Stereoselective synthesis of meso-1,5-cyclodecadiynes

Article abstract of DOI:10.1021/jo901404f

(Figure Presented) Reduction of Co₂(CO)₆-stabilized bis-propargyl cations with cobaltocene occurs with high mesodiastereoselectivity (up to 97%), affording, upon decomplexation, meso-1,5-cyclodecadiynes, otherwise hardly accessible.

Full text of DOI:10.1021/jo901404f

pubs.acs.org/joc
Stereoselective Synthesis of meso-1,5-Cyclodecadiynes
Gagik G. Melikyan,* Ryan Spencer, and Edwin Abedi
Department of Chemistry and Biochemistry, California State University Northridge, Northridge,
California 91330-8262
gagik.melikyan@csun.edu
Received July 1, 2009
Reduction of Co2(CO)6-stabilized bis-propargyl cations with cobaltocene occurs with high meso-
diastereoselectivity (up to 97%), affording, upon decomplexation, meso-1,5-cyclodecadiynes, other-
wise hardly accessible.
Introduction
cobalt-complexed propargyl cations that benefit from a bent
geometry of the coordinated carbon-carbon triple bonds.6
The same methodology, via the respective bis-cationic
species, afforded 3,4-diphenyl-1,5-cyclodecadiyne in a 51%
yield, as a mixture of d,l- and meso-diastereomers (90:10).6
Recently, we reported on the diastereoselectivity of Co2(CO)6-
mediated, Zn-induced intramolecular cyclizations of topo-
logically diverse (0-, 4-, 3,4-, 3,4,5-)propargyl cations, affor-
ding 1,5-cyclodecadiynes.7 The d,l:meso ratios in cyclized
products varied in a wide range, from 80:20 to 54:46, with
d,l-diastereomers being the dominant isomers. In the case
of smaller rings, 1,5-cyclononadiyne8a and 1,5-cycloocta-
diyne,8b d,l-configuration is still highly preferred (>98%).
Analogously, trans-cyclized products were isolated from
the cationic bis(1,3-pentadienyl)irontricarbonyl complexes
when treated with zinc, a reducing agent.9 Overall, thermo-
dynamically more stable d,l-stereoisomers of 1,5-cyclodeca-
diynes appear to be formed predominantly, while meso-
counterparts, more crowded and less stable, remain elusive
synthetic targets. Herein we present the first stereoselective
synthesis of meso-1,5-cyclodecadiynes.
Synthesis of cyclic acetylenic compounds, in particular
1,5-cycloalkadiynes, has long been a synthetic challenge.1
Existing methods suffer from a low step economy, inherent
structural limitations, inability to control the stereoselecti-
vity of cyclization, and low overall yields.1,2 1,5-Cyclodeca-
diynes occupy a unique niche in synthetic chemistry given
their structural relationship to the cyclic enediynes, known
anticancer agents.3 They can act as the substrates for Cope
rearrangement4a and trans-annular C-C bond forming
reactions,4b,c serve as models for probing the through-space
electronic interaction of the alkyne moieties,5 and also
provide an entry to a variety of classes of organic compounds
(1,5-cyclodecadienes, 1,4-/1,5-cyclodecanediones, cyclode-
cynones). Parent 1,5-cyclodecadiyne was synthesized in
8 steps in a 1.9% overall yield.2a It is also accessible via
(1) (a) Gleiter, R.; Merger, R. In Modern Acetylene Chemistry; Stang P. J.,
Diederich F., Eds.; VCH Publishers: Weinheim, Germany, 1995; Chapter 8.
(b) Hirama, M. Pure Appl. Chem. 1997, 69, 525. (c) Scott, L. T.; DeCicco,
G. J.; Hyun, J. L.; Reinhardt, G. J. Am. Chem. Soc. 1985, 107, 6546.
(2) (a) Lange, G. L.; Hall, T. J. Org. Chem. 1974, 39, 3819. (b) Gleiter, R.;
Kratz, D.; Schehlmann, V. Tetrahedron Lett. 1988, 29, 2813. (c) Gleiter, R.;
Kratz, D.; Schafer, W.; Schehlmann, V. J. Am. Chem. Soc. 1991, 113, 9258.
(3) (a) Nicolaou, K. C.; Smith, A. L. In Modern Acetylene Chemistry; Stang
P. J., Diederich F., Eds.; VCH Publishers: Weinheim, Germany, 1995; Chapter 7,
pp 203-283. (b) Magnus, P. D. J. Am. Chem. Soc. 1995, 117, 12017. (c) Kraka,
E.; Cremer, D. J. Am. Chem. Soc. 2000, 122, 8245. (d) Basak, A.; Mandal, S.;
Bag, S. S. Chem. Rev. 2003, 103, 4077. (e) Grissom, J. W.; Gunawardena, G. U.;
Klingberg, D.; Huang, D. Tetrahedron 1996, 52, 6453.
(6) Melikyan, G. G.; Combs, R. C.; Lamirand, J.; Khan, M.; Nicholas,
K. M. Tetrahedron Lett. 1994, 363.
(7) Melikyan, G. G.; Wild, C.; Toure, P. Organometallics 2008, 27, 1569.
(8) (a) Melikyan, G. G.; Deravakian, A.; Myer, S.; Yadegar, S.;
Hardcastle, K. I.; Ciurash, J.; Toure, P. J. Organomet. Chem. 1999, 578,
68. (b) Melikyan, G. G.; Khan, M. A.; Nicholas, K. M. Organometallics
1995, 14, 2170.
(9) (a) Mahler, J. E.; Gibson, D. H.; Pettit, R. J. Am. Chem. Soc. 1963, 85,
3959. (b) Sapienza, R. S.; Riley, P. E.; Davis, R. E.; Pettit, R. J. Organomet.
Chem. 1976, 121, C35.
(4) (a) Iida, K.; Hirama, M. J. Am. Chem. Soc. 1994, 116, 10310.
(b) Wempe, M. F.; Grunwell, J. R. J. Org. Chem. 1995, 60, 2714. (c) Gleiter,
R.; Ritter, J.; Irngartinger, H.; Lichtenthaler, J. Tetrahedron Lett. 1991, 32, 2883.
(5) Gleiter, R.; Schafer, W. Acc. Chem. Res. 1990, 23, 369.
DOI: 10.1021/jo901404f
r
Published on Web 10/15/2009
J. Org. Chem. 2009, 74, 8541–8546 8541
2009 American Chemical Society

Melikyan et al.
JOCArticle
SCHEME 1. Cp2Co-Mediated Intramolecular Cyclization Affording meso-1,5-Cyclodecadiynes
TABLE 1. Diastereoselectivity vs. Reducing Agent
diastereoselectivity
diastereoselectivity
Cp2Co
Cp2Co
Zn7
bis-
propargyl
alcohol
substitution
pattern
bis-
cluster
decomplexation
product
entry
meso:d,l
dea
meso:d,l
dea
meso:d,l
deb
1
2
3
1
2
3
0
4-
3,4-
10
11
12
95:5
90:10
97:3
90
80
94
13
14
15
95:5
95:5
97:3
90
90
94
33:67
20:80
33:67
34
60
34
aMajor diastereomer is meso. bMajor diastereomer is d,l.
Results and Discussion
impact of intermolecular interaction, formation of high-
molecular assemblies, and H-atom abstraction from the
solvent. In the purely organic setting, the formation of
carbocycles is most complicated by the conformational free-
dom of the carbon chain, putting the reacting termini far
apart from each other. The presence of the bulky Co2(CO)6-
cores reduces the carbon chain flexibility and brings radical
centers into a closer proximity due to the bent structure of the
complexed triple bond.15,16 Intramolecular cyclization affor-
ded bis-complexes 10-12 with meso-diastereomers being
the dominant components. The quantitative data on diaster-
eoselectivity are summarized in Table 1. The highest stereo-
selectivity was observed in the case of 3,4-dimethoxy
derivative 12 (meso:d,l, 97:3);17 the presence of the 4-isopro-
pyl group somewhat lowered the stereoselectivity (11, meso:
d,l, 90:10) with the parent molecule 10 exhibiting an inter-
mediate level of stereocontrol (meso:d,l, 95:5). Decomplexa-
tion of the crude bis-complexes 10-12 with ceric ammonium
nitrate (6-9 equiv; -78 °C, acetone) afforded the organic
counterparts, meso-1,5-cyclodecadiynes 13-15. The stereo-
chemical composition remained nearly unchanged in the
Bis-propargyl alcohols 1-3 were synthesized in two steps
by the condensation of the respective benzaldehydes with
bis-lithio derivatives of 1,7-octadiyne,10 followed by the
treatment of organic bis-propargyl alcohols with a 2-fold
excess of dicobaltoctacarbonyl.11 Tetrafluoroboric acid7,12
was then used in a 12-fold excess to effect an elimination
reaction and precipitation of the requisite bis-cations 4-6
(Scheme 1). Reduction with cobaltocene was carried out with
an optimized molar ratio of propargyl diol:Cp2Co, 1:4,13 in
dichloromethane, at -78 °C. The transfer of a single electron
from cobaltocene, a 19e- reducing agent,14 toward cationic
centers, occurs rapidly even at low temperatures (-78 °C,
15 min), generating transient bis-radicals 7-9. Nearly con-
current generation of radical centers, at a high dilution,
promotes an intramolecular process while minimizing the
(10) Brandsma, L.; Verkruijsse, H. D. Synthesis of Acetylenes, Allenes and
Cumulenes; Elsevier: New York, 1981; p 80.
(11) Greenfield, H.; Sternberg, H. W.; Friedel, R. A.; Wotiz, J. H.;
Markby, R.; Wender, I. J. Am. Chem. Soc. 1956, 78, 120.
(12) (a) Muller, T. J. J. Eur. J. Org. Chem. 2001, 2021. (b) Teobald, B. J.
Tetrahedron 2002, 58, 4133. (c) Melikyan, G. G.; Nicholas, K. M. In Modern
Acetylene Chemistry; Stang P. J., Diederich F., Eds.; VCH Publishers: Weinheim,
Germany, 1995; Chapter 4.
(15) Dickson, R. S.; Fraser, P. J. Advances in Organometallic Chemistry
12; Academic Press: New York, 1974; p 323.
(13) Larger excess of cobaltocene, up to 100 equiv, resulted in a rapid
decomposition of the cyclized products, allegedly because of the overreduc-
tion of metal cores.
(14) (a) Tyler, D. R. Acc. Chem. Res. 1991, 24, 325. (b) Zavarine, I. S.;
Kubiak, C. P. Coord. Chem. Rev. 1998, 171, 419. For the X-ray structure of
cobaltocene see: (c) Antipin, M. Yu.; Boese, R.; Augart, N.; Schmid, G.
Struct. Chem. 1993, 4, 91.
(16) (a) McGlinchey, M. J.; Girard, L.; Ruffolo, R. Coord. Chem. Rev.
1995, 143, 331. (b) Amouri, H. E.; Gruselle, M. Chem. Rev. 1996, 96, 1077.
(c) Went, M. Adv. Organomet. Chem. 1997, 41, 69.
(17) Complex [μ-η2-1,10-bis(30,40-dimethoxyphenyl)-2,8-decadiyne]bis-
(dicobalthexacarbonyl) (16) was formed as a side product, supposedly by
the H-atom abstraction from methylene chloride. Its structure was confirmed
by independent synthesis by quenching bis-cation 6 with tributyltinhydride.
8542 J. Org. Chem. Vol. 74, No. 22, 2009

Melikyan et al.
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course of decomplexation;isolation (PTLC; silica gel) with
the concentration of meso-diastereomers varying in the
narrow range of 95-97% (Table 1). The methodology thus
developed allows one to circumvent an isolation of bis-
clusters 10-12, proceeding directly to decomplexation with-
out any additional purification.
The relative configuration of meso-12 was determined by
X-ray crystallography (Figure 1).18 The disposition of sub-
stituents around the central C9-C10 bond confirms the
stereochemical assignment and illustrates how strained the
ring system is adopting meso-configuration with bulky Co2-
(CO)6 cores present. The dihedral angle between propargyl
H-atoms is equal to 82.6° (H9A-C9-C10-H10A), shedding
light on a long observed, unusual NMR signature of these
hydrogens: each of them is represented by a singlet, some
0.2 ppm apart from each other (4.57-4.67 and 4.76-
4.86 ppm).7 Another two pairs of substituents around the
internal C9-C10 bond;alkyne moieties and phenyl groups;
are positioned under nearly right angles (C8-C9-C10-C1
86.7°; C19-C9-C10-C11 86.7°, respectively). For compar-
ison, in the d,l-diastereomer7 all three pairs of substituents
around the internal bond were found to be nearly eclipsed
(0.2°; 12.6°; 12.6°). The metal cores, Co2C2, represent dis-
torted tetrahedrons wherein the angles between Co-Co and
C-C triple bonds deviate, to a different degree, from the
expected perpendicular arrangement (78.4°; 85.6°).12,16,19
Curiously enough, in the case of d,l-diastereomer7 the level
of distortion was significantly higher and nearly identical for
both cluster moieties (73.1°; 73.4°). Other noteworthy struc-
tural features of meso-12 include the following: (a) a dis-
torted planarity of alkyne moieties (C3-C2-C1-C10 6.4°,
C6-C7-C8-C9 11.3°) that is less emphasized than that in the
d,l-diastereomer (10.4°, 12.4°);7 (b) a lengthened coordinated
FIGURE 1. ORTEP diagram of molecular structure of meso-12
˚
with 30% probability ellipsoids. Selected bond distances (A) and
angles (deg): C(1)-C(2) 1.317; C(7)-C(8) 1.304; C(9)-C(10) 1.568;
C(2)-C(1)-C(10) 144.7; C(7)-C(8)-C(9) 149.1; C(1)-C(2)-C(3)
141.0; C(6)-C(7)-C(8) 147.3; C(3)-C(2)-C(1)-C(10) 6.4; C(6)-
C(7)-C(8)-C(9) 11.3; C(3)-C(4)-C(5)-C(6) 66.6; H(9A)-
C(9)-C(10)-H(10A) 82.6; C(1)-C(10)-C(9)-H(9A) 30.4; C(8)-
C(9)-C(10)-H(10A) 160.2; C(8)-C(9)-C(10)-C(1) 86.7; C(8)-
C(9)-C(10)-C(11) 45.0; C(19)-C(9)-C(10)-C(11) 86.7.
˚
˚
C-C triple bond (1.304-1.317 A vs. 1.21 A for the free
ligand) and bent geometry for coordinated alkyne units
(144-149°), both indicative of the nature of bonding between
transition metal and π-bonded unsaturated ligand;12,16,19
and (c) inequivalency of alkyne units attested by the bond
angles around the coordinated triple bonds (C1-C2-C3
141.0°; C2-C1-C10 144.7°; C6-C7-C8 147.3°; C7-C8-C9
149.1°); the angles are somewhat higher, but still comparable
with those reported for d,l-diastereomer (140.4°; 141.0°;
145.1°; 148.6°).7
The meso-configuration of diyne 15 was independently
established by means of X-ray crystallography (Figure 2).18
The removal of the bulky metal clusters was accompanied by
the significant structural and conformational changes. Thus,
hydrogen atoms around the central C1-C2 bond are posi-
tioned under 46.3° (H1-C1-C2-H2), as opposed to a nearly
perpendicular arrangement (82.6°) in bis-cluster 12. Analo-
gously, phenyl groups are arranged nearly gauche to each
other (C11-C1-C2-C19 49.2°), as well as the alkyne moieties
are (C10-C1-C2-C3 44.8°). Bond angles around the triple
FIGURE 2. ORTEP diagram of molecular structure of meso-15
˚
with 30% probability ellipsoids. Selected bond distances (A) and
angles (deg): C(3)-C(4) 1.196; C(9)-C(10) 1.198; C(1)-C(2) 1.587;
C(9)-C(10)-C(1) 168.6; C(2)-C(3)-C(4) 168.9; C(3)-C(4)-C(5)
170.0; C(8)-C(9)-C(10) 168.6; C(2)-C(3)-C(4)-C(5) 2.4; C(8)-
C(9)-C(10)-C(1) 9.6; C(5)-C(6)-C(7)-C(8) 127.5; H(1)-C(1)-
C(2)-H(2) 46.3; C(10)-C(1)-C(2)-H(2) 160.9; C(3)-C(2)-
C(1)-H(1) 69.8; C(10)-C(1)-C(2)-C(3) 44.8; C(11)-C(1)-
C(2)-C(3) 174; C(11)-C(1)-C(2)-C(19) 49.2.
bond lie within the expected range of 168-170°; planarity of
alkyne moieties is also improved due to breaking away from
the metal bondage (meso-15 C2-C3-C4-C5 2.4°; C8-C9-
C10-C1 9.6°; meso-12 C3-C2-C1-C10 6.4°, C6-C7-C8-C9
11.3°). Dispositions of phenyl groups and vicinal H-atoms
are best defined as gauche- and anti-spatial arrangements
(C11-C1-C2-H2 69.9°; C19-C2-C1-H1 165.4°). In bis-
cluster 12, due to the presence of the bulky metal cores,
one of those angles undergoes a significant change
(C19-C9-C10-H10 28.5°), while the other remains nearly
(18) (a) APEX II, Bruker AXS, Inc., Analytical X-ray Systems, 5465 East
Cheryl Parkway, Madison, WI 53711-5373, 2005. (b) SAINT, Version 6.45A,
Bruker AXS, Inc., Analytical X-ray Systems, 5465 East Cheryl Parkway,
Madison, WI 53711-5373, 2003. (c) A short history of SHELX: Sheldrick,
G. M. Acta Crystallogr. 2008, A64, 112-122. (d) Wilson, A. J. C., Ed. Inter-
national Tables for X-ray Crystallography; Kynoch: Birmingham, England,
1992; Vol. C, Tables 6.1.1.4 (pp 500-502) and 4.2.6.8 (pp 219-222).
(19) Mingos, D. M. P. In Comprehensive Organometallic Chemistry;
Wilkinson, G., Stone, F. G. A., Abel, E. W., Eds.; N.-Y.; Pergamon:
New York, 1982; Vol. 3, p 1.
J. Org. Chem. Vol. 74, No. 22, 2009 8543

Melikyan et al.
JOCArticle
unaltered (C11-C10-C9-H9 162.2°). Overall, in the course
of the decomplexation, the meso-stereoisomer mostly retains
its spatial arrangement with cis-phenyl groups occupying
the axial and equatorial positions of the 10-membered ring
(12 C19-C9-C10-C11 86.7°; 15 C11-C1-C2-C19 49.2°).
For comparison, the respective d,l-diastereomer7 underwent
a drastic change when released from a metal bondage: phenyl
groups being nearly eclipsed in the bis-cluster (0.2°) sprang
up into diaxial positions in the organic molecule (158.3°).7
Stereoselective formation of meso-diastereomers 13-15
could not have been predicted based on the literature pre-
cedence.20-22 In intramolecular cyclization reactions,7-9 the
respective d,l-diastereomers;8-, 9-, and 10-membered;are
formed either exclusively, or with high stereoselectivity
(d,l 95-100%). In intermolecular coupling reactions, sys-
tematic studies on cobalt-complexed propargyl radicals21
revealed the stereochemical dominance of d,l-diastereomers
with a variety of topologically and functionally diverse
substrates. With zinc acting as a reducing agent,7 the ratio
of meso- and d,l-1,5-cyclodecadiynes varies from 33:67 to
20:80 (Table 1). Replacing zinc with Cp2Co allowed us to
fully reverse the stereochemical preference for d,l-configura-
tion and achieve a high level of meso-diastereoselectivity
(90-97%; Table 1). Thus, for 1,5-cyclodecadiyne 10 with
unsubstituted aromatic rings, the 33:67 diastereomeric ratio
of meso:d,l converts to 95:5 (Table 1; entry 1). The impact of
the reducing agent is more pronounced for 4-isopropyl
derivative 11: the highest observed d,l-diastereoselectivity
(meso:d,l 20:80)7 completely reverses (meso:d,l 90:10) with
preponderant formation of meso-diastereomer (Table 1;
entry 2). It is notable that cyclization reactions occur under
kinetic control, producing thermodynamically less favored
stereoisomers. Thus, meso-diastereomer 10 is higher in en-
ergy;by 5.6 kcal/mol;than its d,l-counterpart (PCModel,
v. 9.1). In a separate set of experiments, the coupling reaction
was proven irreversible: no interconversion was detected
under standard conditions with both d,l- and meso-12 pre-
serving their configurational integrity. Over the two steps
(cation generation/cyclization, decomplexation), the total
yields of meso-1,5-cyclodecadiynes 13-15 vary in the range
of 28-36%. With zinc as a reducing agent, the yields of
cyclization products;containing predominantly d,l-diaster-
eomers;fell within the same range (24-39%).7 In com-
parison, by using purely organic means, assembling a
10-membered ring with 1,5-disposed triple bonds can be
done in 8 steps, with a low 1.9% overall yield.2a
The disparity in the stereochemical outcome of radical
coupling reactions;with zinc and Cp2Co as alternative
reducing agents;was first observed by us21f in intermolecu-
lar cross-coupling reactions. In particular, replacing Zn with
Cp2Co decreased the level of d,l-diastereoselectivity in the
case of both terminal and γ-substituted propargyl alcohols,
by 5-18% and 4-15%, respectively.21f Apparently, the rise
in the concentration of the respective meso-diastereomers
points out that Cp2Co does generally favor the meso-config-
uration. In intermolecular reactions the impact is incremen-
tal, while in intramolecular cyclizations it amounts to a full
reversal of the stereochemical outcome.
The observed stereochemical switch might be derived from
the combination of several factors, such as conformational
equilibrium, reaction temperature, reduction rate, ion-
radical interactions, as well as homogeneity of the reaction
mixture. The requisite, preorganized bis-cations can be
represented by two pseudocyclic conformations, A and B,
around the propargylic bond (Figure 3). The reduction with
Cp2Co, a 19e- species,14 rapidly occurs at -78 °C, generat-
ing bis-radicals C and D, respectively. To examine if the
observed reversal of stereoselectivity is a temperature effect,
the reduction reaction was carried out at various tempera-
tures (-40, 0, þ40 °C) and diastereomeric composition was
determined for metal complex 10 and decomplexation pro-
duct 13 (Table 2). As the experimental data indicate, diaster-
eoselectivity is, in fact, dependent upon temperature,
switching from meso:d,l 95:5 at -78 °C to 42:58 at þ40 °C
(entries 1 and 4). The intermediate data;87:13 and 58:42 at
-40 and 0 °C, respectively;further attest to the trend
observed (entries 2 and 3; Table 2). Most importantly,
adding a powerful reducing agent at higher temperatures,
up to þ40 °C, did not compromise the total yield of the
diastereomeric mixtures, further validating the assumption
that the reversal of stereoselectivity does in fact take place.
More studies are in progress to understand the intimate
nature of the temperature effect observed, in particular the
dependence of conformational equilibria and rotational
freedoms in cations (A, B) and radicals (C, D) upon reaction
temperature, as well as the potential impact of cobaltocene-
derived counterion (Cp2CoþBF4-).
(20) (a) Organometallic Radical Processes; Trogler, W. C., Ed.; Elsevier:
Amsterdam, The Netherlands, 1990; Chapters 3, 4, 9, and 10. (b) Astruc, D. Acc.
Chem. Res. 1991, 24, 36. (c) Astruc, D. Electron Transfer and Radical Processes
in Transition-Metal Chemistry; VCH: New York, 1995; Chapters 3, 5, and 6.
(d) Torraca, K. E.; McElwee-White, L. Coord. Chem. Rev. 2000, 206-207, 469.
(e) Melikyan, G. G. In Frontiers in Organometallic Chemistry; Cato, M. A., Ed.;
Nova Science Publishers: New York, 2006; p 155.
(21) (a) Melikyan, G. G.; Deravakian, A. J. Organomet. Chem. 1997, 544,
143. (b) Melikyan, G. G.; Bright, S.; Monroe, T.; Hardcastle, K. M.; Ciurash,
J. Angew. Chem., Int. Ed. 1998, 37, 161. (c) Melikyan, G. G.; Sepanian, S.;
Riahi, B.; Villena, F.; Jerome, J.; Ahrens, B.; McClain, R.; Matchett, J.;
Scanlon, S.; Abrenica, E.; Paulsen, K.; Hardcastle, K. I. J. Organomet. Chem.
2003, 683, 324. (d) Melikyan, G. G.; Villena, F.; Sepanian, S.; Pulido, M.;
Sarkissian, H.; Florut, A. Org. Lett. 2003, 5, 3395. (e) Melikyan, G. G.;
Villena, F.; Florut, A.; Sepanian, S.; Sarkissian, H.; Rowe, A.; Toure, P.;
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Organometallics 2006, 25, 4680. (f) Melikyan, G. G.; Floruti, A.; Devletyan,
L.; Toure, P.; Dean, N.; Carlson, L. Organometallics 2007, 26, 3173.
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(22) (Pentadienyl radical)Fe(CO)3: (a) Pearson, A. J.; Chen, Y.-S.;
Daroux, M. L.; Tanaka, A. A.; Zettler, M. J. Chem. Soc., Chem. Commun.
1987, 155. (b) Hwang, W. S.; Liao, R. L.; Horng, Y. L.; Ong, C. W. Polyhedron
1989, 8, 479. (Propargyl radical)Cp2Mo2(CO)4: (c) Le Berre-Cosquer, N.;
Kergoat, R.; L'Haridon, P. Organometallics 1992, 11, 721. (Benzyl radical)Cr-
(CO)3: (d) Top, S.; Jaouen, G. J. Organomet. Chem. 1987, 336, 143. Ferrocenyl
radical: (e) Cais, M.; Eisenstadt, A. J. Chem. Soc. 1965, 30, 1148. (f) Cais, M.;
Askhenazi, P.; Dani, S.; Gottlieb, J. J. Organomet. Chem. 1977, 540, 127.
CpCο(η5-C7H9)-radical: (g) Geiger, W. E.; Genneth, Th.; Lane, G. A. Organo-
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Conclusions
Reduction of cobalt-complexed bis-propargyl alcohols with
cobaltocene provides an easy, two-step access to meso-1,5-
cyclodecadiynes with an excellent stereoselectivity (90-97%).
To the best of our knowledge, this method represents the first
synthetically viable procedure for the synthesis of this class of
organic compounds with meso-configuration. The method
contributes to the synthetic repertoire of radical chemistry
mediated by transition metals. Its use as a key step in total
synthesis of complex molecular assemblies and as a novel
carbon framework in drug development can be envisioned.
8544 J. Org. Chem. Vol. 74, No. 22, 2009

Melikyan et al.
JOCArticle
FIGURE 3. Conformational equilibrium of the cobalt-complexed bis-cations (A, B) and bis-radicals (C, D).
TABLE 2. Diastereoselectivity as a Function of Temperature
Ce(NH4)2(NO3)6 (219 mg, 0.4 mmol; molar ratio 1:4 assuming
100% yield of 10) in acetone (4 mL, degassed; N2, -78 °C).
Upon addition (4 min), the reaction mixture was stirred at -78
°C for 15 min, and then at -50 °C for 30 min. An additional
portion of Ce(NH4)2(NO3)6 (109.6 mg, 0.2 mmol) was added
(degassed acetone, 2 mL) dropwise at -78 °C (2 min), and the
reaction mixture was stirred for 15 min, then at -50 °C for 30
min (TLC control). A degassed saturated solution of NaClaq (20
mL) was added at -78 °C, and the mixture was transferred to a
separatory funnel and extracted with ether (2 ꢀ 15 mL). The
˚
diastereoselectivity
combined organic layers were dried (molecular sieves 4 A),
organic solvents were removed under reduced pressure, and
the crude mixture was fractionated by preparative TLC (10:1,
PE:E) to afford a mixture of meso-13 and dl-13 (NMR: meso-13:
dl-13, 95:5) as a light yellow solid (10.3 mg, 36.3%). Mp 93-94
°C (sealed capillary; dried at 58 deg/1 mm/5 h). TLC (5:1 PE:E)
Rf 0.53. Spectral characteristics are identical with those reported
earlier.7
bis-cluster 10
meso:d,l
13
meso:d,l
yield, %
(over 2 steps)
entry
temp, °C
1
2
3
4
-78
-40
0
þ40
95:5
95:5
36.3
39.7
45.0
44.0
87:13
58:42
42:58
89:11
60:40
41:59
Under analogous conditions, at -40, 0 and þ40 °C the ratios
and yields of meso-13 and dl-13 were equal to 89:11 (39.7%),
60:40 (45.0%), and 41:59 (44.0%), respectively.
meso-3,4-Bis(40-isopropylphenyl)-1,5-cyclodecadiyne (14). Under
an atmosphere of nitrogen, a solution of the bis-alcohol 2 (97.4 mg,
0.1 mmol) in dry ether (15 mL) was added dropwise (15 min) to a
Experimental Section
meso-3,4-Diphenyl-1,5-cyclodecadiyne (13). Under an atmo-
sphere of nitrogen, a solution of the bis-alcohol 1 (89.0 mg,
0.1 mmol) in dry ether (15 mL) was added dropwise (15 min) to
solution of HBF4 Me2O (161 mg, 1.20 mmol) in dry ether (20 mL)
a solution of HBF4 Me2O (161 mg, 1.20 mmol) in dry ether
3
3
at -20 °C. The reaction mixture was stirred at -20 °C for 15 min,
the ethereal layer was removed, and the bis-cation 5 was washed
with dry ether (3 ꢀ 15 mL) at -10 °C. The residual amount of ether
was removed under reduced pressure, and the cation was dissolved
in dry CH2Cl2 (15 mL) at -78 °C. A solution of Cp2Co (75.6 mg,
0.4 mmol) in CH2Cl2 (5 mL) was added dropwise (2 min) to the
reaction flask at -78 °C and the mixture was stirred for 15 min
(TLC control). The crude mixture was filtered through a short bed
of Florisil (1 cm), and organic solvents were stripped away under
reduced pressure (NMR: meso-11:d,l-11 90:10). The residue was
dissolved in acetone (10 mL, degassed) and treated with a solution
of Ce(NH4)2(NO3)6 (219 mg, 0.4 mmol; molar ratio 1:4 assuming
(20 mL) at -20 °C. The reaction mixture was stirred at -20 °C
for 15 min, the ethereal layer was removed, and the bis-cation 4
was washed with dry ether (2 ꢀ 15 mL) at -30 °C. The residual
amount of ether was removed under reduced pressure, and the
cation was dissolved in dry CH2Cl2 (15 mL) at -78 °C. A
solution of Cp2Co (75.6 mg, 0.4 mmol) in CH2Cl2 (5 mL) was
added dropwise (2 min) to the reaction flask at -78 °C and the
mixture was stirred for 15 min (TLC control). The crude mixture
was filtered through a short bed of Florisil (1 cm), and
organic solvents were stripped away under reduced pressure
(NMR: meso-10:d,l-10 95:5). The residue was dissolved in
acetone (10 mL, degassed) and treated with a solution of
J. Org. Chem. Vol. 74, No. 22, 2009 8545

Melikyan et al.
JOCArticle
100% yield of 11) in acetone (4 mL, degassed). Upon addition
(4 min), the reaction mixture was stirred at -78 °C for 15 min, then
at -50 °C for 30 min. An additional portion of Ce(NH4)2(NO3)6
(219 mg, 0.4 mmol) was dissolved in acetone (4 mL, degassed),
added dropwise (4 min) at -78 °C to the reaction mixture, stirred
for 15 min, then stirred at -50 °C for 30 min (TLC control). The
mixture was treated (-78 °C, N2) with a degassed saturated
solution of NaClaq (20 mL), transferred to a separatory funnel,
and extracted with ether (2 ꢀ 15 mL). The combined organic layers
stirred at -50 °C for 30 min (TLC control). The mixture was
treated (-78 °C, N2) with a degassed saturated solution of NaClaq
(20 mL), transferred to a separatory funnel, and extracted
with ether (2 ꢀ 15 mL). The combined organic layers were dried
˚
(molecular sieves 4 A), organic solvents were removed under
reduced pressure, and the crude mixture was fractionated by
preparative TLC (PE) to afford meso-15 (11.8 mg, 28.1% over
two steps; meso-15:d,l-15 97:3) as a yellow amorphous solid. TLC
(E) Rf 0.43 (PMA); 1H NMR (400 MHz, CDCl3) δ 1.96 (m, 4H),
2.33 (m, 4H), 3.67 (s, 6H), 3.80 (s, 6H), 4.10 (s, 2H), 6.57 (ABC-
spectrum, JH(A)-H(B) = 8.0 Hz, JH(B)-H(C) = 2.0 Hz, 6H); 13C
NMR (100 MHz, C6D6) δ 21.1, 28.0, 46.0, 55.6, 55.8, 83.2, 88.7,
110.4, 112.0, 112.1, 120.8, 130.3, 147.9, 148.1; HRMS (TOF) m/z
calcd for C26H29O4 [MH]þ 405.2060, found 405.2070. Single
crystals suitable for X-ray structure analysis were obtained by
methanol vapor diffusion into a solution of meso-15 in EA (þ5 °C,
3 days).
˚
were dried (molecular sieves 4 A), organic solvents were removed
under reduced pressure, and the crude mixture was fractionated by
preparative TLC (20:1 PE:E) to afford a mixture of meso-14 and dl-
14 (NMR: meso-14:d,l-14, 95:5) (10.1 mg, 28.0%) as a light yellow
oil. TLC (10:1 PE:E) Rf 0.58. Spectral characteristics are identical
with those reported earlier.7 13C NMR (100 MHz, CDCl3) δ 21.1,
24.1, 24.2, 28.0, 33.8, 45.9, 83.3, 88.7, meso- 125.6, d,l- 126.5, 127.8,
meso- 128.6, 135.2, d,l- 138.6, meso- 147.4.
[μ-η2-1,10-Bis(30,40-dimethoxyphenyl)-2,8-decadiyne]bis(dicobal-
meso-[μ-η2-3,4-Bis(30,40-dimethoxyphenyl)-1,5-cyclodecadiyne]-
bis(dicobalthexacarbonyl) (12) and meso-3,4-Bis(30,40-dimethoxy-
phenyl)-1,5-cyclodecadiyne (15). Under an atmosphere of nitrogen,
a solution of the bis-alcohol 3 (101 mg, 0.1 mmol) in dry ether
thexacarbonyl) (16). Under an atmosphere of nitrogen, HBF4
3
Me2O (32.2 mg, 0.24 mmol) was added dropwise (30 s) to a
solution of the bis-alcohol 3 (40.2 mg, 0.04 mmol) in dry ether
(10mL) at0°C and the mixture was stirred for 15 min. The ethereal
layer was removed, then the bis-cation was washed with dry ether
(2 ꢀ 15 mL) at -30 °C and suspended in ether (10 mL).
Tributyltinhydride (46.6 mg, 0.16 mmol) was added dropwise
(30 s) at 0 °C and the mixture was stirred for 30 min (TLC control).
The crude mixture was concentrated under reduced pressure and
fractionated on preparative TLC (1:1 PE:E) to afford 16 (27.2 mg,
(15 mL) was added dropwise (15 min) to a solution of HBF4
3
Me2O (161 mg, 1.20 mmol) in dry ether (20 mL) at -20 °C. The
reaction mixture was stirred at -20 °C for 15 min, the ethereal layer
was removed, and the bis-cation 6 was washed with dry ether (2 ꢀ
15 mL) at -30 °C. The residual amount of ether was removed
under reduced pressure, and the cation was dissolved in dry CH2-
Cl2 (15 mL) at -78 °C. A solution of Cp2Co (75.6 mg, 0.4 mmol) in
CH2Cl2 (5 mL) was added dropwise (2 min) to the reaction flask at
-78 °C and the mixture was stirred for 15 min (TLC control). The
crude mixture was filtered through a short bed of Florisil (1 cm),
and organic solvents were stripped away under reduced pressure
(NMR meso-12:d,l-12:1617 82:3:15, meso-12:d,l-12 97:3). Major
diastereomer;meso-12;can be isolated by preparative TLC (1:2
PE:CH2Cl2, 2 runs). Spectral characteristics are identical with
those reported earlier.7 Single crystals suitable for X-ray structure
analysis were obtained by methanol vapor diffusion into a solution
of meso-12 in CH2Cl2 (þ5°C, 1 day). The residue (meso-12 þ d,l-12
þ 16) was dissolved in acetone (10 mL, degassed) and treated with
a solution of degassed Ce(NH4)2(NO3)6 (438 mg, 0.8 mmol; molar
ratio of 1:8 assuming 100% yield of 12) in acetone (8 mL, degassed;
N2, -78 °C). Upon addition (10 min), the reaction mixture was
stirred at -78 °C for 15 min, then at -50 °C for 30 min. An
additional portion of Ce(NH4)2(NO3)6 (54.8 mg, 0.1 mmol) dis-
solved in acetone (1 mL, degassed) was added dropwise (1 min) at
-78 °C, and the reaction mixture was stirred for 15 min, then
1
70.1%) as a brown-red oil. TLC (CH2Cl2) Rf 0.45; H NMR
(400 MHz, CDCl3) δ 1.81 (m, 4H), 2.88 (m, 4H), 3.87 (s, 6H), 3.89
(s, 6H), 4.05 (s, 4H), 6.76-7.88 (m, 6H); HRMS (TOF) m/z calcd
for C38H30O16ClCo4 [M þ Cl]- 1012.8556, found 1012.8548.
Acknowledgment. This material is based upon work sup-
ported by the National Science Foundation under CHE-
0707865. The authors are also greatly indebted to the Office
of Graduate Studies, Research and International Programs,
and University Corporation, California State University
Northridge for their generous support.
Supporting Information Available: 1H and 13C NMR spec-
tra for products, tables of crystallographic details, bond dis-
tances and angles, atomic coordinates, and equivalent isotropic
displacement parameters, as well as torsion angles for meso-12
and meso-15 (CIF format). This material is available free of
charge via the Internet at http://pubs.acs.org.
8546 J. Org. Chem. Vol. 74, No. 22, 2009