IBX/TBAB-mediated oxidation of primary amines to nitriles

Article abstract of DOI:10.1055/s-0028-1087994

The combination of o-iodoxybenzoic acid (IBX) and tetrabutylammonium bromide (TBAB) efficiently oxidizes primary amines to the corresponding nitriles in good to excellent yield under mild conditions. The reaction is racemization-free when applied to a chiral lysine derivative. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087994

1370
PAPER
IBX/TBAB-Mediated Oxidation of Primary Amines to Nitriles
I
BX/TBAB-
M
l
ediated
e
O
xidation
u
of PrimaryA
r
minestoNitri
Dles rouet, Patrice Fontaine, Géraldine Masson,* Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
Fax +33(1)69077247; E-mail: zhu@icsn.cnrs-gif.fr; E-mail: masson@icsn.cnrs-gif.fr
Received 2 November 2008; revised 18 December 2008
a combined use of o-iodoxybenzoic acid (IBX)20 and tet-
rabutylammonium bromide (TBAB).21 TBAB was found
to play a determinant role in this oxidative transforma-
tion.22 In our initial studies on this reaction, the nitrile re-
sulting from the oxidation of a primary amine was isolated
as a minor product. Stimulated by the potential synthetic
utility of this transformation, we set out to examine this
observation in detail. The recent publication by Kuhakarn
et al. on the use of the reagent combination: IBX and I2,
for the oxidation of primary amines to nitriles23 prompted
us to disclose our own findings. We report herein that a
range of primary amines can be efficiently oxidized by
IBX in the presence of TBAB to afford the corresponding
nitriles (Scheme 1).
Abstract: The combination of o-iodoxybenzoic acid (IBX) and tet-
rabutylammonium bromide (TBAB) efficiently oxidizes primary
amines to the corresponding nitriles in good to excellent yield under
mild conditions. The reaction is racemization-free when applied to
a chiral lysine derivative.
Key words: o-iodoxybenzoic acid (IBX), tetrabutylammonium
bromide (TBAB), amines, nitriles, oxidation, dehydrogenation
The nitrile moiety is a ubiquitous functional group found
in many natural products, and also serves as an important
synthetic handle for the preparation of other functional-
ities and nitrogen-containing heterocyclic compounds.1
Accordingly, substantial work has been dedicated to the
development of efficient methods for its synthesis.
Among these, the direct oxidation of primary amines has
been considered as one of the most direct routes. Conven-
tional methods for this oxidative transformation include
the use of metal oxidants such as lead tetraacetate,2 silver
oxide,3 cobalt and nickel peroxide,4 K2S2O8 with metals,5
OsO4,6 Cu(I) or Cu(II) with O2,7 and ruthenium reagents.8
However, these methods suffer from some disadvantages
such as the toxicity of the reagents, low yields, limited
substrate scope and functional group incompatibility.
Therefore, metal-free conditions using, for example,
NaOCl,9 trichloroisocyanuric acid in combination with
TEMPO,10 molecular iodine11 or 1,3-diiodo-5,5-dimeth-
ylhydantoin12 in aqueous ammonia, and electrochemical
methods,13 have been developed. Surprisingly, hyperval-
ent iodine reagents,14 which are known to be non-toxic,
selective and mild oxidative agents, have rarely been em-
ployed for direct oxidative conversion of primary amines
into nitriles. Moriarty et al. have developed conditions for
the oxidation of amines to nitriles using iodosobenzene,
however, only limited examples were given in this re-
port.15 Nicolaou et al. have shown that Dess–Martin peri-
odinane (DMP) can promote the dehydrogenation of
primary amines to give nitriles, although the protocol was
applicable only to benzylic amines.16 On the other hand,
oxidation of primary amines to nitriles by o-iodoxyben-
zoic acid (IBX) has not yet been investigated in detail.17,18
IBX, TBAB, MeCN, 4 Å MS, r.t.
R
NH2
R
N
1
2
Scheme 1 IBX/TBAB-mediated oxidation of primary amines to ni-
triles
Initial studies were carried out using phenethylamine (1a)
as a model substrate and the results are summarized in
Table 1. Since two equivalents of oxidant are required to
convert one equivalent of amine into the corresponding
nitrile, 2.2 equivalents of IBX was initially used. With
IBX in acetonitrile (MeCN), no oxidation was observed
(entry 1). Addition of TBAB to the reaction mixture pro-
moted the oxidation to afford the phenylacetonitrile (2a)
in 35% yield (entry 2). By running the reaction at a sub-
strate concentration of 0.1 M in acetonitrile, the yield in-
creased to 72% (entry 3). Increasing the amount of IBX/
TBAB (2.5 equiv) significantly accelerated the reaction,
leading to the desired nitrile 2a in 83% yield (entry 4). A
further improvement was obtained by conducting the re-
action in the presence of 4 Å molecular sieves (92% yield,
entry 5). Attempts to use a catalytic amount of TBAB (0.1
equiv, entry 6) failed to produce the desired transforma-
tion. We have also briefly examined the solvent effect and
found that use of dichloromethane or tetrahydrofuran
gave inferior results (entries 7 and 8). Overall, the opti-
mum conditions consisted of performing the reaction in
acetonitrile (~0.1 M) in the presence of IBX, TBAB (2.5
equiv) and 4 Å molecular sieves at room temperature.
In a continuation of our ongoing research program dealing
with the development of new oxidative multi-component
reactions (MCRs),19 we have recently described an effi-
cient three-component synthesis of a-iminonitrile through
In order to examine the scope of the present reaction, the
oxidation of a variety of primary amines were examined
under the optimized reaction conditions. The results are
summarized in Table 2. In most cases, the reaction went
to completion within five minutes to provide the corre-
SYNTHESIS 2009, No. 8, pp 1370–1374
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x
.
x
x
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0
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Advanced online publication: 06.03.2009
DOI: 10.1055/s-0028-1087994; Art ID: T19708SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
IBX/TBAB-Mediated Oxidation of Primary Amines to Nitriles
1371
Table 1 Oxidation of Primary Amines to Nitriles; Survey of Reac-
Table 2 Oxidation of Primary Amines to Nitriles with IBX/TBABa
tion Conditionsa
IBX, TBAB,
4 Å MS
NH2
IBX, TBAB
R
NH2
1b–k
R
N
N
MeCN, r.t.
2b–k
r.t.
1a
2a
Entry
RCH2NH2
Product
Yield (%)b
72
Entry
Solvent
Concn
(mol/L)
IBX/TBAB Time
(mole ratio) (min)
Yield
(%)b
NH2
1
2b
1
2
3
4
5
6
7
8
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
0.8
0.8
0.1
0.1
0.1
0.1
0.1
0.1
2.2/0
60
30
30
5
0
35
72
83
92c
0c
MeO
2.2/2.2
2.2/2.2
2.5/2.5
2.5/2.5
2.5/0.1
2.5/2.5
2.5/2.5
OMe
NH2
NH2
2
2c
84
3
4
5
2d
2e
2f
89
86c
75
5
H2N
NH2
15
5
BocHN
NH2
20c
20c
O
CH2Cl2
5
6
7
2g
2h
76
65
NH2
MeO
a Reagents and conditions: amine (0.1 mmol), solvent (1 mL), r.t.
b Yields after purification by column chromatography.
c The reaction was carried out with 4 Å molecular sieves.
NHCbz
NH2
sponding nitriles in good to excellent yields. 1,6-Diami-
nohexane (1e) was successfully oxidized to adiponitrile
(2e), which is an important precursor for the polymer in-
dustry (86%, entry 4). Both N-carbamate and indolyl units
were tolerated as evidenced by the selective oxidation of
1f, 1g and the tryptamine derivative 1h (entries 5–7).24
The carboxybenzyl-protected lysine methyl ester (1g) was
oxidized to nitrile 2g, without any detectable racemization
(confirmed by chiral HPLC analysis). The oxidation of
benzyl amines bearing electron-donating or withdrawing
groups led to the respective benzonitriles in satisfactory
yields (entries 8–10). For the synthesis of aromatic nitriles
2i–k, the presence of 4 Å molecular sieves was crucial in
order to prevent the hydrolysis of the intermediate ald-
imines to the corresponding aldehydes. With the excep-
tion of 2k, all nitriles were isolated without formation of
the aldehyde. It is noteworthy that aliphatic nitriles were
obtained more readily and with higher yield than their ar-
omatic counterparts. Therefore, the present procedure is
complementary to most of the other conditions used to
generate nitriles from primary amines.
N
Cbz
NH2
NH2
8
9
2i
72
77
50
MeO
O
2j
O
NH2
10
2kd
Cl
a Reagents and conditions: amine (~0.1 M), MeCN, IBX (2.5 equiv),
TBAB (2.5 equiv), r.t.
b Yields after purification by column chromatography.
c Since nitrile 2e is water miscible, no extraction was carried out. The
mixture was directly filtered through a short pad of Celite, concentrat-
ed and purified by column chromatography.
d Aldehyde was isolated as a by-product.
H
NH
Bu4N+—
HO
O
R
O
OH
H2N
R
I
1
While no detailed mechanistic studies have been carried
out, we assumed that the role of TBAB was to increase the
solubility of IBX or intermediates such as 3 (Scheme 2).
The high acidity of IBX25 could indeed favor the forma-
tion of tetrabutylammonium salt, which is known to be
soluble in acetonitrile.26,27 The elimination of a molecule
of water from 3 would afford the aldimine 4 and IBA (the
reduced form of IBX). Further dehydrogenation of imine
4 via the intermediate 5 would then afford the nitrile 2.
Under our reaction conditions, the oxidation of imine 5 to
nitrile 2 apparently proceeded faster than its competitive
hydrolysis to the aldehyde. Alternatively, TBAB may be
oxidized by IBX to tetrabutylammonium tribromide,
O
I
Bu4NBr
O
IBA
Bu4NOH
O
IBX
3
O
H
N
Bu4N+—
HO
O
R
IBX
Bu4NBr
R
HN
R
N
I
O
IBA
H2O
4
5
2
O
Scheme 2 Oxidation of primary amines to nitriles; a mechanistic
proposal
Synthesis 2009, No. 8, 1370–1374 © Thieme Stuttgart · New York

1372
F. Drouet et al.
PAPER
4-Phenylbutyronitrile (2c)
which in turn could act as an oxidizing agent to promote
the observed transformation.28 Further work is required in
order to fully understand the reaction mechanism.
IR (neat): 3140, 2926, 2858, 2246 (C≡N), 1602, 1580, 1496, 1454
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.85–1.95 (m, 2 H), 2.23 (t,
J = 7.0 Hz, 2 H), 2.70 (t, J = 7.0 Hz, 2 H), 7.09–7.28 (m, 5 H, ArH).
13C NMR (75 MHz, CDCl3): d = 16.4 (CH2), 26.9 (CH2), 34.4
(CH2), 119.5 (CN), 126.5 (CHAr), 128.5 (2 × CHAr), 128.7 (2 ×
CHAr), 139.7 (Cq).
In summary, we have demonstrated that a combination of
IBX and TBAB is highly efficient for the oxidation of pri-
mary amines to nitriles. The main attributes of the present
protocol are short reaction times, experimental simplicity
and good yields. In particular, the easy synthesis of ali-
phatic nitriles, which are usually less accessible than their
aromatic counterparts, make this protocol complementary
to other known methodologies.
MS (IE): m/z = 145.0 [M]+·.
Heptanenitrile (2d)
IR (neat): 3120, 2930, 2857, 2248 (C≡N), 1643, 1471, 1427, 823
cm–1.
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 7.0 Hz, 3 H), 1.28–
1.33 (m, 4 H), 1.40–1.49 (m, 2 H), 1.60–1.70 (m, 2 H), 2.31 (t,
J = 7.0 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 13.9 (CH3), 17.1 (CH2), 22.4
(CH2), 25.3 (CH2), 28.3 (CH2), 30.93 (CH2), 119.9 (CN).
Reagents were obtained from commercial suppliers and used with-
out further purification unless otherwise noted. All solvents used in
the reactions were distilled from appropriate drying agents prior to
use. Analytical thin layer chromatography (TLC) was purchased
from Merck KGaA (silica gel 60 F254). Flash column chromatog-
raphy was carried out using Kieselgel 35–70 mm particle sized silica
gel (200–400 mesh). Chromatography was performed using silica
gel 60 (0.040–0.063 mm) purchased from Merck. 1H NMR spectra
were recorded at 500 MHz on a Bruker AC-500 spectrometer and at
300 MHz on a Bruker AC-300 spectrometer. 13C NMR spectra were
recorded at 75 MHz on a Bruker AC-300 spectrometer in CDCl3.
Proton chemical shifts are reported in ppm (d) from tetramethyl-
silane (TMS). Coupling constants (J) are reported in Hz. Infrared
spectra were recorded on neat samples, using a Perkin–Elmer Spec-
trum BX FT-IR spectrometer. Optical rotations were performed on
a Jasco P-1010 polarimeter (589 nm) using a 700 mL cell with a path
length of 1 dm. Mass spectra were determined on an AEI MS-50 in-
strument using electron-impact ionization (EI), AEI MS-9 using
electrospray ionization (ES), and a MALDI-TOF instrument for the
high-resolution mass spectra (HRMS).
MS (IE): m/z = 111.0 [M]+·.
Adiponitrile (2e)
IR (neat): 2944, 2876, 2246 (C≡N), 1460, 1425 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.80–1.84 (m, 4 H), 2.40–2.44 (m,
4 H).
13C NMR (75 MHz, CDCl3): d = 16.7 (2 × CH2), 24.3 (2 × CH2),
118.8 (2 × CN).
tert-Butyl-2-cyanoethylcarbamate (2f)
IR (neat): 3356, 3000–2850, 2246 (C≡N), 1687, 1526, 1365, 1394,
1275 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.45 (s, 9 H), 2.60 (t, J = 6.3 Hz,
2 H, CH2), 3.40 (t, J = 6.3 Hz, 2 H, CH3), 4.94 (br s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 18.9 (CH2), 28.3 (CH3), 36.9
General Procedure
To a stirred suspension of IBX (2.5 mmol) in MeCN under an argon
atmosphere, TBAB (2.5 mmol) was added and the mixture was
stirred for 5 min. To this yellow suspension was added amine (1.0
mmol) and 4 Å molecular sieves, and the mixture was stirred at r.t.
for 5 min. The mixture was quenched with 10% NaHSO3 (2 × 15
mL), and then extracted with EtOAc (3 × 15 mL). The organic phase
was washed with sat. NaHCO3 (2 × 15 mL), H2O (1 × 15 mL), and
brine (1 × 15 mL). The combined organic extracts were dried
(Na2SO2) and concentrated under reduced pressure. Purification by
flash column chromatography (SiO2) afforded the pure nitrile.
(CH2), 80.1 (Cq), 118.2 (CN), 155.6 (Cq).
MS (ESI+): m/z 193.1 [M + Na+].
HRMS (ESI): m/z [M + Na]+ calcd for C8H14N2O2Na: 193.0957;
found: 193.0959.
Benzyl (R)-1-(Methoxycarbonyl)-4-cyanobutylcarbamate (2g)
[a]D25 –8.13 (c 0.98, CHCl3).
IR (neat): 3421, 3089, 2950, 2247 (C≡N), 1744 and 1710 (C=O),
755 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.67–1.83 (m, 4 H), 2.39 (t,
J = 6.5 Hz, 2 H), 3.77 (s, 3 H), 4.38–4.44 (m, 1 H), 5.11 (s, 2 H),
5.34 (br s, 1 H, NH), 7.31–7.38 (m, 5 H, 5 × ArH).
2-Phenylacetonitrile (2a)
IR (neat): 3120, 3033, 2920, 2850, 2251 (C≡N), 1602, 1580, 1496,
1454 cm–1.
13C NMR (75 MHz, CDCl3): d = 16.8 (CH2), 21.5 (CH2), 31.9
(CH2), 52.7 (CH3), 53.0 (CH), 67.3 (CH2), 119.0 (CN), 128.2 (2 ×
CHAr), 128.3 (CHAr), 128.6 (2 × CHAr), 136.0 (Cq), 155.9 (Cq),
172.1 (Cq).
MS (ESI+): m/z = 313.1 [M + Na+].
HRMS (ESI): m/z [M + Na]+ calcd for C15H18N2O4Na: 313.1164;
1H NMR (500 MHz, CDCl3): d = 3.75 (s, 2 H), 7.33–7.40 (m, 5 H,
ArH).
13C NMR (75 MHz, CDCl3): d = 23.6 (CH2), 117.9 (CN), 127.9
(2 × CHAr), 128.0 (CHAr), 129.1 (2 × CHAr), 130.0 (CHAr).
MS (ESI+): m/z = 118.6 [M + H+].
found: 313.1160.
2-(3,4-Dimethoxyphenyl)acetonitrile (2b)
IR (neat): 3065, 2970, 2834, 2242 (C≡N), 1608, 1593, 1514, 1466,
1256, 1234 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.70 (s, 2 H), 3.88 (s, 3 H), 3.89
(s, 3 H), 6.81 (s, 1 H, ArH), 6.84–6.87 (m, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 23.2 (CH2), 56.0 (2 × CH3), 111.0
(CHAr), 111.5 (CHAr), 118.1 (CN), 120.2 (CHAr), 122.2 (Cq),
148.8(Cq), 149.4 (Cq).
N-Carboxybenzyl-3-cyanomethylindole (2h)
IR (neat): 3140, 3000, 2960, 2860, 2252 (C≡N), 1721 (C=O), 1614,
1574, 1498, 1470, 738 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.76 (s, 2 H), 5.46 (s, 2 H), 7.29–
7.34 (m, 2 H, 2 × ArH), 7.34–7.45 (m, 3 H, 3 × ArH), 7.45–7.54 (m,
3 H, 3 × ArH), 7.68–7.70 (m, 1 H, ArH), 8.21 (s, 1 H).
Synthesis 2009, No. 8, 1370–1374 © Thieme Stuttgart · New York

PAPER
IBX/TBAB-Mediated Oxidation of Primary Amines to Nitriles
1373
13C NMR (75 MHz, CDCl3): d = 14.4 (CH2), 69.1 (CH2), 110.5 (Cq),
115.6 (CHAr), 117.0 (CN), 118.4 (CHAr), 123.5 (CHAr), 123.9 (Cq),
125.6 (CHAr), 128.5 (Cq), 128.6 (2 × CHAr), 128.9 (2 × CHAr), 128.9
(CHAr), 134.8 (Cq), 135.6 (Cq), 150.5 (Cq).
MS (ESI+): m/z = 313.1 [M + Na+].
HRMS (ESI): m/z [M + Na]+ calcd for C18H14N2O2Na: 313.0953;
(5) (a) Yamazaki, S.; Yamazaki, Y. Bull. Chem. Soc. Jpn. 1990,
63, 301. (b) Biondini, D.; Brinchi, L.; Germani, R.; Goracci,
L.; Savelli, G. Eur. J. Org. Chem. 2005, 3060.
(6) Gao, S.; Herzig, D.; Wang, B. Synthesis 2001, 544.
(7) (a) Kametani, T.; Takahashi, K.; Ohsawa, T.; Ihara, M.
Synthesis 1977, 245. (b) Capdevielle, P.; Lavigne, A.;
Maumy, M. Synthesis 1989, 453. (c) Capdevielle, P.;
Lavigne, A.; Saparfel, D.; Baranne-Lafont, J.; Nguyen,
K. C.; Maumy, M. Tetrahedron Lett. 1990, 31, 3305.
(d) Maeda, Y.; Nishimura, T.; Uemura, S. Bull. Chem. Soc.
Jpn. 2003, 76, 2399.
(8) (a) Tang, R.; Diamond, S. E.; Neary, N.; Mares, F. J. Chem.
Soc., Chem. Commun. 1978, 562. (b) Green, G.; Griffith,
W. P.; Hollinshead, D. M.; Ley, S. V.; Schröder, M. J. Chem.
Soc., Perkin Trans. 1 1984, 681. (c) Schröder, M.; Griffith,
W. P. J. Chem. Soc., Perkin Trans. 1 1979, 58.
(d) Yamaguchi, K.; Mizuno, N. Angew. Chem. Int. Ed. 2003,
42, 1480. (e) Mori, K.; Yamaguchi, K.; Mizugaki, T.;
Ebitani, K.; Kaneda, K. Chem. Commun. 2001, 461.
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G. A.; Freedman, H. H. Tetrahedron Lett. 1976, 17, 1641.
(10) Chen, F.; Kuang, Y.; Dai, H.; Lu, L.; Huo, M. Synthesis
2003, 2629.
found: 313.0953.
4-Methoxybenzonitrile (2i)
IR (neat): 3100, 3025, 2840 (CH3), 2216 (C≡N), 1604, 1576, 1508,
1458, 1256 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.86 (s, 3 H), 6.85 (d, J = 9.0 Hz,
2 H, ArH), 7.59 (d, J = 9.0 Hz, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 55.6 (CH3), 104.0 (Cq), 114.7 (2 ×
CHAr), 119.2 (CN), 134.0 (2 × CHAr), 162.8 (Cq).
MS (ESI+): m/z = 134.1 [M + H+].
Piperonylnitrile (2j)
IR (neat): 3100, 2921, 2850, 2221 (C≡N), 1618, 1603, 1499, 1442,
1256 cm–1.
1H NMR (500 MHz, CDCl3): d = 6.07 (s, 2 H), 6.86 (d, J = 8.1 Hz,
1 H, ArH), 7.03 (d, J = 1.6 Hz, 1 H, ArH), 7.21 (dd, J = 8.1, 1.6 Hz,
1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 102.2 (CH2), 105.0 (Cq), 109.1
(CHAr), 111.4 (CHAr), 118.9 (CN), 128.2 (CHAr), 148.0 (Cq), 151.5
(Cq).
(11) Iida, S.; Togo, H. Synlett 2006, 2633.
(12) Iida, S.; Togo, H. Synlett 2007, 407.
(13) (a) Feldhues, U.; Schäfer, H. J. Synthesis 1982, 145.
(b) Semmelhack, M. F.; Schmid, C. R. J. Am. Chem. Soc.
1983, 105, 6732. (c) Shono, T.; Matsumura, Y.; Inoue, K.
J. Am. Chem. Soc. 1984, 106, 6075.
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2001, 40, 2812. (c) Tohma, H.; Kita, Y. Adv. Synth. Catal.
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(15) (a) Moriarty, R. M.; Vaid, R. K.; Duncan, M. P.; Ochiai, M.;
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(b) Porta, F.; Crotti, C.; Cenini, S.; Palmisano, G. J. Mol.
Catal. 1989, 50, 333.
2-Chlorobenzonitrile (2k)
IR (neat): 3093, 3067, 2229 (C≡N), 1591, 1566, 1471, 1439, 756
cm–1.
1H NMR (500 MHz, CDCl3): d = 7.39 (t, J = 7.9 Hz, 1 H, ArH),
7.51–7.56 (m, 2 H, ArH), 7.68 (d, J = 7.9 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 113.4 (Cq), 116.0 (CN), 127.2
(CHAr), 130.1 (CHAr), 133.9 (CHAr), 134.0 (CHAr), 136.9 (Cq).
Acknowledgment
Financial support from CNRS and ICSN are gratefully acknowl-
edged. F.D. and P.F. thanks ICSN for a doctoral fellowship.
(16) Nicolaou, K. C.; Mathison, C. J. N. Angew. Chem. Int. Ed.
2005, 44, 5992.
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Chem. Soc. 2004, 126, 5192.
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