Formal [4+2] cycloaddition of 3-phenylcyclobutanones with nitriles

Article abstract of DOI:10.1016/j.tetlet.2018.11.040

Various 3-phenylcyclobutanones reacted with aliphatic and aromatic nitriles in the presence of Me₃SiOTf to afford dihydropyridones by formal [4+2] cycloaddition.

Full text of DOI:10.1016/j.tetlet.2018.11.040

Accepted Manuscript
Formal [4+2] cycloaddition of 3-phenylcyclobutanones with nitriles
Emiko Igarashi, Kenta Sakamoto, Tomoyuki Yoshimura, Jun-ichi Matsuo
PII:
S0040-4039(18)31367-4
https://doi.org/10.1016/j.tetlet.2018.11.040
TETL 50425
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Reference:
Tetrahedron Letters
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8 November 2018
13 November 2018
Please cite this article as: Igarashi, E., Sakamoto, K., Yoshimura, T., Matsuo, J-i., Formal [4+2] cycloaddition of 3-
phenylcyclobutanones with nitriles, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.11.040
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Graphical Abstract
Formal [4+2] cycloaddition of 3-
phenylcyclobutanones with nitriles
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Emiko Igarashi, Kenta Sakamoto, Tomoyuki Yoshimura, and Jun-ichi Matsuo*

1
Tetrahedron Letters
Formal [4+2] cycloaddition of 3-phenylcyclobutanones with nitriles
Emiko Igarashi, Kenta Sakamoto, Tomoyuki Yoshimura, and Jun-ichi Matsuo*
Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
ARTICLE INFO
ABSTRACT
Article history:
Received
Various 3-phenylcyclobutanones reacted with aliphatic and aromatic nitriles in the presence of
Me3SiOTf to afford dihydropyridones by formal [4+2] cycloaddition.
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Cyclobutanone
Nitrile
Dihydropyridone
Lewis acid
Cycloaddition
Dihydropyridones are useful building blocks for nitrogen-
containing six-membered compounds such as indolizidine,
peperidine, and quinolizidine alkaloids [1]. Dihydropyridones
have been prepared by addition of nucleophiles to N-acyl
pyridinium salts of 4-methoxypyridine [2], aza Diels-Alder
reaction of Danishefsky’s diene with imines,[3] or cyclization of
acetonitrile as a solvent (Table 1). It was found that high a
reaction temperature (refluxing acetonitrile) was required for
smooth cycloaddition. Me3SiOTf was the most suitable Lewis
acid for the present [4+2] cycloaddition (entries 1-6). In the
cases of using BF3-OEt2 and SnCl4, substantial amounts of 1a
were recovered (entries 2 and 3). Enone 3, which was formed by
ring cleavage of 1a and successive proton-transfer was obtained
in 22% yield when TiCl4 was used as a Lewis acid (entry 4).
-amino-1,3-diketones [4,5].
We have studied formal [4+2]
cycloaddition of cyclobutanones with various unsaturated
compounds in the presence of Lewis acids [6]. Recently, we
reported that 3-ethoxycyclobutanones reacted with alkynes to
give [4+2] cycloadducts [7]. We then planned formal [4+2]
cycloaddition of cyclobutanones with nitriles (Scheme 1) [8].
Table 1. Effects of Lewis acids.a
There have been limited examples of [4+2] cycloaddition to
nitriles. Formal [4+2] cycloaddition of azetidines with nitriles
[9], nickel-catalyzed [4+2] cycloaddition of 1,3-dienes with
nitriles [10], and gold-catalyzed [4+2] cycloaddition of
propiolates with nitriles [11,12] have been reported, but there has
been no report about cycloaddition between cyclobutanones and
nitriles. In this paper, we describe the first example of formal
[4+2] cycloaddition of 3-phenylcyclobutanones with nitriles.
entry
Lewis acid
2a (% yield)b
recovery of
1a (%)b
1c
2
3
4
5
6
Me3SiOTf
BF3-OEt2
SnCl4
70
17
19
0
0
69
44
0
TiCl4
AlCl3
0
37
13
Scheme 1. Formal [4+2] cycloaddition of cyclobutanones with
nitriles.
Et2AlCl
0
aLewis acid (2.0 equiv) was used.
bIsolated yield.
cReaction time: 2 h.
Reaction conditions for formal [4+2] cycloaddition of
cyclobutanone 1a and acetonitrile [13] were screened by using

2
Tetrahedron
to afford the corresponding dihydropyridones 4b-d in 61-69%
yields (Table 3). Substituens on the aromatic group of 3-
arylcyclobutanones 1e,f affected yields of cyloadducts 4e,f.
Cycloaddition of 3-(4-bromophenyl)cyclobutanone 1e with
acetonitrile proceeded smoothly whereas 4f was obtained in a
low
yield
(46%)
by
cycloaddition
of
3-(4-
methoxyphenyl)cyclobutanone 1f even after a prolonged reaction
time. In the reaction of 1f and acetonitrile, it was found that ring-
opening of 1f took place and unsaturated ketone 6 was
obtained in 10% yield together with 4f [15]. The reactions of 2-
nonsubstituted and mono-substituted cyclobutanones 1g-i
directly gave products 5g-i in 52-54% yields after complete
isomerization of the initially formed 4. It should be noted that 2-
nonsubstituted cyclobutanone 1g smoothly reacted with
acetonitrile to give 5g in 54% yield in spite of poor tendency for
ring cleavage of 1g [14]. Thus prepared 4(1H)-pyridones 5 are
also interesting skeletons for bioactive compounds [16].
Next, formal [4+2] cycloadditions of various aliphatic and
aromatic nitriles were investigated by using Me3SiOTf and 1a
(Table 2). In addition to acetonitrile, substituted acetonitriles
including propionitrile, 2-phenylacetonitrile, and isobutyronitrile
reacted with 1a to give the corresponding dihydropyridones 2b-d
in 46-63% yields (entries 1-3).
However, a reaction of
pivalonitrile did not afford a dihydropyridone 2e but 5,6-dihydro-
4H-1,3-oxazine 2e’ was obtained in 39% yield (entry 4).
Cycloaddition of aromatic nitriles was performed by using 10
equivalents of aromatic nitriles at 100 °C (entries 5-7). It was
found that the reaction of 4-methoxybenzonitrile gave the
corresponding cycloadduct 2g in 61% yield, while the reaction of
4-carbomethoxybenzonitrile gave the product 2h in 22% yield
(entries 6 and 7). Therefore, these results suggested that
stabilization of a cationic intermediate that was formed after
addition of a nitrile was important for the present cycloaddition.
Reaction of aromatic nitriles at a higher reaction temperature
(150 °C) did not improve the yields of cycloadducts. The use of
a solvent such as benzotrifluoride resulted in a substantial
decrease in the yields of products.
Table 3. Reactions of various cyclobutanones.a
Table 2. Reactions of various nitriles.a
entry RCN
Time (h)
2
Yield
(%)b
1
2c
EtCN
2
2b
2c
2d
2e
2f
63
46
49
0d
BnCN
3
3
i-PrCN
1.5
3
4
t-BuCN
5c
6c
7c
PhCN
2
34
61
22
4-MeOC6H4CN
4-MeO2CC6H4CN
2
2g
2h
aTwo equivalents of Me3SiOTf were used. Acetonitrile was used as a solvent.
Yields are isolated yields.
2
aTwo equivalents of Me3SiOTf were used.
bIsolated yield.
bReaction time: 3 h.
cReaction conditions: nitrile (10 equiv), 100 °C.
dCompound 2e’ was obtained in 39% yield.
A proposed reaction mechanism is shown in Scheme 2.
Activation of cyclobutanone 1a with Me3SiOTf followed by
reaction with nitrile gives 8. It was not clarified whether 8 was
formed by an SN2 mechanism between 7 and nitrile or by a
reaction of nitrile with a benzylic cation formed by a carbon-
Cycloaddition of spirocyclobutanones 1b-d having a five-,
six-, or seven-membered ring smoothly reacted with acetonitrile

3
L. Pagenkopf, J. Am. Chem. Soc. 125 (2003) 8122; (c) C.
L.Morales, B. L. Pagenkopf, Org. Lett. 10 (2008) 157; (d) B.
carbon bond cleavage of 7.
Intramolecular 6-endo-dig
cyclization of 8 affords 2a. The present cycloaddition did not
proceed via enone 3 since treatment of a mixture of 3 and
acetonitrile with Me3SiOTf did not afford 2a.
Bajtos, B. L. Pagenkopf, Eur. J. Org. Chem. (2009) 1072; (e) B. L.
Pagenkopf, N. Vemula, Eur. J. Org. Chem. (2017) 2561; (f) M. M.
Abd Rabo Moustafa, B. L. Pagenkopf, Org. Lett. 12 (2010) 3168.
9. (a) B. A. B. Prasad, A.Bisai, V. K. Singh, Org. Lett. 6 (2004)
4829; (b) M. K. Ghorai, K. Das, A. Kumar, A. Das, Tetrahedron
Lett. 47 (2006) 5393; (c) M. K. Ghorai, K. Das, A. Kumar,
Tetrahedron Lett. 50 (2009) 1105.
10. M. Ohashi, I. Takeda, M. Ikawa, S. Ogoshi, J. Am. Chem. Soc.
133 (2011) 18018.
11. S. N. Karad, W.-K. Chung, R.-S. Liu, Chem. Sci. 6 (2015) 5964.
12. For other [4+2] cycloaddition of nitriles, see: F. Liu, C. Li, J. Org.
Chem. 74 (2009) 5699.
13. A review for acetonitrile as a building block and reactant: B. H.
Hoff, Synthesis 50 (2018) 2824.
14. M. Kanie, T. Yoshimura, J. Matsuo, Synthesis 50 (2018) 548.
15. A Me3SiOTf-promoted reaction of 3-ethoxy-2,2-
dimethylcyclobutanone and acetonitrile did not afford the
corresponding cycloadducts.
16. J. M. Bueno, F. Calderon, J. Chicharro, J. C. De la Rosa, B. Díaz,
J. Fernández, J. M. Fiandor, M. T. Fraile, M. García, E. Herreros,
A. García-Pérez, M. Lorenzo, A. Mallo, M. Puente, A. Saadeddin,
S. Ferrer, I. Angulo-Barturen, J. N. Burrows, M. L. León, J. Med.
Chem. 61 (2018) 3422.
Scheme 2. A proposed reaction mechanism.
In conclusion, we developed a formal [4+2] cycloaddition of
3-phenylcyclobutanones
with
nitriles
to
afford
dihydropyridinones by using Me3SiOTf as a Lewis acid.
Various nitriles including alkyl nitriles and aromatic nitriles
reacted with 2,2-dialkyl, 2-monosubstituted, and 2-nonsubstituted
3-phenylcyclobutanones. The present cycloaddition is a unique
method for synthesis of multi-substituted dihydropyridones.
Acknowledgments
This work was supported by JSPS KAKENHI Grant Number
15K07855 and Kanazawa University SAKIGAKE project. We
thank Prof. Hirohisa Ohmiya (Kanazawa University) for the use
of FTIR.
Supplementary Material
Supplementary data associated this article can be found in the
online version at.
References and notes
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217.
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Bull. Chem. Soc. Jpn. 43 (1970) 901.
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4
Tetrahedron
Highlights
·3-Phenylcyclobutanones react with nitriles to
dihydropyridones
·5,6-Dihydro-4H-1,3-oxazine was obtained by a
reaction of a hindered nitrile
·4(1H)-Pyridones were obtained selectively from 2-
alkylcyclobutanones
·A stepwise mechanism is suggested by substituent
effects of arylnitriles

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