Full text of DOI:10.1021/acs.orglett.8b01890

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Ruthenium- and Rhodium-Catalyzed Chemodivergent Couplings of
Ketene Dithioacetals and α‑Diazo Ketones via C−H Activation/
Functionalization
Manman Wang,† Lingheng Kong,‡,§,∥ Qiyue Wu, and Xingwei Li*
,∥
†
,†,‡
†Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, Collaborative Innovation Center of Henan Province
for Green Manufacturing of Fine Chemicals, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang
4
‡
53007, China
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
University of Chinese Academy of Sciences, Beijing 100049, China
§
*
S Supporting Information
ABSTRACT: Chemodivergent coupling of α-acylketene dithioacetals with diazo compounds has been realized under catalyst
control. The Ru(II)-catalyzed C−H activation occurred at the olefinic position, and 1:2 coupling with α-diazoketoesters leads to
furfurylation. In contrast, the Rh(III)-catalyzed C−H functionalization occurred at both the olefinic and the ortho C(aryl)−H
positions, and [4 + 2] annulation afforded naphthalenones. Synthetic applications have been performed to demonstrate the
usefulness of the coupling system.
C−H activation of arenes has been established as an
Scheme 1. C−H Activation of α-Oxoketene Dithioacetals
increasingly important strategy for the construction of complex
1
organic products. In particular, high-valent complexes of
Ru(II) and Rh(III) have exhibited high catalytic activity in
1f,g,i
functionalization of a diverse array of arenes.
Despite
tremendous progress, with the presence of different types of
C−H bonds in arenes, the regio- and chemoselectivity
represents a major challenge. While the ortho selectivity of
C−H activation can be readily realized by taking advantage of
2
a directing group, the chemoselectivity of C−H activation can
be a challenge. Olefinic and aryl C−H bonds are typical
2
subjects in C(sp )−H activation, and the differentiation of
these C−H bonds represents a fundamental topic, especially
3
when the C(olefinc)−H and C(aryl)−H bonds are com-
paratively reactive. The selective functionalization of these
bonds leads to molecular diversity, especially under simple
condition control.
contrast, C(aryl)−H activation is generally favored by a high-
valent metal such as Rh(III) via cyclometalation, including
11c
assistance by electron-rich olefin chelating groups. We chose
We selected α-benzoylketene dithioacetals as a substrate for
4
diazo esters as a typical carbene precursor that can function as
proof-of-concept studies on selectivity (Scheme 1). Pre-
5
6
a C or C coupling partner in C−H activation−annulation, as
viously, only catalytic olefinic C−H alkenylation, allylation,
1
2
7
8
9
they have been extensively employed for the construction of
alkylation, alkoxylation, phosphorylation, and trifluorome-
11 12
1
0
various (hetero)cycles by using Rh(III), Ru(II), and
13
thylation has been realized (Scheme 1a). We reasoned that
Ir(III) catalysts with the C−H activation being assisted by
the electronic effects of the substrates and nature of the catalyst
2
a bifunctional nucleophilic directing group (Scheme 1a). We
can be employed for selective C(sp )−H functionalization. For
coupling with a highly electrophilic substrate where the
electronic effect is predominant, the C(olefinic)−H function-
alization is expected because of the high nucleophilicity. In
Received: June 18, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01890
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
now report chemodivergent coupling of α-oxo ketene
dithioacetals with diazo esters under catalyst control.
Scheme 3. Rh(III)-Catalyzed [4 + 2] Annulation of Ketene
Dithioacetals with Diazo Ketoester
,
a b
We initially studied the Ru(II)-catalyzed coupling of ketene
dithioacetal 1a with ethyl α-diazoacetoacetate 2a (see
Supporting Information (SI), Table 1). When catalyzed by
[
Ru(p-cymene)Cl ] /AgSbF in the presence of PivOH (DCE,
2 2 6
5
1
0 °C), a 1:2 coupling occurred to give product 3aa (CCDC
825600) in 37% yield as a result of olefinic C−H
1
4
furfurylation. The reaction was sensitive to temperature,
and the isolated yield was significantly improved to 78% when
conducted at 90 °C. The yield was further improved to 83%
when the PivOH was omitted. The generality of this coupling
system was then explored (Scheme 2). Introduction of
Scheme 2. Olefinic C−H Furfurylation of Ketene
,
a b
Dithioacetals
a
Reaction conditions B: 1 (0.2 mmol), 2 (0.5 mmol), [Cp*Rh-
(MeCN) ][SbF ] (8 mol %), Zn(OAc) (30 mol %), and PivOH (2
3
6
2
2
b
equiv) in TFE (4.0 mL) at 110 °C for 17 h under Ar. Isolated yield.
Rh(III)-catalyzed coupling of 1a and 2a in the presence of
Zn(OAc) afforded naphthalenone 4aa as a result of [4 + 2]
2
carbo-annulation (Reaction conditions B) and no furfurylation
prouduct 3aa was detected. The scope of this system is also
broad. Ketene dithioacetals bearing halogens (4fa−4ha),
electron-donating (4ba−4ea) and−withdrawing (4ia, 4ja)
groups at the para positions of the benzene ring could tolerate
the reaction conditions, forming the target products in
moderate to good yields (35%−83%). Introduction of different
meta substituents is also tolerated. The reaction tends to occur
at the less hindered ortho site when a meta-methyl group was
used (4ka), whereas 4la was obtained when a meta-fluoro
substrate was used. Furthermore, an ortho-fluoro substrate was
also viable (4ma). Besides benzoyl ketene dithioacetals, the
reaction could be extended to naphthalene (4na) and
thiophene substrates (4oa) under the standard conditions. α-
Diazo compounds derived from other ketoesters also reacted
well (4ab−4ag). In contrast, coupling of α-diazo malonates
only gave arene C−H alkylation (4aa′, 4ab′), indicating that
the ketene dithioacetal is a directing group with possible
nucleophlic cyclization contingent on the electrophilicity of the
acceptor diazo substrate. Also, diazo substrates 2h and 2i failed
to participate in the reaction under the standard conditions.
Derivatization of representative products has been per-
formed to demonstrate synthetic applications. Hydrogenation
of 4aa and 3aa with Raney nickel afforded the hydridesulfu-
rization products 5 and 9, respectively (Scheme 4). Treatment
a
Reaction conditions A: 1 (0.2 mmol), 2a (0.5 mmol), [Ru(p-
cymene)Cl ] (5 mol %), and AgBF (20 mol %) in DCE (2 mL) at
9
2
2
4
b
0 °C for 24 h in a sealed tube under Ar. Isolated yield.
electron-donating and -withdrawing as well as halogen groups
into different positions of the benzene ring was fully tolerated
(
2
3aa−3qa). The substrates with the 2-naphthyl, 2-thienyl, and
-furyl moiety also gave moderate yields (3ra−3ta). Gratify-
ingly, we found that, under the optimized conditions, ketene
dithioacetals with other types of substituents such as ester
(3ua), alkyl acyl (3va), and alkenyl acyl (3wa) were all reactive
and gave the desired products. The diazo substrate was not
limited to ethyl α-diazoacetylacetate. The coupling of diazo
substrates bearing other ester groups and bearing α-alkyl
substituents all proceeded smoothly (3ab−3ag). The ring size
of the dithioacetal had significant effects, and the yield
diminished when a 1,3-dithioacetal was used (3xa). Moreover,
when diazo substrates 2h and 2i were used, no desired
products were obtained.
Having established the Ru(II)-catalyzed coupling system, we
next moved to Rh(III)-catalyzed C−H activation (Scheme 3).
The higher valence of the Rh(III) catalyst conduces to
chelation-assisted C−H activation and the resulting Rh(III)-C
bond interacts favorably with diazo substrates. Indeed, the
of 4aa and 3aa with NaBH led to reduction of the carbonyl
4
group, delivering phenol 6 (72%) and alcohol 10 (87%),
respectively. Deprotection of 6 with NBS/DMSO afforded
aldehyde 7 in 70% yield, and oxidative desulfurization gave o-
naphthoquinone 8. Ir(III)-catalyzed C−H amidation of 4ga
with TsN delivered 11 in moderate yield.
3
Experimental studies have been performed to probe the
reaction mechanism. In the case of ruthenium(II) catalysis
B
DOI: 10.1021/acs.orglett.8b01890
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Derivatization of Coupled Products
Meanwhile, Ru-catalyzed denitrogenation of diazo and carbene
dimerization generates olefin intermediate 12. We cannot
pinpoint the exact stage at which carbene dimerization occurs.
However, it seems less likely that it occurs at the initial RuLX2
catalyst because no dimerization was observed when the diazo
2
a was subjected to the catalytic conditions in the absence of a
dithioacetal substrate. The carbene dimer undergoes dehy-
drative cyclization to give a highly electrophilic, exocyclized
olefin (B). Driven by aromatization, attack of the more
nucleophilic Ru−C(vinyl) group (instead of the Ru−C(aryl)
group) at the activated olefin then furnishes the coupled
product. It should be noted that the carbene dimer is a
common side product in a metal-catalyzed coupling reaction of
diazo compounds. However, it is efficiently utilized in the
construction of a furan ring.
In the case of rhodium(III) catalysis (Scheme 6), H/D
exchange was performed in the presence or absence of diazo
Scheme 6. Mechanistic Studies on Rh(III)-Catalyzed [4 + 2]
Annulation of Ketene Dithioacetals with Diazo Ketoester
(
1
Scheme 5), H/D exchange was performed for the coupling of
a and 2a in the presence of CD COOD (Scheme 5a).
3
Scheme 5. Mechanistic Studies and Plausible Mechanism of
Ru(II)-Catalyzed C−H Furfurylation
ester 2a. Substrate 1a was recovered with deuteration at the
ortho and the olefinic positions. H/D exchange was also
observed at the ortho position of product 4aa (Scheme 6a).
These results indicate reversibility of the C−H cleavage. To
further probe the C−H activation process, the kinetic isotope
effect was determined by intermolecular competition experi-
ments using an equimolar mixture of 1a and 1a-d . The value
5
of k /k = 3.2 suggests that C−H bond cleavage is likely
H
D
involved in the turnover-limiting step (Scheme 6b). Moreover,
a competition experiment was conducted with an equimolar
amount of 1b and 1j, which differ in their electronic properties.
Products 4ba and 4ja were afforded in a ratio of 2.4:1, showing
that the electron-rich arene reacted faster (Scheme 6c).
Competition of ruthenium and rhodium catalysis was also
performed using 1e and diazo 2a (Scheme 6d). The Ru-
catalyzed product 3ea was isolated, but essentially no
naphthalenone was observed. Interestingly, a seven-membered
ring 13 was obtained as a result of the Rh-catalyzed trapping of
the intermediate 12 via olefin insertion and nucleophilic
cyclization. On the basis of these observations and previous
Substrate 1a was recovered with deuteration at the ortho (16%
D) and the olefinic (38% D) positions. Meanwhile, product
3
aa was deuterated (8% D) at the ortho′ position. These
observations indicated reversibility of the C−H cleavage,
although the ortho C−H cleavage is nonproductive. To obtain
reaction intermediates, the coupling of 1f and 2a was
performed at a lower temperature, from which a (Z)-olefin
1
2 was isolated (20%) via carbene dimerization (Scheme 5b).
This olefin proved to be a reactive intermediate in that it
coupled with 1a to yield 3aa in 84% yield. A plausible
mechanism is proposed for this coupling system (Scheme 5c).
Olefinic C−H ruthenation of 1a gives intermediate A.
12a
reports, a plausible catalytic cycle was given (see SI).
C
DOI: 10.1021/acs.orglett.8b01890
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In summary, we have realized chemodivergent C−H
activation of α-oxoketene dithioacetal and coupling with
diazo compounds. The Ru(II)-catalyzed C−H furfurylation
occurred at the olefinic C−H position, where dimerized
carbene was identified as a key intermediate, which is usually a
side product in carbene chemistry. The Rh(III)-catalyzed [4 +
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(
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] annulation of α-benzoylketene dithioacetals with diazo
compounds occurred via both aryl and alkenyl C−H bond
cleavage. The tunable selectivity of C−H activation may find
applications in the development of new catalytic systems.
Further studies on the synthesis of other heterocycles via C−H
activation and functionalization are underway in our
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ASSOCIATED CONTENT
Supporting Information
■
*
S
(
6
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01890.
1
Synth. Catal. 2014, 356, 3157.
Detailed experimental procedures, characterization of
new compounds, crystallographic data of 3aa, and copies
of NMR spectra (PDF)
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(
Accession Codes
(
CCDC 1825600 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: xwli@dicp.ac.cn.
ORCID
Xingwei Li: 0000-0002-1153-1558
Author Contributions
∥M.W. and L.K. contributed equally.
1
1877. (b) Lo, V. K.-Y.; Guo, Z.; Choi, M. K.-W.; Yu, W.-Y.; Huang,
Notes
J.-S.; Che, C.-M. J. Am. Chem. Soc. 2012, 134, 7588. (c) Choi, M. K.-
W.; Yu, W.-Y.; Che, C.-M. Org. Lett. 2005, 7, 1081.
The authors declare no competing financial interest.
(13) (a) Zhang, S.-S.; Jiang, C.-Y.; Wu, J.-Q.; Liu, X.-G.; Li, Q.;
Huang, Z.-S.; Li, D.; Wang, H. Chem. Commun. 2015, 51, 10240.
(b) Xia, Y.; Liu, Z.; Feng, S.; Zhang, Y.; Wang, J. J. Org. Chem. 2015,
80, 223. (c) Phatake, R. V.; Patel, P.; Ramana, C. V. Org. Lett. 2016,
18, 292. (d) Li, Y.; Wang, F.; Yu, S.; Li, X. Adv. Synth. Catal. 2016,
358, 880.
ACKNOWLEDGMENTS
■
The NSFC (Nos. 21525208 and 21472186) and the Research
Fund from Henan Normal University (5101034011009) are
gratefully acknowledged.
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insertion: (a) Zhu, D.; Ma, J.; Luo, K.; Fu, H.; Zhang, L.; Zhu, S.
Angew. Chem., Int. Ed. 2016, 55, 8452. (b) Hong, S. Y.; Jeong, J.;
Chang, S. Angew. Chem., Int. Ed. 2017, 56, 2408. (c) Wang, X.;
Lerchen, A.; Daniliuc, C. G.; Glorius, F. Angew. Chem., Int. Ed. 2018,
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DOI: 10.1021/acs.orglett.8b01890
Org. Lett. XXXX, XXX, XXX−XXX