5688
D. Glynn et al. / Tetrahedron Letters 49 (2008) 5687–5688
Table 2
Acknowledgements
Preparation of various tertiary amides under microwave heating in the presence of
DABAL-Me3
We would like to thank Mr. Andrew Kennedy and GlaxoSmith
Kline for partial support of a studentship (DG). SW is grateful to
EPSRC (GR/S56054/01) and COST ESF for support of activities in
the D40 Innovative Catalysis Action. We thank Timothy Evans
and the Nuffield Foundation for their involvement with this
project.
2
R1
R2
R3
Time (min)
Yielda (%)
2aa
2ba
2cb
2ab
2bb
2ac
2bc
2adb
2bdb
Ph
Cy
crotyl
Ph
Cy
Ph
Cy
Ph
Cy
–(CH2)4–
–(CH2)4–
5
5
16
5
92
92
52
98
92
88
82
76
62
–(CH2)2O(CH2)2–
–(CH2)2O(CH2)2–
–(CH2)2O(CH2)2–
–(CH2)2C6H4 (CH2)–
–(CH2)2C6H4 (CH2)–
5
12
12
10
16
Supplementary data
OMe
OMe
Me
Me
Supplementary data associated with this article can be found, in
a
Isolated yield.
b
Amine 3d (THF solution) was treated with NaH (1.0 equiv., 22 °C, 25 min) and
the resulting free amine NaCl mixture was treated directly with DABAL-Me3 and the
ester.
References and notes
1. Analysis of 128 drug candidate molecules prepared by AstraZeneca,
GlaxoSmithKline and Pfizer: Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M.
T. Org. Biomol. Chem. 2006, 2337–2447. For safety driven rationals in
pharmaceutical route choice see: Butters, M.; Catterick, D.; Craig, A.; Curzons,
A.; Dale, D.; Gillmore, A.; Green, S. P.; Marziano, I.; Sherlock, J.-P.; White, W.
Chem. Rev. 2006, 106, 3002–3027.
2. (a) Sahasrabudhe, K.; Gracial, V.; Aube, J. J. Am. Chem. Soc. 2003, 125, 7914–
7922; (b) Sonntag, N. O. V. Chem. Rev. 1952, 52, 237–416; (c) El Kaim, L.; Grimau,
L.; Oble, J. Angew. Chem. 2005, 117, 8175–8178; (d) Dineen, T. A.; Zajae, M. A.;
Myers, A. G. J. Am. Chem. Soc. 2006, 128, 16406–16409; (e) Azumaya, I.;
Okamoto, T.; Imabeppu, F.; Takayanagi, H. Tetrahedron 2003, 59, 2325–2331.
3. Novak, A.; Humphreys, L. D.; Walker, M. D.; Woodward, S. Tetrahedron Lett.
2006, 47, 5767–5769.
somewhat more hindered amine/ester pairs it was advantageous
to extend the reaction time. However, all the reactions are techni-
cally trivial to carry out: all the components are simply combined
and irradiated in a commercial apparatus.
In Table 2 the following nomenclature is used: the first letter
refers to the parent ester in Scheme 2 and the second to the parent
amine. Thus, 2aa represents 2 with R1 = Ph and R2, R3 = (CH2)4. For-
mation of both the morpholine analogues 2ab, 2bb and the quino-
line analogues 2ac, 2bc occurred in excellent 98%, 92% 88%, and
82% yields, respectively (Table 2).
Direct use of the commercial Weinreb amide source 3d led ini-
tially to very low yields, but this situation could be reversed by
one-pot in situ deprotonation of 3d with NaH followed by a micro-
wave-promoted coupling. Unsaturated esters were not tolerated as
well in the new process and gave only moderate yield transforma-
tions (2cb). Finally, the preparation using hindered acyclic 2°
amines still proved highly challenging giving poor yields.
Overall, we have described a technically very simple procedure
for the direct formation of tertiary amides from secondary amines
and esters under microwave heating. Whilst high temperatures
(130 °C) are required, few other direct procedures are currently
available that are as convenient as those outlined here.
4. (a) Katritzky, A. R.; Cai, C.; Singh, S. K. J. Org. Chem. 2006, 71, 3375–3380; (b)
Galema, S. A. Chem. Soc. Rev. 1997, 26, 233–236; (c) Khadilkar, B. M.; Madyer, V.
R. Synth. Commun. 2005, 32, 1731–1734; (d) Hellal, M.; Bihel, F.; Mongeot, A.;
Bourgignon, J.-J. Org. Biomol. Chem. 2006, 4, 3142–3146.
5. Representative example: A dry microwave vessel (4 ml) was charged with a
magnetic stirrer bar and 1,2,3,4-tetrahydroisoquinoline (125
1.00 mmol). To this, THF (4 ml) was added along with DABAL-Me3 (208 mg,
0.8 mmol) and methyl benzoate (136 mg, 125 l, 1.00 mmol). The microwave
ll, 133 mg,
l
vial was sealed with a plastic microwave cap and placed in a CEM discover
microwave and irradiated (300 W) at 130 °C for 12 min. The reaction mixture
was quenched with 1 M HCl (4 ml), and extracted with DCM (3 Â 30 ml), the
combined organics were dried over magnesium sulfate and evaporated to yield
the crude product. The product was purified using column chromatography with
4:1 petrol/ethyl acetate as eluent.