3.

1,2 AZOLES

3.1 Pyrazoles

3.1.1 General

Pyrazole l di vong lin hp v cha hai nguyn t nit; pyrrole v pyridin, cc vi tr l v -2. Benzo-
fuzil pyrazole c bit n nh l benzopyrazole 276 hoc thng l indazole vi s nh th hin trong
cc cu trc 1 v 276. Pyrazole tn ti trong ba dng gim mt dn 277, 278 v 279 vi cc vi tr khc
nhau ca lin kt i.

Vong Pyrazole c kt hp vo nhiu dc phm, ha cht nng nghip v thuc nhum thng mi.
Mt s dn xut pyrazole quan trng vi hot ng ca chng c lit k nh:
3.1.2 Tng hp

3.1.2.1 (3 + 2) Phn ng Cyclization

Pyrazole c tng hp bng cch c c cc hp cht 1,3-difunctionalized vi hydrazine hoc cc dn

xut ca n lin quan n cyclization (3 + 2).

3.1.2.1.1 Phn ng ca -Diketones vi Hydrazines

y l phng php c s dng rng ri nht v lin quan n phn ng ca -diketones vi

hydrazine hoc hydrazin n vi s c mt ca axit (scheme-102).

Phn ng ny c tin hnh thng qua qu trnh hnh thnh hydrazone 280, sau n
cyclization v kh nc to ra pyrazole 282 tng ng. Tuy nhin, phng php ny chiu nh hng bt
li nh vi cc diceton khng cn xng, ni chung l mt hn hp cc ng phn isomeric pyrazoles
c hnh thnh (scheme -103)
3.1.2.1.2 Phn ng ca , -Cc hp cht Carbonyl khng bo hoa vi Hydrazines

Phn ng ca , -hp cht ethylen carbonyl, c th bng mt vi th thay th c th thay th

vi tr hoc vi tr , vi hydrazines dn n s hnh thnh cc pyrazole d kin (scheme-104).

Tuy nhin, , -hp cht acetylenic carbonyl mt hn hp ca hai isomers thu c do hai qu
trnh phn ng cnh tranh; (i) phn ng u tin tin hnh thng qua hydrazone lin tip, theo sau l
cyclization v dehydration, trong khi (ii) qu trnh th hai lin quan n s gia tng ca Michael, tip theo
l chu k kh nc (scheme-105). Tuy nhin, ng phn ng a thch ph thuc vo tnh cht ca phn
t ang tri qua phn ng v tc ng bi dung mi v nhit .
3.1.2.2 1,3-Dipolar Cycloadditions

(i) 1,3-Dipolar cycloaddition ca diazoalkanes vi chc nng alkynes kt qu trong vic hnh thnh
pyrazoles (schem-106). Phn ng tin hnh thng qua mt trng thi chuyn tip lin quan n s tng
tc hng hi thun li nht ca cc 4-electrons ca 1,3-dipole vi cc 2-electrons ca cht dipolarophile
(methylpropiolate) (HOMO ca diazoalkane - LUMO ca cht dipolarophile ).
(ii) Phn ng ca norbornadiene vi diazoacetat vi Fe (CO) 5 hoc Coz (CO) 8 to ra phn ng tun
hon lng cc 297 bi phn ng cycloreversion trong iu kin phn ng cung cp pyrazole 298 (schem-
107).

(iii) Cc phn ng xyclo phn ng 1,3-Dipolar ca sydnones (cc heterocycles meso-ionic, 1,2,3
oxadiazolium-5-olate) vi cc cht lng cc alkynic to thnh cc pyrazole vi s pht trin ca carbon
dioxide (schem-108)
3.1.3 Cu trc

Cc tham s cu trc trong pyrazole c tm tt (Fig. 29):

Cc lin kt N-H c di chuyn t cc phn t ca gc vong bng gn 5 i vi nguyn t nit th hai.

Cc tham s cu trc trong pyrazole cho thy s phn hy ca tri phiu v s aromaticity. Nng lng
cng hng ca pyrazole c tm thy l 123 kJ / mol v do cho thy pyrazol thm hn imidazole,
mc d c pirazole v imidazole c n inh tng ng.

3.1.3.1 Lin kt Hidro

Pyrazole l cht rn khng mu c m.p. 69-70 C. im si ca pyrazole (186-188 C) cao hn

nhiu so vi cc dn xut N-alkyl (N-methylpyrazole, b.p. = 127 C). im si cao hn ca pyrazole l
do lin kt hydro lin phn t. Nhng vi s thay th hydro bng methyl nhm, im si c gim do s
vng mt ca lin kt lin phn t. Tuy nhin, s ra i ca nhm alkyl carbon lm tng im si. S
lin kt lin phn t trong pyrazole c th l tuyn tnh hoc tun hon (dimer v trimer) (Fig. 30)

3.1.3.2 Tautomerism

Pyrazole tn ti trong hai dng tautomeric ging ht nhau vi s chuyn ng ca proton gia hai
nguyn t nit hnh khuyn. Do hai nguyn t nit khng th phn bit c (Fig. 31a). Tuy nhin,
pirazole c thay th bt thng tn ti trong hai tautomers khng th tch ri do s chuyn i nhanh
ca cc tautomers, mc d mt dng tautomeric chim u th hn cc hnh thc khc (Fig. 31b). Do ,
pyrazole 3 im ging vi pyrazole 5-thay th. Vic nh s trong cc hp cht nh vy c nhn i v
cc nguyn t c xc inh bng hai s. Nu R = CH 3, hp cht c t tn l 3 (5) methylpyrazole.

3.1.4 Phn ng

3.1.4.1 Phn ng
 Pyrazole biu hin cc phn ng c trng ca pyrrol v pyridin v c cha cc nguyn t nit
pyrrole v pyridin cc vi tr l v -2. Nit pyridin loi l d bi tn cng clectrophilic nhng n t
nucleophilic hn nguyn t nit pyridin. Nguyn t hydro gn lin vi nguyn t nit (N-1) trong pyrazol
c tnh axit hn pyrrolic N-H trong pyrrole v c th d dng loi b bng nucleophiles.

Cuc tn cng bng clectrophilic trong pyrazole, tri ngc vi pyrrol C-2 (oc-attack), xy ra
u tin C-4. S tn cng ca cc nucleophiles xy ra C-3, nhng vi cc nucleophiles mnh, s tm
tt ca proton dn n s m vong. Hai loi ion c lin quan n vic chuyn proton trong pyrazole; (i)
pyrazolium cation 302 v (ii) anion pyrazole 303 (schem-109).

3.1.4.2 Tn cng Electrophilic Nit

3.1.4.2.1 Bazo

Pyrazole l mt baz yu (pKa = 2.52) so vi imidazole. Hiu qu gii phng electron trong mi
trng t nhin ca nit loi pyrrole mc d tng mt electron ln nit v to iu kin cho cc phn
ng vi cht phn ng electrophilic, nhng tc dng thu hi in t ca nit ln cn vi tr-2 khin cho
cp n khng sn c cho proton. Trong pyrazole, hiu ng quy np chim u th hn so vi hiu qu
trung gian v do lm cho pirazole t c bn hn imidazole. Hn na, c bn tng i thp hn l do
s mt n inh thm ca lin kt sau khi protonation. S bt n ca lin kt 1 i vi pyrazole ln hn so
vi imidazole bi v cp n trn nit kiu pyrrole (vi tr-l) trong pyrazole khng gp phn ng k n
s phn hy ca in tch dng xut hin nit pyridin vi tr- 2 sau khi protonation. S hin din ca
nhm metyl vi tr-1, m l tng cng c bn trong imidazole, gy ra hiu ng yu c bn trong
pyrazole do steric cn tr.

3.1.4.2.2 Tnh axit

 Pyrazole l mt axit rt yu vi pKa = 14.21 (i vi s mt proton), nhng c tnh axit hn
pyrrole. Nh vy tnh axit ca h vong nm thnh phn tng cng vi vic a nit pyridin (-N =). Tuy
nhin, vi s ra i ca cc nhm thu hi in t (-1 v -M hiu qu) tnh axit tng ng k (3,5-
dinitropyrazole, pKa = 3,14).

3.1.4.2.3 N-Alkylation

yrazole vi nhm NH-NH c d dng alkyl ha bi methyl iodide hoc dimethyl sulfate vi s
hnh thnh N-alkylpyrazole. Trong pirazole khng i xng, vi tr c thc hin bi nhm alkyl i vo
ph thuc vo tnh cht ca cht alkylating v cc iu kin th nghim. Ni chung, N-alkylation xy ra
vi tr t bi cn tr. Nhng nu b thay th ch c mt cp electron, th m c ca nit ln cn c
gia tng do trng tnh in v nh hng n thnh phn ca hn hp (schem-110) . Tuy nhin, pyrazole
vi nhm th dng mui nitrit to thnh khi alkyl ha vi alkyl halogenua.

3.1.4.2.4 N-Acylation

Pyrazoles vi nhm N-H t do tri qua acyl ha khi c iu tri bng acetyl clorua (mt mnh
hoc vi s c mt ca pyridin) hoc anhydrit axetic. Trong cc pyrazole bt i xng, mc d acyl ha
xy ra c nitrogens, sn phm ca N-acylation nit t gy tr ngi c thu c ch yu do s bin
i ca ng phn khng n inh 311 thnh ng phn n inh hn 310 trong mi trng phn ng
(schem-111)
3.1.4.2.5 Michael Addition

N-Cc pyrazole khng th c tri qua s b sung ca Michael vi cc alken v alkyn hot ha.
Tuy nhin, vi alkyn kch hot hai b sung lin tip xy ra nu alkene trung gian thu c trong qu trnh
phn ng l phn ng (scheme-112). Nhng vi metyl ethynyl ketone hai ln lin tip xy ra cng
mt nguyn t cacbon.(scheme-113)
3.1.4.3 Tn cng Electrophilic ti Carbon

3.1.4.3.1 Phn ng v inh hng

phn ng ca pyrazole tng t nh benzene v phn ng vi cc electrophiles, nhng s

hin din ca nit pyridin (-N =) trong pyrazole lm cho n t phn ng hn pyrrole. Pyrazolium cation
c kh hot tnh i vi electrophiles, nhng anion pyrazole phn ng hu nh d dng nh phenol.

Nit lin kt bi (pyridin) loi b cc vi tr-3 v -5 tng ng vi tr oc v y ca pyridin, trong khi

vi tr-4 c kch hot i vi electrophiles do s gii phng in t t kiu pyrrol nit. S thay th
electrophilic trong pyrazole, xy ra vi tr-4 nh hnh di y (Fig. 32)
 Hn na, s tn cng electrophile u tin vi tr-4 trong pyrazole cng c minh chng bng
s n inh tng i ca cc sn phm trung gian do cuc tn cng electrophilic cc vi tr-3, -4 v -5
(Fig 33). Cc cu trc cng hng cho cuc tn cng ti C-3 v C-5 lin quan n nit c cha ion dng
tch cc (azomethine hoc pyridine-type) nhng cu trc cng hng khng thun li ny vi nit cha
cht tch in dng khng lin quan n cc cuc tn cng in ti C-4. Do , cuc tn cng
electrophile xy ra vi tr-4.

3.1.4.3.2 Nitrate

Nitrat ca pyrazol vi hn hp nitrt axit nitric v axit sulfuric c c xy ra vi tr-4(scheme-

114).
 Nu pyrazole c nitrat ha vi axit nitric c c trong anhydrit axetic, s nitrat xy ra vi tr-1
(ti nitrogen) cung cp l-nitropyrazole 316 c chuyn thnh 4-nitropyrazole 315 khi c x l vi axit
sulfuric m c.(scheme-115).

Phn ng tin hnh vi vic chuyn nitro qua cation 317 bi v 1-nitmpyrazole 316 l mt cht
nitrating hiu qu cho cc hydrocacbon thm. Cc vi tr nitrat ha trong cc pyrazole c th vi cc
cht nitrating khc nhau c th hin trong (Fig 34). Nu pirazole c thay th bng nhm phenyl vi
tr-1, n cnh tranh vi vong pyrazole v nitrat xy ra vi tr para (scheme-116).
3.1.4.3.3 Sulfonation

Pyrazole ch c sulfon ha di cc iu kin phn ng mnh m vi s ra i ca nhm axit

sulfonic ti vi tr-4 (scheme-117)

3.1.4.3.4 Halogenation

Halogenation ca pyrazoles thng xy ra vi tr-4. Pyrazole c th c clo bng cc cht kh

clorua nh nc clo, clo trong carbon tetrachloride, axit hypochlorous, clo trong axit axetic v sulfuryl
clorua trong chloroform. Pyrazole c brom vi brom trong chloroform v brom trong acid acetic
(scheme-118)
3.1.4.3.5 Mercuration

Pyrazole c kh clorat vi tr-4 bng phn ng vi Clorua thy ngn cung cp 325. S bt gi
xy ra vi tr-4, nu l-phenylpyrazole 326 c x l bng thy ngn axetat (scheme-119). Phn ng vi
3- hoc 5-phenylpyrazol cng dn n vic a vo nhm acetoximercury vi tr-4.

3.1.4.3.6 Diazo coupling

Ni chung, pyrazole khng bi diazo coupling vi mui diazonium. Nu nhm kch hot vi tr-3
hoc 5, khp ni diazo xy ra d dng vi tr-4 (scheme-120).
3.1.4.4 Qu trnh oxy ha

Vong Pyrazole ni chung n inh n qu trnh oxy ha, tuy nhin vi peroxit chuyn thnh 2-
oxit ca n.(scheme-121).

Qu trnh oxy ha cc pyrazole vi KMnO4 kim to ra chui alkyl bn chuyn thnh nhm
carboxylic (scheme-122).

3.1.4.5 S kh

Vic kh pyrazole bng natri v ru hoc bng hydro ha xc tc trn kt qu palladium trong
2-pyrazolines (scheme-123).

3.1.4.6 Phn ng vi Nucleophiles

3.1.4.6.1 Nucleophilic Attack Carbon

Halopyrazole khng phn ng, nhng nhm rt in t gn vo nguyn t halogen lm phn

ng i vi cc thay th nucleophilic (scheme-124).
 Vic chiu x pyrazole bng thuc th nucleophilic dn n vic to ra hnh nh nucleophilic
bng vic thay th nguyn t hydro bng nucleophile t vi tr-4 (scheme-125). Nu vi tr-4 bi chim
ng, nguyn t hydro c thay th t vi tr-5 (scheme-126).

3.1.4.6.2 Nucleophiclic Attack Hydrogen

3.1.4.6.2.1 Kim loi

N-baz pyrazole c lithiated vi tr-5 khi iu tri vi n-butyllithium. Nu chim vi tr-5, s

kin lithiation xy ra nhm N-alkyl (scheme-127).
3.1.4.6.2.2 Ring Cleavage thng qua Deprotonation

Vong Pyrazole khng bt ti vi tr-3 c ct bi mt baz mnh (NaNHZ) qua s deproton ha

03.(scheme-128)

3.1.4.7 Phn ng vi cht thiu in t

Phn ng ca pyrazole vi dichlorocarbene trong cc iu kin trung hoa s to ra s gin n

vong cung cp 5-chloropirydoxy 344. Tuy nhin, trong cc iu kin c bn phn ng tin hnh vi s
tn cng ca dichlorocarbene ti vi tr-4 vi s hnh thnh ca 4-dichlorometylpyrazoles 345 m khi x l
vi natri ethoxide cung cp m rng vong 6-ethoxymethylpyridazines 346.(scheme-129).
3.1.4.8 Phn ng Cycloadditioneon

Pyrazole d kin s phn ng theo l thuyt khi dng azadiene hoc 1,3-lng cc ca imine
azomethine v bi phn ng xenlide ha vi dienophiles hoc cc cht dipolarophiles (Fig 35).

Hn na, pyrazol c th c xem xt nh l mt alkene hoc imin v tri qua chu k xo trn
vi dienes hoc 1,3-lng phn (Fig 36).

Tuy nhin, cc phn ng v mt l thuyt c th nhng khng thc t kh thi v cc phn ng

lin quan n cycloadditions khng c bit n vi pyrazoles. Pyrazoles tri qua chu k tun hon vi
DMAD lin quan n chui bn (scheme-130)
3.1.4.9 Chuyn i quang ha

Pyrazole c bin i quang ha thnh imidazole lin quan n vic trao i vi tr N-2 v C-3
ca pyrazole vi vi tr 02 v N-3 ca imidazole.

Phn ng quang ha tip tc Vi s phn ct ca lin kt N-N yu nht, tip theo l cyclization
trung gian phn t 350 n azirine 351 v sau sp xp li thnh imidazole (scheme-131).

3.2 isoxazoles

3.2.1 General

Isoxazole l mt heterocycle 1t-qu cn c nm thnh phn vi oxy (furan-type) v nitrogen

(pyridine-type) cc vi tr -l v -2, nhng khc vi oxazole bi s c mt ca lin kt N-O. Hnh thc
gim mt phn isoxazole (dihydroisoxazole hoc isoxazoline) tn ti trong ba dng ng phn; 354, 355,
v 356, ty thuc vo vi tr ca lin kt i. Vi tr ca tri phiu i c th c i din bi tin t A
(ng bng) vi ch hoa. Hnh thc hon ton gim ca isoxazole c bit n nh l 2,3,4,5-
tetrahydroisoxazole (isoxazolidine) 357.
 S kt hp ca benzen vi cc vi tr 4,5 v 3,4 ca h vong vong isoxazole dn n 1,2-
benzisoxazole (hoc indoxazene) 358 v 2,1-benzisoxazole (anthranil) 359. Cc h thng vong "52 c
nh s nh th hin trong cc cu trc 358 v 359.

Isoxazoles th hin mt s hot ng th y v nng nghip. Mt s isoxazoles quan trng vi

hot ng ca chng c trnh by:
 Isoxazole l cht lng khng mu (nhit = 95 C, D.M. = 2,75 I 0.olD trong benzen v 3,1 d:
0.03 D trong dioxan) vi mi mnh nh pirydy. im si ca isoxazole mc d thp hn pyrazole v
imidazole nhng cao hn oxazole v furan. im si cao hn ca isoxazole l do s lin kt lin phn t
ln hn trong cc phn t isoxazole lin quan n nit pyridin v hydro ti C-3 (Fig 37).
 Isoxazole c coi l mt di vong thm v n th hin phn ng thay th electrophilic v cc thay
i ha hc ca NMR cho cc proton vong l ph hp vi cc h thng thm. Tuy nhin, cc nguyn t
vong, tuy nhin, sa i ng k tnh cht thm ca isoxazole. Isoxazole c coi l s cng hng cng
hng ca cc cu trc cng hng sau (Fig 38)

3.2.2 Tng hp

3.2.2.1 Phn ng ca -Diketones vi Hydroxylamine

y l phng php ph bin nht v c s dng rng ri bao gm cyclization ngng t (3 + 2

cyclization) ca B-diketones vi hydroxylamine vi s c mt ca axit. Phn ng tin hnh thng qua
trung gian monoxime trung gian 360, sau v mt nc theo chu k dn n s hnh thnh ca
isoxazoles 363.(scheme-132).
 Cc B-diketon i xng cung cp isoxazole 3,5-dispstdated, nhng B-diketone khng i xng
vi hydroxylamin cung cp mt hn hp ca isoxazoles isomeric (scheme-133). T l cc sn phm ph
thuc vo nng axit v hng i ca s khuych tn (Fig 39).

Phn ng ny c m rng lin quan n phn ng ca hydroxylamine hydrochloride vi

h thng C-C-C ca cc nhm chc nng khc nhau (scheme-134).

3.2.2.2 Phn ng N-Oxit Nitril vi Alkenes v Alkynes

Phn ng ca cc oxit nitril, c sinh ra ti ch bng cch x l chloroxim vi baz

(triethylamine), vi alkenes v alkynes dn n isoxazole thng qua vic tun hon lng cc 1,3
(scheme-135).
3.2.3 Phn ng

3.2.3.1 Phn ng

Isoxazole cha oxy furan v nit pyridin vi tr -l v -2, do n c coi l c phn ng c

trng ca furan v pyridin. Nhng isoxazole tri qua s thay th electrophilic d hn pyridin v t d hn
furan v kt hp hiu qu ca c tc ng cu trc trong isoxazole; (i) nh hng thu hi in t ca nit
pyridin v (ii) nh hng gii phng in t ca oxy furan. Khi vi tr-4 isoxazole c mt electron
cao, th s thay th in di ng xy ra vi tr-4. Cc cht th gii phng electron cc vi tr-3 v / hoc
-5 c tc dng kch hot, trong khi cc nhm th thu hi electron C 3 v / hoc 05 c tc dng kh hot
tnh i vi ht nhn isoxazole vi tr-4. Cc nhm th vi tr-5 kch hot tc ng kch hot hoc lm
mt hiu lc ln vi tr-4 mnh hn hiu ng gy ra bi cc th th nu c vi tr-3.

3.2.3.2 Phn ng vi Electrophriedles

3.2.3.2.1 Tn cng in t Nit

3.2.3.2.1.1 Bazo

Isoxazole l mt baz yu vi pKa = -2.97 v hiu ng lm suy yu c s ca oxy furan. Hn

na, s hin din ca nhm methyl ti vi tr-3 v / hoc vi tr-5 gy ra hiu ng yu hn na c s do
steric tr ngi tng i cao hn nu nhm methyl c mt vi tr-3 ch khng phi vi tr -5 (3-
methylisoxazole, S-methylisoxazole v 3,5-dimethylisoxazole tng ng vi gi tri pKa ln lt l 1,62,
2,01 v 1,61).

3.2.3.2.1.2 N-Alkylation

Isoxazole, mc d t nht l c bn trong s cc azole, bi N-alkylation khi c x l bng alkyl

iodides hoc sulfat vi s hnh thnh ca mui azolium qualmic. Tuy nhin, cc mui isoxazolium vi
cc N-th th cng knh thu c bng cch x l isoxazoles vi ru s hin din ca axit perchloric.
(scheme-136)

3.2.3.2.1 Tn cng in t carbon

C hai nguyn t hng ngoi gy ra s thay th electrophilic trong vong isoxazole. Bn cht thu
hp electron ca nit pyridin lm chm s tn cng ca electrophile, nhng tc ng gii phng electron
ca nguyn t oxy furan to iu kin cho cuc tn cng in trong ht nhn isoxazole (Fig 40). Cuc tn
cng u tin ca electr ophile ti vi tr-4 trong vong isoxazole c th c hp l ho bi s n inh
tng i ca cc kt qu trung gian c pht hin t cuc tn cng cc vi tr-3, -4 v -5 (Fig 41). Cc
kt qu trung gian t cuc tn cng in gii ti C-3 v C-5 lin quan n cc cu trc cng hng khng
thun li vi nitrogen tch in dng c cha cc phn t ca in t. Tuy nhin, cu trc cng hng
cho trung gian do s tn cng ca electrophile ti C-4 khng lin quan n cu trc cng hng khng
thun li nh vy. V vy thay th electrophil trong isoxazoles xy ra vi tr-4, nhng isoxazoles khng
th thay th electrophilic nu vi tr-4 l chim.
3.2.3.2.2.1 H D trao i

Isoxazole tri qua phn ng trao i H D trong D2SO4 vi tr-4 (scheme-137). S hin
din ca nhm methyl ti cc vi tr-3 v -5 kch hot ht nhn isoxazole Vi s tng cng tc trao i
H D. Tc ng kch hot ca nhm methyl, nu c vi tr-5, tng i ln hn so vi hin ti vi
tr-3. Tc ng kch hot trong 3,5-dimetyl-isoxazole l tng ca cc hiu ng gy ra bi c hai nhm
methyl c mt ti cc vi tr-3 v -5 ring bit.

3.2.3.2.2.2 Nitrate
 Isoxazole c nitrat vi tr-4 bng hn hp nitrt axit nitric v axit sulfuric c c trong iu
kin kim sot (35-40 C)(scheme-138).

Nitrate ca S-methylisoxazole 377 Vi hn hp nitrat ha 60-70 C porduces 5-methyl-4-

nitroisoxazole 378 lin quan n c ch phn ng sau (scheme-139)

Tuy nhin, nitrat ha ca 3-metyl-5-phenylisoxazole 379 vi hn hp nitrat ha xy ra vi tr

para ca vong phenyl. Tuy nhin nitrat vi acetyl nitrat din ra vi tr para ca vong phenyl cng nh
vi tr-4 ca vong isoxazole (scheme-140).
3.2.3.2.2.3 Sulfonation

Vong Isoxazole khng sulfonation, tuy nhin sulfonated Vi oleum trong iu kin quyt lit vi
s ra i ca nhm sulfonic acid ti vi tr-4 (scheme-l4l). Nhng 5-phenylisoxazole 383 c sulfon ha
bi axit chlorosulfonic vi sulfonation ca phenyl ring vi tr meta v para- (scheme-142).

3.2.3.2.2.4 Halogenation

Isoxazole tri qua halogen ha vi clo hoc brom vi tr-4 vi s hnh thnh 4-chloro-386 hoc
4-bromo-387 isoxazoles (scheme-143).
 Nu vong phenyl c mt vi tr 3 v / hoc 5, vic halogen ha xy ra vi tr-4 ca vong
isoxazole (scheme-144). Ixaxazole c iodine vi it khi c acid nitric c c (scheme-145).

3.2.3.2.2.5 Chloromethylation v hydroxymethylmetylation

Phn ng ca isoxazole vi formaldehyde v axit clohiric vi s hin din ca clorua km dn

n chloromethylation ti vi tr-4 (scheme-146).
 Tng t, vic x l formaldehyde vi s hin din ca axit sulfuric gy ra
hydroxymethylmetylation vi tr-4 ca vong isoxazole (scheme-147).

3.2.3.2.2.6 Mercuration

Isoxazole c nh gi vi tr-4 khi c iu tri bng thy ngn acetate (scheme-148).

3.2.3.3 Qu trnh oxy ha

Isoxazole n inh i vi cc cht oxy ha, nhng cc chui bn khng bo hoa v cc nhm
chc oxy bi oxy ha thnh axit tng ng ca chng (scheme-149).
 S n inh ca cc di vong khc nhau c th c so snh bng cch s dng cc phn ng oxy
ha, cho thy vong isoxazole n inh hn so vi cc vong furan trong khi khng n inh hn so vi vong
pyrazol (scheme-150).

3.2.3.4 Phn ng vi Nucleophiles

3.2.3.4.1 Chuyn vi Nucleophilic

V isoxazole c mt electron cao nht vi tr-4, nn y l vi tr a thch cho cuc tn cng

in ng. Cc isoxazole c th bng nguyn t halogen ti vi tr-4 s t bi nh hng bi cc phn ng
thay th nucleophilic (SN ). Tuy nhin, nguyn t halogen ti vi tr-5 c th c thay th nu vi tr-4
c thay th bng cc nhm th hot ha ph hp.(scheme-151)
 Cc nguyn t halogen ti vi tr 3- v S c th c thay th bng cc nucleophiles nu kch hot
bng cch quatemization vong (scheme-152)

3.2.3.4.2 Ring Cleavage qua C-Deprotonation

Phn ng ca isoxazole 3-unsubstituted vi mt baz (ion hydroxit hoc ethoxit) tin hnh tn
cng nucleophilic ti C3-H v dn n sn phm m vong B ketonitrile 405 vi s phn ct ca lin kt
N-O.(scheme-153)

Vic cp bc nguyn t nit lm tng phn ng ca vong isoxazole i vi cc nucleophiles.

Mui isoxazolium 3-unsubstituted 406 phn ng nhanh ngay c vi mt baz yu vi s phn ct ca lin
kt N-O v cung cp cc ketoketimines 408 khng n inh chuyn axt cacboxylic thnh cc acylating.
(scheme-154)
 Nu isoxazole c thay th vi tr-3, nhng khng th vi tr-5, s phn tch vong xy ra khc
v cc phn ng ph thuc vo tnh cht ca cc cht th (scheme-155). Nu vi tr-3 c thay th bng
mt nhm c th loi b c nh l mt anion (nh Cl - v CN- ), phn ng s tin hnh m khng lm
mt lin kt C3-C4 ca vong isoxazole vi vic loi b cc th th C-3 nh mt anion.(scheme-156)

Khi 3-acylisoxazoles 416 c x l vi mt baz, phn ng tin hnh thng qua cuc tn cng
ban u ca mt baz cacbon cacbon cung cp mt mui carboxylat v mt -ketonitrile 417
(scheme-157).
3.2.3.4.3 Reducional Ring Cleavage

Vong Isoxazole d dng bi ct theo iu kin gim. S hydro ha xc tc ca isoxazoles dn n

vic m vong vi s hnh thnh cc enaminones 419 trong iu kin nh c thy phn thnh 1,3-
diketones 420 v gim xung aminoketones 421. Enaminones 419 c th chuyn thnh mt s cc
heterocycles 422(scheme-158)

Vic gim isoxazole vi lithium aluminum hydrua to ra aminoketone lin quan n s phn ct
ca lin kt N-O.(scheme-158)
3.2.3.5 Phn ng ngng t

Nhm metyl vi tr-5 s phn ng mnh hn nhm metyl vi tr-3, nu vi tr-4 c thay th
Vi nhm thu hi in t. Do , nhm metyl vi tnh phn ng tng cng c th d dng c c bng
cc aldehy thm vi s c mt ca diethylamine, nhng nhm 3-metyl vn con nguyn vn.(scheme-159)

3.2.3.6 Rearrangement

Isoxazole (cng cc heterocycles khc vi NO bond), c thay th bng cc chui bn cnh ca

ba nguyn t (hydrazone, oximine v imidine) carbon oc- n nit pyridin loi, tri qua loi c bit
ca s sp xp sp xp li nhit v c bn xc tc, c gi l Boulton-Katritzky sp xp li, bng cch
lm theo c ch tng qut.(scheme-160)
3.2.3.7 Phn ng Ha hc v Nhit

Ixaxazole c chuyn i quang ha hoc nhit thnh oxazoles thng qua 2H-azirine trung gian
428.(scheme-161).

3.3 Isothiazoles

3.3.1 Tng hp chung

Ha hc ca isothiazole bt u vo nm 1956 vi tng hp u tin, mc d saccharit dn xut

ca n 430, cht lm ngt khng carbohydrate, c chun bi vo nm 1879. Isotiazole c nh s
nh trong cu trc 3.
 Vong Benzene c kt hp vi vong isothiazole theo hai cch cung cp c th c hai ng phn
ca benzisothiazole58 ty thuc vo vi tr ca vt nh km; 1,2 benzisothiazole hoc benz [d] isothiazole
431 v 2,1-benzisothiazole hoc benz [c] isothiazole 432 v c nh s c h thng nh sau:

Saccharin l dn xut izotiazole tng hp quan trng nht v c s dng nh cht ngt khng
dinh dng. Vong Isotiazole c kt hp vo cc hp cht hot tnh sinh hc ca cc ng dng dc
phm v cng nghip. Mt s dn cht isothiazol c lit k vi hot ng ca chng.
3.3.2 Tng hp

3.3.2.1 Oxy ha Cyclization ca -Iminothiols

y l phng php c s dng rng ri nht cho vic tng hp cc isothiazoles v lin quan
n chu k oxy ha ca y-iminothiols 433b vi cc halogen hoc hydrogen peroxide to ra cc lin kt
N-S (scheme-162).
 Cyclization xy ra bi s thay th nucleophin trn nguyn t lu hunh qua 434. Phng php
tng hp ny c th c m rng c c benzisothiazoles (scheme-163)

3.3.2.2 Chuyn i vong

Isoxazole c th c chuyn i thnh cc ng trng th tng ng bng vic hydro ha xc

tc ban u vi s phn ct ca lin kt N-O, sau l s sunfua ha vi thioamit 441 v cyclization oxy
ho vi chloranil.(scheme-164)
3.3.2.3 T Alkenes

Isothiazoles c th c iu ch bng cch a mt hn hp ca alkene, sulfur dioxide v

ammonia vo cht xc tc oxit nhit cao.(scheme-165)

Propene v isobutene cung cp isothiazole v 4-methylisothiazole tng ng, nhng 1-butene v

2-butene to ra hn hp ca 3 v 5-methylisothiazole v qu trnh ng phn.

3.3.2.4 T ,-Hp cht Carbonyl Khng bo hoa

Phn ng ,- aldehyde cha bo ho hoc xeton, c thay th bng thiosulfonat vi tr 3, vi

amoniac hoc amin nhit thp dn n s hnh thnh cc isothiazoles lin quan n cyclization (4 +
1) (scheme-166)

3.3.3 Cu trc

Isotiazole (cht lng mu vng, hp 1 13 C) l mt heterocycle phng vi su in t delecalized

v hot ng nh mt phn t thm n inh. Mc gn c inh trong isotiazole rt nh so vi di
mi quan h ca cc dn cht isothiazole61 vi cc gi tri chun ca cc lin kt n v i (Fig 42).
 Isotiazole l cht thm nht trong s 1,2-azoles v theo th t nh isothiazole> pyrazole>
isoxazole. Isotiazole c coi l hn hp cng hng ca cu trc cng hng, trong cc nguyn t
cacbon v nguyn t nit chiu ti m, trong khi nguyn t lu hunh c in tch dng nh (Fig 43).

Cu trc cng hng (iv) c n inh bi C = N v C = S+ , v do ng gp ng k cho

s cng hng lai. Hn na, xp x mt in tch cng ch ra C-4 vi mt electron cao nht, trong
khi C-3 c mt electron thp nht. Vi tr-4 trong isothiazole, do , phn ng mnh hn gp 10 4 ln i
vi cc electron in t so vi d on da trn mt -electron.

3.3.4 Phn ng

3.4.1 Phn ng vi electrophiles

Isotiazole l cht phn ng t nht i vi cc in t trong s 1,2-azole vi lnh phn ng nh

sau: pyrazole> isoxazole> isothiazole, tng t nh trong vong nm nhm vi mt heteroatom: pyrrole>
furan> thiophene. S thay th electrophil trong isothiazole xy ra vi tr-4 v tnh n inh ca trng thi
chuyn i cao hn do kt qu in ng ti C-4 so vi kt qu ca s tn cng electrophile ti C-3 v C-
5 (Fig 44) . Cc cu trc cng hng cho cc trng thi chuyn tip do cuc tn cng in gii ti C-3 v
C-5 lin quan n cc cu trc khng thun li vi azomethine nit tch in.
3.3.4.1.1 Nitration

Isotiazole c nitrat ho di iu kin mnh vi tr-4 bng cch s dng hn hp nitrt ca

axit sulfuric v nitric 230 C.(scheme-167)

3.3.4.1.2 Sulfonation

Isotiazole c sulfonat vi tr-4 khi c x l bng oleum (conc.H 2SO4 + SO3) 1500C
(scheme-168)
3.3.4.1.3 N-Alkylation

Nit vong Isotiazole c c bi alkylazit, dimethyl sulfat hoc alkyl halogenua, nu vi tr-3
hoc -5 trong vong isothiazole c thay th bng mt nhm hydroxyl c th c tautom ha n cu
trc NH nhn (scheme-169). Mc d nhm amino vi tr-3 hoc -5 trong vong isothiazole c th c
coi l c s lin quan tng t trong thuyt tautomism, aminoisothiazole tn ti ch yu l amino
tautomer v tri qua qu trnh tng hp diazot.

3.3.4.2 Phn ng chui dy chuyn

3.3.4.2.1 Phn ng vi Aldehyd thm

S-Methylisothiazole c ngng t vi mt cht thm aldehyde do tng cng hot tnh ca

nhm methyl.(scheme-170)

3.3.4.2.2 Decarboxylation

Isotiazoles c th bng cc nhm cacboxylic ti cc nguyn t cacbon vong decarboxylate d

dng nht vi vic loi b mt nhm carboxylic nm st vi vnh ai nguyn t vong.(scheme-171)
3.3.4.3 Phn ng vi nucleophiles

Cc hot tnh tng i ca cc nguyn t halogen i vi s thay th nucleophilic ph thuc vo

vi tr ca chng trong vong isothiazole. Do vi tr-4 c mt electron cao (vi tr a thch nht thay th
clectrophilic), nguyn t halogen vi tr-4 s t nhy cm vi cc thay th nucleophilic. Cc nguyn t
halogen cc vi tr-3 v -5 trong vong isothiazol c phn ng trong cc s thay th nucleophilic, nu vi
tr-4 c th bng mt nhm clectron thu hi. Nhng nguyn t halogen vi tr-3 t phn ng hn
nguyn t halogen vi tr-5.(scheme-172)

3.3.4.3.2 Chuyn i vong

Phn ng ca mui izothiazolium quatric 456 vi phenylhydrazin dn n pyrazole 457.(scheme-

173).
 Tuy nhin, vic x l mui isothiazolium 458 vi cc hp cht methylene phn ng dn n s
hnh thnh dn xut thiophene 459 lin quan n s phn ct ca lin kt N-S.(scheme-174)

3.3.4.3.3 Lithiation

Isothiazoles c lithiated vi tr-5 bi phn ng vi n-butyllithium v cung cp 5-

lithioisothiazoles phn ng vi mt cht phn ng rng ri a cc nhm chc vi tr 5 ca vong
isothiazole.(scheme-175)

3.3.4.3.4 Ring Cleavage

Isotiazoles n inh tn cng ht nhn ca cc ion hydroxit, nhng mui isothiazolium lin
quan n cc cuc tn cng ca cc ion hydroxit ti vong carbon cung cp vong m 466 thng qua 465
vi s phn ct ca lin kt N-S.(scheme-176)

3.3.4.4 Chuyn i quang ha

 Isotiazoles c chuyn i quang ha thnh thiazoles thng qua mt trung gian 467 (scheme-
l77). S cn bng c thit lp gia isothiazole v thiazole.

3.3.4.5 Qu trnh oxy ha

Cc cht ng vi c trisubstituted bi oxy ho bi peracids vi cc oxy ha oxy ca chng 468

v chng c oxy ha thm ti 1,1-dioxide 469. Tuy nhin qu trnh oxy ha cc isothiazoles, khng th
ti vi tr-3, vi hydrogen peroxide trong acetic acid 80 C cung cp 1,2 -tiazol-3 (2H) -on-1, 1-dioxit
470(scheme-178)