Nitromethane with IBX/TBAF as a nitrosating agent: Synthesis of nitrosamines from secondary or tertiary amines under mild conditions

Article abstract of DOI:10.1021/jo202276x

Aliphatic or aromatic N,N-disubstituted nitrosamine was generated in fair to excellent yield from the reaction of a secondary or tertiary amine with o-iodoxybenzoic acid (IBX) or o-iodosylbenzoic acid (IBA)/R₄NX (X = halide) and nitromethane. The product yield was strongly influenced by both the halide of R₄NX and iodanes. IBX gave a higher yield than IBA, while the halides follow F^- > Cl^- > Br^- ～ I^-. Nitrous acid formed in situ from nitromethane and IBX (or IBA)/halides is likely responsible for the observed reaction.

Full text of DOI:10.1021/jo202276x

Article
pubs.acs.org/joc
Nitromethane with IBX/TBAF as a Nitrosating Agent: Synthesis of
Nitrosamines from Secondary or Tertiary Amines under Mild
Conditions
Hima K. Potturi, Ras K. Gurung, and Yuqing Hou*
Meyers Institute for Interdisciplinary Research in Organic and Medicinal Chemistry and Department of Chemistry and Biochemistry,
Southern Illinois University, Carbondale, Illinois 62901, United States
S
* Supporting Information
ABSTRACT: Aliphatic or aromatic N,N-disubstituted nitrosamine was generated in
fair to excellent yield from the reaction of a secondary or tertiary amine with o-
iodoxybenzoic acid (IBX) or o-iodosylbenzoic acid (IBA)/R4NX (X = halide) and
nitromethane. The product yield was strongly influenced by both the halide of R4NX
and iodanes. IBX gave a higher yield than IBA, while the halides follow F− > Cl− >
Br− ∼ I−. Nitrous acid formed in situ from nitromethane and IBX (or IBA)/halides is likely responsible for the observed reaction.
of IBA and a quaternary ammonium bromide may provide a
better regioselectivity than the corresponding IBX combination.
Thus, treating N,N-diethylaniline (3) with two equivalents of
IBA/TMAB in nitromethane produced the expected p-bromo-
N,N-diethylaniline (4) at 80%. Surprisingly, an N-nitrosation−
dealkylation product, 4-bromo-N-ethyl-N-nitrosoaniline (5),
was also observed (Scheme 1). The reaction also turned all IBA
INTRODUCTION
■
N-Nitrosamines have been known as potent carcinogens and
mutagens in lab animals.1,2 Human exposure to such
compounds mainly comes from processed meat products,3
beverages,4 cosmetic products,5 and tobacco smoking.6 The
carcinogenicity and/or mutagenicity of N-nitrosamines are
believed to stem from the DNA-alkylation reactions of their
diazonium metabolites through cytochrome P450 enzymes.7
Additionally, N-nitrosamines are potential nitric oxide
donors, exhibiting intriguing biological activities.8 N-Nitros-
amines are also important intermediates for other useful
organic compounds, such as hydrazines,9 and biologically active
compounds, such as sydnones.10 They are conventionally
synthesized through reactions of amines with either sodium
nitrite/acid11−16 or alkyl nitrites.17,18 Sodium nitrite/acid
method usually requires the use of a strong acid, such as
HCl, limiting the use of this method when there is an acid-labile
group on the substrate. These methods often lead to unwanted
ring nitration and ipso-substitution reactions as well.17,19
Various other nitrosating agents, such as lithium amides/
NO,20 nitrosonium tetrafluoroborate,21 oxyhyponitrite,22 tri-
chloronitromethane,23 and Fremy’s salt,24 have been reported
earlier. However, an efficient synthetic protocol for nitros-
amines with easily available reagents under mild conditions will
be a useful addition to the existing methods.
Hypervalent iodine compounds are becoming increasingly
popular synthetic tools in organic chemistry because of their
low toxicity, ready availability, and ease in handling.25,26
Particularly, o-iodoxybenzoic acid (IBX, 1) has quickly become
the reagent of choice for selective oxidation of alcohols to
aldehydes and ketones. Lately, IBX/tetraethylammonium
bromide (TEAB) has been reported to brominate activated
aromatic compounds.27
However, o-iodosylbenzoic acid (IBA, 2) has not attracted
much attention from synthetic organic chemists, primarily
because it is much less reactive than IBX. We reasoned that
since IBA is a much weaker oxidant than IBX, the combination
Scheme 1. Unexpected Formation of N-Nitrosation−
Dealkylation Product, 5
into o-iodobenzoic acid. A search in the literature showed that
only two brief reports of N-nitrosation of secondary amines by
trichloronitromethane23 or bromonitromethane28 appeared
almost two decades ago. The first reported reaction, however,
was a result of decomposition of trichloronitromethane into
nitrosyl chloride, which was believed to be the active nitrosating
agent,23 while the nitrosation by bromonitromethane was a
result of substitution of the bromine by a secondary amine
followed by nitrite formation.28 To our best knowledge,
nitromethane itself has never been reported as the source of
nitroso group for N-nitrosation reaction. We have, therefore,
explored the scope of this N-nitrosamine formation reaction
and found that this is an effective, fair to high yield, and
selective method to make N-nitrosamine under mild con-
ditions.
Received: November 3, 2011
Published: December 7, 2011
© 2011 American Chemical Society
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Table 1. Effect of Halides and Iodanes on N-Nitrosation−Dealkylation
entry
substrate
iodane/R4NX (equiv)
IBA/(CH3)4NBr (2)
product
yield (%)
1
2
3
4
4
4
4
4
4
4
4
4
3
3
3
3
3
3
3
3
3
3
3
3
5
20
26
IBA/(CH3)4NBr (2)
IBA/(CH3)4NBr (2)
IBA/(CH3)4NBr (4)
IBA/(CH3)4NBr (8)
PhIO/(CH3)4NBr (2)
PhI(OH)(OTs)/(CH3)4NBr (2)
PhI(CO2CF3)/(CH3)4NBr (2)
none/(CH3)4NBr (2)
IBA/none
5
a
b
3
5
26
4
5
45
67
7
5
5
6
5
7
none
none
none
none
none
none
6
0
8
0
9
0
10
11
12
13
14
15
16
17
18
0
IBA/(n-Bu)4NPF6
0
IBA/(n-Bu)4NBF4
0
IBA/(CH3)4NI (2)
19
46
IBA/(C2H5)4NCl·H2O (2)
IBA/(C2H5)4NCl·H2O (8)
IBA/(n-C4H9)4NF (2)
IBA/(n-C4H9)4NF (4)
IBX/(n-C4H9)4NF (2)
IBX/(n-C4H9)4NF (2)
IBX/(n-C4H9)4NF (1)
IBX/(n-C4H9)4NF (1)
IBX/BnMe3NOH
6
c
6
NA
6
53
87
91
0
6
6
d
19
none
6
20
21
22
59
e
6
58
none
0
a
b
Mixture of IBA and (CH3)4NBr was added in small portions over a period of 6 h. A substantial increase in the yield (15%) of aromatic
c
bromination product, 2,4-dibromo-N,N-diethylaniline (30), was observed. A complex mixture of products was observed. No isolation of 6 was
attempted. Reaction was performed at room temperature. THF from the solution of TBAF was evaporated prior to the addition of other reagents.
d
e
Table 2. Effect of Varying Amounts of TBAF on the Yield of 6
entry
molar ratio of 3, IBX, and TBAF
yield (%) of 6
1
2
3
4
5
1:2:2
91
86
82
1:2:1
1:2:0.5
1:2:0.25
1:2:0.25
a
53
b
80
a
b
N,N-diethylaniline was recovered in 24%. The reaction time was prolonged to 8 h.
yield of 5 significantly (Table 1, entries 2 and 3). Higher yield
of 5 was achieved when increased amount of IBA/Me4NBr was
used (Table 1, entries 4 and 5). When a large excess of IBA/
TMAB was used, a number of unidentified side products were
also produced.
Replacing IBA with iodosobenzene, PIFA, or Koser’s reagent
yielded little or no 5 (Table 1, entries 6−8), and no 5 was
observed in the absence of IBA, TMAB, or halide (Table 1,
entries 9−12). Little difference in the yield was observed with
TMAI (Table 1, entry 13), possibly because of the fast
oxidation of iodide to iodine by IBA, consequently leading to
low product yield. Much better yields were obtained when
RESULTS AND DISCUSSION
■
Replacing nitromethane with acetonitrile as the reaction
medium under identical conditions eliminated the formation
of 5, although the bromination went as expected, confirming
that nitromethane is not only a solvent but also a reactant in the
formation of 5. The reaction was further explored with different
substrates, iodanes, and quaternary ammonium salts.
While the ratio of iodane to quaternary ammonium salt was
maintained at 1:1, the ratio of substrate to iodane/quaternary
ammonium salt was varied to see the effect of such alterations
(Table 1). The use of compound 429 as the starting material or
portionwise addition of IBA and TMAB did not increase the
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TEAC or TBAF were used (Table 1, entries 14 and 16), with
IBA/TBAF providing a much cleaner reaction. Surprisingly, 2
equiv of IBX/TBAF was sufficient to induce a clean N-
nitrosation−dealkylation reaction with an excellent yield at 70
°C (Table 1, entry 18), although no reaction was observed at
room temperature (Table 1, entry 19). A small amount of THF
from the commercial TBAF solution did not affect the yield of
6 (Table 1, entries 20 and 21). Thus, the yield of nitrosamine is
greatly affected by the nature of the halides, following this
order: F− > Cl− > Br− ≈ I−. This might be attributed to the
nucleophilicity or basicity of the halides. When 3 was treated
with IBX/benzyltrimethylammonium hydroxide in nitrome-
thane, no reaction was observed (Table 1, entry 22). Thus, it is
reasonable to believe that the superiority exhibited by fluoride
is due to its strongest ability to form a complex with IBX while
not being oxidized easily.
Table 3. Effect of Substrates on the Yield of Nitrosamines
To determine if fluoride is functioning as a catalyst, a series
of experiments with varying amounts of TBAF were carried out
(Table 2). The results clearly show that fluoride is acting as a
catalyst in the reaction, although a stoichiometric amount of
fluoride provided a slightly better yield.
Experiments were also performed on different amines to
evaluate the scope of the reaction (Table 3). While 7, 9, and 10
reacted with IBX/TBAF to provide the expected products in
good yield (Table 3, entries 1, 2, and 3), the treatment of 11−
13 with IBX/TBAF generated complex mixtures (Table 3,
entries 4−6). No nitrosamines were detected by NMR,
although all the starting materials were all consumed. Our
attempt to detect n-decylbenzene in the case of 12 also failed. A
low yield of 4-(N-methyl-N-nitrosoamino)pyridine (15) was
isolated when 14 was subjected to the same treatment (Table 3,
entry 7). An interesting observation was that no reaction
occurred when 16 was used as the substrate (Table 3, entry 8),
indicating that this method should exhibit regioselectivity
between simple amines and amides. Indeed, treating 4-
acetamido-N,N-diethylaniline (17) with IBX/TBAF yielded
18 in 41% with no nitrosation of the amide functionality. When
19 was subjected to the same treatment, 29% of 20 and 23% of
benzaldehyde were obtained, indicating a competition between
the demethylation and debenzylation of the intermediate
(Table 3, entry 10; see also mechanism below). Lastly, the
reaction may also be initiated with other 1° nitroalkanes as
shown by our test reaction with 1-nitropropane (Table 3, entry
11).
To further understand the mechanism, two more experi-
ments were carried out. (1) Treating α-nitrotoluene (21) with
IBX/TBAF in acetonitrile in the absence of amine produced
benzaldehyde (isolated as its 2,4-dinitrophenylhydrazone (22)
in 17% yield). (2) Benzylamine (23) reacted with IBX/TBAF
in nitromethane to afford benzyl 2-iodobenzoate (24) in 22%
yield.30,31 These results indicate that the α-position of the 1°
nitroalkane was oxidized and nitrous acid is a side product of
the oxidation.
Previously, Barton et al. reported that m-iodoxybenzoic acid
and N,N,N′,N′-tetramethyl-N″-t-butyl-guanidine induced the
conversion of secondary nitroalkane into a ketone.32 During
the reaction, a nitrite ion was released through the oxidation of
the conjugate anion of nitroalkanes by m-iodoxybenzoic acid.32
Loeppky et al. have studied N-nitrosation−dealkylation
reaction of tertiary amines with nitrous acid in great detail
and proposed that a radical cation was involved in the
dealkylation step.33−35 Our observations agree with the
mechanisms proposed in these reports. However, fluoride
a
b
Only 1.2 equiv of IBX/TBAF was used. Starting material was all
c
consumed, but N-nitrosamine was not detected with NMR. Starting
d
material was recovered. Benzaldehyde was also observed by 1H NMR
e
in the crude product. 1-Nitropropane was used as the solvent.
does not act as a base in the N-nitrosation−dealkylation but
more likely forms a complex with IBX to induce the reaction.
Based on the observations discussed above and literature
reports, a plausible mechanism is proposed for this reaction
(Scheme 2), illustrated with IBX/fluoride as an example. At
stage 1, fluoride and IBX form a complex, 25, which then reacts
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Scheme 2. Plausible Reaction Mechanism for the Observed N-Nitrosation−Dealkylation
with nitromethane’s tautomer to form cyclic intermediate 26.
The decomposition of 26 generates formaldehyde, nitrous acid,
and IBA. At stage 2, nitrous acid reacts with 3 to form a
quaternary N-nitrosammmonium ion (27), which goes through
a homolytic bond cleavage to release an NO radical and a
radical cation, 28. Radical cation 28 can be further oxidized by
IBX through an electron transfer mechanism to form iminium
ion, 29. Hydrolysis of 29 leads to the formation of a secondary
amine, 9. At stage 3, 9 reacts with another molecule of nitrous
acid to form the final product, 6. This mechanism in Scheme 2
calls for 2 equiv of in situ generated nitrous acid to complete
the reaction with a tertiary amine as the substrate, whereas only
1 equiv of nitrous acid is needed for a secondary amine. This is
also supported by our observation (Table 3, entry 3).
reaction occurs on amines, it does not nitrosate amides, thus
providing a good regioselectivity between amines and amides.
The reaction likely follows the mechanism of oxidative Nef
reaction by generating nitrous acid in situ, which subsequently
reacts with secondary or tertiary amines to provide the final
product.
EXPERIMENTAL SECTION
■
All the reagents, solvents, and starting materials were used as received
1
from commercial suppliers without further purification. H NMR or
13C NMR spectra were recorded on a Varian Mercury 400
spectrometer at 400 or 100 MHz, respectively, in CDCl3, unless
otherwise indicated. Iodosobenzene,36 Koser’s reagent,37 IBA,38 IBX,39
4-bromo-N,N-diethylaniline,29 and N-(4-Diethylamino-phenyl)-acet-
amide40 were synthesized by following previously reported procedures
1
CONCLUSIONS
in the literature and characterized with H NMR.
■
Typical Procedure for the Formation of N-Nitrosamine. In a
50 mL round-bottom flask, N,N-diethylaniline (1 mmol), IBX (2
mmol), and TBAF (2 mmol, in 1 M THF solution) were mixed with
nitromethane (15 mL). The reaction mixture was heated to 70 °C and
maintained at this temperature for 3 h. The mixture was cooled to
room temperature, and 20 mL of saturated sodium bicarbonate
solution was added. The crude product was extracted with ethyl ether,
evaporated, and chromatographed to afford the pure product.
Nitromethane is an inexpensive, stable solvent for organic
reactions. However, under certain conditions, it acts as an
excellent, regioselective nitrosating reagent for amines.
Secondary or tertiary amines reacted with IBX (or IBA)/
R4NX (X = halide) and nitromethane to form nitrosamines in
fair to excellent yields, whereas primary amines produced
complex mixtures. The yield of the product was strongly
influenced by both the halide of R4NX and the structures of the
iodanes. IBX gave a higher yield than IBA, whereas other
iodanes gave very low to zero yield of N-nitrosamines. For the
halides, the following order has been observed: F− > Cl− > Br−
∼ I−. Fluoride is acting as a catalyst in this reaction. While this
1
4-Bromo-N-ethyl-N-nitrosoaniline (5). Spectral data: H NMR
δ 1.09 (t, J = 7.2 Hz, 3H), 3.97 (q, J = 7.2 Hz, 2H), 7.35 (d, J = 8.8 Hz,
2H), 7.53 (d, J = 8.8 Hz, 2H); 13C NMR δ 11.8, 38.8, 120.7, 127.7,
138.6, 140.4. HRMS calculated for C8H10N2OBr, 228.9976; found,
228.9977.
629
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N-Ethyl-N-nitrosoaniline (6). Spectral data: 1H NMR δ 1.19 (t, J
= 7.2 Hz, 3H), 4.08 (q, J = 7.2 Hz, 2H), 7.36 (dd, J = 7.2 Hz, 1.2 Hz,
1H), 7.48 (m, 2H), 7.53 (m, 2H); 13C NMR δ 11.93, 39.42, 119.78,
127.54, 129.73, 141.64. 13C NMR matches with literature report.41
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1
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ASSOCIATED CONTENT
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* Supporting Information
1H and 13C NMR spectra for compounds 5, 15, 18, and 30.
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AUTHOR INFORMATION
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Corresponding Author
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ACKNOWLEDGMENTS
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Financial support for this research from Meyers Institute for
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Southern Illinois University Carbondale is gratefully acknowl-
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