Palladium-catalyzed c-S activation/aryne insertion/coupling sequence: Synthesis of functionalized 2-quinolinones

Article abstract of DOI:10.1002/anie.201310340

The insertion of an aryne into a C-S bond can suppress the addition of an S nucleophile to the aryne in the presence of palladium. Catalyzed by Pd(OAc)₂, a wide range of α-carbamoyl ketene dithioacetals readily react with arynes to selectively afford functionalized 2-quinolinones in high yields under neutral reaction conditions by a C-S activation/aryne insertion/intramolecular coupling sequence. The attractive feature of the new strategy also lies in the versatile transformations of the alkythio-substituted quinolinone products. Within range: Under palladium catalysis a wide range of α-carbamoyl ketene dithioacetals readily react with arynes to selectively afford 2-quinolinones in high yields under neutral reaction conditions by the title sequence (see scheme). An attractive feature of the new strategy also lies in the versatile transformations of the alkylthio-substituted quinolinones.

Full text of DOI:10.1002/anie.201310340

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Angewandte
Communications
DOI: 10.1002/anie.201310340
Synthetic Methods
À
Palladium-Catalyzed C S Activation/Aryne Insertion/Coupling
Sequence: Synthesis of Functionalized 2-Quinolinones**
Ying Dong, Bangyu Liu, Peng Chen, Qun Liu,* and Mang Wang*
À
Abstract: The insertion of an aryne into a C S bond can
suppress the addition of an S nucleophile to the aryne in the
presence of palladium. Catalyzed by Pd(OAc)2, a wide range
of a-carbamoyl ketene dithioacetals readily react with arynes
to selectively afford functionalized 2-quinolinones in high
À
yields under neutral reaction conditions by a C S activation/
aryne insertion/intramolecular coupling sequence. The attrac-
tive feature of the new strategy also lies in the versatile
transformations of the alkythio-substituted quinolinone prod-
ucts.
À
À
T
ransition-metal-catalyzed C S bond activation for C C and
C–heteroatom bond formation has fascinated organic chem-
ists for decades.[1] A variety of organosulfur compounds have
been utilized and have great potential in these processes[1–3]
because of their ready availability, stability, and structural
diversity, as compared to the corresponding organic halide
coupling partners.[4] Cross-coupling chemistry with thioor-
ganics along with new reaction patterns, exceptional selectiv-
ity, or unique reactivity would be highly desirable.
Scheme 1. Reactions of thioorganics with benzyne.
bond. Furthermore, the expected products are 2-quinolinones
(3) which have provoked great interest in chemical and
biological fields.[8] However, the challenge of this strategy lies
in avoiding the addition of the strongly nucleophilic sulfur
atom in the substrates to the arynes (Scheme 1A), and instead
Inspired by palladium-catalyzed desulfitative coupling of
thioesters,[1c,2a–d] we recently became interested in transition-
favoring insertion of the arynes into the C S bond.[9,10] To the
À
À
À
À
metal-catalyzed C S bond cleavage for C C bond formation
during our research[5] on ketene dithioacetals, which are easily
prepared and widely applied as organic intermediates.[6] We
best of our knowledge, transition-metal-catalyzed C S bond
cleavage for aryne insertion has been seldom reported.[10]
Herein, we report that arynes can react with ketene dithio-
À
À
have already achieved copper-catalyzed desulfitative C C
acetals by palladium-catalyzed C S bond activation followed
cross-coupling of a-oxo ketene dithioacetals with arylboronic
acids,[3a] and then palladium-catalyzed/copper-mediated
desulfitative annulation of 2-methylthiobenzofurans with 2-
by cyclization to produce 2-quinolinones, but they remain
inactive towards the nucleophilic S-containing group (Scheme
1B). The new synthetic method is also highlighted by the
versatile transformations of the 4-functionalized 2-quinoli-
nones, which are not easily obtained starting from the
corresponding organic halides because of the difficulty in
the preparation of geminal dihalides.
hydroxyphenylboronic acids.[3b] More recently, a C S bond
À
activation protocol for Heck-type cyclization of a-alkenoyl
ketene dithioacetals was also developed in our group.[3c] To
take advantage of the synthetic power of functionalized
ketene dithioacetals[3,5,6] and the tremendous applications of
arynes in cyclization reactions,[7] we envisioned the palladium-
Initially, the reaction of the a-carbamoyl ketene dithio-
acetal 1a with o-(trimethylsilyl)phenyl triflate (2a), the
benzyne precursor, was selected for screening the reaction
conditions. Upon treatment of 1a with 2a in the presence of
CsF in a mixed MeCN or MeCN/toluene solvent at 808C
under N2 and using 10 mol% of a palladium catalyst (Table 1,
entries 1–8), the desired 2-quinolinone 3a[11] was isolated in
20–63% yield after 18 hours. However, 3a was accompanied
by an E/Z isomer mixture of mixed ketene dithioacetals [4a
and 4a’ (see Ref. [12] for structures) 5–30% overall yields].
The formation of 4a and 4a’ may result from the addition of
the sulfur atom of 1a to benzyne, thus leading to a zwitterionic
intermediate which is converted into 4 after a water quench
(for detailed mechanism, see the Supporting Informa-
tion).[9,10] When we carried out the reaction of 1a and 2a in
the absence of a palladium catalyst under otherwise identical
reaction conditions, a mixture of 4a and 4a’ was isolated in
À
catalyzed C S activation as the key to developing an
annulation between arynes and a-carbamoyl ketene dithio-
À
acetals (1; Scheme 1) by the insertion of an aryne into a C S
[*] Y. Dong, B. Liu, P. Chen, Prof. Q. Liu, Prof. M. Wang
Department of Chemistry, Northeast Normal University
Renmin Street 5268, 130024 Changchun (P. R. China)
E-mail: wangm452@nenu.edu.cn
liuqun@nenu.edu.cn
[**] We gratefully acknowledge the National Natural Sciences Founda-
tion of China (21172031, 21272034 and 21372040), and the New
Century Excellent Talents in Chinese University (NCET-11-0613) for
financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310340.
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Table 1: Screening the reaction conditions.[a]
Table 2: Scope of the ketene dithioacetals 1.[a]
Entry Products 3
Yield [%][b]
92
Entry Pd
Ligand
(mol%)
2a
CsF
Toluene/ Yield
[%][b]
1
2
3
4
5
1a, 3a, R2 =Bn
(equiv) (equiv) MeCN
1b, 3b, R2 =4-MePhCH2 86
1
Pd(OAc)2
–
–
–
–
–
–
–
–
1.5
1.5
1.5
2
3
3
3
3
3
3
3
3
3
4
5
5
5
5
5
5
5
0:1
1:1
3:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
20
33
35
36
41
38
63
54
92
90[c]
87
1c, 3c, R2 =Ph
1d, 3d, R2 =nBu
1e, 3e, R2 =Cy
85
67
73
2
3
4
5
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)
6
7
1 f, 3 f, R2 =Bn
82
76
1g, 3g, R2 =nBu
6
7
8
9
10
11
[Pd(PPh3)4]
[PdCl2(PPh3)2]
[PdCl2dppe]
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
dppf (15)
dppf (15)
Xantphos
(15)
8
9
10
1h, 3h, R2 =Bn
1i, 3i, R2 =Ph
1j, 3j, R2 =nBu
85
76
79
3
12
13
14
15
16
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PCy3 (30)
PPh3 (30)
dppf (8)
dppf (15)
dppf (15)
3
3
3
3
3
5
5
5
5
5
1:1
1:1
1:1
1:1
1:1
26
49
53[d]
28[e]
<5[f]
11
12
1k, 3k, R2 =Bn
1l, 3l, R2 =Ph
82
79
[a] Reaction conditions: 1a (0.3 mmol), 2a, CsF, Pd (10 mol%), toluene/
MeCN (4 mL). Reaction was performed in a sealed tube at 808C under
N2 for 18 h. 2a was added in six increments (3 hꢀ6) to avoid
homocoupling of benzyne. [b] Yields of isolated products. [c] Reaction
was performed in a flask with a condenser under N2. [d] Used 5 mol% of
Pd(OAc)2. [e] At 508C. [f] At room temperature.
13
14
1m, 3m
74
1n, 3n + 3h
27 + 20
63% yield in a ratio of 1:3; no benzyne annulation product 3a
was observed in this case. On the contrary, the use of a ligand
for the palladium catalyst dramatically improved the aryne
annulation and the yield of 3a was increased to 92% by using
15% of 1,1’-bis(diphenylphosphino) ferrocene (dppf,
entries 9 and 10) as the ligand. Under these reaction
conditions, 4a and 4a’ were not detected. Clearly, both
palladium and the ligand play a key role in the insertion of
15
16
1o, 3o, R1 =4-NO2Ph
1p, 3p, R1 =PhCO
88
80
À
benzyne into a C S bond. Other phosphine-containing
17
18
1q, 3q
1r, 3r
73
ligands, including PCy3, PPh3, and 4,5-bis(diphenylphos-
phino)-9,9-dimethylxanthene (Xantphos) were found to be
less efficient than dppf for this annulation (entries 11–13).
Additionally, either decreasing the amount of the catalyst
(entry 14) or lowering the reaction temperature resulted in
unsatisfactory yields of 3a (entries 15 and 16).
<15[c]
[a] Reaction conditions: 1 (0.3 mmol), 2 (0.9 mmol), CsF (1.5 mmol),
Pd(OAc)2 (0.03 mmol), dppf (0.045 mmol), toluene/MeCN (4 mL, 1:1,
v/v) in a sealed tube. 2 was added in six increments (0.15 mmol/3 h).
[b] Yields of isolated products. [c] Yield based on 1H NMR spectroscopy.
3r could be detected by the NMR and HRMS-ESI studies of the product
mixture. However, the isolation of pure 3r failed.
With the optimized reaction conditions in hand (Table 1,
entry 9), we explored the scope of this palladium-catalyzed
selective annulation between the dithioacetals 1 and 2a. As
described in Table 2, a series of a-carbamoyl-a-aryl ketene
dimethylthioacetals (1) bearing a N-protecting group, includ-
ing both N-alkyl (R2 = Bn, Cy and nBu) and N-aryl groups
(R2 = Ph), afforded the desired 2-quinolinones 3a–j in good
yields (entries 1–10). For substrates 1k and 1l, bearing an a-
alkyl group, the reaction afforded the desired products 3k
(82%) and 3l (79%), respectively (entries 11 and 12).
Furthermore, the dithioacetal 1m, having an electron-with-
drawing group (R1 = PhCO) at the a position, also worked
well with 2a to give 3m in 74% yield (entry 13). In
comparison, the reaction was more complex for 1n, which
does not have a substituent at the a-position (R1 = H), and
thus afforded the desired product 3n in only 27% yield
(entry 14) along with 3h in 20% yield. In this case, the
formation of 3h may result from the first a-phenylation of 1n
[6d]
À
with benzyne by a palladium-catalyzed a-C H activation
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to give 1h, and subsequent annulation with benzyne (for
details, see the Supporting Information). In addition, the
ketene dithioacetals 1o–q, having an ethylthio functional
group, also proved to be suitable substrates for this process
(entries 15–17). Finally, the reaction was found to be sensitive
to the substrate 1r bearing a free NH2, and 3r was only
detected by NMR and HRMS-ESI studies of the reaction
mixture after running the reaction for 18 hours (entry 18).
Next, we turned to extending the scope of the annulation
with respect to the arynes. Gratefully, all arynes, bearing both
electron-withdrawing and electron-donating groups, were
compatible with the standard reaction conditions, though
moderate yields were often obtained (Table 3; 3s–u, 3x, and
Table 3: Scope of arynes 2.[a]
Scheme 2. Proposed mechanism for palladium-catalyzed annulation of
1 with benzyne. Ligands omitted for clarity.
À
A into the C S bond of 1 affords the intermediate C, perhaps
via the PdIV B. Then, the intramolecular substitution of C
gives rise to a seven-membered heteropalladacycle D along
with the loss of methanethiol captured by benzyne. Finally,
reductive elimination of D affords the observed annulation
products 3 and regenerates the Pd0 catalyst for the next cycle.
In comparison, the first palladium oxidative addition step in
path b is different from that in path a and involves the direct
insertion of Pd0 into the C S bond of 1 to generate the
À
intermediate E.[3] Then, E reacts with the aryne to afford C,
which goes on to the products 3 by a similar process as in
path a. During the reactions, a second, sacrificial equivalent of
benzyne was required for scavenging the liberated methane-
thiol as the reaction proceeds. PhSMe can be detected by
HRMS-ESI analysis of the reaction mixture ([M+H+], calcd,
125.0419; found, 125.0440). However, we do not have any
particular evidence for favoring either of these pathways at
the presence.
[a] Reaction conditions: 1 (0.3 mmol), 2 (1.5 mmol), CsF (2.1 mmol),
Pd(OAc)2 (0.03 mmol), dppf (0.045 mmol), toluene/MeCN (4 mL, 1:1,
v/v in a sealed tube, 2 was added in six increments (0.25 mmol/3 h).
Yields of isolated products. [b] Yields in parenthesis were obtained by
using 0.9 mmol of 2 and 1.5 mmol of CsF. [c] The by-products 4b and
4b’ were isolated in 26% yield. [d] The ratio of two isomers, based on
1H NMR spectroscopy, are included within parentheses.
To get more information on the selective insertion of
À
3y, yields within parenthesis). The yields of 3 could be
increased (77–87%) when 5 equivalents of an aryne were
used (3s–w, 3z/3z’, and 3aa/3aa’). However, in the case of the
aryne 2c, having an electron-withdrawing group, excess aryne
did not benefit the reaction but led to the formation of mixed
ketene dithiacetals (4b/4b’)[12] in 26% yield. In addition,
when the unsymmetrical aryne, 4-methoxy-2-(trimethylsilyl)-
phenyl trifluoro methanesulfonate (2d) was used in the
annulation, the products 3z/3z’ and 3aa/3aa’ were obtained as
a mixture of two isomers.
arynes into the C S bond in the presence of palladium, we
performed the reaction of N-benzyl-2-(methylthio)benz-
amide (5) with benzyne under the standard reaction con-
ditions. As shown in Scheme 3, the compound 6, resulting
On the basis of the above results and the known work on
the paladium-catalyzed reactions involving arynes,[7] two
possible mechanisms (path a and path b, Scheme 2) are
suggested to account for the present aryne annulation
processes. Clearly, the formation of the arylpalladium(II)
intermediate C is the key for the annulation. In path a, the Pd0
complex initially undergoes oxidative cyclization with the
aryne to generate the palladacycle A. Subsequent insertion of
Scheme 3. Reaction of o-(methylthio)benzamide (5) with benzyne.
from addition of sulfur to benzyne, was isolated as the main
product. The product 7, which underwent sequential insertion
À
of benzyne into the C S bond and cyclization, was isolated
only in 32% yield.
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It is clear that the dithioacetals 1 have a unique selectivity
toward the palladium catalyst in two competing processes, the
insertion versus the addition. Thus, a practical palladium-
catalyzed annulation to rapidly synthesize a variety of 2-
quinolinones (3) has been developed. It is noteworthy that the
alkylthio functional group retained in 3 should enable further
modification of them (Scheme 4). To highlight the synthetic
Experimental Section
General procedure for the palladium-catalyzed annulation of 1 with 2
(taking the reaction of 1a and 2a as example): The dithioacetal 1a
(112 mg, 0.3 mmol), Pd(OAc)2 (7 mg, 0.03 mmol), and dppf (25 mg,
0.045 mmol) were added, in sequence, to a dried pressure tube. The
tube was transferred into a glove box and then CsF (228 mg,
1.5 mmol) and 1 mL of mixed solvent (MeCN/toluene, 1:1) were
added. The tube was sealed by a rubber septum. After taking the tube
out of the glove box, the mixture was stirred at 808C. 2-(Trimethylsi-
lyl)phenyl triflate (2a; 0.218 mL, 0.9 mmol) was pre-dissolved in
3 mL of MeCN/toluene (1:1) and was added by syringe to the reaction
mixture in six increments over an 18 h period (0.15 mmol/3 h). Then,
the reaction mixture was poured into ice water (10 mL) and extracted
with CH2Cl2 (3 ꢀ 6 mL). The combined organic extracts were dried
over anhydrous MgSO4, filtered, and concentrated under reduced
pressure to yield the crude reaction mixture, which was purified by
silica gel chromatography (20:1, petroleum ether/ethyl acetate) to
give 3a (111 mg, 92%) as a yellow crystal. Rf 0.36 (4:1, petroleum
ether/ethyl acetate).
Received: November 28, 2013
Published online: February 20, 2014
À
Keywords: annulation · arynes · C S activation · heterocycles ·
synthetic methods
.
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Scheme 4. Applications of the alkylthio-substituted quinolinones 3.
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yield. Additionally, the direct substitution[5e] of the 4-meth-
ylthio group of 3m with phenylmethanamine was also
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(Scheme 4b). Another application of 3 was presented in the
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À
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À
insertion of arynes into the C S bond. This process represents
the first example for the reaction of arynes with thioorganics
À
based on palladium-catalyzed C S bond activation. The
functionalized 2-quinolinone products are expected to be
useful building blocks in library synthesis for the screening of
potential bio-/pharmacological compounds. We believe that
À
the discovery of the facile C S bond activation should pave
the way for establishing some new and efficient palladium-
catalyzed transformations. Further work on the applications
and extension of the scope of the protocol, as well as the
detailed reaction mechanism are currently under investiga-
tion in our laboratory.
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[11] For crystal data for 3a, see the Supporting Information.
[12] Structures of 4 and 4’:
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