Microwave-assisted combined Mitsunobu reaction-Claisen rearrangement and microwave-assisted phenol oxidation: Rapid synthesis of 2,6-disubstituted-1,4- benzoquinone natural products

Article abstract of DOI:10.1016/j.tetlet.2005.10.096

Microwave irradiation of a phenol, an allylic alcohol, di-isopropyl azodicarboxylate and triphenylphosphine at 220-240°C for 30 min results in a combined Mitsunobu reaction and Claisen rearrangement to give the rearranged 2-allylphenol. Following the firs

Full text of DOI:10.1016/j.tetlet.2005.10.096

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8823–8825
Microwave-assisted combined Mitsunobu reaction–Claisen
rearrangement and microwave-assisted phenol oxidation: rapid
synthesis of 2,6-disubstituted-1,4-benzoquinone natural products
Aouregan M. Jacob and Christopher J. Moody*
Department of Chemistry, University of Exeter, Stocker Road, Exeter EX4 4QD, UK
School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
Received 16 September 2005;revised 10 October 2005;accepted 19 October 2005
Available online 7 November 2005
This paper is dedicated to Professor Steve Ley on the occasion of his 60th birthday
Abstract—Microwave irradiation of a phenol, an allylic alcohol, di-isopropyl azodicarboxylate and triphenylphosphine at 220–
240 °C for 30 min results in a combined Mitsunobu reaction and Claisen rearrangement to give the rearranged 2-allylphenol.
Following the first detailed study of microwave-assisted phenol oxidation, rapid syntheses of the natural products primin and
2-methoxy-6-pentadecyl-1,4-benzoquinone (four reaction steps, total reaction time 1 h) were achieved using this combined Mitsun-
obu–Claisen strategy in combination with two further microwave-assisted steps (alkene hydrogenation and phenol oxidation).
Ó 2005 Elsevier Ltd. All rights reserved.
Microwave-assisted reactions continue to attract
increasing attention from synthetic organic chemists.1
The advent of dedicated microwave reactors has enabled
a wide range of reactions to be carried out rapidly and,
critically, reproducibly in the laboratory. As a simple
thermal process, the aromatic Claisen rearrangement
of allyl aryl ethers is ideally suited to microwave condi-
tions, and reaction times are shortened dramatically.2–10
We have recently reported the use of the microwave-
assisted aromatic Claisen rearrangement as a key step
in the synthesis of a range of naturally occurring 1,4-ben-
zoquinones.11 The substrates for Claisen rearrangement,
the allyl ethers 2 were prepared from the corresponding
phenols 1 and allylic alcohols using the Mitsunobu reac-
tion,12 and underwent rapid Claisen rearrangement to
the 2-allylphenols 3 upon microwave irradiation in
DMF. Although, as far as we are aware, there are only
two reports of microwave-assisted Mitsunobu reac-
tions,13,14 the fact that both the first steps in this reaction
sequence are subject to acceleration by microwave irra-
diation suggested that they could be combined into a
single one-pot operation. We now report the realization
of this strategy in the first microwave-assisted combined
Mitsunobu reaction–Claisen rearrangement protocol.
Additionally, we also report the first examples of the
microwave-assisted oxidation of phenols to 1,4-benzo-
quinones, the combination of these strategies enabling
rapid syntheses of the natural products primin and 2-
methoxy-6-pentadecyl-1,4-benzoquinone (four reaction
steps, total reaction time 1 h).
Initially, a small range of phenols 1 and allylic alcohols
were reacted under standard Mitsunobu conditions
(Ph3P, DIAD, THF) to give the allyl ethers 2 (64–
97%) after ca. 16 h reaction time. The allyl ether 2c
underwent Claisen rearrangement upon heating under
reflux in DMF for 72 h or N,N-dimethylaniline for 4 h
to give phenol 3c. As expected it proved more conve-
nient to carry out the Claisen rearrangement in a micro-
wave reactor, and heating the allyl ethers 2 in DMF for
30 min at 220–290 °C gave the rearrangement products
3 in 43–99% yield. The overall yields of phenols 3 over
the two steps were 28–92% with reaction times of over
18 h even when the second step was microwave-assisted.
In order to effect the combined Mitsunobu reaction–
Claisen rearrangement, phenol 1, the allylic alcohol, tri-
phenylphosphine and DIAD were heated in toluene in a
sealed tube at 220–240 °C in a microwave reactor. This
resulted in the formation of the rearrangement products,
*
Corresponding author. Fax: +44 115 951 3564;e-mail: c.j.moody@
nottingham.ac.uk
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.096

8824
A. M. Jacob, C. J. Moody / Tetrahedron Letters 46 (2005) 8823–8825
Table 1. The combined Mitsunobu reaction–Claisen rearrangement protocol
R1 R3
R1
R1
OH
R2
R3
OH
HO
R2
R3
O
R2
R
Ph3P, DIAD
toluene, 300 W
30 min
R
R
1
2
3
R
R1
H
R3
R2
3
Temperature (°C)
3 Yield (%)
2-OMe
2-OMe
2-OMe
2-NO2
2-Cl
Me
H
H
a
b
c
d
e
f
220
220
220
241
240
220
240
60
58
68
36
84
95
95
–(CH2)3–
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
4-OMe
4-Cl
g
the 2-allylphenols 3, in 36–95% yield (Table 1) in reac-
tion times of just 30 min.15 Hence, although the yields
over the two processes are similar, these first examples
of a microwave-assisted combined Mitsunobu reac-
tion–Claisen rearrangement protocol result in dramati-
cally reduced reaction times.
alkene reduction,1 but as far as we are aware there are
no reports of oxidation of simple phenols to 1,4-benzo-
quinones under microwave conditions, although hydro-
quinones and anilines have been subject to microwave-
assisted oxidation to 1,4-benzoquinones.16,17 Therefore,
we undertook a preliminary study using 2-methoxy-6-
pentyl- and -pentadecyl phenols (4a,b), prepared as pre-
viously described.11 As summarized in Table 2, a range
of reagents/conditions that are known to oxidize phe-
nols were adapted for use in a focussed microwave reac-
tor. Thus, PhI(OAc)2,18 PhI(OCOCF3)2,19 JonesÕ
reagent,20 FremyÕs salt,21 oxygen/salcomine,22,23 hydro-
gen peroxide/methyltrioxorhenium(VII)24 and air/cop-
per(II) chloride25 were all investigated, as were three
other oxidants that although not known to oxidize phe-
Simple 2-methoxy-6-allylphenols, now readily and rap-
idly available by the above method, were key intermedi-
ates in our synthesis of naturally occurring benzo-
quinones,11 and therefore we wished to combine the
microwave Mitsunobu–Claisen protocol with two fur-
ther microwave-assisted steps (alkene reduction and
phenol oxidation) in a rapid route to such natural prod-
ucts. There is ample precedent for microwave-assisted
Table 2. Microwave-assisted oxidation of 2-methoxyphenols to 1,4-benzoquinones
O
O
OH
MeO
R
MeO
R
conditions
4a R = n-C5H11
4b R = n-C15H31
5a R = n-C5H11
5b R = n-C15H31
Conditionsa
Yield (%)
R = n-C5H11
R = n-C15H31
PhI(OAc)2, TFA, aq AcOH, 300 W, 40 °C, 20 min
PhI(OCOCF3)2, TFA, aq AcOH, 300 W, 40 °C, 20 min
CrO3, H2SO4, aq acetone, 10 W, 80 °C, reflux, 20 min
FremyÕs salt, NaH2PO4, aq acetone, 10 W, reflux, 20 min
O2, salcomine, MeCN, 10 W, 90 °C, reflux, 10 min
MeReO3, 30% H2O2, EtOH, 10 W, reflux, 15 min
CuCl2, [bmim]Cl,c aq n-BuOH, 10 W, reflux, 40 min
(NH4)2Ce(NO3)6, aq MeCN, 10 W, 80 °C, reflux, 20 min
54
41
66
82
b
28
b
12
53
45
b
Trace
0
55
26
12
b
16
b
TEMPO, Mn(NO3)2, Co(NO3)2, AcOH, 10 W, reflux, 10 min
TM,d
Magtrieve,
toluene, 100 W, reflux, 30 min
34
a Reflux refers to use of a flask with an open reflux condenser;all other reactions carried out in sealed tubes at the specified temperature.
b Not attempted.
c 1-Butyl-3-methylimidazolium chloride.
d DuPont trademark for the oxidant based on CrO2.

A. M. Jacob, C. J. Moody / Tetrahedron Letters 46 (2005) 8823–8825
8825
R1
10. Kotha, S.;Mandal, K.;Deb, A. C.;Banerjee, S.
hedron Lett. 2004, 45, 9603–9605.
11. Davis, C. J.;Hurst, T. E.;Jacob, A. M.;Moody, C. J. J.
Org. Chem. 2005, 70, 4414–4422.
12. For a review, see: Hughes, D. L. Org. Prep. Proced. Int.
1996, 28, 127–164.
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Tetra-
O
1. Ph3P, DIAD
toluene, 300 W
220 oC, 30 min
OH
MeO
R
MeO
HO
2. NH4OCHO, Pd/C, 10 W, 10 min
O
3. Fremy's salt, NaH2PO4,
aq acetone, 10 W, 20 min or
salcomine, O2, MeCN, 10 W, 20 min
5a R = C5H11
5b R = C15H31
Scheme 1.
15. Combined Mitsunobu reaction–Claisen rearrangement: gen-
eral procedure. Phenol (0.81 mmol), allylic alcohol
(1.21 mmol) and triphenylphosphine (0.359 g, 1.37 mmol)
were dissolved in toluene (2 mL). DIAD (0.21 mL,
1.05 mmol) was added, the tube sealed and the solution
was heated at 220–250 °C for 30 min in a microwave
reactor (300 W). The solvent was removed under reduced
pressure and the crude product was purified by flash
chromatography on basic alumina, eluting with light
petroleum–ether (99.9:0.1) to give the Claisen rearrange-
ment product.
16. Gomez-Lara, J.;Gutierrez-Perez, R.;Penieres-Carrillo,
G.;Lopez-Cortes, J. G.;Escudero-Salas, A.;Alvarez-
Toledano, C. Synth. Commun. 2000, 30, 2713–2720.
17. Hashemi, M. M.;Akhbari, M. Monatsh. Chem. 2003, 134,
1561–1563.
nols to quinones appeared adaptable for use under
microwave conditions, namely cerium(IV) ammonium
nitrate,26 TEMPO27 and MagtrieveTM.28,29 Although
none of the reactions are particularly high-yielding, with
two exceptions they all proceed rapidly and give the
corresponding quinones 5, and were deemed suitable
for use in a synthetic sequence.
Hence using a combination of microwave-assisted reac-
tions, the benzoquinone natural products primin 5a and
2-methoxy-6-pentadecyl-1,4-benzoquinone 5b were syn-
thesized from guaiacol in four reaction steps—the com-
bined Mitsunobu–Claisen process, catalytic transfer
hydrogenation30,31 and phenol oxidation—with a total
reaction time of 1 h in overall yields of 43% and 28%,
respectively (Scheme 1).
18. Kato, N.;Sugaya, T.;Mimura, T.;Ikuta, M.;Kato, S.;
Kuge, Y.;Tomioka, S.;Kasai, M. Synthesis 1997, 625–
627.
19. Barret, R.;Daudon, M. Tetrahedron Lett. 1990, 31, 4871–
4872.
20. Chilin, A.;Pastorini, G.;Castellin, A.;Bordin, F.;
Rodighiero, P.;Guiotto, A. Synthesis 1995, 1190–1194.
21. Parker, K. A.;Su, D.-S. Potassium Nitrosodisulfonate. In
Encyclopedia of Reagents for Organic Synthesis;John
Wiley and Sons: Chichester, 1995;Vol. 6, pp 4271–4274.
22. DeJong, C. R. H. I.;Hageman, H. J.;Hoentjen, G.;Mus,
W. J. Org. Synth. 1988, Coll. Vol. 6, 412–413.
23. Parker, K. A.;Taveras, D. Salcomine. In Encyclopedia of
Reagents for Organic Synthesis;John Wiley and Sons:
Chichester, 1995;Vol. 6, pp 4423–4425.
Acknowledgements
We thank the EPSRC for funding, the EPSRC Mass
Spectrometry Centre at Swansea for mass spectra, the
EPSRC Chemical Database Service at Daresbury,32
and David Lofty and his colleagues at CEM Microwave
Technology Ltd. for their interest in our work.
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