Samarium diiodide-induced couplings of carbonyl compounds with methoxyallene leading to 4-hydroxy 1-enol ethers

Article abstract of DOI:10.1021/ol0342251

(Matrix presented) A surprising samarium diiodide-induced coupling reaction of carbonyl compounds with methoxyallene provided 4-hydroxy 1-enol ethers, which are versatile synthetic building blocks. In this coupling reaction, methoxyallene serves as an acrolein equivalent, which cannot directly be employed.

Full text of DOI:10.1021/ol0342251

ORGANIC
LETTERS
2003
Vol. 5, No. 9
1463-1466
Samarium Diiodide-Induced Couplings
of Carbonyl Compounds with
Methoxyallene Leading to 4-Hydroxy
1-Enol Ethers
Alexandra Ho1lemann and Hans-Ulrich Reissig*
Institut fu¨r Chemie - Organische Chemie, Freie UniVersita¨t Berlin, Takustr. 3,
D-14195 Berlin, Germany
hans.reissig@chemie.fu-berlin.de
Received February 7, 2003
ABSTRACT
A surprising samarium diiodide-induced coupling reaction of carbonyl compounds with methoxyallene provided 4-hydroxy 1-enol ethers,
which are versatile synthetic building blocks. In this coupling reaction, methoxyallene serves as an acrolein equivalent, which cannot directly
be employed.
Samarium diiodide has received considerable attention in the
past two decades. First introduced to synthetic organic
chemistry by Kagan,1 it has rapidly been established as a
powerful one-electron-transfer reagent employed in many
important transformations including various sequential reac-
tions.2 This is mainly attributed to its easy preparation, its
applicability under mild and selective conditions, and the
possibility of tuning its reactivity by assistance of catalysts
and additives. Ketyl-olefin couplings represent one impor-
tant class of samarium(II)-mediated transformations (Scheme
1), and reactions of various carbonyl compounds 1 with
functionalized carbocycles and heterocycles, often in good
yields and with outstanding diastereoselectivities.3
However, investigations with R,â-unsaturated aldehydes,4
in particular with acrolein, but also with allenes,5 are very
rare. As part of our interest in samarium(II)-mediated ketyl-
olefin coupling reactions,3b,c experiments were therefore
carried out with diphenylallene 4 and methoxyallene 6.
(2) Selected reviews on samarium diiodide-mediated reactions, see: (a)
Kagan, H. B.; Namy, J. L. Tetrahedron 1986, 42, 6573-6614. (b) Molander,
G. A.; Harris, C. R. Chem. ReV. 1996, 96, 307-338. (c) Khan, F. A.;
Zimmer, R. J. Prakt. Chem. 1997, 339, 101-104. (d) Molander, G. A.;
Harris, C. R. Tetrahedron 1998, 54, 3321-3354. (e) Krief, A.; Laval,
A.-M. Chem. ReV. 1999, 99, 745-777. (f) Steel, P. G. J. Chem. Soc.,
Perkin Trans. 1 2001, 2727-2751. (g) Ho¨lemann, A. Synlett 2001, 1497-
1498.
Scheme 1
(3) Selected recent references on samarium diiodide-induced ketyl-
coupling reactions: (a) Schmalz, H.-G.; Kiehl, O.; Gotov, B. Synlett 2002,
1253-1256. (b) Berndt, M.; Reissig, H.-U. Synlett 2001, 1290-1292. (c)
Dinesh, C. U.; Reissig, H.-U. Angew. Chem. 1999, 111, 874-876; Angew.
Chem., Int. Ed. Engl. 1999, 38, 789-791. (d) Molander, G. A.; McKie, J.
A. J. Org. Chem. 1995, 60, 872-882. (e) Ohno, H.; Maeda, S.; Okumura,
M.; Wakayama, R.; Tanaka, T. Chem. Commun. 2002, 316-317. (f) Kuo,
Ch.-W.; Fang, J.-M. Synth. Commun. 2001, 31, 877-892.
(4) R,â-Unsaturated aldehydes have been employed in samarium(II)-
induced iodomethylations and Mukaiyama-aldol reactions: Giuseppone,
N.; Collin, J. Tetrahedron 2001, 57, 8989-8998. Imamoto, T.; Hatajima,
T.; Takiyama, N.; Takeyama, T.; Kamiya, Y.; Yoshizawa, T. J. Chem. Soc.,
Perkin Trans. 1 1991, 3127-3135. One cyclization of an R,â-unsaturated
aldehyde to a triple bond leading to a pyrrolidine derivative was reported:
Baldwin, J. E.; MacKenzie, S. C.; Moloney, M. G. Tetrahedron 1994, 50,
9425-9438.
alkenes, alkynes, and arenes 2 have intensively been studied
in recent years. The intramolecular versions lead to highly
(1) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102,
2693-2698.
10.1021/ol0342251 CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/05/2003

Allene 4 (1.1 equiv) reacted smoothly with cyclopentanone
1a in the presence of samarium(II) iodide and HMPA
(hexamethylphosphoramide) affording allylic alcohol 5 in
good yield and excellent diastereoselectivity (Scheme 2). As
nents at first glance, their terminal double bond has consider-
able electrophilic character and can therefore react smoothly
with a nucleophilic radical such as the samarium ketyl.8 In
this novel coupling process, methoxyallene 6 serves as an
equivalent of acrolein providing 4-hydroxy 1-enol ethers 7,
which are intermediates with a masked aldehyde functional-
ity. They are versatile building blocks for further transforma-
tions which motivated us to investigate scope and limitations
of the new coupling reaction.
Scheme 2
Generally, reductive couplings were conducted by addition
of the THF solution of carbonyl component 1 (1.0 equiv),
methoxyallene 6 (2.0 to 3.0 equiv), and tert-butyl alcohol
(2.0 equiv) to the solution of freshly prepared samarium
diiodide (2.2 equiv) and HMPA (18 equiv) in THF at room
temperature. According to previous reports, HMPA was
found to be essential for successful coupling as this cosolvent
significantly increases the reduction power of samarium-
(II).9,10 A variety of ketones was examined, and the results
are summarized in Table 1. Products 7 were generally
obtained as a mixture of (E)- and (Z)-isomers in ratios of
50:50 to 65:35. In most cases, the (E)-isomer was only
slightly preferred.
expected, addition of the ketyl occurred to the central car-
bon of 4 due to the higher stability of the intermediate allyl
radical. Small amounts of 1,3-diphenylpropene were isolated
as a byproduct resulting from reduction of the allene moiety.
We then turned our attention to the highly versatile C3-
building block methoxyallene 6.6 Reaction of this allene with
different carbonyl compounds proceeded under the same
conditions; however, in contrast to allene 4, coupling
occurred at the terminal carbon of methoxyallene leading to
4-hydroxy 1-enol ethers 7 (Scheme 3). In accordance with
First, cyclic ketones were combined with 6 under the
described conditions. Cyclopentanone 1a and cyclohexanone
1b furnished the enol ethers 7a and 7b as the only isolated
products in high yields. Starting with 4-tert-butylcyclohex-
anone, the enol ether 7c was obtained in 58% yield, and 41%
of starting material 1c were recovered. Apparently, conver-
sion of the ketone is not complete in this reaction which
may also happen in other examples where unconsumed
ketones could not be reisolated due to their volatility.11
Scheme 3
With respect to the cyclohexane ring, product 7c was
formed as a single diastereomer (dr > 97:3). The configu-
ration was identified by transferring 7c into the corresponding
lactone 13 (see Scheme 5). By comparing the data of 13
with that of the cis and trans isomers reported in the
literature,12 7c was clearly assigned to be the trans isomer.
This result can be rationalized by assuming that the sterically
demanding samarium alkoxy group and the tert-butyl group
of the intermediate prefer equatorial positions before addition
to 6. Other substituents and even heteroatoms are also
tolerated in the 4-position. Reaction of monoprotected 1,4-
literature reports,3 we propose a ketyl radical anion 8 as the
first intermediate that is generated by electron transfer of
samarium diiodide to the carbonyl functionality. Addition
to 6 then affords vinyl radical 9, which is directly converted
to 7 by abstraction of hydrogen from THF (or HMPA).7
Although alkoxyallenes appear to be nucleophilic compo-
(8) Cuprates add to C-3 of alkoxyallenes: Marek, I.; Alexakis, A.;
Mangeney, P.; Normant, J.-F. Bull. Soc. Chim. Fr. 1992, 129, 171-190.
(9) (a) Inanaga, I.; Ishikawa, M.; Yamaguchi, M. Chem. Lett. 1987,
1485-1486. (b) Shabangi, M.; Flowers, R. A., II. Tetrahedron Lett. 1997,
38, 1137-1140. (c) Prasad, E.; Flowers, R. A., II. J. Am. Chem. Soc. 2002,
124, 6895-6899 and references cited therein.
(10) Attempts to replace HMPA by less toxic cosolvents have so far not
been successful in general. In individual examples, related additives (e.g.,
N-methylpyrrolidinone or other phosphoramide derivatives) were efficient
but unfortunately no rule has yet been recognized in which cases these
additives are applicable. Berndt, M.; Gross, S.; Ho¨lemann, A.; Reissig, H.-
U., unpublished results.
(11) When the reaction was carried out in the presence of 4.2 equiv of
SmI2, only traces of the starting material 1c were detected in the crude
mixture. However, the yield of 7c was not improved. Increasing the amount
of 6 also gave unsatisfactory results, as 6 itself slowly reacts with SmI2
yielding unidentifiable products. Addition of SmI2 to a solution of 1c and
6 slightly increased the yield of 7c; however, 16% of starting material was
again recovered.
(5) One intramolecular coupling of electron-deficient allenyl aldehydes
leading to vinyl-substituted cycloalkanols was reported: Gillmann, T.
Tetrahedron Lett. 1993, 34, 607-610. Methoxyallene itself has only been
used in a samarium(II)-mediated [3+2] cycloaddition with carbonyl
ylides: Hojo, M.; Aihara, H.; Hosomi, A. J. Am. Chem. Soc. 1996, 118,
3533-3534.
(6) Reviews: (a) Zimmer, R. Synthesis 1993, 165-178. (b) Reissig,
H.-U.; Hormuth, S.; Schade, W.; Okala Amombo, M. G.; Watanabe, T.;
Pulz, R.; Hausherr, A.; Zimmer, R. J. Heterocycl. Chem. 2000, 37, 597-
606.
(7) Curran, D. P.; Fevig, T. L.; Jasperse, C. P.; Totleben, M. J. Synlett
1992, 943-961.
(12) Fukuzawa, S.; Nakanishi, A.; Fujinami, T.; Sakai, S. J. Chem. Soc.,
Perkin Trans. 1 1988, 1669-1674.
1464
Org. Lett., Vol. 5, No. 9, 2003

Scheme 4
Table 1. Samarium Diiodide-Induced Coupling of
Methoxyallene 6 with Carbonyl Compounds 1a
Scheme 5
a General conditions: 6 (2.0-3.0 equiv), SmI2 (2.2 equiv), HMPA (18
equiv), t-BuOH (2.0 equiv), THF, rt, 16 h. b Yields for isolated products
after chromatography. E/Z ratios are given in parentheses. c Traces of
cyclopentanol 12 were detected in the crude mixture. d Reisolation of 41%
starting material 1c. e Only trans isomer was detected. f Isolation of 11%
of secondary alcohol. g Small amounts of a bicyclic compound related to
12f were obtained after chromatography. h 7 and 12 were isolated as mixture.
gave 29% of expected 7f and 34% of bicyclic cyclopentanol
derivative 12f. Formation of cyclopentanol 12 can be
rationalized by an intramolecular hydrogen atom transfer to
vinyl radical 9 (Scheme 4) affording alkyl radical 10,13 which
attacks the double bond of the enol ether leading to stabilized
radical 11. A second electron transfer of samarium diiodide
followed by protonation finally yields cyclopentanol deriva-
tive 12. Product 12f was formed as a single diastereomer;
1
Yield was calculated according to the ratio determined by H NMR.
cyclohexadione 1d and Boc-protected piperidinone 1e with
6 furnished the corresponding products 7d and 7e in 54%
and 51% yield, respectively.
In contrast, samarium diiodide-promoted reaction of 6 with
cycloheptanone 1f surprisingly resulted in the formation of
two constitutional isomers. Separation by chromatography
(13) Wilt, J. W. In Free Radicals; Kochi, J. K., Ed.; Wiley: New York,
1973; Vol. 1, pp 333-501.
Org. Lett., Vol. 5, No. 9, 2003
1465

however, the configuration of 12f could so far not be
assigned.
lactol with allyltrimethylsilane in the presence of boron
trifluoride etherate provided allyl-substituted spirocyclic
compound 14 in 79% yield (with respect to 7c). Other
silylated nucleophiles such as triethylsilane and silyl enol
ethers were similarly successful yielding the corresponding
tetrahydrofurans in 64-81% yield.15
Alternatively, aldehydes may be synthesized from 7 and
its derivatives. Thus, TBS-protection of the tertiary alcohol
and subjection to palladium(II) acetate afforded the expected
R,â-unsaturated aldehyde 15 in moderate yield as a single
diastereomer.16
In conclusion, a variety of ketones could be coupled with
methoxyallene 6 in the presence of samarium diiodide in
moderate to good yields. Methoxyallene herein played the
role of a masked equivalent for acrolein allowing a straight-
forward access to 4-hydroxy 1-enol ethers 7 accompanied
in certain cases by cyclopentanols 12 as byproducts. Products
7 are highly versatile building blocks, and their applicability
was demonstrated by different examples. Starting from cyclic
ketones, spiro compounds were easily constructed. As a
consequence of this surprising coupling reaction and the
versatility of the products, the applicability of different
allenes,17 in particular substituted derivatives, is currently
under investigation.
The change from cyclic compounds to acyclic ketones
significantly decreased the yields of coupling product 7.
Starting with acetone, the corresponding adduct 7g was
isolated in only 26% yield, which may be due to the high
volatility of the product. Applying the procedure to diethyl
ketone 1h considerably improved the mass balance (52%
combined yield); however, a mixture of two isomers in a
ratio of 85:15 was isolated. The major product was identified
to be the expected 7h, whereas the minor component was
cyclopentanol derivative 12h. Branched ketones such as
pinacolone 1i gave the desired products 7 even in lower
yields. Only traces of the desired product 7i with 12i being
the major isolated product of this reaction (22% yield) were
isolated. Cyclopentanol 12i was formed as a single diaste-
reomer with a yet unknown configuration. It was also shown
that even aldehydes can be employed in this coupling
process. Reaction of heptanal with 6 yielded the correspond-
ing adduct 7j in moderate 43% yield. Aldehydes are generally
more prone to simple reduction and pinacol coupling, which
may diminish the efficiency of the desired coupling process.
We have demonstrated that various ketones and even
aldehydes can be used in this novel coupling reaction.
Whereas 5- and 6-membered cycloalkanones smoothly
afforded 4-hydroxy 1-enol ethers 7 in moderate to good
yields, the corresponding acyclic ketones gave lower yields
and cyclopentanol byproducts 12. Branched substituents or
more flexible cyclic systems such as cycloheptanone led to
formation of compounds 12 because a hydrogen transfer to
the vinyl radical intermediate is possible through a geo-
metrically favored six-membered transition state.
Acknowledgment. Support of this work by the Fonds
der Chemischen Industrie (Kekule´-Stipendium for A.H.) and
the Volkswagen-Stiftung is gratefully acknowledged. We also
thank the Fonds der Chemischen Industrie and the Schering
AG for general support.
Supporting Information Available: Detailed description
of experimental procedures and characterization data for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
4-Hydroxy 1-enol ethers 7 are masked aldehydes and
therefore useful building blocks for many transformations.
Their versatility is demonstrated in Scheme 5 by different
examples. Acidic hydrolysis of the enol ether unit with
aqueous sulfuric acid followed by oxidation using PCC
furnished γ-lactone 1312 in 86% yield over the two steps.
Reactions of γ-lactols (or their acetals) with silylated
nucleophiles in the presence of Lewis acids furnish substi-
tuted tetrahydrofuran derivatives in good yields and very
often with high diastereoselectivity.14 Acidic hydrolysis of
the enol ether moiety followed by treatment of the obtained
OL0342251
(14) Schmitt, A.; Reissig, H.-U. Eur. J. Org. Chem. 2000, 3893-3901
and references therein.
(15) Ho¨lemann, A.; Reissig, H.-U., unpublished results.
(16) Takayama, H.; Koike, T.; Aimi, N.; Sakai, S. J. Org. Chem. 1992,
57, 2173-2176.
(17) When 1 was combined with a 3-alkyl-substituted methoxyallene
derivative in the presence of SmI2, no reaction occurred. Only starting
material was reisolated by chromatography. However, 3-methoxy-1,2-
butadiene furnished the expected addition product, albeit in very low yield.
1466
Org. Lett., Vol. 5, No. 9, 2003