One-pot synthesis of oxo acid derivatives by RhI-catalyzed chelation-assisted hydroacylation

Article abstract of DOI:10.1002/ejoc.200600236

Various oxo acid derivatives were obtained directly from the reaction of aliphatic and aromatic aldehydes with ω-alkenoic acid derivatives in the presence of rhodium(I) complexes and 2-amino-3-picoline. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200600236

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200600236
One-Pot Synthesis of Oxo Acid Derivatives by RhI-Catalyzed Chelation-
Assisted Hydroacylation
Eun-Ae Jo[a] and Chul-Ho Jun*[a]
Keywords: Homogeneous catalysis / C-H activation / Acylation / Rhodium
Various oxo acid derivatives were obtained directly from the
reaction of aliphatic and aromatic aldehydes with ω-alkenoic
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
acid derivatives in the presence of rhodium(
2-amino-3-picoline.
I) complexes and
γ-Oxo acid derivatives are an important class of com-
pounds that serve as intermediates for various heterocyclic
compounds such as lactones, β-lactam antibiotics and iso-
quinolines.[1] But the synthetic scheme is not simple, be-
cause retrosynthetic analysis shows that the umpoled syn-
thon or masked form of the acyl group should be used.
Therefore, many indirect forms of synthetic protocols have
been developed using nitroalkane,[2] diazo compounds,[3]
etc.[4] One simple way to solve this problem is intermo-
lecular hydroacylation: the direct synthesis of ketones from
aldehydes with alkenes[5] or alkynes[6] through C–H bond
activation by a transition metal catalyst. These types of
catalytic C–H bond activation have been focused on by
many synthetic organic chemists because they are one of
the best ways of avoiding many environmental problems
that can occur with industrial organic synthesis.[7] Willis et
al. utilized functionalized olefins such as acrylic acid deriva-
tives for the hydroacylation with β-alkoxy or β-sulfanyl al-
dehydes,[8] and for the hydroimination with aldimines as an
umpoled synthon, producing γ-oxo acid derivatives after
hydrolysis of the resulting ketimine.[9] Since we have also
developed a direct synthesis of ketones from common alde-
hydes,[10] we were intrigued to use our chelation-assistant
strategy for the synthesis of γ-oxo acid derivatives, and to
extend the use of alkyl ω-alkenoate producing oxo esters
that have different tether lengths.[11]
Scheme 1. Retrosynthetic analysis of various oxo acid derivative.
In our experiment, when the reaction of benzaldehyde
(1a) and methyl acrylate (2a) was carried out at 130 °C for
1 h under the cocatalysis of RhCl(PPh3)3 (3, 5 mol-%), 2-
amino-3-picoline (4, 40 mol-%), and benzoic acid (5,
20 mol-%), γ-oxo ester 6a was isolated in a 96% yield exclu-
sively (Table 1, Entry 1).
Table 1. Chelation-assisted hydroacylation of aldehyde 1 with func-
tionalized olefin 2.
Temp./
time
Entry Aldehyde
Olefin
Product 6
R1 (1)
R2 (2)[a]
yield [%][b]
1
2
3
4
5
6
7
8
Ph (1a)
MeO (2a)
130 °C/1 h 6a, 96 (100)
130 °C/1 h 6b, 94 (100)
130 °C/1 h 6c, 96 (100)
130 °C/1 h 6d, 91 (96)
130 °C/2 h 6e, 83 (85)
130 °C/4 h 6f, 88 (94)
150 °C/6 h 6g, 69 (73)
150 °C/6 h 6h, 75 (100)
150 °C/6 h 6i, 91 (98)
150 °C/6 h 6j, 81 (94)
150 °C/6 h 6k, 0 (0)[c]
In this paper, we wish to report a general direct synthesis
of various oxo acid derivatives from aldehydes and alkenoic
acid derivatives (Scheme 1).
4-MeC6H4 (1b) (2a)
Ph (1a)
Ph (1a)
4-BrC6H4 (1c)
4-CF3C6H4 (1d) (2a)
4-NCC6H4 (1e) (2a)
Ph (1a)
nC5H11 (1f)
Cy (1g)
tC4H9 (1h)
tBuO (2b)
EtO (2c)
MeO (2a)
Me2N (2d)
9
10
11
EtO (2c)
(2c)
(2c)
[a] Department of Chemistry, Yonsei University,
Seoul 120-749, Korea
Fax: +82-2-3147-2644
E-mail: junch@yonsei.ac.kr
[a] 2 equiv. of 2 (based on the aldehyde) were used. [b] Isolated
yield. GC yields are given in parentheses. [c] Compound 12 was
obtained in 64% GC yield.
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Eur. J. Org. Chem. 2006, 2504–2507

Oxo Acid Derivatives by RhI-Catalyzed Chelation-Assisted Hydroacylation
SHORT COMMUNICATION
The reaction proceeded smoothly without any hydrolysis
or condensation steps. Aldehyde 1b bearing an electron-do-
nating group shows a better reactivity than one having an
electron-withdrawing group such as the trifluoromethyl
group since the reaction of 1d requires a longer reaction
time (Entries 2 and 6).
The other functional groups did not show any dramatic
aldehyde 1a with 1-hexene was performed at 130 °C for 1 h
in the presence of an identical catalyst to give only a 29%
isolated yield of heptanophenone.[12] The high efficiency of
the reaction with methyl acrylate compared to 1-hexene is
because with acrylate a stable five-membered metallacycle
through carbonyl coordination[13] as well as a five-mem-
bered (imino)metallacycle like in complex 10 can be
formed, while only a single metallacycle like in complex 13
is generated with 1-hexene. This implies that the rate-de-
termining step of hydroacylation with acrylic ester or amide
is hydrometallation in 9 forming 10.
When the reaction of methyl 2-methyl acrylate (2e) and
1a was carried out in the presence of an identical catalytic
system, a corresponding branched alkyl γ-oxo ester 6l was
obtained (Scheme 3). But the reaction is so sluggish that
96 h are required to complete it. In contrast to 2e, when
the regioisomeric olefin, methyl 2-crotonate (2f), was used,
linear alkylated δ-oxo ester 6m was isolated without form-
ing the branched alkylated γ-oxo ester 6n.
signs of interference in this hydroacylation reaction (Entries
3–5) except for nitrile 1e, which required more vigorous
conditions (Entry 7). In the case of acrylamide (2d), a mod-
erate yield of the corresponding γ-oxo amide 6h was iso-
lated (Entry 8). Instead of aromatic aldehydes, aliphatic al-
dehydes such as 1f and 1g were also applied to this hydroa-
cylation of acrylic ester, and fairly good yields of the ex-
pected γ-oxo esters were obtained for primary and second-
ary alkanals (Table 1, Entries 9–10).
The reaction mechanism can be inferred as shown in
Scheme 2. Initially, aldehyde 1 reacts with 2-amino-3-pico-
line (4) to generate aldimine 7, in which the C–H bond is
cleaved by RhCl(PPh3)3 (3) to generate the iminorhodi-
um() hydride 8. Coordination of acrylic ester or amide 2
to 8 and the subsequent hydride insertion into 9 leads to
complex 10. Reductive elimination in 10 affords 11 and the
rhodium catalyst 3. Ketimine 11 is further hydrolyzed by
H2O, which was previously formed by condensation of 1
and 4, producing a γ-oxo acid derivative 6 with the genera-
tion of 4. Fortunately, a potential competitive side reaction,
a 1,4-addition reaction of 2 with 4, was not observed since
4 is more reactive towards aldehyde 1 than towards 2 gener-
ating 7 in situ. However, in the case of a tertiary alkanal
such as 1h, the expected 6k was not obtained, but only 1,4-
addition product 12 was isolated in 64% yield along with a
33% yield of aldimine 7b based on 4 (Table 1, Entry 11).
The reason must be that the C–H bond of 7b is hardly
cleaved by rhodium() of 3 due to the steric hindrance of
the tert-butyl group in 7b, which drives a 1,4-addition reac-
tion of amine 4 to 2c.
Scheme 3. Comparison of hydroacylation of 2e and 2f with 1a.
The reaction also needed a long reaction time, and was
completed in 72 h. Initially, the hydrometallation of the
Rh–H group into 2f in 14 generates branched alkylrhodium
Scheme 2. Proposed mechanism for hydroacylation of 2 with 1 in
the presence of 3 and 4.
To compare the reactivity of acrylate 2a (Table 1, Entry complex 15 (Scheme 4). The steric congestion at the rho-
1) with that of non-functionalized olefins, the reaction of dium center in 15 allows the skeletal isomerization of the
Eur. J. Org. Chem. 2006, 2504–2507
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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E.-A. Jo, C.-H. Jun
SHORT COMMUNICATION
branched alkyl group to the sterically less congested linear ate through carbonyl coordination. Further applications of
alkylrhodium() complex 10b. This type of isomerization these hydroacylation reactions with functionalized olefins
can be seen in some transition metal catalyzed reactions.[14] are under study.
Experimental Section
Typical Procedures for Hydroacylation (Table 1, Entry1): A screw-
capped pressure vial (1 mL) equipped with a magnetic stirring bar
was charged with benzaldehyde (1a, 26.5 mg, 0.25 mmol), methyl
acrylate (2a, 43 mg, 0.5 mmol), (PPh3)3RhCl (3, 11.6 mg,
0.013 mmol), 2-amino-3-picoline (4, 10.8 mg, 0.1 mmol), benzoic
acid (5, 6.1 mg, 0.05 mmol), and toluene (80 mg). The reaction
mixture was stirred in an oil bath that was preheated at 130 °C
for 1 h. After cooling to room temperature, the organic layer was
extracted with diethyl ether, and dried with anhydrous MgSO4 and
purified by column chromatography (SiO2, n-hexane/ethyl acetate
Scheme 4. Mechanism for the formation of 6m from 1a and 2f.
= 15:1) to afford 39.8 mg (96%) of methyl 4-oxo-4-phenylbutyrate
(6a).
Next, we extended our strategy to prepare oxo esters hav-
ing a lengthy tether from ω-alkenoates; methyl 3-butenoate
(2g) and methyl 4-pentenoate (2h) were applied to hydroa-
cylation with benzaldehyde (Table 2). The reactions were
facile and the required time for completing the reactions
are as follows: 4 h for 2g, 6 h for 2h, and just 1.5 h for 2a
(Entries 1, 2, 3). For comparison, when the reactions of 2a,
2g, and 2h were performed in the same reaction time
(1.5 h), the corresponding δ-oxo ester 6m and ε-oxo ester
6o were isolated in a 59% and 49% yield, respectively, while
a 92% isolated yield of 6a was obtained with 2a (Entries 1,
4, and 5). The highly reactive nature of 2a compared with
2g and 2h can be explained by the fact that a stable five-
membered metallacyclic complex 10 is formed with 2a
whereas stable metallacyclic intermediates seem not to be
formed with 2g and 2h.
Supporting Information (see footnote on the first page of this arti-
cle): General experiments, materials, typical procedures, and data
including 1H NMR, 13C NMR, IR, HRMS, elemental analyses,
and mass spectra.
Acknowledgments
This work was supported by the Korean Research Foundation
Grant Funded by the Korean Government (MOEHRD) (KRF-
2005-201-c00024).
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Entry
n (2)[b]
Reaction time
Product 6
Yield [%][c]
1
2
3
4
5
0 (2a)
1 (2g)
2 (2h)
1 (2g)
2 (2h)
1.5 h
4 h
6 h
1.5 h
1.5 h
6a
6m
6o
6m
6o
92 (100)
96 (100)
93 (100)
59 (68)
49 (58)
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In conclusion, a synthesis of various oxo acid derivatives
has been achieved by direct chelation-assisted hydroacyl-
ation of ω-alkenoic acid derivatives with aromatic and ali-
phatic aldehydes. These olefins are even more reactive than
those having no functional groups, probably due to the for-
mation of a properly sized metallacyclic complex intermedi-
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Oxo Acid Derivatives by RhI-Catalyzed Chelation-Assisted Hydroacylation
SHORT COMMUNICATION
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Received: March 17, 2006
Published Online: April 18, 2006
Eur. J. Org. Chem. 2006, 2504–2507
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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