SmI2/Pd(0)-mediated intramolecular coupling between propargylic esters and tethered aldehydes or ketones

Article abstract of DOI:10.1021/jo9819133

A SmI₂/Pd(0)-promoted intramolecular coupling between propargylic esters and carbonyl compounds is described. The reaction affords homopropargyl cycloalkanol products. Cyclopentanols are formed in high yields when ketones are employed as the carbonyl components, but aldehydes are found not to be suitable partners in these reactions. Particularly remarkable is the efficient formation of products with adjacent functionalized quaternary centers. These cyclizations take place with low diastereoselectivity about the newly created propargylic and carbinol stereogenic centers except when these two centers are quaternary or in the presence of groups capable of both chelating trivalent samarium and facilitating retroaldol-aldol-type equilibria in the product. In this latter case, the strategic combination of chemoselective carbonyl addition and SmI₂/Pd(0)-promoted cyclization provides ready and convenient stereocontrolled access to functionalized cyclopentanols from unprotected 1,5-dicarbonyl starting materials. The analogous formation of cyclohexanols is limited by low cyclization yields and lack of stereoselectivity.

Full text of DOI:10.1021/jo9819133

J . Org. Chem. 1999, 64, 1893-1901
1893
Sm I2/P d (0)-Med ia ted In tr a m olecu la r Cou p lin g betw een
P r op a r gylic Ester s a n d Teth er ed Ald eh yd es or Keton es
J ose´ M. Aurrecoechea,* Roberto Fan˜ana´s, Mo´nica Arrate, J ose´ M. Gorgojo, and
Natalia Aurrekoetxea
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad del Pa´ıs Vasco,
Apartado 644, 48080 Bilbao, Spain
Received September 21, 1998
A SmI2/Pd(0)-promoted intramolecular coupling between propargylic esters and carbonyl compounds
is described. The reaction affords homopropargyl cycloalkanol products. Cyclopentanols are formed
in high yields when ketones are employed as the carbonyl components, but aldehydes are found
not to be suitable partners in these reactions. Particularly remarkable is the efficient formation of
products with adjacent functionalized quaternary centers. These cyclizations take place with low
diastereoselectivity about the newly created propargylic and carbinol stereogenic centers except
when these two centers are quaternary or in the presence of groups capable of both chelating
trivalent samarium and facilitating retroaldol-aldol-type equilibria in the product. In this latter
case, the strategic combination of chemoselective carbonyl addition and SmI2/Pd(0)-promoted
cyclization provides ready and convenient stereocontrolled access to functionalized cyclopentanols
from unprotected 1,5-dicarbonyl starting materials. The analogous formation of cyclohexanols is
limited by low cyclization yields and lack of stereoselectivity.
Sch em e 1
In tr od u ction
Samarium diiodide (SmI2) has become a popular re-
agent in recent years due to its ability to promote chemo-,
regio-, and stereoselective radical and/or organometallic
C-C bond-forming processes from a wide variety of
substrates.1 The SmI2-promoted couplings of carbonyl
groups with other functionalities has been the most
developed area of study, and numerous combinations are
now available to the synthetic chemist. Particularly
valuable are those processes leading to cyclic structures2
that retain some of the functionality present in the
substrates (especially unsaturated groups), as the prod-
ucts can be further elaborated into more complex targets.
The allylation, propargylation, and allenylation of car-
bonyl compounds all fit the latter requirement. SmI2 is
known to promote couplings of carbonyl compounds with
allylic derivatives3 and vinyloxiranes4 where these sub-
strates behave, in a formal sense, as nucleophilic allyl-
ating agents. Analogously, propargylic esters and phos-
phates, as well as alkynyloxiranes, behave as synthetic
equivalents of the propargyl-allenyl anion when treated
with SmI2 in the presence of aldehydes or ketones.5,6
However, while alkynyloxiranes afford allenic alcohols
with complete regioselectivity,5 the intermolecular reac-
tions of propargylic esters and phosphates generally
afford mixtures of homopropargyl and allenic alcohols
where the latter predominate.6 This last reaction requires
the use of catalytic amounts of Pd(0) and is thought6a to
involve the initial formation of an allenylpalladium
complex that is rapidly reduced to an equilibrium mixture
of allenic and propargylic organosamarium intermedi-
ates7 that finally add to the carbonyl group (Scheme 1).
The use of a suitably located tether of appropriately short
length between the carbonyl and propargylic ester func-
tionalities (Scheme 2) was expected8 to result in intramo-
lecular cyclization9 with formation of alkyne products
exclusively because of the strain involved in the genera-
* Corresponding author. Phone: 34-946 01 2578, fax: 34-944 64
8500, e-mail: qopaufem@lg.ehu.es.
(1) Recent reviews: (a) Molander, G. A. Chem. Rev. 1992, 92, 29-
68. (b) Molander, G. A. In Organic Reactions; Paquette, L. A., Ed.; J ohn
Wiley & Sons: New York: 1994; Vol. 46; pp 211-367. (c) Molander,
G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307-338. (d) Molander, G.
A.; Harris, C. R. Tetrahedron 1998, 54, 3321-3354.
(2) Thebtaranonth, C.; Thebtaranonth, Y. Cyclization Reactions;
CRC Press: London, 1994.
(3) (a) Girard, P.; Namy, J . L.; Kagan, H. B. J . Am. Chem. Soc. 1980,
102, 2, 2693-2698. (b) Souppe, J .; Namy, J . L.; Kagan, H. B.
Tetrahedron Lett. 1982, 23, 3497-3500. (c) Tabuchi, T.; Inanaga, J .;
Yamaguchi, M. Tetrahedron Lett. 1986, 27, 1195-1196. (d) Ujikawa,
O.; Inanaga, J .; Yamaguchi, M. Tetrahedron Lett. 1989, 23, 2837-2840.
(e) Fukuzawa, S.; Fujinami, T.; Sakai, S. Chem. Lett. 1990, 927-930.
(f) Molander, G. A.; Mckie, J . A. J . Org. Chem. 1994, 59, 3186-3192.
(g) Molander, G. A.; Mcwilliams, J . C.; Noll, B. C. J . Am. Chem. Soc.
1997, 119, 1265-1276. (h) Kito, M.; Sakai, T.; Shirahama, H.;
Miyashita, M.; Matsuda, F. Synlett 1997, 219-220.
(5) Aurrecoechea, J . M.; Alonso, E.; Solay, M. Tetrahedron 1998, 54,
3833-3850.
(6) (a) Tabuchi, T.; Inanaga, J .; Yamaguchi, M. Chem. Lett. 1987,
2275-2278. (b) Mikami, K.; Yoshida, A.; Matsumoto, S.; Feng, F.;
Matsumoto, Y.; Sugino, A.; Hanamoto, T.; Inanaga, J . Tetrahedron Lett.
1995, 36, 907-908.
(4) (a) Aurrecoechea, J . M.; Iztueta, E. Tetrahedron Lett. 1995, 36,
7129-7132. (b) Molander, G. A.; Shakya, S. R. J . Org. Chem. 1996,
61, 5885-5894.
10.1021/jo9819133 CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/19/1999

1894 J . Org. Chem., Vol. 64, No. 6, 1999
Aurrecoechea et al.
Sch em e 2
Sch em e 3
tion of a cyclic allene. This paper reports the SmI2/Pd(0)-
promoted intramolecular cyclization of tethered propargyl
esters and aldehydes or ketones to afford homopro-
pargyl cycloalkanols. In a formal sense, this strategy
represents a new entry into propargyl anion synthons
suitable for intramolecular carbonyl additions. The ho-
mopropargyl alcohol subunit present in the products has
importance as a component of a number of biologically
interesting molecules10 as well as a versatile functionality
capable of useful synthetic transformations.11
Ta ble 1. P r ep a r a tion of P r op a r gylic Ester s 6 fr om
Ketoa ld eh yd es 5
(7) For a review on the use of other organometallic propargyl-allenyl
reagents in reactions with carbonyl compounds, see: (a) Yamamoto,
H. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 2; pp 81-98. Recent work: Boron,
(b) Brown, H. C.; Khire, U. R.; Narla, G. J . Org. Chem. 1995, 60, 8130-
8131. (c) Carrie´, D.; Carboni, B.; Vaultier, M. Tetrahedron Lett. 1995,
36, 8209-8212. Zirconium: (d) Ito, H.; Nakamura, T.; Taguchi, T.;
Hanzawa, Y. Tetrahedron 1995, 51, 4507-4518. Lithium, (e) Kanda,
T.; Ando, Y.; Kato, S.; Kambe, N.; Sonoda, N. Synlett 1995, 745-747.
(f) Gomez, C.; Huerta, F. F.; Pastor, I. M.; Yus, M. Tetrahedron 1997,
53, 17201-17210. (g) Cabezas, J . A.; Alvarez, L. X. Tetrahedron Lett.
1998, 39, 3935-3938. Titanium, (h) Nakagawa, T.; Kasatkin, A.; Sato,
F. Tetrahedron Lett. 1995, 36, 3207-3210. (i) Yoshida, Y.; Nakagawa,
T.; Sato, F. Synlett 1996, 437-438. (j) Kasatkin, A.; Sato, F. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2848-2849. (k) Okamoto, S.; An, D.
K.; Sato, F. Tetrahedron Lett. 1998, 39, 4551-4554. Silicon, (l)
Suginome, M.; Matsumoto, A.; Ito, Y. J . Org. Chem. 1996, 61, 4884-
4885. (m) Marshall, J . A., Adams, N. D. J . Org. Chem. 1997, 62, 8976-
8977. Zinc: (n) Lorthiois, E.; Marek, I.; Meyer, C.; Normant, J . F.
Tetrahedron Lett. 1996, 37, 6689-6692. (o) Lorthiois, E.; Marek, I.;
Normant, J . F. Tetrahedron Lett. 1996, 37, 6693-6694. (p) Tamaru,
Y.; Goto, S.; Tanaka, A.; Shimizu, M.; Kimura, M. Angew. Chem., Int.
Ed. Engl. 1996, 35, 878-880. (q) Bieber, L. W.; da Silva, M. F.; da
Costa, R. C.; Silva, L. O. S. Tetrahedron Lett. 1998, 39, 3655-3658.
Tungsten, (r) Shu, H.-G.; Shiu, L.-H.; Wang, S.-H.; Wang, S.-L.; Lee,
G.-H.; Peng, S.-M.; Liu, R.-S. J . Am. Chem. Soc. 1996, 118, 530-540.
(s) Shieh, S. J .; Tang, T. C.; Lee, J . S.; Lee, G. H.; Peng, S. M.; Liu, R.
S. J . Org. Chem. 1996, 61, 3245-3249. (t) Shieh, S. J .; Chen, C. C.;
Liu, R. S. J . Org. Chem. 1997, 62, 1986-1990. Tin, (u) Marshall, J .
A.; Wang, X. J . J . Org. Chem. 1992, 57, 3387-3396. (v) Kadota, I.;
Hatakeyama, D.; Seki, K.; Yamamoto, Y. Tetrahedron Lett. 1996, 37,
3059-3062. (x) Marshall, J . A.; Palovich, M. R. J . Org. Chem. 1997,
62, 6001-6005. (y) Marshall, J . A.; Lu, Z. H.; J ohns, B. A. J . Org. Chem.
1998, 63, 817-823.
R1
R2
R3
R5
n
6 (%)a
(CH2)3
(CH2)3
(CH2)4
(CH2)4
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
H
H
n-Bu
H
n-Bu
H
n-Bu
H
1
1
1
1
1
1
1
2
2
6a (32)b
6b (70)c
6c (81)c
6d (70)c
6e (49)c
6f (63)c
6g (69)c,d
6h (63)c
6i (66)c
Me
Me
Me
Me
(CH2)3
(CH2)3
(CH2)4
CO2Et
CO2Et
H
H
a
b
Overall yield from 5 (two steps). Addition of ethynyllithium
to 5. c Addition of ethynyltitanium triisopropoxide to 5. Overall
d
alkynylation yield (see Experimental Section).
Resu lts a n d Discu ssion
The substrates required for this study were prepared
from either suitable monoprotected dicarbonyl deriva-
tives 1 by a straightforward three-step sequence (Scheme
3) or more directly from unprotected keto aldehydes 5
by chemoselective alkynylation of the aldehyde carbonyl
group, followed by acetylation of the resulting crude
alcohol (Scheme 3; Table 1). As shown in Table 1, the
use of Reetz’s procedure12 with alkynyl titanium triiso-
propoxide reagents was much more efficient than the
alternative use of the more conventional lithium reagent.
Syn th esis of Cyclop en ta n ols. Initial studies were
conducted on simple acyclic propargylic esters 4a -h (eq
1, Table 2) by adding a mixture of 4 and Pd(PPh3)4 (5-6
mol % with respect to 4) to SmI2 (2.0-4.8 equiv) in THF
at 25 °C. Substrates 4a ,b and 4e-h , containing a ketone
carbonyl group, produced good yields of the respective
homopropargyl cyclopentanols 7. Both terminal and
internal alkynes participate effectively in the cyclization,
and allenic products derived from an alternative inter-
molecular coupling6a were not detected. Small amounts
of benzyl alcohol, probably the result of competing
elimination13 of alkoxide anion from a presumed orga-
nosamarium intermediate, were also obtained in the
(8) Preliminary communication: Aurrecoechea, J . M.; Fan˜ana´s-San-
Anto´n, R. J . Org. Chem. 1994, 59, 702-704.
(9) Some recent examples of cyclization reactions of allenic-propar-
gylic organometallics: (a) Thebtaranonth, C.; Thebtaranonth, Y.
Cyclization Reactions; CRC Press: London, 1994; pp 63-69. (b)
Danheiser, R. L.; Dixon, B. R.; Gleason, R. W. J . Org. Chem. 1992, 57,
6094-6097. (c) Meyer, C.; Marek, I.; Courtemanche, G.; Normant, J .
F. J . Org. Chem. 1995, 60, 863-871. (d) Lorthiois, E.; Marek, I.; Meyer,
C.; Normant, J . F. Tetrahedron Lett. 1995, 36, 1263-1266. (e) Schinzer,
D.; Ringe, K. Tetrahedron 1996, 52, 7475-7485. (f) Yoshida, Y.;
Nakagawa, T.; Sato, F. Synlett 1996, 437-438. See also refs 7s-v.
(10) See for example: (a) Skuballa, W.; Schillinger, E.; Stu¨rzebecher,
C.-S.; Vorbru¨ggen, H. J . Med. Chem. 1986, 29, 313-315. (b) Ohno, K.;
Nishiyama, H.; Nagase, H. Tetrahedron Lett. 1990, 31, 4489-4492.
(c) Viger, A.; Coustal, S.; Schambel, P.; Marquet, A. Tetrahedron 1991,
47, 7309-7322. (d) Shibasaki, M.; Takahashi, A.; Aoki, T.; Sato, H.;
Yamada, S.; Kudo, M.; Kogi, K.; Narita, S. Chem. Pharm. Bull. 1992,
40, 279-281.
(11) Some recent examples: (a) Quayle, P.; Rahman, S.; Ward, E.
L. M.; Herbert, J . Tetrahedron Lett. 1994, 35, 3801-3804. (b) Okamoto,
S.; Kasatkin, A.; Zubaidha, P. K.; Sato, F. J . Am. Chem. Soc. 1996,
118, 2208-2216. (c) Mcdonald, F. E.; Gleason, M. M. J . Am. Chem.
Soc. 1996, 118, 6648-6659. (d) Taber, D. F.; Wang, Y. J . Am. Chem.
Soc. 1997, 119, 22-26. (e) Liang, K. W.; Li, W. T.; Peng, S. M.; Wang,
S. L.; Liu, R. S. J . Am. Chem. Soc. 1997, 119, 4404-4412. (f) Ogawa,
A.; Kuniyasu, H.; Sonoda, N.; Hirao, T. J . Org. Chem. 1997, 62, 8361-
8365. (g) Ma, S. M.; Negishi, E. J . Org. Chem. 1997, 62, 784-785. (h)
Reference 7y.
(12) (a) Reetz, M. T.; Westermann, J .; Steinbach, R.; Wenderoth,
B.; Peter, R.; Ostarek, R.; Maus, S. Chem. Ber. 1985, 118, 1421-1440.
(b) Krause, N.; Seebach, D. Chem. Ber. 1987, 120, 1845-1851.
(13) Related eliminations of alkoxide anion from organosamarium
intermediates: (a) Molander, G. A.; Mckie, J . A. J . Org. Chem. 1994,
59, 3186-3192. (b) Molander, G. A.; Harris, C. R. J . Org. Chem. 1998,
63, 812-816. (c) Molander, G. A.; Harris, C. R. J . Org. Chem. 1998,
63, 4374-4380. (d) Molander, G. A.; Harris, C. R. J . Org. Chem. 1998,
63, 4374-4380.

SmI2/Pd(0)-Mediated Intramolecular Coupling
J . Org. Chem., Vol. 64, No. 6, 1999 1895
Ta ble 2. P r ep a r a tion of Cyclop en ta n ols 7a -h fr om
Ester sa 4a -h (eq 1)
Sch em e 4
4
R1
R2
R4
R5
7 (%)
cis/ trans ratiob
4a
4b
4c
4d
4e
4f
H
H
H
H
H
H
Me
Me
Bn
Bn
Bn
Bn
H
H
H
H
Me
Me n-Bu
H
H
Me (CH2)2OBn
Me CH2OBn
Me (CH2)2OBn
Me CH2OBn
H
7a (87)
7b (91)
7c (9)e
7d (8)
7e (72)
7f (64)
7g (61)
7h (72)
c
d
d
f
H
n-Bu
1:1.9
1.1:1
6.7:1
7.0:1
be the case for SmI2-induced cyclizations leading to
closely related products under similar aprotic conditions.14a
Thus, in the preferred conformation of the cyclized
samarium alkoxide the alkynyl group would occupy the
convex face of the bicyclic structure generated by chela-
tion (Scheme 4).
4g
4h
a
All esters are benzoates except for acetate 4e. b Cis, trans refer
to isomers with alkynyl and OH groups in a relative cis or trans
orientation, respectively. c Mixture of four diastereomers in a ratio
d
The stereochemical assignments for alcohols 7e,f were
readily made after the observation of NOE’s between H-2
and C1-Me that were larger in the cis-isomers (10-12%
vs 3-5%). Similar NOE studies performed on major 7i
indicated a trans-relationship between the alkynyl and
OH groups (see Supporting Information), and this was
supported by the large pyridine-induced downfield shift15
observed for the propargylic methine protons of the major
7i,j isomers (∆δ ≈ 0.58-0.61). A cis-relationship between
the CO2Et and OH groups in the major 7i,j isomers was
initially assigned based on literature precedent,14 and
confirmed by comparison of the IR carbonyl stretching
frequencies in dilute solutions with relevant literature
examples.14b,c For 7g,h small NOE’s were observed
between the Me groups of the major 7g isomer, but a
meaningful comparison with the minor isomer could not
be made due to the small magnitude of the effects and
overlap between the resonances of the OH and one of the
Me groups in the latter. NOE studies on 7h were
precluded by the impossibility to separate both isomers.
A cis stereochemistry between the alkynyl and OH
substituents was tentatively assigned to the major 7g,h
isomers based on the relative pyridine-induced downfield
shifts of the C2-Me protons that were much more pro-
nounced in the minor (trans) isomers of 7g,h (∆δ ≈ 0.28-
0.33) as compared to the major (cis) ones (∆δ ≈ 0.05-
0.08).
of 1.5 (two isomers):1.5:1. Mixture of four diastereomers in a ratio
of 1.6 (two isomers):1 (two isomers). e 11.2 mol % of catalyst was
used. f A 5.2:1 cis/ trans or trans/ cis ratio.
reactions of substrates 4f and 4h . The effective genera-
tion of two contiguous functionalized quaternary centers
with good stereoselectivity from esters 4g and 4h (eq 1,
Table 2) is particularly remarkable. In contrast to the
behavior observed with ketones, the results obtained for
4c and 4d (eq 1, Table 2) indicate that aldehyde carbonyl
groups are not suitable partners for this cyclization
reaction as complex reaction mixtures and low yields of
products were obtained with those substrates. The method
was also extended to â-ketoesters 6e,f (eq 2). Reaction
conditions for these substrates were worked out after
previous experimentation with substrate 6a (vide infra)
and involved dropwise addition of SmI2 to 6e,f and Pd-
(PPh3)4 at 25 °C.
Syn th esis of Bicyclic Alcoh ols. (a ) F ive-Mem -
ber ed Rin g F or m a tion . We also sought to extend this
cyclization to the formation of bicyclic products. The
successful cyclization of 4i,j (eq 3) underlines the poten-
tial of this methodology for the preparation of bicyclic
structures with three contiguous quaternary centers.
As shown in Table 2, cyclopentanols derived from
tertiary propargyl esters 4g,h were formed with moderate
stereoselectivity, whereas simple secondary propargyl
esters 4a -f reacted in general with low or no selectivity.
In contrast, secondary propargyl esters 6e,f, featuring a
ketone carbonyl group with an R-alkoxycarbonyl sub-
stituent, afforded the corresponding cyclopentanol prod-
ucts 7i,j with very high stereoselectivity (eq 2); out of four
possible isomers one was obtained in at least a 19:1 ratio.
The very high stereoselectivity observed in the formation
of 7i,j probably stems out of both the chelating ability of
the CO2Et group toward Sm(III) and the intervention of
retroaldol-aldol-type processes14 in the cyclized sa-
marium alkoxides (Scheme 4). This has been shown to
Thus, terminal propargylic ester 4i, under the conditions
(14) (a) Molander, G. A.; Etter, J . B.; Zinke, P. W. J . Am. Chem.
Soc. 1987, 109, 453-463. (b) Molander, G. A.; Kenny, C. J . Am. Chem.
Soc. 1989, 111, 8236-8246. (c) Molander, G. A.; Kenny, C. J . Org.
Chem. 1991, 56, 1439-1445.
(15) Demarco, P. V.; Farkas, E.; Doddrell, D.; Mylari, B. L.; Wenkert,
E. J . Am. Chem. Soc. 1968, 90, 5480-5486.

1896 J . Org. Chem., Vol. 64, No. 6, 1999
Aurrecoechea et al.
Ta ble 3. P r ep a r a tion of Cyclop en ta n ols 13 fr om Ester s
utilized for 4a , afforded the desired alcohol 8a (46%, 2.7:1
diastereomeric mixture), accompanied by a product ten-
tatively assigned the dimeric structure 9 (14%). This
assignment is supported by IR, 1H- and 13C NMR, as well
as MS data. The formation of 9 is the result of two
sequential intermolecular6a and intramolecular SmI2/Pd-
(0)-mediated couplings between two molecules of 4i. The
yield of the bicyclic products was slightly improved (51%)
by working at lower concentrations (a factor of 2.5) and
increasing the amount of catalyst to 10 mol %. However,
the amount of dimer isolated remained the same, and
higher dilutions led only to longer reaction times without
noticeable changes in the relative amounts of 8a to 9.
Interestingly, the internal alkyne 4j cyclized in good yield
to afford bicyclic alcohol 8b as a single diastereomer,
along with a small amount of allene 10 (11%), presum-
ably formed by early protonation of an organosamarium
intermediate.16 For best results this reaction had to be
run at 60 °C. Lower temperatures resulted in increasing
amounts of allene 10 at the expense of cyclized product.
6a -d (eq 5)
ester
R
n
13 (%)
diast ratio
6a
H
n-Bu
H
1
1
2
2
13a (87)
13b (62)
13c (88)
13d (70)
a
a
6bb
6cb
6d b
24:1
a
n-Bu
a
b
A single isomer was obtained. 10-12.6 mol % Pd catalyst
was used.
isomer of alcohols 8b and 11 for comparison purposes
precluded any stereochemical assignment for these sub-
stances.
As expected (vide supra), secondary propargylic ac-
etates 6a -d with a tethered â-ketoester provided bicyclic
alcohols 13 with excellent stereocontrol (eq 5, Table 3).
A strong dependence on the order of addition of reagents
was found in these reactions. Thus, when a mixture of
6a and Pd(PPh3)4 was added to SmI2 at room tempera-
ture, the starting material was consumed immediately
and the expected product 13a was obtained as a single
diastereomer. However, the high reactivity toward SmI2
of the â-ketoester14c relative to the propargylic ester
functionality also led to side reactions that produced large
amounts of untractable polar material, significantly
lowering the cyclization yield (24%). By adding the SmI2
solution dropwise to the solution of 6a and Pd(PPh3)4, a
comparatively high concentration of the allenylpalladium
complex, relative to SmI2, is maintained throughout the
reaction, thus avoiding competing side reactions between
the â-ketoester and SmI2. Bicyclic alcohol 13a was
obtained in this way in 87% yield as a single diastere-
omer. Similar reaction conditions were applied to sub-
strates 6b-d (eq 5, Table 3) and 6e,f (vide supra) with
comparable outcomes. Not surprisingly, the cyclic ketone
6g, lacking the ethoxycarbonyl substituent, produced a
mixture of bicyclic alcohols 14 with low selectivity (eq
6).
The reactivity of aldehyde 4k (eq 4) was also explored
in an attempt to gain advantage of the bias toward
cyclization brought about by the existing ring in the
substrate. Addition of 4k and Pd(PPh3)4 to SmI2 at
different temperatures led only to very complex mixtures.
The desired product 11 was obtained in low yield (21%,
one diastereomer) when SmI2 was added to the solution
of 4k and the catalyst at 40 °C. Therefore, it is concluded
that the use of aldehydes is not compatible with this
methodology.
The relative stereochemistry assigned to bicyclic alco-
hols 8a was based on the observation that the endo Me
1
carbinol substituent in the major isomer had H and 13C
NMR resonances that were shielded with respect to the
corresponding resonances in the minor isomer.17a This
preference for a cis-relationship between alkynyl and OH
groups is in line with that observed for similarly substi-
tuted cyclopentanols 7g,h . The absence of the minor
Analogously to the 7i,j cases discussed above, the
stereochemical assignments of bicyclic alcohols 13 relied
on a combination of NOE studies, pyridine-induced shifts,
and IR data. Thus, NOE’s (9-10%) were observed
between the OH and the propargylic methine proton of
13, indicating a trans-relationship between the alkynyl
and OH functionalities in the major cyclization products.
This assignment was supported by the large pyridine-
induced deshielding15 experienced by the propargylic
methine protons (∆δ ≈ 0.51-0.84) when comparing the
(16) (a) Tabuchi, T.; Inanaga, J .; Yamaguchi, M. Tetrahedron Lett.
1986, 27, 5237-5240. (b) It is also interesting that allene 10 was
isolated as a single diastereomer. An example of very high diastereo-
selectivity in allene formation from a propargyl ester and SmI2/Pd(0)
has been previously reported: Vanalstyne, E. M.; Norman, A. W.;
Okamura, W. H. J . Am. Chem. Soc. 1994, 116, 6207-6216.
(17) (a) Whitesell, J . K.; Minton, M. A. Stereochemical Analysis of
Alicyclic Compounds by C-13 NMR Spectroscopy; Chapman and Hall:
London, 1987; pp 137-146. (b) Eliel, E. L.; Wilen, S. H.; Mander, L.
N. Stereochemistry of Organic compounds; J ohn Wiley & Sons: New
York, 1994; p 776.

SmI2/Pd(0)-Mediated Intramolecular Coupling
J . Org. Chem., Vol. 64, No. 6, 1999 1897
1H NMR spectra taken in pyridine-d5 and CDCl3. The
cis-relationship between the CO2Et and OH groups was
based again on the observed carbonyl stretching frequen-
cies in dilute solutions.14b,c For bicyclic products 14 a cis
ring fusion was assumed from ring strain considerations.17b
Stereochemical assignments at C2 followed from the
larger pyridine-induced15 deshielding experienced by the
exo-propargylic proton in the major (trans) isomer (∆δ ≈
0.37) as compared to the corresponding shift in the endo-
proton of the minor (cis) isomer (∆δ ≈ 0.09).
out with either a LiChrosorb Si60 (7 µm, 25 × 2.5 cm, column
1) or a µPorasil (10 µm, 19 × 1.5 cm, column 2) column using
a refraction index detector. Preparative thin-layer chroma-
tography was performed on silica gel plates (Si60+F254, 17
µm, 20 × 20 cm, 0.25 mm). In Kugelrhor distillations the bp
1
refers to the external oven air temperature. H and 13C NMR
spectra were obtained at 250 and 62.9 MHz, respectively, using
CDCl3 as solvent and internal reference (δ 7.26 for 1H and δ
77.0 for 13C). IR data include only characteristic absorptions.
Mass spectra were obtained at 70 eV. GC-MS analysis were
performed at 70-280 °C (20 °C/min) with a stationary phase
of methylphenylsilicone (0.25 µm, 30 m × 0.25 mm).
Syn th esis of Bicyclic Alcoh ols. (b) Six-Mem ber ed
R in g F or m a t ion . The analogous formation of six-
membered rings was much less efficient (eq 7). The
desired products 15 were obtained in low yields as
mixtures of diastereomers with low diastereoselectivity.
The alkynes 16 were formed in significant amounts as
byproducts in these reactions. A likely explanation is that
a slower cyclization rate in these cases would cause the
protonation of the presumed organosamarium intermedi-
ate to compete efficiently with cyclization.
P r ep a r a tion of 1-(1-Ben zyl-4-oxop en tyl)p r op -2-yn yl
Ben zoa te (4a ). A solution of N-(3-phenylpropylidene)cyclo-
hexylamine (4.81 g, 22.39 mmol) in THF (30 mL) was slowly
added to LDA [prepared from diisopropylamine (3.8 mL, 26.82
mmol and n-butyllithium (1.5 M, 15.6 mL, 23.5 mmol) in THF
(75 mL)] at -78 °C under Ar. The resulting solution was
warmed to -20 °C, stirred at this temperature for 90 min, and
recooled to -78 °C. A solution of 2-(2-bromoethyl)-2-methyl-
1,3-dioxolane22 (5.18 g, 26.86 mmol) in THF (15 mL) was then
added, and the mixture was allowed to reach rt and stirred
further 18 h. After quenching with saturated NH4Cl (20 mL),
the aqueous layer was extracted with diethyl ether, and the
combined organic layers were washed successively with 1 M
HCl, 1 M NaOH, and brine, and dried (Na2SO4). Evaporation
of the solvents left an oil that was purified by flash chroma-
tography (20% EtOAc/hexanes) yielding 2.86 g (51%) of 2-ben-
zyl-4-(2-methyl-1,3-dioxolan-2-yl)butanal (1a ) as a yellowish
oil: 1H NMR δ 1.17 (s, 3H), 1.4-1.7 (m, 4H), 2.5-2.7 (m, 2H),
2.90 (dd, J ) 13.4, 6.9 Hz, 1H), 3.7-3.8 (m, 4H), 7.0-7.2 (m,
5H), 9.56 (d, J ) 2.3 Hz, 1H); 13C NMR δ 22.6, 23.5, 34.8, 35.7,
52.8, 64.3, 109.3, 126.1, 128.2, 128.7, 138.5, 203.9.
A solution of 1a (1.10 g, 4.43 mmol) in THF (13 mL) was
added dropwise to a solution of ethynyllithium23 (4.87 mmol)
in THF (36 mL) at -78 °C. The mixture was stirred at the
same temperature for 20 min, allowed to reach rt, and stirred
further 1 h. To the well-stirred solution was added neat
benzoyl chloride (1.03 mL, 8.87 mmol), and the mixture was
stirred at room temperature for 1 h and quenched with water
(13 mL). The whole was extracted with diethyl ether, and the
organic extracts were dried (Na2SO4). The crude product was
purified by flash chromatography (10% EtOAc/hexanes) to
yield 1-[1-benzyl-3-(2-methyl-1,3-dioxolan-2-yl)propyl]prop-2-
ynyl benzoate (3a ) (93%, 7:3 diastereomeric mixture) as a
colorless oil: 1H NMR δ 1.29 (s, 3H, major diast), 1.30 (s, 3H,
minor diast), 1.6-1.9 (m, 4H), 2.2-2.3 (m, 1H), 2.53 (d, J )
2.0 Hz, 1H, minor diast), 2.56 (d, J ) 2.0 Hz, 1H, major diast),
2.7-3.0 (m, 2H), 3.8-3.9 (m, 4H), 5.57 (dd, J ) 4.1, 2.0 Hz,
1H, major diast), 5.62 (dd, J ) 3.9, 2.1 Hz, 1H, minor diast),
7.2-7.6 (m, 8H), 7.9-8.0 (m, 2H); 13C NMR δ 23.3, 23.6, 24.2,
35.8, 36.1, 36.5, 43.6, 43.9, 64.0, 66.0, 66.2, 74.9, 75.1, 77.2,
79.3, 79.4, 109.3, 109.4, 125.7, 128.0, 128.1, 128.6, 128.8, 129.3,
129.4, 132.7, 139.2, 139.6, 164.6; IR (neat) ν 3286, 2119, 1730
cm-1. Anal. Calcd for C24H26O4: C, 76.15; H, 6.92. Found: C,
76.17; H, 6.76.
Con clu sion s
When treated with SmI2/Pd(0), propargylic esters
undergo intramolecular reductive coupling to tethered
aldehydes or ketones to afford homopropargyl cycloal-
kanol products. Efficient couplings, in terms of yield and
diastereoselectivity, are realized for five-membered ring
formation from substrates containing either a ketone
carbonyl group and a tertiary propargylic ester or a
â-ketoester. Resident ether and ester functionalities
incorporated in the substrates have been shown to be
compatible with this chemistry. The available data in
SmI2-promoted reactions indicate that this will also be
the case for other useful functionality.1
A solution of 3a (1.20 g, 3.17 mmol) and p-TsOH (50 mg) in
acetone (100 mL) was stirred at 35 °C for 48 h. After adding
saturated aqueous NaHCO3 (20 mL), the mixture was evapo-
rated to dryness and partitioned between EtOAc (60 mL) and
water (20 mL). The aqueous layer was extracted with EtOAc
and the organic extracts were dried (Na2SO4). The crude
product was purified by flash chromatography (10% EtOAc/
hexanes) to yield the ketone 4a (98%, 7:3 diastereomeric
mixture) as a thick oil: 1H NMR δ 1.8-1.9 (m, 1H), 1.9-2.0
(m, 1H), 2.07 (s, 3H, major diast), 2.10 (s, 3H, minor diast),
2.2-2.3 (m, 1H), 2.4-2.6 (m, 3H), 2.6-2.8 (m, 1H), 2.9-3.0
(m, 1H), 5.56 (dd, J ) 3.8, 2.2 Hz, 1H, major diast), 5.60 (dd,
J ) 3.8, 2.3 Hz, 1H, minor diast), 7.1-7.3 (m, 5H), 7.4-7.5
(m, 2H), 7.5-7.6 (m, 1H), 7.95 (d, J ) 7.9 Hz, 2H, minor diast),
Exp er im en ta l Section
Gen er a l. All reactions involving air- and moisture-sensitive
materials were performed using standard benchtop tech-
niques.18 Diiodoethane was purified as reported.19 Tetrahy-
drofuran (THF) was freshly distilled from sodium/benzophe-
none and, for reactions with SmI2, it was deoxygenated prior
to use. Other solvents were routinely purified using literature
procedures.20 Flash column chromatography21 was performed
on silica gel (230-400 mesh). HPLC purifications were carried
(18) Brown, H. C.; Kramer, G. W.; Levy, A. B.; Midland, M. M.
Organic Synthesis Via Boranes; J ohn Wiley & Sons: New York, 1975;
pp 191-261.
(19) Molander, G. A.; Etter, J . B. J . Org. Chem. 1986, 51, 1778-
1786.
(20) Perrin, D. D.; Armarego, W. F. L. Purification of Laboratory
Chemicals; 3rd ed.; Pergamon Press: Oxford, 1988.
(21) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.
(22) Flannery, R. E.; Hampton, G. K. J . Org. Chem. 1972, 37, 2806-
2810.
(23) Midland, M. M.; McLoughlin, J . I.; Werley, R. T. Org. Synth.
1989, 68, 14-24.

1898 J . Org. Chem., Vol. 64, No. 6, 1999
Aurrecoechea et al.
8.02 (d, J ) 7.8 Hz, 2H, major diast); 13C NMR δ 23.7, 24.1,
29.7, 29.8, 36.5, 37.1, 41.1, 41.2, 43.3, 43.6, 66.1, 66.5, 75.3,
75.4, 79.2, 79.4, 126.2, 126.4, 128.4, 128.5, 128.9, 129.1, 129.4,
129.5, 129.7, 133.3, 139.2, 139.5, 165.2, 207.9, 208.1; IR (neat)
ν 3280, 2110, 1730 cm-1. Anal. Calcd for C22H22O3: C, 79.00;
H, 6.63. Found: C, 78.67; H, 6.64.
66.6, 75.0, 75.2, 79.4, 79.7, 104.3, 104.4, 126.1, 126.3, 128.3,
128.5, 129.0, 129.1, 129.7, 133.1, 139.4, 139.9, 165.2; IR (neat)
ν 3280, 2120, 1730 cm-1. Anal. Calcd for C23H24O4: C, 75.80;
H, 6.63. Found: C, 75.86; H, 6.76.
A solution of 3c (0.95 g, 2.6 mmol) in acetic acid/water (1:1,
2 mL) was stirred and refluxed for 1 h. After cooling, the
solution was made neutral with saturated K2CO3 and extracted
with diethyl ether. The combined organic extracts were washed
with brine and dried (Na2SO4). Purification by flash chroma-
tography (15% EtOAc/hexanes) afforded the aldehyde 4c (0.82
g, 7:3 diastereomeric mixture) as a colorless oil that contained
∼14% of the starting acetal. HPLC purification (Column 2,
15% EtOAc/hexanes, 6 mL/min) provided the pure sample: 1H
NMR δ 1.8-1.9 (m, 1H), 1.9-2.1 (m, 1H), 2.2-2.3 (m, 1H),
2.5-2.6 (m, 3H), 2.60 (d, J ) 2.1 Hz, 1H, overlapped with mult
at 2.5-2.6), 2.7-2.8 (m, 1H), 2.9-3.0 (m, 1H), 5.5-5.6 (m, 1H),
7.1-7.6 (m, 8H), 7.9-8.0 (m, 2H), 9.73 (br s, W1/2 ) 3.6 Hz,
1H); 13C NMR δ 22.1, 22.4, 36.5, 37.1, 41.5, 41.6, 43.3, 43.7,
65.9, 66.5, 75.4, 75.6, 78.9, 79.4, 126.3, 126.5, 128.4, 128.6,
128.9, 129.1, 129.5, 129.7, 133.3, 138.9, 139.3, 165.2, 201.6;
P r ep a r a tion of 1-(1-Ben zyl-4-oxop en tyl)h ep t-2-yn yl
Ben zoa te (4b). n-Butyllithium (1.5 M, 5.1 mL, 7.54 mmol)
was added to a solution of 1-hexyne (1.10 mL, 9.59 mmol) in
THF (15 mL) at -78 °C under Ar, and the resulting solution
was stirred at the same temperature for 30 min. A solution of
1a (1.70 g, 6.85 mmol) in THF (20 mL) was added, the reaction
mixture was allowed to reach rt and stirred further 1 h before
adding neat benzoyl chloride (1.60 mL, 13.71 mmol). After
stirring the mixture 1 h at room temperature, it was quenched
with water (15 mL) and extracted with diethyl ether. The
organic extracts were dried (Na2SO4), and the crude product
was purified by flash chromatography (15% EtOAc/hexanes)
to yield 1-[1-benzyl-3-(2-methyl-1,3-dioxolan-2-yl)propyl]hept-
2-ynyl benzoate (3b) (2.91 g, 98%, ∼2:1 diastereomeric mix-
ture) as a viscous oil: 1H NMR δ 0.92 (t, J ) 7.0 Hz, 3H, minor
diast), 0.93 (t, J ) 7.0 Hz, 3H, major diast), 1.29 (s, 3H, major
diast), 1.30 (s, 3H, minor diast), 1.4-1.8 (m, 8H), 2.2-2.3 (m,
3H), 2.71 (dd, J ) 13.8, 7.3 Hz, 1H, minor diast), 2.76 (dd, J
) 13.8, 7.0 Hz, 1H, major diast), 2.91 (dd, J ) 13.8, 7.3 Hz,
1H, major diast), 2.98 (dd, J ) 13.8, 7.0 Hz, 1H, minor diast),
3.8-4.0 (m, 4H), 5.57 (td, J ) 4.2, 2.1 Hz, 1H, major diast),
5.62 (td, J ) 4.1, 2.0 Hz, 1H, minor diast), 7.2-7.6 (m, 8H),
7.9-8.0 (m, 2H); 13C NMR δ 13.5, 18.4, 21.9, 23.6, 24.2, 24.7,
30.5, 30.6, 36.3, 36.6, 37.2, 44.5, 44.7, 64.5, 67.1, 67.3, 75.9,
75.9, 87.5, 87.6, 109.9, 109.9, 125.9, 126.1, 128.2, 128.3, 129.0,
129.2, 129.6, 130.0, 130.1, 132.8, 139.9, 140.4, 165.4; IR (neat)
IR (neat) ν 3290, 2110, 1730 cm-1
.
P r ep a r a tion of 5-(Ben zyloxy)-1-(4-oxop en tyl)p en t-2-
yn yl Eth a n oa te (4e). A solution of ethyl 4-acetylbutyrate
(11.80 g, 75.0 mmol), ethylene glycol (5.5 mL, 98.6 mmol), and
p-TsOH (1.70 g, 8.8 mmol) in benzene (150 mL) was refluxed
in a Dean-Stark for 4 h. The residue after evaporation of the
solvent was partitioned between H2O (125 mL) and EtOAc (125
mL), and the aqueous layer was extracted with EtOAc. The
combined organic layers were evaporated affording ethyl 4-(2-
methyl-1,3-dioxolan-2-yl)butanoate (14.60 g, 96%) as a color-
less liquid that was used in the next step without further
manipulation: 1H NMR δ 1.17 (t, J ) 7.1 Hz, 3H), 1.24 (s,
3H), 1.61-1.67 (m, 4H), 2.24 (distorted t, 2H), 3.83-3.87 (m,
4H), 4.05 (q, J ) 7.1 Hz, 2H); 13C NMR δ 14.1, 19.4, 23.6, 34.1,
38.1, 60.6, 64.4, 109.5, 173.3. A portion of this material (2.00
g, 10 mmol) was dissolved in toluene (20 mL) at -78 °C under
Ar and DIBALH (1.0 M in hexanes, 10.5 mL, 10.5 mmol) was
added dropwise. The resulting suspension was stirred for 30
min at -78 °C before adding MeOH (0.4 mL). The mixture
was allowed to warm to -10 °C, MeOH/H2O (1:1, 1.10 mL)
was added, and the reaction was allowed to reach rt. Anhy-
drous Na2SO4 (2 g) was added, and the mixture was stirred
for 15 min. The resulting suspension was filtered through
Celite and the solids were washed with EtOAc. The crude after
evaporation was purified by flash chromatography (15%
EtOAc/hexanes) to yield 4-(2-methyl-1,3-dioxolan-2-yl)buta-
nal25 (1c) (900 mg, 57%) as a colorless liquid: 1H NMR δ 1.23
(s, 3H), 1.61-1.66 (m, 4H), 2.39 (distorted t, 2H), 3.84 (m, 4H),
9.67 (d, J ) 1.6 Hz, 1H); 13C NMR δ 16.6, 23.7, 38.3, 43.8,
64.6, 109.7, 202.3.
n-Butyllithium (1.37 M, 2.8 mL, 3.9 mmol) was added
dropwise to a solution of 4-(benzyloxy)but-1-yne (0.64 g, 4.0
mmol) in THF (20 mL) at -78 °C under Ar, and the mixture
was stirred for 30 min. A solution of 1c (0.61 g, 3.9 mmol) in
THF (6 mL) was added, and the mixture was allowed to reach
rt and stirred 3 h at this temperature. Water (20 mL) was
added, the aqueous layer was extracted with EtOAc, and the
combined organic layers were dried (Na2SO4). The crude
product was treated with Et3N (0.87 mL, 6.2 mmol), Ac2O (0.78
mL, 8.2 mmol), and 4-(dimethylamino)pyridine (DMAP) (0.14
g, 1.3 mmol) for 14 h at room temperature. The mixture was
evaporated under reduced pressure, and the residue was
dissolved in diethyl ether (40 mL). The solution was succes-
sively washed with 1 M HCl, 1 M NaOH, and brine and dried
(Na2SO4). The crude product was purified by flash chroma-
tography (20% EtOAc/hexanes) to afford 5-(benzyloxy)-1-[3-
(2-methyl-1,3-dioxolan-2-yl)propyl]pent-2-ynyl ethanoate (3e)
(0.92 g, 65%, over two steps) as a thick oil: 1H NMR δ 1.53 (s,
3H), 1.5-1.7 (m, 6H), 2.04 (s, 3H), 2.51 (t, J ) 7.0 Hz, 2H),
3.56 (t, J ) 7.0 Hz, 2H), 3.88 (m, 4H), 4.52 (s, 2H), 5.34 (m,
1H), 7.2-7.3 (m, 5H); 13C NMR δ 19.6, 20.1, 21.0, 23.7, 35.0,
ν 2230, 1720 cm-1
.
A solution of 3b (2.90 g, 6.70 mmol) and p-TsOH (100 mg)
in acetone/water (40:1, 205 mL) was stirred at 35 °C for 7 h.
After adding a saturated NaHCO3 solution (20 mL), the
mixture was evaporated to dryness and partitioned between
diethyl ether (100 mL) and water (20 mL). The aqueous layer
was extracted with diethyl ether, the combined organic layers
were dried (Na2SO4), and the solvents were evaporated. The
crude product was purified by flash chromatography (15%
EtOAc/hexanes) to yield the diastereomeric mixture (2.2:1) of
ketone 4b (2.60 g, 99%) as a thick oil: 1H NMR δ 0.9 (m, 3H),
1.4-1.6 (m, 4H), 1.7-2.0 (m, 2H), 2.06 (s, 3H, major diast),
2.10 (s, 3H, minor diast), 2.1-2.3 (m, 3H), 2.4-2.7 (m, 3H),
2.95 (dd, J ) 14.1, 6.9 Hz, 1H), 5.6 (m, 1H), 7.1-7.3 (m, 5H),
7.4-7.5 (m, 2H), 7.56 (t, J ) 7.3 Hz, 1H), 7.95 (d, J ) 7.3 Hz,
2H, minor diast), 8.02 (d, J ) 7.2 Hz, 2H, major diast); 13C
NMR δ 13.3, 18.2, 21.7, 23.7, 24.2, 29.4, 29.5, 30.3, 30.4, 36.6,
37.2, 41.0, 41.2, 43.6, 43.9, 66.7, 67.0, 75.5, 75.6, 87.7, 87.8,
125.9, 126.1, 128.2, 128.3, 128.8, 128.9, 129.5, 129.7, 129.8,
132.9, 139.4, 139.8, 165.1, 207.7, 207.8; IR (neat) ν 2220, 1740
cm-1. Anal. Calcd for C26H30O3: C, 79.95; H, 7.74. Found: C,
79.63; H, 7.74.
P r epar ation of 1-(1-Ben zyl-4-oxobu tyl)pr op-2-yn yl Ben -
zoa te (4c). The procedure used in the preparation of 1a was
followed starting from 2-(2-iodoethyl)-1,3-dioxolane24 to yield
2-benzyl-4-(1,3-dioxolan-2-yl)butanal (1b) (63%): 1H NMR δ
1.6-1.8 (m, 4H), 2.6-2.8 (m, 2H), 2.9-3.0 (m, 1H), 3.8-3.9
(m, 4H), 4.83 (t, J ) 4.0 Hz, 1H), 7.1-7.3 (m, 5H), 9.68 (d, J
) 1.9 Hz, 1H); 13C NMR δ 22.4, 30.8, 34.9, 52.7, 64.6, 103.7,
126.2, 128.3, 128.7, 138.5, 203.9; IR (neat) ν 1730 cm-1
.
The procedure used in the preparation of 3a was followed
from 1b to yield 1-[1-benzyl-3-(1,3-dioxolan-2-yl)propyl]prop-
2-ynyl benzoate (3c) (84%, 7:3 diastereomeric mixture) as a
viscous oil: 1H NMR δ 1.6-1.9 (m, 4H), 2.2-2.3 (m, 1H), 2.54
(d, J ) 1.5 Hz, 1H, minor diast), 2.56 (d, J ) 1.5 Hz, 1H, major
diast), 2.7-3.0 (m, 2H), 3.8-3.9 (m, 4H), 4.85 (m, 1H), 5.56
(br s, W1/2 ) 8.0 Hz, 1H, major diast), 5.62 (br s, W1/2 ) 7.7
Hz, 1H, minor diast), 7.2-7.6 (m, 8H), 7.94 (d, J ) 7.7 Hz,
2H, minor diast), 8.02 (d, J ) 7.6 Hz, 2H, major diast); 13C
NMR δ 24.0, 24.5, 31.3, 31.4, 36.4, 36.9, 43.9, 44.3, 64.8, 66.3,
(25) Curran, D. P.; Heffner, T. A. J . Org. Chem. 1990, 55, 4585-
4595.
(24) Larson, G. L.; Klesse, R. J . Org. Chem. 1985, 50, 3627.

SmI2/Pd(0)-Mediated Intramolecular Coupling
J . Org. Chem., Vol. 64, No. 6, 1999 1899
38.4, 64.2, 64.5, 68.2, 72.9, 78.6, 82.7, 109.8, 127.5, 128.3, 138.5,
23.3, 27.7, 32.6, 33.6, 37.4, 59.3, 60.8, 64.2, 109.0, 170.5, 214.2;
169.9; IR (CHCl3) ν 2240, 1745 cm-1
.
IR (neat) ν 1760, 1730 cm-1
.
The hydrolysis procedure used in the preparation of 4b was
applied to 3e to afford the ketone 4e (92%) as a thick oil: 1H
NMR δ 1.6-1.7 (m, 4H), 2.04 (s, 3H), 2.10 (s, 3H), 2.43 (br t,
2H), 2.51 (td, J ) 7.0, 1.7 Hz, 2H), 3.56 (t, J ) 7.0 Hz, 2H),
The alkynylation procedure previously described for the
preparation of 3a was followed from ketone 1e to yield
2-(ethoxycarbonyl)-1-ethynyl-2-[2-(2-methyl-1,3-dioxolan-2-yl)-
ethyl]cyclopentyl benzoate (3i) (94%, 97:3 diastereomeric
mixture) as a thick oil: 1H NMR δ 1.21 (t, J ) 7.1 Hz, 3H),
1.28 (s, 3H), 1.5-1.8 (m, 6H), 2.2-2.4 (m, 3H), 2.60 (s, 1H),
2.8-2.9 (m, 1H), 3.8-3.9 (m, 4H), 4.1-4.2 (m, 2H), 7.3-7.4
(m, 2H), 7.4-7.5 (m, 1H), 8.00 (d, J ) 7.1 Hz, 2H); 13C NMR
δ 13.9, 19.0, 19.7, 23.6, 25.4, 27.3, 29.2, 33.7, 34.0, 34.2, 36.7,
60.5, 62.0, 64.4, 75.1, 76.8, 81.2, 81.8, 85.3, 109.4, 128.1, 129.3,
129.7, 130.1, 130.4, 132.8, 132.9, 164.1, 172.8; IR (neat) ν 3260,
2100, 1730 cm-1. Anal. Calcd for C23H28O6: C, 68.98; H, 7.05.
Found: C, 69.21; H, 6.93.
4.52 (s, 2H), 5.34 (br s, W1/2 ) 11.9 Hz, 1H), 7.32 (m, 5H); 13
C
NMR δ 19.1, 20.1, 20.9, 29.8, 34.1, 42.8, 63.8, 68.1, 72.9, 78.2,
83.0, 127.5, 128.3, 138.0, 169.9, 208.0; IR (CHCl3) ν 2280, 1740,
1720 cm-1; HRMS calcd for C17H21O2 (M - AcO) 257.1542,
found 257.1545; HRMS (FAB) calcd for
317.1753, found 317.1749.
C19H25O4 (M+1)
P r ep a r a tion of 5-(Ben zyloxy)-1-m eth yl-1-(4-oxop en -
tyl)p en t-2-yn yl Ben zoa te (4g). To a solution of LDA (41.3
mmol) in THF (60 mL) at 0 °C under Ar was added dropwise
acetone dimethylhydrazone26 (3.72 g, 37.2 mmol). The resulting
suspension was stirred for 2 h at 0 °C, and 2-(2-iodoethyl)-2-
methyl-1,3-dioxolane24 (10.0 g, 41.3 mmol) was added. The
mixture was allowed to warm to room temperature and was
stirred further 2 h. Water (50 mL) was added, and the aqueous
layer was extracted with diethyl ether. The combined organic
layers were dried (Na2SO4) and evaporated. The residue was
dissolved in a 1:1 mixture of THF and 2.5% HCl (120 mL) at
0 °C, and the mixture was stirred 2 h at the same temperature.
Water (30 mL) and saturated Na2CO3 (30 mL) were added,
and the whole was extracted with diethyl ether. The combined
organic layers were dried (Na2SO4) and evaporated, and the
crude was purified by flash chromatography (40% EtOAc/
hexanes) to yield 5-(2-methyl-1,3-dioxolan-2-yl)pentan-2-one
(1d )27 (3.40 g, 53%) as a yellowish oil: 1H NMR δ 1.25 (s, 3H),
1.5-1.6 (m, 4H), 2.07 (s, 3H), 2.40 (t, J ) 6.8 Hz, 2H), 3.8-3.9
(m, 4H); 13C NMR δ 18.2, 23.6, 29.7, 38.1, 43.4, 64.5, 109.7,
The hydrolysis procedure used in the preparation of 4b was
applied to 3i to yield the ketone 4i (93%, 97:3 diastereomeric
mixture) as an oil: 1H NMR δ 1.27 (t, J ) 7.1 Hz, 3H), 1.7-
1.9 (m, 2H), 1.9-2.0 (m, 2H), 2.16 (s, 3H), 2.3-2.6 (m, 5H),
2.62 (s, 1H), 2.8-2.9 (m, 1H), 4.20 (q, J ) 7.1 Hz, 2H), 7.43 (t,
J ) 7.5 Hz, 2H), 7.5-7.6 (m, 1H), 8.03 (d, J ) 7.5 Hz, 2H); 13
C
NMR δ 13.6, 18.8, 24.6, 29.3, 29.4, 36.4, 38.6, 38.9, 60.4, 61.4,
75.2, 79.2, 80.9, 81.5, 127.9, 129.1, 129.7, 129.9, 132.6, 163.7,
172.3, 206.6, 206.8; IR (KBr) ν 3260, 2120, 1730 cm-1. Anal.
Calcd for C21H24O5: C, 70.76; H, 6.78. Found: C, 70.85; H,
6.84.
P r ep a r a tion of Eth yl 1-(3-Acetoxyn on -4-yn yl)-2-oxo-
cyclop en ta n eca r boxyla te (6b). n-Butyllithium (1.6 M, 1.25
mL, 2 mmol) was added to a solution of 1-hexyne (0.164 g, 2
mmol) in THF (15 mL) at -78 °C. After stirring the resulting
solution for 30 min, chlorotitanium triisopropoxide (0.521 g, 2
mmol) was added and the clear solution stirred at -78 °C for
1 h. This solution was then added via cannula to a stirred
solution of 5a 28 (0.424 g, 2 mmol) in THF (15 mL) which had
been previously cooled to -78 °C. At the end of the addition
(ca. 30 min) the color of the reaction mixture was a light brown.
After stirring at -78 °C for 30 min, the mixture was allowed
to reach rt over a period of 2 h 30 min, kept at the same
temperature for 1 h, and poured over 1 M HCl (25 mL). The
aqueous layer was extracted with diethyl ether, and the
combined organic layers were dried (Na2SO4). The residue after
evaporation was dissolved in Et3N (4.9 mL, 35.2 mmol) and
to this solution were successively added Ac2O (285 µL, 3.02
mmol) and DMAP (47 mg, 0.385 mmol). The resulting solution
was stirred at room temperature for 15 h, after which the
solvent was evaporated and the residue was dissolved in
diethyl ether (30 mL). The solution was successively washed
with 1 M HCl, 1 M NaOH, and brine and dried (Na2SO4). The
crude acetate was purified by flash chomatography (15%
EtOAc/hexanes) to afford 0.472 g (70%, two steps) of pure 6b:
1H NMR δ 0.83 (t, J ) 7.1 Hz, 3H), 1.18 (t, J ) 7.1 Hz, 3H),
1.2-1.5 (m, 4H), 1.5-1.7 (m, 2H), 1.7-2.0 (m, 5H), 1.98 (s,
3H, overlapped with mult at 1.7-2.0), 2.0-2.5 (m, 5H), 4.09
(qd, J ) 7.1, 1.2 Hz, 2H), 5.25 (tt, J ) 6.0, 1.9 Hz, 1H); 13C
NMR δ 13.4, 13.9, 18.2, 19.4, 20.9, 21.7, 28.9, 30.3, 30.3, 32.9,
37.6, 59.5, 61.2, 64.0, 76.8, 86.5, 169.7, 170.6, 214.2; IR (neat)
ν 2240, 1750-1730 cm-1. Anal. Calcd for C19H28O5: C, 67.82;
H, 8.39. Found: C, 67.63; H, 8.49.
208.6; IR (CHCl3) ν 1720 cm-1
.
The alkynylation procedure previously described for the
preparation of 3b was followed from 4-(benzyloxy)but-1-yne
and ketone 1d to afford 5-(benzyloxy)-1-methyl-1-[3-(2-methyl-
1,3-dioxolan-2-yl)propyl]pent-2-ynyl benzoate (3g) (71%) as a
thick oil: 1H NMR δ 1.33 (s, 3H), 1.6-1.7 (m, 4H), 1.78 (s,
3H), 1.8-1.9 (m, 1H), 1.9-2.0 (m, 1H), 2.56 (t, J ) 7.0 Hz,
2H), 3.60 (t, J ) 7.0 Hz, 2H), 3.8-3.9 (m, 4H), 4.54 (s, 2H),
7.2-7.5 (m, 8H), 7.99 (d, J ) 7.8 Hz, 2H); 13C NMR δ 18.9,
20.2, 23.7, 26.8, 38.9, 41.9, 64.5, 68.4, 72.8, 76.0, 81.3, 82.5,
109.8, 127.5, 128.1, 128.2, 129.4, 131.2, 132.5, 138.1, 164.4;
IR (CHCl3) ν 2220, 1715 cm-1
.
The hydrolysis procedure used in the preparation of 4b was
applied to 3g to afford the ketone 4g (85%) as a thick oil: 1H
NMR δ 1.78 (s, 3H), 1.8-2.0 (m, 4H), 2.13 (s, 3H), 2.49 (t, J )
1.7 Hz, 2H), 2.56 (t, J ) 7.0 Hz, 2H), 3.60 (t, J ) 7.0 Hz, 2H),
4.54 (s, 2H), 7.2-7.4 (m, 8H), 7.99 (d, J ) 7.8 Hz, 2H); 13C
NMR δ 18.6, 20.1, 26.8, 29.7, 41.1, 43.2, 68.4, 72.8, 75.7, 81.0,
82.8, 127.5, 128.2, 128.3, 128.7, 129.4, 131.1, 132.6, 138.1,
164.6, 208.3; IR (CHCl3) ν 2230, 1720 cm-1; HRMS calcd for
C
25H28O4 392.1988, found 392.1988.
P r ep a r a tion of 2-(Eth oxyca r bon yl)-1-eth yn yl-2-(3-oxo-
bu tyl)cyclop en tyl Ben zoa te (4i). Ethyl 2-oxocyclopentane-
carboxylate (5.00 g, 32.05 mmol) was added dropwise at room
temperature to a suspension of NaH (0.756 g, 31.52 mmol) in
dry dimethoxyethane. The mixture was stirred until complete
disappearance of solid NaH. 2-(2-Iodoethyl)-2-methyl-1,3-
dioxolane24 (7.15 g, 29.42 mmol) was then added and the
mixture refluxed overnight. After cooling to room temperature,
the solvent was evaporated and the residue was treated with
water (20 mL), acidified with 3 M HCl, and extracted with
diethyl ether. After drying and evaporation of the solvent, the
crude product was purified by flash chromatography (20%
EtOAc/hexanes) to yield ethyl 1-[2-(2-methyl-1,3-dioxolan-2-
yl)ethyl]-2-oxocyclopentanecarboxylate (1e) (53%) as an oil: 1H
NMR δ 1.24 (t, J ) 7.1 Hz, 3H), 1.30 (s, 3H), 1.5-1.7 (m, 3H),
1.8-2.1 (m, 4H), 2.2-2.6 (m, 3H), 3.9-4.0 (m, 4H), 4.14 (q, J
) 7.1 Hz, 1H), 4.16 (q, J ) 7.1 Hz, 1H); 13C NMR δ 13.7, 19.2,
P r ep a r a tion of Eth yl 1-(4-Acetoxyh ex-5-yn yl)-2-oxo-
cyclop en ta n eca r boxyla te (6h ). Ethyl 2-oxocyclopentanecar-
boxylate (10.0 g, 64.03 mmol) was slowly added under Ar to a
suspension of NaH (1.56 g, 65.1 mmol) in dry dimethoxyethane
(100 mL). After the evolution of hydrogen had ceased, 5-bro-
mopent-1-ene (7.08 g, 59.76 mmol) was added, and the mixture
was refluxed for 40 h. After cooling, the resulting suspension
was filtered, the solid was washed with diethyl ether, and the
washings were added to the filtrate. After removing the solvent
under reduced pressure, water (75 mL) was added, the mixture
(28) Prepared following the procedure described in ref 29 for ethyl
1-(2-formylethyl)-2-oxocyclohexanecarboxylate.
(29) Cope, A. C.; Synerholm, M. E. J . Am. Chem. Soc. 1950, 72,
5228-5232.
(30) Molander, G. A.; Cameron, K. O. J . Org. Chem. 1993, 58, 5931-
5943 (cited in Supporting Information).
(26) Wiley: R. H.; Slaymaker, S. C.; Kraus, H. J . Org. Chem. 1957,
22, 204-207.
(27) J oshi, N. N.; Mandapur, V. R.; Chadha, M. S. J . Chem. Soc.,
Perkin Trans. 1 1983, 2963-2966.

1900 J . Org. Chem., Vol. 64, No. 6, 1999
Aurrecoechea et al.
was acidified with concentrated HCl, and the whole was
extracted with diethyl ether. The organic extracts were dried
(Na2SO4) and the crude after evaporation was purified by flash
chromatography (10% AcOEt/hexanes) to afford 12.0 g (90%)
of ethyl 1-(pent-4-enyl)-2-oxocyclopentanecarboxylate as an oil:
1H NMR δ 1.24 (t, J ) 7.1 Hz, 3H), 1.3-1.6 (m, 3H), 1.8-2.1
(m, 6H), 2.2-2.6 (m, 3H), 4.15 (q, J ) 7.1 Hz, 2H), 4.9-5.0
(m, 2H), 5.7-5.8 (m, 1H); 13C NMR δ 13.8, 19.4, 23.9, 32.6,
33.0, 33.7, 37.7, 60.1, 61.0, 114.7, 137.8, 170.7, 214.5; IR (neat)
that was purified by flash chromatography (15% EtOAc/
hexanes) to yield in successive order of elution cis-8a (64 mg),
trans-8a (24 mg) (51% overall yield) and the dimer 9 (22 mg,
14%) as colorless oils. Data for cis-8a : 1H NMR δ 1.29 (t, J )
7.1 Hz, 3H), 1.31 (s, 3H, C4-CH3, overlapped with triplet at
1.29), 1.3-2.1 (m, 8H), 2.26 (s, 1H), 2.6-2.7 (m, 2H), 3.65 (br
s, 1H), 4.1-4.2 (m, 2H); 13C NMR δ 14.1, 21.7 (C4-CH3), 26.7,
35.7, 37.9, 38.6, 40.6, 61.4, 63.6, 64.9, 72.8, 82.2, 85.0, 176.6;
IR (neat) ν 3550, 3430, 3280, 2100, 1730 cm-1; HRMS calcd
for C14H18O2 (M+-18) 218.1307, found 218.1286. Data for trans-
8a : 1H NMR δ 1.27 (t, J ) 7.1 Hz, 3H), 1.3-1.5 (m, 2H), 1.51
(s, 3H, C4-CH3), 1.7-2.0 (m, 6H), 2.0-2.1 (m, 1H), 2.25 (s,
1H), 2.42 (ddd, J ) 13.1, 11.2, 7.6 Hz, 1H), 2.6-2.7 (m, 1H),
4.1-4.2 (m, 2H); 13C NMR δ 14.1, 26.4 (C4-CH3), 27.3, 32.9,
37.8, 39.2, 40.0, 60.8, 61.2, 64.4, 72.8, 81.1, 86.7, 175.4; IR
(neat) ν 3500, 3300, 2100, 1720 cm-1. Anal. Calcd for
ν 1750, 1730, 1640 cm-1
.
A portion of this alkene (0.50 g, 2.23 mmol) was dissolved
in CH2Cl2/CH3OH (16 mL/3 mL) at -78 °C, and a mixture of
ozone/oxygen (0.7 A, 100 L/h) was bubbled through the solution
until this had turned into a light blue. Ar was then bubbled
through the solution at -78 °C until colorless, and the solution
was allowed to reach rt. Dimethyl sulfide (0.3 mL, 4.46 mmol)
was added, and the mixture was stirred at room temperature
for 12 h. The solution was evaporated to a volume of ca. 5 mL,
and the residue was partitioned between CH2Cl2 (50 mL) and
water (15 mL). The aqueous layer was extracted with CH2Cl2,
and the combined organic layers were dried (Na2SO4). The
residue after evaporation was purified by flash chromatogra-
phy to yield 0.38 g (75%) of ethyl 1-(4-oxobutyl)-2-oxocyclo-
pentanecarboxylate (5e) as an oil: 1H NMR δ 1.22 (t, J ) 7.1
Hz, 3H), 1.5-1.8 (m, 3H), 1.8-2.1 (m, 4H), 2.1-2.6 (m, 5H),
4.12 (q, J ) 7.1 Hz, 2H), 9.72 (s, 1H); 13C NMR δ 13.4, 16.8,
19.0, 32.1, 32.4, 37.1, 43.1, 59.5, 60.6, 170.2, 201.1, 213.8; IR
C
14H20O3: C, 71.16; H, 8.53. Found: C, 70.98; H, 8.55. Data
for 9: 1H NMR δ 1.1-1.4 (m, 14H), 1.19 (t, J ) 7.1 Hz,
overlapped with mult at 1.1-1.4), 1.35 (s, overlapped with mult
at 1.1-1.4), 1.4-1.9 (m, 10H), 2.0-2.6 (m, 8H), 3.46 (br s, W1/2
) 7.4 Hz, 2H), 4.0-4.2 (m, 4H), 5.18 (t, J ) 4.2 Hz, 2H); 13C
NMR δ 14.1, 23.9, 28.3, 29.0, 30.1, 32.2, 37.6, 58.8, 61.5, 72.3,
106.6, 111.5, 176.5, 195.0; IR (neat) ν 3540, 3480, 1980, 1720
cm-1; HRMS calcd for C28H40O6 472.2825, found 472.2825.
Eth yl 5-(Hex-1-yn yl)-4-h yd r oxy-4-m eth ylbicyclo[3.3.0]-
octa n eca r boxyla te (8b). Prepared as described for 7a by
adding a solution of 4j (0.24 g, 0.58 mmol) and Pd(PPh3)4 (64
mg, 0.06 mmol) in THF (17 mL) to SmI2 (1.3 mmol) in THF
(38 mL) at 65 °C. After 20 min the usual workup and flash
chromatography (15% EtOAc/hexanes) afforded in order of
elution the allene 10 (27 mg, 16%) and the bicyclic alcohol 8b
(102 mg, 60%) as colorless oils and single isomers. Data for
8b: 1H NMR δ 0.85 (t, J ) 7.0 Hz, 3H), 1.24 (t, J ) 7.1 Hz,
3H), 1.3-1.4 (m, 6H), 1.44 (s, 3H), 1.7-1.9 (m, 6H), 1.9-2.0
(m, 1H), 2.10 (t, J ) 6.7 Hz, 2H), 2.38 (ddd, J ) 13.0, 11.3, 7.5
Hz, 1H), 2.5-2.6 (m, 1H), 4.0-4.2 (m, 2H); 13C NMR δ 13.5,
14.1, 18.5, 21.9, 26.4, 27.2, 31.1, 32.9, 37.7, 39.4, 40.1, 60.5,
61.5, 64.2, 81.4, 82.3, 84.7, 175.6; IR (neat) ν 3490, 2220, 1730
cm-1; HRMS calcd for C18H28O3 291.1960 (M - 1), found
291.1965. Data for ethyl 2-(hex-1-enylidene)-1-(3-oxobutyl)-
cyclopentanecarboxylate (10): 1H NMR δ 0.88 (t, J ) 7.0 Hz,
3H), 1.21 (t, J ) 7.1 Hz, 3H), 1.3-1.4 (m, 4H), 1.5-1.6 (m,
1H), 1.7-1.9 (m, 4H), 1.9-2.1 (m, 3H), 2.11 (s, 3H), 2.2-2.3
(m, 1H), 2.4-2.5 (m, 3H), 4.10 (q, J ) 7.1 Hz, 2H,), 5.19 (tt, J
) 6.7, 3.6 Hz, 1H); 13C NMR δ 13.9, 14.2, 22.1, 24.8, 29.0, 29.8,
31.3, 31.4, 31.6, 35.7, 40.3, 55.3, 60.6, 94.8, 108.1, 174.8, 198.2,
208.3; IR (neat) ν 1960, 1730 cm-1; HRMS calcd for C18H28O3
292.2038, found 292.2036.
1-Eth yn ylbicyclo[4.3.0]n on a n -9-ol (11). A solution of
acetate 4k (0.115 g, 0.518 mmol) and Pd(PPh3)4 (38 mg, 0.036
mmol) in THF (10 mL) was placed in a water bath at 40 °C. A
SmI2 solution [prepared from Sm (0.214 g, 1.42 mmol),
diiodoethane (0.365 g, 1.30 mmol) and THF (10 mL)] was
added dropwise at such a rate as to allow the disappearance
of the SmI2 characteristic blue color before the next drop was
added. The addition was continued until the blue color
persisted (at that point 7 mL had been added over 1 h).
Workup as described above and flash chromatography (20%
EtOAc/hexanes) afforded in order of elution the bicyclic alcohol
11 (18 mg, 21%, one isomer), as a volatile oil, and the
hydroxyester 12 (16 mg, 13%). Data for 11: 1H NMR δ 1.2-
1.8 (m, 12H), 2.0-2.2 (m, 3H), 2.14 (s, overlapped with mult
at 2.0-2.2), 4.2-4.3 (m, 1H); 13C NMR δ 20.4, 22.0, 22.9, 24.5,
25.4, 29.2, 41.7, 44.2, 69.0, 81.5, 90.0; IR (neat) ν 3700-3200,
2140 cm-1; HRMS calcd for C11H16O 164.1201, found 164.1164.
Data for 1-ethynyl-2-(3-hydroxypropyl)cyclohexyl acetate
(12): 1H NMR δ 1.2-1.4 (m, 4H), 1.4-1.9 (m, 9H), 2.03 (s,
3H), 2.60 (s, 1H), 2.73 (br d, J ) 11.9 Hz, 1H), 3.67 (t, J ) 6.5
Hz, 2H); 13C NMR δ 22.0, 23.3, 24.9, 26.3, 28.3, 30.5, 36.1, 45.6,
63.2, 76.4, 80.0, 80.8, 169.3; IR (neat) ν 3430, 3310, 2220, 1750
cm-1; HRMS calcd for C13H20O3 224.1412, found 224.1419.
(1R*,4S*,5S*)-Eth yl 4-Eth yn yl-5-h yd r oxybicyclo[3.3.0]-
octa n eca r boxyla te (13a ). Rep r esen ta tive P r oced u r e for
Sm I2/P d (0) Red u ctive Cycliza tion s of Su bstr a tes 6a -f
a n d 6h ,i. A solution of SmI2 [prepared from Sm (0.291 g, 1.93
(neat) ν 1755, 1730 cm-1
.
The alkynylation procedure used in the preparation of 6b
was followed from ethynyllithium23 and 5e to afford the acetate
6h (63%) as an oil: 1H NMR δ 1.24 (t, J ) 7.1 Hz, 3H), 1.3-
1.7 (m, 3H), 1.7-1.8 (m, 2H), 1.9-2.0 (m, 4H), 2.07 (s, 3H),
2.1-2.6 (m, 4H), 2.43 (d, J ) 2.0 Hz, overlapped with mult at
2.1-2.6), 4.1-4.2 (m, 2H), 5.32 (ddd, J ) 9.0, 6.4, 2.5 Hz, 1H);
13C NMR δ 13.5, 19.1, 19.7, 20.3, 32.2, 32.3, 32.5, 34.1, 37.2,
59.7, 60.7, 62.6, 73.4, 80.4, 169.0, 170.2, 213.8; IR (neat) ν 3270,
2120, 1750, 1730 cm-1. Anal. Calcd for C16H22O5: C, 65.27; H,
7.54. Found: C, 65.15; H, 7.57.
3-Ben zyl-2-eth yn yl-1-m eth ylcyclop en ta n ol (7a ). Rep -
r esen ta tive P r oced u r e for Sm I2/P d (0) Red u ctive Cy-
cliza tion s of Su bstr a tes 4 a n d 6g. A SmI2 solution in THF
was prepared as reported from Sm metal and either diiodo-
ethane,16a diiodomethane,1b or iodine.1b A solution of 4a (0.350
g, 1.05 mmol) and Pd(PPh3)4 (55.2 mg, 0.052 mmol) in THF
(10 mL) was added to the SmI2 solution (2.3 mmol) in THF
(12 mL) at 25 °C under Ar. The mixture was stirred for 2.5 h
and then poured over a saturated K2CO3 solution (4 mL).
Water (2 mL) was then added and the mixture stirred for 3
min. The aqueous layer was extracted with diethyl ether, and
the combined organic layers were dried (Na2SO4). The crude
after evaporation of the solvent was purified by flash chroma-
tography (20% EtOAc/hexanes) to yield the title alcohol as a
mixture of four diastereomers (colorless oil, 194 mg, 87%). One
of the isomers (33% of the mixture) could be separated by
HPLC (column 2, 15% EtOAc/hexanes, 5 mL/min): tR 21 min;
1H NMR δ 1.39 (s, 3H), 1.4-1.6 (m, 1H), 1.6-1.8 (m, 4H), 2.0-
2.2 (m, 1H), 2.24 (d, J ) 2.4 Hz, 1H), 2.47 (dd, J ) 10.7, 2.4
Hz, 1H), 2.55 (dd, J ) 13.4, 9.5 Hz, 1H), 3.07 (dd, J ) 13.4,
4.3 Hz, 1H), 7.2-7.3 (m, 5H); 13C NMR δ 26.0, 27.6, 39.2, 40.7,
46.8, 49.6, 72.3, 80.1, 83.7, 126.0, 128.2, 129.1, 140.6; IR (neat)
ν 3380, 3300, 2110 cm-1; HRMS calcd for C15H18O 214.1358,
found 214.1361.
The other three isomers were characterized as a mixture:
1H NMR δ 1.35, 1.36 and 1.51 (s, 3H), 1.6-3.1 (m, 10H), 7.2-
7.3 (m, 5H); 13C NMR δ 26.1, 27.0, 27.4, 28.1, 28.5, 28.8, 37.5,
38.1, 38.6, 39.4, 42.3, 43.4, 45.8, 47.2, 47.2, 47.6, 49.5, 72.7,
73.9, 75.6, 79.4, 81.4, 82.0, 82.6, 82.7, 125.6, 125.7, 128.1, 128.1,
128.7, 128.8, 128.9, 140.2, 141.3, 141.4; HRMS calcd for
C
15H18O 214.1358, found 214.1359.
(1R*,4S*,5R*)- a n d (1R*,4R*,5R*)-Eth yl 5-Eth yn yl-4-
h yd r oxy-4-m eth ylbicyclo[3.3.0]octa n eca r boxyla te (cis-
8a , tr a n s-8a ). Prepared as described for 7a by adding a
solution of Pd(PPh3)4 (78.7 mg, 0.073 mmol) and 4i (0.260 g,
0.734 mmol) in THF (20 mL) to SmI2 (1.62 mmol) in THF (30
mL). After 90 min the usual workup afforded a crude product

SmI2/Pd(0)-Mediated Intramolecular Coupling
J . Org. Chem., Vol. 64, No. 6, 1999 1901
mmol) and diiodoethane (0.508 g, 1.81 mmol] in THF (11.5
mL) was added dropwise to a solution of 6a (0.198 g, 0.707
mmol) and Pd(PPh3)4 (46.4 mg, 0.04 mmol) in THF (8 mL) at
Ack n ow led gm en t. Financial support by the Direc-
cio´n General de Investigacio´n Cient´ıfica y Te´cnica
(DGICYT PB89-0412, PB92-0449 and PB95-0344) and
by the Universidad del Pa´ıs Vasco (UPV 170.310-0133/
89, UPV 170.310-EC021/92 and UPV 170.310-EC216/
97) is gratefully acknowledged. We also thank the
Departamento de Educacio´n, Universidades e Investi-
gacio´n (Gobierno Vasco), and Ministerio de Educacio´n
y Ciencia (Spain) for Fellowships to R.F. and M.A.,
respectively.
such
a rate as to allow the disappearance of the SmI2
characteristic blue color before the next drop was added. The
addition was continued until the blue color persisted (at that
point approximately 11 mL had been consumed). The usual
workup, followed by flash chromatography (10% EtOAc/
hexanes), afforded 0.136 g (87%) of the product as an oil: 1H
NMR δ 1.27 (t, J ) 7.1 Hz, 3H), 1.5-1.7 (m, 4H), 1.7-1.9 (m,
2H), 2.0-2.1 (m, 2H), 2.14 (d, J ) 2.4 Hz, 1H), 2.2-2.3 (m,
1H), 2.4-2.5 (m, 1H), 2.87 (ddd, J ) 11.7, 6.8, 2.4 Hz, 1H,
H-4), 2.99 (s, 1H, OH), 4.17 (q, J ) 7.1 Hz, 2H); 13C NMR δ
14.0, 24.2, 29.8, 34.9, 37.6, 38.4, 42.8, 60.8, 60.9, 70.4, 83.6,
92.9, 176.0; IR (neat) ν 3490, 3295, 2110, 1720 cm-1; FT-IR
(∼0.01 M in CHCl3) ν 1699 cm-1; HRMS calcd for C13H18O3
222.1256, found 222.1252.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra for 1a , 1b, 1e, 3b, 3d , 3e-h , 3k , 4c-h , 4j, 4k , 5e, 5f,
6e, 6f, 7, cis-8a , 8b, 9-12, 13a , 14 and experimental proce-
dures for 4d , 4f, 4h , 4j, 4k , 6a , 6c-g, 6i, 7b-j, 13b-d , 14-
16. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O9819133