Tandem cyclization of alkynylmetals bearing a remote leaving group via cycloalkylidene carbenes

Article abstract of DOI:10.1021/ol0059145

(Formula presented) Treatment of terminal alkynes bearing a remote leaving group with MNR₂ (M = Li, Na, K) gives bicyclo[n.3.0]-1-alkenes (n = 3, 4). The tandem cyclization proceeds through a mechanism involving exo-cyclization of an alkynylmet

Full text of DOI:10.1021/ol0059145

ORGANIC
LETTERS
2000
Vol. 2, No. 13
1855-1857
Tandem Cyclization of Alkynylmetals
Bearing a Remote Leaving Group via
Cycloalkylidene Carbenes
Toshiro Harada,* Takayuki Fujiwara, Katsuhiro Iwazaki, and Akira Oku
Department of Chemistry, Kyoto Institute of Technology, Matsugasaki,
Sakyo-ku Kyoto 606-8585, Japan
harada@chem.kit.ac.jp
Received April 7, 2000
ABSTRACT
Treatment of terminal alkynes bearing a remote leaving group with MNR (M ) Li, Na, K) gives bicyclo[n.3.0]-1-alkenes (n ) 3, 4). The tandem
2
cyclization proceeds through a mechanism involving exo-cyclization of an alkynylmetal intermediate and intramolecular C-H insertion of the
resulting carbenoid.
Alkylidene carbenes undergo intramolecular C-H insertion
in a regiospecific manner to give cyclopentenes.1 The five-
membered ring construction proceeds at a previously un-
activated C-H site with retention of configuration at chiral
centers. The reaction has been utilized as a key carbon-
carbon bond-forming reaction in natural product syntheses.1,2
Of previously reported methods for generating alkylidene
carbenes (or carbenoids), the addition of nucleophiles to
alkynyliodonium salts is particularly versatile and efficient.3-5
The method not only allows the generation of functionalized
carbenes but also provides a convergent strategy for the
construction of polycyclic molecular frameworks as recently
demonstrated by Feldman et al. (Scheme 1).6,7 Unfortunately,
Scheme 1. Tandem Cyclization of Alkynyliodonium Salts
(1) (a) Stang, P. J. Chem. ReV. 1978, 78, 383. (b) Kirmse, W. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1164. (c) Taber, D. F. Methods of Organic
Chemistry (Houben Weyl); Helmchen, G., Hoffmann, R. W., Mulzer, J.,
Schaumann, E., Eds.; Georg Thieme Verlag: Stuttgart, New York, 1995;
Vol. E21a, p 1127.
(2) (a) Taber, D. F.; Christos, T. E. J. Org. Chem. 1996, 61, 2081 and
references therein. (b) Taber, D. F.; Yu, H.; Incarvito, C. D.; Rheingold,
A. L. J. Am. Chem. Soc. 1998, 120, 13285. (c) Taber, D. F.; Christos, T.
E.; Rheingold, A. L.; Guzei, I. A. J. Am. Chem. Soc. 1999, 121, 5589.
(3) For review, see: (a) Stang, P. J. Angew. Chem., Int. Ed. Engl. 1992,
31, 274. (b) Ochiai, M. ReViews on Heteroatom Chemistry, Volume 2; Oae,
S., Ed.; MYU: Tokyo, 1989; p 92.
(4) (a) Ochiai, M.; Kunishima, M.; Nagao, Y.; Fuji, K.; Shiro, M.; Fujita,
E. J. Am. Chem. Soc. 1986, 108, 8281. (b) Ochiai, M.; Kunishima, M.;
Fuji, K.; Nagao, Y. J. Org. Chem. 1988, 53, 6144. (c) Ochiai, M.; Ito, T.;
Takaoka, Y.; Kunishima, M.; Tani, S.; Nagao, Y. J. Chem. Soc., Chem.
Commun. 1990, 118. (d) Ochiai, M.; Kunishima, M.; Tani, S.; Nagao, Y.
J. Am. Chem. Soc. 1991, 113, 3135.
however, the tandem cyclization is limited to that involving
certain heteroatom nucleophiles (Y ) NTs, O) with an
appropriate reactivity tolerated by alkynyliodonium salts.
(5) (a) Kitamura, T.; Stang, P. J. Tetrahedron Lett. 1988, 29, 1887. (b)
Tykwinski, R. R.; Whiteford, J. A.; Stang, P. J. J. Chem. Soc., Chem.
Commun. 1993, 1800. (c) Williamson, B. L.; Tykwinski, R. R.; Stang, P.
J. J. Am. Chem. Soc. 1994, 116, 93. (d) Tykwinski, R. R.; Stang, P. J.;
Peisky, N. E. Tetrahedron Lett. 1994, 35, 23. (e) Fischer, D. R.; Williamson,
B. L.; Stang, P. J. Synlett 1992, 535.
(6) (a) Schildknegt, K.; Bohnstedt, A. C.; Feldman, K. S.; Sambandam,
A. J. Am. Chem. Soc. 1995, 117, 7544. (b) Feldman, K. S.; Bruendl, M.
M.; Schildknegt, K.; Bohnstedt, A. C. J. Org. Chem. 1996, 61, 5440. (c)
Feldman, K. S.; Bruendl, M. M. Tetrahedron Lett. 1998, 39, 2911.
10.1021/ol0059145 CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/09/2000

In sharp contrast to the electrophilic nature of alkynyl-
iodonium salts in the carbene generation, we recently
reported a method for alkylidene carbene generation from
nucleophilic alkynylmetals.8 We found that alkynyllithiums
bearing a remote leaving group undergo facile exo-cyclization
with carbon-carbon bond formation to give cycloalkylidene
carbenes (Scheme 2). The carbene formation was demon-
Scheme 3. Tandem Cyclization of Propynyloxyethyl
Derivatives 1a-c
Scheme 2. Exo-Cyclization of Alkynyllithiums To Form
Cycloalkylidene Carbenes
strated by trapping experiments with alkynyllithiums to form
enynes, with alkenes to form [2 + 1] adducts, and with 1,3-
diphenylisobenzofuran to form the [4 + 2] adducts of the
rearranged cycloalkynes.
by the acceleration of the initial exo-cyclization of alkynyl-
metal 5 through the modification of a leaving group and/or
a metal atom because it would reduce the lifetime of 5. While
the reaction of p-chlorobenzene sulfonate 1b with BuLi gave
a similar result (entry 3), that of more reactive iodide 1c
with LDA afforded 2 in 76% yield (entry 6). The tandem
cyclization also proceeded through the corresponding al-
kynylsodium and -potassium 7 (M ) Na, K) (entries 4, 5,
and 7). For sulfonate 1b, the reaction through alkynylsodium
was most efficient (entry 4 vs entries 3 and 5).
Herein, we wish to report the first example of tandem
carbocyclization that proceeds through initial exo-cyclization
of alkynylmetals and subsequent intramolecular C-H insertion
of the resulting cycloalkylidene carbenes leading to bicyclo-
[3.3.0]octenes and bicyclo[4.3.0]nonenes.
(Propynyloxy)ethyl tosylate 1a was prepared by TiCl4-
mediated ring cleavage of dioxolane acetal derived from
3-phenylpropanal with bis(trimethylsilyl)acetylene9 followed
by desilylation and subsequent tosylation of the resulting
alcohol. Lithiation of 1a with BuLi (1.0 equiv) in THF at
-85 °C and warming of the resulting alkynyllithium 5 (M
) Li) to room temperature gave tandem cyclization product
210 in 32% yield with high stereoselectivity (92:8) together
with enyne 3a (X ) OTs) (36%) (Scheme 3, entry 1 in Table
1). The formation of 3a as a byproduct suggested that
intermolecular reaction of carbenic species 6 with alkynyl-
lithium 5 competed with intramolecular C-H insertion. Slow
addition of BuLi to a dilute solution (0.02 M) of 1a at room
temperature retarded the undesirable pathway and improved
the yield of 2 (entry 2). Further improvement was anticipated
Information on the nature of carbenic species generated
by exo-cyclization was obtained in the reactions of iodide
Table 1. Tandem Cyclization of (Propynyloxy)ethyl
Derivatives 1a-ca
(7) For a different approach, see ref 5d.
(8) Harada, T.; Iwazaki, K.; Otani, T. Oku, A. J. Org. Chem. 1998, 63,
9007.
(9) Johnson, W. S.; Elliott, R.; Elliot, D. J. J. Am. Chem. Soc. 1983,
105, 2904.
(10) The stereochemistry of the major isomer was established by an NOE
experiment after converting 2 into alcohol i ((CH3)2CHC(CH3)2BH2, THF,
then NaOOH; 41%).
a Unless otherwise noted, reactions were carried out by adding a base
(1.2 equiv) to a solution of 1 in THF (0.02 M) slowly over 4-5 h at room
temperature. b NaHMDS ) sodium hexamethyldisilazide; KHMDS )
potassium hexamethyldisilazide.
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Org. Lett., Vol. 2, No. 13, 2000

with a variety of alkynyl iodides and sulfonates (Table 2).
The reaction of a homologous substrate 7 with LDA also
proceeded in an efficient manner at 40 °C to give oxabicy-
clononene 812 stereoselectively (entry 3). Tricyclic com-
pounds 10 and 12 were obtained in a highly convergent
manner through the tandem cyclization of 9 and 11,
respectively (entries 4-6). The reaction is equally applicable
to substrates bearing no oxygen atom in a main chain. For
iodide 13 (X ) I), the use of NaHMDS as a base gave a
better result than that of LDA (entry 7 vs 8). The reactions
of sulfonates 13 (X ) p-ClC6H4SO3) with KHMDS also gave
a satisfactory result (entry 9). Intramolecular insertion into
the C-H bond R to the oxygen atom also proceeded
smoothly to furnish functionalized bicyclooctene 19 and 21
(entries 13 and 14). An alkynylmetal derived from secondary
iodide 15 would undergo exo-cyclization to give the same
intermediate that is generated from primary substrate 13.
Indeed, the reaction of 15 afforded bicyclooctene 14 stereo-
selectively albeit in lower yield (entry 10).13
Table 2. Tandem Cyclization of Alkynylmetals with Remote
Leaving Groudsa
In summary, we have shown a novel tandem carbo-
cyclization involving exo-cyclization of alkynylmetals and
C-H insertion of the resulting carbenes. Substrates in Table
2 were accessible in few steps either through TiCl4-mediated
ring cleavage of cyclic acetals or through alkylation of
trilithio derivatives of ω-alkynols (LiCtCCH(Li)(CH2)nCH2-
OH; n ) 2, 3).14 The reaction, therefore, serves as a useful
method for the convergent synthesis of polycyclic com-
pounds.
Acknowledgment. We thank the Ministry of Education,
Science, Sports, and Culture, Japan (Grant-in-Aid for No.
11650892) for financial support.
Supporting Information Available: Preparation of start-
ing materials 7 and 13 and characterization data for products
10, 12, 14, 17, 19, 21, and i. This material is available free
for charge via the Internet at http://pubs.acs.org.
OL0059145
(11) Palladium-catalyzed cross-coupling reaction of 4 (PhZnCl, PdCl2-
(dppf), THF) gave (E)-3-(phenylmethylidene)-2-(2-phenylethyl)tetrahydro-
furan (87%), whose E-geometry was determined by an NOE experiment.
(12) The stereochemistry of the major isomer was established by NOE.
(13) Procedure for the preparation of 8-phenyl-5-oxabicyclo[4.3.0]-
nona-1(9)-ene (8) (Table 2, entry 3): To a solution of iodide 7 (154 mg,
0.50 mmol) in THF (25 mL) at 40 °C was slowly added LDA (THF
complex, 1.5 M in cyclohexane) (0.40 mL, 0.60 mmol) during 4 h by using
a syringe pump. After being stirred for 1 h at 40 °C, the mixture was poured
into brine and extracted twice with ether. The organic layers were dried
over MgSO4 and concentrated in vacuo. Purification of the residue by flash
chromatography (SiO2, 5% ethyl acetate in hexane) gave 8 (75.8 mg, 76%)
as a 73:27 mixture of diastereomers. The major isomer was isolated by a
recycling preparative HPLC equipped with a GPC column (JAIGEL-1H
column, Japan Analytical Industry) using CHCl3 as an eluent: 1H NMR
(500 MHz, CDCl3) δ 1.71 (1H, ddd, J ) 6.5, 7.7, and 13.4 Hz), 1.76 (1H,
m), 1.85 (1H, tq, J ) 4.5 and 13.0 Hz), 2.32 (1H, br t, J ) ca. 14 Hz), 2.64
(1H, br d, J ) ca. 14 Hz), 2.84 (1H, td, J ) 7.7 and 13.5 Hz), 3.66 (1H,
dt, J ) 2.1 and 11.9 Hz), 3.80 (1H, m), 4.09 (1H, br d, J ) 11.5 Hz), 4.42
(1H, t, J ) 6.9 Hz), 5.48 (1H, s), 7.15-7.35 (5H, m) [the minor isomer
resonated at 4.60 (1H, t, J ) 6.2 Hz) and 5.59 (1H, s)]; 13C NMR (125.8
MHz, CDCl3) δ 26.01, 27.41, 41.17, 48.17, 67.49, 83.19, 126.14, 127.11,
127.35, 128.32, 142.40, 145.72 [the minor isomer resonated at 26.20, 27.64,
40.17, 49.15, 67.62, 83.39, 125.99, 126.95, 127.16, 128.38, 142.31, 146.00];
IR (liquid film) 1600, 1080, 760, 700 cm-1. Anal. Calcd for C14H16O: C,
83.96; H, 7.99. Found: C, 83.67; H, 7.93.
a Unless otherwise noted, reactions were carried out by adding a base
((1.2 equiv) to a solution of a substrate in THF (0.2 M) slowly over 4-5
h at room temperature. b Isolated yield unless otherwise noted. c Ratio of
stereoisomers determined by 1H NMR analysis. d The reaction was carried
out at 40 °C. e The stereochemistry was tentatively assigned by analogy
1
with that of 2 and 8. The yield was determined by H NMR.
1c (entries 6 and 7). Iodoalkene (E)-411 was formed as a
byproduct despite the complete retardation of enyne forma-
tion. The observation suggests the involvement of carbenoid
6 (X ) I) which might be protonated by 1c to give 4. The
observed increase of the byproduct in the reaction involving
alkynylsodium (entry 7) can be understood in terms of the
higher basicity of sodium carbenoids in comparison with
lithium carbenoids. Absence of such byproducts in the
reactions of sulfonates 1a,b is probably due to the more
dissociated character of the corresponding carbenoid.1a
The scope of the new tandem cyclization was investigated
(14) Brandsma, L.; Verkruijsse, H. D. Syntheses of Acetylenes, Allenes,
and Cumulenes; Elsevier: Amsterdam, 1980; p 48.
Org. Lett., Vol. 2, No. 13, 2000
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