A facile construction of Bi-or tricyclic skeletons by nickel-catalyzed stereoselective cyclization of alkynylcycloalkanone

Article abstract of DOI:10.1021/ol101329d

(Equation Presented). A nickel-catalyzed intramolecular cyclization of alkynylalkanone in the presence of Et₃SiH using an NHC ligand produced various carbo-and heterocycles in a stereoselective manner. The reaction would proceed via formation o

Full text of DOI:10.1021/ol101329d

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3494-3497
A Facile Construction of Bi- or Tricyclic
Skeletons by Nickel-Catalyzed
Stereoselective Cyclization of
Alkynylcycloalkanone
Nozomi Saito, Yasuyuki Sugimura, and Yoshihiro Sato*
Faculty of Pharmaceutical Sciences, Hokkaido UniVersity, Sapporo 060-0812, Japan
biyo@pharm.hokudai.ac.jp
Received June 10, 2010
ABSTRACT
A nickel-catalyzed intramolecular cyclization of alkynylalkanone in the presence of Et3SiH using an NHC ligand produced various carbo- and
heterocycles in a stereoselective manner. The reaction would proceed via formation of oxanickelacycle followed by σ-bond metathesis with
silane to give a bi- or tricyclic compound.
The development of a novel strategy for efficient construction
of polycyclic skeletons is important in synthetic organic
chemistry because such carbo- or heterocyclic frameworks are
ubiquitous in many biologically active compounds.1 A transi-
tion-metal-catalyzed cyclization of multiple bonds is a powerful
and promising methodology for the synthesis of various types
of cyclic compounds in recent organic synthesis.2 We have
reported nickel-catalyzed stereoselective cyclization of 1,3-diene
and tethered aldehyde in the presence of silane.3,4 In this
reaction, a variety of cyclic alcohol derivatives having an
olefin tether were produced in a highly stereoselective
manner, and synthesis of biologically active natural products
by using the cyclization as a key step was also
demonstrated.3c-e,j A nickel-catalyzed reductive coupling
between alkynes and carbonyl groups is also an attractive
strategy for the construction of cyclic molecules, and many
excellent examples of alkyne-aldehyde coupling by a nickel
catalyst have been demonstrated.5 On the other hand, nickel-
(3) For intramolecular cyclization of 1,3-diene and tethered aldehyde,
see: (a) Sato, Y.; Takimoto, M.; Hayashi, K.; Katsuhara, T.; Takagi, K.;
Mori, M. J. Am. Chem. Soc. 1994, 116, 9771. (b) Sato, Y.; Takimoto, M.;
Mori, M. Tetrahedron Lett. 1996, 37, 887. (c) Sato, Y.; Takimoto, M.; Mori,
M. Synlett 1997, 734. (d) Sato, Y.; Saito, N.; Mori, M. Tetrahedron Lett.
1997, 38, 3931. (e) Sato, Y.; Saito, N.; Mori, M. Tetrahedron 1998, 54,
1153. (f) Sato, Y.; Takanashi, T.; Hoshiba, M.; Mori, M. Tetrahedron Lett.
1998, 39, 5579. (g) Sato, Y.; Takanashi, T.; Mori, M. Organometallics 1999,
18, 4891. (h) Sato, Y.; Takimoto, M.; Mori, M. J. Am. Chem. Soc. 2000,
122, 1624. (i) Sato, Y.; Saito, N.; Mori, M. J. Am. Chem. Soc. 2000, 122,
2371. (j) Sato, Y.; Takimoto, M.; Mori, M. Chem. Pharm. Bull. 2000, 48,
1753. (k) Sato, Y.; Saito, N.; Mori, M. J. Org. Chem. 2002, 67, 9310. (l)
Sato, Y.; Takanashi, T.; Hoshiba, M.; Mori, M. J. Organomet. Chem. 2003,
688, 36. For cyclization of 1,3-diene and aldehyde using Me3SiSnBu3 instead
of silane, see: (m) Sato, Y.; Saito, N.; Mori, M. Chem. Lett. 2002, 18. (n)
Saito, N.; Mori, M.; Sato, Y. J. Organomet. Chem. 2007, 692, 460.
(4) (a) Kimura, M.; Tamaru, Y. In Modern Organonickel Chemistry;
Tamaru, Y., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2005;
pp 137-170. (b) Shibata, K.; Kimura, M.; Shimizu, M.; Tamaru, Y. Org.
Lett. 2001, 3, 2181.
(1) For a recent review on cyclization reactions, see: Handbook of
Cyclization Reactions; Ma, S., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA:
Weinheim, 2010.
(2) For reviews on transition-metal-catalyzed cyclization reactions, see:
(a) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. ReV. 1996,
96, 635. (b) Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49. (c)
Saito, S.; Yamamoto, Y. Chem. ReV. 2000, 100, 2901. (d) Varela, J. A.;
Saa´, C. Chem. ReV. 2003, 103, 3787. (e) Kotha, S.; Brahmachary, E.; Lahiri,
K. Eur. J. Org. Chem. 2005, 4741. (f) Chopade, P. R.; Louie, J. AdV. Synth.
Catal. 2006, 348, 2307.
10.1021/ol101329d  2010 American Chemical Society
Published on Web 06/30/2010

Treatment of 1a with Et3SiH (2, 5 equiv) in the presence of
Ni(cod)2 (10 mol %) and PPh3 (20 mol %) in THF at room
temperature provided the bicyclo[3.3.0]octane derivative in 44%
yield as a single isomer. The regiochemistry of the alkene part
in 4a was determined to be the E configuration by a NOESY
experiment. Furthermore, the product 4a was transformed into
the bicyclic compound 5, whose 1H and 13C NMR spectral data
were identical to those reported previously.11,12 Therefore, the
stereochemistry of the ring junction of 4a was assigned to
be the syn-orientation.
Scheme 1
Scheme 2
catalyzed reductive coupling between alkynes and ketones
has been limited to a few cases: coupling of 1,3-enynes and
aromatic ketones or R,ꢀ-unsaturated ketone6 or coupling
reaction of alkynes and cyclobutanones.7 In this context, we
planned nickel-catalyzed cyclization of alkynlcycloalkanone
in the presence of silane as a new method for the construction
of polycyclic skeletons (Scheme 1). That is, oxidative
cycloaddition of a carbonyl group and alkyne part to a
zerovalent nickel complex could proceed to give oxanick-
elacycle 3.8,9 The reaction of nickelacycle 3 with silane
would afford bicyclic compound 4 including an allylic
alcohol part at the bridgehead carbon, which might be used
for further transformations.10
Encouraged by these results, we investigated the cycliza-
tion using various ligands to improve the yield of 4a. The
results are summarized in Table 1. The reaction of 1a and 2
using PBu3 as a ligand gave 4a in 72% yield (run 1). After
screening various types of ligands, we found that N-
heterocyclic carbene (NHC) ligands were effective for
cyclization of 1a in the presence of Et3SiH (2) (runs 2-5).
Among the NHC ligands employed, IPr [1,3-bis(2,6-diiso-
propylphenyl)imidazol-2-ylidene] gave the best result. That
is, when IPr was used as a ligand, the reaction proceeded
smoothly to give 4a in quantitative yield (run 4).
To examine the feasibility of this plan, we investigated the
cyclization of 2-(pent-3-ynyl)cyclopentanone 1a (Scheme 2).
(5) For recent reviews, see: (a) Ikeda, S.-i. In Modern Organonickel
Chemistry; Tamaru, Y., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA:
Weinheim, 2005; pp 102-106. (b) Montgomery, J. Angew. Chem., Int. Ed.
2004, 43, 3890, and references cited therein. (c) Moslin, R. M.; Miller-
Moslin, K.; Jamison, T. F. Chem. Commun. 2007, 4441, and references
cited therein. For recent reports on Ni(0)-catalyzed reductive coupling of
alkynes and aldehydes, see: (d) Knapp-Reed, B.; Mahandru, G. M.;
Montgomery, J. J. Am. Chem. Soc. 2005, 127, 13156. (e) Luanphaisarnnont,
T.; Ndubaku, C. O.; Jamison, T. F. Org. Lett. 2005, 7, 2937. (f) Miller,
K. M.; Colby, E. A.; Woodin, K. S.; Jamison, T. F. AdV. Synth. Catal.
2005, 347, 1533. (g) Moslin, R. M.; Jamison, T. F. Org. Lett. 2006, 8, 455.
(h) Sa-ei, K.; Montgomery, J. Org. Lett. 2006, 8, 4441. (i) Moslin, R. M.;
Miller, K. M.; Jamison, T. F. Tetrahedron 2006, 62, 7598. (j) Chaulagain,
M. R.; Sormunen, G. J.; Montgomery, J. J. Am. Chem. Soc. 2007, 129,
9568. (k) Moslin, R. M.; Jamison, T. F. J. Org. Chem. 2007, 72, 9736. (l)
Chrovian, C. C.; Knapp-Reed, B.; Montgomery, J. Org. Lett. 2008, 10,
811. (m) Saito, N.; Katayama, T.; Sato, Y. Org. Lett. 2008, 10, 3829. (n)
Malik, H. A.; Chaulagain, M. R.; Montgomery, J. Org. Lett. 2009, 11, 5734.
(o) Sa-ei, K.; Montgomery, J. Tetrahedron 2009, 65, 6707. (p) Malik, H. A.;
Sormunen, G. J.; Montgomery, J. J. Am. Chem. Soc. 2010, 132, 6304.
(6) Miller, K. M.; Jamison, T. F. Org. Lett. 2005, 7, 3077.
Table 1. Effect of Ligand
(7) (a) Murakami, M.; Ashida, S.; Matsuda, T. J. Am. Chem. Soc. 2005,
127, 6932. (b) Murakami, M.; Ashida, S.; Matsuda, T. J. Am. Chem. Soc.
2006, 128, 2166. (c) Murakami, M.; Ashida, S.; Matsuda, T. Tetrahedron.
2006, 62, 7540. (d) Murakami, M.; Ashida, S. Bull. Chem. Soc. Jpn. 2008,
81, 885.
(8) For the isolation of oxanickelacyclopentene from alkyne and
aldehyde, see: Ogoshi, S.; Arai, T.; Ohashi, M.; Kurosawa, H. Chem.
Commun. 2008, 1347
.
(9) For computational studies on the mechanism of Ni(0)-catalyzed
reductive coupling of alkyne and aldehyde, see: (a) McCarren, P. R.; Liu,
P.; Cheong, P. H.-Y.; Jamison, T. F.; Houk, K. N. J. Am. Chem. Soc. 2009,
131, 6654. (b) Liu, P.; McCarren, P.; Cheong, P. H.-Y.; Jamison, T. F.;
run
ligand
PBu3
IMes·HCl
SIMes·HBF4
IPr·HCl
time (h)
yield (%)
1a
2
3
4
5
48
8
9
1
1
72
84
79
quant
93
Houk, K. N. J. Am. Chem. Soc. 2010, 132, 2050
.
(10) Jamison reported one example of Ni(0)-catalyzed reductive cy-
clization of a ketone and an alkyne in their synthetic study of (-)-terpestacin
and related molecules. When an alkynal including a cyclopentanone moiety
was treated with a Ni(0)-PBu3 catalyst and Et3B, the intramolecular cyclization
of the alkyne and the cyclopentanone part proceeded unexpectedly as a side
reaction to give the corresponding cyclized product. See: Chan, J.; Jamison,
T. F. J. Am. Chem. Soc. 2004, 126, 10682.
SIPr·HCl
a The reaction was carried out in the presence of 20 mol % of phosphine
t
ligand without BuOK.
Org. Lett., Vol. 12, No. 15, 2010
3495

With optimal conditions in hand, we investigated the
effectsofsubstituentsontheformationofabicyclo[3.3.0]octane
skeleton (Table 2). The reaction of 2-(but-3-ynyl)cyclopen-
tanone (1b) and Et3SiH (2) gave 4b in 83% yield (run 1).
The cyclization of alkynylcyclopentanones having a si-
loxymethyl group 1c or a phenyl group 1d on the alkyne
part afforded the corresponding cyclized products 4c or 4d
in high yields (runs 2 and 3). On the other hand, the reaction
of 1e or 1f gave the cyclized product 4e or 4f in moderate
yield (runs 4 and 5). Furthermore, 2,2-disubstitued cyclo-
pentanone 1g or 1h also reacted with Et3SiH (2) in the
presence of a Ni-IPr catalyst to give the cyclic compound
4g or 4h having two consecutive tetrasubstituted carbon
centers in high yield, respectively (runs 6 and 7).
Furthermore, nitrogen heterocycles 4s and 4t were also
synthesized by cyclization of 1s and 1t in the presence of
Et3SiH (2) in 92% and 95% yields, respectively (runs 11
and 12).
Table 3. Cyclization of Various Substratesa
Table 2. Effects of Substituents
run
substrate
time (h)
product (%)
1
2
3
4
5
6
7
1b: R1 ) R2 ) H
0.5
0.5
0.5
48
40
0.5
0.5
4b: 83
4c: 99
4d: 97
4e: 26
4f: 26
1c: R1 ) H, R2 ) CH2OTBS
1d: R1 ) H, R2 ) Ph
1e: R1 ) H, R2 ) CO2Me
1f: R1 ) H, R2 ) TMS
1g: R1 ) R2 ) Me
4g: quant
4h: 96
1h: R1 ) CH2OTBS, R2 ) Me
Next, we turned our attention to the construction of various
cyclic skeletons (Table 3). The reaction of 2-(hex-4-ynyl)-
cyclopentanone (1i) and Et3SiH (2) provided cis-hydrindan
derivative 4i in quantitative yield (run 1). Cyclohexanone
derivatives 1j-l were also applicable to the nickel-catalyzed
cyclization, and the corresponding cyclic compounds having
cis-hydrindan or cis-decalin skeletons 4j-l were obtained
in good yields (runs 2-4). The cyclization of alkynyl-R-
tetralones 1m and 1n with Et3SiH (2) provided the corre-
sponding hexahydrophenanthrene derivatives 4m and 4n in
73% and 79% yields, respectively (runs 5 and 6). The 1,3-
dioxan-5-one derivative 1o was also applicable to the
cyclization, giving 4o in 99% yield (run 7). When cyclo-
hexanone 1p bearing an alkynyl group on ꢀ-position was
reacted with Et3SiH (2), bicyclo[3.3.1]octane derivative 4p
was obtained in 99% yield as a single diastereomer (run 8).
On the other hand, the reaction of cycloalkanone derivatives
having an oxygen atom in a tether 1q and 1r was carried
out under the same conditions, giving corresponding bicyclic
furan derivatives 4q and 4r in good yields (runs 9 and 10).
a Reaction conditions: Ni(cod)2 (10 mol %), IPr·HCl (10 mol %), tBuOK
(12 mol %), Et3SiH (2, 5 equiv), THF, room temperature
A possible reaction mechanism of the cyclization is shown
in Scheme 3. First, coordination of alkyne and carbonyl group
in substrate 1 to a zerovalent nickel complex (depicted as 6)
followed by oxidative cyclization would proceed to give
(11) Shono, T.; Kise, N.; Fujimoto, T.; Tominaga, N.; Morita, H. J.
Org. Chem. 1992, 57, 7175.
(12) Determination of the stereochemistry is described in the Supporting
Information.
3496
Org. Lett., Vol. 12, No. 15, 2010

oxanickelacycle 3 in a stereoselective fashion. Then cleavage
of the nickel-oxygen bond by σ-bond metathesis of the
nickelacycle 3 with Et3SiH (2) would afford hydridenickel
species 7. Finally, the reductive elimination from 7 would
give the cyclized product 4 as a single stereoisomer.
In summary, the cyclization of 2- or 3-alkynylcycloal-
kanone with Et3SiH in the presence of a zerovalent nickel
complex and IPr as a ligand provided various carbo- and
heterocyclic compounds having two consecutive stereo-
genic centers including tetrasubstituted carbon in a ste-
reoselective fashion. The reaction would proceed via the
formation of oxanickelacycle followed by σ-bond me-
tathesis of the nickelacycle and silane to give bi- or
tricyclic compounds.
Scheme 3
Further studies along this line are in progress.
Acknowledgment. Part of this work was supported by a
Grant-in-Aid for Science Research on Priority Areas (Nos.
19027005 and 20036005, Synergy of Elements) from MEXT,
Japan, and a Grant-in-Aid for Scientific Research (B) (No.
19390001) from JSPS. N.S. acknowledges the Research
Foundation for Pharmaceutical Sciences for financial support.
Supporting Information Available: Experimental pro-
cedure and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL101329D
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