Asymmetric synthesis of C2-symmetric vicinal diamines via reductive dimerization of N-acylpyridinium and related salts

Article abstract of DOI:10.1021/ol702595d

(Chemical Equation Presented) A new route to C₂-symmetric diamines via an asymmetric reductive dimerization of 1-acylpyridinium salts and their benzo derivatives is described. This method is practical as the starting heterocycles and chiral aux

Full text of DOI:10.1021/ol702595d

ORGANIC
LETTERS
2008
Vol. 10, No. 2
221-223
Asymmetric Synthesis of C2-Symmetric
Vicinal Diamines via Reductive
Dimerization of N-Acylpyridinium and
Related Salts
Pandi Bharathi and Daniel L. Comins*
Department of Chemistry, North Carolina State UniVersity,
Raleigh, North Carolina 27695-8204
Daniel_Comins@ncsu.edu
Received October 25, 2007
ABSTRACT
A new route to C2-symmetric diamines via an asymmetric reductive dimerization of 1-acylpyridinium salts and their benzo derivatives is
described. This method is practical as the starting heterocycles and chiral auxiliaries are readily available. The titanium reducing agent is
inexpensive and easy to prepare. Several novel enantiopure C2-symmetric diamine derivatives were synthesized using this method.
C2-Symmetric 1,2-diamines and their derivatives are impor-
tant in medicinal chemistry, natural products, coordination
chemistry, and asymmetric catalysis.1 They have been
extensively used as ligands and catalysts in asymmetric
synthesis with impressive results.2 Because they are so
effective as chiral ligands, much work has been reported on
the development of methods for their preparation.3 An
attractive approach to vicinal diamines is the reductive
coupling of imine species promoted by a metal reducing
(3) For leading references, see: (a) Mun˜iz, K.; Nieger, M.; Mansikka-
ma¨ki, H. Angew. Chem., Int. Ed. 2003, 42, 5958. (b) Mun˜iz, K.; Iaseto, A.;
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Fonseca, I.; Andre´, I.; Rodr´ıguez, A. Chem. Eur. J. 2003, 9, 2867. (f) Ooi,
T.; Sakai, D.; Takeuchi, M.; Tayama, E.; Maruoka, K. Angew. Chem., Int.
Ed. 2003, 42, 5868. (g) Gille, S.; Cabello, N.; Kizirian, J.-C.; Alexakis, A.
Tetrahedon: Asymmetry 2006, 17, 1045. (h) Feng, G.-Q.; Wang, D.-X.;
Zheng, Q.-Y.; Wang, M.-X. Tetrahedron: Asymmetry 2006, 17, 2775.
(4) For recent examples of intermolecular coupling, see: (a) Yamada,
R.; Negoro, N.; Okaniwa, M.; Miwa, Y.; Taga, T.; Yanada, K. Fujita, T.
Synlett 1999, 537. (b) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi,
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T. J. Org. Chem. 1998, 63, 9421. (f) Alexakis, A.; Aujard, I.; Mangeney,
P. Synlett 1998, 873. (g) Liu, X.; Liu, Y.-K.; Zhong, Y.-M. Tetrahedron
Lett. 2002, 43, 6787. (h) Kise, N.; Ueda, N. Tetrahedron Lett. 2001, 42,
2365. (i) Ortega, M.; Rodriguez, M. A.; Campos, P. J. Tetrahedron 2004,
60, 6475.
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1998, 37, 2580-2627. (b) Bennani, Y. L.; Hanessian, S. Chem. ReV. 1997,
97, 3161-3195. (c) Saibabu, Kotti, S. R. S.; Timmons, C.; Li, G. Chem.
Biol. Drug Des. 2006, 67, 101-114. (d) Fache, F.; Schultz, E.; Tommasino,
M. L.; Lemaire, M. Chem. ReV. 2000, 100, 2159.
(2) (a) Ma, Y.; Liu, H.; Chen, L.; Cui, X.; Zhu, J.; Deng, J. Org. Lett.
2003, 5, 2103. (b) Mealy, M. J.; Luderer, M. R.; Bailey, W. F.; Sommer,
M. B. J. Org. Chem. 2004, 69, 6042. (c) Bassindale, M. J.; Crawford, J. J.;
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10.1021/ol702595d CCC: $40.75
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Published on Web 12/20/2007

agent. Most of the systems developed to effect this conver-
sion have resulted in low stereoselectivity and produce
racemic products.4 A recent reductive homocoupling of chiral
N-tert-butanesufinyl imines with SmI2/HMPA generated C2-
symmetric 1,2-diamine derivatives in a highly diastereose-
lective and enantioselective fashion.5 A limitation of this
method is the destruction of the chiral inducing groups on
their removal from the diamine product.
the C2-symmetric dimer 3 as the only diastereomer isolated
(Scheme 2).
Scheme 2
The dimerization of N-acylpyridinium salts has the po-
tential for providing unique vicinal diamines. Although some
reports of this transformation have appeared, the result is
often a mixture of regio- and stereoisomers.6 If the regiose-
lectivity and facial selectivity can be controlled during the
dimerization, then chiral C2-symmetric 1,2-diamines would
result. In this letter we report our successful efforts at
dimerizing chiral N-acylpyridinium and related salts to afford
novel vicinal diamines in an asymmetric fashion.
The addition of organometallic nucleophiles to chiral
auxiliary-containing N-acylpyridinium salt 1 has proven to
be a versatile method for the asymmetric synthesis of various
heterocycles and natural products.7,8 We envisaged that
addition of an electron to 1 would give delocalized radical
2 which, on dimerization at C6 with auxiliary-directed facial
selectivity, would provide a C2-symmetric dimer. Regiose-
lective reaction at C6 was anticipated due to the methoxy
and TIPS groups blocking the C2 and C4 positions (Scheme
1).
The assigned stereochemistry of 3 was confirmed by single-
crystal X-ray analysis. In a search for a less expensive and
more convenient reducing agent, it was found that a low-
valent titanium species generated from TiCl4/Mg9 was
effective and gave a 64% yield of dihydropyridone dimer 3
on workup with aqueous acid.
Scheme 1
As with related N-acyldihydropyridones,7 the chiral aux-
iliaries could be removed and recovered in high yield by
treatment of 3 with NaOMe to give 4 as a white solid that
was recrystallized from ether.
To examine other pyridine derivatives in the asym-
metric dimerization reaction, our attention turned to 4-meth-
oxyquinoline (6). As before, it was anticipated that a
4-methoxy substituent would act as a blocking group to effect
regioselective dimerization at the C2 position of the hetero-
cycle. Commercially available 4,7-dichloroquinoline was
converted to 610 via 511 on a 10-g scale as shown in
Scheme 3.
Initially, SmI2 was used as the one electron reductant.
Addition of a THF solution of SmI2 to chiral salt 1 did afford
(5) Zhong, Y.-W.; Izumi, K.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2004, 6,
4747.
Scheme 3
(6) (a) Carelli, V.; Liberatore, F.; Casini, A.; Tortorella, S.; Scipione,
S.; Di Renzo, B. New J. Chem. 1998, 999. (b) Forster, R. J. Phys. Chem.
Chem. Phys. 1999, 1, 1543. (c) Carelli, V.; Liberatore, F.; Tortorella, S.;
Rienzo, B. D.; Scipione, L. J. Chem. Soc., Perkin Trans. 1 2002, 542.
(7) (a) Comins, D. L.; Joseph, S. P. In AdVances in Nitrogen Hetero-
cycles; Moody, C. J., Ed.; JAI Press Inc.: Greenwich, CT, 1996; Vol. 2, p
251. (b) Comins, D. L.; Joseph, S. P. In ComprehensiVe Heterocyclic
Chemistry, 2nd ed.; McKillop, A., Ed.; Pergamon Press: Oxford, England.
1996; Vol. 5, p 37. (c) Comins, D. L. J. Heterocycl. Chem. 1999, 36, 1491.
(d) Joseph, S. P.; Comins, D. L. Curr. Opin. Drug DiscoVery DeV. 2002,
5, 870.
(8) For recent examples and leading references, see: (a) Kuethe, J. T.;
Comins, D. L. J. Org. Chem. 2004, 69, 2863. (b) Kuethe, J. T.; Comins, D.
L. J. Org. Chem. 2004, 69, 5219. (c) Comins, D. L.; Kuethe, J. T.; Miller,
T. M.; Fe´vrier, F. C.; Brooks, C. A. J. Org. Chem. 2005, 70, 5221. (d)
Comins, D. L.; Sahn, J. J. Org. Lett. 2005, 7, 5227.
222
Org. Lett., Vol. 10, No. 2, 2008

Addition of (+)-TCC chloroformate12 to 4-methoxyquinoline
in toluene formed the N-acylquinolinium salt in situ. A
solution of the low-valent titanium (LVT) was added
dropwise, followed by workup with aqueous HCl, to afford
the C2-symmetric dimer 7 in 47% yield (Scheme 4).
Scheme 5
Scheme 4
Again, only one diastereomer was observed.13 Unlike dihy-
dropyridone dimer 3, the auxiliaries on 7 could not be
removed with NaOMe/MeOH.
Since reductive coupling of isoquinoline with Zn/Ac2O,
presumably via an N-acylisoquinolinium salt, has been
reported,14 we decided to apply our asymmetric method to
this conversion. A solution of LVT in THF was added to
the mixture of isoquinoline and (+)-TCC chloroformate in
toluene to afford an 80% yield of a mixture (60:40) of the
desired dimer 8 and the diastereomer 9 (Scheme 5).
Hydrogenation of 8 over Raney nickel provided derivative
10 which was reduced with LAH to afford the known
diamine 11. The spectral properties of our (-)-11 are in
agreement with reported data for the racemic compound.14
Elliott and Williams14b prepared racemic 11 and found that
the basicity of this diamine was unusually high.14c In addition
to its potential as a chiral base, 11 and derivatives hold
obvious value as ligands for catalytic asymmetric reac-
tions.15,16
In conclusion, a new route to C2-symmetric diamines via
an asymmetric reductive dimerization of pyridines and their
benzo derivatives has been developed. The method is
practical, as the starting heterocycles are readily available
and the recoverable chiral auxiliary (TCCOH) can be
prepared on multigram scale (>100 g) as either enantiomer.
The titanium reducing agent is inexpensive and easy to
prepare. Most importantly, numerous variations of C2-
symmetric diamines should be accessible by using readily
available substituted heterocycles as starting material, or by
modifying the intermediates, i.e., 4, 7, 8, and 10. The scope
of this method and the application of the enantiopure C2-
symmetric diamine derivatives to catalytic asymmetric
synthesis are under study in our laboratories.
Acknowledgment. Dedicated to Prof. Mariappan Peri-
asamy on the occasion of his 56th birthday. This work was
supported by the National Institutes of Health (Grant GM
34442). We thank Dr. Paul Boyle (NCSU) for X-ray
crystallographic analysis of 3. NMR, X-ray analysis and mass
spectra were obtained at NCSU instrumentation laboratories,
which were established by grants from the North Carolina
Biotechnology Center and the National Science Foundation
(Grant CHE-0078253).
(9) Pons, J.-M.; Santelli, M. Tetrahedron 1990, 46, 513.
(10) Sugiura, M.; Sakurai, Y.; Hamada, Y. Heterocycles 1992, 34, 561.
(11) Heindel, N. D.; Fine, S. A. J. Heterocycl. Chem. 1969, 6, 961.
(12) (a) Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am. Chem.
Soc. 1994, 116, 4719. (b) Comins, D. L.; Salvador, J. M. J. Org. Chem.
1993, 58, 4656.
(13) The absolute stereochemistry shown for 7 is based on its optical
rotation and the anticipated auxiliary-directed facial selectivity.
(14) (a) Nielsen, A. T. J. Org. Chem. 1970, 35, 2498. (b) Elliott, M. C.;
Williams, E. Org. Biomol. Chem. 2003, 1, 3038. (c) Elliott, M. C.; Williams,
E.; Howard, S. T. J. Chem. Soc., Perkin Trans. 2 2002, 201. (d) Cavell, K.
J.; Elliott, M. C.; Nielsen, D. J.; Paine, J. S. Dalton Trans. 2006, 4922.
(15) (a) Preparation of potential ligand systems based on a tetramethoxy
bis-isoquinoline skeleton has been reported, see: Busato, S.; Craig, D. C.;
Judeh, Z. M. A.; Read, R. W. Tetrahedron 2003, 59, 461. (b) Chan, B. K.
H.; Deng, B.; Jones, M. W.; Read, R. W. Tetrahedron 2006, 62, 4979.
(16) Optical resolution of racemic octahydrobiisoquinolines (bis N-H)
has been achieved, and their complexes with Cu(I) have been used in
catalytic asymmetric oxidative coupling of â-naphthols. Arai, S.; Takita,
S.; Nishida, A. Eur. J. Org. Chem. 2005, 5262.
Supporting Information Available: Experimental pro-
cedures, characterization, and NMR data for 3-8 and 11,
and ORTEP plot and X-ray crystal data (cif format) for 3.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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