Facile synthesis of substituted phenanthroline ligands by samarium-promoted coupling of phenanthroline with ketones.

Article abstract of DOI:10.1021/ol990284w

[formula: see text] 1,10-Phenanthroline undergoes coupling with ketones promoted by samarium diiodide to produce 2-(1-hydroxyalkyl)-1,10-phenanthrolines. O-Methylation of these derivatives provides the corresponding 2-(1-methoxyalkyl)phenanthrolines. Deme

Full text of DOI:10.1021/ol990284w

ORGANIC
LETTERS
1999
Vol. 1, No. 10
1659-1662
Facile Synthesis of Substituted
Phenanthroline Ligands by
Samarium-Promoted Coupling of
Phenanthroline with Ketones
David J. O’Neill and Paul Helquist*
Department of Chemistry and Biochemistry, 251 Nieuwland Science Hall,
UniVersity of Notre Dame, Notre Dame, Indiana 46556
paul.helquist.1@nd.edu
Received September 14, 1999
ABSTRACT
1,10-Phenanthroline undergoes coupling with ketones promoted by samarium diiodide to produce 2-(1-hydroxyalkyl)-1,10-phenanthrolines.
O-Methylation of these derivatives provides the corresponding 2-(1-methoxyalkyl)phenanthrolines. Demethoxylation with samarium diiodide
then affords 2-alkylphenanthrolines. This process may be repeated to obtain 2,9-disubstituted phenanthrolines. A variety of new, substituted
phenanthrolines are thus obtained. These compounds have numerous potential applications as ligands in metal-promoted reactions, including
asymmetric catalysis.
Several approaches have been developed for the asymmetric
synthesis of nonracemic organic compounds. An especially
important strategy is the use of metal catalysts containing a
number of types of chiral ligands.1 1,10-Phenanthroline has
long been known as a commonly used, nearly universal
ligand that forms complexes with a wide range of metals.2
Chiral derivatives of phenanthroline may therefore be
expected to have many applications as ligands in asymmetric
catalysis employing any of several metals. In fact, uses of
chiral phenanthrolines have been limited,3 due in part to the
small number of methods that have been reported previously
for the synthesis of these ligands.3,4 Nonetheless, we have
recently demonstrated the usefulness of substituted phenan-
throlines in asymmetric, palladium-catalyzed reactions.5 The
rational design of these ligands was guided by the use of
specially parametrized molecular mechanics calculations for
(1) (a) Kagan, H. B. In ComprehensiVe Organometallic Chemistry. The
Synthesis, Reactions and Structures of Organometallic Compounds; Wilkin-
son, G., Stone, F. G. A., Abel, E. W., Eds.; Pergamon: Oxford, 1982; Vol.
8, Chapter 53. (b) Asymmetric Synthesis. Chiral Catalysis; Morrison, H.,
Ed.; Academic Press: New York, 1985; Vol. 5. (c) Asymmetric Catalysis;
Bosnich, B., Ed.; Martinus Nijhoff: Dordrecht, 1986. (d) Handbook of
EnantioselectiVe Catalysis with Transition Metal Compounds; Brunner, H.,
Zettlmeier, W., Eds.; VCH: New York, 1993; Vol. I and II. (e) Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993. (f) Shibasaki,
M. In AdVances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI
Press: Greenwich, CT, 1996; Chapter 3. (g) Procter, G. Asymmetric
Synthesis; Oxford University Press: New York, 1996.
(2) (a) Holyer, R. H.; Hubbard, C. D.; Kettle, S. F. A.; Wilkins, R. G.
Inorg. Chem. 1965, 4, 929-935. (b) McWhinnie, W. R.; Miller, J. D. In
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Eds.; Academic Press: New York, 1969; pp 135-215. (c) McBryde, W.
A. E. A Critical ReView of Equilibrium Data for Proton- and Metal
Complexes of 1,10-Phenanthroline, 2,2′-Bipyridyl and Related Compounds;
Pergamon Press: Oxford, 1978.
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J. Organomet. Chem. 1987, 327, C15-C17. (b) Schionato, A.; Paganelli,
S.; Botteghi, C.; Chelucci, G. J. Mol. Catal. 1989, 50, 11-18. (c) Gladiali,
S.; Chelucci, G.; Soccolini, F.; Delogu, G.; Chessa, G. J. Organomet. Chem.
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S.; Zassinovich, G.; Mestroni, G. Tetrahedron: Asymmetry 1990, 1, 635-
648. (e) Gladiali, S.; Pinna, L.; Delogu, G.; Graf, E.; Brunner, H.
Tetrahedron: Asymmetry 1990, 1, 937-942. (f) Chelucci, G. Gazz. Chim.
Ital. 1992, 122, 89-98. (g) Weijnen, J. G. J.; Koudijs, A.; Engbersen, J. F.
J. J. Mol. Catal. 1992, 73, L5-L9. (h) Weijnen, J. G. J.; Koudijs, A.;
Engbersen, J. F. J. J. Org. Chem. 1992, 57, 7258-7265. (i) Chelucci, G.;
Falorni, M.; Giacomelli, G. Tetrahedron 1992, 48, 3653-3658. (j) Kandzia,
C.; Steckhan E.; Knoch, F. Tetrahedron: Asymmetry 1993, 4, 39-42. (k)
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37, 2145-2149.
10.1021/ol990284w CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/10/1999

the prediction of structures of ground-state complexes and
reaction transition states.5,6 However, the extension of these
studies to the wealth of reactions in which chiral phenan-
throline ligands may potentially be employed is dependent
upon more general methods for the synthesis of substituted
phenanthrolines. The availability of additional methods
would also have an impact on other numerous uses of
phenanthrolines and their metal complexes.7 Herein we report
a very simple method for the synthesis of substituted
phenanthrolines by the straightforward samarium-promoted
coupling of ketones with the parent compound, 1,10-
phenanthroline.
types of couplings are well-known for carbonyl compounds,
imines, oximes, nitriles, amides, indoles, and related sub-
strates employing various reducing agents. Especially promi-
nent in recent years has been the use of samarium diiodide.9,10
Indeed, when 1,10-phenanthroline and ketones are allowed
to react with a THF solution of freshly prepared samarium
diiodide,11 the desired substituted phenanthrolines 1 are
obtained (eq 1).12 The scope of the reaction is indicated by
One possible strategy for the generation of substituted
phenanthrolines would be the metal-halogen exchange
reaction of 2-halophenanthrolines4i,8 followed by addition of
the resulting 2-metalated derivatives to carbonyl compounds
to give 2-(1-hydroxyalkyl)phenanthrolines (1). However,
attempted exchange reactions of 2-halophenanthrolines with
typical alkyllithium reagents result mainly in addition/
substitution of the alkyllithiums on the phenanthroline
nucleus. Reaction of 2-halophenanthrolines with active
metals and metalation of 1,10-phenanthroline with strong
bases also fail to give useful intermediates for carbonyl
addition reactions. A much simpler variation of this strategy
which would give the desired substituted ligands more
directly from 1,10-phenanthroline itself would be pinacol-
like coupling of this parent compound with ketones. These
the examples in Table 1 whereby aliphatic ketones may be
employed in general, but aromatic ketones and aldehydes
are not useful substrates due to other competing reductive
processes such as self-couplings and carbonyl reductions.
The racemic products from the use of prochiral ketones
(entries c, d, and e) are potentially resolvable, but alterna-
tively, chiral ketones such as thujone (entry f) and menthone
(entry g) can be employed to give chiral, nonracemic
products directly.13
Table 1. Samarium Diiodide-Promoted Coupling of Ketones
with 1,10-Phenanthroline and Subsequent O-Methylation and
Demethoxylation
(4) (a) Graham, B. In The Chemistry of Heterocyclic Compounds: Six-
Membered Heterocyclic Nitrogen Compounds with Three Condensed Rings;
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1999, 40, 3395-3396.
(5) (a) Pen˜a-Cabrera, E.; Norrby, P.-O.; Sjo¨gren, M.; Vitagliano, A.; De
Felice, V.; Oslob, J.; Ishii, S.; O’Neill, D.; Åkermark, B.; Helquist, P. J.
Am. Chem. Soc. 1996, 118, 4299-4313. For related studies of palladium
complexes of substituted phenanthrolines, see: (b) Åkermark, B.; Hansson,
S.; Vitagliano, A. J. Am. Chem. Soc. 1990, 112, 4587-4588. (c) Sjo¨gren,
M.; Hansson, S.; Norrby, P.-O.; Åkermark, B.; Cucciolito, M. E.; Vitagliano,
A. Organometallics 1992, 11, 3954-3964. (d) Hansson, S.; Norrby, P.-O.;
Sjo¨gren, M.; Åkermark, B.; Cucciolito, M. E.; Giordano, F.; Vitagliano,
A. Organometallics 1993, 12, 4940-4948. (e) Sjo¨gren, M.; Hansson, S.;
Åkermark, B.; Vitagliano, A. Organometallics 1994, 13, 1963-1971.
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J. F. J.; Koudijs, A.; van der Plas, H. C. J. Org. Chem. 1990, 55, 3647-
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Walker, A. K.; MacDonnell, F. M. J. Am. Chem. Soc. 1997, 119, 10364-
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1996, 61, 346-355. (e) Miller, M. T.; Gantzel, P. K.; Karpishin, T. B. J.
Am. Chem. Soc. 1999, 121, 4292-4293. (f) Goodbrand, H. B.; Hu, Nan-
Xing J. Org. Chem. 1999, 64, 670-674. (g) Marko´, I. E.; Giles, P. R.;
Tsukazaki, M.; Chelle´-Regnaut, I.; Gautier, A.; Brown, S. M.; Urch, C. J.
J. Org. Chem. 1999, 64, 2433-2439. (h) Stengone, C. N.; Widenhoefer,
R. A. Tetrahedron Lett. 1999, 40, 1451-1454. (i) Kiyomori, A.; Marcoux,
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D.; Knochel, P. Tetrahedron Lett. 1999, 40, 3685-3688.
a Stereochemical assignments tentatively assigned on the basis of 1H and
13C NMR data. b Racemic menthone was used in this series.
(8) Ogawa, S.; Yamaguchi, T.; Gotoh, N. J. Chem. Soc., Perkin Trans.
1 1974, 976-978.
1660
Org. Lett., Vol. 1, No. 10, 1999

Attempts were made without success to extend this
reaction to other, related substrates such as pyridine and
isoquinoline in place of phenanthroline. Likewise, R,â-
unsaturated ketones, in place of saturated ketones, do not
generally give useful results, but in the case of pulegone,
product 2 is obtained which results from conjugate addition
and reduction of the phenanthroline nucleus (eq 2).
diiodide-promoted coupling of a ketone with a product of
the preceding sequence of reactions. This approach to
obtaining 2,9-disubstituted phenanthrolines is illustrated with
the formation of cyclohexanone-derived product 5 (eq 5).
Our preliminary results have shown that the reaction of
1,10-phenanthroline with ketones and samarium diiodide
provides a simple method for the synthesis of substituted
phenanthroline ligands. The possibility exists of extending
these preparations to the use of other reducing agents and to
additional classes of substrates. Also, O-alkylations and
O-acylations beyond the simple methylations reported here
may be employed to introduce additional stereochemical
features and other metal-coordinating groups based upon
oxygen, nitrogen, sulfur, phosphorus, unsaturated func-
tional groups, heterocycles, and even additional phenan-
throline moieties. The further enhancement of these prepara-
tions and the use of the resulting ligands in asymmetric
catalysis are subjects of further investigations in our labora-
tory.
The substituted phenanthrolines 1 may be employed in
further reactions for the purpose of obtaining modified
ligands. For example, O-alkylations may be effected straight-
forwardly as exemplified by methylation with methyl iodide
to give the 2-(1-methoxyalkyl)phenanthrolines 3 (eq 3). In
turn, the alkoxyalkyl derivatives 3 may be subjected to
reductive cleavage, again with samarium diodide,9 to give
the simpler 2-alkylphenanthrolines 4 (eq 4). The results of
these further modifications are included in Table 1.
Acknowledgment. We thank Professors Per-Ola Norrby
(Royal Danish School of Pharmacy, Copenhagen), Bjo¨rn
Åkermark (Royal Institute of Technology, Stockholm), and
Jan Ba¨ckvall (University of Stockholm) for valuable
(12) A representative procedure is given for use of cyclohexanone. To
a stirred solution of 1,10-phenanthroline (0.1 g, 0.55 mmol) in THF (5 mL)
was added a freshly prepared 0.1 M solution of SmI2 in THF (12.2 mL,
1.22 mmol)11 at 25 °C. After 5 min, cyclohexanone (0.120 g, 1.22 mmol)
was added, and the resulting mixture was stirred for 12 h at 25 °C. Saturated
aqueous NH4Cl was added, and the mixture was extracted with CH2Cl2.
The organic extracts were washed with brine, dried over MgSO4, filtered,
and concentrated. The product was purified by flash chromatography
(alumina, ethyl acetate/hexane gradient) to give 0.134 g (88%) of 2-(1-
hydroxycyclohexyl)-1,10-phenanthroline (1a) as a colorless oil: 1H NMR
(300 MHz, CDCl3) δ 9.18 (dd, J ) 4.20, 1.80 Hz, HP9), 8.28 (d, J ) 8.40
Hz, HP4), 8.27 (dd, J ) 8.40, 1.80 Hz, HP7), 7.82 and 7.79 (two d, J ) 8.80
Hz, HP5 and HP6), 7.76 (d, J ) 8.40 Hz, HP3), 7.65 (dd, J ) 8.10, 4.50 Hz,
The potential exists for introducing another group at C(9)
of these phenanthroline derivatives by a second samarium
(9) For reviews, see: (a) Molander, G. A. In The Chemistry of the Metal-
Carbon Bond; Hartley, F. R., Ed.; Wiley: New York, 1990; Vol. 5, Chapter
8. (b) Molander, G. A. Chem. ReV. 1992, 92, 29-68. (c) Imamoto, T.
Lanthanides in Organic Synthesis; Academic Press: London, 1994. (d)
Molander, G. A. Org. React. 1995, 46, 211-368. (e) Molander, G. A.;
Harris, C. R. Chem. ReV. 1996, 96, 307-338. (f) Molander, G. A. Acc.
Chem. Res. 1998, 31, 603-609.
H
P8), 2.08-1.71 (m, 10H, cyclohexyl); 13C NMR (75 MHz) δ 166.52,
(10) For related coupling reactions, see: (a) Imamoto, T.; Nishimura,
S. Chem. Lett. 1990, 1141-1142. (b) Hanamoto, T.; Inanaga, J. Tetrahedron
Lett. 1991, 31, 3555-3556. (c) Ogawa, A.; Takami, N.; Sekiguchi, M.;
Ryu, I.; Kambe, N.; Sonoda, N. J. Am. Chem. Soc. 1992, 114, 8729-8730.
(d) Akane, N.; Hatano, T.; Kusui, H.; Nishiyama, Y.; Ishii, Y. J. Org. Chem.
1994, 59, 7902-7907. (e) Yamashita, M.; Okuyama, K.; Kawasaki, I.; Ohta,
S. Tetrahedron Lett. 1996, 37, 7755-7756. (f) Marco-Contelles, J.; Gallego,
P.; Rodriguez-Fernandez, M.; Khiar, N.; Destabel, C.; Bernabe, M.;
Martinez-Grau, A.; Chiara, J. L. J. Org. Chem. 1997, 62, 7397-7412. (g)
Molander, G. A.; Wolfe, C. N. J. Org. Chem. 1998, 63, 9031-9036. (h)
Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Raimondi, L.
Tetrahedron Lett. 1998, 39, 3333-3336. (i) Lin, S.-C.; Yang, F.-D.; Shiue,
J.-S.; Yang, S.-M.; Fang, J.-M. J. Org. Chem. 1998, 63, 2909-2917. (j)
Miyabe, H.; Torieda, M.; Inoue, K.; Tajiri, K.; Kiguchi, T.; Naito, T. J.
Org. Chem. 1998, 63, 4397-4407. (k) Boiron, A.; Zillig, P.; Faber, D.;
Giese, B. J. Org. Chem. 1998, 63, 5877-5882. (l) Zhou, L. H.; Zhang, Y.
M.; Shi, D. Q. Tetrahedron Lett. 1998, 39, 8491-8494. (m) Machrouhi,
F.; Namy, J.-L. Tetrahedron Lett. 1999, 40, 1315-1318. (n) Yang, S.-M.;
Fang, J.-M. J. Org. Chem. 1999, 64, 394-399.
150.31, 145.81, 143.96, 137.15, 136.06, 129.00, 127.46, 126.28, 126.20,
122.93, 119.21, 73.50, 38.63, 23.70, 22.15; IR (CHCl3) 3352 (OH), 3048
(C-H Ar), 2928 (CH), 909 (C-H Ar) cm-1; HRMS m/e calcd for
C18H19N2O (MH+) 279.1497, found 279.1490.
(13) In this initial survey of the reactivity of various types of ketones,
the stereochemistry of the products from addition to chiral ketones has not
been rigorously established. Only single stereoisomers of the products 1f
and 1g from the reactions of (-)-thujone and DL-menthone were detected
in the crude reaction mixtures. For the (-)-thujone-derived series of
products, a NOESY NMR study of the methoxy derivative 3f provided the
cross-correlations shown below in support of the assigned stereo-
chemistry.
(11) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980,
102, 2693-2698.
Org. Lett., Vol. 1, No. 10, 1999
1661

discussions, Donald Schifferl and Dr. Jaroslav Zajicek for
NMR assistance, and Dr. William Bogess and Nonka Sevova
for mass spectrometry assistance. We are grateful for
financial support from the National Science Foundation, the
National Institutes of Health, and the University of Notre
Dame. D.J.O. is grateful for a Reilly Fellowship.
Supporting Information Available: Experimental pro-
cedures and NMR spectra for the substituted phenanthrolines
1-5. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL990284W
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Org. Lett., Vol. 1, No. 10, 1999