Diastereoselective photocyclization to dihydroindolinols

Article abstract of DOI:10.1055/s-1999-2902

Photocyclization of substituted o-aminophenylketone lb leads in high yields to indolinol 3b. Depending upon the substituent R² and on the solvent either cis-products (10: R²=COX) or transproducts (12: R²=Ph) are formed predominantly.

Full text of DOI:10.1055/s-1999-2902

1588
LETTER
Diastereoselective Photocyclization to Dihydroindolinols
Martin Seiler, Andreas Schumacher, Ute Lindemann, Frédérique Barbosa, Bernd Giese*
Department of Chemistry, University of Basel, St. Johanns Ring 19, CH-4056 Basel, Switzerland
Fax +41-61-2671105; E-mail:giese@ubaclu.unibas.ch
Dedicated to Prof. U. Schmidt on the occasion of his 75 birthday
Received 13 July 1999
CO2Me
O
Abstract: Photocyclization of substituted o-aminophenylketone 1b
leads in high yields to indolinol 3b. Depending upon the substituent
d,e,f,g
a,b,c
OH
NH2
OH
R2
R2 and on the solvent either cis-products (10: R2=COX) or trans-
products (12: R2=Ph) are formed predominantly.
R2
N
N
Tf
Tf
Keywords: cyclizations, diastereoselectivity, indoles, substituent
effect, photochemistry
5
6
4
a: TBDMS-Cl, imidazole, 96%, b: Tf2O, Na2CO3, 55%, c: Br-CH2-R2,
K2CO3; HF, pyridine, 86-91%, d: PDC, 90-91%, e: NaCN, NH4Cl,
84-96%, f: CH3OH/HCl, 72-75%, g: CrO3 / H2SO4, 20°C, 86-90%
Dihydrobenzofuranols 3a can be easily synthesized by
Norrish-Yang photocyclization of phenylketones 1a,
whereby biradicals 2a are the decisive intermediates.1,2
Surprisingly, analogous photocyclizations of 1b leading
to dihydroindolinols 3b were impossible until now.3,4
Ph
Ph
O
O
a,b
NH2
N
R2
R1
X
R1
.
R1
X
Tf
OH
R2
7
8
O
OH
.
hν
a: Tf2O, pyridine, 53%, b: Br-CH2-R2, K2CO3, 81-99%
R2
X
R2
Scheme 2
2
3
1
b: X = NR
a: X = O
Scheme 1
Because some antagonists of neurotransmitters have dihy-
droindolinols as substructures,5 it was appealing to find
out whether appropriate conditions for a photoinduced
ring closure of 1b exist. From studies of photocyclization
reactions of amino acids it is known that strong electron-
withdrawing substituents at the nitrogen atom increase the
yield of photocylization products.6 We therefore intro-
duced a trifluoromethanesulfonyl group at the aniline ni-
trogen of 1b and observed photocyclizations to
dihydroindolinols 3b in high yields and high stereoselec-
tivities. The phenyl ketones 6 and 8 were synthesized us-
ing standard procedures.7,8,9
Photolysis10 of the ester or amide containing phenyl ke-
tones 9a-c led predominantly to cis-products cis-10a-c
(Table 1).11 Thus, from amide 9c the cis-isomer 10c is
formed in 90% yield with a 98:2 cis:trans stereoselectivi-
ty. This cis-orientation of the OH- and the COX-groups is
not unexpected because OH is less bulky than CO2Me or
Ph and it can form H-bridges with the COX substituent.
Surprisingly, the corresponding phenyl substituted photo-
educts 11a,b yielded mainly trans-12a,b,12 the less stable
products where the bulky groups R1 and Ph are cis to each
other (Table 2). Starting from 11a products 12a are
formed in 90% yield with a 4:96 cis:trans ratio.
Synlett 1999, No. 10, 1588–1590 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Diastereoselective Photocyclization to Dihydroindolinols
1589
In conclusion, the photocyclization of o-aminophenylke-
tones 9 and 11 afforded in high yields and high stereose-
lectivities the corresponding dihydroindolinols 10 and 12,
respectively.
Acknowledgement
The photochemistry starts by intramolecular H-abstrac-
tion from triplet ketones.13 For a cyclization of the inter-
mediate biradical a triplet-singlet interconversion has to
occur. This interconversion is favored by a twisted con-
formation 13 in which two radical p-orbitals can interact
with each other.14 Ab initio calculations15 demonstrate that
in analogous monoradicals the barriers of rotation around
the benzylic α-bond are much higher than those around
the β- and γ-bonds. If this holds also for triplet biradical
13, the conformation 14 in which the OH-group adopts a
sterically favorable conformation can be reached easily.
Triplet-singlet interconversion of 14 and a rapid cycliza-
tion of the singlet biradical16 leads to the thermodynami-
cally less favored trans-products (11 → trans-12). In
reactions where R2 carries a carbonyl group intramolecu-
lar H-bridging between the hydroxyl and carbonyl groups
can overcompensate the steric effect.2 This leads to a pre-
dominant formation of cis-products (9 → cis-10).
This work was supported by the Swiss National Science Foundati-
on. We thank M. Neuburger and M. Neuburger-Zehnder / Basel for
the X-ray analyses, and P. Wessig/ Berlin for helpful discussions
and phosphorescence measurements.
References and Notes
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Heterocycl. Chem. 1991, 28, 1273.
(2) Sharshira, E. M.; Shimada, S.; Okamura, M.; Hasegawa, E.;
Horaguchi, T. J. Heterocycl. Chem. 1996, 33, 1797. Sharshira,
E. M.; Okamura, M.; Hasegawa, E.; Horaguchi, T. J.
Heterocycl. Chem. 1997, 34, 861. Sharshira, E. M.;
Horaguchi, T. J. Heterocycl. Chem. 1997, 34, 1837.
(3) Aoyama, H.; Nishio, T.; Hirabayashi, Y.; Hasegawa, T.;
Noda, H.; Sagiyama, N. J. Chem. Soc., Perkin Trans. I 1975,
298. Hasegawa, T.; Kasaku, S.; Ueno, J.; Oguchi, S. Bull.
Chem. Soc. Jpn. 1982, 55, 3659.
R1
R1
.
α
OH
.
(4) A successful photocyclization of o-benzoyl-N-alkylanilinium
ions is described in Wagner, P. J.; Cao, Q. Tetrahedron Lett.
1991, 32, 3915.
C
R2
OH
Tf
N
N
γ
β
R2
C
H
Tf
(5) Liesch, J. M.; Hensens, O. D.; Springer, J. P.; Chang, R. S.;
Lotti, V. J. J. Antibiot. 1985, 38, 1638. Goetz, M. A.;
Monaghan, R. L.; Chang, R. S.; Ondeyka, J.; Chen, T. B.;
Lotti, V. J. J. Antibiot. 1988, 41, 875. Liesch, J. M.; Hensens,
O. D.; Zink, D. L.; Goetz, M. A. J. Antibiot. 1988, 41, 878.
Houk, D. R.; Ondeyka, J.; Zink, D. L.; Inamine, E.; Goetz, M.
A.; Hensens, O. D. J. Antibiot. 1988, 41, 882. Chang, R. S. L.;
Lotti, V. J.; Monaghan, R. L.; Birnbaum, J.; Stapley, E. O.;
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Copper, R. J. Antibiot. 1993, 46, 545.
14
13
Figure
In polar solvents the amount of trans-products increases
because polar solvents increase the bulk of the OH-group
by solvation and break possible H-bridges between the
hydroxyl and carbonyl groups.2 These solvent effects are
shown in Table 3.
(6) Gold, E. H. J. Am. Chem. Soc. 1971, 93, 2793.
(7) Ketones 6 were prepared according to analogous procedures:
Just, G.; Zamboni, R. Can. J. Chem. 1978, 56, 2720.
Hendrickson, J. B.; Bergeron, R. Tetrahedron Lett. 1973, 39,
3839. Nicolaou, K. C.; Webber, S. E. Synthesis 1986, 453.
Synlett 1999, No. 10, 1588–1590 ISSN 0936-5214 © Thieme Stuttgart · New York

1590
M. Seiler et al.
LETTER
Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 5, 399.
Wagner, A. F.; U. S. Patent 2892847, 1959; Chem. Abstr.
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quaternary carbon atom of the phenyl group at C(3) and the
proton at C(2) corresponds to the expected dihedral angle of
120° for trans-12b. Representative data for cis- and trans-
compounds: cis-12a: 13C NMR (75.5 MHz, CDCl3) d 173.0
(s), 140.6 (s), 134.5 (s), 131.2 (d), 131.0 (s), 129.1 (d), 128.6
(d, 2xC), 127.5 (d), 126.0 (d, 2xC), 125.0 (d), 119.8 (q), 114.8
(8) Ketones 8 were prepared according to the literature or
analogous procedures: Moore, G. G. I.; Harrington, J. K.;
Swingle, K. F. J. Med. Chem. 1975, 18, 386 (with the
modification of using pyridine as base). Hendrickson, J. B.;
Bergeron, R. Tetrahedron Lett. 1973, 39, 3839.
(d), 80.8 (s), 73.7 (d), 54.1 (q). trans-12a: m.p. 83–84°C; 13
NMR (75.5 MHz, CDCl3) d 171.4 (s), 141.4 (s), 135.5 (s);
C
131.3 (d), 129.8 (s), 128.8 (d), 128.4 (d, 2xC), 126.3 (d, 3xC),
126.2 (d), 120.1 (q), 115.0 (d), 85.4 (s), 78.9 (d), 52.9 (q).
(13) Quenching experiments with 2,5-dimethyl-2,4-hexadiene
showed that the hydrogen abstraction occurred from the triplet
state of the ketone. Triplet energies of 62.5 kcal mol-1 and 67.5
kcal mol-1 for 9a and 11a, respectively, were determined by
measurement of phosphorescence spectra performed in Et2O/
i-pentane/EtOH 5:5:2 at 77 K.
(14) Böckmann, M.; Klessinger, M.; Zerner, M. C. J. Phys. Chem.
1996, 100, 10570. Böckmann, M.; Klessinger, M. Angew.
Chem. 1996, 108, 2681; Angew. Chem., Int. Ed. Engl. 1996,
35, 2502. Klessinger, M.; Michl, J. Excited States and
Photochemistry of Organic Molecules; VCH Publishers INC,
New York, 1995; p 219.
(15) All the geometries for the rotation profiles were calculated
using the UHF/3-21G* available in the Gaussian 94 package
(Gaussian 94, Revision E.2, Frisch, M. J.; Trucks, G. W.;
Schlegel, H. B.; Gill, P. M. W.; Johnson, B. G.; Robb, M. A.;
Cheeseman, J. R.; Keith, T.; Petersson, G. A.; Montgomery, J.
A.; Raghavachari, K.; Al-Laham, M. A.; Zakrzewski, V. G.;
Ortiz, J. V.; Foresman, J. B.; Cioslowski, J.; Stefanov, B. B.;
Nanayakkara, A.; Challacombe, M.; Peng, C. Y.; Ayala, P. Y.;
Chen, W.; Wong, M. W.; Andres, J. L.; Replogle, E. S.;
Gomperts, R.; Martin, R. L.; Fox, D. J.; Binkley, J. S.;
Defrees, D. J.; Baker, J.; Stewart, J. P.; Head-Gordon, M.;
Gonzalez, C.; Pople, J. A. Gaussian, Inc., Pittsburgh PA,
1995).
(9) All compounds were characterized by NMR, IR, MS and
elementary analysis.
(10) General procedure for the irradiation of ketones 9 and 11:
Compounds 9 and 11 (ca. 4 mg in 1 ml solvent) were
dissolved in MeCN, toluene or chloroform (HPLC grade),
rinsed with argon for 15 min and irradiated with a 500 W-
mercury-arc lamp (OSRAM HBO-500) using a WG 320 filter
(Schott). Evaporation of the solvent, followed by flash
chromatography afforded the racemic products 10 or 12. For
simplicity only one enantiomer is depicted.
(11) The structures of products trans-10a, trans-10b and cis-10c
were confirmed with X-ray crystal analyses. Detailed data
were deposited in the Cambridge Crystallographic Data
Base: trans-10a (No. CCDC-125683), trans-10b (No. CCDC-
125680) and cis-10c (No. CCDC-125681).The products cis-
10b and cis-10c exhibit a NOE effect of 5% between H-C(2)
and the aromatic ortho-protons of the phenyl group (R1 = Ph)
whereas the spectra of trans-10b and trans-10c show a NOE
effect of 2-4% between H-C(2) and the hydroxyl proton.
Representative data for cis- and trans-compounds: cis-10a:
m.p. 116–118°C; 13C NMR (75.5 MHz, CDCl3) d 171.7, 165.9
(2s), 140.1 (s), 131.5 (d), 129.7 (s), 125.8 (d), 124.3 (d), 119.8
(q), 114.4 (d), 79.7 (s), 70.5 (d), 54.4, 53.1 (2q). trans-10a:
m.p. 153–154°C; 13C NMR (75.5 MHz, CDCl3) d 171.1, 166.8
(2s), 140.2 (s), 131.5 (d); 130.3 (s), 126.1 (d), 124.5 (d), 119.9
(q), 115.0 (d), 82.3 (s), 75.0 (d), 54.1, 53.3 (2q).
(12) Indolinol trans-12a was converted into the appropriate
benzoyl ester according to Danishefsky, S. J.; De Ninno, M.
P.; Chen, S. J. Am. Chem. Soc. 1988, 110, 3029. The structure
of this ester was determined by X-ray analysis (No. CCDC-
125682). Product trans-12b exhibits a NOE of 6% between
(16) Griesbeck, A. G.; Mauder, H.; Stadtmüller, S. Acc. Chem. Res.
1994, 27, 70. Scaiano, J. C. Tetrahedron 1982, 38, 819.
Article Identifier:
1437-2096,E;1999,0,10,1588,1590,ftx,en;L11799ST.pdf
the hydroxyl proton and H-C(2). Additionally, the 3JC,H
coupling constant of approximately 1.4 Hz between the
-
Synlett 1999, No. 10, 1588–1590 ISSN 0936-5214 © Thieme Stuttgart · New York