Direct synthesis of nitriles from aldehydes using chloramine-T/KI in aqueous ammonia

Article abstract of DOI:10.1080/00397911.2012.752852

A convenient method for direct conversion of aldehydes into nitriles has been developed using chloramine-T/KI in aqueous ammonia.

Full text of DOI:10.1080/00397911.2012.752852

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Direct Synthesis of Nitriles from
Aldehydes Using Chloramine-T/KI in
Aqueous Ammonia
a
a
a
a
Yi-Zhong Zhu , Xi-Quan Zhang , Fei Liu , Hong-Mei Gu & Hai-
b
Liang Zhu
a
Jiangsu Chia Tai Tianqing Pharmaceutical Co. Ltd. , Nanjing ,
Jiangsu , China
b
State key Laboratory of Pharmaceutical Biotechnology, School of
Life Sciences, Nanjing University , Nanjing , Jiangsu , China
Accepted author version posted online: 31 May 2013.Published
online: 25 Jul 2013.
To cite this article: Yi-Zhong Zhu , Xi-Quan Zhang , Fei Liu , Hong-Mei Gu & Hai-Liang Zhu (2013)
Direct Synthesis of Nitriles from Aldehydes Using Chloramine-T/KI in Aqueous Ammonia, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:21, 2943-2948, DOI: 10.1080/00397911.2012.752852
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1
Synthetic Communications , 43: 2943–2948, 2013
Copyright # Jiangsu Chia Tai Tianqing Pharmaceutical Co. Ltd.
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.752852
DIRECT SYNTHESIS OF NITRILES FROM ALDEHYDES
USING CHLORAMINE-T/KI IN AQUEOUS AMMONIA
1
1
1
Yi-Zhong Zhu, Xi-Quan Zhang, Fei Liu, Hong-Mei Gu,
1
2
and Hai-Liang Zhu
1
Jiangsu Chia Tai Tianqing Pharmaceutical Co. Ltd., Nanjing, Jiangsu,
China
2
State key Laboratory of Pharmaceutical Biotechnology,
School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
GRAPHICAL ABSTRACT
Abstract A convenient method for direct conversion of aldehydes into nitriles has been
developed using chloramine-T/KI in aqueous ammonia.
[Supplementary materials are available for this article. Go to the publisher’s online
1
edition of Synthetic Communications for the following free supplemental resource: Full
experimental and spectral details.]
Keywords Aldehydes; aqueous ammonia; chloramine-T; nitriles; oxidation
INTRODUCTION
Nitriles are important compounds not only for their interesting biological
properties but also because of their use as versatile starting materials for many
[
1,2]
important aromatic compounds, including acids, ketones, oximes, and amines.
Various methods for the synthesis of nitriles have been reported. Among these
methods, the most widely used are based on the transitionmetal–mediated displace-
[
3–18]
ment of aromatic halides and triflates by the cyanide ion.
On the other hand, an
important alternative for the synthesis of nitriles is to use aldehydes as substrates.
Generally, the conversion of aldehydes into nitriles was achieved by dehydration
of the corresponding aldoximes using reagents such as NH OH ꢀ HCl=NEt =phthalic
2
3
[
19]
[20]
anhydride,
NH OH ꢀ HCl=peroxymonosulfate-alumina,
NH OH ꢀ HCl=
2
2
[
21]
[22]
N-methylpyrrolidine,
[
NH OH ꢀ HCl=ammonium acetate,
NH OH=MgSO =
2
4
4
[25]
23]
[24]
MnO2,
NH OH ꢀ HCl=dry-Al O =MeSO Cl,
NH OH ꢀ HCl=HY-Zeolite,
2
2
3
2
2
Received October 22, 2012.
Address correspondence to Yi-Zhong Zhu, Jiangsu Chia Tai Tianqing Pharmaceutical Co. Ltd.,
Nanjing 210042, Jiangsu, China. E-mail: zhuyzhong@yahoo.cn
2
943

2944
Y.-Z. ZHU ET AL.
Scheme 1. Formation of nitriles from aldehydes.
[
26]
[27]
[29]
NH OH ꢀ HCl=Graphite=MeSO Cl,
NH OH ꢀ HCl=NaI=MeCN,
NH OH ꢀ
2
2
2
2
[28]
˚
HCl=KF-Al O =DMF,
2
NH OH ꢀ HCl=DBU=EtOPOCl =MS3 A,
NH OH ꢀ
3
2
2
2
[30]
HCl=KI=ZnO=CH CN,
and furthermore, the one-pot synthesis of nitriles direct
3
from aldehydes and ammonia water by oxidation of the aldimines, formed in situ by
condensation of aldehydes and ammonia, is considered an expedient method and has
[
31]
been studied with NH =O =CuCl ꢀ H O=MeONa in MeOH,
NH =Pb(OAc) in
3 4
3
2
2
2
[32]
[33]
[34]
dry benzene, NH =I =MeONa in MeOH, NH =S =NaNO , NH =H O =CuCl
3
2
3
8
2
3
2 2
[35]
[36]
in 2-propanol, NH =I in THF–water, NH =ceric ammonium nitrate (CAN),
[37]
3
2
3
[38]
NH =N-bromosuccinimide (NBS),
NH =iodoxybenzonic (IBX) in acetonitrile–
3
3
[39]
[40]
water, NH =NaICl , NH =trichloroisocyanuric acid (TCCA),
[41]
NH =NaIO =
3 4
3
2
3
[42]
[43]
KI, and NH =H IO =KI. Some of these methods present advantages over other
3
5
6
reaction pathways in that the reactions could be carried out at low temperatures and
without the use of expensive transition metal catalysts and ligands. Herein we report
a convenient method for direct transformation of aldehydes to nitriles using
chloramine-T (N-chloro 4-methylbenzenesulfonamide, sodium salt)=KI in aqueous
ammonia under mild conditions (Scheme 1).
RESULTS AND DISCUSSION
First, benzaldehyde was chosen as a model substrate. The reaction of benzal-
dehyde in ammonia water without chloramine-T or KI resulted in poor conversion
(Table 1, entries 1–3). When chloramine-T and KI were introduced into the reaction
mixture, the yield of the product was drastically increased to 90% in 1.5 h (Table 1,
entry 4). Further, decreasing the amount of chloramine-T or KI led to the slightly lower
conversion of benzaldehyde to benzonitrile (Table 1, entries 5 and 6). At last, we
found that the optimal conditions were benzaldehyde (2 mmol), chloramine-T (1.5
equiv), KI (1.5 equiv), tetrahydrofuran (THF) (1mL), and ammonia water (10 mL)
at room temperature for 1.5 h, which provided the desired product 2a in 90% yield.
a
Table 1. Evaluation of various reaction conditions
b
Entry
Chloramine-T
KI
Yield (%)
1
2
3
4
5
6
—
3 mmol
—
—
—
<1
<3
<1
90
3 mmol
3 mmol
3 mmol
2 mmol
3 mmol
2 mmol
3 mmol
78
82
a
Reaction conditions: aldehyde (2 mmol), aqueous ammonia (10 mL), THF
1 mL), rt, 1.5 h.
(
b
Isolated yields.

SYNTHESIS OF NITRILES
2945
a
Table 2. Conversion of aldehydes into nitriles
b
Entry
RCHO
RCN
Period (h)
Yield (%)
1
2
3
4
5
6
7
8
9
C
6
H
5
CHO
C
6
H
5
CN (2a)
1.5
3
90
91
90
89
82
83
83
81
81
84
82
4-ClC
3-ClC
2-ClC
6
6
6
H
4
H
4
H
4
CHO
CHO
CHO
4-ClC
3-ClC
2-ClC
4-CF
4-FC
4-CH
4-CH OC
3-Cyanopyridine (2i)
CH (CH CN (2j)
CH (CH CN (2k)
6 4
H CN (2b)
6
H
4
CN (2c)
CN (2d)
3
6
H
4
4
4-CF
4-FC
4-CH
4-CH OC
3-Pyridinecarboxaldehyde
3
C
6
H
4
CHO
CHO
CHO
CHO
3
C
6
H
4
CN (2e)
CN (2f)
CN (2 g)
CN (2 h)
8
6
H
4
6
H
4
8
3
C
6
H
4
3
C
6
H
4
5
3
6
H
4
3
6
H
4
6
8
1
0
1
CH
CH
3
(CH
(CH
2
)
)
3
CHO
CHO
3
2
)
3
10
10
1
3
2
5
3
2 5
)
a
Reaction conditions: aldehyde (2 mmol), aqueous ammonia (10 mL), THF (1 mL),
chloramine-T (3 mmol), KI (3 mmol), rt.
b
Isolated yields.
Encouraged by that result, we set out to examine a range of aldehydes
Table 2). As shown in Table 2, various aromatic, heterocyclic, and aliphatic
(
aldehydes were efficiently transformed into their corresponding nitriles in good
yields. Aryl aldehydes with electron-withdrawing groups such as chloro, fluoro,
and trifluoromethyl could afford good yields, and substrate with chloro group gave
the better yields (Table 2, entries 2–6). Additionally, steric effects had only a minor
influence on the reaction (Table 2, entry 4). Also, aryl aldehydes having
electron-donating substituents converted into the corresponding nitriles in good
yields (Table 2, entries 7 and 8). Even with 3-pyridinecarboxaldehyde, a heterocyclic
aldehyde, good yield was obtained (Table 2, entry 9). Aliphatic aldehydes also under-
went this transformation smoothly after prolonged reaction times (Table 2, entries
1
0 and 11).
A plausible reaction pathway for the conversion of aldehydes into the
corresponding nitriles with chloramine-T=KI is similar to that with molecular iodine
[
44]
suggested by Mori and Togo (Scheme 2). Thus, the reaction proceeded via
oxidation of aldimine with I or ICl (from chloramines-T=KI) to give an N-iodo
2
Scheme 2. Plausible reaction pathway for the formation of nitriles form aldehydes.

2946
Y.-Z. ZHU ET AL.
aldimine intermediate, which eliminated an HI molecule by NH to afford the nitrile
3
product.
In summary, we disclosed a new and efficient one-pot reaction for the synthesis
of nitriles from aldehydes through oxidation of in situ formed corresponding
aldimines using chloramine-T=KI=aqueous NH , which offered a useful synthetic
3
method for the preparation of nitriles because of its simplicity and good yields.
EXPERIMENTAL
A suspension of an aldehyde (2 mmol), KI (3 mmol), THF (1 mL), and
ammonia water (10 mL) was stirred for 10 min at room temperature, resulting in
formation of a turbid solution. Chloramine-T (3 mmol) was added slowly to this tur-
bid solution at room temperature. Then the mixture was stirred strongly for an
appropriate time (see Table 1), as indicated by thin-layer chromatography (TLC),
until no more product was formed. After the reaction was completed, the mixture
was extracted with ethyl acetate (2 ꢁ 25 mL). The combined organic layer was
washed with H O (2 ꢁ 15 mL). Then the organic layer was dried over Na SO , fil-
2
2
4
tered, and concentrated in vacuo. Finally, the product was isolated by flash chroma-
tography on silica gel with EtOAc–petroleum ether as the eluent. All prepared
nitriles are known compounds.
Please see the Supplemental Data, available online, for complete experimental
and spectral details.
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