1122-58-3 Usage
Chemical Description
4-dimethylaminopyridine is a catalyst that is commonly used in organic synthesis reactions.
Description
4-Dimethylaminopyridine (DMAP), also known as Valaciclovir EP Impurity G and Valacyclovir USP Related Compound G, is a highly efficient catalyst for acylation reactions. It is a colorless, crystalline substance that is soluble in various organic solvents and has a melting point of 112-113°C. DMAP has been widely used in organic synthesis since the late 1960s and has been found to be superior to pyridine as a catalyst for difficult acetylations or acylations. It has a wide applicability in various fields of chemistry, including organic, polymer, analytical, and biochemistry.
Uses
1. Used in Organic Synthesis:
4-Dimethylaminopyridine is used as a highly efficient catalyst for acylation reactions, improving the yield, reducing the reaction time, and improving the relaxation process conditions.
2. Used in Perfumes, Dyes, Pigments, Pesticides, and Pharmaceuticals:
4-Dimethylaminopyridine is used as a versatile hypernucleophilic acylation catalyst, widely applied in various fields to enhance the synthesis of different compounds.
3. Used in Polymer Compounds:
4-Dimethylaminopyridine is used as a catalyst for the synthesis of polyurethane, a curing agent, and a blowing catalyst.
4. Used in Esterifications with Anhydrides:
4-Dimethylaminopyridine is used as a highly basic nucleophilic catalyst for a variety of reactions, including esterifications with anhydrides.
5. Used in the Baylis-Hillman Reaction:
4-Dimethylaminopyridine is used as a catalyst in the Baylis-Hillman reaction, a carbon-carbon bond-forming reaction.
6. Used in Hydrosilylations:
4-Dimethylaminopyridine is used as a catalyst in hydrosilylation reactions, which involve the addition of a silane to an alkene or alkyne.
7. Used in the Steglich Rearrangement:
4-Dimethylaminopyridine is used as a catalyst in the Steglich rearrangement, a reaction that involves the migration of an aldehyde or ketone group.
8. Used in the Synthesis of Oligonucleotides:
4-Dimethylaminopyridine is used as a highly fluorescent adenosine analogue, which can be site-specifically inserted into oligonucleotides through a 3'-5' phosphodiester linkage using an automated DNA synthesizer.
9. Used in the Production of Pharmaceutical and Agricultural Products:
4-Dimethylaminopyridine is used in the synthesis of various pharmaceutical and agricultural products, relying on its superior catalytic properties in their synthetic sequences.
10. Used in Full-Scale Production Processes:
4-Dimethylaminopyridine is utilized in several full-scale production processes, with more than 11,000 US patents granted mentioning DMAP or dimethylaminopyridine since 1976.
Reactions
DMAP reacts readily with electrophilic reagents. It is possible to quaternize DMAP in high yield with either methyl iodide or ethyl bromide, decomposes quantitatively in the presence of aqueous alkali to N-methy1-4-pyridone[17].
Addition of DMAP to S, S'-diethyl-S, S'-dimethyl-S, S-1, 2vinylenedisulfonium salts results in the smooth formation of the salt with concomitant generation of ethyl methyl sulfide[19]. Reaction of DMAP with acetylenedicarboxylic acid leads spontaneously to the bis-adduct in high yields[20].
On reaction with perbenzoic acid the strongly polar N-oxide is formed. Nitration of DMAP with HNO3/H2SO4 gives the 3-nitro derivatives in 81 % yield and, under forcing condition; the 3,5-dinitro compounds are obtained[16]. Reaction with O-(p-toluenesulfony1)hydroxylamine affords the N-amino compound in 67% yield which is isolated as the perchlorate. By treatment with D2O it is possible to selectively exchange the a-protons in DMAP, with DClO4 to exchange the P-protons to furnish and with D2O/NaOD to replace all aromatic protons by deuterium[18].
Application as acylation catalysts
Acylation of alcohol
The high catalytic activity of DMAP and PPY can be used for acylating sterically hindered secondary or tertiary alcohols with carboxylic anhydrides or acyl halides when the pyridine method fails. In most cases, it is necessary to use only 0.05-0.2 mol of catalyst per mol of substance and the acid that is formed can be bound with an equivalent amount of trimethylamine[21, 22] or pyridine[20]. Such solvents as hexane, toluene, benzene, methylene chloride, chloroform, ethyl acetate, tetrahydrofuran, triethylamine, pyridine, or acetic anhydride are suitable for use with these catalysts.
Among the tertiary alcohols which can be easily acylated with DMAP and PPY, mention should be made of l-methyl cyclohexanol, 1-ethynylcyclohexanol, 1,l-diphenylethanol, linalool, l, l-dimethoxy-2-methyl-3-buten-2-ol, 5,5-dimethoxy-2-methyI-3-pentyn-2-ol, and cis-4- (1-hydroxyisopropyl)-2-methylcyclohexanone.
Acylation of phenols
In the acylation of phenols, DMAP and PPY effect a similar increase in reaction rate as is found in the case of alcohols. Hence, the method is of interest for the acylation of sterically hindered phenols. For example, mesitol can be smoothly acetylated with acetic anhydride/DMAP to 2,5-ditert-butylphenol and analogous compounds can be transformed into acyl derivatives of the type in high yields[24]. 11,12-Dihydroglaziovine smoothly affords the acyl derivative[23, 25].
Acylation of amines
DMAP and PPY have been seldom used for the acylation of amines. The kinetic investigations of Lituinenko and Kirichenko [26] have shown that an enormous increase in reaction rate is observed when acylations are carried out in aprotic solvents. These authors have determined the following relative rate constants (in parentheses) for the amine-catalyzed acylation of m-chloroaniline with benzoyl chloride in benzene: N, N-dimethylaniline (0.1); triethylamine (0.072); 2,6-dimethylpyridine (0.03); pyridine (1.80); 4-methylpyridine (10.0); and DMAP (10600).
Acylation of enolates
Acylations involving CH-acid compounds which can be performed with pyridine or triethylamine as catalyst are found to proceed at a much higher rate when DMAP or PPY is used. The Dakin-West reaction of N-acyl amino acids, in which a 2-oxazolin-5-one is acetylated at C-4 with a carboxylic anhydride in pyridine with formation of a new C-C bond, has been extensively investigated[27]. The combination products, consisting of the ambident oxazolin-5-one anions and N-acylpyridinium cations initially formed under kinetic control, are transformed via the ion pair into the thermodynamically most stable product[28]. Decarboxylative ring opening by the subsequently formed carboxylic acid yields the a-acyl amino ketone[29, 30].
Reactions of isocyanates
Pyridine-catalyzed reactions of isocyanates with carboxylic acids to form amides are found to be strongly accelerated on replacement of pyridine by DMAP. Phenylacetic acid is found to react with phenyl isocyanate in 1,2-dichloroethane at 24°C to give the amide in 66 % yield in less than 5 min; whereas on using the same amount of pyridine only 53% could be isolated after 2h. With triethylamine, only very little is formed besides diphenylurea[31].
Miscellaneous Applications
DMAP has been used in the hardening of epoxy resins with dicyanodiamine, in the transformation of nitriles into thionamides, and in the transfer of silyl groups to tertiary hydroxyl groups[32, 33].
Transfer of Functional Groups
Dimethylarninopyridinium salts are interesting reagents for the transfer of acyl and also cyano and phosphono groups in aqueous medium[34, 35].
References
Litvinenko, L. M.; Kirichenko, A. I. Dok. Akad. Nauk SSSR, Ser. Khim. 1967, 176, 97;
Steglich, W.; H?fle, G. Angew. Chem. 1969, 81, 1001; Angew. Chem. Int. Ed. 1969, 8, 981.
Scriven, E. F. V.; 4-Dialkylaminopyridines: Super Acylation and Alkylation Catalysts; Chem. Soc. Rev.
H. Vorbriiggen, Angew. Chem. 84, 348 (1972); Angew. Chem. Int.
Ed. Engl. 11, 305 (1972). L. Pentimalli, Gazz. Chim. Ital. 94, 902 (1964).
R. W Taft, C. A. Grob, J . Am. Chem. SOC. 96, 1236 (1974).
C. W N. Cumper, A. Singleton, J . Chem. SOC. B 1967, 1096.
A. R. Katritzky, E. Fi! Randall, L. E. Sutton, J. Chem. SOC. 1957 1769.
H. Lumbroso, J. Barassin, Bull. SOC. Chim. Fr. 1965, 3143.
C. D. Johnson, I. Roberts, P. G. Taylor, J. Chem. SOC.C hem. Commun 1977, 897.
M. R. Chakrabarty, C. S. Handloser, M. W Mosher, J. Chem. SOC. Perkin Trans. I1 1973, 938
Pyridine syntheses, 1st Communication.-2nd Communication: H. Vorbriiggen, J. Kottwitz, K. Krolikiewicz, Chem. Ber., in preparation. This publication gives a complete survey of the various syntheses of DMAP and PPY; H. Vorbriiggen, DOS 2517774 (1975), Schering AG; Chem. Abstr. 86, 55293d (1977).
W Steglich, G. Hofle, Tetrahedron Lett. 1970, 4727.
E. Koenigs, H. Friedrich, H. Jurany, Ber. Dtsch. Chem. Ges. 58, 2571 (1925).
A. C. Satterthwait, W P. Jencks, J. Am. Chem. SOC. 96, 7031 (1974).
A. G. Burton, R. D. Frampton, C. D. Johnson, A. R. Katritzky, J. Chem. SOC. Perkin Trans. 11 1972, 1940.
G. B. Barlin, J. A. Benbow, J . Chem. SOC. Perkin Trans. I1 1975,1385.
J. A. Zoltewicz, J. D. Meyer, Tetrahedron Lett. 1968, 421.
H. Braun, A. Amann, M. Richter, Angew. Chem. 89,488 (1977); Angew. Chem. lnt. Ed. Engl. 16, 471 (1977).
B. P. Schaffner, H. Wehrli, Helv. Chim. Acta 55, 2563 (1972).
4-Dialkylaminopyridines as acylation catalysts, 4th Communication.-3rd Communication: G. Hofle, W Steglich, Synthesis 1972, 619.
W Steglich, G. Hofle, Angew. Chem. 81, 1001 (1969); Angew. Chem. Int. Ed. Engl. 8, 981 (1969).
J. E. McMurry, J . H. Musser, M. S. Ahmad, L. C. Blaszczak, J. Org. Chem. 40, 1829 (1975).
D. J. Zwanenburg, W A. P. Reynen, Synthesis 1976, 624.
1. S. Bindra, A. Grodski, J. Org. Chem. 42, 910 (1977).
H. Paulsen, H. Hohne, Carhohydr. Res. 58, 484 (1977).
W Steglich, G. Hiiye, Tetrahedron Lett. 1968, 1619.
W Steglich, G. HoJe, Chem. Ber. 104, 3644 (1971).
W Steglich, G. HoJe, Chem. Ber. 102, 1129 (1969).
G. HiiJe, A. Prox, W Steglich, Chem. Ber. 105, 1718 (1972).
P. W Henniger, J. K. Van der Drift, DOS 2235390 (1973), Koninklijke Nederlandsche Gist-en Spiritusfabriek N. V.; Chem. Abstr. 78, 124608j
J. Maurer, DOS 180867O(US Pat. 3530093) (1967), Ciba-Geigy; Chem. Abstr. 71, 1032541 (1969).
P . C . Sriuastaua, M, Pickering, L. B. Allen, D. G. Streeter, M . 7: Campbell, J. R. Witkowski, R. W Sidwell, R. K. Robins, J. Med. Chem. 20, 256 (1977).
S. D. Larsen, S. A. Monti, J. Am. Chem. SOC. 99, 8015 (1977).
M. Wakselman, E. Guibl-Jampel, Tetrahedron Lett. 1970, 1521.
Flammability and Explosibility
Nonflammable
Purification Methods
Recrystallise DMAP from toluene [Sadownik et al. J Am Chem Soc 108 7789 1986]. [Beilstein 22 V 112.] § A polystyrene supported version (PS-DMAP) is commercially available.
Check Digit Verification of cas no
The CAS Registry Mumber 1122-58-3 includes 7 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 4 digits, 1,1,2 and 2 respectively; the second part has 2 digits, 5 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 1122-58:
(6*1)+(5*1)+(4*2)+(3*2)+(2*5)+(1*8)=43
43 % 10 = 3
So 1122-58-3 is a valid CAS Registry Number.
InChI:InChI=1/C7H10N2/c1-9(2)7-3-5-8-6-4-7/h3-6H,1-2H3/p+1
1122-58-3Relevant articles and documents
Models for B12-conjugated radiopharmaceuticals. Cobaloxime binding to new fac-[Re(CO)3(Me2bipyridine)(amidine)]BF4 complexes having an exposed pyridyl nitrogen
Lewis, Nerissa A.,Marzilli, Patricia A.,Fronczek, Frank R.,Marzilli, Luigi G.
, p. 11096 - 11107 (2014)
New mononuclear amidine complexes, fac-[Re(CO)3(Me2bipy)(HNC(CH3)-(pyppz))]BF4 [(4,4′-Me2bipy (1), 5,5′-Me2bipy (2), and 6,6′-Me2bipy (3)] (bipy = 2,2′-bipyridine), were synthesized by treating the parent fac-[ReI(CO)3(Me2bipy)(CH3CN)]BF4complex with the C2-symmetrical amine 1-(4-pyridyl)piperazine (pyppzH). The axial amidine ligand has an exposed, highly basic pyridyl nitrogen. The reaction of complexes 1-3 with a B12model, (py)Co(DH)2Cl (DH = monoanion of dimethylglyoxime), in CH2Cl2 yielded the respective dinuclear complexes, namely, fac-[Re(CO)3(Me2bipy)(μ-(HNC(CH3)(pyppz)))Co-(DH)2Cl]BF4 [(4,4′-Me2bipy (4), 5,5′-Me2bipy (5), and 6,6′-Me2bipy (6)]. 1H NMR spectroscopic analysis of all compounds and single-crystal X-ray crystallographic data for 2, 3, 5, and 6 established that the amidine had only the E configuration in both the solid and solution states and that the pyridyl group is bound to Co in 4-6. Comparison of the NMR spectra of 1-3 with spectra of 4-6 reveals an unusually large wrong-way upfield shift for the pyridyl H2/6 signal for 4-6. The wrong-way H2/6 shift of (4-Xpy)Co(DH)2Cl (4-Xpy = 4-substituted pyridine) complexes increased with increasing basicity of the 4-Xpy derivative, a finding attributed to the influence of the magnetic anisotropy of the cobalt center on the shifts of the 1H NMR signals of the pyridyl protons closest to Co. Our method of employing a coordinate bond for conjugating the fac-[ReI(CO)3] core to a vitamin B12 model could be extended to natural B12derivatives. Because B12 compounds are known to accumulate in cancer cells, such an approach is a very attractive method for the development of 99mTc and 186/188Re radiopharmaceuticals for targeted tumor imaging and therapy. (Chemical Equation Presented).
N-Heteroarylphosphonates, Part II. Synthesis and reactions of 2- and 4- phosphonatoquinolines and related compounds
Haase, Mirko,Guì?nther, Wolfgang,Goì?rls, Helmar,Anders, Ernst
, p. 2071 - 2081 (1999)
We extend our synthetic method for the efficient preparation of dialkoxyphosphoryl- and phosphonio-disubstituted pyridines to include the preparation of other phosphonato substituted N-heterocycles. The key to the success of this method lies in the employment of cationic N- (trifluoromethylsulfonyl)heteroarylium triflates that are activated towards nucleophilic attack. The P(O)(OR)2 group can be transformed into the P(S)(OR)2 functionality. We report first attempts to substitute the P(O)(OR)2 moiety with C-nucleophiles. In addition to our synthetic results, the X-ray structures of two (dimethoxyphosphoryl)trifluoromethanesulfonyldihydro-N-heteroarenes are discussed. We also give complete carbon (13C) and phosphorus (31P)-NMR spectra of a series of 2- and 4-phosphonic ester substituted heteroaryl compounds and their dihydro analogs.
Synthesis of aminopyridines via an unprecedented nucleophilic aromatic substitution of cyanopyridines
Penney, Jonathan M.
, p. 2667 - 2669 (2004)
The direct reaction of 2- and 4-cyanopyridines with lithium amides affords good yields of the corresponding aminopyridines via displacement of cyanide. Addition of CsF accelerates the reaction and can lead to significantly higher yields.
A simple synthesis of aminopyridines: Use of amides as amine source
Kodimuthali, Arumugam,Mungara, Anitha,Prasunamba, Padala Lakshmi,Pal, Manojit
, p. 1439 - 1445 (2010)
A transition metal/microwave irradiation (or base) free synthesis of aminopyridines has been accomplished via C-N bond forming reaction between chloropyridine and a variety of simple amides under refuxing conditions.
-
Jameson,Lawlov
, p. 53,55 (1970)
-
Formation of Singlet Oxygen in the Deoxygenation of Heteroarene N-Oxides by Dimethyldioxirane
Adam, Waldemar,Briviba, Karlis,Duschek, Frank,Golsch, Dieter,Kiefer, Wolfgang,Sies, Helmut
, p. 1831 - 1832 (1995)
4-Dimethylaminopyridine-N-oxide 2 and 2',3',5'-triacetyladenosine-N1-oxide 4 are partially deoxygenated by dimethyldioxirane (DMD) to the corresponding amines 1 and 3; the formation of singlet oxygen suggests a polar rather than a radical mechanism, in which we propose SN2 attack of the N-oxide on the dioxirane peroxide bond.
CO2-tuned highly selective reduction of formamides to the corresponding methylamines
Chao, Jianbin,Guo, Zhiqiang,Pang, Tengfei,Wei, Xuehong,Xi, Chanjuan,Yan, Leilei
supporting information, p. 7534 - 7538 (2021/10/12)
We herein describe an efficient, CO2-tuned and highly selective C-O bond cleavage of N-methylated formanilides. With easy-to-handle and commercially available NaBH4 as the reductant, a variety of formanilides could be turned into the desired tertiary amines in moderate to excellent yields. The role of CO2 has been investigated in detail, and the mechanism is proposed on the basis of experiments.
Photocatalytic deoxygenation of N-O bonds with rhenium complexes: From the reduction of nitrous oxide to pyridineN-oxides
Anthore-Dalion, Lucile,Cantat, Thibault,Kjellberg, Marianne,Nicolas, Emmanuel,Ohleier, Alexia,Thuéry, Pierre
, p. 10266 - 10272 (2021/08/12)
The accumulation of nitrogen oxides in the environment calls for new pathways to interconvert the various oxidation states of nitrogen, and especially their reduction. However, the large spectrum of reduction potentials covered by nitrogen oxides makes it difficult to find general systems capable of efficiently reducing variousN-oxides. Here, photocatalysis unlocks high energy species able both to circumvent the inherent low reactivity of the greenhouse gas and oxidant N2O (E0(N2O/N2) = +1.77 Vvs.SHE), and to reduce pyridineN-oxides (E1/2(pyridineN-oxide/pyridine) = ?1.04 Vvs.SHE). The rhenium complex [Re(4,4′-tBu-bpy)(CO)3Cl] proved to be efficient in performing both reactions under ambient conditions, enabling the deoxygenation of N2O as well as synthetically relevant and functionalized pyridineN-oxides.
A Lewis Base Nucleofugality Parameter, NFB, and Its Application in an Analysis of MIDA-Boronate Hydrolysis Kinetics
García-Domínguez, Andrés,Gonzalez, Jorge A.,Leach, Andrew G.,Lloyd-Jones, Guy C.,Nichol, Gary S.,Taylor, Nicholas P.
supporting information, (2022/01/04)
The kinetics of quinuclidine displacement of BH3 from a wide range of Lewis base borane adducts have been measured. Parameterization of these rates has enabled the development of a nucleofugality scale (NFB), shown to quantify and predict the leaving group ability of a range of other Lewis bases. Additivity observed across a number of series R′3-nRnX (X = P, N; R′ = aryl, alkyl) has allowed the formulation of related substituent parameters (nfPB, nfAB), providing a means of calculating NFB values for a range of Lewis bases that extends far beyond those experimentally derived. The utility of the nucleofugality parameter is explored by the correlation of the substituent parameter nfPB with the hydrolyses rates of a series of alkyl and aryl MIDA boronates under neutral conditions. This has allowed the identification of MIDA boronates with heteroatoms proximal to the reacting center, showing unusual kinetic lability or stability to hydrolysis.
