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Notes and references
‡ General procedure for the monomethylation of primary amines. MeOTf
(164 ml, 1.5 mmol) was added to a solution of primary amines (1 mmol) in
HFIP (1 mL) under stirring at room temperature. After 1 h, the reaction
mixture was quenched by an aq. sol. of HCl 2 N (1 mL) and volatiles were
evaporated under reduced pressure. The composition of the reaction
solution was analysed by 1H NMR spectroscopy using 3-bromotoluene
(123 ml, 1 mmol) as the internal standard for aromatic amines.
Scheme 2 Ethylation of benzylamine.
with 2 eq. of MeI while a H-bonding interaction is evidenced by
the linear variation of Dd with an increasing amount of MeOTf
and Me2SO4.14
1 For a review, see: R. N. Salvatore, C. H. Yoon and K. W. Jung,
Tetrahedron, 2001, 57, 7785.
2 For selected examples, see: (a) B. Basu, S. Paul and A. K. Nanda,
Green Chem., 2009, 11, 1115; (b) R. N. Salvatore, A. S. Nagle and
K. W. Jung, J. Org. Chem., 2002, 67, 674.
The scope of the best monomethylation conditions (1.5 eq.
of MeOTf in HFIP at room temperature for 1 h) was then
extended to various primary amines (Table 2). Benzylamine
derivatives with different substituents on the aryl ring under-
went successful methylation to afford the corresponding
monoadducts 2a–e in 54–66% yields (entries 1–5). Similar
results were obtained by varying the nature of the aromatic
moiety (naphthyl in 2g: 71%, and furyl in 2h: 66%; entries 6 and
7). Finally, in the a-methylarylamine series, the best yield was
obtained starting from a-methylbenzylamine (78% yield,
entry 8). Anilines also behaved very well (entries 9–12) with
the noteworthy example of 2,6-xylidine affording 2m in 96%
yield. In aliphatic series, dodecylamine gave good results
(52% yield; entry 13). Interestingly, this method also offers an
easy entry into N-methyl aminoesters from glycine and
L-valine ethyl esters (54% and 69% yields, respectively;
entries 14 and 15).‡
3 (a) T. Lebleu, H. Kotsuki, J. Maddaluno and J. Legros, Tetrahedron Lett.,
2014, 55, 362; (b) F. F. Blicke and C.-J. Lu, J. Am. Chem. Soc., 1952, 74, 3933.
4 (a) K. Beydoun, T. vom Stein, J. Klankermayer and W. Leitner, Angew.
Chem., Int. Ed., 2013, 52, 9554; (b) Y. Li, I. Sorribes, T. Yan, K. Junge and
M. Beller, Angew. Chem., Int. Ed., 2013, 52, 12156; (c) Y. Li, X. Fang,
K. Junge and M. Beller, Angew. Chem., Int. Ed., 2013, 52, 9568;
(d) X. Cui, X. Dai, Y. Zhang, Y. Deng and F. Shi, Chem. Sci., 2014, 5, 649.
5 R. M. Yebeutchou and E. Dalcanale, J. Am. Chem. Soc., 2009, 131, 2452.
6 Monomethylation of anilines in Me2CO3 in the presence of zeolite at
high temperatures has also been reported: (a) M. Selva, P. Tundo
and T. Foccardi, J. Org. Chem., 2005, 70, 2476; (b) M. Selva, P. Tundo
and A. Perosa, J. Org. Chem., 2001, 66, 677.
¨
7 For reviews, see: (a) I. A. Shuklov, N. V. Dubrovina and A. Borner,
´
´
Synthesis, 2007, 2925; (b) J.-P. Begue, D. Bonnet-Delpon and
B. Crousse, Synlett, 2004, 18.
8 For selected recent contributions, see: (a) C. C. Malakar, S. Stas,
W. Herrebout and K. A. Tehrani, Chem.–Eur. J., 2013, 19, 14263;
(b) Y. Hu, T. Kamitanaka, Y. Mishima, T. Dohi and Y. Kita, J. Org. Chem.,
2013, 78, 5530; (c) A. Yoshimura, K. R. Middleton, M. W. Luedtke, C. Zhu
and V. V. Zhdankin, J. Org. Chem., 2012, 77, 11399; (d) A. Kirste, B. Elsler,
G. Schnakenburg and S. R. Waldvogel, J. Am. Chem. Soc., 2012, 134, 3571.
9 (a) D. Vuluga, J. Legros, B. Crousse, A. M. Z. Slawin, C. Laurence,
P. Nicolet and D. Bonnet-Delpon, J. Org. Chem., 2011, 76, 1126;
Finally, the same conditions have been applied to ethylation
of benzylamine with EtOTf. The reaction also proceeded very
well and N-ethylbenzylamine 5a was obtained in 57% yield
along with only 2% of diadduct 6a (Scheme 2).
¨
(b) A. Berkessel, J. A. Adrio, D. Hu¨ttenhain and J. M. Neudorfl, J. Am.
Chem. Soc., 2006, 128, 8421; (c) S. P. de Visser, J. Kaneti, R. Neumann
and S. Shaik, J. Org. Chem., 2003, 68, 2903.
In conclusion, we describe a very simple method for the
direct N-monomethylation of primary amines in HFIP with
MeOTf as an electrophilic source of methyl. The key point of
this method rests on the original role of HFIP that avoids
overmethylation by the selective deactivation of secondary and
tertiary amines through H-bonding. The reaction conditions are
compatible with functional groups and are easy to implement
at a lab scale (readily available chemicals, room temperature
within 1 h). The potential of this reaction seems extendable
to other alkyl triflates, thus providing a powerful method for
monoalkylation of primary amines.
10 (a) J. Chen, D. Vuluga, B. Crousse, J. Legros, J. Duchet-Rumeau,
A. Charlot and D. Portinha, Polymer, 2013, 54, 3757; (b) A. Berkessel,
¨
¨
J. Kramer, F. Mummy, J. M. Neudorfl and R. Haag, Angew. Chem.,
Int. Ed., 2013, 52, 739; (c) J. Legros, D. Bonnet-Delpon, B. Crousse
and A. M. Z. Slawin, Catal. Sci. Technol., 2012, 2, 934; (d) D. Vuluga,
J. Legros, B. Crousse and D. Bonnet-Delpon, Chem. Commun., 2008,
´
4954; (e) J.-F. Berrien, M. Ourevitch, G. Morgant, N. E. Ghermani,
B. Crousse and D. Bonnet-Delpon, J. Fluorine Chem., 2007, 128, 839.
11 In the opening of epoxides by amines in HFIP, piperidine is inert while
the poorer nucleophile aniline reacts: U. Das, B. Crousse, V. Kesavan,
´
´
D. Bonnet-Delpon and J.-P. Begue, J. Org. Chem., 2001, 65, 6749.
12 For reviews, see: (a) K. S. Elvira, X. C. i Solvas, R. C. R. Wootton and
A. J. deMello, Nat. Chem., 2013, 5, 905; (b) J.-i. Yoshida, Y. Takahashi and
A. Nagaki, Chem. Commun., 2013, 49, 9896; (c) J.-i. Yoshida, Chem. Rec.,
2010, 10, 332.
This project was funded by the European INTERREG IV A
France (Channel)–England Cross-border Cooperation Programme
AI-Chem and co-financed by ERDF. The authors also thank the
13 For recent examples, see: (a) A. Nagaki, D. Ichinari and J.-i. Yoshida,
Chem. Commun., 2013, 3242; (b) D. Webb and T. F. Jamison, Org.
Lett., 2012, 14, 568.
´
Region Haute-Normandie for financial support.
14 See ESI† for details.
1838 | Chem. Commun., 2014, 50, 1836--1838
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