Vibrating_Lights (Hive Addict)
06-14-03 00:15
No 439864
      Imine reduction  Bookmark   

Is anhydrous IPA a suitable replacement for MeOH WHen reducing an Imine with NaBH4.  Is MeAm just as soluable in IPa As it is in MeOH?

Start thinking more like a chemist and less like a criminal
(Hive Addict)
06-14-03 00:32
No 439869
      IPA  Bookmark   

IPA should do just fine as a substitute.  Don't know about the relative solubility, but it should still be soluble enough.  Try making a concentrated solution at low temperature and then bring to RT outside/in good ventilation.  (if freebase) If HCl salt, just filter off the excess.  Titrate.

Act quickly or not at all.
06-14-03 04:43
No 439898
      No. Wrong.
(Rated as: excellent)

"" Sodium borohydride reductions are generally conducted in solvents such as methanol or ethanol due to its high solubility in them.
However, the efficiency of sodium borohydride in these solvents is very poor due to the high rate of decomposition.""
And therefor you add the boro in many small portions, hence the ratio imine to NaBH4 stays always big to tiny.

""In the absence of acid hydrogen evolution slows down due to the increase in pH caused by the formation of the basic metaborate ions. Hence dissolving sodium borohydride in a basic solution prevents initial hydrolysis and permits the reagents to be used or stored in aqueous solution.
Sodium borohydride is soluble in water, lower aliphatic alcohols and amines and not appreciably soluble in diethyl ether, dioxane, hydrocarbons such as benzene, toluene and dichloromethane. The reported values of solubility of sodium borohydride are given in Table I.
Due to the high solubility of sodium borohydride in methanol, most of the borohydride reactions are conducted using methanol as the solvent. However, the great disadvantage of methanol in borohydride reduction is that borohydride undergoes an appreciable rate of decomposition even at -40°C thus releasing 4 moles of hydrogen and inhibiting the formation of hydride ion for the reduction (Equation 3). Therefore, large excess of sodium borohydride (4-5 moles) has to be used for the reduction reaction.

This decomposition reaction is very slow in ethanol and only 33% of the available hydrogen is liberated in 4 h. As the carbon length of the aliphatic alcohol increases, the solubility of the sodium borohydride in it decreases but its stability increases. In isopropyl alcohol and tert-butanol, sodium borohydride exhibits excellent stability and no formation of hydrogen is observed over a period of 24 h, but it has poor solubility in these solvents (Table I).""

See Post 295754 (not existing) for Table I :

Table I - Solubility of sodium borohydride in different solvents (g / 100 g solvent)

Solvent.........................Temperature [°C].....................Solubility

Methanol..............................-40..........................Highly soluble

Ethanol................................20.........................4 (reacts slowly)

Isopropyl alcohol......................20........................0.25 (reacts slowly)

Use Methanol, never IPA for imine reduction. So next question is irrelevant. LT/

(Hive Addict)
06-14-03 07:45
No 439928
      LaBTop,i've seen many posts saying that rx mix  Bookmark   

LaBTop,i've seen many posts saying that rx mix must be anhydrous and if water is present,yields are low(~30%) while others say(Barium for example) that water doesn't disturb imine formation/reduction.Which is correct?If raf wants to do borohydride reductive amination in one pot,should he keep everything anhydrous?

For those about to synth,we salute you
06-14-03 16:28
No 439979
      Ahh, this is the right place and time to  Bookmark   

start this interesting discussion.

Terbium has already told it before, and Barium has luckily for all of us proved then undoubtedly  that aqueous conditions also work for these reductions in acceptable good to very good yields (so much more than 30% !), which is in accordance with many cited references, however, IMHOP, the anhydrous GAS approximation leads to the highests molar yields for the phenethylamines him and I have personally synthesized (Methamphetamine, MDMA and MDA), if I compare his posted molar yields to mine.
I have once cited that I accidentally sucked back approximately 10 liter water out of a wash bottle into my imine reaction vessel while adding NaBH4, and it didn't affect the end yield in desastrous amounts. But it still was about 10% lower.

Raffike, if you want to and can, you can do a 1 mole boro reduction following my procedure and a 1 mole one following Bariums procedure.
Then you and we can compare results.
Please follow instructions to the letter in all your tests.
And tell if you use high grade chems or homemade.
If you don't have commercially grade MeAm gas from a gas supplier firm (which is DRY!), but synth your MeAm gas at home, the comparison becomes already difficult, but if you dry your homemade MeAm gas thoroughly before bubbling it in dry methanol at -10 to -20 Celsius you can compare both methods in a scientific manner.

In fact, I must admit, it is OFCOURSE much easier to work with easy homemade MeAm salt soluted in water, than risking ordering or blackmarketing pure MeAm GAS!
A 10% or perhaps more yield can't outsmart in that case the risks and perhaps smells involved with my anhydrous MeAm-gas procedure.
For small scale production, Bariums method is far better, for BIG scale production my method is far better, IF you posess MeAm gas cylinders.
It's always a simple comparison between risk and GREED. tongue

I'm sure Barium (I hope so), Terbium(I hope so) and many other members who have personally (or from hearsay by a knowledgeable researcher, ynwimeansmile) tested imine reductions with NaBH4 or perhaps even Zincborohydride will joyfully join this highly interesting discussion.

I will post my "Exellent Boro info" from 04-10-02 (that I let read some very important members) in this thread, so everybody can read it at last, I totally forgot to post it in the forums.
Especially the literature list had some good reads in it, which I haven't seen here.

ESPECIALLY  14. T.N. Sorrell and P.S. Pearlman; Tetrahedron Letters 21 3963 (1980)
Reduction of carbonyl compounds by in situ generation of quaternary ammonium borohydrides.  LT/

(Hive Addict)
06-14-03 20:10
No 440028
      SwiRaf was once introduced to some guys.  Bookmark   

SwiRaf was once introduced to some guys.They asked raf how large-scalers do they things.Raf said catalytic hydrogenation with 3 atm H2 pressure or sodium borohydride.They thought that catalytic is bit expensive and also bit dangerous so they wanted to know more about sodium borohydride.
Never saw them again.

Now raf got curious and is testing different methods to come up with one that should work.
If bees are interested,raf may post his test results.He probably starts small-scale as he has never messed with borohydride.

For those about to synth,we salute you
(Hive Addict)
06-15-03 14:33
No 440141
      Imine reduction  Bookmark   

I agree with LabTop that this is a classic interesting topic.

I never tried to optimize the method I posted about, but I'm sure the yields can be pushed up to 80-90%. Especially using phase transfer catalysis. The Hive would appreciate (I think I can speak for most of us here) if someone like Raffike would go through the trouble and run both LabTops and mine reaction parallell since it hasn't been done. A 250 mmol scale would do just fine.

What I would change in mine method though, is to use a higher concentration of the aqueous methylamine solution. E.g. to a solution of the ketone in toluene I would add a saturated solution of methylamine in water, then I would add a 50% aqueous NaOH solution to liberate the amine. This would very effectively push out the liberated methylamine into the ketone solution where we want it. For the borohydride reduction I would optionally use a PTC like Aliquat 336 (this PTC is cheap and easy to handle and still non-watched). When the imine formation is complete the aqeous phase is removed and a stablized aqueous solution of sodium borohydride is added along with 1-5 mol% Aliquat 336. This would presumably lower the need of borohydride tremendously as can be seen in the C=C reduction method. I estimate a yield of 85-90% actually, but this is just my gut feeling.

Damn, I think I'm going to try this myself. Yet again this is a simple modification I havent thought of before. tongue

06-15-03 22:26
No 440189
      Excellent Boro info I page 1
(Rated as: excellent)

Part I

Merits of sodium borohydride reductions under phase transfer catalysis - Part I

Many organic transformations in pharmaceutical and agrochemical industries involve molecules containing multifunctional group, which need to be selectively hydrogenated by using a suitable hydrogen source. In this respect sodium borohydride is found to be highly desirable in comparison with other reducing agent as it is mild and a more selective catalyst. Sodium borohydride selectively reduces functional groups such as aldehydes, ketones, acid chloride and imines in presence of esters, epoxides, amides, nitriles and nitro group. Sodium borohydride reductions are generally conducted in solvents such as methanol or ethanol due to its high solubility in them. However, the efficiency of sodium borohydride in these solvents is very poor due to the high rate of decomposition. Conducting the reaction in two phases using non-polar aprotic solvents such as hydrocarbons and a phase transfer catalyst can alleviate this problem. In hydrocarbon solvents sodium borohydride is stable and does not undergo decomposition reaction and thus its complete utilization can be realized. For the reduction of functional groups such as nitro, ester, amide etc., the reducing power of sodium borohydride can be varied over a wide range by mixing the sodium borohydride with metal salts such as LiCl, AlCl3, CoCl2, MgCl2, TiCl4, BF3, I2, thiols such as ethanethiol, carboxylic acid such as acetic acid, trifluoroacetic acid and quaternary ammonium salts. This paper is published in two parts. Part I delineates the prowess of sodium borohydride reductions under phase transfer catalysis and in situ synthesis of quaternary ammonium borohydrides. Part II will deal with reductions using preformed quaternary ammonium salts and effect of solvents in sodium borohydride reduction.


Many organic transformations in pharmaceutical and agrochemical industries involve molecules containing multifunctional groups, which need to be selectively hydrogenated by a suitable hydrogen source. Sodium borohydride being a milder and a more selective reducing agent than lithium aluminium hydride is found to be ideal to achieve this type of transformations. Sodium borohydride selectively reduces aldehydes, ketones, acid chlorides and imines in presence of esters, epoxides, amides, nitriles or nitro group. Also sodium borohydride is an excellent reducing agent for sugar molecules which are soluble in water and where lithium aluminium hydride cannot be used. Sodium borohydride reductions are usually conducted in methanol as solvent where it reacts vigorously with the solvent at room temperature liberating 4 moles of hydrogen immediately. Therefore, an excess of reducing agent (4-5 moles) per mole of the aldehyde or ketone has to be used. To overcome this problem such reductions can be performed in biphasic medium by using a phase transfer catalyst and a non-polar solvents such as benzene, toluene etc. or a preformed quaternary ammonium borohydride salt and solvents such as higher aliphatic alcohol, dichloromethane and THF etc.


Properties of sodium borohydride
Complex borohydrides are compounds that contain the elemental hydrogen in a reduced or electron rich state. Among the borohydrides, the alkali metal borohydrides, particularly sodium borohydride is the most important for it is specific, easy to handle and highly selective. Sodium borohydride is a stable white crystalline solid and undergoes decomposition above 400°C. It is stable in aqueous alkaline solution and slowly decomposes in water, the rate of which increases with increasing acidity, temperature and presence of transition metal salts such as Ni, Co, Fe and Cu chlorides. Hydrogen gas is generated in situ by two ways as given below:

In the absence of acid hydrogen evolution slows down due to the increase in pH caused by the formation of the basic metaborate ions. Hence dissolving sodium borohydride in a basic solution prevents initial hydrolysis and permits the reagents to be used or stored in aqueous solution.
Sodium borohydride is soluble in water, lower aliphatic alcohols and amines and not appreciably soluble in diethyl ether, dioxane, hydrocarbons such as benzene, toluene and dichloromethane. The reported values of solubility of sodium borohydride are given in Table I.
Due to the high solubility of sodium borohydride in methanol, most of the borohydride reactions are conducted using methanol as the solvent. However, the great disadvantage of methanol in borohydride reduction is that borohydride undergoes an appreciable rate of decomposition even at -40°C thus releasing 4 moles of hydrogen and inhibiting the formation of hydride ion for the reduction (Equation 3). Therefore, large excess of sodium borohydride (4-5 moles) has to be used for the reduction reaction.

This decomposition reaction is very slow in ethanol and only 33% of the available hydrogen is liberated in 4 h. As the carbon length of the aliphatic alcohol increases, the solubility of the sodium borohydride in it decreases but its stability increases. In isopropyl alcohol and tert-butanol, sodium borohydride exhibits excellent stability and no formation of hydrogen is observed over a period of 24 h, but it has poor solubility in these solvents (Table I).

06-15-03 22:32
No 440190
      Excellent Boro info I page 2
(Rated as: Excellent)

Part II

Table I - Solubility of sodium borohydride in different solvents (g / 100 g solvent)

Solvent Temperature [°C] Solubility
Water 20 55
Methanol -40 Highly soluble
Ethanol 20 4 (reacts slowly)
Isopropyl alcohol 20 0.25 (reacts slowly)
Tert-butanol 25,60 0.11, 0.18
Pyridine 25,75 3.1, 3.4
Diglyme 25,40 0.13, 0.29
Triglyme 25,40 0.13, 0.29
Acetonitrile 28 0.9

Acid chlorides are reduced by suspending sodium borohydride in dioxane or other inert solvent. The reaction is vigorous with aliphatic acid chlorides but aromatic acid chlorides require heating.

Sodium borohydride is available as powder, pellets and a 12% solution in caustic soda. In all three forms it is stable indefinitely. In the case of 12% solution, it is used directly for reduction without any further dilution.

Mechanism of the reaction

The mechanism of reduction using sodium borohydride is as follows:

.......Drawing missing......

The aliphatic n-alkyl borates are very rapidly hydrolysed during the course of the reaction. In the reduction of aromatic aldehydes and ketones, the intermediate borate salts are not easily hydrolysed and therefore, in such cases heating with alkali is necessary in order to liberate the alcohols.

Reduction power of sodium borohydride and its modified derivatives
Sodium borohydride is a milder but a more selective reducing agent than LiAlH4, selectively allowing the reduction of aldehydes, ketones, acid chlorides and imines in presence of esters, epoxides, amides, nitriles or nitro group. Also sodium borohydride is an excellent reducing agent for sugar molecules which are soluble in water and where lithium aluminium hydride cannot be used. For the reduction of other functional group such as ester, amide etc. the reducing power of the sodium borohydride can be varied over a wide range by mixing the borohydride with metal salts such as LiCl, AlCl3, CoCl2, MgCl2, TiCl4, BF3, I2, thiols such as ethanethiol, carboxylic acid such as acetic acid, trifluoroacetic acid, using different solvents such as polar aprotic solvents or non-polar aprotic solvents and a phase transfer catalysts (Table II) (1-3).

06-15-03 22:36
No 440191
      Excellent Boro info I page 3
(Rated as: Excellent)

Part III

Table II - Reduction power of sodium borohydride and its modified derivatives

Reducing agent Reducing species Functional groups reduced Comments
NaBH4 BH4ion Aldehyde, ketones, acid chloride, imines Very selective reducing agent compared to LiAlH4 / LiBH4
LiAlH4 AlH4ion Aldehydes, ketones, epoxides, acid chlorides, acids, anhydrides, esters, nitriles, nitro, amides, alkenes Non selective reducing agent
NaBH4 + BF3.Et2O, Me3SiCl, R2SeX2, TiCl4, SnCl4 Diborane Primary, secondary, tertiary amides, nitro, acid, SO2, alkene no comments
NaBH4 + H2SO4 / HCl / BF3 / MeI / Me2SO4 / MeSO4 Diborane Amides, unsaturated acids, lactams, chiral diketo-piperazines, alpha-amino acids Unsaturated acids are selectively reduced to unsaturated alcohol. A mild reducing agent with appreciable chemoselectivity for amide reduction
Quaternary ammonium triboro octahydride (3) Diborane Aldehydes, aromatic and aliphatic ketones, acid chlorides no comments
NaBH4+ diethylseleniumdihalide(4) Diborane Primary, secondary and tertiary amides Sodium borohydride and dialkylselenium dibromides / dichlorides selectively reduces tertiary amides in presence of secondary and primary amides
NaBH4 + LiCl LiBH4 Epoxides, esters, anhydrides, nitriles, and olefins These groups are reduced selectively in presence of nitro or amide groups. LiBH4 is soluble in ether, THF, diglyme and is more powerful than sodium borohydride. Its reducing power lies between sodiumborohydride and lithium aluminium hydride. Hence a very useful reagent. It is not selective i.e. it reduces esters as well as aldehydes and ketones
NaBH4+ lanthanide halides such as samarium and cerium (5) Lanthanide borohydride alpha,beta-unsaturated ketones in presence of acids, esters, amides, halides, nitriles, nitro groups Selective reduction to a,b-unsaturated alcohol. Steric hindrance has no effect on the rate of reduction and exclusively undergoes 1,2-reduction. Suitable for selective reduction of steroid, terpenoid and prostanoid a-enones
NaBH4 + CaCl2 / MgCl2 / AlCl3 CaBH4 / MgBH4 / AlBH4 Esters Selectively reduces esters in presence of amide and nitro groups. 1-olefin is selectively reduced in presence of 2-olefin
NaBH4 + ZrCl4 (6) ZrBH4 Imines, oximes, nitriles This reagent reduces oximes smoothly to give primary amines !!! whereas diborane gives hydroxyl amines
NaBH4 / I2 (7) RCOOBH2 Unsaturated acids Selectively reduces acid group in presence of ester and a double bond. This is because of the reductive species is RCOOBH2 which is less reactive than diborane
NaBH4 / acetic acid (8) NaBH2(OAc)2 / NaBH3(OAc) Aldehydes no comments  LT/: remember the Amm.acetate One Pot with a bit acetic acid added!
NaBH(OAc)3 / quaternary triacetoxy borohydride BH(OAc)3 Aldehydes, b-ketone aldehydes Chemoselective reduction of aldehydes in presence of ketones !!!, b-keto aldehydes are reduced to anti diols
NaBH(COOCF3)3 (9) no comment Epoxides, lactams Very reactive
NaBH(OR)3 BH(OR)3 Esters More reactive compared to sodium borohydride but less selective. More sensitive to decomposition
NaBH(R )3 (10) R = sec. butyl BH(R)3 Ketones Outstanding stereo selective reduction of ketones
NaBH2 (ethanethiol)2 (11) no comment CHO, CO, COCl, COOEt, nitro group no comment
NaBH2(anilido) (11) no comment Esters Selectively reduces esters
NaBH3CN /Quaternary ammonium cyanoboro-hydride (12,13) BH3CN Reductive amination, dehalogenation - especially of iodo or bromo group Less reactive and stable under acidic pH of 3

06-15-03 22:46
No 440192
      Excellent Boro info I page 4
(Rated as: Excellent)

Part IV

Application of sodium borohydride reduction in the industry.
Figure 1 shows examples of certain commercial important molecules in the pharmaceutical and agrochemical industries where sodium borohydride reductions are exclusively used.

.......Drawings missing.......

Figure 1 - Some examples of sodium borohydride reduction used in pharmaceutical and agrochemical industries

Disadvantages of using methanol/water/polar aprotic solvents as solvent in sodium borohydride reduction:
Sodium borohydride reductions are usually conducted in methanol as solvent due to its high solubility in methanol.
Other popular solvents for reductions using sodium borohydride as reducing agent are water and polar aprotic solvents such as DMF etc.
Following disadvantages are encountered when these solvents are employed :
1. Reacts vigorously with lower aliphatic alcohol such as methanol and ethanol at room temperature liberating 4 moles of hydrogen.
2. Promotes side reactions such as ketals, acetals, hydrates, etc.
3. Protonolysis takes place in aqueous solution, rate increasing rapidly with increasing temperature and decreasing pH.
4. Organic molecules to be reduced are not soluble in water.
5. Sodium borohydride exhibits useful solubility in diglyme and DMF and could be used for the reduction but these solvents due to water miscibility and high boiling points make work-up of the reaction quite inconvenient, further ketones react very slowly in diglyme.

To overcome the above mentioned problems such reduction reactions are conducted in two phase system using non-polar aprotic solvents such as benzene, toluene, dichloromethane, diethyl ether and tetrahydrofuran (THF) using phase transfer catalyst.


There are two ways for conducting reductions using sodium borohydride and quaternary ammonium salts and they are as follows:
1. In situ synthesis of quaternary ammonium borohydrides by using 12% sodium borohydride solution and quaternary ammonium salts (Figure 2).

.......Drawing missing.......

Figure 2 - Schematic representation of phase transfer catalysed borohydride reduction of ketones

2. Synthesizing quaternary ammonium borohydrides by metathesis from solid sodium borohydride and quaternary ammonium salts and using them for the reduction reactions (14,15).

In situ synthesis of quaternary ammonium borohydrides.
Borohydride anion is phase transferred from an aqueous basic solution of sodium borohydride solution into non-polar solvent by an onium salt such as quaternary ammonium salts.
It has been reported in literature (16,17) that catalysts containing a b-hydroxyl group such as N-dodecyl-N-methylephedrinium bromide and N- methyl-N-dodecyl-N,N-bis-hydroxyethylammonium bromide appear to be more effective catalysts. The activating effect of the hydroxyl group is due to the electrophilic catalysis involving a hydrogen bond from hydroxyl to carbonyl group (Refer Part II). Many ketones and aldehydes are reduced quantitatively by this procedure (Table III) (14).

Table III - Reduction of carbonyl compounds by in situ generation of quaternary ammonium borohydrides :

Carbonyl compound Reaction temperature [°C] Reaction time [h] Yield [%]
C6H5CHO 0 0.1 95
4-Cl-C6H5-CHO 0 0.2 94
i-C3H7COC3H7-i 25 7 86
n-C6H13COCH3 25 0.5 100
C6H5COCH3 25 1 97
C6H5COC2H5 25 2 100
4-t-butylcyclohexanone 25 0.1 100
C6H5COC6H5 25 1 100
C6H5CH2COCH2C6H5 25 0.5 100

06-15-03 22:51
No 440193
      Excellent Boro info I page 5
(Rated as: Excellent)

Part V

2-Octanone is reduced by aqueous sodium borohydride, yielding 80% of 2-octanol in 6.5 h, at room temperature in benzene solution using tricaprylmethylammonium chloride.
With N-dodecyl-N-methylephedrinium bromide 100% conversion of 2-octanone is obtained in 0.5 h at room temperature whereas the more lipophilic dicyclohexyl-18-crown-6 in boiling benzene solution gave 92% yield in 2.5 h (17).
Phase transfer catalysts such as 18-crown-6 and dibenzo-18-crown-6 catalyzed sodium borohydride reduction of several ketones in boiling toluene solvent. By this method, acetophenone, cyclohexanone and 2-heptanone are reduced in 49%, 50% and 41% yield respectively( 18).

1. Sreela Sengupta et al; Indian Journal of Chemistry 33B 285 (1994)
2. Atsushi Abiko and Satoru Masamune; Tetrahedron Letters 33 5517 (1992)
3. H.T. Williams et al; Tetrahedron Letters 23 3337 (1982)
4. Sadatoshi Akabon et al; J. Chem. Soc. Perkin Trans 1 3121 (1991)
5. Jean-Louis Luche, J. Am. Chem. Soc. 100 7 (1978)
6. Shinichi Itsuno, Yoshiki Sakurai and Koichi Ito; Synthesis 995 (1998)
7. J.V. Bhaskarkanth and M. Periasamy; J. Org. Chem. 56 5964 (1991)
8. T.E.A. Nieminan and T.A. Hase; Tetrahedron Letters 28 4725 (1987)
9. C.F. Nutaltin; J. Chem. Ed. 66 No.8 (1989)
10. H.C. Brown, E.J. Mead and C.J. Shoaf; J. Am. Chem. Soc. 78 3616 (1956)
11. Ullman; Encyclopedia of Chemical Technology
12. R.O. Hutchim and D. Kandasamy; J. Am. Chem. Soc. 95 6131 (1973)
13. R. O. Hutchim and M. Markowitz; J. Org. Chem. 46 3574 (1981)
14. T.N. Sorrell and P.S. Pearlman; Tetrahedron Letters 21 3963 (1980)
15. R.W. Bragdon, M.D. Banus and T.R.P. Gibb Jr.; J. Am. Chem. Soc. 74 2346 (1952)
16. S. Colonna and R. Fornasier; Synthesis 53 (1975)
17. M. Cinquini, F. Montanari and P. Tundo; J. C.S. Chem. Commun. 393 (1975)
18. T. Matsuda and K. Koida; Bull. Chem. Soc. Jap. 46 2259 (1973)

There are really interesting combinations in that table II.

Please let someone post those references nr's 14 and 15 !!!!

And when your at it, get references nr's 6-8-10-11-12 and 13 also, you definitely will collect a bunch of karma, smile LT/

PS: and a real nosy researcher gets ofcourse ALL of them.

(Chief Bee)
06-16-03 13:43
No 440281
      Preparation of Quaternary Ammonium Borohydrides  Bookmark   

Ref #15:
Preparation of Quaternary Ammonium Borohydrides from Sodium and Lithium Borohydrides
J. Am. Chem. Soc.; 1952; 74(9); 2346-2348. (../rhodium/pdf /quaternary.ammonium.borohydrides.pdf)
(Hive Addict)
06-16-03 21:51
No 440349
      JACS 74(9), 2346-2348 (1952)
(Rated as: excellent)

Hey LT, there's one ASCII'd for you- Do you want the others Rhodiums posted to be ASCII'd?

Preparation of Quaternary Ammonium Borohydrides from Sodium and Lithium Borohydride

JACS, (1952), 74(9), 2346-2348.

By M. Douglas Banus, Robert W. Bragdon, and Thomas R.P. Gibb Jr.1


The metathetical preparation of a new type of borohydride containing a quaternary ammonium cation is described.  Tetramethyl, tetraethyl, and benzyltrimethyl ammonium borohydrides have been prepared by metathetical reactions from sodium borohydride and lithium borohydride.  (Several properties thereof are described.)

The metathetical reaction of alkali metal borohydrides with unsubstituted or partially substituted ammonium salts might be expected to yield ammonium borohydrides.  This reaction, however, evidently gives other products, the nature of which leads in some cases to the supposition that while an ammonium borohydride may be formed momentarily, it decomposes almost immediately.  Thus, ethereal lithium borohydride reacts with ammonium chloride2 and with mono-, di-, and tri-methylammonium chlorides3 according to the over-all equations.

NH4Cl + LiBH4 to NBH4 + LiCl + H2
3CH3NH3Cl + 3LiBH4 to B3N3H3(CH3)3 + 3LiCl + 9H2
(CH3)2NH2Cl + LiBH4 to (CH3)2NBH2 + LiCl + 2H2
(CH3)3NHCl + LiBH4 to (CH3)3N:BH3 + LiCl + H2

The instability of the unsubstituted or partially substituted ammonium borohydrides is due in part to the presence of a hydrogen atom on the nitrogen4 and in part to the weakly basic character of the cation.  Thus, the borohydrides of the more strongly basic alkali metals are far more stable both thermally and toward hydrolysis.  Accordingly, it may be expected that a borohydride having a quaternary ammonium cation, will be more stable than a borohydride having, say, a dimethylammonium cation.  Unfortunately, most quaternary ammonium salts are insoluble in non-aqueous, non-hydroxylic solvents such as ether; and in fact, show appreciable solubility only in a very few highly polar solvents, especially water.  Therefore, it is not feasible to attempt metathetical reaction under the conditions employed previously in the case of partly substituted ammonium compounds.  Moreover, the reactivity of the metal borohydride with water has militated against the use of this medium for preparation of new borohydrides.  However, we have shown that aqueous phase metathesis constitutes an excellent method for the preparation of the quaternary ammonium borohydrides and that hydrolytic losses are less than anticipated.

Aqueous Metathesis with Sodium Borohydride

Aqueous phase reactions were carried out in accordance with the general equation:
R4NX + NaBH4 to R4NBH4 + NaX

Here, X represents hydroxide, halide, phosphate, carbonate, acetate or oxalate.  Both water and dilute ethyl alcohol were employed as solvents and the vacuum dried reaction products were washed with water or 95% ethyl alcohol. 

For tetramethylammonium borohydride, the best procedure was found to be a metathesis involving the quaternary hydroxide, since the resulting dried mixture of borohydride and sodium hydroxide could then be leached with 95% ethanol in which the latter is quite soluble and the former is almost insoluble.  Moreover, sodium borohydride reacts more rapidly with ethyl alcohol than with water and (if present in the reaction product) would thus be removed.  High yields of 99+ % tetramethylammonium borohydride were obtained in this manner.  The tetraethyl compound is more soluble in 95% ethyl alcohol and is also more susceptible to hydrolysis.  Thus it was obtained in variable but considerably poorer yields. 

Similar metathesis employing tetramethylammonium chloride and bromide were successful, but as expected from the solubilites of the four solids involved, none of the reactions gave more than 70-90% yields.  Tetramethylammonium chloride in 95% ethanol gave a crude product containing 76% of the expected quaternary borohydride with evident reaction of the sodium borohydride with the solvent.  Aqueous metathesis of the quaternary fluoride and phosphate appear preferable to those of the chloride or bromide on the basis of the lower solubility of sodium fluoride and triphosphate. ( The latter metathesis is successful only at 0*C)  Neither acetate nor oxalate metathesis offers any apparent advantages.

Aqueous Metathesis with Lithium Borohydride

Although lithium borohydride ordinarily reacts violently with water, it was discovered that if the pure compound is introduced anaerobically at or below 0*C, a solution results with but minor loss of activity.  Air-free distilled water is employed.  The resulting solution is sufficiently stable to permit its use over a period of hours.

The insolubility of lithium fluoride and phosphate permits almost quantitative reaction of the respective quaternary ammonium salts with lithium borohydride.  Of the two metatheses, that employing the fluoride gave better yields in the case of benzyltrimethylammonium borohydride and quantitative yields of tetramethyl- and tetraethylammonium borohydrides.  Various mixtures of lower amines, alcohols, and water were investigated in a rather cursory manner and appear to offer no advantages over water.  Those solvents in which lithium borohydride is soluble, e.g., lower ethers and amines, do not dissolve quaternary ammonium salts.  Aqueous amines are apparently no better than water (90% isopropylamine 10% water dissolves only 0.27g/100g of tetramethylammonium borohydride); aqueous cyclic ethers were not investigated nor were secondary or tertiary alcohols.


The three borohydrides prepared are stable hygroscopic microcrystalline solids comparable to sodium borohydride and lithium borohydride.  They burn quietly but rapidly on ignition, leaving a slight ash.  They are not ignited by friction nor by moistening with water or ethyl alcohol.  Spontaneous ignition by pouring or handling in humid air has not been observed although the tetramethyl- and benzyltrimethyl compounds deteriorate very rapidly when so handled.  The materials keep well in an ordinary screw-top bottle, however.  The densities at 25*C of the tetramethyl-, tetraethyl-, and benzyltrimethyl-  compounds are respectively, 0.813, 0.927, 0.638g/cc., all measured by helium displacement.

All three compounds are soluble in water with reaction and they react with methanol.  The tetramethyl compound has the solubilities shown in Table 1 and is insoluble in diethyl ether, isopropylamine, pyridine, chloroform, dioxane, THF, ethyl cellosolve, N-methylmorpholine.  The rate of reaction with water at RT follows approximately the increasing sequence: tetramethyl-, benzyltrimethyl-, tetraethylammonium borohydride, although the pH and presence of trace impurities such as heavy metal ions have profound effect.  The tetramethyl compound is less reactive toward water than sodium borohydride and the tetraethyl compound is considerably less reactive than lithium borohydride.  Hydrolysis yields four mols of hydrogen per mol of borohydride and is presumed to proceed according to the reaction equation:

R4NBH4 + 2H2O to (R)4NBO2 + 4H2

(The resulting quaternary ammonium salt of a weak acid should be capable of further hydrolysis to yield the labile hydroxide which decomposes in boiling water to give volatile ROH and R3N compounds)  The rate of hydrolysis of tetramethylammonium borohydride (5.8M) in water @ 40*C is nearly constant over a period of 100 hours at 0.04% of original weight per hour based on the above equation.  This rate is decreased to 0.02% per hour by the presence of (CH3)4NOH in the amount of 5% of the weight of borohydride.

Solid tetramethylammonium borohydride decomposes slowly in vacuo at 150*C, rapidly at 250*C yielding principally trimethylamineborine and methane.  It does not ignite spontaneously in air at this temperature, but volatilizes leaving no residue.  In an evacuated sealed glass bulb, it decomposes at the average rate of 0.095%/hour @ 150*C, 4.1% @ 175*C, 33.3%@195*C and 41.6%edited from 4.16%
Per minute @ 225*C.  The natural log rate of decomposition is evidently inversely proportional to the reciprocal of the absolute temperature over this range.  At 220-225*C, the trimethylamineborine rapidly sublimes away from the borohydride in the form of pure, acicular crystals (96% yield).  Hydrogen and trimethylamine (4% yield) were observed as decomposition products, indicating two possible courses for the reaction.  The small amount of pure white non-volatile residue (2% of original weight) contained sodium, carbon, hydrogen and nitrogen and presumably boron and oxygen, which could not be determined.  It is thought consist of NaBO2, NaBH4 and possibly polymeric substances.


Commercial sodium and lithium borohydrides were purified by extraction with water and isopropylamine5 and diethyl ether, respectively, to yield products approaching 100% purity as measured by hydrogen evolved from acidified water.  Tetramethyl- and tetraethylammonium chloride, bromide and iodide and hydroxide were obtained from Eastman Kodak Co. and the Paragon Division of the Matheson Co.  Benzyltrimethylammonium chloride was provided by the Commercial Solvents Co.  All were used as received.  (Exposure of the hydroxides to air was kept to a minimum)  The quaternary salts other than those cited above were made by metathesis of by neutralization of the base by the desired acid to the appropriate end-point.  Benzyltrimethylammonium hydroxide was prepared from the aqueous chloride via solid silver oxide.  (it was necessary to stir under an inert atmosphere for four days.)  A preferable method for preparing fluorides from the chlorides or bromides was used subsequently and involved the aqueous reaction with soluble silver fluoride prepared by dissolving silver oxide in dilute HF to a pH of from 6-7.  The quaternary chloride or bromide is added to the solution of silver fluoride until a trace of chloride ion is detected.  After a brief boiling to coagulate the precipitated silver chloride or bromide, the solution is filtered and evaporated.  The crystalline compound (CH3)4NF-2H2O is obtained by evaporation at 80*C.  It is extremely hygroscopic.  Tetramethylammonium carbonate was prepared by saturating the aqueous hydroxide with CO2 to a phenolphthalein end-point and subsequently adding an equal amount of the hydroxide to convert the bicarbonate to carbonate.  The acetates were prepared from the iodides and silver acetate in preference to neutralization of the hydroxide.

Preparation of Tetramethylammonium Borohydride:

Solid sodium borohydride 8.5g (0.22mol) was added to 20g of (CH3)4NOH (0.22mol) dissolved in 90g of water, the mixture giving an almost clear solution.  This was evaporated to dryness in vacuo and the white solid broken up in a dry-box under dry argon.  It was then extracted without precaution to exclude air with 90cc of 95% ethanol and filtered by suction without precaution to exclude air.  The filter cake was washed with two 50cc portions of cold 95% ethanol, the dried in vacuo for 18 hours at 70-80*C.  Yield of 18.5g (93%) of a white, microcystalline solid.  (a similar run in which the product was recrystallized three times from water without extraction with alcohol gave a 61% yield with a 94% purity)

An aqueous metathesis using the quat. Phosphate with filtration at 0-2*C of the precipitated Na2PO4 gave a 90% crude product containing less than 1% phosphate, the balance being borate.  A similar metathesis using the oxalate gavea  79% crude product containing 6.8% sodium oxalate and considerable borate.  Similarly, an acetate metathesis gave an 86% crude product  containing 12% NaBO2.  Metathesis based on the quat. Chloride, bromide and iodide with NaBH4 were shown by solubility considerations not to be feasible in water.  Use of aqueous isopropylamine and aqueous ethyl alcohol as media resulted in no substantial improvement. 

With Lithium Borohydride:

An aqueous solution containing 2.11g (0.97mol) of lithium borohydride was prepared by adding 50cc of distilled, degassed, ice-water to the hydride under argon.  The solution was promptly added to 8.92g of (CH3)4)NF (0.96mol) and stirred.  The precipitated LiF was removed on a sintered glass funnel and the clear filtrate evaporated in vacuo at RT.  The solid was taken up in the minimum amount of water, filtered, evaporated and finally dried 3 hours at 100*C in high vacuum.  Crude yield 98.5% with purity 95%.

Preparation based on metathesis involving the other cations cited were carried out in substantially the same manner using stoichiometric proportions. 

Aqueous phosphate metathesis with filtration of the precipitated Li3PO4 gave a crude product of 78% purity containing borate.  Aqueous carbonate metathesis with filtration of precipitated Li2CO3 gave a product of 89% purity containing 1.1% Li and significant amounts of borate.  Aqueous oxalate metathesis similarly gave a product of 72% purity. 

Preparation of Tetraethylammonium Bromide:

The preparation from the quat. hydroxide and sodium borohydride was complicated by the greater reaction of the product with water.  The preparation from the quat. fluoride and lithium borohydride was carried out exactly as described in the analogous case of the tetramethyl compound.  An 82% yield of the 95% purity product was obtained.

Preparation of Benzyltrimethylammonium Borohydride:

The only preparative method investigated was the aqueous reaction of the quat. fluoride with lithium borohydride.  Stoichiometric proportions of the reactants in water solution were mixed and evaporated to dryness in vacuo as in the case of the tetraethyl compound.  A crude yield of only 100% was obtained, but only 89% purity. (the final product had a slight yellow tinge)

Act quickly or not at all.
(Hive Addict)
06-16-03 21:52
No 440350
      More  Bookmark   


1.  Dept. of Chemistry, Tufts College, Medford, Massachusetts.

2.  H.I. Schlesinger and G.W. Schaffer, et. al. University of Chicago, Final Report, Navy Contract N6ori-20 T.O. 10 (1947-1948)

3.  G.W. Schlesinger and E.R. Anderson, THIS JOURNAL, 71, 2143 (1949)

4.  We are indebted to one of the referees for this observation and the comment that the case is analogous to the increasing ease of formation of N-dimethylaminoborine from trimethylamineborine and dimethylamineborine, respectively.

5.  W. D. Davis, L.S. Mason and G. Stegeman, THIS JOURNAL, 71, 2775 (1949)

Act quickly or not at all.
(Chief Bee)
06-17-03 01:28
No 440379
      Reference 2 & 14 + one related article  Bookmark   

Ref #2:
An Improved, Convenient Procedure for Reduction of Amino Acids to Aminoalcohols: Use of NaBH4-H2SO4
Tet. Lett.; 1992; 33(38); 5517-5518. (../rhodium/pdf /borohydride-h2so4.pdf)

Ref #14:
Selective Reduction of Aldehydes with In Situ Tetraethylammonium Borohydride
Tet. Lett.; 1980; 21; 3963-3964. (../rhodium/pdf /in.situ.et4n-bh4.pdf)

Reductions with Quaternary Ammonium Borohydrides
J. Org. Chem.; 1962; 27(10); 3731-3733. (../rhodium/pdf /reductions.quaternary.ammonium.borohydrides.pdf)

I have copied Ref #3, #4, #8 and #17 too, so they will soon be uploaded too.
(Chief Bee)
06-17-03 15:41
No 440523
      Ref #8 & #17 - NaBH4 with Crown Ethers or GAA  Bookmark   

Ref #8:
Selective Reduction of Ketones with Sodium Borohydride-Acetic Acid
Tetrahedron Letters 28(40), 4725-4728 (1987) (../rhodium/pdf /triacetoxyborohydride-ketones.pdf)

Ref #17:
Macrobicyclic Polyethers: Highly Efficient Catalysts In Two-Phase Reactions
J.C.S. Chem. Commun. 393 (1975) (../rhodium/pdf /
(Hive Addict)
06-17-03 23:27
No 440608
      Tetrahedron Lett. 21, 3963-3964 (1980) Ref # 14
(Rated as: excellent)

Selective reduction of aldehydes
Sorrell, Thomas N.; Pearlman, Paul S.  

Tetrahedron Lett.  (1980),  21(41),  3963-4.


Aldehydes were selectively reduced to alcs. in high yield on treatment with Et4N+ BH4- (I).  E.g., treatment of PhCHO with I (CH2Cl2, 25°, <25h) gave 89% PhCH2OH.  Ketones reacted much more slowly with <15% of the starting material being reduced.

During the course of our investigation on transition metal tetrahydroborate complexes as stoichiometric reducing agents,1-4 we recognized that, in organic solvents, the BH4- ion reacts preferentially with aldehydes.4  We report here on the reactions of tetraethylammonium borohydride.

Alkali metal borohydride compounds have gained wide use as reducing agents in organic synthesis, in contrast to their tetraalkylammonium analogues which have been known for almost 30 years.5  The tetramethyl derivative exhibits solubility and reactivity properties similar to those of the alkali metal borohydrides, and therefore offers no advantages as a synthetic reagent.  Cetyltrimethylammonium and tricaprylmethylammonium borohydrides6 reduce aldehydes and carboxylic acid chlorides in non-polar solvents to the corresponding alcohols, although they react with ketones only slowly, even at elevated temperatures.  In 1976, Raber7 reported the reduction of aldehydes and ketones by tetrabutylammonium borohydride in DCM using four equivalents of hydride in order to get convenient rates in the reduction of ketones.  No attempt was made in that work to cultivate the selectivity of the reagent.

Tetraethylammonium borohydride is commercially available8 as a stable, white crystalline solid.  It is considerably less soluble in non-polar solvents than the longer chain tetraalkylammonium derivatives and for that reason has received little attention as a reagent.  However, tetraethylammonium borohydride reduces aldehydes to the corresponding alcohols in DCM at 25*C within 20 hours (Eq. 1) , and the isolated yields are high. (Table).  Ketones react more slowly with the reagent under similar conditions, and less than 15% disappearance of the ketone is generally observed.9  Even unhindered ketones such as 4-t-butylcyclohexanone are relatively inert to this reagent, comparable with the best of other reagents that have been used for selective reduction of the aldehydes.10  Tetraethylammonium borohydride offers advantages over other reagents in that it is commercially available, and its use requires no special equipment or conditions.11,14

Equation 1:

R-CHO  (1)---Et4N+BH4-, DCM  (2)---H2O2, OH- to R-CH2OH

Table 1    
Starting Material Product Yielda(%)
benzaldehyde benzyl alcohol 89
p-chlorobenzaldehyde p-chlorobenzyl alcohol 87 (71-72*C)
p-nitrobenzaldehyde p-nitrobenzyl alcohol 88 (92-93.5*C)
p-anisaldehyde p-methoxybenzyl alcohol 53b
nonanal 1-nonanol 75
citronellal citronellol 77
furfural furfuryl alcohol 83
cyclohexanone cyclohexanol 10c (80)d
acetophenone alpha-hydroxyethylbenzene 13c (83)d
2-octanone Z-octanol 12c (83)d
4-s-butylcyclohexanone 4-t-butylcyclohexanol 12c

a) Yields are for isolated, distilled or recrystallized products (see ref. 12). MP are in [ ]
b) gc yield; 47% unreacted starting material after 24 hr.
c) Number refers to % disappearance of starting material determined by gc; product determined qualitatively by gc.
d) Yield of recovered starting material as its 2,4-DNP derivative.


1. T.N. Sorrell and R.J. Spillane, Tetrahedron Lett., 2473-2474 (1978).

2. T.N. Sorrell, Tetrahedron Lett., 4985-4986 (1978).

3. T.N. Sorrell and P.S. Pearlman, JOC, in press.

4. T.N. Sorrell and P.S. Pearlman, submitted to JOC

5. M.D. Banus, R.W. Bragdon, T.R.P. Gibb, Jr., JACS, 74, 2346-2348 (1952).

6. E.A. Sullivan, and A.A. Hinckley, JOC, 27, 3731-3733, (1962).

7. D.J. Raber and W. C. Guida, JOC, 41, 690-696, (1976).

8. The reagent was purchased from Alfa Products, Thiokol/Ventron Division, Danvers, Mass.

9. A DCM solution of nonanal and 2-octanone treated with 0.25eq. of Et4NBH4 (1 eq. of hydride ion) for 20 hours at 25*C showed 94% reduction of nonanal and 6% loss of 2-octanone.
10. G.H. Posner, A.W. Runquist, M.J. Chapdelaine, JOC, 42, 1202-1208, (1977).

11. The preparation of furfuryl alcohol is representative. To a stirred solution of 0.97 g of furfural in 3 mL of methylene chloride was added, in one portion, 20 mL of 0.15 M Et4NBH4 in dichloromethane. After 20 hr, 20 mL of 3% hydrogen peroxide was added to the reaction mixture followed by 10 mL of 10% NaOH. This mixture was stirred for 2 hr, the layers separated, the aqueous layer extracted with three 30-mL portions of methylene chloride, and the combined organic layers washed with saturated sodium sulfite.
The organic layer was dried over MgSO4, filtered, and the solvent was evaporated. The crude furfuryl alcohol was purified by bulb-to-bulb distillation at reduced pressure to give 0.829 (83%)of product, 95% pure by gc (see references 12 and 13).

12. All isolated compounds were at least 95% pure by gc and nmr.

13. Solid alcohols obtained as crystalline products after evaporation of the solvent were greater than 90% pure and were further purified by recrystallization.

14. In alcoholic or aqueous solvents, the reactivity of tetraethylammonium borohydride is similar to the alkali metal borohydride reagents.

Yeah!! I can use tables!!! Yay me!

Act quickly or not at all.
(Active Asperger Archivist)
06-18-03 05:40
No 440652
      Tetrahedron Lett. (1992) 33,38,5517-5518 Ref #2
(Rated as: excellent)

An Improved, Convenient Procedure for Reduction of Aminoacids to Aminoalcohols: Use of the Sodium Borohydride-Sulfuric Acid System.

Atsushi Abiko* and Satoru Masamune

Tetrahedron Letters, Vol 33, No. 38, pp. 5517-5518. (1992)


The use of sodium borohydride and sulfuric acid for the reduction of alpha-amino acids to the corresponding aminoalcohols offers definitive advantages: 1. operational simplicity, 2. ease of scaling up the reaction without risking explosion, and 3. use of the inexpensive reagents.

During the course of our recent studies of bisoxazoline chemistry1 we needed to develop a convenient and reliable procedure for the mole-scale synthesis of alpha, beta-aminoalcohols from the corresponding alpha-aminoacids.  Although there exist several methods,2 including those described in Organic Syntheses2a,b, (and also some aminoalcohols are commercially available,) these methods require the use of rather expensive reagents (e.g., LiBH4, BH3-SMe2) and/or careful control of reaction conditions to minimize the risk of explosion that may occur after the induction period.  We recommend herein the use of the two inexpensive reagents, NaBH4, and H2SO4, as exemplified by the reduction of D-phenylglycine.


To a stirred suspension of NaBH4 (100g, 2.5mol) in THF (1L, reagent grade w/o further purification) was added D-phenylglycine (151g, 1.0mol).  The flask was immersed in an ice-water bath, and a solution of (fresh) conc. H2SO4 (66ml, 1.25mol) in ether (total volume of 200ml) was added dropwise at such a rate as to maintain the reaction mixture below 20*C (addition time, approximately 3 hours).  Stirring of the reaction mixture was continued at RT overnight and MeOH (100ml) was added carefully to destroy excess BH3.  The mixture was concentrated to ca. 500ml and 5N NaOH (1L) was added.  After removing the solvent that distilled below 100*C, the mixture was heated at reflux for 3 hours.  The turbid aqueous mixture was cooled and filtered through a thin pad of Celite which was washed with water.  The filtrate and the washings were combined and diluted with additional water to ca. 1L. The DCM extraction (4x500ml) followed by evaporation of the solvent left solid phenylglycinol, which was recrystallized from ethyl acetate and hexane to yield 115g (84% including the second crop) of the pure product (MP: 74-76*C, >98% ee by analysis of the 1H NMR of the bis-MTPA derivative.)

The application of this system procedure to other amino-acids is summarized in Table 1.  Protected amino acids were also reduced; alanine benzamide was reduced to N-benzylalaninol, while the N-Cbz and N-tosyl groups remained unaffected.
Table I: Reduction of Amino acids and Their Derivatives with Borohydride/Sulfuric Acid
Amino Acid Yield of Aminoalcohol (%) MP (bp*C/mmHg) Amino Acid Yield of Aminoalcohol (%) MP (bp*C/mmHg)
L-Val. 89 (100/26) D-PhGly. 84 74-76
L-Met. 91 (133-136/8) Bz.Ala. 80(N-Bn-alaninol) (100/0.2)
L-Phe. 98 90-91 Ts-Ala. 91(N-Ts-alaninol) 58-60
L-tert-Leu. 81 (100-102/18) Z-Pro. 91(N-Cbz-Prolinol) ---

Table II : Reduction of L-Valine to L-Valinol with Borohydride-Reagent
Reagent Reaction Temp (*C) Yield of Valinol (%) Reagent Reaction Temp (*C) Yield of Valinol (%)
HCl 0 88 Me2SO4 40 83
BF3-OEt2 25 76 MeOTs 40 83
I2 0 83 MeSO3H 0 56
MeI 40 82      

The reduction of the carboxyl group was obviously effected by diborane generated in situ.  Therefore, sulfuric acid can be replaced by other reagents such as HCl3a, BF3-OEt23a, I23b, MeI3c, Me2SO43c, MeOTs3c, and MeSO3H3d as shown in Table II.  Although, the yields of valinol from valine are comparible with that shown in Table I, the borohydride-sulfuric acid system offers the definitive advantages: 1. the reduction can be scaled up w/o risking explosion, 2. sodium borohydride and sulfuric acid are inexpensive, and 3. the execution of the reduction is simple, and even the rigorous drying of the solvent is unnecessary.


1.a. Lowenthal, R.E.; Abiko, A.; Masamune, S. Tetrahedron Lett. (1990), 31, 6005.
b. Lowenthal, R.E.; Masamune, S. Tetrahedron Lett., (1991), 32, 7373.
2.a. Dickman, D.A.; Meyers, A.I.; Smith, G.A.; Gawley, R.E. Org. Synth. Coll. Vol., VII, 530.
b. Gage, J.R.; Evans, D.A. Org. Synth., (1990), 68, 77.
c. Pridgen, L.N.; Prol, Jr. J.; Alexander, B.; Gillyard, L. JOC, (1989), 54, 3231.
d. Giannis, A.; Sandhoff, K. Agnew. Chem., Int. Ed. Engl., (1989), 28, 218.
3.a. Zweifel, G.; Brown, H.C. Org. Reactions, (1963), 13, 1.
b. Freeguard, G.F.; Long, L.H. Chem. Ind., (1965), 471.
c. Bell, H.M.; Vanderslice, C.W.; Spehar, A. JOC, (1969), 34, 3923.
d. Iami, T.; Tamura, T.; Yamamuro, A.; Sato, T.; Wollmann, T.A.; Kennedy, R.M.; Masamune, S. JACS, (1986), 108, 7402.

Act quickly or not at all.
(Active Asperger Archivist)
06-18-03 07:02
No 440672
      Tetrahedron Lett. (1987) 28,40,4725-28 Ref # 8
(Rated as: excellent)

Selective Reduction of Ketones with Sodium Borohydride – Acetic Acid

Tuula, E.A., Nieminen and Tapio, A. Hase.

Tetrahedron Letters, Vol 28, No. 40, pp 4725-4728, (1987).


Aliphatic ketones, and aromatic ketones having o-hydroxy, or o-amino substituents are reduced rapidly to the alcohols by sodium borohydride and acetic acid; other types of ketones react much more slowly.

Sodium borohydride reacts with glacial acetic acid to form acetoxyborohydrides.1-3 Presumably, adjusting the stoichiometry will determine the number of acetoxy groups but all acetoxyborohydrides have by no means been fully characterized.

Mono-, Di-, and triacetoxyborohydrides are apparently formed rapidly even at RT, while the last hydride is released very slowly. 2,4 NaBH(OAc)34,  and NaBH3(OAc)5,6 have been isolated and their IR spectra measured, and the first-mentioned has quite recently become commercially available.7  Some chiral amine mono-, di- and triacyloxyborohydride complexes have also been isolated and analyzed with IR, NMR and MS.3

NaBH4 in the presence of excess of acetic acid has been used for reductions of enamines, imines, vinylogous carbamates, aromatic and aliphatic alpha, beta- unsaturated tosylhydrazones, pyrylium salts9, for reduction of reductive N-alkylation of amines, oximes,10 and nitrogen containing heterocycles.2  Various reactions have also been run in non-polar solvents (e.g. THF) using one or three moles equivalents of acetic acid relative to NaBH4.  Reactions corresponding to the use of the diacetoxyborohydride have not been reported.  One equivalent of HOAc (i.e. the monoacetoxyborohydride) has been used for hydroboration of alkenes and for reduction of amides and carbamates.2  Three mole equivalents [i.e., triacetoxyborohydride] have been used for reduction of cyclic imines and aldehydes in the presence of ketones.2

Aldehydes and especially ketones are reduced more slowly to alcohols with sodium borohydride in glacial acetic acid than in alcoholic solutions.  Aromatic ketones such as acetophenone and benzophenone are not reduced completely with borohydride in acetic acid.  Chemoselective reduction of aldehydes in the presence of ketones using the triacetoxyborohydride is therefore feasible.2  An amino group alpha to carbonyl has also proved advantageous in reduction with sodium borohydride in acetic acid,11 1 being reduced in good yield:

Some diastereoselective reductions of beta-hydroxyketones have been reported with the borohydride/acetic acid system.12-14  Cyclic imines have been reduced with chiral sodium acyloxyborohydrides to optically active amines in 55-60% yield.8  Very recently, aliphatic beta-ketols were shown to be reduced selectively to the anti- diols with tetramethylammonium triacetoxyborohydride.15

We now wish to report a new type of selective reduction of ketones to the corresponding alcohols using sodium borohydride in glacial acetic acid solvent, or sodium borohydride in THF in the presence of a stoichiometric amount of acetic acid.

Reductions in Glacial Acetic Acid:

General Procedure:

310mg of sodium borohydride (8.2mmol) is added slowly with cooling to the ketone (2.5mmol) in 10ml of glacial acetic acid, the reaction temperature being maintained at 16-21*C.  After ten minutes the reduction is interrupted by adding 10ml of water, the mixture neutralized with aqueous NaHCO3 and the reaction product isolated by extraction with ether, drying and evaporation, and identification by the usual methods.

Aldehydes such as vanillin and aliphatic ketones such cyclohexanone are reduced rapidly and completely with sodium borohydride in HOAc at RT, whereas arylalkylketones such as acetophenone react much more slowly.  Diarylketones such as benzophenone are not reduced at all even with extended reaction times. 

Table I:  Reduction of Substituted Acetophenones

X Y Conversion (%) by NMR
H H 23
OH H 100
NMe2 H 100
NH2 H 88
OMe H 18
Br H 18
H OH 12
H NMe2 12
H NH2 23
H Br 20
m-NH2   36
3,5,-dihydroxy   0

As seen in Table I, acetophenone is reduced with this system to the corresponding alcohol with only 23% conversion, and in 24 hours not more than 60% of acetophenone was reduced.  Butyrophenone is essentially stable towards sodium borohydride in acetic acid.  However, aralkylketones carrying a hydroxy group in the ortho-position undergo a rapid and complete reduction.  Similarly, o-(N,N-dimethylamino)-acetophenone was cleanly and rapidly reduced to the corresponding alcohol.  o-Aminoacetophenone was reduced in 80% conversion in ten minutes with this system.  Further reduction of the remaining ketone was inefficient and only caused the appearance of numerous by-products.

Reductions in THF using Stoichiometric Amounts of Acetic Acid

Reducing o-Aminobenzophenone with the sodium borohydride in acetic acid gave considerable amounts of by-products in addition to the expected alcohol.  However, reduction with sodium borohydride in THF in the presence of two equivalents of acetic acid proceeds smoothly to give the alcohol in essentially quantitative yields (Table II).  Similarly, o-hydroxybenzophenone is readily reduced whereas other o-substituents are less effective or do not promote the reaction at all.

General Procedure:

Acetic acid (18mmol) is added slowly with cooling to sodium borohydride (9 mmol) in 10 ml of THF.  After the evolution of hydrogen has ceased the ketone (45mmol) is added at RT.  After complete disappearance (TLC) of the starting material the reaction is worked up as before.

Table II: Reduction of o-Substituted Benzophenones
Z Time for Complete Reduction
H 60hours
OH 5minutes
NH2 1 hour
NHMe 3 hours
OMe 30 hours

In summary, we have shown that aralkyl or diaryl ketones carrying o-hydroxy or o-amino substituents can be rapidly reduced to the alcohols using one of the sodium borohydride/acetic acid reagent systems.  Other o-substituted ketones, or ketones having hydroxy or amino functions elsewhere in the ring are relatively stable towards reduction.  It is possible that the hydroxyketones react by first forming a borate ester, facilitating the delivery of a hydride ion via a six-membered transition state.  This is in keeping with the failure of ortho-halo or alkoxy groups to promote the reaction, or of hydroxy groups at sites other than ortho.  Amino groups apparently react via the nitrogen lone electron pair to form a N-B coordination complex, again furnishing favorable geometry for the delivery of a hydride ion.

Regarding the identity of the reducing species in our reactions, we only have circumstantial evidence to suggest that in acetic acid solvent, the reducing agents are the mono- and diacetoxyborohydride reagents.  As for the reductions in THF using the 1:2 sodium borohydride : acetic acid reagent combination, we assume that the reducing species in the one that corresponds to this stoichiometry, namely the diacetoxyborohydride.  These arguments are supported by the data shown in Table III, showing that reductions using the triacetoxyborohydride proceed much more slowly than the same reductions with mono- or diacetoxyborohydride.  Especially reduction of o-aminobenzophenone or the parent  acetophenone is practically at standstill in THF using the 1:3 reagent ratio which corresponds to the triacetoxyborohydride, known to be ineffective in reductions of aromatic ketones.

Table III: The Effect of Stoichiometry on the Reduction of Ketones in THF
Ketone Ratio of Borohydride to Acetic Acid Time for complete Reduction
o-Aminobenzophenone 1:1 or 2; 1:3 1hour; 12 days
o-Hydroxyacetophenone 1:2 ; 1:3 2 minutes ; 10-15 minutes
Acetophenone 1:1 or 2 ; 1:3 1.5 hours ; <10% reduction in 2 days


1. G.W. Gribble, Eastman Org. Chem. Bull, 51, (1979), 1.

2. G.W. Gribble, and C.F. Nutaitis, Org. Prep. Preced. Int., 17, (1985), 317.

3. B.T. Cho, Synth. Commun., 15, (1985), 917.

4. P. Marchini, G.Liso, and A. Reho, JOC 40, (1975), 3453.

5. T. Reetz, JACS, 82, (1960), 5039.

6. P.G. Egan, and K.W. Morse, Polyhedron, 1, (1982), 299.

7. Aldrich Chemical Co., 31, 639-3.

8. K. Yamada, M. Takeda, and T. Iwakuma, J.Chem. Soc. Perkin Trans., 1, (1983), 265.

9. T-S. Balaban, and A.T. Balaban, Tetrahedron Lett., 28, (1987), 1341.

10. G.W. Gribble, Ventron Alembic, No. 8, (1977).

11. Finn. Pat. 61474 (1982)

12. A.K. Saksena, and P. Mangiaracina, Tetrahedron Lett., 24, (1983), 273.

13. M.D. Turnbull, G. Hatter and D.E. Ledgerwood, Tetrahedron Lett., 25, (1984), 5449.

14. D.A. Evans, and M. DiMare, JACS, 108, (1986), 2476.

15. D.A. Evans, and K.T. Chapman, Tetrahedron Lett., 27, (1986), 5939.

Act quickly or not at all.
(Active Asperger Archivist)
06-18-03 09:18
No 440729
      J.Chem.Soc.Chem.Commun 393 (1975) Ref #17
(Rated as: excellent)

Alkyl Substituted Aza-macrobicyclic Polyethers: Highly Efficient Catalysts in Two-phase Reactions

Mauro Cinquini and Fernando Montanari and Pietro Tundo

J. Chem. Soc. Chem. Commun.  393, (1975)


Alkyl substituted aza-macrobicyclic polyethers are highly efficient catalysts in anion promoted two-phase reactions, such as nucleophilic substitutions, C-alkylations, cyclopropanations, and borohydride reductions.

Large organic cations derived from elements of groups V or VI are normally used as catalysts in phase-transfer reaction.1  A similar catalytic activity has been found for crown ethers.2,3 especially for those having a high organophilic character.2  Other factors being equal, the reactivity of the anion must increase with the distance from the cation within the ion pair.

Aza-macrobicyclic polyethers, which are able completely to surround the cation, are powerful anionic activators.4  We have found that these systems are highly efficient catalysts in aqueous, organic two-phase reactions, provided that alkyl chains confer a sufficient organophilicity to the molecule.

Compounds (Ia) and (Ib) were prepared by condensation of diaza-18-crown-6 (II) with the chlorides of acids (IIIa) and (IIIb) respectively, followed by reduction with diborane of the resulting cyclic diamide.*

The catalytic activity of (Ia) and (Ib) has been tested for some classical nucleophilic substitutions, as well as for alkylation at carbon, cyclopropanation, and borohydride reduction, and compared with that of hexadecyltributylphosphonium bromide.(IV)1 and of perhydrodibenzo-18-crown-6 (V)2 (see Table).  The catalytic activities of (Ia) and (Ib) are of the same order of magnitude, and in most of the cases examined, are of higher catalytic activity than that of the phosphonium salt (IV) and much higher than that of the crown ether (V).

Catalytic activity depends, however, on the nature of the reaction; being particularly high in Br-I and Cl-I substitutions, in the reduction with BH4-, and in alkylation, and comparible to to that of the phosphonium salt (IV) in Cl-CN and OSO2Me-F substitutions.  Cyclopropanation is much slower than the other reactions examined and seems to be less sensitive to the nature of the catalyst.**

The simple aza-macrobicyclic polyether (Ic) still shows some catalytic activity, which is much lower than that of (Ia) and (Ib), apparently because of its great solubility in water coupled with a low solubility in organic solvents.

Table I

Substratea Reagent Catalystg T/*C Time/hr Yield/%1 Productk
n-C8H17Br KIb (Ia) 60 0.2 100 n-C8H17I
” ” (Ib) 60 0.5 92 ”
” ” (Ic) 60 14 90 ”
” ” (IV) 60 1 93 ”
” ” (V)h 80 3 100 ”
n-C8H17Cl ” (Ia) 80 5 77 ”
” ” (Ib) 80 4 85 ”
” ” (IV) 80 24 80 ”
” KCNb (Ia) 80 5 93 n-C8H17CN
” ” (IV) 80 5 94 ”
n-C8H17OSO2Me KFb (Ib)1 120 4 85 n-C8H17F
” ” (IV)1 120 2 94 ”
n-C8H17Br PhSNac (Ia) 20 0.1 100 n-C8H17SPh
” ” (IV) 20 0.1 100 ”
n-C6H13CH(Br)Me KIb (Ia) 80 3 86 n-C6H13CH(I)Me
” ” (IV) 80 6 89 ”
PhCH2COMe BunBrd (Ia) 20 0.75 94 PhCH(Bun)COMe
” ” (IV) 20 2.5 90 ”
” ” (V)h 80 1.5 93 ”
n-C6H13COMe NaBH4e (Ia) 20 4 97 n-C6H13CH(OH)Me
” ” (IV) 20 6 78 ”
” ” (V)h 80 2.5 92 ”
Styrene NaOHf, CHCl3 (Ia) 20 24 60 1,1-dibromo-2-phenylethane

aBenzene was used as solvent in the borohydride reduction, otherwise no solvent was used for the substrate; the reactions were carried out with saturated aqueous solution of the reagent. 
b5 Mol equiv.
c1 Mol equiv.
d1.2 Mol equiv. in 50% aq. NaOH
e1.5 Mol equiv.
f2.5 Mol equiv.
g0.05 Mol equiv.
hFrom Ref. 2.
i0.1 Mol equiv.
jBy G.L.C.  analysis
kThe products were characterized by G.L.C. retention time and by comparison (IR and H NMR spectra) with authentic samples

*Compounds (Ia) and (Ib) were isolated as NaBF4 complexes, MP: 91.5-92.5*C and 94.5-95.5*C respectively and used as such.
**In the case of crown ethers it was found5 that cyclopropanation is probably favoured by the aromatic rings in the catalyst.


1. C.M. Starks, JACS, (1971), 93, 195;
J. Dockx, Synthesis, (1973), 441;
E.V. Dehmlow, Agnew. Chem. Internat. Edn. , (1974), 13, 170

2. D. Landini, F. Montanari, and F. M. Pirisi, J.C.S.Chem. Commun., (1974), 879

3. M. Makosza and M. Ludwikow, Agnew. Chem. Internat. Edn., (1974) 13, 665.

4. B. Dietrich, J.M. Lehn, J.P. Sauvage, and J. Blanzat, Tetrahedron, (1973), 29, 1629.
B. Dietrich and J.M. Lehn, Tetrahedron Lett., (1973), 1225.

5. D. Landini, A.M. Maia, F. Montanari, and F.M. Pirisi, Gazzetta, In the press.

Act quickly or not at all.
(Chief Bee)
06-18-03 12:48
No 440779
      Ref #3 - Tetraalkylammonium Octahydrotriborate(I)  Bookmark   

Ref #3:
Polynyclear Borane Anions as Mild Reducing Agents 1. The Octahydrotriborate(I) Anion
Tetrahedron Letters 23 3337-3340 (1982) (../rhodium/pdf /octahydrotriborate.pdf)

(No need to type this one, Aurelius, I suppose this is a too exotic reagent for most bees...)
(Chief Bee)
06-20-03 22:34
No 441387
      Ref #5, #7, #12, and #13 (retrieved by GC_MS)  Bookmark   

Ref #5:
Lanthanides in organic chemistry 1. Selective 1,2-reductions of conjugated ketones
J Am Chem Soc 100(7), 2226 (1978) (../rhodium/pdf /nabh4-lncl3.pdf)

Ref #7:
Selective reduction of carboxylic acids into alcohols using NaBH4 and I2
J Org Chem 56, 5964 (1991) (../rhodium/pdf /borohydrideiodine.pdf)

Ref #12:
Tetrabutylammonium cyanoborohydride - a new, exceptionally selective reducing agent
J Am Chem Soc 95(18), 6132 (1973) (../rhodium/pdf /bu4nbh3cn.pdf)

Ref #13:
Tetraalkylammonium trihydridocyanoborates. Versatile, selective reagents for reductive aminations in nonpolar media
J Org Chem 46, 3571 (1981) (../rhodium/pdf /r4nbh3cn.pdf)
(Active Asperger Archivist)
07-11-03 18:48
No 446432
      Quat Ammonium borohydrides JOC (1962) 27(10) 3731
(Rated as: excellent)

Reductions with Quaternary Ammonium Borohydrides

JOC, (1962), 27(10), 3731-3733

Edward A. Sullivan and Alfred A. Hinckley

Research and Development Laboratories, Metal Hydrides, Incorporated, Beverly, Massachusetts


Examples of the use of Cetyl trimethylammonium and tricapryl methylammonium borohydrides in reduction of various substrates.

The ability of borohydrides to reduce certain organic functional groups is well documented in the literature.  Sodium borohydride reduces the carbonyl group of aldehydes and ketones in water, alcohol, or amines, and reduces acid chlorides in THF or dioxane.1  Aldehydes, ketones, acid chlorides, and esters are reduced by sodium borohydride in THF solution by the addition of lithium,2 magnesium, or calcium halides,3 whereby the corresponding borohydride is formed in situ.  In addition to the above functional groups, nitriles, disulfides, 1-olefins, oxides, acids, and acid anhydrides are reduced by sodium borohydride in diglyme or triglyme,4 on the addition of aluminum halides5 or lithium halides.  All of the above listed reductions require a polar or an oxygenated solvent.  Nonpolar hydrocarbons cannot be used because of the lack of solubility of commercially available borohydrides.  Aluminum borohydride is known and is soluble in hydrocarbons,6 but it not available commercially and is also hazardous to handle, reacting violently with air or moisture.

The preparation of quaternary ammonium borohydrides [RR’R”R’’’N]BH4, by metathesis from commercial borohydrides, has been known since 1952.7  The compounds reported in the literature, however, contained three or four short aliphatic groups (methyl or ethyl) and were only sparingly soluble in hydrocarbons.  Recently, successful preparations have been made in these laboratories in which the quaternary ammonium cation contained longer chain hydrocarbon groups, thereby providing increased hydrocarbon solubility to these borohydrides.  Cetyl trimethyl ammonium borohydride [C16H35(CH3)3N]BH4, mol. wt. 229.4, and tricapryl methyl ammonium borohydride [(C8H17)3CH3N]BH4, mol. wt. 383.5, have been prepared.  The former is a white granular solid and the latter, a grease.  Both materials are stable with respect to storage, as indicated by identical active hydrogen analyses three months apart.

The improved hydrocarbon solubility of cetyl trimethyl ammonium borohydride and tricarpryl methyl ammonium borohydride suggested testes of their reducing ability in nonpolar solvents.  Accordingly, reductions of representative organic compounds, containing functional groups known to be reduced by borohydrides, were tried using one or both of the new quaternary ammonium borohydrides in hydrocarbon solvents, principally benzene.  For comparison with the usual solvents for borohydride reductions, similar reductions were tried in isopropyl alcohol and water.  Reductions were tested at room temperature or 65*C or both.  The results are summarized in Table 1 in terms of yield obtained in the specified time intervals.

The general utility of the long-chain quaternary ammonium borohydrides in various hydrocarbon solvents is indicated by several reductions listed in Table II, in which hexane and mineral oil were used as reaction solvents.

From Table I, it can be seen that there is no essential difference in reducing power between the two borohydrides used.  A comparison of the results obtained in benzene shows that, as would be expected, aldehydes are reduced readily; ketones, only very slowly, even at elevated temperatures; and esters, not at all at room temperature and only slowly at higher temperatures.  Peroxides and acid halides are readily reduced, while nitriles are not.

The exceptions to these generalizations are aromatic derivatives containing the p-nitro group.  No reduction occurs at room temperature, regardless of solvent, and the p-nitro analog is also not reduced under these conditions.  At 65*C, however, ethyl p-nitrobenzoate and p-nitrobenzoyl chloride are reduced rapidly, regardless of solvent, while the unnitrated analog is either not reduced or only slowly.  Furthermore, incomplete reduction of the nitro group itself is indicated in several of the runs in hydrocarbons, as shown by yields of 135-145%.  The values are beyond experimental error, and are reproducible, as shown by the results with p-nitrobenzoyl chloride in benzene.  Additional proof of this side reaction is provided by the fact that nitrobenzene itself consumes hydridic hydrogen when treated with the quaternary ammonium borohydrides at 65*C in benzene.  In six hours, reaction amounts to 31%, based on 1:1 stoichiometry.  Additional work is planned to clarify the nature of this side reaction.

A comparison of solvents shows that specific reductions occur most easily in water, less so in an alcohol, and slowest in the hydrocarbons.  Such a comparison must be made cautiously, however, for variations in solubility of a particular compound among the different solvents undoubtedly also contribute to the ease of reduction observed.  The results in Table II indicate no difference among the three hydrocarbon solvents tested.


Materials—the cetyl trimethylammonium borohydride used was 93% pure, based on hydrogen evolution on acid hydrolysis; the tricapryl methyl ammonium borohydride, 90%.  The principal contaminants were quaternary ammonium halide, and small amounts of free amine and amine-borane.

Commercial organic reagents and solvents were used without further purification.

Reductions were carried out in conventional glass equipment on a 0.1-0.2 mole scale, using 50 to 100% excess borohydride (corrected for purity).  Yields were calculated, based on the known stoichiometry of the reactions, from the volume of hydrogen evolved upon acid hydrolysis of unreacted borohydride at the end of each run.  The known quantity of borohydride added permitted calculation of the amount of hydrogen consumed by the reaction after correction to STP, and thence, the per cent yield.

The extent of experimental error in this rapid survey resulting from the limited quantities and techniques used, is estimated at a maximum of 15%.

Table I

Compound Reduced Temp. in *C BH4a Time (Hr.) Yield (%)b BH4a Time (Hr.) Yield (%)c BH4a Time (Hr.) Yield (%)d
p-hydroxybenzaldehyde 25 --- --- --- A 2 95 A 2 100
” 25 B 4 100 B 2 73 B 2 100
” 65 A 3 95 --- --- --- --- --- ---
2-Ethyl Hexaldehyde 25 B 4 78 --- --- --- B 1 100
” 65 A 4 86 --- --- --- --- --- ---
Acetophenone 25 A 4 0 A 2 59 A 2 100
” 25 B 4 21 B 2 64 B 2 100
” 65 A 3 10 --- --- --- --- --- ---
65 B 2 8 --- --- --- --- --- --- ---
Methyl Nonyl Ketone 65 A 1 0 A 1.5 47 --- --- ---
Methyl Undecyl Ketone 65 B 3 0 --- --- --- --- --- ---
Ethyl Benzoate 25 A 6.5 0 --- --- --- --- --- ---
” 65 A 3 0 A 3 14 --- --- ---
” 65 B 2 12 B 5 0 B 7 48
Ethyl p-nitrobenzoate 25 A 16 0 A 4.5 0 --- --- ---
” 25 B 2.5 0 --- --- --- --- --- ---
” 65 A 2.5 100 A 3 92 --- --- ---
” 65 B 2.5 100 B 2 77 --- --- ---
Benzonitrile 65 A 4.5 0 A 4.5 11 --- --- ---
” 65 --- --- --- B 6 0 --- --- ---
Benzoyl Chloride 65 A 5 100 --- --- --- --- --- ---
p-Nitrobenzoyl Chloride 65 A 2 135* --- --- --- --- --- ---
” 65 A 2 131* --- --- --- --- --- ---
Benzoyl Peroxide 25 A 3 65 A 6 100 --- --- ---
” 65 --- --- --- A 2 92 --- --- ---

aA = cetyl ammonium, B = tricapryl methyl ammonium.
b = reactions with yields in this column were carried out in benzene
c = reactions with yields in this column were carried out in isopropyl alcohol (isopropanol)
d = reactions with yields in this column were carried out in water

* these are not typos (at least not on the part of the transcriber for this web site)

Act quickly or not at all.
(Active Asperger Archivist)
07-14-03 19:17
No 447129
      Ref #13- JOC (1981) 46, 3571-3574 R4NBH3CN
(Rated as: excellent)

Tetraalkylammonium Trihydridocyanoborates. Versatile, Selective Reagents for Reductive Aminations in Nonpolar Media

JOC (1981), 46, 3571-3574.


Tetrabutylammonium cyanoborohydride or the combination of sodium cyanoborohydride with Aliquat 336 provides useful, convenient reagents for reductive amination of aldehydes and ketones in aprotic or protic media.

Trihydridocyanoborate (cyanoborohydide)1 is well established as a mild, selective, acid-stable reducing agent for a variety of conversions including aldehydes and ketones to alcohols,2 tosylhydrazones,3 polar alkenes,4 and alkyl halides5 to hydrocarbons, and numerous carbon-nitrogen pi-bond derivatives (imines, oximes, enamines) to amines.2  This latter transformation has been particularly exploited as an excellent procedure for the reductive amination of aldehydes and ketones.1,2,6  However, the commercial available sodium derivative suffers the limitation that solubility is restricted to a few polar protic (water, low molecular weight alcohols), aprotic (dimethylsulfate, HMPA), or ether (THF, diglyme) solvent.8  The reagent is almost totally insoluble and unreactive in most other useful solvents including DCM, chloroform, aromatic and aliphatic hydrocarbons, and diethyl ether.

To circumvent the solubility problem and hence augment the utility of cyanoborohydride, we have explored the use of the tetrabutylammonium derivative9 and other phase-transfer techniques10 for typical cyanoborohydride reductions in nonpolar media.5,9,11  This communication reports the successful application of phase transfer to reductive amination, which extends the useful media for these conversions to include most common organic solvents, including DCM, hexane, benzene and diethyl ether.

Tetrabutylammonium cyanoborohydride (TBACB), prepared as previously described,9,11 is an air and moisture-stable crystalline solid (MP 144-145*C) which, in contrast to the sodium counterpart, is not hygroscopic.  Phase transfer was also used to solubilize sodium cyanoborohydride by employing Aliquat 336, an inexpensive liquid reagent composed of methyltrialkylammonium chlorides with C8-C10 chains.  Successful reductive aminations were obtained under a variety of conditions, but the most convenient consisted of simply dissolving the aldehyde or ketone (10mmol), amine (60mmol), and TBACB (7mmol) or sodium cyanoborohydride (7mmol) plus Aliquat 336 (7mmol) in 21ml of solvent followed by addition of HCl (20mmol) conveniently added as a 2.5-5.0N solution in methanol or other solvent.  Approximately 1g of 4A molecular sieves was added (to absorb water formed), and the mixture was stirred at ambient temperature.  Progress of the reactions could be followed by monitoring the disappearance of the carbonyl by IR.  Upon completion, isolations were accomplished in standard fashion (experimental), the products purified by short-path distillation, and identified comparison (IR and/or NMR) with authentic samples.

The results for a range of carbonyls and amines are presented in Table I.  Examples using the standard method (sodium cyanoborohydride, methanol, 2-3days)2 are included for comparisons.  As illustrated, aromatic and aliphatic aldehydes and ketones react readily with unhindered primary and secondary amines to afford respectable to excellent isolated yields of amines in reasonable times, usually 2.5-24 hours for aldehydes and 24-48 hours for ketones.  Two limitations were encountered.  Relatively hindered secondary amines (i.e., diethylamine) reacted only reluctantly with ketones and gave inferior yields (<40%) of amine products.  Also ammonium and tetraalkylammonium salts generally failed to react in aprotic solvents in which solubility is a problem.  In such cases, methanol solvent is clearly superior.2

General Reaction Procedure:

The general reaction procedure is illustrated for the preparation of N-cyclohexylpyrrolidine.  To a solution containing pyrrolidine (4.26g, 60mmol) in 21ml of DCM was added HCl (20mmol, 8ml of a 2.5N solution in methanol) followed by cyclohexanone (0.98g, 10mmol), sodium cyanoborohydide (0.44g, 7mmol), and Aliquat 336 (2.93g, 7mmol).  Approximately 1g of 4A molecular sieves was added, and the mixture was stirred at RT for 48hours.  The mixture was filtered, the filtrate acidified (methyl orange indicator), and the solvent removed on a rotary evaporator.  The residue was taken up with 10ml of water and extracted with 3x20ml portions of ether (discarded).  The aqueous phase was basified (solid KOH, phenolphthalein indicator), 20ml of brine was added, and the mixture was extracted exhaustively with ether.  These combined extracts were dried (magnesium sulfate), concentrated, and distilled in a Kugelrohr apparatus to yield 1.43g (94%) of N-cyclohexylpyrrolidine, identified by comparison (IR) with an authentic sample.  GLC analysis indicated >98% purity.

In conclusion, phase-transfer techniques greatly augment the utility of cyanoborohydride for reductive aminations of carbonyls and complement analogous conversions in protic media.

Acknowledgement:  We gratefully thank The National Science Foundation for support of our programs on hydride chemistry.


(1)For reviews of cyanoborohydride chemistry, see (a) Hutchins, R. O.; Natale, N. R. Org. Prep. Proced. Int., (1979), 11, 201. (b) Lane, C.F. Synthesis, (1975), 135; Lane, C.F. Aldrichemica Acta, (1975), 8,3.

(2) Borch, R.F.; Bernstein, M.D.; Durst, H.D. JACS, (1971), 93, 2897. Recently, the intermediacy of iminium ions in certain reductive aminations has been questioned: Tadanier, J.; Hallas, R.; Martin, J.R.; Stanaszek, R.S. Tetrahedron Letters, (1981), 37, 1309; Kapnang, H.; Charles, G.; Sondengam, B.L.; Hemo, J.H. Tetrahedron Letters, (1977), 3469.

(3)Hutchins, R.O.; Maryanoff, B.E.; Milewaki, C.A. JACS, (1975), 40, 923.

(4) Hutchins, R.O.; Rotstein, D.; Natale, N.R.; Fanelli, J.; Dimmel, D. JOC, (1976), 41, 3328.

(5) Hutchins, R.O.; Kandasamy, D.; Maryanoff, C.A.; Masilamani, D.; Maryanoff, B.E. JOC, (1977), 42, 82.

(6) Other reagent systems recently introduced for reductive amination include:

(a)potassium hydridotetracarbonylferrate, Bodrini, G.P.; Panunzio, M.; Umani-Ronchi, A. Synthesis (1974), 261;

(b) NaBH4/H2SO4, Giumanini, A.G.; Chiavari, G.; Musiani, M.M.; Rossi, P. Synthesis, (1980), 743;

(c) the Leukart reaction; see, for example, Baeh, R.D. JOC, (1968), 33, 1647.

(d) NaBH4 in carboxylic solvents, Schellenburg, K.A. JOC, (1963), 28, 3259; Gribble, G.W.; Lord, P.D.; Skotnicki, J; Dietz, S.E.; Eaton, J.T.; Jonson, J.L. JACS, (1974), 96, 7812; Marchini, P.; Liso, G.; Reho, A.; Liborate, F.; Moracci, F.M. JOC, (1975), 40, 3453.

(e) ion-exchange resin supported BH3CN-, Hutchins, R.O.; Natale, N.R.; Taffer, I.M. J. Chem. Soc. Commun., (1978), 1088.

(7) From Alfa or Aldrich Chemical

(8) Wade, R.C.; Sullivan, E.A.; Bershied, J.R.; Purcell, K.F. Inorg. Chem., (1970), 9, 2146.

(9) Hutchins, R.O.; Kandasamy, D. JACS, (1973), 95, 6131; a number of other tetraalkylammonium cyanoborohydrides are also readily available: Reparasky, J.E.; Weidig, C.; Kelly, H.C. Syn. React. Inorg. Met-Org. Chem. , (1975), 5, 337.

(10) For excellent, general reviews of phase-transfer reactions, including reductions, see Weber, W.P.; Gokel, G.W. “Phase Transfer Catalysis in Organic Synthesis”; Springer-Verlag: New York, (1977),; Keller, W.E. “Compendium of Phase-Transfer Reactions and Related Synthetic Methods”; Fluka AG, Ch-9470 Buchs, Switzerland, (1979).

(11) Hutchins, R.O.; Kandasamy, D. JOC, (1975), 40, 2530.

Would somebody please pick up and post the articles in Reference (6) (a) and (e)

Act quickly or not at all.
(Active Asperger Archivist)
07-14-03 19:19
No 447131
      Table I of Ref#13 (previous post)  Bookmark   

Table I: Reductive Aminations with Tetraalkylammonium Trihydridoborates

Carbonyl Amine Hydride Solvent (time,h) Product (picrate, mp, *C)a % Yieldb
C6H5CHO pyrrolidine NaBH3CN CH3OH (72) N-benzylpyrrolidine (123-4) 70
” ” TBACB DCM (2.5) ” 76
” ” TBACB THF (2.5) ” 75
” ” TBACB hexane (2.5) ” 66
” ” TBACB benzene (2.5) ” 64
” ” TBACB acetonitrile (2.5) ” 58
” ” NaBH3CN, Aliquat 336 DCM (48) ” 84
” morpholine NaBH3CN, Aliquat 336 DCM (48) N-benzylmorpholine (185-86) 41
” Et2NHc + Et2NH2+Cl- NaBH3CN, Aliquat 336 DCM (42) C6H5CH2NEt2 (116-17) 53
” n-PrNH2 TBACB DCM (2) C6H5CH2NH-n-Pr 79
” ” NaBH3CN, Aliquat 336 DCM (48) ” 60
” IsoPrNH2 TBACB DCM (2.5) C6H5CH2NHCH(CH3)2 58
p-Br-benzaldehyde pyrrolidine TBACB DCM (23) N-(p-Br-benzyl)-pyrrolidine (140-41) 83
m-Cl-benzaldehyde ” TBACB DCM (21) N-(m-Cl-benzyl)-pyrrolidine (153-54) 89
2,6-di-Cl-benzaldehyde ” TBACB DCM (2.5) N-(2,6-di-Cl-benzyl)-pyrrolidine (180-81) 57
” ” NaBH3CN, Aliquat 336 DCM (48) ” 79
p-cyanobenzaldehyde pyrrolidine TBACB DCM (17) N-(p-cyanobenzyl)-pyrrolidine (166-67) 58
n-nonylaldehyde ” NaBH3CN Methanol (46) N-decylpyrrolidine (73-74) 67
” ” TBACB DCM (2.5) ” 64
” Iso-PrNH2 TBACB DCM (42) CH3(CH2)8CH2NHCH(CH3)2 52
Methyl Benzoate pyrrolidine NaBH3CN methanol (70) N-(alpha-methylbenzyl)-pyrrolidine (125-26) 82
” ” TBACB DCM (72) ” 89
” ” TBACB hexane (72) ” 69
” ” TBACB benzene (72) ” 61
” ” NaBH3CN, Aliquat 336 DCM (48) ” 74
” ” NaBH3CN, Aliquat 336 benzene (48) ” 70
” MeAm-HCl TBACB methanol (90) C6H5CH(CH3)NHCH3 (182-83) 71
” ” TBACB DCM (90) ” <5
” NH4OAc TBACB methanol (45) C6H5CH(CH3)NHs2 49
” n-PrNHs[ub]2[/sub] NaBH3CN, Aliquat 336 DCM (48) C6H5CH(CH3)NHCH2CH2CH3 36
p-Br-benzaldehyde pyrrolidine TBACB DCM (48) N-(p-Br-alpha-methylbenzyl)-pyrrolidine (164-64) 82
cyclohexanone pyrrolidine NaBH3CN methanol (72) N-cyclohexylpyrrolidine (163-64) 71
” ” TBACB DCM (47) ” 90
” ” NaBH3CN, Aliquat 336 DCM (48) ” 94
” ” NaBH3CN, Adogen 464 DCM (48) ” 78
” ” NaBH3CN, Aliquat 336 diethyl ether (42) ” 73
” ” NaBH3CN, Aliquat 336 hexane (42) ” 67
” morpholine TBACB DCM (2.5) N-cyclohexylmorpholine (169-170) 58
” ” NaBH3CN, Aliquat 336 DCM (48) ” 52
” n-PrNH2 TBACB DCM (2.5) cyclohexylpropylamine 55
” Iso-PrNH2 NaBH3CN, Aliquat 336 DCM (48) cyclohexylisopropylamine 48
” Et2NHc + Et2NH2+Cl- NaNBH3CN, Aliquat 336 DCM (48) N,N-diethylcyclohexylamine 36
4-t-butylcyclohexanone pyrrolidine TBACB methanol (45) 4-t-butylcyclohexanol (~145, mixture) 73 (67t, 33c)
Methyl heptanoate ” NaBH3CN, Aliquat 336 DCM 2-pyrrolidinyloctane (86-87) 73
” aniline TBACB DCM CH3(CH2)5CH(CH3)NHC6H5 31
” ” NaBH3CN acetonitrile (48) dimethylaniline 66
” ” NaBH3CN, Aliquat 336 DCM ” 61

a All known products were identified by comparisons with authentic samples.  New compounds showed IR, NMR, and elemental analysis consistent with the assigned structures.
b Isolated and purified by distillation.
c No added acid.

Act quickly or not at all.