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Synthesis of 3,5-diaryl-1,2,4-oxadiazoles from trichloromethylarenes and areneamidoximes
Tetrahedron Vol 46, No 5, pp 1659.1668. 1990
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SYNTHESIS OF 3,5-DIARYLl,2,4-OXADIAZOLES FROM TRICHLOROMETHYLARENES AND ARENEAMIDOXIMES L.I.Belen'kll*, D.B.Brokhovetskii, M.M.Krayushkin N.D.Zellnsky Institute of Organic Chemistry, USSR Academy of Sciences,ll7913, Moscow, USSR (Recewed m UK 2 August 1989)
Abstract. The Interaction of trlchloromethylarnesArCC13 f 1, Ar = Ph (a>, 2,4-Me2C6H3 (b), 2,4,6-Me3C6H2 (cl, 2,4,5Me3C6H2 (d)] with areneamldoximes Ar'C(NH2)=NOH [2, Ar' = Ph (a), 4-N02C6H4 (b), 4-MeOC6H4 (c) ] was studied. The reaction in the absence of a solvent at 140-150 OC leads to the formation of 3,5-diaryl-1,2,4-oxadlazoles(2). The reactlon carried out in solvents (benzene, toluene, nitrobenzene, pyrldlne) In the broad temperature range (O-150 OC) showed the first stage of the process to be obviously an electrophilit attack of (l_>on O-atom of (z),products of which undergo cyclization converting into oxadiazoles (2), or side processes, 1.e. rearrangement into N-substituted derivatives, or fragmentation with the formation of nitriLe Ar'CN (4) which corresponds to starting amidoxime along with acid ArCOOH (2) corresponding to trlchloromethylarene (11, being formed during the treatment of the reactlon mixture. Introduction Recently various substituted benzotrichlorldes have become quite accessible1-4. This accounts for their extended use in organic synthesis. For instance, the formation of a number of heterocycllc systems under the action of trichloromethylarenes on aminoalcohols, hydrazlnes and semicarbazide derivatives was shown5-10 . As early as 1884, Tlemann and Kruger reported the formation of 3,5diphenyl-1,2,4-oxadlazolefrom benzotrlchlorlde and benzamidoxlme11, but they did not present either reactlon condltlons, or data on the yield. As far as we know, for more than 100 years the reaction under discussion has not been reproduced. Besides, the choice of obJects was not optimal due to the easy conversion of benzamldoxlme into dlphenyl-1,2,4-oxadlazole, for example, under the action of heating and aclds12.
1659
1660
L I BELENWIer al
Results and Dlscusslon The aim of this paper was to study the perspectives of the synthesis of 1,2,4-oxadiazoles from aryltrichloromethanes and areneamidoximes. It is essential to note that not only benzotrichloride and benzamidoxlme but also their derivatlves bearing electron-releasing and electron-withdrawlng substltuents were used. Trlchloromethylarenes ArCC13 [I, Ar = Ph (a), 2,4-Me2C6H3 (b), 2,4,6-Me3C6H2 (c), 2,4,5-Me3C6H2 (d) ] were introduced into the reaction with areneamidoximes ArtC(NH2)=NOH [Z!,Ar' = Ph (a), 4-N02C6H4 (b), 4-MeOC6H4 (c) 1. In the course of the reaction of la-d with zb,c in the absence of a solvent at 140-150 OC 3,5-diaryl-1,2,4-oxadiazoles (2) were obtained In 40-60% ylelds. The end of the hydrogen chloride release served as a criterion for the reaction completion. The products were separated by means of column chromatography. For benzamidoxime 2a the above conditions are too drastic and mainly lead to the product of thermal destructlon of la, 1.e. benzonltiile &.a. The proposed general method for diaryloxazole (2) synthesis can be considered as an analogue of preparative synthesis of 1,2,4-oxadiazoles from amldoxlmes and various derivatives of carboxylic acids13. It 1s known that in the process of the reaction between carboxylic acid chlorides and amidoxlmes the 0-acylation of amidoxlme is the first stage accompanled by cyclization14, however the cases of obtaining N-mono- as well as N,O-diacyl-substituted amidoxlmes were also described13,14. Unfortunately, when reactions of trlchloromethylareneswith amidoximes were carried out in the absence of a solvent we did not manage to obtain any intermediate products. To establish the course of the reaction, as well as to carry out syntheses of 3-phenyl-5-aryl-1,?,4-oxadiazoles(from a) various solvents (benzene, toluene, pyrldine, nltrobenzene) were used. While boiling in benzene trichloromethylarenesLb-d with 4-fold excess of a for HCl neutralization corresponding oxadiazoles (3b-d) in 50-70$ yields and benzonitrile (15-20%) were obtarned. Under these conditions benzotrichlorlde (la) gives 3,5-dlphenyl-1,2,4-oxadiazole(la) In the yield as low as 5%. The temperature growth when the reaction was carried out in boiling toluene allows the increase of the yield for la up to 50%. It should be noted that neither 2a nor Its hydrochloride while boiling in toluene gives even traces of 3a and this proves the trichloride Ia partlclpation In the formatron of Ia under these condltlons. The Interaction of trichloromethylareneJ,cwith 4-methoxybenzamidoxime (2~) In bolllng benzene leads after hydrolysis of the reactlon mixture to N-acylamidoxlme (10) which failed to undergo cycllzation into corres-
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3,5-Dmryl-1,2,4-oxa&azoles
ponding 1,2,4-oxadiazole. 4-Nltrobenzamldoxime (gb) is insoluble in nonpolar solvents, so to carry out the reactlon under the same condltlons we had to use pyrldlne which played simultaneously a role of an acceptor for HCl, thus taking advantage of equlmolar ratios of components. It was found that while bolllng in pyridine amidoxlmes a-c reacted in the same manner, nitriles Ar'CN (4) and acids ArCOOH (2) being the main products of the reaction. In the case of bensamidoxime (ga) along with the above products of fragmentation oxadiazoles (la-d) were also formed m the yields no more than 2m. In addition, oxadiazoles lb-d contained some diphenyl-substituted derivative (la) formed as the result of amldoxime 1" *ldimerizationll. Analogous results were obtained for the Interaction of l_b,cwith 2b in nitrobenzene (100-120 V, 3 h with subsequent treatment with water). The propertles of the obtained compounds are llsted In Table 1. As a whole, the transformations under consideration can be described by Scheme 1. ArCC13 + Ar'$NH2 e NOH
+ Ar'CN
rArCC120N=~Ar1stArCC120NH~Ar' NH2
c
ArCOON=CAr' NH2
H20 ArCOOH r
and 2 a) Ar = Ph; b) Ar = 2,4-Me2C6H3; c) Ar = 2,4,6-Me3C6H2; d) Ar = 2,4,5-Me3C6H2. and 3 a) Ar' = Ph; b) Ar' = 4-N02C6H4; c) Ar' = 4-MeOC6H4. a) Ar = Ar' = Ph; b) Ar = 2,4-Me2C6H3, Ar' = Ph; c) Ar = 2,4,6-Me3C6H2, Ar' = Ph; d) Ar = 2,4,5-Me3C6H2, Ar' = Ph; e) Ar = Ph, Ar' = 4-N02C6H4; f) Ar = 2,4-Me2C6H3, Ar' = 4-N02C6H4: g) Ar = 2,4,6-Me3C6H2, Ar' = 4-N02C6H4; h) Ar = 2,4,5-Me3C6H2, Ar' = 4-N02C6H4; 1) Ar = Ph, Ar' = 4-MeOC6H4; J) Ar = 2,4,5-Me3C6H2, Art = 4-MeOC6H4. a) Ar = 2,4,6-Me3C6H2, Ar' = Ph; b) Ar = 2,4,6-Me3C6H2, Ar' = 4-MeCC6H4. Scheme 1 We did not succeed In lsolatlon of lntermedlate dlchlorldes (6). The lsolatlon of the product resulting from hydrolysis of of one of such dichlorides, 1.e. O-mesltoylbenzamldoxIme (8a) in 30$ yield along with
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L I BELENKJI~~U~
oxadiazole lc (40$) when the reaction time was unsufflcient (1.5 h) can be regarded as the confirmation of the existence of similar compounds in the reaction mixture. When the reaction was carried out during 3 h the yield of zc rised to 68%. Our unsuccessful attempts to carry out the cyclization of ga as well as of specially prepared 0-benzoylbenzamidoxime and 0-benzoyl-4-methoxybenzamidoxlmewhen boiling their benzene solutions indlrectly prove the fact that compounds of the type 8 are not intermedlate heterocycllzation products. We consider rather dichlorides 5 or their tautomers 1 to be the intermedlates. It is natural that the structures of non-identified products (6, '7,2) are suggestive, the real intermediates could be formed also as a result of nucleophilic substitution of not one but two or three chlorine atoms of starting trichloromethylarene1. The formation of N-acylated amidoxime (10) while boiling j_cwith gc in benzene can be accounted for transalkylatlon of the Initially formed O-substituted derivative of the types 6 or 1. Hydrolysis products of the latter, i.e. 0-mesitoyl-4-methoxybenzamidoxlme(gb) was ldentlfied when the reaction of Ic with 2c was carried out In pyridine at 0 OC. The presence of an electron-releasing substituent in gb should promote the transalkylatlon (Scheme 2).
15
=
I-
ArCC12NHzAr' NOH 1
ArCONHCAr' &OH -10
Ar = 2,4,6-Me3C6H2, Ar' = 4-MeOC6H4 Scheme 2 The presence of nltrlles (4) In the products of the reactlon proved unexpected, though It is known that during thermal decomposltlon of the amidoxime 2a nitrile Aa and benzamlde were the main products'5. A possibillty of the formation of nltrlles from amldoximes za-c or from oxadiazole lh while bolllng in pyridlne in the presence of pyrldlne hydrochloride was not conflrmed. This allows the conclusion that nitrlles (4) and acids (2) can be formed from dichlorides of the type 1 which are tautomers of 6. The presence of a base in the reaction medium should promote an equilibrium shift to the tautomerlc form 2 and, naturally, facilitate the formation of fragmentation products 4 and 2. The increase In the yield of &a from 15-20% m benzene up to 50-65% in pyridine proves the above. The fragmentation can proceed via intermediate formatlon of an Osubstituted hydroxylamine (2). It should be noted that the fragmentatl-
3,5-Dmryl-1,2,4-oxad1azoles
1663
on was not observed when the interaction of areneamidoxlmes with acyl 16 chlorides instead of trlchloromethylarenes was carried out In pyridine . As it was mentioned above, an N-acyl derivative of amidoxime 2c (10) was not obtained In pyrldine but the reaction gave the nitrlle (&c> with an admlxture of 0-acylated 4-methoxybenzamldoxime (eb). We failed to obtaln neither N-, nor 0-substituted derivatives of amidoxlme 2b in its reactions with la-d. However the isoIatlon of 4-nitrobenzonitrlle (3b) and corresponding carboxylic acids (zb,c) when the reaction was carried out not only in pyrldine, but also in nltrobenzene allows the electrophilic attack to be dlrected on the oxygen atom of the amldoxlme group. Both structures and compositions of the obtalned compounds were confirmed by PMR, IR, mass spectra as well as by elmental analysis. Mass spectra of oxadlazoles 2 contalned peaks corresponding to the fragmentation according to the scheme of 1,3-dlpolar cycloreverslon, the latter, as known for 1,2,4-oxadlazoles, lesdlng to ArCN and Ar*CN017. IR spectra of 2 contain a set of bands characterlstlc of aryl-substituted l,2,4-oxadiazoles (1608-1612, 1555-1576, 1448-1552, 1350-1370 cm")18. PMR data are given m Table 2. Experimental PMR spectra were recorded on JEOL FX-90Q (90 MHz) and Bruker NM-250 (250 MHz) spectrometers In CDC13. IR spectra (tablets In XBr) were obtalned on Perkln-Elmer 577 and Specord M-80 znstruments. Mass spectra were recorded on Varian MAT CH-6 spectrometer at lonlzation energy of 70 eV with the direct lntroductlon of a sample into the lonlc source. Melting points were determlned on a Boetlus heated plate. Starting trlchIoromethyIareneswere prepared according to the procedures described Inl,4, the syntheses of areneamldoximes were performed as described 1n12. Synthesis of 3~5=Dharyl-1,2,4-oxadlazoles(Ja-3) -----_Method A. Areneamidoxlme (zb,c) (0.2 mO1) was added by portions to ---0.1 mol of trlchloromethylarene (la-d) heated up to 120 OC. Then the mixture was heated up to 140-145 OC and maintalned at this temperature until the end of HCl evolution (time 1s given In Table 1). The reaction being completed, the products were extracted with chloroform, the extract was evaporated and the residue separated by means of column chromatography on slllca, eluent - benzene. Method --- B. Benzamldoxlme (2a) (0.4 mol) was dissolved while heating m benzene (50 ml). Then 0.1 mol of trichloromethylarene (la-d) was added. The reactlon mixture was bolled during the time given m Table 1. The reactlon control was carried out by TLC on Sllufol, eIuent _ chIoroform.
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L I BELEN'KII~~U~
On the reactlon completion hydrochloride of 2a was filtered off, the benzene solution was washed with water, then evaporated. The products were separated as described in Method A. &nierac$&on of_T'ri~h~orome4~r~n~s_w~t~ &zneamidoximes in Qridine __-_-V-V --Amidoxlme @a-c) (0.1 mol) was dissolved in pyridine (15 ml), 0.1 mol of trichloromethylarene (la-d)was then added. The reaction mixture was refluxed for 3 h. Then pyrldine was distilled off and the residue was separated using column chromatography on silica (hexane - ethyl acetate, 3:1 as eluent). The following products were successively eluted: nltrioxadiazoles (Ja-d) and, finally, a resinous coloured product, les (Aa-c), hydrolysis of which (cont. H2S04) leads to carboxylic acids (za-d). The yields of the products are listed in Table 3. anthesis of Acylamidoximes ---------_--a) In the interaction of j_cwith 2a under the conditions similar to those described in Method B, but during 1.5 h, after alkaline hydrolysss (aqueous NaOH) along with 40% of oxadiazole lc, 0-mesitoylbenzamidoxime (sa) was obtained In 30% yield, m.p. 133-140 OC, M' 282. Found, %: C 72.23; H 6.31; N 9.75. C,6H18N202. Calcd., %: C 72.34; H 6.38; N 9.93. IR spectrum, cm": 3n80, 3330 (NH2), 1735 (CO). b) Under similar conditions 25% of N-mesltoyl-4-methoxybeneamldoxlme (u), m.p. 198-199 OC, M+ 312 was obtalned from J_cand zc after the reaction completion (1 h) followed by the treatment with water and column chromatography (silica, eluent - benzene). Found, %: C 69.14; H 6.40; N zi06. C18H20N203. Calcd., %: C 69.23; H 6.41; N 8.97. IR spectrum, cm : 3208, 3120, 1696. c) 4-MethoxybenzamidoxIme (0.1 mol) was dissolved in pyridlne (10 ml), cooled to 0 OC. Then 0.1 mol of trlchloromethylarenej_cwas added. The reaction mixture was stirred for 3 h at 0 'V, pyridine was then distilled off In vacuum. Along with nitrile &c (60%) 0-mesltoyl-4-methoxybenzamldoxlme (gb) was separated by means of column chromatography of residue on silica (hexane - ethyl acetate, 3:1), yield IO%, m.p. 172-180 OC, M+ 312. Found, Z: C 69.30; H 6.40; N 8.90. C,8H20N203. Calcd., %: C 69.23; H 6.41; N 8.97. IR spectrum, cm-': 3500, 3350 (NH~), 1735 (co). d) 0-Benzoylbenzamidoxime (m-p. 151-155 OC) and 0-benzoyl-4-methoxybenzamldoxime (m.p. 140-148 OC) were obtained from benzoyl chloride and corresponding amldoxlmes according to the procedure given In '9. IR spectra contain characterlstlc bands: ca. 3505, 3375 (NH2) and 1730 (CO) cm-1 .
';&g 183-184 (EtOH) 170-172 (EtOH) 97-98*** (EtOH) 116-118 (EtOH)
e "?M50~Y 194** (EtOH)
106-107* (EtOH) 83-84 (MeOH) 56-57 (MeOH)
55
1
A
40 45
1
2
2
A
A
A 294
252
309
309
295
267
6.01
4.82
66.21
73.20
4.74
4.30
5.98
6.04
5.80
H
66.36
63.51
77.42
77.25
77.03
C
Found, %
77.27
98 0~.
9.32 C,8H,8N202 73.47
C15H12N202
13.45 C,7H,5N303 66.39
13.40 C17H,5N303 66.39
13.91 C16H13N303 63.79
C14H9N303
10.59 C,7H,6N20
77.27
10.49 C,7H,6N20
C
76.80
C14H10N20
Formula
11.08 C,6H,4N20
N
**Ref. 21: m.p. 195 OC. ***Ref. 22: m.p.
55
1
A
60
50
1
A
264
50
6
B
264
68
3
B
222 250
18
B
50 50
16
B
*Ref. 20: m.p. 108 “C.
23
21
2h
2g
2f
2e
2d
2C
2b
2a
M.p., "C Method Reac- Yield, M+ (solvent of pre- tion % pound for reoaratl- time. crystal- bn(see hS llzatlon) experimental)
Corn-
3,5-Dlaryl-1,2,4-oxadlazoles(2)
10.60
6.06
9.52
13.50
4.88
6.12
13.50
4.88
13.95
10.60 6.06
4.32
11.20
N
5.60
H
Calcd., %
Table 1
e-m
--we
7.19s broad. 6.98s
H3
H5
H6
-
-
8.02d 7.19s broad. 6.98s -
8.21m (5H) - - - -
H4
, wm
-
-
-
-
7.03s
7.15s
. X: 6.90s
6.90s
7.05a
8.18d
6.90s
6.90s -
7.88s broad. 7.69d
6.93d
7*76dd - - - -
-
7.03d
8.14d
7.05d
7.03d
8.39s
8.38s
8.39s
8.40s
-
6.93a
7.42m (3H) - -
-
-
8.39s
-
-
8.38s
7.03s
-
-
7.79d
7.76dd
8.18d
8.14d
8.24dd
8.24dd - - - - 7.58m (3H) - - 8.40s
8.24dd
_ _ _
H6’
8.24dd - - - - 7.58m (3H) - - -
8.39s
-
H5’
7.55m (5H) - - -
H4’
8.24dd
H3’
, wm
8.24dd - - - - 7.58m (3H) - - -
_______
H2’
Group Ar',
8.07d 7.18s broad.
ES . broad. 8.23dd - - - 7.56m (3H) - - - 8.23dd
-
7.18s broad.
7.88s 7.11s broad. broad. 8.25dd - - - 7.72m (3H) - - - 8.25dd
H2
Group Ar,
wm
(6H), (3I-I)
2.35s 2.64s
2.32s 2.63s 2.31s 2.38s 2.31s 2.39s
2.35s 2.71s
2.34s 2.38s
(6~)
(6H), (3H) (3H), (6H) (3H),
(6H), (3H)
(6H), (3H)
2.43~3, 2.73s
(3H)
2.36s
2.27s (6H),
2.40s, 2.68s
Me,
6.85d 6.85d 7.38d 6.91s 6.91s 7.38a 2.39s (9H) ?o = 8 Hz (In lb,f), J23 = J2,3, = J56 = J5,6, = 7.5 Hz; J26 = J2,6, = 1.5 Hz. * Coupling constants: J 56 Chemical shifts (IvIein 21,~): 3.89 and 3.90 (5). ** Chemical shifts of MeO: 3.84s; of NH2 (in &,b): 5.13, 5.06 resp. (s, broad.); of NH in 10: 9.30s (broad.); of OH in lo: 10.55s (broad.).
ComPOuna
Table 2 PMR Spectra of 3,5-Diaryl-1,2,4-oxadlazoles(2)* and Acylamidoximes (ga,b, E)**
r Y
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3,5Dmyl- 1,2,4-oxahazoles
Table
3
Yields of Products Formed from Trlchloromethylarenes and Areneamldoxlmes in Pyridine Solution Yields
Starting compounds Trlchloromethyl- Areneamldoxlme (2) arene (1) La
2a
Ib
2a
1C
a
Id
a
lb 1c lb
2b 2b 2c
Ic
2c
of reactlon products, %
Oxadiazoles (2)
za, zb, 15 Jc, 20 2d, 15
20 +
Ja,
IO
+ +
za, 10 la, 15
NItrile (4) Acid (2) $a, 65
za,
32
ia,
50
zb,
24
&a,
50
zc,
27
&a, &b, &b, &C* &c,
60 45 45 -100 '100
d, zb, zc, zb, zc,
30 30 35 70 57
References
5 6 7 8 9 10 11
12 13 14 15 16
Hart H.; Fish R.W. J. Am. Chem. SOC. 1961, 2, 4460-4466. US Pat.4,575,565 (1986); Chem. Abstr. 1986, 105, 6305. US Pat. 4,419,514 (1983); Chem. Abstr. 1984, 100, 85412. Belen'kil L.I.; Brokhovetsky D.B.; Krayushkin M.M. Chem. Scrlpta 1989, 3, 81-84. US Pat. 3,402,178 (1968); Chem. Abstr. 1968, 69, 96750. Suzuki T. ; Mltsuhashl K. Selkel Dalgaku Kuaakubu Kogaku Hokoku 1976, 22, 1579-1580; Chem. Abstr. 1977, S6, 139916. Ger. Offen. 2,619,547 (1977); Chem. Abstr. 1978, 88, 62380. Golfier M.; Millcent R. Synthesis 1979, 946-948. Hasaneen H.M.; Shetta A.H.: Elwan N.M.; Shawall A.S. Heterocycles 1982, 19, 1477-1482. Barber0 M.; Cadamuro S. Synthesis 1986, 1074-1076. Tiemann F.; Kruger P. &. 1884, 17, 1685-1698. Eloy F.; Lenaers R. Chem. Rev. 1962, 62, 155-183. Clapp L.B. Adv. Heterocycl. Chem. 1976, 20, 65-116. Poplavskaya I.A.; Kurmangalleva R.G. Khlmiya Amldokslmov (Amldoxlme Chemistry), Nauka, Alma-Ata, 1988, 142 p. Leendrl G.; Rebora P. Ann. Chim. (Roma) 1956, 46, 953-959; Chem. Abstr. 1957, 5?_,6607f. Chlcu Sh.; Shine H.J. J. HeterocycI. Chem. 1989, 26, 125-128.
1668
I7 18
L I BELENXII~~U~
Selva
A.; ZerUli L.F.; Cavalleri B.; Fall0 F. Org. Mass Spectr.
1974,
2,
558-566.
Physical Methods In Heterocyclic Chemstry, Ed. A.R.Katrltzky, Vol. 2, Academic Press, New York - London, 1963, p. 232. 19 Clarke K. J. Chem. Sot. 1954, 4251-4253. 2o Bell& ., H. 27, S. 587. 21 Bergmann E.D.; Bendas H.: D'Avllla V. J. Org. Chem. 1953, l8, 64-69. Leandrl G.; Palottl M. Ann. Chum. (Roma) 1957, 47, 376-384. 22
cao4020/90
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0 1990 Pergamon Pms plc
III Great Bra.un
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SYNTHESIS OF 3,5-DIARYLl,2,4-OXADIAZOLES FROM TRICHLOROMETHYLARENES AND ARENEAMIDOXIMES L.I.Belen'kll*, D.B.Brokhovetskii, M.M.Krayushkin N.D.Zellnsky Institute of Organic Chemistry, USSR Academy of Sciences,ll7913, Moscow, USSR (Recewed m UK 2 August 1989)
Abstract. The Interaction of trlchloromethylarnesArCC13 f 1, Ar = Ph (a>, 2,4-Me2C6H3 (b), 2,4,6-Me3C6H2 (cl, 2,4,5Me3C6H2 (d)] with areneamldoximes Ar'C(NH2)=NOH [2, Ar' = Ph (a), 4-N02C6H4 (b), 4-MeOC6H4 (c) ] was studied. The reaction in the absence of a solvent at 140-150 OC leads to the formation of 3,5-diaryl-1,2,4-oxadlazoles(2). The reactlon carried out in solvents (benzene, toluene, nitrobenzene, pyrldlne) In the broad temperature range (O-150 OC) showed the first stage of the process to be obviously an electrophilit attack of (l_>on O-atom of (z),products of which undergo cyclization converting into oxadiazoles (2), or side processes, 1.e. rearrangement into N-substituted derivatives, or fragmentation with the formation of nitriLe Ar'CN (4) which corresponds to starting amidoxime along with acid ArCOOH (2) corresponding to trlchloromethylarene (11, being formed during the treatment of the reactlon mixture. Introduction Recently various substituted benzotrichlorldes have become quite accessible1-4. This accounts for their extended use in organic synthesis. For instance, the formation of a number of heterocycllc systems under the action of trichloromethylarenes on aminoalcohols, hydrazlnes and semicarbazide derivatives was shown5-10 . As early as 1884, Tlemann and Kruger reported the formation of 3,5diphenyl-1,2,4-oxadlazolefrom benzotrlchlorlde and benzamidoxlme11, but they did not present either reactlon condltlons, or data on the yield. As far as we know, for more than 100 years the reaction under discussion has not been reproduced. Besides, the choice of obJects was not optimal due to the easy conversion of benzamldoxlme into dlphenyl-1,2,4-oxadlazole, for example, under the action of heating and aclds12.
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1660
L I BELENWIer al
Results and Dlscusslon The aim of this paper was to study the perspectives of the synthesis of 1,2,4-oxadiazoles from aryltrichloromethanes and areneamidoximes. It is essential to note that not only benzotrichloride and benzamidoxlme but also their derivatlves bearing electron-releasing and electron-withdrawlng substltuents were used. Trlchloromethylarenes ArCC13 [I, Ar = Ph (a), 2,4-Me2C6H3 (b), 2,4,6-Me3C6H2 (c), 2,4,5-Me3C6H2 (d) ] were introduced into the reaction with areneamidoximes ArtC(NH2)=NOH [Z!,Ar' = Ph (a), 4-N02C6H4 (b), 4-MeOC6H4 (c) 1. In the course of the reaction of la-d with zb,c in the absence of a solvent at 140-150 OC 3,5-diaryl-1,2,4-oxadiazoles (2) were obtained In 40-60% ylelds. The end of the hydrogen chloride release served as a criterion for the reaction completion. The products were separated by means of column chromatography. For benzamidoxime 2a the above conditions are too drastic and mainly lead to the product of thermal destructlon of la, 1.e. benzonltiile &.a. The proposed general method for diaryloxazole (2) synthesis can be considered as an analogue of preparative synthesis of 1,2,4-oxadiazoles from amldoxlmes and various derivatives of carboxylic acids13. It 1s known that in the process of the reaction between carboxylic acid chlorides and amidoxlmes the 0-acylation of amidoxlme is the first stage accompanled by cyclization14, however the cases of obtaining N-mono- as well as N,O-diacyl-substituted amidoxlmes were also described13,14. Unfortunately, when reactions of trlchloromethylareneswith amidoximes were carried out in the absence of a solvent we did not manage to obtain any intermediate products. To establish the course of the reaction, as well as to carry out syntheses of 3-phenyl-5-aryl-1,?,4-oxadiazoles(from a) various solvents (benzene, toluene, pyrldine, nltrobenzene) were used. While boiling in benzene trichloromethylarenesLb-d with 4-fold excess of a for HCl neutralization corresponding oxadiazoles (3b-d) in 50-70$ yields and benzonitrile (15-20%) were obtarned. Under these conditions benzotrichlorlde (la) gives 3,5-dlphenyl-1,2,4-oxadiazole(la) In the yield as low as 5%. The temperature growth when the reaction was carried out in boiling toluene allows the increase of the yield for la up to 50%. It should be noted that neither 2a nor Its hydrochloride while boiling in toluene gives even traces of 3a and this proves the trichloride Ia partlclpation In the formatron of Ia under these condltlons. The Interaction of trichloromethylareneJ,cwith 4-methoxybenzamidoxime (2~) In bolllng benzene leads after hydrolysis of the reactlon mixture to N-acylamidoxlme (10) which failed to undergo cycllzation into corres-
1661
3,5-Dmryl-1,2,4-oxa&azoles
ponding 1,2,4-oxadiazole. 4-Nltrobenzamldoxime (gb) is insoluble in nonpolar solvents, so to carry out the reactlon under the same condltlons we had to use pyrldlne which played simultaneously a role of an acceptor for HCl, thus taking advantage of equlmolar ratios of components. It was found that while bolllng in pyridine amidoxlmes a-c reacted in the same manner, nitriles Ar'CN (4) and acids ArCOOH (2) being the main products of the reaction. In the case of bensamidoxime (ga) along with the above products of fragmentation oxadiazoles (la-d) were also formed m the yields no more than 2m. In addition, oxadiazoles lb-d contained some diphenyl-substituted derivative (la) formed as the result of amldoxime 1" *ldimerizationll. Analogous results were obtained for the Interaction of l_b,cwith 2b in nitrobenzene (100-120 V, 3 h with subsequent treatment with water). The propertles of the obtained compounds are llsted In Table 1. As a whole, the transformations under consideration can be described by Scheme 1. ArCC13 + Ar'$NH2 e NOH
+ Ar'CN
rArCC120N=~Ar1stArCC120NH~Ar' NH2
c
ArCOON=CAr' NH2
H20 ArCOOH r
and 2 a) Ar = Ph; b) Ar = 2,4-Me2C6H3; c) Ar = 2,4,6-Me3C6H2; d) Ar = 2,4,5-Me3C6H2. and 3 a) Ar' = Ph; b) Ar' = 4-N02C6H4; c) Ar' = 4-MeOC6H4. a) Ar = Ar' = Ph; b) Ar = 2,4-Me2C6H3, Ar' = Ph; c) Ar = 2,4,6-Me3C6H2, Ar' = Ph; d) Ar = 2,4,5-Me3C6H2, Ar' = Ph; e) Ar = Ph, Ar' = 4-N02C6H4; f) Ar = 2,4-Me2C6H3, Ar' = 4-N02C6H4: g) Ar = 2,4,6-Me3C6H2, Ar' = 4-N02C6H4; h) Ar = 2,4,5-Me3C6H2, Ar' = 4-N02C6H4; 1) Ar = Ph, Ar' = 4-MeOC6H4; J) Ar = 2,4,5-Me3C6H2, Art = 4-MeOC6H4. a) Ar = 2,4,6-Me3C6H2, Ar' = Ph; b) Ar = 2,4,6-Me3C6H2, Ar' = 4-MeCC6H4. Scheme 1 We did not succeed In lsolatlon of lntermedlate dlchlorldes (6). The lsolatlon of the product resulting from hydrolysis of of one of such dichlorides, 1.e. O-mesltoylbenzamldoxIme (8a) in 30$ yield along with
1662
L I BELENKJI~~U~
oxadiazole lc (40$) when the reaction time was unsufflcient (1.5 h) can be regarded as the confirmation of the existence of similar compounds in the reaction mixture. When the reaction was carried out during 3 h the yield of zc rised to 68%. Our unsuccessful attempts to carry out the cyclization of ga as well as of specially prepared 0-benzoylbenzamidoxime and 0-benzoyl-4-methoxybenzamidoxlmewhen boiling their benzene solutions indlrectly prove the fact that compounds of the type 8 are not intermedlate heterocycllzation products. We consider rather dichlorides 5 or their tautomers 1 to be the intermedlates. It is natural that the structures of non-identified products (6, '7,2) are suggestive, the real intermediates could be formed also as a result of nucleophilic substitution of not one but two or three chlorine atoms of starting trichloromethylarene1. The formation of N-acylated amidoxime (10) while boiling j_cwith gc in benzene can be accounted for transalkylatlon of the Initially formed O-substituted derivative of the types 6 or 1. Hydrolysis products of the latter, i.e. 0-mesitoyl-4-methoxybenzamidoxlme(gb) was ldentlfied when the reaction of Ic with 2c was carried out In pyridine at 0 OC. The presence of an electron-releasing substituent in gb should promote the transalkylatlon (Scheme 2).
15
=
I-
ArCC12NHzAr' NOH 1
ArCONHCAr' &OH -10
Ar = 2,4,6-Me3C6H2, Ar' = 4-MeOC6H4 Scheme 2 The presence of nltrlles (4) In the products of the reactlon proved unexpected, though It is known that during thermal decomposltlon of the amidoxime 2a nitrile Aa and benzamlde were the main products'5. A possibillty of the formation of nltrlles from amldoximes za-c or from oxadiazole lh while bolllng in pyridlne in the presence of pyrldlne hydrochloride was not conflrmed. This allows the conclusion that nitrlles (4) and acids (2) can be formed from dichlorides of the type 1 which are tautomers of 6. The presence of a base in the reaction medium should promote an equilibrium shift to the tautomerlc form 2 and, naturally, facilitate the formation of fragmentation products 4 and 2. The increase In the yield of &a from 15-20% m benzene up to 50-65% in pyridine proves the above. The fragmentation can proceed via intermediate formatlon of an Osubstituted hydroxylamine (2). It should be noted that the fragmentatl-
3,5-Dmryl-1,2,4-oxad1azoles
1663
on was not observed when the interaction of areneamidoxlmes with acyl 16 chlorides instead of trlchloromethylarenes was carried out In pyridine . As it was mentioned above, an N-acyl derivative of amidoxime 2c (10) was not obtained In pyrldine but the reaction gave the nitrlle (&c> with an admlxture of 0-acylated 4-methoxybenzamldoxime (eb). We failed to obtaln neither N-, nor 0-substituted derivatives of amidoxlme 2b in its reactions with la-d. However the isoIatlon of 4-nitrobenzonitrlle (3b) and corresponding carboxylic acids (zb,c) when the reaction was carried out not only in pyrldine, but also in nltrobenzene allows the electrophilic attack to be dlrected on the oxygen atom of the amldoxlme group. Both structures and compositions of the obtalned compounds were confirmed by PMR, IR, mass spectra as well as by elmental analysis. Mass spectra of oxadlazoles 2 contalned peaks corresponding to the fragmentation according to the scheme of 1,3-dlpolar cycloreverslon, the latter, as known for 1,2,4-oxadlazoles, lesdlng to ArCN and Ar*CN017. IR spectra of 2 contain a set of bands characterlstlc of aryl-substituted l,2,4-oxadiazoles (1608-1612, 1555-1576, 1448-1552, 1350-1370 cm")18. PMR data are given m Table 2. Experimental PMR spectra were recorded on JEOL FX-90Q (90 MHz) and Bruker NM-250 (250 MHz) spectrometers In CDC13. IR spectra (tablets In XBr) were obtalned on Perkln-Elmer 577 and Specord M-80 znstruments. Mass spectra were recorded on Varian MAT CH-6 spectrometer at lonlzation energy of 70 eV with the direct lntroductlon of a sample into the lonlc source. Melting points were determlned on a Boetlus heated plate. Starting trlchIoromethyIareneswere prepared according to the procedures described Inl,4, the syntheses of areneamldoximes were performed as described 1n12. Synthesis of 3~5=Dharyl-1,2,4-oxadlazoles(Ja-3) -----_Method A. Areneamidoxlme (zb,c) (0.2 mO1) was added by portions to ---0.1 mol of trlchloromethylarene (la-d) heated up to 120 OC. Then the mixture was heated up to 140-145 OC and maintalned at this temperature until the end of HCl evolution (time 1s given In Table 1). The reaction being completed, the products were extracted with chloroform, the extract was evaporated and the residue separated by means of column chromatography on slllca, eluent - benzene. Method --- B. Benzamldoxlme (2a) (0.4 mol) was dissolved while heating m benzene (50 ml). Then 0.1 mol of trichloromethylarene (la-d) was added. The reactlon mixture was bolled during the time given m Table 1. The reactlon control was carried out by TLC on Sllufol, eIuent _ chIoroform.
1664
L I BELEN'KII~~U~
On the reactlon completion hydrochloride of 2a was filtered off, the benzene solution was washed with water, then evaporated. The products were separated as described in Method A. &nierac$&on of_T'ri~h~orome4~r~n~s_w~t~ &zneamidoximes in Qridine __-_-V-V --Amidoxlme @a-c) (0.1 mol) was dissolved in pyridine (15 ml), 0.1 mol of trichloromethylarene (la-d)was then added. The reaction mixture was refluxed for 3 h. Then pyrldine was distilled off and the residue was separated using column chromatography on silica (hexane - ethyl acetate, 3:1 as eluent). The following products were successively eluted: nltrioxadiazoles (Ja-d) and, finally, a resinous coloured product, les (Aa-c), hydrolysis of which (cont. H2S04) leads to carboxylic acids (za-d). The yields of the products are listed in Table 3. anthesis of Acylamidoximes ---------_--a) In the interaction of j_cwith 2a under the conditions similar to those described in Method B, but during 1.5 h, after alkaline hydrolysss (aqueous NaOH) along with 40% of oxadiazole lc, 0-mesitoylbenzamidoxime (sa) was obtained In 30% yield, m.p. 133-140 OC, M' 282. Found, %: C 72.23; H 6.31; N 9.75. C,6H18N202. Calcd., %: C 72.34; H 6.38; N 9.93. IR spectrum, cm": 3n80, 3330 (NH2), 1735 (CO). b) Under similar conditions 25% of N-mesltoyl-4-methoxybeneamldoxlme (u), m.p. 198-199 OC, M+ 312 was obtalned from J_cand zc after the reaction completion (1 h) followed by the treatment with water and column chromatography (silica, eluent - benzene). Found, %: C 69.14; H 6.40; N zi06. C18H20N203. Calcd., %: C 69.23; H 6.41; N 8.97. IR spectrum, cm : 3208, 3120, 1696. c) 4-MethoxybenzamidoxIme (0.1 mol) was dissolved in pyridlne (10 ml), cooled to 0 OC. Then 0.1 mol of trlchloromethylarenej_cwas added. The reaction mixture was stirred for 3 h at 0 'V, pyridine was then distilled off In vacuum. Along with nitrile &c (60%) 0-mesltoyl-4-methoxybenzamldoxlme (gb) was separated by means of column chromatography of residue on silica (hexane - ethyl acetate, 3:1), yield IO%, m.p. 172-180 OC, M+ 312. Found, Z: C 69.30; H 6.40; N 8.90. C,8H20N203. Calcd., %: C 69.23; H 6.41; N 8.97. IR spectrum, cm-': 3500, 3350 (NH~), 1735 (co). d) 0-Benzoylbenzamidoxime (m-p. 151-155 OC) and 0-benzoyl-4-methoxybenzamldoxime (m.p. 140-148 OC) were obtained from benzoyl chloride and corresponding amldoxlmes according to the procedure given In '9. IR spectra contain characterlstlc bands: ca. 3505, 3375 (NH2) and 1730 (CO) cm-1 .
';&g 183-184 (EtOH) 170-172 (EtOH) 97-98*** (EtOH) 116-118 (EtOH)
e "?M50~Y 194** (EtOH)
106-107* (EtOH) 83-84 (MeOH) 56-57 (MeOH)
55
1
A
40 45
1
2
2
A
A
A 294
252
309
309
295
267
6.01
4.82
66.21
73.20
4.74
4.30
5.98
6.04
5.80
H
66.36
63.51
77.42
77.25
77.03
C
Found, %
77.27
98 0~.
9.32 C,8H,8N202 73.47
C15H12N202
13.45 C,7H,5N303 66.39
13.40 C17H,5N303 66.39
13.91 C16H13N303 63.79
C14H9N303
10.59 C,7H,6N20
77.27
10.49 C,7H,6N20
C
76.80
C14H10N20
Formula
11.08 C,6H,4N20
N
**Ref. 21: m.p. 195 OC. ***Ref. 22: m.p.
55
1
A
60
50
1
A
264
50
6
B
264
68
3
B
222 250
18
B
50 50
16
B
*Ref. 20: m.p. 108 “C.
23
21
2h
2g
2f
2e
2d
2C
2b
2a
M.p., "C Method Reac- Yield, M+ (solvent of pre- tion % pound for reoaratl- time. crystal- bn(see hS llzatlon) experimental)
Corn-
3,5-Dlaryl-1,2,4-oxadlazoles(2)
10.60
6.06
9.52
13.50
4.88
6.12
13.50
4.88
13.95
10.60 6.06
4.32
11.20
N
5.60
H
Calcd., %
Table 1
e-m
--we
7.19s broad. 6.98s
H3
H5
H6
-
-
8.02d 7.19s broad. 6.98s -
8.21m (5H) - - - -
H4
, wm
-
-
-
-
7.03s
7.15s
. X: 6.90s
6.90s
7.05a
8.18d
6.90s
6.90s -
7.88s broad. 7.69d
6.93d
7*76dd - - - -
-
7.03d
8.14d
7.05d
7.03d
8.39s
8.38s
8.39s
8.40s
-
6.93a
7.42m (3H) - -
-
-
8.39s
-
-
8.38s
7.03s
-
-
7.79d
7.76dd
8.18d
8.14d
8.24dd
8.24dd - - - - 7.58m (3H) - - 8.40s
8.24dd
_ _ _
H6’
8.24dd - - - - 7.58m (3H) - - -
8.39s
-
H5’
7.55m (5H) - - -
H4’
8.24dd
H3’
, wm
8.24dd - - - - 7.58m (3H) - - -
_______
H2’
Group Ar',
8.07d 7.18s broad.
ES . broad. 8.23dd - - - 7.56m (3H) - - - 8.23dd
-
7.18s broad.
7.88s 7.11s broad. broad. 8.25dd - - - 7.72m (3H) - - - 8.25dd
H2
Group Ar,
wm
(6H), (3I-I)
2.35s 2.64s
2.32s 2.63s 2.31s 2.38s 2.31s 2.39s
2.35s 2.71s
2.34s 2.38s
(6~)
(6H), (3H) (3H), (6H) (3H),
(6H), (3H)
(6H), (3H)
2.43~3, 2.73s
(3H)
2.36s
2.27s (6H),
2.40s, 2.68s
Me,
6.85d 6.85d 7.38d 6.91s 6.91s 7.38a 2.39s (9H) ?o = 8 Hz (In lb,f), J23 = J2,3, = J56 = J5,6, = 7.5 Hz; J26 = J2,6, = 1.5 Hz. * Coupling constants: J 56 Chemical shifts (IvIein 21,~): 3.89 and 3.90 (5). ** Chemical shifts of MeO: 3.84s; of NH2 (in &,b): 5.13, 5.06 resp. (s, broad.); of NH in 10: 9.30s (broad.); of OH in lo: 10.55s (broad.).
ComPOuna
Table 2 PMR Spectra of 3,5-Diaryl-1,2,4-oxadlazoles(2)* and Acylamidoximes (ga,b, E)**
r Y
1667
3,5Dmyl- 1,2,4-oxahazoles
Table
3
Yields of Products Formed from Trlchloromethylarenes and Areneamldoxlmes in Pyridine Solution Yields
Starting compounds Trlchloromethyl- Areneamldoxlme (2) arene (1) La
2a
Ib
2a
1C
a
Id
a
lb 1c lb
2b 2b 2c
Ic
2c
of reactlon products, %
Oxadiazoles (2)
za, zb, 15 Jc, 20 2d, 15
20 +
Ja,
IO
+ +
za, 10 la, 15
NItrile (4) Acid (2) $a, 65
za,
32
ia,
50
zb,
24
&a,
50
zc,
27
&a, &b, &b, &C* &c,
60 45 45 -100 '100
d, zb, zc, zb, zc,
30 30 35 70 57
References
5 6 7 8 9 10 11
12 13 14 15 16
Hart H.; Fish R.W. J. Am. Chem. SOC. 1961, 2, 4460-4466. US Pat.4,575,565 (1986); Chem. Abstr. 1986, 105, 6305. US Pat. 4,419,514 (1983); Chem. Abstr. 1984, 100, 85412. Belen'kil L.I.; Brokhovetsky D.B.; Krayushkin M.M. Chem. Scrlpta 1989, 3, 81-84. US Pat. 3,402,178 (1968); Chem. Abstr. 1968, 69, 96750. Suzuki T. ; Mltsuhashl K. Selkel Dalgaku Kuaakubu Kogaku Hokoku 1976, 22, 1579-1580; Chem. Abstr. 1977, S6, 139916. Ger. Offen. 2,619,547 (1977); Chem. Abstr. 1978, 88, 62380. Golfier M.; Millcent R. Synthesis 1979, 946-948. Hasaneen H.M.; Shetta A.H.: Elwan N.M.; Shawall A.S. Heterocycles 1982, 19, 1477-1482. Barber0 M.; Cadamuro S. Synthesis 1986, 1074-1076. Tiemann F.; Kruger P. &. 1884, 17, 1685-1698. Eloy F.; Lenaers R. Chem. Rev. 1962, 62, 155-183. Clapp L.B. Adv. Heterocycl. Chem. 1976, 20, 65-116. Poplavskaya I.A.; Kurmangalleva R.G. Khlmiya Amldokslmov (Amldoxlme Chemistry), Nauka, Alma-Ata, 1988, 142 p. Leendrl G.; Rebora P. Ann. Chim. (Roma) 1956, 46, 953-959; Chem. Abstr. 1957, 5?_,6607f. Chlcu Sh.; Shine H.J. J. HeterocycI. Chem. 1989, 26, 125-128.
1668
I7 18
L I BELENXII~~U~
Selva
A.; ZerUli L.F.; Cavalleri B.; Fall0 F. Org. Mass Spectr.
1974,
2,
558-566.
Physical Methods In Heterocyclic Chemstry, Ed. A.R.Katrltzky, Vol. 2, Academic Press, New York - London, 1963, p. 232. 19 Clarke K. J. Chem. Sot. 1954, 4251-4253. 2o Bell& ., H. 27, S. 587. 21 Bergmann E.D.; Bendas H.: D'Avllla V. J. Org. Chem. 1953, l8, 64-69. Leandrl G.; Palottl M. Ann. Chum. (Roma) 1957, 47, 376-384. 22