One-pot transformation of carboxylic acids into nitriles

Article abstract of DOI:10.1002/ejoc.201300629

A variety of aromatic and aliphatic carboxylic acids were smoothly converted into the corresponding nitriles in good yields in a one-pot procedure by treatment with ethyl iodide/K₂CO₃/18-crown-6, followed by sodium diisobutyl-tert-butoxyaluminium hydride (SDBBA-H), and finally treatment with molecular iodine or 1,3-diiodo-5,5-dimethylhydantoin (DIH), and aqueous ammonia. This method is useful for the conversion of various aromatic and aliphatic carboxylic acids into the corresponding nitriles in a one-pot procedure. A variety of aromatic and aliphatic carboxylic acids were smoothly converted into the corresponding nitriles in good yields in a one-pot procedure by treatment with ethyl iodide/K₂CO₃/18-crown-6, followed by sodium diisobutyl-tert-butoxyaluminium hydride (SDBBA-H), and finally treatment with molecular iodine or 1,3-diiodo-5,5-dimethylhydantoin (DIH), and aqueous ammonia. Copyright

Full text of DOI:10.1002/ejoc.201300629

FULL PAPER
DOI: 10.1002/ejoc.201300629
One-Pot Transformation of Carboxylic Acids into Nitriles
Kotaro Miyagi,[a] Katsuhiko Moriyama,[a] and Hideo Togo*[a]
Keywords: Carboxylic acids / Cyanides / Iodine / Ammonia / One-pot reactions
A variety of aromatic and aliphatic carboxylic acids were
smoothly converted into the corresponding nitriles in good
yields in a one-pot procedure by treatment with ethyl iodide/
K2CO3/18-crown-6, followed by sodium diisobutyl-tert-but-
oxyaluminium hydride (SDBBA-H), and finally treatment
with molecular iodine or 1,3-diiodo-5,5-dimethylhydantoin
(DIH), and aqueous ammonia. This method is useful for the
conversion of various aromatic and aliphatic carboxylic acids
into the corresponding nitriles in a one-pot procedure.
CuCN (the Sandmeyer reaction).[6] On the other hand, the
one-pot preparation of nitriles from carboxylic acids is a
very attractive concept, as various carboxylic acids are com-
mercially available. Today, nitriles can be directly prepared
by the reaction of carboxylic acids with TsNH2 and PCl5 at
200 °C;[7a] the reaction of carboxylic acids with NH3 and
silica gel at 500 °C;[7b] the carboxylic acid–nitrile exchange
reaction at 285 °C;[7c] the reaction of carboxylic acids with
NH3 and ethyl polyphosphate (PPE) at 80 °C;[7d] the reac-
tion of carboxylic acids with (COCl)2, followed by reaction
with 2,4-dinitrobenzenesulfonamide and Et3N at r.t.–
70 °C;[7e] the reaction of carboxylic acids with bis(2-meth-
oxyethyl)aminosulfur trifluoride (Deoxo-Fluor), NaN3, and
Ph3P via acyl azides at room temperature;[7f] the reaction of
carboxylic acids with P2I4 and ammonium carbonate at
room temperature;[7g] and the reaction of arenecarboxylic
acids with cyanohydrins, Pd(OTf)2, and Ag2CO3 in a de-
carboxylation reaction at 100 °C,[7h] etc. However, those re-
actions have drawbacks, such as high reaction temperatures,
the requirement for acidic dehydration reagents, or the use
of toxic metal azides, moisture-sensitive reagents, or expens-
ive reagents such as palladium, etc. Thus, practical and mild
methods for the one-pot preparation of nitriles from easily
available carboxylic acids are still required.
Introduction
Nitriles are very useful and important intermediates in
organic chemistry.[1] The nitrile group is one of the most
important and versatile functional groups, as it can be
easily converted into numerous other functional groups,
such as aldehydes, ketones, amines, and amides, and also
into nitrogen-containing heterocycles, such as oxaz-
oles,[2a–2c] thiazoles,[2d,2e] tetrazoles,[2f–1] triazolo[1.5-c]pyr-
imidines,[2j] 1,2-diarylimidazoles,[2k] etc. One-carbon ho-
mologated nitriles are typically obtained by the reaction of
alkyl halides with toxic metal cyanides.[3] Alternatively, the
dehydration of primary amides and aldoximes, or the oxi-
dation of primary amines, provide the corresponding ni-
triles while retaining the same number of carbon atoms.
Thus, nitriles are generally prepared by the dehydration of
primary amides with SOCl2, TsCl/pyridine, P2O5, POCl3,
COCl2, TiCl4, (CF3CO)2O/pyridine, (EtO)3P/I2, or Ph3P/
CCl4,[3] and recently, aromatic nitriles have been prepared
by the dehydration of aromatic amides with (CH2O)n/
HCO2H,[4a] (COCl)2/DMSO,[4b] dibutyltin oxide/microwave
irradiation,[4c] Cp2Zn(CH3)2,[4d] Cl2P(O)OEt/DBU (1,8-di-
azabicycloundec-7-ene),[4e] or Ru3(CO)7/R3SiH.[4f] The oxi-
dative conversion of primary amines into the corresponding
nitriles has also been studied well using AgO,[5a] Pb-
(OAc)4,[5b–5e] cobalt peroxide,[5f] nickel peroxide,[5g]
Na2S2O8 or (Bu4N)2S2O8 together with metals,[5h–5k] Na-
OCl,[5l–5n] K3Fe(CN)6,[5o] CuI or CuII together with oxy-
gen,[5p–5s] RuCl3 or related Ru reagents,[5t–5x] PhIO,[5y] or
trichloroisocyanuric acid toegther with TEMPO [(2,2,6,6-
In this paper, as part of our basic research into molecular
iodine and related iodine reagents for organic synthesis,[8]
we would like to report the mild one-pot conversion of a
wide range of carboxylic acids into the corresponding ni-
triles. The reaction proceeds through ethylation of carb-
oxylic acids, subsequent reduction with sodium diisobutyl-
tert-butoxyaluminium hydride (SDBBA-H),[9] and then
treatment with molecular iodine and aqueous ammonia.
Tetramethyl-piperidin-1-yl)oxyl].[5z]
meanwhile, are usually prepared from aromatic amines by
treatment with NaNO2 and aqueous HCl, followed by
Aromatic
nitriles,
[a] Graduate School of Science, Chiba University,
Yayoi-cho 1-33, Japan
Results and Discussion
E-mail: togo@faculty.chiba-u.jp
Recently, we reported the one-pot conversion of iso-
propyl esters and of N,N-disubstituted amides into the cor-
responding nitriles by treatment with diisobutylaluminium
Homepage: http://reaction-2.chem.chiba-u.jp/index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300629.
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Eur. J. Org. Chem. 2013, 5886–5892

One-Pot Transformation of Carboxylic Acids into Nitriles
hydride (DIBAL-H), followed by reaction with molecular with ethyl iodide, K2CO3, and 18-crown-6, then with
iodine and aqueous Ammonia.[8o] We also reported the one- SDBBA-H, and finally with molecular iodine and aqueous
pot conversion of ethyl esters into the corresponding nitriles ammonia, to give the corresponding aromatic nitriles in
by treatment with sodium diisobutyl-tert-butoxyaluminium good yields, as shown in Table 2, entries 2–12. These arene-
hydride (SDBBA-H), followed by reaction with molecular carboxylic acids included 2-naphthoic acid, p-nitrobenzoic
iodine and aqueous ammonia.[8q] Based on those studies, acid, p-fluorobenzoic acid, p-chlorobenzoic acid, p-bromo-
we planned to perform a one-pot conversion of carboxylic benzoic acid, m-bromobenzoic acid, o-bromobenzoic acid,
acids into nitriles, through esterification. Thus, 1-naphthoic p-iodobenzoic acid, o-iodobenzoic acid, p-trifluoromethyl-
acid was treated with ethyl iodide in the presence of K2CO3 benzoic acid, and p-cyanobenzoic acid. For m-bromoben-
and 18-crown-6, and subsequently the reducing agent zoic acid, p-iodobenzoic acid, o-iodobenzoic acid, and p-tri-
SDBBA-H was added. This was followed by treatment with fluoromethylbenzoic acid, which have an electron-with-
molecular iodine and aqueous ammonia at 0 °C to room drawing group on the aromatic ring, the reduction of the
temperature to give 1-naphthonitrile, as shown in Table 1, esters with SDBBA-H (in the second step) was carried out
entries 1–5.
at –70 to 0 °C over 4 h, to improve the yields of the aro-
The reduction of the ethyl ester to the hemiacetal anion matic nitriles (Table 2, entries 7 and 9–11). When the re-
is the key point. SDBBA-H should be added at –40 °C, and duction of the esters with SDBBA-H was carried out at –40
then the mixture should be slowly warmed to 0 °C, to sup- to 0 °C over 4 h, the yields of aromatic nitriles were in the
press the over-reduction to the alcohol. When DIBAL-H range 54–61%, and the corresponding benzylic alcohols
was used instead of SDBBA-H, mainly the alcohol was ob- were formed with yields of 12–25%. On the other hand,
tained, together with ethyl ester (Table 1, entry 6). Other ethyl esters derived from electron-rich arenecarboxylic
monohydride reducing agents, such as LiAlH(OtBu)3 and acids, such as benzoic acid, p-methylbenzoic acid, p-meth-
NaBH(sBu)3, were used at –78 to 0 °C, or at 0 °C to room oxybenzoic acid, benzofuran-2-carboxylic acid, and benzo-
temperature. However, 1-naphthonitrile was not formed at thiophene-2-carboxylic acid, did not react with SDBBA-H
all because no reduction occurred (Table 1, entries 7–10). at –40 °C. Therefore, for those substrates, the reduction of
The effect of changing the alkylating agent used for 1- the esters with SDBBA-H was carried out at 0 °C or at 0 °C
naphthoic acid was studied under the same conditions and to room temperature, and then the reaction mixtures were
using the same procedure for the conversion of 1-naphthoic treated with molecular iodine and aqueous ammonia at
acid into 1-naphthonitrile. Methyl iodide, ethyl iodide, 0 °C to room temperature to give the corresponding aro-
propyl iodide, isobutyl iodide, butyl iodide, and meth- matic nitriles in good yields (Table 2, entries 13–17). Next,
oxymethyl bromide were tested, and ethyl iodide was found aliphatic carboxylic acids bearing an sp3 hybridized alkyl
to give the best result (Table 1, entries 5 and 11–15). Based group, such as 3-phenylpropanoic acid, palmitic acid, stea-
on these results, and using the best reaction conditions and ric acid, oleic acid, and adamantane-1-carboxylic acid, were
procedure, a variety of arenecarboxylic acids were treated treated with ethyl iodide, K2CO3, and 18-crown-6, then
Table 1. Transformation of 1-naphthoic acid into 1-naphthonitrile.
Entry
Second step
Temp.
Third step
NH3 (aq.) [mL]
Yields [%][a]
Nitrile
Red. agent[b] [equiv.]
Time [h]
I2 [equiv.]
Ester
1
2
3
4
5
6
7
8
9
10
11[d]
12[e]
13[f]
14[g]
15[h]
1.5
1.8
2.0
2.2
–40 to 0 °C
–40 to 0 °C
–40 to 0 °C
–40 to 0 °C
–40 to 0 °C
–78 °C
–70 to 0 °C
0 °C to r.t.
–70 to 0 °C
0 °C to r.t.
–40 to 0 °C
–40 to 0 °C
–40 to 0 °C
–40 to 0 °C
–40 to 0 °C
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
6
6
6
6
6
6
6
6
6
6
6
4.1
4.1
4.1
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
37
58
44
73
56
22
18
10
trace
48
95
83
86
78
11
42
27
39
2.2
77
DIBAL-H, 1.5
LiAlH(OtBu)3, 1.5
LiAlH(OtBu)3, 1.5
NaHB(sBu)3, 1.5
trace (45)[c]
0
0
0
NaHB(sBu)3, 1.5
0
2.2
2.2
2.2
2.2
2.2
47
15
50
47
35
15
[a] Isolated yields. [b] SDBBA-H unless otherwise stated. [c] Yield of 1-naphthalenemethanol. [d] CH3I was used instead of EtI. [e] nPrI
was used instead of EtI. [f] iBuI was used instead of EtI. [g] nBuI was used instead of EtI. [h] CH3OCH2Br was used instead of EtI.
Eur. J. Org. Chem. 2013, 5886–5892
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K. Miyagi, K. Moriyama, H. Togo
FULL PAPER
Table 2. Transformation of carboxylic acids into nitriles.
[a] Isolated yields. [b] SDBBA-H was prepared with additional NaOtBu (0.25 equiv.). [c] Reaction was carried out on a 1 mmol scale.
[d] I2 (6.0 equiv.) was used. [e] THF (4 mL) was used in the first step. [f] First step conditions: EtI (1.8 equiv.), K2CO3 (1.8 equiv.), 18-
crown-6 (0.5 equiv.), THF/CH2Cl2 (3:1; 6 mL), reflux, 21 h. [g] DIH (3.0 equiv.) was used instead of I2, and reaction was carried out at
0 °C in the third step.
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Eur. J. Org. Chem. 2013, 5886–5892

One-Pot Transformation of Carboxylic Acids into Nitriles
with SDBBA-H at 0 °C, and finally with DIH (1,3-diiodo- 0 °C over 4 h, followed by treatment with molecular iodine
5,5-dimethylhydantoin) and aqueous ammonia, to give the (5.0 equiv.) and aqueous ammonia (4 mL) at 0 °C to room
corresponding nitriles in good yields (Table 2, entries 18– temperature over 2 h (second and third steps of the overall
22). Here, molecular iodine was not an efficient oxidant, reaction) generated 1-naphthonitrile in 86% yield. We have
but the iodination ability of DIH is stronger than that of previously reported the direct conversion of alcohols into
molecular iodine. An olefinic group was not affected in the nitriles, maintaining the same number of carbon atoms.[10]
reaction (Table 2, entry 21). However, treatment of cin- In that process, aldehydes were rapidly converted into the
namic acid under the same conditions and with the same corresponding nitriles at room temperature on treatment
procedure provided cinnamonitrile only in 20% yield, due with molecular iodine and aqueous ammonia. These results
to reduction of the α,β-unsaturated carbon–carbon double support that the present reaction proceeds by the reaction
bond by SDBBA-H. The same treatment of N-Boc-pro- pathway shown in Scheme 1.
tected l-proline (Boc = tert-butyloxycarbonyl) with ethyl
iodide and K2CO3, then with SDBBA-H at 0 °C, and finally
with DIH and aqueous ammonia gave the corresponding
Conclusions
nitrile in good yield, and retaining a high ee (Table 2, en-
In conclusion, a variety of aromatic and aliphatic carb-
try 23).
oxylic acids were smoothly converted into the correspond-
A plausible reaction mechanism is shown in Scheme 1.
ing nitriles in good yields in a one-pot procedure by treat-
ment with ethyl iodide/K2CO3/18-crown-6, and sub-
sequently with sodium diisobutyl-tert-butoxyaluminium hy-
dride (SDBBA-H), and finally with molecular iodine or
DIH, and aqueous ammonia. This reaction is another use-
ful method for the one-pot conversion of various aromatic
and aliphatic carboxylic acids into the corresponding ni-
triles.
Initially, ethyl ester a is formed by the reaction of carboxylic
acid 1 with ethyl iodide in an SN2 reaction. Then, the re-
duction of ethyl ester a by SDBBA-H takes place to form
aldehyde c by β-cleavage of hemiacetal anion b. Aldehyde c
reacts further with aqueous ammonia to form imine d. Im-
ine d reacts further with molecular iodine or DIH in aque-
ous ammonia to form N-iodo imine e. Once N-iodo imine
e has been formed, HI elimination occurs smoothly by reac-
tion with ammonia to generate nitrile 2. Practically, treat-
ment of 1-napthoic acid with ethyl iodide (1.8 equiv.),
Experimental Section
General Remarks: 1H and 13C NMR spectra were obtained with
JEOL-JNM-ECX400, JEOL-JNM-ECS400, and JEOL-JNM-
ECA500 spectrometers. Chemical shifts are expressed in ppm
downfield from TMS in δ units. Mass spectra were recorded with
JMS-T100GCV, JMS-HX110, and Thermo LTQ Orbitrap XL
spectrometers. IR spectra were measured with a JASCO FT/IR-
4100 spectrometer. Melting points were determined with a Yamato
melting-point apparatus model MP-21. Silica gel 60F254 (Merck)
was used for TLC, and Silica gel 60 (Kanto Kagaku Co.) was used
for short column chromatography.
K2CO3 (1.8 equiv.), and 18-crown-6 (0.2 equiv.) in THF un-
der refluxing conditions for 21 h gave ethyl 2-naphthoate in
94% yield (first step of the overall reaction). Treatment of
ethyl 2-naphthoate with SDBBA-H (2.2 equiv.) at –40 to
Preparation of SDBBA-H Solution:[9] NaOtBu (96.10 g/mol, 98%
purity; 441.28 mg, 4.5 mmol) was dried using a vacuum pump for
30 min at room temperature. The NaOtBu was dissolved in THF
(3 mL), and DIBAL-H (1.02 m; 4.31 mL, 4.4 mmol) was added at
0 °C under an argon atmosphere. The reaction mixture was stirred
for 1 h at room temperature to give SDBBA-H. This solution was
used directly for the reduction of esters.
Typical Procedure 1 for the Conversion of Aromatic Carboxylic
Acids into Aromatic Nitriles: Iodoethane (561 mg, 1.8 equiv.) was
added to a mixture of 1-naphthoic acid (344 mg, 2 mmol), 18-
crown-6 (106 mg, 0.2 equiv.), and K2CO3 (332 mg, 1.8 equiv.) un-
der an argon atmosphere. The mixture was stirred for 21 h at reflux.
Then, SDBBA-H (2.2 equiv.) in dry THF (4 mL) was added at
–40 °C. The resulting mixture was stirred for 4 h under an argon
atmosphere at –40 °C, and gradually warmed to 0 °C. Finally, NH3
(28.0–30.0% aq.; 6 mL) and I2 (2.54 g, 5.0 equiv.) were added at
0 °C, and the resulting mixture was stirred for 2 h at room tempera-
ture. Then the reaction mixture was poured into Na2SO3 (saturated
aq.; 10 mL) and the mixture was extracted with ethyl acetate (3ϫ
15 mL). The organic phase was dried with Na2SO4 and filtered.
After removal of the solvent under reduced pressure, the residue
was purified by flash short column chromatography on silica gel
(hexane/diethyl ether, 30:1) to give 1-naphthonitrile (236 mg, 77%).
Scheme 1. Plausible reaction mechanism.
Eur. J. Org. Chem. 2013, 5886–5892
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K. Miyagi, K. Moriyama, H. Togo
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Typical Procedure 2 for the Conversion of Aromatic Carboxylic
Acids into Aromatic Nitriles: Iodoethane (561 mg, 1.8 equiv.) was
added to a mixture of 4-iodobenzoic acid (496 mg, 2 mmol), 18-
crown-6 (106 mg, 0.2 equiv.), and K2CO3 (332 mg, 1.8 equiv.) in
dry THF (6 mL) under an argon atmosphere. The mixture was
stirred for 21 h at reflux. Then, SDBBA-H (2.2 equiv.) in dry THF
(4 mL) was added at –70 °C. The resulting mixture was gradually
warmed to 0 °C and stirred for 4 h under an argon atmosphere.
Finally, NH3 (28.0–30.0% aq.; 6 mL) and I2 (2.54 g, 5.0 equiv.)
were added at 0 °C, and the resulting mixture was stirred for 2 h at
room temperature. Then the reaction mixture was poured into
Na2SO3 (saturated aq.; 10 mL), and the mixture was extracted with
ethyl acetate (3ϫ 15 mL). The organic phase was dried with
Na2SO4 and filtered. After removal of the solvent under reduced
pressure, the residue was purified by flash short column chromatog-
raphy on silica gel (hexane/diethyl ether, 30:1) to give 4-iodobenzo-
nitrile (362 mg, 79%).
CDCl3): δ = 7.47 (d, J = 8.6 Hz, 2 H), 7.61 (d, J = 8.6 Hz, 2 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 110.8, 118.0, 129.7, 133.4,
139.5 ppm.
4-Bromobenzonitrile: Yield 291 mg (80%), m.p. 113–115 °C (comm.
avail., m.p. 113 °C). IR (neat): ν = 2224 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 7.52 (d, J = 8.2 Hz, 2 H), 7.64 (d, J = 8.1 Hz, 2 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 111.2, 118.0, 128.0, 132.6,
133.4 ppm.
3-Bromobenzonitrile: Yield 273 mg (75%), m.p. 42–43 °C (comm.
1
avail., m.p. 40 °C). IR (neat): ν = 2230 cm–1. H NMR (400 MHz,
˜
CDCl3): δ = 7.37 (t, J = 8.2, 7.7 Hz, 1 H), 7.61 (d, J = 7.7 Hz, 1
H), 7.75 (d, J = 8.2 Hz, 1 H), 7.81 (s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 114.2, 117.3, 122.9, 130.6, 130.7, 134.8,
136.1 ppm.
2-Bromobenzonitrile: Yield 269 mg (74%), m.p. 55 °C (comm.
1
avail., m.p. 54 °C). IR (neat): ν = 2230 cm–1. H NMR (400 MHz,
˜
CDCl3): δ = 7.40–7.50 (m, 2 H), 7.65–7.72 (m, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 115.9, 117.1, 125.3, 127.6, 133.2, 133.9,
134.3 ppm.
Typical Procedure 3 for the Conversion of Aliphatic Carboxylic
Acids into Aliphatic Nitriles: Iodoethane (561 mg, 1.8 equiv.) was
added to a mixture of 3-phenylpropionic acid (300 mg, 2 mmol),
18-crown-6 (106 mg, 0.2 equiv.) and K2CO3 (332 mg, 1.8 equiv.) in
dry THF (6 mL) under an argon atmosphere. The mixture was
stirred for 21 h at reflux. Then, SDBBA-H (2.2 equiv.) in dry THF
(4 mL) was added at 0 °C. The resulting mixture was stirred for 4 h
under an argon atmosphere at 0 °C. Finally, NH3 (28.0–30.0% aq.;
6 mL) and DIH (2.35 mg, 3.0 equiv.) were added at 0 °C, and the
resulting mixture was stirred for 2 h at 0 °C. Then, the reaction
mixture was poured into Na2SO3 (saturated aq.; 10 mL), and the
mixture was extracted with ethyl acetate (3ϫ 15 mL). The organic
phase was dried with Na2SO4 and filtered. After removal of the
solvent under reduced pressure, the residue was purified by flash
short column chromatography on silica gel (hexane/diethyl ether,
30:1) to give 3-phenylpropanenitrile (197 mg, 75%).
4-Iodobenzonitrile: Yield 362 mg (79%), m.p. 125–126 °C (comm.
avail., m.p. 127 °C). IR (neat): ν = 2225 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 7.37 (d, J = 8.4 Hz, 2 H), 7.85 (d, J = 8.0 Hz, 2 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 100.3, 111.8, 118.2, 133.2,
138.5 ppm.
2-Iodobenzonitrile: Yield 348 mg (76%), m.p. 55 °C (comm. avail.,
m.p. 55 °C). IR (neat): ν = 2225 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 7.29 (t, J = 7.9 Hz, 1 H), 7.46 (t, J = 7.7 Hz, 1 H),
7.62 (d, J = 7.7 Hz, 1 H), 7.94 (d, J = 7.7 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 98.5, 119.4, 120.8, 128.4, 133.7, 134.4,
139.7 ppm.
4-(Trifluoromethyl)benzonitrile: Yield 243 mg (71%), m.p. 39–40 °C
(comm. avail., m.p. 37 °C). IR (neat): ν = 2225 cm–1. 1H NMR
˜
Most of the nitriles formed in this study are commercially available
(comm. avail.) and they were identified by comparison with authen-
tic samples.
(400 MHz, CDCl3): δ = 7.74–7.79 (d, J = 8.4 Hz, 2 H), 7.80–7.84
(d, J = 8.4 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 116.0,
117.4, 123.0 (q, JC,F = 271.8 Hz), 126.2 (q, JC,F = 3.6 Hz), 132.7,
134.5 (q, JC,F = 33.4 Hz) ppm.
1-Naphthonitrile: Yield 236 mg (77%), m.p. 35–36 °C (comm. avail.,
m.p. 35 °C). IR (neat): ν = 2219 cm–1. 1H NMR (500 MHz,
˜
Terephthalonitrile: Yield 179 mg (70%), m.p. 218–220 °C (comm.
CDCl3): δ = 7.52 (dd, J = 7.1, 8.3 Hz, 1 H), 7.62 (t, J = 8.3 Hz, 1
H), 7.69 (t, J = 8.4 Hz, 1 H), 7.94–7.89 (m, 2 H), 8.07 (d, J =
8.3 Hz, 1 H), 8.23 (d, J = 8.6 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 110.2, 117.8, 124.9, 125.1, 127.5, 128.6, 128.6, 132.3,
132.6, 132.9, 133.2 ppm.
avail., m.p. 228 °C). IR (neat): ν = 2231 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 7.80 (s, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
116.7, 117.0, 132.8 ppm.
Benzonitrile: Yield 151 mg (73%). Colorless oil (comm. avail., oil).
1
IR (neat): ν = 2228 cm–1. H NMR (400 MHz, CDCl ): δ = 7.48
˜
2-Naphthonitrile: Yield 214 mg (70%), m.p. 66–68 °C (comm. avail.,
3
m.p. 67 °C). IR (neat): ν = 2225 cm–1. 1H NMR (400 MHz,
(t, J = 7.7 Hz, 2 H), 7.61 (t, J = 7.7 Hz, 1 H), 7.67 (d, J = 7.7 Hz,
2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 112.3, 118.8, 129.0,
132.0, 132.7 ppm.
˜
CDCl3): δ = 7.59–7.68 (m, 3 H), 7.88–794 (m, 3 H), 8.24 (s, 1 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 109.4, 119.2, 126.3, 127.6,
128.0, 128.4, 129.0, 129.2, 132.2, 134.1, 134.6 ppm.
4-Methylbenzonitrile: Yield 171 mg (73%). Colorless oil (comm.
avail., oil). IR (neat): ν = 2227 cm–1. 1H NMR (400 MHz, CDCl ):
˜
4-Nitrobenzonitrile: Yield 228 mg (77%), m.p. 145–147 °C (comm.
3
avail., m.p. 147 °C). IR (neat): ν = 2233 cm–1. 1H NMR (400 MHz,
δ = 2.42 (s, 3 H), 7.27 (d, J = 8.6 Hz, 2 H), 7.53 (d, J = 8.6 Hz, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.5, 109.0, 118.9,
129.6, 131.7, 143.5 ppm.
˜
CDCl3): δ = 7.89 (d, J = 8.8 Hz, 2 H), 8.36 (d, J = 8.8 Hz, 2 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 116.8, 118.3, 124.3, 133.4,
150.0 ppm.
4-Methoxybenzonitrile: Yield 184 mg (69%), m.p. 60–61 °C (comm.
1
avail., m.p. 60 °C). IR (neat): ν = 2217 cm–1. H NMR (400 MHz,
4-Fluorobenzonitrile: Yield 199 mg (82%), m.p. 34–35 °C (comm.
˜
1
avail., m.p. 34 °C). IR (neat): ν = 2233 cm–1. H NMR (400 MHz,
CDCl3): δ = 3.86 (s, 3 H), 6.95 (d, J = 8.8 Hz, 2 H), 7.59 (d, J =
8.8 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 55.5, 104.0,
114.7, 119.2, 134.0, 162.8 ppm.
˜
CDCl3): δ = 7.18 (dd, JH,H = 9.1, JH,F = 8.4 Hz, 2 H), 7.69 (dd,
JH,H = 9.1, JH,F = 5.2 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 108.7 (d, JC,F = 4.0 Hz), 117.0 (d, JC,F = 23.0 Hz), 118.1, 134.8
(d, JC,F = 9.5 Hz), 165.1 (d, JC,F = 257.7 Hz) ppm.
Benzofuran-2-carbonitrile: Yield 212 mg (74%), m.p. 36–38 °C
(comm. avail.). IR (neat): ν = 2227 cm–1. 1H NMR (500 MHz,
˜
4-Chlorobenzontrile: Yield 226 mg (82%), m.p. 92–94 °C (comm.
CDCl3): δ = 7.36 (t, J = 7.5 Hz, 1 H), 7.46 (s, 1 H), 7.49–7.58 (m,
avail., m.p. 92 °C). IR (neat): ν = 2225 cm–1. H NMR (400 MHz, 2 H), 7.68 (d, J = 7.8 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3):
1
˜
5890
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5886–5892

One-Pot Transformation of Carboxylic Acids into Nitriles
111.8, 112.0, 118.4, 122.6, 124.5, 125.5, 127.3, 128.4,
C. W. Rees), Pergamon, Oxford, UK, 1995; c) S.-I. Murahashi,
Synthesis from Nitriles with Retention of the Cyano Group, in:
Science of Synthesis vol. 19, Thieme, 2004, p. 345–402; d) S. J.
Collier, P. Langer, Applications of Nitriles as Reagents for Or-
ganic Synthesis with Loss of the Nitrile Functionality, in: Science
of Synthesis vol. 19, Thieme, 2004, p. 403–425.
δ
=
155.6 ppm.
Benzothiophene-2-carbonitrile: Yield 197 mg (62%). Oil; (comm.
avail., m.p. 24–28 °C). IR (neat): ν = 2215 cm–1. 1H NMR
˜
(500 MHz, CDCl3): δ = 7.47 (t, J = 7.5 Hz, 1 H): δ = 7.53 (t, J =
7.5 Hz, 1 H), 7.84–7.58 (m, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 109.6, 114.4, 122.4, 125.2, 125.7, 127.8, 135.0, 137.4,
141.3 ppm.
[2]
a) P. Wipf, Chem. Rev. 1995, 95, 2115–2134; b) P. Wipf, F.
Yokokawa, Tetrahedron Lett. 1998, 39, 2223–2226; c) P. C. Du-
cept, S. P. Marsden, Synlett 2000, 692–694; d) M. Chihiro, H.
Nagamoto, I. Takemura, K. Kitano, H. Komatsu, K. Sekigu-
chi, F. Tabusa, T. Mori, M. Tominaga, Y. Yabuuchi, J. Med.
Chem. 1995, 38, 353–358; e) X.-H. Gu, X.-Z. Wan, B. Jiang,
Bioorg. Med. Chem. Lett. 1999, 9, 569–572; f) P. K. Kadaba,
Synthesis 1973, 71–84; g) G. D. Diana, D. Cutcliffe, D. L. Volk-
ots, J. P. Mallamo, T. R. Bailey, N. Vescio, R. C. Oglesby, T. J.
Nitz, J. Wetzel, V. Giranda, D. C. Pevear, F. J. Dutko, J. Med.
Chem. 1993, 36, 3240–3250; h) S. J. Wittenberger, B. G.
Donner, J. Org. Chem. 1993, 58, 4139–4141; i) J.-J. Shie, J.-M.
Fang, J. Org. Chem. 2003, 68, 1158–1160; j) J. B. Medwid, R.
Paul, J. S. Baker, J. A. Brockman, M. T. Du, W. A. Hallett,
J. W. Hanifin, R. A. Hardy Jr., M. E. Tarrant, L. W. Torley, S.
Wrenn, J. Med. Chem. 1990, 33, 1230–1241; k) I. K. Khanna,
R. M. Weier, Y. Yu, X. D. Xu, F. J. Koszyk, P. W. Collins, C. M.
Koboldt, A. W. Veenhuizen, W. E. Perkins, J. J. Casler, J. L.
Masferrer, Y. Y. Zhang, S. A. Gregory, K. Seibert, P. C. Isak-
son, J. Med. Chem. 1997, 40, 1634–1647.
3-Phenylpropanenitrile: Yield 197 mg (75%). Colorless oil (comm.
avail.). IR (neat): ν = 2247 cm–1. 1H NMR (400 MHz, CDCl3): δ
˜
= 2.62 (t, J = 7.5 Hz, 2 H), 2.96 (t, J = 7.5 Hz, 2 H), 7.23 (d, J =
8.2 Hz, 2 H), 7.26 (t, J = 8.2 Hz, 1 H), 7.34 (t, J = 8.2 Hz, 2 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 19.3, 31.5, 119.1, 127.2,
128.2, 128.8, 138.0 ppm.
Hexadecanenitrile: Yield 351 mg (74%), m.p. 32–33 °C (comm.
avail., m.p. 27–33 °C). IR (neat): ν = 2247 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.24–1.34 (m, 22
H), 1.40–1.49 (m, 2 H), 1.57–1.70 (m, 2 H), 2.33 (t, J = 7.1 Hz, 2
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 14.1, 17.1, 22.7, 25.3,
28.6, 28.7, 29.3, 29.3, 29.5, 29.6, 29.6 (4), 31.9, 119.8 ppm.
Octadecanenitrile (Stearonitrile): Yield 335 mg (63%), m.p. 43 °C
(comm. avail., m.p. 40 °C). IR (neat): ν = 2242 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.24–1.34 (m, 26
H), 1.39–1.49 (m, 2 H), 1.60–1.70 (m, 2 H), 2.33 (t, J = 7.1 Hz, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.1, 17.1, 22.7, 25.4,
28.7, 28.8, 29.3, 29.4, 29.5, 29.6, 29.7 (6), 31.9, 119.9 ppm.
[3]
[4]
R. C. Larock, Nitriles, Carboxylic Acids and Derivatives, in:
Comprehensive Organic Transformations, 2nd ed., Wiley-VCH,
New York, 1999, p. 1621–1996.
a) M. Heck, A. Wagner, C. Mioskowski, J. Org. Chem. 1996,
61, 6486–6487; b) N. Nakajima, M. Ubukata, Tetrahedron Lett.
1997, 38, 2099–2102; c) D. S. Bose, B. Jayalakshmi, J. Org.
Chem. 1999, 64, 1713–1714; d) R. T. Ruck, R. G. Bergman,
Angew. Chem. 2004, 116, 5489–5491; Angew. Chem. Int. Ed.
2004, 43, 5375–5377; e) C. Kuo, J. Zhu, J. Wu, C. Chu, C.
Yao, K. Shia, Chem. Commun. 2007, 301–303; f) S. Hanada,
Y. Motoyama, H. Nagashima, Eur. J. Org. Chem. 2008, 4097–
4100.
cis-9-Octadecenenitrile: Yield 385 mg (73%). Colorless oil (comm.
avail.). IR (neat): ν = 2242 cm–1. 1H NMR (400 MHz, CDCl3): δ
˜
= 0.88 (t, J = 6.8 Hz, 3 H): δ = 1.26–1.37 (m, 20 H), 1.63–1.69 (m,
2 H), 1.99–2.03 (m, 2 H), 2.33 (t, J = 7.1 Hz, 2 H), 5.31–5.39 (m,
2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.1, 17.1, 22.6, 25.3,
27.0, 27.2, 28.6, 28.6, 28.9, 29.3 (2), 29.5, 29.5, 29.7, 31.9, 119.8,
129.5, 130.1 ppm. HRMS (APPI): calcd. for C18H33N [M]+
263.2608; found 263.2604.
[5]
a) T. G. Clarke, N. A. Hampson, J. B. Lee, J. R. Morley, B.
Scanlon, Tetrahedron Lett. 1968, 9, 5685–5688; b) L. Vargha,
M. Remenyi, J. Chem. Soc. 1951, 1068–1069; c) J. Cason, in:
Org. Synth. Coll. Vol. 3, New York, 1955, p. 3–7; d) M. L.
Mihailovic, A. Stojiljkovic, V. Andrejevic, Tetrahedron Lett.
1965, 6, 461–464; e) A. Stojiljkovic, V. Andrejevic, M. L. Mi-
hailovic, Tetrahedron 1967, 23, 721–732; f) J. S. Below, C.
Garza, J. W. Mathieson, J. Chem. Soc. C 1970, 634–635; g) K.
Nakagawa, T. Tsuji, Chem. Pharm. Bull. 1963, 11, 296–301; h)
E. I. Troyanskii, I. V. Svitanko, V. A. Ioffe, G. I. Nikishin, Izv.
Akad. Nauk SSSR, Ser. Khim. 1982, 2180–2185; i) S. Yama-
zaki, Y. Yamazaki, Bull. Chem. Soc. Jpn. 1990, 63, 301–303; j)
D. Biondini, L. Brinchi, R. Germani, L. Goracci, G. Savelli,
Eur. J. Org. Chem. 2005, 3060–3063; k) E. Chen, Z. Peng, H.
Fu, J. Liu, L. Shao, J. Chem. Res. Synopses 1999, 726–727; l)
G. A. Lee, H. H. Freedman, Tetrahedron Lett. 1976, 17, 1641–
1644; m) S. Yamazaki, Synth. Commun. 1997, 27, 3559–3564;
n) B. Jursic, J. Chem. Res. Synop. 1988, 168–169; o) G. I. Niki-
shin, E. I. Troyanskii, V. A. Joffe, Izv. Akad. Nauk SSSR, Ser.
Khim. 1982, 2758–2762; p) T. Kametani, K. Takahashi, T. Ohs-
awa, M. Ihara, Synthesis 1977, 245–248; q) P. Capdevielle, A.
Lavigne, M. Maumy, Synthesis 1989, 453–454; r) P. Capdevi-
elle, A. Lavigne, D. Sparfel, J. Baranne-Lafont, K. C. Nguyen,
M. Maumy, Tetrahedron Lett. 1990, 31, 3305–3308; s) Y.
Maeda, T. Nishimura, S. Uemura, Bull. Chem. Soc. Jpn. 2003,
76, 2399–2403; t) R. Tang, S. E. Diamond, N. Neary, F. Mares,
J. Chem. Soc., Chem. Commun. 1978, 562–563; u) M. Schroder,
W. P. Griffith, J. Chem. Soc., Chem. Commun. 1979, 58–59; v)
A. J. Bailey, B. R. James, Chem. Commun. 1996, 2343–2344; w)
K. Mori, K. Yamaguchi, T. Mizugaki, K. Ebitani, K. Kaneda,
Chem. Commun. 2001, 461–462; x) K. Yamaguchi, N. Mizuno,
Angew. Chem. 2003, 115, 1518–1521; Angew. Chem. Int. Ed.
1-Cyanoadamantane: Yield 200 mg (62%), m.p. 191–194 °C (comm.
avail., m.p. 195 °C). IR (neat): ν = 2230 cm–1. 1H NMR (500 MHz,
˜
CDCl3): δ = 1.70–1.78 (m, 6 H) 2.00–2.08 (m, 9 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 27.0, 30.1, 35.7, 39.8, 125.3 ppm.
N-(tert-butoxycarbonyl)-L-proline: Yield 314 mg (80%). Colorless
oil. IR (neat): ν = 2248, 1696 cm–1. 1H NMR (400 MHz, [D6]-
˜
DMSO): δ = 1.42 (s, 9 H), 1.82–1.99 (m, 2 H), 2.08–2.28 (m, 3 H),
3.24 (q, J = 8.3 Hz, 1 H), 4.59–4.65 (m, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 23.7, 24.5, 28.2, 30.7, 30.8, 31.5, 45.6, 45.9,
46.9, 47.0, 80.8, 81.2, 119.0, 152.9, 153.5 ppm. HRMS (ESI): calcd.
for C10H17N2O2 [M + H]+ 197.1285; found 197.1284.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra of all the nitriles
prepared.
Acknowledgments
Financial support by the Ministry of Education, Culture, Sports,
Science, and Technology in Japan in the form of a Grant-in-Aid
for Scientific Research (grant number 25105710) and by Chiba
University (Iodine Research Project) is gratefully acknowledged.
[1] a) K. Friedrick, K. Wallensfels, in: The Chemistry of the Cyano
Group (Ed.: Z. Rappoport), Wiley–Interscience, New York,
1970; b) M. North, in: Comprehensive Organic Functional
Group Transformations (Eds.: A. R. Katritzky, O. Meth-Cohn,
Eur. J. Org. Chem. 2013, 5886–5892
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5891

K. Miyagi, K. Moriyama, H. Togo
FULL PAPER
2003, 42, 1480–1483; y) R. M. Moriarty, R. K. Vaid, M. P.
Duncan, M. Ochiai, M. Inenaga, Y. Nagao, Tetrahedron Lett.
1988, 29, 6913–6916; z) F. Chen, Y. Kuang, H. Dai, L. Lu, M.
Huo, Synthesis 2003, 2629–2631.
H. Togo, Tetrahedron 2009, 65, 6257–6262; k) S. Ushijima, H.
Togo, Synlett 2010, 1067–1070; l) R. Ohmura, M. Takahata,
H. Togo, Tetrahedron Lett. 2010, 51, 4378–4371; m) Y. Suzuki,
Y. Ishiwata, K. Moriyama, H. Togo, Tetrahedron Lett. 2010,
51, 5950–5953; n) S. Takahashi, H. Togo, Heterocycles 2010,
82, 593–601; o) Y. Suzuki, T. Yoshino, K. Moriyama, H. Togo,
Tetrahedron 2011, 67, 3809–3814; p) H. Baba, K. Moriyama,
H. Togo, Tetrahedron Lett. 2011, 52, 4303–4307; q) Y. Suzuki,
K. Moriyama, H. Togo, Tetrahedron 2011, 67, 7956–7962; r) S.
Ushijima, S. Dohi, K. Moriyama, H. Togo, Tetrahedron 2012,
68, 1436–1442; s) H. Baba, K. Moriyama, H. Togo, Synlett
2012, 23, 1175–1180; t) S. Ushijima, K. Moriyama, H. Togo,
Tetrahedron 2012, 68, 4701–4709; u) S. Ushijima, K. Mori-
yama, H. Togo, Tetrahedron 2012, 68, 4588–4595; v) S. Dohi,
K. Moriyama, H. Togo, Tetrahedron 2012, 68, 6557–6564; w)
H. Kikui, K. Moriyama, H. Togo, Synthesis 2013, 791–797.
[6] T. Sandmeyer, Ber. Dtsch. Chem. Ges. 1884, 17, 1633–1639.
[7] a) C. S. Miller, in: Org. Synth. Coll. Vol. 3, 1955, p. 646–648;
b) A. C. Cope, R. J. Cotter, L. L. Estes, in: Org. Synth. Coll.
Vol. 4, 1963, p. 62–64; c) D. A. Klein, J. Org. Chem. 1971, 36,
3050–3051; d) T. Imamoto, T. Takaoka, M. Yokoyama, Synthe-
sis 1983, 142–143; e) V. J. Huber, R. A. Bartsch, Tetrahedron
1998, 54, 9281–9288; f) C. O. Kangani, B. W. Day, D. E. Kelley,
Tetrahedron Lett. 2007, 48, 5933–5937; g) V. N. Telvekar, R. A.
Rane, Tetrahedron Lett. 2007, 48, 6051–6053; h) K. Ouchaou,
D. Georgin, F. Taran, Synlett 2010, 2083–2086.
[8] Review articles: a) H. Togo, S. Iida, Synlett 2006, 2159–2175;
b) H. Togo, J. Synth. Org. Chem. Jpn. 2008, 66, 652–663. Arti-
cles: c) N. Mori, H. Togo, Synlett 2004, 880–882; d) N. Mori,
H. Togo, Tetrahedron 2005, 61, 5915–5925; e) M. Ishihara, H.
Togo, Synlett 2006, 227–230; f) S. Iida, H. Togo, Synlett 2006,
2633–2635; g) M. Ishihara, H. Togo, Tetrahedron 2007, 63,
1474–1480; h) S. Iida, H. Togo, Synlett 2007, 407–410; i) S.
Iida, H. Togo, Synlett 2008, 1639–1642; j) S. Iida, R. Ohmura,
[9]
J. I. Song, D. K. An, Chem. Lett. 2007, 36, 886–887.
[10] a) N. Mori, H. Togo, Synlett 2005, 1456–1458; b) S. Iida, H.
Togo, Tetrahedron 2007, 63, 8274–8281.
Received: May 1, 2013
Published Online: August 1, 2013
5892
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5886–5892