Copper-Catalyzed Formal Carbene Migratory Insertion into Internal Olefinic C=C Bonds with N-Tosylhydrazones to Access Iminofuran and 2(3H)-Furanone Derivatives

Article abstract of DOI:10.1021/acs.orglett.7b01668

Efficient copper-catalyzed formal carbene migratory insertion into the olefinic C=C bonds of internal olefins, that is, α-oxo ketene N,S-acetals, has been achieved by means of N-tosylhydrazones of ketones as the carbene precursors. Iminofuran derivatives

Full text of DOI:10.1021/acs.orglett.7b01668

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Formal Carbene Migratory Insertion into Internal
Olefinic CC Bonds with N‑Tosylhydrazones To Access Iminofuran
and 2(3H)‑Furanone Derivatives
Fei Huang,†,‡,∥ Zhuqing Liu,†,‡,∥ Quannan Wang,†,‡ Jiang Lou,†,‡ and Zhengkun Yu*,†,§
†Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
‡University of Chinese Academy of Sciences, Beijing 100049, China
§State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354
Fenglin Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: Efficient copper-catalyzed formal carbene migra-
tory insertion into the olefinic CC bonds of internal olefins,
that is, α-oxo ketene N,S-acetals, has been achieved by means of
N-tosylhydrazones of ketones as the carbene precursors.
Iminofuran derivatives were obtained and further transformed
to the corresponding 2(3H)-furanones and 4-oxobutanoates (γ-ketoesters), respectively, under mild conditions. In a similar
fashion, α-thioxo ketene N,S-acetals reacted with N-tosylhydrazones of ketones to afford iminothiophenes. It is suggested that
formal carbene migratory insertion into the olefinic CC bond is involved in the overall catalytic cycle, demonstrating a new
type of carbene insertion reaction for five-membered heterocycle construction.
α-Oxo ketene N,S-acetals feature an unusual internal olefin
arbene migratory insertion reactions have demonstrated
Cversatile applications in the construction of various structure with three electron-withdrawing and donating
functionalities, that is, carbonyl, alkylthio, and amino groups,
which are attached to the two ends of the olefinic CC bond,
and can exhibit unusual reactivities.16 During the ongoing
investigation of C−H activation of internal olefins,17 we
reasonably envisioned carbene migratory insertion into the
olefinic C(sp2)−H bond of α-oxo ketene N,S-acetals with diazo
compounds. Unexpectedly, in their reactions with ethyl 2-
diazo-2-phenylacetate and analogues, no such carbene
migratory insertion reactions were observed under copper
catalysis, while carbene migratory insertion into the olefinic
CC bond occurred by using a copper salt as the catalyst and
N-tosylhydrazones of ketones as the carbene precursors,
affording iminofuran products. Iminofurans and related
2(3H)-furanones which can be readily converted from the
corresponding iminofurans, are usually bioactive and abundant
in many natural products and synthetic compounds.18
Development of synthetic methods for such biologically active
compounds has been strongly desired. Herein, we disclose the
synthesis of iminofurans and related derivatives from the
reactions of α-oxo (thioxo) ketene N,S-acetals with N-
tosylhydrazones.
chemical bonds. Diazo compounds and N-tosylhydrazones
have recently been paid much attention because they can be
used as carbene precursors in diverse organic synthesis.1 In this
regard, carbene migratory insertion into X−H bonds (X = C,2
N,3 O,4 S,5 Si,6 and B,7 etc.) has been applied for the
construction of C−X bonds. A few examples of carbene
insertion into C−heteroatom bonds have also been docu-
mented.8−11 Carbene migratory insertion into the C−C single
bonds of cyclic ketones and alcohols were reported for ring
expansion and synthesis of homologated ketones.12 In 1885,
Buchner et al. documented the seminal work on carbene
̈
insertion into arene CC bonds in the reactions of diazo
compounds with arenes,13 which provide a unique approach to
accessing cycloheptatriene derivatives14 via intermolecular
cyclopropanation. N-Tosylhydrazones have recently been
utilized for the same purpose.15 However, to the best of our
knowledge, carbene migratory insertion into an olefinic CC
bond has not yet been reported. Despite being synthetically
very useful and readily available, diazo compounds are usually
associated with toxicity and explosion hazards, and methods for
in situ preparation and use of their surrogates have been
desired.1 Thus, N-tosylhydrazones have recently been paid
more and more attention for use as masked diazo compounds
because they can be readily prepared.1e,h A transition metal is
usually required to stabilize a diazo substrate or diazo
intermediate and to moderate the reactivity of the in situ
generated carbene species. In this respect, copper catalysts are
preferably used to promote the reactions of diazo compounds
or N-tosylhydrazones under relatively mild conditions.1h
Initially, the reaction of (E)-3-(benzylamino)-3-(methyl-
thio)-1-phenylprop-2-en-1-one (1a) with the N-tosylhydrazone
of acetophenone (2a) was conducted to screen the reaction
conditions (eq 1; see the Supporting Information for details).
With 20 mol % of CuI as the catalyst and 2.5 equiv of K2CO3 as
Received: June 2, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01668
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Letter
the benzyl thioacetal substrate could not efficiently react to
form 3a (62%) due to an obvious steric effect. It is noted that
the reactions of α-acetyl ketene N,S-acetals and α-oxo ketene
N,S-acetals bearing an arylamino group (NHAr) with 2a only
gave inseparable mixtures.
The scope of ketene N,S-acetals 1 was further explored by
introducing a secondary alkylamino group, that is, diethylami-
no, to replace the primary amino moiety NHR in 1. Thus, 1u
was applied to react with N-tosylhydrazone 2a under the
standard conditions. Unexpectedly, no carbene migratory
insertion into the olefinic CC bond could occur to form
the product of type 3, whereas the reaction underwent in the
presence of 2 equiv of water to afford γ-ketoamide 4a (40%). In
a similar manner, 4b (40%) and 4c (48%) were also obtained
(eq 2). The molecular structure of compound 4a was
the base, treatment of 1a and 2a in a 1.0:1.5 molar ratio in
refluxing toluene for 12 h afforded the target iminofuran
product 3a in 35% yield. Among the screened bases, tBuONa
did not promote the reaction, while tBuOLi acted most
effectively. Increasing both the loadings of 2a and tBuOLi to 3
equiv remarkably enhanced the yield to 72%. Lowering
temperature to 90 °C or performing the reaction in 1,4-
dioxane or 1,2-dichloroethane deteriorated the reaction
efficiency. Copper(I) salts such as CuCl, CuBr, and CuOAc
could not efficiently promote the reaction, whereas use of
CuBr2 gave the best yield (75%). A <20 mol % catalyst loading
led to a lower product yield. Eventually, the reaction conditions
were optimized to 20 mol % of CuBr2 as the catalyst, use of 3
equiv of both 2a and tBuOLi, toluene as the solvent, 110 °C, 12
h, under a nitrogen atmosphere.
Under the optimal conditions, the scope of α-oxo ketene
N,S-acetals 1 was explored by reacting them with 2a (Scheme
1). Substituted analogues of 1a, that is, 1b−f, behaved similarly
confirmed by its X-ray single-crystal structural analysis (see
the SI). These results have revealed the occurrence of formal
carbene migratory insertion into the C−C single bond between
the carbonyl carbon and the vicinal olefinic carbon in 1, which
was reported in the cases of cyclic ketones and alcohols.12
Next, the generality of N-tosylhydrazones 2 was investigated
(Scheme 2). The N-tosylhydrazones of fluoro- and trifluor-
omethyl-substituted acetophenones reacted with 1a to form
3s−v (52−82%), respectively, exhibiting obvious steric effects
from the substituents on the aryl moieties of the N-
tosylhydrazones. By means of the N-tosylhydrazones of 4-
a
Scheme 1. Scope of α-Oxo Ketene N,S-Acetals 1
a
Scheme 2. Scope of N-Tosylhydrazones 2
a
Conditions: 1 (0.5 mmol), 2a (1.5 mmol), CuBr2 (0.1 mmol),
tBuOLi (1.5 mmol), toluene (5 mL), 0.1 MPa N2, 110 °C, 12 h. Yields
b
refer to the isolated products. Scale-up reaction conditions: 1r (1.37
g, 5 mmol), 2a (2.88 g, 10 mmol), CuBr2 (1 mmol), tBuOLi (10
c
mmol), toluene (20 mL), 0.1 MPa N2, 110 °C, 18 h. From 1s (R2 =
d
Et). From 1t (R2 = Bn).
to yield iminofurans 3b−f (69−79%). Bulky 2-naphthyl and
heteroaryl-based N,S-acetals 1g−i reacted with 2a to give the
corresponding products 3g−i (65−68%), exhibiting moderate
steric and electronic effects. Variation of the amino groups in 1
to methyl-, ethyl-, or allylamino led to 3j−n in 74−77% yields.
However, placement of a moderate to long-chain or cyclic
aliphatic alkylamino group in 1 deteriorated the product yields
to 54−67%. Furan-2-ylmethylamino-bearing ketene N,S-acetal
1r reacted smoothly to yield 3r (79%), and a 5 mmol scale
reaction also efficiently afforded 3r (71%). Replacement of the
MeS group by EtS in 1 slightly reduced the yield to 73%, while
a
Conditions: 1 (0.5 mmol), 2 (1.5 mmol), CuBr2 (0.1 mmol), tBuOLi
(1.5 mmol), toluene (5 mL), 0.1 MPa N2, 110 °C, 12 h. Yields refer to
the isolated products.
B
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a
substituted acetophenones, products 3w−z2 were obtained in
56−80% yields, showing electronic effects from the 4-
substituents. A negative steric effect was present in the cases
of using the N-tosylhydrazones of acetonaphthone, propiophe-
none, and benzophenone, leading to 3z3 (52%), 3z4 (53%),
and 3z5 (69%), respectively. N-Tosylhydrazones of 2-
acetylfuran and thiophene also underwent the reactions with
1a to afford the corresponding iminofuran products 3z6 (53%)
and 3z7 (68%). It is noteworthy that the N-tosylhydrazones
derived from aromatic aldehydes such as benzaldehyde and 4-
fluorobenzaldehyde were also used to react with 1a. However,
no desired reactions occurred to form the target iminofurans
3z8 and 3z9 or their furan isomers 3z8′ and 3z9′. In these
cases, most of the starting α-oxo ketene N,S-acetals were
recovered. The molecular structures of products 3 were further
confirmed by the X-ray single-crystal structural determination
of 3z5 (see the SI).
Scheme 4. Hydrolysis of Iminofurans 3
a
Conditions: 3 (0.2 mmol), 10% aq H2SO4 (0.2 mL), ROH (2 mL),
reflux, air. Yields refer to the isolated products.
In order to extend the substrate scope, α-thioxo ketene N,S-
acetals of type 5 were employed to react with N-
tosylhydrazones of ketones 2 under the standard conditions.
To our delight, the structural analogues of iminofurans 3, that
is, iminothiophenes 6, were conveniently obtained in 33−86%
yields (Scheme 3). As compared to the corresponding α-oxo
(82−92%), revealing easy hydrolysis of 2(3H)-furanones 7
under the stated conditions. These results have demonstrated
the potential application of the synthetic protocol in the
synthesis of furanone derivatives.
The control experiments were then conducted to probe into
the reaction mechanism (Scheme 5). Addition of a radical
a
Scheme 3. Scope of α-Thioxo Ketene N,S-Acetals 5
Scheme 5. Control Experiments
scavenger, i.e., 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)
or 2,6-di-tert-butyl-4-methylphenol (BHT), to the reaction of
1a and 2a only slightly reduced the yield of 3a, suggesting that
the reaction did not occur through a radical pathway (Scheme
5a). Treatment of 2a with equimolar amount of tBuOLi base at
110 °C followed by reacting the resultant mixture with 1a in
the presence of CuBr2 catalyst gave product 3a in 70% yield
(Scheme 5b), implicating that diazo compound 2a′ generated
from 2a is involved as the reaction intermediate in the overall
catalytic cycle. However, the α-aroyl ketene N,O-acetals 9, N,N-
acetal 10, and enamine 11 could not react with 2a under the
standard conditions to form the target product 3a (Scheme 5c),
which is presumably attributed to both the better leaving group
capability of the alkylthio moiety compared to OMe, OEt,
NHBn, and Me groups and the higher reactivity of the ketene
N,S-acetals.20 This work has demonstrated the first example of
formal carbene migratory insertion into olefinic CC
bonds.1,21 The reaction mechanism may involve initial
cyclopropanation of the internal olefin substrate, that is, α-
oxo ketene N,S-acetal, followed by a simple rearrangement of
the push−pull cyclopropane intermediate.14 However, no
a
Conditions: 5 (0.5 mmol), 2 (1.5 mmol), CuBr2 (0.1 mmol), tBuOLi
(1.5 mmol), toluene (5 mL), 0.1 MPa N2, 12 h. Yields refer to the
isolated products.
ketene N,S-acetals of type 1, compounds 5 usually exhibited a
lower reactivity. The steric effects from the N-tosylhydrazones
were obvious, which deteriorated the reaction efficiencies. In
contrast to the α-acetyl ketene N,S-acetal, α-thioxo ketene N,S-
acetal 5s (R1 = Me, R3 = Bn) could undergo the reaction with
2a, yielding iminothiophene 6s in 68% yield.
Derivation of iminofurans 3 was carried out in the presence
of 10% aq H2SO4 in an alcohol solvent.19 Compounds 3 were
thus efficiently hydrolyzed to the corresponding 2(3H)-
furanones 7 (81−91%) in refluxing ethanol within 5 min
(Scheme 4). Extension of the reaction time to 12 h led to the
ring-opening products 4-oxobutanoates, that is, γ-ketoesters 8
C
DOI: 10.1021/acs.orglett.7b01668
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experimental evidence has been obtained to clarify the reaction
pathway at this stage.
In conclusion, copper-catalyzed synthesis of iminofurans and
iminothiophenes has been efficiently realized by means of the
reactions of α-oxo (thioxo) ketene N,S-acetals with N-
tosylhydrazones of ketones. This is the first report on the
formal carbene migratory insertion into olefinic CC bonds.
The iminofurans can be readily transformed to potentially
bioactive 2(3H)-furanones and γ-ketoesters. The synthetic
protocol provides a concise route to iminofurans, iminothio-
phenes, and 2(3H)-furanones.
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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.7b01668.
Experimental materials and procedures, NMR of
compounds, and X-ray crystallographic analysis (PDF)
X-ray crystallographic data for compounds 4a and 3z5
(CIF)
(10) Miura, T.; Fujimoto, Y.; Funakoshi, Y.; Murakami, M. Angew.
Chem., Int. Ed. 2015, 54, 9967.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zkyu@dicp.ac.cn.
ORCID
(13) Buchner, E.; Curtius, T. Ber. Dtsch. Chem. Ges. 1885, 18, 2377.
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(14) (a) Galan, B. R.; Gembicky, M.; Dominiak, P. M.; Keister, J. B.;
Fei Huang: 0000-0002-5290-2490
Zhuqing Liu: 0000-0002-5225-1771
Quannan Wang: 0000-0002-4136-0016
Jiang Lou: 0000-0002-5653-1359
Zhengkun Yu: 0000-0002-9908-0017
Diver, S. T. J. Am. Chem. Soc. 2005, 127, 15702. (b) Maestre, L.;
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Author Contributions
∥F.H. and Z.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (21472185) and the National Basic Research Program of
China (2015CB856600) for support of this research.
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