Synthesis, structure, and metal complexation behavior of a new type of functionalized chiral phenanthroline derivative

Article abstract of DOI:10.1021/jo702566m

SmI₂ serves as an effective promoter for the coupling of 1,10-(Chemical Equation Presented) phenanthroline with an epoxide to generate a new class of chiral, functionalized ligands that readily form complexes with metals. Structural studies of the resulting phenanthroline derivative and two of its metal complexes are reported.

Full text of DOI:10.1021/jo702566m

Synthesis, Structure, and Metal Complexation
Behavior of a New Type of Functionalized Chiral
Phenanthroline Derivative
Jacob M. Plummer,† Jeremy A. Weitgenant,† Bruce C. Noll,†
Joseph W. Lauher,‡ Olaf Wiest,† and Paul Helquist*,†
Department of Chemistry and Biochemistry and the Notre
Dame Cancer Center, 251 Nieuwland Science Hall,
UniVersity of Notre Dame, Notre Dame, Indiana 46556, and
Department of Chemistry, State UniVersity of New York,
Stony Brook, New York 11794
phelquis@nd.edu
ReceiVed December 11, 2007
SmI2 serves as an effective promoter for the coupling of 1,10-
FIGURE 1. Examples of nitrogen ligands containing hydroxy groups
as additional coordinating sites.
1,10-Phenanthrolines are well-known for their ability to form
many useful metal complexes,7 and their chiral derivatives have
proven roles in enantioselective reactions that include ketone
reductions,8 enolate allylations,9 oxidations,10 and cyclopropa-
nations11 among others.12 A potentially important modification
of phenanthrolines to extend their utility would be the incor-
poration of additional coordination sites analogous to those in
the previous examples 1-4. However, the corresponding (hy-
droxyalkyl)phenanthrolines (e.g., 5 or 6) have not seen signifi-
cant previous development. Compared to some of the previous
ligands, 5 or 6 would have chirality in a different proximity to
the coordination sites, which may be important for designing
new enantioselective catalysts. An earlier preparation of a few
analogues of 5 required a multistep route.13 We were therefore
interested in developing a more direct synthesis of this new class
of ligands. In this note, we are pleased to report a one-step
method for the synthesis of this ligand class and structural
studies of both a free ligand and two of its metal complexes to
lay the groundwork for further studies of their applications.
phenanthroline with an epoxide to generate a new class of
chiral, functionalized ligands that readily form complexes
with metals. Structural studies of the resulting phenanthroline
derivative and two of its metal complexes are reported.
The development of new chiral ligands for use in metal-
catalyzed enantioselective reactions remains an important need
in synthetic organic chemistry. Among the many classes of well-
established ligands are those that provide two nitrogen atoms
for coordination to a variety of metals.1 Examples are numerous,
a few of which include 2,2′-bipyridines, 1,10-phenanthrolines,
and bis(oxazolines). However, in many cases, the nitrogen atoms
are complemented by additional coordinating sites such as
hydroxyl groups. Specific examples include the popular salens
(e.g., 1),2 bis(hydroxyalkyloxazoline) 2,3 functionalized bipy-
ridine 3,4,5 and Schiff base 4 (Figure 1).6
(7) (a) Chelucci, G.; Addis, D.; Baldino, S. Tetrahedron Lett. 2007, 48, 3359.
(b) Luman, C. R.; Castellano, F. N. In ComprehensiVe Coordination Chemistry
II; McCleverty, J. A., Meyer, T. J., Eds.; Elsevier: Oxford, 2004; Vol. 1, pp
25-39.
† University of Notre Dame.
(8) Gladiali, S.; Pinna, L.; Delogu, G.; Graf, E.; Brunner, H. Tetrahedron:
Asymmetry 1990, 1, 937.
‡ State University of New York.
(1) (a) Belda, O.; Moberg, C. Coord. Chem. ReV. 2005, 249, 727. (b) Togni,
A.; Venanzi, L. M. Angew. Chem., Int. Ed. Engl. 1994, 33, 497.
(2) (a) Baleiza˜o, C.; Garcia, H. Chem. ReV. 2006, 106, 3987. (b) Venkat-
aramanan, N. S.; Kuppuraj, G.; Rajagopal, S. Coord. Chem. ReV. 2005, 249,
1249. (c) Achard, T. R. J.; Clutterbuck, L. A.; North, M. Synlett 2005, 12, 1828.
(d) Larrow, J. F.; Jacobsen, E. N. Top. Organomet. Chem. 2004, 6, 123.
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Chem. 1999, 2327. (c) 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.
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(5) For related bipyridines, see: (a) Ogawa, C.; Wang, N.; Boudou, M.;
Azoulay, S.; Manabe, K.; Kobayashi, S. Heterocycles 2007, 72, 589. (b)
Kobayashi, S.; Ogino, T.; Shimizu, H.; Ishikawa, S.; Hamada, T.; Manabe, K.
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10.1021/jo702566m CCC: $40.75
Published on Web 04/10/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 3911–3914 3911

We and others have previously demonstrated the utility of
samarium diiodide14 for effecting coupling reactions of phenan-
throlines and related substrates with aldehydes and ketones.13,15,16
On the basis of this prior experience, we hypothesized that an
approach for obtaining both mono- (5) and bis-2-(2-hydroxy-
alkyl) (6) derivatives would be the coupling between 1,10-
phenanthroline and epoxides.17,18 To test this idea for the
purpose of this initial study, we have focused on the use of
readily available (R)-1,2-epoxybutane. The reaction was per-
formed by combining 1,10-phenanthroline with the epoxide and
SmI2 in THF at 23 °C for between 2 and 4 d to provide both 5
and 6 (eq 1). The isolated yields varied in different runs with
up to 13% of 5 as the minor product and up to 42% of 6 as the
major product as one pure diastereomer. Longer run times
resulted in no additional product formation as the SmI2 appeared
to be completely consumed after 4 days. Analysis of the crude
products by 1H NMR typically showed nearly total conversion
of the 1,10-phenanthroline to 6. Significant material loss
occurred in the purification process needed to isolate pure
samples of the products. To date, all attempts to employ SmI2
catalytically by using an excess of a reducing agent such as
Mischmetall19 resulted in no product formation.
FIGURE 2. Monomer crystal structure of 6.
FIGURE 3. Hydroxyl group chain in 6.
The absolute configuration of 6 follows from the X-ray studies
reported below. On the other hand, when racemic 1,2-epoxybu-
tane was employed as the substrate, the expected mixture of
diastereomers was obtained in a 3:2 ratio favoring the racemic
diastereomer over the meso form.
As an initial exploration of coordination properties using
metals that are especially relevant for later studies of applications
in catalytic reactions, the complexes 6(Cu) and 6(Zn) were
obtained by straightforward reactions of the free ligand with
Cu(OTf)2and Zn(OTf)2, respectively.
(14) (a) Kagan, H. B. Chem. ReV. 2002, 102, 1805. (b) Williams, D. B. G.;
Caddy, J.; Blann, K. Org. Prep. Proc. Int. 2003, 35, 307. (c) Berndt, M.; Gross,
S.; Hoelemann, A.; Reissig, H.-U. Synlett 2004, 422. (d) Molander, G. A.; Harris,
C. R. Tetrahedron 1998, 54, 3321.
FIGURE 4. Thermal ellipsoid plot for 6(Cu). H-atoms and second
molecule of asymmetric unit omitted for clarity. Ellipsoids drawn at
50% probability.
(15) (a) Aulenta, F.; Berndt, M.; Brüdgam, I.; Hartl, H.; So¨rgel, S.; Reißig,
H.-U. Chem.-Eur. J. 2007, 13, 6047. (b) Reißig, H.-U.; Khan, F. A.; Czerwonka,
R.; Dinesh, C. U.; Shaikh, A. L.; Zimmer, R. Eur. J. Org. Chem. 2006, 4419.
(c) Bolt, V.; Reißig, H.-U. Eur. J. Org. Chem. 2006, 4989. (d) Berndt, M.;
Hlobilova´, I.; Reissig, H.-U. Org. Lett. 2004, 6, 957. (e) Ohno, H.; Wakayama,
R.; Maeda, S.-i.; Iwasaki, H.; Okumura, M.; Iwata, C.; Mikamiyama, H.; Tanaka,
T. J. Org. Chem. 2003, 68, 5909. (f) Edmonds, D. J.; Muir, K. W.; Procter,
D. J. J. Org. Chem. 2003, 68, 3190. (g) Gross, S.; Reissig, H.-U. Org. Lett.
2003, 5, 4305.
X-ray quality crystals were readily obtained for the free ligand
and for each of these complexes. The structure solution for the
ligand 6 (Figure 2) was in chiral space group P212121 (No. 19).
The absolute configuration could not be determined reliably.
The ligand exists in the solid state as a one-dimensional
R-network formed by a chain of hydrogen bonded hydroxy
groups (Figure 3).
The structure solution of 6(Cu) (Figure 4) was in chiral space
group P21 (No. 4). The absolute configuration was determined
from the Flack test, x ) 0.078(18). The asymmetric unit is
comprised of two independent molecules. Pseudoinversion
symmetry is broken by the pendant groups of the phenanthroline
ligands. The Cu of each molecule lies in the planes of the
chelating atoms. Each Cu is also coordinated to two triflates;
distances are 2.442(5), Cu1-O3; 2.454(6), Cu1-O6; 2.390(5);
Cu2-O11; 2.461(5), Cu2-O14.
(16) (a) Weitgenant, J. A.; Mortison, J. D.; O’Neill, D. J.; Mowery, B.;
Puranen, A.; Helquist, P. J. Org. Chem. 2004, 69, 2809. (b) O’Neill, D. J.;
Helquist, P. Org. Lett. 1999, 1, 1659.
(17) For Ti-promoted reductive couplings of epoxides, see (a) Gansa¨uer,
A.; Barchuk, A.; Keller, F.; Schmitt, M.; Grimme, S.; Gerenkamp, M.; Mück-
Lichtenfeld, C.; Daasbjerg, K.; Svith, H. J. Am. Chem. Soc. 2007, 129, 1359.
(b) Chakraborty, T. K.; Samanta, R.; Das, S. J. Org. Chem. 2006, 71, 3321. (c)
Barrero, A. F.; Quílez del Moral, J. F.; Sa´nchez, E. M.; Arteaga, J. F. Org. Lett.
2006, 8, 669. (d) Ferna´ndez-Mateos, A.; de la Nava, E. M.; Coca, G. P.; Silvo,
A. R.; Gonza´lez, R. R. Org. Lett. 1999, 1, 607. (e) RajanBabu, T. V.; Nugent,
W. A. J. Am. Chem. Soc. 1994, 116, 986.
(18) For Sm-promoted reactions of epoxides, see: (a) Aurrecoechea, J. M.;
Pe´rez, E. Tetrahedron Lett. 2003, 44, 3263. (b) Aurrecoechea, J. M.; Pe´rez, E.;
Solay, M. J. Org. Chem. 2001, 66, 564. (c) Molander, G. A.; Shakya, S. R. J.
Org. Chem. 1996, 61, 5885. (d) Molander, G. A.; Hahn, G. J. Org. Chem. 1986,
51, 2596.
(19) Lannou, M.-I.; He´lion, F.; Namy, J.-L. Tetrahedron 2003, 59, 10551.
3912 J. Org. Chem. Vol. 73, No. 10, 2008

FIGURE 5. Copper H-bonded dimer 6(Cu).
FIGURE 7. Zinc H-bonded dimer 6(Zn).
features of the free ligand 6 and its two metal complexes can
be found in the Supporting Information.
We have studied a few additional cases of the ligand
preparation to give an indication of potential generality. When
racemic epoxypropane was used, both mono- and bis(hydroxy-
alkyl) adducts were formed in a 1.0:1.2 ratio (35% isolated
yield). The bis adduct was isolated as a 2:1 mixture of
diastereomers, which is similar to the previous result obtained
using racemic 1,2-epoxybutane (vide supra). The racemic and
meso diastereomers from epoxypropane were not specifically
assigned in this mixture. When the more sterically hindered
racemic 3,3-dimethyl-1,2-epoxybutane was employed, only the
mono adduct 7 was formed (34% isolated yield).
Although we have not performed any mechanistic studies, it
is reasonable to suggest that these reactions may occur by an
initial electron transfer from samarium to the phenanthroline
nucleus followed by nucleophilic attack of the reduced phenan-
throline intermediate on the epoxide followed by aerobic
rearomatization of the phenanthroline during product isolation.
This scenario is consistent with the observed regioselectivity
of the epoxide ring opening at C(1) and retention of configu-
ration at C(2) of the epoxybutane. On the other hand, an
alternative pathway involving initial electron transfer to the
epoxide and ring cleavage17 followed by attack of the resulting
intermediate on the phenanthroline would appear to be incon-
sistent with the observed regio- and stereoselectivity.
FIGURE 6. Thermal ellipsoid plot for 6(Zn). H-atoms and minor parts
of disorder omitted for clarity. Only one of two molecules of asymmetric
unit shown. Ellipsoids drawn at 50% probability.
The supramolecular chemistry of the Cu(OTf)2 complex is
dominated by hydrogen bonds from the coordinated hydroxyl
groups to a single oxygen atom of one of the axial triflate ligands
of a neighboring Cu complex (Figure 5).
The structure solution for 6(Zn) (Figure 6) was in chiral space
group P1 (No. 1). The absolute configuration was determined
from the Flack test, x ) –0.028(6). Two crystallographically
independent molecules occupy the asymmetric unit and the unit
cell. Pseudoinversion symmetry is broken by the pendant groups
of the phenanthroline ligands. Zn1 and Zn2 are displaced from
the plane of the coordinating atoms, 0.323 Å toward O3 for
Zn1 and 0.204 Å toward O14 for Zn2. Some disorder is
observed in the system. The triflate oxygen positions O11 to
O13 show rotational disorder, evidenced by a second set of O sites.
Site occupancies for the two groups were set to a sum of 1. No
additional constraints were applied. The site occupancy for the
primary set refined to 0.620(5). Additional disorder was seen in
the position of Zn1. A second site for Zn1 was observed to lie
nearly in the plane of the base of the square pyramid, 0.061 Å
away from Zn1 and the coordinated triflate. As a result, distances
to the triflate anions are almost identical, 2.247 Å to O6 and 2.279
Å to O3. Site occupancy for Zn1 refined to 0.658(10).
As one example of further derivatization of these ligands to alter
their potential coordination behavior, we have found that the
mono(hydroxyalkyl)phenanthroline 7 reacts straightforwardly with
phenylisocyanate to give the carbamate derivative 8 (eq 2).
In conclusion, the SmI2-promoted coupling of epoxides with
1,10-phenanthroline provides a new class of functionalized
ligands that form metal complexes having potential applications
Details of the solid state structure of 6(Zn) are shown in
Figure 7. A more thorough discussion of the supramolecular
J. Org. Chem. Vol. 73, No. 10, 2008 3913

Hz, 1H), 7.75 (d, J ) 8.8 Hz, 1H), 7.73 (d, J ) 9.4 Hz, 1H), 7.61
(dd, J ) 8.0, 4.4 Hz, 1H), 7.55 (d, J ) 8.2 Hz, 1H), 4.24 (m, 1H),
3.29 (m, J ) 14.8, 2.8 Hz, 1H), 3.21 (dd, J ) 15.0, 9.2 Hz, 1H),
1.70 (m, 2H), 1.08 (t, J ) 7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 161.2, 150.4, 145.6, 145.0, 136.7, 136.2, 128.9, 127.1, 126.4,
126.0, 124.0, 123.1, 72.5, 44.1, 30.5, 10.3; IR (film) cm-1 3340,
3047, 2962, 2925, 2875, 1507, 1499, 1394, 846, 736; HRMS
(FAB+, m/z) calcd for C16H16N2O (M + H+) 253.1341, found
253.1348. 6: mp ) 123–126 °C; TLC Rf ) 0.45 (EtOAc, basic
alumina); [R]20D ) –24.4° (c ) 0.45, ethanol); 1H NMR (500 MHz,
CDCl3) δ 8.18 (d, J ) 8.2 Hz, 2H), 7.75 (s, 2H), 7.50 (d, J ) 8.2
Hz, 2H), 4.26 (m, 2H), 3.25 (dd, J ) 15.5, 2.5 Hz, 2H), 3.17 (dd,
J ) 15.5, 9.0 Hz, 2H), 1.76 (m, 2H), 1.65 (m, 2H), 1.07 (t, J ) 7.5
Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 161.3, 144.6, 136.7, 127.3,
125.8, 124.0, 72.3, 43.5, 30.2, 10.4; IR (film) 3306, 2962, 1591,
1497, 1368, 1113, 980, 849 cm-1; HRMS (FAB+, m/z) calcd for
C20H24N2O2 (M + H+) 325.1916, found 325.1922.
in catalytic reactions. Although the coupling product yields are
low to modest at this stage of development, the reaction
nonetheless has the attractive feature of providing the ligands
of interest in just one simple step from readily available starting
materials. We are currently studying modified versions of these
reactions to extend them to pyridines, bipyridines, and quino-
lines, to use aziridines as substrates, and to apply the resulting
ligands in metal-promoted enantioselective reactions. Upon
extension to other nitrogen heterocycles, the epoxide coupling
reaction may also be useful in alkaloid synthesis.
Experimental Section
Synthesis of R-2-(2-Hydroxybutyl)-1,10-phenanthroline (5)
and R,R-2,9-Bis(2-hydroxybutyl)-1,10-phenanthroline (6). In a
flame-dried, 250-mL round-bottom flask, 361 mg (1.00 mmol) of
1,10-phenanthroline was dissolved in 10 mL of anhyd THF. To
this solution was added 0.70 mL (8.00 mmol) of R-(+)-1,2-
epoxybutane followed by 100 mL (10.0 mmol) of 1 M SmI2 in
THF. The solution was covered with aluminum foil and allowed
to stir for 3.5 d at 23 °C. The reaction was quenched with satd
NH4Cl (100 mL). The layers were separated, and the aq layer was
extracted with CH2Cl2 (3 × 50 mL). The organic layers were
combined, washed with brine (100 mL), dried over MgSO4, and
concentrated under reduced pressure. The residual oil was purified
by column chromatography (50:50, hexanes/EtOAc, basic alumina)
followed by an additional column chromatography (1:19, concd
NH4OH/CH3CN, silica) yielding 67 mg (13%) of 5 as an off-white
solid. The remaining material was purified by repeating the previous
two column chromatography systems and recrystallized from hot
CH3CN to yield 73 mg (11%) of 6 as a slightly yellow solid.
Additionally, 6 could be isolated in up to 42% yield in other runs.
X-ray quality crystals of 6 were obtained by recrystallization from
a mixture of EtOAc and hexanes at –20 °C. 5: mp ) 69–114 °C
Acknowledgment. We thank the University of Notre Dame,
Proctor and Gamble Pharmaceuticals, and the Wolf Fellowship
(J.M.P.) for financial support of this research. We also acknowl-
edge NSF award CHE-0443233 for X-ray instrumentation and
collaboration with the Walther Cancer Institute.
Note Added in Proof. After acceptance of this paper, a key
report appeared of metal complexes and uses of additional
hydroxyalkyl-functionalized nitrogen donor ligands related to
those summarized in Figure 1: Montoya, V.; Pons, J.; Brancha-
dell, V.; Garcia-Anto´n, J.; Solans, X.; Font-Bardía, M.; Ros, J.
Organometallics 2008, 27, 1084.
Supporting Information Available: Additional experimental
procedures, preparation of metal complexes, spectroscopic char-
acterization data, and X-ray crystallographic details. This material
is available free of charge via the Internet at http://pubs.acs.org.
(dec); TLC Rf ) 0.30 (EtOAc, basic alumina); [R]20 ) +18.4°
D
1
(c ) 0.30, CHCl3); H NMR (500 MHz, CDCl3) δ 9.15 (dd, J )
4.3, 0.9 Hz, 1H), 8.24 (dd, J ) 8.0, 1.0 Hz, 1H), 8.20 (d, J ) 8.2
JO702566M
3914 J. Org. Chem. Vol. 73, No. 10, 2008