Synthesis of nitriles from aldehydes with trimethylphenylammonium tribromide and ammonium acetate

Article abstract of DOI:10.3987/COM-16-13542

Various aromatic and heterocyclic aldehydes were easily converted to respective nitriles with the combination of trimethylphenylammonium tribromide and ammonium acetate in good yields at room temperature.

Full text of DOI:10.3987/COM-16-13542

HETEROCYCLES, Vol. 92, No. 10, 2016, pp. -. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 25th July, 2016, Accepted, 19th August, 2016, Published online, 25th August, 2016
DOI: 10.3987/COM-16-13542
SYNTHESIS OF NITRILES FROM ALDEHYDES WITH TRIMETHYL-
PHENYLAMMONIUM TRIBROMIDE AND AMMONIUM ACETATE1
Shinsei Sayama*
Department of Chemistry, Fukushima Medical University, Hikarigaoka,
Fukushima 960-1295, Japan; E-mail: pbtbw009@yahoo.co.jp
Abstract – Various aromatic and heterocyclic aldehydes were easily converted to
respective nitriles with the combination of trimethylphenylammonium tribromide
and ammonium acetate in good yields at room temperature.
Nitriles have been known to be effective for the synthetic intermediates of amides, amines, esters2 and for
the preparation of bioactive heterocycles such as imidazoles, tetrazoles, thiazoles.3 Aromatic nitriles from
aryl diazonium salts were synthesized by Sandmeyer reaction and other alkyl nitriles were also prepared
by the nucleophilic reaction of alkyl halides with inorganic cyanides.
As those methods using a stoichiometric amounts of inorganic cyanides were harmful and hazardous,
there have been reported alternative methods such as methylarenes with NBS,4a aryl halides with
CuSCN,4b or Zn (CN)2,4c and alkyl halides with TBACN.4d Further, convenient transformation of primary
alcohols,5a,5b amines,5b,5c and oxiranes5d to nitriles was also reported respectively.
Moreover transformations of aldehydes to nitriles have been studied independently.6 The methods for
producing nitriles via aldehyde derivatives such as aldoximes,7 aldehyde N-tosylimines,8a aldehyde
trimethylhydrazonium iodides,8b were also investigated. The Fe3O4-catalyzed one-pot three-component
synthesis of -aminonitriles from aldehydes, amines, and TMSCN was reported.9 The simple and
economical synthesis of nitriles from aldehydes with hydroxylamine hydrochloride catalyzed by
KF/Al2O3 was explored.10 Therefore, there is still considerable interest in investigating an alternative
synthesis of various nitriles from aldehydes.
On the other hand, the methods for the oxidation of secondary alcohols to ketones,11a the chemoselective
conversion of aromatic epoxide to 1,3-dioxane derivatives,11b and the transformation of alkoxyfurans to
3(2H)-furanones11c,11d were achieved with commercially available trimethylphenylammonium tribromide
(phenyltrimethylammonium tribromide, PTAB). The regioselective one-pot synthesis of
6-bromobenzothiazoles form arylaldehydes was also achieved with PTAB-SbBr3.12 The oxidation of

carbohydrates to keto-sugars was recently developed with PTAB-K2CO3 in the presence of organotin
catalyst.13 Thus, the use of PTAB was expected to be attractive in oxidative organic syntheses. Zhu and
Cai reported the synthesis of nitrile with tetrabutylammonium tribromide in aqueous ammonia.14
Therefore, it was seemed to be significant in finding a new oxidative procedure for preparation of nitriles
from aldehydes with PTAB. Recently preparation of aromatic nitriles from aldehydes with
pentylpridinium tribromide in aqueous NH4OAc was also reported by Bagherzade, Zali, and Sokrolahi.15
As we have also presented preliminary alternative reports for conversion of aldehydes to nitriles, we
would like to report on the results of our studies concerning the one-pot synthesis of heterocyclic and
aromatic nitriles from aldehydes with PTAB-NH4OAc.1
At first, the reaction of 2-pyridinecarbaldehyde (1), chosen as a representative heterocyclic aldehyde for
this study, was carried out with various molar ratios of PTAB and NH4OAc over 1 for obtaining
2-pyridinenitrile (2). The results are summarized in Table 1. At 2.0 molar ratios of PTAB and 10.0 molar
ratios of NH4OAc over 1 in CH2Cl2 at room temperature, 2-pyridinenitrile (2) was afforded in good yield
(run 1). To examine the optimum amounts of PTAB for the synthesis of nitrile 2, the reaction of 1 with
0.0-1.5 molar ratios of PTAB was carried out in the presence of 10.0 molar ratios of NH4OAc over 1. At
1.5 molar ratios of PTAB, the yield of 2 was 92%, accompanied by small amounts of recovered 1 (run 2).
A mixture of nitrile 2 (84%) and recovered 1 (10%) was afforded at 1.0 molar ratio of PTAB over 1 (run
3). A complex mixture was given without PTAB under the same reaction conditions (run 4).
Consequently, there is need to use at least more than 1.5 molar equivalents of PTAB over 1 for obtaining
nitrile 2 in moderate yield.
To clarify the optimum amounts of NH4OAc for conversion of 1 to nitrile 2, the reaction of 1 with 1.0-8.0
molar ratios of NH4OAc was also carried out in the presence of 2.0 molar ratios of PTAB over 1
respectively. At 8.0 molar ratios of NH4OAc over 1, the reaction of 1 with PTAB gave nitrile 2 in 95%
yield(run 5). At 4.0-6.0 molar ratios of NH4OAc over 1, nitrile 2 was afforded in 84-87% yields,
accompanied by 8-9% recovered 1 (runs 6, 7). The yields of 2 were not fully satisfactory, accompanied
by recovered 1 (29-48%) at 1.0-2.0 molar ratios of NH4OAc in the presence of 2.0 molar ratios of PTAB
over 1 (runs 8, 9). The satisfactory yield of nitrile 2 was not observed at 1.0 molar ratio of PTAB and 6.0
molar ratio of NH4OAc (run 10). In the present experiments, there is need to use at least 6.0-10.0
equivalents of NH4OAc in the presence of 2.0 equivalents of PTAB over 1 for producing nitriles 2
quantitatively. Further, the reaction of 1 with ammonium oxalate or NH4Cl instead of NH4OAc was
carried out to examine the effect of NH4OAc in this method. At 6.0 molar ratios of ammonium oxalate in
the presence of 2.0 molar ratios of PTAB, the yield of nitrile 2 was not fully satisfactory accompanied by
recovered 1 (run 11). At 10.0 molar ratios of NH4Cl, aldehyde 1 was recovered unchanged under the
same reaction conditions (run 12). Accordingly, this one-pot synthesis of 2-pyridinenitrile 2 from

Table 1. Reaction of 2-pyridinecarbaldehyde 1 and NH4OAc with PTAB a
PTAB
N
CHO
N
CN
NH4OAc
1
2
PTAB NH4OAc
Product
Yield (%)
Product
Yield (%)
PTAB NH4OAc
Run
1
Run
12
Solv. Time
(h)
Solv.
Time
(Molar ratio / 1)
(Molar ratio / 1)
(h)
15
2
1
2
1
10.0d
2.0
CH2Cl2
--
CH2Cl2
16
--
2.0
95
98
10.0
CH2Cl2
CH2Cl2
MeOH
MeCN
--
--
--
1.5
17
17
92
84
13
14
2.0
2.0
10.0
10.0
15
93
2
2
3
10.0
21 95
21 93
10.0
10
1.0
--
CH2Cl2
CH2Cl2
CH2Cl2
--
--
hexane
benzene
H2O
--b
95
10.0
8.0
15
16
17
2.0
2.0
2.0
10.0
10.0
10.0
21
21
15
4
5
6
2.0
2.0
48
21
47
--
6.0
9
21 93
87
2.0e
2.0e
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
MeCN
--
--
2.0
2.0
2.0
21
22
22
84
67
48
21
22
21
10.0
10.0
7
8
9
4.0
2.0
8
18
19
94
92
29
2.0e
CH2Cl2
CH2Cl2
CH2Cl2
--
1.0
6.0
48
18
10.0
20
94
93
93
2.0e
2.0e
--
--
hexane
H2O
1.0
2.0
17
17
77
21
22
10.0
10.0
21
21
10
11
6.0c
76 18
a 1: 0.5 mmol; Solvent: 6 mL; Temp: rt. b Complex mixture was obtained. c (CO2NH4)2. dNH4Cl. e PHPB was
used insted of PTAB.
2-pyridinecarbaldehyde 1 was suggested to rest on the complemental function of PTAB and NH4OAc.
To test the suitable solvents in this method, the conversion of 1 to 2 was carried out with PTAB-NH4OAc
in various solvents such as MeOH, MeCN, hexane, benzene, H2O under the same reaction conditions. In
MeOH, MeCN, hexane, 1 was converted to 2 in good yields respectively (runs 13-15). A mixture of
nitrile 2 (48%) and recovered aldehyde 1 (47%) was afforded in benzene (run 16). H2O was also found to
be appropriate solvent for conversion of 1 to 2 (run 17). Consequently, it was found that the preparation
of nitrile 2 from aldehyde 1 by PTAB-NH4OAc was not rest on solvents excepting for benzene.
To examine the effect of ammonium tribromides, the conversion of 1 to 2 was carried out with
pyridinium hydrobromide perbromide(PHPB) instead of PTAB in the presence of NH4OAc in various
solvents. Nitrile 2 was respectively given with PHPB in 92-94% yields in CH2Cl2, MeOH, MeCN, hexane,
H2O under the same reaction conditions (runs 18-22). Accordingly, the combination of ammonium
tribromides, PTAB or PHPB and NH4OAc was confirmed to be alternative convenient one-pot procedure
for conversion of 2-pyridinecarbaldehyde 1 to 2-pyridinenitrile 2.

Table 2. Reaction of aldehydes and NH4OAc with PTAB a
PTAB
RCHO
S
RCN
NH4OAc
Products,
Yield (%)
Time
Time
(h)
Substrate (S)
Products,
Run
1
Substrate (S)
Yield (%)
Run
6
(h)
17
11d
13d
2
4
95
78
12 94
1
3b
5
29
29
CHO
CHO
CN
CN
N
N
N
N
N
N
CHO
CN
CHO
CN
7
8
14
16
2
3
94
94
17
21
N
N
CHO
CN
N
CHO
CN
15d
94
92
6
8
17
N
N
N
17d
19b
4
5
14
21
18 93
20 69
16
16
9
7
N
CHO
N
N
CHO
CHO
N
CN
CN
Me
Me
NC
CN
N
N
S
9c
10 91
CHO
CN
10
N
N
OHC
S
a S: 0.5 mmol; PTAB: 1.0 mmol; NH4OAc: 5.0 mmol; CH2Cl2: 6.0 mL; Temp: rt. b MeCN was used insted of
CH2Cl2. c 9: 0.25 mmol. d S: 0.25 mmol; PTAB: 1.0 mmol; NH4OAc: 5.0 mmol; MeCN: 6.0 mL; Temp: rt.
To elucidate the limitations for this conversion of heterocyclic aldehydes to nitriles, the reaction of
various heterocyclic aldehydes was examined with PTAB-NH4OAc. The results of the reaction of
heterocyclic aldehydes are shown in Table 2. The reaction of 3-pyridinecarbaldehyde (3),
4-pyridinecarbaldehyde (5), and 6-methyl-2-pyridinecarbaldehyde (7) took place to give corresponding
nitriles (4), (6), (8) respectively (runs 2-4). 2,6-Pyridinedicarbaldehyde (9) was similarly converted to
dinitrile(10) in good yield (run 5).
The reaction of quinolinecarbaldehydes, 2-formylthiazole was also carried out with PTAB-NH4OAc to
clarify the chemoselectivity for conversion of heterocyclic aldehydes to nitriles. The reaction of 2-, 3-, 4-,
and 8-quinolinecarbaldehydes (11), (13), (15), (17) also took place to give corresponding nitriles (12),
(14), (16), (18) in good yields (runs 6-9). 2-Formylthiazole (19) was converted to nitrile (20)(run 10).
A variety of heterocyclic nitriles were found to be easily prepared from respective aldehydes with
PTAB-NH4OAc.
To test the application for other aldehydes by this PTAB-NH4OAc system, the reaction of various
aromatic aldehydes was carried out under the same reaction conditions. The results of aromatic aldehydes
are shown in Table 3. Benzaldehyde (21) was converted to benzonitrile (22) (run 1). The reaction of o-,
m-, and p-tolualdehydes (23), (25), (27) took place to give corresponding nitriles (24), (26), (28) in
64-73% yields, accompanied by respective recovered aldehydes (runs 2-4). o-, and p-Nitrobenzaldehydes

Table 3. Reaction of aldehydes and NH4OAc with PTAB a
PTAB
RCHO
RCN
S
NH4OAc
Yield (%)
Yield (%)
Products,
Substrate (S)
Products,
Substrate (S)
Run
Time
(h)
Run
Time
(h)
R
R
Cl
Cl
35e
37e
39e
CN
22 91
36
1
2
3
21 17
64
94
94
94
8
9
CN
Me
Me
CN
73b
64c
23
25
Cl
Cl
CN
15
16
64
15
16
38
40
24
26
Me
Me
Br
Br
10
CN
CN
CN
Br
Br
28 69d
41e
43e
Me
27
29
Me
CN
11
12
42 89
4
5
16
16
NO2
NO2
CN
92
93
Br
16 Br
CN
30
32
89
44
Me
Ph
Ph
Me
Ph
6
7
NO2
NO2
CN
45
47
CN
93
93
17
64
17
17
46
48
13
14
31
Cl
Cl
CN
33e
34 93
Ph
CN
a S: 0.5 mmol; PTAB: 1.0 mmol; NH4OAc: 5.0 mmol; MeCN: 6.0 mL; Temp: rt. b Recovered 23: 22%.
c Recovered 25: 32%. d Recovered 27: 28%. e S: 0.25 mmol; PTAB: 1.0 mmol; NH4OAc: 5.0 mmol; MeCN: 6.0 mL;
Temp: rt.
(29) (31) were converted to nitriles (30), (32) (runs 5,6). o-, m-, and p-Chlorobenzaldehydes (33), (35),
(37) were converted to corresponding nitriles (34), (36), (38). o-, m-, and p-Bromobenzaldehydes (39),
(41), (43) were also converted to respective nitriles (40), (42), (44) in good yields (runs 7-12). Further,
2-phenylpropionaldehyde (45) and 3-phenylpropionaldehyde (47) were similarly converted to nitriles (46),
(48) (runs 13, 14). Thus, the conversion of aromatic aldehydes to nitriles with PTAB-NH4OAc was not
rested on the substituents of aromatic ring.
The PTAB-NH4OAc system was confirmed to be useful for conversion of heterocyclic and aromatic
aldehydes to corresponding nitriles in various solvents.1
Since aromatic and heterocyclic nitriles are of particular interest as key intermediates in the syntheses of
biologically active compounds by amidation and ester exchange reactions, the combination of ammonium
tribromides, PTAB or PHPB and NH4OAc provides a significant alternative method for the synthesis of
various nitriles from aldehydes.1,16,17

REFERENCES AND NOTES
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16. Typical procedure: To a solution of 2-pyridinecarbaldehyde 1 (54 mg, 0.5 mmol) and ammonium
acetate (385 mg, 5.0 mmol) in MeCN (6 mL), was added trimethylphenylammonium tribromide
(376 mg, 1.0 mmol) at room temperature. After stirring for 21 h at rt, the reaction mixture was
treated with 0.5 M aq. Na2S2O3(10 mL), 1.0 M NaHCO3 (15 mL) and extracted with EtOAc (60 mL).
The organic layer was washed with 0.5 M Na2S2O3 and successively washed with saturated aq. NaCl,
and dried over MgSO4. After removal of solvent in vacuo, the residue was purified by column
chromatography on silica gel (Wako C-200) with CCl4, CCl4-CHCl3 (2:1 v/v). 2-Pyridinenitrile 2 (49
mg, 0.47 mmol) was obtained in 95% yield. 2: IR (neat, cm-1) 3059, 3021. 2926, 2236, 1597, 1581,
1
1571, 1462, 1432, 1287, 1248, 1217, 1154, 1091, 1045, 992, 780, 756, 667, 631. H NMR (CDCl3)
13
7.53-7.58(1H, m), 7.73(1H, d, J=8.1 Hz), 7.88(1H, dd, J=8.1, 2.7 Hz), 8.75(1H, d, J=2.7 Hz). C
NMR (CDCl3) 117.16, 126.89, 128.49, 133.93, 136.99, 151.08.
17. The reaction of 2-pyridinecarbaldehyde 1 (10 mmol, 1.07 g) was carried out as follows: To a
solution of 2-pyridinecarbaldehyde (1.07 g) in MeCN (50 mL) were added NH4OAc (7.70 g, 0.1
mol) and PTAB (7.53 g, 20 mmol). After stirring for 18 h at rt, the precipitated trimethylphenyl
ammonium bromide (ca. 8.32 g) was filtered off, washed with MeCN (15 mL). The combined
filtrate was treated with 0.5 M aq. Na2S2O3 (30 mL), 1.0 M aq. NaHCO3 (60 mL) and extracted with
EtOAc (100 mL) The organic layer was washed with 0.5 M aq. Na2S2O3 (30 mL), successively
saturated aq. NaCl (50 mL), and dried over MgSO4. After removal of solvent in vacuo, the residue
was purified by column chromatography( 20 mm, L 140 mm) on silica gel (Merck, Kieselgel Type
60, 230-400 mesh) with CCl4, CCl4 and CHCl3(2:1 v/v). 2-Pyridinenitrile 2 (852 mg) was obtained.