One-step synthesis of spiropyridines, a novel class of C2-symmetric chiral ligands, by cobalt(l)-catalyzed [2 + 2 + 2] cycloadditions between bis-alkynenitriles and alkynes

Article abstract of DOI:10.1021/ol991195m

matrix presented Spiropyridines, a novel series of C₂-symmetric ligands, can be obtained in moderate yields by means of Co(l)-catalyzed double cocyclization between bis-alkynenitriles and alkynes. This one-step method allowed the first synthesis of the interesting 7,7′-and 8,8′-spyropyridines from acyclic precursors.

Full text of DOI:10.1021/ol991195m

ORGANIC
LETTERS
1999
Vol. 1, No. 13
2141-2143
One-Step Synthesis of Spiropyridines,
a Novel Class of C -Symmetric Chiral
2
Ligands, by Cobalt(I)-Catalyzed
[2 + 2 + 2] Cycloadditions between
Bis-Alkynenitriles and Alkynes†
Jesu´s A. Varela, Luis Castedo, and Carlos Saa´*
Departamento de Qu´ımica Orga´nica y Unidad Asociada al CSIC,
Facultad de Qu´ımica, UniVersidad de Santiago de Compostela,
15706 Santiago de Compostela, Spain
qocsaa@usc.es
Received October 28, 1999
ABSTRACT
Spiropyridines, a novel series of C -symmetric ligands, can be obtained in moderate yields by means of Co(I)-catalyzed double cocyclization
2
between bis-alkynenitriles and alkynes. This one-step method allowed the first synthesis of the interesting 7,7′- and 8,8′-spyropyridines from
acyclic precursors.
The rational design and synthesis of novel chiral ligands for
catalysis of asymmetric reactions is currently a major focus
of attention in synthetic organic chemistry.1 Biaryls, most
notably 1,1′-binaphthalene phosphane derivatives, occupy a
prominent position among C2-symmetric chiral auxiliaries
and ligands for asymmetric synthesis.1 By contrast, spiranes,
which also have axial chirality2 and possess a quaternary
center that makes their racemization virtually impossible,
have scarcely been used in ligand design.3 In addition, the
major rigidity of its framework compared to that of the
biaryls means that any conformational change must neces-
sarily involve distortion of the entire molecule, not merely
rotation about a single bond.3 This latter property is a
potentially useful attribute of chiral catalysts (since it should
minimize the number of possible conformations of the
catalytic species) and also makes spiranes promising building
(4) Spirosilanes: Tamao, K.; Nakamura, K.; Ishii, H.; Yamaguchi, S.;
Shiro, M. J. Am. Chem. Soc. 1996, 118, 12469-12470.
(5) (a) Stang, P. J. Chem Eur. J. 1998, 4, 19-27 and references therein.
(b) Small, J. H.; McCord, D. J.; Greaves, J.; Shea, K. J. J. Am. Chem. Soc.
1995, 117, 11588-11589.
† Initial results were presented at OMCOS 10, Versailles, July 1999.
(1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley:
New York, 1994. (b) Ojima, I., Ed. Catalytic Asymmetric Synthesis; VCH:
New York, 1993.
(2) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
John Wiley & Sons: New York, 1994; pp 1138-1142.
(3) (a) SpirOP ligands: Hu, W.; Yan, M.; Lau, C.; Yang, S. M.; Chan,
A. S. C.; Jiang, Y.; Mi, A. Tetrahedron Lett 1999, 40, 973-976 and
references therein. (b) Spinol ligands: Birman, V. B.; Rheingold, A. L.;
Lam, K. Tetrahedron: Asymmetry 1999, 10, 125-131 and references
therein.
(6) Tour, J. M. Chem. ReV. 1996, 96, 537-553.
(7) For pioneering work on the synthesis of pyridines by Co(I)-catalyzed
[2 + 2 + 2] cycloadditions, see: (a) Wakatsuki, Y.; Yamazaki, H. J. Chem.
Soc., Dalton Trans. 1978, 1278-1282 and references therein. (b) Bo¨nne-
mann, H. Angew. Chem., Int. Ed. Engl. 1978, 17, 505-515 and references
therein. (c) Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1984, 23,
539-556 and references therein.
(8) For synthesis of bipyridines and terpyridines using Co(I)-catalyzed
[2 + 2 + 2] cycloadditions, see: (a) Varela, J. A.; Castedo, L.; Saa´, C. J.
Am. Chem. Soc. 1998, 120, 12147-12148. (b) Varela, J. A.; Castedo, L.;
Saa´, C. J. Org. Chem. 1997, 62, 4189-4192.
10.1021/ol991195m CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/09/1999

blocks4 for the construction of chiral macromolecules such
as metallacyclic polygons and polyhedra5 and polymers.6
In this paper we report a one-step synthesis of the novel
C2-symmetric spirocyclic 7,7′- and 8,8′-bicycloalka[b]py-
ridines (4 and 5), hereafter 7,7′-, 8,8′-spiropyridines, respec-
tively, by Co(I)-catalyzed [2 + 2 + 2] cycloaddition7
between bis-alkynenitriles (malononitriles 1 and 2) and
alkynes 3 (Schemes 1).8
remarkable that it was possible to assemble the skeleton of
this interesting novel type of C2-symmetric spirocyclic
compound in only one step from acyclic starting materials.
In an effort to improve the yield of 4a and minimize the
amount of byproduct, we used milder conditions (atmo-
spheric pressure and room temperature) and the more active
catalyst CpCo(C2H4)2,15 but unfortunately, the reaction yield
was lower (4a, 21%; 6, 11%).16 When typical Co(I)-catalyzed
cycloaddition conditions were used (irradiation, in a sealed
tube, of a boiling toluene solution of 1 saturated with
acetylene and containing 30% CpCo(CO)2 as catalyst),8 the
yield of 4a was even worse (7%). To explore the versatility
of the above method for preparing other 7,7′-spiropyridines,
we performed CpCo(CO)2-catalyzed [2 + 2 + 2] cycload-
ditions between bis-alkynenitrile 1 and other alkynes. Double
cocyclization between 1 and bis(trimethylsilyl)acetylene (3b,
used as cosolvent) produced a 33% yield of the expected
(()-7,7′-spiropyridine 4b. Irrespective of the electronic
nature of the substituents, when the quantity of alkyne partner
was reduced to 2 or 3 equiv, the yield of the reaction
dropped: under these conditions diphenylacetylene (3c),
DMAD (3d), and 1,4-bis(trimethylsilyl)-1,3-butadiyne (3e)
afforded the (()-7,7′-spiropyridines 4c, 4d, and 4e in 9%,
7%, and 8% yields, respectively.17 Similar results were found
when the bis-alkynenitrile 2 was used: double cocylization
between 2 and 3b (as cosolvent) or 3e (2 equiv) gave (()-
8,8′-spiropyridines 5b and 5e in 32% and 6% yields,
respectively.18 The moderate or low yields of these reactions
may be due to the gem-dinitrile unit of malononitriles 1 and
2 reducing the donor character of the nitrile, disfavoring
stabilization of the cobaltacycle intermediate.19
Scheme 1. Co(I)-Catalyzed Double Cocyclization between
Bis-Alkynenitriles 1 and 2 and Alkynes 3
The bis-alkynenitriles 1 and 2 were easily prepared by
dialkylation of malononitrile with tosylates of the corre-
sponding alkyn-1-ols.9 Gratifyingly, we found that double
cocyclization between bis-alkynenitrile 1 and acetylene (3a),
catalyzed at 2.3 bar10 by 30% CpCo(COD)11 in toluene,12
took place in a 32% yield to give the desired (()-7,7′-
spiropyridine 4a.13 Dipyridine 6 was also obtained, in 14%
yield, as a byproduct originated by multiple cocyclization
(Figure 1). The 1H NMR spectrum of 4a showed a
Finally, our first test of formation of coordination com-
plexes with 7,7′-spiropyridines was promising since (()-4a
almost quantitatively gave the tetracoordinate complex
[CuIL2] as a diastereomeric mixture (7, obtained as pale
yellow crystalls of the hexafluorophosphate salt) when
[CuI(CH3CN)]PF6 was added to solution of (()-4a in CH2-
Cl2 at room temperature (Figure 2). A salient feature of its
Figure 1.
characteristic series of four well-resolved multiplets corre-
sponding to each one of the diastereotopic aliphatic hydro-
gens of the molecule. The two enantiomers of 4a were easily
separated by HPLC using a Chiralcel OJ column.14 It is
Figure 2.
1H NMR spectrum in CDCl3 is the deshielding of the
hydrogen para to the nitrogen, which appears at 7.6 ppm vs
7.4 ppm in the free ligand.
To sum up, we have developed the first method for
synthesizing a novel series of C2-symmetric ligands, the
(9) For preparation of bis-alkynenitrile 1 it was necessary to add 2.5
equiv of NaI. See Supporting Information.
(10) Other pressures, whether higher (5.3 bar) or lower (1.2 bar), gave
poorer yields of 4a (20% and 9%, respectively).
(11) King, R. B.; Treichel, P. M.; Stone, F. G. A. J. Am. Chem. Soc.
1961, 83, 3593-3597.
(12) A similar set of conditions has previously been used to prepare
pyridines from nitriles and acetylene. See: Chelucci, G. Tetrahedron:
Asymmetry 1995, 6, 811-826.
(13) All new compounds gave satisfactory analytical and spectroscopic
data.
2142
Org. Lett., Vol. 1, No. 13, 1999

spiropyridines, from acyclic precursors. This one-step method
consists of Co(I)-catalyzed double cocyclization between bis-
alkynenitriles and alkynes. Studies of the coordination
behavior of these ligands are in progress and will be reported
on in due course.
Acknowledgment. This work was supported under
Projects 20901A95 and 20903B97 by the Xunta de Galicia,
which J. A. Varela also thanks for a research grant.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
1H and 13C NMR spectra of 4a, 5b′, and 5e, 1H NMR of 7,
CD spectra of (+) and (-) 4a. This material is available
free of charge via the Internet at http://pubs.acs.org.
(14) HPLC: tR first enantiomer, 17.50 min; tR second enantiomer, 22.20
min (Daicel Chiralcel OJ, 90:10 hexane/2-propanol, 0.5 mL/min). First
enantiomer: CD (EtOH) λ (nm): 212 (+), 258 (+), 276 (-), 281 (-).
Second enantiomer: CD (EtOH) λ (nm): 212 (-), 258 (-), 276 (+), 281
(+).
(15) The catalyst was prepared as described by Cammack, J. K.; Jalisatgi,
S.; Matzger, A. J.; Negro´n, A.; Vollhardt, K. P. C. J. Org. Chem. 1996, 61,
4798-4800.
(16) Both 4a and 6 appeared at the beginning of the reaction. To consume
all starting material, a substoichiometric amount of catalyst (60%) was
necessary.
OL991195M
(18) After purification steps, desilylation of TMS in R of 5b occurred to
give 5b′ (R2 ) H). See ref 8 and Supporting Information.
(19) Naiman, A.; Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1977,
16, 708-709.
(17) See Supporting Information for experimental details.
Org. Lett., Vol. 1, No. 13, 1999
2143