Id.Eng. Chem. prod. Res. Dav. 1901. 20, 32-78
32
REVIEW SECTION Oxazoie Chemistry. A Review of Recent Advances
Oxazole and ils derbathres are an impatant class of heterocyclic compounds. m i review covers the recent lbrature of oxazole chemistry including synthesis. reactbns, spectroscopy.
and some applications.
Ignatius J. Turcbireceived his B.S. degree in chemistry from Drexel University (1971) and the Ph.D. degree from The University of Texas with ProfessorMichael J. S. Dewar (1975).'He spent a year at The Uniuersity of Munich as an Alexander uon HumboMt Postdoctoral fellow with Professor Rolf Huisgen. After two years as a postdoctoral fellow with Professor Edward C. Taylor at F'rinceton University he joined the Organic Chemistry Department, Research and Development Division, at Smith Kline and French Laboratories in 1978.
I
1. Introduction
The chemistry of oxazole 1 and its derivatives is an
1
intriguing facet of the chemistry of heterocyclic compounds. The present review of oxazole chemistry is an update of two previous reviews (I,2) covering the literature from 1974 to the beginning of 1980. A short review of oxazole chemistry has appeared in "Comprehensive Organic Chemistry" (3). No leas than 300 papera have been published in the past 5 years concerning the synthesis, spectroscopy, and chemical reactions of oxazoles and many others which are outside the scope of this review have appeared conceming the chemical physics of oxazoles. The present coverage includes new synthetic methods leading to oxazoles as well as modifications of older procedures. When applicable, mention is made of the use of the oxazoles prepared by these procedures. Methods for the preparation and reactions of aminooxazoles, alkoxyoxazoles,sulfur-containing oxazoles, and oxazole carboxaldehydes are covered. Also described are reactions in which the oxazole nucleus remains intact, ring cleavage reactions which yield acyclic products, and rearrangements to new heterocyclic systems. Synopses of several publications which describe the synthesis of certain natural products which have been prepared via oxazole intermediates are given. A few naturally occurring oxazolea have recently been discovered and new synthetic approaches to these oxazole natural products are reviewed. Some new applications of mesoionic oxazole chemistry to heterocyclic synthesis are described. An important, new development in the organic spectroscopy of oxazoles discussed herein is the measurement and interpretation of the '% NMR spectra of a variety of oxazole derivatives. Only mononuclear oxazoles are incorporated in the present review. A discussion of reduced oxazoles such as oxazolines, oxazolidines. oxazolinones. and oxazolidones is outside its scope.
2. Synthesis A. From 2-Acylaminoketones (Robinsoncabriel Synthesis) a n d Related Systems. A classical method for preparing oxazoles is the cyclodehydration of 2-acylpinoketones otherwise known as the RobinsonGabriel oxazole synthesis ( 1 , Z ) . Several recently reported examples of this procedure are outlined in eq 1-10. The cyclodehydration reagents required for this transformation are PCl,, P205,POCl,, or SOC1,.
R' =
R1 =
I
q:
;R' = F'h, X-Ph
E:
; R' = Ph, X-Ph (3245%) (ref 6 )
A~-Y-CONHCH~COA~~
'Chemical Research and Development Center, Agricultural Chemical Group, FMC Corporation, Princeton,N J 08540. 019&4321/81/1220-0032$01.00/0
(ref 4 )
nzso.
(ref 7) (2)
A:Y% ' Ar2
Ar'. A r 2 = X - P h : Y * C H 2 .
-0CHz
Ind. Eng. Chem. Prod. Res. Dev., Vol. 20, No. 1, 1981 33 0
0 HN
-
0
II
b N N = C H C N H C H 2 C A rI
I P O C I ,
I
Y
0
HN \ N N = CI H ' A A r
(ref 8) (3)
/)f
0
4 PhCONHCHCOPh
I CH2C02H
0
(ref 9 ) (4)
~ f h 2 c 0 2 H
II
ROzC(CH2 ),CNHCHCPh
I Ph
II II
0
Ar
R' CONHCHCOR~
++
9
10
(ref 10) ( 5 )
Ph
11 (55-95%)
R1 = H, Ph; Rz = Me, CH,C1, NMe,, Ph; Ar = Ph = NMe2, the sulfonic acid derivative 11, R' = H, Ar = 4-H03SPh, R2 = NMe2,was obtained. The 2-acylaminoketones 10, R' = H, Ph, Ar = Ph, R2 = OEt, are stable in concentrated H2S04. The reaction of 2-aminoketones 12 with orthoformates gives 5-aryloxazoles 13 in moderate to good yields (16).
5 ( n = 0,1, 2)
-
+
6 ( n = 0,S) R:PO
R1
8
H p N C N H C ( C H 2 )#
R %OCH NHCO
R
R'C
R'
Ph NH
0
II
-
fluorescent whiteners (11). Compounds 4 are useful as muscle relaxants (8)while the oxazole-N-amidinocarboxamides 5 possess natriuretic properties (10). Oxazoles 7 are potential specific inhibitors of amino acid decarboxylase (13). 4-Oxazolin-2-ones 8 N-acylated with anhydrides or acid chlorides give 3-acyl-4-oxazolin-2-ones 9. When treated with concentrated sulfuric acid, these acylated derivatives 9 undergo hydrolytic ring opening with C02 elimination to provide the 2-acylaminoketones 10 which in most cases react further under these dehydrating conditions yielding oxazoles 11 (15). In the case of 9, R' = H, Ar = Ph, R2
RCH(OE113
ArCOCH2NH,CI-
0 II
12
I
R ' CNHCHCPh
II
II0
13 (33-7976)
0
(57-90%)
+
Ar = Ph, 4BrPh, 4NO,Ph, 4-pyridyl; R = H, Me,Et
+ clod-
7Ph3
1
R'CNHCHCPh
II
I1
0
(ref 12) (8)
Ph
0
(5442%)
-
I
Me
Jxc::R
(ref 13) (9)
7
tH2R
XPhCH=NCH2CH(OMe)2
0 R C02R2
I
S C M e : CH2SMe: COC02Me: C02H
R3
I
(13) XPh
II0
-
X
14
3-F3CPhOCHCONHCH2CHCI, 4-CI
a
17
R'
16
16
The 2-acylamino-1,l-dichloroethane 17 affords 2-[a-(3trifluoromethylphenoxy)-4-chlorobenzyl]oxazole18 when
soc12
R'CNHCHCCH2CHPh-X
II 0
+
H2so, p205 AN
I1
8
The yield of isoquinolines 15 obtained in the Pomeranz-Fritsch reaction is largely dependent upon the substituents on the phenyl group of the starting 2-phenyliminoacetaldehyde acetal 14. When electron-attracting groups are present, the 2-aryloxazoles 16 are produced along with isoquinolines 15 while oxazoles 16 are the sole products isolated when X = NO2 (17). When X = Me, however, the isoquinolines 15 (X = Me) are formed along with only trace amounts of oxazoles 16 (X = Me).
CHZCHPh-X
I '
(ref 1 4 ) (IO)
k3
The 2,5-diaryloxazoles3 were prepared in order to study their luminescence properties (4-6). The bisoxazoles 6 are
3-F3CPh0
C 'H
I
4-Clbh
18
treated with sodium ethoxide in ethanol (18). Compounds of this type are claimed to lower the concentration of cholesterol, triglycerides and other lipids in blood serum. When tert-butyl2-acetylamino-3-bromocrotonate 19 is treated with triethylamine, cyclization takes place to yield
34
Ind. Eng. Chem. Prod. Res. Dev., Vol. 20, No. 1, 1981
tert-butyl 2,5-dimethyloxazole-4-carboxylate20 (19).
carboxylation of 30, X = s,gives 2-(2-thienyl)oxazole (31).
C02-t -Bu
U
28
B. From Aldehydes and Cyanohydrins (Fiseher Oxazole Synthesis). The reaction of aromatic aldehydes with aromatic cyanohydrins in the presence of anhydrous HCl gives 2,5-diaryloxazoles ( I , 2). 2-(4-Bromophenyl)-5-phenyloxazole has been obtained by this method starting with benzaldehyde cyanohydrin and 4-bromobenzaldehyde (20). With 4-bromobenzaldehyde and its cyanohydrin, however, oxazole ring chlorination occurs to give 2,5-bis(4-bromopheny1)-4chlorooxazole (21) along with 2,5-bis(4-bromophenyl)-4oxazolidinone (22). The latter compound is in general a
29
30
31 (20% from 30)
D. From 2-Hydroxyketones. 4,5-Diaryloxazolesare produced in the reaction of acyl benzoin derivatives with ammonium acetate ( I , 2). Several (4,5-diaryloxazol-2-yl) propionic (24, 25) and butyric (25) acid derivatives 33 possessing antiinflammatory activity have been prepared in this manner (eq 20). The 2-acyloxyketones 32 were
1
0 (CH2)nC02H
L
NH40Ac
Ar’CO HAr2
HOAc
32 22
Ar = 4-BrPh
side-product in the Fischer synthesis. A variation of the Fischer synthesis is the reaction of aroyl cyanides 23 with aromatic aldehydes and HCl or HBr. This procedure produces 2,5-diaryl-4-chloro- or bromooxazoles 24 in moderate to good yields (21). The proposed mechanism is outlined in eq 17.
Ar’
&
Ar2
H02C(H2C)n
Ailr2
(20)
33 n = 2, 3; Ar’, Arl = Ph, XPh, C,,H,, furyl, thienyl
obtained by the reaction of the 2-hydroxyketones with succinic or glutaric anhydride in pyridine or DMF. In a similar fashion a number of bisoxazoles 34 were prepared (26).
(17)
24 (50-78%) 34 n = 0-4
Ar’, Ar” = YPh; X = C1, Br
C. From Amides and 2-Haloketones. This classical oxazole synthesis due to Blumlein and Lewy was reported in 1884 and is still useful today (1,2). Kost et al. prepared a number of oxazoles 27 in fair yields by the reaction of 2-bromoketones 25, generated regiospecifically from the corresponding ketones and dioxane dibromide, with amides 26 at 110 OC (22).
25
.SI
R’ = H, Me, n-Pr, nPenty1; RZ = Me, f-Bu; R3 = H, n-Pr, i-Pr, n-Bu, n-hexyl (20-43%)
Diethyl 2-heteroaryloxazole-2,5-dicarboxylates 30 have been prepared from the amides 28 and diethyl 2-oxo-3chlorosuccinate (29) (23). Hydrolysis and thermal de-
The fonnimidates 35 provide 4-methyloxazole (37) when treated with acetol (36) in the presence of base (27). NH
II +
HCOR
MeCOCHZOH
35 R = alkyl
36
-
,Me
(22)
37
4,5-Disubstituted oxazoles are also accessible from 2hydroxyketones and formamide or nitriles in acid media, from benzoins and formamidine, and from ammonia and benzil (1,2).Oxazole-N-oxides are derived from the reaction of 2-hydroxyiminoketonea with aldehydes and HC1. These compounds are deoxygenated with Zn in acetic acid ( 1 , 2). E. From Ketoximes. A one-pot oxazole synthesis from ketoximes 38 has been reported and is outlined in eq 23 (28).
Ind. Eng. Chem. Prod. Res. Dev., Vol. 20, No. 1, 1981 35
azolines 49 and ultimately the oxazoles 50 after elimination of toluenesulfinic acid (eq 27, path a). Alternatively, a 45 or
R' = Me, PhCH,, Ph; R2 = Me, Ph; R', R' = -(CHJ4- ( 5 8 4 3 % )
+&=
+-
--
R\
X , ~ - ~ ~ ~ ~ ~ ~
46
-+-/Tos RC=NC,
47
H
48
I
Several 2-chloromethyloxazoles39 have been prepared by the reaction of ketoximes 38 with chloroacetyl chloride (29).
b ArCHO
-To& 1-X-
1
= Rl
39 R&*r
/R'
49 40
R' = Me, t-Bu; R2 = Ph, SR4, OPh; R3 = Me, Et When allowed to react with potassium salts of dithiophosphonic or phosphoric acids the oxazolylmethylthiophosphonates or phosphates 40 are isolated. These compounds have been tested as insecticides and miticides. F. 1,3-Dipolar Additions to Nitrile Y€ides. The nitrile ylides 42 are produced when the 1-azirines 41 are photolyzed (section 2.H). When the irradiation is carried out in the presence of acid chlorides and triethylamine, the oxazoles 44 are isolated in moderate yields (30).
*
AR' 2
P h C e N+ C- P I
H
Ph
H'
41
50 (49-63%)
mechanism involving a 1,3-anionic cycloaddition of 47 to the aldehyde (eq 27, path b) play be operating. Under the same conditions, 45 or 46 in combination with C,N-diarylilpines or Michael acceptors give 1,5-diarylimidazoles or pyrroles, respectively (32). The hydroxymethylnitrile ylides 52 are generated by irradiation of the corresponding 2-phenyl-3-hydroxymethyl-1-azirines 51 (33). Proton transfer to the monosubstituted carbon of the ylides followed by cyclization of the resulting zwitterion 53 affords the 2-phenyl-3-oxazolines 54. The overall process is an intramolecular 1,3-dipolar addition of ROH to the nitrile ylides. The 3-oxazolines 54 were smoothly converted to the 2-phenyloxazoles 55 by oxidation with dichlorodicyanobenzoquinone(DDQ).
42
J
H--d
44
H--d
43
52
R' = R' = Ph, 25%; R' = Ph, R2 = t-Bu, 31%; R' = Me, R' = Ph, 32%
1,3-Dipolaraddition of 42 to the carbonyl group of the acid chloride affords the 5-chloro-3-oxazolines 43 which in bsse undergo elimination of HC1 to give 44. The regiochemistry of the cycloadduct is that expected from the addition of simple alkyl, aryl, or aralkylnitrile ylides to carbonyl compounds (31). The N-hylmethylimines 45 and 46 have been prepared as outlined in eq 26 (32). When these species are treated 0 TosCH~N=C,
/Me
11
MeOS02F
R;Ma TosCH~NHCR
p4s10
R
53
55 ..
54
R = H, 65% R = Ph, 85%
R = H, 70% R = Ph, 90%
G. 1,5-Dipolar Cyclizations. The title reaction of carbonylnitrile ylides 56 to afford oxazoles 57 (along with 1,5-dipolar cyclizations of other types of 1,3-dipoles)has been the subject of a recent review (34)and is not dimwed in detail.
'OMe
45
1-
TosCHzNHCR
MeOSO*F
TosCH~N=C /R 'SMe
(26)
46
8
57
56
R = Me, Ph, SMe
with a base (NaH or KOt-Bu) in the presence of aromatic anhydrides, 5-aryloxazoles 50 are isolated. A 1,3-dipolar addition of the nitrile ylides 48, formed from the azaallyl anions 47, to the aldehydes gives the 4-tosyl-5-aryl-%ox-
2-Aryl-1-phthalimidoaziridines (58) substituted at the 3-position by acyl groups undergo thermal ring opening to azomethine ylides 59. The products isolated from this reaction are the oxazolines 61 and the oxazoles 62 (35).
36 Ind. Eng. Chem. Prod. Res. Dev., Vol. 20, No. 1, 1981 Y
I Ph
Ph
63
k
i
58
59b
65 64
lhv Ph
p
O A R
+-/X Arcw\C-R
59a
P
d/ 60 X = CN, R = Ph X = CO,Me, R = Me X = COMe, R = Me y = -N
The amount of oxazole 62 formed increases at the expense of the oxazoline upon increasing the reaction temperature. A mechanism involving 1,Bdipolar cyclization of azomethine ylides 59a to give oxazolines 61 followed by elimination of phthalimide from 61 to give oxazole 62 was postulated. An alternative rationale involving elimination of phthalimide from the azomethine ylides 59a to provide the carbonylnitrile ylides 60 and electrocyclization of these species to oxazoles 62 was also presented (eq 30). The reaction of a-isocyanoketones, -esters and amides with electrophiles and subsequent deprotonation of the ensuing nitrilium ion formed via attack of the electrophile on the isocyanide carbon is a potential route to carbonylnitrile ylides and thus to oxazoles. This type of process involving a-isocyanoacetamides has been reported and is discussed in section 2.1. H. The Isoxazole-Azirine-Oxazole (IAO) Interconversion and Related Reactions. The photochemical IAO process has been discussed in a number of reviews on oxazole (1, 2) and azirine (36, 37) chemistry. The photochemically induced carbon-carbon bond cleavage of acylazirines affords carbonyl nitrile ylides which provide oxazoles by electrocyclic ring closure (34). A study of the photochemistry of aryloxazoles has been published (38). When irradiated, 2-phenyloxazole (63) yields 2-phenyl-1-azirine-3-carboxaldehyde (65; 12% ), 4-phenyloxazole (69; 2%) and a trace of 3-phenylisoxazole (66) along with unchanged 63 (35%). The 1-azirine 65 is not derived from the isoxazole 66 but arises directly from 2-phenyloxazole 63 possibly by ring opening to the nitrile ylide 64 followed by photochemical electrocyclic ring closure of the ylide. Whereas ring closure of nitrile ylides to azirines does not occur thermally, this reaction pathway is open to the ylides photochemically (39). A photochemical, disrotatory ring closure of 2-phenyloxazole (63) to the oxazole valence tautomer 67 followed by l,&oxygen migration provides the valence tautomer, of 4-phenyloxazole 68. Disrotatory opening of 68 produces 4-phenyloxazole (69). Several other examples of aryloxazole photoreactivity are presented (38). Whereas the photochemical IAO interconversion is reasonably well understood, the same thermal reaction is
69
more complex. Flash pyrolysis of 3,5-diphenylisoxazole (70) a t 960 "C affords 2,5-diphenyloxazole (71; 29%), 2phenylindole (72; 25.4%), benzamide (73; 11.0%), 1,2-diphenyl-1-azirine (74; 2.0%), benzonitrile, naphthalene, biphenyl, diphenylmethane, fluorene, phenalene, stilbene, phenanthrene, and benzyl cyanide, the last nine products in 3.4% overall yield (40). '3c labeling experiments suggest the mechanistic pathway given in eq 32 to rationalize the formation of the major products, 71,72,74, and fluorene. Ph Ph
70
i
71 (32)
..
74
*
72
Thermolysis of the vinyl azide 75 provides the 1-azirine 76 (41). This azirine is unstable (as are all 1-azirines unsubstituted a t the 2-position) and rearranges further to
In+ PhCO\ ,CHN=C Me
79
(33)
-
Ph
80
Ind. Eng. Chem. Prod. Res. Dev., Vol. 20, No. 1, 1981 97
4-methyl-5-phenylisoxazole(77) and 4-methyl-&phenyloxazole (80). Bases such as pyridine and DBU catalyze the conversion of 76 to oxazole 80 via the a-ketoisonitrile 79. Thus the formation of 80 is catalyzed by bases such as isoxazole 77 and is also self-catalyzed. The effect of concentration on the reaction rate and product distribution supports these contentions. The mechanism of the conversion of 1-azirine 76 to the ketoisonitrile is unclear. The effect of acids on the product distribution in the thermal rearrangement of 1-azirines 81 to isoxazoles 82 and oxazoles 83 was investigated (41). While 81, R' = Ph, R2 0
R'
aR:. RI/!xR3 R2
(34)
+
R'
N
81
thermolyzed (230 "C), 2-phenyl-3-acetyl-3-bemyl-l-azirine (87) is presumably formed in equilibrium with the starting isoxazoles. Azirine 87 suffers ring opening to the nitrile ylide 88 which undergoes 1,5-dipolar cyclization to 2,5diphenyl-4-acetyloxazole(89, 30% ) and 2-phenyl-4benzoyl-5-methyloxazole (90, 38% ). In contrast, the photolysis of isoxazole 85 affords only the oxazole 89. In this case it was postulated that nitrile ylide 88 is formed directly from excited isoxazole 85* in the conformation 88a. Ring closure occurs much more rapidly than rotation around the C-N bond yielding only 89. Recent MIND0/3 (43)and ab initio (44)molecular orbital calculations show that the C-N-C angle of nitrile ylides is about 168"
82
7 H, R3 = H gives 82 and 83 in a ratio of 91:9 when thermolyzed in the absence of 'acid; in the presence of BF3.E&0 (10 mol %) only the oxazole 83, R' = Ph, R2 = H, R3 = H, is formed. The acid-catalyzed formation of oxazoles is believed to occur by the ring expansion of the intermediate azirinium ion 84.
phz,] /o-
83 85
Phl*
M
85* P h v O
PhQ-
H(BF3) R'
89 (36)
Me+.
3GR3
! b l :
A
-
== P h
SH
356
l 0 L c & n ' - M e Me
0 CO2 R
EOpR
365
366
357 (73-93%)
R
+-/.X-p-Tol 110 *C
-
- ph-Ye 8
358
+ E
-
0
(133)
With amines, 355 gives the imines. Spectroscopic measurements, however, suggest that the thiols 356 exist in equilibrium with the thiones 357; the latter predominates. p-Tolyl 2-phenyl-5-methoxyoxazole-4-thiocarboxylate (358) undergoes a Cornforth rearrangement to give methyl 2-phenyl-5-p-tolylthiooxazole-4-carboxylate (359) in 94% yield when heated under reflux in toluene (110 "C)for 17 h (107).
Ph
to the 4-imino-5mercaptooxazole 371 (59%) when treated with triethylamine (TEA) (147). The authors propose a mechanism involving cleavage of the sulfur-containii ring to give the intermediate 367 followed by nucleophilic attack by the thiolate anion on the carbonyl carbon of 367 yielding the 1,Cthiazepinone 368 which cyclizes to the oxazolothiazepin 370. The latter suffers cleavage of the seven-membered ring to afford the oxazole 371. We offer
pho5ci -
355 Ph
SMe
368
367
369
I
J
P hO
370 Me
Me
(137)
&C -';OzR
359
Other examples of 5-alkylthiooxazolesbearing a 4-substituent at the carboxylic acid oxidation level, i.e., 361, have been prepared in good yields by the reaction of the ketene thioacetals 360 with silver carbonate in acetonitrile (145). X ( R1S),C=C
NNHCOMe
4Ag2C03
(135)
MeCN
X'
Me
-
SR' -
360 361 (44-96%) X = CN, CO,Me, CONHR; R' = Me, Et,Ph
The reaction of (2,2-dichloro-l-benzamidovinyl)triphenylphosphonium chloride (362) with sodium hydrogen sulfide affords the novel phosphorus ylides 363 (146). Alkylation of 363 with methyl iodide yields the phosphonium salt 364. The penicillin imino chloride derivative 365 rearranges
P hO
371
a revised mechanism which invokes the nitrile ylides 366 and 369 a~ intermediates. Hirai et al. studied the reaction of penicillin imino chlorides with diazabicyclononaneand trapped nitrile ylide intermediates with dipolarophiles (148). The 1,3-elimination of HCl from imino chlorides to give nitrile ylides is a facile process which is known to be reversible (149). Thus the first step in the pathway outlined in eq 137 is reversible formation of nitrile ylide 366. Rearrangement of 365 or 366 then occurs leading to the new imino chloride 368. 1,5-Eliminationof HC1 gives the nitrile ylide 369 which undergoes a 1,Bdipolar electrocyclization to 370. These workers also demonstrated that the ketenimines 372 (X = H, NO,; R = CH20CO-tBu) can be converted to the oxazoles 373 in low yield with TEA.
54
Ind. Eng. Chem. Prod. Res. Dev., Vol. 20, No. 1, 1981
TEA _ I
379
373
X = H,NO,; R = CH,OCO-t-Bu
A recently reported synthesis of 2-phenylthieno[3,2-
Oxazole-4-acid chlorides are reduced to 4-formyloxazoles by standard techniques such as the Stevens (155) or Rosenmund (156) procedures. It appears that no 2-formyloxazoles are known with the which was exception of 2-formyl-4-styryl-5-ethoxyoxazole prepared from 2-( 1-pentenyl)-4-styryl-5-ethoxyoxazole by oxidation with H202/Os04(157). The first 5-formyloxazole to be reported is 2,4-dimethyl-5-formyloxazole (382),prepared by the vacuum pyrolysis of the lithium salt of the 2-arylsulfonylhydrazine 381 (158).
dloxazole (375) from the oxazolin-5-thione374 is outlined in eq 139 (150).
n
380
Me
-
1 I1-
A
C-iNHS02Ar Ll+
(143) Me
CHO
382 (68%)
0
381
7. Spectroscopy
374
A. NMR. A study of the interaction of N-butyl-N-(4methyloxazol-2-yl)-2-methylpropionamide 383 with various Ph
A
n
-HBr
SCH2COMe
II0
'-PrCY
n-Bu
383 375
A series of 7-aminocephalosporanic acid (7-ACA) derivatives including the oxazole-4-thiocarboxylicester 376 have been prepared and are well absorbed following oral administration to mice (151).
376
6. Formyloxazoles 4-Formyloxazoles are the best known of these species since they are readily available by several classical methods. Vilsmeier formylation of 2-phenyl-5-methyloxazole gives the corresponding 4-formyl derivative (152). This product can be converted to the 2,4-DNP and oxime and also undergoes a Perkin condensation with ethyl cyanoacetate. The Sommelet reaction of the 2-aryl-4-chloromethyloxazoles 377 provides the 4-formyloxazoles 378 (153). CHO
377
378 (R= H,Br)
2-(3-Thienyl)-4-chloromethyloxazole(379) is transformed into the 4-formyl derivative 380 with 2-nitropropane in Me2S0 in the presence of NaOEt (154).
fluorinated and nonfluorinated lanthanide shift reagents E u ( f ~ d(Hfod ) ~ = n-C3F,COCH2CO-t-Bu) and E ~ ( t h d ) ~ (Hthd = t-BuCOCH,CO-t-Bu), respectively, revealed that in the presence of the former the doublet for the oxazole 4-methyl protons underwent extensive broadening and the greatest downfield shift was observed for this substituent (159). With the nonfluorinated reagent these phenomena were not observed and the greatest downfield shift was experienced by the protons in the vicinity of the amide carbonyl group. Thus Eu(fod), probably coordinates with the heteroatoms of the o w l e ring and the amide carbonyl oxygen to give a six-membered chelated structure while the bulkier, weaker Lewis acid Eu(thd), coordinates only to the amide carbonyl oxygen. Correlations between 'H NMR chemical shift data and calculated charge distributions for methyl substituted heterocycles including oxazoles have been reported (160). The I3C NMR spectra of oxazole and a number of substituted oxazoles has been published (161). The carbon chemical shifts of oxazole are: C2,150.6; C4,125.4; C5, 138.1 ppm. Substituents at C2 such as phenyl, methyl, or methoxy produce a downfield shift of C2of 10-12 ppm. A methyl substituent at C4shifts this carbon downfield approximately 6 ppm; a phenyl group exerts a similar effect of -15 ppm and a tosyl group shifts C4approximately 17 ppm downfield. A d o d i e l d shift of 5-12 ppm is observed for C5 bearing a p-chlorophenyl moiety. The carbonproton coupling constants for oxazole are: J c ~ H231.1; ~, J w , 10.7; J m , 7.9; Jc,H*,8.9; Jcfi, 195.3; J c f i 16.5; Jca2, 4.1; JCA, 18.9; and Jca6,209.1 Hz. These values were compared with the corresponding JCH values for thiazole and 1-methylimidazole. The 13C NMR spectrum of 2,4,5-triphenyloxazole ex-
Ind. Eng. Chem. Prod. Res. Dev., Vol. 20, No. 1, 1981 55
hibits resonances a t 160.4 ppm for Cz, 137.1 ppm for C4, and 145.7 ppm for C5 (162). Benzo fusion (i.e., benzoxazole) produces a 11-15 ppm downfield shift of C4 and C5of the oxazole ring protons while only a 2 ppm downfield shift for Cz was noted (161, 163). B. Mass Spectra. A detailed study of the mass spectral fragmentation mechanisms €or oxazole has been reported (164). Support for the proposed mechanisms is derived from deuterium labeling, metastable ion studies, AP measurements, and also from molecular orbital calculations. Loss of CO and then HCN is observed in the mass spectra of the 4-aryloxazoles 384 (165).
C. UV Spectra. Siegrist and co-workers prepared a number of styryl derivatives of various heterocycles and recorded their UV spectral data (168-170). These values are given below for the oxazoles 388-392. A, nm Ph
E
x
385
8.84
384
8.80
384
8.02
373
7.50
363
6.17
388 (168) Ph
389 (168)
