α-alkylation of ketones by trialkylamines under heterogeneous Pd/C catalysis

Article abstract of DOI:10.1021/om500228b

Ketones are regioselectively α-alkylated with trialkylamines in toluene at 120 °C in the presence of Pd/C.

Full text of DOI:10.1021/om500228b

Note
pubs.acs.org/Organometallics
α‑Alkylation of Ketones by Trialkylamines under Heterogeneous
Pd/C Catalysis
Il Chul Yoon, Tae Gyun Kim, and Chan Sik Cho*
Department of Applied Chemistry, Kyungpook National University, Daegu 702-701, Republic of Korea
ABSTRACT: Ketones are regioselectively α-alkylated with trialkyl-
amines in toluene at 120 °C in the presence of Pd/C.
t is known that the synthetic usefulness of trialkylamines as
an alkylating reagent can be achieved by transition-metal
Table 1. Pd/C-Catalyzed α-Alkylation of 1a with 2a under
a
I
Various Conditions
catalysis. Among these procedures, transition-metal-catalyzed
alkyl group transfer between alkylamines has been known as an
amine exchange reaction and used for the synthesis of
unsymmetrical amines and N-heterocycles and the study of
the metabolism of amines.1−3 During the course of our ongoing
studies on the activation of carbon−nitrogen bonds of trialkyl-
amines and their availabilities,4 we developed an alkyl group
(or alkanol group) transfer from trialkylamines (or trialkanol-
amines) to the N atoms of anilines, which eventually leads to
quinolines and indoles.5,6 Such a carbon−nitrogen bond activation
of trialkylamines was also exemplified by ruthenium-catalyzed alkyl
group transfer from trialkylamines to the α-carbon of ketones.7
This transfer intrinsically shows a regioselective α-alkylation of
ketones by trialkylamines. Under these circumstances on the
studies of the activation of carbon−nitrogen bond of trialkyl-
amines and their availabilities, the protocol of α-alkylation of
ketones by trialkylamines led us to seek a catalyst alternative which
exhibits a similar catalytic activity under much milder reaction
conditions. Herein, this report describes a practical and useful
α-alkylation of ketones by the transfer of the alkyl group of
trialkylamines under heterogeneous Pd/C catalysis.
b
b
conversn (%)
yield (%)
entry
temp (°C)
time (h)
1a
2a
3a
4
1
2
3
4
120
120
100
150
120
120
120
20
40
40
40
40
40
40
43
97
44
95
92
28
20
62
99
62
98
88
48
48
33
78
37
36
64
20
2
trace
1
0
10
1
c
5
d
6
e
2
7
0
a
Reaction conditions: 1a (1 mmol), 2a (1 mmol), 5% Pd/C (0.1 mmol),
b
c
toluene (10 mL), under Ar. Determined by GLC. [2a]/[1a] = 1.2.
d
e
5% Pd/C (0.05 mmol). H2O (0.5 mL) was further added.
aldehydes and secondary amines in the presence of a palladium
catalyst and H2O.8 However, further addition of H2O did not
work at all for the present alkylation reaction (entry 7). Not shown
in Table 1, the reaction did not proceed at all in the absence of
Pd/C catalyst. As a result, the best result in terms of both yield and
complete conversion of 1a is accomplished by the standard set of
reaction conditions shown in entry 2 of Table 1.9
After the reaction conditions had been established, various
ketones 1 were subjected to the reaction with trialkylamines
2 in order to investigate the reaction scope, and several
representative results are summarized in Table 2. Aryl methyl
ketone 1a was readily alkylated with trialkylamines 2a−c having
straight alkyl chains to give α-alkylated ketones in high yields,
and the chain length of 2a−c had no relevance to the product
yield. On comparison ruthenium-catalyzed reactions,7a higher
reaction rate and yield were observed with tribenzylamine (2d),
whereas the reaction did not proceed effectively with branched
trialkylamines (2e,f). Dialkyl ketones such as 2-heptanone (1b)
and 4-phenyl-2-butanone (1c) were also α-alkylated with various
trialkylamines to give the corresponding coupled ketones 3g−k in
high yields, and the coupling took place exclusively at the less
hindered methyl position. Similar regioselectivity was observed
by several reports on transition-metal-catalyzed α-alkylation of
RESULTS AND DISCUSSION
■
The results of several tentative Pd/C-catalyzed α-alkylations of
acetophenone (1a) with tributylamine (2a) for the optimiza-
tion of conditions are given in Table 1. Treatment of 1a with an
equimolar amount of 2a in toluene in the presence of a catalytic
amount of Pd/C (10 mol %) at 120 °C for 20 h afforded
hexanophenone (3a) in 33% yield along with concomitant
formation of 1-phenylhexane (4) with incomplete conversion
of 1a and 2a (entry 1). The yield of 3a increases on prolonging
the reaction time up to 40 h with nearly complete conversion of
1a, which was monitored until 1a had disappeared on TLC
(entry 2). The reaction temperature was critical for the effective
formation of 3a (entries 3 and 4). A lower reaction rate and
yield were observed at 100 °C, whereas complete selectivity for
3a was achieved (entry 3). When the reaction was carried out at
150 °C, a considerable amount of 4 was obtained with many
unidentifiable side products on GLC. The higher molar ratio
[2a]/[1a] = 1.2 rather resulted in a lower yield of 3a (entry 5).
On the other hand, the use of a smaller amount of Pd/C under
the employed conditions did not afford 3a satisfactorily (entry 6).
It is known that tertiary amines are readily decomposed to
Received: March 5, 2014
Published: April 1, 2014
© 2014 American Chemical Society
1890
dx.doi.org/10.1021/om500228b | Organometallics 2014, 33, 1890−1892

Organometallics
Note
trialkylamine catalyzed by Pd/C along with adventitious H2O
in solvent.8 The aldehyde triggers aldol condensation with the
starting ketone to form an α,β-unsaturated ketone, which is
followed by reduction by PdH2 produced concomitantly during
aldehyde formation to form the coupled ketone.10a
Table 2. Pd/C-Catalyzed α-Alkylation of Ketones 1 with
Trialkylamines 2
a
CONCLUSION
■
In summary, it has been shown that ketones are regioselectively
α-alkylated with various trialkylamines in toluene at 120 °C in
the presence of a catalytic amount of heterogeneous Pd/C. The
present reaction provides an example for the synthetic usefulness
of trialkylamines under heterogeneous Pd/C catalysis.
EXPERIMENTAL SECTION
■
1
General Procedures. H and 13C NMR spectra were recorded at
400 and 100 MHz, respectively, using TMS as an internal standard.
GLC analyses were carried out with an instrument equipped with a
fused silica capillary column (0.33 mm × 25 m, 0.25 μm film
thickness) using nitrogen as carrier gas. The isolation of pure products
was carried out via thin-layer chromatography (silica gel 60 GF254
,
Merck). Commercially available organic and inorganic compounds
were used without further purification except for toluene, which was
distilled by known methods before use. The starting 1f was prepared
from 4′-bromoacetophenone and 3-buten-2-ol by a Heck reaction.17
Typical Procedure for Palladium-Catalyzed α-Alkylation of
Ketones 1 by Trialkylamines 2. In a 50 mL pressure vessel were
placed 4-(4-acetylphenyl)butan-2-one (1f; 0.095 g, 0.5 mmol),
tributylamine (2a; 0.278 g, 1.5 mmol), 5% Pd/C (0.212 g, 0.1 mmol),
and toluene (10 mL). After the system was flushed with argon, the
reaction mixture was stirred at 120 °C for 40 h. The reaction mixture
was passed through a short silica gel column (ethyl acetate/hexane) to
eliminate black precipitate. Removal of the solvent left a crude mixture,
which was separated by thin-layer chromatography (silica gel, ethyl acetate/
hexane 1/5) to give 1-(4-hexanoylphenyl)octan-3-one (5; 0.083 g, 55%),
1-(4-acetylphenyl)octan-3-one (6; 0.026 g, 21%), and 1-(4-(3-oxobutyl)-
phenyl)hexan-1-one (7; 0.004 g, 3%). Except for 5 and 7, all products
prepared by the above similar procedure are known.7,10,18−21
a
Reaction conditions: 1 (1 mmol), 2 (1 mmol), Pd/C (0.1 mmol),
b
toluene (10 mL), 120 °C, for 40 h, under Ar. Isolated yield.
c
d
Determined by GLC. [2a]/[1e] = 5.
ketones with primary alcohols.10−16 As is the case for ruthenium-
catalyzed reactions, the benzo-fused cyclic ketone 1d, which has
only a methylene reaction site, was also readily α-alkylated with
various trialkylamines 2a−f. In contrast to the reaction with aryl
methyl ketone, 1d readily reacted with the branched trialkylamine
2f. However, even though a higher molar ratio of trialkylamine to
ketone was used, the reaction did not proceed at all with
propiophenone (1e), which has only a methylene reaction site.
To test for regioselectivity between aryl(methyl) and
alkyl(methyl), the diketone 1f having aryl methyl ketone and
alkyl methyl ketone groups was employed.17 Similar treatment
of 1f with 3 equiv of 2a in the presence of Pd/C (20 mol %
based on 1f) under the employed conditions afforded the
dialkylated ketone 5 and monoalkylated ketones 6 and 7 in
55%, 21%, and 2% yields, respectively (eq 1). This result
1-(4-Hexanoylphenyl)octan-3-one (5): solid; mp 54−55 °C (from
1
hexane/chloroform); H NMR (400 MHz, CDCl3) δ 0.85−0.92 (m,
6H), 1.19−1.39 (m, 8H), 1.52−1.59 (m, 2H), 1.69−1.76 (m, 2H),
2.38 (t, J = 7.5 Hz, 2H), 2.75 (t, J = 7.5 Hz, 2H), 2.91−2.96 (m, 4H),
7.26−7.28 (m, 2H), 7.87−7.89 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 14.05, 14.12, 22.57, 22.68, 23.61, 24.28, 29.77, 31.49, 31.70,
38.65, 43.15, 43.73, 128.50, 128.71, 135.31, 146.88, 200.33 (CO),
209.91 (CO); HRMS (EI) calcd for C20H30O2 (M+) 302.2246,
found 302.2249.
1-(4-(3-Oxobutyl)phenyl)hexan-1-one (7): viscous oil; 1H NMR
(400 MHz, CDCl3) δ 0.91 (t, J = 7.1 Hz, 3H), 1.33−1.38 (m, 4H),
1.69−1.76 (m, 2H), 2.15 (s, 3H), 2.79 (t, J = 7.4 Hz, 2H), 2.91−2.97
(m, 4H), 7.26−7.28 (m, 2H), 7.87−7.89 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 14.20, 22.76, 24.35, 29.78, 30.33, 31.78, 38.74, 44.77,
128.61, 128.75, 135.43, 146.72, 200.46 (CO), 207.56 (CO);
HRMS (EI) calcd for C16H22O2 (M+) 246.1620, found 246.1623.
AUTHOR INFORMATION
indicates that the alkylation took place regioselectively at the
methyl reaction site of the alkyl methyl ketone portion in
preference to that of the aryl methyl ketone portion.
Similar treatment of acetone (1g) with 2 equiv of 2a under
the employed conditions afforded 2-heptanone (1b) and
6-undecanone (3g) in 9% and 55% yields, respectively (eq 2).
■
Corresponding Author
*E-mail fir C.S.C.: cscho@knu.ac.kr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science, and
Technology (2010-0007563).
Although the details of the reaction pathway are not certain,
it seems to proceed via initial formation of aldehyde from
1891
dx.doi.org/10.1021/om500228b | Organometallics 2014, 33, 1890−1892

Organometallics
Note
REFERENCES
■
(1) (a) Murahashi, S.-I.; Yoshimura, N.; Tsumiyama, T.; Kojima, T. J.
Am. Chem. Soc. 1983, 105, 5002. (b) Khai, B.-T.; Concilio, C.; Porzi,
G. J. Org. Chem. 1981, 46, 1759.
(2) (a) Shvo, Y.; Laine, R. M. J. Chem. Soc., Chem. Commun. 1980,
753. (b) Khai, B. T.; Concilio, C.; Porzi, G. J. Organomet. Chem. 1981,
208, 249. (c) Arcelli, A.; Khai, B. T.; Porzi, G. J. Organomet. Chem.
1982, 231, C31.
(3) Murahashi, S.-I. Angew. Chem., Int. Ed. 1995, 34, 2443.
(4) Guo, S.; Qian, B.; Xie, Y.; Xia, C.; Huang, H. Org. Lett. 2011, 13,
522.
(5) (a) Cho, C. S.; Oh, B. H.; Shim, S. C. Tetrahedron Lett. 1999, 40,
1499. (b) Cho, C. S.; Kim, J. S.; Oh, B. H.; Kim, T.-J.; Shim, S. C.;
Yoon, N. S. Tetrahedron 2000, 56, 7747. (c) Cho, C. S.; Oh, B. H.;
Kim, J. S.; Kim, T.-J.; Shim, S. C. Chem. Commun. 2000, 1885.
(d) Cho, C. S.; Kim, T. K.; Kim, B. T.; Kim, T.-J.; Shim, S. C. J.
Organomet. Chem. 2002, 650, 65. (e) Cho, C. S.; Kim, T. G.; Yoon, N.
S. Appl. Organomet. Chem. 2010, 24, 291.
(6) (a) Cho, C. S.; Lim, H. K.; Shim, S. C.; Kim, T. J.; Choi, H.-J.
Chem. Commun. 1998, 995. (b) Cho, C. S.; Kim, J. H.; Shim, S. C.
Tetrahedron Lett. 2000, 41, 1811. (c) Cho, C. S.; Kim, J. H.; Kim, T.-J.;
Shim, S. C. Tetrahedron 2001, 57, 3321.
(7) (a) Cho, C. S.; Kim, B. T.; Lee, M. J.; Kim, T.-J.; Shim, S. C.
Angew. Chem., Int. Ed. 2001, 40, 958. (b) Cho, C. S. Catal. Commun.
2006, 7, 1012.
(8) Murahashi, S.-I.; Watanabe, T. J. Am. Chem. Soc. 1979, 101, 7429.
(9) The reaction of 1a with 2a in dioxane at 180 °C for 40 h in the
presence of RuCl3−PPh3 afforded 3a in 61% yield.7a
(10) (a) Cho, C. S.; Kim, B. T.; Kim, T.-J.; Shim, S. C. Tetrahedron
Lett. 2002, 43, 7987. (b) Cho, C. S. J. Mol. Catal. A: Chem. 2005, 240,
55.
(11) (a) Taguchi, K.; Nakagawa, H.; Hirabayashi, T.; Sakaguchi, S.;
Ishii, Y. J. Am. Chem. Soc. 2004, 126, 72. (b) Suzuki, T. Chem. Rev.
2011, 111, 1825.
(12) (a) Martínez, R.; Brand, G. J.; Ramon
Lett. 2005, 46, 3683. (b) Martínez, R.; Ramon
Tetrahedron 2006, 62, 8988. (c) Guillena, G.; Ramon
́
, D. J.; Yus, M. Tetrahedron
, D. J.; Yus, M.
, D. J.; Yus, M.
́
́
Angew. Chem., Int. Ed. 2007, 46, 2358. (d) Alonso, F.; Riente, P.; Yus,
M. Eur. J. Org. Chem. 2008, 4908.
(13) Kwon, M. S.; Kim, N.; Seo, S. H.; Park, I. S.; Cheedrala, R. K.;
Park, J. Angew. Chem., Int. Ed. 2005, 44, 6913.
(14) Onodera, G.; Nishibayashi, Y.; Uemura, S. Angew. Chem., Int. Ed.
2006, 45, 3819.
(15) (a) Yamada, Y. M. A.; Uozumi, Y. Org. Lett. 2006, 8, 1375.
(b) Yamada, Y. M. A.; Uozumi, Y. Tetrahedron 2007, 63, 8492.
(16) Dobereiner, G. E.; Crabtree, R. H. Chem. Rev. 2010, 110, 681.
(17) de Vries, A. H. M.; Mulders, J. M. C. A.; Mommers, J. H. M.;
Henderickx, H. J. W.; de Vries, J. G. Org. Lett. 2003, 5, 3285.
(18) Cho, C. S.; Shim, S. C. J. Organomet. Chem. 2006, 691, 4329.
(19) Ishibayashi, K.; Takahashi, M.; Yokota, Y.; Oshima, K.;
Matsubara, S. Chem. Lett. 2005, 34, 664.
(20) Bhattacharya, A.; Segmuller, B.; Ybarra, A. Synth. Commun.
1996, 26, 1775.
(21) Calo,
72, 2596.
̀
V.; Nacci, A.; Monopoli, A.; Ferola, V. J. Org. Chem. 2007,
1892
dx.doi.org/10.1021/om500228b | Organometallics 2014, 33, 1890−1892