Cobalt(diamine)-catalyzed cross-coupling reaction of alkyl halides with arylmagnesium reagents: Stereoselective constructions of arylated asymmetric carbons and application to total synthesis of AH13205

Article abstract of DOI:10.1021/ja057560o

A cobalt-diamine complex catalyzes the cross-coupling reactions of primary and secondary alkyl halides with aryl Grignard reagents. It is confirmed that oxidative addition of alkyl halide to cobalt proceeds via a radical process. Optically pure Ueno-Stork halo acetals undergo diastereoselective cross-coupling reactions, the products of which are transformed into optically active THF derivatives. A sequential radical cyclization/arylation reaction under cobalt catalysis provides extremely short access to a synthetic prostaglandin AH13205.

Full text of DOI:10.1021/ja057560o

Published on Web 01/20/2006
Cobalt(diamine)-Catalyzed Cross-coupling Reaction of Alkyl
Halides with Arylmagnesium Reagents: Stereoselective
Constructions of Arylated Asymmetric Carbons and
Application to Total Synthesis of AH13205
Hirohisa Ohmiya, Hideki Yorimitsu,* and Koichiro Oshima*
Contribution from the Department of Material Chemistry, Graduate School of Engineering,
Kyoto UniVersity, Kyoto-daigaku Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
Received November 5, 2005; E-mail: yori@orgrxn.mbox.media.kyoto-u.ac.jp; oshima@orgrxn.mbox.media.kyoto-u.ac.jp
Abstract: A cobalt-diamine complex catalyzes the cross-coupling reactions of primary and secondary
alkyl halides with aryl Grignard reagents. It is confirmed that oxidative addition of alkyl halide to cobalt
proceeds via a radical process. Optically pure Ueno-Stork halo acetals undergo diastereoselective cross-
coupling reactions, the products of which are transformed into optically active THF derivatives. A sequential
radical cyclization/arylation reaction under cobalt catalysis provides extremely short access to a synthetic
prostaglandin AH13205.
Table 1. Cobalt-Diamine-Catalyzed Cross-coupling Reaction
Introduction
Transition-metal-catalyzed cross-coupling reactions are in-
dispensable tools for the construction of organic molecules. Use
of alkyl halides that can suffer from â-elimination in cross-
coupling reactions is now attracting increasing attention as a
new repertoire of cross-coupling strategy.1 Especially, coupling
of secondary2 and tertiary2d,2e,2q,2r alkyl halides with organo-
metallic reagents is a challenging target to establish the uni-
versality of cross-coupling reactions.
During the course of our study on cobalt-catalyzed cross-
coupling reactions,2q,2r,3 we found that catalytic amounts of
cobalt(II) chloride and diamine (R,R)-1 promote cross-coupling
reactions of alkyl halides with arylmagnesium reagents (Table
1). This will significantly expand the utility of cobalt as a
(1) (a) Frisch, A. C.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674-688.
(b) Terao, J.; Kambe, N. J. Synth. Org. Chem. Jpn. 2004, 62, 1192-1204.
(c) Netherton, M. R.; Fu, G. C. AdV. Synth. Catal. 2004, 346, 1525-1532.
(d) Fu¨rstner, A.; Martin, R. Chem. Lett. 2005, 34, 624-629.
(2) Cu: (a) Burns, D. H.; Miller, J. D.; Chan, H.-K.; Delaney, M. O. J. Am.
Chem. Soc. 1997, 119, 2125-2133. Pd: (b) Sustmann, R.; Lau, J.; Zipp,
M. Tetrahedron Lett. 1986, 27, 5207-5210. (c) Castle, P. L.; Widdowson,
D. A. Tetrahedron Lett. 1986, 27, 6013-6016. (d) Ishiyama, T.; Abe, S.;
Miyaura, N.; Suzuki, A. Chem. Lett. 1992, 691-694. (e) Donkervoort, J.
G.; Vicario, J. L.; Jastrzebski, J. T. B. H.; Gossage, R. A.; Cahiez, G.; van
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G. C. J. Am. Chem. Soc. 2003, 125, 14726-14727. (g) Zhou, J.; Fu, G. C.
J. Am. Chem. Soc. 2004, 126, 1340-1341. (h) Powell, D. A.; Fu, G. C. J.
Am. Chem. Soc. 2004, 126, 7788-7789. (i) Powell, D. A.; Maki, T.; Fu,
G. C. J. Am. Chem. Soc. 2005, 127, 510-511 (j) Fisher, C.; Fu, G. C. J.
Am. Chem. Soc. 2005, 127, 4594-4595. (k) Arp, F. O.; Fu, G. C. J. Am.
Chem. Soc. 2005, 127, 10482-10483. Fe: (l) Nakamura, M.; Matsuo, K.;
Ito, S.; Nakamura, E. J. Am. Chem. Soc. 2004, 126, 3686-3687. (m)
Nagano, T.; Hayashi, T. Org. Lett. 2004, 6, 1297-1299. (n) Fu¨rstner, A.;
Martin, R. Angew. Chem., Int. Ed. 2004, 43, 3955-3957. (o) Nakamura,
M.; Ito, S.; Matsuo, K.; Nakamura, E. Synlett 2005, 1794-1798. (p)
Bedford, R. B.; Bruce, D. W.; Frost, R. M.; Goodby, J. W.; Hird, M. Chem.
Commun. 2004, 2822-2823. Co: (q) Tsuji, T.; Yorimitsu, H.; Oshima, K.
Angew. Chem., Int. Ed. 2002, 41, 4137-4139. (r) Ohmiya, H.; Tsuji, T.;
Yorimitsu, H.; Oshima, K. Chem. Eur. J. 2004, 10, 5640-5648.
(3) (a) Wakabayashi, K.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2001,
123, 5374-5375. (b) Ohmiya, H.; Yorimitsu, H.; Oshima, K. Chem. Lett.
2004, 33, 1240-1241. (c) Mizutani, K.; Yorimitsu, H.; Oshima, K. Chem.
Lett. 2004, 33, 832-833.
a When the reaction was performed on a 10 mmol scale, an 87% yield
of the product was obtained. b CoCl2 (10 mol %) and (R,R)-1 (36 mol %)
were used. c No cyclopentane ring was observed.
catalyst.4 Specifically, the present cobalt-diamine-catalyzed
method allows us to arylate secondary alkyl halides whereas
our previous arylation reaction3a is applicable to the reaction
of primary alkyl halides.
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Cobalt-Catalyzed Cross-coupling Reaction
A R T I C L E S
Table 2. Ligand Effect
Results and Discussion
Scope and Limitation. Diamine 1 (0.06 mmol)5 was added
to a suspension of CoCl2 (0.05 mmol) in THF (3 mL) to form
a clear-blue solution. Substrate (1.0 mmol) and then a Grignard
reagent (1.2 mmol, 1 M THF solution) were added over 5 s at
0 °C. An exothermic reaction immediately took place. After
the mixture was stirred at 25 °C for 15 min, the usual workup
followed by silica gel column purification afforded the corre-
sponding coupling product. Representative examples are listed
in Table 1. Several comments are worth noting: (1) Not only
primary alkyl halides but also secondary ones underwent the
cross-coupling reaction. In contrast, phenylation took place only
with primary alkyl halides under our previous cobalt-diphos-
phine catalysis.3a Unfortunately, neither tert-butyl bromide nor
iodide couple with any aryl Grignard reagents tested. (2) Alkyl
iodides and bromides are the choice of the coupling partner.
The reaction of 1-chlorooctane resulted in poor yield (entry 6).
(3) The reaction was readily scalable. Treatment of 10 mmol
of bromocyclohexane with phenylmagnesium bromide (12
mmol) in the presence of 1 (0.6 mmol) and CoCl2 (0.5 mmol)
in THF (30 mL) in a similar manner provided cyclohexylben-
zene in 87% yield (entry 2). (4) An alkenylmagnesium reagent
(entry 9) as well as arylmagnesium reagents were available for
the cross-coupling reaction. (5) Functional groups such as an
ester linkage were compatible. (6) Allylic bromide also under-
went the phenylation reaction (entry 15), wherein no cyclization
was observed (vide infra).2n On the other hand, a cyclic product
was obtained exclusively in the reaction of 6-iodo-1-undecene
to yield 1-benzyl-2-pentylcyclopentane (diastereomer ratio )
3:1) in good yield (eq 1).2l,2n,2o,2q,2r,3a The relevant bromide was
less reactive.
Scheme 1. Justification of the Existence of Carbon-centered
Radicals; Conditions Are the Same as Those in Table 1
radical processes (Scheme 1): (1) The phenylations of endo-
and exo-2 yielded 3 with the same endo/exo selectivity, which
indicates the existence of a planer carbon center with no origi-
nal stereochemical information. (2) The reaction of 4 with
phenylmagnesium bromide yielded cyclic product 5 in 80%
yield. Notably, no enantioselectivity for the cyclization was
observed. We tested several other cyclization reactions un-
der the chiral cobalt catalysis. However, all the reactions ex-
hibited no enantioselectivity. The complete lack of the enan-
tioselectivity implies that the 5-exo-trig cyclization step pro-
ceeds via a free radical mechanism, not via enantioface-
discriminating intramolecular carbocobaltation. (3) Some enan-
tioselectivity was observed in the phenylations of cyclic halides
such as 6. The enantioselection would take place upon recom-
bination of a cobalt complex with a planer carbon-centered
radical.2q,2r,3a Unfortunately, no kinetic resolution of 6 was
observed.
Cobalt-Catalyzed Highly Stereoselective Arylations and
Their Applications. Next we turned our attention to the
coupling reaction of Ueno-Stork halo acetals6 that have a
stereogenic center next to the halogenated carbons (Table 3).
The coupling reactions proceeded smoothly without suffering
from possible â-alkoxy elimination. Virtually no stereoselectivity
was observed in the reactions of tetrahydropyran derivatives
(entries 1 and 2). On the other hand, the phenylations of
tetrahydrofurans were highly diastereoselective (entries 3 and
The diamine (R,R)-1 is the best ligand among ligands we
tested (Table 2). N,N,N′,N′-Tetramethylethylenediamine and (1S,
2S)-N,N,N′,N′-tetramethyl-1,2-diphenylethylenediamine were
less effective (entries 2 and 3). The difference in efficiency
would originate from the very subtle changes in the conforma-
tions, bite angles, and/or steric hindrance of the diamine ligands.
Naturally, a shorter or a longer methylene tether completely
deactivated the cobalt catalysts (entries 4 and 5). The reactions
with the aid of primary 1,2-cyclohexanediamine (entry 7), a
bidentate phosphine (entry 8), and a pybox ligand (entry 9)
provided none of the coupling product.
Evidence of Carbon-Centered Radical Intermediates. The
intermediacy of a carbon-centered radical in the arylation
reaction is strongly supported by the following new facts, in
addition to our accumulative efforts to certify cobalt-mediated
(4) For recent reports on cobalt-catalyzed coupling reactions, see: (a) Cahiez,
G.; Avedissian, H. Tetrahedron Lett. 1998, 39, 6159-6162. (b) Avedissian,
H.; Be´rillon, L.; Cahiez, G.; Knochel, P. Tetrahedron Lett. 1998, 39, 6163-
6166. (c) Nishii, Y.; Wakasugi, K.; Tanabe, Y. Synlett 1998, 67-69. (d)
Korn, T. J.; Knochel, P. Angew. Chem., Int. Ed. 2005, 44, 2947-2951. (e)
Sezen, B.; Sames, D. Org. Lett. 2003, 5, 3607-3610. (f) Gomes, P.;
Gosmini, C.; Pe´richon, J. Org. Lett. 2003, 5, 1043-1045. (g) Amatore,
M.; Gosmini, C.; Pe´richon, J. Eur. J. Org. Chem. 2005, 989-992.
(5) Racemic diamine 1 worked as well.
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J. AM. CHEM. SOC. VOL. 128, NO. 6, 2006 1887

A R T I C L E S
Ohmiya et al.
Table 3. Diastereoselective Cross-coupling of Halo Acetals
Scheme 4. Synthesis of a Corey Lactone Analogue
entry
n
X
R
yield
trans/cis
1
2
3
4
1
1
0
0
I
I
Br
Br
Me
iPr
83%
81%
82%
80%
51:49
60:40
95:5
Me
iPr
96:4
ing optically pure 2-alkoxy-3-aryl-1-oxacyclopentanes, (2R,3R)-9
and (2S,3S)-9, respectively. The absolute stereochemistry of
(2R,3R)-9 was determined by X-ray crystallographic analysis.7
The major isomers produced in the arylation reactions were
separated from the minor isomers and were subjected to several
transformations. Lewis-acid-mediated reductions of (2R,3R)-
9b and (2S,3S)-9b furnished (R)-10 and (S)-10, respectively, in
excellent yield with high enantiomeric excess. Jones oxidation
of (2R,3R)-9a afforded optically active lactone (R)-11. The
reactions of (2R,3R)-9a with silyl enolate 13 constructed a new
carbon-carbon bond diastereoselectively.
Scheme 2. Preparation of Bromo Acetal Having Chiral Auxiliary
Sequential Cyclization/Arylation Reactions: Total Syn-
thesis of AH13205. Iodoetherification of butyl vinyl ether with
optically pure 14 yielded 15 (Scheme 4). Treatment of 15 under
the present conditions leads to sequential radical cyclization/
cross-coupling reaction to afford a phenylated analogue of Corey
lactone8 16. The sequential version also allowed the construction
of a secondary alkyl-aryl bond in a highly stereoselective
manner.
Scheme 3. Arylation of Chiral Bromo Acetal 8a
The sequential cyclization/arylation reaction is applicable for
the synthesis of a synthetic prostaglandin AH13205, an EP2-
receptor agonist that lowers intraocular pressure.9,10 The syn-
thesis is outlined in Scheme 5. Cobalt-catalyzed reaction of 15
with Grignard reagent 17 followed by Jones oxidation provided
bicyclic lactone 18 in 54% yield. Removal of the acetoxy group
in 18 was performed in three steps. Namely, deacetylation,
formation of thiocarbonate, and tin-free radical reduction11
afforded lactone 19 in 60% overall yield. Reduction of 19
followed by Wittig olefination allowed installation of the R side
chain of AH13205 with high efficiency. Hydroxy alcohol 20
was oxidized. Finally, simultaneous deprotection and reduction
by catalytic hydrogenation completed the total synthesis of
AH13205. The only byproduct identified was benzylated
AH13205, which can be subjected to additional deprotection
conditions. AH13205 is a mixture of epimers. The mixture was
used to serve as the agonist.9 The synthesis is extremely short,
which highlights the synthetic utility of the cobalt-catalyzed
arylation process.
a Abbreviations: (+)IM, (+)-isomenthyl; 1-Np, 1-naphthyl; 2-Np,
2-naphthyl; 1-Py, 1-pyrenyl. Conditions: (a) CoCl2 (5 mol %), (R,R)-1 (12
mol %), ArMgBr (1.2 mmol), THF, 25 °C, 15 min; (b) chromatographic
isolation of the anti-isomer; (c) Et3SiH, BF3‚OEt2, CH2Cl2; (d) CrO3,
acetone; (e) Me2CdC(Ph)OSiMe3 (13), BF3‚OEt2, CH2Cl2.
(6) (a) Salom-Roig, X. J.; De´ne`s, F.; Renaud, P. Synthesis 2004, 1903-1928.
(b) Ueno, Y.; Chino, K.; Watanabe, M.; Moriya, O.; Okawara, M. J. Am.
Chem. Soc. 1982, 104, 5564-5566. (c) Stork, G.; Mook, R., Jr.; Biller, S.
A.; Rychnovsky, S. D. J. Am. Chem. Soc. 1983, 105, 3741-3742.
(7) See Supporting Information.
4). Five-membered rings have less flexibility than six-membered
ones, which leads to the efficient shielding by the alkoxy group
on one face of the ring. Note again that no kinetic resolution of
the halo acetals was observed. Attempted butylation, vinylation,
and allylation reactions resulted in failure, leaving most of the
starting bromo acetal.
Bromoetherification with enantiomerically pure (+)-isomen-
thol allowed the separation of the diastereomers, (2R,3S)-8 and
(2S,3R)-8, from each other by purification on silica gel under
atmospheric pressure (Scheme 2). With the enantiomerically
pure bromo acetals in hand, the arylation reactions of 8 were
examined (Scheme 3). As expected, (2R,3S)-8 and (2S,3R)-8
underwent highly diastereoselective arylation reactions, furnish-
(8) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; John Wiley
& Sons: New York, 1989; Chapter 11.
(9) (a) Nials, A. T.; Vardey, C. J.; Denyer, L. H.; Thomas, M.; Sparrow, S. J.;
Shephaerd, G. D.; Coleman, R. A. CardioVasc. Drug ReV. 1993, 11, 165-
179. (b) Woodward, D. F. U.S. Patent, 5,462,968, Oct 31, 1995. (c) Borman,
R. A.; Coleman, R. A.; Clark, K. L.; Mills, K.; Oxford, A. W.; Zhang, J.
European Patent,WO2005061449, July 7, 2005. (d) Stumpff, F.; Boxberger,
M.; Krauss, A.; Rosenthal, R.; Meissner, S.; Choritz, L.; Wiederholt, M.;
Thieme, H. Exp. Eye Res. 2005, 80, 697-708. (e) Richter, M.; Krauss, A.
H.-P.; Woodward, D. F.; Lu¨tjen-Drecoll, E. InVest. Ophthalmol. Vis. Sci.
2003, 44, 4419-4426.
(10) The only published total synthesis of AH13205: Kobayashi, Y.; Nakata,
K.; Ainai, T. Org. Lett. 2005, 7, 183-186.
(11) Robin, M. J.; Wilson, J. S.; Hansske, F. J. Am. Chem. Soc. 1983, 105,
4059-4065.
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Cobalt-Catalyzed Cross-coupling Reaction
A R T I C L E S
Scheme 5. Total Synthesis of AH13205
was then added over 5 s to the reaction mixture at 0 °C. While the
Grignard reagent was being added, the mixture turned brown. After
being stirred for 15 min at 25 °C, the reaction mixture was poured into
saturated ammonium chloride solution. The products were extracted
with hexane (20 mL × 2). The combined organic layer was dried over
Na2SO4 and concentrated. Silica gel column purification (hexane) of
the crude product provided cyclohexylbenzene (152 mg, 0.95 mmol)
in 95% isolated yield. The addition of phenylmagnesium bromide was
performed over 10 s in the 10 mmol scale reaction (1.39 g, 8.7 mmol,
87% yield).
Conclusion
The cobalt-diamine catalyst system is promising for com-
bining aryl Grignard reagents with primary and secondary alkyl
halides. The reaction is powerful and reliable enough to realize
stereoselective construction of asymmetric carbon centers. The
high stereoselectivity observed depends on the generation of
planer carbon-centered radicals followed by approaches of cobalt
complexes from the less congested faces. High stereoselectivity
was also observed in the sequential cyclization/arylation reac-
tion, leading to the short total synthesis of the synthetic
prostaglandin AH13205.
Acknowledgment. This work was supported by Grants-in-
Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Government of Japan.
Experimental Section
Supporting Information Available: Experimental details,
characterization data for new compounds, and assignment of
the absolute configurations of 8 and 9 (PDF) and crystal-
lographic data for 9 (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org. See any current
masthead page for ordering information and Web access
instructions.
Typical Procedure for Cobalt-Catalyzed Arylation Reaction. The
reaction of bromocyclohexane with phenyl Grignard reagent (Table 1,
entry 2) is representative. Anhydrous cobalt(II) chloride (6.5 mg, 0.05
mmol) was placed in a 20-mL reaction flask and was heated with a
hair-dryer in vacuo for 2 min. After the color of the cobalt salt became
blue, anhydrous THF (3 mL) and (R,R)-1 (10 mg, 0.06 mmol) were
sequentially added under argon. The mixture was stirred for 3 min at
room temperature. Bromocyclohexane (163 mg, 1.0 mmol) was added.
Phenylmagnesium bromide (1.0 M THF solution, 1.2 mL, 1.2 mmol)
JA057560O
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