Copper-catalyzed aerobic conversion of the C=O bond of ketones to a C≡N bond using ammonium salts as the nitrogen source

Article abstract of DOI:10.1039/c5cc02578h

The conversion of the C=O bond of ketones to a C≡N bond is described. This conversion is catalyzed by copper salts with ammonium salts as the nitrogen source in the presence of molecular oxygen. A wide variety of ketones can be converted into the corresponding compounds containing a C≡N bond. Based on the preliminary experiments, a plausible mechanism of this transformation is disclosed.

Full text of DOI:10.1039/c5cc02578h

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: B. Xu, Q. Jiang, J.
Jia, A. Zhao, Q. Liu, W. Luo and C. guo, Chem. Commun., 2015, DOI: 10.1039/C5CC02578H.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/chemcomm

Please do not adjust margins
Page 1 of 4
ChemComm
View Article Online
DOI: 10.1039/C5CC02578H
ChemComm
COMMUNICATION
Copper-catalyzed aerobic conversion of C=O bond of ketones to
C≡N bond using ammonium salt as nitrogen source
Received 00th January 20xx,
Accepted 00th January 20xx
Bin Xu, Qing Jiang, An Zhao, Jing Jia, Qiang Liu, Weiping Luo and Cancheng Guo*
DOI: 10.1039/x0xx00000x
www.rsc.org/
35 ammonium salt as nitrogen source in the present of molecular
oxygen.
A conversion of C=O bond of ketones to C≡N bond is described.
This conversion is catalyzed by copper salts with ammonium salts
as the nitrogen source in the present of molecular oxygen. A wide
variety of ketones can be converted into the corresponding
compounds containing C≡N bond. Based on the preliminary
experiments, a plausible mechanism of this transformation is
disclosed.
5
Scheme 1 The methodologies for the conversion of C=O to C≡N
The conversion of C=O bond to C≡N bond has been widely used in
organic synthesis1 and attracted continuous attention of chemists
The initial survey of the reaction conditions was performed
with acetophenone (1a) as the model substrate, and the results were
40 summarized in Table S1 of SI (Supporting Information). To our
delight, acetophenone (1a) could be converted into benzonitrile (2a)
in 80% yield with 1.0 equiv of (NH4)2CO3, 0.3 equiv of Cu(OAc)2
and 0.3 equiv of TBAI in DMSO under 1 atm O2 at 120 oC (Scheme
2). Comparing the reactant with the product, this reaction achieved
45 the conversion of C=O bond of ketones to C≡N bond. The results in
Table S1 also showed that other copper salts, such as CuI, CuBr,
CuBr2 and so on, proved to be less effective than Cu(OAc)2. On the
other hand, other metal catalysts like FeCl2, FeCl3, Ni(OAc)2 and
AgNO3 could not accomplish this conversion which suggested the
50 copper salts showed the unique ability in this transformation (Table
S1, entries 1-12). Subsequently, the investigation on the influences
of solvents represented other solvents exhibited inferior reactivity in
this transformation (Table S1, entries 13-17). When other nitrogen
sources were used instead of (NH4)2CO3, none showed the higher
55 efficiency than (NH4)2CO3 (Table S1, entries 18-22). Furthermore,
an evaluation of additives revealed that TBAI provided a significant
improvement in yield (Table S1, entries 23-29). In addition, varying
the loading of (NH4)2CO3 and the temperature had little effect on
the yield (Table S1, entries 30-33). Control experiments highlighted
60 the essential roles of Cu catalysts and oxygen in this transformation
(Table S1, entries 34-37).
10 because the compounds contained C≡N bond are versatile
intermediates in the synthesis of useful medicines and functional
materials.2 Generally, the fundamental methodology for this
conversion of C=O bond to C≡N bond is the transformation from
aldehydes through the Schmidt reaction with azide or the catalytic
15 oxidation condensation with ammonia.3 Alternatively, the
transformation from primary amides4 or carbonyl acids5 is another
attractive method for this conversion (Scheme 1). Recently, a few
elegant examples for the conversion of C=O bond to C≡N bond
have been reported. Muldoon reported an efficient protocol using
20 the Cu-TEMPO-air catalytic system to achieve the conversion of
C=O bond of aldehydes to C≡N bond.3d Beller’s group represented
the conversion of C=O bond of amides to C≡N bond with
hydrosilanes as the dehydrating agents.4b, 4c Kappe developed a
continues-flow protocol for this conversion from carboxylic acid in
25 one-step without any catalyst or additives under high-
temperature/pressure (350 oC, 65 bar).5c Togo and co-workers
reported a facile conversion of C=O bond of esters to C≡N bond by
the treatment of SDBBA-H and I2 in aq ammonia.6 Despite
impressive progress on the conversion of C=O bond to C≡N bond.
30 Besides, the oxidative cleavage of C-C bond of ketones under Cu-
catalyzed conditions has been known.7 To the best of our
knowledge, the conversion of C=O bond of ketones to C≡N bond
has not been established to date. Herein, we present the copper-
catalyzed conversion of C=O bond of ketones to C≡N bond using
College of Chemistry and Chemical Engineering, Hunan University, Changsha
410082, P.R. China .Fax: +86-731-88821488; Tel: +86-731-88821488.
E-mail: ccguo@hnu.edu.cn.
Electronic Supplementary Information (ESI) available: Detailed experimental
procedures, analytical data. See DOI: 10.1039/x0xx00000x
Scheme
conditions
2
Conversion of acetophenone under the optimal
This journal is © The Royal Society of Chemistry 20xx
Chem. Commun., 20xx, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 4
ChemComm
COMMUNICATION
important conclusions could be drawn as follows: (1) The
Subsequently, the scope of the (hetero)aryl methyl ketones was
investigated under the standard reaction conditions (Scheme 2). It
conversion of C=O bond of ketones to C≡N bond could be applied
in the aryl ketones with a long-chain alky groupVibewutAritniclelOonwlineer
DOI: 10.1039/C5CC02578H
was found that the C=O bond of the (hetero)aryl methyl ketones 30 efficiency (Table 2, entries 1-5). (2) Aliphatic ketones could also
5
could be converted into C≡N bond in 49-90% yield (Table 1). As
shown in Table 1, acetophenone derivatives bearing electron-
donating substituents (MeO, EtO, t-Bu, Me) could achieve this
conversion in 71-90% yield (Table 1, entries 1-9). Nevertheless, the
achieve this conversion in moderate yield (Table 2, entries 6-8).
Thereinto, when 1,2-diphenylethanone (3i) was chosen as the
substrate, not only 62% yield of benzonitrile was obtained, but also
benzamide was produced as the other product in 40% yield. (3) The
C=O bond of the acetophenone derivatives with electron- 35 methylene at the α-position of the carbonyl group is essential in this
10 withdrawing substituents (F, Cl, Br, I, NO2, CN) could be converted
into C≡N bond in yields ranging from 49 to 85% (Table 1, entries
10-17). Furthermore, acetophenone bearing the same substituents at
different positions had influence on the efficiency of this
conversion (Table 2, entries 9 and 10).
For further investigation, other compounds contained C=O
bond, such as benzaldehyde (4a), benzoic acid (4b), benzamide (4c)
and methyl benzoate (4d), were employed as the substrate (Scheme
transformation. For example, 2-methyl-acetophenone (1f) gave 40 3). Disappointingly, only the C=O bond of benzaldehyde (4a) could
15 lower yield than 4-/3-methyl-acetophenone (1e/1g) (Table1, entries
5-7). Importantly, halogen substituents on the phenyl ring were well
tolerated with this conversion, which enable a potential application
in further functionalization (Table 1, entries 10-15). Furthermore, 2-
acetonaphthone (1r) and 2-acetylthiophene (1s) could also realize
20 the conversion of C=O bond to C≡N bond in moderate yield (Table
1, entries 18 and 19).
be converted into C≡N bond in 87% yield (Scheme 3a).
Table 2 Substrate Scope of Alkyl Ketones 3a
Entry
R1 =
R2 =
3
yield of 2b
Table 1 Substrate Scope of (Het)Aryl Methyl Ketones 1a
1
2
3
4
5
6
7
Ph
4-MeOC6H4
4-MeC6H4
4-ClC6H4
Me
Me
Me
Me
n-Pr
H
3a
3b
3c
3d
3e
3f
46% (2a)c
48% (2b)
49% (2e)
45% (2k)
49% (2a)c
59% (2b)
47% (2j)
Ph
Entry
1
1
yield of 2b
80% (2a)c
90% (2b)
88% (2c)
80% (2d)
86% (2e)
68% (2f)
79% (2g)
89% (2h)
71% (2i)
65% (2j)
85% (2k)
77% (2l)
70% (2m)
78% (2n)
82% (2o)
75% (2p)
49% (2q)
4-MeOC6H4CH2
4-FC6H4CH2
H
3g
R1 = H (1a)
8
9
C6H4CH=CH2
Ph
H
3h
3i
35% (2t)
2
4-OMe (1b)
Ph
62%(2a)c,d
3
4-OEt (1c)
4-tBu (1d)
4-Me (1e)
2-Me (1f)
4
5
10
11
3j
0
0
6
7
3-Me (1g)
3,4-dou-OMe (1h)
1,3,5-tri-Me (1i)
4-F (1j)
3k
8
a
9
Standard conditions: ketones (1.0mmol), (NH4)2CO3 (1.0equiv),
Cu(OAc)2 (0.3mmol,30mol%), TBAI (0.3mmol,30mol%), DMSO (3.0
mL) ,120oC for 5 h. b Isolated yield after column chromatography. c GC
yield. d benzamide(4c) was isolated in 40% yield.
10
11
12
13
14
15
16
17
4-Cl (1k)
4-Br (1l)
2-Br (1m)
3-Br (1n)
4-I (1o)
4-NO2 (1p)
4-CN (1q)
18
19
(1r)
(1s)
63% (2r)
51% (2s)
a
Standard conditions: ketones (1.0mmol), (NH4)2CO3 (1.0equiv),
Cu(OAc)2 (0.3mmol), TBAI (0.3mmol), DMSO (3.0 mL), 120oC for 5 h.
b Isolated yield after column chromatography. c GC yield.
Scheme 3 the application of this conversion in other carbonyl
compounds
To expand the substrate scope of this transformation, aryl
25 ketones with long chain alkyl and aliphatic ketones were
investigated. From the experimental results shown in Table 2, the
45
To explore the mechanism of this transformation, some control
2 | Chem. Commun., 20xx, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 4
ChemComm
ChemComm
Please do not adjust margins
COMMUNICATION
experiments were carried out. When acetophenone (1a) reacted
In order to identify the fragment of the ketones, substrate
under the standard conditions without (NH4)2CO3, 35% yield of
benzaldehyde (4a) and 25% yield of benzoic acid (4b) were 35 (3e) were tested under the standard conditDioOnIs:.10A.1s03e9x/pCe5cCteCd0,2a5p78aHrt
acetophenone (1a), propiophenone (3a) and 1-phenylpentan-1-one
View Article Online
detected by GC with using bromobenzene as an internal standard
(Scheme 4a). It implied that benzaldehyde may be further oxidized
under the present conditions which is in accord with the literature.8
And benzaldehyde (4a) can afford benzonitrile (2a) in 87% yield
under the standard conditions (Scheme 3a). Even though
benzaldehyde (4a) was formed in low yield under this catalyst
from the generation of benzonitrile (2a), trace amount of formamide
(7a), acetamide (7b) and n-butyramide (7c) could be detected by
GC-MS, respectively (see Supporting Information).
5
10 system, combining the above results, we can hypothesize that once
benzaldehyde is formed, it will convert to benzonitrile, thus
decreasing the overoxidation of the benzaldehyde. Interestingly,
when benzaldehyde reacted with (NH4)2CO3 under N2 atmosphere,
not only trace (<5%) of benzonitrile was obtained, but also trace
15 amount (<1%) of the corresponding benzaldimine (5) could be
detected by GC-MS (Scheme 4b, details see Supporting
Information). These results implied that the condensation of
benzaldehyde with ammonia could occur without oxygen. However,
the benzaldimine (5) cannot be obtained in higher yield or isolated
20 because of their chemically labile nature. Notably, when imines (6)
and (7) were chosen as the substrate, benzonitrile could be obtained
in 92% and 61% yields, respectively. Furthermore, when
benzylamine (8) reacted with or without (NH4)2CO3, nitriles could
be obtained in 85% or 86% yield. The above preliminary results
25 revealed that imines can be oxidized to nitriles under the standard
conditions. On the other hand, when benzaldoxime (9) reacted with
(NH4)2CO3 under the standard conditions, only trace amount of
benzonitrile was obtained, but 42% of 3,5-diphenyl-1,2,4-
oxadiazole (10) was produced, which suggested that Beckmann
30 rearrangement was not the major reaction path.
Scheme 5 The proposed reaction mechanism.
40
On the basis of the above preliminary results and related
reports,8-9
a plausible mechanism of this copper-catalyzed
conversion of C=O bond from ketones to C≡N bond was proposed
(Scheme 3). Initially, the substrate is oxidized to give the
45 corresponding aldehyde and carboxylic acid through the oxidation
cleavage of C-C bond in the present of Cu slats and molecular
oxygen (step a). Subsequently, aldehyde reacts with ammonia to
produce the corresponding imine (step b). Finally, the imine is
readily transformed to product catalyzed by the Cu/O2 system (step
50 c). Meanwhile, carboxylic acid reacted with the ammonia to
produce the corresponding amide under the present conditions (step
d).
In summary, we have described a copper-catalyzed conversion
of C=O bond of ketones to C≡N bond. A wide range of ketones can
55 be subjected to this transformation. Moreover, the usage of the
oxygen as the sole oxidation and ammonium salt as nitrogen source
makes this transformation very practical. Preliminary mechanistic
research showed the aldehyde might be an intermediate in this
conversion through the oxidation C-C bond cleavage of ketones.
60 Based on the above results, this protocol represents a novel
approach to realize the conversion of C=O bond to C≡N bond,
which should be of importance in organic chemistry and medical
chemistry.
We gratefully acknowledge the financial support from the
65 National Natural Science Foundation of China (No. 21372068).
Notes and references
1. (a) R. C. Larock, Comprehensive organic transformations; (b)
J. S. Miller and J. L. Manson, Accounts of chemical research,
2001, 34, 563-570; (c) N. Ono, The nitro group in organic
70
synthesis, John Wiley & Sons, 2003.
2. (a) F. Fleming, Natural Product Reports, 1999, 16, 597-606;
(b) F. F. Fleming, L. Yao, P. Ravikumar, L. Funk and B. C.
Shook, Journal of medicinal chemistry, 2010, 53, 7902-7917;
(c) A. Kleemann, J. Engel, B. Kutscher and D. Reichert,
Scheme 4 Investigations into the reaction mechanism.
This journal is © The Royal Society of Chemistry 20xx
Chem. Commun., 20xx, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 4
ChemComm
COMMUNICATION
Pharmaceutical substances: syntheses, patents, applications,
Thieme Stuttgart, 1999; (d) T. Wang and N. Jiao, Accounts of
chemical research, 2014, 47, 1137-1145.
organic chemistry, 2013, 78, 10567-10571; (d) K. Miyagi, K.
25
30
35
Moriyama and H. Togo, European Journal of Organic
View Article Online
DOI: 10.1039/C5CC02578H
Chemistry, 2013, 2013, 5886-5892.
3. (a) M. B. Madhusudana Reddy and M. A. Pasha, Synthetic
Communications, 2010, 40, 3384-3389; (b) S. Laulhe, S. S.
Gori and M. H. Nantz, The Journal of organic chemistry, 2012,
77, 9334-9337; (c) B. V. Rokade and K. R. Prabhu, The
Journal of organic chemistry, 2012, 77, 5364-5370; (d) L. M.
Dornan, Q. Cao, J. C. Flanagan, J. J. Crawford, M. J. Cook and
M. J. Muldoon, Chem Commun (Camb), 2013, 49, 6030-6032;
(e) V. P. Gozum and R. C. Mebane, Green Chemistry Letters
and Reviews, 2013, 6, 149-150; (f) G. C. Nandi and K. K.
Laali, Tetrahedron Letters, 2013, 54, 2177-2179.
4. (a) C. W. Kuo, J. L. Zhu, J. D. Wu, C. M. Chu, C. F. Yao and
K. S. Shia, Chem Commun (Camb), 2007, 301-303; (b) S.
Zhou, D. Addis, S. Das, K. Junge and M. Beller, Chem
Commun (Camb), 2009, 4883-4885; (c) S. Zhou, K. Junge, D.
Addis, S. Das and M. Beller, Organic letters, 2009, 11, 2461-
2464.
6. Y. Suzuki, K. Moriyama and H. Togo, Tetrahedron, 2011, 67,
7956-7962.
5
10
15
7. (a) C. Tang and N. Jiao, Angew Chem Int Ed Engl, 2014, 53,
6528-6532; (b) F. Chen, T. Wang and N. Jiao, Chemical
Reviews, 2014, 114, 8613-8661; (c) X. Huang, X. Li, M. Zou,
S. Song, C. Tang, Y. Yuan and N. Jiao, Journal of the
American Chemical Society, 2014, 136, 14858-14865; (d) W.
Zhou, W. Fan, Q. Jiang, Y.-F. Liang and N. Jiao, Organic
letters, 2015; (e) X. Huang, X. Li, M. Zou, J. Pan and N. Jiao,
Organic Chemistry Frontiers, 2015, 2, 354-359; (f) C. Zhang,
P. Feng and N. Jiao, Journal of the American Chemical Society,
2013, 135, 15257-15262.
8. L. Zhang, X. Bi, X. Guan, X. Li, Q. Liu, B. D. Barry and P.
Liao, Angew Chem Int Ed Engl, 2013, 52, 11303-11307.
9. (a) L. Sayre and S. Jin, The Journal of organic chemistry, 1984,
49, 3498-3503; (b) S. U. Dighe, D. Chowdhury and S. Batra,
Advanced Synthesis & Catalysis, 2014, 356, 3892-3896; (c) L.
Gu and C. Jin, Chemical Communications, 2015.
40
20 5. (a) V. N. Telvekar and R. A. Rane, Tetrahedron Letters, 2007,
48, 6051-6053; (b) Y.-Q. Cao, Z. Zhang and Y.-X. Guo,
Journal of Chemical Technology & Biotechnology, 2008, 83,
1441-1444; (c) D. Cantillo and C. O. Kappe, The Journal of
45
4 | Chem. Commun., 20xx, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins