Synthesis of α-Nitro Ketoximes from Styrenes and tert-Butyl Nitrite

Article abstract of DOI:10.1080/00397911.2015.1062988

We have discovered that various α-nitro ketoximes can be synthesized in good yields starting from styrenes and tert-butyl nitrite. The success of the reaction was critically dependent on the use of a mixture solvent of dimethylsulfoxide and water. The reaction can tolerate a wide variety of substituents including electron-withdrawing and electron-donating groups.

Full text of DOI:10.1080/00397911.2015.1062988

This article was downloaded by: [New York University]
On: 20 July 2015, At: 02:59
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: 5 Howick Place,
London, SW1P 1WG
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Synthesis of α-Nitro Ketoximes from Styrenes and tert-
Butyl Nitrite
a
a
a
a
a
a
Qi Cao , Jidan Liu , Lin Yu , Qingwen Gui , Xiang Chen & Ze Tan
a
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and
Chemical Engineering, Hunan University, Changsha, P. R. China
Accepted author version posted online: 15 Jul 2015.
Click for updates
To cite this article: Qi Cao, Jidan Liu, Lin Yu, Qingwen Gui, Xiang Chen & Ze Tan (2015): Synthesis of α-Nitro Ketoximes from
Styrenes and tert-Butyl Nitrite, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, DOI: 10.1080/00397911.2015.1062988
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1062988
Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a service
to authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting,
typesetting, and review of the resulting proof will be undertaken on this manuscript before final publication of
the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the
content, and all legal disclaimers that apply to the journal relate to this version also.
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any

form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

Synthesis of α-nitro ketoximes from styrenes and tert-butyl nitrite
1
1
1
1
1
1
Qi Cao , Jidan Liu , Lin Yu , Qingwen Gui , Xiang Chen , Ze Tan
1
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry
and Chemical Engineering, Hunan University, Changsha, P. R. China
Corresponding Author to Ze Tan, E-mail: ztanze@gmail.com
Abstract
We have discovered that various α-nitro ketoximes can be synthesized in good yields
starting from styrenes and tert-butyl nitrite. It was found that the success of the reaction
was critically dependent on the use of a mixture solvent of DMSO and water. The
reaction can tolerate a wide variety of substituents including electron-withdrawing and
electron-donating groups.
KEYWORDS: α-nitro ketoxime, styrene, tert-butyl nitrite, free radical, NO
INTRODUCTION
1

The synthesis of nitro-substituted compounds is particularly important because they can
not only serve as valuable intermediates for polymers, dyes, but also for pharmaceuticals
[
1],[2]
and agrochemicals.
and carbonyl compounds via reduction and Nef reaction.
development of new and improved methods for the synthesis of nitro-compounds has
They are frequently transformed into the corresponding amines
[
1],[2]
Consequently, the
[
1-4]
always attracted the attention of synthetic chemists.
For the synthesis of nitroalkanes,
the classical nucleophilic substitution reaction (S 2 type reaction) of an alkyl halide with
N
a nitrate salt as the nucleophilic reagent is the bench mark method. As for the synthesis of
nitroarenes, the classical electrophilic aromatic nitration using a cationic nitronium
[
5]
species is the method of choice in cases where it is applicable. Though these methods
are efficient, they do suffer from problems such as lack of regioselectivity or having to
employ strong acidic reaction conditions. As a result, chemists are seeking other
[
6]
alternative methods for the synthesis of nitro compounds.
RESULTS AND DISCUSSION
One of the most straightforward ways to synthesize nitroalkanes would be from an olefin
and a nitro group donor. Indeed, the reaction of an olefin with a nitro donor has been
[
7]
[8]
studied extensively. Up to now, a number of reagents such as NaNO
2
, RONO
2
,
[
9]
[10]
[11]
[12]
[13]
[14]
(NO
2
)
4
, CeNH
4
(NO
3
)
4
,
N
2
O
4
,
NO
2
,
HNO
3
and NO have been utilized for
the nitration of olefins. However, the products derived from the nitration of olefin can be
2

rather diverse. Sometimes, nitroalkenes are produced instead of the desired nitroalkanes,
other times oximes are obtained as well. Among the nitrating reagents utilized, the use of
alkyl nitrite, especially tert-butyl nitrite (TBN) has attracted considerable attention
because TBN is a relatively stable liquid and its reaction usually does not employ
strongly acidic condition. For example, Maiti has shown that in the presence of
stoichiometric amount of TEMPO, the reaction of tert-butyl nitrite with olefins can give
[
15]
rise to nitroalkenes. Okamoto and Tanimoto have shown that using a Co complex as
-
the catalyst, and BH
4
as the hydrogen donor, the reaction of ethyl nitrite with styrenes
[
16]
can produce oximes as the exclusive product. In 1998, Sugamoto was able to effect the
Ⅱ
same transformation using Et
3
SiH as the hydride donor employing Co (tpp) as the
[
17]
[18]
catalyst. This was later extended by Beller to use Fe(pc) as the catalyst. On the other
hand, Ishibashi has tested the reaction of tert-butyl nitrite with styrenes under oxygen in a
mixture solvent of hexane and water. They have found that α-nitro nitrate ester was
[
19]
formed as the major product. From all these studies, we can see that the chemistry of
tert-butyl nitrite with olefins is very rich and can furnish all kinds of products depending
on the reaction conditions. In this paper, we would like to report by running the reaction
in DMSO and water under air, α-nitro ketoximes can be efficiently synthesized in good
yields from tert-butyl nitrite and styrenes (Scheme 1, Eq.1).
3

The synthesis of α-nitro ketoximes from styrene is actually known. In 2001, Grossi and
co-workers reported the radical nitration of styrene using peroxynitrite to give
2
-nitro-1-phenylethyl nitrite along with 2-nitro-1-phenylethyl nitrate, benzaldehyde and
[
20]
α-nitro acetophenone and the combined yield is only 57% (Scheme 1, Eq. 2).
Shaabani and coworkers have studied the reaction of styrene with sodium nitrite in the
presence of a cationic exchange resin (Rexyn 101H) under solvent free condition.
Surprisingly, they have discovered that the product they have obtained is the tautomeric
isomer of α-nitro ketoxime, i.e., 2-nitro-1-nitrosoethylbenzene instead of α-nitro
[
21]
ketoxime. They also found that 2-nitro-1-nitrosoethylbenzene can readily undergo
tautomerization to form the more stable α-nitro ketoxime (Scheme 1, Eq.3).
We became our study by using the reaction of styrene 1a with tert-butyl nitrite 2 as the
o
model reaction. When 1a was treated with 0.5 equiv of TBN in DMSO under air at 50 C,
we were able to isolate a major product in 20% yield. Originally, we thought the product
was α-nitro acetophenone. However, analysis of the isolated product’s mass spectrum
revealed that it was in fact α-nitro ketoximes 3a. Next we tried to optimize the reaction
conditions to increase the product yield and the results are shown in Table 1. We were
pleased to find the yield can be increased to 26% if a small amount of water was added to
the reaction mixture. The yield could be further increased to 38% if the solvent consists
of a 2:1 mixture of DMSO and water. Disappointedly, running the reaction at higher
4

temperature actually had a detrimental effect on the product yield. However, lowering the
reaction temperature to room temperature did benefit the reaction and a 46% yield could
o
be achieved. Further lowering temperature to 0 C slowed down the reaction considerably.
Switching the solvent from DMSO to acetonitrile or toluene did not help either. In the
end, we were delighted to find that an 84% yield could be achieved if two equiv of TBN
2
was added. Test also indicated that though the reaction still proceeded under N , the yield
was much lower. On the basis of the above results, we decided to set running the reaction
of 1a (1 equiv) with TBN (2 equiv) in a mixture of DMSO/water (2/1) at room
temperature for 12 hours as our standard procedure.
With the optimized protocol in hand, we next turned our attention to explore the scope of
the reaction. Starting from diversely substituted styrenes, a series of α-nitro ketoximes
were synthesized in good yields and the results were summarized in Table 2. From Table
2
, we could see that a wide variety of functional groups could be tolerated on the phenyl
ring. Styrenes with substituents such as methyl, tert-butyl, methoxy, ethoxy, chloro,
cyano as well as nitro group reacted smoothly under the standard reaction conditions to
give the corresponding ketoximes in 40-82% yields. Substrates with electron donating
groups tend to furnish the desired products in higher yields than styrenes with electron
withdrawing groups. For example, styrene 1k with a nitro group on the 4-position of the
phenyl only produced the desired ketoxime 3k in 51% yield whereas styrenes with
5

4
-ethoxy or 4-methoxy groups generated the desired products in yields higher than 70%.
It is worthwhile to point out that even a benzyl chloride functional group can survive in
our reaction as in the case of 3e, highlighting the mildness of our reaction condition. We
also noticed that substituents on the ortho-position of the styrene did have a negative
impact on the product yield. For example, substrate 1c with a methyl group on the
2
-position reacted with TBN to give product 3c in 46% while substrate 1n with a chloro
group on the 2-position afforded the corresponding ketoxime 3n in only 40% yield. These
results indicated that the reaction was sensitive to steric hindrance. We were pleased to
find that a disubstituted styrene such as 1q could also participate in the reaction,
affording the desired ketoxime 3q in 75% yield. Unfortunately, aliphatic alkenes such as
1
-octene gave a complex mixture. It should be mentioned that some ketoximes did exist
as an Z/E mixture.
Though the exact mechanism is still unknown at present, a plausible mechanism based on
[
19,20]
literature precedents
is proposed and depicted in Scheme 2. First, TBN reacted with
water to generate nitrous acid and two molecules of nitrous acid disproportionate to give
nitrogen monoxide and dioxide. In air, nitrogen monoxide would be oxidized to nitrogen
dioxide as well. Nitrogen dioxide would subsequently react with the double bond of
styrene to generate the benzyl radical A. Next intermediate A would be captured by
another molecule of nitrogen monoxide to give intermediate B. Finally, the α-nitro
6

ketoxime was produced after tautomerization. Alternatively, nitrogen monoxide could be
formed directly from tert-butyl nitrite as depicted in the alternative pathway.
In summary, we have discovered that under suitable reaction conditions, styrenes can
react with tert-butyl nitrite to give α-nitro keoximes as the major product. We found that
the use of a mixture solvent of DMSO and water is critical for the success of the reaction.
The reaction was found to tolerate a variety of functional groups including electron
withdrawing and electron donating groups on the phenyl ring of styrene.
EXPERIMENTAL
All solvents and reagents were purchased from the suppliers and used without further
1
13
purification. H NMR and C NMR were recorded in CDCl
3
6
or d -DMSO at room
1
temperature on the Varian INOVA-400 spectrometer (400 MHz H) and Bruker
1
spectrometer (400 MHz H). The chemical-shifts scale is based on internal TMS. All
reactions were carried out in the air atmosphere.
General Reaction Procedure
2
To a 25 mL round bottom flask charged with a magnetic stir-bar was added H O (0.5
mL), Styrene (0.5 mmol), tert-butyl nitrite (1 mmol) and DMSO (1 mL). Then the
reaction mixture was stirred at room temperature for 12 h. After the reaction was finished,
7

the mixture was diluted with CH
2 2
Cl , washed with brine and extracted with CH
2 2
Cl . The
combined organic extracts were dried over Na
2
SO , concentrated in vacuum, and the
4
resulting residue was purified by silica gel column chromatography (petroleum
ether/ethyl acetate=5:1) to afford the desired product (3a).
1
2
-Nitro-1-phenyl-ethanone oxime (3a): Yield: 84%; Yellow oil; H NMR (400 MHz,
1
3
3
CDCl ) δ 9.01 (s, 1H), 7.55-7.53 (m, 2H), 7.38-7.33 (m, 3H), 5.57 (s, 2H); C NMR (100
MHz, CDCl
3
) δ 148.6, 132.8, 130.5, 129.0, 126.1, 68.4; HRMS (ESI) calcd for
+
C
8
H
8
N
2
O
3
K (M+K) 219.0172, found 219.0165.
ACKNOWLEGMENTS
Z.T. would like to thank the National Science Foundation of China (No. J1210040) and
the Fundamental Research Funds for the Central Universities, Hunan University for
financial support.
SUPPORTING INFORMATION:
1
13
Full experimental detail, H NMR and C NMR spectra and references for all the
products can be accessed on the publisher’s website.
8

REFERENCES
[
1] (a) Lawrence, S. A. in: Amine: Synthesis properties, and applications, Cambridge
University, Cambridge, 2004.
[2] Ono, N. The Nitro Group in Organic Synthesis, Wiley-VCH, New York, 2001.
[3] Schofield, K. Aromatic Nitration, Cambridge University Press, Cambridge, 1980.
[4] (a) Campos, P. J.; Garcia, B.; Rodriguez, M. A. Tetrahedron Lett., 2000, 41,
9
79-982; (b) Nishiwaki, Y.; Sakaguchi, S.; Ishii, Y. J. Org. Chem., 2002, 67, 5663-5668;
c) Jayakanthan, K.; Madhusudanan, K. P.; Vankar, Y. D. Tetrahedron, 2004, 60,
97-403; (d) Jovel, I.; Prateeptongkum, S.; Jackstell, R.; Vogl, N.; Weckbecker, C.;
Beller, M. Adv. Synth. Catal., 2008, 350, 2493-2497.
5] Olah, G. A.; Malhotra, R.; Narang, S. C. Nitration: Methods and Mechanisms, VCH,
New York, 1989.
6] (a) Reddy, K. R.; Maheswari, C. U.; Venkateshwar, M.; Kantam, L. Adv. Synth.
Catal., 2009, 351, 93-96; (b) Rozen, S.; Carmeli, M. J. Am. Chem. Soc., 2003, 125,
118-8119; (c) Stefan, S.; Jürgen, S.; Prakash, G. K. S.; Petasis, N. A.; Olah, G. A.
(
3
[
[
8
Synlett, 2000, 1485-1487; (d) Manna, S.; Maity, S.; Rana, S.; Agasti, S.; Maiti, D. Org.
Lett., 2012, 14, 1736-1739; (e) Das, J. P.; Sinha, P.; Roy, S. Org. Lett., 2002, 4,
3
055-3058; (f) Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc., 2009, 131, 12898-12899;
(g) Yang, H. J.; Li, Y.; Jing, M.; Wang, J. M.; Fu, H. Chem.–Eur. J., 2011, 17,
5
652-5660; (h) Yan, G.; Zhang, L.; Yu, J. Lett. Org. Chem., 2012, 9, 133-135; (i) Liu, Y.
9

K.; Lou, S.-J.; Xu, D.-Q.; Xu, Z.-Y. Chem.-Eur. J., 2010, 16, 13590-13593; (j) Zhang, W.;
Lou, S.; Liu, Y.; Xu, Z. J. Org, Chem., 2013, 78, 5932-5948.
[7] Hwu, J. R.; Chen, K-L.; Ananthan, S.; Patel, H. V. Organometallics, 1996, 15,
4
99-505;
[8] Stepanov, A. V.; Veselovsky, V. V. Russ. Chem. Rev., 2003, 72, 327-341.
[9] Butts, C. P.; Calvert, J. L.; Eberson, L.; Hartshorn, M. P.; Robinson, W. T. J. Chem.
Soc., Perkin Trans, 1994, 7, 1485-1490.
[10] Grenier, J.-L.; Catteau, J.-P.; Cotelle, P. Synth. Commun. 1999, 29, 1201-1208.
[11] Siri, O.; Jaquinod, L.; Smith, K. M. Tetrahedron Lett., 2000, 41, 3583-3587.
[12] Tanaka, M.; Muro, E.; Ando, H.; Xu, Q.; Fujiwara, M.; Souma, Y.; Yamaguchi, Y.
J. Org. Chem., 2000, 65,
13] Panke, G.; Schwalbe, T.; Stirner, W.; Moghadam, S. T.; Wille, G. Synthesis, 2003,
827-2830.
2972-2978.
[
2
[14] Hata, E.; Yamada, T.; Mukaiyama, T. Bull. Chem. Soc. Jpn., 1995, 68, 3629-3636.
[15] Manna, S.; Jana, S.; Saboo, T.; Maji, A.; Maiti, D. Chem. Commun., 2013, 49,
5
286-5288.
16] Okamoto, T.; Kobayashi, K.; Oka, S.; Tanimoto, S. J. Org. Chem., 1988, 53,
897-4901.
17] Sugamoto, K.; Hamasuna, Y.; Matsushita, Y.-I.; Matsui, T. Synlett, 1998,
270-1272.
[
4
[
1
10

[18] Prateeptongkum, S.; Jovel, I.; Jackstell, R.; Vogl, N.; Weckbecker, C.; Beller, M.
Chem. Commun., 2009, 1990-1992.
[19] Taniguchi, T.; Yajima, A.; Ishibashi, H. Adv. Synth. Catal., 2011, 353, 2643-2647.
[20] Grossi, L.; Montevecchi, P. C.; Strazzari, S. Eur. J. Org. Chem., 2001, 741-748.
[21] Shaabani, A.; Bijanzadeh, H. R.; Karimi, A. R.; Teimouri, M. B.; Soleimani, K.
Can. J. Chem., 2008, 86,
248-252.
11

Table 1. Reaction condition optimization
Entry 1a:2
Atmosphere Solvent(mL)
Temperature
Yield
o
a
(
C)
(%)
1
2
3
4
5
6
7
8
9
1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
1:2
1:2
1:2
air
air
air
air
air
air
air
air
air
DMSO(1)
50
O(0.05) 50
O(0.5) 50
O(0.5) 75
O(0.5) r.t.
20
26
38
34
46
28
27
14
84
36
37
DMSO(1):H
DMSO(1):H
DMSO(1):H
DMSO(1):H
DMSO(1):H
2
2
2
2
2
O(0.5)
0
CH
3
CN(1):H
2
O(0.5) r.t.
Toluene(1):H
2
O(0.5) r.t.
O(0.5) r.t.
O(0.5) r.t.
DMSO(1):H
DMSO(1):H
2
2
0
1
N
2
1
air
3 2
CH CN(1):H O(0.5) r.t.
a
Isolated yields.
12

a
Table 2. Synthesis of α-nitro ketoximes from styrenes and tert-butyl nitrite
b,
Yield
Yield (%)
Entry Substrate
Product
Entry Substrate Product
b
c
c
(
%) (Z/E)
(Z/E)
1
1
1
R = 4-CH
3
3b
9
R =
3j
64(＞20:1)
51(＞20:1)
69(＞20:1)
50(9.5:1)
2
R = H (1b)
64(13.4:1)
4-CN
2
R = H
(
1j)
1
1
2
R = 2,5-CH
3
3c
10
R =
3k
2
R = H (1c)
46(7.0:1)
4-NO
2
2
R = H
(
1k)
1
1
3
4
R = 4-t-Bu
3d
3e
82(＞
11
12
R = 4-Cl 3l
2
2
R = H (1d)
20:1)
R = H
(
1l)
1
1
R = 4-CH
2
Cl
73(＞
R = 3-Cl 3m
2
2
R = H (1e)
20:1)
R = H
(1m)
13

1
1
5
6
7
8
R = 4-MeO
3f
3g
3h
3i
13
14
15
16
R = 2-Cl 3n
2
2
R = H (1f)
76(12.5:1)
59(4.9:1)
R = H
40(1.7:1)
(
1n)
1
1
R =2-MeO
R = 4-Br 3o
62(＞20:1)
2
2
R = H (1g)
R = H
(
1o)
1
1
R = 4-EtO
71(＞
R =3-Br 3p
52(＞20:1)
2
2
R = H (1h)
20:1)
R = H
(
1p)
1
1
R =4-CH
3
COO
61(＞
R =
3q
75(1.8:1)
2
R = H (1i)
20:1)
3
4-CH O
2
R = CH
3
(1q)
a
All reactions were carried out by treating styrene (1 equiv.) with tert-butyl nitrite (2
equiv.) in DMSO (1 mL) and H
2
O (0.5 mL) at room temperature for 12 h.
b
Isolated yields.
c
1
The Z/E ratios were determined from the H NMR spectra of the isolated product
mixtures.
14

Scheme 1.
15

Scheme 2. Possible mechanism
16