Mild organocatalytic α-methylenation of aldehydes

Article abstract of DOI:10.1021/jo052529q

A rapid and extremely convenient method for α-methylenation of aldehydes with aqueous formaldehyde is described. Two optimal catalytic systems are presented that allow short reaction times and afford the functionalized products in good to excellent yields (up to 99%) and chemoselectivity.

Full text of DOI:10.1021/jo052529q

dehyde and propionaldehyde, using variable amounts of second-
ary amine (typically dimethyl- or diethylamine) and an acid
cocatalyst.6 Although these procedures can be used industrially
for the production of simple unsaturated aldehydes, their
application in the synthesis of more complex aldehydes present
serious problems. With more complex aldehydes, stoichiometric
amounts of the amine salt are typically required.6f-h As a result
of the slow reaction rates and relatively drastic conditions
(typically reflux overnight), yields tend to be lower and the
reactions are often characterized by the formation of polymeric
side products.7 From an atom economic and process chemistry
points of view, the use of a stoichiometric amount of the amine
salt and the long reaction time are major disadvantages.
Mild Organocatalytic r-Methylenation of
Aldehydes†
Anniina Erkkila¨ and Petri M. Pihko*
Laboratory of Organic Chemistry, Helsinki UniVersity of
Technology, P.O.B. 6100, FI-02015 TKK, Finland
petri.pihko@tkk.fi
ReceiVed December 8, 2005
For the synthesis of more complex, functionalized R-substi-
tuted acroleins, milder methods have been sought. In these cases,
the Horner-Wadsworth-Emmons reaction of phosphorus ylides
with paraformaldehyde8 or the Mannich reaction of aldehydes
with methylenedimethylammonium chloride (Eschenmoser’s
salt) have been the most popular choices.9,10 The latter has been
the method of choice in a total synthesis setting, where the
mildness of reaction conditions is most important.11 A particu-
larly mild method based on dibromomethane has also been
described.12
A rapid and extremely convenient method for R-methylena-
tion of aldehydes with aqueous formaldehyde is described.
Two optimal catalytic systems are presented that allow short
reaction times and afford the functionalized products in good
to excellent yields (up to 99%) and chemoselectivity.
Herein we wish to report a very simple and mild catalytic
protocol for the direct R-methylenation of aldehydes using only
1 equiv of aqueous formaldehyde.13
R,â-Unsaturated aldehydes, especially those with an R-sub-
stituent (R-substituted acroleins), provide a range of possibilities
for further transformations such as nucleophilic addition,1
conjugate addition,2 Baylis-Hillman reaction,3 Diels-Alder
reaction,4 and a number of organocatalytic transformations.5
Several synthetic methods have been developed for the
construction of R-substituted acroleins. Simple alkyl-substituted
acroleins, such as methacrolein, can be produced at high
temperatures and preferably under high pressure from formal-
(6) For examples of previous base- and acid-catalyzed Mannich-type
reactions, see: (b) Deshpande, R. M.; Diwakar, M. M.; Mahajan, A. N.;
Chaudhari, R. V. J. Mol. Catal. A 2004, 211, 49-53. (b) Matsuoka, K. JP
04173757, 1992. (c) Nagareda, K.; Yoshimura, N. JP 06263683, 1994.
JP3324820, 2002. (d) Duembge, G.; Fouquet, G.; Krabetz, R.; Lucas, E.;
Merger, F.; Nees, F. DE3213681, 1983. (e) Merger, F.; Fo¨rster, H. J.
EP58927, 1982. (f) Bernhagen, W.; Bach, H.; Brundin, E.; Gick, W.;
Springer, H.; Hack, A. DE285504, 1980. (f) For examples of stoichiometric
Mannich R-methylenations, see: Marvel, C. S.; Myers, R. L.; Saunders:
J. H. J. Am. Chem. Soc. 1948, 70, 1694-1699. (g) Snider, B. B.; Lobera,
M.; Marien, T. P. J. Org. Chem. 2003, 68, 6451-6454. (h) Basu, K.;
Richards, J.; Paquette, L. A. Synthesis 2004, 2841-2844. This paper also
includes an excellent introduction to the state-of-the-art methods for the
synthesis of R-substituted acroleins.
(7) For experimental examples with more complex aldehydes, see: (a)
Yoshida, K.; Grieco, P. J. Org. Chem. 1984, 49, 5257-5260. (b)
Heckendorn, R.; Allgeier, H.; Baud, J.; Gunzenhauser, W.; Angst, C. J.
Med. Chem. 1993, 36, 3721-3726. (c) In our hands, these protocols often
failed to give any useful yields of the product, especially with aldehydes
prone to polymerization.
(8) (a) Boehm, H. M.; Handa, S.; Pattenden, G.; Roberts, L.; Blake, A.
J.; Li, W.-S. J. Chem. Soc., Perkin Trans. 2000, 3522-3538. (b) Villie´ras,
J.; Rambaud, M. Synthesis 1984, 406-408.
(9) Kinast, G.; Tietze, L.-F. Angew. Chem. 1976, 88, 261-262.
(10) Takano, S.; Inomata, K.; Samizu, K.; Tomita, S.; Yanase, M.;
Suzuki, M.; Iwabuchi, Y.; Sugihara, T.; Ogasawara, K. Chem. Lett. 1989,
1283-1284.
(11) (a) Total synthesis of brevetoxin B (second to last step): Nicolaou,
K. C.; Rutjes, F. P. J. T.; Theodorakis, E. A.; Tiebes, J.; Sato, M.;
Untersteller, E. J. Am. Chem. Soc. 1995, 117, 1173-1174. See also:
Nicolaou, K. C.; Reddy, K. R.; Skokotas, G.; Fuminori, S.; Xiao, X.-Y. J.
Am. Chem. Soc. 1992, 114, 7935-7936. (b) Total synthesis of laulimalide:
Crimmins, M. T.; Stanton, M. G.; Allwein, S. P. J. Am. Chem. Soc. 2002,
124, 5958-5959. (c) Ahmed, A.; Hoegenauer, E. K.; Enev, V. S.; Hanbauer,
M.; Kaehlig, H.; Ohler, E.; Mulzer, J. J. Org. Chem. 2003, 68, 3026-
3042. (d) Pinnatoxin A: Ishiwata, A.; Sakamoto, S.; Noda, T.; Hirama, M.
Synlett 1999, 692-694.
(12) (a) Hon, Y.-S.; Chang, F.-J.; Lu, L. J. Chem. Soc., Chem. Commun.
1994, 2041-2042. (b) Hon, Y.-S.; Chang, F.-J.; Lu, L.; Lin, W.-C.
Tetrahedron 1998, 54, 5233-5246. (c) Hon, Y.-S.; Lin, W.-C. Tetrahedron
Lett. 1995, 36, 7693-7696.
† Dedicated to the memory of Professor Hans Krieger (1929-2005).
(1) For selected examples of aldol reactions with R-substituted acroleins,
see: (a) Evans, D. A.; Ratz, A. M.; Huff, B. E.; Sheppard, G. S. J. Am.
Chem. Soc. 1995, 117, 3448-3467. (b) Paterson, I.; Bower, S.; Tillyer, R.
D. Tetrahedron Lett. 1993, 34, 4393-4396. (c) Mann, R. K.; Parsons, J.
G.; Rizzacasa, M. A. J. Chem. Soc., Perkin Trans. 1 1998, 1283-1294.
(2) For reviews, see: (a) Perlmutter, P. Conjugate Addition Reactions
in Organic Synthesis; Pergamon: Oxford, 1992. (b) Rossiter, B. E.; Swingle,
N. M. Chem. ReV. 1992, 92, 771-806. (c) Recently Michael additions of
R-substituted R,â-unsaturated aldehydes with R-nitrocycloalkanones have
been reported; see: Giorgi, G.; Miranda, S.; Lo´pez-Alvarado, P.; Avendan˜o,
C.; Rodriguez, J.; Mene´ndez, J. C. Org. Lett. 2005, 7, 2197-2200.
(3) For reviews, see: (a) Basavaiah, D.; Dharma Rao, P.; Suguna Hyma,
R. Tetrahedron 1996, 52, 8001-8062. (b) Basavaiah, D.; Jaganmohan Rao,
A.; Satyanarayana, T. Chem. ReV. 2003, 103, 811-891 and references
therein.
(4) For a review, see: (a) Kagan, H. B.; Riant, O. Chem. ReV. 1992, 92,
1007-1019.
(5) R,â-Unsaturated aldehydes are key starting materials for several
organocatalytic transformations utilizing iminium catalysis. For representa-
tive examples, see the following. Diels-Alder reaction: (a) Northrup, A.
B.; MacMillan, D. W. E. J. Am. Chem. Soc. 2002, 124, 2458-2460. [3 +
2] Cycloaddition: (b) Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. E. J.
Am. Chem. Soc. 2000, 122, 9874-9875. Hydride reduction: (c) Yang, J.
W.; Hechavarria Fonseca, M. T.; Vignola, N.; List, B. Angew. Chem., Int.
Ed. 2005, 44, 108-110. (d) Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2005, 127, 32-33. Very recently, R-substituted R,â-
unsaturated aldehydes have also emerged as viable partners for iminium
catalysis: (e) Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2005, 127, 10504-
10505. (f) King, H. D.; Meng, Z.; Denhart, D.; Mattson, R.; Kimura, R.;
Wu, D.; Gao, Q.; Macor, J. E. Org. Lett. 2005, 7, 3437-3440.
10.1021/jo052529q CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/23/2006
2538
J. Org. Chem. 2006, 71, 2538-2541

TABLE 2. Proline and Imidazolidinone Derivatives as Catalysts
FIGURE 1. Possible reaction modes of formaldehyde with simple
aldehydes.
entry
catalyst
temp
rt
rt
rt
rt
rt
45 °C
rt
45 °C
time (h)
conversiona (%)
TABLE 1. Screening of Different Amine Salts as Catalysts
1
2
3
4
5
6
7
8
8
9
>24
4
9
0
0
12
73
75
78
90
10
11
12
12
13
13
4
4
24
4
4
4
1
a Determined by H NMR.
TABLE 3. Optimization Studies with Citronellal
conversiona (%)
entry
catalyst
30 min
135 min
1
2
3
4
1
2
3
4
19
9
8
37
19
29
75
conversionb (%)
70
1
a Determined by H NMR.
entry
catalyst
conditionsa
3 h
14
24 h
1
2
3
4
5
6
7
12
13
13
13
13
4
45 °C, neat
rt, neat
45 °C, neat
45 °C, i-PrOHd
45 °C, i-PrOHe
rt, neat
36
35
54
5c
The reaction of formaldehyde with simple R-monosubstituted
aldehydes can afford either the aldol product14 or the dehydrated
R-substituted acrolein (Figure 1). The latter product might arise
from a Mannich-type reaction with a catalytic amount of
secondary amine base.15
To prevent any unwanted crossed-aldol or polymerization
reactions, we sought to develop conditions that were as mild
and neutral as possible. In our initial study, different secondary
amine/carboxylic acid combinations were screened (Table 1).
Pyrrolidine was found to be the optimal amine component in a
reaction between propionaldehyde and formaldehyde in room
temperature.
24
32
67
4
100
100
100
11
4
45 °C, neat
ndf
a Temperature, solvent. b Determined by 1H NMR. c 2 h. d 200 µL/mmol
i-PrOH. e 100 µL/mmol i-PrOH. f Not determined.
A variety of amino acids and dipeptides were thus screened
(Table 2). We discovered that under the same reaction conditions
the dipeptide L-Pro-â-Ala 13 affords the desired product in 78%
conversion in 4 h at room temperature (entry 7). Slightly higher
yields were obtained by raising the temperature to 45 °C (entry
8).16 Again, the unsaturated aldehyde was the only product
observed.
Inspired by these results, we reasoned that pyrrolidine
derivatives that would contain also the acid functionality in the
molecular structure might be potential catalysts for this reaction.
Further screening of the reaction conditions was then carried
out in the reaction between citronellal and formaldehyde by
varying the catalyst, temperature, and solvent (Table 3). In this
study, citronellal was used as the test aldehyde to probe the
generality of the protocol with less water-soluble aldehydes.
Both pyrrolidine/propionic acid 4 as well as L-Pro-â-Ala 13
catalyzed the reaction in neat conditions. However, especially
with 13, the poor solubility of citronellal seemed to limit the
reaction rate. This problem was alleviated by the addition of a
small amount of isopropyl alcohol. In this case, raising the
temperature to 45 °C was essential for good conversions. We
were especially delighted that with both catalyst systems,
complete conversion of the starting material to the aldehyde
(13) Recently, an organocatalytic method for the synthesis of R,â-
unsaturated ketones was reported: (a) Wang, W.; Mei, Y.; Li, H.; Wang,
J. Org. Lett. 2005, 7, 601-604.
(14) (a) Co´rdova and co-workers have reported that reactions between
aldehydes with formaldehyde under proline catalysis afford hydroxymethy-
lated aldehydes enantioselectively. This would suggest that the reaction
proceeds via an aldol-dehydration mechanism. However, in our hands
reactions of aldehydes with aqueous formaldehyde only afforded the
corresponding unsaturated aldehydes. Casas, J.; Sunde´n, H.; Co´rdova, A.
Tetrahedron Lett. 2004, 45, 6117-6119. (b) Interestingly, Ishikawa and
co-workers have reported a pyrrolidine/benzoic acid catalyzed dimerization
of aldehydes that proceeds at room temperature: Ishikawa, T.; Uedo, E.;
Okada, S.; Saito, S. Synlett 1999, 4, 450-452. For related examples, see:
(c) Treibs, W.; Krumbholz, K. Chem. Ber. 1952, 85, 1116-1119. (d)
Schreiber, J.; Wermuth, C. G. Bull. Soc. Chim. Fr. 1965, 2242-2249. (e)
For an oxa-Michael/aldol/dehydration protocol for the preparation of R,â-
substituted aldehydes, see: Habib-Sahmani, H.; Hacini, S.; Bories, C.; Faure,
R.; Rodriguez, J. Synthesis 2005, 2151-2156.
(16) With simple amines, raising the temperature afforded higher
conversions to the product. However, polymerization and loss of product
by evaporation resulted in erratic and irreproducible yields in the case of
methacrolein.
(15) (a) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573-
575. For a review on the Mannich reaction, see: (b) Arend, M.; Westermann,
B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1045-1070.
J. Org. Chem, Vol. 71, No. 6, 2006 2539

TABLE 4. Synthesis of r-substituted Acroleins from Different Aldehydes
a Reaction conditions: 10 mol % of catalyst, 100 µL of i-PrOH/1 mmol of starting material, 45 °C; see Supporting Information for details. b Conversion
1
by H NMR. c Determined by chiral GC (see Supporting Information). d Significant decomposition was observed.
could be obtained with both reasonable temperature (45 °C)
and reaction time (3-24 h) and therefore selected these two
conditions (entries 5 and 7) for further exploration.
The scope of the reaction was then assessed with a repre-
sentative selection of aldehydes (Table 4).
As shown in Table 4, a wide variety of R-monosubstituted
aldehydes can be converted reliably to the corresponding
R-substituted acroleins in good to excellent yields with both
catalysts. Considerable latitude in both steric demands of the
aldehyde (entries 1-5) as well as choice of alcohol and amine
protecting groups (benzyl, silyl, Boc, acetonide) and function-
alities (ketone, carbamate, alkene) are tolerated (entries 6-12).
Further, no isomerization of the double bond was detectable
even with aromatic â-substituents (entries 5 and 6), and no
epimerization at the â carbon was observed with citronellal
(entry 4). In the case of aldehydes 26, 28, and 30, the dipeptide
2540 J. Org. Chem., Vol. 71, No. 6, 2006

catalyst 13 gave significantly cleaner reactions and superior
yields (entries 8-10). Catalyst 13 would thus appear to be a
catalyst of choice with particularly sensitive aldehydes. Finally,
R-oxy and R-amino substituents are readily tolerated, giving
access to protected enol and enamine derivatives (entries 11
and 12) in high yields (85-98% with catalyst 4). Hydroxy
groups are, of course, also tolerated by these aqueous conditions;
however, 5-hydroxyvaleraldehyde and unprotected 2-deoxy-
ribose, both existing predominantly in the hemiacetal form, did
not perform well under these conditions.17 As such, at present
the method is limited to aldehydes that exist in the open-chain
form.
Experimental Section
General Procedure A for the R-Methylenation of Aldehydes.
To a mixture of aqueous formaldehyde solution (37% formaldehyde
in water, 1.0 mmol, 100 mol %) and aldehyde (1.0 mmol) in i-PrOH
(100 µL) were added propionic acid (0.1 mmol, 10 mol %) and
pyrrolidine (0.1 mmol, 10 mol %). The reaction mixture was
stirred at 45 °C for 1-25 h. NaHCO3 was added, and the mix-
ture was extracted with CH2Cl2 (3 × 5 mL). The combined
extracts were washed with brine, dried (Na2SO4), and concentrated
in vacuo. If necessary, the crude product thus obtained was purified
by a passage through a short pad of silica gel using Et2O as the
eluent.
General Procedure B for the R-Methylenation of Aldehydes.
To catalyst 13 (L-Pro-â-Ala) (0.1 mmol, 10 mol %) in i-PrOH (100
µL) in a 5-mL vial were added aqueous formaldehyde solution (37%
formaldehyde in water, 1.0 mmol, 100 mol %) and aldehyde (1.0
mmol, 100 mol %) at room temperature. The mixture was stirred
at 45 °C for 1-25 h. H2O (5 mL) was then added, and the mixture
was extracted with CH2Cl2 (3 × 5 mL). The combined extracts
were washed with brine, dried (Na2SO4), and concentrated in vacuo.
If necessary, the crude product thus obtained was purified by a
passage through a short pad of silica gel using Et2O as the eluent.
In summary, a mild, chemoselective, and catalytic method
for the synthesis of R-substituted acroleins has been developed,
and two different optimized catalysts are described. The
mildness of the reaction conditions and the high chemoselec-
tivity of the reaction allows the rapid and easy preparation of
functionalized R-substituted acroleins in high yields under very
benign reaction conditions. In comparison with previously
reported Mannich methods,6f-h,7 drastic cuts in the amount of
amine salt (10 vs 100 mol %, reaction time (typically 2 vs 12-
18 h), temperature (45 vs 80-100 °C), and the amount of
solvent were realized in this study. The ease with which these
reactions can be performed facilitates their use in tandem
processes. Studies along these lines will be reported in due
course.
Acknowledgment. Financial support from Helsinki Univer-
sity of Technology, the Academy of Finland (Project No.
203287), Tekes, and COST D-28 is gratefully acknowledged.
We thank Prof. Ari Koskinen for material support and Dr. Jari
Koivisto for NMR assistance.
Supporting Information Available: Experimental procedures
for the preparation of the starting materials and the catalysts,
characterization data, and copies of NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
(17) With catalyst 4, 5-hydroxyvaleraldehyde gave ca. 55-60% yield
of the R-methylenation product after 24 h reaction time, accompanied by
significant decomposition. 2-Deoxyribose afforded less than 5% of the
product under similar conditions.
JO052529Q
J. Org. Chem, Vol. 71, No. 6, 2006 2541