Photocatalytic reaction of 4-cyanopyridine with tertiary amines

Article abstract of DOI:10.1007/s10593-019-02423-7

[Figure not available: see fulltext.] The reaction of 4-cyanopyridine with tertiary aliphatic amines photocatalyzed by fac-tris[2-phenylpyridinato-C²,N]iridium(III) complex was studied. The reactions led to arylation of the α-C–H bond of the amine to form the corresponding pyridin-4-yl derivatives along with unsubstituted pyridine.

Full text of DOI:10.1007/s10593-019-02423-7

DOI 10.1007/s10593-019-02423-7
Chemistry of Heterocyclic Compounds 2019, 55(1), 90–92
SHORT COMMUNICATION
Photocatalytic reaction of 4-cyanopyridine with
tertiary amines
Aleksey Yu. Vorob'ev1,2*
1 N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences,
9 Akademika Lavrentieva Ave., Novosibirsk 630090, Russia; е-mail: vor@nioch.nsc.ru
2 Novosibirsk State University,
2 Pirogova St., Novosibirsk 630090, Russia
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(1), 90–92
Submitted September 12, 2018
Accepted after revision December 10, 2018
R1 NR2R3
fac-Ir(ppy)3
(0.5 mol %)
R1 NR2R3
CN
N
H
N
+
MeCN
h , 450 nm
18–65%
N
R1, R2 = H, Me, Et, n-Pr, i-Pr; R3 = Et, i-Pr, n-Bu, (CH2)2OH, (CH2)2NMe2
The reaction of 4-cyanopyridine with tertiary aliphatic amines photocatalyzed by fac-tris[2-phenylpyridinato-C2,N]iridium(III) complex
was studied. The reactions led to arylation of the α-C–H bond of the amine to form the corresponding pyridin-4-yl derivatives along with
unsubstituted pyridine.
Keywords: 4-cyanopyridine, tertiary amines, arylation, С–Н activation, visible-light photocatalysis.
Visible- and UV-light photocatalysis has become a
convenient and widely used tool of organic synthesis in
recent years.1,2 One of the uses of photocatalysis is the
functionalization of α-С–Н bonds in tertiary amines.3–5 In
these reactions, substituted benzylamines and their analogs,
for example, tetrahydroisoquinolines, or N,N-dialkyl-
substituted arylamines are the most often used substrates.
Photocatalytic activation of aliphatic amines is also
possible. For instance, the reaction of tertiary amines with
trimethylsilyl cyanide in the presence of the rose bengal
dye and air when irradiated with visible light led to α-amino-
nitriles.6 The possibility of α-C–H arylation of aliphatic
amines with 2-chloroazoles in the presence of fac-tris-
[2-phenylpyridinato-C2,N]iridium(III) complex (fac-Ir(ppy)3)
under blue light irradiation has also been demonstrated.7 In
addition, aromatic nitriles can be used in photocatalytic
arylation reactions.8 Among other things, the photocatalytic
benzylation of 4-cyanopyridine and its analogs with
1-benzyl-1,2,3,4-tetrahydroisoquinolines is known.9 In the
present study, the photocatalytic reaction of 4-cyano-
pyridine with tertiary aliphatic amines was investigated.
Irradiation of 4-cyanopyridine and Et3N in MeCN in the
presence of fac-Ir(ppy)3 with blue light (450 nm) until
complete conversion of cyanopyridine results in a mixture
of 4-alkylaminopyridine 1a and unsubstituted pyridine 2
(Scheme 1, Table 1). Aminonitrile 3a was also detected in
1
the reaction mixture by H NMR spectroscopy. In the
absence of irradiation or iridium complex, the reaction does
not occur. Other widely used photocatalysts, such as tris-
(2,2'-bipyridyl)ruthenium dichloride, eosin, rose bengal,
and rhodamine 6G, lead to only trace amounts of products.
Replacing MeCN with Me2CO, DMF, THF, or PhH leads
to a significant decrease in the reaction rate, and pyridine is
found as the only reaction product in DMSO. Reducing
catalyst loading to less than 0.5 mol % leads to a signifi-
cant decrease in the reaction rate; at the same time, an
increase in the loading of fac-Ir(ppy)3 does not lead to a
noticeable increase in the rate and yield of the reaction (see
the Supplementary information file).
Previously, compound 1a was obtained by irradiating a
mixture of pyridine and Et3N (in a 1:1 ratio by volume)
with shortwave UV radiation (253 nm).10 However, the
yield of the target compound was extremely low — ~ 0.4%
mixed with other products, and its isolation necessitated the
use of preparative GLC. In this regard, the technique using
a photocatalyst, despite the low yield of the product, is
more preferable.
Other tertiary aliphatic amines also form α-C–H-
arylation products (Scheme 1, Table 1). In sterically
hindered diisopropylethylamine, arylation occurs solely at
0009-3122/19/55(1)-0090©2019 Springer Science+Business Media, LLC
90

Chemistry of Heterocyclic Compounds 2019, 55(1), 90–92
Scheme 1
low reactivity of tributylamine in regards to the α-C–H
arylation appears to be related to its poor solubility in
MeCN — the reaction actually takes place in a two-phase
system.
The structure of the obtained compounds was confirmed
1
by NMR spectroscopy data. In the H NMR spectra of
compounds 1a–e, the characteristic signals of the
4-substituted pyridyl ring are observed at 8.42–8.49 ppm
(signals of protons H-2,6) and in the 7.17–7.35 ppm range
(signals of protons H-3,5). Also, the carbon atoms of the
4-substituted pyridyl ring appear in the 13С NMR spectrum
in the intervals of 123.0–123.9 and 148.1–156.9 ppm. For
all compounds, the peaks of the corresponding molecular
ions are observed in the high-resolution mass spectra.
Table 1. Yields of compounds 1a–d
and ratios of products 1a–d:2 in reaction mixtures
according to NMR spectroscopy data
The proposed mechanism for the formation of
compounds 1a–e (Scheme 2) is similar to that previously
described8 and consists of photoexcitation of the sensitizer
fac-Ir(ppy)3 followed by electron transfer to 4-cyano-
pyridine with the formation of the corresponding anion
Compound
Yield, %
Ratio 1a–d:2
25
18
1:2.4
1:3.6
2.8:1
5.5:1
1:4.8
1а
1b
1c
1d
1e
+
radical 4 and fac-Ir(ppy)3 . Further, anion radical 4 under-
65
goes fragmentation with the formation of pyridyl radical 5.
+
14 (54)*
–** (8)
In turn, the fac-Ir(ppy)3 ion oxidizes the tertiary amine to
cation radical 6, which, when deprotonated, forms amino-
alkyl radical 7. Recombination of radicals 5 and 7 leads to
products 1a–e. The formation of unsubstituted pyridine
apparently occurs by the abstraction of a hydrogen atom
from radical cation 6 by radical 5, due to the significantly
lower energy of the homolytic cleavage of the α-C–H bond
as compared to that in the original amine.4 The mechanism
for the formation of aminonitriles is apparently the same as
for photocatalytic cyanation of amines.6
* Yield determined by NMR spectroscopy of the reaction mixture is given
in parentheses.
** Compound was not isolated.
the ethyl group to form product 1b. However, the main
product of the reaction is unsubstituted pyridine. Methyl-
substituted amines form arylation products with
significantly higher yields. Thus, N,N-dimethyl-
ethanolamine reacts selectively with the 4-pyridyl fragment
addition at the methyl group. Along with product 1c,
aminonitrile 3c was isolated. Arylation of only the methyl
group also occurs in the case of tetramethyl-
ethylenediamine (TMEDA). However, analysis of the
reaction mixture by GC-MS showed that, along with the
To conclude, we have discovered the possibility of
photocatalytic arylation of tertiary aliphatic amines at the
α-C–H bond with 4-cyanopyridine with the formation of
the corresponding pyridin-4-yl derivatives. The reaction is
accompanied by hydrodecyanation of 4-cyanopyridine, and
the ratio of products highly depends on the structure of the
amine. The highest yields are achieved in the case of
methyl-substituted amines.
monoarylated product,
a set of isomeric TMEDA
diarylation products was obtained, which was not observed
in the previous cases. Tributylamine forms product 1e in
admixture with a number of other substances, among
which, according to GC-MS, predominates aminonitrile 3e;
it was not possible to isolate pyridine 1e in pure form. The
Experimental
1H NMR spectra were acquired on a Bruker AV-400
(400 MHz) spectrometer and 13C NMR spectra were
Scheme 2
91

Chemistry of Heterocyclic Compounds 2019, 55(1), 90–92
acquired on a Bruker AV-300 (300 MHz) spectrometer.
NCH2CH2OH); 7.18–7.20 (2H, m, Н-3,5 Py); 8.45–8.47
(2Н, m, Н-2,6 Py). 13C NMR spectrum (CDCl3), δ, ppm:
41.9; 58.7; 58.9; 61.2; 123.8; 148.1; 149.7. Found, m/z:
166.1103 [M]+. C9H14ON2. Calculated, m/z: 166.1101.
N,N,N'-Trimethyl-N'-(pyridin-4-ylmethyl)ethane-1,2-
diamine (1d). Yield 26 mg (14%), yellowish oil, Rf 0.18
(EtOAc). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.17
(6Н, s, N(CH3)2); 2.19 (3Н, s, NCH3); 2.38–2.40 (2Н, m,
СН2); 2.42–2.44 (2Н, m, СН2); 3.47 (2Н, s, NCH2Py); 7.21–
7.24 (2Н, m, Н-3,5 Ру); 8.46–8.48 (2Н, m, Н-2,6 Ру).
13C NMR spectrum (CDCl3), δ, ppm: 42.7; 45.9; 55.5;
57.4; 61.8; 123.9; 148.5; 149.8. Found, m/z: 193.1581 [M]+.
C11H19N3. Calculated, m/z: 193.1579.
Dibutyl[1-(pyridin-4-yl)butan]amine (1е) and 2-(di-
butylamino)pentanenitrile (3е), a mixture containing
60% compound 1е and 31% compound 3е according to
GC-MS, yellow oil, Rf 0.30 (EtOAc–hexane, 1:1). Mass
spectrum of compound 1е, m/z (Irel, %): 262 [M]+ (2), 219
[M–C3H7]+ (100), 134 [M–N(C4H10)2]+ (60), 119 (12), 92
(16), 41 (14), 29 (14). Mass spectrum of compound 3е, m/z
(Irel, %): 210 [M]+ (2), 183 [M–HCN]+ (9), 167 [M–C3H7]+
(100), 140 (28), 125 (61), 98 (23), 84 (44), 57 (32), 41 (37),
29 (32).
Chemical shifts were assigned relative to the signal of the
1
solvent (7.26 ppm for Н nuclei and 77.2 ppm for 13С
nuclei). High-resolution mass spectra were recorded on a
DFS Thermo Electron mass spectrometer, EI ionization
(70 eV). Mass spectra were recorded on an Agilent 5973
MSD-N mass spectrometer with an Agilent 6890N gas
chromatograph, EI ionization (70 eV). Neutral alumina was
used for column chromatography. Monitoring of the
reaction progress was done by TLC on Sorbfil plates (silica
gel), visualization by UV light.
4-Cyanopyridine, amines, and fac-Ir(ppy)3 were purchased
from commercial sources and used without additional
purification. MeCN was distilled from P2O5 and kept over
4 Å molecular sieves. An LED strip with a total power of
LEDs of 5 W was used for irradiation, the maximum
emission wavelength was 450 nm.
Synthesis of substituted (pyridin-4-yl)amines 1a–e
(General method). A solution of 4-cyanopyridine (100 mg,
0.96 mmol), tertiary amine (1.92 mmol), and fac-Ir(ppy)3
(1.3 mg) in MeCN (5 ml) was irradiated with blue light
until the disappearance of 4-cyanopyridine by TLC. MeCN
was then removed under reduced pressure, and the residue
was purified by column chromatography on neutral Al2O3
to afford fac-Ir(ppy)3 and the respective target amine 1a–d.
1
Supplementary information file containing H and 13C
[1-(Pyridin-4-yl)ethyl]diethylamine
(1a).10 Yield
NMR spectra of all synthesized compounds and mass
spectra of compounds 1d, 3d, as well as data on the
optimization of the reaction conditions of α-С–Н arylation
of triethylamine with 4-cyanopyridine is available at the
journal website at http://link.springer.com/journal/10593.
42 mg (25%), colorless oil, Rf 0.31 (EtOAc–hexane, 1:1).
1H NMR spectrum (ССl4–CDCl3), δ, ppm (J, Hz): 0.92
(6Н, t, J = 7.0, 2СН2СН3); 1.21 (3Н, d, J = 6.8, СHCH3);
2.39–2.45 (4Н, m, 2СН2СН3); 3.70 (1Н, q, J = 6.8,
СHCH3); 7.22–7.24 (2Н, m, Н-3,5 Ру); 8.41–8.43 (2Н, m,
Н-2,6 Ру). Found, m/z: 178.1473 [M]+. C11H18N2.
Calculated, m/z: 178.1470.
References
1. Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev.
2013, 113, 5322.
N-Isopropyl-N-[1-(pyridin-4-yl)ethyl]propan-2-amine
(1b). Yield 36 mg (18%), colorless oil, Rf 0.35 (EtOAc–
2. Romero, N. A.; Nicewicz, D. A. Chem Rev. 2016, 116, 10075.
3. Hu, J.; Wang, J.; Nguyen, T. H.; Zheng, N. Beilstein J. Org.
Chem. 2013, 9, 1977.
1
hexane, 1:1). H NMR spectrum (CDCl3), δ, ppm (J, Hz):
0.97 (6Н, d, J = 6.7, 2CH(CH3)2); 1.06 (6Н, d, J = 6.7,
2CH(CH3)2); 1.42 (3Н, d, J = 6.9, СНСН3); 3.03 (2Н, sept,
J = 6.7, 2CH(CH3)2); 4.04 (1Н, q, J = 6.9, СНСН3); 7.33–
7.35 (2Н, m, Н-3,5 Py); 8.45–8.47 (2Н, m, Н-2,6 Py).
13C NMR spectrum (CDCl3), δ, ppm: 18.8; 22.6; 23.5;
45.5; 51.4; 123.0; 149.4; 156.9. Found, m/z: 206.1780 [M]+.
C13H22N2. Calculated, m/z: 206.1783.
4. Beatty, J. W.; Stephenson, C. R. J. Acc. Chem. Res. 2015, 48,
1474.
5. Nakajima, K.; Miyake, Y.; Nishibayashi, Y. Acc. Chem. Res.
2016, 49, 1946.
6. Orejarena Pacheco, J. C.; Lipp, A.; Nauth, A. M.; Acke, F.;
Dietz, J.-P.; Opatz, T. Chem.–Eur. J. 2016, 22, 5409.
7. Singh, A.; Arora, A.; Weaver, J. D. Org. Lett. 2013, 15, 5390.
8. McNally, A.; Prier, C. K.; MacMillan, D. W. C. Science 2011,
334, 1114.
2-[Methyl(pyridin-4-ylmethyl)amino]ethanol
(1c).
Yield 104 mg (65%), colorless oil, Rf 0.26 (EtOAc).
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.18 (3Н, s,
NCH3); 2.55 (2H, t, J = 5.5, NCH2CH2OH); 3.18 (1H, br. s,
OH); 3.51 (2H, s, NCH2Py); 3.60 (2Н, t, J = 5.5,
9. Lipp, B.; Lipp, A.; Detert, H.; Opatz, T. Org. Lett. 2017, 19,
2054.
10. Gilbert, A.; Krestonosich, S. J. Chem. Soc., Perkin Trans. 1
1980, 2531.
92