Fluorous dienophiles are powerful diene scavengers in diels-alder reactions

Article abstract of DOI:10.1021/ol035214a

(Matrix presented) Three fluorous dienophiles have been synthesized, and their value in scavenging an excess diene after Diels-Alder reactions is shown. The resulting fluorous derivatives are separated by solid-phase extraction on fluorous silica gel (FSP

Full text of DOI:10.1021/ol035214a

ORGANIC
LETTERS
2003
Vol. 5, No. 18
3293-3296
Fluorous Dienophiles Are Powerful
Diene Scavengers in Diels−Alder
Reactions†
Stefan Werner and Dennis P. Curran*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
curran@pitt.edu
Received June 30, 2003
ABSTRACT
Three fluorous dienophiles have been synthesized, and their value in scavenging an excess diene after Diels−Alder reactions is shown. The
resulting fluorous derivatives are separated by solid-phase extraction on fluorous silica gel (FSPE). The fluorous [1,2,4]triazoline-3,5-dione 10
reacted with most dienes within seconds or minutes.
Scavenging methods for removing excess reactants or
reagents are increasingly popular, especially in solution-phase
parallel synthesis. Many polymer-bound scavengers are now
available;1 however, large excesses are typically used,
scavenging times can be long, and solvent use is sometimes
limited by polymer swelling characteristics.
A series of recent papers suggests that fluorous scavengers
typically do their job rapidly in solution, and large excesses
are not needed.2 After the reaction, the separation of target
products from scavenged products and excess scavenger is
readily accomplished by a fluorous solid-phase extraction
(FSPE).3 Fluorous compounds are retained on fluorous silica
gel on a first-pass elution with MeOH/water, while the target
non-fluorous compounds are not. A second-pass elution with
diethyl ether then gives the fluorous compounds.
Current fluorous scavengers are mostly electrophiles or
nucleophiles.2 We present here the first fluorous dienophiles
and validate their utility as diene scavengers. Target adducts
and scavenged products are separated by FSPE.
We made three reactive fluorous dienophiles by the
reactions summarized in Scheme 1. Using Toru’s procedure4
afforded the benzylmaleimide 4 and the phenylmaleimide 5
in 83 and 76% yields, respectively, starting from maleic
anhydride 1 and commercially available fluorous amines 2
and 3.5 N-Phenyl maleimide 5 has no spacer and bears a
shorter C6F13 tag, while N-benzylmaleimide 4 has an ethylene
spacer and a longer C8F17 tag.
† Dedicated to Prof. Shuji Kanemasa on the occasion of his 60th birthday.
(1) (a) Booth, R. J.; Hodges, J. C. Acc. Chem. Res. 1999, 32, 18-26.
(b) Parlow, J. J.; Devraj, R. V.; South, M, S. Curr. Opin. Chem. Biol. 1999,
3, 320-336. (c) Thompson, L. A. Curr. Opin. Chem. Biol. 2000, 4, 324-
337. (d) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach,
A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S.
J. J. Chem. Soc., Perkin Trans. 1 2000, 3815-4195. (e) Eames, J.;
Watkinson, M. Eur. J. Org. Chem. 2001, 1213-1224.
(2) (a) Linclau, B.; Singh, A. K.; Curran, D. P. J. Org. Chem. 1999, 64,
2835-2842. (b) Wipf, P.; Reeves, J. T.; Balachandran, R.; Guiliano, K.
A.; Hamel, E.; Day, B. W. J. Am. Chem. Soc. 2000, 122, 9391-9395. (c)
Palmacci, E. R.; Hewitt, M. C.; Seeberger, P. H. Angew. Chem., Int. Ed.
2001, 40, 4433-4437. (d) Lindsley, C. W.; Zhao, Z.; Leister, W. H.
Tetrahedron Lett. 2002, 43, 4225-4228. (e) Lindsley, C. W.; Zhao, Z.;
Leister, W. H.; Strauss, K. A. Tetrahedron Lett. 2002, 43, 6319-6323. (f)
Zhang, W.; Curran, D. P.; Chen, C. H. T. Tetrahedron 2002, 58, 3871-
3875. (g) Zhang, W.; Chen, C. H. T.; Nagashima, T. Tetrahedron Lett.
2003, 44, 2065-2068.
[1,2,4]Triazoline-3,5-diones are very reactive dienophiles,
so we used Cookson’s procedure6 to make fluorous [1,2,4]-
(3) (a) Curran, D. P.; Hadida, S.; He, M. J. Org. Chem. 1997, 62, 6714-
6715. (b) Curran, D. P; Luo, Z. J. Am. Chem. Soc. 1999, 121, 9069-9072.
(c) Curran, D. P. Synlett 2001, 9, 1488-1496.
(4) Reddy, P. Y.; Kondo, S.; Toru, T.; Ueno, Y. J. Org. Chem. 1997,
62, 2652-2654.
(5) Commercially available from Fluorous Technologies, Inc., http://
www.fluorous.com. DPC holds an equity interest in this company.
10.1021/ol035214a CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/14/2003

Scheme 1. Synthesis of Fluorous Dienophiles 4, 5, and 10
triazoline-3,5-dione 10 from ethyl hydrazinecarboxylate 6
and the commercially available fluorous isocyanate 7.5 Ring
closure of 8 with KOH and oxidation of 9 with tBuOCl7 gave
10 in an overall yield of 51%. Triazoline dione 10 is a
beautiful pink solid that was purified by sublimation. It
decomposes on silica gel, allowing easy separation of Diels-
Alder adducts from 10.
Next, we explored the reactivity of the three dienophiles
in Diels-Alder reactions with 1,2,3,4,5-pentamethylcyclo-
pentadiene (PMCP,11), cyclohexadiene (CHD, 12), R-ter-
Figure 1. Structures 16-31.
pinene (TP, 13), anthracene (ANT, 14), and 1,4-diphenyl-
1,3-butadiene (DPBD, 15). The structures of the products
obtained are shown in Figure 1, while the results are
summarized in Table 1. We obtained the fluorous Diels-
Table 1. Diels-Alder Reactions of the Fluorous Dienophiles 4, 5, and 10
fluorous
isomer ratiob
(anti/syn)
isolated yieldc
(%)
retention timed
(min)
entry
diene
dienophile
DA adduct
reaction conditionsa
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
PMCP11
PMCP11
PMCP11
CHD 12
CHD 12
TP13
4
5
10
4
10
5
10
4
5
10
4
5
16 + 19
17 + 20
18 + 21
22
23
24
25
26
27
28
DCM, 30 min, rt
DCM, 30 min, rt
THF, 1 s, rt
DCE, 2 day, 60 °C
DCM, 1 s, rt
DCE, 1 day, 110 °C
DCM, 1 s, rt
toluene, 1 day, 120 °C
toluene, 1 day, 120 °C
THF, 2 h, rt
83/17
82/18
70/30
68e
68e
52e
96
87
73
87
93
85
69
55
66
75
65.0 + 70.7
13.4 + 14.3
31.2 + 33.3
26.0
13.8
14.9
25.1
26.0
8.5
14.8
TP13
ANT14
ANT14
ANT14
DPBD15
DPBD15
DPBD15
29
30
31
toluene, 2 day, 155 °C
toluene, 2 day, 155 °C
THF, 20 min, rt
30.5
9.3
15.2
24.7
10
4f
5f
7.9
a Heated reactions were carried out in a pressure tube under 2 atm argon; DCM is dichloromethane; DCE is 1,2-dichloroethane. b By 1H NMR integration.
c After column chromatography. d Retention times of the Diels-Alder adducts using a FTI PF-C8 HPLC/LC column (150 × 4.6 mm) on a HP 1100 series
MSD LC-MS system with UV-detection at 231 nm, elution with MeCN/H2O 80/20, flow rate 1 mL/min; no retention time for 10 was available because of
decomposition on silica gel. e After F-HPLC separation. f Retention times of dienophiles.
3294
Org. Lett., Vol. 5, No. 18, 2003

Alder adducts 16-31 in 52-96% yields. The Diels-Alder
adducts 16-21 were obtained in about the same anti/syn
ratios as the corresponding non-fluorous adducts.8 Although
the anti and the syn isomers 16/19, 17/20, and 18/21 have
the same fluorous tag, they were easily separated on a
semipreparative FluoroFlash HPLC column.9 In contrast,
separation on a reverse-phase HPLC column10 or on flash-
grade silica gel was not possible.
Comparison of reaction times in Table 1 shows that the
fluorous maleimides 4 and 5 have a similar reactivity, but
that the fluorous [1,2,4]triazoline-3,5-dione 10 is much more
reactive. Kinetic studies showed that 10 is at least 1000 times
more reactive toward DPBD 15 than 4 or 5.
all these adducts have C8F17 tags. All Diels-Alder adducts
from 4 and 5 had longer retention times than the correspond-
ing polar dienophiles themselves (entries 14, 15). Small,
nonpolar organic domains in the Diels-Alder adduct pro-
duced longer retention times than larger, more polar domains
(compare 16/19 in entry 1 with 26 in entry 8, for example).
We used a standard protocol to compare fluorous dieno-
philes 4, 5, and 10 in typical scavenging reactions (Figure
2). An excess of a diene (0.15 mmol) was reacted with
We calibrated the reactivity of 10 against that of 4-phenyl-
[1,2,4]triazoline-3,5-dione (32), which is one of the most
reactive dienophiles known. These results are shown in
Scheme 2.
Scheme 2. Competition Experiment between 10, 32, and 33
Figure 2. Standard Procedure for the Scavenging Reactions.
0.10 mmol of maleic anhydride (MA, 1), N-phenylmaleimide
(PMI, 36), or DMAD (37), respectively. When TLC analysis
showed that the diene was consumed, a fluorous scavenger
4, 5, or 10 was added. Separation was done by FSPE on
5 g FluoroFlash cartridges5 eluting with MeOH/H2O 8/2.
The results of a series of scavenging experiments are
summarized in Table 2. After FSPE, the Diels-Alder adducts
were isolated in 77-99% yield and in 84-97% purity. These
F
Equimolar amounts of 10, 32, and DEAD 335,11 were
1
adducts were analyzed by GC and their H NMR spectra,
which were consistent with literature data.12,13 A second
elution with diethyl ether provided the excess of the
scavengers 4 and 5 and the corresponding fluorous Diels-
Alder adducts, which had been previously prepared (Table
1). The excess of 10 decomposed on the fluorous silica gel,
in those cases (Table 2, entries 4, 6, and 11) the diethyl ether
elution gave pure compounds 18/21 or 28. The anthracene/
maleic anhydride adducts decomposed selectively in a
methanolysis reaction to give the half-methyl ester (not
shown; see Supporting Information) during the FSPE (entries
7 and 11). This problem was solved by using a MeCN/H2O
mixture for elution during FSPE instead of MeOH/H2O.
MeCN/H2O in an 8/2 ratio was used for the C8F17-tagged
scavenger 4 (entries 8 and 14), while for the C6F13-tagged
scavenger 5, the ratio was 6/4 (entries 9 and 10).
allowed to compete for a deficiency of the diene 15 (0.33
equiv) in CD2Cl2 at rt. After 45 min, H NMR analysis
1
showed that diene 15 was consumed and 31 and 34 were
present in a 51/49 ratio; 35 was not detected. This shows
that 10 and 32 have similar reactivities and both are in turn
much more reactive than 33.
The last column of Table 1 also collects the retention times
of all the adducts on a FluoroFlash HPLC column eluting
with 80/20 MeOH/water. Non-fluorous-tagged compounds
elute at or near the solvent front under these conditions. The
Diels-Alder adducts from 5 with the C6F13-tag showed
shorter retention times than those from 4 and 10 with the
C8F17-tag. Adducts from the more polar 10 eluted prior to
adducts from 4 (compare entries 1/3, 4/5, etc.), even though
(6) Cookson, R. C.; Gupte, S. S.; Stevens, I. D. R.; Watts, C. T. Org.
Synth. 1971, 51, 121-127.
(12) (a) Kalindjian, S. B.; Buck, I. M.; Cushnir, J. R.; Dunstone, D. J.;
Hudson, M. L.; Low, C. M. R.; McDonald, I. M.; Pether, M. J.; Steel, K.
I. M.; Tozer, M. J. J. Med. Chem. 1995, 38, 4294-4302. (b) Ballistreri, F.
P.; Maccarone, E.; Perrini, G.; Tomaselli, G. A.; Torre, M. J. Chem. Soc.,
Perkin Trans. 2 1982, 273-277.
(7) Mintz, M. J.; Walling, C. Org. Synth. 1969, 49, 9-12.
(8) Letourneau, J. E.; Wellman, M. A.; Burnell, D. J. J. Org. Chem.
1997, 62, 7272-7277.
(9) FluoroFlash HPLC column (FTI), 20 × 250 mm.
(10) Symmetry C-18 5 µm (Waters), 3.9 × 150 mm.
(11) Dandapani, S.; Curran, D. P. Tetrahedron 2002, 58, 3855-3864.
(13) Compounds 39, 40, 46, and 47 were separately synthesized and
characterized.
Org. Lett., Vol. 5, No. 18, 2003
3295

Table 2. Use of the Fluorous Dienophiles 4, 5, and 10 in Scavenging Excess Diene after a Diels-Alder Reactiona
solvent for
yield
(%)d
puritye
(%)
entry
diene
dienophile scavenger DA adductb
reaction conditionsc
FSPE elution
1
2
3
4
5
6
7
8
9
PMCP11
PMCP11
PMCP11
PMCP11
PMCP11
PMCP11
ANT14
ANT14
ANT14
ANT14
ANT14
MA1
4
4
5
10
4
10
4
4
5
5
39 + 40
41 + 42
41 + 42
41 + 42
43 + 44
43 + 44
45
45
45
45
45
DCM, 2 × 30 min, rt
MeOH/H2O 8/2f
MeOH/H2O 8/2f
MeOH/H2O 8/2
MeOH/H2O 8/2
MeOH/H2O 8/2
MeOH/H2O 8/2
MeOH/H2O 8/2
MeCN/H2O 8/2
MeCN/H2O 8/2
MeCN/H2O 6/4
MeOH/H2O 8/2
84
89
97
97
99
97
99
93
-
89
95
91
91
95
97
PMI36
PMI36
PMI36
DMAD37
DMAD37
MA1
MA 1
MA1
MA1
MA1
DCM, 2 × 30 min, rt
DCM, 2 × 30 min, rt
DCM, 30 min, rt; 1 s, rt
DCM, 2 × 30 min, rt
DCM, 30 min, rt; 1 s, rt
toluene, 2 × 1 day, 120 °C
toluene, 2 × 1 day, 120 °C
toluene, 2 × 1 day, 120 °C
toluene, 2 × 1 day, 120 °C
toluene, 1 day, 120 °C;
5 min, 70 °C
methanolysisg
96
47
97
10
11
82
81
10
methanolysisg
12
13
14
15
ANT14
DPBD 15
ANT14
PMI36
DMAD37
MA1
4
4
4
5
46
47
45
48
toluene, 2 × 1 day, 120 °C
MeOH/H2O 8/2f
81h
77
83
79
84
96
93
90
toluene, 6 h, 155 °C; 12 h 155 °C MeOH/H2O 8/2
MWi: neat, 2 × 10 min, 160 °C
MeCN/H2O 8/2
MeCN/H2O 6/4
DPBD15
MA1
MWi: neat, 2 × 10 min, 160 °C
a Standard procedure: 0.15 mmol of the diene was allowed to react with 0.10 mmol of the dienophile. After the reaction was complete, 0.10 mmol of the
fluorous scavenger was added. After the scavenging reaction was complete, the solvent was evaporated and the crude mixture was loaded in 0.6 mL of THF
onto a 5 g FluoroFlash cartridge5 that had been preconditioned with MeOH/H2O or MeCN/H2O. The cartridge was eluted with 4 × 8 mL of the mentioned
solvent mixture to give the non-fluorous Diels-Alder adducts, followed by elution with 2 × 8 mL of diethyl ether to give the excess of the fluorous
scavenger and the scavenger adducts. b Non-fluorous Diels-Alder adduct from the mentioned diene and dienophile; structures not shown. c Reaction conditions
for Diels-Alder reaction; reaction conditions for scavenging reaction. d After FSPE workup. e By GC analysis. f Purification by a 2 g FluoroFlash cartridge
is possible. g Only the Diels-Alder adduct and the corresponding methanolysis adduct could be detected by 1H NMR. h Further elution is necessary. i CEM
Microwave Reactor SP-1188 (ramp time, 1 min; power, 300 W).
We tested two scavengers in Diels-Alder reactions under
microwave conditions.14 The reactions of the dienes 14 and
15 with maleic anhydride were complete after 10 min of
irradiation in a microwave reactor at 160 °C under solvent-
free conditions. Under the same conditions, the scavengers
4 and 5 reacted with the excess diene, and the Diels-Alder
adducts were obtained after FSPE in 79-83% yield and with
a purity of 90-93% (entries 14 and 15).
The intense pink color of 10 allows scavenging reactions
with reactive dienes to be conducted as titrations. For
example, a solution of 10 in dichloromethane was used to
scavenge an excess of PCMP 11 after reaction with DMAD
(Figure 3). On dropwise addition of the pink solution of 10
to the reaction mixture, the color persisted only after all the
excess PCMP 11 had reacted. The endpoint was readily
detected even with dilute 0.005 M solutions 10. For suitably
reactive dienes, this titration method bypasses the need to
use excess scavenger to ensure complete diene consumption.
In summary, we have synthesized three fluorous dieno-
philes and proved their usefulness as diene scavengers. The
fluorous [1,2,4]triazoline-3,5-dione 10 shows superior re-
activity, and its pink color allows convenient titrations in
some cases. Triazoline diones are also reactive in ene and
other reactions, so the scavenging ability of 10 extends
beyond Diels-Alder reactions.
Acknowledgment. We thank the National Institutes of
Health for funding this work and CEM for the microwave
reactor.
Supporting Information Available: Procedures for di-
enophile synthesis and reactions, spectroscopic and analytical
data for compounds 4, 5, 8-10, 16-31, 38-40, 46, and 47,
and descriptions of the reactivity studies, the competition
experiment, and the titration experiment. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL035214A
Figure 3. Use of the scavenger 10 in a Diels-Alder titration
experiment, scavenging an excess of 11 after a Diels-Alder reaction
with DMAD: left, 0.005 M solution in CH2Cl2; middle, before
equivalence point; right, at equivalence point.
(14) (a) Giguere, R. J.; Bray, T. L.; Duncan, S. M.; Majetich, G.
Tetrahedron Lett. 1986, 27, 4945-4948. (b) Rongshun, Z.; Pinjie, H.
Shushan, D. Synth. Commun. 1994, 24 (17), 2417-2421.
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Org. Lett., Vol. 5, No. 18, 2003