Synthesis of macrocyclic ketones exploiting palladium-catalyzed activation of carboxylic acids as an enabling step

Article abstract of DOI:10.1039/c3nj40943k

The novel synthesis of macrocyclic arylketones via palladium-catalyzed cross-coupling of arylboronic acids and carboxylic acids, activated by the treatment with di(N-succinimidyl) carbonate, is disclosed. This allows the high yielding synthesis of various

Full text of DOI:10.1039/c3nj40943k

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Synthesis of macrocyclic ketones exploiting
palladium-catalyzed activation of carboxylic acids
as an enabling step†
Cite this: NewJ.Chem., 2013,
37, 961
Anant R. Kapdi*ab and Ian J. S. Fairlamb*a
Received (in Montpellier, France)
17th October 2012,
Accepted 10th January 2013
The novel synthesis of macrocyclic arylketones via palladium-catalyzed cross-coupling of arylboronic
acids and carboxylic acids, activated by the treatment with di(N-succinimidyl) carbonate, is disclosed.
This allows the high yielding synthesis of various functionalized arylketones, which can be converted
into macrocycles via a Mitsunobu protocol.
DOI: 10.1039/c3nj40943k
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Aryl ketones play a central role in the synthesis of a wide variety require stronger nucleophilic reagents such as Grignard or
of organic compounds. They are important building blocks in organolithium compounds. However, addition of the organo-
natural products as well as in functional materials (Scheme 1).1 metallic reagent to the ketone to form tertiary alcohols is the main
The classical routes to the synthesis of aryl ketones rely on the drawback of all these methods.6
reaction of various carboxylic acid derivatives with carbon
Metal-mediated processes have undergone tremendous develop-
nucleophiles making them some of the most common and ment in the last few decades. The application of transition-metal
efficient C–C bond forming reactions in organic synthesis.2 complexes as homogeneous as well as heterogeneous catalysts has
Acid chlorides are regarded as the most reactive carboxylic acid led to the development of simple and efficient methods for carbon–
derived electrophilic coupling partner. Organo-tin, -zinc, -copper, carbon and carbon–heteroatom bond formation.7 Such complexes
and -boron reagents which act as mild nucleophiles are the most have shown a wide range of applications such as in catalysis,8
common organometallic reagents employed for effecting such material synthesis,9,10 photochemistry and biological systems.11
transformations.3–5 Similarly, other less reactive acid derivatives More recently, palladium-catalyzed cross-coupling of acid chlorides
such as anhydrides, nitriles as well as amides (Weinreb amides) with boronic acids12 and organotin reagents13 has been reported.
Although, mild organotin reagents are less preferred over organo-
boronic acids, mainly due to their inherent toxicity. Conversely, the
availability, low toxicity and excellent shelf-life make organoboronic
acids an attractive alternative for this type of transformation.14
The utilisation of coupling reagents for the activation of
carboxylic acids has become an indispensable tool in organic
synthesis due to their ease of handling and high functional
tolerance. Mild coupling reagents such as DCC, HOBt and CDI
are known to cleanly convert carboxylic acids into stable inter-
mediates and have been employed efficiently in peptide
synthesis.15 Recently, Gooben and Ghosh reported a novel
palladium-catalyzed synthesis of arylketones from carboxylic acids
and organoboron reagents using pivalic anhydride as the coupling
reagent (Scheme 2).16 However, the protocol suffers from a major
Scheme 1 Arylketone containing natural products.
drawback as the use of pivalic anhydride makes it very difficult to
separate the product from the pivalic acid by-product formed
during the reaction.
An improved procedure was developed by Gooben and
Ghosh17 which utilises N-alkoxysuccinimides as an alternative
coupling partner due to their high stability and ease of handling.
Although such a methodology has been developed it is yet to be
applied for the synthesis of arylketones with further application
a Department of Chemistry, University of York, York, YO10 5DD, UK.
E-mail: ian.fairlamb@york.ac.uk
b Department of Chemistry, Institute of Chemical Technology, Matunga,
Mumbai 400019, India. E-mail: ar.kapdi@ictmumbai.edu.in;
Fax: +91 22-33611020; Tel: +91 22-33612682
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3nj40943k
c
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Scheme 2 Arylketone synthesis using pivalic anhydride.
towards the formation of macrocyclic ring systems. Herein we
report the novel synthesis of arylketones via palladium-catalyzed
cross-coupling of arylboronic acids and N-alkoxysuccinimide
esters of carboxylic acids. A protocol for the in situ activation
of carboxylic acids using di(N-succinimidyl) carbonate (DSC)17,18
has also been employed towards the synthesis of two novel
macrocyclic ketones.
At the outset of our studies, N-alkoxysuccinimide esters 7a
and 7b of carboxylic acids 6a and 6b were synthesized in the
presence of a mild coupling reagent DCC (Scheme 3).19 N-
Alkoxysuccinimides are stable intermediates which are reactive
enough to undergo smooth coupling reaction with different
nucleophilic reagents such as aryl boronic acids.
Scheme 4 Synthesis of substituted arylboronic acids.
Table 1 Ligand screening studies for arylketone synthesisa
In the literature Gooben and Ghosh have already shown that the
reactivity of N-alkoxysuccinimide esters in palladium catalysis is
poorer when triarylphosphines are used as ligands.17 This may
indicate that oxidative addition is the rate determining step which is
facilitated by increasing the electron density on the palladium
centre with sterically demanding and highly electron-rich phos-
phines such as tricyclohexylphosphine. Accordingly, to test the
reactivity of the esters several substituted arylboronic acids 9a–f
were synthesized with the view of obtaining arylketones (Scheme 4).
Borylation of different substrates proceeded in good yields
allowing access to sterically hindered aryl boronic acids. Incorpora-
tion of more labile silyl protecting groups (9c and 9e) enhances the
possibility of further functionalization of the cross-coupled product.
Initial studies were focussed on understanding the effect of
different ligands on the coupling of N-alkoxysuccinimides with
2-methoxyphenyl boronic acid (Table 1).
S. no. Ligand employed Amount of ligand (X mol%) Yieldb (%)
1
2
3
4
5
6
7
8
PPh3
P(o-Tol)3
DPPE
12
12
12
12
12
12
12
12
12
5
0
0
o2
o2
16
DPPB
X-Phos
P(tBu)3
SIPrÁHCl
MesÁHCl
PCy3
PCy3
PCy3
19
o2
o2
61
32
50
9
10
11
15
a
Conditions: 0.37 mmol N-alkoxysuccinimide, 0.41 mmol phenyl-
boronic acid, 5 mol% Pd(OAc)2, X mol% ligand, 0.74 mmol Na2CO3,
b
3.7 mmol H2O, 60 1C, 15 h. Isolated yields following chromatography
Triarylphosphines such as PPh3 and P(o-Tol)3 when employed
for catalyzing the above transformation led to complete recovery of
starting N-alkoxysuccinimides. Similar observations were made in
the case of diphosphines such as DPPE and DPPB. Highly electron-
rich ligands P(tBu)3 and X-Phos gave improved yields of the desired
products suggesting a definitive activating effect on the coupling
reaction. Interestingly, N-heterocyclic carbenes when employed as
ligands failed to furnish the desired cross-coupled product.
on silica gel.
Tricyclohexylphosphine gave the best yields as also suggested by
Gooben. The metal to ligand ratio in each of these transformations
was maintained at 1 : 2.4. Any alteration in the ratio of metal to
ligand (PCy3) brought about a drastic reduction in the yield of the
product.
With these optimum conditions in hand we then set about
exploiting the cross-coupling of N-alkoxysuccinimides 7a and
7b with different aryl boronic acids (9a–d). Unfortunately, 2,4,5-
trimethoxyphenylboronic acid 9b when cross-coupled with N-
alkoxysuccinimides under the standard conditions resulted in
quantitative formation of the hydrodeborylation product
(Scheme 5 and Table 2). This suggests that the rate of hydrolysis
of the organoboron species is much faster than the rate of
transmetallation. In contrast, a promising conversion of the
starting materials was observed when employing other substituted
arylboronic acids (9b–d). Interestingly, silyl-protected arylboronic
acid 9c gave a good yield from the cross-coupling utilising
Scheme 3 Synthesis of N-alkoxysuccinimide esters of carboxylic acids.
c
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relatively mild conditions,20–23 can later serve as coupling sites
for the macrocyclization to occur.‡ Synthesis of macrocyclic
ring structures is important due to their occurrence in biologi-
cally important natural products,24 polymers25 and polydentate
molecules.26 Macrocyclic ring size can vary considerably from
8–19 membered macrocyclic rings, in addition to supra-
molecular ring structures. The ring-strain associated with these
macrocyclic structures has been shown to reduce dramatically
moving from smaller rings (e.g. 7 to 8) to the larger 16- or
17-membered rings which exhibit the least ring strain.
However, in spite of these factors, suggesting that the for-
mation of larger rings would be favoured, the efficient synthesis
of such macrocyclic structures is still a synthetic challenge as
these rings need to overcome their high conformational
entropy – a particular challenge for alkyl-containing macro-
cyclic structures.27
To achieve the synthesis of macrocyclic ketones the deprotection
of the labile silyl protection was accomplished with tetra-
n-butylammonium fluoride (TBAF) in THF in near quantitative yield.
The subsequent step is crucial, and macrocyclisation of the diols
could be achieved using the Mitsunobu reaction. In the literature
formation of cyclic ethers via intramolecular Mitsunobu condensa-
tion has been shown to proceed in good yield.28 Accordingly, we
submitted the diols obtained from deprotection of the coupled
products to Mitsunobu conditions at high dilution. The reaction
was carried out in the presence of diisopropylazodicarboxylate
(DIAD) to give good yield of two novel 16- and 17-membered
macrocyclic ketones (Scheme 7). Development of such a methodo-
logy could facilitate the synthesis of more challenging naturally-
occurring compounds having similar structural motifs, such as
smenochromene D (likonides A and B), in the future.29
In summary we have reported a versatile protocol for the
synthesis of arylketones. In comparison to the available protocols
for arylketone synthesis the work presented in this manuscript
represents a valuable methodology for the efficient formation of
16- and 17-membered novel macrocyclic arylketones which could
be employed as a key step towards the synthesis of a variety of
natural products.
Scheme 5 Cross-coupling of N-alkoxysuccinimides.
Table 2 Pd-catalyzed synthesis of arylketonesa
Entry
R
From 7a (yieldb %)
From 7b (yieldb %)
1
2
3
4
2-Methoxy
2,4,5-Trimethoxy
4-Silyloxy
61 (10a)
0c
72 (10c)
71 (10e)
81 (10b)
0c
42 (10d)d
79 (10f)
4-Fluoro
a
Conditions: 0.37 mmol N-alkoxysuccinimide, 0.41 mmol phenyl-
boronic acid, 5 mol% Pd(OAc)2, 12 mol% PCy3, 0.74 mmol Na2CO3,
b
3.7 mmol H2O, 60 1C, 15 h. Isolated yields following chromatography
c
d
on silica gel. Hydrodeborylated product obtained. Addition product
10d obtained.
N-alkoxysuccinimide 7a, while desilylation followed by etherification
of the deprotected phenol with N-alkoxysuccinimide 7b occurred
resulting in poor yields of the coupled product 10d. The catalytic
system thus allowed the efficient synthesis of arylketones bearing
useful functionalities.
An efficient protocol for the in situ activation of carboxylic
acids using coupling reagent di(N-succinimidyl)carbonate (DSC)
followed by cross-coupling with arylboronic acid for the synth-
esis of arylketones in a one-pot procedure was developed by
Gooben and Ghosh.17 The formation of the intermediate
N-alkoxysuccinimide was found to proceed quantitatively. Func-
tionalized arylketones possessing labile functional groups are
synthetically important intermediates with the possibility of
further manipulation of the coupled product. The one-pot
procedure developed by Gooben provided us with an opportunity
to introduce labile functional groups such as an hydroxyl group in
the alkyl chain, thus enabling the development of an efficient
protocol for the synthesis of macrocyclic ketone motifs.
Following the literature procedure for the coupling of in situ
generated N-alkoxysuccinimides of 12-hydroxy dodecanoic acid
11 with arylboronic acids 9a, 9c and 9e using DSC as the
coupling reagent a variety of differently substituted arylketones
were synthesized in good yields (Scheme 6).
Strategically, the introduction of an hydroxyl group can act
as a useful handle for formation of macrocyclic motifs. The
successfully synthesized arylketones 12a–c containing labile
silyl protecting groups, which can be deprotected under
‡ Synthesis of 1-(4-[1-(tert-butyl)-1,1-dimethylsilyl]oxyphenyl)-12-hydroxy-1-dode-
canone (12b): a 10 mL flask was charged with [Pd(OAc)2] (15.00 mg, 0.05 mmol,
5.0 mol%), tricyclohexylphosphine (33.00 mg, 0.12 mmol, 12 mol%), 12-hydro-
xydodecanoic acid 11 (0.21 g, 1.0 mmol), Na2CO3 (0.21 g, 2.0 mmol), and di(N-
succinimidyl) carbonate (0.33 g, 1.3 mmol). The reaction vessel was purged with
argon and degassed THF (5 mL) was added. The yellow mixture was stirred at
60 1C for a few minutes until the gas evolution had ceased. Then, the solution was
cooled down to 25 1C, a solution of 4-silyloxyphenylboronic acid 9c (0.30 g,
1.2 mmol) in THF (3 mL) was added and the purple reaction mixture was stirred
at 60 1C for 15 h. The reaction slurry was then poured into water (10 mL) and
extracted 3 times with 10 mL portions of ethyl acetate. The combined organic
layers were dried over MgSO4, filtered, and the volatiles were removed in vacuo.
The residue was purified by column chromatography with hexane : EtOAc (60 : 40)
to give the title compound in good yield (0.27 g, 79%) as colourless oil. dH (400
MHz, CDCl3) 0.16 (s, 6H), 0.91 (s, 9H), 1.25–1.40 (m, 14H), 1.49–1.51 (m, 2H),
1.63–1.65 (m, 2H), 2.84 (t, 2H, J = 1.5 Hz), 3.56–3.58 (m, 2H), 6.80 (d, 2H, J =
7.8 Hz), 7.82 (d, 2H, J = 8.0 Hz); dC (100 MHz, CDCl3) À4.4, 18.4, 24.5, 25.5, 25.6,
29.3, 29.4, 29.5, 32.7, 38.0, 63.0, 119.8, 130.1, 130.6, 160.0, 199.4; LRMS (CI) m/z
(rel.%): 407 (M+ + H+, 100%), 331 (10); HRMS (CI) m/z exact mass calculated for
C24H43O3Si + H+ 407.3016, found 407.2976.
Scheme 6 Synthesis of functionalized arylketones for macrocyclization.
c
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