Curtius rearrangement and Wolff homologation of functionalized peroxides

Article abstract of DOI:10.1016/j.tetlet.2004.08.059

The Curtius and Wolff rearrangements of peroxide-containing alkanoyl azides and diazoketones provide an efficient entry to peroxy-substituted amines, isocyanates, carbamates, and peroxyalkanoates.

Full text of DOI:10.1016/j.tetlet.2004.08.059

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7455–7457
Curtius rearrangement and Wolff homologation of
functionalized peroxides
Patrick H. Dussault* and Chunping Xu
Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0304, USA
Received 2 July 2004; revised 1 August 2004; accepted 9 August 2004
Available online 27 August 2004
Abstract—The Curtius and Wolff rearrangements of peroxide-containing alkanoyl azides and diazoketones provide an efficient entry
to peroxy-substituted amines, isocyanates, carbamates, and peroxyalkanoates.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
O
C
N
O
ROO
NH2
n
Synthetic approaches to peroxides are typically con-
strained by the limited methodology available for intro-
duction of the peroxide functional group.1 For example,
our recent investigations into redox-based enzyme inacti-
vators2 required preparation of 2-peroxyl and 3-perox-
ylalkylamines, poorly explored functional motifs.3 We
now report the successful Curtius rearrangement of per-
oxyalkanoyl azides as a method for synthesis of peroxy-
substituted isocyanates, amines, and carbamates. In
addition, we discovered that the corresponding Wolff
rearrangement of peroxide-containing diazoketones pro-
vides a very effective method for homologation of peroxy-
alkanoates (Scheme 1).
ROO
ROO
N3
n
n
O
ROO
ROO
OH
n
O
C
O
ROO
CO2Me
n+1
N2
ROO
CH
n
n
Scheme 1. Curtius and Wolff rearrangements on peroxidic substrates.
Preparation of peroxyalkanoic acid substrates is
illustrated in Scheme 2. The synthesis of substrate 4a
includes the first example of acid-catalyzed intermolecu-
lar reaction of a hydroperoxide with a secondary epox-
ide, a reaction that was found to proceed with only
moderate regioselectivity in favor of the more substi-
tuted peroxide.4
O
O
O O
a,b
OH
1a
OH
50%
OOt-Bu
2a
Br
OO-tBu
CO2H
OO-tBu
OH
e
c,d
98%
75%
3a
OO-tBu
OO-tBu
d
e
O
73%
hexyl
CO2H
95%
Keywords: Peroxide; Curtius; Wolff; Peroxyalkanoate.
*
hexyl
Corresponding author. Tel.: +1 402 4723634; fax: +1 402 4722044;
e-mail: pdussault1@unl.edu
4a
OH
Scheme 2. Substrate preparation. Reagents and conditions: (a)
t-BuO2H, CsOH; (b) KMnO4; (c) m-CPBA; (d) t-BuO2H, BF3OEt2;
(e) H2CrO4.
All new compounds were purified to homogeneity and characterized
by 1H, 13C, IR, and HRMS, except for 1d–4d, where no molecular
ions were observed.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.059

7456
P. H. Dussault, C. Xu / Tetrahedron Letters 45 (2004) 7455–7457
Table 2. Homologation via diazoketones
2. Curtius rearrangements
O
C
O
C
H
H
c or d
a or b
Conversion of the peroxyalkanoic acids to acyl azides was
readily achieved via the mixed anhydrides, with the excep-
tion of the hindered acid 3a, which required activation as
the acid chloride (Table 1).5 The azides were stable to
extractive isolation but decomposed upon attempted puri-
fication. Heating the crude azides with ethanol in refluxing
benzene directly furnished the ethyl carbamates 1b, 2b,
and 4b as stable products. In the case of the hindered azide
derived from 3a, thermolysis resulted in decomposition
with loss of the peroxide functional group.6
R
CHN2
R
CO2Me
R
OH
R
Diazoketone
Ester
1a
2a
t-BuOO(CH2)3
a
a
1c (78%)
1d (99%)
2d (99%)
O O
2c (82%)
3c (75%)
4c (70%)
OOt-Bu
3a
4a
b
a
3d (75%)
4d (83%)
We also briefly investigated aprotic thermolysis of an
azide as an approach to a peroxide-containing isocyan-
ate. Refluxing the acyl azide derived from 2a in dry ben-
zene furnished a dioxolane isocyanate, which was not
isolated but which could be observed by IR (Scheme
3). Hydrolysis of the isocyanate in aqueous acid fur-
nished the aminomethyl dioxolane 5, which underwent
coupling with CBZ-Phe to furnish a peroxide-containing
amino acid 6.
hexyl
t-BuOO
(a) EtOC(O)Cl then CH2N2; (b) ClCOCOCl then CH2N2; (c) AgOBz
(0.1equiv), Et3N, MeOH; (d) hm, MeOH, HOAc.
rangement for preparation of peroxyalkanoates, a func-
tional motif found in
a
number of marine
natural products.7 As shown in Table 2, the peroxyalk-
anoic acids were easily converted, via the mixed anhy-
drides or the acid chlorides, to isolable diazomethyl
ketones. Reaction of diazoketones 1c or 2c with silver
benzoate and triethylamine in methanol furnished the
homologated peroxyalkanoates 1d or 2d in excellent
yield.8
3. Wolff rearrangement
The success of the Curtius rearrangements described
above led us to consider the potential of the Wolff rear-
Table 1. Curtius rearrangement of peroxylalkanoyl azides
O
C
O
C
Application of these conditions to substrate 4c resulted
in a poor yield of homologated product, accompanied
by significant amounts of the oxodiazoketone, appar-
ently derived from base-promoted decomposition of
the starting material (Eq. 1).9 Photochemical Wolff rear-
rangement (254nm, methanol) furnished a much better
yield of the homologated peroxyalkanoate 4d, accompa-
nied by small amounts of 2,3-epoxynonanoate, which
presumably arises via intramolecular attack of a devel-
oping ester enolate on the peroxide. Performing the pho-
tochemical rearrangement in the presence of a trace
amount of acetic acid resulted in an improved yield of
peroxyalkanoate. The tertiary peroxide substrate 3c,
which failed to give any homologation product in the
presence of AgOBz/Et3N, underwent photochemical
rearrangement to afford peroxyalkanoate 3d.
c
a or b
RNHCO2Et
R
R
OH
N3
R
Method
a
Carbamate
Yield (%)
47
t-BuOOðCH2Þ3ꢀ
1a
2a
1b
a
b
a
2b
55
—
60
O O
OOt-Bu
3a
4a
—
hexyl
4b
t-BuOO
(a) EtOC(O)Cl then NaN3; (b) (ClCO)2 then NaN3; (c) EtOH, ben-
zene, reflux.
ð1Þ
O O
a,b
c
2a
OCN
d
In conclusion, we have demonstrated the ability to
employ the Curtius and Wolff rearrangements for syn-
thesis of peroxylamines or homologated peroxyalkano-
ates. The ability to homologate 2- and 3-peroxyalkanoic
acids holds particular promise for synthesis of peroxide
natural products while the ability to perform the Curtius
rearrangement opens new possibilities for the introduc-
tion of natural or unnatural peroxide-containing groups
onto polymers and biomolecules.
Ph
O
O O
O O
H
Cbz
N
H2N
N
H
5
6
Scheme 3. Synthesis of dioxolane isocyanate and aminomethyl dioxo-
lane. Reagents and conditions: (a) EtOC(O)Cl then NaN3; (b) C6H6,
reflux; (c) aq HCl; (d) CBZ-Phe, DCC.

P. H. Dussault, C. Xu / Tetrahedron Letters 45 (2004) 7455–7457
7457
S., Greenberg, A., Liebman, J. F., Eds.; Blackie A&P:
London, 1995; pp 141–203.
4. Caution
2. Dussault, P. H.; George, A. D.; Trullinger, T. K. Bioorg.
Med. Chem. Lett. 1999, 9, 3255–3258.
While we experienced no particular problems, any re-
search involving peroxides, azides, and similar func-
tional groups should be conducted with appropriate
3. Brunker, H.-G.; Adam, W. J. Am. Chem. Soc. 1995, 117,
¨
3976–3982; Murahashi, S.-i.; Naota, T.; Kuwabara, T.;
Saito, T.; Kumobayashi, H.; Akutagawa, S. J. Am. Chem.
Soc. 1990, 112, 7820–7822.
precautions
decomposition.
against
spontaneous
exothermic
4. Intermolecular reactions of tertiary epoxides are well
established: Richardson, W. H.; Smith, R. S. J. Org. Chem.
1968, 33, 3882–3885; Higuchi, Y.; Matsuyama, K.; Komai,
T. Bull. Chem. Soc. Jpn. 1988, 61, 1821–1823.
5. Shioiri, T. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1988; Vol. 6, pp
795–828.
6. Smith, L. L.; Hill, F. L. J. Chromatogr. 1972, 66, 101–109.
7. Casteel, D. A. Nat. Prod. Rep. 1999, 16, 55–73.
8. Kirmse, W. Eur. J. Org. Chem. 2002, 2193–2256.
9. Kropf, H.; Nurnburg, W. In Methods in Organic Chemistry:
Organische Peroxo-Verbindungen; Kropf, H., Ed.; George
Thieme Verlag: Stuttgart, 1988; Vol. E13, pp 1068–1084;
Jefford, C. W.; Rossier, J. C.; Boukouvalas, J. J. Chem.
Soc., Chem. Commun. 1986, 1701–1702.
Supplementary data
Experimental procedures and spectral listings for new
compounds. Supplementary data associated with this
article can be found, in the online version, at
doi:10.1016/j.tetlet.2004.08.059.
References and notes
1. Organische Peroxo-Verindungen; Kropf, H., Ed.; Georg
Thieme Verlag: Stuttgart, 1988; Dussault, P. H. In Active
Oxygen in Chemistry; Dussault Foote, C. S., Valentine, J.