Synthesis of Seven-Membered Benzolactones by Nickel-Catalyzed C?H Coupling of Benzamides with Oxetanes

Article abstract of DOI:10.1002/chem.201900543

A NiCl₂(PEt₃)₂-catalyzed regioselective C?H coupling of 8-aminoquinoline-derived benzamides with oxetanes has been developed. The reaction proceeds with concomitant removal of the 8-aminoquinoline auxiliary to directly for

Full text of DOI:10.1002/chem.201900543

A Journal of
Accepted Article
Title: Synthesis of Seven-Membered Benzolactones by Nickel-
Catalyzed C–H Coupling of Benzamides with Oxetanes
Authors: Masahiro Miura, Shibo Xu, Kazutaka Takamatsu, and Koji
Hirano
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To be cited as: Chem. Eur. J. 10.1002/chem.201900543
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COMMUNICATION
Synthesis of Seven-Membered Benzolactones by Nickel-
Catalyzed C–H Coupling of Benzamides with Oxetanes
Shibo Xu,[a] Kazutaka Takamatsu,[a] Koji Hirano,*[a] and Masahiro Miura*[a]
Abstract: A NiCl2(PEt3)2-catalyzed regioselective C–H coupling of 8-
aminoquinoline-derived benzamides with oxetanes has been
developed. The reaction proceeds with concomitant removal of the
8-aminoquinoline auxiliary to directly form the corresponding seven-
membered benzolactones, which are frequently occurring in natural
products and bioactive molecules. Additionally, no stereochemical
erosion is observed during the course of the reaction, and the use of
enantioenriched substituted oxetane thus provides a new avenue to
the optically active benzolactone.
coupling reaction of quinoline amides with oxetanes via the N,N-
double chelation-assisted C–H cleavage (Scheme 1b). As
observed in our previous work with epoxides,[9a] the successive
ring-closing reaction occurred[12] to directly deliver the
corresponding seven-membered benzolactones of prevalent
medium-sized ring system found in natural products and bioactive
molecules.[13]
a) Ni-catalyzed C–H coupling of benzamides with epoxides leading to six-membered benzolactones
(previous work)
O
O
cat. NiII
Oxetane constitutes an important class of cyclic ethers in organic
synthetic chemistry and polymer synthesis. Owing to its high
strain energy,[1] it can undergo a variety of ring-opening reactions
with highly reactive organometallic reagents and heteroatom
nucleophiles in the presence or absence of Brønsted and Lewis
acid promotors to form the corresponding three-carbon
homologated, oxygenated products and/or polyethers.[2]
However, redox-active transition-metal-catalyzed coupling
reactions with oxetane are relatively limited, compared to a three-
membered analogue, epoxide, probably because of a little bit less
distortion energy (oxetane: 107 kJ/mol vs epoxide: 114 kJ/mol).[1]
As an early work, Murai and coworkers developed the rhodium-
catalyzed silylformylation of oxetanes with hydrosilanes and
carbon monoxide.[3] Gansäuer also reported the titanocene-
catalyzed ring-opening reductive dimerization to provide 1,6-
hexanediols.[4] Recently, some research groups developed
unique coupling reactions of oxetanes, including the rhodium-
catalyzed carbene insertion,[5] gold-nanoparticle-catalyzed
silaboration,[6] and iron-catalyzed oxidative C–H coupling,[7] but
synthetic utility of oxetanes under transition metal catalysis still
remains underdeveloped.
Meanwhile, our research group recently reported the nickel-
catalyzed C–H coupling reaction[8] of benzamides with epoxides
(Scheme 1a).[9,10] The reaction was promoted by the N,N-doubly
coordinated aminoquinoline auxiliary, which was originally
developed by Daugulis,[11] and the corresponding six-membered
benzolactones were directly obtained with the concomitant
removal of aminoquinoline directing group. During our continuing
interest in this chemistry, we next envisioned the C–H coupling
reaction with oxetanes. Herein, we report a nickel-catalyzed
O
O
N
+
R
6
R
H
N
R’
H
R’
b) Ni-catalyzed C–H coupling of benzamides with oxetanes leading to seven-membered benzolactones
(this work)
O
O
O
cat. NiII
O
N
H
+
R’
R
R
7
N
R’
H
Scheme 1. Nickel-catalyzed C–H couplings of quinoline benzamides with
epoxides (a) and oxetanes (b).
We selected benzamide 1a and parent oxetane (2a) as model
substrates and started optimization studies (Table 1). In an early
experiment, treatment of 1a with 2a (4.0 equiv) and 20 mol%
NiCl2(PCy3)2 in diglyme at 160 ˚C (our previous optimal
conditions[9a]) afforded the seven-membered benzolactone 3aa in
30% 1H NMR yield (entry 1). Subsequent brief screening of nickel
catalysts revealed that NiCl2(PEt3)2 showed better performance
(entries 2–4). Solvent and concentration effects were also critical:
DMF further increased the yield to 56% yield, particularly under
higher concentration (entries 5 and 6), while the reaction in other
solvents including NMP, DMSO, and toluene was almost sluggish
(entries 7–9). On the other hand, additional survey of phosphine
ligands combined with the NiCl2•glyme salt in the DMF solvent
provided no improvement of the yield (entries 10–14). The use of
nickel(0) catalyst, Ni(cod)2, also gave almost no conversion (entry
15). The higher nickel catalyst loading (30 mol%) slightly
improved the yield (entry 16), however, at this point we found the
formation of the ester 4aa as the major byproduct (~30%), which
apparently suggests the ring-opening side reaction of oxetane
(2a) with contaminated water. We thus tested the addition of
several dehydrating agents (entries 17–20). Pleasingly, 3Å MS
effectively suppressed the byproduct 4aa to furnish 3aa in 74%
isolated yield (entry 20) with good reproducibility. Finally, with the
Et3N additive (20 mol%), the targeted benzolactone 3aa was
isolated in slightly higher yield of 78% (entry 21). Additional
observations are to be noted: other organic bases such as 1,4-
diazabicyclo[2.2.2]octane (DABCO) and 4-dimethylaminopyridine
(DMAP) were detrimental (data not shown); the aminoquinoline
auxiliary was indispensable, and other monodentately and
bidentately coordinating amide substrates showed sluggish
[a]
S. Xu, K. Takamatsu, Prof. Dr. K. Hirano, Prof. Dr. M. Miura
Department of Applied Chemistry
Graduate School of Engineering, Osaka University
Suita, Osaka 565-0871 (Japan)
Fax: (+81) 6-6879-7362
E-mail: k_hirano@chem.eng.osaka-u.ac.jp;
miura@chem.eng.osaka-u.ac.jp
Supporting information for this article is available on the WWW
under http://www.xxx.
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10.1002/chem.201900543
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COMMUNICATION
reactivity under the present conditions; unfortunately, both long
reaction time and high reaction temperature were necessary for
good conversion and reproducibility.
With good conditions in hand (entry 20 in Table 1), we
investigated the scope and limitations of benzamide substrates 1
with the parent oxetane (2a; Scheme 2). The nickel catalyst was
equally compatible with electron-neutral, -donating, and
withdrawing groups (tBu, MeO, CF3) at the para position to form
the corresponding benzolactones 3ba–da in good yields. In the
case of meta-substituted benzamides, the reaction occurred
selectively at the more sterically accessible C–H bond, regardless
of the electronic nature of substituents (3ea–ga). Albeit with
somewhat lower efficiency, the substitution at the ortho position
was also tolerated (3ha). Higher fused naphthalene derivatives
1i and 1j could also be employed: the 2-naphthalenecarboxamide
was coupled with 2a at the sterically less hindered C3 position to
form the corresponding tricyclic system 3ia in 80% yield, whereas
the 1-naphthyl isomer showed lower reactivity (3ja, 31%)
probably due to steric factors similar to the result of 3ha.
Unfortunately, the reaction of chloro-substituted benzamide 1k
was sluggish, and only the protodechlorinated product 3aa was
observed (not 3ka); however, the unsuccessful result can give
information about an oxidation state of active nickel species (vide
Table 1. Optimization studies for nickel-catalyzed C–H coupling of
benzamide 1a with oxetane (2a) for the synthesis of seven-membered
benzolactone 3aa.[a]
O
O
O
Ni catalyst
additives
O
O
O
OH
N
H
+
N
solvent
4aa
detectable major byproduct
160 ˚C, 22 h
1a
2a
3aa
Entry
1
Ni cat. (mol%)
Additives
none
Solvent (mL)
diglyme (1.0)
diglyme (1.0)
diglyme (1.0)
diglyme (1.0)
DMF (1.0)
DMF (0.5)
NMP (1.0)
DMSO (1.0)
toluene (1.0)
DMF (0.5)
DMF (0.5)
DMF (0.5)
DMF (0.5)
DMF (0.5)
DMF (0.5)
DMF (0.5)
DMF (0.5)
DMF (0.5)
DMF (0.5)
DMF (0.5)
DMF (0.5)
Yield [%][b]
NiCl2(PCy3)2 (20)
NiCl2(PEt3)2 (20)
NiCl2•glyme (20)
Ni(acac)2 (20)
30
36
25
0
none
2
none
3
none
4
infra).
Additional advantage is accommodation of some
NiCl2(PEt3)2 (20)
NiCl2(PEt3)2 (20)
NiCl2(PEt3)2 (20)
NiCl2(PEt3)2 (20)
NiCl2(PEt3)2 (20)
none
33
56
8
5
heteroaromatics: thiophene-, pyrrole-, and indole-derived
carboxamides underwent the C–H coupling-cyclization cascade
to deliver 3la–na in synthetically acceptable yields.[14]
none
6
none
7
O
O
NiCl2(PEt3)2
3Å MS, Et3N
none
0
8
O
O
N
H
+
R
R
N
DMF, 160 ˚C, 22 h
none
0
9
1
2a
3
NiCl2•glyme (20)
dppbz (20)
none
30
9
10
11
12
13
14
15
16
17
18
19
20
21
O
O
O
O
O
O
NiCl2•glyme (20)
dppe (20)
O
O
none
F3C
MeO
tBu
NiCl2•glyme (20)
PPh3 (40)
none
30
8
3aa 78%
3ba 63%
3ca 59%
3da 62%
NiCl2•glyme (20)
PBu3 (40)
O
Me
O
O
O
none
F3C
O
Me
MeO
O
O
O
NiCl2•glyme (20)
P(tBu)3 (40)
none
26
trace
59
41
39
56–68[c]
(74)
(78)
3ea 66%
3fa 53%
3ga 52%
3ha 43%
Ni(cod)2 (20)
none
O
O
O
O
O
NiCl2(PEt3)2 (30)
NiCl2(PEt3)2 (30)
NiCl2(PEt3)2 (30)
NiCl2(PEt3)2 (30)
NiCl2(PEt3)2 (30)
NiCl2(PEt3)2 (30)
none
O
O
O
S
Cl
Na2SO4
MgSO4
4Å MS
3Å MS
3ka 0%
(3aa 21%)[a]
3ia 80%
3ja 31%
3la 49%
O
O
Me
N
Me
O
O
N
3ma 63%
3na 47%
3Å MS
Et3N[d]
Scheme 2. Nickel-catalyzed C–H coupling of various benzamides 1 with
oxetane (2a). Conditions: 1 (0.20 mmol), 2a (0.80 mmol), NiCl2(PEt3)2 (0.060
mmol), Et3N (0.040 mmol), 3Å MS (100 mg), DMF (0.50 mL), 160 ˚C, 22 h, N2.
Yields of isolated products are given. [a] Only the protodechlorinated product
3aa was formed.
[a] Conditions: 1a (0.20 mmol), 2a (0.80 mmol), Ni cat., additives, solvent,
160 ˚C, 22 h, N2. [b] Estimated by 1H NMR with triphenylmethane as an
internal standard. Isolated yield in parentheses. [c] Poor reproducibility.
[d] 20 mol% of Et3N. acac = acetylacetonate, cod = 1,8-cyclooctadiene,
DMF = N,N-dimethylformamide, DMSO = dimethylsulfoxide, dppbz = 1,2-
bis(diphenylphosphino)benzene,
bis(diphenylphosphino)ethane, NMP = N-methylpyrrolidone.
dppe
=
1,2-
An additional feature of this nickel catalysis is the
spontaneous removal and successful recycling of directing group
(Scheme 3). The model reaction of 1a with 2a could also be
performed on a 2.0 mmol scale, and the desired 3aa was isolated
in 66% yield along with 55% recovery of 8-aminoquinoline
auxiliary; the result deserves some attention from synthetic point
no or less reactive substrates under conditions in entry 6
(1H NMR yield of 3aa is shown)
O
O
O
O
N
H
N
H
N
H
N
N
Me
N
N
O
0%
0%
27%
trace
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10.1002/chem.201900543
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COMMUNICATION
of view, because the removal of such a bidentate directing group
often requires tedious and additional experimental operations.[12]
exact reductant remains to be elucidated, the benzamide
substrate or PEt3 can be a good candidate.[17] The coordination
of benzamide 1a (6 to 7) is followed by N,N-bidentate-
coordination-assisted reversible C–H cleavage to form the
nickelacycle 8. The chelated nickel complex 8 then undergoes
oxidative addition with 2a (8 to 9), and subsequent reductive
elimination generates the C–H alkylated intermediate 10.
Acceleration of the aforementioned somewhat challenging
oxidative addition of oxetane can be an additional role of PEt3
ligand. Upon the protonolysis with HCl, the corresponding alcohol
11 is liberated along with regeneration of the starting nickel 6.
Final intramolecular alcoholysis delivers the observed seven-
membered benzolactone 3aa and free 8-aminoquinoline. The
role of Et3N additive is unclear at this stage, but it can work as a
proton shuttle in the catalytic cycle. The cyclization event can also
be accelerated by the nickel catalyst: the NiCl2(PEt3)2 catalyst
successfully converted the independently prepared 11ha to the
lactone 3ha whereas no reaction occurred in the absence of any
nickel catalyst (Scheme 7).[18]
O
O
NiCl2(PEt3)2
O
3Å MS, Et3N
O
N
H
+
+
H2N
N
DMF, 160 ˚C, 22 h
N
3aa
66%
1a 2.0 mmol
2a (4.0 equiv)
55%
Scheme 3. Reaction on 2.0 mmol scale.
The scope and limitation of oxetanes 2 was then briefly
surveyed. In the reaction with the C2-substituted oxetane (S)-2b,
the more sterically accessible C4–O bond was selectively cleaved
to form the benzolactone (R)-3ab as the sole regioisomer
(Scheme 4a).
Additionally, its chirality was successfully
transferred without erosion of enantiomeric excess, thus providing
a new route to chiral seven-membered benzolactones from
relatively easily prepared enantioenriched oxetanes. The C3-
substituted oxetane 2c was also coupled with 1a, and the
corresponding 3ac was obtained in 57% yield (Scheme 4b). On
the other hand, unsuccessful oxetanes included 2,2- and 3,3-
disubstituted oxetanes. In the former case, the ring-opening
isomerization predominantly occurred to form the corresponding
homoallylic alcohol whereas the latter substrates resulted in no
conversion probably because of steric factors (data not shown).
a) reaction of oxetane (2a) without benzamide 1
NiCl2(PEt3)2
3Å MS, Et3N
O
N.R.
DMF, 160 ˚C, 20 h
2a
b) reaction of 1a with 3-chloropropanol (5) instead of oxetane (2a)
O
NiCl2(PEt3)2
a) reaction with chiral C2-substituted oxetane 2b
3Å MS, Et3N
N
Cl
OH
+
N.R.
H
O
O
N
DMF, 160 ˚C, 22 h
NiCl2(PEt3)2
O
Ph
*
3Å MS, Et3N
1a
5 (4.0 equiv)
O
N
H
*
+
N
DMF, 160 ˚C, 22 h
Ph
c) deuterium-labeling experiments with [D5]-1a
1a
(S)-2b
(R)-3ab
98:2 e.r.
50% D
54%, 98:2 e.r.
D
O
D
D/H
O
b) reaction with C3-substituted oxetane 2c
NiCl2(PEt3)2
3Å MS, Et3N
D
D
D
D
N
H
N
O
O
O
H
NiCl2(PEt3)2
3Å MS, Et3N
N
N
DMF, 160 ˚C, 3 h
D/H
O
N
H
+
D
D
50% D
DMF, 160 ˚C, 22 h
N
Ph
[D5]-1a (>99% D)
Ph
30% D
1a
2c
29% D
3ac 57%
O
D/H
O
D/H
NiCl2(PEt3)2
3Å MS, Et3N
[D5]-1a (>99% D)
+
D
D
D
+
O
N
Scheme 4. Nickel-catalyzed C–H coupling of benzamide 1a with some
substituted oxetanes 2. Conditions: see the footnote in Scheme 2.
H
N
DMF, 160 ˚C, 3 h
2a (4.0 equiv)
D/H
D
D
D
30% D
14%
To get some insight into the reaction mechanism, we
implemented the following control experiments. In the absence of
the benzamide 1, the parent oxetane (2a) gave no detectable
amount of ring-opening side products (Scheme 5a). Additionally,
the reaction of 1a with 3-chloropropanol (5), which is the most
conceivable ring-opening side product promoted by the NiCl2 salt,
resulted in no conversion (Scheme 5b). These outcomes suggest
that the oxetane itself is directly coupled with 1a. Deuterium-
labeling experiments with [D5]-1a were also performed (Scheme
5c): in the presence and absence of oxetane (2a), the significant
ortho-H/D scrambling occurred even at an early stage of the
reaction, thus indicating that the C–H cleavage process is facile
and not the rate-limiting step.[15]
Scheme 5. Control experiments. N.R. = no reaction.
HCl
OH
N
OH
LnNi
Cl
N
+
H2N
N
3aa
N
LnNi
N
7
8
1a
cat. Ni
alcoholysis
NiCl2(PEt3)2
2a
LnNiCl
6
O
N
H
N
OH
OH
HCl
OH
11
N
N
Based on the above findings, we are tempted to propose that
the reaction mechanism of 1a with 2a is as follows (Scheme 6).
First, the nickel(II) precatalyst NiCl2(PEt3)2 is believed to be
reduced to nickel(I) species 6.[16] The observed incompatibility
with the Ar-Cl moiety (Scheme 2, 3ka) can support the
intermediacy of nickel at the lower oxidation state. Although the
LnNi
N
LnNi
N
O
O
9
10
Scheme 6. Plausible mechanism. L = ligand.
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10.1002/chem.201900543
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COMMUNICATION
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Me
O
O
Me
NiCl2(PEt3)2
3Å MS, Et3N
O
N
H
31%
N
0% w/o NiCl2(PEt3)2
DMF, 160 ˚C, 10 h
OH
11ha
3ha
Scheme 7. Effects of nickel catalyst in intramolecular alcoholysis.
In conclusion, we have developed a nickel-catalyzed C–H
coupling of 8-aminoquinoline-derived benzamides with oxetanes.
The reaction occurs with the spontaneous removal of 8-
aminoquinoline bidentate auxiliary to form the corresponding
seven-membered benzolactones directly. The present nickel
catalysis can provide a new avenue to such medium-sized
lactones of frequent occurrence in bioactive molecules and
natural products. Additionally, this is one of the limited successful
applications of oxetanes under the redox-active transition metal
catalysis. Further improvement of catalyst turnover, expansion of
substrate scope, and development of related C–H coupling with
other strained heterocycles are under investigation in our
laboratory.
[9]
[10] For selected seminal work and reviews on nickel-catalyzed C–H
couplings with the assistance of aminoquinoline N,N-double coordination,
see: a) H. Shiota, Y. Ano, Y. Aihara, Y. Fukumoto, N. Chatani, J. Am.
Chem. Soc. 2011, 133, 14952; b) Y. Aihara, N. Chatani, J. Am. Chem.
Soc. 2013, 135, 5308; c) Y. Aihara, N. Chatani, J. Am. Chem. Soc. 2014,
136, 898; d) L. C. M. Castro, N. Chatani, Chem. Lett. 2015, 44, 410.
[11] Pioneering work: a) V. Z. Zaitsev, D. Shabashov, O. Daugulis, J. Am.
Chem. Soc. 2005, 127, 13154. Selected reviews: b) M. Corbet, F. De
Campo, Angew. Chem. Int. Ed. 2013, 52, 9896; Angew. Chem. 2013,
125, 10080; c) G. Rouquet, N. Chatani, Angew. Chem. Int. Ed. 2013, 52,
11726; Angew. Chem. 2013, 125, 11942; d) N. Chatani, Top. Organomet.
Chem. 2016, 56, 19; e) J. Liu, G. Chen, Z. Tan, Adv. Synth. Catal. 2016,
358, 1174; f) Y. Kommagalla, N, Chatani, Coord. Chem. Rev. 2017, 350,
117.
Acknowledgements ((optional))
This work was supported by JSPS KAKENHI Grant Nos.
17J00349 (Grant-in-Aid for JSPS Research Fellow) to K.T., JP
15H05485 (Grant-in-Aid for Young Scientists (A)) and 18K19078
(Grant-in-Aid for Challenging Research (Exploratory)) to K.H.,
and JP 17H06092 (Grant-in-Aid for Specially Promoted
Research) to M.M. S.X. thanks Japanese government (MEXT)
scholarship.
Conflict of Interest
[12] For limited successful examples of C–H couplings with concomitant
removal of bidentate directing groups, see: a) K. Takamatsu, K. Hirano,
M. Miura, Org. Lett. 2015, 17, 4066; b) T. Uemura, T. Igarashi, M.
Noguchi, K. Shibata, N. Chatani, Chem. Lett. 2015, 44, 621; c) P.
Gandeepan, P. Rajamalli, C.-H. Cheng, Angew. Chem. Int. Ed. 2016, 55,
4308; Angew. Chem. 2016, 128, 4380; d) C. Yamamoto, K. Takamatsu,
K. Hirano, M. Miura, J. Org. Chem. 2017, 82, 9112; e) J. Liu, J. Zou, J.
Yao, G. Chen, Adv. Synth. Catal. 2018, 360, 659.
The authors declare no conflict of interest.
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff)
Keywords: C–H coupling · lactones · medium-sized rings ·
nickel · oxetanes
[13] Selected examples: a) H. Fujimoto, M. Inagaki, Y. Satoh, E. Yoshida, M.
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[2]
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[3]
[4]
[5]
[6]
[7]
[8]
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[14] Unfortunately, attempts to apply aliphatic amides such as pivalamide
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[15] The source of H might be still contaminated water. We confirmed the
partial deuterium incorporation (22% D) at the ortho position of 1a when
a mixture of 1a, D2O (1.0 equiv), and nickel catalyst was simply heated
in DMF.
E. Vasilikogiannaki, A. Louka, M. Stratakis, Organometallics 2016, 35,
3895.
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Recent selected reviews on the metal-promoted C–H functionalization,
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10.1002/chem.201900543
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G. C. Fu, J. Am. Chem. Soc. 2014, 136, 16588; d) R. A. Jagtap, C. P.
Vinod, B. Punji, ACS Catal. 2019, 9, 431.
[18] Ohshima reported the related nickel(II)-catalyzed alcoholysis of 8-
aminoquinoline amides. T. Deguchi, H.-L. Xin, H. Morimoto, T. Ohshima,
ACS Catal. 2017, 7, 3157. The yield of 3ha was lower than that observed
in Scheme 2, which suggests another lactonization pathway, such as the
direct conversion of Ni-associated intermediate 10 to the benzolactone
3aa (Scheme 6).
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salts to them of lower oxidation state at high reaction temperature; a) T.
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10.1002/chem.201900543
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
S. Xu, K. Takamatsu, K. Hirano,* M.
Miura*
O
O
cat. NiCl2(PEt3)2
3Å MS, Et3N
O
Ph
*
O
N
H
*
+
Page No. – Page No.
DMF
N
Ph
98:2 e.r.
98:2 e.r.
Synthesis of Seven-Membered
Benzolactones by Nickel-Catalyzed
C–H Coupling of Benzamides with
Oxetanes
Breaking the fourth wall: A NiCl2(PEt3)2-catalyzed regioselective C–H coupling of 8-
aminoquinoline-derived benzamides with oxetanes has been developed. The
reaction proceeds with concomitant removals of the 8-aminoquinoline auxiliary to
directly form the corresponding seven-membered benzolactones, which are
frequently occurring in natural products and bioactive molecules. Additionally, the
use of enantioenriched substituted oxetane provides a new avenue to the optically
active benzolactone.
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