Strong Bicyclic Guanidine Base-promoted Wittig and Horner-Wadsworth-Emmons Reactions

Article abstract of DOI:10.1021/ol0001665

formula presented A convenient procedure to effect the Wittig and Horner-Wadsworth-Emmons reactions employs guanidine TBD and MTBD as base-promoters; mild reaction conditions, high efficiency, and facile isolation of the final products make the present methodology, at least in some cases, a practical alternative to known procedures.

Full text of DOI:10.1021/ol0001665

ORGANIC
LETTERS
2000
Vol. 2, No. 24
3765-3768
Strong Bicyclic Guanidine
Base-Promoted Wittig and
Horner−Wadsworth−Emmons Reactions
Daniele Simoni,*† Marcello Rossi,† Riccardo Rondanin,† Angelica Mazzali,†
Riccardo Baruchello,† Cinzia Malagutti,† Marinella Roberti,‡ and
Francesco Paolo Invidiata§
Dipartimento di Scienze Farmaceutiche, UniVersita` di Ferrara, Via Fossato di
Mortara 17-19, 44100 Ferrara, Italy, Dipartimento di Scienze Farmaceutiche,
UniVersita` di Bologna, Via Belmeloro 6, 40126 Bologna, Italy, and Dipartimento
Farmacochimico Tossicologico e Biologico, Via Archirafi 32, UniVersita` di Palermo,
90123 Palermo, Italy
smd@dns.unife.it
Received June 21, 2000
ABSTRACT
A convenient procedure to effect the Wittig and Horner−Wadsworth−Emmons reactions employs guanidine TBD and MTBD as base-promoters;
mild reaction conditions, high efficiency, and facile isolation of the final products make the present methodology, at least in some cases, a
practical alternative to known procedures.
We have recently stated that uncharged nitrogen bases have
never achieved the same success as the more widely known
ionic bases, and we have suggested that, at least in some
cases, their potentialities have not received full recognition.1
Indeed, simplicity of handling and mildness of reaction
conditions render nonionic nitrogen bases excellent tools for
generating carbanions, which can in turn participate in
interesting and useful transformations, thus allowing new
improved synthetic methodologies.
in organic synthesis. It is worth noting that recently chiral
bicyclic guanidines have received particular attention as
promoters of enantioselectivity.5-7 Results from our labora-
tory demonstrated that tetramethylguanidine (TMG)-cata-
lyzed addition of primary nitroalkanes and dialkyl phosphites
to a variety of unsaturated systems constitutes a practical
means to perform the nitroaldol reaction (Henry reaction)
and to achieve phosphonate synthons.8,9
Guanidine bases have been known for some time,2-4 but
there is still little work on their use as general strong bases
(4) Barton, D. H. R.; Elliot, J. D.; Ge´ro`, S. D. J. Chem. Soc., Perkin
Trans. 1 1982, 2085.
(5) van Aken, E.; Wynberg, H.; van Bolhuis, F. J. Chem. Soc., Chem.
Commun. 1992, 629.
(6) Boyle, P. H.; Convery, M. A.; Davis, A. P.; Hosken, G. D.; Murray,
B. A. J. Chem. Soc., Chem. Commun. 1992, 239.
(7) Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157.
(8) Simoni, D.; Invidiata, F. P.; Manfredini, S.; Ferroni, R.; Lampronti,
I.; Rondanin, R.; Pollini, G. P. Tetrahedron Lett. 1997, 38, 2749 and
references therein.
(9) Simoni, D.; Invidiata, F. P.; Manfredini, S.; Lampronti, I.; Rondanin,
R.; Roberti, M.; Pollini, G. P. Tetrahedron Lett. 1998, 39, 7615 and
references therein.
† Universita` di Ferrara.
‡ Universita` di Bologna.
§ Universita` di Palermo.
(1) Simoni, D.; Rondanin, R.; Morini, M.; Baruchello, R.; Invidiata, F.
P. Tetrahedron Lett. 2000, 41, 1607.
(2) Schwesinger, R.; Willaredt, J.; Schlemper, H.; Keller, M.; Schmitt,
D.; Fritz, H. Chem. Ber. 1994, 127, 2435 and references therein.
(3) Smith, P. A. S. In The Chemistry of Open Chain Nitrogen
Compounds; Benjamin: New York, 1965; Vol. 1, Chapter 6, pp 233-290
and references therein.
10.1021/ol0001665 CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/03/2000

Since 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) (1) and
its methyl derivative MTBD (2) were proven to be ap-
proximately 100 times more basic than TMG (3),10 and since
they were widely utilized as powerful organic bases for
tautomerizing pyrrocorphins,11,12 we have recently studied
their behavior as strong, nonionic, basic catalysts for synthetic
purposes. We found that TBD and MTBD catalyze the
addition of different nucleophiles to a variety of unsaturated
systems.1
Table 1. Product Yields and Stereoisomer Ratios of Some
Representative Wittig Reactions, as in Schemes 1 and 2
Thus, in our continued search for reactions in which strong
guanidine bases may provide improved synthetic methodol-
ogy over conventional approaches, we have found that TBD
and MTBD may represent, in some cases, surprisingly useful
new promoters of the Wittig reaction. While many efforts
have been devoted to the study of the reactivity of the
phosphorane intermediates, as well as of the reaction
conditions that may improve the steric course of the reaction,
less is known about the capability of nonionic strong bases
to generate phosphonium ylids.13,14 As a general rule, the
Wittig reaction must be conducted under anhydrous condi-
tions and in an inert atmosphere, because these ylids react
both with oxygen and water.
Our procedure is simpler than that using organolithium
compounds or other ionic strong bases and has the added
advantage that it can be used to prepare phosphoranes from
compounds containing functional groups, such as the car-
boxylic ester groups, which would react with organolithium
compounds or during the workup in the presence of a strong
basic medium. The scope of the proposed methodology was
explored using a representative panel of aldehydes and
phosphonium salts; reactions were attempted in many cases
with TBD, MTBD, or TMG (Scheme 1, Table 1). Routinely,
Scheme 1
the reaction is conveniently effected by mixing together
stoichiometric amounts of the phosphonium salt 4, the
carbonyl compound 5, and the bicyclic guanidine in a THF
solution. The reaction occurs at room temperature or at reflux
depending on the nature of the carbonyl compound used.
As shown in Table 1, the most promising promoter appears
to be the bicyclic guanidine base TBD; with this base yields
were in many cases good or very good. With aromatic
aldehydes bearing an electron-withdrawing group yields were
in general very high; alkyltriphenylphosphonium salts were
slightly less reactive than the benzyltriphenylphosphonium
salts. However, also in the case of the less electrophilic
p-methoxybenzaldehyde the yield was appreciable.
(10) Schwesinger, R. Chimia 1985, 39, 169.
(11) Johansen, J. E.; Piermattie, V.; Angst, C.; Diener, E.; Kratky, C.;
Eschenmoser, A. Angew. Chem., Int. Ed. Engl. 1981, 20, 261.
(12) Angst, C.; Kratky, C.; Eschenmoser, A. Angew. Chem., Int. Ed. Engl.
1981, 20, 263.
(13) Carruthers, W. Some Modern Methods of Organic Synthesis, 3rd
ed.; Cambridge University Press: New York, 1986; pp 125-144.
(14) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863.
3766
Org. Lett., Vol. 2, No. 24, 2000

Scheme 2
Remarkable is that by means of the proposed methodology
Concerning the use of MTBD, we found that less reactive
aldehydes such as the p-methoxybenzaldehyde, as well as
benzaldehyde, gave rise to the corresponding olefines in
modest yields. With aliphatic aldehydes complex mixtures
of products were obtained as a result of the concomitant side
aldol reaction.
unstable ylids may be generated in high yields. Indeed, the
alkyltriphenylphosphonium salts (entries 1-6) reacted ef-
ficiently in the presence of TBD with aromatic aldehydes.
On the contrary, reaction with aliphatic aldehydes resulted
in low yields, possibly as a result of the preferential self-
condensation reaction. In this regard, it is worth noting that
the reaction with pivalaldehyde offered good yields (entries
11 and 16) of the corresponding alkene. In contrast, ketones
are unaffected under these conditions. Additionally, TBD
proved also very satisfactory toward generation of stabilized
ylids (entries 18-21), and the reaction works very well with
both aromatic and aliphatic aldehydes.
Of interest, with more reactive aldehydes (entries 1, 2,
10, and 15), the reaction was completed in a few hours at 0
°C. We were also very surprised to ascertain that in many
cases anhydrous solvents or reagents and inert atmosphere
conditions are not required. Since it is well-known that
benzylidenetriphenylphosphorane, for example, reacts with
water to give triphenylphosphine oxide and toluene, whereas
its reaction with oxygen gives the carbonyl compound and
triphenylphosphine oxide, it seems reasonable to hypothesize
that when more electrophilic aldehydes are used, the reaction
with the phosphorane counterpart is faster than that with
water and oxygen; on the other hand, the presence of small
amounts of water do not affect the reactivity of the base. As
a consequence, in the case of reactive aldehydes, only a
slightly decrease of the yield was observed when the reaction
was carried out in the absence of inert conditions.
However, MTBD was demonstrated to be an interesting
promoter with more reactive aldehydes; in some cases the
reaction produced high yields also at 0 °C, and we did not
observe any appreciable difference between MTBD and
TBD. Additionally, as phosphonium salts bearing â-electron-
withdrawing groups are more readily deprotonated than the
corresponding alkyltriphenylphosphonium salts, TBD and
MTBD (entries 18-21) proved also advantageous in gen-
erating stabilized ylids. On the contrary, TMG leads in
general modest yields with both nonstabilized and stabilized
ylids, and only in few cases proved positively as the more
basic MTBD. Therefore, since the formation of the phos-
phorane is a reversible process and its concentration at
equilibrium clearly depends on the strength of the base used,
it is likely that the greater basicity of TBD may explain its
greater reactivity. However, the relatively higher steric
hindrance offered by MTBD could also be responsible for
the lower yields.
Finally, we have also investigated the behavior of the
strong guanidine bases TMG, TBD, and MTBD toward the
Horner-Wadsworth-Emmons reaction (Scheme 3). It is
An example is seen in the synthesis of some stilbene
derivatives structurally related to the known vitamin A
analogue TTNPB 9 (R ) Me, R′) CO2Me). As we recently
needed access to a novel class of stilbene analogues of
vitamin A, our attention was drawn by the idea that the strong
bicyclic guanidine bases TBD or MTBD could be effective
promoters of the reaction between the phosphonium salts 7
and the p-methoxycarbonylbenzaldehyde 8 (Scheme 2). Thus,
while over the years this reaction has been largely described
by means of strong ionic bases in an inert atmosphere, we
found that with TBD the corresponding stilbene derivatives
may be obtained in appreciable yields, comparable with and
in many cases superior to those described in the literature.
In particular TTNPB was obtained in 55% yield, whereas
its demethyl analogue 9 (R ) H, R′ ) CO2Me) produced
90% yield.15Interestingly, compound 9 was also obtained in
83% yield in the absence of anhydrous conditions.
Scheme 3
well-known that the reaction of phosphonates 10 with a
suitable base gives the corresponding carbanions, which react
readily with the carbonyl group of aldehydes and ketones
11 to form an alkene and a water-soluble phosphate ester.
Since phosphonates are relatively strong acid compounds, it
was easy to hypothesize that strong guanidine bases could
effectively deprotonate such derivatives. To this regard, it
is worth noting that a closer reaction has been reported to
occur utilizing LiCl and an amine, e.g., DBU or diisopro-
(15) Loeliger, P.; Bollag, W.; Mayer, H. Eur. J. Med. Chem. 1980, 15,
9.
Org. Lett., Vol. 2, No. 24, 2000
3767

reaction, efforts were also devoted to study possible effects
of LiCl in our olefination procedures. Quite surprisingly,
under the same conditions as described in the literature,16
the presence of LiCl did not affect positively the course of
our reactions.
Table 2. Yields of Horner-Wadsworth-Emmons Reactions,
as in Scheme 3
yielda
R
R′
R′′
C6H5
C6H13
(CH2)5
C9H19
C6H5
C6H13
C6H4 4-NO2
MTBD
TBD
TMG
In summary, as shown in Tables 1 and 2, the present
methodology is particularly suitable using phosphonium salts
and phosphonates in the presence of aromatic and, in some
cases, aliphatic aldehydes. When phosphonates are utilized
results are comparable with those described previously by
means of DBU and DIPEA in the presence of LiCl.16 The
steric course of the reaction is in general the same observed
with the strong ionic bases. Importantly, the reaction condi-
tions are compatible with many common functional groups.
Indeed, substrates containing ether, ester, or nitro groups are
suitable substrates and furnish in good yields the desired
alkene derivatives. In many cases, anhydrous or inert
conditions are not required. There is also the practical
advantage that TBD and MTBD are commercially available,
and they were used, in all of the described entries, without
any additional purification. Therefore, although the literature
enumerates hundreds of different ionic base-promoted Wittig
procedures, its simplicity, environmental friendliness, and
low costs make our procedure, at least in some cases, a
practical alternative. The additional advantages of operation
and workup simplicity make this methodology a serious
candidate for widespread industrial applications such as
generating combinatorial stilbene libraries.
1
2
3c
4c
5
CO2Et
CO2Et
CO2Et
CO2Et
COC5H11
COC5H11
CN
H
H
CH3
CH3
H
87b
71
92b
80
75b
68
83
80
ND
88
79
100
71
70
ND
6
7
H
H
a When not specified the reaction occurs in THF at reflux for 24 h.
b Room temperature for 5 h. c No condensation products were detected. All
reactions except entry 7 gave only the E stereochemistry. Entry 7 gave a
mixture 4/6 of the Z/E olefine.
pylethylamine (DIPEA), proving of particular interest for use
with base-sensitive aldehydes and phosphonates.16
Briefly, the reaction promoted by TBD and MTBD works
very well with both aromatic and aliphatic aldehydes (Table
2); we found the same pattern of reactivity as described above
for stabilized ylids, and TMG proved less satisfactory than
TBD. However, very surprisingly and clearly in conflict with
the known reactivity of phoshonates with ketones, cyclo-
hexanone and aliphatic ketones failed to give the olefination
reaction; the yields were unexpectedly low. Finally, as
lithium cations affect the course of the Wittig reaction and
its modified version, the Horner-Wadsworth-Emmons
Acknowledgment. This work was in part supported by
the Ministero dell′Universita` e della Ricerca Scientifica e
Tecnologica (Rome).
(16) Blanchette, M. A.; Choy, W.; Davis, J. T. Tetrahedron Lett. 1984,
251, 2183.
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3768
Org. Lett., Vol. 2, No. 24, 2000