CN109053631A - One kind passing through the synthetic method of isothiocyanates and 2- Sulfonylalkyl phenol synthesis benzo [1,3] oxazines -2- thioketones - Google Patents
One kind passing through the synthetic method of isothiocyanates and 2- Sulfonylalkyl phenol synthesis benzo [1,3] oxazines -2- thioketones Download PDFInfo
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- CN109053631A CN109053631A CN201810980752.7A CN201810980752A CN109053631A CN 109053631 A CN109053631 A CN 109053631A CN 201810980752 A CN201810980752 A CN 201810980752A CN 109053631 A CN109053631 A CN 109053631A
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- phenol
- sulfonylalkyl
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- isothiocyanates
- phenyl
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- 150000002540 isothiocyanates Chemical class 0.000 title claims abstract description 28
- 238000010189 synthetic method Methods 0.000 title claims abstract description 19
- CGACGSHTSCXSSO-UHFFFAOYSA-N 2h-1,3-benzoxazine Chemical class C1=CC=C2C=NCOC2=C1 CGACGSHTSCXSSO-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 10
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 21
- 239000002994 raw material Substances 0.000 claims abstract description 21
- 238000000926 separation method Methods 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 31
- 239000000047 product Substances 0.000 claims description 26
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical group [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 12
- -1 methoxyl group Chemical group 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000004802 cyanophenyl group Chemical group 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 150000002012 dioxanes Chemical class 0.000 claims description 3
- 230000002045 lasting effect Effects 0.000 claims description 3
- 150000004893 oxazines Chemical class 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 238000002390 rotary evaporation Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 2
- PDQRQJVPEFGVRK-UHFFFAOYSA-N 2,1,3-benzothiadiazole Chemical compound C1=CC=CC2=NSN=C21 PDQRQJVPEFGVRK-UHFFFAOYSA-N 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 239000000758 substrate Substances 0.000 abstract description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 4
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 abstract description 4
- 239000001301 oxygen Substances 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract description 3
- 230000009257 reactivity Effects 0.000 abstract description 3
- 241000534944 Thia Species 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 50
- QKFJKGMPGYROCL-UHFFFAOYSA-N phenyl isothiocyanate Chemical compound S=C=NC1=CC=CC=C1 QKFJKGMPGYROCL-UHFFFAOYSA-N 0.000 description 20
- 239000000126 substance Substances 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
- LZETYGKTFLGIIN-UHFFFAOYSA-N 2-(4-benzylphenyl)sulfonylphenol Chemical compound C1(=CC=CC=C1)CC1=CC=C(C=C1)S(=O)(=O)C1=C(C=CC=C1)O LZETYGKTFLGIIN-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- 229940117953 phenylisothiocyanate Drugs 0.000 description 10
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 4
- 238000007115 1,4-cycloaddition reaction Methods 0.000 description 3
- CMLFRMDBDNHMRA-UHFFFAOYSA-N 2h-1,2-benzoxazine Chemical compound C1=CC=C2C=CNOC2=C1 CMLFRMDBDNHMRA-UHFFFAOYSA-N 0.000 description 3
- 125000005605 benzo group Chemical group 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 238000011017 operating method Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- MDKCFLQDBWCQCV-UHFFFAOYSA-N benzyl isothiocyanate Chemical compound S=C=NCC1=CC=CC=C1 MDKCFLQDBWCQCV-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000005611 electricity Effects 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 238000005935 nucleophilic addition reaction Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- XQACWEBGSZBLRG-UHFFFAOYSA-N 1-bromo-4-isothiocyanatobenzene Chemical class BrC1=CC=C(N=C=S)C=C1 XQACWEBGSZBLRG-UHFFFAOYSA-N 0.000 description 1
- MZZVFXMTZTVUFO-UHFFFAOYSA-N 1-chloro-4-isothiocyanatobenzene Chemical compound ClC1=CC=C(N=C=S)C=C1 MZZVFXMTZTVUFO-UHFFFAOYSA-N 0.000 description 1
- NFIUJHJMCQQYDL-UHFFFAOYSA-N 1-fluoro-4-isothiocyanatobenzene Chemical compound FC1=CC=C(N=C=S)C=C1 NFIUJHJMCQQYDL-UHFFFAOYSA-N 0.000 description 1
- VRPQCVLBOZOYCG-UHFFFAOYSA-N 1-isothiocyanato-4-methoxybenzene Chemical class COC1=CC=C(N=C=S)C=C1 VRPQCVLBOZOYCG-UHFFFAOYSA-N 0.000 description 1
- NXHSSIGRWJENBH-UHFFFAOYSA-N 1-isothiocyanato-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(N=C=S)C=C1 NXHSSIGRWJENBH-UHFFFAOYSA-N 0.000 description 1
- QMCXTVATFCDODA-UHFFFAOYSA-N 2-(4-benzylphenyl)sulfonyl-4-methylphenol Chemical compound CC1=CC(=C(C=C1)O)S(=O)(=O)C1=CC=C(CC2=CC=CC=C2)C=C1 QMCXTVATFCDODA-UHFFFAOYSA-N 0.000 description 1
- MPFYLTOGHSUSKE-UHFFFAOYSA-N 2-[4-[(2-methylphenyl)methyl]phenyl]sulfonylphenol Chemical compound CC1=C(C=CC=C1)CC1=CC=C(C=C1)S(=O)(=O)C1=C(C=CC=C1)O MPFYLTOGHSUSKE-UHFFFAOYSA-N 0.000 description 1
- DZFKAXLNKZXNHD-UHFFFAOYSA-N 4-isothiocyanatobenzonitrile Chemical class S=C=NC1=CC=C(C#N)C=C1 DZFKAXLNKZXNHD-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- XUEYJIHVQUJWOQ-UHFFFAOYSA-N C(=O)OCCOC#N.[S] Chemical compound C(=O)OCCOC#N.[S] XUEYJIHVQUJWOQ-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- QAADZYUXQLUXFX-UHFFFAOYSA-N N-phenylmethylthioformamide Natural products S=CNCC1=CC=CC=C1 QAADZYUXQLUXFX-UHFFFAOYSA-N 0.000 description 1
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical class C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 239000000460 chlorine Chemical group 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 230000002254 contraceptive effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000006077 hetero Diels-Alder cycloaddition reaction Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 238000011877 intramolecular nucleophilic addition Methods 0.000 description 1
- ZBKFYXZXZJPWNQ-UHFFFAOYSA-N isothiocyanate group Chemical group [N-]=C=S ZBKFYXZXZJPWNQ-UHFFFAOYSA-N 0.000 description 1
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 125000001979 organolithium group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012048 reactive intermediate Substances 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- PYVFWTPEBMRKSR-UHFFFAOYSA-N tanaproget Chemical compound CN1C(C#N)=CC=C1C1=CC=C(NC(=S)OC2(C)C)C2=C1 PYVFWTPEBMRKSR-UHFFFAOYSA-N 0.000 description 1
- 229950001471 tanaproget Drugs 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000005323 thioketone group Chemical group 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
- C07D279/08—1,3-Thiazines; Hydrogenated 1,3-thiazines condensed with carbocyclic rings or ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The present invention has developed a kind of synthetic method that 2- Sulfonylalkyl phenol synthesis benzo [1,3] oxazines -2- thioketones is utilized under weak basic condition.Using 2- Sulfonylalkyl phenol and isothiocyanates as substrate, polyfunctional group benzo [1,3] oxazines -2- thioketones of nitrogen, oxygen, thia ring structure is contained using one-step synthesis method, expands the application of isothiocyanates and the reaction method of o-QMs.Synthetic method provided by the invention can react at room temperature, and reaction condition is mild, and substrate universality is good, be not necessarily to catalyst, but alkaline reagent simple and easy to get, easy to operate, economical and efficient；The reactivity of the method for the present invention is high, and yield is up to 92%, and raw material conversion is complete；Convenient product separation, and react with green economy, it is environmentally friendly.
Description
Technical field
The invention belongs to chemosynthesis technical fields, and the present invention relates to one kind to pass through isothiocyanates and 2- Sulfonylalkyl benzene
The synthetic method of phenol synthesis benzo [1,3] oxazines -2- thioketones.
Background technique
Heterocyclic compound becomes the hot spot of drug research field research and development due to extensive bioactivity, wherein oxazines-
2- thioketones belong to it is a kind of containing nitrogen, oxygen, sulfur heteroatom polycyclic compound, such compound have anticancer, antitumor, analgesia,
The bioactivity such as desinsection and sterilization.For example, the synthetic progestin Tanaproget of on-steroidal, it is clinical to enter the second phase in 2010
Test, future possibly serve for effective contraceptive.
But at present for the synthetic method of oxazines -2- thioketones, including the use of corresponding oxazines -2- ketone be substrate and
Lawesson reagent carries out substitution reaction (Bioorg.Med.Chem.Lett.2003,13,1313-1316), or utilizes organolithium
It is catalyzed phenyl isothiocyanate and carries out intramolecular nucleophilic displacement of fluorine (New J.Chem., 2017,41,7824-7835).
2015, Kazuhiro Kobayashi et al. utilized 2- (1- alkylisothiocyanate) phenol, in temperate condition
Lower carry out intramolecular cyclization generates benzoxazine -2- thioketones (Heterocycles, 2016,93,63-74).Although the reaction can
It effectively to synthesize benzoxazine -2- thioketones, but is carried out for the ease of reaction, and the synthetic strategy of intramolecular cyclization is taken to lead
Cause substrate relatively limited；And substrate 2- (1- alkylisothiocyanate) phenol is complicated for operation by five step synthesis processes.
Isothiocyanates may participate in various organic reactions, special for synthesizing a plurality of types of sulfur-bearings, nitrogen, the compound of oxygen
It is heterocyclic compound.It is located at the electrophilicity that the C in-N=C=S has height in isothiocyanic acid ester molecule, can be sent out with nucleopilic reagent
Raw nucleophilic addition.Such as in above-mentioned synthetic schemes, intramolecular nucleophilic addition cyclization occurs for isothiocyanate group.Due to
The classical reaction pattern of isothiocyanates is confined to nucleophilic addition, and be applied to the natural products containing glycosyl heterocycle and its
Analog it is fully synthetic, limit isothiocyanates in the development of drug chemical field.
O-quinone methides (o-QMs) are a kind of transient state, the very high reactive intermediate of reactivity, and there are two types of typical for it
Existence form: diradical substance or polarization amphoteric ion.But asymmetric [4+2] cycloaddition of catalysis that o-QMs is participated in is anti-
It answers difficult point to be not only in that its of short duration service life, further includes that catalyst and o-QMs effect too weak are not enough to promote reaction.And
And at present in a variety of generting machanisms of o-QMs, Lewis acid andAcid catalysis substituent group leave away operating method simplicity, answer
With in extensive range, but the o-QMs precursor containing acid-sensitive functional group (such as phenolic hydroxyl group) is not particularly suited for these acidic catalysts.
Therefore, under neutral or weak basic condition, elimination reaction will be carried out containing the compound of the groups such as hydroxyl and generate o-QMs, it can be with
Effectively expand the synthetic reaction type that o-QMs is participated in.
Therefore, in order to realize efficiently synthesizing for benzoxazine -2- thione compounds, and isothiocyanates and o- are expanded
The application of the reaction method of QMs needs a kind of strategy of new benzo [1,3] oxazines -2- thione compounds synthesis conversion.
Summary of the invention
The purpose of the present invention is to provide pass through isothiocyanates and 2- Sulfonylalkyl phenol synthesis benzo [1,3] oxazines-
The synthetic method of 2- thioketones.Operation of the present invention is simple and practical, and yield is good, and reacts with green economy, environmentally friendly.
Synthetic method provided by the present invention, specifically:
2- Sulfonylalkyl phenol and isothiocyanates, under alkaline reagent effect, reaction generates the benzo [1,3] and dislikes
Piperazine -2- thioketones.
Above-mentioned benzo [1,3] oxazines -2- thioketones is compound shown in formula I:
In formula I, dotted line indicates optional singly-bound；
R1In methyl, methoxyl group, halogen any one；And
R2、R3It is each independently selected from C1-C3Alkyl, phenethyl, phenyl, trifluoromethyl, cyano-phenyl, halogen take
For phenyl, C1-C3Alkyl-substituted phenyl, C1-C3Any one in alkoxy substituted phenyl.
Above-mentioned 2- Sulfonylalkyl phenol is compound shown in formula II, and above-mentioned isothiocyanates is compound shown in formula III:
In formula II, formula III, dotted line indicates optional singly-bound；
R1In methyl, methoxyl group, halogen any one；And
R2、R3It is each independently selected from C1-C3Alkyl, phenethyl, phenyl, trifluoromethyl, cyano-phenyl, halogen take
For phenyl, C1-C3Alkyl-substituted phenyl, C1-C3Any one in alkoxy substituted phenyl.
Above-mentioned alkaline reagent be cesium carbonate, potassium carbonate, triethylamine, 11 carbon -7- alkene of 1,8- diazabicylo [5.4.0],
Any one in tetramethylguanidine.
Above-mentioned reaction carries out in a solvent, and solvent is methylene chloride, tetrahydrofuran, any one in dioxanes.
The molar ratio of above-mentioned 2- Sulfonylalkyl phenol and isothiocyanates is 2:3.
The molar ratio of above-mentioned alkaline reagent and 2- Sulfonylalkyl phenol is 2.5:1；The dosage of the solvent is every mole of 2-
Sulfonylalkyl phenol adds 10L solvent.
Above-mentioned reaction carries out under the conditions of 25 DEG C.
The above-mentioned reaction time is 1-16h.
The present invention provides one kind and passes through isothiocyanates and 2- Sulfonylalkyl phenol synthesis benzo [1,3] oxazines -2- thioketones
Synthetic method, specifically includes the following steps:
2- Sulfonylalkyl phenol 0.2mmol is added in 2mL solvent, then to isothiocyanates is added in solvent
0.3mmol and alkaline reagent 0.5mmol；Control system temperature is 25 DEG C of room temperature, lasting to stir, by chromatographic sheet point sample with
Track is reacted to raw material fully reacting；
After reacting 12h, using reaction product in silica gel post separation solution, by obtaining product after concentrated by rotary evaporation.
Compound of the present invention can exist in the form of one or more kinds of stereoisomers.Various isomers packets
Include enantiomter, diastereoisomer, geometric isomer.These isomers include the mixture of these isomers in this hair
In bright protection scope.
Technical solution of the present invention achieves as follows the utility model has the advantages that under alkaline condition, and 2- Sulfonylalkyl phenol is sloughed to first
With isothiocyanates [4+2] cycloaddition reaction occurs for benzenesulfonyl in-situ preparation o-QMs.The reaction is strong because of isothiocyanates
The difficult of inverse electrical requirements hetero Diels Alder reaction occurs for short of electricity subsystem, but undergoes a kind of series connection cyclisation anti-
It answers.Since the property of isothiocyanates is influenced the product very big, different substituents cause reaction acquisition different by substituent effect,
And not it is only benzo [1,3] oxazines -2- thioketones.It is specifically expressed as follows: firstly, 2- Sulfonylalkyl phenol sloughs tolysulfonyl
Base in-situ preparation o-QMs, then the short of electricity center carbon of the oxygen atom attack isothiocyanates of o-QMs, forms the mistake of two kinds of resonance
State amphoteric ion TS2 and TS2 ' is crossed, when R is methoxyl group, methyl, fluorine, chlorine, bromine and trifluoromethyl substituted-phenyl, with the shape of TS2
Formula generates product 3；When R is p-nitrophenyl, product 4 is generated in the form of TS2 '；When R is to cyano-phenyl, two kinds of shapes
Formula exists to arrive mix products.But when R is ester group, o-QMs is not undergone, but phenolic hydroxyl group is directly as nucleophilic
Reagent carries out addition reaction to isothiocyanates, generates product 5.
The present invention has developed one kind and has utilized 2- Sulfonylalkyl phenol synthesis benzo [1,3] oxazines -2- under weak basic condition
The synthetic method of thioketones.Using 2- Sulfonylalkyl phenol and isothiocyanates as substrate, using one-step synthesis method contain nitrogen,
Polyfunctional group benzo [1,3] oxazines -2- thioketones of oxygen, thia ring structure.This method reaction substrate is conveniently easy to get, substrate universality
It is good, and the position of substrate substituent group does not influence reaction yield significantly.Alkaline reagent is simple and easy to get, easy to operate, economical
Efficiently；Reactivity is higher, and raw material conversion is complete；Convenient product separation, and react with green economy, it is environmentally friendly.
Specific embodiment
The specific embodiment provided by following embodiment carries out further specifically above content of the invention
It is bright, for the technical staff of this research field, this should not be interpreted as the above-mentioned theme of the present invention range be only limitted to it is following
Example；The techniques implemented on the basis of the foregoing are all within the scope of the present invention.
Experimental method used in following example is conventional method unless otherwise specified；Institute in following embodiments
Reagent, material, instrument etc., are commercially available unless otherwise specified.
Embodiment 1
2- (α-phenyl p-toluenesulfonyl) phenol of 0.2mmol is taken in reaction flask, to sequentially add 2mL solvent,
0.3mmol phenyl isothiocyanate finally adds 0.5mmol alkaline reagent.It is 25 DEG C of control system temperature, lasting to stir, pass through
The tracking of chromatographic sheet point sample is reacted to raw material fully reacting.
To after the reaction was completed, be isolated and purified using silicagel column, product after purification is rotated into obtain target product.
Using above-mentioned reaction equation, 10 groups of parallel test groups are set up, different alkaline reagents, solvent and reaction time are used.
Alkaline reagent is respectively cesium carbonate Cs2CO3, potassium carbonate K2CO3, 11 carbon of triethylamine TEA, 1,8- diazabicylo [5.4.0]-
7- alkene DBU, tetramethylguanidine TMG.Solvent is respectively methylene chloride DCM, tetrahydrofuran THF, dioxanes Dioxane.Test group tool
Alkaline reagent, solvent type and the concentration that body uses are as shown in table 1:
1. 2- of table (α-phenyl p-toluenesulfonyl) phenol and phenyl isothiocyanate reaction yield table
| Serial number | Alkaline reagent | Solvent | Reaction time (h) | Yield (%) |
| 1 | Cs2CO3 | DCM | 12 | 92 |
| 2 | Cs2CO3 | Dioxane | 12 | 86 |
| 3 | Cs2CO3 | THF | 12 | 79 |
| 4 | TEA | DCM | 12 | 63 |
| 5 | DBU | DCM | 12 | 54 |
| 6 | TMG | DCM | 12 | 62 |
| 7 | K2CO3 | DCM | 12 | 75 |
| 8 | Cs2CO3 | DCM | 1 | 19 |
| 9 | Cs2CO3 | DCM | 8 | 72 |
| 10 | Cs2CO3 | DCM | 16 | 80 |
Note: yield is separation yield.
According to the above parallel test interpretation of result, reduction or increase reaction time will lead to the reduction of reactant yield, anti-
Answer middle selection metal salt reagent and organic alkali agents that can obtain higher purpose product yield.
Embodiment 2
According to the operating procedure and reagent dosage of embodiment 1, in reaction system, 2- (α-phenyl p-toluenesulfonyl) phenol
It is reacted respectively with 4- cyano-phenyl isothiocyanates, 4- nitro phenylisothiocyanate, different sulphur cyanato- Ethyl formate, alkaline reagent
For dosage 0.5mmol cesium carbonate, solvent is made with 2mL DCM, is persistently stirred to react at a temperature of 25 DEG C, reaction was completed by 12h.
According to the above test result analysis, one of reaction raw materials are the isothiocyanates with different electrical substituent groups, instead
Its different addition product that carried out what [4+2] cycloaddition obtained from o-QMs during answering, benzo [1,3] oxazines -2- thioketones
Yield can significantly reduce.
In the following example 3-16, according to the operating procedure of embodiment 1, in reaction system, raw material 1- Sulfonylalkyl phenol
It is respectively 0.2mmol, 0.3mmol with isothiocyanates, alkaline reagent is dosage 0.5mmol cesium carbonate, is made with 2mL DCM molten
Agent is persistently stirred to react at a temperature of 25 DEG C, and by 12h, reaction was completed.
Embodiment 3
Raw material: 2- (α-phenyl p-toluenesulfonyl) phenol, phenyl isothiocyanate
Product: chemical formula: C20H15NOS
Molecular weight: 318.4126
Structural formula:
Yield: 92%
1H NMR(500MHz,CDCl3) δ 7.39-7.31 (m, 8H), 7.21-7.14 (m, 3H), 7.04 (d, J=7.1Hz,
3H),5.69(s,1H).13C NMR(125MHz,CDCl3) δ=182.9,147.9,143.8,140.2,129.6,129.5,
129.2,128.9,128.5,127.6,127.4,126.2,125.5,121.8,116.5,67.1.HRMS(ESI)Calcd for
C20H15NOS[M+H]+:318.4121,Found:318.4126.
Embodiment 4
Raw material: 4- methyl -2- (α-phenyl p-toluenesulfonyl) phenol, phenyl isothiocyanate
Product: chemical formula: C21H17NOS
Molecular weight: 332.4386
Structural formula:
Yield: 81%
1H NMR(500MHz,CDCl3)δ7.39–7.30(m,6H),7.21-7.15(m,4H),7.02(s,2H),6.81
(s,1H),5.63(s,1H),2.28(s,3H).13C NMR(125MHz,CDCl3) δ=183.1,146.0,143.9,140.3,
135.3,130.2,129.5,129.2,128.9,128.4,127.6,127.4,126.3,121.4,116.2,67.2,
20.8.HRMS(ESI)Calcdfor C21H17NOS[M+H]+:332.4381,Found:332.4386.
Embodiment 5
Raw material: 2- methoxyl group -6- (α-phenyl p-toluenesulfonyl) phenol, phenyl isothiocyanate
Product: chemical formula: C21H17NO2S
Molecular weight: 348.4386
Structural formula:
Yield: 62%
1H NMR(500MHz,CDCl3)δ7.31-7.26(m,6H),7.20(s,2H),7.08–7.02(m,3H),6.90
(d, J=8.0Hz, 1H), 6.58 (d, J=7.6Hz, 1H), 5.65 (s, 1H), 3.94 (s, 3H)13C NMR(125MHz,
CDCl3) δ=182.5,147.0,143.8,140.1,137.6,129.4,129.1,128.8,128.3,12 7.5,127.2,
125.5,122.8,117.0,111.5,66.9,56.0.HRMS(ESI)Calcd for C21H17NO2S[M+H]+:348.4381,
Found:348.4386.
Embodiment 6
Raw material: the chloro- 2- of 4- (α-phenyl p-toluenesulfonyl) phenol, phenyl isothiocyanate
Product: chemical formula: C20H14ClNOS
Molecular weight: 352.8577
Structural formula:
Yield: 71%
1H NMR(500MHz,CDCl3) δ 7.39-7.30 (m, 7H), 7.26 (d, J=3.2Hz, 1H), 7.16 (dd, J=
6.5,3.0Hz, 2H), 7.00 (d, J=2.2Hz, 3H), 5.62 (s, 1H)13C NMR(125MHz,CDCl3) δ=182.4,
146.4,143.6,139.5,130.5,129.7,129.6,129.4,129.2,128.6,127.5,127.3,126.0,
123.3,118.0,66.7.HRMS(ESI)Calcd for C20H14ClNOS[M+H]+:352.8572,Found:352.8577.
Embodiment 7
Raw material: 2- (α-aminomethyl phenyl p-toluenesulfonyl) phenol, phenyl isothiocyanate
Product: chemical formula: C21H17NOS
Molecular weight: 332.4392
Structural formula:
Yield: 83%
1H NMR(500MHz,CDCl3) δ 7.38-7.28 (m, 5H), 7.21-7.10 (m, 3H), 7.02 (d, J=7.2Hz,
3H), 6.96 (d, J=8.7Hz, 2H), 5.62 (s, 1H), 2.29 (s, 3H) .HRMS (ESI) Calcd for C21H17NOS[M+
H]+:332.4387,Found:332.4392.
Embodiment 8
Raw material: 2- (α-is to benzyloxy p-toluenesulfonyl) phenol, phenyl isothiocyanate
Product: chemical formula: C21H17NO2S
Molecular weight: 348.4386
Structural formula:
Yield: 86%
1H NMR(500MHz,CDCl3) δ 7.32-7.14 (m, 5H), 7.04 (t, J=7.2Hz, 1H), 6.96 (d, J=
8.7Hz, 2H), 6.90 (d, J=7.7Hz, 3H), 6.72 (d, J=8.6Hz, 2H), 5.55 (s, 1H), 3.67 (s, 3H) .HRMS
(ESI)Calcd for C21H17NO2S[M+H]+:348.4381,Found:348.4386.
Embodiment 9
Raw material: 2- (α-o-methyl-phenyl p-toluenesulfonyl) phenol, phenyl isothiocyanate
Product: chemical formula: C21H17NOS
Molecular weight: 332.4392
Structural formula:
Yield: 71%
1H NMR(500MHz,CDCl3)δ7.36–7.28(m,5H),7.24–7.14(m,4H),7.14–7.02(m,3H),
6.90 (d, J=7.6Hz, 1H), 6.05 (s, 1H), 1.97 (s, 3H) .HRMS (ESI) Calcd for C21H17NOS[M+H]+:
332.4387,Found:332.4392.
Embodiment 10
Raw material: 2- (α-phenyl p-toluenesulfonyl) phenol, to Tolueneisothiocyanate
Product: chemical formula: C21H17NOS
Molecular weight: 332.4392
Structural formula:
Yield: 83%
1H NMR(500MHz,CDCl3) δ 7.38-7.27 (m, 5H), 7.22-7.09 (m, 5H), 7.01 (d, J=7.5Hz,
1H), 6.89 (d, J=7.0Hz, 2H), 5.65 (s, 1H), 2.34 (s, 3H)13C NMR(125MHz,CDCl3) δ=183.0,
147.9,141.3,140.3,138.5,130.2,129.5,129.2,128.9,127.4,127.2,126.2,125.4,
121.8,116.5,67.1,21.2.HRMS(ESI)Calcd for C21H17NOS[M+H]+:332.4387,Found:
332.4392.
Embodiment 11
Raw material: 2- (α-phenyl p-toluenesulfonyl) phenol, Tolueneisothiocyanate
Product: chemical formula: C21H17NOS
Molecular weight: 332.4392
Structural formula:
Yield: 73%
1H NMR(500MHz,CDCl3) δ 7.29-7.17 (m, 6H), 7.17-7.02 (m, 5H), 6.94 (d, J=7.3Hz,
1H), 6.74 (d, J=34.9Hz, 2H), 5.58 (s, 1H), 2.20 (s, 3H)13C NMR(125MHz,CDCl3) δ=182.8,
147.9,143.7,140.2,139.6,129.5,129.2,129.2,129.1,128.8,127.8,127.3,126.1,
125.4,124.6,121.8,116.4,67.0,21.2.HRMS(ESI)Calcd for C21H17NOS[M+H]+:332.4387,
Found:332.4392.
Embodiment 12
Raw material: 2- (α-phenyl p-toluenesulfonyl) phenol, 4- methoxyphenyl isothiocyanates
Product: chemical formula: C21H17NO2S
Molecular weight: 348.4386
Structural formula:
Yield: 74%
1H NMR(500MHz,CDCl3) δ 7.39-7.28 (m, 5H), 7.21-7.11 (m, 3H), 7.01 (d, J=7.2Hz,
1H), 6.92 (s, 2H), 6.83 (d, J=8.7Hz, 2H), 5.64 (s, 1H), 3.79 (s, 3H)13C NMR(125MHz,CDCl3)
δ=183.2,159.1,147.9,140.3,136.7,129.5,129.2,128.9,128.6,12 7.5,126.2,125.4,
121.8,116.5,114.6,67.3,55.4.HRMS(ESI)Calcd for C21H17NO2S[M+H]+:348.4381,Found:
348.4386.
Embodiment 13
Raw material: 2- (α-phenyl p-toluenesulfonyl) phenol, 4- fluorophenylisothiocyanate
Product: chemical formula: C20H14FNOS
Molecular weight: 336.4031
Structural formula:
Yield: 85%
1H NMR(500MHz,CDCl3) δ 7.39-7.29 (m, 5H), 7.17-7.14 (m, 3H), 7.01 (d, J=7.8Hz,
5H),5.64(s,1H).13C NMR(125MHz,CDCl3) δ=183.0,161.9 (d, J=249.1Hz), 147.7,139.7
(d, J=2.5Hz), 139.6,129.6,129.5 (d, J=7.0Hz), 129.2,129.0,127.4,126.2,125.5,
121.5,116.6,116.4,67.1.HRMS(ESI)Calcd for C20H14FNOS[M+H]+:336.4026,Found:
336.4031.
Embodiment 14
Raw material: 2- (α-phenyl p-toluenesulfonyl) phenol, 4- chlorophenyl isothiocyanate
Product: chemical formula: C20H14ClNOS
Molecular weight: 352.8577
Structural formula:
Yield: 94%
1H NMR(500MHz,CDCl3) δ 7.38-7.29 (m, 7H), 7.17-7.13 (m, 3H), 7.01 (d, J=7.6Hz,
1H), 6.95 (d, J=7.5Hz, 2H), 5.63 (s, 1H)13C NMR(125MHz,CDCl3) δ=182.9,147.8,142.2,
139.9,134.3,129.8,129.7,129.3,129.1,127.4,126.3,125.6,121.5,116.5,67.1.HRMS
(ESI)Calcd forC20H14ClNOS[M+H]+:352.8572,Found:352.8577.
Embodiment 15
Raw material: 2- (α-phenyl p-toluenesulfonyl) phenol, 4- bromophenyl isothiocyanates
Product: chemical formula: C20H14BrNOS
Molecular weight: 397.3087
Structural formula:
Yield: 81%
1H NMR(500MHz,CDCl3) δ 7.47 (d, J=7.9Hz, 2H), 7.40-7.27 (m, 5H), 7.24-7.12 (m,
3H), 7.03 (d, J=7.5Hz, 1H), 6.90 (d, J=6.8Hz, 2H), 5.65 (s, 1H)13C NMR(125MHz,CDCl3)δ
=182.8,147.7,142.7,139.8,132.8,129.7,129.4,129.3,129.1,12 7.3,126.2,125.6,
122.4,121.4,116.4,67.0.HRMS(ESI)Calcd for C20H14BrNOS[M+H]+:397.3082,Found:
397.3087.
Embodiment 16
Raw material: 2- (α-phenyl p-toluenesulfonyl) phenol, benzyl isothiocyanate
Product: chemical formula: C21H17NOS
Molecular weight: 332.4392
Structural formula:
Yield: 73%
1H NMR(500MHz,CDCl3) δ 7.40-7.31 (m, 6H), 7.30-7.20 (m, 4H), 7.05 (t, J=7.6Hz,
1H), 6.90 (d, J=7.2Hz, 1H), 6.32 (d, J=15.1Hz, 1H), 5.34 (s, 1H), 4.10 (d, J=15.2Hz, 1H)
.13CNMR(125MHz,CDCl3) δ=183.6,147.6,140.0,134.6,129.5,129.4,129.0,128.3,128.2,
126.9,126.4,126.3,126.3,125.3,116.3,61.2,56.2.HRMS(ESI)Calcd for C21H17NOS[M+
H]+:332.4387,Found:332.4392.
The above described is only a preferred embodiment of the present invention, being not that the invention has other forms of limitations, appoint
What those skilled in the art changed or be modified as possibly also with the technology contents of the disclosure above equivalent variations etc.
Imitate embodiment.But without departing from the technical solutions of the present invention, according to the technical essence of the invention to above embodiments institute
Any simple modification, equivalent variations and the remodeling made, still fall within the protection scope of technical solution of the present invention.
Claims (9)
1. one kind passes through the synthetic method of isothiocyanates and 2- Sulfonylalkyl phenol synthesis benzo [1,3] oxazines -2- thioketones,
It is characterized in that:
2- Sulfonylalkyl phenol and isothiocyanates, under alkaline reagent effect, reaction generates benzo [1, the 3] oxazines -2-
Thioketones.
2. synthetic method according to claim 1, it is characterised in that:
Benzo [1,3] oxazines -2- thioketones is compound shown in formula I:
In formula I, dotted line indicates optional singly-bound；
R1In methyl, methoxyl group, halogen any one；And
R2、R3It is each independently selected from C1-C3It is alkyl, phenethyl, phenyl, trifluoromethyl, cyano-phenyl, halogen-substituted
Base, C1-C3Alkyl-substituted phenyl, C1-C3Any one in alkoxy substituted phenyl.
3. synthetic method according to claim 1 or 2, it is characterised in that:
The 2- Sulfonylalkyl phenol is compound shown in formula II, and the isothiocyanates is compound shown in formula III:
In formula II, formula III, dotted line indicates optional singly-bound；
R1In methyl, methoxyl group, halogen any one；And
R2、R3It is each independently selected from C1-C3It is alkyl, phenethyl, phenyl, trifluoromethyl, cyano-phenyl, halogen-substituted
Base, C1-C3Alkyl-substituted phenyl, C1-C3Any one in alkoxy substituted phenyl.
4. synthetic method according to claim 3, it is characterised in that: the alkaline reagent is cesium carbonate, potassium carbonate, three second
Amine, 11 carbon -7- alkene of 1,8- diazabicylo [5.4.0], any one in tetramethylguanidine.
5. synthetic method according to claim 4, it is characterised in that: the reaction carries out in a solvent, and solvent is dichloro
Methane, tetrahydrofuran, any one in dioxanes.
6. synthetic method according to claim 5, it is characterised in that: the 2- Sulfonylalkyl phenol and isothiocyanates
Molar ratio is 2:3.
7. synthetic method according to claim 6, it is characterised in that: the alkaline reagent rubs with 2- Sulfonylalkyl phenol
You are than being 2.5:1；The dosage of the solvent is that every mole of 2- Sulfonylalkyl phenol adds 10L solvent.
8. synthetic method according to claim 7, it is characterised in that: the reaction carries out under the conditions of 25 DEG C.
9. synthetic method according to claim 1-8, it is characterised in that: specifically includes the following steps:
2- Sulfonylalkyl phenol 0.2mmol is added in 2mL solvent, then to addition isothiocyanates 0.3mmol in solvent
With alkaline reagent 0.5mmol；Control system temperature is 25 DEG C of room temperature, lasting to stir, and is tracked and is reacted by chromatographic sheet point sample
To raw material fully reacting；
After reacting 12h, using reaction product in silica gel post separation solution, by obtaining product after concentrated by rotary evaporation.
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