CN108383803A - A kind of synthetic method of 2,4 2 substituted oxazoline - Google Patents
A kind of synthetic method of 2,4 2 substituted oxazoline Download PDFInfo
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- CN108383803A CN108383803A CN201810430448.5A CN201810430448A CN108383803A CN 108383803 A CN108383803 A CN 108383803A CN 201810430448 A CN201810430448 A CN 201810430448A CN 108383803 A CN108383803 A CN 108383803A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The invention discloses one kind 2, the synthetic method of 4 two substituted oxazolines, this method is that methyl ketone compounds are carried out cyclization in the DMSO solution system containing ammonium persulfate and haloid and/or halogen simple substance, up to 2,4 two substituted oxazolines, this method is using cheap methyl ketone compounds, quaternary ammonium salt and dimethyl sulfoxide (DMSO) etc. as raw material, in mild reaction conditions and under without a huge sum of money or precious metal catalyst effect, 2 are synthesized by one kettle way high yield, 4 two substituted oxazoline class compounds, are conducive to industrialized production.
Description
Technical field
The present invention relates to a kind of synthetic methods for disliking azole compounds, more particularly to one kind is by methyl ketone compounds and nothing
Machine quaternary ammonium and dimethyl sulfoxide (DMSO) build method of the oxazole cyclization at 2,4 two substituted oxazolines jointly, belong to pharmaceutical intermediate synthesis neck
Domain.
Background technology
It is a kind of compound using oxazole ring as parent to dislike azole compounds, and oxazole ring is the five-ring heterocycles containing N and O, is disliked
Azole compounds are widely present in many pharmacological activity molecules and natural products, are that field of medicaments is a kind of highly important organic
Compound, the molecular formula with pharmaceutical activity common at present are as follows：
In early days, evil azole compounds, which are relied primarily on, is extracted from natural products by physical method, but relies solely on physics
Extraction cannot meet the needs of existing society.A large amount of research staff carry out the chemical synthesis process for disliking azole compounds
Research, achieves some achievements.Report that more is to synthesize two substituted oxazoline class chemical combination using methyl ketone for raw material at present
Object, such as ([1] Jiang, H.F.；Huang,H.W.；Cao,H.；Qi,C.R.Org.Lett.2010,12,5561.[2]Gao,
Q.H.；Fei,Z.；Zhu,Y.P.；Lian,M.；Jia,F.C.；Liu,M.C.；She,N.F.；Wu,
A.X.Tetrahedron.2013,69,22.[3]Xue,W.J.；Li,Q.；Zhu,Y.P.；Wang,J.G.；Wu,
A.X.Chem.Comm.2012,48,3485.[4]Xue.W.J.；Zhang,W.；Zheng,K.L.；Dai,Y.；Guo,Y.Q.；
Li,H.Z.；Gao,F.F.；Wu,A.X.Asian.J.Org.Chem.2013,2,638.[5]Chatterjee,T.；Cho,
J.Y.；Cho,E.J.；J.Org.Chem.2016,81,6995-7000；[6]Liu,C.K.；Yang,Z.；Zeng,Y.；Guo,
K.；Fang, Z.Asian.J.Org.Chem.2017,6,1104.) these document reports use methyl ketone can be at for raw material
Work(, which obtains, dislikes azole compounds.Other than disliking azole compounds using methyl ketone synthesis, also it has been reported use there are many more method
In synthesis oxazole derivatives, such as ([7] Forsyth, C.J.；Ahemd,F.；Cink,R.D.；Lee,
C.S.J.Am.Chem.Soc.1998,120,5597.[8]Feldman,K.S.；Eastman,K.J.；Lessene,
G.Org.Lett.2002,4,3525.[8]Burgett,A.W.J.；Li,Q.Y.；Wei,Q.；Harran,
P.G.Angew.Chem.Int.Ed.2003,115,5111.[9]Conqueron,P.Y.；Didier,C.；Ciufolini,
M.A.Angew.Chem.Int.Ed.2003,42,1411.[10]Nicolaou,K.C.；Hao,J.L.；Reddy,M.V.；Rao,
P.B.；Rassias,G.；Snyder,S.A.；Huang,X.H.；Chen,D.Y.K.；Brenzovich,W.E.；
Giuseppone,N.；Giannakakou,P.；O’Brate,A.J.Am.Chem.Soc.2004,126,12897.[11]
Zhang,J.M.；Ciufolini,M.A.Org.Lett.2009,11,2389.[12]Zhang,J.M.；Ciufolini,
M.A.Org.Lett.2011,13,390.) reporting can be obtained using N- alkylamide derivatives by intramolecular cyclization reaction
Azole compounds must be disliked, following reaction formula is typically reacted：
In addition, the synthesis of the evil azole compounds of report in the prior art all uses the conducts such as noble metal or heavy metal
Catalyst, such as document ([13] He, W.M.；Li,C.Q.；Zhang,L.M.J.Am.Chem.Soc.2011,133,8482.[14]
Peng,H.H.；Akhmedov,N.G.；Liang,Y.F.；Jiao,N.；Shi,X.D.J.Am.Chem.Soc.2015,137,
8912.[15]Mai,S.Y.；Rao,C.Q.；Chen,M.,Su,J.H.；Du,J.F.；Song,Q.L.Chem.Comm.2017,
53,10366.[16]Grotkopp,O.；Ahmad,A.；Frank,W.；Müller,T.J.J.Org.Biomol.Chem.2011,
9,8130.[17]Zheng,M.F.；Huang,L.B.；Huang,H.W.；Li,X.W.；Wu,W.Q.；Jiang,
H.F.Org.Lett.2014,16,5906.[18]Bathula,S.R.,Reddy,M.P.；Viswanadhan,K.K.D.R.；
Sathyanarayana,P.；Reddy, M.S.Eur.J.Org.Chem.2013,2013,4552-4557.) disclose using Au,
Au-Fe, Au-Cu, Pd, NBS etc. are as the catalyst to azole compounds are disliked in catalytic cyclization synthesis.There are some for these methods obviously
Technological deficiency, the catalyst of use is of high cost, and easily causes environmental pollution, and the cost of material of substrate is also higher, reaction condition
It is required that high, yield is relatively low, is unfavorable for industrialized production, and especially these methods can only obtain the oxazole ring of 2,5 substitutions.
2016, document ([19] Chen, L.L.；Li,H.J.；Li,P.H.；Wang, L.Org.Lett.2016,18,3646) it discloses
It is a kind of to carry out alkyl coupling under the visible light catalytic of 9- phenyl -10- methylacridine perchlorates by oxazole ring, obtain 2,4
Disubstituted evil azole compounds.But this method catalyst and cost of material are high.
Invention content
For the construction method of existing oxazole ring, that there are costs of material is high, yield is relatively low, need to use heavy metal or your gold
Belong to and be used as catalyst, it is difficult to obtain 2, the defects of 4 substituted oxazoline, cheap first is utilized the purpose of the invention is to provide a kind of
Base ketone compounds, quaternary ammonium salt and dimethyl sulfoxide (DMSO) etc. are used as raw material, are urged in mild reaction conditions and without a huge sum of money or noble metal
Under change effect, pass through the method for one kettle way high yield 2,4 two substituted oxazoline class compounds of synthesis.
In order to achieve the above technical purposes, the present invention provides a kind of synthetic method of 2,4 two substituted oxazolines, this method is
Methyl ketone compounds carry out cyclization in the DMSO solution system containing ammonium persulfate and haloid and/or halogen simple substance,
To obtain the final product；
The methyl ketone compounds have 1 structure of formula：
2,4 2 substituted oxazoline has 2 structure of formula：
Wherein, R is alkyl, aryl or aromatic heterocyclic.
Preferred scheme, R are isobutyl group, naphthalene, the naphthalene containing substituent group, benzene, the phenyl containing substituent group, thienyl, furan
It mutters base or pyrrole radicals.More preferably scheme, R can be alkyl, and alkyl includes predominantly branched alkyl, or cycloalkanes
Base, common alkyl such as isobutyl group etc..R can be the phenyl containing substituent group, and the phenyl containing substituent group includes halogen-substituted
Base, alkyl-substituted phenyl, nitro substituted-phenyl, alkoxy substituted phenyl or alkylthio group substituted-phenyl.Halogen substituted phenyl includes
The phenyl that fluorine, chlorine, bromine or iodine replace, it can be common that the phenyl that fluorine, chlorine or bromine replace.Substituted quantity can be 1~5, often
The substituent group quantity seen is 1~3, and the position of substitution on phenyl ring can be commutable any position on phenyl ring, substituent group
Position the synthesis of oxazole ring is influenced it is little.Alkyl-substituted phenyl is mainly the phenyl of short-chain alkyl substitution, such as C1~C5Alkane
The quantity of base substituted-phenyl, substituent group is generally 1~3, common for mono-substituted alkyl-substituted phenyl, taking on phenyl ring
Subrogate that set can be commutable any position on phenyl ring, the position of substituent group influences the synthesis of oxazole ring little.Alkoxy
Substituted-phenyl is mainly the phenyl of lower alkyloxy substitution, such as C1~C5Alkoxy substituted phenyl, the quantity of substituent group is generally
1~2, common for mono-substituted alkoxy substituted phenyl, the position of substitution on phenyl ring can be commutable on phenyl ring
Any position.Sulphur oxygroup substituted-phenyl is mainly the phenyl of short chain sulphur oxygroup substitution, such as C1~C5Sulphur oxygroup substituted-phenyl, take
The quantity of Dai Ji is generally 1~2, common for mono-substituted sulphur oxygroup substituted-phenyl, and the position of substitution on phenyl ring can be with
For commutable any position on phenyl ring.Nitro substituted-phenyl is common for mono-substituted nitro substituted-phenyl, on phenyl ring
The position of substitution can be commutable any position on phenyl ring.Cyano substituted-phenyl is common for mono-substituted cyano substituted benzene
Base, the position of substitution on phenyl ring can be commutable any position on phenyl ring.R can be the naphthalene containing substituent group, packet
Containing at least one of halogen, alkyl, alkoxy, alkylthio group, nitro, cyano substituent group.Theoretically, the naphthalene containing these substituent groups
Methyl ketone is suitable for synthesizing corresponding oxazole ring, and the present invention enumerates typical acetonaphthone and enumerated as synthesis oxazole ring
Explanation.
Preferred scheme, the haloid include at least one of TBAI, KI, TBAB；The halogen simple substance includes I2.Most
Preferred haloid is TBAI, and quaternary ammonium salt of other iodine alkali metal salts or other halogens etc., which has, relatively preferably promotes to dislike
The positive effect that azoles ring generates.I2Also there is facilitation to the generation of oxazole ring, but effect is much worse than TBAI.
Preferred scheme, ammonium persulfate are 1~2.5 times of methyl ketone compounds mole.Most preferably 1.5 times.
The integral molar quantity of preferred scheme, haloid and halogen simple substance be methyl ketone compounds mole 10~
30%.Most preferably 15~25%.
Preferred scheme, a concentration of 0.1~1mol/L of the methyl ketone compounds in DMSO solution system.Most preferably
0.15~0.25mol/L.
Preferred scheme, DMSO solution system can include water or other solvents, and DMSO mixed solution systems include volume
Than no more than 1/3 water and/or other organic solvents.But pure DMSO system is most beneficial for the synthesis of oxazole ring, such as water/DMSO
Water content is higher in mixed solution system, and under the same terms, relative to pure DMSO solution system, the yield of target product reduces.
The temperature of preferred scheme, the cyclization is 100~140 DEG C, and the reaction time is 1~6 hour.More preferably
The temperature of scheme, cyclization is 110~130 DEG C, and the reaction time is 1.5~2.5 hours.Reaction temperature is too high or too low
Cyclisation product is reduced, and reaction time extension causes side reaction to increase, the reaction time is too short, and conversion ratio is relatively low.
A kind of synthetic reaction equation of 2,4 2 substituted oxazoline of the present invention is as follows：
The ammonium root that α methyl that the reaction is provided by two methyl ketone molecules, ammonium persulfate molecule provide from
The oxygen that son and dimethyl sulfoxide (DMSO) molecule provide carries out asymmetric cyclisation, synthesizes oxazole ring, and 2,4 contain substituent group, and 5 are
Hydrogen, 2,4 bit substituents are the substituent R that methyl ketone introduces.
The present invention also provides the synthetic reaction mechanism of 2,4 2 substituted oxazolines：It is sub- with acetophenone and ammonium persulfate and diformazan
Sulfone coupling builds oxazole ring to be illustrated to reaction mechanism：By consulting and referring to pertinent literature, a series of machine is devised
Research experiment is managed, shown in following reaction equation (1), equation (2) and equation (3).Reaction equation (1) presses down for free radical
System experiment.The synthesis that 2,4 two substituted oxazolines are carried out under standard laboratory conditions, adds suitable 2,2,6,6- in the reaction system
Tetramethyl piperidine oxygroup (TEMPO) or butylated hydroxy-methylbenzene (BHT) find reaction or obtain 2,4 two with good yield
Substituted oxazoline target compound 3a.To illustrate that the reaction is not carried out according to radical reaction mechanism.Reaction equation (2) is
The experiment for detecting intermediate, stopped reaction after reacting 30 minutes at the standard conditions, is detected by GC-MS in reaction system
Thus intermediate A is further used as starting material and replaces acetophenone by intermediate A that may be present.It is worth noting that, intermediate
Body A can only be converted into 2,4 two substituted oxazoline of final products at the standard conditions, and work as I2Or S2O8 2-When being removed respectively, do not have
Final products can obtain, to illustrate that intermediate A is necessary intermediate in 2,4 two substituted oxazoline building-up processes.Then, I
Further use A and C in S2O8 2-With reacted at the standard conditions in the presence of DMSO, can be obtained with good yield target production
Object, such as equation (3).And b, c and d can be seen that DMSO and S from equation (3)2O8 2-It is that follow-up cyclization must can not
Few compound, while demonstrating acetophenone A and generating intermediate C under the conditions of standard reaction.
Standard reaction condition：Substrate (1.0 equivalent), (NH4)2S2O8(3.0 equivalent), TBAI (20mol%), DMSO
(3mL) is stirred 2 hours at 120 DEG C.
It is proposed that acetophenone reacts possible conjunction with ammonium persulfate, dimethyl sulfoxide coupling structure nitrogen oxa- ring according to above-mentioned experiment
Reaction mechanism is managed, shown in following reaction route.- the Csp of part acetophenone3- H keys are by I-Aoxidize the I generated2Activation, replaces
Reaction forms intermediate A, and intermediate A is in S2O8 2-Under oxidation, a methyl H atom of intermediate A, the carbon of generation are removed
Negative atom attack DMSO is coupled, then removes small molecule DMS, obtains intermediate B (can be detected by GC-MS).Meanwhile
Quaternary ammonium radical ion is heated to discharge ammonia, and part acetophenone, which is easy to be condensed with ammonia generation, generates intermediate C, and intermediate C and centre
Substitution reaction occurs for body B, and amino replaces iodine, and in substitution reaction product includes unstable hydroxyl and active methyl, holds
Intramolecular cyclization easily occurs, obtains target product (TM).
Compared with the prior art, the advantageous effects that technical scheme of the present invention is brought：
1) it is avoided in 2,4 two substituted oxazoline building-up processes of the invention using heavy metal or noble metal as catalyst,
And halogen or haloid cheap and easy to get is used not only to save cost, and avoid the pollution of environment as catalyst.
2) methyl ketone and the works such as dimethyl sulfoxide (DMSO) and ammonium persulfate are used in 2,4 2 substituted oxazoline building-up processes of the invention
For base stock, these raw materials are all existing conventional industrial chemicals, of low cost, are conducive to industrialized production.
3) in 2,4 2 substituted oxazoline building-up processes of the invention using inorganic quaternary ammonium radical ion as oxazole cyclization at
Nitrogen source, the middle organic amine used, has absolute advantage in cost compared with the prior art.
4) one pot reaction is used in 2,4 two substituted oxazoline building-up processes of the invention, and reaction condition is mild, Ke Yi
It is reacted in air environment, it is easy to operate, meet demand of industrial production.
5) raw material availability is high in building-up process in 2,4 two substituted oxazoline building-up processes of the invention, and product yield reaches
80% or so.
Description of the drawings
Fig. 1 is the nucleus magnetic hydrogen spectrum figure of 2,4 2 substituted oxazolines prepared by embodiment 1；
Fig. 2 is the nuclear-magnetism carbon spectrogram of 2,4 2 substituted oxazolines prepared by embodiment 1；
Fig. 3 is the nucleus magnetic hydrogen spectrum figure of 2,4 2 substituted oxazolines prepared by embodiment 4；
Fig. 4 is the nuclear-magnetism carbon spectrogram of 2,4 2 substituted oxazolines prepared by embodiment 4；
Fig. 5 is the nucleus magnetic hydrogen spectrum figure of 2,4 2 substituted oxazolines prepared by embodiment 13；
Fig. 6 is the nuclear-magnetism carbon spectrogram of 2,4 2 substituted oxazolines prepared by embodiment 13；
Fig. 7 is the nucleus magnetic hydrogen spectrum figure of 2,4 2 substituted oxazolines prepared by embodiment 16；
Fig. 8 is the nuclear-magnetism carbon spectrogram of 2,4 2 substituted oxazolines prepared by embodiment 16；
Fig. 9 is the nucleus magnetic hydrogen spectrum figure of 2,4 2 substituted oxazolines prepared by embodiment 18；
Figure 10 is the nuclear-magnetism carbon spectrogram of 2,4 2 substituted oxazolines prepared by embodiment 18.
Specific implementation mode
Following embodiment is intended to further illustrate the content of present invention, rather than limits the protection model of the claims in the present invention
It encloses.
Unless otherwise stated, all reactions carry out in the seal pipe (25mL) of threaded end.
All reaction raw materials solvents are obtained from commercial source, and are used without further purification.
Product separation uses silica gel chromatographic column, silica gel (300 mesh of granularity~400 mesh).
All target compounds are based on GC-MS and NMR (1H and 13C) spectroscopic data is characterized.
1H NMR (400MHz) and 13C NMR (100MHz) detections use Bruker ADVANCE III spectrometers, with
CDCl3For solvent, using TMS as internal standard, chemical shift is reference with the 0.0ppm of tetramethylsilane in terms of parts per million (ppm)
Displacement.Multiplicity is explained using following abbreviation (or combinations thereof)：S=is unimodal, and d=is bimodal, t=triplets, q=quartets, m
=multiplet, br=broad peaks.The unit of coupling constant J is hertz (Hz).Chemical shift is indicated with ppm, is existed with reference to deuterochloroform
Center line of the center line or the deuterated DMSO of reference of 77.0ppm triplets in 39.52ppm septets.
GC-MS is detected using GC-MS QP2010 equipment, and HRMS is measured using electron ionization (EI) method, mass-synchrometer
Type is TOF, and EI is detected using Esquire 3000plus instruments.
1, condition optimizing is tested：
For using acetophenone as reaction base stock, seeks best reaction condition, to quaternary ammonium salt type and dosage, urge
Multiple influence factors such as agent type and dosage, reaction temperature and time, reaction dissolvent and dosage are inquired into.
Table 1. optimizes reaction conditiona
From table 1 it follows that compared with other solvents, DMSO is the unique active solvent (table for participating in being formed oxazole ring
1, entry 2~5), individually use the common solvents such as DMF, toluene, methanol, acetonitrile that can not all obtain target product, main cause
It is the oxygen source that DMSO is oxazole ring structure, therefore, in solvent has to containing suitable DMSO, oxazole ring can be just successfully generated.
Simultaneously it is demonstrated experimentally that the mixed solvent of DMSO, such as DMSO/H can also be used2O, with the raising of dampening ratio, yield can be appropriate
Reduce (table 1, entry 6 and 7).
From table 1 it follows that ammonium persulfate has played key effect in oxazole cyclization in, in not ammonium persulfate
In the case of product structure can change, what is obtained is not oxazole ring product, other quaternary ammonium salts such as ammonium acetate, ammonium iodide and carbonic acid
Ammonium etc. (table 1 is entry 8 to 10 respectively), cannot get oxazole ring product.
From table 1 it follows that TBAI is oxazole cyclization into catalyst important in the process, although TBAB, I2And I-Equal liquid
With certain catalytic action, but effect is much less than use TBAI as catalyst (table 1, entry 11 to 13).Especially
It is noted that the oxazole ring synthetic reaction of the present invention is unable to get target product (table in the case of no addition catalyst
1, entry 14).
From table 1 it follows that temperature is also to influence another key factor of target product yield.Fully at 120 DEG C
Under stirring, reaction can smoothly complete in 2h, but be reacted more than 4h at a temperature of 100 DEG C, moreover it is possible to detect a certain amount of benzene second
Ketone does not convert, and reaction is more than 12h at a temperature of 80 DEG C, and can only obtain micro target product, (table 1 is entry respectively
15 and 16), and extend the reaction time at 120 DEG C to 12h, product yield is substantially reduced.Reaction is further respectively in O2With Ar's
It is carried out in atmosphere, the two can obtain similar result (table 1, respectively entry 18 and 19).
To sum up Optimal Experimental, obtain oxazole cyclization at optimum reaction condition：Acetophenone (0.5mmol), (NH4)2S2O8
(3.0 equivalents, 0.75mmol), TBAI (20mol%), DMSO (3mL), 120 DEG C of reaction temperature, reaction time 2h.
2, substrate Optimal Experimental：
Determine oxazole cyclization at optimum reaction condition after, further to the range of choice of acetophenone derivs carry out
It probes into, experimental result is as shown in table 2, the electronic effect for the different substituents for including on the phenyl ring of acetophenone derivs is to oxazole
The synthesis of ring influences smaller.Meanwhile the position of the benzene ring substituents of acetophenone derivs there almost is not the synthesis of oxazole ring yet
Have an impact, the acetophenone derivs of various positions substitution can obtain oxazole ring with fabulous yield.When such as substituent group to align,
Acetophenone derivs can obtain oxazole ring (3b to 3g, respectively 70 to 88% yields) with fabulous yield.When substituent group
When meta position is changed into position from contraposition, the acetophenone derivs containing methyl (3h) and halogen (3i, 3j and 3k) can also be well
Oxazole ring is synthesized, respectively obtains 85%, 80%, 78% and 62% yield, and meta position is when haling electron group nitro, it can be with
Oxazole ring (3l, 47%) is obtained with moderate yield.When the position of substituent group be ortho position when, methyl, methoxyl group or halogen etc. all with
Higher yield obtains oxazole ring, and such as with 85%, 75% and 78% yield acquisition required product 3m, 3n and 3o, (3m is extremely respectively
3o)。
The range of 2. acetophenone derivs substrate of table optimizationa,b
aReaction condition：Acetophenone (0.5mmol), (NH4)2S2O8(3.0 equivalents, 0.75mmol, 170mmg), TBAI
(20mol%), DMSO (3mL), 120 DEG C of reaction temperature, reaction time 2h.
bSeparation yield.
cThe x-ray crystal structure of product is shown.
dReaction carries out 6 hours.
After having studied the range of choice of acetophenone derivs, it is intended to convert other methyl ketone to the disubstituted evils of 2,4-
Azoles.Many experiments show that 2- acetonaphthones can obtain product 4a as acetophenone with excellent yield (75%).It is astonishing
, when studying heterocyclic methyl ketone (2- furans acetone and 2- acetyl thiophenes) at optimum conditions, reaction can also carry out
Very well (4b, 58%；And 4c, 52%).In addition, in the reaction of certain reports, there is no stable conjugated structure the case where
Under, aliphatic methyl ketone is not controlled by desired approach.And pinacoline successfully obtains mesh with 46% yield at the standard conditions
Mark compound 4d.
The range of other methyl ketone derivatives of table 3a,b
aReaction condition：Acetophenone (0.5mmol), (NH4)2S2O8(3.0 equivalents, 0.75mmol170mmg), TBAI
(20mol%), DMSO (3mL), 120 DEG C of reaction temperature, reaction time 2h.
bSeparation yield.
It presses following operation and carries out in following example 1~18：
By methyl ketone compounds (0.5mmol), (NH4)2S2O8(3 equivalents, 0.75mmol, 170mg), TBAI
(20mol%, 18mg), DMSO (3mL) are added in seal pipe.Reactant is vigorously stirred 2 hours at 120 DEG C.Reaction is completed
Afterwards, mixture is cooled to room temperature, is washed out and uses H2O and ethyl acetate (EA) extraction.Finally, it is concentrated with rotary evaporator
Extract liquor and by using silica gel (200-300 mesh size) and petroleum ether (PE)/column color of the ethyl acetate (EA) as eluant, eluent
Spectrometry is purified.
Embodiment 1
(phenyl)(4-phenyloxazol-2-yl)methanone(3a)
52.9mg, yield 85%, dark yellow solid.
1H NMR(400MHz,CDCl3) δ 8.60 (d, J=7.7Hz, 2H), 8.15 (s, 1H), 7.85 (d, J=7.5Hz,
2H), 7.68 (t, J=7.3Hz, 1H), 7.56 (d, J=15.1Hz, 2H), 7.46 (d, J=7.5Hz, 2H), 7.39 (t, J=
7.2Hz,1H).
13C NMR(101MHz,CDCl3)δ178.71,157.52,142.68,136.22,134.94,134.03,
131.03,129.91,128.89,128.86,128.49,125.83.
Embodiment 2
(4-methylphenyl)(4-(4-methylphenyloxazol)-2-yl)methanone(3b)
60.9mg, yield 88%, crocus solid.
1H NMR(400MHz,CDCl3) δ 8.49 (d, J=7.6Hz, 2H), 8.08 (s, 1H), 7.72 (d, J=7.1Hz,
2H), 7.34 (d, J=7.8Hz, 2H), 7.25 (d, J=5.3Hz, 2H), 2.45 (s, 3H), 2.39 (s, 3H)13C NMR
(101MHz,CDCl3)δ178.40,157.59,145.10,142.64,138.77,135.67,132.49,131.16,
129.54,129.22,127.17,125.73,21.81,21.32.
Embodiment 3
(4-methoxylphenyl)(4-(4-methoxylphenyloxazol)-2-yl)methanone(3c)
63.5mg, yield 82%, yellow solid.
1H NMR(400MHz,CDCl3) δ 8.64 (d, J=7.7Hz, 2H), 8.04 (s, 1H), 7.77 (d, J=7.4Hz,
2H), 7.00 (dd, J=17.3,7.6Hz, 2H), 3.91 (s, 3H), 3.85 (s, 3H)
13C NMR(101MHz,CDCl3)δ177.11,164.37,160.02,157.67,142.29,134.90,
133.56,127.97,127.16,122.70,114.26,113.80,55.52,55.32.
Embodiment 4
(4-fluorophenyl)(4-(4-fluorolphenyloxazol)-2-yl)methanone(3d)
60.6mg, yield 85%, yellow solid.
1H NMR(400MHz,CDCl3)δ8.77–8.56(m,2H),8.11(s,1H),7.87–7.77(m,2H),7.22
(d, J=8.7Hz, 2H), 7.16 (t, J=8.4Hz, 2H)
13C NMR(101MHz,CDCl3) δ 176.87,166.45 (d, J=257.1Hz), 163.04 (d, J=
248.9Hz), 157.37,141.84,135.94,133.88 (d, J=9.6Hz), 132.78 (d, J=9.9Hz), 131.21 (d,
), J=2.8Hz 130.64 (d, J=9.3Hz), 127.65 (d, J=8.3Hz), 115.89 (t, J=22.4Hz)
Embodiment 5
(4-chlorophenyl)(4-(4-chlorophenyloxazol)-2-yl)methanone(3e)
61.2mg, yield 77%, yellow-brown solid.
1H NMR(400MHz,CDCl3) δ 8.55 (d, J=8.2Hz, 2H), 8.14 (s, 1H), 7.76 (d, J=8.1Hz,
2H), 7.53 (d, J=8.2Hz, 2H), 7.43 (d, J=8.1Hz, 2H)
13C NMR(101MHz,CDCl3)δ177.16,157.31,141.75,140.86,136.47,134.79,
133.09,132.39,129.17,128.90,128.25,127.07.
Embodiment 6
(4-iodophenyl)(4-(4-iodophenyloxazol)-2-yl)
methanone(3f)
91.5mg, yield 73%, faint yellow solid.
1H NMR(400MHz,CDCl3) δ 8.29 (d, J=7.6Hz, 2H), 8.16 (s, 1H), 7.92 (d, J=7.9Hz,
2H), 7.79 (d, J=7.2Hz, 2H), 7.56 (d, J=7.5Hz, 2H)
13C NMR(101MHz,CDCl3)δ177.73,157.31,141.89,138.56,138.05,137.91,
134.05,132.22,131.04,129.44,129.27,127.45,115.48,102.91,94.62.
Embodiment 7
(4-sulfurmethylphenyl)(4-(4-sulfurmethylphenyloxazol)-2-yl)methanone
(3g)
59.7mg, yield 70%, yellow solid.
1H NMR(400MHz,CDCl3) δ 8.45 (d, J=8.2Hz, 2H), 8.01 (s, 1H), 7.65 (d, J=8.0Hz,
2H),7.36–7.09(m,4H),2.46(s,3H),2.43(s,3H).
13C NMR(101MHz,CDCl3)δ177.30,157.51,147.62,142.07,139.52,135.73,
131.30,131.00,126.57,126.43,126.09,124.60,15.46,14.54.
Embodiment 8
(3-methylphenyl)(4-(3-methylphenyloxazol)-2-yl)methanone(3h)
58.9mg, yield 85%, dark yellow solid.
1H NMR(400MHz,CDCl3) δ 8.44 (d, J=7.3Hz, 1H), 8.30 (s, 1H), 8.13 (s, 1H), 7.71-
7.60 (m, 2H), 7.46 (q, J=7.9Hz, 2H), 7.35 (t, J=7.5Hz, 1H), 7.20 (d, J=7.5Hz, 1H), 2.48
(s,3H),2.43(s,3H).
13C NMR(101MHz,CDCl3)δ179.02,157.60,142.77,138.62,138.32,136.14,
134.99,134.86,131.16,129.84,129.63,128.79,128.49,128.37,126.46,122.96.
Embodiment 9
(3-fluorophenyl)(4-(3-fluorophenyloxazol)-2-yl)methanone(3i)
58.9mg, yield 80%, white-yellowish solid.
1H NMR(400MHz,CDCl3) δ 8.42 (d, J=7.8Hz, 1H), 8.30 (d, J=9.6Hz, 1H), 8.17 (s,
1H), 7.65-7.48 (m, 3H), 7.40 (dt, J=16.1,7.5Hz, 2H), 7.08 (t, J=8.3Hz, 1H)13C NMR
(101MHz,CDCl3) δ 177.04 (d, J=2.6Hz), 164.03 (d, J=66.1Hz), 161.58 (d, J=67.4Hz),
157.18,141.74 (d, J=2.7Hz), 136.94,136.53 (d, J=7.0Hz), 131.85 (d, J=8.3Hz), 130.58
(d, J=8.3Hz), 130.21 (d, J=7.7Hz), 126.83 (d, J=3.0Hz), 121.42 (d, J=2.9Hz), 121.20
(d, J=21.5Hz), 117.69 (d, J=23.5Hz), 115.83 (d, J=21.2Hz), 112.86 (d, J=23.2Hz)
Embodiment 10
(3-chlorophenyl)(4-(3-chlorophenyloxazol)-2-yl)methanone(3j)
62mg, yield 78%, pink colour yellow solid.
1H NMR(400MHz,CDCl3) δ 8.52 (d, J=7.0Hz, 2H), 8.18 (s, 1H), 7.83 (s, 1H), 7.71 (d,
J=7.0Hz, 1H), 7.65 (d, J=7.9Hz, 1H), 7.52 (t, J=7.4Hz, 1H), 7.43-7.31 (m, 2H)
13C NMR(101MHz,CDCl3)δ177.09(s),157.20(s),141.63(s),136.98(s),136.19
(s),135.01(s),134.81(s),134.06(s),131.48(s),130.77(s),130.25(s),129.88(s),
129.22(s),129.02(s),125.91(s),123.92(s).
Embodiment 11
(3-bromophenyl)(4-(3-bromophenyloxazol)-2-yl)methanone(3k)
63.1mg, yield 62%, dark yellow solid.
1H NMR(400MHz,CDCl3) δ 8.68 (s, 1H), 8.58 (d, J=7.8Hz, 1H), 8.18 (s, 1H), 7.99 (s,
1H), 7.79 (dd, J=17.3,7.9Hz, 2H), 7.53 (d, J=7.9Hz, 1H), 7.46 (t, J=7.8Hz, 1H), 7.34 (t,
J=7.8Hz, 1H)
13C NMR(101MHz,CDCl3)δ177.11,157.20,141.53,136.99,136.41,133.68,
131.97,131.74,130.52,130.14,129.70,128.83,127.20,124.40,123.12,122.77.
Embodiment 12
(3-nitrophenyl)(4-(3-nitrophenyloxazol)-2-yl)methanone(3l)
39.8mg, yield 47%, dark yellow solid.
1H NMR(400MHz,CDCl3) δ 9.54 (s, 1H), 8.93 (d, J=7.7Hz, 1H), 8.67 (s, 1H), 8.55 (d,
J=8.2Hz, 1H), 8.38 (s, 1H), 8.24 (dd, J=17.7,7.9Hz, 2H), 7.82 (t, J=7.9Hz, 1H), 7.70 (t,
J=8.0Hz, 1H)
13C NMR(101MHz,CDCl3)δ175.92,157.09,148.75,148.33,141.04,137.99,
136.31,135.74,131.59,131.27,130.24,129.94,128.34,126.08,123.75,120.70.
Embodiment 13
(2-methylphenyl)(4-(2-methylphenyloxazol)-2-yl)
methanone(3m)
59.0mg, yield 85%, bright yellow solid.
1H NMR(400MHz,CDCl3) δ 8.09 (d, J=7.6Hz, 1H), 7.97 (s, 1H), 7.75 (d, J=32.5Hz,
1H), 7.45 (t, J=7.4Hz, 1H), 7.32 (t, J=7.6Hz, 5H), 2.54 (s, 3H), 2.47 (s, 3H)13C NMR
(101MHz,CDCl3)δ182.13,182.13,157.38,142.02,139.56,138.06,135.71,134.94,
132.20,131.59,131.55,130.92,129.19,128.85,128.64,126.14,125.29,21.61,20.73.
Embodiment 14
(2-chlorophenyl)(4-(2-chlorophenyloxazol)-2-yl)methanone(3n)
62mg, yield 78%, yellow solid.
1H NMR(400MHz,CDCl3) δ 8.56 (s, 1H), 8.09 (d, J=7.6Hz, 1H), 7.78 (d, J=7.5Hz,
1H), 7.51 (s, 2H), 7.44 (dd, J=14.2,5.9Hz, 2H), 7.38-7.27 (m, 2H)
13C NMR(101MHz,CDCl3)δ180.26,156.51,140.28,139.49,135.67,132.90,
132.74,131.76,130.93,130.58,130.28,130.17,129.56,128.54,127.12,126.57.
Embodiment 15
(naphthyl)(4-naphthyl-2-yl)methanone(4a)
65.4mg, yield 75%, yellow solid.
1H NMR(400MHz,CDCl3) δ 9.37 (s, 1H), 8.50 (d, J=7.6Hz, 1H), 8.41 (s, 1H), 8.28 (s,
1H), 8.10 (d, J=5.9Hz, 1H), 8.03-7.83 (m, 6H), 7.74-7.58 (m, 2H), 7.54 (s, 2H)
13C NMR(101MHz,CDCl3)δ178.61,157.81,142.78,136.53,136.01,134.16,
133.44,132.39,132.27,130.25,130.25,129.14,128.72,128.38,128.30,127.80,127.27,
126.83,126.66,126.55,125.51,125.01,123.43,119.07.
Embodiment 16
(furan)(4-furan-2-yl)methanone(4b)
33.2mg, yield 58%, brownish black solid.
1H NMR(400MHz,CDCl3)δ8.20(s,1H),8.06(s,1H),7.81(s,1H),7.48(s,1H),6.85
(s,1H),6.68(s,1H),6.52(s,1H).
13C NMR(101MHz,CDCl3)δ165.50,156.71,150.03,149.10,145.62,142.89,
135.85,135.15,124.64,112.91,111.52,108.33.
Embodiment 17
(thiophene)(4-thiophene-2-yl)methanone(4c)
33.9mg, yield 52%, yellow solid.
1H NMR(400MHz,CDCl3) δ 8.72 (s, 1H), 8.04 (s, 1H), 7.83 (d, J=4.5Hz, 1H), 7.48 (s,
1H), 7.37 (d, J=4.7Hz, 1H), 7.26 (s, 1H), 7.12 (s, 1H)
13C NMR(101MHz,CDCl3)δ170.41,156.78,140.48,137.82,137.41,136.69,
135.39,132.33,128.64,127.85,126.03,125.24.
Embodiment 18
(tert-butyl)(4-tert-butyl-2-yl)methanone(4d)
24mg, yield 46%, yellow liquid.
1H NMR(400MHz,CDCl3)δ7.41(s,1H),1.43(s,9H),1.29(s,9H).13C NMR(101MHz,
CDCl3)δ193.72,155.81,152.07,133.69,43.85,31.14,29.18,26.86.
Claims (10)
1. the synthetic method of 2,4 two substituted oxazoline of one kind, it is characterised in that：Methyl ketone compounds are containing ammonium persulfate and halogen
In the DMSO solution system of salt and/or halogen simple substance carry out cyclization to get；
The methyl ketone compounds have 1 structure of formula：
2,4 2 substituted oxazoline has 2 structure of formula：
Wherein, R is alkyl, aryl or aromatic heterocyclic.
2. according to claim 1 a kind of 2, the synthetic method of 4 two substituted oxazolines, it is characterised in that：R is isobutyl group, naphthalene
Base, the naphthalene containing substituent group, benzene, the phenyl containing substituent group, thienyl, furyl or pyrrole radicals.
3. according to claim 2 a kind of 2, the synthetic method of 4 two substituted oxazolines, it is characterised in that：
The phenyl containing substituent group includes at least one of halogen, alkyl, alkoxy, alkylthio group, nitro, cyano substituent group；
The naphthalene containing substituent group includes at least one of halogen, alkyl, alkoxy, alkylthio group, nitro, cyano substituent group.
4. according to the synthetic method of 2,4 two substituted oxazoline of claims 1 to 3 any one of them one kind, it is characterised in that：It is described
Haloid includes at least one of TBAI, KI, TBAB；The halogen simple substance includes I2。
5. according to the synthetic method of 2,4 two substituted oxazoline of claims 1 to 3 any one of them one kind, it is characterised in that：It is described
Ammonium persulfate dosage is 1~2.5 times of methyl ketone compounds mole.
6. according to the synthetic method of 2,4 two substituted oxazoline of claims 1 to 3 any one of them one kind, it is characterised in that：Halogen
The integral molar quantity of salt and halogen simple substance is the 10~30% of methyl ketone compounds mole.
7. according to the synthetic method of 2,4 two substituted oxazoline of claims 1 to 3 any one of them one kind, it is characterised in that：Methyl
A concentration of 0.1~1mol/L of the ketone compounds in DMSO solution system.
8. according to claim 7 a kind of 2, the synthetic method of 4 two substituted oxazolines, it is characterised in that：The DMSO mixing
Solution system includes the water and/or other organic solvents that volume ratio is no more than 1/3.
9. according to the synthetic method of 2,4 two substituted oxazoline of claims 1 to 3 any one of them one kind, it is characterised in that：It is described
The temperature of cyclization is 100~140 DEG C, and the reaction time is 1~6 hour.
10. according to claim 9 a kind of 2, the synthetic method of 4 two substituted oxazolines, it is characterised in that：The cyclization
Temperature be 110~130 DEG C, the reaction time be 1.5~2.5 hours.
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| CN107629028A (en) * | 2017-10-31 | 2018-01-26 | 沅江华龙催化科技有限公司 | A kind of method based on intermolecular ring-closure reaction synthesis furan derivatives |
| CN107739353A (en) * | 2017-10-31 | 2018-02-27 | 沅江华龙催化科技有限公司 | A kind of synthetic method of 2,3,5 trisubstituted furans |
| CN107793385A (en) * | 2017-10-31 | 2018-03-13 | 沅江华龙催化科技有限公司 | A kind of synthetic method of furan derivatives |
| CN107805232A (en) * | 2017-10-31 | 2018-03-16 | 沅江华龙催化科技有限公司 | A kind of synthetic method of the derivative containing thiomethylfuran |
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| CN107629028A (en) * | 2017-10-31 | 2018-01-26 | 沅江华龙催化科技有限公司 | A kind of method based on intermolecular ring-closure reaction synthesis furan derivatives |
| CN107739353A (en) * | 2017-10-31 | 2018-02-27 | 沅江华龙催化科技有限公司 | A kind of synthetic method of 2,3,5 trisubstituted furans |
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