New synthetic routes toward enantiopure nitrogen donor ligands

Article abstract of DOI:10.1021/jo0612372

(Chemical Equation Presented) New polypyridylic chiral ligands, having either C₃ or lower symmetry, have been prepared via a de novo construction of the pyridine nucleus by means of Kroehnke methodology in the key step. The chiral moieties of these ligands originate from the monoterpen chiral pool, namely (-)-α-pinene ((-)-14, (-)-15) and (-)-myrtenal ((-)-9, (-)-10). Extension of the above-mentioned asymmetric synthesis procedure to the preparation of enantiopure derivatives of some commonly used polypyridylic ligands has been achieved through a new aldehyde building block ((-)-16). As an example, the synthesis of a chiral derivative of N,N-bis(2-pyridylmethyl) ethylamine (bpea) ligand, (-)-19, has been performed to illustrate the viability of the method. The coordinative ability of the ligands has been tested through the synthesis and characterization of complexes [Mn((-)-19)Br₂], (-)-20, and [RuCl((-)-10)(bpy)](BF₄), (-)-21. Some preliminary results related to the enantioselective catalytic epoxidation of styrene with the ruthenium complex are also presented.

Full text of DOI:10.1021/jo0612372

New Synthetic Routes toward Enantiopure Nitrogen Donor Ligands
†
†
,†
†
Xavier Sala, Anna M. Rodr ´ı guez, Montserrat Rodr ´ı guez,* Isabel Romero,
‡
,§
,‡,||
||
Teodor Parella, Alexander von Zelewsky,* Antoni Llobet,* and Jordi Benet-Buchholz
Departament de Qu ´ı mica, UniVersitat de Girona, Campus MontiliVi s /n, E-17071 Girona, Spain,
Departament de Qu ´ı mica, UniVersitat Aut o` noma de Barcelona, Cerdanyola del Vall e` s, E-08193 Barcelona,
Spain, Department of Chemistry, UniVersity of Fribourg, P e´ rolles, 1700-Fribourg, Switzerland, and Institut
Catal a` d’InVestigaci o´ Qu ´ı mica (ICIQ), AVgda. Pa ¨ı sos Catalans 16, E-43007 Tarragona, Spain
montse.rodriguez@udg.es; antoni.llobet@iciq.es; alexander.Vonzelewsky@unifr.ch
ReceiVed June 15, 2006
3
New polypyridylic chiral ligands, having either C or lower symmetry, have been prepared via a de novo
construction of the pyridine nucleus by means of Kr o¨ hnke methodology in the key step. The chiral moieties
of these ligands originate from the monoterpen chiral pool, namely (-)-R-pinene ((-)-14, (-)-15) and
(-)-myrtenal ((-)-9, (-)-10). Extension of the above-mentioned asymmetric synthesis procedure to the
preparation of enantiopure derivatives of some commonly used polypyridylic ligands has been achieved
through a new aldehyde building block ((-)-16). As an example, the synthesis of a chiral derivative of
N,N-bis(2-pyridylmethyl)ethylamine (bpea) ligand, (-)-19, has been performed to illustrate the viability
of the method. The coordinative ability of the ligands has been tested through the synthesis and
characterization of complexes [Mn((-)-19)Br
2
], (-)-20, and [RuCl((-)-10)(bpy)](BF ), (-)-21. Some
4
preliminary results related to the enantioselective catalytic epoxidation of styrene with the ruthenium
complex are also presented.
4
Introduction
tartrate derivatives, biarylic phosphines or alcohols,5 and
6
cinchona alkaloids are top examples of these “privileged
Transition-metal asymmetric catalysis is one of the most
powerful tools for the synthesis of optically active compounds,
7
1
ligands”. Nevertheless, there is still an increasing need for new
and improved ligands.
and the development of new chiral ligands represents a crucial
part in this area. A wide range of chiral mono-, bi-, and
multidentate ligands with different coordinating atoms are
known today and used extensively for all kinds of catalytic
reactions, but only a relatively small number of structural classes
2
Transition-metal complexes with sp -nitrogen(s) as coordinat-
ing atoms constitute also an important class of coordination
compounds able to perform a wide range of asymmetric
transformations. Within this group, substituted mono- and
bisoxazolines have received major attention during the past
8
2
3
stand out due to their broad applicability. Bisoxazolines, salens,
9
three decades. Recently, chiral versions of C2-symmetric 2,2′-
bipyridyl, 2,2′:6′,2′′-terpyridines and 1,10-phenanthrolines have
been prepared as promising new compounds in this area,
†
Universitat de Girona.
Universitat Aut o` noma de Barcelona.
University of Fribourg.
Institut Catal a` d’Investigaci o´ Qu ´ı mica.
1) (a) For reviews, see: Noyori, R.; Ed. Asymmetric Catalysis in Organic
‡
§
|
10
offering novel opportunities such as electronic tuning of the
ligating nitrogen via the substitution pattern at the pyridine
(
Synthesis; Wiley: New York, 1994. (b) Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds. ComprehensiVe Asymmetric Catalysis; Springer:
Berlin, 1999. (c) Catalytic Asymmetric Synthesis, 2nd ed.; Ojiwa, I., Ed.;
Wiley: New York, 2000. (d) Seyden Penne, J. Chiral Auxiliaries and
Ligands in Asymmetric Synthesis; Wiley: New York, 1995.
11
ring. However, despite the intrinsic interest of chiral ligands
containing C3 symmetry, their polypyridylic derivatives have
12,13
received less attention.
Upon coordination to a metal center,
1
0.1021/jo0612372 CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/15/2006
J. Org. Chem. 2006, 71, 9283-9290
9283

Sala et al.
they can reduce the number of possible diastereomeric inter-
mediates or transition states in a catalytic reaction,14 as has been
shown for C2-symmetric bidentate ligands in the case of
geometry of the tridentate ligand and thus will also be explored
in the near future.
With all this in mind, we have been working toward the
design of new enantiopure C3-symmetric polypyridylic ligands
where chirality could be introduced from naturally occurring
monoterpenes, as well as in the synthesis of other commonly
used polypyridylic compounds through the new aldehyde
building block (-)-16 (Scheme 3). We describe here on the
preparation and characterization of chiral “pineno”-fused tris-
15
tetrahedral and square-planar complexes. C3-Symmetric tri-
dentate ligands could be potentially used to prepare metal
complexes for a number of asymmetric catalytic reactions such
as allylic substitutions, epoxidations, cyclopropanations, hy-
10
drosilylations, etc. In this context, it will be of special interest
to assert the effect of facial versus meridional geometry in
octahedral type of complexes, for instance when the more
accessible tridentate trpy C2-meridional type of ligand (trpy is
(
(
2-pyridyl) tripod ligands (-)-9, (-)-10, (-)-14, and (-)-15
Schemes 1 and 2) as examples of C3-symmetric ligands. On
the other hand, the viability of the chiral design to lower
symmetry ligands is exemplified by the synthesis of a chiral
derivative of N,N-bis(2-pyridylmethyl)ethylamine (bpea) ligand
2
,2′:6′,2′′-terpyridine) is replaced by the tripodal ligands
described in this work. Metal centers with higher and lower
coordination numbers will also be strongly influenced by the
(-)-19. Furthermore, the coordinative behavior of some of the
ligands to Mn and Ru, as well as the catalytic activity of the
Ru complex prepared, are described. Finally, it is also interesting
to point out that the synthetic route we have designed for the
preparation of the chiral tridentate ligands uses dipyridyl ketones
(
2) (a) Pfaltz, A. Acc. Chem. Res. 1993, 26, 339-345. (b) Ghoshb, A.
K.; Mathivanan, P.; Cappiello, J. Tetrahedron: Asymmetry 1998, 8, 1-45.
c) Jorgensen, K. A.; Johannsen, M.; Yao, S.; Audrain, H.; Thornauge, J.
Acc. Chem. Res. 1999, 32, 605-613.
(
(
3) (a) Jacobsen, E. N. Acc. Chem. Res. 2000, 33, 421-431. (b) Myers,
(
(-)-8 and (-)-13) as intermediates. These synthetic intermedi-
J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959-8960. (c) Ruck,
T. R.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 2882-2883.
16
ates are also potentially exciting bidentate chiral ligands that
have been studied to a much lesser extent and that might open
up new research territories.
(
4) (a) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1-299. (b)
Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem., Int. Ed. 2001, 1, 92-
39. (c) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis;
Ojiwa, I., Ed.; Wiley-VCH: New York, 1993; Chapter 4.1.
1
(
5) Noyori, R. AdV. Synth. Catal. 2003, 345, 5-32.
Results and Discussion
(
6) (a) Kolb, H. C.; van Nieuwenze, M. S.; Sharpless, K. B. Chem. ReV.
1
8
1
994, 94, 2483-2547. (b) Calter, M. A. J. Org. Chem. 1996, 61, 8006-
007. (c) Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc.
984, 106, 446-447. (d) Corey, E. J.; Xu, F. Noe, M. C.; J. Am. Chem.
The basic ligands synthesized within this report consist of
tris(2-pyridyl)methanols and bis(pyridyl)ethylamine as parent
structures. Our strategy was to introduce chirality in commonly
used molecules by enantiomerically pure monoterpenes. The
synthetic pathway follows the general method for pyridine
Soc. 1997, 119, 12414-12415. (e) Beller, M.; Sharpless, K. B. In Applied
Homogeneous Catalysis with Organometallic Compounds; Cornils, B.,
Herrmann, W. A., Eds.; VCH: Weinheim, 1996; Vol. 2, pp 1009-1024.
(7) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691-1693.
8) (a) Togni, A.; Venanzi, L. M. Angew. Chem., Int. Ed. Engl. 1994,
17
synthesis introduced by Kr o¨ nke. The chirality is introduced
(
via the commercially available natural products (-)-myrtenal
(-)-3 and (-)-R-pinene (-)-4, giving annulated compounds in
the 4,5- and 5,6-position of a pyridine ring, respectively.
Design of the C3-Symmetric Tripodal Ligands. Although
C2-symmetric ligands have been extensively used for metal-
mediated enantioselective organic transformations,18 analogous
3
3, 497-526. (b) Fache, F.; Schulz, E.; Lorraine, A.; Tommasino, M. L.;
Lemaire, M. Chem. ReV. 2000, 100, 2159-2231.
9) Selected references: (a) Gomez, M.; Muller, M.; Rocamora, M.
(
Coord. Chem. ReV. 1999, 193, 769-835. (b) Evans, D. A.; Scheidt, K. A.;
Johnston, J. N.; Willis, M. C. J. Am. Chem. Soc. 2001, 123, 4480-4491.
(
c) Christensen, C.; Juhl, K.; Jorgensen, K. A. Chem. Commun. 2001, 2222-
2
223. (d) Glorius, F.; Pfaltz, A. Org. Lett. 1999, 1, 141-144. (e) Bellemin-
Laponnaz, S.; Gade, L. H. Angew. Chem., Int. Ed. Engl. 2002, 41, 3473-
3
14
C3-symmetric systems have been used to a lesser extent. Metal
475. (f) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336-345.
10) For an overview, see: Chelucci, G.; Thummel, R. P. Chem. ReV.
002, 102, 3129-3170. Selected references: (a) Fletcher, N. C. J. Chem.
catalysts containing ligands possessing C3 or higher rotational
symmetry are expected to permit a higher degree of stereocontrol
and reduce the number of possible transition states (in, for
instance, octahedral complexes) compared to those for the C2-
symmetric counterparts and thus may find applications in
asymmetric catalysis. These particular characteristics jointly with
our experience in the synthesis of chiral pineno-fused pyridines
have directed us toward chiral tris-pyridylic ligands. Although
the first synthesis of tris(2-pyridyl)methanol ligand dates from
(
2
Soc., Perkin Trans. 2002, 1831-1842. (b) Ziegler, M.; Monney, V.;
Stoeckli-Evans, H.; von Zelewsky, A.; Sasaki, I.; Dupie, G.; Daran, J.-C.;
Balavoine, G. G. A. J. Chem. Soc., Dalton Trans. 1999, 667-675. (c)
Loetscher, D.; Rupprecht, S.; Collomb, P.; Belser, P.; Viebrock, H.; von
Zelewsky, A.; Burger, P. Inorg. Chem. 2001, 40, 5675-5681. (d) Malkov,
A. V.; Baxendale, I. R.; Bella, M.; Langer, J. W.; Russell, D. R.; Mansfield,
J.; Valko, M.; Koc oˆ vsk y´ , P. Organometallics 2001, 20, 673-690. (e)
Malkov, A. V.; Pernazza, D.; Bell, M.; Bella, M.; Massa, A.; Tepl y´ , F.;
Meghani, P.; Koc oˆ vsk y´ , P. J. Org. Chem. 2003, 68, 4727-4742. (f)
Harmata, M.; Ghosh, S. K. Org. Lett. 2001, 3, 3321-3323.
19
more than 50 years ago, work related to the synthesis of
(11) (a) Kinnunen, T.-J. J.; Haukka, M.; Nousiainen, M.; Patrikka, A.;
20
12a
trisubstituted and chiral derivatives is rare, which is surpris-
ing considering their potential applications. This can, at least
in part, be attributed to the complexity of the pyridyllithium
Pakkanen, T. A. J. Chem. Soc., Dalton Trans. 2001, 2649-2654. (b) Bush,
P. M.; Whitehead, J. P.; Pink, C. C.; Gramm, E. C.; Eglin, J. L.; Watton,
S. P.; Pence, L. E. Inorg. Chem. 2001, 40, 1871-1877.
(12) (a) Adolfsson, H.; W a¨ rnmark, K.; Moberg, C. Chem. Commun. 1992,
2
1
chemistry used to prepare this kind of molecules.
1
054-1055. (b) Castaldi, M. P.; Gibson, S. E.; Rudd, M.; White, A. J. P.
Angew. Chem., Int. Ed. 2005, 44, 3432-3435. (c) Hamann, C.; von
Zelewsky, A.; Neels, A.; Stoeckli-Evans, H. J. Chem. Soc., Dalton Trans.
(16) Kwong et al. Eur. J. Inorg. Chem. 2000, 1997-2002.
(17) Kr o¨ hnke, F. SynthesissStuttgart 1976, 1-24.
(18) Selected references: (a) Fletcher, N. C. J. Chem. Soc., Perkin Trans.
2002, 1831-1842. (b) Yoon, P. Y.; Jacobsen, E. N. Science 2003, 299,
1691-1693. (c) Noyori, R. AdV. Synth. Catal. 2003, 345, 5-33. (d) Plaftz,
A. Acc. Chem. Res. 1993, 26, 339-345. (e) Dang, T. P.; Kagan, H. B. J.
Chem. Soc. D, Chem. Commun. 1971, 481.
(19) Wibaut, J. P.; De Jonge, A. P.; Van Der Voort, H. G. P.; Otto, P.
Ph. H. L. Rec. TraV. Chim. Pays-Bas 1951, 70, 1054-1066.
(20) (a) Li, X.; Gibb, C. L. D.; Kuebel, M. E.; Gibb, B. C. Tetrahedron
2001, 1175-1182. (b) Gong, J.; Gibb, B. C. Org. Lett. 2004, 6, 1353-
1356.
2
004, 402-406. (d) Schaffner-Hamann, C.; von Zelewsky, A.; Barbieri,
A.; Barigelletti, F.; Muller, G.; Riehl, J. P.; Neels, A. J. Am. Chem. Soc.
2
004, 126, 9339-9348. (e) Castaldi, M. P.; Gibson, S. E.; Rudd, M. White,
A. J. P. Chem. Eur. J. 2006, 12, 138-148. (f) Motson, G. R.; Mamula, O.;
Jeffery, J. C.; McCleverty, J. A.; Ward, M. D.; von Zelewsky, A. J. Chem.
Soc., Dalton Trans. 2001, 1389-1391.
(13) Cotton, F. A. Chemical Applications of Group Theory; Wiley: New
York, 1971.
(
14) Moberg, C. Angew. Chem., Int. Ed. 1998, 37, 248-268.
(15) Burk, M. J.; Harlow, R. L. Angew. Chem., Int. Ed. Engl. 1990, 29,
1
467-1469.
284 J. Org. Chem., Vol. 71, No. 25, 2006
9

Synthetic Routes toward Enantiopure Nitrogen Donor Ligands
SCHEME 1
with DMF as solvent did not work, and the starting material
-)-6 was quantitatively recovered. Only a stronger procedure
without any solvent (140 °C, 2.5 h) afforded (-)-7 with a
(
1
9a
moderate yield (30%). A two-step approach to trispyridyl
ligands (-)-9 and (-)-10 was then chosen since the one pot
formation of similar molecules from the constituent pyridine
24a
derivatives proved to be a rather inefficient process. Accord-
ingly, lithiation of (-)-7 via metal-halogen exchange with
n-BuLi (THF, -78 °C, 30 min) followed by the slow addition
of a solution of diethyl carbonate (THF, -78 °C 2 h) gave the
2
4
expected ketone (-)-8 in a reasonable yield (51%).
Ketone (-)-8 was then itself treated with the aforementioned
lithiate (THF, -78 °C, 1 h; -40 °C, 1 h) to generate the tris-
pyridyl methanol ligand (-)-9 (56%). (-)-9 achiral analogues
have shown three different coordination behaviors (N, N′, N′′
2
5
26
symmetric mode, N, N′, O′′ asymmetric mode, and N, N′,
2
7
O-O, N′′ bridging mode between two metal centers ), whereas
O-alkylated derivatives have undergone only symmetric N, N′,
2
7
N′′-coordination. Thus, (-)-9 alkylation was performed to
achieve a ligand able to generate C3-symmetric coordination
compounds, avoiding isomeric mixtures. Alkylated ligand (-)-
1
0 (Scheme 1) was prepared with a combination of sodium
hydride and methyl iodide (THF, 60 °C, 16 h). Although the
ligand contains three nitrogen atoms which could potentially
undergo alkylation, attack by the alkoxide was the kinetically
favored reaction as indicates the 84% yield afforded for ether
(-)-10.
The synthesis of ligands (-)-14 and (-)-15 (Scheme 2)
started with the ene reaction of (-)-R-pinene (-)-4 with singlet
2
8
oxygen that afforded pinocarvone (+)-5 (O2, tetraphenylpor-
phirine, (AcO)2O, DMAP, CH2Cl2, 20 °C, 6 h; 99%), which
after condensation with pyridinium salt 2 and ammonium
Synthesis of C3-Symmetric Tripodal Ligands. (-)-Myrtenal
(
-)-3 was employed as the starting material in the synthesis of
ligands (-)-9 and (-)-10 (Scheme 1). Kr o¨ hnke salt 2 is obtained
1
6
acetate, again under the Kr o¨ nke conditions, led to pyridone
(-)-11 (2, AcONH4, piperidine, EtOH, 80 °C, 1 h; then
HCONH2, acetic acid, 210 °C, 1 h; 45%). Bromination of
pyridone (-)-11 proved to be more problematic. An analogous
process to that shown in Scheme 1 (2 equiv of POBr3, 140 °C,
no solvent) was first attempted, but several byproducts were
formed. Subsequent reactions modifying the solvent amount and
POBr3 equivalents guided us to the optimal reaction conditions
from reaction of ethyl 2-bromoacetate with pyridine, according
to the literature procedure.10e Then, pyridone (-)-6 has been
prepared by condensation of the aldehyde (-)-3 with pyridinium
22
salt 2 and dry ammonium acetate under the Kr o¨ hnke conditions
applying initially low reaction temperatures (2, AcONH4,
formamide, 40 °C, 3 days; then 80 °C, 3 days, 150 °C, 6 h;
2
7%). This procedure led to a significant yield improvement
10d
with respect to the procedure developed by Koc oˆ vsk y´ , where
higher temperatures are employed from the beginning. A
measured rise of the reaction temperature during 6 days was
needed to avoid the decomposition of (-)-3. Faster reaction
profiles were unsuccessful or gave poor yields. Synthesis of
bromopyridine (-)-7 was first attempted using inexpensive and
(1.4 equiv of POBr3, 2.5 h; then 1.4 equiv of POBr3, 2.5 h)
leading to bromopyridine (-)-12 in a moderate yield (31%).
Slight changes in reagent proportions lead to a remarkable
increase of side products. One- and two-step approaches to
trispyridyl ligands (-)-14 and (-)-15 were assayed in this case.
In a first attempt we tried the lithiation of (-)-12 with n-BuLi
23
environmentally friendly phosphonium salts under refluxing
conditions, but no conversion at all was achieved. Bromination
with POBr3 was then tried. However, commonly used conditions
(THF, -78 °C, 15 min) followed by the slow addition of a
solution of triphosgene (THF, -78 °C, 2 min to rt). Unfortu-
nately, only traces of the expected tripodal ligand (-)-14 were
obtained, with ketone (-)-13 being the major product (18%).
Therefore, a two-step procedure similar to the one showed in
(21) See, for example: (a) Peterson, M. A.; Mitchell, J. R. J. Org. Chem.
1
1
997, 62, 8237-8239. (b) Gu, Y. G.; Bayburt, E. K. Tetrahedron Lett.
996, 37, 2565-2568. (c) Cai, D.; Hughes, D. L.; Verhoeven, T. R.
Tetrahedron Lett. 1996, 37, 2537-2540. (d) Parham, W. E.; Piccirilli, R.
M. J. Org. Chem. 1977, 52, 257-260. (e) Mallet, M.; Branger, G.; Marsais,
F.; Queguiner, G. J. Organomet. Chem. 1990, 282, 319-332.
(24) (a) Hannon, M. J.; Mayers, P. C.; Taylor, P. C. Tetrahedron Lett.
1998, 39, 8509-8512. (b) Li, X.; Gibb, C. L. D.; Kuebel, M. E.; Gibb, B.
C. Tetrahedron 2001, 1175-1182.
(22) For Kr o¨ hnke annelation, see: (a) Kr o¨ hnke, F.; Heffe, W. Chem.
(25) (a) Canty, A. J.; Chaichit, N.; Gatehouse, B. M.; George, E. E. Inorg.
Chem. 1981, 20, 4293-4300. (b) Szalda, D.; Keene, G. R. Inorg. Chem.
1986, 25, 2795-2799.
Ber. 1937, 70, 864. For recent overview of its application in the synthesis
of terpenoid pyridines and bipyridines, see: (b) Knof, U.; von Zelewsky,
A. Angew. Chem., Int. Ed. 1999, 38, 303-322. (c) D u¨ ggeli, M.; Goujon-
Ginglier, C.; Richard, S.; Mauron, D.; Bonte, C.; von Zelewsky, A.; Stoeckli-
Evans, H.; Neels, A. Org. Biomol. Chem. 2003, 1, 1894-1899. (d) Chelucci,
G.; Thummel, R. P. Chem. ReV. 2002, 102, 3129-3170.
(26) White, D. L.; Faller, J. W. Inorg. Chem. 1982, 21, 3119-3122. (b)
Keene, F. R.; Szalda, D. J.; Wilson, T. A. Inorg. Chem. 1987, 26, 2211-
2216.
(27) Watanabe, M.; Nankawa, T.; Yamada, T.; Kimura, T.; Namiki, K.;
Murata, M.; Nishihara, H.; Tachimori, S. Inorg. Chem. 2003, 42, 6977-
6979.
(28) Mihelich, E. D.; Eickhoff, D. J. J. Org. Chem. 1983, 48, 4135-
4137.
(23) (a) Froyen, P. Phosphorus Sulfur Silicon Relat. Elem. 1995, 102,
2
53-259. (b) Sugimoto, O.; Mori, M.; Moriya, K.; Tanji, K. I. HelV. Chim.
Acta 2001, 1, 1112-1118. (c) Sugimoto, O.; Mori, M.; Tanji, K. I.
Tetrahedron Lett. 1999, 40, 7477-7478.
J. Org. Chem, Vol. 71, No. 25, 2006 9285

Sala et al.
SCHEME 2
general way to obtain the chiral variants of a wide range of
29
polypyridylic ligands. In this sense, the bis(pyridyl)ethyl amine
ligand (bpea) was chosen to illustrate the feasibility of the
synthetic method due to our previous experience working with
3
0
its achiral counterpart.
Synthesis of the Chiral bpea Tridentate Ligand. (-)-R-
Pinene (-)-4 was also employed as the starting material in the
synthesis of ligand (-)-19, initially following the three-step
synthetic procedure described in Scheme 2 to obtain the
intermediate bromopyridine (-)-12. Then, formation of (-)-
12 lithiate (n-BuLi, THF -78 °C, 30 min) and subsequent slow
addition of DMF in THF (-78 °C, 2 h; then -78 °C to rt)
produced aldehyde (-)-16 in 78% yield (Scheme 3). Slow and
careful addition of NaBH4 was then employed for the almost
quantitative reduction of (-)-16 to alcohol (-)-17 (MeOH, 0
°
C to rt, 1 h, then rt, 4 h; 99%). Subsequent formation of
hydrochloride (-)-18 was achieved with a dropwise addition
of SOCl2 (CH2Cl2,, overnight; 97%). Synthesis of ligand (-)-
1
9 was finally performed by a double nucleophilic attack of
31
ethylamine over hydrochloride (-)-18 under basic conditions
(
1
(-)-18, CH3CN/H2O 1:1, EtNH2, 60 °C, 5 min; then NaOH
0% dropwise, 60 °C, 1 h; then 60 °C to rt; 59%).
Coordination Chemistry and Catalytic Activity. In a
preliminary attempt to explore the coordinating ability of the
synthesized ligands, chiral bpea (-)-19 was treated with
manganese(II) dibromide. Et2O addition led to white crystals
that where identified as [Mn Br2 ((-)-19)], complex (-)-20,
by X-ray crystallography. An ORTEP plot of the complex
structure is shown in Figure S1 of the Supporting Information.
The structure shows ligand (-)-19 coordinating to the Mn(II)
center through its N atoms, resulting in a highly distorted
trigonal bipyramidal environment. The angle between the two
equatorial bromine ligands is 129.5°, and the axial N3a-Mn1a-
N1a angle is around 150°, far from the 180° of the regular
geometry. These distortions are mainly due to the structural
constrains imposed by the coordination of the chiral bpea ligand
which binds the metal center by adopting a quite unusual planar
Scheme 1 was attempted. Diethyl carbonate (THF, -78 °C, 2
h) was added slowly to a solution of (-)-12 lithiate. Ketone
(
-)-13 was obtained in a reasonable yield (42%). Subsequent
slow addition of (-)-13 over the aforementioned lithiate (THF,
78 °C, 2 h to rt) afforded ligand (-)-14 (69%). Alkylated
-
ligand (-)-15 was prepared again with a combination of sodium
hydride and methyl iodide (THF, 60 °C, 16 h) but with a slightly
modified procedure due to the acidic nature of the pinene
benzylic protons. Slow addition of NaH over a solution of (-)-
3
2
disposition, with the two pyridyl rings nearly coplanar. The
Mn-Br bond distances are 2.53 and 2.51 Å, and the Mn-N
bond distances are all slightly larger than 2.2 Å.
1
4 and MeI in THF led to ligand (-)-15 in a good yield (80%)
avoiding the formation of side products from pinene alkylation.
All of the 4,5- and 5,6-”pineno-fused” tripodal ligands have
The coordination behavior of one of the C3-symmetric ligands
synthesized is exemplified by the synthesis of the complex
1
13
been thoroughly characterized via H and C NMR techniques,
which have allowed unambiguous assignment of all the reso-
[RuCl((-)-10)(bpy)]BF4, (-)-21 (bpy ) 2,2′-bipyridine, see the
Supporting Information for experimental details). The structural
characterization has been performed in solution through NMR
1
nances. In a typical H NMR, a series of signals comprised in
the δ ) 0.5-3.2 ppm region can be found, corresponding to
the methyl and methylene groups of the pinene moieties. The
resonances corresponding to the pyridyl rings appear in the
aromatic region at δ ranging from 6.3 to 8.1 ppm, as singlet or
doublet signals depending on the 4,5- or 5,6-substitution on the
pyridine ring, respectively. Finally, ESI-MS and elemental
analysis measurements were used to precisely confirm the
tripodal nature of the ligands, discarding the potential mono-
and bipodal products which would show relatively similar NMR
spectra.
6
spectroscopy. Ru(II) d ions generally present an octahedral type
of geometry, as is the case of (-)-21 with the (-)-10 ligand
acting in a facial fashion. The bidentate bpy and the Cl ligands
complete the remaining opposite coordination face of the
complex.
(29) Other chiral ligands synthesized using this method: G o´ mez, L.;
Company, A.; Sala, X.; Costas, M.; Llobet, A.; Benet-Buchholz, J.
Unpublished results.
(30) (a) Rodr ´ı guez, M.; Romero, I.; Llobet, A.; Deronzier, A.; Biner,
M.; Parella, T.; Stoeckli-Evans, H. Inorg. Chem. 2001, 40, 4150-4156.
(b) Rodr ´ı guez, M.; Romero, I.; Sens, C.; Llobet, A.; Deronzier, A.
Electrochim. Acta. 2003, 48, 1047-1054. (c) Romero, I.; Rodr ´ı guez, M.;
Llobet, A.; Collomb-Dunand-Sauthier, M.-N.; Deronzier, A.; Parella, T.;
Stoeckli-Evans, H. J. Chem. Soc., Dalton Trans. 2000, 1689-1694. (d)
Collomb, M.-N.; Deronzier, A.; Romero, I. J. Electroanal. Chem. 1997,
436, 219-225.
Design of the Bis(pyridyl)ethylamine Tridentate Ligand.
Having developed synthetic routes toward chiral C3-symmetric
“
pineno”-fused tpmOR ligands, we envisaged extending these
procedures to other commonly used polypyridylic ligands which
in some cases involved a reduction in the symmetry while
maintaining the chiral character. With this aim in mind, building
block (-)-16 (Scheme 3) was synthesized as a potentially
powerful tool in ligand design. Aldehyde (-)-16 provides us a
(
31) Pal, S.; Chan, M. K.; Armstrong, W. H. J. Am. Chem. Soc. 1992,
14, 6398-6406.
32) Baffert, C.; Romero, I.; P e´ caut, A.; Llobet, A.; Deronzier, A.;
Collomb, M.-N. Inorg. Chim. Acta 2004, 357, 3430.
1
(
9286 J. Org. Chem., Vol. 71, No. 25, 2006

Synthetic Routes toward Enantiopure Nitrogen Donor Ligands
SCHEME 3
Preliminary results in the catalytic ability of complex (-)-
(200 mL), and the product was extracted with CH
mL). The combined organic layers were washed with brine (150
mL) and dried (MgSO ), and the solvent was removed in vacuo to
give a brown oil. That crude was redissolved in formamide (100
mL) and washed with hexane (6 × 100 mL). The formamide phase
2
Cl
2
(5 × 150
2
1 have been obtained for the epoxidation of styrene in CH2-
Cl2 at room temperature and using PhI(OAc)2 as co-oxidant,
with a cat:subs ratio of 1:100. After 48 h reaction time, 0.038
mM styrene epoxyde (48% conversion) is obtained with a
moderate enantioselectivity (36% ee) together with traces of
benzaldehyde. While this result clearly manifest the capacity
of Ru-complex, containing the pinene ligand, to enantiodiffer-
entiate a prochiral substrate such as styrene, it is obvious that
the enantiomeric excess obtained needs to be significantly
improved in order to be able to have a meaningful synthetic
application. Therefore, further work is in progress to optimize
reaction conditions for this system in order to improve enan-
tioselectivities. Furthermore, we are also in the process of
developing the coordination chemistry of all of the pinene
ligands described in this paper, including bidentate chiral
ketones, together with their enantioselective reactivity toward
prochiral substrates, with the aim of establishing the best system
performances.
4
was extracted again with CH
2
Cl
2
(5 × 100 mL), washed with brine
(
200 mL), and dried (MgSO
vacuo to give a brown-yellow oil, which was purified via flash
chromatography on silica gel with a mixture of CH Cl /ethyl acetate
1:1) for the elution of secondary products, and with ethyl acetate/
methanol (9:1) to give pure (+)-6 as white crystals (yield 3.146 g,
27%): mp 141-143 °C; [R] -50.3 (c 1.0, CH Cl ); IR ν 2930
m, 1586 w, 1550 m, 1463 s, 1360 s, 1065 s cm ; H NMR (200
MHz, CDCl
4
), and the solvent was removed in
2
2
(
D
2
2
-
1 1
3
) δ 0.66 (s, 3H), 1.16 (d, J ) 8.2 Hz, 1H), 1.33 (t,
H), 2.15 (m, 1H), 2.60 (m, 2H), 2.88 (d, J ) 2.4 Hz, 2H), 6,39 (s,
H), 6.87 (s, 1H); 13C NMR (50 MHz, CDCl
) δ 21.5 (CH ), 25.8
), 32.2 (CH ), 32.8 (CH ), 39.4 (C), 40.1 (CH), 43.8 (CH),
18.1 (CH), 126.3 (C), 127.5 (CH), 152.3 (C), 165.1 (C); ESI-MS
3
1
3
3
(CH
3
2
2
1
(
+
m/z) 190 [M + H] . Anal. Calcd for C12H15NO (189.25): C, 76.16;
H, 7.99; N, 7.40. Found: C, 76.10; H, 8.02; N, 7.38.
Bromopyridine (-)-7. Pyridone (-)-6 (5.2 g, 27.5 mmol) and
POBr (13.8 g, 48.1 mmol) were heated, without solvent, at 140
3
Conclusions
°C for 2.5 h and then cooled to 0 °C. The reaction was quenched
with ice followed by addition of aqueous 1 M NaHCO (100 mL).
3
Novel, C3-symmetrical trispyridylic ligands have been pre-
pared from (-)-R-pinene and (-)-myrtenal via a de novo
construction of the pyridine nucleus using Kr o¨ hnke annulation
as the crucial step. This asymmetric synthetic procedure has
been applied, involving a reduction in symmetry, to other
commonly used polypyridylic ligands through building block
The product was extracted with ether (3 × 100 mL), the combined
organic layers were washed with brine (100 mL) and dried
4
(MgSO ), and the solvent was evaporated in vacuo. The crude
product was purified via flash chromatography on silica gel (40 g)
with a hexane/ethyl acetate mixture (10:3) to give crude (-)-7 as
a pale yellow oil, which employed in the next step without further
purification. An ethyl acetate/methanol mixture (9:1) was then used
to recover the not reacted starting material (yield 2.052 g, 30%;
(-)-16 to obtain chiral bpea (-)-19, synthesized to illustrate
the feasibility of the method. The coordination behavior of the
ligands has been illustrated through the syntheses of a Mn and
a Ru metal complexes, and preliminary catalytic results
performed with the Ru complex (-)-21 show moderate enan-
tioselectivities in styrene epoxidation with PhI(AcO)2.
5
7.1% from starting recovered material): [R]
Cl ); IR ν 2930 m, 1586 w, 1550 m, 1463 s, 1360 s, 1065 s cm
H NMR (200 MHz, CDCl ) δ 0.60 (s, 3H), 1.11 (d, J ) 9.4 Hz,
1H), 1.36 (s, 3H), 2.25 (m, 1H), 2.67 (m, 2H), 2.90 (d, J ) 3.0,
2H), 7.31 (s, 1H), 7.85 (s, 1H); 13C NMR (50 MHz, CDCl
) δ
1.4 (CH ), 25.9 (CH ), 31.6 (CH ), 32.6 (CH ), 39.1 (C), 39.7
CH), 44.1 (CH), 127.2 (CH), 139.4 (C), 142.0 (C), 146.1 (CH),
D
2
-57.8 (c 3.7, CH -
-1
2
;
1
3
3
2
(
1
3
3
2
2
Experimental Section
+
48.0 (C); ESI-MS (m/z) 253 [M + H] .
Syntheses. Starting materials (-)-myrtenal (-)-3 98% ee, (-)-
R-pinene (-)-4 97% ee, and ethyl 2-bromoacetate 1 are com-
Ketone (-)-8. Bromopyridine (-)-7 (3.058 g, 12.1 mmol) was
dissolved in THF (61 mL) and the resulting solution cooled to -78
°C. A solution of n-BuLi in hexanes (12.7 mmol, 7.96 mL of a 1.6
M solution) was added dropwise to the cooled solution. After the
lithiate solution was stirred for 30 min, a solution of diethyl
carbonate (6.1 mmol, 0.74 mL in 15 mL THF) was slowly added.
After further stirring for 2 h at -78 °C, the reaction was allowed
to warm to ca. 0 °C and quenched with 10% HCl until acidic. The
10d
28
mercially available. Kr o¨ hnke salt 2, (+)-pinocarvone (+)-5,
and pyridone (-)-1110d were obtained following the methods
previously described in the literature.
Pyridone (-)-6. Kr o¨ hnke salt 2 (15 g, 60.9 mmol) and NH -
4
OAc were added to a solution of the aldehyde (-)-3 (8.338 g, 55.5
mmol) in formamide (170 mL). The solution was stirred for 3 days
at 40 °C, 3 days at 80 °C, and 6 h at 150 °C. The mixture was
cooled to room temperature, the reaction was quenched with water
2 3
resulting mixture was basified with 10% aqueous K CO and then
partitioned between CHCl and water, and the organic layers were
3
J. Org. Chem, Vol. 71, No. 25, 2006 9287

Sala et al.
combined and dried with anhydrous MgSO4. The solvent was
removed under reduced pressure, and the crude product was purified
via flash chromatography on silica gel (40 g) starting with a hexane/
ethyl acetate mixture (10:3) to elute impurities and continuing with
solvent was evaporated in vacuo. The crude product was purified
via flash chromatography on silica gel (40 g) with a hexane/ethyl
acetate mixture (10:3) to give (-)-12 as a pale yellow which was
employed in the next step without further purification. An ethyl
acetate/methanol mixture (9:1) was used to recover the not reacted
starting material (yield 2.540 g, 31%; 46% from starting recovered
a CH
solid (yield 1.147 g, 51%): mp 56-58 °C; [R]
Cl ); IR ν 2928 s, 1673 vs, 1591 w, 1555 w, 1308 m, 1249 s cm
H NMR (200 MHz, CDCl ) δ 0.64 (s, 6H), 1.23 (d, J ) 9.4 Hz,
H), 1.40 (s, 6H), 2.33 (m, 2H), 2.70 (m, 2H), 2.88 (m, 2H), 3.03
2
Cl
2
/ethyl acetate mixture (10:1) to give pure (-)-8 as a white
D
-90 (c 0.78, CH
2
-
-
1
2
;
material): [R]
D
-55.4 (c 3.9, CH
2
Cl
2
); IR ν 2924 m, 1580 w, 1555
1
-1 1
3
m, 1428 s, 1096 s cm ; H NMR (200 MHz, CDCl
3
) δ 0.62 (s,
2
3H), 1.22 (d, J ) 9.4 Hz, 1H), 1.36 (s, 3H), 2.32 (m, 1H), 2.69 (m,
2H), 3.07 (d, J ) 3.5 Hz, 2H), 7.03 (d, J ) 7.9 Hz, 1H), 7.14 (d,
1
3
(
d, J ) 2.9, 4H), 7.45 (s, 2H), 8.04 (s, 2H); C NMR (50 MHz,
CDCl ) δ 21.5 (CH ), 26.0 (CH ), 31.4 (CH ), 32.9 (CH ), 39.1
C), 40.0 (CH), 44.8 (CH), 124.8 (CH), 145.2 (C), 145.7 (CH),
1
3
3
3
3
2
2
J ) 8.1 Hz, 1H); C NMR (50 MHz, CDCl
3
) δ 21.2 (CH
3
), 25.9
(
1
(CH ), 31.7 (CH ), 36.4 (CH
3
2
2
), 39.2 (C), 39.9 (CH), 45.8 (CH),
+
46.0 (C), 153.2 (C), 193.5 (C); ESI-MS (m/z) 373 [M + H] .
124.3 (CH), 135.5 (CH), 138.0 (C), 142.1 (C), 158.2 (C); ESI-MS
+
Anal. Calcd for C26
N, 7.31. Found: C, 78.69; H, 7.98; N, 7.30.
H
32
N
2
O·0.6H
2
O (383.02): C, 78.34; H, 7.68;
(m/z) 253 [M + H] .
Ketone (-)-13. Method A. Bromopyridine (-)-12 (1.9 g, 7.52
mmol) was dissolved in THF (10 mL) and the resulting solution
cooled to -78 °C. A solution of n-BuLi in hexanes (8.21 mmol,
5.182 mL of a 1.6 M solution) was added dropwise to the cooled
solution. After the solution was stirred for 30 min, a solution of
triphosgene (3.11 mmol, 0.922 g in 1.85 mL THF) was added
slowly over 1 min. Stirring was continued at -78 °C for 2 min
before removal of the cooling bath. After the mixture had warmed
to room temperature, 2 N H SO (5 mL) was added and shaken
tpmOH (-)-9. Bromopyridine (-)-7 (1.083 g, 4.3 mmol) was
dissolved in THF (60 mL) and the resulting solution cooled to -78
°
C. A solution of n-BuLi in hexanes (4.5 mmol, 2.84 mL of a 1.6
M solution) was added dropwise to the cooled solution. After the
lithiate solution was stirred for 30 min, a solution of ketone (-)-8
(3.8 mmol, 1.438 g in 9 mL THF) was slowly added. After further
stirring for 2 h at -78 °C, the reaction was allowed to warm to ca.
°C and quenched with 10% HCl until acidic. The resulting mixture
was basified with 10% aqueous K CO , the crude product was
partitioned between CHCl and water, and the organic layers were
combined and dried with anhydrous MgSO . The solvent was
0
2
4
2
3
well. The organic layer was separated and further extracted with 2
3
N H SO4 (4 × 5 mL). The combined acidic extracts were
2
4
neutralized (40% aqueous KOH) and extracted with diethyl ether
removed under reduced pressure, and the crude product was purified
via flash chromatography on silica gel (40 g) with a ethyl acetate/
hexane mixture (10:6) to give pure (-)-9 as a white solid (yield
(4 × 50 mL). The combined ether extracts were dried (MgSO ),
4
filtered, and evaporated. The crude oil was purified by flash
chromatography on silica gel (40 g) with a hexane/ethyl acetate
mixture (1:2) to give pure (-)-13 as a white solid (yield 0.250 g,
18%). Method B. Bromopyridine (-)-12 (1.0 g, 3.7 mmol) was
dissolved in THF (20 mL) and the resulting solution cooled to -78
°C. A solution of n-BuLi in hexanes (4.2 mmol, 2.63 mL of a 1.6
M solution) was added dropwise to the cooled solution. After the
lithiate solution was stirred for 10 min, a solution of diethyl
carbonate (1.24 mmol, 0.150 mL in 7 mL THF) was slowly added.
After being stirred for 2 h at -78 °C, the reaction was allowed to
warm to ca. 0 °C and was quenched with 10% HCl until acidic.
The resulting mixture was basified with 10% aqueous K CO , the
1
.150 g, 55%): mp 91-93 °C; [R]
300 m, 2920 s, 1600 w, 1476 c, 1425 m, 1368 m cm ; H NMR
) δ 0.59 (s, 9H), 1.20 (d, J ) 9.4 Hz, 3H), 1.35
s, 9H), 2.23 (m, 3H), 2.61 (m, 3H), 2.72 (m, 3H), 2.91 (d, J ) 1.8
D
-71 (c 0.69, CH
2 2
Cl ); IR ν
-
1
1
3
(200 MHz, CDCl
3
(
13
Hz, 6H), 7.45 (s, 3H), 8.04 (s, 3H); C NMR (50 MHz, CDCl
3
) δ
2
1.4 (CH ), 26.0 (CH ), 31.6 (CH ), 32.8 (CH ), 39.2 (C), 40.1
3
3
2
2
(
CH), 44.3 (CH), 80.9 (C), 121.8 (CH), 14.7 (C), 144.0 (C), 144.7
+
(CH), 161.4 (C); ESI-MS (m/z) 547 [M + H] . Anal. Calcd for
37 43 3
C H N O (545.76): C, 81.43; H, 7.94; N, 7.70. Found: C, 81.24
;
H, 8.20; N, 7.50.
2
3
tpmOMe (-)-10. NaH (7.2 mmol, 0.176 g of a 60% oil
crude product was partitioned between CHCl
layers were combined and dried with anhydrous MgSO
solvent was removed under reduced pressure. The crude product
was purified via flash chromatography on silica gel (40 g) starting
with a hexane/ethyl acetate mixture (10:3) to elute impurities and
3
and water, the organic
, and the
dispersion) was washed twice with pentane and added to 60 mL of
THF. To this stirring mixture were added alcohol (-)-9 (0.8 g, 1.5
mmol) and MeI (0.45 mL, 7.2 mmol). The reaction was stirred at
4
6
0 °C for 16 h. After being cooled to room temperature, the mixture
was quenched with 10% HCl until acidic and then basified with
0% aqueous K CO . The crude product was then partitioned
between CHCl and water, and the aqueous layer was washed twice
with CHCl . The organic layers were combined and dried with
anhydrous MgSO , and the solvent was removed under reduced
continuing with a CH
(-)-13 as a white solid (yield 0.310 g, 42%): mp 61-63 °C dec;
[R] -157.7 (c 0.37, CH Cl ); IR ν 2922 s, 1668 vs, 1567 m, 1422
m, 1244 m, 1000 m cm ; H NMR (200 MHz, CDCl
2 2
Cl /ethyl acetate mixture (10:1) to give pure
1
2
3
3
D
2
2
-
1 1
3
) δ 0.67 (s,
3
6H), 1.28 (d, J ) 9.4 Hz, 2H), 1.41 (s, 6H), 2.39 (m, 2H), 2.71 (m,
4
pressure. The crude product was purified via flash chromatography
on silica gel (30 g) with a acetone/hexane/triethylamine mixture
2H), 2.84 (m, 2H), 3.18 (d, J ) 2.9 Hz, 4H), 7.32 (d, J ) 7.7 Hz,
1
3
2H), 7.85 (d, J ) 7.6 Hz, 2H); C NMR (50 MHz, CDCl
3
) δ 21.4
2
), 39.5 (C), 40.1 (CH),
(
4:10:0.2) to give pure (-)-10 as a white solid (yield 0.7 g, 84%):
mp 109-111 °C; [R] -56.3 (c 0.36, CH Cl ); IR ν 2912 s, 1600
w, 1479 m, 1425 m, 1382 m, 1086 s cm ; H NMR (200 MHz,
CDCl
(CH ), 26.0 (CH ), 31.6 (CH ), 36.6 (CH
3
3
2
46.9 (CH), 123.8 (CH), 133.0 (CH), 145.5 (C), 151.7 (C), 156.9
D
2
-
2
1
1
+
(C), 192.1 (C); ESI-MS (m/z) 373 [M + H] . Anal. Calcd for
) δ 0.59 (s, 9H), 1.23 (d, J ) 9.4 Hz, 3H), 1.33 (s, 9H), 2.22
m, 3H), 2.61 (m, 3H), 2.74 (m, 3H), 2.91 (d, J ) 2.7 Hz, 6H),
C
26
H
32
N
2
2
O·0.4H O (379.42): C, 79.08; H, 7.65; N, 7.38. Found:
3
(
3
C, 79.29; H, 8.01; N, 7.51.
.24 (s, 3H), 7.41 (s, 3H), 8.08 (s, 3H); 13C NMR (50 MHz, CDCl
), 26.0 (CH ), 31.7 (CH ), 32.9 (CH ), 39.2 (C), 40.2
CH), 44.3 (CH), 52.8 (CH ), 88.1 (C), 123.0 (CH), 140.4 (C), 144.3
C), 144.7 (CH), 159.7 (C); ESI-MS (m/z) 560 [M + H] . Anal.
O (559.78): C, 81.53; H, 8.10; N, 7.51.
3
)
tpmOH (-)-14. Bromopyridine (-)-12 (0.174 g, 0.69 mmol)
was dissolved in THF (9 mL) and the resulting solution cooled to
-78 °C. A solution of n-BuLi in hexanes (0.71 mmol, 0.448 mL
of a 1.6 M solution) was added dropwise to the cooled solution.
After the lithiate solution was stirred for 10 min, a solution of ketone
(-)-13 (0.68 mmol, 0.230 g in 1.4 mL THF) was slowly added.
After being stirred for 2 h at -78 °C, the reaction was allowed to
warm to ca. 0 °C and quenched with 10% HCl until acidic. The
δ 21.4 (CH
3
3
2
2
(
(
3
+
45 3
Calcd for C38H N
Found: C, 81.25; H, 8.35; N, 7.29.
Bromopyridine (-)-12. Pyridone (-)-11 (6.2 g, 37.79 mmol)
3
was dissolved in DMF (13.8 mL), and POBr (13.8 g, 44.2 mmol)
was added. The resulting solution was heated at 140 °C for 2.5 h
and then cooled to 0 °C. The reaction was quenched with ice
resulting mixture was basified with 10% aqueous K
product was partitioned between CHCl water, the organic layers
were combined and dried with anhydrous MgSO , and the solvent
was removed under reduced pressure. The crude product was
purified via flash chromatography on silica gel (40 g) with a hexane/
2 3
CO , the crude
3
followed by aqueous 1 M NaHCO
extracted with ether (3 × 100 mL), the combined organic layers
were washed with brine (100 mL) and dried (MgSO ), and the
3
(100 mL). The product was
4
4
9288 J. Org. Chem., Vol. 71, No. 25, 2006

Synthetic Routes toward Enantiopure Nitrogen Donor Ligands
acetone mixture (10:1) to give pure (-)-14 as a white solid (yield
1476 s, 1363 s, 1064 s cm-1; 1H NMR (200 MHz, CDCl
) δ 0.60
3
0
.230 g, 69%): mp 92-94 °C; [R]
D
-80.5 (c 0.41, CH
2
Cl
2
); IR ν
(s, 3H), 1.22 (d, J ) 9.1 Hz, 1H), 1.37 (s, 3H), 2.34 (m, 1H), 2.66
-
1
3
307 m, 2918 s, 1575 w, 1442 m, 1424 m, 1253 w, 1094 m cm
;
(m, 2H), 3.05 (d, J ) 2.7 Hz, 2H), 6.91 (d, J ) 7.7 Hz, 1H), 7.15
1
13
H NMR (200 MHz, CDCl
3
) δ 0.67 (s, 9H), 1.23 (d, J ) 9.4 Hz,
(d, J ) 7.4 Hz, 1H); C NMR (50 MHz, CDCl
3
) δ 21.2 (CH
3
),
3
6
H), 1.34 (s, 9H), 2.25 (m, 3H), 2.57 (m, 6H), 2.91 (d, J ) 2.4 Hz,
26.0 (CH
64.3 (CH
3
), 32.0 (CH
2 2
), 36.3 (CH ), 39.4 (C), 40.2 (CH), 46.2 (CH),
), 117.2 (CH), 133.6 (CH), 140.5 (C), 155.1 (C), 156.0
(C); ESI-MS (m/z) 204 [M + H] . Anal. Calcd for C13H17NO
(203.13): C, 76.81; H, 8.43; N, 6.89. Found: C, 76.57; H, 8.49;
N, 6.62.
13
H), 6.31 (d, J ) 7.9 Hz, 3H), 7.17 (d, J ) 8.5 Hz, 3H); C NMR
), 26.2 (CH ), 31.9 CH ), 36.4 (CH ),
2
+
(50 MHz, CDCl
3
) δ 21.2 (CH
3
3
2
2
3
1
9.4 (C), 40.3 (CH), 46.3 (CH), 81.0 (C), 119.3 (CH), 132.8 (CH),
+
39.7 (C), 154.9 (C), 160.6 (C); ESI-MS (m/z) 547 [M + H] .
Anal. Calcd for C37
H
43
N
3
O (545.76): C, 81.43; H, 7.94; N, 7.70.
Chloride (-)-18. Alcohol (-)-17 (0.85 g, 4.18 mmol) was
Found: C, 81.24; H, 8.20; N, 7.50.
dissolved in CH Cl (10 mL). A solution of SOCl (0.938 mL, 12.5
2
2
2
tpmOMe (-)-15. Alcohol (-)-14 (0.136 g, 0.255 mmol) and
MeI (0.45 mL, 7.2 mmol) were mixed in 10 mL of dry THF. Then,
NaH (0.4 mmol, 0.016 g of a 60% oil dispersion) washed twice
with pentane was added to the former solution. The reaction was
stirred at 60 °C for 4 h. After being cooled to room temperature,
the mixture was quenched with 10% HCl until acidic and then
2 2
mmol) in CH Cl (8 mL) was added dropwise to the first solution.
The reaction was allowed to stir overnight. Then, the solvent was
removed under reduced pressure and the residue partitioned between
CH
was separated and the aqueous phase extracted with CH
100 mL). Combined organic phases were dried over MgSO
filtered, and evaporated to obtain the title product as a yellow oil
(yield 0.91 g, 98%): [R] -74.3 (c 0.88, CH Cl ); IR ν 2922 s,
1583 m, 1448 m, 1442 m, 1253 s cm ; H NMR (200 MHz,
CDCl ) δ 0.53 (s, 3H), 1.15 (d, J ) 9.4 Hz, 1H), 1.29 (s, 3H), 2.27
(m, 1H), 2.60 (m, 2H), 3.00 (d, J ) 2.3 Hz, 2H), 4.02 (s, 1H), 7.03
2
Cl
2
(100 mL) and NaOH 0.4 M (100 mL). The organic phase
2
Cl
2
(2 ×
4
,
basified with 10% aqueous K
partitioned between CHCl and water, and the aqueous layer was
washed twice with CHCl . The organic layers were combined and
dried with anhydrous MgSO , and the solvent was removed under
2 3
CO . The crude product was then
3
D
2
2
-
1
1
3
4
3
reduced pressure. The crude product was purified via flash
chromatography on silica gel (30 g) with a acetone/hexane/
triethylamine mixture (4:10:0.2) to give pure (-)-15 as a white
13
(d, J ) 7.6 Hz, 1H), 7.1 (d, J ) 7.7 Hz, 1H); C NMR (50 MHz,
CDCl ) δ 21.0 (CH ), 25.8 (CH ), 31.6 (CH ), 36.2 (CH ), 39.2
(C), 39.9 (CH), 46.1 (CH), 46.8 (CH ), 119.3 (CH), 133.5 (CH),
3
3
3
2
2
solid (yield 0.140 g, 84%): mp 107-109 °C; [R]
CH Cl
); IR ν 2920 s, 1574 w, 1466 m, 1423 m, 1094 m cm-1; 1H
NMR (200 MHz, CDCl ) δ 0.59 (s, 9H), 1.23 (d, J ) 9.4 Hz, 3H),
.33 (s, 9H), 2.22 (m, 3H), 2.61 (m, 3H), 2.74 (m, 3H), 2.91 (d, J
D
-118.2 (c 1.1,
2
+
2
2
141.2 (C), 153.1 (C), 156.1 (C); ESI-MS (m/z) 223 [M + H] .
bpea (-)-19. Chloride (-)-18 (1.1 g, 2.65 mmol) was dissolved
in a CH CN/H O mixture 1:1 (5.4 mL). Et NH (1.32 mmol, 0.2
3
1
3
2
3
2
)
2.6 Hz, 6H), 3.24 (s, 3H), 7.41 (d, J ) 7.9 Hz, 3H), 8.08 (d, J
7.6 Hz, 3H). 13C NMR (50 MHz, CDCl
) δ 21.2 (CH ), 26.0
), 29.7 (CH ), 31.8 (CH ), 35.6 (C), 39.4 (CH), 46.3 (CH),
20.6 (CH), 132.7 (C), 139.6 (CH), 155.3 (C), 159.1 (C); ESI-MS
mL of a 70% aqueous solution) was added dropwise to the first
solution and the mixture stirred at 60 °C. After 5 min, 1 0M NaOH
(0.284 mL, 2.84 mmol) was added slowly. After being stirred for
1 h at 60 °C, the reaction was allowed to cool to rt, the crude product
3
)
3
3
(CH
3
2
2
1
+
(
8
m/z) 561 [M + H] . Anal. Calcd for C38
H
45
N
3
O (559.78): C,
was partitioned between CHCl and water, the organic layers were
1.53; H 8.10; N7.51. Found: C, 81.69; H, 8.30; N, 7.31.
combined and dried with anhydrous MgSO , and the solvent was
4
Aldehyde (-)-16. Bromopyridine (-)-12 (1.369 g, 5.42 mmol)
removed under reduced pressure. The crude product was purified
was dissolved in THF (61 mL) and the resulting solution cooled to
-
via flash chromatography on neutral alumina (40 g) with CH
to give pure (-)-19 as a yellow oil (yield 0.52 g, 59%): [R] -96.2
(c 1.1 CH Cl ); IR ν 2926 s, 1583 w, 1550 m, 1463 s, 1360 s,
2 2
Cl
78 °C. A solution of n-BuLi in hexanes (5.66 mmol, 3.55 mL of
D
a 1.6 M solution) was added dropwise to the cooled solution. After
the lithiate solution was stirred for 30 min, DMF (0.46 mL, 5.93
mmol in 0.903 mL of THF) was added. After being stirred for 2 h
at -78 °C, the reaction was allowed to warm to ca. 0 °C and
quenched with 6 N HCl (2 mL). The crude product was partitioned
2
-
2
1 1
3
1067 s cm ; H NMR (200 MHz, CDCl ) δ 0.62 (s, 6H), 1.10 (t,
J ) 7.2 Hz, 3H), 1.25 (d, J ) 9.5 Hz, 1H), 1.39 (s, 6H), 2.35 (m,
2H), 2.68 (m, 6H), 3.07 (d, J ) 3.0 Hz, 4H), 3.81 (s, 4H), 7.15 (d,
13
J ) 7.6 Hz, 2H), 7.26 (d, J ) 6.9 Hz, 2H); C NMR (50 MHz,
between CHCl
dried with anhydrous MgSO
3
and water, the organic layers were combined and
CDCl
(CH ), 39.4 (C), 40.2 (CH), 46.2 (CH), 48.2 (CH
118.9 (CH), 133.3 (CH), 139.6 (C), 155.7 (C), 157.1 (C); ESI-MS
3
) δ 12.0 (CH
3
3
), 21.2 (CH ), 26.0 (CH
3
), 32.0 (CH
2
), 36.5
4
, and the solvent was removed under
2
2
), 60.0 (CH
2
),
reduced pressure. The crude product was purified via flash
chromatography on silica gel (40 g) starting with a hexane/ethyl
acetate mixture (10:2) to give pure (-)-16 as an orange-yellow oil
+
(m/z) 416 [M + H] . Anal. Calcd for C28
H, 8.97; N, 10.11. Found: C, 80.63; H, 9.28 ; N, 9.89.
[Mn(Br )((-)-19)], (-)-20. Manganese(II) dibromide (0.010 g,
0.046 mmol) was dissolved in CH CN (1 mL), and a solution of
(-)-19 (0.020 g, 0.046 mmol) in CH CN (1 mL) was added. The
mixture stirred for 1 h at room temperature. After the addition of
1 mL of Et O, a white precipitate was formed. This precipitate was
37 3
H N (415.61): C, 80.92;
(
1
yield 0.85 g, 78%): [R]
D
-84.4 (c 1.35, CH
2
Cl
2
); IR ν 2925 s,
2
-
1
1
705 vs, 1570 m, 1421 m, 1233 m cm ; H NMR (200 MHz,
3
CDCl
3
) δ 0.66 (s, 3H), 1.28 (d, J ) 9.7 Hz, 1H), 1.44 (s, 3H), 2.44
3
(
m, 1H), 2.80 (m, 2H), 3.21 (d, J ) 3.3 Hz, 2H), 7.38 (d, J ) 7.6
13
Hz, 1H), 7.70 (d, J ) 7.9 Hz, 1H), 10.04 (s, 1H); C NMR (50
MHz, CDCl ) δ 21.2 (CH ), 25.9 (CH ), 31.5 (CH ), 36.3 (CH ),
9.4 (C), 39.9 (CH), 46.9 (CH), 119.6 (CH), 133.5 (CH), 146.6
C), 150.7 (C), 157.8 (C), 193.1 (CH); ESI-MS (m/z) 202 [M +
2
3
3
3
2
2
filtered, washed with a small amount of cold acetonitrile, and dried
3
(
under vacuum (yield 0.016 g, 55%): IR ν 2919 m, 1594 w, 1450
-
1
+
m, 1371 w, 1118 s, 1031 s cm ; ESI-MS (m/z) 551 [M - Br] .
+
H] . Anal. Calcd for C13
.95. Found: C, 77.36; H, 7.82; N, 7.55.
Alcohol (-)-17. Aldehyde (-)-16 (0.85 g, 4.1 mmol) was
dissolved in CH OH (10 mL). The solution was cooled to 0 °C
with an ice bath, and NaBH (0.302 g, 8.0 mmol) was added
portionwise (caution, reaction is exothermic and H vapors are
H15NO (201.12): C, 77.58; H, 7.51; N,
Anal. Calcd for MnC28
6.70. Found: C, 53.1; H, 6.23; N, 6.48.
[RuCl((-)-10)(bpy)](BF ), (-)-21. A sample of (-)-10 (55 mg,
0.099 mmol) was added to a 50 mL round bottomed flask containing
a solution of RuCl ·2H O (24.2 mg, 0.099 mmol) in dry EtOH,
37 3 2
H N Br (630.4): C, 53.35; H, 5.92; N,
7
4
3
4
3
2
2
and the mixture was heated at reflux for 2.5 h. The hot solution
was filtered off in a frit, the volume was reduced in a rotary
evaporator, and water (2 mL) was added upon which a green
precipitate appeared. A 60 mg sample of the solid obtained in this
manner was added to a 25 mL round-bottomed flask containing a
vigorously expelled). The reaction was then warmed to room
temperature and allowed to stir for 4 h. Then, the solvent was
removed under reduced pressure and the residue partitioned between
CH
and the aqueous phase extracted with CH
Combined organic phases were dried over MgSO
evaporated to obtain the title product as a colorless oil (yield: 0.85
g, 99%): [R] -62 (c 1.0, CH Cl ); IR ν 3319 m, 2923 s, 1535 m,
Cl
2 2
(10 mL) and H
2
O (8 mL). The organic phase was separated
Cl
(2 × 15 mL).
, filtered, and
2
2
solution of LiCl (8 mg, 0.263 mmol) in EtOH/H
under magnetic stirring. Then, NEt (0.023 mL) was added and
2
O (3:1) (12 mL),
4
3
the reaction mixture stirred at room temperature for 30 min, at which
point bpy (12 mg, 0.077 mmol) was added and the resulting mixture
D
2
2
J. Org. Chem, Vol. 71, No. 25, 2006 9289

Sala et al.
heated at reflux for 1 h. The hot solution was filtered off in a frit
and the volume reduced to dryness in a rotary evaporator under
reduced pressure after the addition of an aqueous saturated solution
mmol) were stirred at room temperature in dichloromethane (2.5
mL). The end of the reaction was indicated by the disappearance
of solid co-oxidant. After addition of an internal standard, an aliquot
was taken for GC analysis. GC conditions for the analysis of the
oxidized products were as follows: initial temperature 80 °C for
25 min, ramp rate 10 °/min, final temperature 220 °C, injection
temperature 220 °C, detector temperature 250 °C, carrier gas He
at 25 mL/min. All catalytic oxidations were carried out under
nitrogen atmosphere.
of NaBF
filtered in a frit, washed with Et
4
4
(1.5 mL). A brown-red dust was obtained which was
O, and dried under vacuum: yield
3% (40 mg, 0.043 mmol); H NMR (500 MHz, CDCl , 25 °C) δ
0.37 ppm (s, 3H, H91a-c), 0.61 (s, 3H, H80a-c) , 0.77 (s, 3H,
2
1
3
)
H66a-c), 0.95 (m, 1H, H86a), 1.21 (s, 3H, H92a-c), 1.24 (m, 1H,
H61a), 1.38 (m, 1H, H47a), 1.39 (s, 3H, H79a-c), 1.46 (s, 3H, H67a-
3
3
c), 2.20 (m, 1H, H85a), 2.25 (t, J87a-86a ) J87a-86b ) 7.7 Hz, 1H,
H87a), 2.39 (m, 2H, H60a, H73a), 2.69 (m, 1H, H61b), 2.82 (m,
Acknowledgment. This research has been financed by the
MCYT of Spain (Project No. BQU2003-02884, CTQ2006-
3
3
1
2
H, H74b), 2.90 (t, J62a-61a ) J62a-61b ) 6.3 Hz, 1H, H62a), 2.97-
3
.99 (m, 2H, H75a, H84), 3.17 (d, J72ab-73a ) 15.2 Hz, 2H, H59a-
1
5634, and CSD2006-0003) and by CIRIT from Catalonia
b, H72a-b), 4.11 (s, 3H, H93a-c), 6.20 (s, 1H, H89a), 7.36-7.40
through SGR2001-UG-291. X.S. is grateful for the award of a
doctoral grant from the University of Girona (UdG). A. Roglans
from UdG is thanked for helpful discussions. A.v.Z. thanks the
Swiss National Science Foundation for financial support.
(
m, 2H, H95a, H102a), 7.79 (s, 1H, H82a), 7.80 (s, 1H, H57a),
3
8
)
.04-8.15 (m, 4H, H103a, H96a, H101a, H94a), 8.60 (dd, J97a-96a
3
4
4
J100a-101a ) 1.8 Hz / J97a-95a ) J100a-102a ) 7.2 Hz, 2H, H97a,
13
H100a), 8.81 (s, 1H, H77a), 8.83 (s, 1H, H64a); C NMR
3
(CDCl ): δ ) 21.1 (C91), 21.8 (C80, C66), 25.3 (C91), 25.8 (C79,
C67), 31.1 (C86), 31.2 (C61), 31.6 (C74), 32.8 (C84), 33.2 (C59,
C72), 38.0 (C78), 38.4 (C90), 39.0 (C65), 39.4 (C85), 39.7 (C60,
C73), 43.5 (C87), 44.2 (C62, C75), 57.9 (C93), 88.9 (C88), 121.2
Supporting Information Available: CIF file for complex (-)-
1
13
2
1
0, H and C NMR spectra of the final ligands and intermediates,
D and 2D NMR spectra of complex (-)-21, and further experi-
(C82), 121.4 (C57), 121.5 (C70), 124.1 (C100, C97), 125.3 (C95,
mental information. This material is available free of charge via
the Internet at http://pubs.acs.org. The supplementary crystal-
lographic data for this paper (CCDC 606513) can also be obtained
free of charge via www.ccdc.cam.ac.uk/retrieving.html (or from
the Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, U.K.; fax +44, 1223336033 or e-mail
deposit@ccdc.cam.ac.uk).
C102), 136.5 (C96), 136.7 (C101), 148.0 (C89), 151.2 (C94, C103),
+
1
(
C
52.0 (C64), 152.2 (C77). ESI-MS (m/z) 852.1 [M - BF
V) (CH Cl ) ) 0.741 V vs SSCE. Elemental Anal. Calcd for
RuClBF : C, 58.57; N, 7.11; H, 5.94. Found: C, 58.25;
4
] ; E1/2
2
2
48 53
H N
5
O
1
4
N, 6.97; H, 6.33.
Catalytic Oxidation of Styrene. Experiments have been per-
formed in CH Cl dried over CaH at rt. In a typical run, ruthenium
catalyst (0.002 mmol), alkene (0.2 mmol), and PhI(OAc) (0.4
2
2
2
2
JO0612372
9290 J. Org. Chem., Vol. 71, No. 25, 2006