1,5,7-Triazabicyclo[4.4.0]dec-1-ene (TBD), 7-methyl-TBD (MTBD) and the polymer-supported TBD (P-TBD): Three efficient catalysts for the nitroaldol (Henry) reaction and for the addition of dialkyl phosphites to unsaturated systems

Article abstract of DOI:10.1016/S0040-4039(99)02340-0

The 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) and its 7-methyl derivative (MTBD) have been proven to be of great synthetic utility as catalysts in the nitroaldol (Henry) reaction and for the addition of dialkyl phosphites to a variety of carbonyl compounds. The catalysts were in many cases superior to the parent tetramethylguanidine (TMG). In general the reaction proceeds in a few minutes at 0°C. The polymer-supported-TBD (P- TBD) was also proven to be an efficient promoter of the above cited nucleophilic additions. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02340-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1607–1610
1,5,7-Triazabicyclo[4.4.0]dec-1-ene (TBD), 7-methyl-TBD
(MTBD) and the polymer-supported TBD (P-TBD): three
efficient catalysts for the nitroaldol (Henry) reaction and for the
addition of dialkyl phosphites to unsaturated systems
Daniele Simoni,a,∗ Riccardo Rondanin,a Massimo Morini,a Riccardo Baruchello a and
Francesco Paolo Invidiata b
aDipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17-19, 44100 Ferrara, Italy
bDipartimento Farmacochimico Tossicologico e Biologico, Via Archirafi 32, Università di Palermo, 90123 Palermo, Italy
Received 22 October 1999; accepted 16 December 1999
Abstract
The 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) and its 7-methyl derivative (MTBD) have been proven to be of
great synthetic utility as catalysts in the nitroaldol (Henry) reaction and for the addition of dialkyl phosphites to
a variety of carbonyl compounds. The catalysts were in many cases superior to the parent tetramethylguanidine
(TMG). In general the reaction proceeds in a few minutes at 0°C. The polymer-supported-TBD (P-TBD) was also
proven to be an efficient promoter of the above cited nucleophilic additions. © 2000 Elsevier Science Ltd. All
rights reserved.
While a large body of work has been devoted to the study of the chemistry of ionic bases, and their
utility in organic synthesis is very well established,1,2 non-ionic nitrogen bases have never achieved
the same success and it is likely that, in many cases, their potential has not received full recognition.
However, since they are easy to handle and used under mild reaction conditions, non-ionic nitrogen
bases are employed as reagents or catalysts. A great variety of non-ionic bases with weak to medium basic
strength and low to very high steric hindrance are available. In many cases these compounds are endowed
with very low nucleophilicity so that sterically hindered tertiary amines and amidines are widely used
in organic synthesis as proton acceptors.3,4 Stronger amidine bases DBN (1,5-diazabicyclo[4.3.0]non-
5-ene) and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) also have great synthetic utility and are being
extensively used in dehydrohalogenation reactions.5,6
∗
Corresponding author. Tel: +39 0532 291 291; fax: +39 0532 291 296; e-mail: smd@dns.unife.it (D. Simoni)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02340-0
tetl 16268

1608
Strong guanidine bases have been known for some time,7,8 but there is little work on their use as bases
in organic synthesis. Results from our laboratory demonstrated that the tetramethylguanidine (TMG)-
catalyzed addition of primary nitroalkanes to aldehydes and alicyclic ketones constitutes a practical
means to perform the nitroaldol reaction (Henry reaction).9 Moreover, the TMG-catalyzed addition of
dialkyl phosphites to α,β-unsaturated carbonyl compounds, alkenenitriles, aldehydes and ketones was
found to provide a practical route to a variety of phosphonate synthons.10 It is also worth noting that
optically pure bicyclic guanidine bases have received particular attention recently as effective promoters
in a novel catalytic enantioselective Strecker synthesis of chiral α-amino nitriles and α-amino acids.11
Since the 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) (2a) and its methyl derivative MTBD (2b) were
proven to be ca. 100 times more basic than TMG,12 and they were widely utilized as powerful
organic bases for tautomerizing pyrrocorphins,13,14 their use as strong, non-ionic, basic catalysts seemed
especially interesting for synthetic purposes. In this letter we report our preliminary results concerning
the TBD- and MTBD-catalyzed addition of different nucleophiles to a variety of unsaturated systems.
Specifically, we explored (Schemes 1 and 2) their utility as strong base catalysts for the addition of
dialkyl phosphites (P–H bond) and nitroalkanes to carbonyl compounds such as α,β-unsaturated esters
and ketones or saturated aldehydes and ketones as well as to imines. Thus, we have found that the bicyclic
guanidine bases TBD and MTBD are superior catalysts for the nitroaldol (Henry) reaction and the
addition of dialkyl phosphites to a variety of carbonyl compounds and imines. In addition, the polymer-
supported-TBD (P-TBD) was also proven to be an efficient promoter of the above cited additions.
Scheme 1.
We initially choose for our experiments some representative carbonyl compounds which showed
greater resistance to undergo the TMG-assisted addition of nucleophiles.9,10 We focused our attention
in particular on alicyclic ketones, imines and some aromatic aldehydes. Afterwards, the reaction was
extended to other carbonyl compounds, i.e., α,β-unsaturated ketones and esters as well as to ketones
and aldehydes (aromatic and aliphatic). Thus, we were very surprised to ascertain that the addition of
diethyl phosphite to benzylideneaniline (4) (Scheme 1) occurred in very high yield in just a few minutes
at room temperature; moreover, when the reaction was repeated at 0°C the rate and the yield of the
reaction were not substantially affected. Likewise, the reaction of cyclohexanone and cyclopentanone
with dialkylphosphites (Scheme 2) was equally successful and the corresponding phosphonates were
obtained in high yields at 0°C (78% and 75%, respectively).
Additionally, we found that the reaction can be applied successfully to α,β-unsaturated ketones and

1609
Scheme 2.
esters as well as to aromatic and aliphatic ketones or aldehydes (Scheme 2, yields 70–98%);15 it is worth
noting that the reaction also works very well in the presence of the polymer-supported guanidine base
P-TBD thus allowing a very simplified work-up of the reaction. As a general rule, the reaction proceeds
cleanly under very mild conditions (in general at 0°C) and no side reactions are observed.16
In summary, when compared to the TMG-assisted addition of dialkyl phosphites to carbonyl com-
pounds, the proposed procedure offers significant advantages, especially in terms of milder reaction
conditions and shorter reaction times.
Finally, we have also investigated the bicyclic guanidine bases 2a,b as promoters for the nitroaldol
(Henry) reaction. In order to avoid problems stemming from the possible production of the unsaturated
nitro compounds, as well as to avoid formation of the Nef by-products, the quest for new catalysts to
promote the nitroaldol reaction is still the focus of many research interests.17 In this context, we found
that the bicyclic guanidines 2a,b and the polymer-supported P-TBD 3 were very efficient promoters of
the addition of nitromethane to aldehydes and alicyclic ketones (Scheme 2). The addition of nitromethane
to cyclohexanone was completed in 1 h at 0°C and, usually, the addition produced very high yields also
with aldehydes (both aliphatic and aromatic) (80–95%), and with α,β-unsaturated carbonyl compounds
(70–90%);15 the dehydrated by-products were observed only in traces. However, the reaction was not
generally applicable as aliphatic ketones and acetophenone did not react in the presence of bicyclic
guanidine bases.
In conclusion, we have demonstrated the ability of TBD, MTBD and P-TBD to accomplish the addition
of dialkyl phosphites to a variety of carbonyl compounds. We have also demonstrated that these bicyclic
guanidine bases are highly efficient promoters of the Henry reaction (Scheme 3: some selected results
by means of the TBD base are reported). Thus, we believe that the TBD- and MTBD-catalyzed addition
of nucleophiles reported here offers significant advantages over existing methods, especially in terms of
milder reaction conditions and shorter reaction times.
To the best of our knowledge, the proposed methodology represents the most effective approach for the
preparation of some nitroalkane derivatives such as 6a9,18 and 7a10 as well as for the aminophosphonate
5.10 The use of the polymer-supported P-MTBD may be of particular interest due to the simplicity of the
work-up and, in addition, for the nitroaldol reaction, when acidification of the reaction mixture may lead
to the Nef reaction.
Future work in this area will extend the study to optically pure bicyclic guanidine, it is likely that the

1610
Scheme 3.
use of such chiral bases may induce, at least in part, enantiospecificity in the above described addition
reactions.
Acknowledgements
This work was in part supported by the Ministero dell’Università e della Ricerca Scientifica e
Tecnologica (Rome)
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dialkyl phosphite (or the nitroalkane) (5 ml) were mixed together in the presence of a catalytic amount (10%) of the bicyclic
guanidine base, and the reaction was stirred. At the end of the reaction the mixture was diluted with diethyl ether, washed
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