Hydroperoxides and aryl diazonium salts as reagents for the functionalization of non-activated olefins

Article abstract of DOI:10.1016/j.tetlet.2010.01.098

Hydroperoxides, olefins, and arenediazonium salts selectively combine to give azo compounds via an iron(II)-mediated three-component reaction. Starting with a fragmentation liberating acetic acid, the hydroperoxides act as radical source and the diazonium ions as nitrogen-centered radical scavengers.

Full text of DOI:10.1016/j.tetlet.2010.01.098

Tetrahedron Letters 51 (2010) 1758–1760
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Hydroperoxides and aryl diazonium salts as reagents for the functionalization of
non-activated olefins
Olga Blank a, Nicole Raschke a, Markus R. Heinrich a,b,
*
a Organische Chemie 1, Technische Universität München, Lichtenbergstraße 4, 85747 Garching b. München, Germany
b Pharmazeutische Chemie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, 91052 Erlangen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Hydroperoxides, olefins, and arenediazonium salts selectively combine to give azo compounds via an iro-
n(II)-mediated three-component reaction. Starting with a fragmentation liberating acetic acid, the hydro-
peroxides act as radical source and the diazonium ions as nitrogen-centered radical scavengers.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 8 January 2010
Revised 25 January 2010
Accepted 26 January 2010
Available online 2 February 2010
Keywords:
Radical reactions
Hydroperoxides
Olefin functionalization
Arenediazonium salts
While aryl diazonium salts have been widely employed as
sources of aryl radicals in Meerwein,1 Gomberg–Bachmann,2
Pschorr,3 and Sandmeyer4 type reactions, their use and applicabil-
ity as nitrogen-centered radical scavengers has so far only been
marginally explored.5,6 Among the other known nitrogen-centered
radical scavengers, sulfonyl azides especially have proved to be
versatile and useful reagents in recent years.7
Our activities in the field of aryl radicals and aryl diazonium
salts began with the development of carbodiazenylation reactions
for the functionalization of non-activated olefins.8 By employing
aryl diazonium salts as aryl radical sources9 and nitrogen-centered
radical scavengers simultaneously, a broad range of olefinic sub-
strates can be converted into b-aryl azo compounds. The products
easily accessible by the previously developed procedures can serve
as valuable starting materials for ketones, hydrazones, amino acids,
and a broad range of heterocycles.
In this Letter, we present a new type of olefin functionalization
which is based on aryl diazonium salts acting as nitrogen-centered
radical scavengers only. For this purpose, the reaction conditions
had to be found, under which electrophilic radicals can be gener-
ated in the presence of olefinic substrates and diazonium ions.10
The electrophilic character of the initially formed radical is neces-
sary to ensure fast addition to non-activated olefins and to avoid
direct trapping of the radical by the diazonium ion.11 Due to the
pH-dependent reduction potential of iron(II) ions, most diazonium
ions are no longer reduced to aryldiazenyl radicals when the pH
value of the solution is slightly acidic, for example, by using acetic
acid as co-solvent. Despite the decreased reductive power, iron(II)
remains capable of cleaving hydroperoxides under the same condi-
tions.12 To explore the applicability of this principle, we investi-
gated the reaction shown in Scheme 1.
In the first step, hydroperoxide 2 was prepared by treatment of
ethyl 3-oxobutanoate (1) with hydrogen peroxide.13,14 The result-
ing solution was then added slowly to a mixture of diazonium salt
3, olefin 4 and iron(II)-sulfate in acetic acid, and water. The forma-
tion of product 5 can be rationalized by an iron(II)-induced cleav-
age of 2 and subsequent fragmentation of the oxyl radical 6 to give
O
R1
EtO2C
1
3
R1
H2O2,
H2SO4
N2 BF4
R2
4
OH
N
HO
O
N
FeSO4
R2
R2
EtO2C
EtO2C
EtO2C
EtO2C
2
5
Fe2+
3
HO
O
4
EtO2C
8
6
7
AcOH
* Corresponding author. Tel.: +49 9131 85 24115; fax: +49 9131 85 22585.
E-mail address: Markus.Heinrich@medchem.uni-erlangen.de (M.R. Heinrich).
Scheme 1. Iron(II)-mediated olefin functionalization with hydroperoxides and aryl
diazonium salts.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.098

O. Blank et al. / Tetrahedron Letters 51 (2010) 1758–1760
1759
Table 1
Table 3
Hydroperoxide 2 formation from ethyl-3-oxo-butanoate (1)
Application to various substrates
R1
H2O2,
R1
N
OH
O
HO
O
H2SO4
EtO2C
EtO2C
R2
conditions
1
2
R3
4a-i
FeSO4
N2 BF4
3a-e
OH
N
HO
O
Temperature
Reaction time (min)
H2O2 (equiv)
Yielda (2) (%)
EtO2C
R2
EtO2C
0 °C
rt
rt
rt
rt
rt
rt
rt
rt
120
10
1.5
1.0
4.0
1.0
2.0
3.0
1.5
4.0
8.0
16.0
2.0
10
5
9
R3
2
5a-m
10
60
60
60
Diazonium salt
Olefin 4
Product
Yielda
(%)
13
18
23
32
39
40
37
40b
3
5
R1
=
R2
CH2OAc
=
R3
=
120
120
120
120
30
p-OMe
p-COOMe
p-OMe
o-COOMe
p-OMe
H
p-OMe
p-OMe
p-OMe
p-OMe
p-OMe
p-F
3a
H
H
H
H
H
H
Me
Me
H
4a 5a
50
41
61
55
67
35
58
22
71
62
76
47
56
3bb CH2OAc
4a 5b
4b 5c
4b 5d
4c 5e
4c 5f
4d 5g
4e 5h
3a
3c
3a
3d
3a
3a
3a
3a
3a
3e
3a
CH2OH
CH2OH
(CH2)2OH
(CH2)2OH
CH2OH
rt
50 °C
Formation of hydroperoxide 2 from ketoester 1 determined by 1H NMR after
a
extraction with CDCl3.
OAc
OAc
b
Numerous by-products observed.
4f
5i
(CH2)4OH
(CH2)2COMe
(CH2)2COMe
2,5-
H
H
H
4g 5j
4h 5k
4h 5l
Table 2
p-OMe
4i
5m
Extraction of hydroperoxide
2
with different solvents for the synthesis of azo
Norbornadiene
compound 5a
a
Reaction carried out under the conditions described in the general procedure15
(1.25 equiv of diazonium salt 3a, c–e and 4 equiv of olefin 4a–i per hydroperoxide
2); yield based on hydroperoxide 2.
Diazonium salt 3b was used as sulfate without intermediate isolation. For a
detailed protocol, see Supplementary data.
OMe
b
OMe
3a
N2 BF4
OAc
4a
OH
N
it is often required in Sandmeyer or Meerwein protocols—was
not necessary when shifting from donor—to acceptor-substituted
diazonium salts. Sufficient polarity of the diazonium salt or aryl
radical appears to be beneficial, as is indicated by the compara-
tively low yield of product 5f (35%) obtained from unsubstituted
phenyldiazonium tetrafluoroborate. The formation of the tricyclic
azo compound 5m from 2,5-norbornadiene (4i) in 56% yield shows
that lipophilic olefins are well tolerated (Fig. 1).16
HO
O
N
FeSO4
EtO2C
OAc
EtO2C
2
5a
Extraction with Ketoester 1a (equiv) Olefin 4aa (equiv) Yield (%) Ab/Bc
(neat)
EtOAc
CH2Cl2
CH2Cl2
0.6
0.6
1.2
2.0
1.0
6.4
6.4
3.2
>90/26
>90/25
58/28
50/40
The synthesis of azo compound 5h is complicated by an unde-
sired single-electron transfer step (Fig. 1, Scheme 2).17 While the
intermediate radical 9, arising from the addition of radical 7 to
the isopropenyl acetate (4e), is usually trapped by diazonium ions
(to give 5h), 9 is oxidized by diazonium ion 3a to give cation 10 and
the aryldiazenyl radical 11. As a consequence, ethyl levulinate (12)
and azo compound 13 (formation via the carbodiazenylation se-
quence)8 were isolated from the reaction mixture (yields over
60%) along with only minor amounts of 5h (22%). The structural
modification from isoprenyl acetate (4e) to vinyl acetate (4f) ren-
ders the radical intermediate less reducible (compared to 9) and
leads to a good yield of the desired product 5i (71%).
a
b
c
Equivalents related to diazonium salt 3a.
Yield A based on hydroperoxide 2 (40% conversion from 1).
Yield B based on diazonium salt 3a.
acetic acid and 7. Addition of the electrophilic radical 7 to the ole-
finic substrate 4 and trapping of the nucleophilic adduct 8 by a dia-
zonium ion 3 lead to the desired product 5 via a final reductive
step.
The following series of experiments was carried out to investi-
gate the hydroperoxide formation from ethyl 3-oxobutanoate (1)
(Table 1).
In conclusion, we have shown that a-acetic acid ester radicals can
be generated from ethyl 3-oxobutanoate via hydroperoxides under
slightlyreductiveconditions whichdo notleadto the decomposition
The best ratio in favor of the desired hydroperoxide 2 with no
by-products observable by 1H NMR spectroscopy was obtained
within 2 h reaction time using 8.0 equiv of aqueous hydrogen per-
oxide at room temperature. In the next step, the hydroperoxide 2
was added to a mixture of the olefin, the diazonium salt, and iro-
n(II)-sulfate in aqueous acetic acid. Preliminary experiments with
4-methoxyphenyldiazonium tetrafluoroborate (3a) and allyl ace-
tate (4a) revealed that the best results are obtained by intermedi-
ate extraction of the hydroperoxide 2 from its acidic aqueous
solution with dichloromethane (Table 2).
OMe
OMe
N
N
N
EtO2C
N
The optimized conditions15 were then applied to a range of ole-
fins and diazonium salts (Table 3).
With most substrate combinations, synthetically useful yields
of the products 5 were obtained. An adjustment of conditions—as
EtO2C
OAc
5m (56%)
5h (22%)
Figure 1. Azo compounds 5h and 5m.

1760
O. Blank et al. / Tetrahedron Letters 51 (2010) 1758–1760
Fe2+
3. For a first report, see: Pschorr, R. Chem. Ber. 1896, 29, 496–501.
4e
3a
Fe2+
EtO2C
OAc
Ar
7
5h
2
4. For a review on Sandmeyer reactions, see: (a) Minisci, F.; Fontana, F.; Vismara,
E. Gazz. Chim. Ital. 1993, 123, 9–18; (b) Merkushev, E. B. Synthesis 1988, 923–
937.
5. For a first report, see Al Adel, I.; Salami, B. A.; Levisalles, J.; Rudler, H. Bull. Soc.
Chim. Fr. 1976, 934–938.
6. (a) Citterio, A.; Minisci, F.; Albinati, A.; Bruckner, S. Tetrahedron Lett. 1980, 21,
2909–2910; (b) Packer, J. E.; Heighway, C. J.; Muller, H. M.; Dobson, B. C. Aust. J.
Chem. 1980, 13, 965–977; (c) Citterio, A.; Minisci, F. J. Org. Chem. 1982, 47,
1759–1761.
7. (a) Ollivier, C.; Renaud, P. J. Am. Chem. Soc. 2000, 122, 6496–6497; (b) Ollivier,
C.; Renaud, P. J. Am. Chem. Soc. 2001, 123, 4717–4727; (c) Panchaud, P.; Renaud,
P. J. Org. Chem. 2004, 69, 3205–3207; (d) Panchaud, P.; Ollivier, C.; Renaud, P.;
Zigmantas, S. J. Org. Chem. 2004, 69, 2755–2759; (e) Chabaud, L.; Landais, Y.;
Renaud, P. Org. Lett. 2005, 7, 2587–2590; (f) Nyfeler, E.; Renaud, P. Org. Lett.
2008, 10, 985–988; (g) Chabaud, L.; Landais, Y.; Renaud, P.; Robert, F.; Castet, F.;
Lucarini, M.; Schenk, K. Chem. Eur. J. 2008, 14, 2744–2756; (h) Godineau, E.;
Landais, Y. Chem. Eur. J. 2009, 15, 3044–3055.
- AcOH
9
+
Ar N2
3a
N2
EtO2C
EtO2C
OAc
10
12
11
3a, 4e - N2
N
Ar
O
Ar
N
OAc
13
Ar = 4-MeOC6H4
8. (a) Heinrich, M. R.; Blank, O.; Wölfel, S. Org. Lett. 2006, 8, 3323–3325; (b)
Heinrich, M. R.; Blank, O.; Wetzel, A. J. Org. Chem. 2007, 72, 476–484.
9. Cao, L.; Li, C. Tetrahedron Lett. 2008, 49, 7380–7382.
Scheme 2. Formation of ethyl levulinate (12) and azo compounds 5h and 13.
10. Elofson, R. M.; Gadallah, F. F. J. Org. Chem. 1969, 34, 854–857.
11. For polarity effects in radical diazonium trapping reactions, see: (a) Citterio, A.;
Minisci, F.; Vismara, E. J. Org. Chem. 1982, 47, 81–88; (b) See also Ref. 6c.
12. (a) Walling, C. Acc. Chem. Res. 1975, 8, 125–131; (b) Schreiber, S. L. J. Am. Chem.
Soc. 1980, 102, 6163–6165; (c) Dichtl, A.; Seyfried, M.; Schoening, K.-U. Synlett
2008, 12, 1877–1881.
13. (a) Minisci, F.; Galli, R.; Cecere, M.; Malatesta, V.; Caronna, T. Tetrahedron Lett.
1968, 54, 5609–5612; (b) See also Ref. 6c.
14. For a synthesis of hydroperoxides from ozonides, see: Schreiber, S. L.; Liew, W.-
F. J. Am. Chem. Soc. 1985, 107, 2980–2982.
15. Representative procedure for the preparation of compounds 5a,c–m: Preparation
of the hydroperoxide 2. To a mixture of ethyl 3-oxobutanoate (0.63 mL, 0.65 g,
5.0 mmol) and aqueous hydrogen peroxide (35% solution, 3.4 mL, 40 mmol)
was added one drop of 50% sulfuric acid. After stirring at room temperature for
2 h, satd aqueous sodium chloride (2 mL) was added and the resulting mixture
was extracted twice with dichloromethane (2 Â 5 mL). The combined organic
of radical aryldiazonium ions. In this way, a new type of multicom-
ponent olefin functionalization was developed, in which diazonium
ions serve as highly effective and selective nitrogen-centered radical
scavengers.7h Compared with our previously reported procedure,
which was based on iodine transfer,18a,19 the new protocol does
not rely on diazonium ions as radical sources and does not therefore
produce iodobenzenes as by-products. Only non-toxic reagents
were used and the excess olefin and ketoester—the latter resulting
from the hydroperoxide equilibrium—were recovered by distillation
in vacuo. The method has been shown to be applicable to a range of
non-activated olefins and not to be sensitive to electron-donating or
electron-withdrawing substituents on the aromatic core of the dia-
zonium ions. The structurally diverse azo compounds, which are
phases were concentrated under reduced pressure to
a volume of 2 mL
containing ca. 2 mmol of hydroperoxide 2. 1H NMR analysis of several samples
extracted with CDCl3 had shown a 3:2 ratio of hydroperoxide 2 to ethyl 3-
oxobutanoate (1) which corresponds to a 40% conversion of 1. Hydroperoxide
2: 1H NMR (CDCl3, 360 MHz) d 1.29 (t, J = 7.1 Hz, 3H), 1.54 (s, 3H), 2.86 (s, 2H),
4.21 (q, J = 7.1 Hz, 2H). Since organic peroxides are flammable and potentially
explosive materials they should not be prepared in large quantities.
accessible from this simple sequence, can serve as precursors of c-
amino acids (by reductive N–N bond cleavage), numerous heterocy-
cles (including pyrroles and indoles) and functionalized
tricyclanes.8,18b
Olefin functionalization. To a mixture of diazonium salt 320 (2.5 mmol) and
olefin
4 (8.0 mmol) in water (6 mL) and acetic acid (2 mL) was added
Acknowledgments
FeSO4Á7H2O (4.17 g, 20.0 mmol). The previously prepared hydroperoxide
solution (2 mmol in 2 mL CH2Cl2) was added dropwise by a syringe over
10 min. After stirring for 15 min, water (50 mL) was added and the mixture
was extracted with CH2Cl2 (3 Â 75 mL). The combined organic phases were
washed with satd aqueous sodium chloride and dried over sodium sulfate.
Excess olefin and ethyl 3-oxobutanoate (1) were removed in vacuo and the
product 5 was purified by flash chromatography on silica gel. Analytical data for
compound 5a: Rf 0.60 (pentane/EtOAc 2:1); IR:
(vs), 1603 (m), 1587 (w), 1513 (s), 1443 (w), 1420 (w), 1367 (w), 1247 (vs),
1179 (s), 1146 (s), 1104 (w), 1031 (s), 840 (s) cmÀ1 1H NMR (C6D6, 250 MHz): d
This project was financed by the Fonds der Chemischen Industrie
(Liebig habilitation fellowship). We are thankful to the Aus-
bildungszentrum (N.R.) of the Technische Universität München.
The generous help and support of Professor Dr. Thorsten Bach
and his group are gratefully acknowledged. We would also like
to thank Dr. Werner Spahl (LMU München) for HR-ESI analysis.
mꢀ = 2978 (w), 2836 (w), 1732
;
0.90 (t, J = 7.1 Hz, 3H), 1.55 (s, 3H), 1.92-2.06 (m, 1H), 2.09-2.27 (m, 3H), 3.17
(s, 3H), 3.88 (q, J = 7.1 Hz, 2H), 3.99 (m, 1H), 4.34 (dd, J = 4.2 Hz, J = 11.4 Hz, 1H),
4.58 (dd, J = 8.0 Hz, J = 11.4 Hz, 1H), 6.67 (d, J = 9.0 Hz, 2H), 7.81 (d, J = 9.0 Hz,
2H); 13C NMR (C6D6, 62.9 MHz) d 14.2 (CH3), 20.2 (CH3), 25.6 (CH2), 30.6 (CH2),
54.9 (CH3), 60.2 (CH2), 65.2 (CH2), 75.1 (CH), 114.3 (2 Â CH), 124.8 (2 Â CH),
146.6 (Cq), 162.3 (Cq), 169.9 (CO), 172.2 (CO); MS (ESI) [M++H] 323; HRMS (ESI)
C16H23N2O5 [M++H] calcd: 323.1602, found: 323.1591.
Supplementary data
Supplementary data (experimental procedures, analytical data
and NMR spectra are available for all new compounds) associated
with this article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.01.098.
16. (a) Giese, B.; Jay, K. Chem. Ber. 1977, 110, 1364–1376; (b) Giese, B.; Jay, K. Chem.
Ber. 1979, 112, 298–303.
17. (a) Minisci, F.; Coppa, F.; Fontana, F.; Pianese, G.; Zhao, L. J. Org. Chem. 1992, 57,
3929–3933; (b) Molinaro, C.; Mowat, J.; Gosselin, F.; O’Shea, P. D.; Marcoux, J.-
F.; Angelaud, R.; Davies, I. W. J. Org. Chem. 2007, 72, 1856–1858.
18. (a) Blank, O.; Heinrich, M. R. Eur. J. Org. Chem. 2006, 4331–4334; (b) Blank, O.;
Wetzel, A.; Ullrich, D.; Heinrich, M. R. Eur. J. Org. Chem. 2008, 3179–3189.
19. For a review on radical atom and group transfer reactions, see: Byers, J., first
ed.. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH:
Weinheim, 2001; vol. 1, pp 72–89.
References and notes
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1939, 152, 237–266; For a recent review, see: (b) Heinrich, M. R. Chem. Eur. J.
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W. J. Org. Chem. 1984, 49, 1594–1603.
20. For the preparation of aryl diazonium salts, see Ref. 8b.