Catalytic enamines from dialkylamide-dialkylacetals

Article abstract of DOI:10.1016/j.tetlet.2012.03.028

The formation of a transient enamine derived from DMF-DMA provides an effective alternative to the harsh conditions normally required for the nucleophilic addition of base-activated methylene compounds to a carbonyl group. Organocatalysts formed from dialkylamide-dialkylacetals in this manner may provide extensive synthetic utility for a number of well-established reactions in which the formation of enolates and enamines has been employed.

Full text of DOI:10.1016/j.tetlet.2012.03.028

Tetrahedron Letters 53 (2012) 2537–2539
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Tetrahedron Letters
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Catalytic enamines from dialkylamide-dialkylacetals
Roger M. Davey a,b, N. Patrick J. Stamford a,c,
⇑
a Organic Synthesis Centre, School of Chemistry, University of Sydney, Sydney, NSW 20006, Australia
b Silverbrook Research Pty Ltd, 393 Darling Street, Balmain, NSW 2041, Australia
c Ultraceuticals Pty Ltd, Suite 2, Level 4, 436-484 Victoria Road, Gladesville, NSW 2111, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
The formation of a transient enamine derived from DMF-DMA provides an effective alternative to the
harsh conditions normally required for the nucleophilic addition of base-activated methylene com-
pounds to a carbonyl group. Organocatalysts formed from dialkylamide-dialkylacetals in this manner
may provide extensive synthetic utility for a number of well-established reactions in which the formation
of enolates and enamines has been employed.
Received 8 February 2012
Revised 23 February 2012
Accepted 7 March 2012
Available online 16 March 2012
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
Keywords:
Organocatalyst
Enamine
Carbonyl
Hann–Lapworth reaction
Reaction mechanism
A great deal of effort has been devoted to explore general and
efficient routes for carbonyl olefination. One interesting approach
involves the dehydrative decarboxylation of b-hydroxy carboxylic
acids into olefins, in the presence of N,N-dimethylformamide
dimethylacetal (DMF-DMA) in synthetically useful yields.1 Follow-
ing on from our recent work,2 it was considered that just such a
route might provide a novel extension to the Hann–Lapworth reac-
tion3 whereby the b-hydroxy carboxylic acid intermediate gener-
ated might be redirected towards the synthesis of novel alkenes.
Unfortunately, when utilising isovanillin (1) under standard
Hann–Lapworth conditions, the addition of DMF-DMA furnished
a less than 5% yield (by 1H NMR spectroscopy) of the desired
styrene.
Whilst investigating methods to improve this yield, it was dis-
covered that DMF-DMA seemed able to enhance the rate of the
Hann–Lapworth reaction itself (Scheme 1). Further analysis re-
vealed that the reaction gave the corresponding trans-cinnamic
acid 2 in quantitative yield within 4 h (Table 1). Under otherwise
identical conditions, and in the absence of DMF-DMA, isovanillin
remained largely unreacted within this time frame suggesting that
triethylamine alone is not a strong enough base to promote effec-
tively the Hann–Lapworth reaction. Although not recorded here,
the stronger base DBU was required to achieve significant conver-
sions in the absence of DMF-DMA. Additional experiments demon-
strated that DMF-DMA is truly catalytic for the reaction and that
the presence of a strong base seemed unnecessary for the reaction
to proceed. Furthermore, when methylmalonic acid was utilised
instead of malonic acid, DMF-DMA was similarly able to catalyse
the reaction, albeit at an evidently slower rate (Table 1).
An enamine intermediate
When using dimethyl malonate as the substrate and an excess
of DMF-DMA (Table 2) none of the expected dimethyl ester prod-
uct was observed to accumulate. However, flash column chroma-
tography of the crude product mixture afforded isovanillin (1)
and an enamine 3 in high yield. In all the reactions monitored by
1H NMR spectroscopy in which DMF-DMA was present and di-
methyl malonate was used, formation of an enamine (Scheme 2)
was observed.6 Indeed, this enamine can be synthesised and com-
parison of the 1H NMR spectrum of the isolated material (consis-
tent with the literature7) with spectra recorded for the reaction
confirmed the presence of this enamine in these reactions. The
enamine was also isolated from the reactions.
CO H
2
O
HO C CO H
2
2
OH
OH
OMe
1
2
OMe
⇑
Corresponding author. Tel.: +61 (02) 9660 3066; fax: +61 (02) 9660 3166.
E-mail address: pats@ultraceuticals.com.au (N.P.J. Stamford).
Scheme 1. Reagents and condition: DMF-DMA, Et3N, PhMe, reflux, 4 h.
0040-4039/$ - see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.028

2538
R. M. Davey, N.P.J. Stamford / Tetrahedron Letters 53 (2012) 2537–2539
Table 1
Reagent (equiv)
DMF-DMA (equiv)
Et3N (equiv)
Time (h)
Conversiona(%)
Malonic acid
4
4
4
4
0
5
5
5
0
0
4
4
4
4
3.6
1.5
0.2
1.5
0.2
100b
88.5
95.2
100
2.5
16
Methylmalonic acid
2.5
2.5
2.5
0
0.1
1.0
1
1
1
16
16
16
0
40.2
90.1
a
The corresponding trans-cinnamic acid was the only product observed by 1H NMR spectroscopy in these reactions.4
No remaining starting material was observed by 1H NMR analysis of the reaction. Typical experimental procedures are given.5
b
Table 2
Reagent (equiv)
Solvent
PhMe
Acid (equiv)
—
DMF-DMA (equiv)
0.1
Conversion4 (%)
91.7a
Malonic acid
2.5
Dimethylmalonate
2.5
2.5
2.5
2.5
2.5
PhMe
PhMe
THF
MeCN
CHCl3
—
—
—
—
0.1
1.5
1.5
1.5
1.5
0a
0b
0b
30b
41.0b
—
TFA
—
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
0.15
61.2b
63.0b
67.5b
71.1b
54.3b
28.6b
2.0b
0.1
0.375
0.5
0.75
1
1.5
2.5
0.05
0b
67.7b
TsOH
—
0.5
2.5
2.5
PhMe
PhMe
1.5
1.5
0c
86.8c
a
b
c
Reactions were performed for 24 h at reflux.
Reactions were performed for 16 h at 60 °C.
Reactions were performed for 16 h at reflux.
RO2C
Me2N
CO2R
RO2C
CO2R
NMe2
A series of 1H NMR experiments in CDCl3 were therefore under-
taken to gauge the effect of acid catalysis on the reaction of di-
methyl malonate and isovanillin (1) (Table 2). This study clearly
demonstrated that the formation of the expected dimethyl ester
increased with increasing molar equivalents of TFA. Optimum con-
version was achieved at 0.5 equiv of TFA, which, notably, is also the
molar excess of DMF-DMA used. However, this trend was reversed
when TFA was present at quantities greater than 0.5 equiv, and no
product was formed when TFA was present in greater quantity
than DMF-DMA. This observation implies that acid was required
to drive the reaction, but at high relative concentration also
impedes the action of DMF-DMA. Therefore, the quantities of
DMF-DMA and the acid used must be carefully balanced to ensure
optimum rate enhancement. Indeed, this necessity is exemplified
by the observation that similar results were obtained using only
a catalytic quantity of DMF-DMA.
The formation of the enamine in this study was shown also to
be enhanced by acid catalysis, and followed a similar trend to that
of the expected product of the reaction. Notably, it was discovered
that the enamine was formed in toluene in significant quantity, yet
none of the expected dimethyl ester was formed under those con-
ditions. This suggests that the addition of an acid catalyst is not
strictly necessary for enamine formation, but is required for end
+
3
OMe
+
2MeOH
OMe
Scheme 2.
Acid catalysis
The initial failure of the reaction to proceed when using di-
methyl malonate as the substrate and an excess of DMF-DMA
was surprising given the success when malonic acid was used. It
was thought that the carboxylic acid groups of malonic acid might
be of consequence. That is, that some degree of acid catalysis is re-
quired to drive the reaction catalysed by DMF-DMA.
Investigation of the reaction in various solvents demonstrated
that THF afforded a similar result to toluene, whilst acidic solvents
such as acetonitrile and chloroform were required to afford any
product. These observations further support the idea that acid
catalysis is required for the reaction.

R. M. Davey, N.P.J. Stamford / Tetrahedron Letters 53 (2012) 2537–2539
2539
Table 3
demonstrated that these reactions, which are typically achieved
under harsh, basic conditions, can now be performed under very
mild conditions. Additionally, we are certain that a variety of
organocatalysts of this type might be employed in a wide array
of not dissimilar synthetically useful reactions. For example, the
importance of enolate anions as synthetic intermediates is well-
established and the use of enamines as enolate anion surrogates
has been extensively utilised in synthetic organic chemistry.9
Technology in which catalytic enamines are formed from dialkyla-
mide-dialkylacetals as demonstrated here may therefore provide
the first step towards a more expansive synthetic utility for a num-
ber of well-established reactions in which the formation of eno-
lates and enamines has been employed.
Enamine (equiv) TFA (equiv) MeOH (equiv) Time (h) Conversiona (%)
1.5
1.5
0.5
0.5
5.0
0
16
16
58.0
0
a
Reactions were performed in CDCl3 for 16 h at 60 °C.4
NMe2
CO2R
RO2C
O
HO
+ H+
RO2C
CO2R
NMe2
+
Acknowledgment
- H+
OH
OH
OMe
OMe
1
4
3
The authors gratefully acknowledge the support of the Organic
Synthesis Centre, University of Sydney, for enabling the work de-
scribed in this paper.
Scheme 3.
product formation. This idea was confirmed by conducting the
reaction in toluene at reflux in the presence of p-toluenesulfonic
acid (Table 2).
References and notes
1. Rüttimann, A.; Wick, A.; Eschenmoser, A. Helv. Chim. Acta 1975, 58, 1450; Hara,
S.; Taguchi, H.; Yamamoto, H.; Nozaki, H. Tetrahedron Lett. 1975, 19, 1545;
Mulzer, J.; Bruentrup, G. Angew. Chem., Int. Ed. Engl. 1977, 16, 255.
Catalyst recovery
2. Simpson, C. J.; Fitzhenry, M. J.; Stamford, N. P. J. Tetrahedron Lett. 2005, 46, 6893.
3. Hann, A. C. O.; Lapworth, A. J. Chem. Soc. 1904, 85, 46; Tanaka, M.; Oota, O.;
Hiramatsu, H.; Fujiwara, K. Bull. Chem. Soc. Jpn. 1988, 61, 2473.
Formation of the enamine from DMF-DMA and dimethyl mal-
onate involves the loss of two moles of methanol (Scheme 2). To
probe whether this methanol is required for the DMF-DMA-
catalysed reaction to proceed, the enamine (isolated in pure form
from a previous reaction) was reacted with isovanillin both in
the presence and absence of methanol (Table 3).
The fact that these experiments clearly show that the reaction
requires methanol to proceed suggests that, in the absence of
methanol the enamine adds to the aldehyde to give an iminium
intermediate 4, which being unable to proceed down any further
reaction pathway, presumably decomposes to regenerate the en-
amine 3 and isovanillin (1) (Scheme 3). This experiment also sug-
gests that an alternative mechanism whereby DMF-DMA is a
source of dimethylamine (formed by H+-catalysed elimination)
which might catalyse the reaction, as demonstrated earlier with
the stronger base DBU, is unlikely.
4. Analyses of reactions were carried out using the 1H NMR spectra of crude
products. Determination of conversions were obtained from comparative
integration of either the aldehyde peak of the starting material and the
protons furthest downfield in the exocyclic double bonds of the product or the
methoxy protons of the starting material and products.
5. To
a suspension of isovanillin (1) (152 mg, 1.00 mmol) and malonic acid
(416 mg, 4.00 mmol) in toluene (5 mL) were added Et3N (0.70 mL, 5.00 mmol)
and DMF-DMA (0.20 mL, 1.50 mmol). The resulting mixture was heated at reflux
for 4 h, then allowed to cool to room temperature, and concentrated on a rotary
evaporator. The residue was dissolved in 1 M NaOH solution (20 mL), and the
resulting solution washed with CH2Cl2 (3 Â 20 mL). The aqueous phase was then
acidified to pH 1 by addition of 3 M HCl. The creamy precipitate was collected in
a Hirsch funnel, washed with dilute HCl and allowed to air dry. The precipitate
was then recrystallised (MeOH–H2O) and dried in a vacuum desiccator over
P2O5 to afford trans-isoferulic acid (164 mg, 85%) as a cream-coloured crystalline
solid. The 1H NMR data were consistent with the literature (McCorkindale, N. J.;
McCulloch, A. W.; Magrill, D. S.; Caddy, B.; Martin-Smith, M.; Smith, S. J.;
Stenlake, J. B. Tetrahedron 1969, 25, 5475).
6. For the conversion of methylmalonic acid (Table 1) the intermediate enamine
cannot be formed without undergoing
a decarboxylation during enamine
formation. It seems reasonable that the reaction product (iminium
intermediate) formed from methylmalonic acid and DMF-DMA can eliminate
MeOH and CO2 in either an E1 or antiperiplanar E2-type mechanism. Indeed,
this same mechanism could equally apply for the case of malonic acid, although
this was not observed.
Catalytic efficiency
Finally, the operational efficiency of DMF-DMA, determined
using a kinetic study8 analysed by 1H NMR spectroscopy in CDCl3,
revealed that, under these conditions, the catalyst initially func-
tioned at above 8 turnovers per hour and on average exceeded
420 turnovers prior to catalyst deactivation. Under identical condi-
tions in the absence of catalyst, no product accumulation was
observed.
We believe that this is the first instance in which a catalytic en-
amine is generated in this way within a reaction in order to pro-
mote a nucleophilic attack of this nature. Moreover, we have
7. Le Menn, J. C.; Sarazin, J.; Tallec, A. Electrochim. Acta 1991, 36, 819.
8. To two solutions of isovanillin (9.99 Â 10À5 mol) and malonic acid
(25.38 Â 10À5 mol) in CDCl3 (0.5 mL) at 30 °C was added either DMF-DMA
(8.27 Â 10À8 mol) or an equivalent volume of CDCl3. The reaction solutions were
maintained at 30 °C and 1H NMR analysis was performed at 30 °C at appropriate
time intervals over 3 days. Determinations of conversions were obtained from
comparative integration of the methoxy protons of the starting material and the
protons of the exocyclic double bond of the product.
9. Cook, A. G., Ed.Enamines; Synthesis Structure, and Reactions, second edition;
Marcel Dekker: New York, 1988.