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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
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
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
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).
3.1.4.2.1 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.
3.1.4.2.3 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
3.1.4.3.2 Nitrate
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
3.1.4.3.4 Halogenation
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.
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).
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).
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
3.2.2 Tng hp
3.2.3.1 Phn ng
3.2.3.2.1.1 Bazo
3.2.3.2.1.2 N-Alkylation
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).
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).
3.2.3.2.2.6 Mercuration
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).
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)
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
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
Ixaxazole c chuyn i quang ha hoc nhit thnh oxazoles thng qua 2H-azirine trung gian
428.(scheme-161).
3.3 Isothiazoles
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
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)
3.3.3 Cu trc
3.3.4 Phn ng
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.
3.3.4.2.2 Decarboxylation
3.3.4.3.3 Lithiation
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)