0798.
127.8, 122.8; IR(KBr) m .
: 2360, 1649, 1505, 1385, 1274, 1098, 917, 778 cmÀ1
HRMS-ESI calcd for C15H10N2O2 [M+Na]+: 273.0640, found 273.0640. Compound
10. Tomchin, A. B. Zh. Org. Khim 1987, 23, 1305.
11. Moderhack, D.; Beissner, A. J. Prakt. Chem. /Chem-Ztg. 1997, 339, 582.
4b: yellow solid, mp 121–123 °C, 1H NMR (400 MHz, CDCl3) d 8.56 (d, J = 7.2 Hz,