Procedure for the deprotection of benc¿licos etheries (Machine-translation by Google Translate, not

专利摘要:
Deprotection procedure of benzylic ethers. The invention relates to a process of deprotection or removal of the arylmethyl group (debenzylation) in benzylic ethers in order to release the corresponding alcohols using infinitesimal amounts of a nickel compound and a triazole derivative, and exclusively using molecular oxygen as the oxidizing agent and in an ether or polyol type solvent. (Machine-translation by Google Translate, not legally binding)
公开号:ES2638009A1
申请号:ES201630471
申请日:2016-04-14
公开日:2017-10-18
发明作者:Garazi URGOITIA GABIKAETXEBARRIA；Raul SANMARTÍN FACES；María Teresa HERRERO CORRAL；Esther Domínguez Pérez
申请人:Euskal Herriko Unibertsitatea；
IPC主号:

专利说明:

PROCEDURE FOR THE DISPROTECTION OF BENCIETAL ETERES
Field of the Invention The present invention is part of the chemical and / or pharmaceutical sector. In particular, the invention relates to a method of deprotection or removal of the arylmethyl group in benzyl ethers in order to release the corresponding alcohols using infinitesimal amounts of a nickel compound and a triazole derivative, and using molecular oxygen as an oxidizing agent and in a ether or polyol solvent
BACKGROUND OF THE INVENTION The synthesis of many compounds of industrial interest implies the protection of functional groups to avoid unwanted side reactions during the manufacturing process of such compounds [Yu, Q .; Ma,
s. Eur. J. Org. Chem. 2015,1596: Wilson, l. E .: Fenner, S .: Ley, S. V. Angew, Chem. In !. Ed. 2015, 54, 1284]. The protection of the hydroxyl group in alcohols is a very common stage in the synthesis of complex organic compounds [Biswas, K., Lin, H., Njardarsoo, JT, Chappell, MD, Chou, T.-C., Guan, Y. , Tong, WP, He, L., Horwitz, s. B .: oanishefsky, S. J. J. Am. Chem. Soco 2002, 124.9825: Germany, O .: Kumar, N .: Moore, c. G .: Thomas, E. J. Org. Biomol Chem. 2012, 10, 9709], and among the most commonly used protective groups, the benzyl group stands out, since the preparation of benzyl ethers from the corresponding alcohol alcohols is simple, and said ethers are chemically stable against a large number of reaction conditions [Wuts,
P. G M .: Greene, T. W. Protective Groups in Organic Synlhesis, 4th ed .: W iley-VCH: Hoboken (NJ), 2007, pp 164311
With regard to the deprotection of O-benzyl alcohols, it has traditionally been carried out bypalladium catalyzed hydrogenolysis medium [Weissman, S. A .; lewge, or. Tetrahedron 2005, 61, 7833;Pandarus, V., Béland, F .; Ciriminna, R, Pagliaro, M. ChemCatChem 2011, 3, 1146].There are other alternative ways, such as the use of Lewis acids [Okano, K .; Okuyama, K .: Fukuyama, T .:Tokuyama, H. Synlet! 2008, 13, 1977], strong protic acids [Bhalerao, U. T .: Raju, B. C .: Neelakantan, PSynth Commun. 1995, 25, 1433], and reductive ruptures by treatment with lithium, potassium, magnesium,naphthalenides and other energetic reducing agents [Alonso, E., Ramón, o. J., Yus, M. Tetrahedron 1997, 53,14355: Ren, Y.-L .; Tian, M .; Tian, x.-Z .; Wang, Q .; Shang, H .; Wang, J.: Zhang, Z. C. Catal. Commun. 2014, 52,361
However, these methods can be problematic in the case of some multifunctional substrates. So,for example, the presence of hydrogenatable groups (olefinic or alkenyl fragments, carbooyl groups,halogen, or even other alkoxy groups, etc.) prevents selective O-debenzylation through hydrogenationcatalytic [Okamoto, K .: Akiyama, R; Kobayashi, S. J. Org. Chem. 2004, 69, 2871; Llácer, E .; Romea, P .: Urpi, FTetrahedron Let !. 2006, 47, 58151. Something similar occurs with debenzylation mediated by protic acids.and Lewis, in which again the type of substrates to be used is limited to aryl benzyl ethers [Haraldsson, GG., Baldwin, J. E. Tetrahedron 1997, 53, 215; Petchmanee, T., Ploypradith, P., Ruchirawat, S. J. Org. Chem2006, 71,2892: Rajakumar, P .; Murali, V. Synth. Commn 2003, 33, 3891; Bao, K .: Fan, A .: Dai, Y .: Zhang, L .;lhang, W .: Cheng, M .: Yao, K Org. Biomol Chem. 2009, 7, 5084]
There are different alternatives to those raised above, which solve some of the problemsthat create traditional techniques [Yin, l.-J .; Wang, B .; Li, Y.-B .; Meng, K-B .; Li, l.-J. Org. Let! 2010, 12, 536;Lu, P .: Hou, T .; Gu, K; Li, P. Org. Let! 2015, 17, 1954] but that sometimes are not selective,providing by-products from unwanted desalkyments, [Chauhan, S. M. S., Jain, N. J. Chem.Res. 2004, 693] or are limited in terms of the nature of the ethers to be dissociated [lhou, L .; Wang, W .: luo,
L., Yao, 8 .: Wang, w .: Duan, W. Tetrahedron Let !. 2008, 49, 4876; Holland, H. L .; Coon, M .: Chenchaiah, P. C .; Brown, F. M. Tetrahedron Let !. 1988, 29, 6393] Oxidative rupture is presented as a convenient alternative to conventional methods [Schmidt, W .; Steckhan, E. Angew. Chem. In !. Ed. 1979, 18,801; Chen, F-E .; Peng, l.-l .; Fu, H .: Meng, G .: Cheng, Y .: Lü, Y.-X. Synlett 2000, 5, 627; He, L., Wang, a., Zhou, G.-C., Guo, L., Yu, x.-O. ARKIVOC 2008,103; Moriyama, K., Nakamura, Y., Toga, H. Org. Lett. 2014, 16, 3812) although again there are limitations regarding the nature of the substrates to be unprotected [Madsen, J., Bols, M. Angew. Chem. Inl. Ed. 1998, 37, 3177]. In the context of O-debenzylation, nickel catalysts have been used occasionally [Perosa, A., Tundo, P .; l inovyev, S. Green Chem. 2002, 4, 492; Sergeev, A. G .; Webb, J. D .; Harwig, J. F. J. Am. Chem. Soc 2012, 134, 20226), especially in catalytic hydrogenolysis, and the use of a nickel alloy with aluminum as a reducing method for deprotection by debencylation of aryl alcohols has also been described [Naidu,
M. V .; Rao, G. S. K. J. India n Insl. ScL 1980, 62, 177]. Nair's group has recently published an also reductive process, mediated by the NaBH4 reducer catalyzed by a nickel salt, although again limited to aryl benzyl ethers [Chouhan, M., Kumar, K., Sharma, R, Grover, V ., Nair, VA Tetrahedron Lett. 2013, 54, 4540].
In general, in the vast majority of O-debenzylation methods of ethers described above it is necessary to use over-stoichiometric amounts of unsafe or harmful reagents and / or relatively high catalytic charges (1-20 mol%) of catalysts, which originates considerable quantities of the corresponding by-products or toxic waste.
In view of the above, and despite the progress achieved so far, there is still a need to provide an alternative O-debenzulation procedure that overcomes at least in part the disadvantages of the aforementioned methodologies.
Surprisingly, the present inventors have discovered an advantageous alternative for the O-debenzylation of alcohols using molecular oxygen, an abundant and environmentally benign oxidant, at near atmospheric pressure, combined with a nickel compound (11) and a derivative of 1, 2,4-triazole, in an ether or polyol solvent, with low or no toxicity
DESCRIPTION OF THE INVENTION In a first aspect the invention relates to a new process, hereinafter process of the invention, for the deprotection of a compound of formula (11)
15 R-O-CH2-A,
(eleven )
where R represents a group selected from C14 alkyl, C2.14 alkenyl, C4-C10 alkynyl, C14 aryl, CJ.14 cycloalkyl, C14 J14 heterocycloalkyl, optionally substituted with one or more selected substituents C 1 -t 1 alkyl, CNI alkenyl, Ce.lO aryl, heteroaryl, alkoxy (-O - (CI-6 ", and aryloxy (-O- (C6-10",
A represents a C6-14 aryl group, optionally substituted with one or more substituents selected from C 1-6 alkyl, alkoxy (-O- (C 1-6 ", halogen and haloalkyl (CI-6), 25
with molecular oxygen (02) at a pressure between 1 and 1.2 atm, in an ether or polyol solvent, and in the presence of a nickel compound, an alkaline acetate salt, and a derivative of 1, 2,4-triazole of formula
(111)
where, the substituents R 'and R2, the same or different from each other are selected from hydrogen, C'-6 alkyl, and aryl Ce, and the substituent R3 is selected from hydrogen, C 1-6 alkyl, and "C" alkoxycarbonyl - 6} -OC (O) -), 35 to obtain a compound of formula (1):
R-OH (1),
40 where R has the same meaning defined above
The process involves the deprotection or debenzylation of an alcohol, and a compound of formula (IV) is obtained as a reaction byproduct:
45 A-COOH
(IV),
where A has the meaning defined above
The starting compounds of the process of the invention of formula (11) are commercially available or can be synthesized by conventional synthesis processes by an expert in a simple manner. For example, in a particular embodiment, they can be obtained by reacting a compound of formula (1) with a compound of general formula (V)
A-CHz-X
(SAW,
where X is a leaving group, for example a halogen, such as bromine. The reaction can be carried out byexample in the presence of a suitable base, such as sodium hydride in a suitable solvent such astelrahydrofuran (THF)
The term stainless ~ C'.14 ~ alkyl should be understood as a linear or branched, saturated monovalent hydrocarbon grouphaving 1 to 14 carbon atoms, preferably 1 to 10, for example 1, 2, 3, 4, 5, or 6 atoms ofcarbon, such as a methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, iso-butyl, sec-butyl, tert groupbutyl, iso-pentyl. Particularly, said group has 1, 2, 3 or 4 carbon atoms, for example a methyl group,ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, more particularly 1, 2, 6, 3 carbon atoms,for example a methyl, ethyl, n-propyl- or iso-propyl group.When the ~ alkyl group "represents a substituent and contains in particular up to 6 carbon atoms,expressly indicated as C'-6 alkyl.
The term "C ~ 14" alkenyl alkenyl should be understood as a linear or branched monovalent hydrocarbon group of 2 to14 carbon atoms, which contains one or more double bonds, and which preferably has 2 to 10carbon atoms, for example 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms,It should be understood that in the case in which said alkenyl group contains more than one double bond, thensaid double bonds may be isolated or conjugated to each other. Said alkenyl group is, for example, avinyl group, or allyl. In the context of the present invention, an alkenyl group may also have one orMore triple links.
When the "alkenyl" group represents a substituent and contains in particular from 2 to 6 carbon atoms, itexpressly indicated as CM alkenyl. Optionally this substituent can present one or more linkstriple, in addition to the doubles or instead of
The term "C4.10 alkynyl" should be understood as a linear or branched monovalent hydrocarbon group of 4 to10 carbon atoms, which contains one or more triple bonds, which has for example 5, 6, 7, 8, or 9 atoms ofcarbon. Said group is, for example, an ethynyl group. In the context of the present invention, a groupAlkynyl may also have one or more double bonds.
In the context of the present invention the term "C6-14 aryl" should preferably be understood as a ringmonovalent, aromatic or partially aromatic monovalent mono, bi or tricyclic hydrocarbon having 6, 7, 8, 9, 10, 11,12, 13 or 14 carbon atoms, particularly a ring having 6 carbon atoms, for example a groupphenyl, or an ring that has 9 carbon atoms, for example an indanyl or indenyl group, or a ring that has10 carbon atoms, for example a tetra linyl, dihydronaphthyl, or naphthyl group, or an ring having 13 atoms ofcarbon, for example a fluorenyl group, or a ring having 14 carbon atoms, for example a groupanthranyl, or a phenanthryl group.When the "a ryl" group represents a substituent and contains in particular 6 to 10 carbon atoms, itexpressly indicates as C & 'aryl, or or as C6 aryl if it has 6 carbon atoms in particular.
The term "C3-14 'dcloalkyl" refers to a saturated or partially unsaturated cyclic group (for example, acycloalkenyl group) containing one or more rings (preferably 1 or 2), and containing from 3 to 14 atoms ofannular carbon, preferably 3 to 10 (especially 3, 4, 5, 6 or 7) annular carbon atoms. ByFor example, illustratively, it may be a cyclopropyl, cyclobutyl, cyclopentyl, spiro [4,5] decanyl groupnorbcrnyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo [4.3.0] nonyl, tetralin,cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-yl.
The term "C3-14 heterodcloalkyl" refers to a cycloalkyl group as defined above, in which they have beensubstituted one or more (preferably 1, 2 or 3) annular carbon atoms with an oxygen, nitrogen atom,
or sulfur. A heterocycloalkyl group preferably has 1 or 2 ring (s) containing (n) from 3 to 10 (especially 3, 4, S, 6 or 7) ring atoms (preferably selected from C, O, N, and S). Illustrative examples are a piperidyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl, urotropinyl, pyrrolidinyl, telrahydrothiophenyl, telrahydropyranyl, tetrahydrofuryl or 2 pyrazolinyl groups, as well as clama, lactones, cyclic imides and cyclic anhydrides.
The term "heteroaryl" is preferably understood as a monovalent, mono or bicyclic aromatic ring system having S, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a heteroaryl group of 5 to 14 members "), particularly 5 or 6 or 9 or 10 atoms, and which contains one or more heteroatoms, the same or different, where said heteroatom is oxygen, nitrogen or sulfur, and can be monocyclic, bicyclic or tricyclic, and also in each case it can be benzocondensed, in particular, the heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, Iriazolyl, thiadiazolyl, thia-4H-pyrazolyl, etc., and benzo derivatives thereof, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, bencisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc., or
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, etc., or azocin yl, indolizinyl, purinyl, etc., and benzo derivatives of the same; or cinnolinyl, flalazinyl, quinazolinyl, quinoxalinyl, naflpyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, or oxepinyl, etc. More particularly, heteroaryl is selected from pyridyl, benzofuranyl, bencisoxazolyl, indazolyl, quinazolinyl, thienyl, quinolinyl, benzothienyl, pyrazolyl, or furanyl
The term "halogen" or "halo_" should be understood as a fluorine, doro, bromine or iodine atom.
The term "halo-Cl-6 alkyl" should be understood as a saturated linear or branched monovalent hydrocarbon group in which the term "alkyl" has 1 to 6 carbon atoms, and in which one or more hydrogen atoms is replaced by a halogen atom or more, these being the same or different Particularly, said halogen atom is F. Said halo-alkyl group is, for example, -CF3, -CHF2, -CH2F, -CF2CF3, or CH2CF: J
The term ~ O- (Cl-6) alkoxy "should be understood as a linear or branched saturated monovalent hydrocarbon group of the formula -O- (Cl-6 alkyl), in which the term" alkyl · has 1 to 6 carbon atoms, for example a methoxy, ethoxy, n-propoxy, iso-pmpoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, pentoxy, isopentoxy, or n-hexoxy group
The term inoo-aryloxy (-O- (Ce-10) "should be understood as a group ~ -O-aryl C6-10" where the term ~ aryl Ce-1O 'represents a substituent containing 6 to 10 carbon atoms In a particular embodiment it is -O-C6 aryl, with 6 carbon atoms.
The term "alkoxycarbonyl" should be understood as a group "(Cl-6} -OC (O} -" alkyl, where Cl-6 alkyl is as defined above. For example: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso- propoxycarbonyl, tertbutoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl
In a particular embodiment of the process of the invention the nickel compound is a nickel salt (11) In a particular embodiment the nickel salt (11) is selected from nickel bromide (II), nickel chloride (II), dichlorobis (triphenylphosphine) nickel (II), [1,3-bis (diphenylphosphine) propane] -nickel (II) chloride, nickel (II) acetate, nickel nitrate (lI) and mixtures thereof, and preferably is nickel bromide (II).
The amount of nickel used in the procedure can vary within a wide range and can be determined in each case. The amount may, for example, be equal to less than 5 mole% with respect to the moles of the compound of formula (11), although preferably less amounts are used, for example equal to or less than 1 mole percent with respect to the moles of the compound of formula (11) ). More preferably, the amount used is 0.01% to 0.00001% molar relative to the moles of the compound of formula (11), for example equal to or less than 0.001% molar, or to 0.0001% molar.
In a particular embodiment of the process of the invention in the 1,2,4-triazole derivative of formula (111) the substituents Rl and R2, are the same or different from each other, are selected from hydrogen and Cl-6 alkyl, and the R3 is selected from hydrogen and alkoxycarbonyl. In a preferred embodiment the 1,2,4-triazole derivative of the formula
(111) is the methyl compound 3,5-bis - {(1 H-1,2,4-triazol-1-yl) methyl) benzoate. In the process of the present invention the triazole derivative acts as a ligand, possibly coordinating the nickel species present in the reaction. Without wishing to be bound by a specific theory, the inventors of the present invention believe that it may be possible for said triazole derivative to participate in the formation of reaction intermediates.
The amount of 1,4-triazole derivative used in the process can vary within a wide range and can be determined in each case. The amount may be for example equal to or less than 5 mole% with respect to the moles of the compound of formula (11), although preferably amounts less than, for example equal to or less than 1 mole percent with respect to the moles of the compound of formula ( eleven). More preferably, the amount used is 0.01% to 0.00001% molar relative to the moles of the compound of formula (11), for example equal to less than 0.001% molar, or equal to less than 0.0001% molar.
In a particular embodiment, the same molar percentage amount of nickel as of 1,2,4-triazole derivative is used.
In a particular embodiment the alkaline acetate salt is Lí, Na, K, Rb, Cs, or Fr acetate, preferably sodium.
The amount of alkaline acetate salt used can vary within a wide range and can be determined in each case. Typically 5 to 30 mol% is used relative to the moles of the compound of formula (II), preferably 6 to 20 mol%, more preferably 7 to 15%, and even more preferably 10 mol%

In a particular embodiment the solvent is selected from the group of ethers. In another particular embodiment the solvent is selected from the group of polyols. In another particular embodiment, the solvent is selected from 1,4-dioxane and tetrahydrofuran. In another particular embodiment, ethylene glycol, propylene glycol, glycerol, polyethylene glycol 400 (PEG-400) 400, PEG-1500 and mixtures thereof are selected. In a preferred embodiment the solvent is selected from PEG 400. PEG 1500, glycerol and mixtures thereof
In each particular embodiment of the process of the invention the expert can determine the most suitable temperature in a simple manner. Typically the reaction temperature is between 110 ° C-130OC, for example 115 ° C, 120 ° C, or 125 ° C.
The reaction times vary according to each particular embodiment and can be determined in each case in a conventional manner by the expert.
The pressure between 1 and 1.2 atmosphere can be for example 1.1
In a particular embodiment of the process of the invention, in the compound of formula (11) A represents a group selected from phenyl, 4-ftuorophenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4- (trifluoromethyl) phenyl and naflyl .
In another particular embodiment of the process of the invention, the compound of formula (11) is selected from the group consisting of '
[1] "Pentyloxy) methyl) benzene.
[2] [(2-Methoxyethoxy) methyl] benzene
[3] [(Cyclohexyloxy) methyl] benzene [4) [(Heptyloxy) methyl] benzene
[5] [(3,3-Dimethylbutoxy) methyl] benzene [6) «(1 R, 2S, 5R} -2-lsoprapil-5-methy Icicloh exyloxy) methyl) benzene
[7] (2- (Benzyloxy} ethoxy) benzene
[8] "Decan-2-yloxy) methyl) benzene.
[9] "But-3-in-1-yloxy) methyl) benzene
[10] "Pent-4-in-1-yloxy) methyl) benzellO
[11] "Heptan-2-yloxy) methyl) benzene
[12] 5- "Benzyloxy) methyl) benzo [d] [1, 3) dioxal
[13] (2- (Benzyloxy) ethyl) benzellO
[14] (E) - «(3, 7-Dimethylocta-2,6-dien-1-yl) oxy) methyl) benzene
[15] (1 R, 2R, 4S} -2- (Benzyloxy} -1, 7.7 -trimethylbicyclo [2.2.1] heptane [16] 1 -Fluoro-4 - [(pentyloxy) methyl] benzene [17] 1-Methyl-4 - [(pentyloxy) methyl) benzene [1B] 1-Methoxy-3 - [(pentyloxy) methyl] benzene [19] 1-Methoxy-4 - [(pentyloxy) methyl] benzene
[20] 1- [(Pentyloxy) methyl] -4- (trifluoromethyl) benzene. [21] 2 - [(Pentyloxy) methyl] naphthalene
[22] (Benzyloxy) benzene
In another particular embodiment the compound of formula (1) obtained after deprotection is selected from:
[1] Fenal [2) 1-Pentanol
[3] 2-Methoxyetan-1-o1
[4] Cyclohexanol [5) 1-Heptanol [6) 3, 3-0imethyl-1-butanol [7) (1 R, 2S, SR} -2-isopropyl-S-methylcyclohexan-1-o1 «1 S, 2R , SS} - (+) -Menthol) [B] 2-Phenoxyethanol [9] 2-Decanol [10] 3-Butin-1-o1 [11] 4-Pentin-1-o1 [12] 2-Heptanol
[13] Benzo [d] [1, 3) dioxol-5-ylmethanol (Piperonyl alcohol) [1 4] 2-Phenylethanol
[15] (E) -3,7-Dimethylocta-2,6-dien-1-01 (Geraniol); Y
[16] (1 R, 2R, 4S) -1, 7.7-Trimethylbicyclo [2.2.1) heptan-2-o1 (D - (+) - Bomeol)
The process of the invention allows the deprotection or debenzylation of alcohols with molecular oxygen
in the presence of sub-stoichiometric amounts of a nickel compound (11) and a 1,2,4-triazole derivative of formula (111) and, in addition, an alkaline salt of acetic acid, advantageously from a point of view Economic and procedural. In addition, the protocol set up allows the scaling of the process to a multigram scale, so its application at industrial scale is evident.
Another advantage of the process of the invention is associated with the use of molecular oxygen as an abundant and environmentally benign oxidant, and in addition to its use at atmospheric pressure similar to what prevents the complication of the reaction system. In addition, the type of solvent used has a toxicity between low and zero
The following are examples to illustrate the process of the invention that should not be considered in any case as limiting the scope thereof.
Examples
Example 1
Preparation of "pentyloxy) methyl) benzene.
In a round bottom flask, sodium hydride (132 mg, 5.5 mmol) was dissolved in previously dried and degassed tetrahydrofuran (25 mL) under an inert atmosphere. On the suspension obtained 1pentanol (0.54 mL, 5 mmol) was added, and after a period of 5 minutes under vigorous stirring benzyl bromide was added
25 (0.59 mL, 5 mmol). Then, the mixture was heated at reflux for 5 hours. It was allowed to temper and H20 (10 mL) was added. This aqueous phase was then extracted with ethyl ether (EI.20) (4 x 6 mL), the combined organic phases were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue thus obtained was purified by flash chromatography (ethyl acetate (EtOAc) / Hexane 4:96) to provide the "pethyloxy) methyl) benzene as a yellow oil (873 mg, 98%). NMR-Hl (6, ppm) 1.05-1.10 (m, 3H, CH3), 1.49
30 1.53 (m, 4H, OCH2CH¡CH2CH. <CH3), 1.76-1.81 (m, 2H, OCH2CH. <CH2CH2CH3), 3.59 (t, J = 6.6, 2H, OCH2CH2CH2CH2CH3), 4.62 (s, 2H, PhCH2Ü) , 7.37-7.50 (m, 5H, Harem); NMR_13C (6, ppm) 14.1 (CH3), 22.6 (OCH2CH2CH2CH. <CH3) 28.5 (OCH2CH2CH. <CH2CH3), 29.6 (OCH2CH2CH2CH2CH3), 70.6 (OCH2CH2CH2CH2CH3l. 72.9 (PhCH2Ü). 127.5 (Carom-Car.6) 127.5 (Carom-Car.6) 127.5 (Carom-Car.6) 127.5 (Carom-Car.6) 127.5 (Carom-Car.6) 127.5 (Carom-Car.6) 127.5 (Carom-Car.6) 127.5 (Carom-Car.6) 127.5 (Carom-Car.6) 127.5 (Carom-Car.6) 127.5 (Carom-Car.6) 127.5 (Carom-H 6 -H), 128.4 (Carom.H), 138.8 (Cq..rom); MS (mIz)
179.1 (MW); HRMS calculated for C12H1S0 178.1358; shrunk 178,1357.
Example 2
Preparation of «2-methoxyethoxy) methyl) benzene.
In a round bottom flask, sodium hydride (132 mg, 5.5 mmol) was dissolved in previously dried and degassed tetrahydrofuran (25 mL) under an inert atmosphere. On the suspension obtained, 245 meloxethanol (0.39 mL, 5 mmol) was added, and benzyl bromide (0.59 mL, 5 mmol) was added for 5 minutes with vigOfOse stirring. Then, the mixture was heated at reflux for 5 hours. After the manufacturing and purification steps described in Example 1, the "2-methoxyethoxy) methyl) benzene was obtained as a yellow oil (756 mg, 91%). NMR-H1 (6, ppm) 3.26 (s, 3H, OCH3), 3.42-3.56 (m, 2H, OCH2CH2ÜCH3), 3.48-3.52 (m, 2H, OCH.CH20CH3), 4.45 (s, 2H, PhCH2Ü) , 7.16-7.28 (m, 5H, Harom); NMR_13C (6, ppm) 58.9 (OCH3), 69.3
50 (OCH2CH20CH3) 71 .9 (OCH2CH2ÜCH3), 73.2 (PhCH2Ü), 127.5 (Carom-H), 127.7 (Carom-H), 128.3 (Carom-H), 138.3 (Cc¡.arem); MS (miz) 167.1 (MW); EMAR calculated for ClOH140 2166.0994; found 166.0994.
Example 3
Preparation of "cyclohexyloxy) methyl] benzene.
In a round bottom flask, sodium hydride (132 mg, 5.5 mmol) was dissolved in previously dried and degassed tetrahydrofuran (25 mL) under an inert atmosphere. On the suspension obtained, 5 cyclohexanol (0.77 mL, 5 mmol) was added, and after a period of 5 minutes under vigorous stirring, benzyl bromide (0.59 mL, 5 mmol) was added. The mixture was then heated at reflux for 5 hours. After the manufacturing and purification steps described in Example 1, the "cyclohexyloxy) methyl) benzene was obtained as a yellow acetyl (71 3 mg, 75%). NMR-Hl (6, ppm) 1.34-1.58 (m, 5H, CHz), 1.66-1.68 (m, 1H, GHz), 1.87-1 .92 (m, 2H, GH2), 2.05-2.11 (m, 2H , GH2), 3.45-3.52 (m, 1H, CH), 4.66 (s, 2H, PhCH2Ü), 7.37-7.50 (m, 5H, Harom); NMR-13C
10 (6, ppm) 24.2 (GHz), 26.1 (CH2), 32.4 (CH2), 69.8 (PhCH2Ü), 76.9 (eH), 127.4 (earom-H). 127.5 (earom-H), 128.4 (Carom-H), 139.5 (Cq • arom); MS (miz) 191 .1 (MW); EMAR calculated for C13H1S0 190.1358; found 190.1360
Example 4
Preparation of "heptyloxy) methyl] benzene.
In a round bottom flask, sodium hydride (132 mg, 5.5 mmol) was dissolved in previously dried and degassed telrahydrofuran (25 mL) under an inert atmosphere. On the suspension obtained, 1-heptanol (0.71 mL, 5 mmol) was added, and after a period of 5 minutes under vigorous stirring, benzyl bromide (0.59 mL, 5 mmol) was added. Then, the mixture was heated at reflux for 5 hours. After the preparation and purification steps described in Example 1, the "heptyloxy) methyl) benzene was obtained as a yellow oil (618 mg,
25 60%). NMR_Hl (6, ppm) 0.97 (1, J = 6.6, 3H, eH3), 1.37-1.49 (m, 8H, eHzCHz (CHz) "cH3), 1.71 (q, J = 6.6, 2H, eH2CH2 (CHz) 4CH3 ), 3.55 (t, J = 6.6, 2H, CHzCH2 (CHz) 4eH3), 4.58 (s, 2H, PhCH2Ü), 7.32-7.44 (m, 5H, Harom); NMR_13e (6, ppm) 14.2 (CH3), 22.7 (CHz), 26.3 (CHz), 29.3 (CH2), 29.9 (CH2), 31.9 (CH2), 70.6 (CHzCH2 (CHz) 4eH3), 72.9 (PheH2Ü), 127.4 (e "'' '' '' ' 'H), 127.6 (Carom.H), 128.4 (Carom-H), 138.8 (Cctarom); MS (miz)
207.1 (MW); EMAR calculated for e 14H220 206.1671, shrunk 206.1669.
Example 5
Preparation of [(3, J-dimethylbutoxy) methyl] benzene.
In a round bottom flask, sodium hydride (132 mg, 5.5 mmol) was dissolved in tetrahydrofuran previously
40 dried and degassed (25 mL) under inert atmosphere. On the suspension obtained, 3,3-dimethyl-1-butanol (0.60 mL, 5 mmol) was added, and after a period of 5 minutes under vigorous stirring, benzyl bromide (0.59 mL, 5 mmol) was added. Then, the mixture was heated at reflux for 5 hours. After the preparation and purification steps described in example 1, [(3,3-dimethylbutoxy) methyl) benzene was obtained as a yellow oil (672 mg, 70%). NMR-Hl (i5, ppm) 0.96 (s, 9H, eH3), 1.62 (t, J = 6.8, 2H, CH2CH2 (eH3) 3), 3.55-3.60 (m, 2H,
45 eH2eH2 (CH3) 3), 4.53 (s, 2H, PhCH2Ü), 7.28-7.38 (m, 5H, Harom); NMR_13C (i5, ppm) 29.8 «CH3) 3), 43.1 (OeH2CH2 (CH3) 3), 67.9 (OCHzCHz (eH3) 3), 73.0 (PhCH2Ü), 127.5 (earom.H), 127.6 (Carom-H), 128.4 (Carom-H), 138.8 (Cctarom); MS (miz) 193.1 (MW); HRMS calculated for C13H200 192.1514; found 192.1515
50 Example 6
Preparation of «(1R, 2S, 5R) -2-isopropyl-5-methylcyclohexytoxy) methyl) benzene.
In a round bottom flask, sodium hydride (132 mg, 5.5 mmol) was dissolved in previously dried and degassed tetrahydrofuran (25 mL) under an inert atmosphere. On the suspension obtained (1R, 2S, 5R) -25 isopropyl-5-methylcyclohexanol (781 mg, 5 mmol) was added, and after a period of 5 minutes under vigorous stirring, benzyl bromide (0.59 mL, 5) was added mmol). Then, the mixture was heated at reflux for 5 hours. After the preparation and purification steps described in example 1, the "(1 R, 2S, 5R} -2-isopropyl-5-methylcyclohexyloxy) methyl) benzene was obtained as a yellowish oil (618 mg, 81%). NMR-H '(6, ppm) 0.97 (1, J = 6.6, 3H, CH3), 1.37-1.49 (m, 8H, CH2CH2 (CH2) 4CH3), 1.71 (q, J = 6.6, 2H, CH2CH2 (CH2 ) 4CH3). 3.55 (t, J = 6.6, 2H, 10 CH2CH2 (CH2} 4CH3), 4.58 (s, 2H, PhCH2Ü), 7.32-7.44 (m, 5H, Harom); NMR_13C (6, ppm) 14.2 (CH3), 22.7 (CH2),
26.3 (CH2), 29.3 (CH2), 29.9 (CH2), 31.9 (CH2), 70.6 (CH2CH2 (CH2) 4CH3), 72.9 (PhCH2Ü), 127.4 (Carom-H), 127.6 (Carom-H), 128.4 ( Carom-H), 138.8 (Cq.arom); MS (miz) 207.1 (MW); EMAR calculated for CnH260 246.1984; found 246.1983
Example 7
Preparation of {2- (benzyloxy) ethoxy) benzene.
In a round bottom flask, sodium hydride (132 mg, 5.5 mmol) was dissolved in pre-dried and degassed tetrahydrofuran (25 mL) under an inert atmosphere. On the suspension obtained, 2-phenoxyethanol (0.62 mL, 5 mmol) was added, and after a period of 5 minutes under vigorous agitation, benzyl bromide (0.59 25 mL, 5 mmol) was added. The mixture was then heated under reflux for 5 hours. After the manufacturing and purification steps described in Example 1, the «2-phenoxyethoxy) methyl) benzene was obtained as a yellow oil (1.09 g, 96%). NMR-H '(6, ppm) 3.93-3.96 (m, 2H, OCH2CH20Ph), 4.244.27 (m, 2H OCH2CH2ÜPh), 4.76 (s, 2H, PhGH2Ü), 7.10-7.15 (m, 3H, Harom), 7.4-7.57 (m, 7H, Harom); NMR_13C (6, ppm) 67.5 (CH2), 68.7 (CH2), 73.5 (PhCH2Ü), 114.8 (Carom_H), 121.0 (Carom_H), 127.8 (Carom.H), 127.9 (Carom-H), 128.6 (C "" OfYI.H). 129.6 (Carom.H), 138.3
30 (Cq.arom), 158.9 (Cq4lrom); MS (miz) 229.1 (M +); HRMS calculated for C1sH1S02 228.1150; found 228.1152
Example 8
Preparation of {(decan-2-yloxy) methyl) benzene.
In a round bottom flask, sodium hydride (132 mg, 5.5 mmol) was dissolved in tetrahydrofuran previously
40 dried and degassed (25 mL) under inert atmosphere. On the suspension obtained, 2-decanol (0.95 mL, 5 mmol) was added, and after a period of 5 minutes under vigorous stirring, benzyl bromide (0.59 mL, 5 mmol) was added. Then, the mixture was heated at reflux for 5 hours. After the processing and purification steps described in example 1, the "decan-2-yloxy) methyl) benzene was obtained as a yellow oil (906 mg, 73%). 1 H NMR (6, ppm) 0.97 (t, J = 6.6, 3H, CH3), 1.27 (d, J = 6.6, 3H, CH3), 1.38-1.78 (m, 14H, CH (CHz) 7CH3),
45 3.58 (td, J = 6.3, 4.9, 1 H, GH (CH2) 7CH3), 4.53 (d, J = 11 .8, 1H, PhGHzQ), 4.64 (d, J = 11 .9, 1 H, PhGHzQ ), 7.32
7.45 (m, 5H, Harom); NMR_13C (O, ppm) 14.2 (CH3), 19.7 (CH3), 22.8 (CH2), 25.6 (CH2), 29.4 (CH2), 29.7 (CH2),
29.8 (CH2), 32.0 (CH2), 36.8 (CH2), 70.3 (PhGHzQ), 74.9 (CH), 127.4 (Carom.H), 127.6 (Carom.H), 128.3 (Carom.H),
139.3 (Cq.arom); MS (miz.) 249.2 (M +); HRMS calculated for C17H2S0 248.2140; found 248.2139
Example 9Preparation of "but-3-in-1-yloxy) methyl) benzene.
5 In a round bottom flask, sodium hydride (132 mg, 5.5 mmol) was dissolved in previously dried and degassed tetrahydrofuran (25 mL) under an inert atmosphere. On the suspension obtained, 3-bulin-1 -ol (0.38 mL, 5 mmol) was added, and benzyl bromide (0.59 mL, 5 mmol) was added for a period of 5 minutes under vigorous stirring. Then, the mixture was heated at reflux for 5 hours. After the processing and purification steps described in Example 1, the "but-3-in-1-yloxy) methyl) benzene was obtained as a yellow oil (512
10 mg, 64%). NMR-H '(i5, ppm) 2.10 (1, J = 2.7, 1H, CH), 2.56 (Id, J = 6.9, 2.6, 2H, CH2CH2C ::::: CH), 3.65 (1, J = 7 , 2H, CH2CH2C ::::: CH), 4.6 (s, 2H, PhCH2Ü), 7.33-7.45 (m, 5H, Harom); NMR_13C (i5, ppm) 19.9 (CH2), 68.3 (CH2), 69.8 (CH), 72.9 (PhCH2Ü), 81 .4 (C =: CH), 127.7 (Carom.H), 127.9 (Carom.H), 128.5 (Carom-H), 138.3 (Cq • arom); MS (mIz)
161.1 (MW); HRMS calculated for C "H, 20 160.0888; found 160.0890
Example 10
Preparation of ((pent-4-in-1-yloxy) methyl) benzene.
In a round bottom flask, sodium hydride (132 mg, 5.5 mmol) was dissolved in previously dried and degassed tetrahydrofuran (25 mL) under an inert atmosphere. On the suspension obtained 4-pentin-1-o1 (0.46 mL, 5 mmol) was added, and after a period of 5 minutes under vigorous stirring benzyl bromide (0.59 25 mL, 5 mmol) was added. Then, the mixture was heated at reflux for 5 hours. After the processing and purification steps described in Example 1, the "penl-4-in-1-yloxo) methyl) benzene was obtained as a yellow oil (627 mg, 72%). H-NMR '(i5, ppm) 1.84-1.99 (m, 2H, CH2CH2CH2C =: CH), 2.06 (t, J = 2.7, 1H, CH), 2.40 (td, J = 7_1, 2.6, 2H, CH2CH2CH2C = : CH), 3.64 (t, J = 7, 2H, CH2CH2CH2C =: CH), 4.58 (s, 2H, PhCHzO), 7.33-7.47 (m, 5H, Harom); NMR -3C (i5, ppm): 15.4 (CH2), 28.8 (CH2), 68.7 (CH2), 68.8 (CH), 73 (PhCHzO), 84 (C =: CH), 127.6 (Car <> mH) ,
30 127.7 (Carom.H), 128.5 (Carom.H), 138.7 (C. ~ .arom); MS (miz) 175.1 (MW); HRMS calculated for C, 2H, 40 174,1045; found 174,1044
Example 11
Preparation of «heptan-2-yloxy) methyl) benzene.
In a round bottom flask, sodium hydride (132 mg, 5.5 mmol) was dissolved in previously dried and degassed tetrahydrofuran (25 mL) under an inert atmosphere. On the suspension obtained 2-heptanol (O, 71 mL, 5 mmol) was added, and after a period of 5 minutes under vigorous stirring benzyl bromide (0.59 mL, 5 mmol) was added. Then, the mixture was heated at reflux for 5 hours. After the preparation and purification steps described in example 1, the "heptan-2-yloxy) melyl) benzene was obtained as a yellow oil (845
45 mg, 82%). NMR-H '(5, ppm) 1.03 (1, J = 6.8, 3H, CH3), 1.31 (d, J = 6.2, 3H, CH3), 1.39-1.79 (m, 8H, CH (CH2) aCH3), 3.56-364 (m, 1H, CH), 4.56 (d, J = 11.8, 1H, PhCHzO), 4.58 Id, J = 11.8, 1H, PhCHzO), 7.33-7.48 (m, 5H, H. ~); NMR- "C (O, ppm) 14.2 (CH,), 19.7 (CH,) 22.8 (CH2), 25.4 (CH2), 32.1 (CH2), 36.8 (CH2), 70.4 (PhCH2Ü), 74.9 (CH), 127.4 (Carom_H), 127.6 (Carom-H), 128.3 (Carom.H), 139.3 (Cq.arom); MS (miz) 207.1 (MW); EMAR calculated for C14HnO 206.1671; found for 206.1673
Example 12
Preparation of IS - [(phenylmethoxy) methyl] 1,3-benzodioxol.
In a round bottom flask, sodium hydride (132 mg, 5.5 mmol) was dissolved in tetrahydrofuran previously
5 dried and degassed (25 ml) under inert atmosphere. On the suspension obtained piperon il alcohol (761 mg, 5 mmol) was added, and after a period of 5 minutes under vigorous stirring benzyl bromide (0.59 ml, 5 mmol) was added. Then, the mixture was heated at reflux for 5 hours. After the preparation and purification steps described in example 1, 5 - [(phenylmethoxy) methyl) 1,3-benzodioxol was obtained as a yellow oil (1.01 g, 84%). NMR-H1 (6, ppm) 4.55 (s, 2H, PhCH2Ü), 4.63 (s, 2H, OCH2), 5.97 (s, 2H, OCHzO), 6.86-6.91 (m,
10 2H, H.rom), 7.01 (s, 1H, H.rom), 7.38-7.48 (m, 5H, Harom); NMR-13C (6, ppm) 71.9 (PhCH2Ü), 72.0 (OCH2), 101 .1 (OCH2Ü), 108.1 (Carom-H), 108.6 (Carom-H), 121.4 (Carom.H), 127.7 (C. ..om-H), 127.8 (C ... om-H), 128.5 (C ... om-H), 132.3 (Cq.arom), 138.5 (Cq-arom), 147.3 (Cq-arom), 147.9 (Cq-arom); MS (miz) 243.1 (MW); HRMS calculated for C15H1403 242.0943; found for 242.0942.
Example 13
Preparation of ((2-phenylethoxy) methyl) benzene.
In a round bottom flask, sodium hydn.HO (132 mg, 5.5 mmol) was dissolved in previously dried and degassed tetrahydrofuran (25 ml) under an inert atmosphere. Phenylethyl alcohol (0.60 ml, 5 mmol) was added to the suspension obtained, and after a period of 5 minutes under vigorous stirring, benzyl bromide (0.59 25 ml, 5 mmol) was added. Then, the mixture was heated at reflux for 5 hours. After the manufacturing and purification steps described in Example 1, the "2-phenylethoxy) methyl) benzene was obtained as a yellow oil (530 mg, 50%). 1 H NMR (6, ppm) 3.09 (1, J = 7.1, 2H, OCH2CH2Ph), 3.84 (t, J ::: 7.2, 2H, OCHzCHzPh), 4.67 (s, 2H, PhCH2Ü), 7.35-7.48 (m , 5H, Harom); NMR_13C (c :: i, ppm) 36.6 (OCHzCH2Ph), 71.4 (PhCHzQ), 73.1 (OCH2CH2Ph),
126.4 (Carom.H), 127.7 (Carom-H), 127.7 (Carom-H), 128.5 (Can¡rn.H), 129.1 (Carom-H), 138.6 (C <¡-arom), 139.1 (Cq • arom); MS 30 (miz) 213.1 (MW); HRMS calculated for C15H160 212,1201; found for 212.1199
Example 14
Preparation of benzyl geranyl ether ((E) - (((3,7-Dimethylocta-2,6-dien-1-yl) oxy) methyl) benzene)
In a round bottom flask, sodium hydride (132 mg, 5.5 mmol) was dissolved in letter hydrofuran previously
40 dried and degassed (25 ml) under inert atmosphere. On the suspension obtained, geraniol (0.87 ml, 5 mmol) was added, and after a period of 5 minutes under vigorous stirring, benzyl bromide (0.59 ml, 5 mmol) was added. Then, the mixture was heated at reflux for 5 hours. After the preparation and purification steps described in example 1, benzyl geranyl ether was obtained as a yellow oil (1.09 g, 90%) 1 H-NMR (6, ppm) 1.72 (s, 3H, GH3), 1.75 ( s, 3H, GH3), 1.80 (s, 3H, GH3), 2.14-2.26 (m, 4H, GHz), 4.13 (d, J = 6.1,
45 2H, OCHzCH = C), 4.58 (s, 2H, PhCH2Ü), 5.23 (1, J ::: 6.1, 1H, CH = C (CH3) 2), 5.54 (t, J ::: 6.1, 1H, OCH2CH = C), 7.33-7.46 (m, 5H, Harom); NMR-13C (c :: i, ppm) 16.5 (CH3), 17.7 (CHJ), 25.8 (CHJ), 26.5 (CH2), 39.7 (CH2), 66.6 (CHz), 71 .9 (PhCH2Ü), 121. 2 (CH = C (CH3) Z), 124.2 (OCHzCH = C), 127.5 (Carom-H), 127.7 (Carom-H), 128.3 (Carom-H),
131.4 (CH = C (CH3) 2), 138.8 (Cq-arom), 140.1 (OCH2CH = C}); MS (miz) 245.8 (MW); HRMS calculated for C17H240 244.1827; found for 244.1828.
Example 15Preparation of benzyl bornyl ether «(1 R, 2R, 4S) -2- (Benzyloxy) -1, 7, 7-trimethylbicyclo (2.2.1] heptane)
In a round bottom flask, sodium hydride (132 mg, 5.5 mmol) was dissolved in previously dried and degassed telrahydrofuran (25 mL) under an inert atmosphere. On the suspension obtained bomeol (771 mg, 5 mmol) was added, and after a period of 5 minutes under vigorous stirring, benzyl bromide (0.59 mL, 5 mmol) was added. Then, the mixture was heated at reflux for 5 hours. After the processing and purification steps J 10 described in Example 1, benzyl bomil ether was obtained as a yellow oil (1,119, 91%). NMR-H '(6, ppm)
0.98 (s, CH3), 1.00 (s, CH3), 1.06 (s, CH3), 1.25 (dd, J = 3A, 13.0, 1H, CH), 1.37-1A6 (m, 2H, CH2), 1.78-1_92 (m, 2H, CH2), 2.22-2.32 (m, 2H, CH2), 3.84 (dd, J = 1.8, 9.8, 1H, OCH), 4.57 (d, J = 12.2, 1H, OCH2Ph), 4.71 (d , J = 12.2, 1H, OCH2Ph), 7.34-7.50 (m, 5H, Harom); NMR-, 3C (6, ppm) 14.2 (CH3), 19.0 (CH3), 19.9 (CH3), 26.9 (CH2), 28A (CH2), 36.3 (CH2), 45.2 (CH), 47.9 (C), 49.5 (C), 71.7 (OCH2Ph), 86.5 (OCH), 127.3 (Carom.H), 128.3 (C.rom-H),
15 139.7 (Cq.arom); MS (miz) 245.2 (MW); HRMS calculated for C17H240 244.1827; found for 244.1825.
Example 16
Preparation of I1-f1uoro-4 - [(pentyloxy) methyl] benzene.
~ or ~
F ~
In a round bottom flask, sodium hydride (132 mg, 5.5 mmol) was dissolved in tetrahydrofuran previously
25 dried and degassed (25 mL) under inert atmosphere. On the suspension obtained, pentanol (0.54 mL, 5 mmol) was added, and after a period of 5 minutes under vigorous stirring, 4-fluorobenzyl bromide (0.62 mL, 5 mmol) was added. Then, the mixture was heated at reflux for 5 hours. After the preparation and purification steps described in example 1, 1-fluoro-4 -! (Pentyloxy) methyl) benzene was obtained as a yellow oil (530mg, 75%). NMR-H '(6, ppm) 0.92-0.97 (m, 3H, CH3), 1.35-1.41 (m, 4H, OCH2CH2CH2CH2CH3), 1.63-1 .68 (m,
30 2H, OCH2CH2CH2CH2CH3), 3.48 (t, J = 6.6, 2H, OCH2CH2CH2CH2CH3), 4 A6 (s, 2H, PhCH2Ü), 7.01-7.06 (m, 2H, H.rom), 7.29-7.34 (m, 2H, Harom); NMR-, 3C (6, ppm) 13.9 (CH3), 22.6 (OCH2CH2CH2CH2CH3) 28A (OCH2CH2CH2CH2CH3), 29.5 (OCH2CH¡CH2CH2CH3), 70.5 (OCH¡CH2CH2CH2CH3), 72.1 (PhCH..o), 115.8 (d, J = 21 .3, C ... om.H), 129.2 (d, J = 8.1, Carom-H), 134.6 (d, J = 3.2, ~ arom), 162.3 (d, J = 245.2, Cq.F ); MS (miz) 197.1 (MW); HRMS calculated for C'2H17FO 196,1263; found for 196.1264
Example 17
Preparation of I1-methyl-4 - [(pentyloxy) methyl] benzene.
In a round bottom flask, sodium hydride (132 mg, 5.5 mmol) was dissolved in previously dried and degassed tetrahydrofuran (25 mL) under an inert atmosphere. On the suspension obtained, pentanol (0.54 45 mL, 5 mmol) was added, and after a period of 5 minutes under vigorous stirring 4-methylbenzyl bromide (925 mg, 5 mmol) was added. Then, the mixture was heated at reflux for 5 hours. After the preparation and purification steps described in example 1, 1-methyl-4 - [(pentyloxy) methyl) benzene was obtained as a yellow oil (384mg, 40%). H-NMR '(6, ppm) 1.02-1.06 (m, 3H, CH3), 1A5-1.50 (m, 4H, OCH2CH2CH2CH2CH3), 1.72-1.77 (m, 2H, OCH2CH2CH2CH2CH3), 2A5 (s, 3H, CH3) , 3.56 (t, J = 6.6, 2H, OCH2CH2CH2CH2CH3), 4.57 (s, 2H, PhCH2Ü),
50 7.25 (d, J = 7.8, 2H, Harom), 7.35 (d, J = 8.1, 2H, H •• om); NMR_13C (6, ppm) 14.2 (CH3), 21.2 (CH3), 22.7 (OCH2CH2CH2CH2CH3) 28.5 (OCH2CH2CH2CH2CH3), 29.6 (OCH2CH2CH2CH2CH3), 70A (OCH ~ H2CH2CH2CH3). 72.8 (PhCH2Ü), 127.8 (Car (lrn.H), 129.1 (Car (lrn.H), 135.8 (Cq4IIrom), 137.1 (Cq4lrom); MS (miz)
193.1 (MW); HRMS calculated for C13H200 192.1514; shrunk to 192.1514.
Example 18 Preparation of I-1-methoxy-3 - [(pentyloxy) methyl] benzene.
10 15 20 In a round bottom flask, sodium hydride (132 mg, 5.5 mmol) was dissolved in previously dried and degassed tetrahydrofuran (25 mL) under an inert atmosphere. On the suspension obtained, pentanol (0.54 mL, 5 mmol) was added, and after a period of 5 minutes under vigorous stirring, 3-methoxybenzyl bromide (0.70 mL, 5 mmol) was added. Then, the mixture was heated at reflux for 5 hours. After the preparation and purification steps described in example 1, 1-methoxy-3 - [(pentyloxy) methyl) benzene was obtained as a yellow oil (624 mg, 60%). 1 H NMR (6, ppm) 0.91 0.96 (m, 3H, CH3), 1.36--1A2 (m, 4H, OCH2CH2CH2CH ~ H3), 1.63-1.68 (m, 2H, OCH2CH ~ H2CH2CH3), 3A3 (t, 2H, J = 6.6, 2H, OCH ~ H2CH2CH2CH3), 3.82 (s, 3H, OCH3), 4.51 (s, 2H, PhCH2Ü), 6.84 (d, J = 8.1, 1H, Harom), 6 .59 (s, 2H, Harom), 7.27 (t, 1H, J = 7.9, Harom); NMR_13C (6, ppm) 14.1 (CH3), 22.6 (OCH2CH2CH2CH ~ H3) 28A (OCH2CH2CH2CH2CH3), 29.5 (OCH2CH ~ H2CH2CH3), 55.1 (OCH3), 70.5 (OCH.cH2CH2CH2CH3), 72A (PhCH2om), 112.9 (PhCH2om), 112.9 (PhCH2om), 112.9. H), 113.1 (Carom-H), 119.8 (Carom.H), 129.1 (Carom-H), 140A (Cq_orom), 159.8 (Cq_arom); MS (miz) 209.1 (MH '); EMAR calculated for C13H200 2 208, 1463; found for 208.1465.
25 Example 19
Preparation of I-1-methoxy-4 - [(pentyloxy) methyl] benzene.
3D 35 40 In a round bottom flask, sodium hydride (132 mg, 5.5 mmol) was dissolved in previously dried and degassed tetrahydrofuran (25 mL) under an inert atmosphere. On the suspension obtained, pentanol (0.54 mL, 5 mmol) was added, and after a period of 5 minutes under vigorous stirring, 4-methoxybenzyl bromide (0.74 mL, 5 mmol) was added. Then, the mixture was heated at reflux for 5 hours. After the preparation and purification steps described in example 1, 1-methoxy-3 - [(pentyloxy) methyl) benzene was obtained as a yellow oil (406 mg, 39%). 1 H NMR (O, ppm) 0.91 0.96 (m, 3H, CH3), 1.35--1AO (m, 4H, OCH2CH2CH2CH.cH3), 1.59--1.67 (m, 2H, OCH2CH2CH2CH2CH3), 3.56 (t, J = 6.6, 2H, OCH ~ H2CH2CH2CH3), 3.79 (s, 3H, OCH3), 4.57 (s, 2H, PhCH2Ü), 6.89 (d, J = 8.7, 2H, Harom), 7.28 (d, J = 8.7, 2H , Harom); NMR_13C (6, ppm) 14.1 (CH3), 22.6 (OCH2CH2CH2CH.cH3). 28.4 (OCH2CH2CH ~ H2CH3), 29.5 (OCH2CH.cH2CH2CH3), 55.1 (OCH3), 70.2 (OCH ~ H2CH2CH2CH3). 72.5 (PhCH2Ú), 113.7 (Carom-H), 129.1 (Car (lrn.H), 130.8 (Cq-arom), 159.3 (Cq.arom); MS (miz) 209.1 (MW);, EMAR calculated for C13 H200 2 208, 1463; found for 208, 1462.
Four. Five Example 20 Preparation of 1 - [(pentyloxy) methyl] -4- (trifluoromethyl) benzene.
In a round bottom flask, sodium hydride (132 mg, 5.5 mmol) was dissolved in tetrahydrofuran previously
dried and degassed (25 mL) under inert atmosphere. On the suspension obtained, pentanol was added (0.54
ml, 5 mmol), and after a period of 5 minutes under vigorous stirring 4- (trifluoromethyl) benzyl (0.77 ml,
5 mmol). Then, the mixture was heated at reflux for 5 hours. After the processing and purification steps described in example 1, 1 - [(pentyloxy) methyl) -4- (trifluoromethyl) benzene was obtained as a yellow oil (1.0 g, 82%). NMR-H '(6, ppm) 0.91 -0.96 (m, 3H, CH3), 1.35-1.40 (m, 4H, OCH2CH2CH2CH2CH3), 1.61
1.68 (m, 2H, OCH2CH2CH2CH2CH3), 3.50 (1, J = 6.6, 2H, OCH2CH2CHzCH2CH3), 4.56 (s, 2H, PhCH2Ü), 7.46 (d,
5 J = 7.9, 2H, Harom). 7.61 (d, J = 8, 2H, Harom); 13 C NMR (6, ppm) 13.9 (CH3), 24_5 (OCH2CHzCHzCH., CH3), 28.3 (OCH2CH2CHzCH2CH3l. 29.3 (OCH2CHzCHzCHzCH3) .70.9 (OCHzCHzCHzCHzCH3). 72.0 (PhCHzO. , J = 3.8, Carom.H), 127.1 (Carom_H), 127.4 (Cq.a <om), 129.1-130.2 (m, Cq-arom), 142.9 (CF3); MS (miz) 247.1 (MW); EMAR calculated for C13H17F30 246.1231; found for 246.1232.
Example 21
Preparation of 2 - [(pentyloxy) methyl] nafaltalene.
In a round bottom flask, sodium hydride (132 mg, 5.5 mmol) was dissolved in previously dried and degassed tetrahydrofuran (25 mL) under an inert atmosphere. On the suspension obtained, pentanol (0.54 mL, 5 mmol) was added, and after a period of 5 minutes under vigorous stirring, 2- (bromomethyl) naphthalene (1.1 g, 5 mmol) was added. Then, the mixture was heated at reflux for 5 hours. After the preparation and purification steps described in example 1, 2 - [(pentyloxy) methyl] naphthalene was obtained as a yellow oil (650mg, 57%). NMR-H '(6, ppm). 0.95-0.99 (m, 3H, CH3), 1.38-1.45 (m, 4H, OCH2CH2CH2CH2CH3), 1.65-1.74 (m, 2H, OCH2CH2CH2CH2CH3), 3.56 (1, J = 6.6, 2H, OCH2CH2CH2CH2CH3), 4.71 (s, 2H, PhCH2Ü), 7.49-7.54 (m, 3H, H.rom), 7.83-7.89 (m, 4H, Harom); NMR-13C (6, ppm) 14.1 (CH3), 22.6 (OCH2CH2CH2CHzCH3), 28.4
25 (OCH2CH2CHzCH2CH3l. 29.5 (OCH2CHzCH2CH2CH3), 70.6 (OCH2CH2CH2CH2CH3), 73.0 (PhCHzO), 125.7 (Carom-H), 125.8 (Carom-H), 126.0 (Carom-H), 126.3 (Carom.H), 127.7 (Carom. -H), 127.8 (Carom-ll), 127.9 (Carom-H), 128.1 (Carom-H), 132.9 (Cc.arom), 133.4 (Cq.arom), 136.3 (Cq.arom); MS (mIz ) 229.1 (MW); EMAR calculated for C, aH200 228.1514; found for 228.1513.
Example 22
22.1. Obtaining phenol using NiBr2 and 3,5-bis «1 H-1,2,4-triazol-1-yl) methyl) methyl benzoate
6 OH
In a round bottom flask, benzyl phenyl ether (184 mg, 1 mmol), sodium acetate (8 mg, 0.1 mmol), nickel bromide (lI) (20 ~ L of a 5 x 10 · 3M solution were mixed in DMA, 0.0001 mmol) and 3,5-bis- «1H-1,2,4-triazol-1-yl) methyl) methyl benzoate (20 ~ L of a 5 x 10 · 3M solution in DMA, 0.0001 mmol) in PEG 400 (1 40 mL) at room temperature under oxygen atmosphere (1 atm). The mixture was heated at 120 ° C for 24 hours, maintaining vigorous stirring at all times. It was allowed to temper, 0.5M HCI (10 mL) was added by heating the mixture at reflux for 5 hours. It was allowed to temper, and H20 (30 mL) was added. This aqueous phase was then extracted with diethyl ether (4 x 6 mL). The combined organic phases were washed with a saturated solution of NaCl in water (1 x 15 mL), dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue thus obtained was purified by flash chromatography (AcOEUHexano 3: 7) to provide the phenol as a white-colorless solid (37 mg, 40%). NMR-'H (CoCh, 6H, ppm) 6.98-7.09 (m, 3H, Harom), 7.31-7.37 (m, 2H, Harom); NMR_13C (COCh, Oc, ppm) 115.7 (Carom-H), 121 .2 (Carom-H), 130.0 (Carom-H),
155.3 (Cq.arom); MS (miz): 95.1 (MW); HRMS calculated for CaH60 94.0419; shrunk to 94.0420.
22.2. Obtaining phenol using NiCh and 3,5-bis «1 H-1,2,4-triazol -1-yl) methyl) methyl benzoate
In a round bottom flask, benzyl phenyl ether (184 mg, 1 mmol), sodium acetate (8 mg, 0.1 mmol), nickel chloride (lI) (20 ~ L of a 5 x 10 · 3M solution were mixed in DMA, 0.0001 mmol) and 3,5-bis- «1H-1,2,455 triazol-1-yl) methyl) methyl benzoate (20 ~ L of a 5 x 10-3M solution in DMA, 0.0001 mmol ) in PEG 400 (1 mL) at room temperature under oxygen atmosphere (1 atm). The mixture was heated at 120 ° C for 24 hours,
maintaining vigorous agitation at all times_After the processing and purification steps described in example 22.1, the phenol was obtained as a white-colorless solid (33 mg, 35%).
5 22.3. Obtaining phenol using Ni (PPh3) 2CIz and 3,5-bis «1H-1,2,4-triazol-1-yl) methyl) methyl benzoate
In a round bottom flask, benzyl phenyl ether (184 mg, 1 mmol), sodium acetate (8 mg, 0.1) were mixed
mmol), dichlorobis (triphenylphosphine) nickel (lI) (20 ~ L of a 5 x 10 · 3M solution in DMA, 0.0001 mmol) and 3, S-bis
«1H-1,2,4-triazol-1-yl) methyl) methyl benzoate (20 ~ L of a 5 x 1 solution ()" JM in DMA, 0.0001 mmol) in PEG
10 400 (1 mL) at room temperature under oxygen atmosphere (1 atm). The mixture was heated at 120 ° C for 24 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in example 22.1, the phenol was obtained as a white-colorless solid (23 mg, 25%).
22.4. Obtaining phenol using [Ph2P (CH2) 3PPh2] NiCIz and 3,5-bis «1H-1,2,4-triazol-1-yl) methyl) methyl benzoate 15
In a round bottom flask, benzyl phenyl ether (184 mg, 1 mmol), sodium acetate (8 mg, 0.1 mmol), [1,3-bis (diphenylphosphine) propane]-nickel (ll) chloride (11) ( 20 ~ L of a 5 x 10 · 3M solution in DMA, 0.0001 mmol) and 3,5-bis- «1H-1,2,4-triazol-1-yl) methyl) methyl benzoate (20 ~ L of a 5 x 10 · 3M solution in DMA,
20 0.0001 mmol) in PEG 400 (1 mL) at room temperature under oxygen atmosphere (1 atm). The mixture was heated at 120 ° C for 24 hours, maintaining vigorous stirring at all times. _ After the processing and purification steps described in example 22.1, the phenol was obtained as a white-colorless solid (18 mg, 20%).
25 22.5. Obtaining phenol using Ni (OAc) 2 and 3,5-bis «1H-1,2,4-triazol-1-yl) methyl) methyl benzoate
In a round bottom flask, benzyl phenyl ether (184 mg, 1 mmol), sodium acetate (8 mg, 0.1 mmol), nickel acetate (lI) (20 ~ L of a 5 x 10 JM solution were mixed in DMA, 0.0001 mmol) and methyl 3,5-bis- «1H-1,2,4-triazol-1-yl) methyl) benzoate (20 ~ L of a 5 x 10.JM solution in DMA, 0, 0001 mmol) in PEG 400 (1
30 mL) at room temperature under oxygen atmosphere (1 atm). The mixture was heated at 120 ° C for 24 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in example 22_1, the phenol was obtained as a white-colorless solid (34 mg, 36%)
22.6. Obtaining phenol using Ni (N03) 2 and 3,5-bis «1H-1,2,4-triazol-1-yl) methyl) methyl benzoate
In a round bottom flask, benzyl phenyl ether (184 mg, 1 mmol), sodium acetate (8 mg, 0.1 mmol), nickel nitrate (LI) (20 ~ L of a 5 x 10 JM solution) were mixed. in DMA, 0.0001 mmol) and 3,5-bis - ((1H-1, 2,4-lriazol1-yl) methyl) methyl benzoate (20 ~ L of a 5 x 10 · 3M solution in DMA, 0 .0001 mmol) in PEG 400 (1 mL) at room temperature under oxygen atmosphere (1 atm). The mixture was heated at 120 ° C for 24 hours,
40 maintaining vigorous agitation at all times. After the preparation and purification steps described in example 22_1, phenol was obtained as a white-colorless solid (5 mg, 5%)
22.7. Obtaining 1-pentanol using NiBr2 and 3,5-bis «1H-1,2,4-triazol-1-yl) methyl) methyl benzoate
HO ~
In a round bottom flask ((pentoxy) methyl) benzene (178 mg, 1 mmol), sodium acetate (8 mg, 0.1 mmol), nickel bromide (11) (20 jJL of a 5 x 10 solution) were mixed .f! M in PEG-400, 0.0000001 mmol) and 3.5bis "1H-1,2,4-triazol-1-yl) methyl) methyl benzoate (20 ~ L of a 5 x 10-6M solution in PEG-400, 0.0000001 50 mmol) in PEG 400 (1 mL) at room temperature under oxygen atmosphere (1 atm) _ The mixture was heated at 120 OC for 48 hours, maintaining vigorous stirring at all times _ After processing and purification steps described in example 22_1, 1-pentanol was obtained as a colorless liquid (67 mg, 76%) _ NMRlH (CDCb, i5H, ppm) 0.86 (t, 3H, J = 7, CH3), 1.18- 1.24 (m, 4H, HOCH2CH2 (CH2) 2CH3), 1.39-1.48 (m, 2H, HOCH2CH2 (CH2) 2CH3), 3.46 (t, 2H, J = 6_8, HOCH.cH2 (CHÚ2CH3), 3.75 (s, 1H , OH); NMR_13C (CDCb, i5c, ppm) 55 13_6 (CH3), 22_3 (CH2l. 27_8 (CH2), 32_1 (CH2), 61_9 (HOCH2); MS (mIz) · 89_1 (MH '); EMAR calculated for CSH120 88.0888; found for 88.0886.
22.8. Obtaining 1-pentanol using NiBr2 and 3,5-bis {(1 H-1, 2,4-triazol-1-yl) methyl) methyl benzoate in 60 dioxane
In a round bottom flask "pentoxy) methyl) benzene (178 mg, 1 mmol), sodium acetate (8 mg, 0.1 mmol), nickel bromide (lI) (20 jJL of a 5 x 10 solution) were mixed 6M in PEG-400, 0.0000001 mmol) and 3.5bis "1H-1,2,4-triazol-1-yl) methyl) methyl benzoate (20 ~ L of a 5 x 10.f! M solution in PEG-400, 0.0000001 65 mmol) in dioxane (1 mL) at room temperature under oxygen atmosphere (1 atm). The mixture was heated to 120
or for 48 hours, maintaining vigorous agitation at all times. After the preparation and purification steps described in example 22.1, 1-pentanol was obtained as a colorless liquid (35 mg, 40%).
22.9. Obtaining 1-pentanol using NiBr2 and J, 5-bis {(1H-1, 2,4-triazol-1-yl) methyl) methyl benzoate in 5 tetrahydrofuran
In a round bottom flask "pentoxy) methyl) benzene (178 mg, 1 mmol), sodium acetate (8 mg,
0.1 mmol), nickel bromide (lI) (20 IJL of a 5 x 10-tlM solution in PEG-400, 0.0000001 mmol) and 3.5
bis «1H-1,2,4-triazol-1-yl) methyl) methyl benzoate (20 ~ L of a 5 x 10-tlM solution in PEG-400, 0.0000001
10 mmol) in tetrahydrofuran (1 mL) at room temperature under oxygen atmosphere (1 atm). The mixture was heated at 120 ° C for 48 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in example 21.1, 1-pentanol was obtained as a colorless liquid (4 mg, 5%).
15 22.10. Obtaining 1-pentanol using NiBr2 and 3, S-bis «1H-1, 2,4-triazol-1-yl) methyl) methyl benzoate in PEG-1SOO
In a round bottom flask "pentoxy) methyl) benzene (178 mg, 1 mmol), sodium acetate (8 mg, 0.1 mmol), nickel bromide (ll) (20 IJL of a 5 x 10 solution) were mixed tlM in PEG-400, 0.0000001 mmol) and 3.5
20 bis «1H-1,2,4-triazol-1-yl) methyl) methyl benzoate (20 ~ L of a 5 x 10-6M solution in PEG-400, 0.0000001 mmol) in PEG-1500 (1 mL) at room temperature under oxygen atmosphere (1 atm). The mixture was heated at 120 OC for 48 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in example 22.1, el-pentanol was obtained as a colorless liquid (2 mg, 2%).
25 22.11. Obtaining 1-pentanol using NiBr2 and 3, S-bis «1H-1,2,4-triazol-1-yl) methyl) methyl benzoate in glycerol
In a round bottom flask "pentoxy) methyl) benzene (178 mg, 1 mmol), sodium acetate (8 mg, 0.1 mmol), nickel bromide (lI) (20 IJL of a 5 x 10 solution) were mixed -6M in PEG-400, 0.0000001 mmol) and 3.5
30 bis «1H-1,2,4-triazol-1-yl) methyl) methyl benzoate (20 ~ L of a 5 x 10-tlM solution in PEG-400, 0.0000001 mmol) in glycerol (1 mL) at room temperature under oxygen atmosphere (1 atm). The mixture was heated at 120 ° C for 48 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in example 22.1, 1-pentanol was obtained as a colorless liquid (59 mg, 68%)
35 22.12. Obtaining 1-pentanol using NiBr2 and 3,5-bis «1H-1,2,4-triazol-1-yl) methyl) methyl benzoate in glycerol on a larger scale
In a round bottom flask "pentoxy) methyl) benzene (3.56 g, 0.02 mol), sodium acetate (160 mg, 2 mmol), nickel bromide (li) (400 IJL of a 5 x 10 solution) were mixed 6M in PEG-400, 0.000002 mmol) and 3.5
40 bis «1H-1,2,4-triazol-1-yl) methyl) methyl benzoate (400 IJL of a 5 x 10-6M solution in PEG-400, 0.000002 mmol) in PEG 400 (19 mL) at room temperature under oxygen atmosphere (1 atm). The mixture was heated at 120 OC for 48 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in example 22.1, el-pentanol was obtained as a colorless liquid (1.30 g, 74%)
45 Example 23 Preparation of 2-methoxyethanol
........ O /'-....../ OH
[(2-Methoxyethoxy) methyl)] benzene (166 mg, 1 mmol), sodium acetate (8) were mixed in a round bottom flask
50 mg, 0.1 mmol), nickel bromide (lJ) (20 IJL of a 5 x 10-tlM solution in PEG-400, 0.0000001 mmol) and 3.5bis "1H-1,2,4-triazole -1-yl) methyl) methyl benzoate (20 ~ L of a 5 x 10-6M solution in PEG-400, 0.0000001 mmol) in PEG 400 (1 mL) at room temperature under oxygen atmosphere (1 atm) . The mixture was heated at 120 OC for 48 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in example 22.1, 2-methoxyethanol was obtained as a colorless liquid (55 mg, 73%). NMR
55 lH (COCh, OH, ppm) 3.20 (s, 3H, OCH3), 3.49--3.54 (m, 2H, HOCH2CH., OCH3), 3.56-3.60 (m, 2H, HOCH2CH20CH3), 3.56-3.60 (m, 1H, OH); NMR_13C (CDCb, &, ppm) 58.5 (OCH3), 61.3 (HOCH2CH2ÜCH ~), 73.8 (HOCH2CH20CH3); MS (miz): 77.1 (MW); HRMS calculated for C3He0276.0524; found for 76.0522.
Example 24 Preparation of cyclohexanol.
In a round bottom flask, Claroo «cyclohexyloxy) methyl) benzene (190 mg, 1 mmol), sodium acetate (8 mg, 0.1 mmol), nickel bromide (lI) (20 IJL of a 5 x solution) is mixed 10 ~ M in PEG-400, 0.0000001 mmol) and 3.55 bis "1H-1,2,4-triazol-1-yl) methyl) methyl benzoate (20 IJL of a 5 x 10 ~ M solution in PEG-400, 0.0000001 mmol) in PEG 400 (1 mL) at room temperature under oxygen atmosphere (1 atm). The mixture was heated at 120 OC for 48 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in example 22.1, cyclohexanol was obtained as a colorless oil (76 mg, 76%). NMR-'H (COCh, OH, ppm) 1.11-1.33 (m, 5H, CH2), 1.48-1.56 (m, 1H, OH), 1.66-1.91 (m, 5H, CH2), 3.55-3.62 (m, 1H, CH);
10 NMR_13C (COCh, Oc, ppm) 24.3 (CH2), 25.4 (CH2), 35.5 (CH2), 70.26 (CH); MS (miz) '101 .1 (MW); EMAR calculated for C6H120 100.0888; found for 100.0887
Example 25 Preparation of 1-heptanol.
HO ~
"Heptyloxy) methyl) benzene (206 mg, 1 mmol), sodium acetate (8 mg, 0.1 mmol), nickel bromide (ll) (20 IJL of a 5 x solution) were mixed in a round bottom flask 10 ~ M in PEG-400, 0.0000001 mmol) and 3.520 bis «1H-1,2,4-triazol-1-yl) methyl) methyl benzoate (20 IJL of a 5 x 10 ~ M solution in PEG- 400, 0.0000001 mmol) in PEG 400 (1 mL) at room temperature under oxygen atmosphere (1 atm). The mixture was heated at 120 OC for 48 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in example 22.1, 1-heptanol was obtained as a colorless liquid (81 mg, 70%). NMR_1H (COCh, OH, ppm) 0.82-0.87 (m, 3H, CH3), 1.23--1.31 (m, 8H, HOCH2CH2 (CHz) 4CH3), 1.49--1.54 (m, 2H, 25 HOCH2CH2 (CH2) 4CH3 ), 2.51 (s, 1H, OH), 3.57 (t, 2H, J = 6.7, HOCH2CH2 (CH2) 4CH3); NMR_13C (COCh, Oc, ppm)
14.0 (GH3), 22.6 (CH2), 25.7 (GH2), 29.1 (GH2), 31 .8 (CH2), 32.7 (GH2), 62.7 (CH2ÜH); MS (miz): 117.2 (MW); EMAR calculated for C1H160 116,1201, found for 116,1200.
Example 26 Preparation of 3,3-dimethyl-1-butanol
HO ~
[(3,3-Dimethylbutoxy) methyl] benzene (192 mg, 1 mmol), sodium acetate were mixed in a redode bottom flask
35 (8 mg, 0.1 mmol), nickel bromide (11) (20 IJL of a 5 x 10 ~ M solution in PEG-400, 0.0000001 mmol) and 3.5bis "1H-1.2.4 -triazol-1-yl) methyl) methyl benzoate (201JL of a 5 x 10 ~ M solution in PEG-400, 0.0000001 mmol) in PEG 400 (1 mL) at room temperature under oxygen atmosphere (1 atm) . The mixture was heated at 120 OC for 48 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in example 22.1, eI3,3-dimethyl-1-butanol was obtained as a colorless liquid (52 mg, 51%).
40 NMR-1H (COCh, OH, ppm) 0.86 (s, 9H, HOCH2CH2C (CH3) 3), 1.42-1.47 (m, 2H, HOCH2CH2C (CH3) 3), 2.90-2.97 (m, 1H, OH), 3.57-3.63 m, 2H, HOCH2CH2C (CH3p); NMR_13C (COCh, Oc, ppm) 29.4 (HOCH2CH2C (CH3) 3), 29.4 (HOCH2CH2C (CH3) 3), 45.9 (HOCH2CH2C (CH3) 3), 59.3 (HOCH2CH2C (CH3P); MS (miz): 103.2 (MW ); EMAR calculated for C6H140 102,1045; found for 102,1047.
Example 27 Preparation of (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexanol.
50 «((1 R, 2S, 5R} -2-isopropyl-5-methylcyclohexyloxy) methyl) benzene (206 mg, 1 mmol), sodium acetate (8 mg, 0.1 mmol) were mixed , nickel (lI) bromide (20 IJL of a 5 x 10-6M solution in PEG400, 0.0000001 mmol) and 3,5-bis «1 H-1,2,4-lriazol-1-yl) methyl) methyl benzoate (20 IJL of a 5 x 10-6M solution in PEG-400, 0.0000001 mmol) in PEG 400 (1 mL) at room temperature under oxygen atmosphere (1 atm). The mixture was heated at 120 ° C for 48 hours, maintaining vigorous stirring at all times. After
The processing and purification steps described in Example 22.1 gave (1R, 2S, 5R} -2-isopropyl-5-methylcyclohexanol as a white-colorless crystalline solid (117 mg, 75%). NMR_1H (COCb, OH, ppm) 0.77 (dd,
3H, J = 6.9, 1.2, CH3), 0.80-1.02 (m, 8H, CH2), 1.08 (ddt, 1 H, J = 15.1, 10, 2.9, CH), 1.27-1.46 (m, 1 H, CHz ), 1.60 (ddt, 2H, J = 14, 12.6, 3, CH), 1.88-1.97 (m, 1H, CH2), 2.15 (pd, 1H, J = 7, 2.7, CH), 3.56 (td, 1H , J = 10.4, 4.3, CHOH); NMR-13C (COCb, Oc, ppm) 16.1 (CH3), 21 (GH3), 22.2 (CH3), 23.5 (GH2), 25.8 (GH), 31 .6 (CH), 34.5 (CHz), 45 (CHz ), 50.2 (CH), 71.6 (CHOH); 172.1 (COOH); MS (miz): 157.2 (MW); EMAR calculated for CloH200
5 156.1514; found for 156.1515
Example 28 Preparation of 2-phenoxyethanol.
In a round bottom flask «2-phenoxyethoxy) meti!) Benzene (228 mg, 1 mmol), sodium acetate (8 mg, 0.1 mmol), nickel bromide (lI) (201 Jl of a 5 x solution) were mixed 10 ~ M in PEG-400, 0.0000001 mmol) and 3.5bis "1H-1,2,4-triazol-1-yl) methyl) methyl benzoate (201 Jl of a 5 x 10-6M solution in PEG- 400, 0.0000001 15 mmol) in PEG 400 (1 ml) at room temperature under oxygen atmosphere (1 atm). The mixture was heated at 120 OC for 48 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in example 22.1, 2-phenoxyethanol was obtained as a colorless oil (98 mg, 71%). NMR-1H (COCb, OH, ppm) 3.23 (s, 1H, OH), 3.93-3.98 (m, 2H, HOCH2CH20Ph), 4.04-4.08 (m, 2H, HOCH2CHzOPh), 6.92-7.03 (m, 3H, Harorn ), 7.28-7.34 (m, 2H, Harom); NMR_13C (COCh, Oc, ppm) 62.3
20 (HOCH2CH20Ph), 69.2 (HOCH2CHzOPh), 114.6 (Carom-H), 121.1 (Carom_H), 139.6 (C, .. om-H), 158.7 (Cq.arom); MS (miz): 139.1 (MW); HRMS calculated for CaHlo0 2138.0681; found for 138.0679.
Example 29 Preparation of 2-decanol.
OH
~
In a round bottom flask, «decan-2-yloxy) meti!) Benzene (248 mg, 1 mmol), sodium acetate (8 mg, 0.1 mmol), nickel bromide (lI) (20 IJl of one 5 x 10-6M solution in PEG-400, 0.0000001 mmol) and 3.53D bis «1H-1,2,4-triazol-1-yl) methyl) methyl benzoate (20 IJl of a 5 x 1o solution -6M in PEG-40o, 0.0000001 mmol) in PEG 400 (1 ml) at room temperature under oxygen atmosphere (1 atm). The mixture was heated at 120 OC for 48 hours, maintaining vigorous stirring at all times. After the manufacturing and purification steps described in example 22.1, 2-decanol was obtained as a colorless viscous oil (15 mg, 73%). NMR-1H (COCh, t'SH, ppm) 0.78 (t, 3H, J = 6.5, CH3), 1.06 (d, 3H, J = 6.1, CH3), 1 16-1.39 (m, 14H, CHz),
3.06-3.08 (m, 1H, CH), 3.63 (s, 1H, OH); NMR-13C (CDCb, Oc, ppm) 13.9 (CH3), 22.6 (CH2), 23.1 (CH3), 25.8 (CHz), 29.2 (CH2), 29.6 (CH2), 29.7 (CHz), 31.8 (CHz), 67.6 (CH); MS (mIz): 159.3 (MW); EMAR calculated for ClOH220 158.1671; found for 158, 1671
40 Example 30 Preparation of 3-butin-1-01. HO ~
In a round bottom flask, "but-3-in-1-yloxy) methyl) benzene (160 mg, 1 mmol), sodium acetate were mixed
45 (8 mg, 0.1 mmol), nickel bromide (! I) (20 IJl of a 5 x 10 ~ M solution in PEG-400, 0.0000001 mmol) and 3.5bis "1H-1.2, 4-Triazol-1-yl) methyl) methyl benzoate (20 ml of a 5 x 10-6M solution in PEG-400, 0.0000001 mmol) in PEG 400 (1 ml) at room temperature under oxygen atmosphere (1 atm). The mixture was heated at 120 OC for 48 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in example 22.1, 3-butin-1-o1 was obtained as a colorless liquid (42 mg, 60%). NMR
50 lH (COCh, OH, ppm) 2.01 (t, 1H, J = 2.7, CH), 2.42 (Id, 2H, J = 6.3, 2.7, OHCHzCH2C :: CH), 2.59 (s, 1H, OH), 3.70 (t, 2H, J = 6.3, OHCH2CH2G: = CH); NMR_13C (CDCb, Oc, ppm) 22.6 (OHCH2CH2C == CH), 60.75 (OHCH2CH2C ::: CH), 70.1 (CH), 81.3 (C ::: CH); MS (m / z.): 71 .1 (MW); HRMS calculated for C4HaO 70.0419; found for 70, 0421
Example 31 Preparation of 4-pentin-1-o !.
HO ~
In a round bottom flask, "pent-4-in-1-yloxy) methyl) benzene (174 mg, 1 mmol), sodium acetate were mixed(8 mg, 0.1 mmol), nickel bromide (lI) (20 fJL of a 5 x 10-6M solution in PEG-400, 0.0000001 mmol) and 3.5bis "1H-1,2,4- triazol-1-yl) methyl) methyl benzoate (20 fJL of a 5 x 10-6M solution in PEG-400, 0.0000001mmol) in PEG 400 (1 mL) at room temperature under oxygen atmosphere (1 atm). The mixture was heated to5 120 OC for 48 hours, maintaining vigorous agitation at all times. After the elaboration stagesand purification described in example 1.1, 4-pentin-1. 1 was obtained as a colorless liquid (49 mg, 58%). NMRl H (COCh, iSH, ppm) 1.64-1.72 (m, 2H, HOCH2CH2CH2C :: CH), 1.92 (t, 1H, J = 2.6, C :: CH), 2.22 (td, 2H, J = 7,2.7, HOCH2CH2CH2C :::: CH), 3.21 (s, 1H, OH), 3.63 (t, 2H J = 6.3, HOCH2CH2CH2C :::: CH); NMR_13C (COCb, Oc,ppm) 14.8 (HOCH2CH2CHzC :: CH), 30.9 (HOCH2CHzCH2C :: CH), 60.9 (HOCHzCH2CH2C :: CH), 68.7 (C :: CH), 83.9
10 (G :: CH); MS (mIz): 85.1 (MW); HRMS calculated for CsHaO 84.0575; found for 84.0576.
Example 32 Preparation of 2-heptanol.
OH
15 ~
In a round bottom flask, «hepta-2-yloxy) methyl) benzene (206 mg, 1 mmol), sodium acetate (8 mg, 0.1 mmol), nickel bromide (lI) (20 IJL of a solution) were mixed 5 x 10-6M in PEG-400, 0.0000001 mmol) and 3.5bis «1H-1,2,4-triazol-1-yl) methyl) methyl benzoate (20 fJL of a 5 x 10-6M solution in PEG-400, 0.0000001 20 mmol) in PEG 400 (1 mL) at room temperature under oxygen atmosphere (1 alm). The mixture was heated at 120 OC for 48 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in example 22.1, 2 + heptanol was obtained as a colorless liquid (66 mg, 57%). NMRlH (COCh, i5H, ppm) 0.69-0.86 (m, 3H, CH ~), 1.05 (d, 3H, J = 6.2, CH ~), 1.15-1.35 (m, 8H, CH2), 2.97 (d, 1H , J =
4.6, OH), 3.51-3.77 (m, 1H, CH); NMR-13C (COCh, tic, ppm) 13.8 (CH3), 22.5 (CH2), 23.1 (CH2), 25.4 (CH3), 25 31.8 (CH2), 39.2 (CH2), 67.6 (CH); MS (mfz) · 117.2 (MW); HRMS calculated for C7H1S0 116,1201; found for 116,1202
Example 33 Preparation of piperonyl alcohol.
In a round bottom flask 5- "benzyloxy) methyl)] - 1,3-benzo [dldioxol (242 mg, 1 mmol), acetate were mixedsodium (8 mg, 0.1 mmol), nickel bromide (ll) (20 IJL of a 5 x 10-6M solution in PEG-400, 0.0000001 mmol)35 and 3,5-bis «1H-1,2,4-triazol-1-yl) methyl) methyl benzoate (20 fJL of a 5 x 10-6M solution in PEG-4oo,0.0000001 mmol) in PEG 400 (1 mL) at room temperature under oxygen atmosphere (1 atm). It warmed upmix at 120 oC for 48 hours, maintaining vigorous stirring at all times. After the stages ofPreparation and purification described in example 22.1, piperonyl alcohol (benzo [dl [1, 3] dioxol-5-methanol) was obtained as a white solid (102 mg, 67%). NMR-1H (COCb, OH, ppm) 4.54 (s, 2H, HOCH2), 5.93 (s, 2H,40 OCH20), 6.77-6.84 (m, 3H, Harem); NMR_13C (COCh, i5c, ppm) 65.2 (HOCH2), 101.0 (OCH20), 107.9 (Carem),
108.2 (C "rQ <n), 120.5 (C" rQ <n), 134.9 (Cq..rom), 147.1 (Cq4IrQ <n), 147.8 (Cq. "RQ <n); MS (mfz): 153.1 ( MW); EMAR calculated for CaHa03152.0473; found for 152.0471.
Example 34 Preparation of 2-phenylethanol.
~ OH
V
In a round bottom flask «2-fen ile10xi) methyl) benzene (212 mg, 1 mmol), sodium acetate (8
50 mg, 0.1 mmol), nickel bromide (lI) (20 IJL of a 5 x 10-6M solution in PEG-400, 0.0000001 mmol) and 3.5bis "1H-1,2,4-triazole -1-yl) methyl) methyl benzoate (20 fJL of a 5 x 10-6M solution in PEG-400, 0.0000001 mmol) in PEG 400 (1 mL) at room temperature under oxygen atmosphere (1 alm). The mixture was heated at 120 OC for 48 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in example 22.1, 2-phenylethanol was obtained as a colorless liquid (73 mg, 60%).
55 NMR-1H (COCb, t'lH, ppm) 2.90 (t, 2H, J = 6.9, PhCH2CH20H), 3.50 (s, 1H, OH), 3.85 (t, 2H, J = 6.9, PhCH2CHzQH), 7.27- 7.41 (m, 5H, Harom); NMR-13C (CDCb, i5c, ppm) 39.2 (CH2), 63.5 (CH2ÜH), 126.4 (C "rom-H),
128.6 (CN.,., ... H), 129.4 (C "'' '' '' 'H), 138.8 (Cc.arQ <n); MS (miz): 123.1 (MW); EMAR calculated for CaHlo0 122.0732; found for 122.0733
Example 35 Preparation of geraniol.
HO ~
5 In a round bottom flask, benzyl geranyl ether (244 mg, 1 mmol), sodium acetate (8 mg, 0.1 mmol), nickel bromide (lI) (20DDL of a 5 x 10-6M solution in PEG were mixed -4oo, 0.0000001 mmol) and 3,5-bis «1H1, 2,4-triazol-1-it) methyl) methyl benzoate (20 :: JDL of a 5 x 10-6M solution in PEG-400, 0.0000001 mmol) in PEG 400 (1 mL) at room temperature under oxygen atmosphere (1 atm). The mixture was heated at 120 ° C for 48 hours, maintaining vigorous stirring at all times. After the elaboration stages and
10 purification described in example 22.1, geraniol was obtained as a colorless liquid (92 mg, 60%). NMR_1H (COCh, & l, ppm) 1.58 (s, 3H, CH3), 1.65 (s, 3H, CH3), 1.66 (s, 3H, CH3), 2.10 (m, 4h, CH1), 4.12 (d, 2H, J = 6.9, CH2ÜH), 5.05--5.10 (m, 1H, CH = C (CH3) 2), 5.36-5.41 (m, 1H, CH = CCH2 (CH3 »; NMR_13C (COCh, c5c, ppm) 16.2 ( CH3), 17.6 (CH3), 25.6 (CH3), 26.4 (CH2), 39.5 (CH2), 59.2 (CH2ÜH), 123.4 (CH = CCH2 (CH3 », 123.9 (CH = C (CH3) 2), 131.66 ( CH = C (CH3) 2), 139.4 (CH = CCH2 (CH3 »; MS (miz): 155.1 (MW); EMAR calculated for
ClOH1S0 154.1358; found for 154,1359
Example 36 Preparation of Borneol.
In a round bottom flask, benzyl bomyl ether (244 mg, 1 mmol), sodium acetate (8 mg, 0.1 mmol), nickel bromide (lI) (20L of a 5 x 10-6M solution in PEG-) were mixed. 400, 0.0000001 mmol) and 3,5-bis «1H1,2,4-triazol-1-yl) methyl) methyl benzoate (2000l of a 5 x 10-6M solution in PEG-400, 0.0000001 mmol ) in 25 PEG 400 (1 mL) at room temperature under oxygen atmosphere (1 atm). The mixture was heated at 120 ° C for 48 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in example 22.1, borneol was obtained as a white solid (89 mg, 58%). NMR-1H (COCb, OH, ppm) 0.84 (s; 3H, CH3), 0.85 (s, 3H, CH3), 0.86 (s, 3H, CH3), 0.94 (dd, 1H, J = 3.5,13.4, CH2 ), 1.20
1.35 (m, 1 H, CH2), 1.45 (d, 1 H, J = 5.1, CH2), 1.62 (t, 1H, J == 4.5, CH2), 1.67-1.96 (m, 2h, CH2), 2.27 (dddd, 1H, J
30 = 3.4, 4.8, 9.9, 13.4, CH), 4.00 (ddd, 1H, J = 3.1, 5.2, 8.9, CHOH); NMR_13C (COCh, c5c, ppm) 13.3 (CH3), 18.7 (CH3), 20.2 (CH3), 25.9 (CH2), 28.3 (CH2), 39.0 (CH2), 45.1 (CH), 48.0 (C (CH3) ( C (CH3) 2 », 49.5 (C (CH3) (C (CH3) 2)), 77.4 (CHOH); MS (miz) 155.1 (MW); EMAR calculated for ClOH1S0 154.1358; found for 154.1360.
Example 37 Preparation of 1-pentanol from 1-fluoro-4- "pentoxy) methyl) benzene
1-ftuOfo-4- "pentoxy) methyl) benzene (196 mg, 1 mmol), sodium acetate (8 mg, 0.1 mmol), nickel bromide (lI) (20 I-) were mixed in a round bottom flask 'L of a 5 x 10-6M solution in PEG-400, 0.0000001 mmol)
40 and 3,5-bis «1H-1, 2,4-triazol-1-yl) methyl) methyl benzoate (20 I-'L of a 5 x 10-6M solution in PEG-4oo, 0.0000001 mmol ) in PEG 400 (1 mL) at room temperature under oxygen atmosphere (1 atm). The mixture was heated at 120 ° C for 48 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in example 22.1, el-pentanol was obtained as a colorless liquid (59 mg, 68%)
Example 38 Preparation of 1-pentanol from 1-methyl-4- "pentoxy) methyl) benzene
1-Methyl-4- "pentoxy) methyl) benzene (192 mg, 1 mmol), acetate were mixed in a round bottom flask
50 sodium (8 mg, 0.1 mmol), nickel bromide (lJ) (20I-'L of a 5 x 10-6M solution in PEG-400, 0.0000001 mmol) and 3,5-bis «1H- 1, 2,4-triazol-1-yl) methyl) methyl benzoate (20 I-'L of a 5 x 10-6M solution in PEG-4oo, 0.0000001 mmol) in PEG 400 (1 mL) at temperature environment under oxygen atmosphere (1 atm). The mixture was heated at 120 ° C for 48 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in example 22.1, el-pentanol was obtained as a colorless liquid (61 mg,
55 69%)
Example 39 Preparation of 1-pentanol from 1-methoxy-J- "pentoxy) methyl) benzene
In a round bottom flask 1-methoxy-3- "pentoxy) methyl) benzene (208 mg, 1 mmol), sodium acetate (8 mg, 0.1 mmol), nickel bromide (ll) (20 ~ L) were mixed of a 5 x 10-6M solution in PEG-400, 0.0000001 mmol) and 3,5-bis «1H-1, 2,4-triazol-1-yl) methyl) methyl benzoate (20 ~ L of a 5 x 10-6M solution in PEG-4oo, 5 0.0000001 mmol) in PEG 400 (1 mL) at room temperature under oxygen atmosphere (1 atm). The mixture was heated at 120 ° C for 48 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in example 22.1, el-pentanol was obtained as a colorless liquid (51 mg,
58%).
Example 40 Preparation of 1-pentanol from 1-methoxy-4- (pentoxy) methyl) benzene
1-Methoxy-4- "pentoxy) methyl) benzene (208 mg, 1 mmol), sodium acetate (8 mg, 0.1 mmol), nickel bromide (lI) (20 ~ L) were mixed in a round bottom flask of a 5 x 10-6M solution in PEG-400, 0.0000001 mmol)
15 and 3, S-bis «1H-1,2,4-lriazol-1-yl) methyl) methyl benzoate (20 ~ L of a 5 x 10-6M solution in PEG-4oo, 0.0000001 mmol) in PEG 400 (1 mL) at room temperature under oxygen atmosphere (1 atm). The mixture was heated at 120 ° C for 48 hours, maintaining vigorous stirring at all times. After the manufacturing and purification steps described in example 22.1, el-pentanol was obtained as a colorless liquid (59 mg, 67%)
Example 41 Preparation of 1-pentanol from 1- (pentoxy) methyl) -4- (trifluoromelyl) benzene
In a round bottom flask, 1- "pentoxy) methyl) -4- (triftuoromethyl) benzene (246 mg, 1 mmol) was mixed,
25 sodium acetate (8 mg, 0.1 mmol), nickel bromide (lI) (20 IJL of a 5 x 10-6M solution in PEG-400, 0.0000001 mmol) and 3, S-bis «1H-1 , 2,4-triazol-1-yl) methyl) methyl benzoate (20 ~ L of a 5 x 10-6M solution in PEG-400, 0.0000001 mmol) in PEG 400 (1 mL) at room temperature under atmosphere of oxygen (1 alm). The mixture was heated at 120 ° C for 48 hours, maintaining vigorous stirring at all times. After the elaboration and purification steps described in example 22.1, 1-pentanol was obtained as a liquid
30 colorless (49 mg, 56%).
Example 42 Preparation of 1-pentanol from 2- (pentoxy) melyl) naphthalene
35 2- 2- Pentoxy) methyl) naflalene (228 mg, 1 mmol), sodium acetate (8 mg, 0.1 mmol), nickel bromide (lI) (20 IJL of a solution 5) were mixed in a round bottom flask 10-6M in PEG-400, 0.0000001 mmol) and 3.5bis ((1H-1,2,4-triazol-1-yl) methyl) methyl benzoate (20 ~ L of a 5 x 10 solution) 6M in PEG-400, 0.0000001 mmol) in PEG 400 (1 mL) at room temperature under oxygen atmosphere (1 atm). The mixture was heated at 120 OC for 48 hours, maintaining vigorous stirring at all times. After the elaboration stages
40 and purification described in example 22.1 el1-pentanol was obtained as a colorless liquid (62 mg, 70%).

权利要求:
Claims (12)
[1]
1. A process comprising treating a compound of formula (11)
 5 R-O-CH2-A,
(eleven)
where R represents a group selected from Cl.14 alkyl, C2.14 alkenyl, C4-ClO alkynyl, Cs.14 aryl, C3-14 cycloalkyl, C3-14 heterocycloalkyl optionally substituted with one or more substituents selected from Cl alkyl. t1, C2-6 alkenyl, G & .10 aryl, heteroaryl, alkoxy (O- (Cl-6ll, and aryloxy (-O- (G & .loll,
A represents a Ce.14 aryl group, optionally substituted with one or more substituents selected from Cl-6 alkyl, alkoxy (O- (Cl-6 », halogen and haloalkyl (Cl -6)),
with molecular oxygen (02) at a pressure between 1 and 1.2 alm, in an ether or polyol solvent, and in the presence of a nickel compound, an alkaline acetate salt, and a 1,2,4-triazole derivative of formula
(111)
where, the substituents Rl and R ', the same or different from each other are selected from hydrogen, Cl-6 alkyl, and aryl Ce, and the substituent R3 is selected from hydrogen, Cl-6 alkyl, and "Cl-6 alkoxycarbonyl" - OC (O) -), 25 to obtain a compound of formmu la (1) '
R-OH (1),
30 where R has the same meaning defined above
2 A method according to claim 1, wherein the nickel compound is a nickel salt (11).
3. A method according to claim 2 wherein the nickel salt (11) is selected from nickel (II) bromide, nickel (1I) chloride, dichlorobis (triphenylphosphine) nickel (II), [1, 3-bis (diphenylphosphine) propane] nickel (II), nickel acetate (II), nickel nitrate (11) and mixtures thereof
4 A method according to claim 3 wherein the nickel salt (11) is nickel bromide (ll)
[5]
5. A process according to claim 2-4, wherein the amount of nickel used is 0.01% to 0.00001 mol% relative to the moles of the compound of formula (11).
[6]
6. A method according to any one of the preceding claims, wherein in the derivative of 1.2.4
45 triazole of formula (111) Rl and R '. the same or different from each other are selected from hydrogen and Cl-6 alkyl, and R3 is selected from hydrogen and "Cl-6) -O-C (O) -) alkoxycarbonyl.
[7]
7. A process according to claim 6, wherein the 1,2,4-triazole derivative of formula (111) is the compound 3,5-bis- «1H-1, 2,4-triazol-1-yl ) melit) methyl benzoate
[8]
8. A process according to any one of claims 6 or 7, wherein the amount of 1,2,4-triazole derivative used is from 0.01% to 0.00001% mole relative to the moles of the compound of formula (eleven).
[9]
9. A process according to any one of the preceding claims, wherein the alkaline acetate salt 55 is sodium acetate.
[10]
10. A process according to claim 1 or 9, wherein the amount of alkaline salt used is 10 mol% relative to the moles of the compound of formula (11).
11 A process according to any one of the preceding claims, wherein the solvent is
selects from 1,4-dioxane, tetrahydrofuran, ethylene glycol, propylene glycol, glycerol, polyethylene glycol 400 (PEG
400) 400, PEG-1500 and mixtures thereof.
[12]
12. A process according to claim 11, wherein the solvent is selected from PEG 400, PEG 1500, glycerol and mixtures thereof.
[13]
13. A process according to any one of the preceding claims, wherein the reaction temperature is between 110 ° C-130 ° C.
[14]
14. A process according to any one of the preceding claims, wherein in the compound of formula (11) A represents a group selected from phenyl, 4-fluorophenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4- (trifluoromethyl) fen ilo and naphthyl0
[15]
fifteen. A process according to any one of the preceding claims, wherein the compound of formula
(11) is selected from:
[1) "Pentyloxy) methyl) benzene.
[2) [(2-Methoxyethoxy) methyl] benzene
[3) [(Cyclohexyloxy) methyl) benzene
(4) [(Heptyloxy) methyl) benzene [5) [(3,3-Dimelylbutoxy) methyl) benzene [6) «(1 R, 2S, 5R) -2-lsopropyl-5-methyl-Icicloh exyloxy) methyl) benzene [7) (2- (Benzyloxy) ethoxy) benzene [8) "Decan-2-yloxy) methyl) benzene [9)" But-3-in-1-yloxy) methyl) benzene [10) "Pent-4- in-1-yloxy) methyl) benzene.
[11] "Heptan-2-yloxy) methyl) benzene [12) 5- ((Benzyloxy) methyl) benzo [d) [1, 3) dioxol [13) (2- (Benzyloxy) ethyl) benzene [14) ( E) - «(3,7-Dimethylocta-2,6-dien-1-yl) oxy) methyl) benzene [15) (1 R, 2R, 4S) -2- (Benzyloxy} -1, 7,7 - trimethylbicyclo [2.2.1) heptallO [16) 1 -Fluoro-4 - [(pentyloxy) methyl) benzene
[17] 1-Methyl-4 - [(pentyloxy) methyl) benzene [18) 1-Methoxy-3 - [(pentyloxy) melyl) benzene [19) 1-Methoxy-4 - [(pentyloxy) methyl) benzene [20 ) 1 - [(Pentyloxy) methyl) -4- (trifluoromethyl) benzene [21] 2 - [(Pentyloxy) melyl) naphthalene [22) (Benzyloxy) benzene
[16]
16. A process according to any one of the preceding claims, wherein the compound of formula
(1) obtained is selected from:
[1) Phenol
[2) 1-Pentanol
[3) 2-Methoxyetan-1-o1
[4) Cyclohexanol
[5) 1-Heptanol
[6) 3, 3-0-methyl-1-butanol
[7) (1 R, 2S, 5R) -2-isopropyl-5-methylcyclohexan-1-o1; «1 S, 2R, 5S} - (+) - Menthol)
[8) 2-Phenoxyethanol
[9) 2-Decanol
[10) 3-Butin-1-o1
[11) 4-Pentin-1-o1
[12) 2-Heptanol
[13) Benzo [d) [1,3) dioxol-5-ylmethanol; (Piperonil alcohol)
[14) 2-Phenylethanol
[15) (E) -3,7-Dimethylocta-2,6-diene-1-o1; (Geraniol)
[16) (1 R, 2R, 4S) -1, 7.7-Trimethylbicyclo [2.2.1) heptan-2-o1; (D- (+) - BOfneol)

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