Chelation-assisted β-alkylation of α,β-unsaturated ketone using Rh(I) catalyst and dialkyl amine

Article abstract of DOI:10.1016/S0040-4039(02)00769-4

A new Rh(I)-catalyzed β-alkylation of 4-phenyl-3-buten-2-one (1) was developed by utilizing diethylamine (5a) as a chelation-assistant tool. The key feature of this reaction is the vinyl C-H activation driven by amine-assisted cyclometalation to give the

Full text of DOI:10.1016/S0040-4039(02)00769-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4233–4236
Chelation-assisted b-alkylation of a,b-unsaturated ketone using
Rh(I) catalyst and dialkyl amine
Chul-Ho Jun,* Choong Woon Moon, Young-Min Kim, Hyuk Lee and Jun Hee Lee
Department of Chemistry, Yonsei University, Seoul 120-749, South Korea
Received 18 March 2002; revised 10 April 2002; accepted 12 April 2002
Abstract—A new Rh(I)-catalyzed b-alkylation of 4-phenyl-3-buten-2-one (1) was developed by utilizing diethylamine (5a) as a
chelation-assistant tool. The key feature of this reaction is the vinyl CꢀH activation driven by amine-assisted cyclometalation to
give the b,g-unsaturated ketones 7 as a major product. © 2002 Elsevier Science Ltd. All rights reserved.
The activation of CꢀH bonds by transition-metal com-
plexes is becoming more attractive in synthetic organic
chemistry since it is not only atom economic but also
highly chemoselective.1,2 One of the most promising
strategies for the CꢀH bond activation is to utilize the
chelation-assisted cyclometalation.3 By employing
amines as a chelation-assistant tool, we have developed
a series of Rh(I)-catalyzed hydroacylation of olefins via
a CꢀH bond activation.4 Recently, we also reported the
Rh(I)-catalyzed ortho-alkylation of aromatic ketimines
and ketones using the same strategy.5 So far, only a few
examples using Ru(0) catalysts for the b-alkylation of
a,b-unsaturated ketones with specific alkenes were
reported.6 Herein, we wish to describe a new Rh(I)-cat-
alyzed b-alkylation of a,b-unsaturated ketone for the
preparation of highly functionalized ketones employing
amines as a chelation auxiliary.7
products were obtained in an excellent yield of 89%
with an almost same ratio of 6a and 7a (entry 5).
Using optimized reaction conditions (5 mol% of 3, 10
mol% of 4, 50 mol% of 5a, 130°C, and 24 h), various
1-alkenes were tested in the b-alkylation of 1 and the
results are summarized in Table 1.8 All reactions pro-
ceeded smoothly and good isolated yields were
obtained still giving the b,g-enone 7 with a ca. 2:1 ratio
of E/Z isomer as a major product over the a,b-enone 6.
Especially, ethylene (2b) and trimethylvinylsilane (2e)
were the most efficient and nearly quantitative isolated
yields were obtained in both cases after simple column
chromatography on silica gel (entries 8 and 11). For
example, the reaction with trimethylvinylsilane (2e)
gave the b,g-unsaturated ketone 7e predominantly in
99% isolated yield (entry 11).
Initially, we investigated the b-alkylation of a,b-enone
using 4-phenyl-3-buten-2-one (1) as a model substrate.
Thus, as shown in Scheme 1, the enone 1 was reacted
with excess 1-hexene (2a, R=n-C4H9, 10.0 equiv.) in
the presence of RhCl(PPh3)3 (3, 5.0 mol%), benzoic acid
(4, 10.0 mol%), and diethylamine (5a, 50.0 mol%) at
130°C for 12 h. After the reaction, a mixture of b-alkyl-
ated products was obtained in 59% yield in a 34:66
ratio of 6a and 7a (entry 1 in Table 1). Increasing the
reaction time showed a positive effect on the yield of
the reaction but little effect on the ratio of 6a and 7a.
Therefore, when the reaction was carried out for 24 h
with fixing all other reaction conditions, the b-alkylated
To confirm the structure of the b-alkylated products,
the mixture was hydrogenated over Pd/C to afford
the saturated ketone 8 as a sole product (Scheme 1).
It is noteworthy that the reaction catalyzed by
Keywords: CꢀH activation; alkylation; b,g-unsaturated ketone;
Wilkinson catalyst.
* Corresponding author. Tel.: +82-2-2123-2644; fax: +82-2-364-7050;
e-mail: junch@yonsei.ac.kr
Scheme 1. Rh(I)-catalyzed b-alkylation of 4-phenyl-3-buten-
2-one (1) with 1-alkene.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00769-4

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C.-H. Jun et al. / Tetrahedron Letters 43 (2002) 4233–4236
Table 1. Rh(I)-catalyzed b-alkylation of 4-phenyl-3-buten-2-one (1) with various 1-alkenes in the presence of sec-aminea
Entry
R (2)
sec-Amine (5)
Time (h)
6/7b
E/Z ratio of 7b
Yieldc (%)
1
2
3
5
n-C4H9 (2a)
n-C4H9 (2a)
n-C4H9 (2a)
n-C4H9 (2a)
n-C4H9 (2a)
n-C4H9 (2a)
H (2b)
Cyclohexyl (2c)
t-C4H9 (2d)
Si(CH3)3 (2e)
Et2NH (5a)
Cy2NH (5b)
i-Pr2NH (5c)
Et2NH (5a)
12
12
12
24
24
24
24
24
24
24
34:66 (6a/7a)
32:68 (6a/7a)
–
35:65 (6a/7a)
–
67:33
68:32
–
72:28
–
59
6
0
89 (71)
0
0
100 (99)
87 (77)
73 (57)
100 (99)
d
6
–
7e
8f
9
Et2NH (5a)
Et2NH (5a)
Et2NH (5a)
Et2NH (5a)
Et2NH (5a)
–
–
24:76 (6b/7ba)
23:77 (6c/7c)
15:85 (6d/7d)
5:95 (6e/7e)
68:32
64:36
68:32
65:35
10
11
a All reactions were carried out at 130°C in dry toluene (1:2:3:4:5=1/10/0.05/0.1/0.5), unless otherwise stated.
b Determined by GC-analyses.
c Combined GC-yield of 6 and 7. Isolated yield is given in a parenthesis.
d In the absence of Et2NH.
e Carried out at 150°C using 5.0 mol% of RuH2(CO)(PPh3)3.
f Carried out in dry benzene using a Parr reactor.
RuH2(CO)(PPh3)3, which is known to be highly
efficient in a similar b-alkylation process,6a did not
proceed even when it was carried out at somewhat
higher reaction temperature of 150°C (entry 7).
This result shows that the facile chelation of a rhodium
species to the nitrogen functionality of 9 is an impor-
tant factor for the efficiency of the reaction.9 (3) a,b-
Unsaturated carbonyl compounds with no a-hydrogen
(e.g. a,b-unsaturated phenyl ketones, a,b-unsaturated
t-butyl ketones, a,b-unsaturated aldehydes, etc.) did
not participate in this b-alkylation reaction, presumably
due to the impossibility in generating the corresponding
dienamines.
A plausible mechanism for this reaction is illustrated in
Scheme 2. Precoordination of a rhodium species on the
nitrogen functionality of the dienamide 9, derived from
the condensation of the enone 1 with 5, can facilitate
the cleavage of the vinylic CꢀH bond to generate the
stable 5-membered metalacyclic rhodium hydride 10.
Coordination of an olefin 2 followed by the migratory
insertion of the olefin 2 into the RhꢀH bond gives the
alkylrhodium species 11. Reductive elimination in 10
furnishes the b-alkylated dienamine 12 that equilibrates
with the regioisomer 13 and regenerates a rhodium
catalyst to complete the catalytic cycle. Following
acidic hydrolysis of both 12 and 13 leads to the b-alkyl-
ated products 6 and 7.
Although at this moment no clear explanation is avail-
able, it is quite interesting that the b,g-enone 7, which is
generally not easy to be prepared, is a major compo-
nent compared with the a,b-enone 6. We hypothesize
that the olefin isomerization from 6 to 7 takes place
after the crucial CꢀC bond formation stage (Scheme 2).
As can be seen in Scheme 3, a couple of experiments
were devised to support our hypothesis. Acidic hydroly-
sis of the dienamine 14, which was prepared from
(E)-4-phenyl-3-hexen-2-one10 and piperidine using
TiCl4,11 gave the a,b-unsaturated ketone 6b as a sole
product. It demonstrates that the isomerization does
not take place during the hydrolysis. In contrast, the
dienamine 14 was isomerized upon treatment with
RhCl(PPh3)3 (3) to generate b,g-unsaturated ketone 7b
after hydrolysis. Thereby, we believe that a rhodium
complex probably plays a key role in causing deconju-
gation of the dienamine 14.
Some experimental results support the proposed mecha-
nism: (1) b-Alkylation did not proceed at all and only
the starting enone 1 was completely recovered in the
absence of dialkylamine 5, which implied that the dien-
amine 9 might be a key intermediate of the reaction. (2)
Steric requirement of the diakylamines 5 also affects so
strongly on the overall catalysis that no b-alkylated
product is obtained when sterically more demanding
diisopropylamine (5c) is used instead of 5a (entry 3).
R2N
R2N [Rh]
H
2
1
Ph
Ph
9
10
R
R2N [Rh]
R2NH
5
3
H2O
Ph
11
R
R
R2N
R2N
6 + 7
Ph
Ph
13
12
Scheme 2. A plausible mechanism for the Rh(I)-catalyzed b-alkylation of 1 with 1-alkenes.

C.-H. Jun et al. / Tetrahedron Letters 43 (2002) 4233–4236
4235
O
7. For a recent overview, see: Breit, B. Chem. Eur. J. 2000,
1519–1524.
i) RhCl(PPh3)3
toluene, 130 oC
Ph
O
8. General procedure for the b-alkylation of 1 is exemplified
by entry 5 in Table 1. A screw-capped pressure vial (1
mL) equipped with a magnetic stirring bar was charged
H+/H2O
6b
+
N
Ph
ii) H+/H2O
O
6b
(sole product)
Ph
14
Ph
with
1 (0.216 mmol), 1-hexene (2a, 2.16 mmol),
7b (E/Z = 78:22)
6b:7b = 11:89
RhCl(PPh3)3 (3, 11.0 mmol), benzoic acid (4, 22.0 mmol),
diethylamine (5a, 108 mmol), and dry toluene (100 mg).
The vial was closed and stirred at 130°C for 24 h. After
cooling the vessel to room temperature, the reaction
mixture was purified by column chromatography (n-hex-
ane/EtOAc=10:1) on silica gel to afford (E)-4-phenyl-3-
decen-2-one (6a)12 and (E/Z)-4-phenyl-4-decen-2-one
(7a)13 as a mixture. Isomeric ratio of the crude mixture
was determined by a GC analysis. The mixture of 6a and
7a in EtOH was stirred under H2 atmosphere (balloon) in
the presence of 10% palladium on activated charcoal for
12 h. After the reaction, the reaction mixture was filtered
on a small plug of silica gel, concentrated, and purified by
column chromatography to afford 4-phenyl-2-dode-
Scheme 3. Acidic hydrolysis and isomerization of 13.
As described above, we developed a new Rh(I)-cata-
lyzed b-alkylation of the a,b-unsaturated ketone 1 with
various 1-alkenes employing diethylamine (5a) as a
highly efficient chelation-assistant tool. By comparison
with Ru-catalyzed b-alkylation of enones,6 our Rh-cat-
alyzed reaction exhibited higher efficiency and broad
applicability to most 1-alkenes. The key feature of this
reaction is the vinyl CꢀH bond activation driven by
amine-assisted cyclometalation to give the b,g-unsatu-
rated ketones 7 as a major product. Extension of the
scope of this reaction and mechanistic studies are cur-
rently under investigation.
1
canone (8a) as a pale yellow oil. H NMR data for 6 and
7 are as follows. (E)-4-Phenyl-3-decen-2-one (6a)12 and
(E/Z)-4-phenyl-4-decen-2-one:13 1H NMR (250 MHz,
CDCl3): l 7.44–7.11 (m, 15H), 6.37 (s, 1H, 6a), 5.97 (t,
J=7.2 Hz, 1H, (E)-7a), 5.58 (t, J=7.3 Hz, 1H, (Z)-7a),
3.56 (s, 2H, (E)-7a), 3.40 (s, 2H, (Z)-7a), 3.04 (t, J=7.4
Hz, 2H, 6a), 2.23 (s, 3H, 6a), 2.17 (q, J=7.2 Hz, 2H,
(E)-7a), 2.04 (s, 3H, (E)-7a), 2.02 (s, 3H, (Z)-7a), 2.02–
1.96 (m, 2H, (Z)-7a), 1.50–1.21 (m, 18H), 0.93–0.82 (m,
9H); (E)-4-phenyl-3-hexen-2-one (6b)14 and (E/Z)-4-
Acknowledgements
This work was supported by the National Research
Laboratory Program (2000-N-NL-01-C-271) adminis-
tered by Ministry of Science and Technology. Authors
acknowledge the Brain Korea 21 project.
1
phenyl-4-hexen-2-one (7b): H NMR (250 MHz, CDCl3):
l 7.26–7.05 (m, 15H), 6.37 (s, 1H, 6b), 6.06 (q, J=6.9 Hz,
1H, (E)-7b), 5.68 (q, J=6.9 Hz, 1H, (Z)-7b), 3.57 (s, 2H,
(E)-7b), 3.40 (s, 2H, (Z)-7b), 3.04 (t, J=7.5 Hz, 2H, 6b),
2.24 (s, 3H, 6b), 2.07 (s, 3H, (E)-7b), 2.02 (s, 3H, (Z)-7b),
1.79 (d, J=7.0 Hz, 3H, (E)-7b), 1.65 (d, J=6.5 Hz, 3H,
(Z)-7b), 1.05 (t, J=7.4 Hz, 3H, 6b); (E)-6-cyclohexyl-4-
phenyl-3-hexen-2-one (6c) and (E/Z)-6-cyclohexyl-4-
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