One-Step Synthesis of Nitriles from Acids, Esters and Amides Using DIBAL-H and Ammonium Chloride

Article abstract of DOI:10.1055/s-0034-1381060

A convenient, one-step procedure is presented for the conversion of carboxylic acids or their derivatives (esters, lactones, amides) to nitriles with an aminoalane reagent prepared from diisobutylaluminum hydride (DIBAL-H) and ammonium chloride.

Full text of DOI:10.1055/s-0034-1381060

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©
Georg Thieme Verlag Stuttgart · New York
2015, 26, 2288–2292
2288
letter
Synlett
A. Wojtkielewicz et al.
Letter
One-Step Synthesis of Nitriles from Acids, Esters and Amides
Using DIBAL-H and Ammonium Chloride
Agnieszka Wojtkielewicz*
Zenon Łotowski
aminoalane reagent
(prepared from DIBAL-H and NH4Cl)
O
R
CN
Jacek W. Morzycki
THF, reflux,16 h
R
X
X = OH, alkoxy, NH2
R = alkyl, aryl
14 examples
63–98% yield
Institute of Chemistry, University of Białystok,
Ciołkowskiego 1K, 15-245 Białystok, Poland
jeremy@uwb.edu.pl
Received: 11.06.2015
Accepted after revision: 09.08.2015
Published online: 03.09.2015
acids and their derivatives can be found in the literature,
most of them consist of two or more step procedures and
often require the isolation of intermediates. Only a few ex-
amples of the direct conversion of carboxylic acids or inac-
DOI: 10.1055/s-0034-1381060; Art ID: st-2015-d0437-l
Abstract A convenient, one-step procedure is presented for the con-
version of carboxylic acids or their derivatives (esters, lactones, amides)
to nitriles with an aminoalane reagent prepared from diisobutylalumi-
num hydride (DIBAL-H) and ammonium chloride.
10
tivated esters into nitriles have been reported. In 1979
Weinreb described one-step preparation of nitriles from es-
ters.11 In this procedure the ester substrate is treated with
aluminum amide prepared from trimethylaluminum and
anhydrous liquid ammonia in a refluxing xylene to afford
nitrile. The other method of nitrile synthesis from carboxyl-
ic acids is based on the use of diphosphorus tetraiodide and
Key words nitrile, carboxylic acid, diisobutylaluminum hydride, alumi-
num amide, ammonium chloride
12
Nitriles constitute an important class of organic com-
pounds. They can be easily converted to aldehydes, ketones,
carboxylic acids, amines, amides, and nitrogen-containing
heterocycles (e.g., oxazoles, thiazoles, tetrazoles).1 There-
fore, nitriles are used for the preparation of various prod-
ucts of commercial significance, e.g., polyamides, pharma-
ammonium carbonate in anhydrous carbon disulfide. Car-
boxylic acids and esters can also be transformed into ni-
triles in multistep but one-pot synthesis by treatment with
ethyl iodide, K CO , 18-crown-6 and, subsequently, with so-
2
3
dium diisobutyl-tert-butoxyaluminum hydride (SDBBA-H)
and, finally, with iodine and aqueous ammonia in the case
of carboxylic acid substrates or by using SDBBA-H followed
2
ceuticals, agrochemicals, dyes, and fine chemicals. More-
over, the cyano group itself is present in biologically active
compounds, such as Letrazole (used in the treatment of
breast cancer), Periciazine (an antipsychotic drug), Citalo-
pram (an antidepressant drug), HIV protease inhibitors, and
by treatment with iodine and aqueous ammonia in the case
of ester substrates.1
3,14
The analogous strategy may be em-
ployed to convert amides to nitriles, however, the reaction
with ammonia and iodine must be preceded by amide re-
5
-lipoxygenase inhibitors.3–5 So far, numerous methods of
duction with diisobutylaluminum hydride (DIBAL-H).
15
nitrile preparation have been developed. The most common
synthetic strategies include nucleophilic substitution of ha-
Herein we report an alternative facile transformation of
carboxylic acids or their derivatives (esters, lactones, and
amides) into nitriles using aminoalane reagent prepared
from DIBAL-H and ammonium chloride (Scheme 1). Previ-
ously, scientists from China employed aluminum N-substi-
tuted amides obtained from DIBAL-H and an appropriate
amine or its hydrochloride for amide synthesis from esters
and lactones.16 To the best of our knowledge, this way of
preparing N-unsubstituted diisobutylaluminum amide as
well as the direct synthesis of nitriles using DIBAL-H and
6
7
lides by the CN ion, oxidation of amines, and dehydration
6,8
9
of amides or aldoximes. Most of the described syntheses
of nitriles involve the use of high temperatures (>150 °C),
acidic dehydrating reagents, or toxic reagents (e.g., metal
cyanides, ruthenium compounds, sodium azide, pyridine,
liquid ammonia). Due to the great practical importance of
nitriles, alternative methods for their preparation under
mild, non-acidic conditions are still needed. Although many
protocols for the preparation of nitriles from carboxylic
NH Cl has not been reported.
4
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A. Wojtkielewicz et al.
Letter
from carboxylic acids and their derivatives. To prove the
usefulness of the proposed method, we examined reactions
of various carboxylic acids, esters, and amides with alumi-
aminoalane reagent
prepared from DIBAL-H and NH4Cl,
THF, 0 °C to r.t., up to 2 h)
(
O
R
CN
R
X
THF, reflux, 16 h
num amide obtained in situ from DIBAL-H and NH Cl (Table
4
X = OH, alkoxy, NH2
R = alkyl, aryl
18
2).
The results clearly indicate that various carboxylic acids
Scheme 1 Synthesis of nitriles from carboxylic acids, esters, and am-
(aliphatic, unsaturated, aromatic) as well as their deriva-
tives (lactones, esters, and amides) can be conveniently
converted to corresponding nitriles in good yields (Table 2).
However, in most cases amide was obtained as a by-prod-
uct. Its formation was dependent on the amount of alumi-
num amide. An increase in the aminoalane amount resulted
in higher nitrile yields (Table 2, entries 1 vs. 2 or 9 vs. 10).
The reactions of carboxylic acids or their esters with a car-
boxyl group bound to the tertiary carbon atom were
stopped at the amide stage. Nitriles were not formed from
these substrates (Table 2, entries 7, 8, and 14). Esters of var-
ious alcohols appear to have a similar reactivity (Table 2,
entries 9 and 11). Almost no racemization was observed in
the case of chiral acids or esters having a stereogenic center
at the α position (Table 2, entries 6 and 13) under reaction
conditions.
ides using DIBAL-H and NH Cl
4
Our study was inspired by the observation made during
attempts to prepare a primary amide from lactone 1 using
16
aminoalane reagent (Table 1). Based on a report from Chi-
nese researchers and the fact that the Al–C bond is stronger
than the Al–H bond, we prepared the desired aluminum
amide from DIBAL-H instead of trimethylaluminum that is
11
used in the Weinreb method. Additionally, this procedure
seems to be more convenient from a practical point of view
in comparison to the Weinreb method, which requires the
use of trimethylaluminum and anhydrous liquid ammonia.
The desired aminoalane was synthesized in a reaction of
DIBAL-H with ammonium chloride under mild reaction
17
conditions (0 °C to r.t., THF, up to 2 h). The reaction of lac-
tone 1 with 20 equivalents of the prepared aluminum am-
ide at room temperature led to the formation of the prima-
ry amide in 59% yield (Table 1, entry 1).
It seems that the reagent formed from DIBAL-H and am-
monium chloride exhibits greater reactivity than that gen-
erated from Me Al and liquid NH . First of all, the present
3
3
reagent appeared to be effective not only for the conversion
of esters and lactones, but also of carboxylic acids to ni-
triles. The corresponding nitriles were obtained from all
substrate types in good yields (Table 2). The reaction condi-
tions applied here (boiling THF) were much milder than
those previously used for the synthesis of nitriles, with
Table 1 Reaction of Lactone 1 with Aminoalane Prepared from
DIBAL-H and NH Cl under Various Reaction Conditions
4
Tol
CN
OH
+
O
Tol
O
Me AlNH prepared from Me Al (boiling xylene). This reac-
DIBAL-H, NH4Cl
THF
2 2 3
tivity difference may result from replacing the methyl
groups by isobutyl ones in the dialkylaluminum amide.
However, it is also possible that a species of a different
structure [e.g. (i-Bu) AlNH xHCl or (i-Bu)ClAl-NH ], other
O
1
Tol
NH2
OH
2
2
2
than the expected aminoalane [(i-Bu) AlNH ], is formed.
2
2
Entry
Aluminum amide Temp
Product yield
Nitrile
Unfortunately, the structure has not been determined yet.
In subsequent experiments we investigated the influ-
ence of ammonium salt on the reactivity of the obtained re-
agent. The aluminum amides obtained from DIBAL-H with
various ammonium salts, chloride, nitrate, and carbonate
were examined in the model reaction (Table 3). All synthe-
sized aluminum complexes were reactive and led to the ni-
trile formation. The best product yield was obtained for the
reagent prepared from ammonium chloride, albeit only
slight differences were observed (Table 3).
The use of another aluminum hydride, i.e. LiAlH(t-BuO)3,
to prepare the aluminum amides was also studied. The re-
agent obtained from this aluminum hydride appeared to be
less reactive and less stable. It did not react with carboxylic
acids, but it did promote limited conversion (less than 20%)
of lactone 1 to amide. The nitriles were not formed with
this reagent.
Amide
1
2
3
4
5
20 equiv
20 equiv
10 equiv
5 equiv
r.t.
0%
98%
75%
64%
<2%
59%
0%
66 °C
66 °C
66 °C
66 °C
21%
35%
12%
2 equiv
When the reaction temperature was increased to 66 °C
refluxing THF), nitrile was obtained as the only product in
8% yield (Table 1, entry 2). Nitrile was also the major prod-
uct in the reaction with lower excess of reagent (10 or 5
equiv) in refluxing THF (Table 1, entries 3 and 4). With only
two equivalents of aluminum reagent, conversion of the re-
action was poor (Table 1, entry 5). The results of these ex-
(
9
periments prompted us to investigate the DIBAL-H–NH Cl
4
system as a novel, efficient reagent for nitrile preparation
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Table 2 Synthesis of Nitriles from Carboxylic Acids, Esters, and Amides with Aluminum Amide Obtained from DIBAL-H and NH Cla
4
Entry Substrate
DIBAL-H NH
4
Cl
Product (yield)
(equiv)
(equiv)
1
O
20
21
CN
0
(37%)
O
(60%)
1
OH
NH2
10
10
2
40
20
40
42
21
42
(75%)
(0%)
(<2%)
(0%)
3b
4
O
CN
(67%)
O
(15%)
8
8
OH
8
NH2
CONH2
5
6
COOH
40
40
42
42
CN
(67%)
(30%)
MeO
MeO
MeO
OMe
OMe
OMe
(52%,
(40%,
ee 95%)
ee 88%)
COOH
CN
CONH2
MeO
HO
MeO
HO
MeO
(ee > 98%)
7
40
42
(90%)
O
COOH
O
CONH2
8
9
40
20
42
21
(64%)
(59%)
COOH
CONH2
O
0
CN
0
O
10 NH2
(41%)
1
1
OEt
1
0
40
20
42
21
(78%)
(63%)
(12%)
(30%)
11
O
CN
0
O
1
Oi-Pr
OMe
(
NH2
10
1
0
1
1
2
CO2Et
20
20
21
21
CN
(77%)
CONH2
(23%)
MeO
MeO
MeO
OMe
OMe
3
4
5
(68%,
ee 88%)
(23%,
ee 94%)
CO2Et
CN
CONH2
MeO
HO
MeO
HO
MeO
ee 98%)
1
1
20
20
21
21
(96%)
(70%)
O
CO2Et
O
CONH2
(<1%)
O
OH
CN
OH
CONH2
O
OMe
OMe
OMe
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Letter
Table 2 (continued)
Entry Substrate
DIBAL-H NH
4
Cl
Product (yield)
(equiv)
(equiv)
1
6
7
O
40
42
CN
(70%)
1
0
NH2
1
0
1
CONH2
40
20
42
21
CN (98%)
OH
OH
TBSO
OH
TBSO
OH
H
H
18
(48%)
a
Reaction temperature: 66 °C; reaction time: 16 h.
Reaction was carried out at r.t.
b
Table 3 Reactivity of Aminoalane Prepared from Various Ammonium
Salts
References and Notes
(1) Friedrick, K.; Wallensfels, K. In The Chemistry of the Cyano
DIBAL-H (40 equiv)
ammonium salt (42 equiv)
O
Group; Rappoport, Z., Ed.; Wiley Interscience: New York, 1970.
(2) Pollak, P.; Romeder, G.; Hagedorn, F.; Gelbke, H.-P. In Ullmann’s
Encyclopedia of Industrial Chemistry; Wiley-VCH: Weinheim,
O
CN
10
+
1
0
OH
10 NH2
THF, reflux, 16 h
2012.
(
3) Jones, L. H.; Summerhill, N. W.; Swain, N. A.; Mills, J. E. Med.
Chem. Commun. 2010, 1, 309.
Entry
Ammonium salt
Product yield
Nitrile
Amide
(
4) Janakiraman, M. N.; Watenpaugh, K. D.; Tomich, P. K.; Chong, K.-
T.; Turner, S. R.; Tommasi, R. A.; Thaisrivongs, S.; Strohbach, J.
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1
2
3
NH
NH
4
Cl
75%
56%
61%
<2%
15%
25%
4
NO
3
(
5) Dubé, D.; Blouin, M.; Brideau, C.; Chan, C.-C.; Desmarais, S.;
Ethier, D.; Falgueyret, J.-P.; Friesen, R. W.; Girard, M.; Girard, Y.;
Guay, J.; Riendeau, D.; Tagari, P.; Young, R. N. Bioorg. Med. Chem.
Lett. 1998, 8, 1255.
4 2 3
(NH ) CO
In summary, a simple one-step protocol was developed
for the synthesis of nitriles from carboxylic acids or their
derivatives (lactones, esters, amides). A new aminoalane re-
agent was prepared in situ from DIBAL-H and ammonium
salt. By employing this method, various substrates, e.g., ali-
phatic, unsaturated, aromatic acids (or their esters and am-
ides), excluding those with a carboxyl group at the tertiary
carbon atom, were transformed in good yields into the cor-
responding nitriles under relatively mild conditions.
(
6) Larock, R. C. Nitriles, Carboxylic Acids and Derivatives in Compre-
hensive Organic Transformations; Wiley: New York, 1999, 2nd
ed., 1621.
(7) (a) Yamaguchi, K.; Mizuno, N. Angew. Chem. Int. Ed. 2003, 42,
1480. (b) Chen, F.; Kuang, Y.; Dai, H.; Lu, L.; Huo, M. Synthesis
2003, 2629. (c) Biondini, D.; Brinchi, L.; Germani, R.; Goracci, L.;
Savelli, G. Eur. J. Org. Chem. 2005, 3060.
(
8) (a) Kuo, C.; Zhu, J.; Wu, J.; Chu, C.; Yao, C.; Shia, K. Chem.
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(
3
b) Patil, U. B.; Shendage, S. S.; Nagarkar, J. M. Synthesis 2013, 45,
295.
Acknowledgment
Financial support from the University of Białystok within the project
BST-124 is gratefully acknowledged. The equipment for the Center of
Synthesis and Analysis BioNanoTechno of the University of Białystok
was funded by EU, as a part of the Operational Program Development
of Eastern Poland 2007-2013, project: POPW.01.03.00-20-034/09-00.
(10) (a) Tsuneo, I.; Tomoko, T.; Masataka, Y. Synthesis 1983, 142.
(b) Hulkenberg, A.; Troost, J. J. Tetrahedron Lett. 1982, 23, 1505.
(c) Vincent, J. H.; Richard, A. B. Tetrahedron 1998, 54, 9281.
(d) Knagani, C. O.; Day, B. W.; Kelley, D. E. Tetrahedron Lett.
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(
11) Wood, J. L.; Khatri, N. A.; Weinreb, S. M. Tetrahedron Lett. 1979,
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4
Supporting Information
(
Supporting information for this article is available online at
(14) Suzuki, Y.; Moriyama, K.; Togo, H. Tetrahedron Lett. 2011, 67,
http://dx.doi.org/10.1055/s-0034-1381060.
S
u
p
p
ortioIgnfrm oaitn
S
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Letter
(
16) Huang, S.-Q.; Zheng, X.; Deng, X.-M. Tetrahedron Lett. 2001, 42,
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ester and lactone substrates or from 40 equiv in case of carbox-
ylic acid and amide substrates) was added to a solution of car-
boxylic acid (1 equiv) or its derivative (lactone, ester or amide, 1
equiv) in anhyd THF at r.t. Stirring was continued for 16 h at 66
°C. After this time, the reaction mixture was cooled, quenched
9
(17) Experimental Procedure for the Preparation of Aminoalane
Reagent: A solution of DIBAL-H in toluene (1 M, 1 equiv) was
added to a cooled (0–5 °C) suspension of NH Cl (1.05 equiv) in
4
anhyd THF under argon. The reaction was stirred for 15 min in
an ice bath and then for 1.5 h at r.t. After this time, the obtained
complex solution was used directly for nitrile synthesis.
with aqueous solution of KHSO and the product was extracted
4
with CHCl . The extract was washed with H O, dried over anhyd
3
2
Na SO , and the solvent was evaporated. The crude product was
2
4
(
18) Experimental Procedure for the Synthesis of Nitrile from
Carboxylic Acid, Ester, Lactone or Amide: The solution of ami-
noalane reagent (prepared from 20 equiv of DIBAL-H in case of
purified by silica gel chromatography with hexane–EtOAc elu-
tion.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2288–2292