Highly practical synthesis of nitriles and heterocycles from alcohols under mild conditions by aerobic double dehydrogenative catalysis

Article abstract of DOI:10.1021/ol400459y

A mild, aerobic, catalytic process for obtaining nitriles directly from alcohols and aqueous ammonia is described. The reaction proceeds via a dehydrogenation cascade mediated by catalytic CuI, bpy, and TEMPO in the presence of O₂. The substrate scope is broad including various functionalized aromatic and aliphatic alcohols. This protocol enabled the one-pot synthesis of various biaryl heterocycles directly from commercially available alcohols.

Full text of DOI:10.1021/ol400459y

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Highly Practical Synthesis of Nitriles
and Heterocycles from Alcohols under
Mild Conditions by Aerobic Double
Dehydrogenative Catalysis
Weiyu Yin, Chengming Wang, and Yong Huang*
Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology,
Peking University, Shenzhen Graduate School, Shenzhen, China
huangyong@pkusz.edu.cn
Received February 19, 2013
ABSTRACT
A mild, aerobic, catalytic process for obtaining nitriles directly from alcohols and aqueous ammonia is described. The reaction proceeds via a
dehydrogenation cascade mediated by catalytic CuI, bpy, and TEMPO in the presence of O2. The substrate scope is broad including various
functionalized aromatic and aliphatic alcohols. This protocol enabled the one-pot synthesis of various biaryl heterocycles directly from
commercially available alcohols.
Nitriles are vital synthetic intermediates for pharmaceu-
ticals, material, agricultural, and fine chemicals. Numer-
ous methods have been developed for nitrile production.1
Representative general synthetic strategies include halide/
CN exchange,2 oxidation of amines,3 and dehydration of
amides and aldoximes.4,5 Often, high temperature, pres-
sure, toxic reagents, and wastes or their combinations are
employed to promote efficient nitrile formation. There is a
growing demand for a highly practical nitrile synthesis
from cheap commercially available starting materials such
as alcohols and aqueous ammonia under ambient condi-
tions. Formation of the unique CtN functionality often
requires chemical stripping of hydrogen, oxygen, or other
heteroatoms off a CdN moiety. This elimination is quite
difficult, as bonds on sp2 atoms are significantly stronger
compared with their sp3 counterparts.6 Therefore, such a
transformation requires the use of stoichiometric amounts
of oxidants.7 Quite recently, catalytic aerobic reactions
have emerged as one of the preferred green oxidation
strategies.8 In this vein, the direct synthesis of a nitrile,
via a transition-metal catalyzed aerobic oxidative reaction,
(1) (a) Friedrich, K.; Wallenfels, K. Chemistry of the Cyano Group;
Rappoport, Z., Ed.; Wiley: London, U.K., 1970. (b) Fatiadi, A. J. In
Preparation and Synthetic Applications of Cyano Compounds; Wiley:
New York, 1983. (c) Miller, J. S.; Manson, J. L. Acc. Chem. Res. 2001, 34,
563.
(2) (a) Anbarasan, P.; Schareina, T.; Beller, M. Chem. Soc. Rev. 2011,
40, 5049. (b) Yan, G.; Yu, J.; Zhang, L. Chin. J. Org. Chem. 2012, 32,
294.
(3) (a) Schumperli, M. T.; Hammond, C.; Hermans, I. ACS Catal.
2012, 2, 1108. (b) Zhang, Y.; Xu, K.; Chen, X.; Hu, T.; Yu, Y.; Zhang, J.;
Huang, J. Catal. Commun. 2010, 11, 951. (c) Yamaguchi, K.; Mizuno, N.
Angew. Chem., Int. Ed. 2003, 42, 1480.
(4) (a) Enthaler, S. Chem.;Eur. J. 2011, 17, 9316. (b) Sueoka, S.;
Mitsudome, T.; Mizugaki, T.; Jitsukawa, K.; Kaneda, K. Chem. Com-
mun. 2010, 46, 8243. (c) Zhou, S.; Addis, D.; Das, S.; Junge, K.; Beller,
M. Chem. Commun. 2009, 4883.
(5) (a) Yamaguchi, K.; Fujiwara, H.; Ogasawara, Y.; Kotani, M.;
Mizuno, N. Angew. Chem., Int. Ed. 2007, 46, 3922. (b) Ishihara, K.;
Furuya, Y.; Yamamoto, H. Angew. Chem., Int. Ed. 2002, 41, 2983.
(6) Blanksby, S. J.; Ellison, G. B. Acc. Chem. Res. 2003, 36, 255.
(7) (a) Yamazaki, S.; Yamazaki, Y. Chem. Lett. 1990, 571. (b)
McAllister, G. D.; Wilfred, C. D.; Taylor, R. J. K. Synlett 2002, 1291.
(c) Chen, F.-E.; Li, Y.-Y.; Jia, H.-Q. Synthesis 2002, 1804. (d) Iida, S.;
Togo, H. Tetrahedron 2007, 63, 8274. (e) Mori, N.; Togo, H. Synlett
2005, 1456. (f) Iida, S.; Tago, H. Synlett 2007, 407. (f) Zhu, C.-J.; Sun,
C.-G.; Wei, Y.-Y. Synthesis 2010, 4235. (g) Reddy, K. R.; Maheswari,
C. U.; Venkateshwar, M.; Prashanthi, S.; Kantam, M. L. Tetrahedron
Lett. 2009, 50, 2050. (i) Veisi, H. Synthesis 2010, 2631.
(8) (a) Wendlandt, A. E.; Suess, A. M.; Stahl, S. S. Angew. Chem., Int.
Ed. 2011, 50, 11062. (b) Campbell, A. N.; Stahl, S. S. Acc. Chem. Res.
2012, 45, 851. (c) Shi, Z.; Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev.
2012, 41, 3381. (d) Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012,
41, 3464.
r
10.1021/ol400459y
XXXX American Chemical Society

from an inexpensive commodity source, such as alcohols
and ammonia, would be a highly valuable process.
two examples (15% and 30% yield) of nitrile synthesis
from aldehyde and ammonia.13a The poor yields might be
attributed to the formation of Werner’s amine complexes
Cu[NH3]4X2. Subsequently, Capdevielle reported that aro-
matic nitriles could be obtained in high yield from benzalde-
hyde derivatives and ammonium chloride using stoichiomet-
ric (1.5À2.0 equiv) copper powder in pyridine.13b In addition,
enolizable aliphatic aldehydes were not tolerated.
Scheme 1. Catalytic Aerobic Oxidation of Alcohols to Nitriles
Table 1. Preliminary Study of Cu/TEMPO Catalyst System for
the Synthesis of Nitriles from Alcoholsa
Intrigued by the old industrial method of ammoxida-
tion,9 we were interested in developing a highly practical
method for converting alcohols to nitriles using molecular
oxygen and ammonia. To the best of our knowledge, direct
conversion of alcohols to nitriles using oxygen and ammo-
nia only existed in the heterogeneous catalysis paradigm
(Scheme 1). Recently, Mizuno reported a direct nitrile
synthesis from alcohols using a heterogeneous Ru(OH)x/
Al2O3 catalyst and excess aqueous ammonia under 6 atm
of air pressure at 120 °C.10c Ishida et al. subsequently dis-
closed a parallel process using metal oxide (MnO2) under
pressured oxygen (0.85 MPa) and NH3 gas (0.5 MPa) at
100 °C.10a Challenges for this particular transformation
include (1) the formation of catalytically dead Werner
complexes in the presence of ammonia and homogeneous
transition metals; (2) difficulty in undergoing “NÀH acti-
vation” due to the high strength of the NÀH bond of
ammonia (107 kcal/mol);11 and (3) a double dehydrogena-
tive mechanism which requires strong oxidative condi-
tions, preventing an efficient aerobic catalytic cycle.
Cu/TEMPO has been extensively studied as an efficient
catalyst for alcohol oxidation to the aldehyde.12 Recently,
a simple Cu/TEMPO/NMI/bpy system was developed
by Stahl et al. that permitted room temperature aerobic
oxidation of alcohols to aldehydes.12e We decided to
explore the possibility of double dehydrogenation of alco-
hols to access nitriles directly via in situ aldehyde/imine
formation. However, aerobic oxidation of aldehydes to
nitrilesinthe presenceofammonia and atransition metal is
a challenging task. In 1963, Brackman and Smit reported
entry
Cu
L
add.
none
sol.
conv (%)b
1
2
3
4
5
6
7
8
9c
CuBr2
CuBr2
CuBr2
CuBr2
CuBr
CuOTf
CuCl
CuI
none
none
bpy
bpy
bpy
bpy
bpy
bpy
bpy
DMSO
DMSO
DMSO
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
N.R.
45
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
64
80
86
93
91
100
100
CuI
a Reaction conditions: 1.0 mmol of alcohol, 5 mol % Cu, 5 mol %
ligand, 5 mol % additive, 2.0 equiv of aqueous ammonia (25À28%,
w/w), 2 mL of solvent, oxygen balloon, 55 °C, 24 h. b Determined by GC
using biphenyl as an internal standard. c The reaction was carried out at
room temperature for 24 h.
Our initial investigation involved mixing benzyl alcohol,
a copper salt, a ligand, an additive, and 2 equiv of aqueous
ammonia under an oxygen atmosphere. After the reac-
tion mixture was stirred for 24 h at 55 °C, aliquots were
taken and conversions were determined by GC (Table 1;
for complete condition screening, see the Supporting
Information). Gratifyingly, aqueous ammonia did not
inhibit the initial aldehyde formation and we were able to
eliminate NMI required in the Stahl protocol without
effecting the catalytic activity. Preliminary screening re-
vealed the following characteristics: (1) Cu alone did not
catalyze nitrile formation; (2) TEMPO was essential for
both alcohol-to-aldehyde and aldehyde-to-nitrile steps; (3)
a chelating bpy ligand significantly improved nitrile for-
mation by accelerating the aldehyde formation step. Cu(I)
and Cu(II) salts were equally effective.14 By using CuI, we
were able to achieve a 100% GC yield.
€
(9) (a) Martin, A.; Kalevaru, N. V.; Lucke, B.; Sans, J. Green Chem.
2002, 4, 481. (b) Denton, W. I.; Bishop, R. B.; Caldwell, H. P.; Chapman,
H. D. Ind. Eng. Chem. 1950, 42, 796.
(10) (a) Ishida, T.; Watanabe, H.; Takei, T.; Hamasaki, A.; Tokunaga,
M.; Haruta, M. Appl. Catal. A: Gen. 2012, 425À426, 85. (b) Yamaguchi, K.;
Kobayashi, H.; Oishi, T.; Mizuno, N. Angew. Chem., Int. Ed. 2012, 51, 544.
(c) Yamaguchi, K.; He, J.; Oishi, T.; Mizuno, N. Chem.;Eur. J. 2010, 16,
7199. (d) Oishi, T.; Kazuya, Y.; Mizuno, N. Angew. Chem., Int. Ed. 2009,
48, 6286.
(11) (a) Klinkenberg, J. L.; Hartwig, J. F. Angew. Chem., Int. Ed.
2011, 50, 86. (b) van der Vlugt, J. I. Chem. Soc. Rev. 2010, 39, 2302.
(12) (a) Brackman, W.; Gaasbeek, C. J. Recl. Trav. Chim. Pays-Bas.
To our delight, the reaction at room temperature was
equally effective (Table 1, entry 9). The substrate scope
was explored under the optimized ambient conditions.
Good-to-quantitative yields were achieved for a broad
(13) (a) Brackman, W.; Smit, P. J. Recl. Trav. Chim. 1963, 82, 757. (b)
Capdevielle, P.; Lavigne, A.; Maumy, M. Synthesis 1989, 6, 451. There
was one example using substoichiometric copper in this literature, where
0.7 equiv of copper accomplished an 83% yield.
(14) There was a greater rate difference between Cu(I) and Cu(II) for
the alcohol oxidation to aldehyde step in Stahl’s studies; see ref 12e.
ꢀ
1966, 85, 257. (b) Semmelhack, M. F.; Schmid, C. R.; Cortes, D. A.;
Chou, C. S. J. Am. Chem. Soc. 1984, 106, 3374. (c) Mannam, S.;
Alamsetti, S. K.; Sekar, G. Adv. Synth. Catal. 2007, 349, 2253. (d) Figiel,
P. J.; Sibaouih, A.; Ahmad, J. U.; Nieger, M.; Raisanen, M. T.; Leskela,
M.; Repo, T. Adv. Synth. Catal. 2009, 351, 2625. (e) Hoover, J. M.; Stahl,
S. S. J. Am. Chem. Soc. 2011, 133, 16901.
€ €
€
B
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Table 2. Scope of Alcohols for Aerobic Double Dehydrogenationa
a 1.0 mmol of alcohol, 2 mL of solvent, oxygen balloon, 24 h. b Isolated yield. Reactions of aromatic alcohols occurred in EtOH at rt. Reactions
of aliphatic alcohols occurred in MeCN at 50 °C. c Yield in parentheses reflected a 3 g scale reaction. d GC yield due to low boiling point of the
product.
Scheme 2. A Proposed Reaction Mechanism
range of benzyl alcohols (Table 2). A number of functional
groups were tolerated. The reactions were particularly
efficient for electron-rich and -neutral benzyl alcohols.
Over 90% isolated yields were obtained uniformly. Halo-
gen, basic amine, and heterocyclic substituents did not
interfere with this double dehydrogenation reaction. The
reactions involving strongly electron-deficient benzyl alco-
hols were compromised by the competing oxidation of an
in situ generated hemiacetal, due to the strong electrophilic
nature of the corresponding aldehydes. For 4-nitro benzyl
alcohol, the corresponding benzoic acid ethyl ester was
isolated as the major side product and the corresponding
nitrile was obtained in 60% isolated yield. Heteroaromatic
substrates and vinylogous benzyl alcohols were also suc-
cessfully oxidized in good-to-excellent yields. The robust-
ness of this process was challenged using KU0063794
(Stemolecule, 1v),15 a potent and selective inhibitor for
(15) Juan, M. G. M.; Jennifer, M.; Rosemary, G. C.; Alex, G.;
Sabina, C. C.; Chrisine, M. C.; Dario, R. A. Biochem. J. 2009, 421, 29.
Org. Lett., Vol. XX, No. XX, XXXX
C

mTORs (mammalian target of rapamycin). The corre-
sponding nitrile analogue was isolated in high yield despite
the rich functionality present in this molecule. The reac-
tions of aliphatic alcohols were very slow at room tem-
perature. The first alcohol-to-aldehyde oxidation was the
rate limiting step for those substrates, which justified the
usage of EtOH as solvent for benzyl alcohol substrates.
Gratifyingly, heating to50 °C (in acetonitrile) rendered full
conversions to the corresponding aliphatic nitriles in high
yields. Regardless of the steric hindrance, primary alcohols
bearing secondary, tertiary, and quaternary carbon side
chains afforded the corresponding nitriles in excellent
yields. The appealing synthetic practicality is underscored
by the workup procedures. For most substrates, simple
evaporation and filtration through a silica gel plug led to
analytically pure products. Reproducible yields were ob-
tained on 3 g scales.
which could trigger the second oxidation cycle to afford
the nitrile product 2.
This aerobic double dehydrogenative nitrile synthesis
was tied to various heterocyclization processes, to provide
a one-pot synthesis of substituted tetrazoles,17 imidazolines,18
oxazoline,19 thiazoline,20 and triazolopyridines21 (Scheme 3).
Generally, the reagents for the heterocyclizations were intro-
duced after a full conversion of nitrile had been achieved. For
imidazolines, oxazolines, and thiazolines, no oxidation to the
corresponding heteroaromatics was observed.
Scheme 3. One-Pot Synthesis of Biaryl Heterocycles
Itisunambiguousthatthe aldehyde isa keyintermediate
in these reactions. The first dehydrogenation is faster than
the second oxidation step, as evidenced by early stage
aldehyde accumulation. Independent experiments have
shown that TEMPO plays central roles in both oxidation
steps. The detailed mechanism of Cu/TEMPO catalyzed
dehydrogenative oxidation is quite complicated. Very
recently, Stahl reported detailed mechanistic studies on
Cu(I)/TEMPO catalyzed aerobic oxidation of an alcohol
to an aldehyde. The authors found that this particular
catalyst system resembled binuclear type 3 Cu enzymes for
O2 activation.16 Combining our experimental data and
Stahl’s mechanism, we propose a Cu(II)ÀOH mediated
TEMPO oxidation pathway (Scheme 2). Cu(I)ÀL is con-
verted to Cu(II)ÀOH (A) by O2 and TEMPOH. Ligand
exchange would lead to Cu(II)ÀOR (B) which could be
oxidized by TEMPO through a hydrogen abstraction
mechanism, to generate the corresponding aldehyde. The
aldehyde is then converted to the imine rapidly in the
presence of ammonia. The transient imine intermediate,
being a better ligand than either the aldehyde or the nitrile,
would form a more favored Cu(I)Àimine complex (E)
In summary, we have reported a general and practical
protocol for the synthesis of nitriles under mild condi-
tions using cheap commercially available reagents: CuI,
TEMPO, bipyridine, and alcohols. Both functionalized
benzyl and aliphatic alcohols are well suited for this protocol.
This aerobic dehydrogenation cascade reaction enables a
series of one-pot syntheses of pharmaceutically attractive
heterocycles. Preliminary experiments suggest a radical
mechanism mediated by a copper(II)ÀOH complex.
Acknowledgment. This work is financially supported
by the National Basic Research Program of China
(2012CB722602), grants of Shenzhen special funds
for the development of biomedicine (JC201104210111A
and JC201104210112A), Shenzhen innovation funds
(GJHZ20120614144733420), and the Shenzhen Peacock
Program (KQTD201103).
(16) Hoover, J. M.; Ryland, B. L.; Stahl, S. S. J. Am. Chem. Soc. 2013,
135, 2357.
(17) Zhou, W.; Zhang, L.-R.; Jiao, N. Angew. Chem., Int. Ed. 2009,
48, 7094.
(18) Nasr-Esfahani, M.; Montazerozohori, M.; Mehrizi, S. J. Het-
erocycl. Chem. 2011, 48, 249.
(19) Li, X.-N.; Zhou, B.-Y.; Zhang, J.; She, M.-Y.; An, S.-J.; Ge,
H.-X.; Li, C.; Yin, B.; Li, J.-L.; Shi, Z. Eur. J. Org. Chem. 2012, 1626.
(20) McCutcheon, D. C.; Paley, M. A.; Steinhardt, R. C.; Prescher,
J. A. J. Am. Chem. Soc. 2012, 134, 7604.
Supporting Information Available. Experimental proce-
dures and compound characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
(21) Ueda, S.; Nagasawa, H. J. Am. Chem. Soc. 2009, 131, 15080.
D
Org. Lett., Vol. XX, No. XX, XXXX