Cu-mediated nitrogen atom transfer via C≡N bond cleavage

Article abstract of DOI:10.1039/c5ob01738f

A nitrogen atom transfer to organic molecules via Cu-mediated C-N triple bond cleavage is firstly developed, which provides a variety of functionalized aryl nitriles from the readily accessible acetonitrile and aryl aldehydes.

Full text of DOI:10.1039/c5ob01738f

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: L. Liu, J. Dong, Y.
Zhang, Y. Zhou and S. Yin, Org. Biomol. Chem., 2015, DOI: 10.1039/C5OB01738F.
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/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 4
View Article Online
DOI: 10.1039/C5OB01738F
Journal Name
COMMUNICATION
Cu-Mediated Nitrogen Atom Transfer via C≡N Bond Cleavage
Lixin Liu, Jianyu Dong, Yaxing Zhang, Yongbo Zhou,* and Shuang-Feng Yin*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A nitrogen atom transfer to organic molecules via Cu-mediated C- bond cleavage, but it produces ketones, carboxylic acid and
N triple bond cleavage is firstly developed, which provides a their derivatives etc. and the nitrogen atom transfer is not
variety of functionalized aryl nitriles from the readily accessible involved.
acetonitrile and aryl aldehydes.
We accidently discovered this N-atom transfer reaction
during our studies aiming at direct cyanation of aryl aldehyde
via the inert Ar-C(O)H bond cleavage. By treatment of 4-anisic
aldehyde 1a with 1.5 equiv of CuCl in valeronitrile under O2 at
130 °C for 24 h, anisonitrile 2a was observed in 72% yield.
Replacement of valeronitrile with acetonitrile resulted in a 40%
yield of 2a (Scheme 1). It seemed that a novel cross-
decarbonylative coupling via Ar-C(O)H and C-CN bond cleavage
was successfully achieved. To confirm this expectation, the 13C
isotope labeling CH313CN was subjected to this reaction system,
to our surprise, 13C was not incorporated into the product and
the cleavage of Ar-C(O)H bond did not take place. It was
further confirmed by the use of p-MeOPh13CHO (Scheme 2).
Comparable to carbon atom, nitrogen atom is the fundamental
unit in organic compounds. Nitrogen atom transfer from
simple nitrogen sources to organic molecules is a topic of
significant importance in organic chemistry, biochemistry and
industrial chemistry.1 Acetonitrile is one of the simplest N-
containing organic compounds, which is easily available and
often used as solvent in organic synthesis. Given that C≡N
bond of acetonitrile contains a sp hybridized nitrogen atom,
cleavage of C≡N bond is regarded as an analogue of N≡N bond
activation of molecular nitrogen. Therefore, the transfer of
nitrogen atom to organic molecules via C≡N bond cleavage
presents a potential model for N2 transformation.2,3
Complete C≡N bond scission has attracted much attention in
the past decades.4-8 In this context, transition metals such as
W,4 Mo,5 Ru,6 and Os,7 have been used for the formation of
metal nitrides, which are frequently produced in fixation of
molecular nitrogen.9 However, in-situ transfer of the nitrogen
atom to organic molecule via C≡N bond cleavage has not been
successfully achieved.10 Herein, we report a nitrogen atom
transfer to aldehyeds via copper-mediated C≡N bond cleavage
affording aryl nitriles (Eq. 1). It is noted that the hydration of
nitriles catalyzed by acids or bases,11 enzymes,12 and transition
metals13 is well known as an efficient way for complete C≡N
Scheme 1 The expected cross-decarbonylative coupling.
Scheme 2 Isotope labeling experiments.
The above results suggested that a novel nitrogen atom
transfer reaction via C≡N bond cleavage was achieved,
producing aryl nitriles from the available starting materials.14
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 4
COMMUNICATION
Journal Name
Table 2 N-atom transfer to aryl aldehydes from CH3CNa
Aromatic nitriles are key structural motifs in various natural
products, pharmaceuticals and fine chemicals,15 and also are
versatile precursors for numerous functional groups,16 such as
amines, imidazoles, amides, tetrazoles.
View Article Online
DOI: 10.1039/C5OB01738F
Encouraged by the initial finding, we then investigated the
optimum
reaction
conditions.
Reaction
of
4-
methylbenzaldehyde 1b with 1.5 equiv of CuCl in CH3CN at
130 °C for 24 h under O2 produced p-tolunitrile 2b in 40% yield
(Table 1, entry 1). Addition of an appropriate amount of N,N-
dimethylacetamide (DMAc) could remarkably increase the
reaction efficiency (entries 2-5), and the ratio of CH3CN to
DMAc at 2 : 1 gave the best yield (90%, entry 4), whereas, the
desired product 2b was not observed in the absence of
acetonitrile (entry 6). Screening of the copper salts revealed
that CuCl had the unique reactivity toward this reaction,
whereas, other copper salts, such as Cu powder, CuBr, CuI, and
CuCl2 were not effective for the present N-atom transfer
reaction (entries 7-10). To confirm the unique ability of CuCl,
the 99.999% ultrahigh purity CuCl was examined, which gave a
comparable yield of 2b (91%, entry 11). Molecular oxygen was
also crucial for the current reaction and only a negligible
amount of 2b was produced under air (entries 12-13; for
details, see ESI).
Table 1 Optimization of the reaction conditionsa
aReaction conditions: 1b (0.2 mmol), [Cu] (0.3 mmol), solvent (1.0 mL), GC
yield using dodecane as an internal standard. b99.999% CuCl. cunder N2.
dunder air.
As shown in Table 2, aryl aldehydes, with a broad range of
functional groups, are tolerable to this N-atom transfer
reaction, giving the corresponding aryl nitriles in good to
excellent yields. Despite being liable to be oxidized to inactive
benzoic acids, benzaldehydes bearing electron-donating
groups, such as alkyl, alkoxyl, phenyl, and halogen, worked
well, giving the corresponding benzonitriles in high to excellent
yields, regardless of their positions on the phenyl rings
aReaction conditions: aldehyde
1
(0.2 mmol), CuCl (0.3 mmol), CH3CN (0.67
mL), DMAc (0.33 mL) in 25 mL tube under O2, 130 °C, 24 h, isolated yields.
bbenzeneacetonitrile (0.3 mmol), CH3CN (1.0 mL). cGC yields.
(Table 2, 2a
amino (2l), alkynyl (2m) and alkenyl (2n) were well tolerable in
this oxidation system, and the desired products 2l 2n were
-2k). Notably, the versatile functional groups acetyl
-
produced in satisfactory yields (65-81%). Although low yields
(20-44%) of aryl nitriles were observed by the treatment of
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 4
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
electron-deficient aryl aldehydes with acetonitrile (2o
reaction was accelerated by the replacement of DMAc with
stoichiometric benzeneacetonitrile, and electron-withdrawing
groups, such as CF3-, NO2-, CN-, and CH3OC(O)-, were
successfully introduced to aryl nitriles (63-76% yields). When
COMMUNICATION
-
2r), the
View Article Online
DOI: 10.1039/C5OB01738F
4-bromobenzaldehyde
and
4-iodobenzaldehyde
were
employed as the substrates, the side product 4-
chlorobenzonitrile 2i was detected in 17% and 23% yields,
respectively. Whereas, the side reactions were suppressed by
the use of benzeneacetonitrile (2s-2t, for details, see ESI).
In addition to substituted benzaldehydes, other aryl
aldehydes were also good substrates for this reaction.
Treatment of 1-naphthaldehyde and 2-naphthaldehyde with
acetonitrile mediated by CuCl gave the corresponding products
in high yields
carbaldehyde, moderate yield was observed (2w). 1-methyl-
1H-indole-3-carbaldehyde and 1-phenyl-1H-indole-3-
(2u-2v), in the case of anthracene-9-
carbaldehyde were well applicable to the present
transformation, and the corresponding heteroaryl nitriles 2x
and 2y were obtained in 79% and 70% yields, respectively.
Other heteroaryl aldehydes such as thiophene-3-carbaldehyde
also worked well, giving the corresponding product 2z in
moderate yield. In addition, cinnamaldehyde reacted with
acetonitrile smoothly to produce the α,β-unsaturated nitrile
2za in 66% yield.
To gain an insight into the reaction mechanism, several
control experiments were carried out under standard
conditions (Scheme 3). Firstly, radical inhibitors, such as 2,6-di-
tert-butyl-4-methylphenol
(BHT)
and
2,2,6,6-
tetramethylpiperidine N-oxide (TEMPO) could block this
reaction, suggesting that free-radical mechanism involved in
this N-atom transfer reaction (Eq. 1, Scheme 3). Indeed, the
Scheme 3 The control experiments.
including an analogous Fischer oxazole synthesis19
subsequent O2 insertion reaction.20 Next, rearrangement of
(C to D') and
radical
adduct
2-(2,2,6,6-tetramethylpiperidin-1-
E
yloxy)acetonitrile was detected by the treatment of 2.0 equiv
of TEMPO with CH3CN for 2 h (Eq. 2, Scheme 3).14d,17
Compared with pentanenitrile, acetonitrile and isobutyronitrile,
benzeneacetonitrile showed the highest reactivity (Eq. 3,
Scheme 3), attributing to its excellent ability to form the
cyanomethyl radical. Whereas, no desired product was
detected even by the use of a large amount of pivalonitrile,
without sp3 C-H bond adjacent to CN. In a sharp contrast,
reaction of pivalamide with 4-methylbenzaldehyde gave 2b in
47% yield (Eq. 4, Scheme 3). These results suggested that the
reaction did not proceed via the hydration of nitrile. It was
further confirmed by the detrimental effect on this reaction of
water. When 2.0 equiv of water was added, only a trace
amount of 2b was observed (Eq. 1, Scheme 3).
results in
F
, which is further oxidized to benzonitrile 220 with
concomitant generation of CO2.
On the basis of the above experimental results, a reaction
mechanism was proposed as shown in Scheme 4. Initially,
similar to the reaction of TMEPO with acetonitrile, the
oxidation of sp3 C-H bond adjacent to CN forms a cyanomethyl
radical adduct
reaction of with HCl produces the iminochloride
was converted into the aldehydecyanohydrin
aldehydes through nucleophilic reaction. The formation of
the oxazole peroxide from involves series of reactions,
A
with the deliverance of HCl.18 The addition
Scheme 4 The possible reaction pathway
A
B, then
B
C
with aryl
1
Conclusions
E
C
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 4
COMMUNICATION
Journal Name
Fryzuk, J. B. Love, S. J. Rettig, V. G. Young, Science, 1997, 275
DOI: 10.1039/C5OB01,73786F;
(d) F. Akagi, T. Matsuo, H. Kawaguchi, Angew. Chem. Int. Ed.,
2007, 46, 8778; (e) T. Shima, S. Hu, G. Luo, X. Kang, Y. Luo, Z.
Hou, Science, 2013, 340, 1549.
,
In summary, we have discovered the first copper promoted
aerobic oxidative N-atom transfer via simultaneous cleavage of
C-N triple bond and C-CN bond of acetonitrile to produce aryl
nitriles in high yields. It provides not only a new approach for
complete C-N triple bond cleavage, but also an alternative way
for the synthesis of aryl nitriles. Further studies toward the
elucidation of the exact reaction mechanism and the synthetic
utility of this novel protocol are currently underway.
View Article Online
1445; (c) D. V. Yandulov, R. R. Schrock, Science, 2003, 301
10 Metal nitrides mediated nitriles metathesis have been
reported, see: (a) M. H. Chisholm, E. E. Delbridge, A. R.
Kidwell, K. B. Quinlanb, Chem. Commun., 2003, 2, 126; (b) A.
M. Geyer, R. L. Gdula, E. S. Wiedner, M. J. A. Johnson, J. Am.
Chem. Soc., 2007, 129, 3800; (c) A. M. Geyer, E. S. Wiedner, J.
B. Gary, R. L. Gdula, N. C. Kuhlmann, M. J. A. Johnson, B. D.
Dunietz, J. W. Kampf, J. Am. Chem. Soc., 2008, 130, 8984; (d)
B. A. Burroughs, B. E. Bursten, S. Chen, M. H. Chisholm, A. R.
Kidwell, Inorg. Chem., 2008, 47, 5377; (e) E. S. Wiedner, K. J.
Gallagher, M. J. A. Johnson, J. W. Kampf, Inorg. Chem., 2011,
50, 5936.
Acknowledgements
Financial support by the National Natural Science Foundation
of China (Grant Nos. 21172062, 21273066, 21273067), the
Doctoral Fund of Chinese Ministry of Education
(20110161120008) is gratefully appreciated.
11 (a) H. R. Sydner, C. T. Elston, J. Am. Chem. Soc., 1954, 76
3039; (b) C. R. Hauser, C. J. Eby, J. Am. Chem. Soc., 1957, 79
725; (c) N. Kornblum; S. Singaram, J. Org. Chem., 1979, 44
4727; (d) J. N. Moorthy, N. Singhal, J. Org. Chem., 2005, 70
,
,
,
,
1926; (e) G. C. Midya, A. Kapat, S. Maiti, J. Dash, J. Org. Chem.,
2015, 80, 4148.
Notes and references
12 (a) K. Ingvosersen, J. Kamphuis, In Enzyme Catalysis in
Organic Synthesis; K. Drauz, H. Waldmann, Eds.; VCH:
1
For reviews on nitrogen atom transfer, see: (a) T. Wang, N.
Jiao, Acc. Chem. Res., 2014, 47, 1137; (b) J. Roizen, M. E.
Harvey, J. D. Bois, Acc. Chem. Res., 2012, 45, 911; (c) K. S.
Weinheim, Germany, 1995,
1, 365; (b) S. Prasad, T. Bhalla,
Biotechnol. Adv., 2010, 28, 725.
Williamson, D. J. Michaelis, T. P. Yoon, Chem. Rev., 2014, 114
,
13 For reviews, see: (a) S. I. Murahashi, H. Takaya, Acc. Chem.
Res., 2000, 33, 225; (b) V. Yu. Kukushkin, A. J. L. Pombeiro,
Chem. Rev., 2002, 102, 1771; (c) V. Yu. Kukushkin, A. J. L.
Pombeiro, Inorg. Chim. Acta, 2005, 358, 1; (d) T. J. Ahmed, S.
M. M. Knapp, D. R. Tyler, Coord. Chem. Rev., 2011, 255, 949;
(e) R. G. Álvarez, P. Crochet, V. Cadierno, Green Chem., 2013,
15, 46; (f) L. Yang, H. Huang, Chem. Rev., 2015, 115, 3468.
14 The use of acetonitrile as a simple CN source via C-CN bond
cleavage has been recognized, see: (a) R.-J. Song, J.-C. Wu, G.
-B. Deng, Y. Liu, C.-Y. Wu, W.-T. Wei, J.-H. Li, Synlett, 2012, 23
2491; (b) X. Kou, M. Zhao, X. Qiao, Y. Zhu, X. Tong, Z. Shen,
Chem. Eur. J., 2013, 19, 16880; (c) C. Pan, H. Jin, P. Xu, X. Liu,
Y. Cheng, C. Zhu, J. Org. Chem., 2013, 78, 9494; (d) Y. Zhu, M.
Zhao, W. Lu, L. Li, Z. Shen, Org. Lett., 2015, 17, 2602; (e) F.-H.
Luo, C.-I. Chu, C.-H. Cheng, Organometallics, 1998, 17, 1025.
15 A. Kleemann, J. Engel, B. Kutscher, D. Reichert,
Pharmaceutical Substance: Synthesis, Patents, Applications,
4th ed., Georg Thieme, Stuttgart, 2001.
8016; (d) T. G. Driver, Org. Biomol. Chem., 2010, , 3831; (e) J.
8
D. Bois, C. S. Tomooka, J. Hong, E. M. Carreira, Acc. Chem.
Res., 1997, 30, 364.
2
Fixations of molecular nitrogen and subsequently transferring
it to organic compounds are known in the biochemical
processes with the aid of nitrogenase and transaminase, see:
(a) J. B. Howard, D. C. Rees, Chem. Rev., 1996, 96, 2965; (b) B.
M. Hoffman, D. Lukoyanov, Z.-Y. Yang, D. Dean, L. C. Seefeldt,
Chem. Rev., 2014, 114, 4041; (c) B. M. Hoffman, D. R. Dean, L.
C. Seefeldt, Acc. Chem. Res., 2009, 42, 609-619; (d) K. Drauz,
H. Gröger, O. May, Enzyme Catalysis in Organic Synthesis, 3rd
ed., Wiley-VCH, Weinheim, 2012, 779.
Nitrogen atom transfer to organic molecules via N≡N bond
cleavage is a long-standing challenge in chemistry, which has
been reported in harsh conditions in lab. For review, see: (a)
M. Mori, J. Organomet. Chem., 2004, 689, 4210; For selected
examples, see: (b) J. J. Curley, E. L. Sceats, C. C. Cummins, J.
Am. Chem. Soc., 2006, 128, 14036; (c) K. Ueda, Y. Sato, M.
Mori, J. Am. Chem. Soc., 2000, 122, 10722; (d) J. G. Andino, S.
Mazumder, K. Pal, K. G. Caulton, Angew. Chem. Int. Ed., 2013,
52, 4726.
,
3
16 (a) The Chemistry of the Cyano Group; Z. Rappoport, Ed.;
Interscience: London, 1970; (b) R. C. Larock, Comprehensive
Organic Transformations, 2nd ed., Wiley-VCH, Weinheim,
1999.
4
5
(a) R. R. Schrock, M. L. Listemann, L. G. Sturgeoff, J. Am. Chem.
Soc., 1982, 104, 4291; (b) J. H. Freudenberger, R. R. Schrock,
17 For selected examples, see: (a) J. Shen, D. Yang, Y. Liu, S. Qin,
J. Zhang, J. Sun, C. Liu, C. Liu, X. Zhao, C. Chu, R. Liu, Org. Lett.,
2014, 16, 350; (b) A. Bunescu, Q. Wang, J. Zhu, Chem. Eur. J.,
2014, 20, 14633; (c) A. Bunescu, Q. Wang, J. Zhu, Org. Lett.,
2015, 17, 1890; (d) C. C. Sazepin, Q. Wang, G. M. Sammis, J.
Zhu, Angew. Chem. Int. Ed., 2015, 54, 5443; (e) D. Zhou, Z.-H.
Li, J. Li, S.-H. Li, M.-W. Wang, X.-L. Luo, G.-L. Ding, R.-L. Sheng,
M.-J. Fu, S. Tang, Eur. J. Org. Chem., 2015, 1606.
Organometallics, 1986,
M. L. Lynn, D. B. Tiedtke, F. Lemoigno, O. Eisentein, Chem.
Eur. J., 1999, , 2318; (d) M. H. Chisholm, K. Folting-Streib, D.
5, 398; (c) M. H. Chisholm, K. Folting,
5
B. Tiedtke, F. Lemoigno, O. Eisenstein, Angew. Chem. Int. Ed.
Engl., 1995, 34, 110.
(a) H. Seino, Y. Ishii, Y. Tanabe, M. Hidai, Inorg. Chim. Acta,
1998, 280, 163; (b) Y. Tanabe, H. Seino, Y. Ishii, M. Hidai, J.
Am. Chem. Soc., 2000, 122, 1690; (c) B. Li, S. Xu, H. Song, B.
Wang, J. Organomet. Chem., 2008, 693, 87; (d) H. Seino, Y.
Mizobe, M. Hidai, Chem. Rec., 2001, 1, 349.
T. Kawashima, T. Takao, H. Suzuki, Angew. Chem. Int. Ed.,
2006, 45, 485.
B. K. Bennett, S. Lovell, J. M. Mayer, J. Am. Chem. Soc., 2001,
123, 4336.
(a) W.-X. Zhang, S. Zhang, X. Sun, M. Nishiura, Z. Hou, Z. Xi,
Angew. Chem. Int. Ed., 2009, 48, 7227; (b) X. Sun, C. Wang, Z.
Li, Z. Xi, J. Am. Chem. Soc., 2004, 126, 7172.
Activation of dinitrogen to form metal nitrides, see: (a) C. E.
Laplaza, C. C. Cummins, Science, 1995, 268, 861; (b) M. D.
18 At the beginning of the reaction, a white fog was formed.
Finally, the reaction system became acidic.
19 (a) E. Fischer, Ber., 1896, 29, 205; (b) B. H. Ingham, J. Chem.
Soc., 1927, 692.
20 (a) H. H. Wasserman, F. J. Vinick, Y. C. Chang, J. Am. Chem.
Soc., 1972, 94, 7180; (b) M. L. Graziano, M. R. Lesce, A.
Carotenuto, R. Scarpati, J. Heterocycl. Chem., 1977, 14, 261;
(c) M. L. Graziano, M. R. Lesce, R. Scarpati, J. Heterocycl.
Chem., 1979, 16, 129; (d) D. Cantillo, C. O. Kappe, J. Org.
Chem., 2013, 78, 10567.
6
7
8
9
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins