A mild oxidative aryl radical addition into alkenes by aerobic oxidation of arylhydrazines

Article abstract of DOI:10.1002/chem.201003060

A mild and practical oxyarylation of alkenes by oxidative radical addition has been developed by using aerobic oxidation of hydrazine compounds. The use of a catalytic amount of potassium ferrocyanide trihydrate (K₄[Fe(CN) ₆]·3 H₂O) and water accelerated this radical reaction to give peroxides or alcohols from simple alkenes in good yields. The environmentally friendly and economical radical reactions were achieved at room temperature in the presence of iron catalyst, oxygen gas, and water. A method involving aniline as a radical precursor is also described. Copyright

Full text of DOI:10.1002/chem.201003060

FULL PAPER
DOI: 10.1002/chem.201003060
A Mild Oxidative Aryl Radical Addition into Alkenes by Aerobic Oxidation
of Arylhydrazines
Tsuyoshi Taniguchi,* Hisaaki Zaimoku, and Hiroyuki Ishibashi[a]
Abstract: A mild and practical oxyary-
lation of alkenes by oxidative radical
addition has been developed by using
aerobic oxidation of hydrazine com-
pounds. The use of a catalytic amount
of potassium ferrocyanide trihydrate
(K4[Fe(CN)6]·3H2O) and water acceler-
ated this radical reaction to give perox-
ides or alcohols from simple alkenes in
good yields. The environmentally
friendly and economical radical reac-
tions were achieved at room tempera-
ture in the presence of iron catalyst,
oxygen gas, and water. A method in-
volving aniline as a radical precursor is
also described.
Keywords: iron · oxygen · perox-
ides · radical reactions · water
Introduction
ported copper-mediated addition of an aryl radical formed
from arylhydrazines to electron-withdrawing olefins.[5] Sever-
al examples of aryl–aryl coupling reactions that are per-
formed in the presence of Pd0, HgII, or MnIII as an oxidant,
have also been reported.[6] Myers and co-workers have re-
ported the generation of an alkyl radical by treatment of al-
cohols with p-nitrobenzenesulfonylhydrazine under Mitsu-
nobu conditions.[7] The addition of an aryl radical generated
from diazonium salts to alkenes (Meerwein arylation) has
also been reported.[8] However, many of these radical reac-
tions still have some limitations, such as the use of an excess
amount of toxic transition metals.
À
Radical reactions have been used as powerful tools for C C
bond formation in synthetic chemistry.[1] As well as classical
tin-mediated radical reactions, many useful radical reactions
based on new concepts have recently been reported.[2]
Hydrazines have been reported to generate radical species
by treatment with an oxidant, such as oxygen or metallic
compounds, through the formation of diazenes (diimides)
[Scheme 1, Eq. (1)].[3] Corey and Gross reported the forma-
tion of tert-butyl radicals by PbIV-mediated oxidation of tert-
butylhydrazine and the reaction of the radical with nitroso
compounds, providing a new preparation of N,O-di-tert-
butyl hydroxylamines.[4] Asensio and co-workers have re-
Recently, iron has received attention as an inexpensive,
less toxic substitute for rare metals such as palladium, and
À
many efficient iron-catalyzed reactions such as C C bond
formation, have been developed.[9] Several iron-mediated
radical reactions have also been reported.[10] Herein, we
report an environmentally friendly potassium ferrocyanide
trihydrate (K4[Fe(CN)6]·3H2O) promoted aryl radical addi-
tion and subsequent aerobic oxidation of alkenes through
the use of arylhydrazines in the presence of water
[Scheme 1, Eq. (2)].[11–13]
Results and Discussion
Treatment of a mixture of a-methylstyrene (1a) and phenyl-
hydrazine (2a) (2.0 equiv) with oxygen gas[3a] in water for
33 h and subsequent reduction of the resultant peroxide 3a
by treatment of the reaction mixture with a 10% solution of
Na2S2O3 and PPh3 (1 equiv), gave tertiary alcohol 4a in
51% yield (Table 1, entry 1). When the reaction was carried
out in the presence of a catalytic quantity (10 mol%) of po-
tassium ferrocyanide(II) trihydrate, the reaction time was
shortened (from 33 to 7.5 h) and the yield of 4a was signifi-
cantly improved (from 51 to 81%) (Table 1, entry 2). The
Scheme 1. Radical generation from hydrazine compounds.
[a] Dr. T. Taniguchi, H. Zaimoku, Prof. Dr. H. Ishibashi
School of Pharmaceutical Sciences
Institute of Medical, Pharmaceutical
and Health Sciences
Kanazawa University
Kakuma-machi, Kanazawa 920-1192 (Japan)
Fax : (+81)76-234-4439
E-mail: tsuyoshi@p.kanazawa-u.ac.jp
reaction using potassium ferricyanideACHTNUTRGENNG(U III) (K3[Fe(CN)6]), as
a catalyst afforded no improved yield compared to that
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003060.
Chem. Eur. J. 2011, 17, 4307 – 4312
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4307

Table 1. Optimization of reaction conditions.
Entry
2a
[equiv]
[Fe]
ACHTUNGTRNE(NUNG mol%)
Solvent
Time
[h]
Yield
[%][a]
U
1
2
2.0
2.0
2.0
2.0
2.0
1.2
3.0
2.0
2.0
2.0
none
10
10
10
10
10
10
20
5
H2O
H2O
H2O
DMF
MeOH
H2O
H2O
H2O
H2O
H2O
33
7.5
6
8
16
8
10
11
9.5
24
51
81
71
48
–
63
88
82
75
69
3[b]
4
5
6
7
8
9
10[c]
10
Scheme 3. Plausible mechanism of oxyarylation.
[a] Isolated yield of 4a. [b] K3[Fe(CN)6] was employed instead of
K4[Fe(CN)6]·3H2O. [c] Under air.
ates this reaction (Table 1, entry 2).[16] Hence, it is
reasonable that the iron catalyst accelerates the oxidation of
phenylhydrazine (2a).[17] Because phenyldiazene (6) is
known to be rapidly oxidized by O2,[18] it is thought that the
rate-determining step in the oxidation of phenylhydrazine is
the first single-electron oxidation step. Therefore, single-
electron transfer between phenylhydrazine (2a) and an iron
catalyst would certainly take place to give phenylhydrazyl
radical (5) in the initiating step.[19] Because radical species 5
would be expected to have high reactivity, radical 5 would
be rapidly oxidized into phenyldiazene (6) by O2.[19] As de-
scribed above, phenyldiazene (6) is rapidly oxidized to the
diazenyl radical 7 by O2, and phenyl radical 8 is formed
from radical 7 with release of molecular nitrogen.[18,19] Addi-
tion of phenyl radical 8 to a-methylstyrene (1a), followed
by coupling of the resultant radical intermediate 9 with O2
gives the peroxy radical 10. Finally, redox reaction between
hydrogen peroxide radical 11, generated by the reduction of
O2 or peroxy radical 10, and the FeII species, leads to the
production of peroxide 3a or hydroperoxide (H2O2) and re-
generation of the FeIII species.[20] Improvement in the yield
of the product by using water as a solvent can be explained
by the hydrophobic effect. The concentration of generated
phenyl radical 8 and alkene 1a by its hydrophobic nature in
water might promote the radical addition reaction.[21]
using ferrocyanide(II) (Table 1, entry 3). The use of N,N-di-
methylformamide (DMF) instead of water as a solvent gave
an unsatisfactory result (Table 1, entry 4), and the use of
methanol caused decomposition of the substrate or product
(Table 1, entry 5).[14] Decreasing or increasing the amount of
2a resulted in only slight changes in yield (Table 1, entries 6
and 7). No significant change was observed by employing
20 mol% or 5 mol% iron catalyst (Table 1, entries 8 and 9).
It was also found that a similar reaction using air instead of
oxygen gas required prolonged reaction time (Table 1,
entry 10).
When phenylhydrazine hydrochloride (2a’) was used as a
radical precursor in the presence of K2CO3, a similar reac-
tion took place to give alcohol 4a in good yield [Scheme 2,
Eq. (1)]. Peroxide product 3a was readily isolated in good
yield when PPh3 was not present to reduce peroxide 3a into
alcohol 4a [Scheme 2, Eq. (2)].[15]
Various hydrazines 2 were then subjected to the reaction
with a-methylstyrene (1a). Arylhydrazines 2b–d, bearing a
halogen atom on the 4-position of the aromatic ring, gave
products 4b–d in good yields (Table 2, entries 2–4). The re-
action of arylhydrazines 2e–g, bearing an electron-donating
group at either the 4- or 3-position of the aromatic ring,
gave the corresponding alcohols 4e–g in good yields
(Table 2, entries 5–7), whereas 2-methylphenylhydazine (2h)
gave a lower yield of product 4h due to steric effects
(Table 2, entry 8). Arylhydrazines 2i and 2j, bearing 4-tri-
fluoro and 4-nitro groups on the aromatic ring, were insolu-
ble in water and, hence, DMF was used as a solvent to give
the desired products 4i and 4j, respectively (Table 2, en-
tries 9 and 10).[22] The reaction of aliphatic hydrazine 2k was
found to be very sluggish (Table 2, entry 11).
Scheme 2. The reaction using phenylhydrazine hydrochloride salt 2a’ and
isolation of peroxide 3a.
A plausible mechanism for the formation of hydroperox-
ide 3a from a-methylstyrene (1a) by oxidation of phenylhy-
drazine (2a) is shown in Scheme 3. Although the present re-
action proceeds slowly with only O2 (Table 1, entry 1),[3] ex-
perimental results indicate that the addition of an iron cata-
lyst that is a stronger oxidant than O2 significantly acceler-
4308
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Chem. Eur. J. 2011, 17, 4307 – 4312

Oxidative Aryl Addition into Alkenes
FULL PAPER
Table 2. Radical reactions of various hydrazines.
Table 3. Radical reactions of various alkenes.
Entry
R
Time
[h]
Yield
[%][a]
Entry
1
Time Product[a]
[h]
Yield
[%]
1
Ph
4-FC6H4
a
b
c
d
e
f
g
h
i
7.5
9
10
8
4
9
14
6
20
11
18
81
81
71
61
74
71
70
47
59
70
41
2[b]
3[b]
4[b]
5[b]
6[b]
7[b]
8[b]
9[c]
4-ClC6H4
4-BrC6H4
4-MeOC6H4
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-CF3C6H4
4-NO2C6H4
cyclohexyl
1
2
3
4
Ar=C6H5
1a 7.5
81
80
85
78
Ar=4-MeOC6H4 1b
Ar=4-NO2C6H4
Ar=4-BrC6H4
9
1c 10
1d 11
5
6
1e
1 f
9
7
56
82
10[c]
11[b,d]
j
k
[a] Isolated yield of 4a–k. [b] Hydrazine hydrochloride salt was used with
K2CO3 (3 equiv). [c] DMF was used as solvent. [d] 2k (4 equiv) was used
at 508C.
7
1g
8
53
8
9
1h 11
75
51
Reactions of various alkenes 1 with phenylhydrazine (2a)
were then examined. a-Methylstyrene derivatives 1b–d,
bearing methoxy, nitro, and bromo groups on the aromatic
ring, gave alcohols 13b–d in good yields (Table 3, entries 2–
4). The reaction of styrene (1e) gave secondary alcohol 13e,
although the yield was moderate (Table 3, entry 5). Other
styrene-type alkenes 1 f–j also gave the corresponding terti-
ary alcohols 13 f–j in good to moderate yields (Table 3, en-
tries 6–10). In the case of addition of the phenyl radical to
1h, opening of the cyclopropane ring was not observed due
to the stability of the resultant radical.[23] When diene 1k
was employed as a substrate, tertiary alcohol 13k was ob-
tained along with an equal amount of the regioisomer 13k’
(Table 3, entry 11). Reaction of enyne 1l readily proceeded
to give propargyl alcohol 13l in good yield (Table 3,
entry 12). Reactions of nonconjugated alkenes 1m–o were
sluggish and gave the corresponding alcohols 13m–o in
moderate yields (Table 3, entries 13–15). a,b-Unsaturated
esters 1p and 1q also gave a-hydroxyesters 13p and 13q, re-
spectively (Table 3, entries 16 and 17). In these cases, no Mi-
chael addition product with phenylhydrazine (2a) was de-
tected. Unfortunately, the reaction of methacrylic ester 1r,
bearing a chiral auxiliary, showed no diastereoselectivity
(Table 3, entry 18).[24]
1i
8
37
(2:1)
10
11
1j
9
7
26
(13k)
25
1k
(13k’)
12
1l 12
82
13[b]
14[c]
15[b]
1m 11
1n 19
1o 26
31
52
30
16
17
1p
1q
6
7
63
40
(2:1)
66
(1:1)
18
1r
8
When radical clock 14 was employed as a substrate, ho-
moallyl alcohol 16 was obtained (Scheme 4). This strongly
suggests that cyclopropylmetylene radical A, generated by
addition of phenyl radical, undergoes a ring-opening reac-
tion to give benzyl radical B, followed by trapping by O2 to
afford peroxide 15.[23] Therefore, there is no doubt that the
present reaction proceeds by a radical mechanism.
[a] Yield of isolated product. [b] Compound 2a (10 equiv) was used.
TBDPS=tert-butyldiphenylsilyl.
to give alcohol 4a in good yield after reduction of the corre-
sponding hydroperoxide 3a with PPh3 (Scheme 5).
Finally, we found that the present reaction proceeded by
formation of arylhydrazines in situ from aromatic amines
with hydroxylamine-O-sulfonic acid. A mixture of 1a and
aniline (17) (2 equiv) was treated with hydroxylamine O-sul-
fonic acid (5 equiv) in water, in the presence of an iron cata-
lyst and potassium carbonate, under an oxygen atmosphere,
Conclusion
We have developed the oxidative arylation of alkenes by
oxygen-mediated formation of aryl radicals from arylhydra-
Chem. Eur. J. 2011, 17, 4307 – 4312
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4309

T. Taniguchi et al.
organic layer was washed successively with brine and dried with MgSO4.
After removal of the solvent under reduced pressure, the residue was pu-
rified by silica gel chromatography (hexane/EtOAc) to give the desired
product.
General procedure for reactions using aryl hydrazine hydrochloride salts:
Phenylhydrazine hydrochloride (145 mg, 1.0 mmol) and K2CO3 (207 mg,
1.5 mmol) were added to
a mixture of alkene (0.50 mmol) and
K4[Fe(CN)6]·3H2O (21.0 mg, 0.050 mmol) in water (5 mL), and the mix-
ture was vigorously stirred at room temperature under an O2 atmosphere
(1 atm). After addition of 10% aqueous Na2S2O3 (5 mL), PPh3 (131 mg,
0.50 mmol) was added and the mixture was extracted with CH2Cl2. The
organic layer was washed successively with brine and dried with MgSO4.
After removal of solvent under reduced pressure, the residue was puri-
fied by silica gel chromatography (hexane/EtOAc) to give the desired
product.
Scheme 4. Radical oxyarylation of 14.
Procedure for the reaction with aniline: Aniline (93.1 mg, 1.0 mmol),
K2CO3 (760 mg, 5.5 mmol), and hydroxylamine O-sulfonic acid (283 mg,
2.5 mmol) were added to a mixture of 1a (59.1 mg, 0.50 mmol) and
K4[Fe(CN)6]·3H2O (21.0 mg, 0.050 mmol) in water (5 mL), and the mix-
ture was vigorously stirred at room temperature under an O2 atmosphere
(1 atm) for 28 h. After addition of 10% aqueous Na2S2O3 (5 mL), PPh3
(131 mg, 0.50 mmol) was added and the mixture was extracted with
CH2Cl2. The organic layer was washed successively with brine and dried
with MgSO4. After removal of solvent under reduced pressure, the resi-
due was purified by silica gel chromatography (hexane/EtOAc, 10:1) to
give 4a (88.9 mg, 84%).
Compound 4a: 81% yield; colorless oil; 1H NMR (500 MHz, CDCl3):
d=1.55 (s, 3H), 1.87 (s, 1H), 3.01 (d, J=12.7 Hz, 1H), 3.12 (d, J=
12.7 Hz, 1H), 6.97–6.99 (m, 2H), 7.17–7.25 (m, 4H), 7.30–7.33 (m, 2H),
7.37–7.40 ppm (m, 2H); 13C NMR (125 MHz, CDCl3): d=29.4, 50.5, 74.4,
125.0, 126.61, 126.62, 128.0, 130.6, 136.7, 147.6 ppm; IR (CHCl3): n˜ =
3596, 1603, 1497, 1447, 1221 cmÀ1; HRMS (FAB): m/z calcd for C15H17O:
213.1280 [M+H]+; found: 213.1286.
Scheme 5. The radical reaction using an aromatic amine as a precursor.
zines in the presence of
a
catalytic amount of
K4[Fe(CN)6]·3H2O and water. Because the reaction involves
the use of environmentally friendly and inexpensive re-
agents (K4[Fe(CN)6]·3H2O, oxygen gas, and water), the pres-
ent reaction provides a mild and economical method for the
Compound 3a (from 1a without PPh3): 83% yield; colorless oil;
1H NMR (270 MHz, CDCl3): d=1.57 (s, 3H), 3.00 (d, J=15.5 Hz, 1H),
3.16 (d, J=15.5 Hz, 1H), 6.96–6.98 (m, 2H), 7.15–7.21 (m, 3H), 7.25–7.39
(m, 5H), 7.48 ppm (s, 1H); 13C NMR (67.5 MHz, CDCl3): d=22.1, 46.0,
86.5, 125.9, 126.4, 127.5, 127.7, 128.4, 130.7, 136.2, 143.5 ppm; IR
(CHCl3): n˜ =3529, 1603, 1497, 1448, 1331 cmÀ1; HRMS (FAB): m/z calcd
for C15H17O2: 229.1229 [M+H]+; found: 229.1230.
À
synthesis of peroxides and alcohols through new C C bond
formation. Further applications of the reaction in the pres-
ence of an iron catalyst are underway in our laboratory.
Compound 16: 28% yield (mixture of two isomers, trans/cis, 4:1); color-
less oil; 1H NMR (600 MHz, CDCl3; major and minor isomers): d=2.10
(br s, 2H; major and minor isomers), 2.44–2.52 (m, 2H; major isomers),
2.56–2.60 (m, 1H; minor isomer), 2.66–2.70 (m, 1H; minor isomer), 3.34
(d, J=7.2 Hz, 2H; major isomer), 3.35 (d, J=7.2 Hz, 2H; minor isomer),
4.70 (dd, J=7.2, 6.0 Hz, 1H; major isomer), 4.74 (dd, J=7.4, 5.4 Hz, 1H;
minor isomer), 5.46–5.51 (m, 1H; major isomer), 5.52–5.56 (m, 1H;
minor isomer), 5.67–5.74 (m, 2H; major and minor isomers), 7.09–
7.37 ppm (m, 20H; major and minor isomers); 13C NMR (150 MHz,
CDCl3; major and minor isomers): d=33.6, 37.2, 39.0, 42.5, 73.6, 73.9,
125.7, 125.8, 125.9, 126.0, 127.1, 127.4, 127.6, 128.29, 128.35, 128.37,
128.42, 129.5, 129.6, 131.6, 133.1, 140.4, 140.6, 143.86, 143.9 ppm; IR
(CHCl3): n˜ =3600, 1601, 1495, 1452 cmÀ1; HRMS (FAB): m/z calcd for
C17H19O: 239.1436 [M+H]+; found: 239.1440.
Experimental Section
General methods: All reagents were purchased commercially and used
without further purification. IR spectra were recorded with a commercial
FT/IR spectrometer (Shimadzu FTIR-8100). 1H NMR spectra were re-
corded with 270, 500, or 600 MHz spectrometers (JEOL EX270 (270
MHz), JEOL JNM ECS400 (400 MHz) or JEOL JNM ECA600 (600
MHz)); chemical shifts (d) are quoted relative to tetramethylsilane.
13C NMR spectra were recorded at 67.5, 125, or 150 MHz with complete
proton decoupling; chemical shifts (d) are quoted relative to the residual
signals of chloroform. Silica gel column chromatography was carried out
on silica gel 60N. Mass spectra were recorded with a high-resolution mass
spectrometer (JEOL JMS-SX-102A mass spectrometer) in fast atom
bombardment modes (FAB).
Starting materials: Compounds 1a, 1e, 1 f, 1j, 1p, 1q, 2a–k, and 2a’ were
commercially available. Compounds 1b,[25] 1c,[26] 1d,[25] 1g,[27] 1h,[28]
1i,[29]1k,[30] 1l,[31]1m,[32] 1n,[33] 1o,[34] 1r,[35] and 14[36] were prepared accord-
ing to literature methods.
Acknowledgements
This research was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and Technology
of Japan.
General procedure for reactions using aryl hydrazines: Phenylhydrazine
(104 mg, 1.0 mmol) was added to a mixture of alkene (0.50 mmol) and
K4[Fe(CN)6]·3H2O (21.0 mg, 0.050 mmol) in water (5 mL), and the mix-
ture was vigorously stirred at room temperature under an O2 atmosphere
(1 atm). After addition of 10% aqueous Na2S2O3 (5 mL), PPh3 (131 mg,
0.50 mmol) was added and the mixture was extracted with CH2Cl2. The
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 4307 – 4312

Oxidative Aryl Addition into Alkenes
FULL PAPER
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Received: October 22, 2010
Published online: March 7, 2011
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publication in Chemistry–A European Journal Early View. The Editor
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