1294
J. S. Foot et al.
LETTER
most all of the reactions went cleanly giving the product These conditions were applied to a range of substrates and
methyl ester in spectroscopically pure form without the amines (Table 3).10 With benzyl alcohol (entry i),
need for chromatographic purification (i.e. after simple benzamide12 and its N-methyl, N-iso-butyl and N,N-dime-
filtration and aqueous work-up). The isolated yields thyl derivatives were made in good to excellent yields via
ranged from 46–70% but repeating those reactions with this one pot procedure. The use of diethylamine proved
yields lower than 50% using conditions B greatly im- less satisfactory (25%), whereas pyrrolidine gave a 62%
proved the efficiency, although, as expected, reaction yield of the corresponding amide. This result suggests that
times were increased (Table 2, entries iii and v).
the transformation is sensitive to steric hindrance, a hy-
pothesis reinforced by the observation that the yield with
tert-butylamine was less than 5%.
Attempts to extend this methodology to unactivated alco-
hols such as decanol1b were unsuccessful (Method A, 99%
recovered decanol after reflux for 20 hours).
The process also worked well with electron rich and elec-
tron poor benzylic alcohols (entries ii and iii), and with
pyridine, thiophene and furan examples (entries iv–vi). To
date, we have not obtained practical yields with allylic and
propargylic alcohols, in part due to apparent Michael ad-
dition of cyanide,13 but success was achieved with an un-
activated alcohol, tetrahydrofurfuryl alcohol (entry vii).
Table 2 In Situ Oxidation-Esterification Reactionsa
Entry Alcohol
(i)
Product
Isolated
Yielda,b
CO2Me
A: 53% (18 h)
OH
In conclusion, we have successfully developed straight-
forward one-pot procedures for the conversion of activat-
ed primary alcohols into methyl esters and amides. The
procedure is mild and practically straightforward, does
not require anhydrous conditions, and affords good to ex-
cellent yields of the products after a simple filtration-
aqueous work-up. We are currently optimising and ex-
tending these processes, and looking at applications in
natural product synthesis.
(ii)
A: 57% (15 h)
CO2Me
OH
MeO
MeO
Br
(iii)
A: 46% (15 h)
B: 80% (3 d)
CO2Me
OH
Br
(iv)
A: 64% (2 h)
CO2Me
OH
N
N
(v)
A: 41% (20 h)c
B: 77% (7 d)
Acknowledgement
OH
OH
CO2Me
CO2Me
We are grateful to the EPSRC and GlaxoSmithKline for CASE stu-
dentship support (J. S. F.) and to Kureha Chemical Industry for in-
dustrial studentship support (H. K.).
O
O
(vi)
A: 66% (18 h)
A: 70% (5 h)
Ph
Ph
(vii)
CO2Me
Ph
Ph
OH
References
a Conditions A:15 MnO2, 1 NaCN, THF-MeOH,
;
8
(1) (a) Wei, X.; Taylor, R. J. K. Tetrahedron Lett. 1998, 39,
3815. (b) Blackburn, L.; Wei, X.; Taylor, R. J. K. Chem.
Commun. 1999, 1337. (c) Wei, X.; Taylor, R. J. K. J. Org.
Chem. 2000, 65, 616. (d) Runcie, K. A.; Taylor, R. J. K.
Chem. Commun. 2002, 974.
Conditions B: 20 MnO2, 5 NaCN, 1.5 AcOH, MeOH, r.t.
b Yields refer to material isolated after filtration and solvent evapora-
tion and shown to be essentially pure by NMR spectroscopy: after
chromatographic purification isolated yields are 1–2% lower.
c NMR yield quoted as a trace of starting alcohol remained.
(2) Blackburn, L.; Pei, C.; Taylor, R. J. K. Synlett 2002, 215.
(3) Blackburn, L.; Taylor, R. J. K. Org. Lett. 2001, 3, 1637.
(4) Kanno, H.; Taylor, R. J. K. Synlett 2002, 1287.
(5) McAllister, G. D.; Wilfred, C. D.; Taylor, R. J. K. Synlett
2002, 1291.
We next moved on to study amide formation. Preliminary
studies were carried out using benzyl alcohol with iso-bu-
tylamine, and the optimum conditions developed (Equa-
tion 3).11 Efficient conversion was achieved in THF
(dichloromethane could also be used; 84% yield with 5
equiv amine), and yields were higher when the reaction
was carried out at room temperature rather than reflux (at
higher temperatures the corresponding imine3 tended to
predominate).
(6) Corey, E. J.; Gilman, N. W.; Ganem, B. E. J. Am. Chem. Soc.
1968, 90, 5616.
(7) Gilman, N. W. J. Chem. Soc., Chem. Commun. 1971, 733.
(8) (a) To a mixture of cinnamyl alcohol (134 mg, 1 mmol),
sodium cyanide (49 mg, 1 mmol) and activated manganese
dioxide (Aldrich 21764-6, 1.31 g, 15 mmol) stirring in
tetrahydrofuran (10 mL), was added methanol (0.2 mL, 5
mmol). The reaction was heated to reflux and left to stir for
5 hours. The resulting mixture was then filtered through
Celite® and the solvent removed under reduced pressure.
Extraction with dichloromethane (50 mL), was followed by
washing with water (2 10 mL) and then saturated sodium
chloride solution (10 mL), before drying over magnesium
sulfate. Filtration and removal of solvent in vacuo gave
methyl trans-cinnamate (113 mg, 70%), as light yellow
30 MnO2
1 NaCN
1.5 equiv. iBuNH2: 67%
PhCONHBui
PhCH2OH
5 equiv. iBuNH2: 86%
x iBuNH2
THF, r.t.
Equation 3
Synlett 2002, No. 8, 1293–1295 ISSN 0936-5214 © Thieme Stuttgart · New York