Continuous-Flow Hydrogenation and Reductive Deuteration of Nitriles: a Simple Access to α,α-Dideutero Amines

Article abstract of DOI:10.1002/cplu.201900526

A simple and efficient continuous flow methodology has been developed for hydrogenation and reductive deuteration of nitriles to yield primary amines and also valuable α,α-dideutero analogues. Raney nickel proved to be a useful catalyst for the transformation of a wide range of nitriles under reasonably mild conditions with excellent deuterium incorporation (>90 %) and quantitative conversion. Among known model compounds, three new deuterated primary amines were prepared. The large-scale synthesis of deuterated tryptamine was also carried out to deliver 1.1 g product under flow conditions.

Full text of DOI:10.1002/cplu.201900526

Communications
DOI: 10.1002/cplu.201900526
1
2
3
4
5
6
7
8
9
Continuous-Flow Hydrogenation and Reductive
Deuteration of Nitriles: a Simple Access to α,α-Dideutero
Amines
Rebeka Mészáros,[a] Bai-Jing Peng,[a, b] Sándor B. Ötvös,[a, c, d] Shyh-Chyun Yang,[b, e, f] and
Ferenc Fülöp*[a, c]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
developing sustainable, inexpensive and simple methods can
be crucial in this area. In H/D exchange reactions induced by
heterogeneous metal catalysts, the most commonly used
deuterium sources are D2O, deuterated protic solvents and
gaseous deuterium.[6] In such reactions, the most widely used
combinations of catalysts and deuterium sources are
PtO2À D2À D2O,[7] Pd/CÀ D2[8] and Rh/SiO2À D2.[9]
A simple and efficient continuous flow methodology has been
developed for hydrogenation and reductive deuteration of
nitriles to yield primary amines and also valuable α,α-dideutero
analogues. Raney nickel proved to be a useful catalyst for the
transformation of a wide range of nitriles under reasonably mild
conditions with excellent deuterium incorporation (>90%) and
quantitative conversion. Among known model compounds,
three new deuterated primary amines were prepared. The
large-scale synthesis of deuterated tryptamine was also carried
out to deliver 1.1 g product under flow conditions.
Amines have a pivotal role in synthetic organic chemistry
and they are widely present in pharmaceutical drugs and
bioactive natural products and are frequently used in medicinal
chemistry.[10] Various methods have been developed to trans-
form nitriles to amines, including metal hydride reductions,[11]
catalytic hydrogenations[12] and dissolving metal reductions.[13]
Of these, catalytic hydrogenation is applied the most frequently.
It is also the method of choice for the preparation of varied
amines in industry. Hydrogenation of nitriles is generally
performed in the presence of heterogeneous transition metal
catalysts, such as nickel, cobalt, palladium or platinum.[14]
Deuterated amines are relevant building blocks in the field
of drugs, deuterium labelled probes and functional materials.[15]
however their synthesis is relatively rare in the literature. An
important strategy to prepare deuterated amines is transfer
deuteration.[16] This method can be applied in the reductive
amination of ketones or aldehydes in D2O. Preformed imines
can also undergo transfer deuteration in D2O. These ap-
proaches, however, have several drawbacks. For example, only
low degrees of deuterium incorporations were observed.[16]
From an environmental and industrial point of view, reductive
deuteration of nitriles is an attractive strategy and valuable
transformation for the synthesis of deuterated amines. An
intriguing example was reported by An and co-workers. They
exploited sodium-mediated electron transfer reactions for the
synthesis of α,α-dideutero amines in the presence sodium
dispersions in EtODÀ d1.[15a]
The exchange of a hydrogen atom for deuterium in a drug
candidate molecule may improve its pharmacological profile.[1]
This is nicely exemplified by Austedo®, the first deuterated drug
marketed and also by numerous further representatives in
various clinical trials.[2] Given the importance of deuterated
drugs, much effort has been undertaken to develop suitable
methods for deuteration.[3] In many cases, deuterium-containing
materials are synthesized utilizing environmentally harmful and
costly deuterium sources,[4] such as LiAlD4 or NaBD4.[5] Thus,
[a] R. Mészáros, B.-J. Peng, Dr. S. B. Ötvös, Prof. F. Fülöp
Institute of Pharmaceutical Chemistry
University of Szeged
Eötvös u. 6, 6720 Szeged (Hungary)
E-mail: fulop@pharm.u-szeged.hu
[b] B.-J. Peng, Prof. S.-C. Yang
School of Pharmacy, College of Pharmacy
Kaohsiung Medical University
Kaohsiung 807 (Taiwan)
[c] Dr. S. B. Ötvös, Prof. F. Fülöp
MTA-SZTE Stereochemistry Research Group
Hungarian Academy of Sciences
Eötvös u. 6, 6720 Szeged (Hungary)
[d] Dr. S. B. Ötvös
Institute of Chemistry
University of Graz
NAWI Graz
Conventional deuterium labelling techniques involve seri-
ous difficulties. For example, D2 gas as a deuterium source has
high cost and imposes additional operational challenges.[4]
Catalytic HÀ D exchange reactions often require long reaction
times, and alternatively, the costs of deuterated reagents and
deuterated solvents as isotopic sources severely limit the
practical applicability.[17] Therefore, our research group estab-
lished an individual flow-chemistry-based method for deutera-
tion reactions by exchanging the hydrogen source to deuter-
ated water in an H-Cube® system.[18] In fact, heterogeneous
catalytic hydrogenations and deuterations can achieve impor-
tant benefits from the features of flow chemistry,[19] especially
Heinrichstrasse 28, 8010 Graz (Austria)
[e] Prof. S.-C. Yang
Department of Fragrance and Cosmetic Science
College of Pharmacy
Kaohsiung Medical University
Kaohsiung 807 (Taiwan)
[f] Prof. S.-C. Yang
Department of Medical Research
Kaohsiung Medical University Hospital
Kaohsiung Medical University
Kaohsiung 807 (Taiwan)
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cplu.201900526
ChemPlusChem 2019, 84, 1508–1511
1508
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communications
Table 1. Optimization of reaction conditions for the hydrogenation of 4-
phenylbutyronitrile.
1
2
3
4
5
6
7
8
Conversion [%][a]
Selectivity [%][a]
°
Entry
p [bar]
T [ C]
1
2
3
4
5
6
7
8
40
40
40
40
20
40
60
80
20
40
60
80
60
60
60
60
0
–
–
traces
100
100
51
100
100
100
>99
>99
>99
>99
>99
>99
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
1
[a] Determined by H NMR analysis of the crude product.
Table 2. Hydrogenation of diversely substituted aliphatic and aromatic
nitriles to primary amines under optimized flow conditions.
Figure 1. Schematic outline of the continuous-flow reactor (H-Cube®).
Entry Starting material
Product
Conv.
[%][a]
Sel.
[%][a]
through the unprecedented level of control over the most
important reaction conditions, the enhanced heat and mass
transfer, and the improved mixing properties.[20] However, in
terms of safety the application of the H-Cube® system provides
further advantages for lab-scale hydrogenations/deuterations as
H2 or D2 gas is generated in situ by electrolysis.[21]
Herein, we report a simple and sustainable method for the
hydrogenation and reductive deuteration of nitriles producing
primary amines and valuable α,α-dideutero analogues in a
continuous-flow system with Raney nickel as heterogeneous
catalyst.
Hydrogenation and reductive deuteration reactions were
performed in an H-Cube® flow system, where the hydrogen
source (H2O) was changed to D2O in the case of deuterations.
The schematic representation of the reactor is shown in
Figure 1. Raney nickel catalyst was charged into a stainless steel
column, which ensured excellent ease of use. To avoid DÀ H
exchange and to maximize deuterium incorporation in the
reductive deuterations the use of an aprotic medium was
necessary. Therefore, the reactions were carried out in EtOAc as
solvent.
Our investigation was started by optimizing reaction
conditions of nitrile reduction to primary amines using 4-
phenylbutyronitrile as the model compound (Table 1). In this
reaction, two key parameters – temperature and pressure –
were optimized at a fixed flow rate of 1 mL/min. At 20 and
1
2
3
100
100
100
>99
>99
>99
4
100
>99
5
6
7
100
100
100
>99
>99
>99
8
9
100
>99
100
100
>99
>99
°
40 C, practically no product formation was observed, while full
10
°
°
conversion was detected at 60 C and 80 C (entries 1–4). As for
the pressure, an efficient reaction required the use of at least
40 bar, because at lower pressure the conversion was merely
51% (entries 5–8). Consequently, the optimal parameters of the
reduction of 4-phenylbutyronitrile were 40 bar pressure and a
1
[a] Determined by H NMR analysis of the crude product.
°
temperature of 60 C affording quantitative conversion and a
aliphatic and aromatic nitriles were tested under optimum flow
conditions (Table 2). Quantitative conversions and selectivity
values of >99% were observed for aromatic nitriles with
electron-donating or electron-withdrawing functional groups
selectivity of >99%.
After the successful optimization of synthesis parameters,
we investigated the reaction scope. A wide range of substituted
ChemPlusChem 2019, 84, 1508–1511
www.chempluschem.org
1509
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communications
(entries 1 and 2). Similarly good results were found for linear or
branched aliphatic nitriles bearing various substituents includ-
ing (hetero)aromatic rings (entries 3–7). Nitriles with bulky
substituents, such as adamantane-1-carbonitrile and diphenyla-
cetonitrile, were also nicely tolerated (entries 8 and 9). 3-(1-
Piperidinyl)propanenitrile was successfully transformed into the
corresponding amine (entry 10), yielding a significant intermedi-
ate for the synthesis of pharmaceutically relevant ω-piperidi-
noalkanamine derivatives with fluorescent moieties.[22]
After successful hydrogenation experiments, we next turned
our attention to continuous flow reductive deuterations to
access α,α-dideutero amines. For this, the hydrogen source in
the H-Cube® reactor was simply changed to D2O, and reaction
conditions optimized earlier for the hydrogenations were
Table 3. Reductive deuteration of diversely substituted aliphatic and
aromatic nitriles to α,α-dideutero amines under optimized flow conditions.
1
2
3
4
5
6
7
8
9
Entry Starting material
1
Product[a]
Conv. [%][b] D [%][c]
100
>99
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
2
3
100
100
>99
90
°
utilized without any change (p=40 bar, T=60 C, 1 mL/min
flow rate, Raney nickel as catalyst, EtOAc as solvent).
Excellent deuterium incorporations, quantitative conver-
sions and high selectivities were observed for a wide variety of
nitriles in their reduction to the corresponding α,α-dideutero
amines (Table 3). The reaction was successful for aromatic
nitriles possessing electron-donating or electron-withdrawing
functional groups (entries 1 and 2), and as well as for diversely
substituted aliphatic nitriles (entries 3–10), including adaman-
tane-1-carbonitrile and diphenylacetonitrile (entry 8 and 9).
Deuterated amines in Table 3 entries 8, 9 and 10, are new
materials, not known in the literature.
Finally, we investigated the applicability of the continuous
flow reductive deuteration method for the gram-scale synthesis
of deuterated tryptamine (Scheme 1). Tryptamine is a pharma-
ceutically active compound, found in trace amounts in the brain
of mammals and it is believed to play a significant role as
neurotransmitter or neuromodulator in the brain.[23] Samples
were taken and conversion and selectivity were determined in
every hour to obtain a clear view of catalyst activity (Figure S1
in the Supporting Information). We were delighted to find that
the Raney nickel catalyst worked for 20 hours without loss of
activity and change in selectivity during this time. Deuterated
tryptamine was formed with quantitative conversion, >99%
chemoselectivity and deuterium incorporation ratios of �95%
in all samples investigated. In the scale-out experiment, we
managed to produce 1.1 g of the deuterated product which
corresponded to an isolated yield of 92%.
A novel continuous-flow method has been developed for
hydrogenation and reductive deuteration of nitriles with Raney
nickel catalyst under mild conditions. The applicability of the
reactions was demonstrated with a wide range of nitriles with
varied substitution patterns affording outstanding conversions,
selectivities and deuterium incorporations. Importantly, valua-
ble α,α-dideutero amines were achieved in a simple, safe and
sustainable manner utilizing heterogenous catalysis, EtOAc as
environmentally-benign solvent and D2O as electrolytic deute-
rium source. The preparative capabilities of the synthesis
method were tested with a large-scale deuteration experiment
producing 1.1 gram of deuterated tryptamine.
4
100
>99
5
6
100
100
90
91
7
8
100
100
95
96
9
100
100
98
90
10
[a] Chemoselectivity was >99% in all reactions. [b] Determined by 1H NMR
analysis of the crude product. [c] Deuterium contents (represent deuterium
incorporation rate over incidental hydrogenation).
Scheme 1. Gram-scale synthesis of deuterated tryptamine under flow
conditions.
Acknowledgements
The authors thank the Ministry of National Economy, National
Research Development and Innovation Office [GINOP-2.3.2-15-
ChemPlusChem 2019, 84, 1508–1511
www.chempluschem.org
1510
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communications
[11] a) S. W. Heinzman, B. Ganem, J. Am. Chem. Soc. 1982, 104, 6801–6802;
b) A. S. B. Prasad, J. V. B. Kanth, M. Periasamy, Tetrahedron 1992, 48,
4623–4628; c) G. W. Gribble, Chem. Soc. Rev. 1998, 27, 395–404.
[12] a) C. de Bellefon, P. Fouilloux, Catal. Rev. Sci. Eng. 1994, 36, 459–506;
b) S. Gomez, J. A. Peters, T. Maschmeyer, Adv. Synth. Catal. 2002, 344,
1037–1057; c) M. Freifelder, Practical Catalytic Hydrogenation, John
Wiley and Sons: New York, 1971; d) Y. Saito, H. Ishitani, M. Ueno, S.
Kobayashi, ChemistryOpen 2017, 6, 211–215.
2016-00038], the EU-funded Hungarian Grant [EFOP-3.6.1-16-
2016-00008], and the Ministry of Human Capacities, Hungary
Grant, 20391-3/2018/FEKUSTRAT. SBÖ acknowledges the Premium
Post Doctorate Research Program of the Hungarian Academy of
Sciences. Financial support is highly appreciated. We are grateful
to Prof. Árpád Molnár for proofreading our manuscript.
1
2
3
4
5
6
7
[13] a) A. R. Doumaux, J. Org. Chem. 1972, 37, 508–510; b) Y. Kamochi, T.
Kudo, Chem. Pharm. Bull. 1994, 42, 402–404;
[14] J. Krupka, J. Pasek, Curr. Org. Chem. 2012, 16, 988–1004.
[15] a) Y. Ding, S. Luo, A. Adijiang, H. Zhao, J. An, J. Org. Chem. 2018, 83,
12269–12274; b) B. Belleau, J. Burba, M. Pindell, J. Reiffenstein, Science
1961, 133, 102–104.
8
9
Conflict of Interest
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
The authors declare no conflict of interest.
[16] a) M. Ruiz-Castañeda, M. C. Carrión, L. Santos, B. R. Manzano, G. Espino,
F. A. Jalón, ChemCatChem 2018, 10, 5541–5550; b) L. Neubert, D.
Michalik, S. Bähn, S. Imm, H. Neumann, J. Atzrodt, V. Derdau, W. Holla,
M. Beller, J. Am. Chem. Soc. 2012, 134, 12239–12244; c) Y. Hu, L. Liang,
W. Wei, X. Sun, X. Zhang, M. Yan, Tetrahedron 2015, 71, 1425–1430;
[17] a) Y. Sawama, Y. Monguchi, H. Sajiki, Synlett 2012, 23, 959–972; b) N.
Modutlwa, T. Maegawa, Y. Monguchi, H. Sajiki, J. Labelled Compd.
Radiopharm. 2010, 53, 686–692; c) A. Di Giuseppe, R. Castarlenas, J. J.
Pérez-Torrente, F. J. Lahoz, V. Polo, L. A. Oro, Angew. Chem. Int. Ed. 2011,
50, 3938–3942; Angew. Chem. 2011, 123, 4024–4028; d) W. J. S. Lockley,
D. Hesk, J. Labelled Compd. Radiopharm. 2010, 53, 704–715.
[18] a) I. M Mándity, T. A. Martinek, F. Darvas, F. Fülöp, Tetrahedron Lett.
2009, 50, 4372–4374; b) S. B. Ötvös, I. M. Mándity, F. Fülöp, Mol. Diversity
2011, 15, 605–611; c) C.-T. Hsieh, S. B. Ötvös, Y.-C Wu, I. M. Mándity, F.-R.
Chang, F. Fülöp, ChemPlusChem. 2015, 80, 859–864; d) S. B. Ötvös, C.-T.
Hsieh, Y.-C. Wu, J.-H. Li, F.-R. Chang, F. Fülöp, Molecules 2016, 21, 318.
[19] a) M. B. Plutschack, B. Pieber, K. Gilmore, P. H. Seeberger, Chem. Rev.
2017, 117, 11796–11893; b) R. Gérardy, N. Emmanuel, T. Toupy, V.-E.
Kassin, N. N. Tshibalonza, M. Schmitz, J.-C. M. Monbaliu, Eur. J. Org.
Chem. 2018, 2301–2351; c) F. M. Akwi, P. Watts, Chem. Commun. 2018,
54, 13894–13928.
[20] a) M. Irfan, T. N. Glasnov, C. O. Kappe, ChemSusChem 2011, 4, 300–316;
b) I. M. Mándity, S. B. Ötvös, F. Fülöp, ChemistryOpen 2015, 4, 212–223;
c) M. Irfan, E. Petricci, T. N. Glasnov, M. Taddei, C. O. Kappe, Eur. J. Org.
Chem. 2009, 1327–1334; d) J. Britton, C. L. Raston, Chem. Soc. Rev. 2017,
46, 1250–1271; e) J. Wegner, S. Ceylan, A. Kirschning, Chem. Commun.
2011, 47, 4583–4592.
[21] a) B. Desai, C. O. Kappe, J. Comb. Chem. 2005, 7, 641–643; b) R. V. Jones,
L. Godorhazy, N. Varga, D. Szalay, L. Urge, F. Darvas, J. Comb. Chem.
2006, 8, 110–116.
Keywords: amines · continuous flow chemistry · deuteration ·
nitriles · Raney nickel
[1] S. L. Harbeson, R. D. Tung, MedChem News 2014, 2, 8–22.
[2] a) P. Chen, S. Ren, H. Song, C. Chen, F. Chen, Q. Xua, Y. Kong, H. Sun,
Bioorg. Med. Chem. 2019, 27, 116–124; b) F. Wang, H. Jiang, Y. Deng, J.
Yu, M. Zhan, L. Zhaoc, Y. Chen, Bioorg. Med. Chem. Lett. 2018, 28, 2399–
2402.
[3] a) T. Kurita, F. Aoki, T. Mizumoto, T. Maejima, H. Esaki, T. Maegawa, Y.
Monguchi, H. Sajiki, Chem. Eur. J. 2008, 14, 3371–3379; b) Y. Y. Loh, K.
Nagao, A. J. Hoover, D. Hesk, N. R. Rivera, S. L. Colletti, I. W. Davies,
D. W. C. MacMillan, Science 2017, 358, 1182–1187; c) K. Burglova, S.
Okorochenkov, J. Hlavac, Org. Lett. 2016, 18, 3342–3345.
[4] a) Y. Jaemon, Deuterium: Discovery and Applications in Organic
Chemistry, Elsevier: Cambridge, 2016; b) J. Atzrodt, V. Derdau, T. Fey, J.
Zimmerman, Angew. Chem. Int. Ed. 2007, 46, 7744–7765; Angew. Chem.
2007, 119, 7890–7911; c) T. Pirali, M. Serafini, S. Cargnin, A. A. Genazzani,
J. Med. Chem. 2019, 62, 5276–5297.
[5] a) D. Klomp, T. Maschmeyer, U. Hanefeld, J. A. Peters, Chem. Eur. J. 2004,
10, 2088–2093; b) J. Thiem, H. Mohn, A. Heesing, Synthesis 1985, 8, 775–
778.
[6] a) J. J. Philipson, R. L. Burwell, J. Am. Chem. Soc. 1970, 92, 6125–6133;
b) P. Lesot, M. Sarfati, D. Merlet, B. Ancian, J. W. Emsley, B. A. Timini, J.
Am. Chem. Soc. 2003, 125, 7689–7695; c) G. Bond, P. B. Wells, J. Catal.
1994, 150, 329–334.
[7] a) M. Yamamoto, K. Oshima, S. Matsubara, Org. Lett. 2004, 6, 5015–5017;
b) H. Sajiki, N. Ito, H. Esaki, T. Maegawa, K. Hirota, Tetrahedron Lett.
2005, 46, 6995–6998.
[8] a) J. Azran, M. Shimoni, O. Buchman, J. Catal. 1994, 148, 648–653;
b) A. V. Filikov, N. F. Myasoedov, J. Radioanal. Nucl. Chem. 1985, 93,
355–362.
[9] D. K. Takehara, J. B. Butt, R. L. Burwell, Jr., J. Catal. 1992, 133, 294–308.
[10] a) S. A. Lawrence, Amines: synthesis, properties and applications, Cam-
bridge University Press, 2004; b) F. Blei, F. Baldeweg, J. Fricke, D.
Hoffmeister, Chem. Eur. J. 2018, 24, 10028–10031; c) K. J. Broadley,
Pharmacol. Ther. 2010, 125, 363–375.
[22] a) M. Amon, X. Ligneau, J.-C. Schwartz, H. Stark, Bioorg. Med. Chem. Lett.
2006, 16, 1938–1940; b) J. Lavrado, A. Paulo, J. Gut, P. J. Rosenthal, R.
Moreira, Bioorg. Med. Chem. Lett. 2008, 18, 1378–1381; c) J. Lavrado,
G. G. Cabal, M. Prudencio, M. M. Mota, J. Gut, P. J. Rosenthal, C. Díaz,
R. C. Guedes, D. J. V. A. dos Santos, E. Bichenkova, K. T. Douglas, R.
Moreira, A. Paulo, J. Med. Chem. 2011, 54, 734–750.
[23] R. S. G. Jones, Prog. Neurobiol. 1982, 19, 117–139.
Manuscript received: August 28, 2019
Revised manuscript received: September 3, 2019
ChemPlusChem 2019, 84, 1508–1511
www.chempluschem.org
1511
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim