A concise synthesis of (E)-3-Amino-1-phenyl-1-butene, a monoamine oxidase inhibitor

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Organic Preparations and Procedures
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A Concise Synthesis of (E)-3-Amino-1-
phenyl-1-butene, a Monoamine Oxidase
Inhibitor
Wellington Martins Venturaa & Jason Guy Taylora
a Departamento de Química, ICEB, Universidade Federal de Ouro
Preto, Campus Morro do Cruzeiro, CEP. 35400-000, Ouro Preto, Minas
Gerais, Brazil
Published online: 10 Jul 2014.
To cite this article: Wellington Martins Ventura & Jason Guy Taylor (2014) A Concise Synthesis
of (E)-3-Amino-1-phenyl-1-butene, a Monoamine Oxidase Inhibitor, Organic Preparations
and Procedures International: The New Journal for Organic Synthesis, 46:4, 381-385, DOI:
10.1080/00304948.2014.922385
To link to this article: http://dx.doi.org/10.1080/00304948.2014.922385
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Organic Preparations and Procedures International, 46:381–385, 2014
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2014.922385
OPPI BRIEF
A Concise Synthesis
of (E)-3-Amino-1-phenyl-1-butene,
a Monoamine Oxidase Inhibitor
Wellington Martins Ventura and Jason Guy Taylor
Departamento de Qu´ımica, ICEB, Universidade Federal de Ouro Preto, Campus
Morro do Cruzeiro, CEP. 35400-000, Ouro Preto, Minas Gerais, Brazil
The importance of allylic amines as useful building blocks for the synthesis of amino
acids,1–4 alkaloids,5–7 and therapeutic agents8, 9 has been well documented. The title com-
pound is referred to as α-methylcinnamylamine in a report that describes its activity as a
monoamine oxidase (MAO) inhibitor; MAO is an important target enzyme for the develop-
ment of new drugs to treat MPTP-induced Parkinson’s disease.10 In spite of its importance
as a useful building block for organic synthesis, it is not readily commercially available
and is therefore usually prepared in the laboratory. Common synthetic methods include
reductive amination of benzylideneacetone,11,12 palladium-catalyzed substitution reaction
of 4-phenyl-3-buten-2-yl acetate with sodium azide followed by reduction of the azide with
triphenylphosphine,13 or Grignard addition to cinnamonitrile.14 Undoubtedly, the reductive
amination of benzylideneacetone is the most attractive of the aforementioned protocols
given the low cost of the reagent; however, stoichiometric quantities and even excess tita-
nium(IV) isopropylate or zinc metal are usually required. These approaches generate large
quantities of inorganic waste which renders them inconvenient for large scale syntheses. For
this reason, we developed and now report a three-step strategy amenable to the gram-scale
synthesis of (E)-3-amino-1-phenyl-1-butene which begins from inexpensive cinnamalde-
hyde and involves a hydroamination reaction catalyzed by a Cu(OTf)2-2,2ꢀ-bipyridine
complex in the key C-N bond forming step.
For the synthesis of 1-phenyl-1,3-butadiene, we adopted a known procedure15 involving
a Wittig reaction between trans-cinnamaldehyde and methyltriphenylphosphonium iodide
in the presence of t-BuOK, but modified the solvent system and work up procedure to
obtain the desired product as a transparent oil in 89% yield. The addition of carbamates to
Submitted by February 13, 2014.
Address correspondence to Jason Guy Taylor, Departamento de Qu´ımica, ICEB, Universidade
Federal de Ouro Preto, Campus Morro do Cruzeiro, CEP. 35400-000, Ouro Preto, Minas Gerais,
Brazil. E-mail: jason@iceb.ufop.br
381

382
Ventura and Taylor
1,3-dienes had been reported to occur in the presence of a catalytic amount of Cu(OTf)2
and diphosphine ligand.16 Transitions metal salts with weakly coordinating anions generate
Brønsted acids through cation hydrolysis. The active catalytic species is triflic acid which is
generated in situ by trace amounts of water present in the solvent. The best yield was realized
with 1,4-dioxane as solvent. For the present procedure, we employed 2,2ꢀ-bipyridine to
regulate the active triflic acid concentration and avoid competitive polymerization of the
diene which led to an improved yield of the hydroamination adduct. The addition of benzyl
carbamate occurred exclusively at the terminal double bond with complete regioselectivity
to yield E-4-phenyl-3-buten-2-amine N-benzyloxycarbonyl ester as a crystalline white
solid. Finally, the free amine was liberated by straight forward deprotection of the carbamate
group by acid catalyzed hydrolysis to afford the title compound in 58% yield in two steps
(Scheme 1).
O
HN
OBn
HCl (6N), 2h, reflux
79% Yield
NH2
2.5 mol% Cu(OTf)2
2.0 mol% Byp
dioxane, 75 oC, 5h
74% Yield
+
CH3
O
BnO
NH2
Scheme 1
The synthetic protocol for (E)-3-amino-1-phenyl-1-butene presented here was carried
out on gram scale and was completed in only two days of laboratory work. The catalytic
hydroamination reaction does not require an inert atmosphere or anhydrous solvents and
Cu(OTf)2 is more convenient and practical to manipulate than triflic acid. In a report
describing the use of the Cu(OTf)2-2,2ꢀ-bipyridine catalyst for the annulation of phenols
with 1,3-dienes, the paramagnetic blue precipitate observed at the end of the reaction was
recovered.17 This polymeric copper(II) complex was reused in successive reactions, thus
demonstrating the robustness and potential recyclability of the Cu(OTf)2-2,2ꢀ-bipyridine
complex for the hydroamination reaction. The characterization data for all compounds were
in accordance with literature values cited.
Experimental Section
All reagents are commercially available and were used as received. Anhydrous solvents
were purchased from Sigma Aldrich. Column chromatography was performed using silica
gel 200–400 Mesh. TLC analyses were performed using silica gel plates, with ultraviolet
light (254 nm) or vanillin solution used for visualization. Melting points were determined
on a Buchi B-540 apparatus and are uncorrected. IR spectra were recorded on a Bomem
FTIR MB- series B-100 model as either a liquid film between NaCl plates or as KBr pellets.
NMR spectra were acquired on a Bruker 400 MHz spectrometer in CDCl3. The chemical
shifts are reported in δ referenced to residual solvent hydrogen. The coupling constant
values (J) are expressed in Hertz (Hz).

A Concise Synthesis of (E)-3-Amino-1-phenyl-1-butene
Synthesis of 1-Phenyl-1,3-butadiene
383
A suspension of methyltriphenylphosphonium iodide (20.0 g, 49.5 mmol) and potassium
tert-butoxide (8.3 g, 74.1 mmol) in anhydrous THF (120 ml) was stirred for 10 min
at 0◦C under a nitrogen atmosphere. The reaction mixture was then treated with trans-
cinnamaldehyde (6.3 ml, 50.0 mmol) and stirred for 5 h under reflux. Upon completion,
the mixture was diluted with hexanes (50 ml) and the solid phosphine oxide was re-
moved by filtration. The solvent was reduced under vacuum and the product was extracted
from the gummy residue with n-hexanes (3 × 40 ml). Evaporation of the solvents un-
der reduced pressure gave an oily residue which was purified by column chromatography
to afford 1-phenyl-1,3-butadiene (6.4 g, 89%) as a transparent oil.; Rf = 0.7 (hexanes);
1
IR (cm−1): 3059, 3027, 1946, 1803, 1679, 1633, 1602; H NMR (400 MHz) : δ 7.38
(2H, d, J = 7.6), 7.30 (2H, t, J = 7.6), 7.21 (1H, t, J = 7.6), 6.80 (1H, dd, J =
10.8, 15.6), 6.55 (2H, m), 5.32 (1H, d, J = 17.2), 5.15 (1H, d, J = 10.0); 13C NMR
(100 MHz): δ 137.2, 137.1, 132.9, 129.6, 128.6, 127.6, 126.5, 117.7; m/z (EI): 130 (M+,
100%), 111 (25%), 95 (20%), 67 (30%). The NMR data are in accordance with literature
values.18
Synthesis of E-4-Phenyl-3-buten-2-amine N-Benzyloxycarbonyl Ester
In a round bottom flask (250 ml) equipped with a magnetic stir bar and reflux condenser were
placed copper trifluoromethanesulfonate (297 mg, 0.85 mmol), 2,2ꢀ-bipyridine (102 mg,
0.67 mmol) and 1,4-dioxane (60 ml). Benzyl carbamate (5.0 g, 33 mmol) and 1-phenyl-
1,3-butadiene (5.2 g, 40 mmol) were added to the flask and the mixture was stirred at 75◦C
for 5 h. Upon completion, the reaction mixture was diluted with ethyl acetate (40 ml) and
washed with 1M aq. NaHCO3 (40 ml). The layers were separated and the organic layer was
dried over Na2SO4, concentrated under vacuum, and purified by column chromatography
(3:1 hexanes/EtOAc) to provide the product as a crystalline white solid (6.9 g, 74%), mp.
82–84◦C (lit.19 89–90◦C); Rf = 0.3 (hexanes/EtOAc, 4:1); IR (cm−1): 3320, 3026, 2982,
2939, 2898, 1950, 1876, 1681; 1H NMR (400 MHz): δ 7.39–7.28 (10H, m), 6.56 (1H, d,
J = 16.0), 6.22 (1H, dd, J = 6.0, 16.0), 5.15 (2H, s) 4.84 (1H, br s), 4.51–4.55 (1H, br m),
1.38 (3H, d, J = 6.8); 13C NMR (100 MHz): δ 155.6, 136.7, 136.6, 131.2, 129.6, 128.6,
128.2, 127.7, 127.6, 126.5, 126.4, 66.8, 48.5, 21.1; m/z (EI): 281 (M+, 10%), 222 (30%),
190 (50%), 129 (60%), 91 (100%), 65 (15%), 42 (12%). The NMR data are in accordance
with literature values.20
Synthesis of (E)- 3-Amino-1-phenyl-1-butene
In a round bottom flask (250 ml) equipped with magnetic stir bar and reflux condenser
the protected amine (5.0 g, 17.8 mmol) was heated to reflux in 6N HCl (85 ml) with
stirring for 1 h. The cooled solution was then taken up in to a separatory funnel and
washed with dichloromethane (20 ml). The organic extract was discarded and the aque-
ous phase was basified with an aqueous solution of NaOH (10%) to pH 10–12. The
free amine was extracted with dichloromethane (3 × 40 ml) and the combined organic
extracts, dried and concentrated under vacuum on a rotary evaporator. The oily residue
was purified by column chromatography (8:1:1 hexanes/EtOAc/Et3N) to provide the

384
Ventura and Taylor
1
product as a pale yellow oil (2.1 g, 79%). IR (cm−1): 3267, 3027, 2969, 1587,; H
NMP (400 MHz): δ 7.39–7.20 (5H, m), 6.45 (1H, d, J = 16.0), 6.20 (1H, dd, J = 6.6,
16.0), 3.70–3.62 (1H, m, 1H), 1.27 (3H, d, J = 6.5); 13H NMP (100 MHz): 137.3, 136.1,
128.7, 127.6, 127.2, 126.4, 49.1, 23.9. The NMR data are in accordance with literature
values.21
Acknowledgements
This work was supported by the Brazilian Funding Agency Fundac¸a˜o de Amparo a` Pesquisa
do Estado de Minas Gerais (FAPEMIG) under research grant project codes APQ-00307-12,
APQ-00356-13 and the Conselho Nacional de Desenvolvimento Cient´ıfico e Tecnolo´gico
(CNPq) under research grant project code 473461/2013-7. The authors gratefully acknowl-
edge the generous financial support from the Universidade Federal de Ouro Preto and
the Conselho Nacional de Desenvolvimento Cient´ıfico e Tecnolo´gico (CNPq) for graduate
research studentships and bursaries.
References
1. T. Hayashi, A. Yamamoto, Y. Ito, E. Nishioka, H. Miura and K. Yanagi, J. Am. Chem. Soc., 111,
6301 (1989).
2. K. Burgess, L. T. Liu and B. Pal, J. Org. Chem., 58, 4758 (1993).
3. J. F, Brower, R. Jumnah, A. C. Williams and J. M. Williams, J. Chem. Soc. Perkins, 1., 1411
(1997).
4. C. Gnamm, G. Franck, N. Miller, T. Stork, K. Broedner and G. Helmchen, Synthesis, 20, 3331
(2008).
5. A. D. Brosius, L. E. Overman and L. Schwink, J. Am. Chem. Soc., 121, 700 (1999).
6. S. Krishnan, J. T. Bagdanoff, D. C. Ebner, Y. K. Ramtohul, U. K. Tambar and B. M. Stoltz, J.
Am. Chem. Soc., 130, 13745 (2008).
7. T. L. Suyama and W. H. Gerwick, Org. Lett., 10, 4449 (2008).
8. C. E. Jakobsche, G. Peris and S. J. Miller, Angew. Chem., Int. Ed., 47, 6707 (2008).
9. A. J. Blacker, M. Roy, S. Hariharan, A. Upare, A. Jagtap, K. Wankhede, S. K. Mishra, D. Dube,
S. Bhise, S. Vishwasrao and N. Kadam. Org. Process. Res. Dev., 14, 1364 (2010).
10. C. K. Hiebert and R. B. Silverman, J. Med. Chem., 31, 1566 (1988).
11. B. Miriyala, S. Bhattacharyya and J. S. Williamson, Tetrahedron., 60, 1463 (2004).
12. T. G. Schenck and B. Bosnich, J. Am. Chem. Soc., 107, 2058 (1985).
13. S. Murahashi, Y. Taniguchi, Y. Imada and Y. Tanigawa, J. Org. Chem., 54, 3292
(1989).
14. B. T. Gregg, K. C. Golden, J. F. Quinn, H-J Wang, W. Zhang, R. Wang, F. Wekesa and D. O.
Tymoshenko, Tetrahedron Lett., 50, 3978 (2009).
15. S. Maity, T. Naveen, U. Sharma, and D. Maiti, Org. Lett., 15, 3384 (2013).
16. J. G. Taylor, N. Whittall and K. K. Hii, Org. Lett., 8, 3561 (2006).

A Concise Synthesis of (E)-3-Amino-1-phenyl-1-butene
385
17. L. A. Adrio and K. K. Hii, Chem. Commun., 2325 (2008).
18. K. E. Lutz, D. A. Mundal and R. J. Thomson, Org. Lett., 11, 465 (2009).
19. C. J. Moody, A. P. Lightfoot, A. M. Slawin and P. T. Gallagher, J. Org. Chem., 64, 4419 (1999).
20. B. G. Das, P. Ghorai and R. Nallagonda, J. Org. Chem., 77, 5577 (2012).
21. E. G. Klauber, N. Mittal, D. Seidel, and T. K. Shah, Org. Lett., 13, 2464 (2011).