Oxidative nitration of alkenes with tert-butyl nitrite and oxygen

Article abstract of DOI:10.1002/adsc.201100315

A method for the oxidative nitration of alkenes using a combination of tert-butyl nitrite and molecular oxygen to give β-nitro alcohols and their nitrate derivatives has been developed. The present reaction provides a practical method for the synthesis of

Full text of DOI:10.1002/adsc.201100315

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DOI: 10.1002/adsc.201100315
Oxidative Nitration of Alkenes with tert-Butyl Nitrite and
Oxygen
Tsuyoshi Taniguchi,a,* Atsushi Yajima,a and Hiroyuki Ishibashia
a
School of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University,
Kakuma-machi, Kanazawa 920-1192, Japan
Fax : (+81)-76-234-4439; phone: (+81)-76-234-4439; e-mail: tsuyoshi@p.kanazawa-u.ac.jp
Received: April 25, 2011; Revised: June 17, 2011; Published online: October 10, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100315.
Abstract: A method for the oxidative nitration of
alkenes using a combination of tert-butyl nitrite and
molecular oxygen to give b-nitro alcohols and their
nitrate derivatives has been developed. The present
reaction provides a practical method for the synthe-
sis of nitro compounds because of the mild reaction
conditions, the use of inexpensive reagents and a
simple experimental procedure.
Keywords: alkenes; nitration; nitrites; oxygenation;
Scheme 1. Oxidative radical nitrations of alkenes.
radical reactions
report a practical oxidative radical nitration of alk-
AHCTUNGTRENNUNG
Nitro compounds are useful for medicines, industrial (2)].[10]
materials and fuels.[1] Such compounds are also valua-
Treatment of a-methylstyrene (1a) with t-BuONO
ble synthetic intermediates in organic chemistry. For (3 equiv.) in toluene under air gave b-nitro alcohol
example, reduction and Nef reaction of nitro com- compound 2a in moderate yield along with its nitrate
pounds afford the corresponding amines and ke- derivative 3a (Table 1, entry 1). The reaction in
tones.[2] Nitro-aldol reactions and nitro-Michael reac- MeOH gave an improvement in the result to some
À
À
tions have been extensively used for C C and C X extent (entry 2). When water was used as a solvent,
(X=N, O) bond formation.[3] Many nitration methods disappearance of the starting material in shortened
for the synthesis of aromatic and aliphatic nitro com- reaction time was observed (entry 3). Encouraged by
pounds have been developed.[4,5] A method for the ni- this result, addition of an amount of water solvent to
tration of alkenes is an important tool for the synthe- the reaction mixture in toluene (toluene-H2O, 1:1)
sis of nitroalkenes and nitroalkanes. Nitrogen dioxide was tested for improved total yield of products 2a and
gas (NO2), which is a free radical, is one of the sim- 3a (entry 4). After screening several solvents (en-
plest and most common nitration reagents.[6] Suzuki tries 5–8), we found that the use of hexane as a sol-
and Mori reported the oxidative nitration of styrene vent gave the b-nitro alcohol compound 2a in good
derivatives using a combination of NO2 and ozone yield in a short reaction time (entry 8). A decrease in
(O3).[7] Grossi and co-workers reported the radical ni- the amount of water (3 equiv.) added to the reaction
tration of styrene using peroxynitrite to give 2-nitro- mixture in hexane was ineffective (entry 9). An un-
1-phenylethyl nitrite along with some by-products changed result was obtained under diluted conditions
[Scheme 1, Eq. (1)].[8,9] NO2 is an economic nitrogen (entry 10). When isoamyl nitrite (i-AmONO) or pure
source in industrial chemistry, but its extreme reactivi- oxygen gas was used, the yield of the product was not
ty and toxicity restrict its application to reactions. improved (entries 11 and 12).
Also, the complication of handling NO2 gas has limit-
Next, reactions of several styrene-type alkenes
ed its use by chemists in the laboratory. Herein, we were examined (Table 2). Our preliminary experi-
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Tsuyoshi Taniguchi et al.
Table 2. Nitration of various styrene-type alkenes.[a]
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Table 1. Optimizations of nitration reaction of a-methylstyr-
ene.[a]
Entry Solvent
Time
[h]
Yield
[%][b]
Conversion
[%][c]
2a 3a
1
2
3
4
5
6
7
8
toluene
MeOH
H2O
120
48
2.5
3
3
2
2
3
6
3
32 20 93
51 9[d] >99
45
48 28 94
60 95
–
>99
toluene-H2O (1:1)
THF-H2O (1:1)
CH2Cl2-H2O (1:1)
EtOAc-H2O (1:1)
hexane-H2O (1:1)
hexane
hexane-H2O (1:1)
hexane-H2O (1:1)
hexane-H2O (1:1)
–
40 31 95
41 19 93
74
–
>99
9[e]
10[f]
11[g]
12[h]
26 32 96
71
56
54
–
–
–
>99
>99
97
[a]
[b]
Reaction conditions: 1a–h (0.4 mmol), t-BuONO
(1.2 mmol) in hexane (5 mL)-H2O (5 mL) under air
(1 atm) (conditions of Table 1, entry 10).
Including the addition time (1 h) of a t-BuONO solution
in hexane.
17
1.5
[a]
Reaction conditions: 1a (0.4 mmol), t-BuONO (1.2 mmol)
and in solvent (2.5 mL) under air (1 atm).
Isolated yield.
Conversion was determined by GC analysis with dodec-
ane as an internal standard.
[b]
[c]
[c]
[d]
Isolated yield.
Conversion was determined by GC analysis with dodec-
ane as an internal standard.
[d]
2-Methoxy-1-nitro-2-phenylpropane was obtained instead
of 3a.
[e]
[f]
3 equivalents of water (21.6 mL) were added.
A solution of t-BuONO (1.2 mmol) in hexane (2.5 mL)
was added to a solution of 1a (0.4 mmol) in hexane
(2.5 mL)-H2O (5 mL) over 1 h and the mixture was fur-
ther stirred for 2 h.
isfactory results for the yields of products 5a and 6a
were obtained (Table 3, entry 1). Therefore, we tried
to optimize the conditions of the reaction using
alkene 4a. The use of pure oxygen gas instead of air
gave a slightly improved result (entry 2). A decrease
in the amount of water added to the reaction mixture
gave an improved yield of products in this case
(entry 3). After examination of some solvents (en-
tries 4–6), we found that the use of CH2Cl2 as a sol-
[g]
[h]
i-AmONO was employed instead of t-BuONO.
Under O2 atmosphere (1 atm).
ments showed that diluted conditions (Table 1, vent almost exclusively gave nitrate product 6a in
entry 10) gave better results than normal conditions good yield in a short reaction time (entry 6) and dilut-
(Table 1, entry 8) in many of reactions using styrene- ed conditions were unnecessary in this reaction
type alkenes except 1a.[11] Reactions of a-methylstyr- (entry 7).
ene derivatives bearing p-methoxyphenyl, p-nitro-
Finally, the oxidative nitrations of various alkenes
phenyl, p-halophenyl and b-naphthyl groups gave b- were investigated (Table 4). Like the reaction of sty-
nitro alcohol compounds 2b–f as major products rene-type alkenes, yields of isolated products were in-
(Table 2, entries 2–6). In the case of styrene (1g), b- ferior to conversion ratios of starting materials due to
nitro alcohol compound 2g and its nitrate derivative the generation of decomposition by-products, but no
3g were obtained in moderate yields, respectively regioisomer was observed at all. Reactions of other
(entry 7). Nitration of 1,1-diphenylethene (1h) gave b- a,b-unsaturated esters 4b and 4c similarly afforded ni-
nitro alcohol compound 2h in moderate yield trate products 6b and 6c, respectively (Table 4, en-
(entry 8). In the most of cases, small amounts of aro- tries 2 and 3). When aliphatic alkene 4d was em-
matic ketone derivatives (e.g., acetophenone) as de- ployed as a substrate, a low yield (26%) of nitrate de-
composition by-products were observed,[8] whereas no rivative 6d was obtained under conditions using an
regioisomer (2-nitro-1-hydroxy or nitroxy product) excessive amount of water in hexane (hexane-H2O,
was detected.[7]
1:1 under air), whereas treatment of alkene 4d with t-
The reaction of ethyl methacrylate (4a) under con- BuONO in the presence of 3 equivalents of water in
ditions similar to those in reactions of styrene deriva- CH2Cl2 gave compound 6d in 75% yield (entry 4). Re-
tives (Table 1, entry 10) was not completed and unsat- actions of several aliphatic alkenes 4e–h also led to
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Oxidative Nitration of Alkenes with tert-Butyl Nitrite and Oxygen
Table 3. Optimizations of nitration reaction of ethyl meth-
with NO2 gives nitrate product.[8] It is presumed that
a b-nitro alcohol compound is mainly produced by hy-
drolysis of a nitrate compound. The dominant produc-
tion of b-nitro alcohol compounds 2a–h from styrene
derivatives 1a–h can be explained by an SN1 hydroly-
sis and/or simple ester hydrolysis of a nitrate ester
compound in the presence of excessive water. Simple
ester hydrolysis of nitrate esters is unlikely to be a
fast process because the reaction of a,b-unsaturated
ester 4a gave nitrate compound 6a, which would not
be hydrolyzed via an SN1 mechanism, in a reasonable
yield along with b-nitro alcohol compound 5a even
under conditions in the presence of excessive water
(Table 3, entries 1 and 2). Additionally, since the reac-
tion in the absence of water proceeded slowly
(Table 1, entry 1), another mechanism for the genera-
tion of NO2 must be considered as well. A homolytic
ACHTUNGTRENNUNG
acrylate.[a]
Entry Solvent H2O
(equiv.)
Time
[h]
Yield Conversion
[%][b] [%][c]
5a 6a
1[d,e] hexane excess
46
46
7
7
10
4
20 22 83
27 21 88
39 26 >99
29 38 >99
34 35 >99
2[d]
3
hexane excess
hexane
toluene 3
3
4
5
THF
CH2Cl2
CH2Cl2
3
3
3
6
8
2
52 >99
66 >99
7[f]
2
À
cleavage of the N O bond of t-BuONO might take
[a]
Reaction conditions: 4a (0.4 mmol), t-BuONO (1.2 mmol)
in solvent (10 mL) under O2 atmosphere (1 atm).
Isolated yield.
Conversion was determined by GC analysis with dodec-
ane as an internal standard.
A solution of t-BuONO (1.2 mmol) in hexane (2.5 mL)
was added to a solution of 4a (0.4 mmol) in hexane
(2.5 mL)-water (5 mL) over 1 h and the mixture was fur-
ther stirred for 45 h.
place slowly to give tert-butoxy radical and NO fol-
lowed by generation of NO2 in the presence of
oxygen [Scheme 2, Eqs. (3) and (4)].[17] Perhaps, t-
BuONO might be directly oxidized by molecular
oxygen to generate NO2 via peroxynitrite radical
(ONOOC)[16c] [Scheme 2, Eq. (5)]. The production of
b-nitro alcohol compounds could be explained by a
direct hydrogen abstraction by alkoxy radical inter-
mediate D from the solvent.
In conclusion, we have developed an efficient oxi-
dative nitration of alkenes. The addition of water has
been demonstrated to be important for obtaining a
good result in the present reaction. This reaction has
[b]
[c]
[d]
[e]
[f]
Under air (1 atm).
The reaction was performed in 2 mL of CH2Cl2.
the corresponding nitro compounds 5e–h and 6e–h in the following advantages: (i) all reagents herein em-
good total yields (entries 5–8). This reaction enabled ployed are easily available and inexpensive and (ii)
an access to cyclic nitro compounds 5i, j and 6i, j reaction conditions are mild and the experimental
from cycloalkenes 4i and 4j, respectively (entries 9 procedure is very simple and safe. Therefore, the
and 10). When 1,6-diene 4k was employed as a sub- present reaction will provide a general and practical
strate, five-membered ring compounds 5k and 6k method for the synthesis of b-oxygenated nitro com-
were obtained (entry 11). Compounds 5k and 6k were pounds.
certainly produced via 5-exo-trig cyclization of a radi-
cal generated by addition of NO2 to one olefin, there-
fore, this result supports the radical mechanism in the Experimental Section
present nitration reaction.[12]
A plausible mechanism of this oxidative nitration is General Procedure of Reactions using Styrene-Type
shown in Scheme 2. Water would cause a gradual hy- Materials
drolysis of t-BuONO to generate nitrous acid (HNO2)
To a solution of alkene (0.4 mmol) in hexane (2.5 mL) and
water (5 mL) was added a solution of t-BuONO (123.7 mg,
1.2 mmol) in hexane (2.5 mL) over 1 h under air (1 atm),
[Scheme 2, Eq. (1)].[13] It is known that HNO2 is an
unstable compound and that its decomposition gives
NO2 and nitrogen monoxide (NO) [Scheme 2, Eq.
(2)].[14,15] NO is rapidly oxidized into NO2 in the pres-
ence of oxygen [Scheme 2, Eq. (3)].[16] Addition of
NO2 to alkene would give radical intermediate A.
Trapping of radical A by molecular oxygen leads to
the formation of peroxy radical intermediate B fol-
lowed by reaction with t-BuONO to give peroxyni-
trite C. The cleavage of the O O bond of peroxyni-
trite C would easily takes place to generate alkoxy
radical intermediate D, and radical coupling of D
and the mixture was further stirred at room temperature
until disappearance of the starting material. The reaction
mixture was diluted with water and extracted with EtOAc.
The organic phase was washed with brine and dried with
MgSO4 and filtered. After removal of the solvent, the resi-
due was purified by silica gel chromatography (hexane-
EtOAc) to give nitrated products.
À
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Tsuyoshi Taniguchi et al.
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Table 4. Nitration of various alkenes.[a]
[a]
Reaction conditions: 4a–k (0.4 mmol), t-BuONO (1.2 mmol) and H2O (1.2 mmol) in CH2Cl2 (2 mL) under O2 atmosphere
(1 atm).
Isolated yield.
[b]
[c]
[d]
[e]
Conversion was determined by GC analysis with dodecane as an internal standard.
Diastereomeric ratio was estimated by H NMR analysis.
The reaction was carried out under conditions of Table 1, entry 10 [in hexane-H2O (1:1), under air, 24 h].
1
Scheme 2. Plausible mechanism of radical nitration.
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Adv. Synth. Catal. 2011, 353, 2643 – 2647

Oxidative Nitration of Alkenes with tert-Butyl Nitrite and Oxygen
Synth. Catal. 2008, 350, 2493; f) B. P. Fors, S. L. Buch-
wald, J. Am. Chem. Soc. 2009, 131, 12898; g) T. Tanigu-
chi, T. Fujii, H. Ishibashi, J. Org. Chem. 2010, 75, 8126
and references cited therein.
General Procedure of Reactions using a,b-
Unsaturated Esters or Aliphatic Alkenes
To a solution of alkene (0.4 mmol) in CH2Cl2 (2 mL) was
added water (21.6 mL, 1.2 mmol) and t-BuONO (123.7 mg,
1.2 mmol) under O2 atmosphere (1 atm), and the mixture
was further stirred at room temperature until disappearance
of the starting material. The reaction mixture was diluted
with water and extracted with CH2Cl2. The organic phase
was washed with brine and dried with MgSO4 and filtered.
After removal of solvent, the residue was purified by silica
gel chromatography (hexane-EtOAc) to give the nitrated
products.
[6] A review on nitrations using NO2: M. Shiri, M. A. Zol-
figol, H. G. Kruger, Z. Tanbakouchian, Tetrahedron
2010, 66, 9077.
[7] H. Suzuki, T. Mori, J. Org. Chem. 1997, 62, 6498.
[8] L. Grossi, P. C. Montevecchi, S. Strazzari, Eur. J. Org.
Chem. 2001, 741.
[9] A review on peroxynitrate: S. Goldstein, J. Lind, G.
Merꢂnyi, Chem. Rev. 2005, 105, 2457.
[10] The nitration of phenols with t-BuONO and air has
been reported: D. Koley, O. C. Colꢃn, S. N. Savinov,
Org. Lett. 2009, 11, 4172.
[11] See the Supporting Information.
Acknowledgements
[12] For reactions of nitrogen dioxide with dienes: a) V.
Jꢄger, J. Gꢅnther, Angew. Chem. 1977, 89, 253; Angew.
Chem. Int. Ed. Engl. 1977, 16, 246; b) N. Tanaka, Y.
Kajii, K. Shibuya, M. Nakata, J. Phys. Chem. 1993, 97,
7048; c) R. P. Claridge, A. J. Deeming, N. Paul, D. A.
Tocher, J. H. Ridd, J. Chem. Soc. Perkin Trans. 1 1998,
3523. Recently, we reported iron-mediated radical ni-
tration-cyclization sequence of 1,6-dienes to give five-
membered ring compounds; d) T. Taniguchi, H. Ishiba-
shi, Org. Lett. 2010, 12, 124.
[13] For hydrolysis of alkyl nitrites in neutral conditions:
M. P. Doyle, J. W. Terpstra, R. A. Pickering, D. M. LeP-
oire, J. Org. Chem. 1983, 48, 3379.
[14] For decomposition of nitrous acid in aqueous solution:
J.-Y. Park, Y.-N. Lee, J. Phy. Chem. 1988, 92, 6294.
[15] For nitration of alkenes using nitrous acid: S. Rangana-
than, S. K. Kar, J. Org. Chem. 1970, 35, 3962.
This research was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology of Japan.
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