Author Topic: Sodium dithionite reductive alkylation -Lilienthal  (Read 1760 times)

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Sodium dithionite reductive alkylation -Lilienthal
« on: April 19, 2000, 03:45:00 PM »

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Author  Topic:   Sodium dithionite reductive alkylation 
Member   posted 12-21-98 08:30 AM          
Some days ago I found this nice reductive amination with sodium dithionite (Na2S2O4):
Aust. J. Chem. 32, 205 1966 P. M. Pojer.
The conditions are: 30 mmol ketone + 30 mmol amine in 70 ml DMF, 110°C, + 120 mmol NaHCO3, + Na2S2O4 + 30 ml H2O, 30 min 110 °C, + 300 ml H2O, ether extraction. The yields are around 70%.
Member   posted 12-21-98 01:09 PM          
This looks interesting. Can I assume the amine is monomethylamine? Also how much Na2S2O4 was used?
drone 342
Member   posted 12-22-98 03:17 PM          
I'm sitting here with a copy of the Austrailian Journal of chemistry, 1966, and I have it opened to p. 205. Sadly, it has nothing to do with reductive amination.
drone 342
Member   posted 12-22-98 03:25 PM          
I noted that the volume in 1966 was 19, not 32, so I looked up volume 32. Still no luck. What gives? Where did you get this ref from? Would you be willing to scan it in as a holiday present to The Hive?
-drone #342

Member   posted 12-23-98 05:41 AM          
 Aust. J. Chem. 32, 201, 1979 P. M. Pojer.
 60 mmol Na2S2O4
The interesting reaction was cyclohexylamine + cyclohexanone = dicyclohexylamine in 73%, the imine was either preformed or generated in situ. Every aliphatic prim. or sec. amine should work.

Member   posted 12-23-98 11:22 AM          
Drone: If that's the one, could you scan and post it for Christmas?
drone 342
Member   posted 12-24-98 02:02 PM          
So be it. I'll do it, but I'm warning it will be a belated holiday gift.
Member   posted 01-06-99 09:01 AM          
I seem to remember reading a rather simple prep for the thionite. I am just racking my brains to remember where...
Member   posted 01-12-99 10:24 AM          
You don't have to prepare sodium dithionite, it's commonly used to discolour/bleach textiles. You can buy it in every drugstore.
The Cook
Member   posted 01-12-99 03:52 PM          
A textile bleach, eh? Dithionite might be chem. of the month. It deacetylates Melatonin w/ NaOH, too. It likes bases, what could it do in acid? Maybe mdp2pol still lurks in the shadows...
Member   posted 01-13-99 10:10 AM          
It's also sold as sodium hydrosulfite. I accidently bought this substance when trying to buy sodium bisulfite, a.k.a. sodium metabisulfite. It's used in photography too. Lr/
The Cook
Member   posted 01-14-99 12:00 AM          
Hee hee hee. A mystery unravels! Once upon a time A little bee bisulfited it's ketone with bisulfite & hydrosulfite. Then a spontaneous amination of the bisulfite product ruined the whole batch, and forced her to throw it out. But the bee never had the bisulfite product alone aminate itself. I guess this is what was wrong with it. :-)

rev drone
Member   posted 02-10-99 12:54 PM          
I said I would post it, and I said it would take a while. Regardless, here it is. There are certainly typo's and other errors, but what do you expect for free anyways?
Aust. J. Chem., 1979, 32, 201-4

The Use of Sodium Dithionite for the Reduction of Imines and the Cleavage of Oximes

Peter M. Pojer

School of Chemistry, Macquarie University, North Ryde, N.S.W. 2113.


Sodium dithionite reduces a variety of imines to secondary amines. Oximes are cleaved by the reagent to the parent carbonyl compound.


Sodium dithionite is a powerful, inexpensive, safe and readily available reducing agent. It has been used for more than 70 years in the reduction of aromatic nitro compounds,1 diazonium salts,2 a variety of pyridinium compounds,3,4 some complex oximes 5,6 and other nitrogen-containing functional groups.7 Recently, two reports 4,8 appeared on the reduction of aldehydes and ketones with hot solutions of sodium dithionite.

It is surprising, therefore, that no investigations of its use in the reductive alkylations of amines have been described. In a related reaction, Hawthorne and coworkers9 reported that sodium dithionite converts the diimines of biphenyl-2,2'-dicarbaldehyde into 6-substituted 6,7-dibydro-5H-dibenz[c,e]azepines. This group9 also described the reduction of biphenyl-2,2'-dicarbaldehyde monooxime to 6,7-dihydro-5H-dibenz[c,e]azepine. Sodium dithionite has also been employed in the Knorr pyrrole synthesis where the intermediate ethyl 2-hydroxyiminoacetoacetate was reduced to an amine (which was not isolated)5 and in the reduction of 2,3,5-trimethyl-1,4-benzoquinone I-oxime to 2,3,6-trimethyl-4-aminophenol.6 Both of these oximes are highly conjugated and are therefore expected to be susceptible to reduction.

The use of metal hydrides and catalytic hydrogenation in the reduction of imines10 and oximes, and derivatives of oximes,11 is well documented but many of the procedures suffer from the expensiveness or inconvenience of the reagents.

Reductive Alkylation of Amines

We found methanol/water4,9 or dioxan/water8 mixtures unsuitable for the reduction of imines with sodium dithionite since the slow reduction was preceded by hydrolysis of the imines. The use of dimethylformamide as a cosolvent with water was reported8 to increase the reduction rate of aldehydes and ketones. However, in the reduction of imines, the conditions employed by the Dutch group8 gave products which resulted from hydrolysis of the starting materials.

The method described here overcomes the above difficulties simply by introducing excess sodium dithionite to the solution of imine in hot dimethylformamide, followed immediately by the addition of water. The reaction takes less than 30 min at 110'. Under these conditions, N-cyclohexylidenebenzylamine and N-cyclohexylidenecyclohexylamine give good yields of benzylcyclohexylamine and dicyclohexylamine respectively, while N-benzylidenebenzylamine is converted into dibenzylamine in 55 % yield. The more stable and unreactive N-benzylideneaniline is reduced only in moderate yield (40 %) to the corresponding amine. While cinnamic acid is unaffected by hot, alkaline sodium dithionite solutions (that is, the conjugated carbon-carbon double bond is not reduced), the reductions of imines of cinnamaldehyde under analogous conditions lead to low yields of complex mixtures.

Lithium aluminium hydride12 or hydrogen and catalyst13 reductions of imines containing aromatic carbon-halogen bonds are often accompanied by carbon-halogen bond cleavage; aromatic iodides are particularly susceptible.12 Sodium dithionite appears to be the reducing agent of choice in such cases. Both iodobenzene and 4-iodobenzoic acid are recovered unchanged after prolonged heating under the normal reducing conditions while N-(3-bromobenzylidene)benzylamine, prepared in situ from 3-bromobenzaldehyde and benzylamine, is reduced cleanly to N-(3bromobenzyi)benzylamine.

Conversion of Oximes into Corresponding Carbonyl Compounds

When oximes are treated at room temperature with aqueous sodium dithionite, either alone or in the presence of sodium hydrogen carbonate or sodium acetate, the organic material gradually dissolves. The parent carbonyl compound is obtained from this mixture by the addition of acid, preferably, or base.

Two possible mechanisms for the deoximation follow. Firstly, solutions of the dithionite anion are not very stable and decompose in a complex manner to the hydrogen sulfite ion. 14 Hence, the cleavage of oximes with sodium dithionite can occur by a hydrolytic pathway15 analagous to the reaction of oximes with sodium hydrogen sulfite described by Pine and and coworkers16. Alternatively, the cleavage might occur by a reductive pathway, the oxime is first reduced to the imine which is immediately hydrolyzed to the carbonyl compound as in scheme 1.

The latter mechanism is supported by the observation that addition of a base apparently increases the rate of the deoximation reaction. Under these conditions, sodium dithionite is known to be a powerful reducing agent.17 Furthermore, the dithionite deoximations take place under conditions milder than those reported for the hydrogen sulfite reaction.16 The mechanism is also in keeping with the known reduction of nitro1 and nitroso 5,18 compounds and oximes 5,11 to amines with sodium dithionite and is, furthermore, analogous to the mechanism proposed by Corey and Richman15 and Timms and Wildsmith19 for reductive deoximation with chromium(II) and titanium(III) salts respectively.

The dithionite cleavage of oximes competes favourably with known procedures for regeneration of carbonyl compounds from oximes.15,19 The reaction offers the following advantages:

(i) Sodium dithionite is inexpensive and readily available.

(ii) The reaction conditions are mild (room temperature at neutral pH).

(iii) The regeneration is rapid (several hours at 40').

(iv) Both aldehydes and ketones are regenerated successfully.


Extracts into organic solvents were dried over MgSO4 and evaporated under reduced pressure with a rotary m evaporator. 1H n.m.r. spectra were recorded in CDC13 on a Varian A60-D spectrometer; chemical shifts were measured from tetramethylsilane as internal standard.

General Procedure for Reduction of Imines

To a solution of the imine (30 mmol), either preformed or prepared in situ from the amine (30 mmol) and the carbonyl compound (30 mmol), in dimethy1formamide (70 ml) at 110' under nitrogen was added solid sodium hydrogen carbonate (120 mmol). The mixture was stirred vigorously; solid sodium dithionite (60 mmol) was added, followed immediately by water (30 ml). Gas evolution took place some minutes after the addition of the water. Stirring was continued at 110' for 30 min; the reaction n-mixture was allowed to cool to room temperature and then poured into water (300 ml). The aqueous solution was extracted with ether (4 x 75 ml) which was in turn washed with water (4 x 50 ml) and saturated brine (50 ml). The ethereal extract was dried and evaporated to give the amine. The product was purified by distillation or through the hydrochloride.

The amine hydrochlorides were prepared by adding a slight excess of 5 M hydrochloric acid to the neat amine. The mixture was stirred and the solid product was collected by filtration.

(i) N-Cyclohexylidlenebenzylamine (8 g) gave benzylcyclohexylamine (6.8 g, 73 %), b.p. 164'/26 mm (lit 20 145-147'115 min); hydrochloride m.p. 283-284' (sealed tube) (lit 20 284'). (ii) N-Cyclohexylidenecyclohexylamine: (10 g) gave dicyclohexylarnine (6.8 g, 68%), b.p. 117-120/17mm (lit.21 118-120'/17 min); hydrohloride, m.p. 335-337' (lit." 339-342*). (lit.21)

120'/17 N_Benzylidenebenzylamine (5 g) gave -dibenzylamine (2.7 g, 55%), b.p. 180/18
lit 22 160-170'/l 5 min); hydrochloride, m.p. 255-2~60 (lit.23 256’) (Found: C, 72.0 H, 7 .0. Calc. for
C14H16CIN: C, 71.9; H, 6.9%).
(iv) N-(3-Bromobenzylidene)benzylamine, prepared from 3-bromobenzaidehyde (5 g) and benzylamine (2.9 g) and used crude, gave N—(3-bromobenzyl)benzylarnine (3.6 g, 49%)' b.p. 220-222'/118mm. I H n.m.r. spectrum: s, I H, I - 63 (NH); br s, 4H, 3 - 77 (benzylic H); m, 8H, 7 - 2-7 - 45 (aromatic
H); d,IH,7-50,J2Hz(aromaticH ortho to Br). The hydrochloride was recrystallized from 0-5 m
hydrochloric acid, m.p. 203-205' (Found: C, 53.9; H, 4.6; N, 4-5. Ct.H15BrClN requires C,
53-8; H,4-8; N.4-5%).
(v) N-Benzylideneaniline (3 g) gave benzylaniline (1.2 g, 40%), m.p. 36-37’, identical with an authentic sample prepared from aniline and benzyl chloride .24

Cleavage of Oximes to Carbonyl Compounds

General Procedures

Method A.-The oxime (20 mmol) was mixed with water (15 ml) containing sodium dithionite (28 mmol). The suspension was stirred overnight at room temperature. (Warming to 40' reduced reaction times to several hours.) In some cases, a precipitate formed.This product was very high melting and, on treatment with 2 M hydrochloric acid, liberated the carbonyl compound and sulfur dioxide. It was therefore assumed to be the bisulfite addition compound of the carbonyl compound and was not isolated. A slight excess of 2 M hydrochloric acid was added to the reaction mixture and nitrogen was bubbled through the mixture to expel the sulfur dioxide. Solid sodium carbonate was added carefully to alkalinity; the aqueous mixture was allowed to stand for 30 min and was extracted with ether (2 x 10 ml) which was dried (MgSo,) and evaporated. The residue was essentially pure carbonyl compound (by t.l.c.)

Method B- Thee reaction described under Method A was performed in the presence of sodium hydrogen carbonate (28 mmol). Cleavage by means of this modification appeared to proceed considerably faster. The usual workup gave the carbonyl compound in comparable yield.


(i) Cyclohexanone oxime (2 - 3 g) gradually dissolved in the aqueous sodium dithionite solution

when the stirring was continued overnight, a colourless precipitate formed. [This precipitate
and, pidly when sodium hydrogen carbonate (Method B) was included in the reaction
formed more ra (1.9 g, 95%) was isolated essentially pure.

mixture.) Cyclohexanone under the condilions

oxime (2 - 7 g  reacted sluggishly at room temperature

(ii) Acetophenone rnpleteafter4hat4Oo. Acetophenone (2-2 g,93%) was
employed in method A but cleavage was co

isolated essentially Pure.

(iii) Benzaldehyde oxime(2-4 g) reacted under the conditions of Method A to give a clear solution (At 50, the reaction was complete in 2 h.) Benzaldehyde (2 g, 96%) was isolated essentially pure.

(iv) Butanal oxime (2 g) reacted under the conditions of Methods A and B to give a clear solution. Butanal (0- 74 ig) was obtained from the former reaction in 45% yield while, from the latter reaction, butanal was isolated in 54% yield. The relatively low yields were probably due to the high volatility of butanal, b.p. 75*.

I Grandmougin, E-J. Praki. Chem., 1907,76,124.
2 Grandmougin, E_~er. Dtsch. Chem. Ges., 1907, 40, 422.
3 Mauzerall, D., and Westheimer, F. H., J. Am. Chem. Soc., 1955, 77, 2261.

' Minato, H., Fujie, S., Okuma, K., and Kobayashi, M., Chem. Lett., 1977, 1091.
' Treibs, A., Schmidt, R., and Zinsmeister, R., Chem. Ber., 1957, 90, 79.
6 Smith, L. L, and Schubert, W. M., J. Am. Chem. Soc., 1948, 70, 2656.
7 Fieser, L. F., and Fieser, M., 'Reagents for Organic Synthesis' Vol. 1, p. 1081 (John Wiley: New
York 1968).
* De Vries, J. G., van Bergen, T. J., and Kellogg, R. M., Synthesis, 1977, 246.

* Hawthorne, J. 0., Mihelic, E. L., Morgan, M. S., and Wilt, M. H., J. Org. Chem., 1963, 28, 283 1.

'0 Emerson, W. S., Org. React., 1948, 4, 174; Schellenberg, K. A., J. Org. Chem., 1963, 28, 3259.

11 Yoon, N. M., and Brown, H. C., J. Am. Chem. Soc., 1968, 90, 2927; Feuer, H., and Braunstein, D. M., J. Org. Chem., 1969, 34, 1817.

12 Karabatsos, G. J., and Shone, R. L., J. Org. Chem., 1968, 33, 619; Brown, H. C., and Krishnamurthy, S., J. Org. Chem., 1969, 34, 3918.

13 Freifelder, M., J. Org. Chem., 1966, 31, 3875.

14 Lem, W. J., and Wayman, M., Can. J. Chem., 1970, 48, 2778; Burlamacchi, L., Guarini, G., and Tiezzi, E., Trans. Faraday Soc., 1969, 65, 496.
20 Von Braun, i., Blessing, G., and Zobel, F., Ber. Dtsch. Chem. G,,., 1923, 56,1988.
2, Heckel, H., and Adams, R., J. Am. Chem. Soc., 1925, 47, 1712.
2 2 Carothers, W. H., and Jones, G. A., J. Am. Chem. Soc., 1925, 47, 305 L 1,495, 113.
~3 Kindler, K., (and Peschke, W., and Dehn, W.) ' Justus Liebigs Ann. Chem., 193
24 Willson, F. G., and.Wheeler, T. S., Org. Synth., 1932, C111-VOL 1, 102.

-the good reverend drone

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