Rhodium(I)-catalyzed one-pot synthesis of dialkyl ketones from methanol and alkenes through directed sp3 C-H bond activation of N-methylamine

Article abstract of DOI:10.1039/b814166e

The hydroacylation of methanol with alkenes was developed using a catalytic system consisting of Rh(i), 2-amino-4-picoline and benzoic acid; the reaction is speculated to occur by the initial N-methylation of 2-amino-4-picoline with methanol, and the subsequent dehydrogenation of the resulting N-methylamine, followed by double chelation-assisted hydroimination of alkene with the imine to give dialkyl ketones after hydrolysis. The Royal Society of Chemistry.

Full text of DOI:10.1039/b814166e

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Rhodium(I)-catalyzed one-pot synthesis of dialkyl ketones from
methanol and alkenes through directed sp3 C–H bond activation
of N-methylaminew
Eun-Ae Jo, Ji-Hyun Lee and Chul-Ho Jun*
Received (in Cambridge, UK) 15th August 2008, Accepted 3rd September 2008
First published as an Advance Article on the web 1st October 2008
DOI: 10.1039/b814166e
The hydroacylation of methanol with alkenes was developed
using a catalytic system consisting of Rh(I), 2-amino-4-picoline
and benzoic acid; the reaction is speculated to occur by the initial
N-methylation of 2-amino-4-picoline with methanol, and the
subsequent dehydrogenation of the resulting N-methylamine,
followed by double chelation-assisted hydroimination of alkene
with the imine to give dialkyl ketones after hydrolysis.
the nitrogen atom in the pyridine group to the metal center.
Other catalysts such as RuH2(CO)(PPh3)3, IrCl(CO)(PPh3)2 and
[IrCl(coe)2]2 with PPh3 were ineffective except for RhCl(CO)-
(PPh3)2, which exhibited a similar reactivity to 2.6
The reaction of other terminal alkenes (1b–f) with methanol
afforded the corresponding dialkyl ketones in good to moderate
isolated yields (Table 2).
Two possible mechanisms for this one-pot synthesis of
dialkyl ketones from methanol and alkenes can be proposed
as shown in Scheme 2. One mechanism involves the formation
of formaldehyde (6) in situ generated from methanol by transfer
hydrogenation, followed by condensation of 6 with 2-amino-4-
picoline (3) leading to the formation of imine 7. The chelation-
assisted hydroimination of alkene 1 with 7 generates aldimine 9,
which may react further with 1 by hydroimination to give
ketimine 10. The hydrolysis of 10 by H2O, generated from the
condensation of 3 and 6, produces dialkyl ketone 5. To confirm
this mechanism, the reaction of 1 with formaldehyde instead of
methanol was carried out under identical reaction conditions,
and resulted in no ketone 5 being produced.7
The activation of C–H bonds by transition metal complexes is a
current interest in organic synthesis.1 In particular, hydroacyla-
tion of alkenes or alkynes with aldehydes to produce ketones is
quite interesting in terms of atom economy.2 We have success-
fully developed a Rh(I)-catalyzed chelation-assisted hydro-
acylation with a co-catalyst system consisting of rhodium(I)
complex and 2-amino-3-picoline as an organic catalyst.3 This
protocol was further applied to the synthesis of ketones from
primary alcohols instead of aldehydes.4 In this reaction, alde-
hyde may be in situ generated from the primary alcohol by
transition metal-catalyzed transfer hydrogenation with olefins.
Among them, methanol is an interesting substrate since double
hydroacylation of alkenes is possible. As expected, dialkyl
ketones could be prepared from methanol and alkenes using
the chelation-assisted protocol (Scheme 1). To date, there have
been few direct methods to prepare dialkyl ketones from simple
starting materials.5 Herein, we wish to report direct rhodium(I)-
catalyzed synthesis of dialkyl ketones from methanol and
alkenes with a different mechanism from the conventional
chelation-assisted hydroacylation mechanism.
This result implies that formaldehyde is not directly involved
in this reaction. Another possible mechanism is that the reaction
proceeds through the formation of 2-(methylamino)-4-methyl-
pyridine (8), which is generated from the reaction of methanol
and 3. There are some reports on this type of
N-methylation of aromatic amines with methanol on acid media
under transition metal catalyst.8 The subsequent chelation-
assisted dehydrogenation of 8 with alkene affords imine 7, which
reacts with alkene 1 to give ketimine 10.9 The mechanism of this
route can be directly confirmed by stepwise reactions.
In our experiments, when the reaction of methanol and
norbornene (1a) was carried out in toluene at 150 1C for 24 h
in the presence of (Ph3P)3RhCl (2, 5 mol% based on methanol)
and 2-amino-4-picoline (3), dinorbornyl ketone 5a was isolated in
a 84% yield after chromatographic isolation (Table 1, entry 1).
The catalytic activities of various 2-aminopyridine derivatives
as chelation-assisted auxiliaries were examined. Among them,
2-amino-4-picoline showed the best catalytic activity, while
2-amino-6-picoline was least active, probably due to the steric
hindrance of the 6-methyl group causing difficult coordination of
In the absence of alkene, N-methylated compound 8 was
isolated from the reaction of 3 and methanol under the
catalyst mixture of 2 and 4 (Scheme 3). Then, the reaction of
8 with alkene 1a in the presence of 2 (5 mol%), 4 (10 mol%),
and H2O (100 mol%) afforded dialkyl ketone 5a in 83%
isolated yield.10 Other alkenes 1b–e were also applied to this
dialkylation to give dialkyl ketones 5b–e in moderate yields.
Since alkenes serve as both hydrogen acceptors and
Department of Chemistry and Centre for Bioactive Molecular Hybrid
(CBMH), Yonsei University, Seoul, 120-749, Korea.
E-mail: junch@yonsei.ac.kr; Fax: (+82) 2 3147 2644;
Tel: (+82) 2 2123 2627
w Electronic supplementary information (ESI) available: Experimental
procedures and spectral analyses of reaction products. See DOI:
10.1039/b814166e
Scheme 1
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Table 1 Catalytic activities of 2-aminopyridine derivativesa
Scheme 2 Mechanism for the synthesis of dialkyl ketone from
methanol and 1-alkenes.
a
Reaction conditions: 1 mmol of methanol, 6 eq. of norbornene (1a),
50 mg toluene mixture at 150 1C (bath temp.) for 24 h.
Table 2 Reaction of methanol with various alkenesa
Scheme 3 Stepwise synthesis of dialkyl ketone 5 from methanol and
alkene 1 through N-methylamine 8 using Rh(I) catalyst.
Scheme 4
determined by 1H NMR spectra.13 However, compound 11-d3
(Fig. 1) having no coordination site in the proper position did
not exhibit any D/H exchange by H2O under the identical
reaction conditions as in Scheme 4. This result shows that the
pre-coordination of substrate or organic catalyst is important
for the C–H bond activation due to easy access of the metal
center to the C–H bond to be cleaved.
a
Reaction conditions: 1 mmol of methanol, (PPh3)3RhCl (2, 5 mol%),
2-amino-4-picoline (3, 30 mol%), benzoic acid (4, 10 mol%), 6 mmol
of alkene (1), 50 mg toluene mixture at 150 1C (bath temp.) for 24 h.
Another interesting point to be noted is that the reaction
proceeds through the imine 7 because N,N-dimethyl-2-amino-
4-picoline (12), which can barely be dehydrogenated to form
imine, did not react with alkene to produce dialkyl ketone.
In summary, we developed a technique for the direct syn-
thesis of dialkyl ketones from methanol and alkenes using the
catalytic system consisting of Rh(I), 2-amino-4-picoline and
hydroacylation substrates in this reaction, the amount of
alkene required at least three times that of methanol.
For the dehydrogenation of N-methylamine by Rh(I) cata-
lyst, we tried to find evidence for the C–H bond activation of
the N-methyl group in 8. Despite difficult C–H bond cleavage
in the methyl group, there are some reports on the transition
metal-catalyzed chelation-assisted sp3 C–H bond activation of
an alkyl11 methyl group and N-methyl group.12 To identify the
C–H bond activation of the methyl group in 8 by Rh(I), 8-d3
was prepared and allowed to react with H2O in the presence of
2 at 130 1C for 24 h (Scheme 4). It was observed that 68% of
the deuterium in 8-d3 was exchanged with hydrogen of H2O, as
Fig. 1
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benzoic acid. The reaction is speculated to occur by the initial
N-methylation of 2-amino-4-picoline with methanol, followed
by dehydrogenation of the resulting N-methylamine to afford
imine. Then, the double chelation-assisted hydroimination of
alkene with imine and hydrolysis of the resulting ketimine
produces the dialkyl ketone. Further applications of this
protocol to other catalytic systems are currently being studied.
This work was supported by a Korea Research Foundation
Grant funded by the Korean Government (MOEHRD)
(KRF-2005-070-C00072). E.-A. J. and J.-H. L. acknowledge
the fellowships of the BK21 program of the Ministry of
Education and Human Resources Development and CBMH.
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(Ph3P)2(CO)RhCl showed a comparable isolated yield (82%) of 5a
under the identical reaction conditions to those in Table 1.
7 In a separate experiment, the reaction of formaldehyde, in the form
of paraformaldehyde, with 2-amino-4-picoline in the presence of
benzoic acid did not give 7, but resulted in a stable aminal
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and/or hydrolysis of the resulting imine in Scheme 3.
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Chem. Commun., 2008, 5779–5781 | 5781