Two C-O Bond Formations on a Carbenic Carbon: Palladium-Catalyzed Coupling of N-Tosylhydrazones and Benzo-1,2-quinones to Construct Benzodioxoles

Article abstract of DOI:10.1021/acs.orglett.8b00888

A novel and efficient method for the formation of two C-O bonds on a carbenic carbon is reported. This palladium-catalyzed coupling of N-tosylhydrazones and benzo-1,2-quinones were involved the process of carbonyl ylides generation, aromatization, and intramolecular nucleophilic addition, delivering various useful benzodioxoles in high yields.

Full text of DOI:10.1021/acs.orglett.8b00888

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Two C−O Bond Formations on a Carbenic Carbon: Palladium-
Catalyzed Coupling of N‑Tosylhydrazones and Benzo-1,2-quinones
To Construct Benzodioxoles
Huanfeng Jiang,* Fulin Chen, Chuanle Zhu,* Rui Zhu, Hao Zeng, Chi Liu, and Wanqing Wu
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South
China University of Technology, Guangzhou 510640, P. R. China
S
* Supporting Information
ABSTRACT: A novel and efficient method for the formation of two C−O bonds
on a carbenic carbon is reported. This palladium-catalyzed coupling of N-
tosylhydrazones and benzo-1,2-quinones were involved the process of carbonyl
ylides generation, aromatization, and intramolecular nucleophilic addition,
delivering various useful benzodioxoles in high yields.
Scheme 1. C−O Bond Formations on a Carbenic Carbon
ince carbon−heteroatom bonds (C−X) are ubiquitous
motifs that broadly exist in both natural and artificially
S
synthesized molecules, the development of new and efficient
methods for the construction of carbon−heteroatom bonds is
one of the most active research topics in synthetic chemistry.1
Transition-metal catalyzed X−H (X = O, N, S, P, B, Si, etc.)
insertion of metal carbene has represented one of the most
promising methods to construct carbon−heteroatom bonds.2
In particular, the diverse O−H insertion of metal carbenes for
the construction of C−O bond has attracted considerable
attention in the past decades.3−6 In general, these extensively
investigated O−H insertion reactions usually employ diazo
compounds bearing electron-withdrawing groups as carbene
precursors and are treated with highly active copper and
rhodium catalysts to ensure the reactivity and selectivity.
Mechanistically, these O−H insertions of metal carbenes
undergo a stepwise ylide formation and subsequent 1,2-proton
migration pathway (Scheme 1, eq 1).4 When the H atom is
replaced by a carbon, the corresponding insertion reactions are
also involved in the formation of ylide intermediates initially,
but followed by the 1,2-carbon migration or cycloaddition
process (Scheme 1, eq 2).5 These O−H insertions of metal
carbene have also found broad applications in the construction
of bioactive compounds and the total synthesis of natural
products.6 Despite this progress, however, these transforma-
tions inevitably lead to the formation of one C−O bond on the
carbenic carbon, while the method for the formation of two C−
O bonds on the carbenic carbon in the O−H insertion of metal
carbenes has still not been reported.
derived from N-tosylhydrazones, which lead to the construction
of one C−O bond on the carbenic carbon via the migratory
insertion and β-elimination process (Scheme 1, eq 3).11 We
also documented the formation of one C−O bond on the
carbenic carbon of palladium carbene derived from N-
tosylhydrazone involving the ylide intermediate pathway
(Scheme 1, eq 4).12 Inspired by these works, as well as a part
of our continuous effort toward exploiting the potential
reactivity of N-tosylhydrazones,9,10,12,13 herein, we report the
palladium-catalyzed coupling reaction of N-tosylhydrazones
with benzo-1,2-quinones, which leads to the formation of two
Readily available N-tosylhydrazones, as an alternative and
safe source of diazo compounds that do not bear electron-
withdrawing groups, have emerged as attractive metal carbene
precursors,7 especially under palladium catalysis.8−12 Those
palladium carbene intermediates derived from N-tosylhydra-
zones usually undergo migratory insertion,7c carbonylation,8
cyclopropanation,9 and N−H insertion,10 which exhibit diverse
transformation properties. In 2017, Nagaiah and co-workers
reported the O−H insertion reactions of palladium carbenes
Received: March 19, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00888
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Organic Letters
Letter
C−O bonds on the carbenic carbon and delivers various useful
benzodioxoles in high yields (Scheme 1, eq 5).14
When we investigated the palladium-catalyzed oxidative
coupling of N-tosylhydrazones,13a,b an experiment was carried
out with N-tosylhydrazone 1a and benzo-1,2-quinone 2a in
toluene at 90 °C in the presence of Pd(OAc)2 and Cs2CO3
under N2 (Table 1, entry 1). Surprisingly, a new species was
of N-tosylhydrazone 1a was tested under Pd(dba)2, CuI, or
Rh2(OAc)4 catalysis, no corresponding benzodioxole product
was detected.
With the optimized reaction conditions in hand, we next
turned our attention to the generality of this palladium-
catalyzed coupling reaction. The scope of N-tosylhydrazones 1
was first explored with benzo-1,2-quinone 2a as the reaction
partner, and the results are outlined in Scheme 2. In general, N-
a
Table 1. Optimization of Reaction Conditions
a
Scheme 2. Substrate Scope of N-Tosylhydrazones
b
entry
catalyst
Pd(OAc)2
base
solvent
t (°C) yield (%)
1
Cs2CO3
K2CO3
Li2CO3
t-BuOK
t-BuOLi
MeONa
DABCO
DBU
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
MeCN
THF
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
80
100
78 (74)
54
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
3
33
4
38
5
76
6
34
7
<5
8
<5
9
−
<5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
81
45
DCE
52
dioxane
DMF
34
63
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
71
Pd(TFA)2
Pd(CH3CN)2Cl2
Pd(PPh3)4
Pd(dba)2
CuI
84
81
84
92 (86)
40
a
Unless otherwise noticed, the reaction was run at 0.2 mmol scale
b
Rh2(OAc)4
Pd(dba)2
Pd(dba)2
61
under standard reaction conditions. The average isolated yields of
c
d
83
two parallel runs. On 5 mmol scale. ORTEP representation with
50% probability thermal ellipsoids of a crystal structure of 3v; H atoms
were omitted for clarity.
90
a
A mixture of 1a (0.4 mmol, 2 equiv), 2a (0.2 mmol, 1 equiv), base
(0.4 mmol, 2 equiv), catalyst (10 mol %), and solvent (2 mL) was
b
sealed in a 25 mL Schlenk tube at 90 °C for 12 h under N2. Yields
tosylhydrazones with both electron-donating and -withdrawing
substituents at the para, meta, and ortho positions of the phenyl
ring delivered the desired benzodioxoles smoothly (3a−w). It is
worth noting that this palladium-catalyzed system tolerates
various valuable functional groups on the phenyl ring of N-
tosylhydrazones, such as alkoxy, methylthio, amino, halo, cyano,
ester, and trifluoromethyl groups (products 3e−v), providing
ample potential for further synthetic utilities. Significantly,
product 3v was proven to be crystalline, and the structure of
these benzodioxoles was further confirmed by means of X-ray
crystallographic analysis (CCDC 1588105). Furthermore, 1-
tetralone and 1-benzosuberone derived N-tosylhydrazones were
perfectly applicable to this catalytic system, providing the
corresponding spiro benzodioxoles efficiently (3x, y). Different
heteroaromatic groups such as thienyl, furanyl, and pyridyl were
also tolerated on the N-tosylhydrazones, and the desired
products were obtained in high yields (3z−3ad). Additionally,
N-tosylhydrazones derived from other alkyl phenylmethanones,
such as ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, and
tert-butyl phenylmethanones, all afforded the corresponding
products smoothly (3ae−aj). Acyclic aliphatic heptan-4-one
derived N-tosylhydrazone ketone also gave product 3ak in 58%
yield. Although N-tosylhydrazones derived from cyclic aliphatic
ketones such as cyclopentanone, cyclohexanone, and cyclo-
were determined by GC-MS with n-dodecane as internal standard. The
number in the parentheses was isolated yield. dba = dibenzylidenea-
cetone.
detected by GC-MS with a peak m/z = 324.33, which was
tentatively assumed as benzodioxole 3a via two C−O bond
formations on the carbenic carbon, and it was obtained in 74%
isolated yield (Table 1, entry 1). To optimize the reaction
conditions, various inorganic bases such as K2CO3, Li2CO3, t-
BuOK, t-BuOLi, and MeONa and organic bases such as
DABCO and DBU were examined; however, no superior
results were obtained (Table 1, entries 2−8). The absence of
bases was fatal to this transformation (Table 1, entry 9). Next,
diverse organic solvents were screened, and a solvent of MeCN
enhanced the GC-MS yield of the product to 81% (Table 1,
entries 10−14). Furthermore, different types of palladium salts
were investigated (Table 1, entries 15−19). A catalyst of
Pd(dba)2 was found to be optimal, and gave the desired
product 3a in 86% isolated yield. With CuI or Rh2(OAc)4 as
the catalyst, the yields of 3a decreased significantly (Table 1,
entries 20−21). Furthermore, changing the reaction temper-
ature in either direction eroded the yield of 3a slightly (Table 1,
entries 22−23). Additionally, when ethyl diazoacetate instead
B
DOI: 10.1021/acs.orglett.8b00888
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
heptanone led to lower yields of the corresponding products
(3al−an), N-tosylhydrazone derived from cyclic 2-admanta-
none could provide the desired product 3ao in 72% yield.
Additionally, benzaldehyde derived N-tosylhydrazone also gave
the corresponding product 3ap in 25% yield.
Scheme 4. Control Experiments
To further define the generality of our method, the substrate
scope was extended to different benzo-1,2-quinones 2 (Scheme
3). Pleasingly, diverse disubstituted benzo-1,2-quinones with an
a
Scheme 3. Substrate Scope of Benzo-1,2-quinones
3,5-di-tert-butylbenzene-1,2-diol 10 was used as the substrate
instead of benzo-1,2-quinone 2a. No desired product 3a was
detected, indicating that 10 was not one of the reaction
intermediates, and the formation of carbonyl ylide intermediate
might be involved in this transformation (Scheme 4, eq 3).
On the basis of these experimental results, and previous
literature,7−14 we tentatively proposed the reaction mechanism,
as illustrated in Scheme 5. First, formation of palladium carbene
a
The reaction conditions were: 1a (0.2 mmol, 1 equiv), 2 (0.4 mmol,
2 equiv), Cs2CO3 (0.4 mmol, 2 equiv), Pd(dba)2 (10 mol %), and
MeCN (2 mL) was sealed in a 25 mL Schlenk tube at 90 °C for 12 h
under N2. The average isolated yields of two parallel runs.
b
Scheme 5. Proposed Mechanism
alkyl, alkoxyl, bromo, and aryl group at different locations of the
benzo-1,2-quinone ring all delivered the corresponding
benzodioxoles in good to high yields (3aq−bb). It is worth
mentioning that an unprotected hydroxyl group could also
been tolerated under the standard reaction conditions,
delivering the desired product 3ba in 46% yield. Furthermore,
tetrachloro substituted benzo-1,2-quinone also gave the
corresponding product 3bc in 66% yield. However, mono-
substituted benzo-1,2-quinones with both electron-donating
groups such as alkoxyl and alkyl and an electron- withdrawing
bromo group on the benzo-1,2-quinone ring did not afford the
corresponding products 3bd−bg in isolatable yield, as the
corresponding aryl-1,2-diols via oxidative aromatization of
benzo-1,2-quinones were detected as the major byproduct
under our standard reaction conditions.
To cast some light on the mechanism details of this reaction,
some control experiments were performed. First, the reactions
of N-tosylhydrazone 1a with diverse 1,n-diketones and α-
ketoacids 4−9 were examined under the standard reaction
conditions. However, very complex mixtures were obtained for
all these reactions, and no desired two C−O bond formation
products were detected by GC-MS analysis, indicating the
oxidative aromatic potential of benzo-1,2-quinones is very
important for the success of this transformation (Scheme 4, eq
1). Furthermore, acetophenone was used as the substrate
instead of N-tosylhydrazone 1a. The desired product 3a was
not obtained, implying the generation of palladium carbene was
the initial step for this reaction (Scheme 4, eq 2). Additionally,
intermediate A via the decomposition of N-tosylhydrazones 1
in the presence of palladium catalysts and bases further
transformed to the corresponding carbonyl ylide intermediates
B under the treatment of benzo-1,2-quinones 2.12 Subsequent
aromatization of the phenyl ring converted intermediates B to
the more stable carbonyl ylide intermediates C via isomer-
ization, which further transformed to the desired benzodioxoles
3 via intramolecular nucleophilic addition.
In summary, we have documented the palladium-catalyzed
coupling reaction of N-tosylhydrazones with benzo-1,2-
quinones, which leads to the formation of two C−O bonds
on the carbenic carbon. Various useful benzodioxoles were
synthesized in high yields. Primary mechanism studies indicated
this reaction involved the process of carbonyl ylides generation,
aromatization, and intermolecular nucleophilic addition. Efforts
C
DOI: 10.1021/acs.orglett.8b00888
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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are currently underway in our laboratory to investigate the
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the results of which will be reported in the due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00888.
Typical experimental procedures, characterization for all
products (PDF)
Accession Codes
CCDC 1588105 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 Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: cechlzhu@scut.edu.cn.
*E-mail: jianghf@scut.edu.cn.
ORCID
Huanfeng Jiang: 0000-0002-4355-0294
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(14) Alig, L.; Alsenz, J.; Andjelkovic, M.; Bendels, S.; Ben
Bleicher, K.; Bourson, A.; David-Pierson, P.; Guba, W.; Hildbrand, S.;
Kube, D.; Lubbers, T.; Mayweg, A. V.; Narquizian, R.; Neidhart, W.;
́
ardeau, A.;
The authors thank the National Program on Key Research
Project (2016YFA0602900), the National Natural Science
Foundation of China (21420102003), the Guangdong Natural
Science Foundation (2016A030310460), the Pearl River S&T
Nova Program of Guangzhou (201806010138), and the
Fundamental Research Funds for the Central Universities
(2015ZY001 and 2015ZM163) for financial support.
̈
Nettekoven, M.; Plancher, J.-M.; Rocha, C.; Rogers-Evans, M.; Rover,
̈
S.; Schneider, G.; Taylor, S.; Waldmeier, P. J. Med. Chem. 2008, 51,
2115.
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