Intermolecular hydroacylation of acrylate esters: A new route to 1,4-dicarbonyls

Article abstract of DOI:10.1039/b107852f

1,4-Dicarbonyl compounds can be prepared using a Rh(I) mediated hydroacylation reaction between (2-aminopicolyl)imines and acrylate esters followed by acid hydrolysis.

Full text of DOI:10.1039/b107852f

Intermolecular hydroacylation of acrylate esters: a new route to
1,4-dicarbonyls†
Michael C. Willis* and Selma Sapmaz
Department of Chemistry, University of Bath, Bath, UK BA2 7AY. E-mail: m.c.willis@bath.ac.uk;
Fax: (+44) (0)1225 826231; Tel: (+44) (0)1225 826568
Received (in Cambridge, UK) 31st August 2001, Accepted 15th October 2001
First published as an Advance Article on the web 22nd November 2001
1,4-Dicarbonyl compounds can be prepared using a Rh(
I
)
product was isolated in 73% yield as a single regioisomer.
Lowering the catalyst loading or reaction temperature or
decreasing the reaction time resulted in less efficient processes
(entries 2–4). The reaction also proceeds if toluene is employed
as solvent although a more complex reaction mixture is
produced resulting in lower yields (entry 5). Chlorobenzene was
also evaluated but resulted in only low conversion to product.
The use of 1,4-dioxane allowed a reasonable yield of the desired
product to be isolated however solubilty problems were
encountered that were not observed with THF.
mediated hydroacylation reaction between
(2-aminopicolyl)imines and acrylate esters followed by acid
hydrolysis.
The transition metal catalysed hydroacylation reaction in which
an aldehyde and an alkene are combined to generate a ketone is
a relatively unexplored process. The main limitation of this
reaction is the instability of the proposed acyl-metal inter-
mediates and the resulting competitive decarbonylation path-
way.1 Intramolecular variants of the process utilising pent-4-en-
1-als as substrates, leading to cyclopentanones as products, have
been extensively studied,2 however reports leading to larger
ring sizes3 or intermolecular examples are scarce.4 Recently the
Jun group have reported the use of a reaction system employing
Wilkinson’s complex and 2-aminopicoline as catalysts that
allows intermolecular hydroacylation to proceed.5 The success
of the Jun system is attributed to the intermediacy of a
picolylimine capable of forming a chelate stabilised acylrho-
dium species.6 The majority of hydroacylation reactions
reported to date utilise unfunctionalised alkenes as substrates
thus generating simple ketones as products. We speculated that
the use of alkenes substituted directly with either an ester or
ketone group would provide direct access to the synthetically
challenging 1,4-dicarbonyl array (Scheme 1). These 1,4-di-
functionalised motifs are synthetically useful intermediates for
the preparation of substituted furans,7 butyrolactones8 and
succinate derivatives.9 Such 1,4-dicarbonyl systems are not
straightforward to prepare and the approach presented here can
be considered as the equivalent of an acyl-anion addition to an
enoate.10 The related hydroformylation reaction has been
reported although in these cases, by definition, only a single
carbon unit corresponding to the CO molecule is introduced.11
Using variously substituted and functionalised aldehydes in the
corresponding hydroacylation reaction would allow the addi-
tion of functionalised carbon chains.12 In this communication
we report our progress towards this goal.
In order to probe the generality of the process a range of
substituted enoates were evaluated in the reaction with imine 1
(Table 2). Variation in the ester group is tolerated well, with Me
t
and Bu esters both delivering the expected adducts in good
yields (entries 1 and 2).13 Entry 3 demonstrates the tolerance
towards amides with N,N-dimethylacrylamide generating the
corresponding product in 74% yield. The introduction of
substituents to the b-position of the alkene significantly reduces
the reaction efficiency with methyl crotonate and cinnamate
delivering the desired adducts in 24% and 10% yield re-
spectively (entries 4 and 5). Substitution at the a-position has a
similar effect on the reaction efficiency with methyl methacry-
late yielding 16% of the requisite product (entry 6). A b-
substituent could be successfully introduced if it was suffi-
ciently activating, thus the use of N-methyl maleimide as the
alkene component generated the desired hydroacylation product
in 81% yield (entry 7).
The generality with respect to the imine component was next
explored; we were particularly interested in assessing the
influence of electron withdrawing and donating substituents on
the aryl ring. A selection of 2-amino-3-methylpyridylimines
bearing a range of substituents were readily prepared and
evaluated in the reaction with methyl acrylate (Table 3).
Electron withdrawing groups such as -NO2 and -CN had a
beneficial effect on the rate of the reaction with good yields of
the desired products being obtained in only 20 and 80 min
respectively (entries 2 and 3). Electron donating substituents
To assess the feasibility of the process we elected to study the
reactions of imine 1 as an aldehyde equivalent and thus limit
decarbonylation. The reaction of 1 with methyl acrylate under a
variety of reaction conditions is summarised in Table 1.
Reactions were conducted in a sealed tube using Wilkinson’s
complex as the catalyst. Upon completion the reaction mixtures
were treated directly with 1.0 M HCl to liberate the required
1,4-dicarbonyl adducts. Optimal conditions involved heating a
THF solution of the substrates at 135 °C for 6 hours with 10
mol% catalyst (entry 1). Under these conditions the desired
Table 1 Reaction of imine 1 with methyl acrylatea
Entry
Temp./°C
Solvent
Time/h
Yield (%)
1
135
135
70
135
135
THF
THF
THF
THF
PhMe
6
6
7
4
6
73
47
48
59
56
2b
3
4
5
Scheme 1
a Conditions: imine 1 (1.0 eq.), methyl acrylate (2.0 eq), sealed tube,
RhCl(PPh3)3 (10 mol%) followed by HCl (1.0 M). b RhCl(PPh3)3 (5
mol%).
† Electronic supplementary information (ESI) available: experimental
details. See http://www.rsc.org/suppdata/cc/b1/b107852f/
2558
Chem. Commun., 2001, 2558–2559
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b107852f

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had a smaller influence on the rate of reaction; a -OMe
substituent had minimal effect compared to the parent phenyl
system with an 83% yield being achieved after 6 h (entry 4).
para-Methyl and -bromo groups are also well tolerated
delivering the corresponding 1,4-dicarbonyls in 98% and 85%
yield respectively (entries 5 and 6). Exchange of a phenyl for the
more electron rich naphthyl derived imine again showed little
difference with the naphthyl derived adduct being obtained in
86% yield after 6 h reaction (entry 7).
be attempted. Pleasingly, the required tetracarbonyl product 3
was isolated in 76% yield after 6 hours reaction.15
The reason for the rate accelerations observed with the nitro-
and cyano-substituted imines is unclear although destabilisation
of the chelated intermediate is a possibility. Given these rate
accelerations we were interested to see if these more reactive
imines would allow a- and b-substituted acrylate esters to be
employed as substrates. Unfortunately, although a rate accelera-
tion was observed little difference in yield was obtained, with
the nitro-substituted imine delivering products from reaction
with methyl crotonate and methyl methacrylate in only 22% and
14% yield respectively.
In conclusion, we have demonstrated the general viability of
the intermolecular hydroacylation of acrylate esters as a new
regioselective route to 1,4-dicarbonyl systems. The imine
component of the reaction can tolerate a range of substituents
including electron donating and electron withdrawing groups.
The enoate component can contain a variety of ester groups as
well as amide functionalities with little effect on yield, however,
introduction of simple a- or -substituents reduces the efficiency
of the reactions. Efforts to expand the substrate tolerance, to
identify more efficient catalyst systems and to develop a process
that can utilise aldehydes directly are underway in our
laboratory and will be reported in due course.
The use of diimine 2, prepared in good yield from benzene-
1,4-dicarboxaldehyde, offers a potential starting point for two
directional synthesis14 and allowed a double hydroacylation to
a
Table 2 Reaction between 1 and various alkenes using RhCl(PPh3)3
Yield
The EPSRC are thanked for financial support of this project.
We also thank the EPSRC Mass Spectrometry service at the
University of Wales, Swansea, for analyses and Johnson
Matthey PLC for the loan of rhodium salts.
Entry
Alkene
Product
Time/h
(%)
1
2
3
X = OMe
X = OtBu
X = NMe2
R1 = R2 = H
R1 = R2 = H
R1 = R2 = H
6
6
6
73
71
74
Notes and references
1 J. M. O’Connor and M. Junning, J. Org. Chem., 1992, 57, 5075.
2 For leading refs, see: (a) R. W. Barnhart, D. A. McMorran and B.
Bosnich, Inorg. Chim. Acta, 1997, 263, 1; (b) B. Bosnich, Acc. Chem.
Res., 1998, 31, 667; (c) M. Fujio, M. Tanaka, X.-M. Wu, K. Funakoshi,
K. Sakai and H. Suemune, Chem. Lett., 1998, 881.
3 For examples, see: A. D. Aloise, M. E. Layton and M. D. Shair, J. Am.
Chem. Soc., 2000, 122, 12610; K. P. Gable and G. A. Benz, Tetrahedron
Lett., 1991, 32, 3473.
4 For leading refs, see: H. Lee and C.-H. Jun, Bull. Korean Chem. Soc.,
1995, 16, 66; C. P. Lenges, P. S. White and M. Brookhart, J. Am. Chem.
Soc., 1998, 120, 6965; T. Kondo, M. Akazome, Y. Tsuji and Y.
Watanabe, J. Org. Chem., 1990, 55, 1286; T. Kondo, N. Hiraishi, Y.
Morisaki, K. Wada, Y. Watanabe and T.-A. Mitsudo, Organometallics,
1998, 17, 2131.
R1 = Me, R2 = H
X = OMe
4
18
12
12
6
24
10
16
81
R1 = Ph, R2 = H
X = OMe
5
R1 = H, R2 = Me
X = OMe
6
7b
5 C.-H. Jun, D.-Y. Lee, H. Lee and J.-B. Hong, Angew. Chem., Int. Ed.,
2000, 39, 3070.
6 J. W. Suggs, J. Am. Chem. Soc., 1979, 101, 489.
7 W. Friedrichsen, ‘Furans and their benzo derivatives: synthesis’, in
Compr. Heterocycl. Chem. II, ed. C. W. Bird, Elsevier, Oxford, 1996.
8 E.-I. Negishi and M. Kotora, Tetrahedron, 1997, 53, 6707.
9 R. E. Babine and S. L. Bender, Chem. Rev., 1997, 97, 1359.
10 D. Seebach, Angew. Chem., 1979, 91, 259; Umpoled Synthons. A Survey
of Sources and Uses in Synthesis, ed. T. A. Hase, Wiley, New York,
1987.
a Conditions: imine 1 (1.0 eq.), alkene (2.0 eq), THF, 135 °C, sealed tube,
RhCl(PPh3)3 (10 mol%) followed by HCl (1.0 M). b Product isolated as
enamine. pic = 3-picolin-2-yl.
Table 3 Variation in imine substituenta
11 For examples, see: G. Fremy, E. Monflier, J.-F. Carpentier, Y. Castanet
and A. Mortreux, Angew. Chem., Int. Ed. Engl., 1995, 34, 1474; C. W.
Lee and H. Alper, J. Org. Chem., 1995, 60, 499; Y. Hu, W. Chen, A. M.
B. Osuna, J. Xiao, A. M. Stuart and E. G. Hope, Chem. Commun., 2001,
725.
Entry
R
Time/h
Yield (%)
12 For an example of an intramolecular hydroacylation of an acrylate ester
see ref. 2(a).
13 All new compounds have been characterised, see ESI for details.†
14 For a review, see: S. R. Magnuson, Tetrahedron, 1995, 51, 2167.
15 The preparation of 3 serves as a general procedure: a solution of imine
2 (282 mg, 1.79 mmol) in THF (1 mL) was added to a solution of
RhCl(PPh3)3 (167 mg, 10 mol %) in THF (1 mL) at room temperature
and stirred for 1 h. Methyl acrylate (480 mL, 5.37 mmol) in THF (2 mL)
was added and the reaction vessel flushed with argon. The reaction tube
was sealed and then heated at 135 °C for 6 h. The reaction was cooled
to room temperature, diluted with EtOAc (20 mL), poured into aqueous
HCl (1 M, 20 mL) and extracted with EtOAc (3 3 20 mL). The organic
portions were washed with brine (20 mL), dried (MgSO4) and
evaporated in vacuo. The residue was purified by flash chromatography
(SiO2, 25% EtOAc–petrol) to give 3 (212 mg, 76%) as pale yellow
plates.
1
2
3
4
5
6
7
X = H
6 h
73
80
80
83
98
85
86
X = NO2
X = CN
X = OMe
X = Me
X = Br
20 min
80 min
6 h
6 h
6 h
6 h
a Conditions: imine (1.0 eq.), methyl acrylate (2.0 eq), THF, 135 °C, sealed
tube, RhCl(PPh3)3 (10 mol%) followed by HCl (1.0 M).
Chem. Commun., 2001, 2558–2559
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