Categories: C-N Bond Formation > Synthesis of substituted N-heterocycles >
N-alkylation
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In ionic liquids [Bmim][PF6] or [Bmim][BF4], a highly regioselective
N-substitution of pyrrole with alkyl halides, sulfonyl chlorides, and benzoyl
chloride gave substituted pyrroles in excellent yields. Michael addition of
pyrrole with electrophilic olefins was completed in a highly regioselective
manner to afford N-alkylpyrroles.
Z.-G. Lea, Z.-C. Chen, Y. Hu, Q.-G. Zheng Synthesis,
2004,
1951-1954.
Reaction of 4-bromo-NH-1,2,3-triazoles with alkyl halides in the presence
of K2CO3 in DMF produced the corresponding 2-substituted
4-bromo-1,2,3-triazoles in a regioselective process. Subsequent Suzuki
cross-coupling reaction provided an efficient synthesis of 2,4,5-trisubstituted
triazoles, whereas hydrogenation furnished an efficient synthesis of
2,4-disubstituted triazoles.
X.-j. Wang, K. Sidhu, L. Zhang, S. Campbell, N. Haddad, D. C. Reeves, D.
Krishnamurthy, C. H. Senanayake, Org. Lett., 2009,
11, 5460-5493.
A series of N,N′-asymmetrically substituted imidazolium iodides have been
synthesized, starting from N-arylimidazoles and the less expensive, but
less reactive, 1-chlorobutane or (3-chloropropyl)trimethoxysilane. The addition
of potassium iodide and the use of 1,2-dimethoxyethane as a solvent allowed the
synthesis of multigram quantities of these salts.
A. M. Oertel, V. Ritleng, M. J. Chetcuti, Synthesis, 2009,
1647-1650.
N-Methylimidazole is a promising catalyst for aza-Michael reactions.
Various N-heterocycles were introduced to α,β-unsaturated carbonyl compounds
employing N-methylimidazole in a highly efficient, rapid and high
yielding synthesis of N-heterocyclic derivatives.
B. K. Liu, Q. Wu, X. Q. Qian, D. S. Lv, X. F. Lin, Synthesis, 2007,
2653-2659.
Bu4NI catalyzes regioselective N2-alkylations
and N2-arylations of tetrazoles using tert-butyl
hydroperoxide as a methyl source, alkyl diacyl peroxides as primary alkyl source,
alkyl peresters as secondary and tertiary alkyl sources, and aryl diacyl
peroxides as arylating source. These reactions proceed without
pre-functionalization of the tetrazoles and in the absence of any metal
catalysts.
S. Rajamanickam, C. Sah, B. A. Mir, S. Ghosh, G. Sethi, V. Yadav, S.
Venkateramani, B. K. Patel, J. Org. Chem., 2020, 85,
2118-2141.
A convenient, efficient, and selective N-Alkylation of N-acidic heterocyclic compounds with alkyl halides is accomplished in ionic liquids in the presence of potassium hydroxide as a base. In this
manner, phthalimide, indole, benzimidazole, and succinimide can be successfully
alkylated.
Z.-G. Le, Z.-C. Chen, Y. Hu, Q.-G. Zheng, Synthesis, 2004,
208-212.
A consecutive detosylation/alkylation transformation of tosylated indoles and
phenols with alkoxides/alcohols as the alkylation reagents features mild reaction conditions, high
ipso-selectivity, and good
functional group tolerance. A one-pot selective N-alkylation of
unprotected indoles with alcohols and TsCl is also realized.
M.-H. Zhu, C.-L. Yu, Y.-L. Feng, M. Usman, D. Zhong, X. Wang, N. Nesnas, W.-B.
Liu,
Org. Lett., 2019, 21, 7073-7077.
Tetramethylammonium fluoride (TMAF) enables a direct and selective
methylation of various amides, indoles, pyrroles, imidazoles, alcohols, and
thiols. The method is characterized by operational simplicity, wide scope, and
ease of purification.
H.-G. Cheng, M. Pu, G. Kundu, F. Schoenebeck,
Org. Lett., 2020, 22, 331-334.
Due to the poor nucleophilicity
of the nitrogen atom of indoles and the competing
alkylation reaction at the C-3 position, the use of more sterically hindered ketones
with a lower
electrophilicity as N-alkylation
reagents has been a great challenge. A dearomatization-rearomatization strategy
enables a reductive cross-coupling of indoles with ketones in water in good
yield.
Z. Wang, H. Zeng, C.-J. Li,
Org. Lett., 2019, 21, 2302-2306.
A radical-mediated decarboxylative C(sp3)-N cross-coupling of
diacyl peroxides with nitrogen nucleophiles, including indazoles, triazoles,
indoles, and anilines provides a broad range of alkylated products. The primary
and secondary alkyl radicals derived from corresponding diacyl peroxides were
generated by copper catalysis or by merging copper catalysis and photoredox
catalysis, respectively.
Z. -L. Tang, X.-H. Ouyang, R.-J. Song, J.-H. Li, Org. Lett., 2021, 23,
1000-1004.