Ni-Catalyzed Denitrogenative Cross-Coupling of Benzotriazinones and Cyclopropanols: An Easy Access to Functionalized β-Aryl Ketones

Article abstract of DOI:10.1021/acs.orglett.0c01579

A novel Ni-catalyzed denitrogenative cross-coupling between benzotriazinones and cyclopropanols is reported herein. This neoteric reactivity allows for the convenient synthesis of β-(o-amido)aryl ketones from readily available starting materials with good yields (up to 93percent) and general substrate scope.

Full text of DOI:10.1021/acs.orglett.0c01579

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Letter
Ni-Catalyzed Denitrogenative Cross-Coupling of Benzotriazinones
and Cyclopropanols: An Easy Access to Functionalized β‑Aryl
Ketones
Jincan Li, Yan Zheng, Mingxian Huang, and Wanfang Li*
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ABSTRACT: A novel Ni-catalyzed denitrogenative cross-coupling
between benzotriazinones and cyclopropanols is reported herein.
This neoteric reactivity allows for the convenient synthesis of β-(o-
amido)aryl ketones from readily available starting materials with
good yields (up to 93%) and general substrate scope.
Scheme 1. Conception of Ni-Catalyzed Denitrogenative
Cross-Coupling of Benzotriazenones with Cyclopropanol
he search for new reactivities has long been one
Tfundamental task of organic chemistry. Admittedly,
transition-metal-catalyzed cross-coupling reactions harnessed
the reactivities of different electrophiles and nucleophiles in a
broad and delicate way, which engendered an epochal
compilation of synthetically powerful reactions.1 The explora-
tion of nonclassical electrophiles (those besides organo halides
and pseudohalides) and nucleophiles (those besides organo-
metallics) rendered many new possibilities for the facile
construction of C−C bonds within various structural motifs.
Nitrogen is renowned as an excellent electrofugal leaving
group, whereby the employment of aryl diazonium salts and
triazenes as electrophiles is experiencing a renaissance in cross-
coupling chemistry.2 Recently, 1,2,3-benzotriazinones, a type
of readily available cyclic triazenes de facto, witnessed a series
of interesting transformations in the presence of metal
catalysts. In 2008, Murakami and co-workers reported the
first synthesis of isoquinolones by the Ni-catalyzed denitroge-
native alkyne insertion of 1,2,3-benzotriazin-4(3H)-ones.3
Later on, the same group incorporated allenes,4 1,3-dienes5
and isocyanides6 for the denitrogenative transannulation to
form different heterocycles. Other groups achieved the
asymmetric,7 visible-light-promoted,8 or Pd/Cu catalyzed9
version of these reactions using alkynes or arynes.10
Intrigued by the above denitrogenative transannulation
reactions with 1,2,3-benzotriazin-4(3H)-ones and our con-
tinued interest in the denitrogenative cross-coupling reaction
involving aryl triazenes,11 we envisaged that benzotriazinones
might serve as reactive electrophiles to couple with a wide
array of nucleophiles to form new C−C bonds in high
efficiency. In 2018, the Mannathan and the Cheng group12
independently reported Ni-catalyzed denitrogenative cross-
coupling between 1,2,3-benzotriazin-4(3H)-ones and organo-
boronic acids, which allowed for a facile access to ortho-
arylated and alkenylated benzamides (Scheme 1a).
Unmasked cyclopropanols are a class of easily accessible
small ring building blocks which have found versatile
applications in organic synthesis.13 They have received
considerable attention because the catalytically formed cyclo-
propoxides can easily tautomerize to homoenolates which
could be trapped by various electrophiles to afford diverse β-
functionalized ketones (Scheme 1b).14 On the basis of the
burgeoning applications of 1,2,3-benzotriazin-4(3H)-ones and
cyclopropanols, we speculated that the Ni(0) catalyst may
activate both partners to forge new C−C bonds in the
Received: May 8, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01579
© XXXX American Chemical Society
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framework of β-(o-amido)aryl ketones (Scheme 1c). Of note,
these valuable frameworks had only been constructed via Ru,
Rh or Co-catalyzed C−H activation procedures with limited
substrate scope or involving less stable starting materials.15
Initially, N-(p-tolyl)benzotriazinone (1a) and 1-phenyl-
cyclopropan-1-ol (2a) were reacted in dioxane at 80 °C in
the presence of 10 mol % of Ni(COD)2/PPh3. After 18 h, the
desired product 3a was obtained with 34% yield (Table 1,
(Scheme 2). It was found that 6-methyl- and 6-chloro-
substituted 1,2,3-benzotriazinones (1b and 1c) were coupled
Scheme 2. Substrate Scope of 1,2,3-Benzotriazinones
a
Table 1. Optimization of the Reaction Conditions
b
entry
ligand
solvent
T (°C)
yield (%)
1
2
3
4
5
6
7
8
PPh3
PPh3
PPh3
P(t-Bu)3
P(n-Bu)3
P(n-Bu)3
dppb
BINAP
−
PMe3
PMe3
PMe3
PMe3
PMe3
PMe3
PMe3
Pd(OAc)2/PPh3
Pd(PPh3)4
CuI/PPh3
dioxane
dioxane
toluene
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
MeCN
THF
80
100
100
80
34
52
63
23
25
35
<5
<5
15
67
78
91
76
64
57
23
trace
15
80
100
100
100
80
80
90
100
100
100
100
100
100
100
100
c
c
9
10
11
12
13
14
15
16
17
18
19
with 2a to afford 5-chloro-2-(3-oxo-3-phenylpropyl)-N-phenyl-
benzamide (3b) and 5-methyl-2-(3-oxo-3-phenylpropyl)-N-(p-
tolyl)benzamide (3c) in 80% and 81% yield, respectively. A
methyl group on the 8-position depressed the efficiency of this
transformation, and 3d was isolated in 55% yield, which might
be caused by the steric hindrance near the reaction site. 7-
Methoxybenzotriazinone (1e) also gave the product 3e in 57%
yield. In addition, naphthotriazenone (1f) and thienotriaze-
none (1g) were also amenable to the denitrogenative cross-
coupling to form the corresponding functionalized β-aryl
ketones 3g and 3h in preparatively meaningful yield. R2 in the
triazinones are not necessarily to be aryl groups. For instance,
61% yield of aliphatic amide (3h) was obtained when R2 is a 2-
(2-thienyl)ethyl group (1h). It is worth mentioning that
pyridotriazinone (1i) did not offer the corresponding product
(3i).
Encouraged by the wide scope of benzotriazinones, we next
examined the denitrogenative cross-coupling reaction with
various cyclopropanols (Scheme 3), which can be easily
synthesized by Kulinkovich cyclopropanation of esters.16
Gratifyingly, alkyl-substituted cyclopropanols smoothly partici-
pated in the reaction to afford the β-(o-amido)aryl ketones in
good to excellent yields (65−91%, 4a−e), among which the
linear alkyl cyclopropanol (R3 = n-butyl) gave the highest yield
(4a, 91%). 4-tert-Butylbenzylcyclopropanol also reacted with
1a to form the functionalized dialkyl ketone in 65% yield (4e).
Several other aryl cyclopropanols were subjected to the
optimal conditions to define the substitution effect on the
denitrogenative cross-coupling reaction. To our delight, 1-(p-
tolyl)cyclopropan-1-ol reacted with 1a to give 4f in almost
quantitative yield (93%). However, p-methoxy and tert-butyl
substituents led to lower yields of 4g and 4h, i.e., 85% and
47%, respectively. 1-(4-Fluorophenyl)cyclopropan-1-ol reacted
with 1a to form 4i in 74% yield, whereas its chloro counterpart
led to 4j in only 40% yield, which may be attributed to the
higher reactivity of aryl C−Cl bond toward nickel catalyst.17
DMF
dioxane
dioxane
dioxane
nr
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), Ni(COD)2
(0.02 mmol), ligand (0.04 mmol for monophisphines; 0.02 mmol for
b
c
diphosphines); 2.0 mL of solvent, 18 h. Isolated yield. N-
Tolylbenzamide was the main side product. nr = no reaction.
entry 1). Increasing the temperature to 100 °C or changing the
solvent to toluene improved the yield modestly to 52% and
63%, respectively (Table 1, entries 2 and 3). To further
improve the yield of 3a, the ligand effect was examined. Other
monophosphines like P(t-Bu)3 and P(n-Bu)3 gave no better
results than PPh3 (Table 1, entries 4−6). Diphosphine ligands
like dppb and BINAP blocked the cross-coupling reaction
wherein the decomposition of 1a to N-tolylbenzamide became
the main side reaction (Table 1, entries 7 and 8). Omitting the
ligand resulted in the production of 3a with only 15% yield
(Table 1, entry 9). To our delight, when PMe3 was used, the
yield of 3a was optimized up to 91% at 100 °C (Table 1,
entries 10−12). The reaction in other solvents like toluene,
acetonitrile, THF, and DMF was much less efficient than in
dioxane. In a control experiment, only a trace of 3a was
detected in the presence of Pd(OAc)2/PPh3. However, using
Pd(PPh3)4 afforded 3a in 15% yield (Table 1, entry 18). CuI
was totally inert for this reaction (Table 1, entry 19). These
observations indicated that nickel was the unique metal for this
denitrogenative cross-coupling.
With the optimized conditions in hand, we tried to broaden
the substrate scope to other substituted 1,2,3-benzotriazinones
B
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Scheme 3. Substrates Scope of Cyclopropanols
Scheme 5. Mechanistic Studies
reports,12 we assumed that this reaction may probably not
involving a radical process. In addition, when 1a was reacted
with 68% deuterated cyclopropanol 2a19 under the standard
conditions, the deuterium was found to be partially
incorporated at α-position 3a (Scheme 5b; see the Supporting
Information for analysis).
The above screening experiments show that this nickel-
catalyzed denitrogenative cross-coupling between benzotriazi-
nones and cyclopropanols tolerated a wide range of
substituents on both reaction partners. To further demonstrate
the efficiency of this new method for the facile access to β-(o
amido)aryl ketones, we performed several crossover couplings
of the two components (Scheme 4). Moderate to good yields
On the basis of the above experiments and the literature
reports, a possible reaction pathway is proposed (Scheme 6).
Scheme 6. Plausible Catalytic Cycle
Scheme 4. Further Exploration of the Substrate Scope
At first, oxidative addition benzotriazinone with Ni(0) and
subsequent extrusion of gaseous N2 affords the five-membered
azanickelacycle A.20 Then the nickel−nitrogen bond is cleaved
by the cyclopropanol (2) to form nickel cyclopropanoxide B,
which automatically tautomerizes to form aryl alkyl nickel
species C. At this junction, C can undergo ensuing reductive
elimination to release the β-aryl ketone product (3) and
regenerate the Ni(0). Alternatively, it undergoes β-hydride
elimination to form enone-complexed nickel hydride D,21
wherein reinsertion of the enone would lead to intermediate E.
The final product (3) is then released by the protodemeta-
lation by the cyclopropanol (2), which also accounts for the
incorporation of 28% deuterium at the α-position of the ketone
in d-3a. In some cases, the intermediate C directly undergoes
were obtained for all of the examples. These pharmaceutically
interesting scaffolds,18 however, still lack some general and
practical methods for their synthesis.
To gain some insight into the reaction pathway, we first
performed the model reaction in the presence of 1 equiv of
TEMPO and 1,1-diphenylethene as the radical scavengers, and
the yield of 3a was lowered to 75% and 63%, respectively
(Scheme 5a). Based on these observations and the previous
C
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(3) Miura, T.; Yamauchi, M.; Murakami, M. Org. Lett. 2008, 10,
3085−3088.
off-cycle protodemetalation to give the denitrogenated side
product (3′).
(4) Yamauchi, M.; Morimoto, M.; Miura, T.; Murakami, M. J. Am.
Chem. Soc. 2010, 132, 54−55.
In summary, we have discovered a new denitrogenative
cross-coupling reaction between benzotriazinones and cyclo-
propanols catalyzed by simple nickel complex, furnishing a
facile access to the valuable building block of β-(o-amido)aryl
ketones. The innovation of this new transformation utilizes the
oxidative formation of azanickelacycle between Ni(0) and
triazinones after extrusion of nitrogen and the homoenolate
nature of the cyclopropanols. This work extended the scope of
the nickel catalysis in the double activation of unconventional
electrophiles and nucleophiles and will find some useful
applications for the construction of some building blocks that
require otherwise lengthy or detoured synthetic routes. Further
investigations into the new reactivities based on this strategy
are underway in our laboratory.
(5) Miura, T.; Morimoto, M.; Yamauchi, M.; Murakami, M. J. Org.
Chem. 2010, 75, 5359−5362.
(6) Miura, T.; Nishida, Y.; Morimoto, M.; Yamauchi, M.; Murakami,
M. Org. Lett. 2011, 13, 1429−1431.
(7) (a) Fang, Z.-J.; Zheng, S.-C.; Guo, Z.; Guo, J.-Y.; Tan, B.; Liu,
X.-Y. Angew. Chem., Int. Ed. 2015, 54, 9528−9532. (b) Wang, N.;
Zheng, S.-C.; Zhang, L.-L.; Guo, Z.; Liu, X.-Y. ACS Catal. 2016, 6,
3496−3505.
(8) Wang, H.; Yu, S. Org. Lett. 2015, 17, 4272−4275.
(9) Hari Balakrishnan, M.; Mannathan, S. Org. Lett. 2020, 22, 542−
546.
(10) Thorat, V. H.; Upadhyay, N. S.; Murakami, M.; Cheng, C.-H.
Adv. Synth. Catal. 2018, 360, 284−289.
(11) (a) Li, W.; Beller, M.; Wu, X.-F. Chem. Commun. 2014, 50,
9513−9516. (b) Li, W.; Wu, X.-F. Org. Biomol. Chem. 2015, 13,
5090−5093. (c) Li, W.; Wu, X.-F. Org. Lett. 2015, 17, 1910−1913.
(12) (a) Hari Balakrishnan, M.; Sathriyan, K.; Mannathan, S. Org.
Lett. 2018, 20, 3815−3818. (b) Thorat, V. H.; Upadhyay, N. S.;
Cheng, C.-H. Adv. Synth. Catal. 2018, 360, 4784−4789.
(13) (a) Gibson, D. H.; DePuy, C. H. Chem. Rev. 1974, 74, 605−
623. (b) Kulinkovich, O. G. Chem. Rev. 2003, 103, 2597−2632.
(14) (a) Zhao, H.; Fan, X.; Yu, J.; Zhu, C. J. Am. Chem. Soc. 2015,
137, 3490−3493. (b) Guo, L.-N.; Deng, Z.-Q.; Wu, Y.; Hu, J. RSC
Adv. 2016, 6, 27000−27003. (c) Jia, K.; Zhang, F.; Huang, H.; Chen,
Y. J. Am. Chem. Soc. 2016, 138, 1514−1517. (d) Lu, S.-C.; Li, H.-S.;
Xu, S.; Duan, G.-Y. Org. Biomol. Chem. 2017, 15, 324−327.
(e) Zhang, H.; Wu, G.; Yi, H.; Sun, T.; Wang, B.; Zhang, Y.; Dong,
G.; Wang, J. Angew. Chem., Int. Ed. 2017, 56, 3945−3950. (f) Che, C.;
Qian, Z.; Wu, M.; Zhao, Y.; Zhu, G. J. Org. Chem. 2018, 83, 5665−
5673. (g) Liu, H.; Fu, Z.; Gao, S.; Huang, Y.; Lin, A.; Yao, H. Adv.
Synth. Catal. 2018, 360, 3171−3175. (h) Ye, Z.; Cai, X.; Li, J.; Dai, M.
ACS Catal. 2018, 8, 5907−5914. (i) Chen, D.; Fu, Y.; Cao, X.; Luo,
J.; Wang, F.; Huang, S. Org. Lett. 2019, 21, 5600−5605. (j) Mills, L.
R.; Zhou, C.; Fung, E.; Rousseaux, S. A. L. Org. Lett. 2019, 21, 8805−
8809. (k) Yang, J.; Sun, Q.; Yoshikai, N. ACS Catal. 2019, 9, 1973−
1978. (l) Zhang, Y.-H.; Zhang, W.-W.; Zhang, Z.-Y.; Zhao, K.; Loh,
T.-P. Org. Lett. 2019, 21, 5101−5105. (m) Huang, L.; Ji, T.; Rueping,
M. J. Am. Chem. Soc. 2020, 142, 3532−3539.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01579.
■
sı
Details of experimental procedures, characterization data
for the products 3−5, NMR spectra for compounds 3−5
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
Wanfang Li − College of Science, University of Shanghai for
Science and Technology, Shanghai 200093, China;
orcid.org/0000-0002-2544-1756; Email: lwf@usst.edu.cn
Authors
Jincan Li − College of Science, University of Shanghai for Science
and Technology, Shanghai 200093, China
Yan Zheng − College of Science, University of Shanghai for
Science and Technology, Shanghai 200093, China
Mingxian Huang − College of Science, University of Shanghai
for Science and Technology, Shanghai 200093, China;
orcid.org/0000-0002-1151-2381
(15) (a) Rouquet, G.; Chatani, N. Chem. Sci. 2013, 4, 2201−2208.
(b) Zhou, X.; Yu, S.; Kong, L.; Li, X. ACS Catal. 2016, 6, 647−651.
(c) Chirila, P. G.; Adams, J.; Dirjal, A.; Hamilton, A.; Whiteoak, C. J.
Chem. - Eur. J. 2018, 24, 3584−3589.
(16) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevski, D. A. Synthesis
1991, 1991, 234.
Complete contact information is available at:
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Notes
(17) Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Nature 2014, 509,
299−309.
The authors declare no competing financial interest.
(18) For example, β-(o amido)aryl ketones are key intermediates for
the preparation of HIV protease inhibitors, gastrointestinal medicines,
and potassium-competitive acid blockers: (a) Reich, S. H.; Pino, M. J.
WO 199415906, 1994; Chem. Abstr. 1994, 122, 80898. (b) Vittoria,
C. M.; Andreas, P. WO 2006136552, 2006; Chem. Abstr. 2006, 146,
ACKNOWLEDGMENTS
■
We are grateful for the financial support provided by the
National Natural Science Foundation of China (21901163).
We also acknowledge the generous help from Prof. Kaiwu
Dong (East China Normal University) and Prof. Zhaoguo
Zhang and Prof. Xiaomin Xie (Shanghai Jiao Tong University).
100691. (c) Palmer, A. M.; Chiesa, V.; Schmid, A.; Munch, G.;
̈
Grobbel, B.; Zimmermann, P. J.; Brehm, C.; Buhr, W.; Simon, W.-A.;
Kromer, W.; Postius, S.; Volz, J.; Hess, D. J. Med. Chem. 2010, 53,
3645−3674.
REFERENCES
(19) The d-2a was prepared by hydrogen−deuterium exchange of 2a
with D2O by the reported procedure: Yang, J.; Shen, Y.; Lim, Y. J.;
Yoshikai, N. Chem. Sci. 2018, 9, 6928−6934. See also the Supporting
Information.
■
(1) Metal-Catalyzed Cross-Coupling Reactions and More, 2nd ed.;
̈
Meijere, A. d., Brase, S., Oestreich, M., Eds.; Wiley-VCH: Weinheim,
2014.
(20) See ref 3. The postulated azanickelacycle complex was
characterized by X-ray structure by reaction of 1a with equimolar
amounts of Ni(COD)2 and 1,2-bis(diphenylphosphino)benzene
(Dppbenz).
(21) We did not observe the dissociation product of enone (phenyl
vinyl ketone) in the model reaction. In a separate experiment as
(2) (a) Kimball, D. B.; Haley, M. M. Angew. Chem., Int. Ed. 2002, 41,
̃
3338−3351. (b) Roglans, A.; Pla-Quintana, A.; Moreno-Manas, M.
Chem. Rev. 2006, 106, 4622−4643. (c) Kolmel, D. K.; Jung, N.; Brase,
S. Aust. J. Chem. 2014, 67, 328−336. (d) Zhang, Y. H.; Cao, D. W.;
Liu, W. B.; Hu, H. Y.; Zhang, X. M.; Liu, C. J. Curr. Org. Chem. 2015,
19, 151−178.
D
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suggested by the reviewer, we carried out an enone additive
experiment by adding 0.3 equiv of 2-naphthalenyl vinyl ketone to
the reaction between 1a and 2a. However, the 2-naphthalenyl vinyl
ketone was not incorporated into the product.
E
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