Improved palladium-catalysed synthesis of α-benzyl-β-keto esters

Article abstract of DOI:10.1055/s-0030-1258095

This paper describes the development of an imporved protocol for the synthesis of α-benzyl-β-keto esters from aryl bromides via Heck reaction. The use of this protocol to synthesise a variety of diverse α-benzyl-β-keto esters for use in the preparation of new pharmaceutical agents is demonstrated. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258095

1688
LETTER
Improved Palladium-Catalysed Synthesis of a-Benzyl-b-keto Esters
S
ynthesis of
a
-Ben
i
zyl-
b
-k
c
etoEstersholas J. Bennett,*a Anne Goldby,b Rachel Pringlec
a
Chemistry Department, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, LE11 5RH, UK
Fax +44(1509)645571; E-mail: Nicholas.bennett@astrazeneca.com
b
c
School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
Department of Chemistry, Loughborough University, Loughborough, LE11 3TU, UK
Received 28 January 2010
reactivity in this case. Therefore, a range of catalyst sys-
tems were screened to try and discover conditions that
gave a good conversion of starting material into product to
for this reaction. Since 2-(3-bromo-4-methoxyphenyl)ac-
etonitrile (2) appears to be a demanding substrate for this
type of Heck reaction we anticipated that any conditions
that were successful for this substrate would subsequently
be applicable to a range of aryl bromides.
Abstract: This paper describes the development of an imporved
protocol for the synthesis of a-benzyl-b-keto esters from aryl bro-
mides via Heck reaction. The use of this protocol to synthesise a va-
riety of diverse a-benzyl-b-keto esters for use in the preparation of
new pharmaceutical agents is demonstrated.
Key words: palladium, Heck reaction, arylation, Baylis–Hillman,
a-benzyl-b-keto ester
Our initial screen for an improved catalytic system fo-
cused on using homogeneous reaction conditions. In order
to simplify the process we decided try a range of palladi-
um catalysts whilst keeping the base (N-methyldicyclo-
hexylamine, 1.5 equiv), additive [tetrabutylammonium
chloride (TBAC), 10 mol%], and solvent (dimethylaceta-
mide, 0.1 M) constant. The parallel screen of different pal-
ladium complexes showed 10 mol% Pd(dbpf)Cl2 to be the
only catalyst to give an acceptable conversion of starting
material into product by HPLC (Table 1). All other cata-
lysts gave either no or poor conversion. Further parallel
experiments were then completed to optimise the reaction
conditions using Pd(dbpf)Cl2. It was found that increasing
the amount of TBAC present in the reaction mixture from
10 mol% to 20 mol% gave an increased conversion of
starting material into product. Changing the base used in
the reaction had a negative effect on the overall conver-
sion but increasing the loading of N-methyldicyclohexyl-
amine gave complete conversion of starting material into
product. Inceasing the reaction temperature from 80 °C to
100 °C also gave complete conversion of starting material
into product provided the reaction was completed in a
closed tube.5 Solvent screening then indicated DMF to be
optimum for this reaction. Finally, it was established that
the catalyst loading could be reduced from 10 mol% to 2.5
mol% without reducing the conversion of starting materi-
al into product (Table 1).
Palladium catalysis is a well-established tool for organic
synthesis with a wide variety of applications. This in-
cludes the synthesis of new pharmaceutical agents as it al-
lows for the efficient synthesis of carbon–carbon and
carbon–heteroatom bonds.1 The Heck reaction is one of
the most commonly used palladium-catalysed transforma-
tions and this methodology has been used to solve a range
of synthetic challenges.2 We were focused on using Heck
methodology to construct a range of structurally diverse
a-benzyl-b-keto esters from aryl bromides (Scheme 1).3
We envisioned that the use of this methodology would al-
low for the rapid synthesis of a range of structurally di-
verse a-benzyl-b-keto esters that could be subsequently
converted into heterocyclic molecules, such as pyrazoles
or pyrimidines,4 for use in the preparation of pharmaceu-
tically active compounds.
OMe
OH
O
Heck
O
Ar
heterocycles
Br
+
R
OMe
Ar
O
R
Scheme 1
The use of a Heck reaction for the synthesis of a-benzyl-
b-keto esters has been previously reported3a and therefore
we initially investigated the reaction between methyl 3-
hydroxy-2-methylenebutanoate (1) and 2-(3-bromo-4-
methoxyphenyl)acetonitrile (2, Scheme 2) using these
conditions. However, in our hands the previously de-
scribed protocol gave none of the desired product and
only unreacted starting material was observed. We con-
cluded that the presence of the ortho-methoxy substituent
in the starting material could be responsible for the lack of
catalyst
additive
OMe
OMe
O
OMe
base
solvent
OH
O
Br
temperature
+
OMe
see table 1
O
NC
NC
3
1
2
Scheme 2
SYNLETT 2010, No. 11, pp 1688–1690
x
x
.x
x
.2
0
1
0
Advanced online publication: 15.06.2010
DOI: 10.1055/s-0030-1258095; Art ID: D02610ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of a-Benzyl-b-keto Esters
1689
Table 1
Entry Catalyst (loading, mol%)Additive (loading, mol%)Base (loading, equiv) Solvent
Temp (°C) Concn (M) Time (h) Ratio product/2a
1
2
3
4
5
6
Pd(OAc)2 (2)
TBAB (100)
TBAC (10)
TBAC (20)
TBAC (20)
TBAC (10)
TBAC (20)
NaHCO3 (2.5)
NMeCy2 (1.5)
NMeCy2 (1.5)
NMeCy2 (3)
THF
70
80
0.3
0.1
0.1
0.1
0.1
0.3
18
18
18
18
18
18
0:100
50:50
94:6
Pd(dbpf)Cl2 (10)
Pd(dbpf)Cl2 (10)
Pd(dbpf)Cl2 (10)
Pd(dbpf)Cl2 (10)
Pd(dbpf)Cl2 (2.5)
DMA
DMA
DMA
DMA
DMF
80
80
100:0
100:0
100:0c
NMeCy2 (1.5)
NMeCy2 (3)
100b
100b
a Ratio determined by HPLC of reaction mixture.
b Reaction completed in a closed tube.
c Isolated yield 92%.
Our attention then turned to investigating whether these As the catalytic system had worked well for the arylation
optimised conditions could be applied to the Heck reac- of 1 with a range of aryl/heteroaryl bromides we decided
tion between methyl 3-hydroxy-2-methylenebutanoate to investigate if it could be applied to the arylation of other
(1) and a range of aryl bromides containing electron- Baylis–Hilman adducts. Thus, 2-[hydroxyl(phenyl)meth-
donating or -withdrawing substituents (Scheme 3). Pleas- yl]acrylate (4)7 was successfully arylated with both 1-bro-
ingly, all the substrates underwent efficient Heck reaction mo-2-methoxybenzene and methyl-3-bromobenzoate to
with 1. To extend the methodology further, 3-bromopyri- give the Heck products 6h and 6i, respectively, in good
dine and 3-bromothiophene were subsequently reacted yield (Table 2). Similarly, the furanyl Baylis–Hilman ad-
with adduct 1 and again we were delighted to obtain good duct 57 underwent Heck reaction with 2-methoxybenzene
yield of the desired 1,3-dicarbonyl compounds 6f and 6g to yield the desired 1,3-dicarbonyl intermediate 6j in good
(Table 2).6
yield (Table 2).
OMe
O
OH
O
In conclusion, we have developed an optimised protocol
for the efficient synthesis of a-benzyl-b-keto esters from
commercially available aryl bromides. We have demon-
strated that this protocol works for a range of aryl and het-
eroaryl bromides, as well as a number of Baylis–Hillman
adducts, to yield a diverse range of a-benzyl-b-keto esters.
As these compounds represent key intermediates for syn-
thesis of heterocyclic molecules this optimised protocol is
ripe for application in the preparation of new pharmaceu-
ticals.
(i)
R2
Br
R1
OMe
R2
+
R1
O
1 R1 = Me
4 R1 = Ph
6a–j
5 R1 = 2-furyl
Scheme 3 Reagents and conditions: (i) Pd(dbpf)Cl2 (2.5 mol%),
N-methyldicyclohexylamine (3 equiv), TBAC (20 mol%), DMF, 100
°C (closed tube).
Table 2 Synthesis of Compounds 6a–j
Acknowledgment
Entry R1
R2
Product Isolated yield (%)
The authors thank Tom McInally (AstraZeneca), Dr. Steve Christie
(Loughborough University), Professor Neil R. Thomas (University
of Nottingham) and Professor Joe Sweeney (University of Reading)
for their interest in this research and help with the preparation of this
manuscript.
1
2
Me
4-O2NC6H4
2-MeOC6H4
4-MeC6H4
6a
6b
6c
6d
6e
6f
53
85
79
99
56
56
67
60
65
75
Me
Me
Me
Me
Me
Me
Ph
3
4
3-MeO2CC6H4
3-F-5-CNC6H3
3-pyridyl
References and Notes
5
(1) (a) Doucet, H.; Hierso, J.-C. Curr. Opin. Drug Discovery
Dev. 2007, 10, 672. (b) Larsen, R. D. Curr. Opin. Drug
Discovery Dev. 1999, 2, 651.
6
(2) (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem.
Int. Ed. 2005, 44, 4442. (b) Whitcombe, N. J.; Hii, K. K.;
Gibson, S. E. Tetrahedron 2001, 57, 7449. (c) Beletskaya,
I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009.
(d) Cabri, W.; Cardian, I. Acc. Chem. Res. 1995, 28, 2.
(3) (a) Basavaiah, D.; Muthukumaran, K. Tetrahedron 1998, 54,
4943. (b) Kumareswaran, R.; Vankar, Y. D. Synth. Commun.
1998, 28, 2291. (c) Sundar, N.; Bhat, S. V. Synth. Commun.
1998, 28, 2311.
7
3-thiophene
2-MeOC6H4
3-MeO2CC6H4
2-MeOC6H4
6g
6h
6i
8
9
Ph
10
2-furyl
6j
Synlett 2010, No. 11, 1688–1690 © Thieme Stuttgart · New York

1690
N. J. Bennett et al.
LETTER
organic phase was dried over MgSO4, filtered, and
(4) Gilchrist, T. L. Heterocyclic Chemistry, 3rd ed.; Addison
Wesley Longman: Harlow, 1997.
(5) The reaction was completed in a closed tube with a bursting
disc fitted in the top of the tube. The reaction was completed
behind a blast screen and these important safety measures
should be implemented when completing this reaction
particularly when scaling up the procedure.
evaporated. The residue was diluted with MeCN (30 mL)
and loaded on to a 70 g SCX cartridge. The product was
washed through with MeCN (100 mL) and the filtrate
evaporated to give methyl 2-(2-methoxybenzyl)-3-oxo-
butanoate (1.558 g, 85%) as an orange oil. 1H NMR (400
MHz, CDCl3): d = 7.20 (ddd, J = 8.9, 7.6, 2.1 Hz, 1 H, CH),
7.11 (dd, J = 6.8, 3.0 Hz, 1 H, CH) 6.87–6.82 (m, 2 H, CH),
3.92 (dd, J = 8.4, 7.2 Hz, 1 H, CH), 3.83 (s, 3 H, CH3), 3.67
(s, 3 H, CH3), 3.19 (dd, J = 13.9, 7.2 Hz, 1 H, CH2), 3.10 (dd,
J = 13.9, 8.2 Hz, 1 H, CH2), 2.18 (s, 3 H, CH3). 13C NMR
(125 MHz, CDCl3): d = 203.1, 169.9, 157.3, 130.8, 128.1,
126.2, 120.5, 110.2, 59.0, 55.2, 52.2, 29.5, 29.4. HRMS
(TOF-LCMS): m/z calcd for C13H17O4 [M + H]+: 237.1121;
found: 237.1122.
(6) Typical Procedure for Heck Reaction
1-Bromo-2-methoxybenzene (0.958 mL, 7.75 mmol),
methyl 3-hydroxy-2-methylenebutyrate (0.942 ml, 7.75
mmol) and N-methyldicyclohexylamine (4.98 mL, 23.26
mmol) were added to a suspension of Pd(dbpf)Cl2 (0.126 g,
0.19 mmol) and TBAC (0.431 g, 1.55 mmol) in DMF (10
ml) under nitrogen. The resulting suspension was stirred
at 100 °C in a closed tube for 18 h (see ref. 5 for safety
measures). The solution was diluted with EtOAc (50 mL)
and extracted with H2O (50 mL) and brine (2 × 50 mL). The
(7) Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J. Org. Chem.
2003, 68, 692.
Synlett 2010, No. 11, 1688–1690 © Thieme Stuttgart · New York