J. R. Morphy et al. / Tetrahedron Letters 42 (2001) 7509–7511
7511
a
Table 2.
Equiv. amine 5
Yield (%)b
No solventc
DMFd
DMF
(0.03 mL)
DMSO
(0.03 mL)
Perfluorohexaned
Perfluorohexane and
Perfluorohexane and
DMFe (0.03 mL)
DMSOe (0.03 mL)
2
4
6
8
10
15
20
26
44
48
63
65
B5
8
12
13
23
40
56
73
92
41
43
50
70
74
62
\95
\95
\95
\95
\95
\95
75
83
91
95
90
80
94
90
94
95
14
30
28
39
73
72
\95
\95
\95
\95
\95
\95
95
a Michael reaction performed for 2 h. For procedure see Ref. 5.
b Yields determined by 1H NMR using N-methylmaleimide as an internal standard.
c Amine was pipetted onto dry resin.
d All reactions performed with 0.05 mmol resin in 1 mL solvent unless otherwise stated.
e Represents the use of a standard amount (1 mL per 0.05 mmol resin) of perfluorohexane with 0.03 mL DMSO/DMF.
a
Table 3.
translated into a reduction of reaction time or a reduc-
tion in the excess of reagent required to drive the
reaction to completion. The large increases in yield seen
are thought to arise from a reagent concentration
effect, whereby the reagents become trapped inside the
resin bead as a result of their immiscibility in the
perfluorous solvents. Our preliminary studies showed a
similar effect for perfluorous solvents in the quaternisa-
tion step of the REM resin cycle. Further studies
investigating the scope of the FAST concept are cur-
rently underway and will be reported in due course.6
Yield (%)b
Volume of DMF added
DMF onlyc
Perfluorohexane
(mL)
and DMFd
10
30
50
100
200
300
500
1000
18
12
76
75
76
64
60
30
10
B5
B5
B5
B5
B5
B5
B5
References
a Michael reaction (0.05 mmol resin, 0.1 mmol amine) performed for
2 h. For procedure see Ref. 4.
1. Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96,
555–600.
2. Horvath, I. T. Acc. Chem. Res. 1998, 31, 641–650 and
references cited therein.
3. Myers, K. E.; Kumar, K. J. Am. Chem. Soc. 2000, 122,
12025–12026.
b Yields determined by 1H NMR using N-methylmaleimide as an
internal standard.
c Michael reaction performed in DMF.
d Michael reaction performed in perfluorohexane (1 mL) with the
stated amount of DMF added.
4. (a) Morphy, J. R.; Rankovic, Z.; Rees, D. C. Tetrahedron
Lett. 1996, 37, 3209–3212; (b) Brown, A. R.; Rees, D. C.;
Rankovic, Z. R.; Morphy, J. R. J. Am. Chem. Soc. 1997,
119, 3288–3295.
until the yield observed would be the same as that seen
for the same amount of co-solvent alone. As expected,
on increasing the solvent volume the yield of tertiary
amine product decreased as reagent concentration
decreased. This was seen when DMF was the sole
solvent, where product could not be detected at solvent
volumes above 30 mL. Where DMF was used as a
co-solvent with perfluorohexane, decreases in yield were
also seen although reasonable yields were maintained
with solvent volumes of up to 200 mL. This may have
implications for other reactions where appreciable vol-
umes of co-solvent are required to solubilise reagents.
5. Typical reaction conditions: REM resin (0.05 mmol) was
treated with the appropriate solvent and amine. The mix-
ture was then shaken at rt for 2–3 h, filtered and washed
(3×1 mL DMF, DCM, MeOH). The resin was then treated
with DMF (1 mL) and benzyl bromide (0.5 mmol), agi-
tated at rt for 18 h, filtered and washed as above. The
product was then cleaved by treatment with DIEA (0.1
mmol) and K2CO3 (0.4 mmol) in DCM (1 mL), and
agitation at rt for 6 h after which the product was isolated
by filtration and resin washing (3×1 mL DCM).
6. During the preparation of this manuscript a preliminary
report dealing with an increase in rate seen for a polymer
supported hydrogenation catalyst with perfluorous sol-
vents was published: Vinson, S. L.; Gagne, M. R. Chem.
Commun. 2001, 1130–1131.
In summary, the adoption of perfluorous solvents in the
Michael reaction on solid-phase has resulted in a
greater than ten fold increase in yield compared to the
standard solvent system (DMF). Such increases can be