A benzimidazole-based N-heterocyclic carbene derived from 1,10-phenanthroline

Article abstract of DOI:10.1021/ol048393k

(Chemical Equation Presented) A catalytically active palladium-complexed tetracyclic N-heterocyclic carbene (NHC) was prepared in three steps from commercially available 1,10-phenanthroline by using a reduction-cyclization- deprotonation sequence. The new

Full text of DOI:10.1021/ol048393k

ORGANIC
LETTERS
2
004
Vol. 6, No. 20
641-3644
A Benzimidazole-Based N-Heterocyclic
Carbene Derived from
3
1,10-Phenanthroline
Costa Metallinos,* Fred B. Barrett, Jennifer L. Chaytor, and Mary E. A. Heska
Department of Chemistry, Brock UniVersity, 500 Glenridge AVenue,
St. Catharines, Ontario L2S 3A1, Canada
metallic@brocku.ca
Received August 12, 2004
ABSTRACT
A catalytically active palladium-complexed tetracyclic N-heterocyclic carbene (NHC) was prepared in three steps from commercially available
1,10-phenanthroline by using a reduction
−cyclization
−deprotonation sequence. The new carbene framework is a prototype for the development
of a series of chiral N-heterocyclic carbenes.
4
Substituted 1,10-phenanthrolines have a rich history as
ligands for transition-metal catalysis.1,2 The majority of such
compounds reported to date retain the full aromatic backbone
of 1,10-phenanthroline (1) (Figure 1). Much less attention
phenanthrolines (3 and 4) as precursors for new ligands such
as benzimidazole-based N-heterocyclic carbenes (NHCs).5
Previous NHCs with benzimidazole backbones, or their
6
derived metal complexes, have contained pendant acyclic
alkyl groups (5
and 6) or the ferrocene moiety (7) adjacent to the nitrogen
7
8-10
substituents such as achiral and chiral
1
1
(
4) For an example of a tetrahydrophenanthroline ligand, see: Helquist,
P. U.S. Patent 6730788, 2004.
5) Reviews: (a) Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, in
(
press. (b) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290. (c)
Bourissou, D.; Guerret, O.; Gabba ¨ı , F. P.; Bertrand, G. Chem. ReV. 2000,
100, 39. (d) Arduengo, A. J. Acc. Chem. Res. 1999, 32, 913. (e) Herrmann,
W. A.; Koker, C. Angew. Chem., Int. Ed. Engl. 1997, 36, 2162. (f) Perry,
M. C.; Burgess, K. Tetrahedron: Asymmetry 2003, 14, 951.
(
6) (a) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
Figure 1. 1,2,3,4,7,8,9,10-Octahydro-1,10-phenanthrolines (3 and
2
002, 124, 3202. (b) Hahn, F. E.; Wittenbecher, L.; Le Van, D.; Fr o¨ hlich,
4) as a framework for chiral and achiral ligands.
R. Angew. Chem., Int. Ed. 2000, 39, 541. (c) K o¨ cher, C.; Herrmann, W. A.
J. Organomet. Chem. 1997, 532, 261. (d) Raubenheimer, H. G.; Lindeque,
L.; Cronje, S. J. Organomet. Chem. 1996, 511, 177. (e) Bildstein, B.;
Malaun, M.; Kopacka, H.; Ongania, K.-H.; Wurst, K. J. Organomet. Chem.
1998, 552, 45.
(7) Hahn, F. E.; Wittenbecher, L.; Boese, R.; Blaser, D. Chem. Eur. J.
999, 5, 1931.
has been directed toward the use of the partially reduced
3
1
,2,3,4-tetrahydro- (2) or 1,2,3,4,7,8,9,10-octahydro-1,10-
1
(
8) Rivas, F. M.; Riaz, U.; Giessert, A.; Smulik, J. A.; Diver, S. T. Org.
*
To whom correspondence should be addressed.
Lett. 2001, 3, 2673.
(
1) Review: Schoffers, E. Eur. J. Org. Chem. 2003, 1145.
(9) Broggini, D.; Togni, A. HelV. Chim. Acta 2002, 85, 2518.
(10) Marshall, C.; Ward, M. F.; Harrison, W. T. A. Tetrahedron Lett.
2004, 45, 5703.
(11) Bildstein, B.; Malaun, M.; Kopacka, H.; Ongania, K.-L.; Wurst, K.
J. Organomet. Chem. 1999, 572, 177.
(2) For a recent example, see: Zhou, J.; Fu, G. C. J. Am. Chem. Soc.
2
004, 126, 1340.
3) (a) Radivoy, G.; Alonso, F.; Yus, M. Tetrahedron 1999, 55, 14479.
b) Hensen, K.; Klebe, G. J. Organomet. Chem. 1981, 209, 17.
(
(
1
0.1021/ol048393k CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/10/2004

derivative (3). The first of these used borane reduction of
,10-phenanthroline, giving a mixture of 2 and 3 in low
1
1
3
(
<10%) combined yield. The second method employed
high pressure and high-temperature hydrogenation of 1 with
1
4
Raney nickel [27.6 bar (400 psi), 100 °C for 36 h],
providing 3 in 92% yield. We wished to explore a milder
set of conditions with which to prepare 3. Previous reductions
of 1,10-phenanthroline to the tetrahydro derivative (2) have
1
5
used borohydrides such as Zn(BH
4 2
) under sonication or
Figure 2. Examples of benzimidazole-based N-heterocyclic car-
NaBH CN/BF ‚OEt
3
3
2
under anhydrous conditions,16 which
benes.
gave 2 in 80% and 70% yields, respectively. We thought it
should be possible, with appropriate modification of these
procedures, to elicit more complete reduction of 1-3.
atoms (Figure 2). These substituents have typically been
8
11
installed via aryl amination or amidation chemistry (6 and
Initial experiments (NaBH
3
CN, MeOH, pH 6) led only to
) or by direct N-alkylation7 of benzimidazoles (5).
,9
7
isolation of 2 (Scheme 1). Addition of more NaBH
3
CN failed
As part of a program aimed at ligand synthesis in our
laboratory, we envisioned that 1,2,3,4,7,8,9,10-octahydro-
,10-phenanthroline (3, R ) H), prepared by reduction of
to advance the reduction to the desired octahydro product
(3). Further reduction of 2 was likely hampered by the
generation of the more basic piperidine-like nitrogen atom,
and the acidity of the medium was insufficient to pro-
tonate the remaining aromatic nitrogen, a requirement in
1
the pyridyl rings of 1,10-phenanthroline, could serve as a
versatile precursor for a new class of benzimidazole-based
NHCs (Figure 1). The successful preparation of such a
compound would stimulate the development of chiral
analogues with stereogenic centers R to the nitrogen atoms
of reduced 2-substituted and 2,9-disubstituted phenanthrolines
1
7-19
reductions of π-deficient pyridyl rings.
Performing the
2
0
reaction in glacial acetic acid as solvent would ensure the
double protonation of nitrogens in tetrahydro intermediate
2, allowing the reduction to continue. Although this set
of conditions did initially form octahydro 3, the product
surprisingly reacted further, undergoing diethylation with
concomitant decomposition to give the undesired N1,N10-
diethyl-2,3,4,7,8,9-hexahydrophenanthroline (8) as the only
12
(
4). It is anticipated that the greater rigidity afforded by
the structural motif exemplified by 3 will lead to useful
reagents for asymmetric transformations for subsequent chiral
derivatives.
Our proposed N-heterocyclic carbene synthesis required
a reasonable quantity (0.5-2 g) of 1,2,3,4,7,8,9,10-octa-
hydro-1,10-phenanthroline 3 being prepared (Scheme 1).
2
1
isolable product in low 10% yield. In an effort to disfavor
the side reaction of 3 with acetic acid, we diluted the reaction
mixture with methanol. Thus, subjection of 1,10-phenan-
throline to NaBH
acetic acid at reflux provided the desired product 3 in a
modest, but useable, 42% yield after purification. This
reduction process is operationally simple in that it can be
3
CN reduction in 1:1 MeOH and glacial
2
2
23
Scheme 1. Alternate Preparation of
1,2,3,4,7,8,9,10-Octahydrophenanthroline
(
(
13) Keller, P. C.; Marks, R. L.; Rund, J. V. Polyhedron 1983, 2, 595.
14) Eckhard, I. F.; Fielden, R.; Summers, L. A. Aust. J. Chem. 1975,
2
5
8, 1149.
(
(
15) Ranu, B. C.; Jana, U.; Sarkar, A. Synth. Commun. 1998, 28, 485.
16) Srikrishna, A.; Reddy, T. J.; Viswajanani, R. Tetrahedron 1996,
2, 1631.
17) Review: Seller, R. V.; Reshetov, P. V.; Kriven’ko, A. P. Chem.
Heterocycl. Compds. (N.Y.) 2001, 37, 797.
(
(
(
18) Hamilton, T. S.; Adams, R. J. Am. Chem. Soc. 1928, 50, 2260.
19) For reductions of N-alkylpyridinium salts, see: (a) Wenkert, E. Acc.
Chem. Res. 1968, 1, 78. (b) Liberatore, F.; Carelli, V.; Cardellini, M.
Tetrahedron Lett. 1968, 9, 4735. (c) Hutchins, R. O.; Natale, N. R. Synthesis
1
1
979, 281. (d) Lavilla, R.; Gotsens, T.; Gull o´ n, F.; Bosch, J. Tetrahedron
994, 50, 5233. (e) McCullough, K. J.; MacTavish, J.; Proctor, G. R.;
Redpath, J. J. Chem. Soc., Perkin Trans. 1 1996, 2553.
(
20) Booker, E.; Eisner, U. J. Chem. Soc., Perkin Trans. 1 1975, 929.
(21) For a similar reductive ethylation with NaBH4 in AcOH, see:
Gribble, G. W.; Lord, P. D.; Skotnicki, J.; Dietz, S. E.; Eaton, J. T.; Johnson,
J. J. Am. Chem. Soc. 1974, 96, 7812.
(
22) The use of proportionately less acetic acid (e.g., 5:2 MeOH/AcOH)
gave the undesired tetrahydro product 2.
23) With regards to the use of NaBH4 or NaBH(OAc)3 for the
(
preparation of 3, results indicate that NaBH4 is an inferior reducing agent
to NaBH3CN in this reaction. The reaction stops at the stage of tetrahydro
product 2, even under prolonged heating and with excess reagent. Since it
is reasonable to assume that NaBH(OAc)3 is produced in situ under the
reaction conditions, this reagent can also be ruled out as an effective
alternative to NaBH3CN for this process. Reactions performed in neat acetic
acid were found to be difficult to control and stop at product 3. Oftentimes,
Although several methods are known for the preparation of
,2,3,4-tetrahydro-1,10-phenantholine (2) in moderate to
good yields, to the best of our knowledge, only two reports
have appeared regarding the preparation of the octahydro
1
3
3
completely vanished from the reaction mixture (NMR monitoring) to give
(12) For examples of oxazoline-derived imidazoliums, see: Glorius, F.;
a large number of unidentifiable products, of which only 8 could be
Altenhoff, G.; Goddard, R.; Lehmann, C. Chem. Commun. 2002, 2704.
identified concretely after purification.
3642
Org. Lett., Vol. 6, No. 20, 2004

performed in air, requires no hydrogenation equipment, and
can be scaled up without difficulty.
Previous benzimidazolium salts have been shown to serve
as precursors to stable free carbenes via deprotonation when
sufficiently bulky substituents are present on the nitrogens7
(5b, 6, Figure 2). Such NHCs are persistent under anhydrous
,8
With diamine 3 in hand, we turned our attention to
cyclization and NHC preparation. Treatment of 3 with neat
8
13
triethyl orthoformate containing 1 equiv of HCl provided
conditions and typically display C NMR chemical shifts
7
,8
the key tetracyclic benzimidazolium chloride 9 in 89% yield
near δ 224-231 for the carbenoid carbon. In contrast,
benzimidazolium salts with smaller N-methyl substituents
(Scheme 2). To test the propensity of 9 to act as a carbene
7,27,28
(5a) have a propensity to dimerize
to the corresponding
alkenes upon deprotonation. An exception to this is the
N-methyl-N-ferrocenyl NHC 7 which, although it could not
be characterized as the “free” carbene and did not show a
tendency to dimerize, could be trapped with elemental sulfur
to give the corresponding thiourea in a reaction typical of
Scheme 2. Synthesis of Tetracyclic Benzimidazolium
Chloride 9 and NHC Palladium Complexes 10 and 11
1
1
NHCs.
-
To prepare a stable free carbene from 9, the Cl counterion
-
was exchanged for BPh
4
(16) to improve solubility. Given
the range of stabilities of previous benzimidazolium-derived
NHCs, it was difficult to predict on the basis of steric or
electronic factors which of the three preceding types of NHC
(5a, 6, or 7) that compound 16 would behave like. Subse-
quent experiments revealed that the “free” NHC 17, gener-
ated by treatment of 16 with KO-t-Bu or NaH in THF
1
13
(
Scheme 4), was too unstable to characterize by H and
C
Scheme 4. Trapping of NHC 17 with Sulfur To Give
Thiourea 18
11
ligand precursor, it was heated with 0.5 equiv of Pd(OAc)
2
(THF, reflux, 1 h). The reaction mixture underwent a distinct
color change from orange to light gray, from which a pale
gray precipitate was collected. NMR and mass spectral
analysis confirmed the formation of palladium complexes
1
0 and 11 as a 1:1 mixture of cis and trans coordination
2
4
25
isomers, isolated in 84% yield.
Preliminary experiments have revealed that 10 + 11 is an
active catalyst for C-C bond-forming reactions such as
26
Suzuki-Miyaura and Heck couplings. Subjection of 4-bro-
moacetophenone 12 to Suzuki-Miyaura coupling with
phenylboronic acid in the presence of 3 mol % of 10 + 11
(
K
2
CO
yield (Scheme 3). Alternatively, the more electron-rich
-bromoanisole 14 reacts smoothly with butyl acrylate (2
mol % 10 + 11, K CO , DMA, 140 °C, 18 h) to provide
3
, PhMe, 120 °C, 18 h) gave biphenyl 13 in good 79%
NMR in THF-d
8
. However, sequential deprotonation of 16
4
(NaH, THF, 1 h) followed by addition of elemental sulfur
2
3
delivered the thiourea 18 in 78% yield. These results indicate
that the tetracyclic NHC 17 closely resembles the behavior
of N-ferrocenyl NHC 7, both in the instability of its “free”
carbene and in its lack of tendency to dimerize.
Current studies are underway to crystallographically char-
acterize complexes 10 and 11, as is the preparation of chiral
cinnamate 15 in excellent 90% isolated yield.
Scheme 3. Carbon-Carbon Bond-Forming Reactions
Catalyzed by 10 + 11
(
24) Enders, D.; Gielen, H.; Raaba, G.; Runsink, J.; Teles, J. H. Chem.
Ber. 1996, 129, 1483.
25) Compounds 10 and 11 are not separable by chromatography. cis-
0 is configurationally stable and does not isomerize to 11 even after
(
1
prolonged heating (130 °C, 4 days) in DMSO-d6, as determined by periodic
1
H NMR monitoring. No change in the ratio of 10/11 was observed over
this period.
(
26) Herrmann, W. A.; Reisinger, C.-L.; Spiegler, M. J. Organomet.
Chem. 1998, 557, 93.
27) Cetinkaya, E.; Hitchcock, P. B.; Kucukbay, H.; Lappert, M. F.;
Al-Juaid, S. J. Organomet. Chem. 1994, 481, 89.
28) Liu, Y.; Linder, P. E.; Lemal, D. M. J. Am. Chem. Soc. 1999, 121,
0626.
(
(
1
Org. Lett., Vol. 6, No. 20, 2004
3643

versions of 9, including those derived from C
2
-symmetric
contribution possible. J.L.C. thanks NSERC for a USR
Award. M.E.A.H. thanks Human Resources Development
Canada for support. We also thank Prof. Tomas Hudlicky
for invaluable suggestions and advice, Prof. Travis Dudding
for preliminary modeling of 10, and Mr. Tim Jones for
provision of mass spectral data.
reduction products of 2,9-disubstituted phenanthrolines (4,
e.g., neocuproine, R ) Me). The greater rigidity of these
NHCs afforded by the tetracyclic benzimidazole framework
exemplified by 9 is anticipated to provide useful ligands and
reagents for asymmetric synthesis. The results of these studies
will be reported in due course.
Supporting Information Available: Experimental pro-
cedures for 3, 9-11, 13, 15, 16, and 18 and characterization
data for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank NSERC Canada for general
support of research and the Brock University Advancement
Fund for a Seed Grant. F.B. thanks Brock University’s Career
Services for an Experience Works award, which made his
OL048393K
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Org. Lett., Vol. 6, No. 20, 2004