Synthesis of fluorous azodicarboxylates: Towards cleaner Mitsunobu reactions

Article abstract of DOI:10.1016/S0040-4039(02)00322-2

The synthesis of a fluorous analogue of diethyl azodicarboxylate (DEAD) is described and preliminary results for its use in the Mitsunobu reaction given. Use of fluorous extraction methods have shown that chromatography is not necessary for reaction purif

Full text of DOI:10.1016/S0040-4039(02)00322-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2807–2810
Synthesis of fluorous azodicarboxylates: towards cleaner
Mitsunobu reactions
Adrian P. Dobbs* and Caroline McGregor-Johnson
School of Chemistry, University of Exeter, Stocker Road, Exeter EX4 4QD, UK
Received 31 January 2002; accepted 18 February 2002
Abstract—The synthesis of a fluorous analogue of diethyl azodicarboxylate (DEAD) is described and preliminary results for its
use in the Mitsunobu reaction given. Use of fluorous extraction methods have shown that chromatography is not necessary for
reaction purification. © 2002 Elsevier Science Ltd. All rights reserved.
Perfluorocarbon liquids are poor solvents for organic
compounds and also have limited, but thermally con-
trolled miscibility with organic solvents. Horva´th used
these properties to introduce the concept of the
fluorous biphasic system in 19941 and Curran2 further
elaborated this in his concept of an ‘ideal purification.’
The concept is a simple one: the product(s) of a partic-
ular reaction are separated into a different phase from
the starting reagents and reaction byproducts. To date,
fluorous biphasic chemistry has found particular appli-
cation in the field of catalysis, but is rapidly becoming
more important in organic synthesis, since it permits
easy purification or removal of fluorous compounds
from organic ones by simple liquid–liquid extraction.
Fluorous reagents for synthesis are rapidly emerging as
clean alternatives to conventional reagents and recent
examples have included fluorous-tin hydrides,3–5
fluorous-allyltin reagents,6 fluorous-organoselenium
reagents,7,8 fluorous-phosphines9–11 and fluorous-pro-
tecting groups.12–17
hydrazine. Diethyl azodicarboxylate (DEAD) is the
usual carboxylate of choice, along with triphenylphos-
phine, although other combinations are known.18,19
One of the major uses of the Mitsunobu reaction is
with optically active substrates, it proceeds with com-
plete inversion of configuration.18,19
With the development of new technologies for cleaner
synthesis, the Mitsunobu reaction has been the focus of
considerable attention. Triphenylphosphine oxide is
known to be problematic to remove from reactions and
variations have been developed in an attempt to over-
come this e.g. solid-supported triphenylphosphine and
fluorous-triphenylphosphines.9,10 Both reagents have
greatly simplified the ease of purification of many reac-
tions involving triarylphosphines.11,20 While the prob-
lem of the triphenylphosphine has been largely
overcome, it is often the removal of the hydrazine
by-product that has been more problematic. This has
received much less attention,21 although a solid-sup-
ported version of DEAD has been reported.22 There-
fore, we believed this reaction, and in particular the
DEAD reagent, to be ripe for study using fluorous
technologies. Concurrent with this study, the group of
The condensation reaction of an alcohol using the
redox couple of a trialkyl or triaryl phosphine and a
dialkyl azodicarboxylate is known as the Mitsunobu
reaction, based on work performed in the 1960’s. The
reaction has been extensively reviewed18,19 and may be
summarised as in Scheme 1.
R1OH
H
Nu
PPh3
RO2CN NCO2R
An alcohol (R1OH) and an acidic component (H-Nu)
are condensed to form the product (R1-Nu), while
triphenylphosphine is oxidised to triphenylphosphine
oxide and the dialkyl azodicarboxylate is reduced to the
R, R1, R2 = alkyl
Nu = R2CO2-, R22N-
H
R1 Nu
Ph3P O
RO2CN NCO2R
H
* Corresponding author. Tel.: +44 1392 263410; fax: +44 1392
263434; e-mail: a.dobbs@exeter.ac.uk
Scheme 1. The Mitsunobu reaction.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00322-2

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A. P. Dobbs, C. McGregor-Johnson / Tetrahedron Letters 43 (2002) 2807–2810
Curran in Pittsburgh have also been developing a
fluorous-based version of the Mitsunobu reaction,
based on a solid–liquid fluorous separation approach.23
Pleasingly, their results concur with those described
here and will be reported shortly. Herein we describe
the synthesis of a fluorous-DEAD reagent and prelimi-
nary results for its use in the Mitsunobu reaction.
purification in the subsequent reaction with hydrazine
hydrate in ethanol, employing the conditions of Rab-
john.26 The fluorous hydrazine 4 was obtained as a
white solid that could be recrystallised from methanol
(80%).27 The crucial step was the oxidation of the
fluorous diethylcarboxyhydrazine. Several oxidants
were attempted: manganese dioxide (0%), lead
tetraacetate28 (29%) and finally, the reagent of choice,
N-bromosuccinimide29–31 in pyridine (79%). The
fluorous-DEAD reagent 1 was obtained as a pale
cream/yellow solid, after recrystallisation from ethanol
and in 63% overall yield.27
In designing a fluorous-DEAD reagent, we were con-
scious of the need for ca. 60% fluorine content to
ensure selective solubility of the compound in fluorous
solvents,24 while also requiring a spacer group to pro-
tect the azocarboxylate function from the electron with-
drawing effects of the fluorine atoms.24 Thus, 1
appeared to be a suitable target, with 60.9% fluorine
content and also an ethylene spacer group.
The fluorous-DEAD has been utilised in three test
reactions, which are typical examples of Mitsunobu
reactions. First was a simple esterification reaction, to
form ethyl benzoate from benzoic acid and ethanol
(Scheme 3). The reaction was performed twice, using
both DEAD and fluorous-DEAD. Identical reaction
conditions were employed in each case (using ethanol
both as reagent and solvent at room temperature for 12
h) and comparable yields obtained (85% (DEAD) and
84% (fluorous-DEAD)). Column chromatography was
required to purify the traditional reaction. However, for
the fluorous reaction, the excess ethanol was removed
under reduced pressure and the residue partitioned
between dichloromethane and the fluorous solvent FC-
72 (perfluorohexane). Separation of the two phases
showed complete removal of the fluorous-hydrazine
by-product from the reaction mixture, thus leaving only
triphenylphosphine oxide to be separated from the
desired product. Repeating this reaction using S-(+)-2-
O
O
C6F13
C6F13
O
N
N
O
1
The synthesis of the fluorous-DEAD reagent was rela-
tively easy, employing literature methods (Scheme 2).
Commercially
available
1,1,2,2H-tridecafluoro-1-
octanol 2 was chosen as a suitable starting material,
since it possessed a suitable fluorous pony-tail, and also
an ethylene ‘spacer’ unit, to shield the hydrazine from
the fluorous pony-tail. Reaction of this with phosgene25
(commercial solution in toluene) gave, after 24 h reflux,
the fluorous chloroformate 3, in quantitative yields.
Although isolated and purified by column chromato-
graphy, this compound could be used without further
C6F13
C6F13
O
O
C6F13
O
C6F13
O
O
NH2NH2.H2O
Oxidant
Cl
Cl
HN
HN
N
N
O
O
Diethyl ether
Reflux 24 h
100%
EtOH
80%
OH
O
O
Cl
O
O
2
3
4
1
C6F13
C6F13
Scheme 2. Synthesis of fluorous-DEAD.
O
O
O
R
R
R
COOEt
O
O
R = Et 85%
R = (CH2)2C6F13 84%
N
N
N
PPh3
EtOH
COOH
O
N
O
O
C6H13
R
O
O
R = Et 68%
R = (CH2)2C6F13 63%
OH
PPh3/THF
Scheme 3. Fluorous-DEAD in esterification reactions.

A. P. Dobbs, C. McGregor-Johnson / Tetrahedron Letters 43 (2002) 2807–2810
2809
Ph
O
O
R = Et 81%
OH
Ph
N
OH
N
O
O
O
R = (CH2)2C6F13 78%
R
R
O
O
O
O
N
N
PPh3/THF/50oC/3 days
Scheme 4. Fluorous-DEAD in phthalimide coupling reactions.
octanol gave the corresponding R-(−) octyl benzoate in
equally good yield (68% (DEAD) and 63% (fluorous-
DEAD)) and with the expected inversion of configura-
tion, a typical characteristic of the Mitsunobu reaction.
We are currently calculating the partition coefficients of
fluorous-DEAD for a range of fluorous and organic
solvents, and these will be reported shortly.
3. Curran, D. P.; Hadida, S. J. Am. Chem. Soc. 1996, 118,
2531–2532.
4. Horner, J. H.; Martinez, F. N.; Newcombe, M.; Hadida,
S.; Curran, D. P. Tetrahedron Lett. 1997, 38, 2783–2786.
5. Curran, D. P.; Hadida, S.; Kim, S.-Y.; Luo, Z. J. Am.
Chem. Soc. 1999, 121, 6607–6615.
6. Ryu, I.; Curran, D. P. Tetrahedron Lett. 1999, 40, 2367–
2370.
Finally, to demonstrate that the fluorous-DEAD
reagent was not limited just to esterification reactions, a
phthalimide coupling reaction was performed, using
N-hydroxyphthalimide and R-(+)-1-phenylbutanol
(Scheme 4). The traditional reagents gave S-(−)-N-(1-
phenylbutoxy)phthalimide (i.e. complete inversion of
configuration) in 81% after three days and column
chromatography.32 Repeating the reaction using
fluorous-DEAD again required long reaction time and
gave the desired product in almost identical yield and
with complete inversion of configuration.
7. Crich, D.; Hao, X.; Lucas, M. Tetrahedron 1999, 55,
14261–14268.
8. Crich, D.; Hao, X.; Lucas, M. A. Org. Lett. 1999, 1,
269–271.
9. Bhattacharyya, P.; Gudmunsen, D.; Hope, E. G.; Kem-
mitt, R. D. W.; Paige, D. R.; Stuart, A. M. J. Chem.
Soc., Perkin Trans. 1 1997, 3609–3612.
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3700.
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2001, 42, 5424–5427.
12. Curran, D. P.; Ferritto, R.; Hua, Y. Tetrahedron Lett.
1998, 39, 4937–4940.
13. Wipf, P.; Reeves, J. T. Tetrahedron Lett. 1999, 40, 4649–
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In conclusion, a high yielding synthesis of a fluorous
analogue of diethyl azodicarboxylate has been devel-
oped and the reagent utilised in a range of Mitsunobu
reactions. Separation of the fluorous by-products is
easily achieved by fluorous liquid extraction, using a
perfluorosolvent. Thus, this procedure offers an easy
method for the purification of the hydrazine by-product
from Mitsunobu reactions. Further, this method offers
a complementary fluorous-separation technique to the
fluorous solid–liquid separation method of Curran.23
We are currently investigating the use of this reagent in
conjunction with alternatives to triphenylphosphine e.g.
fluorous-phosphines and solid-supported phosphines, in
order to remove completely the need for any form of
chromatography and to further the ‘greening’ of the
Mitsunobu reaction. These results will be reported in
due course.
16. Pardo, J.; Cobas, A.; Guitia´n, E.; Castedo, L. Org. Lett.
2001, 3, 3711–3714.
17. Luo, Z.; Williams, J.; Williams, R. W.; Read, R. W.;
Curran, D. P. J. Org. Chem. 2001, 66, 4261–4266.
18. Mitsunobu, O. Synthesis 1981, 1–28.
19. Hughes, D. L. Organic Reactions; Paquette, L. A., Ed.;
John Wiley & Sons; Vol. 42, pp. 335–645.
20. Pollastri, M. P.; Sagal, J. F.; Chang, G. Tetrahedron Lett.
2001, 42, 2459–2460.
21. Pelletier, J. C.; Kincaid, S. Tetrahedron Lett. 2000, 41,
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22. Tunoori, A. K.; Dutta, D.; Georg, G. I. Tetrahedron
Lett. 1998, 39, 8751–8754.
Acknowledgements
23. Personal communication from Professor Dennis Curran;
Dandapani, S.; Curran, D. P. Tetrahedron, in press.
24. Barthel-Rosa, L. P.; Gladysz, J. A. Coord. Chem. Rev.
1999, 190–192, 587–605.
We are grateful to the University of Exeter for funding
(C.M.-J.).
25. Forbes, J. E.; Saicic, R. N.; Zard, S. Z. Tetrahedron 1999,
55, 3791–3802.
26. Rabjohn, N. Org. Synth. Collect. Vol. III, 375–377.
27. All compounds gave satisfactory analytical data. Both
the fluorous hydrazine (4) and fluorous-DEAD (1)
reagents are now commercially available from Fluorous
Technologies Inc. (www.fluorous.com).
References
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