Concise synthesis of cyclic carbonyl compounds from haloarenes using phenyl formate as the carbonyl source

Article abstract of DOI:10.1039/c4cc09413a

Various cyclic carbonyl compounds were concisely synthesized by carbonylative cyclization of haloarenes bearing nucleophilic moieties under Pd catalysis. A broad substrate scope and a feasible large-scale synthesis clearly demonstrate the high applicability of the reaction as a general, user-friendly method for access to cyclic carbonyl compounds.

Full text of DOI:10.1039/c4cc09413a

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Concise synthesis of cyclic carbonyl compounds
from haloarenes using phenyl formate as the
carbonyl source†
Cite this:DOI: 10.1039/c4cc09413a
Received 25th November 2014,
Accepted 6th December 2014
Hideyuki Konishi, Hiroki Nagase and Kei Manabe*
DOI: 10.1039/c4cc09413a
www.rsc.org/chemcomm
Various cyclic carbonyl compounds were concisely synthesized
by carbonylative cyclization of haloarenes bearing nucleophilic moieties
under Pd catalysis. A broad substrate scope and a feasible large-scale
synthesis clearly demonstrate the high applicability of the reaction as a
general, user-friendly method for access to cyclic carbonyl compounds.
Metal-catalyzed carbonylation using carbon monoxide (CO) is estab-
lished as a fundamental synthetic method for the construction
of carbonyl compounds.1 Carbonylative cyclization of haloarenes
containing a nucleophilic moiety, under an atmosphere of CO, is
one application of metal-catalyzed carbonylations that can afford
Scheme 1 Carbonylative cyclization using phenyl formate as the carbonyl
source.
Although the use of CO surrogates for carbonylative cyclization
various cyclic carbonyl compounds in a single step.2 Due to the would provide useful methods to synthesize cyclic carbonyl com-
importance of these compounds as useful building blocks and pounds, it has not been explored extensively. Since side reactions
biologically active compounds, it is highly desirable to develop a might occur between the CO surrogate and the nucleophilic moieties
practical and robust method for their synthesis.
of the haloarene substrates, to form other formyl compounds that
Because CO gas is difficult to handle and highly toxic, several cannot generate CO, identification of appropriate CO surrogates and
molecules that can act as CO surrogates have been investigated reaction conditions is the key to success. We describe herein a
and the subject continues to attract much attention from general, practical synthetic method for cyclic carbonyl compounds
synthetic chemists.3 These molecules include formic acid,4 via a carbonylative cyclization under Pd catalysis using phenyl
acetic formic anhydride,5 formic acid esters6 and amides,7 metal formate as a commercially available and inexpensive CO surrogate
carbonyls,8 aldehydes,9 acyl chlorides,10 and silacarboxylic (Scheme 1). The reaction can be applied to haloarenes bearing
acids.11 Recently, we and Tsuji et al. have reported that phenyl carbon, nitrogen, and oxygen nucleophiles under relatively mild
formate could act as an easy-to-handle CO surrogate by generating conditions, demonstrating its generality and broad substrate scope.
CO through reaction with weak bases, and that the CO thus
We chose iodoarene 1a, containing a tethered malonate
generated could be used for Pd-catalyzed aryloxycarbonylation.12 moiety, as the model compound. In the pioneering work of
We have also developed 2,4,6-trichlorophenyl formate13 and Negishi, the carbonylative cyclization of 1a was conducted under
N-formylsaccharin14 as highly reactive CO surrogates useful a pressurized CO atmosphere (40 atm).16 While this demon-
for carbonylative transformations. The use of formic acid strated the feasibility of the reaction, it is desirable to eliminate
derivatives as CO surrogates does not require external CO gas the need for CO gas. Later, Morimoto achieved this by applying
and also benefits from a feasible scale-up, without the need for aldehydes to the reaction as CO surrogates.17 Although this
specialized pressure-resistant equipment, as well as the effi- method avoided the use of gaseous CO, a high temperature
cient production and consumption of CO within the reaction (130 1C) was required for the generation of CO from the alde-
system, which ensures a high level of safety and practicality.15 hydes, which could impact the functional group tolerance of the
method and, thus, limit the scope. We chose phenyl formate as
the CO surrogate, because it is relatively stable and easy to
handle and is easily converted to CO, as discussed above.
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku,
Shizuoka 422-8526, Japan. E-mail: manabe@u-shizuoka-ken.ac.jp
Firstly, the solvent was screened for the model reaction of 1a
† Electronic supplementary information (ESI) available: Experimental details and
characterization data. See DOI: 10.1039/c4cc09413a
in the presence of Pd(OAc)2, Xantphos,18 and NEt3 (Table 1).
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Table 1 Effect of solvents on carbonylative cyclizationa
Table 3 Optimization of reaction conditions for carbonylative cyclization
of bromoarene 1ba
Entry
Ligand (mol%)
Yield (%)
Entry
Solvent
Yield of 3 (%)
Yield of 4 (%)
1
2
3
4
Xantphos (6)
Trace
87
93
P(t-Bu)3ÁHBF4 (12)
P(t-Bu)3ÁHBF4 (15)
P(t-Bu)3ÁHBF4 (18)
1
2
3
4
5
6
7
Toluene
DCE
THF
CH3CN
DMF
NMP
7
24
7
53
59
57
81
18
38
93
15
29b
26
a
The reaction was performed using bromoarene 1b (0.30 mmol), 2
(2.0 equiv.), Pd(OAc)2 (3 mol%), ligand, and NEt3 (2.0 equiv.) in DMSO
(1.0 mL) at 80 1C for 5 h. The yields of 3 are isolated yields.
12
Trace
DMSO
a
The reaction was performed using iodoarene 1a (0.30 mmol), 2
(2.0 equiv.), Pd(OAc)2 (3 mol%), Xantphos (6 mol%), and NEt3 (2.0 equiv.)
in solvent (1.0 mL) at 80 1C for 5 h. The yields of 3 and 4 are isolated
revealed that DPPF and Xantphos afforded the best yield for 3,
with the yield deteriorating for others (entries 8–13). A brief
examination of the Pd/P ratio showed that a five-fold amount of
phosphino group to Pd metal was most effective for the reaction,
with the yield of 3 reaching 84% (entry 14). The reason for 1/5 as
the best Pd/P ratio is unclear at this moment.
We next attempted to apply the reaction to bromoarene 1b
(Table 3), as bromoarenes are easier to access and less expen-
sive than iodoarenes. However, only a trace amount of 3 was
detected (entry 1). Most alterations to the reaction parameters,
such as the temperature and base, to improve the yield were
b
yields. NMR yield (mesitylene as an internal standard).
To our delight, polar solvents generally afforded the desired
cyclic carbonyl product 3 in moderate to high yield, without the
use of a high pressure of CO gas, at 80 1C (entries 4–7). However,
in most cases, this was accompanied by the formation of
phenoxycarbonylated byproduct 4. This could be ascribed to
the competing intermolecular attack of a phenoxide ion, gene-
rated from 2, on the Pd intermediate, rather than the desired
intramolecular attack of the tethered nucleophile. Gratifyingly,
the use of DMSO was effective for the selective formation of 3
(entry 7), and was thus revealed to be the optimal solvent.
Since ligands greatly affected the course of our previously
developed carbonylative transformations, a ligand screening was
conducted (Table 2). In the absence of ligands, a low conversion of
1a was obtained (entry 1). The monodentate triarylphosphines and
triaryl phosphite gave 3 in a higher yield than trialkylphosphines
and XPhos (entries 2–7). Screening of bidentate phosphines
19
in vain. However, to our delight, the use of P(t-Bu)3ÁHBF4
drastically improved the yield, which soared to 87% (entry 2).
By varying the amount of the ligand used, 15 mol% was found
to be optimum (entry 3).
With the optimal conditions for both iodo- and bromoarenes in
hand, a variety of haloarenes with different nucleophilic moieties
were screened to examine the scope of the carbonylative cyclization
(Table 4). Malonate 5, with a tether containing one more carbon,
reacted to afford tetralone 6, albeit in a moderate yield (entry 1).
Benzamide derivatives 7 and 9 gave phthalimides 8 and 10 in high
yield (entries 2 and 3). Iodoarene 11, bearing a different nitrogen
nucleophile, was smoothly converted to 1H-isoindol-1-one 12
(entry 4). Indole-substituted bromoarene 13 efficiently reacted to
afford an interesting tetracyclic product 14 (entry 5). Aliphatic alcohols
15a and 15b, although they were deemed to be difficult substrates due
to a potential competing transesterification with phenyl formate,
gratifyingly afforded phthalide 16 in good yield (entries 6 and 7).
The reaction of 2-iodobenzoic acid (17) afforded a low yield of phthalic
anhydride (18) (entry 8), which could be ascribed to the low nucleo-
philicity of the carboxylate ion. To demonstrate the reaction for
another class of oxygen nucleophiles, several anilides were tested
for the synthesis of 4H-3,1-benzoxazin-4-one derivatives, a class of
compounds that are known to have interesting bioactivities.20 The
synthesis of several 4H-3,1-benzoxazin-4-one derivatives was thus
successfully performed (entries 9–16), which was the novel method
using a CO surrogate.21 In some cases, DMF was found to be the
optimal solvent (entries 9–14), which is discussed later, while sub-
stitution with electron-donating or -withdrawing groups did not
greatly affect the reaction, indicating a broad substrate scope.
The catalytic reaction did not require external CO gas or
pressure-resistant equipment, demonstrating a high level of safety
Table 2 Effect of ligands on carbonylative cyclizationa
Entry
Ligand
Yield of 3 (%)
Yield of 4 (%)
1
2
3
4
5
6
7
8
—
PPh3
PCy3
P(t-Bu)3ÁHBF4
P(OPh)3
P(4-F-C6H4)3
XPhos
DPPE
DPPP
DPPB
DPPPE
DPPF
Xantphos
Xantphos
Xantphos
14
76
5
40
72
70
43
5
26
22
53
81
81
84
79
Trace
8
Trace
16
4b
6b
2b
Trace
9
2b
10
11
12
13
14c
15d
2b
12
5
Trace
Trace
Trace
a
The reaction was performed using iodoarene 1a (0.30 mmol),
2
(2.0 equiv.), Pd(OAc)2 (3 mol%), ligand (Pd/P = 1/4), and NEt3 (2.0 equiv.)
in DMSO (1.0 mL) at 80 1C for 5 h. The yields of 3 and 4 are isolated yields.
b
d
NMR yield (mesitylene as an internal standard). c Pd/P = 1/5. Pd/P = 1/6.
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Table 4 Scope of substrates for carbonylative cyclizationa
Yield
(%)
Entry Substrate
1
Ligandb Product
A
54
Scheme 2 Gram-scale synthesis of biologically active compound 36.
2
3
A
B
86
93
These results strongly indicate that the reaction proceeds along
a pathway from 4 to 3, probably through a base-catalyzed
Dieckmann condensation under the catalytic reaction condi-
tions. Similarly, the reaction of isolated 37 also afforded ring-
closing product 20 in high yield (Scheme 3(b)).
4
A
89
The present mechanism is assumed to proceed as shown in
Scheme 4. We believe that the carbonylation step proceeds in a
similar manner to the previously reported Pd-catalyzed alkoxy-
carbonylation.12a Two pathways could be considered for the
nucleophilic attack, one of which proceeds via an intramolecular
attack of the tethered nucleophilic moiety on the acylpalladium
intermediate (Scheme 4, path A). The other proceeds via the
formation of the phenoxycarbonylated byproduct by nucleophilic
attack of a phenoxide ion, generated in situ, which is followed by
intramolecular attack of the tethered nucleophile on the carbonyl
group of the byproduct (Scheme 4, path B). The presence of the
latter path was confirmed experimentally for the reactions of
1 and 19, based on the results shown in Scheme 3. We assume
that the presence of path B allows the reaction to occur without
the need for high CO pressure as, while the reported reaction of 1a
only proceeded under high CO pressure,16 the present method
5
B
88
6
7
A
B
60
70
8
A
22c
9d
A
A
A
63
75
91
10d
11d
12d
13d
14d
A
A
A
81
80
76
15
16
A
A
61
76
a
The reaction was performed using substrate (0.30 mmol), 2 (2.0 equiv.),
Pd(OAc)2 (3 mol%), ligand (Pd/P = 1/5), and NEt3 (2.0 equiv.) in DMSO (1.0 mL)
at 80 1C for 5 h. The yields of the product are isolated yields. b A, Xantphos;
B, P(t-Bu)3ÁHBF4. c NMR yield (mesitylene as an internal standard). d DMF
was used as the solvent.
and expediency. To increase its practicality, a large-scale synthesis
of biologically active compound 36, which inhibits the growth of
prostate cancer cells,22 was conducted (Scheme 2). A gram-scale
synthesis of 36 proceeded with 70% yield to afford 1.77 g in a
single run.
To get insight into the reaction mechanism of the carbonyl-
ative cyclization, the reaction was quenched after 1 h so that
it could be analyzed in its early stages. Byproduct 4 was
observed by NMR in 26% yield, along with cyclized product 3
(Scheme 3(a)). Furthermore, when 4 was isolated and sub-
jected to the catalytic reaction conditions or conditions without
the Pd catalyst, 3 was obtained in 90% yield (Scheme 3(b)).
Scheme 3 Formation of byproduct 4 and conversion of 4 and 37.
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Scheme 4 Assumed reaction mechanism.
does not require this. Therefore, phenyl formate is not simply a
CO surrogate, but it also generates phenol during the reaction,
which promotes the reaction under mild conditions.23
In conclusion, a variety of cyclic carbonyl compounds could
be accessed via a concise, Pd-catalyzed carbonylation and
cyclization of haloarenes bearing nucleophilic moieties. All
the reactions could be performed using phenyl formate as a
CO surrogate, eliminating the need for external CO gas, demon-
strating high levels of efficiency and practicality. Notably, the
catalytic reaction provided several biologically active compounds,
such as 4H-3,1-benzoxazin-4-one derivatives. This general, user-
friendly carbonylative cyclization protocol for the synthesis of
cyclic carbonyl compounds would be preferable to that using CO
gas, and will accelerate the generation of libraries containing a
wide array of cyclic carbonyl products.
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one using aniline, isocyanate, and Mo(CO)6 as a CO surrogate.
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This work was partly supported by the Uehara Memorial
Foundation and Platform for Drug Discovery, Informatics, and
Structural Life Science from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
Notes and references
¨
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Int. Ed., 2009, 48, 4114.
Buchwald, Angew. Chem., Int. Ed., 2007, 46, 8460.
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