The effects of amine and acid catalysts on efficient chelation-assisted hydroacylation of alkene with aliphatic aldehyde

Article abstract of DOI:10.1016/j.tetlet.2009.02.091

Efficient intermolecular hydroacylation of 1-alkene with aliphatic aldehyde was achieved using a catalyst mixture of cyclohexylamine, p-trifluoromethylbenzoic acid, Wilkinson's complex and 2-amino-3-picoline. The formation of unwanted aldol side-product w

Full text of DOI:10.1016/j.tetlet.2009.02.091

Tetrahedron Letters 50 (2009) 3338–3340
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The effects of amine and acid catalysts on efficient chelation-assisted
hydroacylation of alkene with aliphatic aldehyde
*
Eun-Ae Jo, Chul-Ho Jun
Department of Chemistry and Centre for Bioactive Molecular Hybrid (CBMH), Yonsei University, Seoul 120-749, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient intermolecular hydroacylation of 1-alkene with aliphatic aldehyde was achieved using a catalyst
mixture of cyclohexylamine, p-trifluoromethylbenzoic acid, Wilkinson’s complex and 2-amino-3-pico-
line. The formation of unwanted aldol side-product was avoided through the conjugate addition of cyclo-
hexylamine to the aldol intermediate that was initially generated, followed by the retro-Mannich-type
fragmentation of the resulting b-aminoaldimine.
Received 23 January 2009
Revised 7 February 2009
Accepted 12 February 2009
Available online 15 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Intermolecular hydroacylation is a useful synthetic method for
obtaining ketone from aldehyde and olefin by C–H bond
activation.1 We developed an effective general intermolecular
hydroacylation of 1-alkene using a catalyst mixture of Rh(I) com-
plex and 2-amino-3-picoline.2 The reactivity of this hydroacylation
was improved when a mixture of benzoic acid and aniline was
added as a cocatalyst.3 However, substrates tested are generally
aromatic aldehyde, not aliphatic aldehyde, due to the facile forma-
urated ketone can be cleaved to generate ketone and aldehyde, or
their imine derivatives, using cyclohexylamine and benzoic acid.5
Based on these results, we were intrigued by the possibility that
this protocol might be used to regenerate the initial aldehyde 1a
from the homoaldol side-product 7a for hydroacylation.
In this Letter, we will discuss the efficient chelation-assisted
hydroacylation of 1-alkene with aliphatic aldehyde through the
regeneration protocol of aliphatic aldehyde or its imine derivative
from the aldol condensation side-product using amine and acid.
In order to determine the feasibility of the regeneration of alde-
hyde 1a as a transient intermediate from the homoaldol compound
tion of a,b-unsaturated aldehyde from aliphatic aldehyde by aldol
condensation under these conditions.
O
using cyclohexylamine and acid, a,b-unsaturated aldehyde 7a was
O
tBu
prepared6 and allowed to react with 3,3-dimethyl-1-butene (2a)
under the given reaction conditions to generate the hydroacylated
product 6a (Table 1). When 10 mol % benzoic acid (5a) and
40 mol % cyclohexylamine (8) were used, 20% of 7a was trans-
Ph
RhCl(PPh3)3 (3, 2 mol%)
2-A-3-P (4, 30 mol%)
PhCOOH (5a,10 mol%)
PhNH2 (40 mol%)
(6a)
Ph
H
1a
+
O
(
)
+
ð1Þ
toluene, 110 oC,1h
tBu
)
Ph
H
2a
(
Ph
(7a)
Table 1
6a 7a
/
= 61% / 39%
Hydroacylation of 2a with 7a
When the reaction of hydrocinnamaldehyde (1a) and 3,3-di-
methyl-1-butene (2a) was carried out in toluene in the presence
of RhCl(PPh3)3 (3), 2-amino-3-picoline (4), benzoic acid (5a) and
aniline at 110 °C, a mixture of 61% hydroacylated product (6a)
and 39% aldol condensation side-product (7a) was obtained, and
none of the initial aldehyde 1a remained (Eq. 1). In the past, pri-
mary alcohol and allylamine derivatives have been used as sub-
strates to avoid the formation of aldol condensation product.4
During the reaction, a small amount of aldehyde or aldimine is
temporarily generated, and is utilized in the next chelation-as-
3
4
(2 mol%), (30 mol%)
O
5b
(10 mol%),
cyclohexylamine ( 8, 40 mol%)
O
Ph
H
H2O (100 mol%)
toluene, 110 oC
2aa
+
Ph
tBu
Ph
6a
)
7a
(
(
)
Entry
CyNH2 (8)
Acid (5)
Time (h)
GC% of 6a
1
2
3
4
5
6
7
40 mol %
40 mol %
40 mol %
40 mol %
none
5a
5b
5b
5b
5b
5b
5b
1
1
3
6
1
3
6
20
36
78
98
17
18
26
sisted hydroacylation. It has also been determined that a,b-unsat-
none
none
* Corresponding author.
E-mail address: junch@yonsei.ac.kr (C.-H. Jun).
a3.0 equiv based on the 7a were used.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.091

E.-A. Jo, C.-H. Jun / Tetrahedron Letters 50 (2009) 3338–3340
3339
Table 2
Transimination-assisted
Hydroimination
6a
H2O
Cy
Hydroacylation of 2a with 1a on the different temperatures
3
4
(2 mol%), (30 mol%)
Cy
H
2a
6a
7a
+
1a
N
5b
CF3C6H4COOH ( ,10 mol%)
CyNH2 (8, 40 mol%)
O
N
+
2aa
Ph
Ph
3 & 4
tBu
tBu
Ph
tBu
12a
toluene, 1 h
9a
(
)
10a
Cy
HN
Entry
Temperature
Ratio of 6a, 7a and 9a (%)
C-C Bond
2a
Activation
at high temp.
H
1a
3 & 4
6a
7a
9a
retro-Mannich
fragmentation
1
2
3
4
110 °C
130 °C
150 °C
170 °C
77
84
90
89
23
13
1
0
3
9
12
H2O
aldol
-H2O
8
condensation
Cy
H
N
9a
0
5b & 8
7a
Ph
H
a3.0 equiv of 2a based on the aldehyde (1a) were used.
N
Ph
Cy 11a
Scheme 1. Proposed mechanism of hydroacylation of 2a with 1a in the presence of
3, 4, 5b and 8.
formed into 6a in 1 h (entry 1). By replacing benzoic acid (5a) with
p-trifluoromethylbenzoic acid (5b), the conversion rate improved
to 36% (entry 2), and the amount of product 6a was increased dur-
ing a prolonged reaction time. And 7a was completely transformed
to 6a in 6 h (entries 3 and 4). However, without the addition of cyl-
cohexylamine (8), the conversion efficiency and rate were very low
(entries 5–7).
Based on the results noted above, the reaction of 1a and 2a was
carried out in the presence of 3, 4, 5b and 8 for 1 h at various tem-
peratures: 110 °C, 130 °C, 150 °C and 170 °C (Table 2). At the reac-
tion temperature of 110 °C, a mixture of 77% of 6a and 23% of 7a
was obtained. In comparison, 3% of symmetric dialkyl ketone 9a
as well as a mixture of 84% of 6a and 13% of 7a was obtained at
the reaction temperature of 130 °C (entries 1 and 2). As the reac-
tion temperature increased, the proportional rate of 9a and 6a also
increased, and that of 7a decreased (entries 3 and 4). It is specu-
lated that compound 9a was produced by the chelation-assisted
Rh(I)-catalyzed C–C bond activation of 6a. This type of transforma-
tion of ketone bearing b-hydrogen into symmetric dialkyl ketone
through the C–C bond activation has been studied previously un-
der vigorous reaction conditions, such as high temperature (about
170 °C).7 Therefore, the optimum temperature for hydroacylation
with aliphatic aldehyde was selected as 110 °C, at which tempera-
ture C–C bond cleavage product 9a was not produced.
To examine the effect of cyclohexylamine and acid on this
hydroacylation with aliphatic aldehyde, the proportion of the
product mixture from the reaction of 1a with 2a was monitored
over a period of 11 h, as shown in Figure 1.8 In 10 min, 1a was com-
pletely transformed to 7a by aldol condensation, as determined by
gas chromatography (GC). After 30 min, a mixture of 15% of 6a and
85% of 7a was observed. The proportions of hydroacylated product
6a increased, and those of 7a decreased as the reaction time pro-
gressed. The reaction was complete after 11 h. This result indicates
that aldol condensation product 7a must be formed initially and
then during a prolonged reaction time 7a reacts with 2a to produce
6a by chelation-assisted hydroacylation.
Based on the above results, a proposed mechanism for this reac-
tion can be depicted in Scheme 1. The initial step might be base-
catalyzed aldol condensation of 1a to produce 7a.9 In the presence
of cyclohexylamine (8) and acid 5b, the conjugate addition of 8 into
7a followed by retro-Mannich type fragmentation of the resulting
b-aminoaldimine (11a) produces the imine derivative 12a. Transi-
mination-assisted hydroimination of 2a with 12a in the presence
of 3 and 4 leads to the formation of 10a, which is then hydrolyzed
to produce 6a.10 At high temperatures, chelation-assisted C–C bond
activation of 10a takes place to produce 9a after hydrolysis.
3
4
(2 mol%), (30 mol%)
5b (10 mol%), 8 (40 mol%)
2aa
+
+
7a
1a
6a
toluene, 110 oC
Entry
Time
GC Yield (% )
6a
0
7a
100
85
39
17
4
1
10 min
30 min
1 h
2
15
61
83
96
94
93
95
98
99
3
4
2 h
5
3 h
6
4 h
6
7
5 h
7
8
6 h
5
9
7 h
2
10
8 h
1
11
11 h
100
0
a 3.0 equivalents of 2a based on 1a were used.
Figure 1. GC yield (%) of 6a and 7a versus time plot in the reaction of 2a with 1a in the presence of 3, 4, 5b and 8.

3340
E.-A. Jo, C.-H. Jun / Tetrahedron Letters 50 (2009) 3338–3340
Table 3
Hydroacylation of various aliphatic aldehyde with olefin under the different reaction conditions
O
O
(1)
3 (2 mol%), 4 (30 mol%)
(10 mol%), (40 mol%)
O
R
H
5b
8
+
R
H
+
R
R'
toluene, 110 o
C
(2)a
R
R'
6
( )
(7)
Entry
Aldehyde (R, 1)
Olefin (R’, 2)
CyNH2 (8) (mol %)
Time (h)
GC yield (%) of 6 and 7
Isolated yield
(%) of 6
1
2
3
4
5
6
7
8
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
n-C3H7 (1b)
n-C3H7 (1b)
n-C3H7 (1b)
n-C3H7 (1b)
n-C6H13 (1c)
n-C6H13 (1c)
n-C6H13 (1c)
n-C6H13 (1c)
SiEt3 (2b)
SiEt3 (2b)
SiEt3 (2b)
SiEt3 (2b)
Ph (2c)
Ph (2c)
Ph (2c)
Ph (2c)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
0
0
40
40
0
1
12
1
12
1
12
1
12
1
12
1
12
1
12
1
52 (6b)
48 (7a)
38 (7a)
50 (7a)
0 (7a)
20 (7a)
67 (7a)
56 (7a)
0
70 (7b)
51 (7b)
68 (7b)
0
38
43
41
87
6
27
36
82
22
39
23
83
24
43
53
86
62 (6b)
50 (6b)
100 (6b)
11 (6c)
33 (6c)
44 (6c)
100 (6c)
30 (6d)
49 (6d)
32 (6d)
100 (6d)
31 (6e)
51 (6e)
66 (6e)
100 (6e)
0
40
40
0
9
10
11
12
13
14
15
16
0
40
40
0
0
40
40
40 (7c)
49 (7c)
34 (7c)
0
12
a3.0 equiv of 2 based on aldehyde 1 were used.
Nagumo, S.; Kawahara, N.; Suemune, H. J. Org. Chem. 2007, 72, 2543–2546;
Willis, M. C.; Randell-Sly, H. E.; Woodward, R. L.; Currie, G. S. Org. Lett. 2005, 7,
2249–2251; Tanaka, K.; Shibata, Y.; Suda, T.; Hagiwara, Y.; Hirano, M. Org. Lett.
2007, 9, 1215–1218.
Several combinations of varying aliphatic aldehydes and ole-
fins were tested for intermolecular hydroacylation, and the re-
sults are summarized in Table 3. Under standard reaction
conditions (3, 4 and 5b at 110 °C) without cyclohexylamine (8),
the reaction of 1a and vinyltriethylsilane (2b) produced 52%/
48% and 62%/38% mixtures of 6b/7a in the reaction time of 1 h
and 12 h, respectively (entries 1 and 2). It was observed that
with the addition of 8 (40 mol %), a 50%/50% mixture was in-
creased to a 100%/0% mixture of 6b/7a by extending the reaction
time from 1 h to 12 h (entries 3 and 4). This result indicates that
the production of aldol condensation product 7 can be dramati-
cally suppressed with the simple addition of cyclohexylamine
(8) and acid 5b. Similar results were observed in the reaction
of other types of aliphatic aldehydes and olefins (entries 5–16).11
In conclusion, we demonstrated an efficient chelation-assisted
hydroacylation of 1-alkene with aliphatic aldehyde using the
cocatalyst system of cyclohexylamine and acid as well as Rh(I)
and 2-amino-3-picoline. The homoaldol condensation side-prod-
uct that is initially formed can be efficiently converted to a hydro-
acylated ketone product through the addition of cyclohexylamine
to the aldol condensation intermediate and a retro-Mannich type
fragmentation of the resulting b-aminoaldimine.
2. Jun, C.-H.; Jo, E.-A.; Park, J.-W. Eur. J. Org. Chem. 2007, 1869–1881; Jun, C.-H.;
Lee, H.; Hong, J.-B. J. Org. Chem. 1997, 62, 1200–1201.
3. Jun, C.-H.; Lee, D.-Y.; Lee, H.; Hong, J.-B. Angew. Chem., Int. Ed. 2000, 39, 3070–
3072.
4. Jun, C.-H.; Huh, C.-W.; Na, S.-J. Angew. Chem., Int. Ed. 1998, 37, 145–147; Lee, D.-
Y.; Kim, I.-J.; Jun, C.-H. Angew. Chem., Int. Ed. 2002, 41, 3031–3033.
5. Jun, C.-H.; Lee, H.; Moon, C. W.; Hong, H.-S. J. Am. Chem. Soc. 2001, 123, 8600–
8601; Lee, D.-Y.; Hong, B.-S.; Cho, E.-G.; Lee, H.; Jun, C.-H. J. Am. Chem. Soc.
2003, 125, 6372–6373.
6. Synthesis of 2-benzyl-5-phenyl-pent-2-enal (7a): Three millilitres of an
aqueous
NaOH
solution
(10%)
were
slowly
added
to
hydrocinnamaldehyde (1a, 0.05 mol, 6.7 g) diluted in 50 ml of
tetrahydrofuran (THF). Then the reaction mixture was stirred at room
temperature for 12 h and neutralized with an aqueous solution of HCl
(10%), and ether was added. The organic phase was dried on magnesium
sulfate before filtration and purified via column chromatography (n-hexane
ethyl acetate = 10:1) to give 3.9 g of 7a.
7. Jun, C.-H.; Lee, H. J. Am. Chem. Soc. 1999, 121, 880–881; Jun, C.-H.; Lee, H.; Park,
J. B.; Lee, D.-Y. Org. Lett. 1999, 1, 2161–2164.
8. General procedure (Figure 1, entry 3): A screw-capped pressure vial (1 mL)
equipped with a magnetic stirring bar was charged with 26.8 mg (0.2 mmol) of
hydrocinnamaldehyde (1a), 50.4 mg (0.6 mmol) of 3,3-dimethyl-1-butene (2a),
3.7 mg (0.004 mmol) of (PPh3)3RhCl (3), 6.5 mg (0.06 mmol) of 2-amino-3-
picoline (4), 2.4 mg (0.02 mmol) of p-trifluoromethylbenzoic acid (5b), 7.9 mg
(0.08 mmol) of cyclohexylamine (8) and 100 mg of toluene. The reaction
mixture was sealed and stirred for 1 h in an oil bath that was preheated at
110 °C. After cooling to room temperature, the organic layer was analyzed on a
GCD system to be a compound mixture of 6,6-dimethyl-1-phenylheptan-3-one
(6a) and 2-benzyl-5-phenyl-2-pentenal (7a) in 61% and 39% ratio.
Acknowledgements
This work was supported by the Korea Research Foundation
Grant funded by the Korean Government (KRF-2008-313-
C00483) and WCU (World Class University) programme through
the Korea Science and Engineering Foundation funded by the Min-
istry of Education, Science and Technology (R32-2008-000-
102170) and CBMH. E.-A.J. acknowledges the fellowships of the
BK21 programme of the Ministry of Education and Human Re-
sources Development.
9. It can be also speculated that a small amount of aldehyde may be directly
transformed to hydroacylation product without generating aldol condensation
intermediate.
10. Jun, C.-H.; Hong, J.-B. Org. Lett. 1999, 1, 887–889.
11. Compound 6d: 1H NMR (400 MHz, CDCl3): d 2.42–2.33 (m, 4H), 1.59–1.55 (m,
2H), 1.48–1.44 (m, 2H), 1.35–1.24 (m, 4H), 0.90–0.87 (m, 12H). 13C NMR
(100 MHz, CDCl3): d 212.2 (CO), 42.9, 38.5, 37.5, 31.5, 29.2, 23.7, 22.5, 14.0. MS:
m/z (%): 184 (M+, 10), 169 (23), 139 (42), 127 (43), 114 (10), 113 (82), 108 (13),
99 (100), 85 (24), 71 (81), 69 (32), 57 (58), 55 (26), 43 (88), 41 (40), 29 (19), 18
(17). IR (CDCl3): 2957, 1715, 1366 cmꢀ1. HRMS (CI+) calcd for C12H25O ([MH+])
185.1906, found 185.1905. Compound 6e: 1H NMR (250 MHz, CDCl3): d 2.43–
2.32 (m, 4H), 1.58–1.26 (m, 14H), 0.88 (s, 12H). 13C NMR (62.9 MHz, CDCl3): d
211.8 (CO), 42.8, 38.4, 37.4, 31.7, 29.9, 29.3, 29.2, 29.1, 23.9, 22.5, 14.0. MS: m/z
(%): 226 (M+, 6), 211 (32), 169 (93), 141 (87), 129 (17), 113 (87), 99 (17), 85
(24), 81 (12), 71 (89), 57 (100), 55 (29), 43 (61), 41 (40), 29 (19). IR (CDCl3):
References and notes
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McNally, S. J.; Beswick, P. J. Angew. Chem., Int. Ed. 2004, 43, 340–343; Moxham,
G. L.; Randell-Sly, H. E.; Brayshaw, S. K.; Woodward, R. L.; Weller, A. S.; Willis,
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Brookhart, M. J. Am. Chem. Soc. 2007, 129, 2082–2093; Imai, M.; Tanaka, M.;
2925, 1715, 1465, 1363 cmꢀ1 ([MNa+])
. HRMS (CI+) calcd for C15H30O
249.2297, found 249.2193. Anal. Calcd for C15H30O: C, 79.58; H, 13.36;
Found: C, 79.56; H, 13.24.