Diisobutylaluminum borohydride: An efficient reagent for the reduction of tertiary amides to the corresponding amines under ambient conditions

Article abstract of DOI:10.1016/j.tetlet.2017.09.030

A synthetically simple mixed metal hydride, diisobutylaluminum borohydride [(iBu)₂AlBH₄], is easily generated from a 1:1 mixture of borane-dimethylsulfide (BMS) and diisobutylaluminum hydride (DIBAL). The reduction of tertiary amides using (iBu)₂AlBH₄ is complete within five minutes under ambient conditions and the product tertiary amines were isolated in 70–99% yields by a simple acid-base extraction. This new methodology, reported herein, works well for reduction of tertiary aliphatic and aromatic amides as well as lactams to the corresponding amines and product isolation and purification does not require column chromatography.

Full text of DOI:10.1016/j.tetlet.2017.09.030

Accepted Manuscript
Diisobutylaluminum Borohydride: an efficient reagent for the reduction of ter-
tiary amides to the corresponding amines under ambient conditions
Rachel A. Snelling, Gabriella Amberchan, Angel Resendez, Chris L. Murphy,
Lauren Porter, Bakthan Singaram
PII:
S0040-4039(17)31153-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.09.030
TETL 49300
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
16 August 2017
2 September 2017
13 September 2017
Please cite this article as: Snelling, R.A., Amberchan, G., Resendez, A., Murphy, C.L., Porter, L., Singaram, B.,
Diisobutylaluminum Borohydride: an efficient reagent for the reduction of tertiary amides to the corresponding
amines under ambient conditions, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.09.030
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Diisobutylaluminum Borohydride: an efficient reagent for the reduction of tertiary
amides to the corresponding amines under ambient conditions
Rachel A. Snelling, Gabriella Amberchan, Angel Resendez, Chris L. Murphy, Lauren
Porter, and Bakthan Singaram*
Department of Chemistry and Biochemistry, University of California, Santa Cruz,
1
156 High Street, Santa Cruz, California, 95064
singaram@ucsc.edu
Abstract
A synthetically simple mixed metal hydride, diisobutylaluminum borohydride
AlBH ], is easily generated from a 1:1 mixture of borane-dimethylsulfide (BMS)
and diisobutylaluminum hydride (DIBAL). The reduction of tertiary amides using
iBu) AlBH is complete within five minutes under ambient conditions and the product
[
(iBu)
2
4
(
2
4
tertiary amines were isolated in 70 to 99% yields by a simple acid-base extraction. This
new methodology, reported herein, works well for reduction of tertiary aliphatic and
aromatic amides as well as lactams to the corresponding amines and product isolation and
purification does not require column chromatography.
Keywords

Aluminum, Boron, Borohydride, Ambient, Amide, Amine, Hydride, Reduction
. Introduction
Reduction of amides to the corresponding amines is an important process in
1
1
organic chemistry for the synthesis of amines. These reductions are typically difficult
due to the low electrophilicity of the carbonyl carbon and use pyrophoric reducing agents,
2
high reaction temperatures, and/or long reaction times. Extensive use of amines as
3
4
5
starting materials for plastics, agrochemicals, and dyes in industry make amide
reduction an important functional group transformation in organic chemistry. Amines
also play an important role in biological processes and are key functionalities found in
6
many pharmaceuticals in wide use today, such as central nervous system (CNS) drugs,
7-
1
0
Thus, the growing interest in and use of amines has necessitated novel and efficient
methods for their synthesis, including amide reduction. A major challenge in the
synthesis of amines from the corresponding amides is the reduction of the least
electrophilic amide functionalities, which are often difficult functional groups to reduce.
Common reducing reagents employed for these reductions include lithium
1
1
12
3
and borane-tetrahydrofuran (BH :THF) which are
aluminum hydride (LiAlH
4
)
pyrophoric or require refluxing conditions or extended reaction times. Borane-
dimethylsulfide (BMS) can reduce tertiary amides to amines, however, this procedure
1
3
requires refluxing conditions as well as continuously distilling off dimethylsulfide. It
has been reported that diisobutylaluminum hydride (DIBAL) reduces tertiary amides to
14
the corresponding amines but the reaction needs to be carried out at 200 ºC. Non-
pyrophoric lithium aminoborohydride (LAB) reagents can reduce tertiary amides to the
corresponding alcohols or amines depending on the steric requirements of the LAB
1
reagent. Tertiary amides can also be reduced to the corresponding amines using silane
5

1
6-29
mediated reactions.
This methodology often requires transition metal catalysts,
increased temperatures, or longer reaction times and chromatographic purification. A
procedure for the complete reduction of tertiary amides to the corresponding amines at
ambient temperature that does not involve chromatographic purification techniques for
isolation of the product is still elusive. Herein, we report a new reagent that successfully
reduces tertiary amides to the corresponding amines, is relatively safe to handle, and
allows product isolation without use of chromatography.
2
2
. Results and Discussion
.1 Synthesis of diisobutylaluminum borohydride
3
As a part of our interest in generating binary hydride systems, we investigated
0
the reaction of BMS with DIBAL to generate a new binary hydride reagent,
1
1
diisobutylaluminum borohydride (iBu
reaction mixture displayed a quintet at -37 ppm (J=83 Hz) indicating the clean formation
of iBu AlBH (Scheme 1).
2 4
AlBH ). The B NMR spectral analysis of a (1:1)
2
4
3
1
Scheme 1 Synthesis of diisobutylaluminum borohydride
The starting BMS reagent usually displays a quartet at -20 ppm with a coupling constant
1
1
of 103 Hz in the B NMR spectrum. When DIBAL is added to BMS, the quartet at -20
ppm disappears and a new quintet is observed at -37 ppm with a coupling constant of 83
Hz, indicative of formation of a borohydride. Interestingly, while DIBAL and BMS are

both Lewis acids, BMS is a stronger Lewis acid and accepts a hydride from DIBAL,
which is the weaker Lewis acid of the two reagents. We tried the reactions of a variety of
other common Lewis acidic hydrides, such as, pinacolborane (HBPin), chloromagnesium
2
hydride (HMgCl), and HInCl with BMS. Unfortunately these Lewis acid-BMS
interactions did not generate pure binary hydrides as observed with DIBAL.
2
.1 Reduction of aromatic tertiary amides
Most of the known hydrides are capable of reducing carbonyl functional groups
2 4
present in aldehydes, ketones and esters. Preliminary screening showed that iBu AlBH
behaved like other hydride reagents and reduced most electrophilic functional groups.
However, we were interested in the reduction of tertiary amides, as they are difficult to
reduce at ambient temperatures due to the low electrophilicity of the carbonyl
functionality. Consequently, we studied the reduction of a wide variety of aromatic
amides and found that the majority of the tertiary amides tested were rapidly reduced
3
2
2 4
using iBu AlBH at ambient temperature to the corresponding tertiary amines. The
results are summarized in Table 1.
2 4
Table 1 Reduction of aromatic tertiary amides using iBu AlBH

a
Reductions carried out at 25 ºC for 1 hour on a 5 mmol scale with 1 equivalent of amide
and 1.1 equivalent of iBu AlBH . iBu AlBH was added at 0 ºC and the ice bath was
removed after all the hydride was added to the reaction mixture. Product was isolated
2
4
2
4
b
through acid-base extraction; no further purification was required. Isolated yield.
N,N-Diethylbenzamide and N,N-diethyl-m-toluamide (DEET) were reduced to N,N-
diethylbenzylamine and N,N-diethyl-(3-methylbenzyl)amine and isolated in 80% and
9
9% yields respectively (Table 1, entries 1 and 2). These reductions were followed by IR
spectral analysis of aliquots withdrawn periodically from the reaction mixture; the
reduction was considered complete when the carbonyl stretch was no longer visible in the

IR spectrum. The reaction was quenched with methanol. The aluminum-containing
compounds formed a solid polymer that was easily removed by simple filtration followed
by a methanol wash. The combined filtrate was concentrated and the product amine was
isolated by simple acid-base extraction, without the need for column chromatographic
3
3
purification techniques. Sterically hindered N,N-diisopropylbenzylamine was isolated
from the reduction of N,N-diisopropylbenzamide in 99% yield (Table 1, entry 3). The
unsymmetrical aromatic amide N-methyl-N-propylbenzamide was reduced to N-methyl-
N-propylbenzylamine and isolated in 92% yield (Table 1, entry 4). Since tertiary
benzamides were successfully reduced in overall good yields, the influence of both
electron-donating and electron-withdrawing groups was investigated. Benzamides with
electron-withdrawing groups, such as bromo or trifluoromethyl substituents, were
successfully reduced. (3-Bromo-4-methylphenyl)(pyrrolidin-1-yl)methanone and
pyrrolidin-1-yl(4-(trifluoromethyl)phenyl)methanone were reduced to the corresponding
amines in 89% and 84% yields, respectively (Table 1, entries 5 and 6). Since our initial
2 4
functional group screening showed iBu AlBH can reduce most electrophilic compounds,
bifunctional aromatic compounds were not tested for the chemoselective reduction of
amides.
2
.2 Reduction of aliphatic tertiary amides and tertiary lactams
Two different substrates, N,N-dimethylhexamide and 1-(pyrrolidin-1-yl)hexan-1-
one, were chosen as preliminary examples for the reduction of aliphatic tertiary amides
and tertiary lactams, respectively. Substrates that have a long N-alkyl chain on the amide
were selected to facilitate the isolation of the reduction products by using a simple acid-
base extraction.
The reduction products, N,N-dimethylhexylamine and 1-

hexylpyrrolidine were isolated in yields of 84% and 88%, respectively (Table 2, entries 1
and 2). Similarly, 2-(2-bromophenyl)-1-(pyrrolidin-1-yl)ethanone was reduced to 1-(2-
bromophenethyl)pyrrolidine in an isolated yield of 83% (Table 2, entry 7).
When BH
3
:THF is used for reduction of amides, excess of the expensive borane
to
When lactams are reduced using DIBAL, a mixture of the amino-
reagent is required for the complete amide reduction due to the coordination of BH
3
3
4a,b
the amine products.
3
alcohol and cyclic amine products are observed. Methyl-LAB can reduce 1-phenyl-2-
5
3
6
pyrrolidinone to give a mixture of N-phenylpyrrolidine and N-phenylaminobutanol.
However, iBu AlBH reduced lactams to the corresponding cyclic amines in very good
2
4
yields. The alkyl lactam, 1-octyl-2-pyrrolidone, was reduced to 1-octylpyrrolidine in 87%
isolated yield (Table 2, entry 3). Most notably, 1-phenyl-2-pyrrolidone was reduced to 1-
phenylpyrrolidine in a 71% isolated yield (Table 2, entry 4). Reduction of this lactam
with other reducing agents typically gives the ring opened product, 4-
(
phenylamino)butan-1-ol. The lactam nitrogen can coordinate to a Lewis acid making the
N-atom a good leaving group, to give an aldehyde intermediate that gets further reduced
to the amino alcohol product. However this product was not observed when 1-phenyl-2-
pyrrolidone was reduced with iBu
through an imine intermediate, ultimately resulting in the cyclic amine product (Scheme
).
2 4 2 4
AlBH . Reductions using iBu AlBH most likely go
2
2 4
Scheme 2 Reduction of 1-phenyl-2-pyrrolidone using iBu AlBH

N-Methyl-2-piperidone and N-methylcaprolactam were reduced to give the 1-
methylpiperidine-borane complex and 1-methylazepane-borane complex, respectively
(
Table 2, entries 5 and 6). Long N-alkyl chain lactams were reduced to the corresponding
cyclic amines and isolated in pure form free from amino-alcohol side products.
a
2 4
Table 2 Reduction of aliphatic amides and lactams using iBu AlBH
a
Reductions carried out at 25 ºC for 1h on a 5 mmol scale with one equivalent of amide and 1.1
AlBH . iBu AlBH was added at 0 ºC and the ice-bath was removed after all
equivalent of iBu
2
4
2
4

b
the hydride was added to the reaction mixture. Isolated yields. Product isolated through acid-
1
base extraction and were characterized by H NMR analysis. . See ref. 33.
c
A new, easily synthesized reducing agent has been developed for the reduction of
4
tertiary amides. Diisobutylaluminum borohydride (iBuAlBH ) is easily synthesized from
a 1:1 mixture of BMS and DIBAL and can be stored under an inert atmosphere for at
least six months. Even though this reagent can reduce other functional groups, such as
aldehyde, ketones, esters, we mainly highlight the ability of this reagent to reduce tertiary
amides. The reagent is relatively safe to handle and requires only ambient temperatures
and a short reaction time to reduce tertiary amides. This binary hydride can reduce
aromatic and aliphatic tertiary amides as well as tertiary lactams to the corresponding
4 3
amines. This new reducing agent is an attractive alternative to LiAlH or BH :THF. It
should be noted that DIBAL is known to reduce tertiary amides to the corresponding
aldehyde at low temperature. Borane:dimethylsulfide is not a sufficiently strong reducing
agent for the reduction of tertiary amides because the reaction requires long reaction
times with concurrent distillation of dimethylsulfide. Representative tertiary amides
2 4
reduced by iBu AlBH are summarized in Scheme 3.

2 4
Scheme 3 Summary of tertiary amides reduced using iBu AlBH
Acknowledgements
This research did not receive any specific grant from funding agencies in the public,
commercial, or not-for-profit sectors.
References and Notes
1
. Brown, R. S. In The Amide Linkage: Structural Significance in Chemistry,
Biochemistry, and Material Science; Greenberg, A., Breneman, C. M., Liebman, J. F.,
Eds.; John Wiley & Sons, Inc.: Hoboken, NJ, 2000; pp 85−114.
2. Assimomytis, N.; Sariyannis, Y.; Stavropoulos, G.; Tsoungas, P.G.; Varvounis, G.;
Cordopatis, P. Synlett, 2009, 17, 2777.
th
. Ulmann, F.; Ulmann’s Encyclopedia of Industrial Chemistry, 7 ed.; Wiley-VCH:
3
Weinheim, Germany, 2008; Vol. A2, p2.

4. Lawrence, S. A. In Amines: Synthesis, Properties, and Application; Cambridge
University: Cambridge, U. K., 2004.
5
6
7
8
9
1
. Bacelo, H. A. M.; Santos, S. C. R.; Bothelo, C. M. S. Chem. Eng. J. 2016, 303, 575.
. Topczewski, J. J.; Cabrera, P. J.; Saper, N, I.; Sanford M. S. Nature. 2016, 531, 220.
. Berry, M.D. J. Neuorchem. 2004, 90, 257.
. Guan, L.; Liu, B. Eur. J. Med. Chem. 2016, 121, 47.
. Lopez, A. D.; Murray, C. C. Nat. Med. 1998, 4, 1241.
0. Ammendola, S.; Kornreich, C. Rev. Med. 2015, 36, 421.
1
5
1. Ravinder, B.; Reddy, Rajeswar S.; Reddy, Panasa A.; Bandichhor, R. Tet. Lett. 2013,
4, 4908.
1
1
1
1
2. Brown, H. C.; Stocky, H. J. Am. Chem. Soc. 1977, 99, 8218.
3. Brown, H. C.; Choi, Y. M.; Narasimhan, S. J. Org. Chem. 1982, 47, 3154.
4. Zakharkin, L. I.; Khorlina, I. M.; Tet. Lett. 1962, 3, 619.
5. Fisher, G. B.; Fuller, C. J.; Harrison, J.; Alvarez, S. G.; Burkhardt, E. R.; Goralski, C.
T.; Singaram, B. J. Org. Chem. 1994, 59, 6378.
1
6. Augurusa, A.; Mehta, M.; Perez, M. Zhu, J.; Stephan, D. W. Chem. Commun. 2016,
2, 12195.
5
17. Sakai, N.; Takeoka, M.; Kumaki, T.; Asabim H.; konakahara, T.; Ogiwara, Y. Tet.
Lett. 2015, 56, 6448.
18. Li, Y.; Molina de la Torre, J. A.; Grabow, K.; Bentrup, U.; Junge, K.; Zhou, S.;
Bruckner, A.; Beller, M. Angew. Chem. Int. Ed. 2013, 52, 11577.
19. Reeves, J. T.; Tan, Z.; Marsini, M. A.; Han, Z. S.; Xu, Y.; Reeves, D. C.; Lee, H.; Lu,
B. Z.; Senanayake, C. H. Adv. Synth. Catal. 2013, 355, 47.
2
2
2
2
0. Kuwano, R.; Takahashi, M.; Ito, Y. Tet. Lett. 1998, 39, 1017.
1. Selvakumar, K.; Rangareddy, K.;Harrod. J. F. Can. J. Chem. 2004, 82, 1244.
2. Park, S.; Brookhart, M. J. Amer. Chem. Soc. 2012, 134, 640.
3. Pisiewicz, S.; Junge, K.; Beller, M. Eur. J. Inorg. Chem. 2014, 2345.
2
1
4. Bézier, D.; Venkanna, G. T.; Sortais, J.B.; Darcel, C. Chem. Cat. Chem. 2011, 3,
747.

2
3
5. Dombray, T.; Helleu, C.; Darcel, C.; Sortais, J. B. Adv. Synth. Catal. 2013, I355,
358.
2
1
6. Das, S.; Addis, D.; Zhou, S.; Junge, K.; Beller, M. J. Amer. Chem Soc. 2010, 132,
770.
2
2
2
3
7. Das, S.; Addis, D.; Junge, K.; Beller, M. Chem. Eur. J. 2011, 17, 12186.
8. Xie, W.; Zhao, M.; Cui, C. Organometallics, 2013, 32, 7440.
9. Sakai, N.; Fujii, K.; Konakahara, T. Tet. Lett. 2008, 49, 6837.
0. Snelling, R.; Saavedra, J. Z.; Bayrsay, P.; Abdollahian, Y.; Singaram, B. Org. Chem.
Front. 2015, 2, 133.
3
1. An oven-dried 100-mL round-bottom flask was equipped with a magnetic stir bar and
a rubber septum, and cooled under an argon atmosphere. Borane:dimethyl sulfide (BMS,
0.6 M, 4.72 mL, 50 mmol) was added to the flask. Diisobutylaluminum hydride
DIBAL, 1M in hexane or toluene, 50 mL, 50 mmol) was added dropwise over fifteen
minutes. The reaction mixture was allowed to stir for five minutes. An aliquot was taken
1
(
1
1
and analyzed by B NMR spectroscopy. The completion was verified by the observation
of a signal shift from -19.5 ppm (quartet) to -36.8 ppm (quintet) (Scheme 1). There was a
change in the J-value from 105 Hz to 85 Hz, indicating the formation of the borohydride.
Diisobutylaluminum borohydride was then transferred to an argon charged ampule and
stored for no longer than three months for use. Attempting to generate
diisobutylaluminum borohydride by mixing one equiv of diisobutylaluminum chloride
(
iBu
generate diisobutylaluminum borohydride in pure form. The generation of iBu
was also attempted by dissolving one equiv of NaBH in 1 mL N-methylpyrrolidone
NMP) and anhydrous THF (10 mL) followed by addition of one equiv of iBu AlCl.
2
AlCl) and three equiv of sodium borohydride (NaBH
4
) in anhydrous THF did not
2
AlBH
4
4
(
2
Boron NMR analysis revealed NMP was reduced. We were unsuccessful in our attempts
to obtain a X-ray quality crystal.
32. An exception is the reduction of N,N-dimethylbenzamide using iBu
gave benzyl alcohol in 98% isolated yield.
2 4
AlBH which
3
3. The following procedure is a representative. An oven-dried 50-mL round-bottom
flask was equipped with a magnetic stir bar and cooled under an argon atmosphere. N,N-
Diethylbenzamide (0.886 g, 5 mmol, 1 equiv) was added to the flask. The flask was fitted
with a rubber septum and purged with argon and cooled to 0 °C. Anhydrous THF (5 mL)
was added to the flask via a syringe. Diisobutylaluminum borohydride (6.0 mL, 5.5
mmol, 1.1 equiv) was added dropwise over 15 minutes with stirring. Upon the
completion of the addition of diisobutylaluminum borohydride, the ice-bath was removed
and the reaction mixture was allowed to stir at 25 °C for one hour. The reduction was
complete after one hour as evidenced by the disappearance of the signal due to
diisobutylaluminum borohydride (δ -36.81 p, J = 85 Hz) and appearance of a signal due

1
1
to amine-borane complex (δ -7.0 q, J = 96 Hz) in the B NMR spectral analysis of an
aliquot. The reaction mixture was then concentrated under reduced pressure using a rota-
vap and the reaction flask was recapped with a septum. Methanol (15 mL) was added
slowly to the residue (Caution! Hydrogen evolution) and the mixture was stirred for one
hour at 25 °C. The reaction mixture was concentrated under reduced pressure using a
rota-vap to give a white solid. Methanol (15 mL) and then conc. HCl (1 mL) were added
and the mixture was refluxed for 1 hour, then filtered and concentrated. Pentane (10 mL)
and deionized water (5 mL) were added to the filtrate. The layers were separated and to
the aqueous layer was added sodium hydroxide (NaOH pellets) until the pH of the
aqueous layer was 10. The aqueous layer was then extracted with diethyl ether (3 x 10
mL). The combined organic layers were dried with anhydrous MgSO
4
, filtered, and
concentrated in vacuo (25 °C, 1 Torr). The product was essentially pure amine as
1
13
11
evidenced by H, C and B NMR spectroscopic analyses. This workup procedure
allowed the isolation of essentially pure amine products without the need for further
purification techniques, such as column chromatography, distillation, or recrystallization.
34. Saavedra, J. Z.; Resendez, A.; Rovira, A.; Eagon, S.; Haddenham, D.; Singaram, B. J.
Org. Chem. 2011, 77, 221.
a
b
5. Wiselogle, Y.; Sonneborn, J. Org. Syn. Coll. 1941, 1, 90. Winterfeldt, E. Synthesis,
3
1
975, 617.
3
6. Flaniken, J. M.; Collins, C. J.; Lanz, M.; Singaram, B. Org. Lett. 1999, 1, 799.
Supplementary Material
Supplementary data (general experimental details, lists of spectral data, images of H and
1
1
3
C NMR spectra for all compounds associated with this article can be found, in the
online version.

•
•
Development of reducing agent diisobutylaluminum borohydride
Tertiary amides reduced to the corresponding amine under ambient
conditions
•
No column purification technique required for isolation of amine product