Solvent and substituent effects on conjugated eliminations in propargylic systems

Article abstract of DOI:10.1016/S0040-4039(00)00856-X

The deprotonation of 4-methoxy-but-2-ynal diethyl acetal by n- butyllithium induces an acetylenic-allenic isomerization (in diethylether) or a conjugated elimination reaction (in THF), providing the corresponding 1,4- dialkoxycumulene. An allenyllithium, that has been trapped as an allenylstannane, is proposed to be a common intermediate to both pathways. Also, the deprotonation of 4-dialkylamino-but-2-ynal diethyl acetals in the same conditions affords a mixture of (E) and (Z) aminocrotonates of which formation can be explained by a chemioselective removal of the acetalic proton leading to an intermediate allenyllithium that has equally been trapped by stannylation. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00856-X

Tetrahedron Letters 41 (2000) 5367±5371
Solvent and substituent e€ects on conjugated eliminations in
propargylic systems
Frederic Le Strat and Jacques Maddaluno*
   Â
Laboratoire des Fonctions Azotees & Oxygenees Complexes de l'IRCOF, UMR 6014 CNRS, Universite de Rouen,
76821 Mont St Aignan Cedex, France
Received 18 April 2000; accepted 25 May 2000
Abstract
The deprotonation of 4-methoxy-but-2-ynal diethyl acetal by n-butyllithium induces an acetylenic±allenic
isomerization (in diethylether) or a conjugated elimination reaction (in THF), providing the corresponding
1,4-dialkoxycumulene. An allenyllithium, that has been trapped as an allenylstannane, is proposed to be a
common intermediate to both pathways. Also, the deprotonation of 4-dialkylamino-but-2-ynal diethyl
acetals in the same conditions a€ords a mixture of (E) and (Z) aminocrotonates of which formation can be
explained by a chemioselective removal of the acetalic proton leading to an intermediate allenyllithium that
has equally been trapped by stannylation. # 2000 Elsevier Science Ltd All rights reserved.
The base-triggered conjugated elimination reaction on ethylenic acetals 1 provides a short-cut
to 1,4-disubstituted butadienes1 2 that are good partners for cycloadditions.2 Correspondingly,
propargylic acetals lead to dialkoxycumulenes, as described by Brandsma and colleagues as early
as 1970.3 These authors observed that the action of 2 equiv. of n-BuLi in diethyl ether on 4-methoxy-
but-2-ynal diethyl acetal 3 (Y=EtO and R=Et) provides the corresponding 1,4-diethoxy-1,2,3-
butatriene 4 in excellent yield and with a 2:1 selectivity in favor of the E-isomer (Scheme 1).
Scheme 1. Conjugated elimination on functionalized allylic and propargylic acetals
* Corresponding author: Fax: 33 (0) 235 522 971; e-mail: jmaddalu@crihan.fr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd All rights reserved.
PII: S0040-4039(00)00856-X

5368
Albeit these cumulenes have been cleanly isolated and are described as relatively robust species,
their synthetic potential has drawn relatively little attention4 despite an exceptionally high density
of functionalities on such small synthons. Brandsma's procedure, based on acetal 7, is extremely
convenient for preparing these compounds. Two methods can be employed to access 7. The ®rst
one5 is based on the condensation of the Grignard derivative of propargyl ether 6 on phenyl
diethyl orthoformate6 (Scheme 2). The second one relies on the same steps from propargyloxy-
trimethylsilane 8, providing alcohol 9 that is alkylated by dimethylsulfate to a€ord 7 in slightly
better yields (65% versus 52%).
Scheme 2. (a) Me2SO4, NaOH, H2O; (b) EtMgBr then PhOCH(OEt)2; (c) EtMgBr, PhOCH(OEt)2 then K2CO3,
MeOH, 0ꢁC; (d) NaH, THF then Me2SO4; (e) n-BuLi, Et2O, ^40ꢁC; (f) n-BuLi, THF, ^40ꢁC
To our surprise, reacting n-BuLi with 7 (ꢀ0.25 M) in ether did not prompt the expected elimina-
tion step but the quantitative isomerization of 7 into allene 10. By contrast, performing the same
reaction in THF completely reversed the selectivity in favor of cumulene 11 (in an E:Z ratio
identical to that reported by Brandsma3), at the condition that a sucient excess of base is used
(Scheme 2 and Table 1).
Table 1
Elimination/isomerisation selectivity on propargylic acetal 7 as a function of the base
Considering that this discrepancy with Brandsma's observations could stem from the quality of
the n-BuLi, and especially from the well-known in¯uence of lithium halides on the behavior of the
organolithium compound,7 we decided to resort, in ether, to a 1:1 mixture of LiBr and commercial
n-BuLi. This restored the selectivity in favor of 11 (entry 4). But the allene 10 can also be prepared
in THF, replacing butyllithium by potassium hexamethyldisilazane (KHMDS). Slightly warming
up the medium leads indeed, in an almost quantitative yield, to 10 (entry 6).
On a mechanistic point of view, the deprotonation of 7 can yield to either a propargyllithium
derivative such as 12 or to an allenyllithium 13 and these species can equilibrate in solution.8 In

5369
our case, the conversion is total and the two products recovered (10 and/or 11) seem to derive
from 13, which is either protonated to give the allene 10 or undergoes a b-elimination to provide
cumulene 11 (Scheme 3). We have checked that 10 thus obtained cannot be converted into 11
upon treatment with n-BuLi in THF. Trapping of the intermediate 13 has also been achieved.
The treatment of 7 with 2.3 equiv. of n-BuLi in ether at ^40ꢁC has been followed by the addition
of 2.3 equiv. of neat Bu3SnCl and warming up to 0ꢁC (Scheme 3). After 1 h and hydrolysis, the
corresponding tin-substituted allenic acetal 14 was obtained in ꢀ40% yield after puri®cation
by ¯ash-chromatography on silica gel. The predominance of the allenyllithium form 13 is in
®ne agreement with Reich's thorough NMR studies8 that have clearly established that oxygen
substituents on the propargylic position favor this isomer, even with strongly chelating groups
such as MOM, MEM or b-(dimethylamino)ethoxy.8a Regenerating 13 from 14 in THF by action
with n-BuLi at ^40ꢁC triggers the b-elimination and leads to cumulene 11 in quantitative yields.
By contrast, 14 remains inert towards butyllithium in ether in the same conditions.y
Scheme 3. (a) Bu3SnCl, Et2O, 0ꢁC, 1 h
Therefore, the solvent e€ect we observe could be due to di€erences in the structure/aggregation
of 13 in solution. At least two reasons can be invoked to explain these di€erences: (i) NMR
indicates lithiomethoxyallene to be dimeric in THF and tetrameric in diethyl ether;9 (ii) it has
been shown that when the allenyl structure bears a chelating group, it can act as a supplementary
ligand in the lithium coordination sphere in place of a solvent molecule.10 If we assume that one
of the oxygens of the acetal in 13 plays this role, it could endow this group with a leaving character.
Thus, only in THF would the lithium act as an intramolecular Lewis acid for 13.
To extend the scope of this reaction, we then studied the case of propargylic aminoacetals. The
two compounds 15 can be readily prepared by tosylation of 9 and substitution by diethꢁylamine or
pyrrolidine in THF (Scheme 4).11 Their deprotonation with 2.2 equiv. of n-BuLi at ^40 C a€ords,
after 30 min in THF (no reaction was observed in ether), a mixture of E/Z aminocrotonate 16
(E:Z=1:1 for R=NEt2, 1:2 for R=pyrrolidine) in ꢀ35% yield after distillation in a bulb-to-bulb
oven.
y
Warming up the medium would probably make this reaction possible in ether as well as in THF, as described in a
related situation by: Beaudet, I.; Launay, V.; Parrain, J. L.; Quintard, J. P. Tetrahedron Lett. 1995, 36, 389±392.
However, this would not mimic our reaction conditions. See also in relation: (a) Normant, J. F.; Alexakis, A. Synthesis
1981, 841±869. (b) Beaudet, I.; Parrain, J. L.; Quintard, J. P. Tetrahedron Lett. 1991, 32, 6333±6336.

5370
Scheme 4. (a) (i) TsCl, KOH, THF, ^10ꢁC, 1 h; (ii) 3 equiv. amine, THF, rt, overnight; (b) n-BuLi, THF, ^40ꢁC, 30
min
This change in the reaction pathway can be due to the chemioselective deprotonation of the
acetalic position, leading again to a propargyl (17) and/or allenyl (18) lithium intermediate
(Scheme 5). Since the conversion of 15 is total again, it seems that upon hydrolysis, only the
allenyl form 18 is protonated to yield an intermediate ketene ketal, that is hydrolized during the
work-up to provide the aminocrotonates 16. The allenyl 18b can be trapped by Bu3SnCl in conditions
similar to those described above, leading to the pure (Z)-b-stannyl crotonate 19b in 22% yield
after ¯ash-chromatography.
Scheme 5. (a) n-BuLi, THF, ^40ꢁC, 30 min; (b) H2O; (c) Bu3SnCl, THF, 0ꢁC, 40 min
This result is relatively unexpected since the deprotonation in extremely similar conditions of
allylic aminoacetals such as 20 provides in high yields the corresponding elimination product, viz.
dienamine 21 (Scheme 6).2b,12 On the other hand, a comparable deprotonation of the propargylic
acetal 22 has been described13 and gives access to the corresponding ketene ketal 23, following a
reaction pathway identical to that we report here. This swap of the regioselectivity of the depro-
tonation is dicult to rationalize but is probably to be considered in relation to the likely com-
plexation occurring between the amino appendage of the propargylic acetal 15 and butylllithium
prior to the reaction.
Scheme 6. (a) 3 equiv. t-BuOK+3 equiv. n-BuLi, THF, ^70ꢁC, 30 min; (b) Ref. 13

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In conclusion, we have shown that the deprotonation of propargylic acetals can lead at will to
the isomerization into the corresponding allenes or to the conjugated elimination reaction on a
simple solvent swap. We have also observed that aminopropargylic acetals undergo a regioselective
deprotonation of the acetalic position, at the origin of the formation of a ketene ketal that is
hydrolized upon work-up into the corresponding aminocrotonates.
Acknowledgements
Professor Jean Villieras (Universite de Nantes) for fruitful discussion. F.L.S. thanks the Ministere
de la Recherche et de la Technologie for a PhD grant.
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