Hydrogenation of α-enaminoketones with cobalt phosphine-modified catalysts

Article abstract of DOI:10.1016/j.catcom.2012.12.025

The synthesis of α-enamines and hydrogenation of these compounds were studied using cobalt-modified complexes. Cobalt complexes were characterized by ¹H, ¹³C and ³¹P NMR, elemental analysis and IR spectroscopy. Furthermore

Full text of DOI:10.1016/j.catcom.2012.12.025

Hydrogenation of α-enaminoketones with cobalt phosphine-modified catalysts
Manuel Ame´zquita-Valencia, Ricardo Ram´ırez-Garavito, Rube´n A. Toscano,
A. Cabrera
PII:
DOI:
Reference:
S1566-7367(12)00488-8
doi: 10.1016/j.catcom.2012.12.025
CATCOM 3377
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
30 October 2012
22 December 2012
24 December 2012
Please cite this article as:
Manuel Am´ezquita-Valencia, Ricardo Ram´ırez-
Garavito, Rub´en A. Toscano, A. Cabrera, Hydrogenation of α-enaminoketones
with cobalt phosphine-modified catalysts, Catalysis Communications (2012),
doi:
10.1016/j.catcom.2012.12.025
This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.

ACCEPTED MANUSCRIPT
Hydrogenation of -enaminoketones with cobalt phosphine-modified catalysts1
Manuel Amézquita-Valencia*, Ricardo Ramírez-Garavito, Rubén A. Toscano, A. Cabrera*
Instituto de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, Circuito Exterior, Coyoacán 04510,
México D.F.
1Dedicated to the memory of Professor Leopoldo Garcia-Colin S.
E-mail: arcaor1@unam.mx, majo00@yahoo.com
Fax: +52 5 6162217/6162207.
Abstract
The synthesis of -enamines and hydrogenation of these compounds were studied using cobalt-
1
13
31
modified complexes. Cobalt complexes were characterized by H, C and P NMR, elemental
analysis and IR spectroscopy. Furthermore, the molecular structures of complexes C1-C2 and
C4-C5 have been determined by single-crystal X-ray diffraction. All cobalt complexes
investigated were active catalysts for the hydrogenation reaction. The best catalytic activity was
obtained with an ortho-substituent in the phosphine ligand. Noteworthy, the reduction was
chemoselective over the double bond.
Keywords: Dicobalt octacarbonyl, enamines, homogeneous catalysis, hydrogenation,
aminoketones.
1. Introduction
Interest in the chemistry of Co2(CO)8 continues to grow due to its potential applications in
catalysis.[1-7] The main thrust of research in the chemistry of cobalt-modified complex has been
on carbonylation[8] and Pauson-Khand reactions(PKR), since the hydroformylation of olefins to
yield aldehydes and alcohols is one of the largest-scale industrial homogeneous catalytic
processes.[9] Additionally, dicobalt octacarbonyl complexes show catalytic activity towards
polymerization,[10] copolymerization,[11] (PKR) through heterogeneous catalysis,[12] and N-tert-
butyl-trans-α-ethoxycarbonyl-β-phenyl-β-lactam (TBL) synthesis.[13] Recently, we have reported
new features of a cobalt-modified complex in the asymmetric hydrogenation of imines[14] and
one-pot synthesis of secondary amides,[15] under H2/CO and H2 pressure, respectively. In this
study, we found that HCo(CO)4-nLn (n= 1,2) can be formed in situ as an active species from
Co2(CO)8 and ligand (L) under H2/CO pressure. According to recent works, the hydride species

ACCEPTED MANUSCRIPT
can also be involved in the reaction of hydrogenation of enamines carbon-carbon double bonds.
In the last several years, different metal catalysts have been employed for this reaction. Among
the various catalytic systems so far (Ru, Ir, Pd, Rh)[16] have been applied to hydrogenation of
enamines. In contrast, there has been no report on the hydrogenation of -enamines with cobalt-
modified catalysts. In the same context, there are few reports where -enamines were used. Lau
employed a copper complex for allylic amination of ketones,[17] Tamariz et. al have worked with
non-symmetric -ketones obtaining in the reaction mixture -imino and -enamino ketones,
although they worked only with iminoketones as precursors of dienes on Diels-Alder reaction.[18]
On the other hand, Klosin used -enamines from 1,2-cyclohexane-diones to obtain
unsymmetrical imino-enamine ligands.[19] Likewise, Zhang et. al recently worked in asymmetric
hydrogenation of -enamines interesting approach to amphetamines. Herein, we wish to report
the synthesis of several new -aminoketones by the cobalt-modified-catalyzed chemoselective
hydrogenation of -enaminoketones in the presence of H2/CO.
2. Experimental
2.1 General
All reactions and manipulations were carried out under nitrogen atmosphere using Schlenk-type
techniques. Column chromatography was performed on silica (70-230 mesh). The 1H, 13C NMR
spectra were recorded on a Bruker-Advance 300 spectrometer in CDCl3 as solvent at 25°C. Mass
spectra were obtained using a JEOL JMS-SX102A instrument. Elemental analyses for
compounds were obtained on an Elementary Analyzer CE-440. IR spectra were recorded on a
Nicolet FTIR magna 750 spectrophotometer. All chemicals and solvents were used as received
unless otherwise stated. Tetrahydrofuran (Na, benzophenone), hexane (Na, benzophenone), and
methylene chloride (P2O5) were distilled under nitrogen prior to use.
2.2 Typical procedure for synthesis of -enaminoketones
A mixture of 5mmol of -diketone and 5 mmol of aniline derivative in 10 mL of dried
methylene chloride was stirred overnight in the presence of 2 mol % of Mg(ClO4)2 and 2g of
MgSO4 as drying agent. The organic solution was filtered and concentrated to give pure -
enaminoketone through silica gel flash chromatography (hexane/ethyl acetate).

ACCEPTED MANUSCRIPT
2.3 Synthesis of complexes C1-C6
Under a N2 atmosphere, phosphine ligand (2 mmol) (L) was added to a stirred solution of
Co2(CO)8 (1 mmol) in tetrahydrofuran or toluene (10mL). The reaction mixture was stirred for 1
hour under CO bubbling at 50°C. The organic solvent was evaporated under reduced pressure.
The resulting solid was washed several times with diethyl ether and pentane, finally dried under
vacuum to give the desired complex.
2.4 Procedure for hydrogenation of -enaminoketones
To a solution of complex C1-C6 (2 mol %) in THF (5mL) was added a solution of enamine
(100mg) in THF (5mL) under N2 atmosphere, and the mixture was stirred for 15 min. The
solution was transferred to a 45 mL stainless steel Parr reactor under N2 atmosphere. The
reaction vessel was pressurized with H2 and CO (1/3 ratio), then the reactor was immersed in an
oil bath at 120°C during 30 hours. At the end of this time, the reactor was cooled and the gas
mixture was liberated. The solution was concentrated and the product was purified by
chromatography column on silica with hexane/ethyl acetate as eluent.
3. Results and discussion
3.1 Characterization of C1-C6 and crystal structure of C1, C2, C4 and C5 complexes
1
Different dimers were characterized by IR, elemental analysis, H, 13C, and 31P NMR
spectroscopy and X-ray crystallography. Cobalt carbonyl dimers C1-C6 of the type [LCo(CO)3]2
can be synthesized from Co2(CO)8 and phosphine ligand (L) in THF under CO bubbling at 50°C
for 1h. However, in absence of CO, the mixture of dimer and [CoL2(CO)3]+[Co(CO)4]- salt are
formed in few minutes(scheme 1), when this mixture is treated with CO bubbling at 50°C only
the dimer was obtained, the named compounds were identified by comparison with similar cobalt
salts.[20-21] When we used PPh3 as ligand no CO bubbling is necessary.[22] However, using more
basic phosphines the use of CO atmosphere is necessary in order to obtain the dimers as is
previously reported by Klingler et al.[23] All cobalt phosphine salt derivatives shown bands at
1992 and 1868 cm-1, in contrast the dimers showed a very strong single band at 1936 cm-1(See
Table S1 in the supporting information).

ACCEPTED MANUSCRIPT
Scheme 1.
1
The H and 13C NMR spectra of different dimers show only small variations between the
13
chemical shifts of the free and bonding ligands, furthermore in C spectra shows a broad single
signal resonance at  196 ppm(average), which could be assigned to the (CO)terminal groups. The
31P spectra showed only one broad singlet for all complexes. The molecular structure of C1, C2
and C4, C5 complexes are shown in Figs.1-4. Crystallographic data are summarized in Table S2
(See supporting information), while select bond lengths (Å) and angles (°) are given in Table S3
and Table S4 (See supporting information). Several attempts to obtain suitable crystals of
complexes C3 and C6 were unfruitful.
Figure 1. Molecular structure of [Co2(CO)6{P(p-MeO-C6H4)3}2] C1. Hydrogen atoms were
omitted for clarity.[24]

ACCEPTED MANUSCRIPT
Figure 2. Molecular structure of [Co2(CO)6{P(m-MeO-C6H4)3}2] C2. Hydrogen atoms were
omitted for clarity.[24]
Crystals of C1-C2 and C4-C5 suitable for X-ray structure determination were grown by layering
a saturated dichloromethane solution of complexes with diethyl ether. Complexes C1, C4, and
C2, C5 crystallize in hexagonal and triclinic systems, with space groups R-3 and P-1
respectively. The molecular diagrams of C1, C2 and C4, C5, display dinuclear arrangement of
trigonal [Co(L)(CO)3] units, in which the two phosphine ligand are observed in anti-position
with respect to the Co−Co bond. Furthermore, the molecular structure shows that all carbonyl
groups are terminal, and this conformation is associated with these types of molecules.[25] Cone
angles were calculated according to the Tolman model[26] but using the real Co−P bond distance
in all cases. The effective cone angles of molecular C1, C2, C4 and C5 were calculated as 145°,
148°, 145° and 148, respectively.

ACCEPTED MANUSCRIPT
Figure 3. Molecular structure of [Co2(CO)6{P(p-Me-C6H4)3}2] C4. Hydrogen atoms were
omitted for clarity.[24]
Figure 4. Molecular structure of [Co2(CO)6{P(m-Me-C6H4)3}2] C5. Hydrogen atoms were
omitted for clarity.[24]
For molecules C1 and C4, the P−Co−Co angle is 180(°), unlike C2 and C5, where angles are
175.22(2)(°) and 178.59(2)(°) giving a slight deviation from linearity. Furthermore, the distortion
due to the ligand is also manifested in the angles of P−Co−CO, 94.13(°), 93.99(°, average),
94.31(°) and 94.99 (°, average), respectively (See Table S3 and S4). Co−Co bond distances in
C1, C4 and C5 were found to be 2.883(1) Å, 2.671(13) Å and 2.671(5) Å, while that for C2 was
found to be smaller, 2.649(5) Å. The same trend was found for Co−P bond lengths in C1
(2.197(1) Å), C4 (2.193(14) Å), and C5 (2.196(6) Å), which were longer than C2 (2.185(6) Å).
This could be attributed to the bulkiness of the methoxy group; this observation is consistent
with that reported for similar cobalt complexes.[27] With these complexes in hand, we examine
their efficiency in hydrogenation reaction of -enamines.
3.2 Catalytic activities of cobalt carbonyl dimers(C1-C6) in hydrogenation of -
enaminoketones
Initially, we have prepared new -enamino ketones by the reaction of -diketones with aniline
derivatives; the general procedure for preparation of enamines (1a-7a) was as follows. A mixture
of amine derivative (2 mmol), the corresponding-diketone (2 mmol), Mg(ClO4)2 (2 %mmol) in
CH2Cl2 was stirred overnight (Table 1). At the end of the reaction the product was purified by
chromatography column.

ACCEPTED MANUSCRIPT
Table 1. Synthesis of -enaminoketones using Mg(ClO4)2.
Entry
R3
H
Compound
Yield %a
1
86
88
84
83
82
83
80
1a
2a
3a
4a
5a
6a
7a
2
p-MeO
p-Me
p-Cl
p-F
3
4
5
6
7
m-Me
m-Cl
aIsolated product.
All compounds described were characterized by various physicochemical methods. In MS-EI an
m/z molecular ion peak was observed for all compounds, followed by a peak with a loss of the
[M+-COCnHn+2] group. Analysis of these compounds by infrared spectroscopy reveals a strong
band at 1668 cm-1, due to the presence of the carbonyl group and vibrations corresponding to the
1
13
N-H group at 3363 cm-1. All compounds were characterized by H, C, DEPT 135, HETCOR,
HMBC, COSY and NOESY experiments, where we found solely the Z isomer(See Figures S1
1
and S2 in the supporting information). The H-NMR spectra analysis of the products supported
this stereo structure, where the proton of N-H group appeared in the region of 5.97-6.12 ppm.[28]
Next, with the -enaminoketones in hand, we examined hydrogenation for these compounds
with different cobalt complexes synthesized under various conditions. We started our study with
1a as standard substrate to optimize the reaction conditions, the results are summarized in Table
2. When the initial hydrogenation experiment was carried out under 12 hours reaction, it was
found low conversion (entry 1). However, when it was worked upon prolonged reaction time the
conversion is better (entries 2 and 3). When the reaction was carried out in the absence of the
ligand, the product was obtained in low yield (entry 4). Moreover, no catalytic activity was found
when it was worked-up with triarylphosphite, alkyl and tricyclohexyl phosphine ligands (entries
5-7). The same results were found when working only with hydrogen gas pressure (entries 9 and
10). The reactivity was lower when triphenylantimony ligand was used (Entry 8).

ACCEPTED MANUSCRIPT
Table 2. Hydrogenation of -enaminoketones under various conditions.a
H2/COf
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:0
1:0
1:3
1:3
1:3
1:3
Conversion %b
Entry
1c
Co2(CO)8
Ligand
P(C6H5)3
2
2
2
2
2
2
2
2
2
2
2
2
2
2
34
61
83
30
0
2d
3e
P(C6H5)3
P(C6H5)3
4
-
5
P(O-C6H5)3
P(C6H11)3
6
0
7
P(C2H5)3
0
8
Sb(C6H5)3
15
0
9
Sb(C6H5)3
10
11
12
13
14
P(o-CH3C6H4)3, C6
P(p-CH3C6H4)3, C4
P(m-CH3C6H4)3, C5
P(o-CH3C6H4)3, C6
P(p-FC6H4)3
0
43
70
90
32
aReaction conditions: 100mg of -enamine 1a, 2mol% of complex and dry THF (10mL) as solvent, time reaction
b
c
d
e
30h and 450psi (H2/CO) and 120 °C. Conversion determined by GC-MS. 12h. 24h. 30h.fThis H2/CO (1:3) is the
best ratio previously found by our group.[14]
On the other hand, we investigated the substituent effect on the aromatic ring in the phosphine.
An interesting effect was observed using methyl group in different positions on the aromatic
ring. Gratifyingly, we found that the o-methyl substituted catalyst significantly improved the
yield (entries 11-13). In contrast, the reactivity was low when the electron-donating methyl
group was replaced by an electron-withdrawing fluoro group (entry 14).
With the optimized conditions obtained, we tested the previously synthesized (C1-C6)
complexes in the hydrogenation reaction of -enamines. Results are presented in Table 3. All
reactions were carried out in tretrahydrofuran under 450psi (H2/CO, 1:3 ratio) pressure with a
catalyst loading of 2 mol%. Thus, we investigated the difference in the catalytic activity between
the cobalt complexes in the hydrogenation reaction of enamines. It is interesting to note that all
cobalt-modified complexes were active in the reduction reaction. Nevertheless, the conversion is
strongly dependent on the substituent in the phosphine ligand; accordingly, we found that the
general reactivity order for methyl substituted ligand in the catalytic promoters was

ACCEPTED MANUSCRIPT
orthometapara, where the ortho substituent gave the best yield, this behavior is evident for all
results in table 3. In the methoxy cases no good correlation was found.
Table 3. Hydrogenation of -enamines with different cobalt complexes.a
Convb/Yieldc %
Entry
Complex
Product
-enamine
1
C1
C3
41
40/35
1a
1b
2
3
4
5
6
7
C1
C2
C3
C4
C5
C6
C1
C2
C3
C4
C5
C6
C1
C2
C3
C4
C5
C6
C1
C2
C3
C4
C5
C6
C1
C2
C3
C4
C5
C6
C1
C2
C3
C4
C5
C6
65
49
58
61/56
60/50
62/56
95/92
60
90/87
80/77
85/84
99/96
40
60
80
40
93
93/90
80
50
85/82
80
85
87/85
40
60/57
45
40
50
95/93
54
40
99/95
35
45
2a
3a
2b
3b
4b
5b
6b
4a
5a
6a
7a
7b
99/97

ACCEPTED MANUSCRIPT
aReaction conditions: 100mg of -enamine, 2mol% of complex and dry THF (10mL) as solvent, time reaction 30h
and 450psi (H2/CO) and 120 °C. bConversion determined by GC-MS. cIsolated product.
When working with C1 and C3 complexes, the expected product 1b was found in a low yield
(entry 1, table 3. vs entries 11-13, table 2). Additionally, the presence of p-MeO group on the
substrate 2a, resulted in low yields (entry 2, table 3). This last behavior could be attributed to
steric effect of the substituent in the substrate, also the involvement of non-bonding electrons on
p-MeO group promotes electronic delocalization to form an iminic group conjugated with C=C
bond. Consequently, a retardatory effect on hydrogenation rate must be observed. In contrast,
when the reaction was carried out with 3a and the six complexes (C1-C6), gave excellent yields
among the six (entry 3). We also examined the reaction with electron-withdrawing groups. p-Cl
and p-F substituted on the substrate afforded the corresponding products 4b and 5b with good
yields (entries 4 and 5). Whereas m-Cl and m-Me substrates 6a and 7a gave the expected
products 6b and 7b in low yields (entries 6 and 7). However, complexes with substituents in
ortho-position showed the best results (entry 6, C6, 95% and entry 7, C3 and C6, 99%).
Noteworthy, the reduction was chemoselective over double bond. This is an advantage, because
the carbonyl group can be used for additional functionalization or transformation.[29] In order to
evaluate the source of chemoselectivity in this process, we have focused our attention in
enaminic nitrogen on substrate, the lone pair on nitrogen should be coordinated to cobalt ion,
approximating and activating C=C bond more than C=O bond. Additionally, at our experience
with this kind of substrates we have never found carbonyl reduction using HCo(CO)3L species.
4. Conclusion
In summary, we have developed a methodology for the hydrogenation of -enaminoketones to
corresponding -aminoketone compounds with good conversion using cobalt complexes.
Likewise, we have found that all complexes were active in the hydrogenation reaction, obtained
the best result when we used ortho-methyl-substituted ligand. This catalytic system is
straightforward and easy to prepare. The use of this complex in the catalytic asymmetric
hydrogenation is being currently under investigation in our laboratory. Studies conducting to
elucidate the mechanism of this reaction are in progress.

ACCEPTED MANUSCRIPT
Acknowledgments
We thank DGAPA–UNAM for financial support (PAPIIT IN203209), CONACyT (Fellowship
229448) and SNI (340/6732). Also, we gratefully acknowledge S. Hernández-Ortega, J. Pérez-
Flores, L. Velasco, Rocio Patiño Maya, Ma. Ángeles-Peña, Elizabeth Huerta Salazar, Isabel
Chávez-Uribe, L. C. Marquez and E. García for technical support.
Supplementary data
Supplementary data associated with this article can be found, in the online version, at
Notes and references
1. J. Jacob, W.D. Jones, Org. Chem. 68 (2003) 3563-3568.
2. N. Ungvari, E. Fördos, J. Balogh, T. Kegl, L. Parkanyi, F. Ungvary, Organometallics 29
(2010) 3837-3851.
3. D. Díaz, V.S. Martín, Org. Lett. 2 (2000) 335-337.
4. D. Díaz, V.S. Martín, Tetrahedron Lett. 41 (2000) 743-746.
5. J. Kolodziej, J.R. Green. Synlett. 16 (2011) 2397–2401.
6. S. N. Greszler, J.T. Malinowski, J.S Johnson, Org. Lett. 13 (2011) 3206-3209.
7. A. Vázquez-Romero, L. Cárdenas, E. Blasi, X. Verdaguer, A. Riera, Org. Lett. 11 (2009)
3104-3107.
8. F. Hebrard, P. Kalck, Chem. Rev.109 (2009) 4272–4282.
9. B. Breit, Acc. Chem. Res. 36 (2003) 264-275.
10. J. Sóvágó, M.G. Newton, E.A. Mushina, F. Ungváry, J. Am. Chem. Soc. 118 (1996)
9589-9596.
11. J.T. Lee, H. Alper, Macromolecules 37 (2004) 2417-2421.
12. A. Hamasaki, A. Muto, S. Haraguchi, X. Liu, T. Sakakibara, T. Yokoyama, M.
Tokunaga, Tetrahedron Lett. 52 (2011) 6869–6872.
13. E. Fördős, R. Tuba, L. Párkányi, T. Kégl, F. Ungváry, Eur. J. Org. Chem. (2009) 1994–
2002.
14. M. Amézquita-Valencia, A. Cabrera, J. Mol. Catal. A. 366 (2013) 17-21.
15. L. Rubio-Pérez, P. Sharma, F.J. Pérez-Flores, L. Velasco, J.L. Arias, A. Cabrera,
Tetrahedron 68 (2012) 2342-2348.
16. J-H. Xie, S-F. Zhu, Q-L. Zhou, Chem. Rev. 111 (2011) 1713–1760.
17. C.M. Ho, T.C. Lau. New J. Chem. 24 (2000) 859-863.
18. R. Bautista, P. Bernal, R. Herrera, B.M. Santoyo, J.M. Lazcano-Seres, F.
Delgado, J. Tamariz. J. Org. Chem. 76 (2011) 7901–7911.

ACCEPTED MANUSCRIPT
19. R. Figueroa, R.D. Froese, Y. He, J. Klosin, C.N. Theriault. Organometallics 30 (2011)
1695–1709.
20. R. Tuba, E. Fördős, F. Ungváry, J. Mol. Catal. A. 236 (2005) 113–118.
21. A.R.J. Manning, Chem. Soc. A. (1968) 1135.
22. J.L. Arias, A. Cabrera, P. Sharma, N. Rosas, R. Sampere, J. Mol. Catal. A. 246 (2006)
237-241.
23. J.W Rathke, R.J Klingler, M.J Chen, R.E.II. Gerald, K. W Kramarz, Chemist 80 (2003)
9-12.
24. Supplementary Material Crystallographic data for the structural analysis have been
deposited with the Cambridge Crystallographic Data Centre CCDC No. 913966, 913968,
913969 and 914455.
25. N. Casati, P. Macchi, A. Sironi, Angew. Chem. Int. Ed. 44 (2005) 7736 –7739.
26. C.A. Tolman, Chem. Rev. 77 (1977) 313-348.
27. P.N. Bungua, S. Otto, Dalton Trans. 40 (2011) 9238–9249.
28. Z.P. Xiao, J.Y. Xue, S.H. Tan, H.Q Li, H.L. Zhu. Bioorganic & Medicinal Chemistry 15
(2007) 4212–4219.
29. A. Cabrera, P. Sharma, M. Ayala, L. Rubio-Perez, M. Amézquita-Valencia, Tetrahedron
Lett. 52 (2011) 6758–6762.

ACCEPTED MANUSCRIPT
Graphical Abstract
Hydrogenation of -enaminoketones with cobalt phosphine-modified catalysts1
Manuel Amézquita-Valencia*, Ricardo Ramírez-Garavito, Rubén A. Toscano, A. Cabrera*
Instituto de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, Circuito Exterior, Coyoacán 04510,
México D.F.

ACCEPTED MANUSCRIPT
Research Highlights
The first example of catalytic hydrogenation of -enamino-ketones with L(CO)3Co-Co(CO)3L.
Good yields of secondary -amine-ketones were obtained.
Completely chemo selective reaction.
Ortho-substituted phosphines gave the best results.