Stereogenic propargylic centers via base-mediated terminal allne isomerization

Article abstract of DOI:10.1021/jo960276i

A study of alkali metal amide-mediated isomerizations of terminal allenes is described. The isomerizations of substituted ethenylidenecyclohexanes to form diastereomeric mixtures of terminal alkynes have been conducted to determine factors which may influence the stereochemistry at the newly formed propargylic centers. An initial base screen revealed that potassium N-methylbutylamide (KMBA) exhibits the highest level of equatorial to axial alkyne diastereoselectivity. With the severely hindered terminal allene 26, the use of potassium 3-aminopropylamide is required to effect isomerization. A general synthesis of deuterated terminal allenes has also been achieved, and a mechanistic study using d₂-allenes 18a,b has revealed the involvement of a propargylic anion in the course of the KMBA-mediated isomerizations.

Full text of DOI:10.1021/jo960276i

4014
J . Org. Chem. 1996, 61, 4014-4021
Ster eogen ic P r op a r gylic Cen ter s via Ba se-Med ia ted Ter m in a l
Allen e Isom er iza tion
J ohn D. Spence, J ustin K. Wyatt, Daniel M. Bender, David K. Moss, and Michael H. Nantz*
Department of Chemistry, University of CaliforniasDavis, Davis, California 95616
Received February 9, 1996X
A study of alkali metal amide-mediated isomerizations of terminal allenes is described. The
isomerizations of substituted ethenylidenecyclohexanes to form diastereomeric mixtures of terminal
alkynes have been conducted to determine factors which may influence the stereochemistry at the
newly formed propargylic centers. An initial base screen revealed that potassium N-methylbutyl-
amide (KMBA) exhibits the highest level of equatorial to axial alkyne diastereoselectivity. With
the severely hindered terminal allene 26, the use of potassium 3-aminopropylamide is required to
effect isomerization. A general synthesis of deuterated terminal allenes has also been achieved,
and a mechanistic study using d2-allenes 18a ,b has revealed the involvement of a propargylic anion
in the course of the KMBA-mediated isomerizations.
In tr od u ction
The base-mediated isomerization of alkynes has found
numerous applications in organic synthesis, particularly
in connection with transposition of an internal alkyne
along an unbranched, unsubstituted carbon chain to the
terminus.1,2 The synthesis of terminal alkynes in this
manner has been the subject of several mechanistic
investigations,3-5 and these studies have indicated that
the alkyne migration proceeds via a random and revers-
ible sequence of 1,3-proton transfers between alkyne and
allene intermediates (eq 1).6 The use of lithium and
sodium metal amides, particularly those of diamines, was
shown by Wotiz3 to effect the rapid rearrangement of an
internal alkyne and result in the accumulation of a
terminal acetylide anion. Further studies by Brown7
indicated that potassium amides, specifically potassium
3-aminopropylamide (KAPA), are well suited to facilitate
the formation of terminal acetylide anions from internal
alkynes.8,9 The rapid reaction times10 and the high
isolated yields of terminal alkyne products obtained by
protonation of the isomerization mixture have made the
KAPA protocol the current method of choice for the
“acetylene zipper” reaction. Few studies,5,11 however,
have employed the KAPA or other amine base conditions
for the isomerization of allenic starting materials to their
corresponding terminal alkynes.
* Author to whom correspondence should be addressed.
X Abstract published in Advance ACS Abstracts, J une 1, 1996.
(1) (a) Huang, H.; Forsyth, C. J . J . Org. Chem. 1995, 60, 5746. (b)
Heathcock, C. H.; Kath, J . C.; Ruggeri, R. B. J . Org. Chem. 1995, 60,
1120. (c) Balova, I. A.; Zakharova, I. V.; Remizova, L. A. Zh. Org. Khim.
1993, 29, 1732. (d) Brown, H. C.; Iyer, R. R.; Bhat, N. G.; Racherla, U.
S.; Brown, C. A. Tetrahedron 1992, 48, 9187. (e) Swenton, J . S.; Bradin,
D.; Gates, B. D. J . Org. Chem. 1991, 56, 6156. (f) Nantz, M. H.; Fuchs,
P. L. J . Org. Chem. 1987, 52, 5298. (g) Takano, S.; Sekiguchi, Y.; Sato,
N.; Ogasawara, K. Synthesis 1987, 139. (h) Igner, E.; Paynter, O. I.;
Simmonds, D. J .; Whiting, M. C. J . Chem. Soc., Perkin Trans. 1 1987,
2447. (i) Baudler, M. Angew. Chem., Int. Ed. Engl. 1982, 21, 480. (j)
Midland, M. M.; Halterman, R. L.; Brown, C. A.; Yamaichi, A.
Tetrahedron Lett. 1981, 22, 4171.
(2) In the synthesis of ω-acetylenic alkan-1-ols: (a) Okada, S.;
Matsuda, H.; Otsuka, M.; Kikuchi, N.; Hayamizu, K.; Nakanishi, H.;
Kato, M. Bull. Chem. Soc. J pn. 1994, 67, 455. (b) Menger, F. M.;
Yamasaki, Y. J . Am. Chem. Soc. 1993, 115, 3840. (c) Tellier, F.;
Hammoud, A.; Ratovelomanana, V.; Linstrumelle, G.; Descoins, C.
Bull. Soc. Chim. Fr. 1993, 130, 281. (d) Miller, M.; Hegedus, L. S. J .
Org. Chem. 1993, 58, 6779. (e) Yadav, J . S.; Deshpande, P. K.; Sharma,
G. V. M. Tetrahedron 1992, 48, 4465. (f) Negishi, E.; Yoshida, T.;
Abramovitch, A. Tetrahedron 1991, 47, 343. (g) Augustin, K. E.;
Scha¨fer, H. J . Liebigs Ann. Chem. 1991, 1037. (h) Ma, D.; Lu, X.
Tetrahedron 1990, 46, 6319. (i) Almansa, C.; Moyano, A.; Perica`s, M.
A.; Serratosa, F. Synthesis 1988, 707. (j) Blade, R. J .; Robinson, J . E.;
Peek, R. J .; Weston, J . B. Tetrahedron Lett. 1987, 28, 3857. (k) Stille,
J . K.; Simpson, J . H. J . Am. Chem. Soc. 1987, 109, 2138. (l) Remizova,
L. A.; Kryukov, A. V. Zh. Org. Khim. 1985, 21, 1001. (m) Schwarz, M.;
Klun, J . A.; Leonhardt, B. A.; J ohnson, D. T. Tetrahedron Lett. 1983,
24, 1007. (n) Gensler, W. J .; Prasad, R. S.; Chaudhuri, A. P.; Alam, I.
J . Org. Chem. 1979, 44, 3643. (o) Utimoto, K.; Tanaka, M.; Kitami,
M.; Nozaki, H. Tetrahedron Lett. 1978, 2301. (p) Henrick, C. A.
Tetrahedron 1977, 33, 1845. (q) Lindhoudt, J . C.; van Mourik, G. L.;
Pabon, H. J . J . Tetrahedron Lett. 1976, 2565.
We have undertaken an investigation of alkali metal
amide-mediated isomerization reactions of terminal al-
lenes with the objective being synthesis of stereogenic
propargylic centers in conjunction with formation of the
terminal alkyne moiety (eq 2).12 Although this specific
transformation has not been reported previously,13,14 it
(6) (a) Bushby, R. J . Quart. Rev., Chem. Soc. 1970, 24, 585. (b) Hass,
E. C.; Mezey, P. G.; Abrams, S. R. J . Comput. Chem. 1982, 3, 185.
(7) (a) Brown, C. A.; Yamashita, A. J . Am. Chem. Soc. 1975, 97,
891. (b) Brown, C. A.; Yamashita, A. J . Chem. Soc., Chem. Commun.
1976, 959.
(8) Experimental modifications of the Brown procedure (ref 7a) for
KAPA formation have been reported; see: (a) Kimmel, T.; Becker, D.
J . Org. Chem. 1984, 49, 2494. (b) Abrams, S. R. Can. J . Chem. 1984,
62, 1333.
(9) For the preparation of sodium 3-aminopropylamide, see: (a)
Hommes, H.; Brandsma, L. Recl. Trav. Chim. Pays. Bas. 1977, 96, 160.
(b) Macaulay, S. R. J . Org. Chem. 1980, 45, 734.
(10) A minimum of 13 allenyl rearrangements catalyzed by KAPA
were shown to occur within seconds at 0 °C; see ref 7a.
(11) (a) Grattan, T. J .; Whitehurst, J . S. J . Chem. Soc., Perkin Trans.
1 1990, 11. (b) Djerassi, C.; Giner, J .-L. J . Am. Chem. Soc. 1991, 113,
1386.
(3) Wotiz, J . H.; Barelski, P. M.; Koster, D. R. J . Org. Chem. 1973,
38, 489.
(4) The´ron, F.; Verny, M.; Vessie´re, R. In The Chemistry of the
Carbon-Carbon Triple Bond; J ohn Wiley and Sons: New York, 1978;
Part I, Chapter 10, pp 381-345.
(12) Enzyme-mediated propargylic rearrangements to afford alkynes
with stereogenic propargylic centers have been reported; see: (a) Gil,
G.; Ferre, E.; Barre, M.; Le Petit, J . Tetrahedron Lett. 1988, 29, 3797.
(b) Schwab, J . M.; Lin, D. C. T. J . Am. Chem. Soc. 1985, 107, 6046.
(5) Abrams, S. R.; Shaw, A. C. J . Org. Chem. 1987, 52, 1835.
S0022-3263(96)00276-9 CCC: $12.00 © 1996 American Chemical Society

Base-Mediated Terminal Allene Isomerization
J . Org. Chem., Vol. 61, No. 12, 1996 4015
Sch em e 1
ring have been shown to give rise to resonances downfield
from their axial counterparts.19 Additional support for
the structure assignments is found on comparison of the
1
propargylic H NMR signal widths at half-height. The
alkyne diastereomers 2 and 5 exhibit their axial pro-
pargylic resonances at δ 2.28 (w1/2 ) 22.8 Hz) and δ 2.21
(w1/2 ) 24.3 Hz), respectively. The large signal width at
half-height in these signals confirms the presence of a
diaxial H-H coupling to the propargylic proton. In
contrast, the alkynes 3 and 6 exhibit equatorial pro-
pargylic resonances that are downfield and markedly
was anticipated to occur using the KAPA conditions as
a consequence of its involvement within the mechanistic
sequence reported for the “acetylene zipper” reaction. The
narrower than their axial counterparts at δ 2.90 (w1/2
8.4 Hz) and δ 2.77 (w1/2 ) 7.0 Hz), respectively.
)
Treatment of allene 1 with KAPA in propane-1,3-
diamine as solvent (entry 1, Table 1) resulted in rapid
allene isomerization to give a mixture of alkynes 2 and
3 in a 1.2:1 ratio. The potassium amide of ethane-1,2-
diamine (entry 2) mediated the isomerization of 1 with
similar selectivity. No starting allene was observed by
GC after workup of the reactions in which the acetylene
zipper conditions were used (e.g., entries 1, 2). In
contrast, the metalation of allene 1 using n-BuLi (THF,
-78 to 0 °C)20 and quenching the reaction at 0 °C with
aqueous ammonium chloride gave a 1:1 mixture of
starting allene to terminal alkynes.21 The 2:3 selectivity
in this reaction was measured at 4:1, an increase in
selectivity that prompted us to examine the allene
isomerization in THF. The isomerization of 1 in THF
was conducted using the primary potassium amides
KAPA and n-BuNHK, a monoamide structural mimic of
KAPA. Essentially no change in the product selectivity
was noted on using KAPA in THF (entry 3); however,
n-BuNHK mediated the isomerization of 1 with greater
isomerization of a dissymmetrically disubstituted termi-
nal allene (eq 2, 1R * 2R) would constitute a direct method
for the introduction of terminal alkyne functionality onto
a secondary position in a stereogenic fashion. Since the
nucleophilic displacement of a secondary leaving group
by an acetylide anion generally proceeds with very low
conversion to the substitution product,15 the allene
isomerization reaction may serve as a useful alternative
to nucleophilic substitution and other16,17 approaches that
are available for the synthesis of terminal alkynes. We
report the generality of this synthetic transformation and
the selection of amine bases suited for mediating a
diastereoselective terminal allene isomerization.
selectivity, although with low overall conversion.
A
Resu lts a n d Discu ssion
similar mono- vs diamine comparison of potassium
amides derived from secondary amines was performed
(entries 5, 6). The increased basicity that is attained in
going from a primary amide to a secondary amide, a
principal difference on substitution of potassium butyl-
amide with potassium N-methylbutylamide (KMBA),
resulted in a dramatic improvement of allene isomeriza-
tion reactivity. The isomerization of 1 mediated by
KMBA proved to be facile and gave a higher selectivity
for the equatorial alkyne 2 than that exhibited by the
diamine-derived potassium N,N ′-dimethyl-3-amino-
propylamide. Interestingly, treatment of 1 with a steri-
cally encumbered secondary potassium amide, potassium
diisopropylamide (KDA,22 entry 7), resulted in a reversal
of selectivity to favor the axial alkyne 3. A further
increase in the steric bulk of the potassium amide was
found to precipitously slow the allene isomerization.
Thus, treatment of allene 1 with potassium tetrameth-
ylpiperidide (KTMP) did not effect isomerization at 0 °C,
and was incomplete after 48 h at room temperature.
In itia l Ba se Scr een . The terminal allenes 1 and 4
(Scheme 1) were prepared using our previously reported
method.18 The treatment of allenes 1 or 4 with alkali
metal amides induced the 1,3-proton transfer to give a
diastereomeric mixture of axial and equatorial terminal
alkynes in varying ratios. The product distributions were
determined by gas chromatographic analysis on the crude
reaction mixtures and are given in Table 1. The assign-
ment of stereochemistry for the alkyne diastereomers was
made on the basis of the 1H NMR chemical shifts for their
respective propargylic protons. In the absence of com-
plicating factors, equatorial protons in the cyclohexane
(13) The base-mediated isomerization of a monosubstituted allene
has been reported; see: Thompson, H. W. J . Org. Chem. 1967, 32, 3712.
(14) The distinction should be noted between a method that delivers
the chiral terminal alkyne via a 1,3-proton transfer, and methods
wherein the propargylic chirality is established by alkylation of an
allenyl anion; see, for example: (a) Baudouy, R.; Delbecq, F.; Gore, J .
Tetrahedron Lett. 1979, 937. (b) Pyo, S.; Skowron, J . F., III; Cha, J . K.
Tetrahedron Lett. 1992, 33, 4703.
(15) Ben-Efraim, D. A. In The Chemistry of the Carbon-Carbon
Triple Bond; J ohn Wiley and Sons: New York, 1978; Part II, Chapter
18, pp 790-800.
(19) J ackman, L. M.; Sternhell, S. Nuclear Magnetic Resonance
Spectroscopy In Organic Chemistry, 2nd ed.; Pergamon: Oxford, 1969;
pp 238-241.
(20) (a) Linstrumelle, G.; Michelot, D. J . Chem. Soc., Chem. Com-
mun. 1975, 561. (b) Michelot, D.; Linstrumelle, G. Tetrahedron Lett.
1976, 275.
(21) Previous literature reports on the reaction of (3,3-dialkyl-
allenyl)lithium species with electrophiles have shown diverse ambident
reactivity; see: (a) van Kruchten, E. M. G. A.; Haces, A.; Okamura,
W. H. Tetrahedron Lett. 1983, 24, 3939. (b) Condran, P., J r.; Hammond,
M. L.; Mourin˜o, A.; Okamura, W. H. J . Am. Chem. Soc. 1980, 102,
6259. (c) Pasto, D. J .; Chou, S.-K.; Fritzen, E.; Shults, R. H.; Water-
house, A.; Hennion, G. F. J . Org. Chem. 1978, 43, 1389. (d) Creary, X.
J . Am. Chem. Soc. 1977, 99, 7632.
(16) Pattenden, G. In Comprehensive Organic Chemistry; Stoddart,
J . F., Ed.; Pergamon Press: New York, 1979; Vol. 1, pp 193-197.
(17) For terminal alkyne syntheses via functional group intercon-
version, see: (a) Aitken, R. A.; Atherton, J . I. J . Chem. Soc., Perkin
Trans. 1 1994, 1281. (b) Van Hijfte, L.; Kolb, M.; Witz, P. Tetrahedron
Lett. 1989, 30, 3655. (c) Negishi, E.; King, A. O.; Tour, J . M. Org. Synth.
1986, 64, 44. (d) Bryant, M. W.; Smith, R. A. J .; Wong, L. Aust. J .
Chem. 1982, 35, 2529. (e) Shibasaki, M.; Torisawa, Y.; Ikegami, S.
Tetrahedron Lett. 1982, 23, 4607. (f) Gilbert, J . C.; Weerasooriya, U.
J . Org. Chem. 1979, 44, 4997. (g) Colvin, E. W.; Hamill, B. J . J . Chem.
Soc., Perkin Trans. 1 1977, 869. (h) Midland, M. M.; Sinclair, J . A.;
Brown, H. C. J . Org. Chem. 1974, 39, 731. (i) Corey, E. J .; Fuchs, P. L.
Tetrahedron Lett. 1972, 3769.
(18) Nantz, M. H.; Bender, D. M.; J anaki, S. Synthesis 1993, 577.
(22) Raucher, S.; Koolpe, G. A. J . Org. Chem. 1978, 43, 3794.

4016 J . Org. Chem., Vol. 61, No. 12, 1996
Spence et al.
Ta ble 1. Dia ster eoselectivity a s a F u n ction of th e Ba se Em p loyed in th e Isom er iza tion of Allen es 1 a n d 4 (Sch em e 1)
selectivityb
entry
allene
basea
reaction conditions
2:3
5:6
1
2
3
4
5
6
7
8
9
1
KAPA
H2N(CH2)2N(Me)K
KAPA
n-BuNHK
(Me)HN(CH2)3N(Me)K
KMBA
KDA
KAPA
KMBA
H2N(CH2)3NH2, rt, 15 min
H2N(CH2)2NH2, rt, 15 min
THF, 0 °C, 1 h
THF, 0 °C, >12 h
THF, 0 °C, 1 h
1.2:1
1.1:1
1.3:1
3:1c
1.8:1
6.8:1
1:1.7
THF, 0 °C, 15 min
THF, -30 to 0 °C, 1 h
H2N(CH2)3NH2, rt, 15 min
THF, 0 °C, 15 min
4
1:1.1
4.7:1
1.9:1
10
KDA
THF, -30 to 0 °C, 1 h
a
b
Reactions were carried out using 3.5 equiv of potassium amide, and quenched with saturated aqueous NH4Cl. Ratio determined by
capillary GC analysis. c Incomplete isomerization with g40% unreacted starting allene present.
Ta ble 2. KMBA-Med ia ted Allen e Isom er iza tion
The isomerization of allene 4 followed a similar trend
in product diastereoselectivity for the bases screened. The
formation of equatorial alkyne 5 was greatest when using
KMBA (Table 1, entry 9), whereas the KAPA-mediated
isomerization again showed little diastereoselectivity.
The proportion of axial alkyne product, alkyne 6, was
increased on using the more bulky base KDA. These
results suggest that the secondary amide KMBA may be
a useful alternative base for 1,3-prototropic rearrange-
ments that result in the formation of stereogenic pro-
pargylic centers, especially in cases involving exocyclic
allenes. We have found that the KMBA-mediated allene
isomerization may be employed to isomerize terminal
allenes in good yield (Table 2). The reaction avoids the
use of noxious propane-1,3-diamine as solvent and is
amenable to synthesis of terminal alkynes on preparative
scale.
ment of a deuterium label on the terminal allenic carbon
would differentiate the principal mechanisms previously
invoked to account for base-induced 1,3-proton transfers.
Cram et al.24 have demonstrated that the base-mediated
isomerization of 1,3,3-triphenylprop-1-yne proceeds with
intramolecularity, the 1,3-proton transfers occurring via
a “conducted tour” mechanism that does not involve a
discrete propargylic anion.25 Wotiz et al.3 proposed a
mechanism for the base-induced isomerization of 3-hex-
yne which also does not involve the intermediacy of a
propargylic anion. In this instance, the extremely rapid
reaction rates observed when using amides of diamines
such as ethylenediamine were attributed to facile, con-
certed 1,3-proton transfers; however, it was noted that a
(23) For studies on diastereoselective protonation and electrophilic
reactions of cyclohexyllithium derivatives, see: (a) Gerlach, U.;
Haubenreich, T.; Hu¨nig, S.; Keita, Y. Chem. Ber. 1993, 126, 1205. (b)
Reich, H. J .; Medina, M. A.; Bowe, M. D. J . Am. Chem. Soc. 1992, 114,
11003. (c) Keys, B. A.; Eliel, E. L.; J uaristi, E. Isr. J . Chem. 1989, 29,
171.
(24) (a) Cram, D. J .; Willey, F.; Fischer, H. P.; Scott, D. A. J . Am.
Chem. Soc. 1964, 86, 5370. (b) Cram, D. J .; Willey, F.; Fischer, H. P.;
Relles, H. M.; Scott, D. A. J . Am. Chem. Soc. 1966, 88, 2759.
(25) The isomerization of vinyl acetylenes to vinyl allenes has also
Deu ter iu m Isotop e Stu d ies. One of the questions
that arose during the course of these studies was whether
the KMBA diastereoselectivity could be attributed to the
intermediacy of a discrete propargylic anion. An axial
quench23 of such an intermediate anion by reaction with
N-methylbutylamine would result in the formation of an
equatorial alkyne. It was hypothesized that the place-
been postulated to occur via
a conducted tour mechanism; see:
Marshall, J . A.; DuBay, W. J . J . Org. Chem. 1993, 58, 3435.

Base-Mediated Terminal Allene Isomerization
J . Org. Chem., Vol. 61, No. 12, 1996 4017
Sch em e 2a
Sch em e 3
a
Reaction conditions: (i) LiAlD4‚AlCl3, Et2O, 0 °C, 75-84%; (ii)
ClCO2CH3, Et3N, DMAP, CH2Cl2, -78 °C to rt, 90%; (iii) RMgX
(6 equiv), LiBr (6 equiv), CuI (6 equiv), THF, -50 °C to -5 °C.
concerted mechanism with a monoamine anion was
unlikely. Work by Abrams5 has since shown that alkali
metal amides of diamines effect, to some extent, 1,3-
proton transfers through nonconcerted processes that
may involve discrete propargylic anions. In the present
study, a series of deuterated terminal allenes was
prepared to examine the mechanism of the terminal
allene isomerization and to determine the intermediacy
of a distinct propargylic anion.
The reaction sequence shown in Scheme 2 constitutes
an efficient route to deuterated terminal allenes and
represents a general synthesis of geminally labeled
terminal allenes.26 Reduction of the acetylenic ester
13a 27 using the reagent combination LiAlD4‚AlCl3 af-
forded the deuterated propargylic alcohol 14a in good
yield.28 Activation of the hydroxyl group in 14a as a
methyl carbonate derivative was followed by a LiBr-CuI-
promoted SN2′ displacement of the carbonate moiety
using a Grignard reagent according to the method of
Macdonald.29 In this manner, the deuterated terminal
allenes 16a -18a were obtained in excellent yields.
The isomerization of d2-allene 18a to the corresponding
terminal alkyne by a “conducted tour” mechanism would
be expected to transfer deuterium to the propargylic
position. Under this mechanism, the addition of excess
amine (R2NH) to the reaction solution would not be
expected to diminish the extent of propargylic deuterium
incorporation since no distinct propargylic anion would
be available for reaction with the added amine. However,
if a propargylic anion were involved (e.g., [20], Scheme
3), an intermolecular reaction with added amine (R2NH)
may occur to incorporate hydrogen in the propargylic
position to give 12a -H. The recapture of deuterium by
reaction of the propargylic anion with deuterated amine
(R2ND), formed on initial allenic deuterium abstraction,
would compete with the added amine and would occur
to give 12a -D. Thus, the extent of propargylic deuterium
incorporation would be influenced by the presence of
added amine, and the percent deuterium incorporation
would be expected to decrease relative to the equivalents
of added R2NH.
using 3.5 equiv of KMBA, formed by the combination of
equimolar amounts of n-BuLi, N-methylbutylamine, and
KOt-Bu. Under these conditions, the expected product
for both the conducted tour and the discrete propargylic
anion mechanisms would be alkyne 12a -D (Scheme 3).
However, 1H NMR analysis revealed that the product was
terminal alkyne 23, and the extent of deuterium incor-
poration in the benzylic position was measured at >95%.
Only trace deuterium incorporation was detected in the
propargylic position of alkyne 23. For this reaction, the
workup had involved the addition of water. To test
whether the propargylic hydrogen was introduced by a
water quench of propargylic anion [20], the identical
reaction was quenched by the addition of D2O. The
results of this reaction showed no increase in propargylic
deuterium incorporation and suggest that the proton
source may be the pendant benzylic protons or N-
methylbutylamine, formed as a consequence of benzylic
deprotonation.
To circumvent the problems associated with benzylic
deprotonation, the trityl protected terminal allene 18b
(Scheme 2) was prepared and isomerized under identical
conditions. Analysis of the isomerization product showed
that only 32% deuterium incorporation30 had occurred in
the propargylic position, an observation that is inconsis-
tent with a conducted tour mechanism. In this reaction,
the extent of hydrogen incorporation in the propargylic
position under rigorous anhydrous conditions suggests
that the propargylic anion [20] (R1 ) C(Ph)3) is quenched
by reaction with a proton source, presumably N-methyl-
butylamine formed from partial reaction of KMBA with
THF.31 The lack of significant deuterium transfer to the
propargylic position in these examples suggests that the
allene isomerization reaction is a nonconcerted process
As a control experiment, the isomerization of allene
18a was conducted in the absence of excess amine by
(26) For previous syntheses of 1,1-dialkyl-3,3-dideuterioallenes
see: (a) Pasto, D. J .; Warren, S. E.; Morrison, M. A. J . Org. Chem.
1981, 46, 2838. (b) Stang, P. J .; Hargrove, R. J . J . Org. Chem. 1975,
40, 657.
(27) Schlessinger, R. H.; Poss, M. A.; Richardson, S. J . Am. Chem.
Soc. 1986, 108, 3112.
(30) Deuterium incorporation was measured using mass spectrom-
etry according to the method described in: Biemann, K. Mass
Spectrometry: Organic Chemical Applications; McGraw-Hill: New
York, 1962.
(28) The putative reducing agent on using a 1:1 ratio of LiAlD4:AlCl3
is AlD2Cl; see: Kruglikova, R. I.; Babaeva, L. G.; Polteva, N. A.;
Unkovskii, B. B. Zh. Org. Khim. 1974, 10, 956.
(31) KMBA reacts slowly with THF under the isomerization condi-
tions as evidenced by a control experiment in which a solution of KMBA
in THF at 0 °C was quenched by addition of acetic anhydride and
resulted in the detection of vinyl acetate (GC).
(29) Macdonald, T. L.; Reagan, D. R. J . Org. Chem. 1980, 45, 4740.

4018 J . Org. Chem., Vol. 61, No. 12, 1996
Spence et al.
Sch em e 4a
Con clu sion
a
Reaction conditions: (i) KOH (4.0 equiv), CH3I (4.0 equiv),
These studies have led to a new and straightforward
approach for the preparation of stereogenically positioned
terminal alkynes. The axial vs equatorial selectivity in
the isomerization of cyclohexyl terminal allenes was
found to be influenced by the selection of potassium
amide base. The secondary monoamide base KMBA
exhibited excellent conversion and good selectivity in the
formation of the equatorial alkyne product. In the case
of a severely hindered terminal allene, the use of KAPA
under standard acetylene zipper conditions was most
effective. Our study on the KMBA-mediated isomeriza-
tion of deuterated allenes clearly demonstrates the
involvement of a propargylic anion. Extension of this
methodology by using chiral amide bases for the isomer-
ization of prochiral terminal allenes potentially may lead
to a new asymmetric synthesis.
DMSO, rt; (ii) LiAlH4, Et2O, 0 °C to 10 °C; (iii) KAPA (9 equiv) in
APA, rt, 20 h.
and is likely to involve an intermolecular quench of a
discrete propargylic anion.
Isom er iza tion of a Ster ica lly Hin d er ed Ter m in a l
Allen e. In conjunction with our studies on functionalized
spirocyclic allenes,32 we have used the isomerization
reaction to incorporate a terminal alkyne group onto a
secondary neopentyl position in a diastereoselective
fashion (Scheme 4). Spirocyclic allene 24,32 readily
available using the Schinzer approach33 to polycyclic
systems, was converted to allene 26 via O-methylation34
followed by LiAlH4 reduction in 67% yield. Treatment
of allene 26 with excess KMBA (7.0 equiv) in THF at 0
°C for 3 h failed to induce any detectable allene to alkyne
isomerization. The severe crowding of the incipient
propargylic anion by the spirocyclic construct likely
interferes with efficient 1,3-proton transfer, and this
steric problem represents a limitation in the use of
secondary amide bases to effect allene isomerization. We
were gratified to find, however, that application of
Brown’s KAPA conditions7 resulted in the isomerization
of allene 26 to afford equatorial alkyne 27 as the only
detectable isomer. Presumably the lower steric require-
ment of the primary amine in this instance enabled
proton transfer to the congested neopentyl center. The
assignment of alkyne stereochemistry is based on the
Exp er im en ta l Section
1H and 13C NMR spectra were recorded at 300 and 75 MHz,
respectively, using CDCl3 as a solvent. Infrared (IR) spectra
were obtained using neat films unless otherwise noted. Melt-
ing points are uncorrected. High-resolution mass spectra
determinations were conducted at the University of California,
Davis, Facility for Advanced Instrumentation. Elemental
analyses were performed by Midwest Microlab of Indianapolis,
IN. GC analyses were performed on a gas chromatograph
fitted with a capillary column (30 m × 0.25 mm, DB-5).
THF and Et2O were distilled from sodium benzophenone
ketyl immediately prior to use. All amine reagents were
distilled from CaH2 prior to use. A solution of KOt-Bu in THF
was prepared by adding a small quantity of freshly cut
potassium metal to freshly distilled THF containing excess
KOt-Bu(s). The KOt-Bu/K mixture was heated to 60 °C for
15 h and then stored at room temperature under argon. The
titer of KOt-Bu in the stock THF solution was determined
according to a literature procedure.35
All reactions were carried out under an atmosphere of
nitrogen. The potassium amides were prepared by a modifica-
tion of the Raucher procedure22 for synthesis of KDA. Allenes
1, 4, and 7 have been prepared previously.18 Allenes 9 and
11 were prepared according to the method of Alexakis.36
Column chromatography was carried out on 230-400 mesh
silica gel, slurry packed in glass columns, eluting with the
solvents indicated. Yields were calculated for material judged
to be homogeneous by TLC and NMR. TLC was performed
on Merck kieselgel 60 F254 plates, staining with an ethanolic
solution of p-anisaldehyde and sulfuric acid.
1
presence of a characteristric H NMR diaxial coupling
constant for the propargylic hydrogen at δ 2.41 (ddd, J
) 12.0, 3.2, 2.4 Hz). As this example illustrates, the
ready availability of exocyclic allenes from the reactions
of propargylic silanes32,33 (e.g., 24) coupled with base-
induced allene isomerization constitutes an efficient two-
step protocol for the diastereoselective delivery of termi-
nal alkynes.
We have also noted that the hyperbasicity of the
potassium amide bases used to mediate the allene
isomerization may result in undesired elimination reac-
tions. For example, treatment of allene 28, available
from 26 via acid-catalyzed dehydration and concomitant
acetal formation, resulted in extensive elimination and
isomerization to produce terminal alkyne 29, isolated as
the corresponding acetate. Cycloaromatization products
have been previously observed in base-mediated isomer-
izations of exocyclic allenes.5
St a n d a r d P r oced u r e for Allen e Isom er iza t ion .
(1R ,2S ,5R )-1-E t h yn yl-2-(m e t h yle t h yl)-5-m e t h ylcyclo-
h exa n e (2). To a stirred solution of N-methylbutylamine (0.57
mL, 4.8 mmol) in THF (1.0 mL) at -20 °C was added dropwise
(32) Spence, J . D.; Lowrie, L. E.; Nantz, M. H. Tetrahedron Lett.
1995, 36, 5499.
(33) (a) Schinzer, D; So´lyom, S.; Becker, M. Tetrahedron Lett. 1985,
26, 1831. (b) Schinzer, D.; Steffen, J .; So´lyom, S. J . Chem. Soc., Chem.
Commun. 1986, 829.
(35) Ehrlich-Rogozinski, S.; Bosshard, H. R. Anal. Chem. 1973, 45,
2436.
(36) Alexakis, A.; Commercon, A.; Villieras, J .; Normant, J . F.
Tetrahedron Lett. 1976, 2313.
(34) J ohnstone, R. A. W.; Rose, M. E. Tetrahedron 1979, 35, 2169.

Base-Mediated Terminal Allene Isomerization
J . Org. Chem., Vol. 61, No. 12, 1996 4019
n-BuLi (1.7 mL of a 2.5 M solution in hexanes, 4.2 mmol). After
stirring for 10 min, a solution of KOt-Bu in THF (2.6 mL of a
1.6 M solution, 4.2 mmol) was added and the solution was
of a solution of ester 13a (1.01 g, 4.34 mmol) in diethyl ether
(6.0 mL). The reaction was stirred for 2 h at 0 °C and
quenched by addition of 10% NaOH (5 mL) followed by
warming to room temperature. The quenched reaction was
diluted with diethyl ether (10 mL), and the layers were
separated. The organic layer was washed with saturated
aqueous NH4Cl (10 mL), water (10 mL), and brine (10 mL)
and then dried (Na2SO4). The solvent was removed by rotary
evaporation and the crude product was purified by flash
chromatography (5% EtOAc/hexane to 10% EtOAc/hexane
gradient) to give 758 mg (85%) of alcohol 14a as a colorless
warmed to 0 °C and stirred for an additional 20 min.
A
solution of allene 1 (194 mg, 1.20 mmol) in THF (1.0 mL) at 0
°C was then added dropwise via cannula. The reaction was
quenched after 15 min by the addition of saturated aqueous
NH4Cl and diluted with Et2O. The organic layer was sepa-
rated, washed with saturated aqueous NH4Cl and brine and
then dried (MgSO4). The solvent was removed by rotary
evaporation, and the residue was purified by flash chroma-
tography (hexane) to afford a mixture of 2 and 3 as a colorless
oil (150 mg, 77%). A subsequent chromatographic step on the
product mixture eluting with n-pentane afforded an analytical
1
oil: IR 3402, 2250 cm-1; H NMR δ 7.35-7.27 (m, 5H), 4.51
(s, 2H), 3.55 (t, J ) 6.2 Hz, 2H), 2.34 (t, J ) 7.1 Hz, 2H), 1.81
(m, 2H); 13C NMR δ 138.5, 128.4, 127.7, 127.6, 85.8, 78.6, 72.9,
68.7, 28.7, 15.6. HRMS calcd for C13H13D2O2 205.1197, found
205.1186.
sample of 2: IR 3312, 2113 cm-1 1H NMR δ 2.28 (m, 1H),
;
2.19-2.11 (m, 1H), 2.05 (d, J ) 2.3 Hz, 1H), 2.01-1.96 (m,
1H), 1.73-1.69 (m, 2H), 1.65-1.62 (m, 1H), 1.36-1.09 (m, 4H),
0.92 (d, J ) 6.9 Hz, 3H), 0.88 (d, J ) 6.5 Hz, 3H), 0.77 (d, J )
6.9 Hz, 3H); 13C NMR δ 88.0, 68.8, 47.1, 42.4, 34.8, 33.2, 32.4,
28.5, 24.0, 22.2, 21.3, 15.6. Anal. Calcd for C12H20: C, 87.73;
H, 12.27. Found: C, 88.00; H, 12.17.
Meth yl 6-(Ben zyloxy)-1,1-d id eu ter io-2-h exyn yl Ca r -
bon a te (15a ). To a solution of alcohol 14a (660 mg, 3.20
mmol) in CH2Cl2 (15 mL) at room temperature were added
DMAP (79 mg, 0.64 mmol) and Et3N (0.89 mL, 6.4 mmol). The
reaction mixture was cooled to 0 °C, and methyl chloroformate
(0.50 mL, 6.4 mmol) was added dropwise. After stirring for 1
h, the reaction mixture was warmed to room temperature and
quenched by addition of saturated aqueous NH4Cl (5 mL) and
diluted with diethyl ether (15 mL). The layers were separated,
and the organic layer was washed with saturated aqueous
NH4Cl (10 mL), water (10 mL), brine (10 mL), and then dried
(Na2SO4). The solvent was removed by rotary evaporation and
the residue was purified by flash chromatography (5% EtOAc/
cis-1-Eth yn yl-3-(1,1-dim eth yleth yl)cycloh exan e (5): pre-
pared as described above, IR 3314, 2119 cm-1; 1H NMR δ 2.21
(m, 1H), 2.05 (d, J ) 2.2 Hz, 1H), 2.01-1.93 (m, 1H), 1.81-
1.71 (m, 2H), 1.27-1.17 (m, 2H), 1.09-0.95 (m, 4H), 0.84 (s,
9H); 13C NMR δ 89.5, 67.3, 47.6, 34.3, 33.0, 32.5, 30.0, 27.4,
26.5, 26.1; exact mass calcd for C12H20 164.1565, found
164.1560.
tr a n s-1-Eth yn yl-4-(1,1-d im eth yleth yl)cycloh exa n e (8):
1
prepared as described above, IR 3312, 2119 cm-1; H NMR δ
hexane) to afford 761 mg (90%) of carbonate 15a as a colorless
1
oil: IR (neat) 2253, 2240, 1753, 1718, 1286 cm-1
; H NMR δ
2.14 (m, 1H), 2.08-2.05 (m, 2H), 2.02 (d, J ) 2.2 Hz, 1H),
1.79-1.74 (m, 2H), 1.36-1.27 (m, 2H), 1.03-0.92 (m, 3H), 0.82
(s, 9H); 13C NMR δ 89.2, 67.3, 47.3, 33.5, 32.4, 29.5, 27.4, 26.8.
Anal. Calcd for C12H20: C, 87.73; H, 12.27. Found: C, 88.22;
H, 12.44.
7.35-7.27 (m, 5H), 4.50 (s, 2H), 3.79 (s, 3H), 3.55 (t, J ) 6.1
Hz, 2H), 2.35 (t, J ) 7.1 Hz, 2H), 1.81 (quintet, J ) 6.6 Hz,
2H); 13C NMR δ 155.2, 138.4, 128.3, 127.6, 127.5, 87.7, 73.6,
72.9, 68.6, 54.9, 28.4, 15.6; HRMS calcd for C15H15D2O4 (M+
Hbenzylic) 263.1252, found 263.1269.
-
6-(Ben zyloxy)-3-eth yl-1-h exyn e (10): prepared as de-
-1
scribed above, IR 3305, 3031, 2933, 2112, 1455, 1102 cm
;
6-(Ben zyloxy)-1,1-d id eu t er io-3-m et h yl-1,2-h exa d ien e
(16a ). A solution of LiBr (99 mg, 1.14 mmol) and CuI (216
mg, 1.14 mmol) in THF (4 mL) was prepared at room
temperature and cooled to 0 °C. To the reaction mixture was
added dropwise MeMgBr (0.38 mL of a 3.0 M solution in
diethyl ether, 1.14 mmol). After stirring for 5 min, the reaction
mixture was cooled to -5 °C and a solution of carbonate 15a
(50 mg, 0.19 mmol) in THF (1 mL) was added dropwise via
cannula. The reaction was quenched after stirring 0.5 h by
addition of saturated aqueous NH4Cl (3 mL) and diluted with
diethyl ether (15 mL). The organic layer was separated,
washed with saturated aqueous NH4Cl (5 mL), water (10 mL),
and brine (10 mL), and then dried (Na2SO4). The solvent was
removed by rotary evaporation, and the crude product was
purified by chromatography (100% hexane to 2% EtOAc/
hexane gradient) to afford 35 mg (91%) of allene 16a as a
colorless oil: IR 1941 cm-1; 1H NMR δ 7.35-7.27 (m, 5H), 4.50
(s, 2H), 3.50 (t, J ) 6.5 Hz, 2H), 2.02 (t, J ) 7.1 Hz, 2H), 1.76
(m, 2H), 1.68 (s, 3H); 13C NMR δ 206.0, 138.6, 128.3, 127.6,
127.5, 98.2, 72.9, 69.9, 29.9, 27.6, 18.8; HRMS calcd for
C14H15D2O (M+ - Hbenzylic) 203.1404, found 203.1391.
1H NMR δ 7.33-7.25 (m, 5H), 4.52 (s, 2H), 3.51 (t, J ) 6.3 Hz,
2H), 2.31-2.25 (m, 1H), 2.06 (d, J ) 2.4 Hz, 1H), 1.90-1.42
(m, 6H), 1.02 (t, J ) 7.4 Hz, 3H); 13C NMR δ 138.6, 128.3,
127.6, 127.4, 87.5, 72.8, 70.1, 69.4, 33.0, 31.1, 27.9, 27.5, 11.6.
Anal. Calcd for C15H20O: C, 83.29; H, 9.32. Found: C, 83.16;
H, 9.20.
6-(Ben zyloxy)-3-(m eth yleth yl)-1-h exyn e (12): prepared
as described above, IR 3307, 3031, 2962, 2110, 1454, 1103 cm
-1; 1H NMR δ 7.41-7.39 (m, 5H), 4.56 (s, 2H), 3.56 (t, J ) 6.4
Hz, 2H), 2.31-2.25 (m, 1H), 2.1 (d, J ) 2.4 Hz, 1H), 1.95-
1.90 (m, 1H), 1.81-1.53 (m, 4H), 1.05 (d, J ) 5.7 Hz, 3H), 1.03
(d, J ) 5.7 Hz, 3H); 13C NMR δ 138.6, 128.3, 127.6, 127.5, 86.0,
72.8, 70.3, 70.0, 38.5, 31.4, 29.2, 27.9, 21.0, 18.3. Anal. Calcd
for C16H22O: C, 83.43; H, 9.63. Found: C, 83.23; H, 9.57.
Meth yl 6-(Ben zyloxy)-2-h exyn oa te (13a ). To a solution
of 5-(benzyloxy)-1-pentyne27 (8.00 g, 46.2 mmol) in THF (230.0
mL) at -50 °C was added dropwise n-BuLi (31.8 mL of a 1.6
M solution in hexanes, 50.8 mmol). After stirring for 1 h,
methyl chloroformate (5.35 mL, 69.3 mmol) was added drop-
wise. The reaction mixture was warmed to room temperature
after 5 min and stirred for 15 h. The reaction was quenched
by addition of saturated aqueous NaHCO3 (20 mL) and diluted
with diethyl ether (250 mL). The organic layer was separated
and washed with saturated aqueous NaHCO3 (2 × 50 mL),
water (50 mL), and brine (50 mL) and then dried (Na2SO4).
The solvent was removed by rotary evaporation, and the crude
product was purified by flash chromatography (3% EtOAc/
hexane to 12% EtOAc/hexane gradient) to give 7.06 g (66%)
6-(Be n zyloxy)-1,1-d id e u t e r io-3-e t h yl-1,2-h e xa d ie n e
(17a ). Carbonate 15a (50 mg, 0.19 mmol) was reacted at -35
°C according to the procedure described for the preparation of
16a using ethylmagnesium chloride (0.57 mL of a 2.0 M
solution in THF, 1.14 mmol) to afford 39 mg (94%) of allene
17a as a colorless oil: IR 1936 cm-1
; 1H NMR δ 7.35-7.27 (m,
5H), 4.50 (s, 2H), 3.50 (t, J ) 6.5 Hz, 2H), 2.03 (t, J ) 7.2 Hz,
2H), 1.94 (q, J ) 7.4 Hz, 2H), 1.76 (m, 2H), 1.00 (t, J ) 7.4
Hz, 3H); 13C NMR δ 205.3, 138.7, 128.3, 127.6, 127.4, 104.8,
72.9, 69.9, 28.5, 27.7, 25.2, 12.1; HRMS calcd for C15H17D2O
(M+ - Hbenzylic) 217.1561, found 217.1569.
of ester 13a as a light yellow oil: IR 2237, 1715, 1258 cm-1
;
1H NMR δ 7.35-7.28 (m, 5H), 4.51 (s, 2H), 3.75 (s, 2H), 3.56
(t, J ) 6.0 Hz, 2H), 2.48 (t, J ) 7.1 Hz, 2H), 1.87 (quintet, J )
6.5 Hz, 2H); 13C NMR δ 153.9, 138.1, 128.2, 127.4 (2), 88.9,
72.9, 72.8, 68.1, 52.3, 27.7, 15.4. HRMS calcd for C14H15O3
231.1021, found 231.1018.
6-(Be n zyloxy)-1,1-d id e u t e r io-3-isop r op yl-1,2-h e xa -
d ien e (18a ). Carbonate 15a (50 mg, 0.19 mmol) was reacted
at -50 °C according to the procedure described for the
preparation of 16a using isopropylmagnesium chloride (0.57
mL of a 2.0 M solution in diethyl ether, 1.14 mmol) to give 43
6-(Ben zyloxy)-1,1-d id eu ter io-2-h exyn -1-ol (14a ). To a
suspension of LiAlD4 (173 mg, 4.34 mmol) in diethyl ether (5.0
mL) at 0 °C was added via syringe a solution of freshly
sublimed AlCl3 (579 mg, 4.34 mmol) in diethyl ether (6.0 mL).
The reaction was stirred for 5 min before addition via cannula
mg (97%) of allene 18a as a colorless oil: IR 1933 cm-1 1H
;
NMR δ 7.35-7.30 (m, 5H), 4.50 (s, 2H), 3.50 (t, J ) 6.5 Hz,
2H), 2.10 (m, 1H), 2.03 (t, J ) 7.4 Hz, 2H), 1.75 (m, 2H), 1.01

4020 J . Org. Chem., Vol. 61, No. 12, 1996
Spence et al.
(d, J ) 6.7 Hz, 6H); 13C NMR δ 204.5, 138.7, 128.3, 127.5,
127.4, 109.4, 72.8, 69.9, 30.5, 27.8, 26.6, 21.5; HRMS calcd for
C16H19D2O (M+ - Hbenzylic) 231.1717, found 231.1725.
removed by rotary evaporation, and the crude product was
purified by chromatography (0.2% EtOAc/hexane to 1% EtOAc/
hexane gradient) to yield 1.04 g (85%) of allene 18b as a
colorless oil: IR 1933 cm-1 1H NMR δ 7.50-7.23 (m, 15H),
;
Met h yl 6-[(Tr ip h en ylm et h yl)oxy]-2-h exyn oa t e (13b ).
To a solution of 5-[(triphenylmethyl)oxy]-1-pentyne (1.82 g,
5.57 mmol) in THF (55 mL) at -78 °C was added n-BuLi (2.53
mL of a 2.4 M solution in hexanes, 6.13 mmol) dropwise. The
reaction mixture was stirred for 1 h before the dropwise
addition of methyl chloroformate (0.82 mL, 8.36 mmol) and
followed by warming to room temperature over 15 h. The
reaction was quenched by addition of saturated aqueous
NaHCO3 (5 mL) and diluted with diethyl ether (100 mL). The
organic layer was separated, washed with saturated aqueous
NaHCO3, water, and brine, and then dried (Na2SO4). The
solvent was removed by rotary evaporation, and the solid
residue was purified by chromatography (3% EtOAc/hexane
to 10% EtOAc/hexane gradient) to give 2.00 g (93%) of ester
13b as a white solid: mp ) 103.0-103.9 °C; IR 2236, 1715,
3.12 (t, J ) 6.5 Hz, 2H), 2.10 (m, 1H), 2.07 (t, J ) 7.6 Hz, 2H),
1.80 (quintet, J ) 6.9 Hz, 2H), 1.03 (d, J ) 6.8 Hz, 6H); 13C
NMR δ 204.5, 144.5, 128.7, 127.6, 126.8, 109.6, 86.3, 63.2, 30.5,
28.2, 26.8, 21.6; HRMS calcd for C28H28D2O 384.2422, found
384.2440.
7-E t h en ylid en e-1,11-b is(h yd r oxym et h yl)-2-m et h oxy-
sp ir o[5.5]u n d ec-1-en e (26). To a suspension of finely pow-
dered KOH (230 mg, 4.08 mmol) in DMSO (1.5 mL) at room
temperature were added successively a solution of enol 2432
(340 mg, 1.02 mmol) in DMSO (1.5 mL) via cannula and
methyl iodide (0.26 mL, 4.08 mmol). The heterogeneous
solution was stirred for 1 h. The mixture was then diluted
with water and extracted with Et2O. The combined organic
extract was washed with water, saturated aqueous NaHCO3,
and brine and then dried (Na2SO4). Removal of the solvent
by rotary evaporation afforded 330 mg (93%) of the corre-
sponding vinylogous carbonate 25 as a white solid that did
not require further purification: mp 69-72 °C; IR 3041, 1957,
1
1259 cm-1; H NMR δ 7.47-7.23 (m, 15H), 3.78 (s, 3H), 3.20
(t, J ) 5.9 Hz, 2H), 2.54 (t, J ) 7.3 Hz, 2H), 1.88 (quintet, J )
6.5 Hz, 2H); 13C NMR δ 154.0, 144.0, 128.6, 127.7, 126.9, 89.3,
86.5, 73.0, 61.6, 52.4, 28.1, 15.8; HRMS calcd for C26H24O3
384.1725, found 384.1742.
1
1721, 1681, 1627, 1294, 1156 cm-1; H NMR δ 4.64-4.47 (m,
6-[(Tr ip h en ylm et h yl)oxy]-1,1-d id eu t er io-2-h exyn -1-
ol (14b). To a suspension of LiAlD4 (167 mg, 4.21 mmol) in a
5:1 mixture of Et2O:THF (14 mL) at 0 °C was added dropwise
via syringe a solution of freshly sublimed AlCl3 (561 mg, 4.21
mmol) in a 5:1 mixture of Et2O:THF (14 mL). After stirring 5
min, a solution of ester 13b (1.62 g, 4.21 mmol) in a 5:1 mixture
of Et2O:THF (14 mL) was added dropwise via cannula and the
reaction was stirred for 30 min. The reaction was quenched
by addition of 10% NaOH (5 mL) and warmed to room
temperature. The reaction was diluted with diethyl ether (200
mL), and the layers were separated. The organic layer was
washed with 10% NaOH, water, and brine and then dried
(Na2SO4). The solvent was removed by rotary evaporation,
and the crude product was purified by chromatography (10%
EtOAc/hexane to 20% EtOAc/hexane gradient) to give 1.16 g
(77%) of alcohol 14b as a white solid: mp ) 87.1-90.0 °C; IR
2H), 4.23-4.11 (m, 2H), 4.07-4.00 (m, 2H), 3.54 (s, 3H), 3.23-
3.18 (m, 1H), 2.20-2.13 (m, 4H), 2.02-1.97 (m, 1H), 1.80-
1.64 (m, 7H), 1.26 (t, J ) 7.0 Hz, 3H), 1.18 (t, J ) 7.1 Hz, 3H);
13C NMR δ 206.7, 173.4, 167.0, 161.3, 115.7, 104.6, 74.4, 59.4,
59.1, 55.8, 47.3, 43.0, 27.0, 26.6, 25.2, 24.5, 24.4, 17.2, 13.9,
13.8; exact mass calcd for C20H28O5 348.1937, found 348.1958.
To a solution of 25 (330 mg, 0.95 mmol) in THF (6 mL) at
0 °C was added LiAlH4 (3.3 mL of a 1.0 M solution in THF,
3.32 mmol). After stirring for 3 h, the solution was warmed
to 10 °C and stirred an additional 1 h. The solution was then
recooled to 0 °C and quenched by slow dropwise addition of
MeOH. The quenched reaction mixture was diluted with Et2O
and poured into an equal volume of saturated aqueous
Rochelle’s Salt (sodium potassium tartrate), and the resultant
mixture was stirred vigorously until the organic layer was
clear. The organic layer was separated, and the aqueous layer
was extracted with Et2O. The combined organic extract was
washed with brine and dried (Na2SO4). Rotary evaporation
of the solvent gave a yellow oil that was purified using flash
column chromatography (ethyl acetate) to give 180 mg (72%)
of 26 as a white solid: mp 89-91 °C; IR 3356, 3045, 1952,
1
3314, 2214 cm-1; H NMR δ 7.47-7.23 (m, 15H), 3.23 (t, J )
6.0 Hz, 2H), 2.42 (t, J ) 7.1 Hz, 2H), 1.93 (s, 1H), 1.85 (quintet,
J ) 6.5 Hz, 2H); 13C NMR δ 144.1, 128.6, 127.6, 126.8, 86.3,
85.6, 78.6, 61.8, 29.0, 15.7; HRMS calcd for C25H22D2O2
358.1901, found 358.1913.
Meth yl 6-[(Tr iph en ylm eth yl)oxy]-1,1-did eu ter io-2-h ex-
yn yl Ca r bon a te (15b). To a solution of alcohol 14b (1.36 g,
3.79 mmol) in CH2Cl2 (38 mL) at room temperature were added
Et3N (1.06 mL, 7.58 mmol) and DMAP (93 mg, 0.758 mmol).
The reaction was cooled to -78 °C and methyl chloroformate
(0.59 mL, 7.58 mmol) was added dropwise via syringe. The
reaction mixture was stirred and warmed to room temperature
over 15 h. The reaction was quenched by addition of saturated
aqueous NH4Cl (5 mL) and diluted with CH2Cl2 (200 mL). The
organic layer was separated, washed with saturated aqueous
NH4Cl, water, and brine, and then dried (Na2SO4). The solvent
was removed by rotary evaporation, and the crude oil was
purified by chromatography (3% EtOAc/hexane to 10% EtOAc/
hexane gradient) to afford 1.46 g (92%) of carbonate 15b as a
colorless oil: IR 2254, 1754, 1285 cm-1; 1H NMR δ 7.47-7.23
(m, 15H), 3.82 (s, 3H), 3.19 (t, J ) 6.0 Hz, 2H), 2.43 (t, J ) 7.2
Hz, 2H), 1.84 (quintet, J ) 6.4 Hz, 2H); 13C NMR δ 155.3,
144.2, 128.6, 127.7, 126.8, 87.9, 86.4, 73.5, 61.8, 54.9, 28.9, 15.9;
HRMS calcd for C27H24D2O4 416.1957, found 416.1921.
6-[(Tr ip h en ylm eth yl)oxy]-1,1-d id eu ter io-3-isop r op yl-
1,2-h exa d ien e (18b). A solution of LiBr (1.67 g, 19.3 mmol)
and CuI (3.67 g, 19.3 mmol) in THF (65 mL) was prepared at
room temperature and cooled to -50 °C. To the reaction
mixture was added i-PrMgCl (9.63 mL of a 2.0 M solution in
diethyl ether, 19.3 mmol) dropwise. After stirring 10 min, a
solution of carbonate 15b (1.34 g, 3.21 mmol) in THF (15 mL)
was added dropwise via cannula. The reaction mixture after
stirring for 0.5 h was quenched by addition of saturated
aqueous NH4Cl (10 mL) and diluted with diethyl ether (200
mL). The organic layer was separated and washed with
saturated aqueous NH4Cl (2 × 30 mL), water (30 mL), and
brine (35 mL) and then dried (Na2SO4). The solvent was
1
1664, 1214, 1141 cm-1; H NMR δ 4.50-4.41 (m, 3H), 3.74-
3.63 (m, 2H), 3.57 (s, 3H), 3.24 (dd, J ) 11.0, 5.4 Hz, 1H), 2.96
(s, 1H, OH), 2.38 (s, 1H, OH), 2.26-2.00 (m, 4H), 1.95-1.80
(m, 4H), 1.70 -1.11 (m, 5H); 13C NMR δ 205.9, 155.8, 120.1,
106.0, 73.5, 65.6, 57.9, 55.2, 46.7, 45.6, 30.7, 27.5, 26.2, 25.7,
24.2, 18.3; exact mass calcd for C16H24O3 264.1725, found
264.1719.
7-E t h yn yl-1,11-b is(h yd r oxym et h yl)-2-m et h oxysp ir o-
[5.5]u n d ec-1-en e (27). To propane-1,3-diamine (3.0 mL) at
0 °C was added n-BuLi (2.2 mL of a 2.5 M solution in hexanes,
5.5 mmol). After stirring for 10 min, a solution of KOt-Bu in
THF (3.4 mL of a 1.6 M solution, 5.5 mmol) was added
dropwise, and the reaction was warmed to room temperature
and stirred for 25 min. A solution of allene 26 (160 mg, 0.606
mmol) in propane-1,3-diamine (3.0 mL) was then added
dropwise via cannula. After stirring overnight, the reaction
was quenched by slow addition of saturated aqueous NaHCO3
and diluted with Et2O. The organic layer was separated and
washed with saturated aqueous NaHCO3 and brine and then
dried (Na2SO4). The solvents were removed by rotary evapo-
ration and the residue was purified by flash column chroma-
tography (ethyl acetate) to give 95 mg (62%) of 27 as a white
solid: mp 92-95 °C; IR 3376, 3306, 2109, 1660, 1210 cm-1
;
1H NMR δ 4.43 (d, J ) 12.0 Hz, 1H), 3.98 (d, J ) 12.0 Hz,
1H), 3.71 (dd, J ) 10.8, 5.1 Hz, 2H), 3.60 (s, 3H), 3.24 (dd, J
) 10.8, 6.1 Hz., 2H), 2.54 (br s, 2H, OH), 2.41 (ddd, J ) 12.0,
3.2, 2.4 Hz., 1H), 2.22-2.15 (m, 2H), 2.01-1.95 (overlapping
m, 1H), 1.98 (d, J ) 2.4 Hz, 1H), 1.82-1.51 (m, 6H), 1.31-
1.24 (m, 2H); 13C NMR δ 157.0, 119.6, 86.8, 77.2, 70.2, 65.7,
56.4, 55.3, 46.4, 42.2, 39.1, 28.2, 25.4, 25.2, 24.1, 20.7; exact
mass calcd for C16H24O3 264.1725, found 264.1738.

Base-Mediated Terminal Allene Isomerization
J . Org. Chem., Vol. 61, No. 12, 1996 4021
2-Meth oxy-2,6-(m eth ylen em eth a n o)-7-eth en ylid en e-3-
oxa bicyclo[6.4.0]d od eca n e (28). A solution of alcohol 26 (17
mg, 0.063 mmol) in benzene (1.5 mL) was stirred over
powdered 4 Å molecular sieves at room temperature for 1 h.
Pyridinium p-toluenesulfonate (16 mg, 0.063 mmol) was added,
and the reaction mixture was stirred at room temperature for
20 min. The mixture was then diluted with benzene and
filtered through a short column of silica gel. The benzene was
removed by rotary evaporation, and the crude product was
purified by flash chromatography (ethyl acetate) to give 11 mg
(71%) of 28 as a clear oil: IR 3048, 1951, 1739, 1649, 1112
cm-1; 1H NMR δ 5.59 (d, J ) 1.3 Hz, 1H), 5.27 (d, J ) 1.3 Hz,
1H), 4.69 (dd, J ) 2.3, 2.4 Hz, 2H), 3.90 (m, 2H), 3.39 (s, 3H),
2.38-2.20 (m, 4H), 2.18-1.91 (m, 2H), 1.84-1.55 (m, 4H),
1.43-1.22 (m, 2H), 0.88 (m, 1H); 13C NMR δ 205.3, 149.4,
106.2, 105.2, 99.2, 75.7, 68.4, 49.6, 44.1, 37.3, 33.6, 29.1, 28.9,
23.5, 22.6, 21.5; exact mass calcd for C16H22O2 246.1620, found
246.1620.
3-[1-(Acetoxym eth yl)-6-h ep tyn yl]-1-m eth oxy-2-m eth yl-
ben zen e (29). To a solution of allene 28 (98.0 mg, 0.400
mmol) in propane-1,3-diamine (1.2 mL) was added potassium
aminopropylamide7a (2.8 mL of a 1 M solution in propane-1,3-
diamine, 2.8 mmol). The resultant dark brown mixture was
stirred at room temperature for 16 h. The reaction was
quenched by addition of EtOAc/Et2O and followed by addition
of saturated aqueous NaHCO3. The organic layer was sepa-
rated and washed with saturated aqueous NaHCO3 and brine.
The aqueous fractions were extracted with Et2O, and the
combined organic extract was dried (Na2SO4). The solvents
were removed by rotary evaporation to give a crude product
that was purified by flash chromatography (10% ethyl acetate/
hexane) to afford 73.9 mg (64%) of 29 as a light yellow oil: IR
3294, 3072, 2117, 1741, 1583, 1464, 1256 cm-1; 1H NMR δ 7.14
(t, J ) 8.0 Hz, 1H); 6.80 (d, J ) 7.9 Hz, 1H); 6.74 (d, J ) 8.1
Hz, 1H), 4.14 (m, 2H), 3.86 (s, 3H), 3.3 (m, 1H), 2.12 (s, 3H),
2.04 (m, 2H), 1.91 (s, 3H), 1.81 (t, J ) 2.6 Hz, 1H), 1.82-1.47
(overlapping m, 2H), 1.23 (m, 2H), 0.88 (m, 2H); 13C NMR δ
171.0, 157.6, 141.2, 126.2, 125.4, 118.2, 108.2, 84.4, 68.4, 68.2,
55.5, 39.4, 31.9, 28.6, 26.3, 20.9, 18.2, 11.1; exact mass calcd
for C18H24O3 288.1725, found 288.1708.
Ack n ow led gm en t is made to the donors of the
Petroleum Research Fund, administered by the Ameri-
can Chemical Society, for support of this research.
Sincere thanks are given to Dr. A. Daniel J ones for the
mass spectral measurements and helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: 75 MHz 13C NMR
spectra of new compounds lacking combustion data (14 pages).
This material is contained in libraries on microfiche, im-
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J O960276I