Copper(II)-catalyzed oxidative N-nitrosation of secondary and tertiary amines with nitromethane under an oxygen atmosphere

Article abstract of DOI:10.1039/c5cc03675e

The combination of a catalytic amount of Cu(OTf)₂ and less than a stoichiometric amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) under an O₂ atmosphere effectively promoted the N-nitrosation of both secondary aromatic/aliphatic amines and tertiary aromatic amines with nitromethane (CH₃NO₂) leading to the preparation of N-nitrosamine derivatives.

Full text of DOI:10.1039/c5cc03675e

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Copper(II)-Catalyzed Oxidative N-Nitrosation of Secondary and
Tertiary Amines with Nitromethane Under an Oxygen
Atmosphere
Received 00th January 20xx,
Accepted 00th January 20xx
Norio Sakai,* Minoru Sasaki and Yohei Ogiwara
DOI: 10.1039/x0xx00000x
www.rsc.org/
The combination of a catalytic amount of Cu(OTf)2 and less than a solvent in organic synthesis, functions as an alternative nitroso
stoichiometric amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) under source in the presence of an oxidizing reagent, such as IBX (o-
an O2 atmosphere effectively promoted the N-nitrosation of both iodoxybenzoic
acid)/TBAF
and
KI/TBHP
(t-butyl
secondary aromatic/aliphatic amines and tertiary aromatic amines with hydroperoxide).23 However, in both cases, the use of more
nitromethane (CH3NO2) leading to the preparation of N-nitrosamine than stoichiometric amounts (2-3 equiv per amine) of
derivatives
.
IBX/TBAF or the use of a relatively expensive TBHP requires
completing the desired N-nitrosation. Therefore, there is
ample room for the improvement of these procedures. Thus,
we envisioned the development of a novel catalytic procedure
for N-nitrosation of amines with both nitromethane and a
more economical oxidizing agent in the presence of a metal
catalyst. On the basis of oxidative Nef reaction conditions
involving a base and an oxidizing agent,24 we found interesting
results. Under an O2 atmosphere, copper(II) triflate
successfully catalyzed the N-nitrosation of secondary and
tertiary amines with CH3NO2 in the presence of a base. Herein,
we report the preliminary results of this method. This is the
first example of the copper(II)-catalyzed direct N-nitrosation of
secondary and tertiary amines with CH3NO2 under an O2
atmosphere.25
The facile preparation of N-nitrosamine derivatives has been
extensively studied in organic and medicinal chemistry
because a number of these derivatives are strong carcinogens,
the structure of which are found in various biologically active
substances and functional materials.1 The nitrosation of
amines with nitrous acid that is generated from sodium nitrite
and an acid represents a classic approach to the synthesis of N-
nitrosamines.2 In addition to this procedure, others have been
reported using a nitroso source involving alkyl nitrites (RO-
N=O),3
nitrosyl
chloride
(Cl-N=O),4
nitrosonium
tetrafluoroborate (NOBF4),5 thiol-N2O4,6 nitrogen oxides (N2O3
or N2O4),7 oxyhyponitrite (N2O32-),8 NO under O2 atmosphere,9
Fremy’s salt,10 LiNH2-NO,11 [NO+-18-crown-6-H(NO3)2],12
NaNO2-SnCl4,13
(BrCH2NO2).15 Also during the last decade, a heterogeneous
catalytic system has been widely developed using
combination of either sodium nitrate or nitrogen tetroxide and
catalyst support: NaNO2-SiO2-trichloroisocyanuric acid,16
NO-AgNO3,14
and
bromonitromethane
Initially, we examined the nitrosation of N-methyl-p-
toluidine in the presence of nitromethane and DBU with
copper catalysts and several oxidizing reagents (Table 1). For
example, when N-methyl-p-toluidine was treated with
Cu(OTf)2 (10 mol%) and a relatively strong oxidizing agent, tert-
butyl hydroperoxide (TBHP) at 90 ˚C for 5 h, the desired
nitrosation proceeded producing the nitrosation product 1a in
a 38% yield (entry 1). Thus, when H2O2 was then used, the
yield was slightly improved to 41% (entry 2). It is noteworthy
that the use of an abundant and economical oxidizing reagent,
O2, gave 1a in an excellent yield (entry 3). Next, we ran the
reaction using several copper catalysts. Consequently, the use
of CuBr2, Cu(OAc)2 or a copper(I) catalyst reduced the catalytic
effect for N-nitrosation (entries 4-7). Also, under either an
ambient atmosphere or an inert gas atmosphere, both yields
were substantially reduced to approximately 30% (entries 8
and 9). When both the copper catalyst and DBU had been
reduced to 5 mol% and 0.5 equiv per the starting aniline,
a
a
NaNO2-SiO2-OSO3H on SiO2,17 NaNO2-Nafion-H on SiO2,18 N2O4
supported on PVP,19 N2O4-Chacoal,20 nitrite ionic liquid,21 and
NaNO2-molybdate sulfuric acid.22 In general, NaNO2 has a high
degree of toxicity and requires relatively strong acidic
conditions, which are generally unsuitable for substrates
bearing an acid-sensitive substituent. Quite recently, Hou et al.
and Wan and co-workers, found that nitromethane (CH3NO2),
which is economical and has been used as a common reaction
Department of Pure and Applied Chemistry, Faculty of Science and Technology,
Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510, Japan. E-mail:
sakachem@rs.noda.tus.ac.jp; Web: http://www.rs.tus.ac.jp/sakaigroup/
† Footnotes relaꢀng to the ꢀtle and/or authors should appear here.
Electronic Supplementary Information (ESI) available: The experimental procedure,
spectral data and NMR spectra chart. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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Table 1 Examination of reaction conditions
Entry
[Cu]
[O]a
TBHP
Conversion
(%)b
84
Yield of 1a
(%)b
1
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuBr2
38
2
H2O2
O2
86
41
3
>99
83
91
4
O2
59
5
Cu(OAc)2
CuBr
O2
74
54
6
O2
92
63
7
CuI
O2
76
60
8
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
----
air
---- c
O2
55
33
9
54
35
10d
11e
12f
13g
14
>99
>99
>99
>99
24
89
O2
90 (82)
O2
46
O2
16h
7
O2
a Unless otherwise noted, [O] denotes an oxidizing agent, O2 denotes oxygen
b
c
d
a Reaction time = 4 h. b 100 ˚C (bath temperature).
atmosphere. NMR (Isolated) yield. N2 atmosphere. Cu(OTf)2 (5 mol%), DBU:
e
f
(2 equiv). Cu(OTf)2 (5 mol%), DBU: (0.5 equiv). Cu(OTf)2 (5 mol%), DBU: (0.1
equiv), 7 h. g Cu(OTf)2 (5 mol%), without DBU, 7 h. h N,4-dimethyl-N-(2-nitroethyl)
benzenamine was obtained in a 11% NMR yield.
Scheme 1 Scope of the N-nitrosation of secondary aromatic amines
gave the corresponding product 12a in a good yield. Moreover,
Cu(OTf)2 effectively promoted the N-nitrosation of the
substrate with a pyridine ring without a drastic loss in catalyst
activity, producing the corresponding product 13a in 73%
yield.
respectively, the N-nitrosation successively proceeded (entries
10 and 11). However, the use of 0.1 equiv of DBU led to an
extreme decrease in the product yield, and without DBU the
by-product was formed through a nitro-aldol reaction (entries
12 and 13). Without the copper catalyst, the desired N-
nitrosation hardly occurred with the recovery of most of the
starting amine (entry 14). In most cases with a copper(II)
catalyst, the formation of a trace amount of the N-formylated
p-toluidine derivative as a by-product was detected.
The suggested N-nitrosation process could also be
applicable to aliphatic secondary amines (Scheme 2). For
example, when the reaction of N-benzylmethylamine was
carried out under our optimal conditions, the corresponding N-
nitrosation product 14a was obtained in a relatively good yield.
The scope and limitations using a variety of secondary
aromatic amines were next examined under the optimal
conditions, and the results are shown in Scheme 1. In all cases,
a catalytic amount of copper(II) triflate in the presence of DBU
promoted the reaction. Aniline derivatives bearing either an
electron-donating group at the 3- or 4-position or no
substituent, produced N-nitrosation products 2a-5a in
moderate to good yields. In the case of the aniline having a
dimethyl group, the nitrosation successfully proceeded to the
product 6a in 91% yield. In addition, N-methylanilines with a
relatively weak electron-withdrawing group, such as a chloro
or bromo group, also gave the corresponding products 7a and
8a in excellent yields. Although the reaction of the substrate
with a relatively strong electron-withdrawing group, such as an
o-CN or a p-NO2 group, afforded the N-nitrosation products 9a
and 10a in a relatively low yields, the reaction of an aniline
with an acetyl group produced the N-nitrosation derivative 11a
in a practical yield. Also, the N-nitrosation of N-ethylaniline
a Cu(OTf)2 (10 mol%).
Scheme 2 N-nitrosation of secondary aliphatic amines
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The reactions of a cyclic amine, such as tetrahydroisoquinoline effectively promoted the decomposition of a nitroalkane
and morpholine, also proceeded to give the N-nitroso products compound under an O2 atmosphere.26,27 Also, it was found that
15a and 16a in moderate yields. Also, although the yields of only 1 equiv of the nitroalkane for the aniline successfully
the nitrosation product were relatively low, this catalytic functioned as a nitroso source in the nitrosation series.
oxidizing system could be extended to substrates that have
either a hydroxy group or an allyl moiety.
On the basis of the results obtained above and the
observation of changes in the color of the reaction solution
This procedure could also be applied to the nitrosation of a from blue to brown during the initial preparatory step, we
tertiary aromatic amine with an oxidative cleavage of the C-N proposed a plausible mechanism for the copper-catalyzed N-
bond. Initially, when an electron-rich aniline derivative such as nitrosation of secondary amines (Scheme 5).28 We assumed
either N,N-dimethyl-p-toluidine or N,N-dimethyl-p-anisidine that during the N-nitrosation series (first step), the generation
was treated with the optimal conditions for 19 h, the of nitrous acid would be a key step. Nitromethane would be
corresponding nitrosamine derivatives 1a and 5a were initially treated with DBU, followed by a single-electron
obtained in 79% and 77% yields, respectively (Scheme 3). In oxidation with a copper(II) catalyst, producing the radical
contrast, the use of electron-poor anilines with an electron- intermediate
A. The intermediate A would then be coupled
withdrawing group, such as a bromo or a nitro group, under O2 with molecular O2, and subsequently it would abstract a
atmosphere led to a remarkable decrease in the yield and the hydrogen atom from nitromethane to form the hydroperoxide
recovery of the starting material. However, when the reaction intermediate
was performed with 10 mol% of Cu(OTf)2 and a relatively formed copper(I) catalyst to form formaldehyde and NO2
strong oxidizing agent, TBHP, under an N2 atmosphere, the radical species along with the regeneration of a copper(II)
desired N-nitrosation managed to proceed and provided the catalyst and the generation of a base, a hydroxide ion. Finally,
B. The intermediate B would be reduced by the
C
nitrosamines 8a and 10a
.
a NO2 radical would abstract a hydrogen atom to produce
nitrous acid. Subsequently, the reaction of a secondary amine
with in situ generated nitrous acid gave an N-nitrosation
product (second step). On the other hand, when a secondary
amine was treated without DBU (see, entry 13 in Table 1),
there was a tendency to increase the formation of a nitro-aldol
product as a by-product. Consequently, in addition to its role
as a base, DBU seemed to be essential in the present reaction
in order to help to restrain the formation of the side
products.29 For tertiary aromatic amines, we assumed that
after conversion to the corresponding secondary aromatic
amines, nitrosation proceeded through a similar reaction
mechanism.30,31,32
a Cu(OTf)2 (10 mol%) and TBHP (1.5 equiv) under N2 atmosphere.
Scheme 3 N-Nitrosation of tertiary aromatic amines
To confirm the catalytic effect of the copper catalyst,
several control experiments were performed (Scheme 4).
Initially, when N-methyl-p-toluidine was treated with 1 equiv
of a nitroalkane, 1-phenyl-2-nitroethane in acetonitrile, the
expected nitroso compound 1a was obtained in 69% yield. In a
similar manner, when the reaction was carried out without the
copper(II) catalyst, the yield of the nitroso compound was
decreased to only 10% with the recovery of both the aniline
(83% NMR yield) and the nitroalkane (40% NMR yield). From
these results, it appeared that the copper(II) catalyst
a 1-Phenyl-2-nitroethane was not recovered. b N-Methyl-p-toluidine and 1-phenyl-2-
Scheme 5 Plausible mechanism for the nitrosation of an aromatic secondary amine
nitroethane were recovered in 83 and 40% yields.
using a Cu(II)-DBU-O2 system
Scheme 4 Control experiments for the nitrosation of a secondary aromatic amine
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19 N. Iranpoor, H. Firouzabadi and A.-R. Pourali, Synthesis,
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