Samarium-Promoted Coupling of 1,10-Phenanthroline with Carbonyl Compounds for Synthesis of New Ligands

Article abstract of DOI:10.1021/jo0303416

1,10-Phenanthroline reacts with aldehydes and ketones in the presence of samarium diiodide to produce 2-(1-hydroxyalkyl)-1,10-phenanthrolines. The hydroxyalkyl substituent can be functionalized in numerous ways or removed to permit further ligand variatio

Full text of DOI:10.1021/jo0303416

Sa m a r iu m -P r om oted Cou p lin g of 1,10-P h en a n th r olin e w ith
Ca r bon yl Com p ou n d s for Syn th esis of New Liga n d s†
J eremy A. Weitgenant, J onathan D. Mortison, David J . O’Neill, Brendan Mowery,
Anders Puranen, and Paul Helquist*
Department of Chemistry and Biochemistry and Walther Cancer Research Center,
251 Nieuwland Science Hall, University of Notre Dame, Notre Dame, Indiana 46556
phelquis@nd.edu
Received November 5, 2003
1,10-Phenanthroline reacts with aldehydes and ketones in the presence of samarium diiodide to
produce 2-(1-hydroxyalkyl)-1,10-phenanthrolines. The hydroxyalkyl substituent can be function-
alized in numerous ways or removed to permit further ligand variation. The carbonyl coupling
reaction can also be repeated to provide 2,9-disubstituted phenanthrolines. Taken together, these
operations provide ready access to a large number of phenanthroline derivatives to serve as ligand
libraries for catalyst exploration.
In tr od u ction
and alcohols;10 alkene and alkyne cyclizations;11 enolate
allylations,12 arylations,13 alkylations, and Michael reac-
tions;14 conjugate additions to enones;15 alkene cyclopro-
panation,16 reductive carbonylation of nitroaromatics;17
and CO/styrene copolymerization.18 However, compared
to bipyridines and bis(oxazolines), access to chiral forms
The development of new catalysts for enantioselective
syntheses continues to grow in importance.1 The phar-
maceutical industry has demonstrated the crucial need
for developing pure enantiomers of many drugs, and the
most efficient method to obtain these compounds by
stereoselective synthesis is through the use of chiral
catalysts, whether natural (i.e., enzymes) or synthetic.
To improve access to enantiomerically pure compounds,
there is an ongoing need to develop new chiral catalysts.
In turn, these chiral catalysts are most often obtained
by complexation of metals with chiral ligands. Therefore,
the development of suitable catalysts often becomes an
exercise in exploring new ligands and their methods of
preparation.
Included among the numerous types of ligands of
demonstrated utility are bidentates containing two ni-
trogen donor atoms for coordination to metals. Especially
widely investigated have been 2,2′-bipyridines and bis-
(1,3-oxazolin-2-yl)alkanes.2,3 Also closely related in coor-
dination chemistry are the 1,10-phenanthrolines, which
serve as essentially universal ligands for metals of
relevance in catalysis.4 A special feature of phenanthro-
lines is their greater rigidity as a scaffold for ligand
design compared to bipyridines and bis(oxazolines).
Examples of applications of metal complexes of 1,10-
phenanthrolines as catalysts include 1,3-dipolar cyclo-
additions;5 aromatic and alkenyl aminations and ami-
dations;6 Heck reactions;7 oxidation of alkenes,8 arenes,9
(4) (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.
Chemistry of Complexes Containing 2,2′-Bipyridyl, 1, 10-Phenanthro-
line, or 2,2′,6′,2′′-Terpyridyl as Ligands. In Advances in Inorganic and
Radiochemistry; Emele´us, H. J ., Sharpe, A. G., 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. (d) Pallenberg, A. J .; Marschner, T. M.; Barnhart,
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van Leeuwen, P. W. N. M.; Fraanje, J .; Goubitz, K. Organometallics
1995, 14, 3751-61. (b) So¨derberg, B. C. G.; Wallace, J . M.; Tamariz,
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† This paper is dedicated to Professor Bjo¨rn A° kermark on the
occasion of his 70th birthday.
(1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
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10.1021/jo0303416 CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/19/2004
J . Org. Chem. 2004, 69, 2809-2815
2809

Weitgenant et al.
of phenanthrolines19 and their applications in enantio-
selective synthesis have been more limited. Some ex-
amples include Rh-catalyzed asymmetric ketone hydro-
genation20 and hydrosilylation;21 Zn-, Co-, Cu-, Ni-, and
Cd-catalyzed enantioselective hydrolysis of amino acid
esters;22 Pd-catalyzed asymmetric allylation of enolates;23
Cu-catalyzed allylic oxidations;24 and Cu-catalyzed asym-
metric alkene cyclopropanation.25
previously unknown chiral catalysts. Rather than need-
ing to synthesize all of the members of a larger library
of catalysts followed by experimental screening of their
performance, we were able to limit the actual prepara-
tions to only very small, focused libraries of catalysts for
which the best performances were predicted. A conse-
quence of this approach was that we needed appropriate
synthetic methods to access the ligands that resulted
from the computational design efforts. Several of the
chiral ligands for which the best performances were
predicted could in general be derived from 2-(1-hydroxy-
alkyl)phenanthrolines (1). In turn, these compounds were
envisioned as being the products of coupling of the parent
1,10-phenanthroline or 2-halo derivatives with chiral or
prochiral aldehydes and ketones (eq 1). Several phen-
anthrolines potentially derivable from carbonyl-contain-
ing terpenes were especially promising candidates for
catalyst exploration. Therefore, we initiated a study of
methods to effect the desired coupling reactions.
With the limited number of applications to date, there
remains ample opportunity for additional development
of chiral phenanthroline complexes. These further studies
would be facilitated by the availability of several general
methods for the synthesis of substituted phenanthroline
derivatives. Substituted 1,10-phenanthrolines, including
chiral derivatives, are most commonly synthesized by
coupling of 2-halo- or 2,9-dihalo-1,10-phenanthrolines
with various organometallic reagents, by lithiation of C(2)
or C(9) followed by reaction with electrophiles, or by de
novo construction such as the Friedla¨nder synthesis of
phenanthrolines.19,26 However, to meet the goals of our
work, we recognized a need for additional methods to
complement these previously developed procedures.
Our overall aim was to use the parent 1,10-phenan-
throline as a scaffold for chiral catalyst design. In the
first of these studies, we had demonstrated the feasibility
of employing a combined quantum mechanics/molecular
mechanics approach for the design and computational
screening of virtual libraries of catalysts.27-29 This ap-
proach proved to be very successful in predicting the
enantiomeric excesses of products of reactions using
Resu lts a n d Discu ssion
Cou p lin g Rea ction s. Our first efforts to obtain the
targeted phenanthrolines 1 were based upon the genera-
tion of 2-metalated 1,10-phenthrolines and subsequent
addition to carbonyl compounds. We explored the use of
halogen-lithium exchange reactions of 2-halophenan-
throlines with alkyllithium reagents and with active
metals,30 and we attempted direct lithiation of the parent
phenanthroline with strong bases under several sets of
conditions. In none of these attempts were useful results
obtained upon addition of aldehydes or ketones to the
reaction mixtures. In many cases, we obtained substan-
tial quantities of simple 2-alkylphenanthrolines resulting
from addition of alkyllithium reagents to the phen-
anthroline core, which is consistent with earlier methods
of preparation of substituted phenanthrolines.19
As the basis for another approach, we saw a parallel
between the desired overall reaction (eq 1) and pinacol-
like coupling reactions of carbonyl compounds, either
with themselves or, more importantly, with other unsat-
urated partners. In recent years, lanthanide-promoted
reactions of this type have been very well studied,
especially with samarium diiodide as the coupling re-
agent.31 Single-electron-transfer (SET) pathways are
involved in these reactions with several types of coupling
substrates.32 With respect to this previously reported
work, the coupling that we aimed to effect was particu-
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2810 J . Org. Chem., Vol. 69, No. 8, 2004

Samarium-Promoted Coupling of 1,10-Phenanthroline
TABLE 1. Un su ccessfu l Attem p ts To Exten d th e
Cou p lin g Rea ction w ith 1,10-P h en a n th r olin e
larly closely related to reactions of carbonyl compounds
with indoles33 and with thiophenes.34 Other related
reactions include the use of imines,35 oxime ethers,36
hydrazones,37 nitrones,38 nitriles,36b,39 amides,40 benzene
derivatives,41 and related substrates.31,42
Upon investigating the desired reaction, we observed
in our initial studies that the treatment of 1,10-phenan-
throline with SmI2 followed by addition of alkyl ketones
(procedure A) produces the targeted 2-substituted phenan-
throlines 1 (eq 2) as coupling products in good yields (40-
89%; the results are included later in Table 2 together
with the results from using more recently developed
conditions).43 This reaction is very sensitive to moisture
and air. Even very small amounts of water present in
the reaction solutions can inhibit the reaction. 1,10-
Phenanthroline is hygroscopic, and it is important that
is has been thoroughly dried before use. Before realizing
this very high sensitivity toward water, we had difficulty
reproducing this reaction, but when adequate care is
taken to maintain anhydrous conditions, the reaction
reliably gives good results.
a
Procedure A was used in this experiment.
Under the originally developed conditions, this reaction
was limited to the use of dialkyl ketones as substrates
yielding tertiary alcohol products. When aryl ketones or
alkyl and aryl aldehydes were used as substrates, the
corresponding coupling products were not observed.
Instead, pinacol self-coupling products were usually
produced. Being able to perform the coupling of phenan-
throline with substrates beyond simple dialkyl ketones
would permit the generation of a more diverse collection
of ligands. With this goal in mind, improvement of the
reaction conditions for this coupling reaction was there-
fore investigated to permit the use of a broader range of
carbonyl substrates.
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Initial attempts to couple phenanthroline to a wider
variety of carbonyl substrates under different conditions44
failed. Table 1 summarizes these unsuccessful experi-
ments.
After these unsuccessful attempts, we found that our
previously observed coupling reaction with ketones could
be performed more reliably under modified conditions
whereby 1,10-phenanthroline and the ketone were pre-
mixed in solution and then SmI2 was added at room
temperature (procedure B). These conditions were then
applied to the use of aldehydes, since earlier reactions
(procedure A) had failed to produce the desired com-
pounds. In a test reaction, addition of SmI2 to a solution
of 1,10-phenanthroline and propionaldehyde in THF
produced the desired coupling product in 94% yield (eq
3).
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J . Org. Chem, Vol. 69, No. 8, 2004 2811

Weitgenant et al.
TABLE 2. Resu lts of th e Cou p lin g of 1,10-p h en a n th r olin e w ith Keton es a n d Ald eh yd es
a
b
Procedure A was used in this experiment. Procedure B was used in this experiment.
Table 2 summarizes the overall results for the SmI2-
promoted coupling of 1,10-phenanthroline with ketones
and aldehydes under the two sets of conditions. The
yields are usually good to excellent. The reaction has
proven to be general for alkyl-substituted carbonyl
compounds, but it continues to be unsuccessful for
aromatic ketones and aldehydes, as was also the case in
our initial studies.43 Entries 17 and 18 show the expected
compatibility with esters.45 The lower yield in entry 17
may reflect possible formation of the corresponding
lactone, which we did not attempt to isolate and char-
acterize. R,â-Unsaturated carbonyl compounds do not
generally give useful results as substrates in these
coupling reactions. However, the reaction with pulegone
(entry 19) gave a product 2 of undetermined stereochem-
istry, which results from conjugate addition and with the
phenanthroline nucleus obtained in a reduced form. The
addition to (-)-thujone produced a single diastereomer
for which the stereochemistry was determined by NOESY
studies on compound 3f (Table 3). Also, the addition to
dl-menthone produced a single diastereomer that re-
sulted from equatorial attack on the carbonyl carbon as
supported by 13C NMR data.46
F u r th er Rea ction s of th e Cou p lin g P r od u cts. In
general, the new phenanthroline ligands that arise from
our computational design of catalysts do not retain the
hydroxy group that results from the above coupling
reactions. Instead, the desired ligands either incorporate
other substituents that can be derived from alcohols or
the hydroxyl group is completely absent. Therefore, we
needed to investigate methods for either modification or
removal of this group.
One straightforward modification of the hydroxyalky-
lphenanthrolines 1 is O-alkylation to give ether deriva-
tives. Employing sodium hydride and methyl iodide, we
have obtained a series of 2-(1-methoxyalkyl)phenanthro-
lines 3 (eq 4). Similarly, O-acylation can be accomplished
as exemplified by the use of acetic anhydride, pyridine,
and DMAP with 1i to give the acetate 4i (eq 5). The
results of these alkylations and acylations are sum-
marized in Table 3. These reactions can in principle be
extended to a range of other suitable alkylating and
(41) (a) Shiue, J .-S.; Lin, M.-H.; Fang, J .-M. J . Org. Chem. 1997,
62, 4643-4649. (b) Dinesh, C. U.; Reissig, H.-U. Angew. Chem., Int.
Ed. 1999, 38, 789-791. (c) Ohno, H.; Okumura, M.; Maeda, S.; Iwasaki,
H.; Wakayama, R.; Tanaka, T. J . Org. Chem. 2003, 68, 7722-7732.
(42) Ho¨lemann, A.; Reissig, H.-U. Org. Lett. 2003, 5, 1463-1466.
(43) O’Neill, D. J .; Helquist, P. Org. Lett. 1999, 1, 1659-1662.
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2118-2119. (b) Evans, W. J .; Allen, N. T.; Ziller, J . W. J . Am. Chem.
Soc. 2000, 122, 11749-11750.
(46) (a) Ashby, E. C.; Laemmle, J . T. Chem. Rev. 1975, 75, 521-
546. (b) Dimitrov, V.; Panev, S. Tetrahedron: Asymmetry 2000, 11,
1513-1516. (c) Dimitrov, V.; Panev, S. Tetrahedron: Asymmetry 2000,
11, 1517-1526. (d) Trost, B. M.; Florez, J .; J ebaratnam, D. J . J . Am.
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23, 3867-3870.
2812 J . Org. Chem., Vol. 69, No. 8, 2004

Samarium-Promoted Coupling of 1,10-Phenanthroline
TABLE 3. Resu lts of F u r th er Rea ction s of th e Keton e
a n d Ald eh yd e Ad d u cts
complicated by competing deacetylation to regenerate the
free hydroxy derivative 1i as the major product.47 How-
ever, when performed in the presence of 2-propanol at
low temperature, the amount of 1i produced was signifi-
cantly decreased. Nonetheless, the demethoxylation reac-
tion is more useful than the deacetoxylation at this point
in the development of these cleavages. The overall results
of these deoxygenations are compiled in Table 3 along
with the previous functionalizations.
These general types of reductive cleavage reactions are
well-known for SmI2 and related reagents. Very well
developed are cleavages adjacent to carbonyl groups and
similarly functionalized systems.31 Especially relevant to
our observations are the previously reported SmI2-
promoted deoxygenation reactions of (1-hydroxyalkyl)-
pyridines and the corresponding acetates.48
One final observation is that a deoxygenation product
may be resubjected to the initial carbonyl coupling
reaction to provide a 2,9-disubstituted phenanthroline 6
(eq 8).
Con clu sion s
The SmI2-promoted reactions of 1,10-phenanthroline
with ketones and aldehydes provides a broad array of
new substituted phenanthrolines. These coupling reac-
tions together with further reactions of the products,
including O-alkylation, O-acylation, and deoxgenation,
as well as additional coupling at C(2) after initial coupling
at C(9), provide a tremendous level of diversity for
exploration of new catalysts. The diversity elements that
may be investigated in applications of these ligands are
summarized in Figure 1. Many uses in catalysis may be
anticipated in further studies, and applications in the
synthesis of alkaloids and other nitrogen-containing
compounds are also likely. In our own ongoing investiga-
tions, we are now well positioned to prepare the many
ligands that will be generated by means of our virtual
catalyst design and screening efforts.
acylating agents to increase again the diversity of avail-
able ligands.
With respect to the potential need for removal of the
oxygen substituent entirely from these ligands, either the
ether or acetate derivatives are subject to reductive
cleavage with SmI2 to afford the 2-alkylphenanthrolines
5 (eqs 6 and 7). The acetate cleavage is made more
(47) (a) Yanada, R.; Negoro, N.; Bessho, K.; Yanada, K. Synlett 1995,
1261-1263. (b) Kajiro, H.; Mitamura, S.; Mori, A.; Hiyama, T.
Tetrahedron Lett. 1999, 40, 1689-1692. (c) Marcantoni, E.; Massaccesi,
M.; Torregiani, E.; Bartoli, G.; Bosco, M.; Sambri, L. J . Org. Chem.
2001, 66, 4430-4432.
(48) Kato, Y.; Mase, T. Tetrahedron Lett. 1999, 40, 8823-8826.
J . Org. Chem, Vol. 69, No. 8, 2004 2813

Weitgenant et al.
Rep r esen ta tive P r oced u r e for Syn th esis of 2-(Meth -
oxya lk yl)p h en a n t h r olin es (3a -g). 2-(1-Met h oxycyclo-
h exyl)-1,10-p h en a n t h r olin e (3a ). To a stirred solution of
0.320 g (1.15 mmol) of 1a in THF was added 0.110 g (4.6 mmol)
of NaH in one portion followed by 0.65 mL (4.6 mmol) of MeI.
The mixture was stirred at 25 °C and monitored by TLC. Upon
completion of the reaction, satd aq NH4Cl was added to quench
the reaction, and the resulting mixture was extracted with
CH2Cl2. The organic extracts were combined, washed with
brine, dried over MgSO4, filtered, and concentrated. Purifica-
tion by column chromatography (alumina gel, ethyl acetate/
hexane gradient) yielded 0.301 g (90%) of 3a as a colorless oil:
1H NMR (300 MHz, CDCl3) δ 9.24 (dd, J ) 4.5, 1.8 Hz, 1H),
8.25 (d, J ) 8.4 Hz, 1H), 8.25 (dd, J ) 8.1, 2.4 Hz, 1H), 7.96
(d, J ) 8.4 Hz, 1H), 7.82 (d, J ) 8.8 Hz, 1H), 7.75 (d, J ) 8.80
Hz, 1H), 7.61 (dd, J ) 8.1, 4.5 Hz, 1H), 3.11 (s, 3H), 2.23 (m,
4H), 1.74 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 166.3, 150.5,
146.3, 145.1, 136.4, 136.0, 128.8, 127.4, 126.4, 126.0, 122.4,
120.5, 80.5, 50.6, 33.8, 25.1, 21.7; IR (CHCl3) 3048, 2933, 908
cm-1; HRMS (FAB+, m/z) calcd for C19H21N2O (M + H+)
293.1654, found 293.1665.
2-(1-Acetoxyp r op yl)-1,10-p h en a n th r olin e (4i). In a 50
mL flame-dried round-bottom flask under argon was dissolved
95 mg (0.4 mmol) of 2-(1-hydroxypropyl)-1,10-phenanthroline
(1i) in 3 mL of anhydrous THF, and to it were added 0.08 mL
(0.8 mmol) of acetic anhydride, 0.08 mL (1.0 mmol) of pyridine,
and a catalytic amount of DMAP. The reaction was stirred at
room temperature for 17 h, concentrated under reduced
pressure, and purified by column chromatography (50:1, CH2-
Cl2 (saturated with NH3)/MeOH, silica gel) yielding 103 mg
(92%) of 2-(acetoxypropyl)-1,10-phenanthroline as an orange
oil: 1H NMR (500 MHz, CDCl3) δ 9.24 (dd, J ) 4.5, 2 Hz, 1H),
8.24 (d, J ) 7.9 Hz, 1H), 8.23 (dd, J ) 8.2, 1.5 Hz, 1H), 7.78
(d, J ) 8.9 Hz, 1H), 7.76 (d, J ) 8.9 Hz, 1H), 7.69 (d, J ) 8.4
Hz, 1H), 7.62 (dd, J ) 8.2, 4.0 Hz, 1H), 6.26 (dd, J ) 8.2, 4.5
Hz, 1H), 2.22 (m, 1H), 2.20 (s, 3H), 2.11 (m, 1H), 1.01 (t, J )
7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 170.6, 161.0, 150.6,
146.3, 145.8, 137.0, 136.3, 129.2, 128.1, 126.6, 126.5, 123.1,
120.0, 19.0, 77.5, 77.2, 77.0, 29.1, 21.4, 10.0; IR (film) 2971,
2935, 1737, 1620, 1589, 1236, 853 cm-1; HRMS (FAB+, m/z)
calcd for C17H17N2O2 (M + H+) 281.1290, found 281.1297.
Repr esen tative P r ocedu r e for Sm I2-Mediated Dem eth -
oxyla tion of 2-(Meth oxya lk yl)p h en a n th r olin es (5a ,c,d ,f).
2-(Cycloh exyl)-1,10-p h en a n th r olin e (5a ). To a stirred solu-
tion of 0.200 g (0.684 mmol) of 3a in THF (5 mL) was added
17.1 mL (1.71 mmol) of a 0.1 M solution of SmI2 in THF at 25
°C. The mixture was stirred at 25 °C and monitored by TLC.
Upon completion of the reaction, satd aq NH4Cl was added to
quench the reaction, and the resulting mixture was extracted
with CH2Cl2. The organic extracts were combined, washed with
brine, dried over MgSO4, filtered, and concentrated. Purifica-
tion by column chromatography (alumina, ethyl acetate/hexane
gradient) yielded 0.119 g (66%) of 5a as a colorless oil: 1H
NMR (300 MHz, CDCl3) δ 9.19 (dd, J ) 4.5, 1.8 Hz, 1H), 8.16-
(dd, J ) 8.1, 1.8 Hz, 1H), 8.12 (d, J ) 8.4 Hz, 1H), 7.71 (d, J
) 8.8 Hz, 1H), 7.64 (d, J ) 8.8 Hz, 1H), 7.54 (dd, J ) 8.1, 4.2
Hz, 1H), 7.53 (d, J ) 8.4 Hz, 1H), 3.33 (tt, J ) 3.00-3.30 Hz,
1H), 2.12-1.28 (m, 10H); 13C NMR (75 MHz, CDCl3) δ 167.5,
150.2, 146.1, 145.3, 136.3, 135.9, 128.7, 127.1, 126.3, 125.4,
122.5, 120.5, 47.7, 33.3, 26.3, 26.0; IR (CHCl3) 3049, 2929, 908
cm-1; HRMS (FAB+, m/z) calcd for C18H19N2 (M + H+)
263.1548, found 263.1534.
2-P r op yl-1,10-p h en a n th r olin e (5i). In a 25 mL flame-
dried round-bottom flask under argon was dissolved 41 mg
(0.15 mmol) of 2-(1-acetoxypropyl)-1,10-phenanthroline (4i) in
2 mL of anhydrous THF and the mixture cooled to -78 °C. To
this solution was added 0.01 mL of 2-propanol followed by 4
mL (0.4 mmol) of 0.1 M SmI2 in THF, and after being stirred
for 20 min at this temperature the reaction was quenched with
an excess of 2-propanol. The reaction mixture was partitioned
between satd NaHCO3(aq) and CH2Cl2. The layers were
separated, and the aqueous layer was extracted with CH2Cl2
F IGURE 1. Diversity elements generated in the 1,10-phenan-
throline functionalization reactions reported in this paper.
Exp er im en ta l Section
R ep r esen t a t ive P r oced u r e A (1a -g). 2-(1-H yd r oxy-
cycloh exyl)-1,10-p h en a n th r olin e (1a ). To a stirred solution
of 1,10-phenanthroline (0.1 g, 0.55 mmol) in THF (5 mL) was
added a 0.1 M solution of SmI2 in THF (12.2 mL, 1.22 mmol)
at 25 °C. After being stirred for 5 min, 0.120 g (1.22 mmol) of
cyclohexanone was added, and the resulting mixture was
stirred for 12 h at 25 °C and monitored by TLC. Upon
completion of the reaction, satd aq NH4Cl was added to quench
the reaction, and the resulting mixture was extracted with
CH2Cl2. The organic extracts were combined, washed with
brine, dried over MgSO4, filtered, and concentrated. Column
chromatography (alumina, ethyl acetate/hexane gradient)
provided 0.134 mg (88%) of 1a as a colorless oil: 1H NMR (300
MHz, CDCl3) δ 9.18 (dd, J ) 4.20, 1.8 Hz, 1H), 8.28 (d, J )
8.4 Hz, 1H), 8.27 (dd, J ) 8.4, 1.8 Hz, 1H), 7.82 (d, J ) 8.8 Hz,
1H), 7.79 (d, J ) 8.8 Hz, 1H), 7.76 (d, J ) 8.4 Hz, 1H), 7.65
(dd, J ) 8.1, 4.5 Hz, 1H), 2.08-1.71 (m, 10H); 13C NMR (75
MHz, CDCl3) δ 166.5, 150.3, 145.8, 144.0, 137.2, 136.1, 129.0,
127.5, 126.3, 126.2, 122.9, 119.2, 73.5, 38.6, 23.7, 22.2; IR
(CHCl3) 3352, 3048, 2928, 909 cm-1; HRMS (FAB+, m/z) calcd
for C18H19N2O (M + H+) 279.1497, found 279.1490.
Rep r esen ta tive P r oced u r e B (1h -r ). 2-(1-Hyd r oxy-
h ep tyl)-1,10-p h en a n th r olin e (1k ). In a flame-dried 25 mL
round-bottom, one neck flask under argon, 36 mg (0.2 mmol)
of 1,10-phenanthroline was dissolved in 2 mL of degassed
anhydrous THF. To this was added 0.056 mL (0.4 mmol) of
heptaldehyde, and after the mixture was stirred briefly, 5 mL
of 0.1 mL of 0.1 M SmI2 in THF was added and the mixture
was allowed to stir at room temperature for 1 h. The reaction
was quenched with 1 N HCl (aq), and the mixture was
partitioned between satd NaHCO3 (aq) and CH2Cl2. The layers
were separated, and the aqueous layer was extracted with CH2-
Cl2 (2 × 20 mL). The organic solution was dried over MgSO4
and concentrated under vacuum. The residual orange oil was
purified by column chromatography (50:1 CH2Cl2 (saturated
with NH3)/MeOH, silica gel) yielding 50 mg (85%) of 2-(1-
hydroxyheptyl)-1,10-phenanthroline (1k ) as an orange oil: 1H
NMR (300 MHz, CDCl3) δ 9.13 (dd, J ) 4.3, 1.7 Hz, 1H), 8.20
(dd, J ) 7.7, 1.7 Hz, 1H), 8.18 (d, J ) 8.1 Hz, 1H), 7.72 (m,
2H), 7.56 (dd, J ) 8.0, 4.3 Hz, 1H), 5.20 (dd, J ) 7.9, 4.7 Hz,
1H), 1.94 (m, 2H), 1.56 (m, 2H), 1.26 (m, 6H), 0.83 (t, J ) 6.8
Hz, 3H); 13C NMR (75 MHz, CDCl3) d 164.5, 150.3, 145.9,
144.9, 136.8, 136.4, 129.1, 127.9, 126.7, 126.1, 123.0, 120.7,
77.7, 77.2, 76.8, 74.8, 39.0, 32.0, 29.6, 25.9, 22.8, 14.2; IR (film)
3350, 1619, 1591, 852 cm-1; HRMS (FAB+, m/z) calcd for
C
19H23N2O (M + H+) 295.1810, found 295.1790.
2-[1-Met h yl-1-[(4R)-4-m et h yl-2-oxocycloh exyl]et h yl]-
1,2,3,4-tetr a h yd r op h en a n th r olin e (2). Through use of the
above general procedure A, (R)-(+)-pulegone (0.186 g, 1.22
mmol) was converted into 0.092 g (50%) of 2 as a colorless oil:
1H NMR (300 MHz, CDCl3) δ 8.66 (dd, J ) 3.9, 1.5 Hz, 1H),
7.97 (dd, J ) 8.4, 1.8 Hz, 1H), 7.28 (dd, J ) 8.4, 4.5 Hz, 1H),
7.02 (d, J ) 8.1 Hz, 1H), 6.92 (d, J ) 8.10 Hz, 1H), 5.93 (br s,
1H), 4.57 (br s, 1H), 2.71 (dt, J ) 11.6, 4.3 Hz, 1H), 2.46 (m,
2H), 2.25 (m, 1H), 2.10 (m, 2H), 1.93 (m, 3H), 1.24 (m, 3H),
1.1 (s, 3H), 1.09 (s, 3H), 0.92 (d, J ) 6.9 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 213.4, 147.2, 138.4, 136.6, 135.9, 128.9, 128.0,
122.9, 120.6, 112.9, 65.1, 60.3, 55.2, 59.1, 59.0, 29.4, 29.3, 29.0,
28.6, 27.5, 23.9, 19.8; IR (CHCl3) 3436, 2956, 1688, 909 cm-1
;
HRMS (FAB+, m/z) calcd for C22H29N2O (M + H+) 335.2123,
found 335.2134.
2814 J . Org. Chem., Vol. 69, No. 8, 2004

Samarium-Promoted Coupling of 1,10-Phenanthroline
(2 × 20 mL). The organic layers were combined, dried over
MgSO4, and concentrated under reduced pressure. Column
chromatography (50:1, CH2Cl2 (saturated with NH3)/MeOH,
silica gel) yielded 17 mg (50%) of 2-propyl-1,10-phenanthroline
(5i) as an orange oil: 1H NMR (500 MHz, CDCl3) δ 9.23 (dd,
J ) 4.5, 1.5 Hz, 1H), 8.23 (dd, J ) 7.9, 2.0 Hz, 1H), 8.16 (d, J
) 8.4 Hz, 1H), 7.77 (d, J ) 8.9 Hz, 1H), 7.73 (d, J ) 8.9 Hz,
1H), 7.61 (dd, J ) 8.2, 4.5 Hz, 1H), 7.54 (d, J ) 8.4 Hz, 1H),
3.2 (m, 2H), 1.92 (m, 2H), 1.07 (t, J ) 7.4 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 163.7, 150.5, 146.4, 146.0, 136.4, 136.2,
129.9, 127.1, 126.7, 125.7, 123.0, 122.9, 77.5, 77.2, 77.0, 41.7,
MHz, CDCl3) δ 167.0, 165.3, 144.9, 143.4, 137.2, 136.0, 127.5,
127.3, 126.2, 124.9, 121.5, 118.7, 73.2, 47.2, 36.8, 32.8, 26.6,
26.1, 25.8, 22.7; IR (CHCl3) 3338, 3042, 2927, 852 cm-1; HRMS
(FAB+, m/z) calcd for C24H29N2O (M + H+) 361.2280, found
361.2272.
Ack n ow led gm en t. We express our appreciation to
Professors Bjo¨rn A˙ kermark (Stockholm), Tobias Rein
(Stockholm), Per-Ola Norrby (Copenhagen), and Olaf
Wiest (Notre Dame) for valuable discussions. We thank
the Beckman Foundation for a fellowship awarded to
J .D.M. and the National Science Foundation, Procter
& Gamble Pharmaceuticals, and the University of Notre
Dame for support of this research.
24.0, 14.4; IR (film) 2960, 2870, 1620, 1590, 1553, 850 cm-1
;
HRMS (FAB+, m/z) calcd for C15H15N2 (M + H+) 233.1235,
found 233.1223.
9-(1-Cycloh exyl)-2-(1-h yd r oxycycloh exyl)-1,10-ph en a n -
th r olin e (6). Through use of the above general procedure A
for addition of ketones to phenanthrolines, cyclohexanone
(0.094 g, 0.953 mmol) was added to 5a (0.100 g, 0.381 mmol)
and 0.1 M SmI2 (8.38 mL, 0.838 mmol) and converted into
0.083 g (60%) of 6 as a colorless oil: 1H NMR (300 MHz, CDCl3)
δ 8.24 (d, J ) 8.4 Hz, 1H), 8.14 (d, J ) 8.4 Hz, 1H), 7.76 (d, J
) 8.8 Hz, 1H), 7.70 (d, J ) 8.8 Hz, 1H), 7.66 (d, J ) 8.4 Hz,
1H), 7.52 (d, J ) 8.4 Hz, 1H), 3.06 (tt, J ) 11.85, 3.30 Hz,
1H), 2.18-1.74 (m, 10H), 1.52-1.33 (m, 10H); 13C NMR (75
Su p p or tin g In for m a tion Ava ila ble: Details for the
preparation of compounds 1b-j,l-r , 3b-g, and 5c,d ,f as well
as 1H and 13C NMR data for compounds 1a -r , 2, 3a -g, 4i,
5a ,c,d ,f,i, and 6. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O0303416
J . Org. Chem, Vol. 69, No. 8, 2004 2815