LETTER
Reductive Monoalkylation of Aromatic Amines via Amidine Intermediates
was obtained as an amorphous white solid. For non-
645
tures verified by HPLC, H-NMR, and 13C-NMR. Rea-
sonable yields of the monoalkylated products are
generally observed using either the one- or two-pot ap-
proach,16 although the yields of products via the one-pot
approach are slightly higher due to losses during the iso-
lation of the amidines. We are presently examining the ap-
plication of this reaction to the formation of more
complex alkylated amines.
1
nucleosidic substrates dichloromethane was used to wash the
precipitate in the final step.
(6) Meerwein, H.; Florian, W.; Schon, N.; Stopp, G. Liebigs Ann.
Chem. 1961, 641, 1-39.
(7) Brown, B.R. The Organic Chemistry of Aliphatic Nitrogen
Compounds; Clarendon: Oxford, 1994.
(8) McBride, L.J.; Kierzek, R.; Beaucage, S.L.; Caruthers, M.H.
J. Am. Chem. Soc. 1986, 108(8), 2040-2048.
(9) Vincent, S.; Mioskowski, C.; Lebeau, L. J. Org. Chem. 1999,
64(3), 991-997. In this work, aryl amidines did not provide
alkylated products.
(10) Mechanistic studies: Moad, G.; Benkovic, S.J. J. Am. Chem.
Soc. 1978, 100(17), 5495-5499.
Acknowledgement
Financial support from the Robert A. Welch Foundation (Grant
#AA-1355) is gratefully acknowledged.
(11) Meyers, A.I.; Ten Hoeve, W. J. Am. Chem. Soc. 1980, 102,
7125-7126.
(12) Yamamoto, H; Marouka, K. J. Am. Chem. Soc. 1981,
103(14), 4186-4194.
References and Notes
(13) Borch, R. F., Hassid, A. I. J. Org. Chem. 1972, 37(10), 1673–
1674.
(14) Abrams, W. R.; Kallen, R. G. J. Am. Chem. Soc. 1976, 98,
7777-7789.
(1) Brookes, P.; Lawley, P.D. J. Chem. Soc. 1960, 539-545.
(2) Aritomo, K.; Wada, T.; Sekine, M. J. Chem. Soc. Perkin Trans
I 1995, 1837-1844.
(3) Kemal, O.; Reese, C.B. Synthesis 1980, 1025-1028.
(4) Zemlicka, J.; Holy, A. Coll Czech. Chem. Comm. 1967, 32,
3159-3168. Froehler, B.C.; Matteucci, M.D. Nucleic Acids
Res. 1983, 11(22), 8031-8037.
(15) One-pot approach to 6-N-methyladenosine: Adenosine (267
mg, 1 mmol), dried by coevaporation with pyridine, was
dissolved in 2 3 mL anhydrous DMF and then N,N
dimethylformamide dimethyl acetal (1mL, 5.5 mmol, 5.5 eq.)
was added. The resulting solution was stirred under N2 at
40 °C (bath temperature) for 1 hour. After the reaction mixture
cooled to room temperature, sodium borohydride (130 mg,
3.5 mmol, 3.5 eq) was added and the mixture stirred at room
temperature for 2 hours. Saturated sodium bicarbonate was
used to quench the reaction mixture, and the resulting
suspension was filtered and the precipitate washed with 100
mL methanol. The mixture was concentrated and the residue
applied to flash LC (silica gel) with CH2Cl2-CH3OH-NMe3
(9:1:0.05) as eluent. 6-N-methyladenosine (177 mg, 0.63
mmol, 63%) was obtained. For non-nucleosidic substrates
dichloromethane was used in the final extraction.
(16) Overall yields are excellent (>90%) if corrected for recovered
starting materials, which accounts for the majority of the
missing mass balance.
(5) Two-step approach to 6-N-methyladenosine: Adenosine
(267mg, 1 mmol), dried by coevaporation with pyridine, was
dissolved in 2 3 mL anhydrous DMF and N,N dimethyl-
formamide dimethyl acetal (1mL, 5.5 mmol, 5.5 equiv) was
added. The resulting solution was stirred under N2 at 40 °C
(bath temperature) for 1 hour. The solution was then
evaporated to dryness under vacuum and the residue
submitted to flash chromatography on silica gel with
CH2Cl2 CH3OH NMe3 (95:5:0.5) eluent. Fractions
containing 6-N-(1-dimethylamino)methylidene) adenosine
(213 mg, 0.66 mmol, 66%) were evaporated to dryness and
then dissolved in 3 mL DMF in a 10 mL round bottom flask.
Sodium borohydride (130 mg, 3.5 mmole, 5 eq) was added
and the mixture stirred at room temperature for 2 hours.
Saturated sodium bicarbonate was used to quench the reaction
mixture, and the resulting solution was filtered and the
precipitate washed with 100 mL methanol. After evaporation
of the solvent under vacuum the residue was applied to flash
LC (silica gel) with CH2Cl2-CH3OH-NMe3 (9:1:0.05). 6-N-
Methyladenosine (156 mg, 0.56 mmol, 85%, 56% overall)
Article Identifier:
1437-2096,E;2001,0,05,0643,0645,ftx,en;S08500ST.pdf
Synlett 2001, No. 5, 643–645 ISSN 0936-5214 © Thieme Stuttgart · New York