PARAFORMALDEHYDE 1
O OH
Paraformaldehyde
HOH2C CH2OH
35 °C
+ (CH2O)n + H2O HOH2C CH2OH (2)
(CH2O)n
Noteworthy observations in this particular reaction are the
[30525-89-4] CH2O (MW 30.03)
ultimate reduction of the ketone, presumably via a crossed
InChI = 1/CH2O/c1-2/h1H2
Cannizzaro reaction, and the ability to utilize large excesses
InChIKey = WSFSSNUMVMOOMR-UHFFFAOYAT
of paraformaldehyde without major difficulties. Of course, both
phenomena are related to the absence of Ä…-hydrogens and
(convenient source of anhydrous monomeric formaldehyde for resultant inability of formaldehyde to enolize.
aldol condensation;1 electrophilic source of halomethyl2 and hy- While paraformaldehyde can be effective in enolate
droxymethyl groups;3 convenient source of Mannich reaction chemistry,10 the more common practice, when condensation onto
intermediates;4 homologation of alkynes;5 synthesis of macro- a preformed enolate is required, is to generate a solution of mono-
cyclic ligands6) meric formaldehyde through pyrolysis.1,11 One can isolate the
resultant hydroxy ketone (eq 3),12 or force dehydration through
ć%
Physical Data: mp 160 165 C.
the use of Methanesulfonyl Chloride,12 or a variety of organo-
Solubility: sol organic solvents.
metallic agents.13 The monomer generated in this way also reacts
Form Supplied in: solid; widely available.
readily with the dianions of carboxylic acids.14
Handling, Storage, and Precautions: generally stable; irritant.
H H
O O
1. LDA,  78 °C
O O (3)
Original Commentary 2. CH2O (g),  20 °C
H H
>95%
OH
Richard T. Taylor
Miami University, Oxford, OH, USA
Halomethyl and Hydroxymethyl Electrophiles. The chloro-
Introduction. The need to carry out one-carbon homolo-
methylation of aromatic systems.2 and heteroaromatic com-
gations during the course of organic syntheses is widespread.
pounds15 can be accomplished using paraformaldehyde, Zinc
Since Formaldehyde itself is a hygroscopic gas which forms
Chloride, and Aluminum Chloride. Similar chemistry allows bro-
the hydrate easily, the ability to utilize functional equivalents
momethylation of aromatic systems.16 Halomethyl esters can be
of formaldehyde is quite useful. The proper choice for the syn-
obtained from carboxylic acids as well.17 The hydroxymethyla-
thetic equivalent of a tenuous species like formaldehyde is dictated
tion of anthraquinones has been reviewed3 and paraformaldehyde
by the context. Unlike the two other most common precursors,
can be used for the protection of alcohols as the methoxymethyl
formalin and trioxane, paraformaldehyde is rather easy to handle.
group.18 20
It is compatible with most organic systems and displays useful
reaction patterns. The polymeric acetal system cleaves easily
The Mannich Reaction and Other Iminium Ion Reactions.
under acidic conditions and, to a lesser extent, under basic and
While the trapping of an iminium ion (generated by the acid-
neutral conditions, to afford one-carbon homologs. On those
catalyzed reaction of an amine and paraformaldehyde) by enols4
occasions when a solution of the monomeric formaldehyde is
has been well investigated (eq 4),21,22 a variety of other nucle-
needed, the best approach is the thermal cracking of paraformalde-
ophiles are available, such as allylstannanes.23 Of particular note
hyde, with the evolved gaseous monomer bubbled into a solution
are those reactions which bring about cyclization. In this context
and used immediately.
a vinylsilane (eq 5)24 is effective, as is an alkene (eq 6).25
Reactions with Enolates and Enols. As the functional
O
equivalent of formaldehyde, paraformaldehyde can afford aldol O
70%
products, especially under acidic conditions wherein the + (CH2O)n + Et2NH2Cl (4)
enol intermediate is generated and conditions lead to unsaturated
NEt2
carbonyl compounds. Methyl ketones undergo reaction (eq 1)
with paraformaldehyde to afford the vinyl ketones under acidic
conditions.7 Similar results are obtained with other active hy-
TMS (CH2O)n, H+
N
drogen reactants such as the treatment of methyloxazolines with NH (5)
H
60%
paraformaldehyde and acid.8 Under neutral aqueous conditions,
H
H
multiple aldol reactions with cyclohexanone have been reported
(eq 2).9
OMe
H2N OMe
Me
+
(CH2O)n
H2N
(6)
CF3CO2
O O HCO2H
N
+ (CH2O)n (1)
90% Me
Avoid Skin Contact with All Reagents
2 PARAFORMALDEHYDE
OH
Homologation of Alkynes.5 While the terminal alkyne group
is a relatively weak nucleophile, strong Lewis acids can bring
(CH2O)n
about homologation, albeit with some isomerization (eq 7).
MgCl2-triethylamine
R
25 °C
+ (CH2O)n + Me2AlCl
OH OH
H 70%
CHO OHC
(9)
H +
Cl
R R
+ (7)
"
CH2OH
OH
Major
Minor
H
H
OH
(CH2O)n
Macrocyclic Ligands.6 By making use of template control,
MgCl2-triethylamine
aza macrocycles can be formed which act as organometallic lig-
R
ands and sequestering agents (eq 8).
OH
OH
H2N H2N
CHO
NiII + (CH2O)n + + OCH2OCH3 (10)
NH2 N NH2
+
H
HClO4
R
R
(8)
NH NH
NH NH
N N
ortho-Hydroxymethylation of Phenols. Paraformaldehyde
N N
NH N
N NH can be used in place of formaldehyde for the formation of salicyl
alcohols from phenols. The reaction of substituted phenols with
(as nickel complex)
1 equiv. of DME and an excess of paraformaldehyde in xylene
afforded salicyl alcohols in isolated yields of 60-90%.32 Alter-
natively, phenols can be reacted with paraformaldehyde and ex-
cess boric acid in benzene with azeotropic removal of water.33 In
either case, the hydroxymethylation of phenols appears to be gen-
eral only for phenols with electron-donating substituents; phenols
First Update
bearing electron-withdrawing groups failed to react.
Theresa J. O Sullivan
N
Pfizer Inc., Groton, CT, USA N
N-Methylation of Amines. Reductive amination with formal-
dehyde (or a formaldehyde equivalent) is a well-established
ortho-Formylation of Phenols. It has been reported by method for preparing N-methylamines. Because of its ease of
Casiraghi et al. that phenols can be monoformylated exclusively handling and absence of aqueous conditions, paraformaldehyde
at the ortho position by the use of paraformaldehyde, ethylmagne- can be used as a convenient formaldehyde replacement. Sodium
sium bromide, and HMPA in benzene.26,27 Bu et al. have shown cyanoborohydride has been shown to be an effective reducing
that the use of carcinogenic HMPA can be avoided by using tri- agent for the preparation of N-methyl amino acid esters (from the
ethylamine in place of HMPA.28 It is also possible to avoid the N-benzyl intermediate) using paraformaldehyde in methanol.34
use of HMPA by generating the magnesium phenoxide using a This method did not require protection of functionalized side
mixture of magnesium dichloride and triethylamine, followed by chains, and no racemezation was observed. N-methylation of a
refluxing in acetonitrile.29 In contrast to Casiraghi, without the secondary aniline with paraformaldehyde and NaBH4 in the pres-
use of HMPA, benzene was ineffective as a reaction solvent. ence of Lewis acids was ineffective, however, paraformaldehyde
As expected for an electrophilic aromatic substitution reaction, and sodium cyanoborohydride, plus the addition of TMSCl and
substrates containing electron-donating groups showed improved MgSO4, afforded the desired product in 55% yield (eq 11).35
reactivity over substrates with electron-withdrawing groups. For Paraformaldehyde can also be used in conjunction with zinc
instance, 4-cyanophenol exhibited a reported 24% yield, com- borohydride and zinc chloride to methylate a variety of primary
pared to 97% for 4-methoxyphenol. When starting phenols were and secondary amines.36 The nonaqueous, neutral conditions
used which afforded the potential for a mixture of regioisomers, allow for a number of sensitive functional groups to be tolerated.
formylation was observed taking place primarily at the less ster- When primary amines were used, monomethyl primary amines
ically hindered position (eq 9). In many cases where the yields were not isolated. Rather, the reaction proceeded completely to
of formylation were poor, the MOM ether was isolated as a the N,N-dimethylamine product.
byproduct (eq 10). Alternatively, Eschweiler-Clarke conditions can be used to
Other conditions reported for the ortho-formylation of phe- methylate amines. Paraformaldehyde and formic acid were used
nols include the use of paraformaldehyde with magnesium to afford N-methylamines under microwave conditions.37 As seen
methoxide30 or tin(IV) chloride and tri-n-butylamine31 in reflux- in the previous references, primary amines were exhaustively
ing toluene. methylated. A solvent-free Eschweiler-Clarke reaction has been
A list of General Abbreviations appears on the front Endpapers
PARAFORMALDEHYDE 3
reported that used paraformaldehyde and oxalic acid dihydrate EtOOC COOEt
_
(CH2O)n
EtOOC COOEt
COOR
in the molten state with no evidence of amine quaternization.38
+
NH2  H2O
Because of the elevated reaction temperature and acidic
N
H
conditions, this variant would not be appropriate for starting
materials containing thermally unstable or acid-labile moieties.
H
Interestingly, replacing the reagents with deuterated oxalic acid H
EtOOC
N N
EtOOC
or deuterated paraformaldehyde afforded selective N-mono- or
+
(13)
EtOOC
N-bisdeuteromethylation.
EtOOC
ROOC COOR
51%
17%
O
COOEt
(CH2O)n
Ph NHPr
H2N (CH2O)n
NaCNBH3
BzO
N O
TMSCl toluene
N
Bn N OBn
reflux
MgSO4
H
78%
55%
O
COOEt
O
H
Bn
Ph NHPr N
(11)
N
(14)
BzO
N
N
OBn
H
Paraformaldehyde and sarcosine were used to generate azome-
thine ylides in situ, which in turn underwent 1,3-dipolar cycload-
Another method for N-methylation of amino acids involves
dition with 2-arylidene-1,2,3,4-tetrahydronaphthalen-1-ones to
the use of paraformaldehyde and camphorsulfonic acid to gen-
afford the spiropyrrolidines shown (eq 15).45 Another use of the
erate the 5-oxazolidinone of the amino acid, followed by TFA/
ylide formed from sarcosine and paraformaldehyde was in the
triethylsilane cleavage to produce the desired N-methylaminoacid
formation of 3-pyrrolidinyl quinolines (eq 16).46 When the dipo-
while preserving the optical activity of the starting material. By
larophile used was C=O, the N-methyloxazolidine was prepared
judicious choice of reaction conditions and side-chain protecting
in good yield as the sole product (eq 17).47
groups, the N-methyl analogues of the 20 common amino acids
have been prepared by this method (eq 12).39 41 R
O
H
toluene
(CH2O)n N
++
OH
reflux
R
TFA
R
O H
Et3SiH
(CH2O)n/CSA
X O
X
N
R
N COOH benzene, reflux
H O
O
(15)
R
(12)
X
N COOH
N
X = Fmoc, Cbz
COOR
sarcosine
paraformaldehyde
N Cl
1,3-Dipolar Cycloadditions. Azomethine ylides can be
N
formed from paraformaldehyde and suitable amines containing
an acidic proton. As shown by Husinec et al., these ylides can
(16)
undergo 1,3-dipolar cycloaddition to form pyrrolidines using a
COOR
suitable dipolarophile.42 Later, this reaction was reexamined by
N Cl
Heathcock and Blazey,43 who investigated the scope of this
reaction for regioselectivity trends (eq 13). It was found that steric
N
influences appear to play a major role in establishing the relative
ratio of regioisomers formed, with larger R-groups generating a
O
O
sarcosine
trend toward the 2,2,4-trisubstituted heterocycle. (17)
paraformaldehyde
N Cl
An intramolecular version of this reaction was used to construct
N Cl
92%
the bicyclic precursor to the core of sarain A (eq 14).44
Avoid Skin Contact with All Reagents
4 PARAFORMALDEHYDE
1. Stork, G.; d Angelo, J., J. Am. Chem. Soc. 1974, 96, 7114. 27. Casiraghi, G.; Casnati, G.; Puglia, G.; Sartori, G.; Terenghi, G., J. Chem.
Soc., Perkin Trans. 1 1980, 1862.
2. Fieser, L.; Seligman, A. M., J. Am. Chem. Soc. 1935, 57, 942.
28. Wang, R. X.; You, X. Z.; Meng, Q. J.; Mintz, E. A.; Bu, X. R., Synth.
3. Krohn, K., Tetrahedron 1990, 46, 291.
Commun. 1994, 24, 1757.
4. Blicke, F. F., Org. React. 1942, 1, 303.
29. Hofslłkken, N. U.; Skattebłl, L., Acta Chem. Scand. 1999, 53, 258.
5. Rodini, D. J.; Snider, B. B., Tetrahedron Lett. 1980, 21, 3857.
30. Aldred, R.; Johnston, R.; Levin, D.; Neilan, J., J. Chem. Soc., Perkin
6. Kang, S.-G.; Jung, S.-J.; Kweon, J. K.; Kim, M.-S., Polyhedron 1993,
Trans. 1 1994, 1823.
12, 353.
31. Berkessel, A.; Vennemann, M. R.; Lex, J., Eur. J. Org. Chem. 2002,
7. Gras, J.-L., Tetrahedron Lett. 1978, 2955.
2800.
8. Meyers, A. I.; Kovelesky, A. C., Tetrahedron Lett. 1969, 4809.
32. Casiraghi, G.; Casnati, G.; Puglia, G.; Sartori, G., Synthesis 1980, 124.
9. Wittcoff, H., Org. Synth., Coll. Vol. 1963, 4, 907.
33. Belyanin, M. L.; Filimonov, V. D.; Krasnov, E. A., Russ. J. Appl. Chem.
10. Ueno, Y.; Setoi, H.; Okawara, M., Tetrahedron Lett. 1978, 3753.
2001, 74, 103.
11. Stork, G.; Isobe, M., J. Am. Chem. Soc. 1975, 97, 6260.
34. White, K. N.; Konopelski, J. P., Org. Lett. 2005, 7, 4111.
12. Grieco, P. A.; Hiroi, K., J. Chem. Soc., Chem. Commun. 1972, 1317.
35. Ghosh, A.; Sieser, J. E.; Caron, S.; Watson, T. J. N., Chem. Commun.
13. Tsuji, J.; Nisar, M.; Minami, I., Tetrahedron Lett. 1986, 27, 2483.
2002, 1644.
14. Pfeffer, P. E.; Sibert, L. S., J. Org. Chem. 1970, 35, 262.
36. Bhattacharyya, S.; Chatterjee, A.; Duttachowdhury, S. K., J. Chem. Soc.,
15. Kochetkov, N. K.; Khomutova, E. D.; Bazilevskii, M. V., Zh. Obshch. Perkin Trans. 1 1994, 1.
Khim. 1958, 28, 2736 (Chem. Abstr. 1959, 53, 9187).
37. Torchy, S.; Barbry, D., J. Chem. Res. (S) 2001, 292.
16. van der Made, A. W.; van der Made, R. H., J. Org. Chem. 1993, 58, 1262.
38. Rosenau, T.; Potthast, A.; Röhrling, J.; Hofinger, A.; Sixta, H.; Kosma,
17. Knochel, P.; Chou, T.-S.; Joubert, C.; Rajagopal, D., J. Org. Chem. 1993, P., Synth. Commun. 2002, 32, 2002.
58, 588.
39. Aurelio, L.; Brownlee, R. T. C.; Hughes, A. B.; Sleebs, B. E., Aust. J.
18. Edwards, J. A.; Calzada, M. C.; Bowers, A., J. Med. Chem. 1964, 7, 528. Chem. 2000, 53, 425.
19. Kapnang, H.; Charles, G.; Sondengam, B. L.; Hemo, J. H., Tetrahedron 40. Aurelio, L.; Brownlee, R. T. C.; Hughes, A. B., Org. Lett. 2002, 4, 3767.
Lett. 1977, 3469.
41. Aurelio, L.; Box, J. S.; Brownlee, R. T. C.; Hughes, A. B.; Sleebs, M.
20. Barluenga, J.; Bayon, A. M.; Asensio, G., J. Chem. Soc., Chem. Commun. M., J. Org. Chem. 2003, 68, 2652.
1984, 1334.
42. Husinec, S.; Savic, V.; Porter, A. E. A., Tetrahedron Lett. 1988, 29, 6649.
21. Wilds, A. L.; Nowak, R. M.; McCaleb, K. E., Org. Synth., Coll. Vol.
43. Blazey, C. M.; Heathcock, C. H., J. Org. Chem. 2002, 67, 298.
1963, 4, 281.
44. Denhart, D. J.; Griffith, D. A.; Heathcock, C. H., J. Org. Chem. 1998,
22. Hagemeyer, H. J., Jr., J. Am. Chem. Soc. 1949, 71, 1119.
63, 9616.
23. Grieco, P. A.; Bahsos, A., J. Org. Chem. 1987, 52, 1378.
45. Raj, A. A. R.; Raghunathan, R., Synth. Commun. 2003, 33, 1131.
24. Overman, L. E.; Bell, K. E., J. Am. Chem. Soc. 1981, 103, 1851.
46. Menasra, H.; Kedjadja, A.; Debache, A.; Rhouati, S.; Belfaitah, A.;
25. Shiotani, S.; Kometani, T., Tetrahedron Lett. 1976, 767. Carboni, B., Synth. Commun. 2005, 35, 2779.
26. Casiraghi, G.; Casnati, G.; Carnia, M.; Pochini, A.; Puglia, G.; Sartori, 47. Tóth, J.; Blaskó, G.; Dancsó, A.; Tóke, L.; Nyerges, M., Synth. Commun.
G.; Ungaro, R., J. Chem. Soc., Perkin Trans. 1 1978, 318. 2006, 36, 3581.
A list of General Abbreviations appears on the front Endpapers