Branch-selective reductive coupling of 2-vinyl pyridines and imines via rhodium catalyzed C-C bond forming hydrogenation

Article abstract of DOI:10.1021/ja805056g

Hydrogenation of 2-vinyl azines 1a-1e in the presence of N-arylsulfonyl imines 2a-2l at ambient temperature and pressure employing cationic rhodium catalysts ligated by tri-2-furylphosphine results in regioselective reductive coupling to furnish branched

Full text of DOI:10.1021/ja805056g

Published on Web 08/29/2008
Branch-Selective Reductive Coupling of 2-Vinyl Pyridines and Imines via
Rhodium Catalyzed C-C Bond Forming Hydrogenation
Venukrishnan Komanduri, Christopher D. Grant, and Michael J. Krische*
UniVersity of Texas at Austin, Department of Chemistry and Biochemistry, Austin, Texas 78712
Received July 1, 2008; E-mail: mkrische@mail.utexas.edu
Table 1. Hydrogenative Coupling of 6-Bromo-2-vinylpyridine 1a to
N-Arylsulfonyl Aldimines 2a-2l
Nitrogen-bearing heterocycles are among the most prevalent
substructures found in approved therapeutic agents.1 Among all
heterocycles, pyridines most often appear in pharmaceutically active
compounds.2 Modular methods for the catalytic coupling of
pyridines and higher azines are largely limited to metal catalyzed
cross-coupling processes (Suzuki, Stille, Kumada-Corriu, Negishi,
and Hiyama coupling reactions) and ortho-C-H activation initiated
biaryl couplings3 and insertions of olefins or alkynes.4 A notable
exception involves the rhodium catalyzed coupling of 2-vinyl
azines5a and 2-alkynyl azines5b,c to organoboron reagents, which
result in C-C coupling at the ꢀ-position of the vinyl or alkynyl
moiety, respectively. Vinylpyridines also participate in rhodium
catalyzed couplings to olefins, typically initiated Via C-H insertion,
again resulting in functionalization at the ꢀ-position of the vinyl
moiety.6 Despite the significance of azine substructures, there are
remarkably few methods available for catalytic C-C coupling of
azine-containing building blocks.7–9
We have found that diverse π-unsaturated reactants engage in
C-C coupling under the conditions of catalytic hydrogenation.10
For example, rhodium catalyzed hydrogenation of vinyl arenes in
the presence of anhydrides was found to deliver formal products
of acyl substitution with complete branched regioselectivity.11
Additionally, activated olefins in the form of conjugated enones
engage in highly diastereo- and enantioselective reductive aldol and
Mannich couplings when hydrogenated in the presence of aldehydes
and imines.12,13 Here, we report the first catalytic reductiVe C-C
couplings of Vinyl azines. Specifically, we find that catalytic
hydrogenation of 2-vinyl azines in the presence of N-arylsulfonyl
imines results in regio- and diastereoselective reductive coupling
to furnish branched products of imine addition.
a Cited yields are of isolated diastereomeric mixtures. Standard
conditions employ 3 equiv of 1a and 1 equiv of imines 2a-2l. See
Supporting Information for details. b Reaction was performed at 35 °C.
c Reaction was performed using 7.5 mol% [Rh(cod)2]BARF and 18
mol% (2-Fur)3P.
presumably due to strong coordination at nitrogen, 6-substituted-
2-vinyl pyridines 1b-1d couple efficiently to (hetero)aromatic and
aliphatic imines 2f, 2i, and 2k (Tables 2, 3). Higher azines, for
example 2,3-diphenyl-5-vinylpyrazine, couple in diminished yield
under standard conditions.16 However, as exemplified by the
coupling of 8-benzyloxy-2-vinylquinoline 1e to imines 2e, 2f, 2i,
and 2k, fused vinyl azines are effective coupling partners.
Initial studies focused on the hydrogenative coupling of 6-bromo-
2-vinylpyridine 1a and N-ortho-toluenesulfonyl aldimine 2a. After
extensive optimization, it was found that hydrogenation of 6-bromo-
2-vinylpyridine 1a and imine 2a at ambient temperature and
pressure employing a cationic rhodium catalyst ligated by (2-
Fur)3P14leads to formation of the reductive coupling product 3a in
97% isolated yield with complete branched regioselectivity and modest
syn-diastereoselectivity (3:1 dr). Added Na2SO4 was found to suppress
imine hydrolysis. To evaluate scope, these conditions were applied to
aromatic imines 2a-2d, heteroaromatic imines 2e and 2f, R,ꢀ-
unsaturated imine 2g, and aliphatic imines 2h-2l, which were all found
to couple efficiently to provide adducts 3a-3l, respectively, in good
to excellent yield with complete branched regioselectivity and
modest to good levels of syn-diastereoselectivity (3:1-13:1 dr).15 The
stereochemical assignment of adducts 3a and 3f were confirmed by
single crystal X-ray diffraction analysis of diastereomerically pure
samples. The stereochemical assignment of the remaining adducts are
made in analogy to 3a and 3f (Table 1).
To gain insight into the catalytic mechanism, the reductive coupling
of 6-bromo-2-vinylpyridine 1a to imine 2l was performed under an
atmosphere of elemental deuterium (99.6% purity). As corroborated
1
2
by H and H NMR spectroscopy, the branched adduct deuterio-3l
incorporates deuterium exclusively at the former ꢀ-position of the vinyl
moiety (93:7, 2H:1H). Deuterium incorporated at nitrogen is lost
through exchange during chromatographic isolation. The results of
isotopic labeling are consistent with a mechanism in which oxidative
coupling of vinyl azine 1a and imine 2l delivers the indicated cationic
aza-rhodacyclopentane, which upon deuteriolytic cleavage of the
metallacycle17 releases deuterio-3l and regenerates cationic rhodium(I)
to close the catalytic cycle. Mechanisms involving vinyl azine
hydrometalation to form nucleophilic benzylrhodium intermediates
cannot be excluded on the basis of this experiment.
The scope of the vinyl azine partner was evaluated next. Whereas
the parent 2-vinylpyridine does not participate in the coupling,
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12592 J. AM. CHEM. SOC. 2008, 130, 12592–12593
10.1021/ja805056g CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Hydrogenative Coupling of Vinyl Azines 1b-1d to
N-Toluenesulfonyl Aldimines 2f, 2i, and 2k
C-C coupling, byproduct-free protocols for the coupling of diverse
unsaturated feedstocks will be achieved.
Acknowledgment. Acknowledgment is made to Merck, the
Robert A. Welch Foundation, the ACS-GCI Pharmaceutical Round-
table, and the NIH-NIGMS (RO1-GM069445) for partial support
of this research. Dr. Oliver Briel of Umicore is thanked for the
generous donation of [Rh(cod)2]BARF.
Supporting Information Available: Experimental procedures and
spectral data for new compounds. Single crystal X-ray diffraction data
for compounds 3a and 3f. This material is available free of charge Via
the Internet at http://pubs.acs.org.
References
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a Cited yields are of isolated diastereomeric mixtures. Standard
conditions employ 3 equiv of 1b-1d and 1 equiv of imines 2f, 2i, and
2k. See Supporting Information for further details. b Reaction was
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Table 3. Hydrogenative Coupling of Vinyl Azine 1e to
N-Toluenesulfonyl Aldimines 2e, 2f, 2i, and 2ka
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a Cited yields are of isolated material. Standard conditions employ 3
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In summary, we report the first metal catalyzed reductive C-C
coupling of vinyl azines. By simply hydrogenating vinyl azines
1a-1e in the presence of N-arylsulfonyl aldimines 2a-2l, one gains
access to the branched products of reductive coupling 3a-3v, which
appear as single regioisomers. Using a rhodium catalyst ligated by
tri-2-furylphosphine, modest to high levels of syn-diastereoselec-
tivity may be achieved. Future studies will focus on the development
of enantioselective variants of this process and related vinyl azine-
carbonyl reductive couplings. Ultimately, through hydrogenative
(15) In the rhodium catalyzed hydrogenative coupling of vinyl ketones to
aldehydes and imines (refs 12e-h, 13), Fur3P enforces high levels of syn-
diastereoselectivity. Given the structural homology of vinyl ketones and
2-vinyl azines, it is not surprising that analogous ligand effects are observed.
(16) Coupling of 2,3-diphenyl-5-vinylpyrazine to imine 2f under standard
conditions provides the branched adduct in 35% yield and 5:1 dr.
(17) The stoichiometric reaction of isolated rhodacyclopentadienes with elemental
hydrogen delivers the product of hydrogenolysis: Mu¨ller, E.; Thomas, R.;
Zountsas, G. Liebigs Ann. Chem. 1972, 758, 16.
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