Unexpected formal [4 + 2]-cycloaddition of chalcone imines and homophthalic anhydrides: preparation of dihydropyridin-2(1H)-ones

Article abstract of DOI:10.1039/d1ob00534k

A series of medicinally important dihydropyridin-2(1H)-ones have been preparedviaa novel [4 + 2]-formal cycloaddition reaction of chalcone imines and homophthalic anhydrides, which is a rare example of lactam construction from an imine acting as a four-atom building block. In contrast to previous studies on the reactivity of homophthalic anhydrides towards similar substrates,N-tosyl chalcone imines, we found the possibility of switching chemoselectivity by changing substituents at the nitrogen atom, which leads to the formation of heterocycles instead of the expected carbocycles. This reaction is very similar in appearance to the classic 1,2-addition of cyclic anhydrides to imines, often referred to as the Castagnoli-Cushman reaction, but differs in mechanistic details (representing a 1,4-reaction of imine). The developed atom-economical, stereoselective and catalyst- and chromatography-free protocol provided facile access to 28 structurally diverse heterocyclic products (in up to 88% yield) including synthetically challenging annelated tricyclic and previously unreported pentaaryl-substituted dihydropyridin-2(1H)-ones.

Full text of DOI:10.1039/d1ob00534k

Organic &
Biomolecular Chemistry
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Unexpected formal [4 + 2]-cycloaddition of
chalcone imines and homophthalic anhydrides:
preparation of dihydropyridin-2(1H)-ones†
Cite this: Org. Biomol. Chem., 2021,
19, 3829
Received 18th March 2021,
Accepted 5th April 2021
Natalia Guranova, Pavel Golubev, Olga Bakulina, * Dmitry Dar’in, Grigory Kantin
and Mikhail Krasavin
DOI: 10.1039/d1ob00534k
rsc.li/obc
A series of medicinally important dihydropyridin-2(1H)-ones have been studied. Cinnamic aldehyde derivatives (N-alkyl/aryl/sul-
been prepared via a novel [4 + 2]-formal cycloaddition reaction of fonyl imines10–13 and oximes14) reacted with homophthalic
chalcone imines and homophthalic anhydrides, which is a rare (HPA), succinic, glutaric and diglycolic anhydrides via the
example of lactam construction from an imine acting as a four- Castagnoli–Cushman reaction (CCR) pathway, giving vinyl sub-
atom building block. In contrast to previous studies on the reactiv- stituted γ- or δ-lactams (Fig. 1b). This is an example of the
ity of homophthalic anhydrides towards similar substrates, N-tosyl “1,2”-reaction of azadienes, where a heterocyclic core is
chalcone imines, we found the possibility of switching chemo- formed with the incorporation of an N(1)–C(2) fragment (the
selectivity by changing substituents at the nitrogen atom, which CvN double bond reacts). Introduction of a bulky trityl group
leads to the formation of heterocycles instead of the expected car- (Trt) to the nitrogen atom switched the reaction chemo-
bocycles. This reaction is very similar in appearance to the classic selectivity – azadiene atoms 3 and 4 were involved (CvC bond)
1,2-addition of cyclic anhydrides to imines, often referred to as the in this case, giving α-tetralone-derived carbocyclic products,
Castagnoli–Cushman reaction, but differs in mechanistic details thus representing a Tamura-type reaction15 (Fig. 1c). The same
(representing a 1,4-reaction of imine). The developed atom-econ- effect was achieved via introducing an aryl group to the C-2
omical, stereoselective and catalyst- and chromatography-free atom of N-sulfonylazadienes (making them chalcone imines)
protocol provided facile access to 28 structurally diverse hetero- as reported in ref. 16 (Fig. 1d).
cyclic products (in up to 88% yield) including synthetically challen-
In this work, we have expanded the scope of chalcone
ging annelated tricyclic and previously unreported pentaaryl-sub- imines studied by using N-aryl/alkyl/OH/NHPh derivatives and
stituted dihydropyridin-2(1H)-ones.
discovered that in this case the reaction chemoselectivity is
switched again to a rare Castagnoli–Cushman-type reaction
(Fig. 1e). An unusual type of lactam cycle formation, where
imine acts as a four-atom building block (atoms 1 and 4 are
involved), differentiates it from the classic CCR. Herein, we
report the first preparative procedure for the synthesis of dihy-
dropyridin-2(1H)-ones based on this transformation. Such
compounds have been reported previously in Castagnoli–
Cushamn reactions only as minor impurities (2.2% yield)17 or
unstable reaction intermediates.16
Noteworthily, the 2-piperidone (δ-lactam) moiety belongs to
highly relevant cores for medicinal chemistry design. In par-
ticular, dihydropyridin-2(1H)-ones have been reported as lead
molecules in more than twenty patents aimed at the develop-
ment of therapeutic agents for the treatment of heart diseases
(human neutrophil elastase (HNE) inhibitors, Rho-kinase
inhibitors),18,19 pulmonary diseases (HNE inhibitors),20 pro-
static hyperplasia (α-1a-adrenoceptor antagonists)21 and
inflammatory diseases22 (S-nitrosoglutathione reductase
inhibitors and neurokinin-3 receptor antagonists). This aspect
makes the development of a methodology giving access to
Introduction
1-Aza-1,3-dienes (Fig. 1a) have a long and fruitful history of
application in organic synthesis1 and have been recognized as
useful and multifunctional building blocks for the construc-
tion of different carbo- and heterocyclic systems via pericyclic
reactions,2–5 condensations6,7 or Michael addition reaction.8,9
These transformations may involve different combinations of
azadiene atoms, namely, 1,2/1,4 or 3,4. The interaction of aza-
dienes with cyclic anhydrides of dicarboxylic acids has also
Saint Petersburg State University, Saint Petersburg, 199034 Russian Federation.
E-mail: o.bakulina@spbu.ru; Tel: +7 904 618 15 09; Fax: +7 812 428 6939
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, analytical data, copies of the NMR spectra, crystallographic data. CCDC
2067829 and 2067830. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/d1ob00534k
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Fig. 1 (a) 1-Aza-1,3-dienes, general formula with numbering; (b) the CCR of 2-unsubstituted azadienes; (c) the Tamura reaction of 2-unsubstituted
azadienes; (d) the Tamura reaction of 2-R azadienes; (e) Castagnoli-Cushman-type 1,4-reaction of 2R-azadienes developed in this work.
novel types of polysubstituted dihydropyridin-2(1H)-ones lated by centrifugation of precipitates. This protocol allowed
highly desirable.
the preparation of a series of 27 structurally diverse polysubsti-
tuted dihydropyridin-2(1H)-ones 3a–aa in good to high yields
(up to 88%, up to 1 mmol loading) as single trans-diastereo-
mers (dr > 20 : 1). When the product did not precipitate from
the reaction mixture (compound 3ab), successful isolation was
Results and discussion
Having in mind that the nature of the substituent at the nitro- achieved by flash chromatography on silica after esterification
gen atom of the 1-azadiene system affects its reactivity and with diazomethane. The structure and relative configuration of
selectivity drastically and that chalcone imines remain almost compounds 3a and 3ab were confirmed by X-ray crystallogra-
uninvestigated (except for N-tosyl derivatives) in reactions with phy (see the ESI† for details).
cyclic anhydrides, in this work, we aimed at studying the
We introduced seven anhydrides 1a–g into the reaction
behaviour of the corresponding N-aryl/alkyl/OH/NHR deriva- with sixteen chalcone imines 2a–p and found no significant
tives. Homophthalic anhydride was chosen as the second sub- dependence of the reaction yields on the substitution patterns
strate due to its availability and high reactivity, both in the in both reactants. EDG (Me, alkoxy) as well as EWG (Hal,
CCR and Tamura reaction.
CO2Me, NO2) substituents were well tolerated in the anhydride
A brief screening of the reaction conditions (temperature: molecule or aryl component of imine (all possible positions
20–110 °C, solvent: toluene, MeCN, CHCl3, acetone, THF) 1–4 were screened). The diminished yield of the N-propyl sub-
revealed that full conversion, a small amount of by-products stituted compound 3k is most likely caused by its better solu-
1
(according to H NMR of crude reaction mixtures) and simple bility and, consequently, by increased losses during isolation.
isolation can be achieved when chalcone imines 2 were reacted Noteworthily, even tetraaryl-substituted imines were success-
with HPA, 1a, at room temperature using a minimum amount fully involved in this reaction giving products 3d,p,y, which
of dry MeCN (0.25 mmol/0.5 mL) (Scheme 1). A thorough ana- are, to the best of our knowledge, the first reported examples
lysis of the NMR spectra also showed that dihydropyridin-2 of the preparation of pentaaryl dihydropyridines. Using
(1H)-ones were formed, involving atoms 1 and 4 of the aza- cyclic imines derived from tetralone or indanone allowed
diene system, instead of the expected carbocyclic Tamura reac- the isolation of annelated tricyclic products 3e,f,o,w. The
tion products reported in ref. 16 by J. Shaw and co-authors latter represent at the same time quite a rare example of
(“3,4-reaction” of azadienes). High concentrations of reactants 3-alkyl (not aryl or H) substituted chalcone imine employed.
provided both short reaction times (less than 1 h) and con- Unfortunately, N-OH or N-NHR lactams could not be prepared
venient product isolation – all compounds except 3ab were iso- under the same conditions due to the low reactivity of the
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Scheme 1 Preparation and structures of dihydropyridin-2(1H)-ones 3. Reaction conditions: anhydride (0.25 mmol), imine (0.25 mmol), concen-
tration 0.5 M. a Isolated yields. b X-ray crystallographic data: 3a – CCDC 2067829,† 3ab – CCDC 2067830.† c PMP = 4-OMeC6H4. d Yield for two
steps, including esterification.
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Scheme 2 Proposed reaction mechanism.
corresponding oximes and hydrazones derived from chalcones has been investigated. Surprisingly, dihydropyridin-2(1H)-
and hydroxylamine or phenyl hydrazine. ones were formed via the rare Castagnoli–Cushman-type
Remarkably, all products were isolated as single trans- reaction of imine acting as a four-atom building block – we
isomers without any additional purification, which is quite observed the “1,4”-reaction instead of the expected “3,4”-
rare for formal cycloaddition reactions of HPA performed at Tamura reaction. Based on this new transformation, we
room temperature. In most cases, a mixture with a predomi- have developed a convenient and efficient protocol, which
nant content of the kinetically favored cis-isomer is formed. was used for the preparation of a series of 28 structurally
The preparation of the thermodynamically preferred trans- diverse δ-lactams (fully characterized including X-ray ana-
isomer usually requires performing an additional isomerisa- lysis). Variation of the substitution pattern in both reactants
tion step with heating23–25 or deprotonation,26 often after showed no significant effect on the reaction yield, allowing
esterification.13,27
the introduction of both EWG and EDG into the anhydride
Presumably, the reaction mechanism involves nucleophilic and/or imine component of the lactam product. The reac-
addition of HPA enolate to the C-4 atom of the azadiene tion proved to be general, chemo- and stereoselective and
system, followed by intramolecular N-acylation, thus present- high-yielding.
ing an example of imine acting as a four-atom building block
(Scheme 2). Additionally, another difference from the classic
Castagnoli–Cushman reaction is acylation occurring with the
“acetic”, not “benzoic”, carbonyl group of HPA due to the pre-
Author contributions
ferred formation of six-membered cycles over eight-membered
ones. It is also possible to describe this process as formal [4 +
2]-cycloaddition with inverted roles of HPA (normally diene
and dienophile here) and imine (normally dienophile and
diene here). Since the studied reaction involves the same types
of reactants (anhydride + imine) and gives the same type of
product (lactam with a carboxylic group) but differs in
mechanistic details, we refer to it as the Castagnoli–Cushman-
type reaction.
Interestingly, the closest structural analogs, N-tosyl deriva-
tives, were described as unstable reaction intermediates16 only
detected by NMR in reaction mixtures at low temperatures
(−20 °C), quickly transforming into the Tamura product at
25 °C and therefore not isolated. In contrast, our N-aryl/alkyl
products 3 were found to be thermally stable even at 130 °C
when heated in DMSO-d6 with NMR monitoring.
N.G. – investigation, data curation, validation; P.G. – investi-
gation, methodology; O.B. investigation, supervision,
writing – original draft, funding acquisition; D.D. – investi-
gation, conceptualization, writing – review & editing; G.K. –
investigation, validation; M.K. – conceptualization, project
administration, writing – review & editing.
–
Conflicts of interest
The authors declare no competing financial interest.
Acknowledgements
This research was supported by the Russian Science
Foundation (project grant 20-73-10078). We thank the
Research Center for Magnetic Resonance, the Center for
Chemical Analysis and Materials Research and the Center for
Conclusion
The reactivity of N-aryl/alkyl/OH/NHPh chalcone imines X-ray Diffraction Methods of Saint Petersburg State University
towards a series of substituted homophthalic anhydrides Research Park for obtaining the analytical data.
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14 O. Bakulina, A. Bannykh, D. Dar’in and M. Krasavin,
Chemistry, 2017, 23, 17667–17673.
References
1 S. Jayakumar, M. P. S. Ishar and M. P. Mahajan, 15 A. G. Collar, C. Trujillo and S. J. Connon, Chemistry, 2019,
Tetrahedron, 2002, 58, 379–471. 25, 7270–7274.
2 J. M. Neely and T. Rovis, Org. Chem. Front., 2014, 1, 1010– 16 N. P. Burlow, S. Y. Howard, C. M. Saunders, J. C. Fettinger,
1015. D. J. Tantillo and J. T. Shaw, Org. Lett., 2019, 21, 1046–1049.
3 Y. S. Cheng, A. T. Lupo and F. W. Fowler, J. Am. Chem. Soc., 17 A. Georgieva, E. Stanoeva, S. Spassov, M. Haimova, N. De
2002, 105, 7696–7703.
Kimpe, M. Boelens, M. Keppens, A. Kemme and
A. Mishnev, Tetrahedron, 1995, 51, 6099–6114.
18 H. Gielen, V. M.-J. Li, U. Rosentreter, K.-H. Schlemmer,
S. Allerheiligen, L. Telan, L. Baerfacker, J. Keldenich,
M. F. Fitzgerald, K. Nash, B. Albrecht and D. Meurer,
WO2004020410, 2004.
4 M. Komatsu, H. Ogawa, M. Mohri and Y. Ohshiro,
Tetrahedron Lett., 1990, 31, 3627–3630.
5 R. Robles-Machin, A. Lopez-Perez, M. Gonzalez-Esguevillas,
J. Adrio and J. C. Carretero, Chemistry, 2010, 16, 9864–
9873.
6 J. Barluenga, V. Kouznetsov, E. Rubio and M. Tomás, 19 D. Lee and K. B. Goodman, WO2005082890, 2005.
Tetrahedron Lett., 1993, 34, 1981–1984.
7 J. Barluenga, M. Tomás, A. Ballesteros and J.-S. Kong,
Tetrahedron, 1996, 52, 3095–3106.
20 H. Gielen-Haertwig, B. Albrecht, M. Bauser, J. Keldenich,
V. Li, J. Pernerstorfer, K.-H. Schlemmer and L. Telan,
WO2005080372, 2005.
8 D. Hu, Y. Gao, X. Song, W. Du and Y.-C. Chen, Eur. J. Org. 21 J. Barrow, H. G. Selnick and P. G. Nanterment,
Chem., 2020, 2020, 514–518. WO2000025782, 2000.
9 W. Lin, C. Zhang, W. Xu, Y. Cheng, P. Li and W. Li, Adv. 22 X. Sun and J. Qiu, WO2012009227, 2012.
Synth. Catal., 2018, 361, 476–480.
10 H. Braunstein, S. Langevin, M. Khim, J. Adamson,
23 M. I. Adamovskyi, M. M. Avramenko, D. M. Volochnyuk
and S. V. Ryabukhin, ACS Omega, 2020, 5, 20932–20942.
K. Hovenkotter, L. Kotlarz, B. Mansker and T. K. Beng, Org. 24 D. M. Floyd, P. Stein, Z. Wang, J. Liu, S. Castro, J. A. Clark,
Biomol. Chem., 2016, 14, 8864–8872.
M. Connelly, F. Zhu, G. Holbrook, A. Matheny, M. S. Sigal,
J. Min, R. Dhinakaran, S. Krishnan, S. Bashyum, S. Knapp
and R. K. Guy, J. Med. Chem., 2016, 59, 7950–7962.
25 A. Mikheyev, G. Kantin and M. Krasavin, Synthesis, 2018,
2076–2086.
11 S. A. Cronin, A. Gutiérrez Collar, S. Gundala, C. Cornaggia,
E. Torrente, F. Manoni, A. Botte, B. Twamley and
S. J. Connon, Org. Biomol. Chem., 2016, 14, 6955–6959.
12 M. J. Di Maso, K. M. Snyder, F. De Souza Fernandes,
O. Pattawong, D. Q. Tan, J. C. Fettinger, P. H. Cheong and 26 M. Krasavin, A. Safrygin, O. Bakulina and D. Dar’in,
J. T. Shaw, Chemistry, 2016, 22, 4794–4801. Synthesis, 2020, 2190–2195.
13 S. W. Laws, L. C. Moore, M. J. Di Maso, Q. N. N. Nguyen, 27 C. L. Jarvis, J. S. Hirschi, M. J. Vetticatt and D. Seidel,
D. J. Tantillo and J. T. Shaw, Org. Lett., 2017, 19, 2466–2469.
Angew. Chem., Int. Ed., 2017, 56, 2670–2674.
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