Synthesis and Applications of Tetrahydrofuran-Stable Substituted (3-Lithioxyalkyl)- and (4-Lithioxyalkyl)lithiums, Modified with Magnesium 2-Ethoxyethoxide

Article abstract of DOI:10.1021/jo9703010

Substituted hydroxyalkyl phenyl sulfides 3 have been synthesized from the corresponding allylic or homoallylic alcohols 2. Regiospecific cleavage of the C - SPh bond of the sulfides 3 by lithium dispersion in tetrahydrofuran (THF) led to the synthesis of substituted (3-lithioxyalkyl)- and (4-lithioxyalkyl)lithiums 4, most of which share the ω carbon with a carbocyclic ring. The organolithiums were modified with magnesium 2-ethoxyethoxide in order to suppress their reactivity toward THF cleavage, thus offering the advantage of preparing storable ethereal solutions of certain types of (lithioxyalkyl)lithiums. This strategy appears to be of rather broad scope. The functionalized organolithiums prepared in this way react normally with electrophilic reagents with yields in the range 35-55%. Thus, carboxylations of 4 yielded lactones 5, some of which are natural products, while reactions of 4 with benzophenone and cyclic ketones yielded 1,4- and 1,5-diols 6 and 7, respectively.

Full text of DOI:10.1021/jo9703010

J . Org. Chem. 1997, 62, 5575-5577
5575
Syn th esis a n d Ap p lica tion s of Tetr a h yd r ofu r a n -Sta ble Su bstitu ted
(3-Lith ioxya lk yl)- a n d (4-Lith ioxya lk yl)lith iu m s, Mod ified w ith
Ma gn esiu m 2-Eth oxyeth oxid e
Ioannis D. Kostas and Constantinos G. Screttas*
National Hellenic Research Foundation, Institute of Organic and Pharmaceutical Chemistry,
116 35 Athens, Greece
Received February 18, 1997
Substituted hydroxyalkyl phenyl sulfides 3 have been synthesized from the corresponding allylic
or homoallylic alcohols 2. Regiospecific cleavage of the C-SPh bond of the sulfides 3 by lithium
dispersion in tetrahydrofuran (THF) led to the synthesis of substituted (3-lithioxyalkyl)- and (4-
lithioxyalkyl)lithiums 4, most of which share the ω carbon with a carbocyclic ring. The
organolithiums were modified with magnesium 2-ethoxyethoxide in order to suppress their reactivity
toward THF cleavage, thus offering the advantage of preparing storable ethereal solutions of certain
types of (lithioxyalkyl)lithiums. This strategy appears to be of rather broad scope. The function-
alized organolithiums prepared in this way react normally with electrophilic reagents with yields
in the range 35-55%. Thus, carboxylations of 4 yielded lactones 5, some of which are natural
products, while reactions of 4 with benzophenone and cyclic ketones yielded 1,4- and 1,5-diols 6
and 7, respectively.
In tr od u ction
also known. However, the syntheses of these organo-
lithiums according to the above-mentioned procedures
require low temperatures and immediate derivatization,
as organometallics are not stable at room temperature
in ethereal solvents due to metalation of the solvent and
further cleavage.10,11
The synthetic utility of organolithium compounds
increases considerably if the lithium reagents bear an
additional functionality.1 Indeed, such reagents can
introduce, usually in a regiospecific manner, a hydrocar-
byl moiety possessing the additional functionality at a
predetermined position, thus permitting further chemical
elaboration. A number of such reagents have already
been reported.1 The present report provides information
on a methodology for preparing tetrahydrofuran-stable
organometallic reagents capable of introducing a 3-mono-
or 3,3-disubstituted 3-hydroxypropyl group as well as a
4-mono- or 4,4-disubstituted 4-hydroxybutyl group.
Various syntheses of γ- and δ-lithioalkoxides have been
reported. γ-Lithioalkoxides have been prepared by reac-
tion of organolithium reagents with allylic alcohols,2
lithiation of γ-chloroalkoxides,3 tin-lithium exchange of
a γ-(tributylstannyl)alkoxide,4 and reductive lithiation of
phenyl sulfides5 or oxetanes6 by lithium di-tert-butylbi-
phenylide (LDBB). The latter method was extended to
the synthesis of δ-lithioalkoxides by reductive lithiation
of substituted tetrahydrofurans, where the cleavage of
the C-O bond was promoted either via complexation at
the oxygen atom of THF by a Lewis acid or by appending
an alkenyl group to the 2-position of the ring.7 Syntheses
of δ-lithioalkoxides by chlorine-lithium exchange8 or by
reductive lithiation of phenyl sulfides with LDBB9 are
In this work, we report on the development of a new
method of broad applicability for the synthesis of sub-
stituted (3-lithioxyalkyl)- and (4-lithioxyalkyl)metallics
4, most of which share the ω carbon with a carbocyclic
ring. The previously reported12 preparation of organo-
lithium reagents in THF in the presence of magnesium
2-ethoxyethoxide was also applied to the synthesis of
(lithioxyalkyl)lithiums 4, i.e., to the preparation of stor-
able THF solutions of 4.
Resu lts a n d Discu ssion
The method for the synthesis of the (3-lithioxyalkyl)-
and (4-lithioxyalkyl)lithiums 4 involves addition of vinyl-
or allylmagnesium chloride to carbonyl compounds 1
followed by the conversion of the resulting allylic or
homoallylic alcohols13 2 to the corresponding primary
alkyl phenyl sulfides 3 by the anti-Markownikow addition
of thiophenol (Scheme 1). Finally, regiospecific cleavage
of the C-SPh bond of the substituted hydroxyalkyl
phenyl sulfides 3 by lithium metal in the presence of
magnesium 2-ethoxyethoxide leads to the corresponding
organometallic reagents 4 (Scheme 2).
* To whom correspondence should be addressed.
X Abstract published in Advance ACS Abstracts, J uly 15, 1997.
(1) For selected reviews, see: (a) Stowell, J . C. Chem. Rev. 1984,
84, 409. (b) Klumpp, G. W. Recl. Trav. Chim. Pays-Bas 1986, 105, 1.
(c) Yus, M. Chem. Soc. Rev. 1996, 155.
The cleavage of the sulfides 3 was effected by an excess
of lithium dispersion in the presence of magnesium
(2) Crandall, J . K.; Clark, A. C. J . Org. Chem. 1972, 37, 4236.
(3) (a) Na´jera, C.; Yus, M.; Seebach, D. Helv. Chim. Acta 1984, 67,
289. (b) Barluenga, J .; Flo´rez, J .; Yus, M. Synthesis 1985, 846. (c) Yus,
M.; Ramo´n, D. J . J . Chem. Soc., Chem. Commun. 1991, 398.
(4) (a) Meyer, N.; Seebach, D. Chem. Ber. 1980, 113, 1290. (b) Zidani,
A.; Vaultier, M. Tetrahedron Lett. 1986, 27, 857.
(5) Ahn, Y.; Cohen, T. J . Org. Chem. 1994, 59, 3142.
(6) Mudryk, B; Cohen, T. J . Org. Chem. 1989, 54, 5657.
(7) Mudryk, B.; Cohen, T. J . Am. Chem. Soc. 1991, 113, 1866.
(8) Barluenga, J .; Fernandez, J . R.; Florez, J .; Yus, M. Synthesis
1983, 736.
(10) Wakefield, B. J . In Comprehensive Organic Chemistry; Barton,
D., Ollis, W. D., Eds.; Pergamon Press: Oxford, 1979, Vol. 3, pp 943ff.
(11) Review: Maercker, A. Angew. Chem., Int. Ed. Engl. 1987, 26,
972.
(12) Screttas, C. G.; Steele, B. R. J . Org. Chem. 1989, 54, 1013.
(13) For selected examples of similar methods for synthesis of allylic
or homoallylic alcohols, see: (a) Marcou, A.; Normant, H. Bull. Soc.
Chim. Fr. 1965, 12, 3491. (b) Katzenellenbogen, J . A.; Lenox, R. S. J .
Org. Chem. 1973, 38, 326. (c) Masamune, T.; Sato, S.; Abiko, A.; Ono,
M.; Murai, A. Bull. Chem. Soc. J pn 1980, 53, 2895. (d) Oppolzer, W.;
Schneider, P. Tetrahedron Lett. 1984, 25, 3305.
(9) (a) Mudryk, B.; Shook, C. A.; Cohen, T. J . Am. Chem. Soc. 1990,
112, 6389. (b) Liu, H.; Cohen, T. J . Org. Chem. 1995, 60, 2022.
S0022-3263(97)00301-0 CCC: $14.00 © 1997 American Chemical Society

5576 J . Org. Chem., Vol. 62, No. 16, 1997
Kostas and Screttas
Sch em e 1
present in a large variety of natural products and
biologically active compounds.17 5-Hexyldihydro-2-fura-
none (5e) and 6-hexylterahydro-2-pyranone (5e′), for
instance, are aroma constituents of various fruits.18
The reactivity of 4 with benzophenone and cyclic
ketones was also investigated, yielding diols 6 and 7,
respectively (Scheme 2). Carbinols 6 are new compounds,
and the synthesis of the symmetric or unsymmetric bis(1-
hydroxycycloalkyl)alkanes 7 is more convenient for prac-
tical reasons than other methods.19 It may be of interest
to note that, in most cases, there is a consistency between
the yields of the lactones and of diols. For example,
reagent 4a on carboxylation afforded the corresponding
lactone 5a in 43% yield, compared to a 44% yield of the
diol 6a and 45% yield of the diol 7a upon reaction with
benzophenone and cyclopentanone, respectively.
Sch em e 2
In conclusion, a general method has been illustrated
for the synthesis of 3-mono- or 3,3-disubstituted (3-
lithioxypropyl)lithiums and of 4-mono- or 4,4-disubsti-
tuted (4-lithioxybutyl)lithiums 4 , as room temperature-
stable THF solutions, by the regiospecific cleavage of the
C-SPh bond of the corresponding sulfides 3 with lithium
dispersion. The synthetic value of these organolithiums
was demonstrated by the synthesis of certain γ- and
δ-lactones and spirolactones 5, some of which are natural
products, as well as by the synthesis of symmetric and
unsymmetric tetrasubstituted 1,4- and 1,5-diols 7.
Exp er im en ta l Section
P r ep a r a tion of Su lfid es 3. Typ ica l P r oced u r e. 1-[2-
(P h en ylth io)eth yl]cyclop en ta n ol (3a ).20 A solution of the
alcohol 2a (18.2 g, 162.5 mmol) and thiophenol (16.5 mL, 162.0
mmol) in hexane (70 mL) was refluxed under nitrogen for 46
h. During refluxing, a catalytic amount of R,R′-azobis(isobu-
tyronitrile) (1 g) was added in several portions. It was then
diluted with toluene and washed with a 50% aqueous solution
of NaOH (20 mL). The organic phase was dried, filtered, and
evaporated to dryness. Isolation of pure product was carried
out by distillation, yielding the sulfide 3a (21.2 g, 59%). 3a :
bp 140-141 °C (1 mmHg); IR (CHCl3, cm-1) 3610 and 3460
2-ethoxyethoxide in THF/methylcyclohexane ca. 10/1 (v/
v). Our group has previously reported the preparation
of organolithium reagents in THF in the presence of
magnesium 2-ethoxyethoxide.12 The presence of the
magnesium alkoxide markedly diminishes the metalating
ability of the initially formed organolithium reagents,
hence increasing their stability in tetrahydrofuran solu-
tions at room temperature. The reaction temperature for
the cleavage of the C-SPh bond was 0-20 °C. The
presence of methylcyclohexane in the solvent system
results from the butyllithium solution used for the
deprotonation of the hydroxy sulfide 3. The molar ratio
(sulfide)/(magnesium alkoxide) was approximately 1:1.
The yields of the organolithiums were taken to be the
yield of the product after reaction with a given electro-
phile.
Carboxylation and subsequent acidic hydrolysis of 4
yielded lactones 5 (Scheme 2). This reaction provides
simple and efficient one-pot syntheses of substituted
γ-butyro-14 and δ-valerolactones 5 (most of which are
spirolactones).15 The problem of thiophenol in product
isolation was confronted by its conversion to thioanisole
by reaction with dimethyl sulfate.16 Synthesis of such
lactones is of great interest as lactonic functionality is
1
(OH, free and H-bonded); H NMR (CDCl3) δ 7.12-7.35 (m,
5H), 3.03-3.08 (m, 2H), 2.09 (brs, 1H), 1.50-1.91 (m, 10H);
13C NMR (CDCl3) δ 136.39, 128.63, 128.47, 125.52, 81.82,
40.44, 39.35, 28.77, 23.38; MS (EI) m/z (rel intesity) 222 (M+,
100).
Syn th esis of (Lith ioxya lk yl)lith iu m s 4 a n d Th eir Ca r -
boxyla tion . P r ep a r a tion of La cton es 5. Typ ica l P r oce-
d u r e. 1-Oxa sp ir o[4.4]n on a n -2-on e (5a ).15b,c A solution of
the sulfide 3a (2.2 g, 9.9 mmol) in THF (10 mL) was added to
a mixture of magnesium 2-ethoxyethoxide (2.5 g, 12.4 mmol
(17) (a) Comprehensive Organic Chemistry. The Synthesis and
Reactions of Organic Compounds; Chairman and Deputy Chairman
of the Editorial Board Sir Derek Barton, F.R.S. and W. David Ollis,
F.R.S.; Sutherland, I. O., Ed.; Pergamon Press: London, 1979; Vol 2,
pp 869-956. (b) Gutman, A. L.; Zuobi, K.; Bravdo, T. J . Org. Chem.
1990, 55, 3546 and references cited therein.
(18) (a) Engel, K. H.; Ramming, D. W.; Flath, R. A.; Teranishi, R.
J . Agric. Food Chem. 1988, 36, 1003; Chem Abstr. 1988, 109, 127496r.
(b) MacLeod, A. J .; MacLeod, G.; Snyder, C. H. Phytochemistry 1988,
27, 2189; Chem. Abstr. 1988, 109, 148205k. (c) Guichard, E.; Souty,
M. Z. Lebensm-Unters. Forsch. 1988, 186, 301; Chem Abstr. 1988, 109,
109117p. (d) Schreier, P.; Drawert, F. Chem., Mikrobiol., Technd.
Technol. Lebensm. 1981, 7, 23; Chem. Abstr. 1981, 95, 59882d. (e)
Kikuchi, N.; Miki, T. Microchim. Acta 1981, I, 249. (f) Georgilopoulos,
D. N.; Gallois, A. N. Z. Lebensm-Unters. Forsch. 1987, 184, 374; Chem.
Abstr. 1987, 107, 114480q. (g) MacLeod, G.; Ames, J . M. Phytochemistry
1990, 29, 165; Chem. Abstr. 1990, 112, 137790h.
(14) The use of other (3-lithioxypropyl)lithiums in a γ-butyrolactone
synthesis has been reported; see refs 2, 3a, and 6.
(15) For selected examples of syntheses of γ- and δ-lactones, see:
(a) Trost, B. M.; Bogdanowicz, M. J . J . Am. Chem. Soc. 1973, 95, 5321.
(b) Canonne, P.; Foscolos, G. B.; Be´langer, D. J . Org. Chem. 1980, 45,
1828. (c) Canonne, P.; Be´langer, D.; Lemay, G.; Foscolos, G. B. J . Org.
Chem. 1981, 46, 3091. (d) Schlecht, M. F.; Kim, H.-J . Tetrahedron Lett.
1985, 26, 127.
(19) (a) Pinkney, P. S.; Nesty, G. A.; Pearson, D. E.; Marvel, C. S.
J . Am. Chem. Soc. 1937, 59, 2666. (b) Bailey, A. S.; Diaper, D. G. M.;
Schwemin, M. V. H. Can. J . Chem. 1961, 39, 1147. (c) Achyutha Rao,
S.; Periasamy, M. Tetrahedron Lett. 1988, 29, 1583.
(16) Screttas, C. G.; Micha-Screttas, M. J . Org. Chem. 1978, 43,
1064.
(20) Kutner, A.; Perlman, K. L.; Lago, A.; Sicinski, R. R.; Schnoes,
H. K.; DeLuka, H. F. J . Org. Chem. 1988,53, 3450.

Synthesis of Substituted (Lithioxyalkyl)lithiums
J . Org. Chem., Vol. 62, No. 16, 1997 5577
in 25 mL of THF) and n-BuLi (5.3 mL of 1.89 M solution in
methylcyclohexane, 10 mmol) at -78 °C under argon, after
was extracted with toluene. The organic phase was washed
with a 50% aqueous solution of NaOH (10 mL) and then with
water. It was dried and filtered, and the solvent was evapo-
rated, yielding 2.05 g of the crude product, which was
recrystallized from hexane/toluene, yielding 6a (1.3 g, 44%)
as a white solid. 6a : mp 122-124 °C; IR (CHCl3, cm-1): 3620
and 3410 (OH, free and H-bonded); 1H NMR (CDCl3) δ 7.18-
7.45 (m, 10H), 2.49 (t, J ) 7.4 Hz, 2H), 2.32 (brs, 2H), 1.50-
1.79 (m, 10H); 13C NMR (CDCl3) δ 147.27, 128.11, 126.66,
126.06, 82.53, 77.83, 39.84, 37.01, 35.42, 23.65. Anal. Calcd
for C20H24O2: C, 81.04; H, 8.16. Found: C, 80.88; H, 7.91.
which it was stirred at room temperature overnight.
A
suspension of an excess of lithium dispersion (0.4 g, 57 mmol,
free from mineral oil) in THF (15 mL) was then added, with
ice-water bath cooling, after which the mixture was warmed
slowly to room temperature and stirred overnight. The excess
lithium was filtered, and the reaction mixture was poured
rapidly into a beaker containing a slurry of crushed dry ice
and anhydrous diethyl ether. When the carboxylation mixture
had reached room temperature, water was added, and the
volume was reduced by evaporation. After filtration, the
aqueous phase was washed twice with toluene and once with
hexane. Then a 50% aqueous solution of NaOH (3.5 mL) and
dimethyl sulfate (1.6 mL) was added, and the mixture was
refluxed for 2 h. It was washed again with toluene and hexane
and evaporated to dryness. After the addition of about 5 mL
of water, it was acidified with 20% H2SO4, with ice-water bath
cooling. The product was extracted with dichloromethane (5
× 20 mL) and dried. After filtration, the solvent was evapo-
rated, yielding 5a (0.6 g, 43%) as the only component according
to analytical GLC chromatography. A sample of 5a for
spectroscopic analysis was isolated by preparative GLC chro-
1,1′-(1,2-Eth a n ed iyl)bis(cyclop en ta n ol) (7a ).19b The pro-
cedure was identical with that described above for the syn-
thesis of 6a . 7a : yield 45%; mp 128-130 °C (MCH) (lit.19b mp
134 °C); IR (CHCl3, cm-1) 3610 and 3410 (OH, free and
1
H-bonded); H NMR (CDCl3) δ 1.60-1.89 (m, 22H); 13C NMR
(CDCl3) δ 82.25, 39.83, 36.39, 23.79. Anal. Calcd for
C12H22O2: C, 72.68; H, 11.18. Found: C, 72.48; H, 10.98.
Ack n ow led gm en t. The investigation was supported
by the National Hellenic Research Foundation.
1
matography; the H and 13C NMR spectra were in accordance
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal comments, including information for the preparation of
alcohols 2, tables with the yields, mps or bps of the products,
and full details of their spectral data (14 pages). This material
is contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
with those previously reported.15c
Rea ction of (Lith ioxya lk yl)lith iu m s 4 w ith Keton es.
Typ ica l P r oced u r e. 1-(3,3-Dip h en yl-3-h yd r oxyp r op yl)-
cyclop en ta n ol (6a ). To a solution of 4a in THF (50 mL)/
methylcyclohexane (5.3 mL), prepared from 3a (2.2 g, 9.9
mmol) as described above, was added a solution of benzophe-
none (1.6 g, 8.8 mmol) in THF (10 mL), with ice-water bath
cooling, after which it was stirred at room temperature for 1
h. Water was then added, and after filtration, the product
J O9703010