Photochemistry of acyloximes: Synthesis of heterocycles and natural products

Article abstract of DOI:10.1016/j.tet.2010.09.078

New applications of the photochemically generated iminyl radicals ring closure onto phenyl, thiophenyl, and pyridinyl rings are presented. The influence on the reactivity of different substituent throughout the acyloxime structure is discussed. Some obser

Full text of DOI:10.1016/j.tet.2010.09.078

Tetrahedron 66 (2010) 8828e8831
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Photochemistry of acyloximes: synthesis of heterocycles and natural products
*
ꢀ
ꢀ
Rafael Alonso, Alegrıa Caballero, Pedro J. Campos, Miguel A. Rodrıguez
~
ꢀ
ꢀ
ꢀ
Departamento de Quımica, Universidad de La Rioja, Grupo de Sıntesis Quımica de La Rioja, Unidad Asociada al C.S.I.C., Madre de Dios, 51, 26006 Logrono, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 August 2010
Received in revised form 17 September 2010
Accepted 20 September 2010
Available online 24 September 2010
New applications of the photochemically generated iminyl radicals ring closure onto phenyl, thiophenyl,
and pyridinyl rings are presented. The influence on the reactivity of different substituent throughout the
acyloxime structure is discussed. Some observed effects are interpreted from computational studies. This
reaction provides a new, simple, and straightforward method for the preparation of several polycyclic
heteroaromatic compounds and it has been applied to the synthesis of some natural products.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Acyloxime
Radical
Cyclization
Heterocycles
1. Introduction
The rich potential of iminyl radicals, generated by both ther-
mal and photochemical methods, is manifested in cyclization
reactions. However, the literature on iminyl radical cyclizations is
scarce. In most cases, formation of five-membered nitrogen het-
erocyclic rings takes place.1 We described, for the first time, the
use of iminyl radicals, generated from irradiation of acyloximes,
to the preparation of six-membered rings such as phenan-
thridines or isoquinolines (Scheme 1).2 The formation of one or
another cycle has been rationalized by ab initio calculations3 and
observed experimentally,3,4 and the generation of methyl radical
has been detected by EPR spectroscopy.4d Bearing in mind that
aza heterocycles are recurrent structures in important natural
products, we found of interest to extend our methodology to the
synthesis of such heterocycles.
Scheme 1.
2. Results and discussion
In our previous work, we explored simple substitution pat-
terns (mainly phenyl, vinyl, and ethynyl) on the basic structure
with a phenyl group as a spacer, thus producing compounds
2ae2f (Chart 1).2 In the present study, more complex acyloximes
were synthesized in an effort to broaden the scope of this pho-
toreaction to the synthesis of different heterocycles and natural
products.
2.1. Influence of the spacer
First, we tried to use a naphthyl group, rather than a phenyl
group, as a spacer. When subjected to irradiation in acetonitrile
through Pyrex glass, 3 gave a 55% yield of benzo[i]phenanthridine
4, after cyclization of the iminyl radical onto the phenyl ring and the
loss of an H-atom to restore the aromaticity (Scheme 2). However,
the irradiation of indolyl derivative 5 led to the formation of the
nitrile 6, instead of the expected cyclization product (Scheme 3).
Formation of nitriles has also been observed for the previously
described reactions.2
These results suggested that ring closure of intermediate iminyl
radical onto phenyl ring supported on a five-membered spacer
should be slower than that of six-membered one and unable to
* Corresponding author. Tel.: þ34 941299651; fax: þ34 941299621; e-mail
ꢀ
address: miguelangel.rodriguez@unirioja.es (M.A. Rodrıguez).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.078

R. Alonso et al. / Tetrahedron 66 (2010) 8828e8831
8829
Chart 1.
Scheme 2.
ꢁ
Fig. 1. Calculated structures (parameters in A and degrees) and relative energies
(in brackets, kcal/mol) at the B3PW91/6-31G level for the cyclization of iminyl radicals.
*
calculations on structures of 7 substituted by Me, OMe or F. As
shown in Fig.1, the influence of OMe and F on 4 is almost null, while
the presence of OMe on 2 increases the energy barrier to 22.2 kcal/
mol, probably due to steric hindrance. On the contrary, the pres-
ence of Me on
a position decreases the energy barrier to 13.2 kcal/
mol, which reveals that a methyl group on the iminic carbon not
only prevents the formation of nitrile but also favors the cyclization,
probably due to electronic effects.
Consistently, the next step was to extend the exploration of the
cyclization to acyloximes with a five-membered spacer but bearing
a methyl group on the iminic carbon. Thus, more complex acylox-
ime 10 was synthesized and irradiated, which allowed the prepa-
ration of compound 11 in 48% yield (Scheme 4).
Scheme 3.
compete with the formation of nitrile. This effect may be
understood by taking into account the theoretical DFT calculated
structures and energies.5,6 As shown in Fig. 1, according to our
calculations, the ring closure from radical 8 must surpass a barrier
of 10.2 kcal/mol to reach the transition state 8TS, while this barrier
increases to 14.6 kcal/mol from 7 to 7TS, which implies a higher
reaction rate for the first. The key to explain this barrier energy
difference could be found looking at both iminyl radical structures.
The five-membered ring places the substituent angles CeCeC at
Scheme 4.
129.6ꢀ and 132.9ꢀ and the distance NeC at 2.993 A, while these
ꢁ
ꢀ
ꢀ
ꢁ
values are reduced to 124.1 ,123.9 , and 2.896 A, respectively, in the
six-membered structure. For the sake of comparison, Fig. 1 also
shows the calculations for the ring closure onto ethynyl, which led
to the formation of isoquinoline 2d in 64% yield.2 Although model 9
2.2. Influence of substitution
We also explored the iminyl radical ring closure onto hetero-
aromatic rings. The use of a thiophenyl ring as iminyl radical
acceptor led to the preparation of thieno[3,2-c]isoquinoline 13 in
56% yield (Scheme 5). Next, we planned to use our methodology to
the iminyl radical closure onto the pyridine ring. Reports of ring
closure of C-centered radicals onto pyridine rings are rare7 and
there are not many examples describing the analog reaction for
ꢁ
has an NeC distance of 3.262 A, our calculations indicate a barrier of
7.2 kcal/mol. Once again, the substituent angles CeCeC are reduced
to 122.6ꢀ and 122.0ꢀ, which supports its significance on the reaction
course. Finally, in order to study the influence of some substituents
on the reactivity of the intermediate radicals, we carried out

8830
R. Alonso et al. / Tetrahedron 66 (2010) 8828e8831
N-centered radicals either.8 Scheme 5 also shows our result for this
process. Iminyl radical, generated from irradiation of 14 in CH3CN,
did cyclize onto pyridine ring, enabling 6-methylbenzo[c][1,7]
naphthyridine 15 to be prepared in 90% yield.
Irradiation after deprotection of hydroxy group led to 2-(8,9-
dimethoxyphenanthridin-4-yl)ethanol 26 in 53% yield after puri-
fication by column chromatography.10
Scheme 5.
2.3. Application to natural products preparation
The synthesis of some interesting natural products was
approached. Alkaloid trisphaeridine 19 was prepared in four steps
starting with a Suzuki coupling of commercial 6-bromopiperonal
with phenylboronic acid followed by the synthesis of the oxime and
acyloxime derivatives. Irradiation of acyloxime 18 allowed the
preparation of 19 in 39% yield (Scheme 6).
Scheme 7.
3. Conclusions
A general framework for the use of ring closure of iminyl radi-
cals, generated by photolysis of acyloximes, as a tool in organic
synthesis has been outlined. Iminyl radicals did cyclize onto vinyl,
ethynyl, phenyl, thiophenyl and pyridinyl rings. This reaction pro-
vides a new, simple, and straightforward method for the prepara-
tion of several polycyclic heteroaromatic compounds and has been
applied to the synthesis of some natural products.
4. Experimental section
4.1. General
Scheme 6.
1H and 13C NMR spectra were recorded in CDCl3 with TMS as
internal standard. Melting points are uncorrected. All solvents were
purified by standard procedures. Reagents were of commercial
grades.
Our methodology was also used for the preparation of the
vasconine precursor 26 (Scheme 7). The treatment of 26 with PBr3
led to vasconine, which can also be used for the preparation of
assoanine, oxoassoanine, and pratosine.9 The hydroxy group of
commercial 3-bromophenethyl alcohol was protected by reaction
with tert-butyl(chloro)dimethylsilane (TBDMS-Cl) and treated with
trimethyl borate and t-BuLi to obtain the boronic acid 21. The
Suzuki coupling reaction of 21 with 6-bromoveratraldehyde led to
aldehyde 22, therefrom oxime 23 and acyloxime 24 were obtained.
4.2. Typical procedure for the irradiation of acyloximes
The acyloxime (0.6 mmol) was dissolved in dry acetonitrile
(60 mL) and irradiatedat roomtemperatureunderan Aratmosphere
through Pyrex glass with a 400 W medium pressure-mercury lamp

R. Alonso et al. / Tetrahedron 66 (2010) 8828e8831
8831
until the acyloxime was consumed (1e3 h, TLC, hexane/AcOEt, 4:1).
4.9. 2-(8,9-Dimethoxyphenanthridin-4-yl)ethanol (26)
The solvent was removed with a rotary evaporator and the products
were separated by column chromatography (silica gel, hexane/
AcOEt).
Yield: 90 mg, 53%. 1H NMR (300 MHz, CDCl3, 25 ꢀC, TMS):
d¼9.13
(s, 1H), 8.35 (dd, J¼7.91, 1.92 Hz, 1H), 7.91 (s, 1H), 7.6e7.5 (m, 2H),
7.34 (s, 1H), 4.16 (s, 3H), 4.07 (s, 3H), 4.04 (t, J¼6.52 Hz, 2H),
3.52 ppm (t, J¼6.53 Hz, 2H); 13C NMR (300 MHz, CDCl3, 25 ꢀC, TMS):
4.3. Benzo[i]phenanthridine (4)11
d
¼153.5, 150.6, 150.4, 142.8, 140.5, 129.4, 128.9, 126.8, 124.4, 121.8,
Yield: 76 mg, 55%. 1H NMR (300 MHz, CDCl3, 25 ꢀC, TMS):
120.7, 107.9, 102.3, 64.5, 56.4, 56.3, 37.3 ppm; exact mass
(C17H17NO3þH) calculated 284.1287, measured 284.1281.
d
¼10.25 (s, 1H), 8.95 (d, J¼9.0 Hz, 1H), 8.69 (d, J¼6 Hz, 1H), 8.64 (d,
J¼9.0 Hz, 1H), 8.30 (d, J¼9.0 Hz, 1H), 8.22 (d, J¼9.0 Hz, 1H), 8.05 (d,
J¼9.0 Hz, 1H), 7.84e7.33 ppm (m, 4H); 13C NMR (300 MHz, CDCl3,
Acknowledgements
25 ꢀC, TMS):
d¼147.8, 145.2, 132.1, 132.0, 130.1, 130.0, 129.0, 128.9,
We thank the Spanish MEC (CTQ2007-64197) for financial
128.8, 128.0, 127.1, 127.1, 124.2, 122.6, 122.1, 121.7, 119.8 ppm; ES (þ)
ꢀ
support. R.A. thanks the Comunidad Autonoma de La Rioja for his
m/z: 230 (Mþ1).
fellowship. A.C. thanks the CSIC for her grant.
4.4. 2-Phenyl-1H-indole-3-carbonitrile (6)12
Supplementary data
Yield: 24 mg, 18%. 1H NMR (300 MHz, CDCl3, 25 ꢀC, TMS):
d¼8.86
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.09.078. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
(s, 1H), 7.93e7.84 (m, 2H), 7.77 (dd, J¼6.27, 2.83 Hz, 1H), 7.58e7.43
(m, 4H), 7.32e7.28 ppm (m, 2H); 13C NMR (300 MHz, CDCl3, 25 ꢀC,
TMS):
d
¼144.7, 134.9, 132.6, 129.4, 128.8, 128.7, 128.2, 126.8, 124.4,
122.4, 119.6, 116.8, 111.6 ppm; GCeMS m/z: 218 (M, 100), 190 (24).
References and notes
4.5. 2,4-Dimethyl-2H-pyrazolo[4,3-c]quinoline (11)
1. (a) Fallis, A. G.; Brinza, A. M. Tetrahedron 1997, 53, 17543; (b) Gagosz, F.; Zard, S. Z.
Synlett 1999,1978; (c) Uchiyama, K.; Hayashi, Y.; Narasaka, K. Tetrahedron 1999, 55,
8915; (d) Mikami, T.; Narasaka, K. Chem. Lett. 2000, 338; (e) Kitamura, M.; Mori, Y.;
Narasaka, K. Tetrahedron Lett. 2005, 46, 2373.
Yield: 95 mg, 48%. 1H NMR (300 MHz, CDCl3, 25 ꢀC, TMS):
(s, 1H), 7.66e7.63 (m, 2H), 7.42e7.40 (m, 2H), 3.95 (s, 3H), 2.31 ppm
(s, 3H); 13C NMR (300 MHz, CDCl3, 25 ꢀC, TMS):
135.0, 132.7, 129.2, 128.5, 128.05, 121.3, 39.2, 29.2 ppm; exact mass
(C12H11N3þH) calculated 198.1031, measured 198.1026.
d
¼7.93
d
¼192.2, 152.6,
ꢀ
ꢀ
2. Alonso, R.; Campos, P. J.; Garcıa, B.; Rodrıguez, M. A. Org. Lett. 2006, 8, 3521.
ꢀ
3. Alonso, R.; Campos, P. J.; Rodrıguez, M. A.; Sampedro, D. J. Org. Chem. 2008, 73,
2234.
4. (a) Portela-Cubillo, F.; Scott, J. S.; Walton, J. C. Chem. Commun. 2007, 4041; (b)
Portela-Cubillo, F.; Scanlan, E. M.; Scott, J. S.; Walton, J. C. Chem. Commun. 2008,
7189; (c) Portela-Cubillo, F.; Scott, J. S.; Walton, J. C. J. Org. Chem. 2008, 73, 5558;
(d) Portela-Cubillo, F.; Alonso-Ruiz, R.; Sampedro, D.; Walton, J. C. J. Phys. Chem.
A 2009, 113, 10005.
4.6. Thieno[3,2-c]isoquinoline (13)13
Yield: 62 mg, 56%. 1H NMR (300 MHz, CDCl3, 25 ꢀC, TMS):
5. All calculations were carried out using the Gaussian 03 program package.
Geometry was fully optimised without any symmetry constraint for all model
d
¼9.20 (s, 1H), 8.08 (d, J¼8.2 Hz, 2H), 7.78 (t, J¼7.6 Hz, 1H), 7.69 (dd,
compounds at the B3PW91/6-31G level of theory. Optimised structures were
*
J1¼16.9 Hz, J2¼5.4 Hz, 2H), 7.62 ppm (t, J¼7.6 Hz, 1H); 13C NMR
characterized as minima or saddle points by frequency calculations.
6. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman,
J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.;
Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.;
Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Ha-
segawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.;
Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J.
J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D.
K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M.
W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision C.02; Gaussian, Inc.,:
Wallingford, CT, 2004.
(300 MHz, CDCl3, 25 ꢀC, TMS):
126.8, 126.7, 126.7, 126.4, 125.4, 122.9 ppm; ES (þ) m/z: 186 (Mþ1).
d
¼151.2, 131.9, 131.2, 129.4, 129.0,
4.7. 6-Methylbenzo[c][1,7]naphthyridine (15)
Yield: 105 mg, 90%. Mp: 107e109 ꢀC; 1H NMR (300 MHz, CDCl3,
25 ꢀC, TMS):
d
¼9.43 (s, 1H), 8.73 (d, J¼5.51 Hz, 1H), 8.60 (d,
J¼8.05 Hz, 1H), 8.26 (d, J¼6.32 Hz, 2H), 7.87 (td, J¼15.02, 7.23 Hz,
2H), 3.06 ppm (s, 3H); 13C NMR (300 MHz, CDCl3, 25 ꢀC, TMS):
d
¼160.7, 152.6, 144.9, 138.7, 131.0, 130.4, 129.5, 128.7, 126.7, 126.6,
122.8, 115.1, 23.4 ppm; exact mass (C13H10N2þH) calculated
195.0922, measured 195.0917.
ꢀ
7. Bacque, E.; El Qacemi, M.; Zard, S. Z. Org. Lett. 2004, 6, 3671.
8. (a) Servais, A.; Azzouz, M.; Lopes, D.; Courillon, C.; Malacria, M. Angew. Chem.,
Int. Ed. 2
M.; Lacote, E. Angew. Chem., Int. Ed. 2010, 49, 2178.
ˇ
007, 46, 576; (b) Larraufie, M.-H.; Ollivier, C.; Fensterbank, L.; Malacria,
4.8. Trisphaeridine (19)4c
ꢀ
9. Rosa, A. M.; Lobo, A. M.; Branco, P. S.; Prabhakar, S.; Sa-da-Costa, M. Tetrahedron
1997, 53, 299.
Yield: 52 mg, 39%. 1H NMR (300 MHz, CDCl3, 25 ꢀC, TMS):
10. The regioisomer 2-(8,9-dimethoxyphenanthridin-2-yl)ethanol was also obtained
in 27% yield.
11. Yanada, R.; Hashimoto, K.; Tokizane, R.; Miwa, Y.; Minami, H.; Yanada, K.;
Ishikura, M.; Takemoto, Y. J. Org. Chem. 2008, 73, 5135.
12. Reddy, B. V. S.; Begum, Z.; Reddy, Y. J.; Yadav, J. S. Tetrahedron Lett. 2010, 51,
3334.
d
¼9.08 (s, 1H), 8.35 (d, 1H, J¼8.2 Hz), 8.14 (d, 1H, J¼8.2 Hz), 7.88 (s,
1H), 7.7e7.6 (m, 2H), 7.31 (s, 1H), 6.15 ppm (s, 2H); 13C NMR
(300 MHz, CDCl3, 25 ꢀC, TMS):
d
¼151.8, 151.7, 148.3, 144.0, 130.4,
130.0, 128.2, 126.8, 124.4, 123.2, 122.1, 105.6, 102.1, 100.1 ppm; ES
(þ) m/z: 224 (Mþ1).
13. Yang, Y.; Hoernfeldt, A. B.; Gronowitz, S. J. Heterocycl. Chem. 1989, 26, 865.