M. B. Alshammari, G. A. El-Hiti and K. Smith Greener and regioselective lithiation of substituted pyridines International Conference on Green Chemistry and Sustainable Engineering, Faculty of Biology, Barcelona University, Barcelona, Spain, 2931 July 2014.
Greener and regioselective lithiation of substituted pyridines Mohammed B. Alshammaria, Gamal A. El-Hitib and Keith Smithc
a
Chemistry Department, College of Sciences and Humanities, Salman bin Abdulaziz University, P.O. Box 83, Al-Kharij 11942, Saudi Arabia
b
Cornea Research Chair, Department of Optometry, College of Applied Medical Sciences, King Saud University, P.O. BOX 10219, Riyadh 11433, Saudi Arabia c
School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, UK *E-mail:
[email protected]
Variations in the site of lithiation of N-acyl-3-(aminomethyl)pyridine derivatives with different N-substituents using different lithiating reagents has been investigated. Ring lithiation has been achieved by the use of t-BuLi at 78 C followed by reaction with various electrophiles to give the corresponding 4-substituted products in high yields. On the other hand, the reaction was regioselective towards the side-chin when LDA was used as the lithium reagent at 20 to 0 C. A mixture of ring and side-chain substitution products was obtained when n-BuLi was the lithium reagent. Smith’s group has developed several efficient lithiation procedures for preparation of various substituted aromatics and heteroaromatics that might be difficult to prepare by other means.1 As part of such studies they have successfully lithiated and substituted various N-(substituted benzyl)pivalamides and N'-(substituted benzyl)-N-N-dimethylureas selectively using n-BuLi or t-BuLi in THF.2 Such processes have been applied for the production of substituted isoindoline and isoquinoline derivatives.3 Also, Smith group has shown that lithiation of N'-phenethyl-N,N-dimethylurea, N'-(3-phenylpropyl)-N,N-dimethylurea and N'-2-(2methylphenyl)ethylamines with RLi in THF at -78 or 0 C takes place on the nitrogen and on the side-chain of the CH2 next to the phenyl ring (α-lithiation).4,5 Ring lithiation was achieved by bromine-lithium exchange of 2- and 3-bromo derivatives.4 On the other hand, lithiation of N'-(4phenylbutyl)-N,N-dimethylurea with t-BuLi at 0 C has taken place on one of the methyl groups of the urea unit under similar reaction conditions,5 while lithiation of N'-2-(4-methoxyphenyl)ethyl-N,Ndimethylurea at 0 C gave a mixture of lithium reagents in which lithiation had taken place mainly on the ring next to the urea containing unit and on one of the methyl groups of the urea unit. Finally, lithiation of N-(4-methoxyphenethyl)pivalamide and N-(4-methoxyphenethyl)carbamate at 0 C gave ring lithiation next to the pivalamide or carbamate units.6 Very recently, the Smith group has investigated the effect of an extra CH2 between the DMG and the pyridine ring.7 It was found that the lithiation and substitution of 2- and 4-substituted N-(pyridinylmethyl)amines (urea, pivalamide and carbamate containing groups) provided easy access to various side-chain (methylene) substituted derivatives in high yields.7
M. B. Alshammari, G. A. El-Hiti and K. Smith Greener and regioselective lithiation of substituted pyridines International Conference on Green Chemistry and Sustainable Engineering, Faculty of Biology, Barcelona University, Barcelona, Spain, 2931 July 2014.
1) 2.2 t-BuLi, -78 °C, 2 h
Y H N
Z
R
2) Electrophile, -78 °C, 2 h 3) aq. NH4 Cl
Y H N
Z
O
E
5.7
R O
5.8 (71-99%) Z = N, Y = CH; Z = CH, Y = N; R = t -Bu, NMe 2, t -BuO
Ring lithiation of a series of N-acyl-3-(aminomethyl)pyridine derivatives has been achieved by the use of t-BuLi (3.3 mole equivalents) at 78 C.8 The dilithium reagents produced in-situ were allowed to react with various electrophiles to give the corresponding 4-substituted products in high yields.8 On the other hand, the reaction was regioselective towards the side-chin when LDA (3.3 mole equivalents) was used as the lithium reagent at 20 to 0 C.8 A mixture of ring and side-chain substitution products, and also some product resulting from addition of butyllithium on the pyridine double bond followed by oxidation was obtained.8
E
O N H
N
R
-78 °C, 2 h
N H
2) Electrophile 3) aq NH 4Cl
(66-91%)
O
1) 3.3 t-BuLi, THF
N
E
1) 3.3 LDA, THF -20 to 0 °C, 6 h
R
N H
2) Electrophile 3) aq NH 4Cl
R = NMe 2, But, OBut
O R
N (48-75%)
Conclusions: Two independent, green, convenient and simple experimental procedures have been developed for the production of ring and side-chain substitution products of such N-acyl-3(aminomethyl)pyridines. Acknowledgements: We thank the Saudi Government for financial support. References: 1.
2.
3. 4. 5. 6. 7. 8.
See for example, Smith, K.; El-Hiti, G. A.; Abdo, M. A.; Abdel-Megeed, M. F. J. Chem. Soc., Perkin Trans. 1 1995, 1029; Smith, K.; El-Hiti, G. A.; Abdel-Megeed, M. F.; Abdo, M. A. J. Org. Chem. 1996, 61, 647 and 656; Smith, K.; El-Hiti, G. A.; Shukla, A. P. J. Chem. Soc., Perkin Trans. 1 1999, 2305; Smith, K.; El-Hiti, G. A.; Hawes, A. C. Synthesis 2003, 2047; Smith, K.; El-Hiti, G. A.; Abdel-Megeed, M. F. Synthesis 2004, 2121; Smith, K.; El-Hiti, G. A.; Hegazy, A. S. Synthesis 2005, 2951. Smith, K.; El-Hiti, G. A.; Hegazy, A. S. Synlett 2009, 2242; Smith, K.; El-Hiti, G. A.; Hegazy, A. S.; Fekri, A.; Kariuki, B. M. Arkivoc 2009, xiv, 266; Smith, K.; El-Hiti, G. A.; Hegazy, A. S. Synthesis 2010, 1371. Smith, K.; El-Hiti, G. A.; Hegazy, A. S. Chem. Commun. 2010, 46, 2790; Smith, K.; El-Hiti, G. A.; Hegazy, A. S.; Fekri, A. Heterocycles 2010, 80, 941. Smith, K.; El-Hiti, G. A.; Alshammari, M. B. Synthesis 2012, 44, 2013. Smith, K.; El-Hiti, G. A.; Alshammari, M. B. J. Org. Chem. 2012, 77, 11210. Smith, K.; El-Hiti, G. A.; Alshammari, M. B. Synlett 2013, 24, 117. Smith, K.; El-Hiti, G. A.; Fekri, A.; Alshammari, M. B. Heterocycles 2012, 86, 391. Smith, K.; El-Hiti, G. A.; Alshammari, M. B. B.; Fekri, A. Synthesis 2013, 45, 3426.
