Direct Synthesis of Nitriles from Aldehydes Using an O-Benzoyl Hydroxylamine (BHA) as the Nitrogen Source

Article abstract of DOI:10.1021/acs.orglett.5b02547

The direct synthesis of nitriles from commercially available or easily prepared aldehydes has been achieved. O-(4-CF₃-benzoyl)-hydroxylamine (CF₃-BHA) was utilized as the nitrogen source to generate O-acyl oximes in situ with aldehydes, which can be converted to a nitrile with the assistance of a Bronsted acid. Several aliphatic, aromatic, and α,β-unsaturated nitriles that contain different functional groups were prepared in high yields (up to 94% yield). This method has notable advantages, such as simple and mild conditions, high yields, and good functional group tolerance.

Full text of DOI:10.1021/acs.orglett.5b02547

Letter
pubs.acs.org/OrgLett
Direct Synthesis of Nitriles from Aldehydes Using an O‑Benzoyl
Hydroxylamine (BHA) as the Nitrogen Source
Xiao-De An and Shouyun Yu*
State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University,
Nanjing 210093, China
S
* Supporting Information
ABSTRACT: The direct synthesis of nitriles from commercially available or easily prepared aldehydes has been achieved. O-(4-
CF3-benzoyl)-hydroxylamine (CF3-BHA) was utilized as the nitrogen source to generate O-acyl oximes in situ with aldehydes,
which can be converted to a nitrile with the assistance of a Brønsted acid. Several aliphatic, aromatic, and α,β-unsaturated nitriles
that contain different functional groups were prepared in high yields (up to 94% yield). This method has notable advantages,
such as simple and mild conditions, high yields, and good functional group tolerance.
he cyano group is one of the most important functional
groups, and it exists in many natural products and
T
biologically active molecules.1 Furthermore, nitriles can be used
as versatile building blocks in the synthesis of natural products,
pharmaceuticals, agricultural chemicals, and dyes.2 Therefore,
the development of efficient methods for nitrile preparation has
attracted intense interest from synthetic chemists.3 Traditional
methods for preparing nitriles, such as the Sandmeyer
reaction,4 the Rosenmund−von Braun reaction,5 cyanide−
halide exchange reactions,1b,6 and the dehydration of amides or
oximes,7 generally involve complicated operations, heavy metal
waste, toxic reagents (e.g., KCN or CuCN), or harsh reaction
conditions (e.g., POCl3 and high temperature). In recent
decades, aldehydes have been used as ideal synthetic precursors
for nitriles due to their ready availability and ease of use.8−10
These methods suffer from limited substrate scope, complicated
operations, and low functional group compatibility.8 Some
strong oxidants are typically essential for the conversion of
aldehydes to nitriles, which also lowers functional group
tolerance.8,9 Therefore, the direct synthesis of nitriles from
aldehydes under simple conditions with high functional group
compatibility is still a synthetic challenge although it is highly
useful.10,7k Additionally, the selection of the nitrogen source is
crucial to this transformation.
Very recently, we synthesized a series of substituted O-
benzoyl hydroxylamines (BHAs), such as O-(4-cyanobenzoyl)-
hydroxylamine (CN-BHA, 1a) and O-(4-CF3-benzoyl)-hydrox-
ylamine (CF3-BHA, 1b).11 These BHAs can serve as the
nitrogen source for the conversion of aryl or vinyl aldehydes to
aza-arenes under photoredox catalysis (Figure 1a).11b When the
vinyl aldehyde 2, was subjected to the photocatalytic conditions
via irradiation with white LEDs, the quinoline 3 was observed
in a 34% NMR yield. Interestingly, the nitrile 4 was also
produced in a 18% NMR yield (Figure 1b). Further
Figure 1. Serendipitous nitrile formation from an aldehyde and BHA.
experiments demonstrated that the photocatalyst and visible
light irradiation were not necessary for conversion of the
aldehyde 2 to the nitrile 4. Treatment of the aldehyde 2 with
CN-BHA (1a) and p-Cl-benzenesulfonic acid (CBSA) without
Received: September 3, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02547
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Organic Letters
Letter
a photocatalyst and visible light irradiation produced the nitrile
product 4 in a 14% NMR yield, together with the O-acyl oxime
5 in a 58% NMR yield. These results imply that the direct
synthesis of nitriles from aldehydes is feasible when BHA is
used as the nitrogen source (Figure 1c). Next, we produced a
general methodology to directly synthesize nitriles from
aldehydes with BHA as the nitrogen source, based on this
serendipitous discovery.
more inexpensive starting materials compared with CN-BHA,
CF3-BHA was chosen for further investigation.
After determining the optimized reaction conditions, the
synthetic potential of this reaction was investigated, and the
results are summarized in Schemes 1 and 2. First, a series of
a
Scheme 1. Conversion of Aliphatic Aldehydes to Nitriles
The systematic condition screening began with the reaction
of racemic citronellal (( )-6a) with CF3-BHA (1b) to form the
corresponding nitrile ( )-7a. When the solution of ( )-6a
with 1b in DMF was stirred at room temperature without any
additives, the desired nitrile ( )-7a was obtained in a 30% yield
based on the 1H NMR analysis. The major side product, O-acyl
oxime ( )-7a′, was obtained in a 60% yield (Table 1, entry 1).
a
Table 1. Optimized Reaction Conditions
b
b
entry
additive
solvent
7a/%
30
7a′/%
1
−
DMF
60
13
44
40
28
0
2
CBSA
DMF
67
40
24
33
87
74
26
30
35
44
27
83
70
32
22
92
3
CBSA
DMA
4
CBSA
DMSO
NMP
a
Reaction conditions: A mixture of 6 (0.2 mmol), 1b (0.24 mmol),
5
CBSA
and CSA (0.02 mmol, 10 mol %) in MeOH (2.0 mL) was stirred at rt.
6
CBSA
MeOH
EtOH
DCM
b
The yields are for the isolated products. The reaction was performed
7
CBSA
4
c
on a 8.0 mmol scale. The reaction temperature was 50 °C.
8
CBSA
59
56
56
30
63
0
9
CBSA
CH3CN
toluene
THF
10
11
12
13
14
15
16
17
18
CBSA
aliphatic aldehydes were tested (Scheme 1). Generally,
acceptable to good isolated yields (51−91%) were obtained
regardless of the functional groups on the aldehydes (7a−m).
Different functional groups, such as a double bond (7a and 7e),
a triple bond (7f), an ester (7d), an ether (7g), a lactam (7i), a
hydroxyl group (7j), an amide (7k−7m), and a ketal (7m),
tolerated these conditions. The steric effect affected this
formation significantly, and bulky aldehydes, such as the
Garner aldehyde, were converted to the corresponding nitrile
7m, but at an elevated temperature (50 °C). The dialdehyde
also produced the dinitrile 7h in a good yield (91%) with 2.4
equiv of 1b. The reaction was scaled up to the gram scale (8
mmol) with a slightly lower yield (75%).
We next explored the applicability of this strategy to aromatic
aldehydes. The above established conditions were not
applicable to aromatic aldehydes (only 23% yield of the desired
aromatic nitrile was obtained even at 50 °C). However, after a
slight modification, aromatic aldehydes could be also trans-
formed into the corresponding nitriles in DME at 80 °C with
the help of 30 mol % of TFA and using the same nitrogen
source (for the condition optimization, see the Supporting
Information). Satisfactory yields were achieved for a broad
range of aromatic aldehydes under these modified conditions
(Scheme 2a). Several aromatic nitriles (9a−9q) were prepared
in 45−94% yields depending on the position and electronic
properties of the substitutions on the benzene rings. Some
sensitive functional groups, such as free phenol (9h) and
ketone (9j), were compatible with this reaction. Heteroarene-
nitriles, such as indole (9m), pyrrole (9n), pyridine (9o),
CBSA
CH3CO2H
Cl3CCO2H
PhSO3H
PhCO2H
p-CF3-PhCO2H
TFA
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
0
65
74
0
c
CSA
92(89 )
0
d
19
CSA
92
0
a
Reaction conditions: A solution of ( )-6a (0.2 mmol), 1b (0.24
mmol), and an additive (0.02 mmol) in the indicated solvent (2.0 mL)
b
c
d
was stirred at rt for 24 h. 1H NMR yield. Isolated yield. CN-BHA
(1a) was used instead of 1b. CBSA = p-Cl-benzenesulfonic acid. CSA
= L-(−)-camphorsulfonic acid.
The O-acyl oxime ( )-7a′ was converted to the nitrile, ( )-7a,
with the help of a Brønsted acid (vide infra). A catalytic amount
of CBSA (10 mol %) was added to the reaction mixture as an
additive. A cleaner reaction was observed with a 67% yield of
( )-7a and a 13% yield of ( )-7a′ (entry 2). The solvent
screening showed that protic solvents, such as MeOH and
EtOH, are better solvents and gave 87% and 74% yields of the
desired nitrile, respectively (entries 6 and 7). Then, the
Brønsted acid was examined (entries 12−18). CSA and TFA
were more suitable for this transformation with the same NMR
yield (92% yield and 89% isolated yield for CSA). CN-BHA
(1a) also served as the nitrogen source with an identical
efficiency (entry 19). Because CF3-BHA can be prepared from
B
DOI: 10.1021/acs.orglett.5b02547
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
to demonstrate the practicability of this new method (Scheme
3). Commercially available spiramycin (10, 1.69 g) was treated
Scheme 2. Conversion of Aromatic and α,β-Unsaturated
Aldehydes to Nitriles
a
Scheme 3. Gram Scale and Late-Stage Modification of
Spiramycin
with 1b (1.5 equiv) and TFA (30 mol %) in DME at 80 °C to
furnish the corresponding nitrile 11 (1.11 g) in a 66% yield
without flash column chromatography. This strategy afforded a
macrolide-based nitrile, which may possess biological activity.
Additionally, the sensitive functional groups, such as olefin,
tertiary amine, glucoside, lactone, and free hydroxyl, which are
in the same molecule, are compatible with our method.
Control experiments were conducted to determine the
mechanism of this reaction (Figure 2a). Without the Brønsted
Figure 2. Mechanistic details.
a
Reaction conditions: A mixture of 8 (0.2 mmol), 1b (0.3 mmol), and
acid, the aldehyde 6a was fully converted into the O-acyl oxime
7a′ but only less than half of the O-acyl oxime 7a′ was
converted into the nitrile 7a. The preformed O-acyl oxime 7a′
produced the nitrile 7a in an 86% NMR yield with the help of
the Brønsted acid. We observed that almost no conversion of
the preformed O-acyl oxime 7a′ to the nitrile 7a occurred in the
absence of the Brønsted acid. Thus, a possible mechanism was
proposed, as depicted in Figure 2b. First, an O-acyl oxime was
generated from the aldehyde and CF3-BHA. The protonated O-
acyl oxime produced a nitrile after losing a proton and a
carboxylic acid.
In summary, we have described a direct synthesis of nitriles
from commercially available or easily prepared aldehydes. O-(4-
CF3-benzoyl)-hydroxylamine (CF3-BHA) was utilized as the
nitrogen source to generate O-acyl oximes in situ with
aldehydes, which can be converted to a nitrile with the
assistance of a Brønsted acid. Several functionalized aliphatic,
aromatic, and α,β-unsaturated nitriles were prepared in high
yields. The late-stage modification of spiramycin to the
corresponding nitrile on a gram scale was also achieved in a
satisfactory yield. The advantages, such as simple and mild
TFA (0.06 mmol, 30 mol %) in DME (2.0 mL) was stirred at 80 °C.
b
The yields are for the isolated product. The corresponding aldehyde
8y was a 1:1 mixture of the E- and Z-isomers.
thiophene (9p), and ferrocene (9q), were also prepared using
this method.
The success with aliphatic and aromatic nitriles inspired us to
explore the possibility of preparing more synthetically
challenging α,β-unsaturated nitriles from α,β-unsaturated
aldehydes using a similar strategy. To our delight, the identical
conditions for aromatic aldehydes were applicable to α,β-
unsaturated aldehydes. Thus, a series of di- and trisubstituted
α,β-unsaturated nitriles (9r−9z) were produced in 56−92%
yields via this method (Scheme 2b). Notably, no Michael
addition, which was often observed as a major side reaction in
the synthesis of α,β-unsaturated nitriles from the corresponding
aldehydes,10a was observed.
A functional-group-enriched macrolide antibiotic, named
spiramycin,12 which is widely used in clinics to treat
toxoplasmosis and other soft tissue infections was employed
C
DOI: 10.1021/acs.orglett.5b02547
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02547.
■
S
Full experimental and characterization data for all
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: yushouyun@nju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Lindovska, P.; Lewis, W. Tetrahedron 2012, 68, 2899. (n) Antonco
̌
par;
Financial support from the 863 program (2013AA092903), the
National Natural Science Foundation of China (21272113,
81421091), and Qing Lan Project of Jiangsu Province is
acknowledged.
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