eschweiler-clarke.solventfree, biotransformation
[ Pobierz całość w formacie PDF ]
SYNTHETIC COMMUNICATIONS, 32(3), 457–465 (2002)
A SOLVENT-FREE AND
FORMALIN-FREE ESCHWEILER-CLARKE
METHYLATION FOR AMINES
Thomas Rosenau,
1
Antje Potthast,
1
Ju¨ rgen Ro¨ hrling,
1
Andreas Hofinger,
1
Herbert Sixta,
2
and Paul Kosma
1,
*
1
Institute of Chemistry, Christian-Doppler-Laboratory,
University of Agricultural Sciences, Vienna,
Muthgasse 18, A – 1190 Vienna, Austria
2
R&D Lenzing AG, A – 4860 Lenzing, Austria
ABSTRACT
Primaryandsecondaryaminesare N-methylatedbyamixture
of paraformaldehyde and oxalic acid dihydrate in good to
excellent yields. The reaction proceeds without involvement
oforganicsolventsandtoxicformalin.Reactiontemperatures
of 100
C are required for the decomposition of oxalic acid
into the intermediate formic acid which acts as the actual
reductant. The reaction conditions have been optimized, and
the mechanism has been elucidated by means of deuteration
experiments.
*Corresponding author. Fax:
þ
431360066059; E-mail: pkosma@edv2.boku.ac.at
457
Copyright & 2002by MarcelDekker,Inc.
www.dekker.com
458
ROSENAU ET AL.
INTRODUCTION
N-Methylation of nucleophilic nitrogen in amines is a common
procedure in both lab-scale and bulk-scale organic synthesis. The use
of alkylating agents, such as methyl iodide or methyl tosylate, has
often the disadvantage of competing quaternization of the amine, so that
the Eschweiler-Clarke methylation procedure
1,2
is applied instead. This
approach, in principle a variant of the well-known Leuckart-Wallach reac-
tion,
3,4
uses aqueous formaldehyde solution (formalin) together with con-
centratedformicacid.The N-methylationiseffectedintwosteps:formation
of N-(methylene)iminium cation intermediates via the N-hydroxymethyl
derivatives, and subsequent reduction by formic acid, which is oxidized to
carbon dioxide in turn.
Practical application of the Eschweiler-Clarke methylation follows a
well-establishedprotocolthatensuresitswideapplicability.Inthispaper,a
N-methylation approach is presented, which differs from the conventional
practiceandincludessomedistinctimprovementsovertheexistingmethod-
ologyintermsofsimplicityofthework-upanduseofhazardouschemicals:
The use of toxic formaldehyde and organic solvents is avoided, and rather
time-consuming and tedious purification steps, such as column chromato-
graphy purification or steam distillation, which were hitherto required in
most cases, are not required.
RESULTS AND DISCUSSION
During our investigations on deoxygenative demethylations of
N-methylmorpholine-N-oxide (1),
5
we observed that N-methylmorpholine
(2) was found in addition to the expected products morpholine (3) and
formaldehyde (4), if traces of oxalic acid (5) were present. Increasing the
amount of oxalic acid in the reaction mixture shifted the product distri-
bution towards higher yields of N-methylmorpholine. This was evidently
due to a reduction of intermediate N-(methylene)morpholinium cations
(6), so that the formation mechanism resembled a Leuckart-Wallach reac-
tion. This result was intriguing insofar as oxalic acid is well-known as a
reductant,butnotasacryptobaseorhydridetransferreagent
6
asneededfor
these reductions to proceed.
Furtherexperimentsrevealedthatoxalicacidisindeedabletoactasa
reductantinmixturesofprimaryaminesorsecondaryaminesandformalin,
albeit at elevated temperatures around 100
C. The resulting N-methyl-
amines or N,N-dimethylamines, respectively, were obtained in rather low
yieldsbelow10%,however.Theuseofsolidparaformaldehyde(4a)instead
ESCHWEILER-CLARKE METHYLATION FOR AMINES
459
of formalin provided a distinct improvement. The yields were significantly
increased,sothatfurtheroptimizationtowardssyntheticusabilityseemedto
be justified.
Finally,acleanmethylationofsecondaryaminesinyieldsabove90%
was achieved with an equimolar ratio of secondary amine and paraform-
aldehydealongwiththefivefoldmolaramountofoxalicaciddihydrate(5a)
withinonehour.Thesamegoodresultwasobtainedforthebismethylation
of primary amines, now employing amine, 4a and 5a in the molar ratio
1:2:10. Carried out at 100–120
C, the reaction is a solvent-free process
that proceeds in the molten state. The formaldehyde required is generated
in situ fromparaformaldehydebythermaloracid-catalyzeddecomposition.
The primary product obtained is the corresponding ammonium oxa-
late.Thefreebasecanbeconvenientlyobtainedbytreatmentoftheproduct
mixture with aqueous calcium hydroxide followed by extraction, or by
treatment with a suspension of calcium oxide in ethyl acetate or ethanol.
Oneadvantageofthepresented N-methylationprocedureisthepurityofthe
amine obtained which is indicative of an almost complete absence of side
reactions. No quaternization of the amines was observed.
Foroptimizationofthereactionconditionsthesystemmorpholine(3)/N-
methylmorpholine (2) was used. In preliminary experiments it was established
thatanequimolarratiobetweenamineandparaformaldehyde(4a)wasrequired
toavoidsidereactions.Alreadyasmallexcessof10% 4a causedtheformation
ofacomplexproductmixturewithseverediscolorationofthereactionmixture
460
ROSENAU ET AL.
due to condensation processes. The molar ratio of amine and 4a was conse-
quentlykeptconstantat1/1throughouttheexperiments.
Thestoichiometricamountofoxalicacid(5)employedprovedtobea
crucialissueintermsofconversionofthestartingmaterialandpurityofthe
methylated product. At a ratio below 1, relative to the amine 3 and para-
formaldehyde (4a),mainlyunreactedstarting amine besides small amounts
of the methylated amine were found. Formation of byproducts was not
observed. At increasing ratios up to 5, the product yield increased accord-
ingly up to about 80%. Interestingly, small amounts (<10%) of N-formyl-
morpholine(7)werefound,tracesofseveralunidentifiedreactionproducts,
in sum less than 3%, were also detected. The highest yield of byproduct 7
was obtained at a molar ratio 3/4a/5¼1/1/3. The occurrence of such for-
mylatedcompoundsisastrongindicationoftheintermediateoccurrenceof
formic acid from the decomposition of oxalic acid. This is in complete
agreementwithexperimentalandtheoreticalstudiesonthethermaldecom-
position of oxalic acid.
7,8
Experimentalstudieshavefirmlyestablishedthatthemajordecompo-
sition products of pure oxalic acid over the temperature range 400–430K
areequimolarquantitiesofformicacidandcarbondioxide
7
ifotherreaction
routes, such as metal ion catalysis, catalysis by strong acids or decomposi-
tionatthewallsofthereactionvessel,whichleadtoformationofequimolar
amounts of CO
2
, CO and water, can be excluded. High-level quantum
mechanicalcalculations
8
indicatethatthisreactionisabimolecularprocess:
in a first step oxalic acid fragments into carbon dioxide and dihydroxy-
carbene. In the rate determining step dihydroxycarbene reacts with oxalic
acidorwatertoberearrangedtoformicacid.Theunimolecularchannelto
produceCO
2
,COandwaterbecomesmoreprominentonlywithincreasing
temperature.Athighermolarratios,above5,formationofboth7andtrace
byproducts was completely suppressed, but up to an eightfold excess of 5
conversion of 3 to the product was incomplete. A ratio of 1/1/10 reliably
allowedforacompleteconsumptionofstartingamineandneat N-methyla-
tion in quantitative or nearly-quantitative yields.
Asoxalicacid(5)doesnotsolelyactasthereductant,butalsoasthe
hydrogendonorinthesystem,oxalicaciddihydrate(5a),possessinghydrate
waterasanadditionalprotonsource,wasemployedinstead.With 5a asthe
reductant,theamountofoxalicacidrequiredcouldbereducedto50percent
withoutimpairingyieldorproductpurity.Hence,theoptimummolarratio
amine/paraformaldehyde (4a)/oxalic acid dihydrate (5a) employed was
1/1/5.Thisstartingmaterialcompositionwasusedthroughoutthemethyla-
tionexperimentsondifferentaminesandforallfurthermechanisticstudies.
The reactions carried out and the corresponding conditions applied are
summarized in Table 1.
ESCHWEILER-CLARKE METHYLATION FOR AMINES
461
Both oxalic acid (dihydrate) and paraformaldehyde are required to
cause N-methylation of the amines, only one single component shows no
effect. Paraformaldehyde proved to be inert towards the amine under the
applied reaction conditions. However, upon prolonged reaction times a
Table 1. Products and Reaction Conditions
Starting
Amine
Product Amine
(% Yield)
Ratio
Amine/4a/5
2 (8)
a
3
1/2/1
2 (19)
b
3
1/1.1/1
3
2 (12)
1/1/0.2
3
2 (18)
1/1/0.5
3
2 (22)
1/1/1
3
2 (49), 7 (5)
1/1/2
3
2 (67), 7 (9)
1/1/3
3
2 (76), 7 (7)
1/1/4
3
2 (81), 7 (2)
1/1/5
3
2 (80)
1/1/6
3
2 (97)
1/1/8
3
2 (quantitative)
1/1/10
3
2 (98)
1/1/4 (5a used)
3
2 (quantitative)
1/1/5 (5a used)
2 (20)
c
3
1/1/5 (5a used)
2 (58)
d
3
1/1/5 (5a used)
2a (98)
e
3
1/1/5 (5a used)
2b (97)
f
3
1/1/5 (5a used)
2
g
(0)
3
1/1/5 (5a used)
2
h
(2)
3
1/1/5 (5a used)
2
i
(26)
3
1/1/5 (5a used)
2-Aminoethanol
8 (93)
1/1/5 (5a used)
Aniline
9 (quantitative)
1/1/5 (5a used)
Ethylene diamine
10 (96)
1/1/5 (5a used)
HNMe
2
*HCl
11 (84)
1/1/5 (5a used)
a
Discoloration, complex mixture.
b
Discoloration, byproducts.
c
Reaction temperature 60
C.
d
Reaction temperature 80
C.
e
Deuteratedoxalicaciddihydrate((COOD)
2
*2D
2
O)wasused.
f
Deuterated paraformaldehyde ((CD
2
O)
n
) was used.
g
Oxalic acid diethylester.
h
Oxalic acid diethylester
þ
2H
2
O.
i
Oxalic acid diethylester
þ
2H
2
O, morpholine hydrochloride.
[ Pobierz całość w formacie PDF ]