Photochemical transformation of a 1,2-dihydropyridin-3-one: An original tandem retro-[4+2]/[2+2] cycloaddition process

Article abstract of DOI:10.1016/j.tetlet.2013.03.081

The UV irradiation of N-benzyl-2-phenyl-1,2-dihydropyridin-3-one furnished trans-1-benzyl-4-phenyl-3-vinylazetidin-2-one, a structural isomer, as the main product. A novel tandem mechanism involving a [4+2] photocycloreversion followed by a Staudinger cycloaddition reaction is proposed, and is supported with the trapping of the purported vinylketene intermediate by other imines. This process predominates in the presence of ethylene, precluding the formation of an intermolecular [2+2] cyclobutane adduct.

Full text of DOI:10.1016/j.tetlet.2013.03.081

Tetrahedron Letters 54 (2013) 2825–2827
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Photochemical transformation of a 1,2-dihydropyridin-3-one: an original
tandem retro-[4+2]/[2+2] cycloaddition process
David J. Aitken a, Angelo Frongia b, Xavier Gaucher a, Jean Ollivier a, , Hummera Rafique a,
⇑
Carlo Sambiagio a,b, Francesco Secci b
a Université Paris-Sud, ICMMO – CNRS UMR 8182, 15 rue Georges Clemenceau, 91405 Orsay cedex, France
b Dipartimento di Scienze Chimiche, Università degli studi di Cagliari, Complesso Universitario di Monserrato, S.S 554, Bivio per Sestu, 09042 Monserrato, Cagliari, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The UV irradiation of N-benzyl-2-phenyl-1,2-dihydropyridin-3-one furnished trans-1-benzyl-4-phenyl-
3-vinylazetidin-2-one, a structural isomer, as the main product. A novel tandem mechanism involving
a [4+2] photocycloreversion followed by a Staudinger cycloaddition reaction is proposed, and is sup-
ported with the trapping of the purported vinylketene intermediate by other imines. This process pre-
dominates in the presence of ethylene, precluding the formation of an intermolecular [2+2]
cyclobutane adduct.
Received 26 February 2013
Revised 15 March 2013
Accepted 18 March 2013
Available online 28 March 2013
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Dihydropyridinones
Photochemistry
Cycloaddition
Staudinger reaction
b-Lactams
Dihydropyridin-2-ones and dihydropyridin-4-ones have occu-
pied a significant place in heterocyclic chemistry for many years.1
Although less studied, their structural isomers of the dihydropyri-
din-3-one family are also useful intermediates in the synthesis of
natural products.2 As enones, they are potential partners for photo-
chemical [2+2] cycloaddition reaction with alkenes,3 and the pres-
ence of the heteroatom is an asset for targeting diversely-
functional molecular systems through such reactions.4 In the liter-
ature however, there are only two reports of photocycloaddition
reactions involving dihydropyridin-3-ones (Scheme 1). Hanaoka
irradiated a selection of N-functionalized derivatives with vinyl
acetate, and isolated the corresponding cyclobutane adducts as
mixtures of stereo- and regio-isomers.5 Margaretha studied the
photochemical reaction of a carbamate derivative of 6,6-dimethyl
dihydropyridin-3-one with tetramethylethylene, and found that
this sterically challenging reaction provided the cyclobutane ad-
duct in low yield, accompanied by several other products, resulting
from rearrangements of the biradical intermediate (Scheme 1).6
Recently, we developed an efficient synthesis of 2-substituted
(Scheme 2). Esterification then N-allylation gave intermediate 2,
which was then treated with the appropriate electrophile to pre-
pare tosylamide 3a, benzyl and t-butyl carbamates 3b and 3c,
and benzylamine 3d. Cyclopropanation of the N-allyl esters 3a–d
using Kulinkovich conditions8 gave the corresponding 3-
azabicyclo[3.1.0]hexanols 4a–d as non-separated mixtures of
diastereomers. Finally, Saegusa oxidation9 provided the target 3-
dihydropyridinones 5a–d in reasonable overall yields (Scheme 2).
dihydropyridin-3-ones from a
-aminoacids.7 We decided to investi-
gate the photochemical behavior of such materials when irradiated
in the presence of an alkene.
A selection of N-substituted 2-phenyldihydropyridin-3-ones
was prepared from commercially available (R)-phenylglycine 1
⇑
Corresponding author. Tel.: +33 1 6915 3237; fax: +33 1 6915 6278.
E-mail address: jean.ollivier@u-psud.fr (J. Ollivier).
Scheme 1.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.081

2826
D. J. Aitken et al. / Tetrahedron Letters 54 (2013) 2825–2827
Scheme 4.
the two new products 9 and 10 should combine in a Staudinger
cycloaddition reaction to afford the corresponding b-lactam.12
The exclusively trans stereochemistry of 8 was attested by NMR
spectroscopy, notably the observation of a coupling constant of
about 2 Hz (J H(C3)–H(C4)) and NOESY correlations between H(C4)
and H(CH@CH2), and is consistent with the results of Staudinger reac-
tions of imines and ketenes conducted in photochemical condi-
tions reported independently by Podlech13 and Xu.14 Compound
8 was optically inactive, consistent with the suggested mechanism
for its formation (Scheme 4).
The proposed mechanism for the formation of 8 suggests that
the presence of ethylene is superfluous, so we irradiated an ace-
tone solution containing only 5d as solute for 3 h. As anticipated,
work-up provided 8 in 69% isolated yield. A further postulate based
on the mechanism is that if an imine other than 9 were present in
the reaction medium it should be able to trap the proposed vinyl-
ketene intermediate. We therefore irradiated an acetone solution
of 5d in the presence of 10 equiv of either N-benzylidene-2-meth-
oxyethanamine15 (11a) or methyl N-benzylideneglycinate16 (11b)
for 3 h. As predicted, a new trans-disubstituted b-lactam (12a or
12b, respectively) was obtained as the major product in each case
(Scheme 5). These observations are in agreement with the mecha-
nism suggested in Scheme 4.
Scheme 2.
Each of the 3-dihydropyridinones 5a–d was irradiated in solu-
tion in acetone for 3 h (400 W Hg lamp, Pyrex filter) while ethylene
was bubbled through the mixture. After the reaction time, the sol-
vent was evaporated and the crude mixture was examined by tlc
and NMR spectroscopy. From compounds 5a–c, a plethora of prod-
ucts was formed, and the anticipated cyclobutane adducts 6a–c
were not in evidence. After preparative chromatography, 2-phenyl
pyridine-3-ol 7 was isolated in low yield (around 10%), evidently
the result of nitrogen-function cleavage followed by aromatization.
This product had previously been encountered in the palladium
catalyzed hydrogenation of dihydropyridinone 5d.2 Use of other
solvents (acetonitrile, dichloromethane) or a different alkene (vinyl
acetate instead of ethylene) did not simplify the reaction profile,
and the reaction mixtures remained largely intractable. In contrast,
when 3-dihydropyridinone 5d was irradiated in acetone solution
as described above, one major product was obtained. Analysis of
spectroscopic data led us to deduce that this product was not the
anticipated cyclobutane adduct 6d (which we could not detect at
all), but was in fact the trans 2-azetidinone (b-lactam) 8, isolated
in 65% yield (Scheme 3).
To explain the formation of lactam 8, we postulate that the exci-
tation of the enone chromophore is followed by a vinylogous
homolytic cleavage. The biradical intermediate then fragments to
give two discreet species, the imine 9 and vinylketene 10. A related
two-step photochemically-induced formal retro-[4+2] process was
suggested by Zimmermann to explain ring fission of 4,4-diph-
enyldihydropyridin-2-ones,10 and a similar ring opening process
was suggested by Margaretha to occur during the irradiation of di-
hydrothiin-3-one S-oxides.11 The subsequent reaction pathways
deviated in the above-cited studies, but here it seems likely that
The intramolecular [2+2] cycloaddition of 2-pyridones to give
bicyclic b-lactams was first discovered by Corey and Streith,17
and these strained intermediates have been used to make cis-divi-
nyl b-lactams through ring-opening cross metathesis.18 Photorear-
rangement of dihydrothiin-3-ones to thietan-3-ones has been
described, again via a strained bicyclic intermediate (a sulfura-
nyl-alkyl biradical).19 However, the photoisomerization of dihy-
dropyridin-3-ones via the tandem [4+2]-cycloreversion/[2+2]
cycloaddition process described here is, to the best of our knowl-
edge, unprecedented for heterocyclic systems.20
Scheme 3.
Scheme 5.

D. J. Aitken et al. / Tetrahedron Letters 54 (2013) 2825–2827
2827
16. Gemma, L. T.; Spandl, R. J.; Glandsdorp, F. G.; Welch, M.; Bender, A.; Cockfield,
J.; Lindsay, J. A.; Bryant, C.; Brown, D. F. J.; Loiseleur, O.; Rudyk, H.; Ladlow, M.;
Spring, D. R. Angew. Chem., Int. Ed. 2008, 47, 2808–2812.
17. Corey, E. J.; Streith, J. J. Am. Chem. Soc. 1964, 86, 950–951.
18. Adamo, A. F. A.; Disetti, P.; Piras, L. Tetrahedron Lett. 2009, 50, 8765–8767.
19. Er, E.; Margaretha, P. Helv. Chim. Acta 1992, 75, 2265–2269.
20. Experimental procedure: A solution of N-benzyl-1,2-dihydro-2-phenylpyridin-
3(6H)-one 5d (1 mmol) and, where appropriate, imine 11a or 11b (10 mmol) in
acetone (250 mL) was placed in an annular photochemical reactor fitted with a
Pyrex filter. The solution was deoxygenated by the passage of a stream of argon
for 30 min, then irradiated using a 400 W Hg lamp. Progress of the reaction was
monitored by tlc until the disappearance of the starting dihydropyridinone
(ꢀ3 h). The solvent was then evaporated and the residue was taken up in
100 mL of ether. This solution was washed with 1 M HCl (3 Â 10 mL), 10% aq
NaHSO3 solution (10 mL), 10% aq Na2CO3 solution (10 mL), and dried over
MgSO4. The solvent was evaporated and the crude product was purified by
flash chromatography on silica gel (petroleum ether/EtOAc; 90:10) to afford
the trans b-lactam. Selected data: Compound 8, trans-1-benzyl-4-phenyl-3-
vinylazetidin-2-one. 1H NMR (250 MHz, CDCl3) d 7.40À7.15 (m, 10H), 5.94
(ddd, J = 17.5, 10.5, 8.0 Hz, 1H), 5.31 (dt, J = 17.5, 1.2 Hz, 1H), 5.25 (dt, J = 10.5,
Acknowledgments
We are grateful to the French MESR for a Ph.D. Grant for X.G.
We thank the French Embassy in Pakistan and EGIDE for the award
of a Sandwich Ph.D. Scholarship and funds for H.R., visiting from
Quaid-i-Azam University, Islamabad. Financial support from the
University of Cagliari and from the Regione Autonoma of Sardinia
for a visiting scholarship for C.S. is also acknowledged.
References and notes
1. (a) Quirion, J.-C.; Leclerc, E.; Jubault, P. Sci. Synth. 2007, 33, 601–628; (b) Lavilla,
R. J. Chem. Soc., Perkin Trans. 1 2002, 1141–1156.
2. Jida, M.; Ollivier, J. Eur. J. Org. Chem. 2008, 4041–4049. and references cited
therein..
3. Crimmins, M. T.; Reinhold, T. L. Org. React. 1993, 44, 297–588.
4. (a) Bach, T.; Hehn, J. P. Angew. Chem., Int. Ed. 2011, 50, 1000–1045; (b)
Hoffmann, N. Chem. Rev. 2008, 108, 1052–1103.
5. (a) Imanishi, M.; Wada, T.; Inoue, Y.; Hanaoka, M. Heterocycles 1981, 16, 2133–
2136; (b) Imanishi, T.; Inoue, M.; Wada, Y.; Hanaoka, M. Chem. Pharm. Bull.
1983, 31, 1235–1242.
6. (a) Jeandon, C.; Constien, R.; Sinnwell, V.; Margaretha, P. Helv. Chim. Acta 1998,
81, 303–306; (b) Constien, R.; Kisilovski, B.; Meyer, L.; Margaretha, P. Russ.
Chem. Bull. 1999, 48, 510–512.
7. Jida, M.; Guillot, R.; Ollivier, J. Tetrahedron Lett. 2007, 48, 8765–8767.
8. Kulinkovich, O. Russ. Chem. Bull., Int. Ed. 2004, 53, 1065–1086.
9. Ito, Y.; Fujii, S.; Nakatsuka, M.; Kawamoto, F.; Saegusa, T. Org. Synth. Coll. 1988,
6, 327–333.
10. Zimmerman, H. E.; Mitkin, O. D. J. Am. Chem. Soc. 2006, 128, 12743–12749.
11. Kowalewski, R.; Margaretha, P. Helv. Chim. Acta 1993, 76, 1251–1257.
12. (a) Staudinger, H. Liebigs Ann. Chem. 1907, 356, 51–123; (b) Xu, J. Arkivoc 2009,
ix, 21–44.
13. Maier, T. C.; Frey, W.; Podlech, J. Eur. J. Org. 2002, 2686–2689. and references
therein.
1.2 Hz, 1H), 4.35 (AB system, dmAB = 273 Hz, J = 15.0 Hz, 2H), 4.22 (d, J = 2.2 Hz,
1H), 3.70 (dd, J = 8.0, 2.2 Hz, 1H). 13C NMR (63 MHz, CDCl3) d 168.0, 137.1,
135.4, 130.1, 129.0, 128.7, 128.3, 128.3, 127.7, 126.4, 119.1, 63.9, 60.6, 44.5. FT-
IR (NaCl, cmÀ1) 3086, 3063, 2917, 1757, 1456. HRMS (ESI) m/z Calcd for
C
18H17NNaO: 286.1202. Found: 286.1217. Compound 12a, trans-1-(2-
methoxyethyl)-4-phenyl-3-vinylazetidi-2-one. 1H NMR (250 MHz, CDCl3)
d
7.42–7.31 (m, 5H), 6.02 (ddd, J = 17.2, 10.2, 8.0 Hz, 1H), 5.33 (dt, J = 17.2, 1.1 Hz,
1H), 5.29 (dt, J = 10.2, 1.1 Hz, 1H), 4.48 (d, J = 2.25 Hz, 1H), 3.69 (m, 2H), 3.47
(m, 2H), 3.27 (s, 3H), 3.08 (ddd, J = 14.4, 7.0, 4.2 Hz, 1H). 13C NMR (63 MHz,
CDCl3) d 168.4, 137.8, 131.1, 128.9, 128.4, 126.3, 119.0, 69.7, 64.1, 58.3, 40.1.d
FT-IR (NaCl, cmÀ1) 3031, 2925, 1756, 1638, 1495. HRMS (ESI) m/z Calcd for
C
14H17NNaO2: 254.1157. Found: 254.1151. Compound 12b, trans-methyl 2-(2-
oxo-4-phenyl-3-vinylcyclobutyl) acetate. 1H NMR (CDCl3, 250 MHz) d 7.44–
7.31 (m, 5 H), 6.04 (ddd, J = 17.1, 10.4, 8.1 Hz, 1H), 5.35 (d, J = 17.1, 1H), 5.31 (d,
J = 10.4 Hz, 1H), 4.64 (d, J = 2.3 Hz, 1H,), 3.96 (AB system,
dmAB = 233 Hz,
J = 18.1 Hz, 2H), 3.80–3.52 (m, 1H), 3.73 (s, 3H). 13C (CDCl3, 63 MHz) d 168.3,
168.2, 136.7, 130.5, 128.9, 128.6, 126.2, 119.4, 64.5, 61.8, 52.1, 41.2. FT-IR
(NaCl, cmÀ1) 3031, 2953, 1762, 1742, 1639, 1495. HRMS (ESI) m/z Calcd for
14. Liang, Y.; Jiao, L.; Xu, J. J. Org. Chem. 2005, 70, 334–337.
15. Mangeney, P.; Tejeroo, T.; Alexakis, A.; Grosjean, F.; Normant, J. Synthesis 1988,
255–257.
C14H15NNaO3: 268.0950. Found: 268.0941.