Reaction of Diisobutylaluminum Borohydride, a Binary Hydride, with Selected Organic Compounds Containing Representative Functional Groups

pubs.acs.org/joc

Article

Reaction of Diisobutylaluminum Borohydride, a Binary Hydride,

with Selected Organic Compounds Containing Representative

Functional Groups

Gabriella Amberchan, Rachel A. Snelling, Enrique Moya, Madison Landi, Kyle Lutz, Roxanne Gatihi,

and Bakthan Singaram *

Cite This: J. Org. Chem. 2021, 86, 6207 −6227

Read Online

sı

*

Metrics & More

Article Recommendations

Supporting Information

ACCESS

ABSTRACT: The binary hydride, diisobutylaluminum borohy-

dride [(iBu)₂AlBH₄], synthesized from diisobutylaluminum

hydride (DIBAL) and borane dimethyl sulﬁde (BMS) has shown

great potential in reducing a variety of organic functional groups.

This unique binary hydride, (iBu)₂AlBH₄, is readily synthesized,

versatile, and simple to use. Aldehydes, ketones, esters, and

epoxides are reduced very fast to the corresponding alcohols in

essentially quantitative yields. This binary hydride can reduce

tertiary amides rapidly to the corresponding amines at 25 °C in an

eﬃcient manner. Furthermore, nitriles are converted into the

corresponding amines in essentially quantitative yields. These

reactions occur under ambient conditions and are completed in an

hour or less. The reduction products are isolated through a simple

acid−base extraction and without the use of column chromatography. Further investigation showed that (iBu)₂AlBH₄has the

potential to be a selective hydride donor as shown through a series of competitive reactions. Similarities and diﬀerences between

(iBu)₂AlBH₄, DIBAL, and BMS are discussed.

Versatile boranes and borohydrides can be developed by ﬁne

tuning the stereoelectronic nature of the ligands on the B-atom.⁵

Binary hydride reagents are implicated in the hydrogenation of

functional groups using bimetallic catalysts.¹⁰Alternatively,

binary hydride reagents can be generated from NaBH₄and metal

halides. For instance, binary hydride systems containing

dichloroindium hydride (HInCl₂) and BH₃·THF were

generated from indium trichloride (InCl₃) and NaBH₄in

THF.¹¹This result prompted us to investigate the synthesis of

other binary hydride systems by mixing BH₃·THF and BMS

with metal hydrides, such as HInCl₂and DIBAL. Unfortunately,

both BH₃·THF and BMS did not form any binary hydride with

HInCl₂, as evidenced by ¹¹B NMR spectral analysis. However,

the reaction of BH₃·THF and BMS with DIBAL showed the

formation of the single binary hydride, which displayed as a

quintet at δ −37 ppm (J = 83 Hz) in the ¹¹B NMR spectrum

attributable to a unique binary hydride reagent, diisobutylalu-

INTRODUCTION

■

The reduction of functional groups is an integral synthetic

operation. As such, a variety of reducing reagents exist, such as

hydrides,¹hydrogenation catalysts,²boranes,³and silanes.⁴

Metal hydrides, such as lithium aluminum hydride (LiAlH₄),

sodium borohydride (NaBH₄), and diisobutylaluminum

hydride (DIBAL), are conventional reagents used to reduce a

variety of functional groups.⁵Sodium borohydride eﬃciently

reduces aldehydes and ketones,⁶anhydrides, esters and

lactones,⁷and acid chlorides⁵to the corresponding alcohol

products. However, the solubility of NaBH₄is limited to

alcohols and water, which is an added restriction. In addition to

the functional groups reduced by NaBH₄, DIBAL reduces

epoxides, carboxylic acids, nitriles, and tertiary amides.^1aUnlike

NaBH₄, DIBAL is soluble in both ethereal and hydrocarbon

solvents, making it a more versatile reagent.

A seminal work on hydroborations and reductions with

borane tetrahydrofuran (BH₃·THF) and other alkylboranes

established them as signiﬁcant reagents in organic chemistry.⁸

Unfortunately, commercial BH₃·THF is temperature-sensitive

and easily degrades into dialkoxyborane and trialkoxyborane;

thus, it cannot be shipped due to safety and quality concerns.⁹

Later, borane dimethyl sulﬁde (BMS) was developed as a more

stable alternative to BH₃·THF for functional group reduc-

tions.^3b,5

Received: December 30, 2020

Published: April 12, 2021

https://doi.org/10.1021/acs.joc.0c03062

J. Org. Chem. 2021, 86, 6207−6227

6207

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

minum borohydride [(iBu)₂AlBH₄]. A preliminary work

demonstrated that this binary hydride reduced tertiary amides

to amines at 25 °C.¹²Thus, it was decided to examine the

reducing characteristics of (iBu)₂AlBH₄toward representative

organic functional groups at 25 °C. Herein, we report the scope

and limitations of (iBu)₂AlBH₄as a reducing agent.

it with diisobutylaluminum chloride (DIBAL-Cl), (iBu)₂AlBH₄

was produced (Scheme 2).

Scheme 2. NaBH₄Reaction with DIBAL-Cl to Produce

(iBu)₂AlBH₄

RESULTS AND DISCUSSION

■

Synthesis of Diisobutylaluminum Borohydride. Even

though both BMS and DIBAL are Lewis acids, they are not

equivalent in their Lewis acid strength. DIBAL behaves like a

metal hydride and transfers its hydride completely to BMS upon

mixing the two reactants in a 1:1 ratio (Scheme 1). As shown

below, when the two reagents were combined, the BMS quartet

(δ −20 ppm, J = 103 Hz) disappeared and a quintet at δ −36

ppm (J = 83 Hz) appeared (Figure 1).

The ﬁrst hurdle to successfully carry out this reaction was

ﬁnding a compatible solvent. Sodium borohydride is soluble in

water and alcohol solvents but insoluble in ethereal and

hydrocarbon solvents. On the other hand, DIBAL-Cl is water-

reactive and is commercially available as a solution in a

hydrocarbon or ethereal solvents. Fortunately, NaBH₄is also

soluble in N-methyl pyrrolidone (NMP), in a mixed solvent of

THF/NMP (1:1), pyridine, and tetraglyme. Accordingly,

NaBH₄and DIBAL-Cl were combined in a 1:1 ratio in each of

the abovementioned solvents and stirred at 25 °C for 1 h, and

the reaction mixtures were analyzed via ¹¹B NMR (Figure 2).

In NMP and THF/NMP solvent media, the unreacted

NaBH₄was present (quartet, δ −41 ppm) along with a quartet at

δ −10 ppm, likely an amine borane (Figure 2a,b). Similarly, the

reaction in pyridine displayed a quartet at δ −10 ppm, indicating

that NaBH₄liberates “BH₃” with DIBAL-Cl and was trapped by

pyridine to give pyridine·BH₃(Figure 2c).¹³Finally, the addition

of DIBAL-Cl to a tetraglyme solution of NaBH₄successfully

aﬀorded (iBu)₂AlBH₄as the major product [quintet at δ −37

ppm (J = 81 Hz)] along with a quartet at δ −20 ppm (Figure

Scheme 1. Synthesis of Diisobutylaluminum Borohydride

[(iBu)₂AlBH₄] from BMS and DIBAL (1:1)

Ready access to reagents like BMS or DIBAL may be

challenging, and so, we explored other methods to synthesize

(iBu)₂AlBH₄from readily available starting materials. Sodium

borohydride (NaBH₄) is a prevalent reagent, and by combining

Figure 1. ¹¹B NMR (coupled) of (iBu)₂AlBH₄in a mixed solvent system of toluene/Me₂S (7:1).

6208

https://doi.org/10.1021/acs.joc.0c03062

J. Org. Chem. 2021, 86, 6207−6227

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Figure 2. ¹¹B NMR (coupled) spectra of NaBH₄and DIBAL-Cl in (a) NMP, (b) THF/NMP (1:1), (c) pyridine, (d) tetraglyme, (e) addition of 1-

hexene, and (f) tetraglyme/THF (1:4).

Scheme 3. Reduction of Benzaldehyde Using BMS, DIBAL, and (iBu)₂AlBH₄

a

b

c

d

Conversion yields. Isolated yields. Reference 14. Reference 1b.

2d). This quartet at δ −20 ppm disappeared when 1-hexene was

added to the reaction mixture, indicating that it may be a

tetraglyme·BH₃complex (Figure 2e). In order to minimize the

amount of tetraglyme, THF was added as a co-solvent (1:4,

Figure 2f). Using this mixed solvent system, successful synthesis

of (iBu)₂AlBH₄was achieved from NaBH₄and DIBAL-Cl.

However, for the study of the reduction proﬁle in this paper,

(iBu)₂AlBH₄was made using BMS and DIBAL.

Reduction of Aldehydes and Ketones Using Diisobu-

tylaluminum Borohydride. Reduction optimization of

benzaldehyde with (iBu)₂AlBH₄demonstrated that the

aldehyde was eﬃciently converted to the alcohol under ambient

conditions and in 1 h. Only 0.5 equivalence of (iBu)₂AlBH₄was

necessary to complete the reduction because the reduction

requires the addition of one hydride, and as (iBu)₂AlBH₄

contains four potential hydrides, one equivalence would be

excess (Scheme 3). Because (iBu)₂AlBH₄was synthesized from

BMS and DIBAL, the binary hydride was compared to its parent

reagents. Both BMS and DIBAL required excess hydride for the

complete reduction of benzaldehyde to benzyl alcohol at 0 °C

(Scheme 3).^1b,14Even though (iBu)₂AlBH₄reacted similarly to

BMS and DIBAL to produce benzyl alcohol, less binary hydride

was required to achieve complete conversion under ambient

conditions.

A wider scope of aldehyde substrates illustrated the ease with

which (iBu)₂AlBH₄can reduce the carbonyl under ambient

conditions (Table 1). Aliphatic aldehydes, such as cyclo-

hexanecarboxaldehyde, reacted with (iBu)₂AlBH₄to produce

the alcohol in good yields (entry 1). A variety of aromatic

aldehydes were tested, producing the corresponding benzyl

alcohol in high yields (entries 2−9). 2-Phenylpropionaldehyde

was rapidly reduced, producing the alcohol in 81% yield (entry

10). Halides and nitro groups were well tolerated by

(iBu)₂AlBH₄, reducing solely the carbonyl group (entries 5−

9). The lack of reactivity toward the nitro group was similar to

BMS,^3bbut diﬀered from DIBAL, which produced the

corresponding hydroxylamine.^1bA heterocyclic aldehyde, such

as furan-3-carbaldehyde, was also reduced eﬃciently (entry 11).

6209

https://doi.org/10.1021/acs.joc.0c03062

J. Org. Chem. 2021, 86, 6207−6227

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

a

Table 1. Reduction of Aldehydes by (iBu)₂AlBH₄

a

Reaction conditions with (iBu)₂AlBH₄: aldehyde substrate (1 equiv), (iBu)₂AlBH₄(0.5 equiv), anhydrous THF, 25 °C, 1 h, under an argon

b

atmosphere. Reductions were all essentially complete. Moderate yields observed were an artifact of the isolation procedure. Isolated yield.

6210

https://doi.org/10.1021/acs.joc.0c03062

J. Org. Chem. 2021, 86, 6207−6227

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Scheme 4. Reduction of Acetophenone Using BMS, DIBAL, and (iBu)₂AlBH₄

a

b

c

d

Conversion yields. Isolated yields. Reference 14. Reference 1b.

In general, aliphatic and aromatic aldehydes were quickly

reduced by (iBu)₂AlBH₄, without much hindrance from the

substituents present.

reaction (Scheme 5).^3bIn comparison, the reduction of

benzonitrile with DIBAL formed the benzaldehyde imine at 0

°C, which then aﬀorded benzaldehyde following hydrolysis.^1f

With (iBu)₂AlBH₄, benzonitrile reacted within an hour at room

temperature to cleanly produce the primary amine.

Similar to aldehydes, the transformation of ketones to

secondary alcohols was eﬃciently completed with (iBu)₂AlBH₄.

Acetophenone was used to optimize the reaction conditions,

and only half an equivalence of (iBu)₂AlBH₄was necessary to

achieve essentially quantitative conversion to the corresponding

secondary benzylic alcohol (Scheme 4). In comparison, both

BMS and DIBAL required excess hydride for the complete

reduction of the ketone.^1b,14

A variety of ketones were examined showing the generality of

(iBu)₂AlBH₄’s ability to reduce ketones to the corresponding

alcohol (Table 2). The initial work began with the rapid and

quantiﬁable reduction of aliphatic ketones (entries 1 and 2).

Acetophenone analogues, containing diﬀerent functionalities,

underwent reduction (entries 3 and 4). Both naphthalene and

thiophene-based ketones reacted eﬃciently to form the alcohol

(entries 5 and 6). Interestingly, having acidic protons did not

impede the reaction nor did the hydride undergo dehalogena-

tion (entries 7−8).

Reduction of Nitriles Using Diisobutylaluminum

Borohydride. The reduction of nitriles using (iBu)₂AlBH₄is

an important transformation to understand the full reduction

proﬁle of this binary hydride. Amines are chemical motifs

frequently found in natural products, ﬁne chemicals, and

biomolecules¹⁵and can be accessed from nitriles using silanes,¹⁶

samarium diiodide,^2band metal hydrides.¹⁷Metal hydrides, such

as lithium aluminum hydride, dichloroindium hydride,^11band

even NaBH₄, when in the presence of a ruthenium catalyst,^2acan

reduce nitriles to primary amines. Milder reagents, including

aminoborohydrides^1cand boranes,^3awill reduce nitriles, albeit

slowly. Interestingly, bulky aluminum hydride reagents, like

DIBAL, can provide the aldehyde upon hydrolysis of the imine

intermediate.

When mapping the reductive proﬁle of (iBu)₂AlBH₄, it could

act like BMS and give a primary amine or behave like the bulky

DIBAL and aﬀord the corresponding imine, which could

undergo further reduction with BMS to give a primary amine.

Boron dimethyl sulﬁde has been shown to reduce benzonitrile to

the amine, but excess hydride was necessary due to the

formation of the borazine intermediate.^3bAdditionally, the

reaction was sluggish at room temperature and required heating

and continuous removal of dimethyl sulﬁde for a complete

As shown in Table 3, (iBu)₂AlBH₄can reduce aromatic

nitriles containing a variety of substituents. Halogens were

tolerated to generate the amine in good yields (entries 1−3).

Entry 4 demonstrates that (iBu)₂AlBH₄was a selective reagent

and will reduce nitriles in the presence of a nitro group.

Trisubstituted aryl nitriles were reduced to the corresponding

benzyl amine (entries 5−7). However, steric hindrance did

cause a decrease in the product yield (entries 6 and 7). More

complex nitriles, such as 4-(4-methyl-5-thiazolyl)benzonitrile,

were reduced by (iBu)₂AlBH₄, and the product was isolated in

high yields (entry 8). This substrate has historically required

18

heating with LiAlH₄or catalytic hydrogenation¹⁹reactions,

and so, ﬁnding that (iBu)₂AlBH₄can reduce it under mild

conditions, without a metal catalyst, and in high yields

demonstrate the eﬃcacy of the reagent.

Benzylic nitriles were also included in this study to determine

whether the acidic benzylic protons would inhibit the reduction

(Table 4). In this circumstance, the conversion to the amine was

eﬃcient and clean, demonstrating that the acidic protons do not

dramatically hinder the hydride from reduction of the nitrile.

The examples chosen contained electron donating and with-

drawing substituents, which were well tolerated for these

reduction reactions (Table 4, entries 1−3). Similarly, hetero-

cycles, like thiophene, produced the corresponding amine in

good yields (Table 4, entry 4).

Reduction of Epoxides Using Diisobutylaluminum

Borohydride. Hydridic ring opening reactions of epoxides

aﬀord the corresponding alcohol products.^1a,20Because

epoxides require one hydride to react completely, 0.5 equivalent

of (iBu)₂AlBH₄was employed for the reduction proﬁle. As

expected, when cyclohexene oxide was reduced with

(iBu)₂AlBH₄, cyclohexanol was produced as the only product

(Table 5, entry 1). Unsymmetrical epoxides aﬀorded a more

interesting product distribution due to the presence of diﬀerent

reactive sites. Reduction of 1,2-epoxy-hexane at 25 °C gave a

mixture 2-hexanol and 1-hexanol in a 77:23 ratio, respectively

(entry 2). However, at 0 °C, only 2-hexanol was obtained in 70%

isolated yield (entry 3). The regioselectivity exhibited by

(iBu)₂AlBH₄is more similar to DIBAL^1bthan BMS,⁵implying

6211

https://doi.org/10.1021/acs.joc.0c03062

J. Org. Chem. 2021, 86, 6207−6227

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

a

Table 2. Reduction of Ketones by (iBu)₂AlBH₄

a

Reaction conditions: ketone substrate (1 equiv), (iBu)₂AlBH₄(0.5 equiv), anhydrous THF, 25 °C, 1 h, under an argon atmosphere. Reductions

b

c

were all essentially complete. Moderate yields observed were an artifact of the isolation technique employed. Isolated yield. Reaction performed

for 5 h. Reaction performed for 7 h.

d

that (iBu)₂AlBH₄, again, is inﬂuenced by its parent hydrides.

Another unsymmetric epoxide, 2-biphenylyl glycidyl ether, was

reduced regiospeciﬁcally to the secondary alcohol in high yields

(entry 4). This reaction further demonstrated that (iBu)₂AlBH₄

attacks the least hindered carbon atom in a S_N2-like pathway.

It is possible that the bulky aluminum atom coordinates to the

lone pair of electrons on the epoxide oxygen and directs the

hydride to the less sterically hindered carbon atom, providing

the more substituted alcohol product (Scheme 6).^1b

Styrene oxide is an interesting substrate, as the stereo-

electronic eﬀects can inﬂuence the regiochemistry of the hydride

attack. A full equivalent of (iBu)₂AlBH₄was needed to

completely reduce styrene oxide to a mixture of 2-phenyl-

ethanol:1-phenylethanol in a 55:45 ratio. Consequently,

reduction of styrene oxide using (iBu)₂AlBH₄was synthetically

not useful.

Reduction of Carboxylic Acids Using Diisobutylalumi-

num Borohydride. Benzoic acid was used as the representative

6212

https://doi.org/10.1021/acs.joc.0c03062

J. Org. Chem. 2021, 86, 6207−6227

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Scheme 5. Reduction of Benzonitrile Using BMS, DIBAL, and (iBu)₂AlBH₄

a

b

c

Isolated yield. Reference 3b. Reference 1f.

substrate for the reduction of carboxylic acids with the binary

hydride. BMS is known to reduce aliphatic carboxylic acids

rapidly (30 min) and reduce aromatic carboxylic acids more

slowly (4 h), while having a signiﬁcantly lower yield.²¹Addition

of trimethyl borate as an additive showed an increase in yields of

the primary alcohols in this reduction.²¹Similarly, reduction of

benzoic acid with DIBAL aﬀords benzyl alcohol after 12 h

(Scheme 7).^1b,24It should be noted that excess BMS and DIBAL

was required because of the hydride reaction with the acidic

proton.^1b,21For optimized reaction conditions with

(iBu)₂AlBH₄, slightly excess (1.5 equiv) hydride was necessary

due to the reaction with the acidic proton present on the

carboxylic acid group. Complete reduction to the alcohol

product was achieved in high yields, at room temperature, and in

1 h.^1b

Several carboxylic acids were investigated to establish the

generality of the reduction of carboxylic acids using

(iBu)₂AlBH₄(Table 6). Aromatic acid derivatives were reduced

eﬃciently under ambient conditions (entries 1−4). Neither the

acidic benzylic protons nor benzylic chloride in 4-

(chloromethyl)benzoic acid interfered with this hydride

reduction, producing the corresponding alcohol in 95% isolated

yield (entry 2). Aryl carboxylic acid with an electron-donating

group, such as a methoxy group, was reduced successfully (entry

3). Aryl bromides were tolerated in the reduction of 2-

bromophenylacetic acid. However, this reduction required

longer reaction time (3 h) to achieve complete reduction,

most likely due to the steric inhibition of the ortho substituent

(entry 4). Overall, (iBu)₂AlBH₄readily reduced carboxylic acids

to the corresponding alcohols in good yields and under ambient

conditions.

Reduction of Esters Using Diisobutylaluminum Bor-

ohydride. The reduction of esters generates the alcohol

products; however, they are typically slower reactions. The

reduction of esters by BMS can be achieved by simultaneous

distillation of dimethyl sulﬁde.^3bDIBAL undergoes reduction of

esters at 0 °C.^1b,fWith (iBu)₂AlBH₄, methyl benzoate was

reduced completely to benzyl alcohol using a 1:1 ratio of the

binary hydride to ester (Table 7, entry 1). Both aryl halides and

benzylic halides were well tolerated by (iBu)₂AlBH₄, and no

dehalogenation was observed (entries 2−4). Full conversion of

methyl-4-hydroxybenzoate and the pyridine analogue was not

seen, but they demonstrate that (iBu)₂AlBH₄can reduce

phenolic and heterocyclic esters (entries 5 and 6). Additionally,

the propionate derivative was cleanly reduced to the primary

alcohol (entry 7).

Reduction of Amides Using Diisobutylaluminum

Borohydride. Finally, we studied the reductions of amides,

speciﬁcally, the reduction of tertiary amides as they are more

diﬃcult to reduce at ambient temperatures due to the low

electrophilicity of the carbonyl functionality. In general, the

reduction of amides can produce aldehydes or undergo C−O or

C−N bond cleavage to provide an amine or an alcohol,

respectively.²²Boranes will give the C−O bond cleavage to

aﬀord an amine/borane adduct that can then be hydrolyzed to

isolate the amine product.^9b,23Much like the ester reductions,

excess borane and continuous removal of dimethyl sulﬁde were

required to achieve rapid reduction of primary, secondary, and

tertiary amides.^3b

We found that aromatic primary and secondary amides were

not reduced with (iBu)₂AlBH₄.¹²When benzamide, N-

methylbenzamide, and unsubstituted acetanilide were reacted

with the binary hydride, the starting material was recovered.

Even increasing the amount of hydride (2 equiv) and employing

longer reaction times (24 h), the reductions were unsuccessful.

These results indicate that (iBu)₂AlBH₄, just like DIBAL,^1bwas

unsuitable for the reduction of primary or secondary amides. We

were pleased to ﬁnd that tertiary amides included in our study

were rapidly reduced using (iBu)₂AlBH₄at an ambient

temperature to the corresponding tertiary amines (Table 8).

These reductions were followed by infrared (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. An

exception to this was the reduction of N,N-dimethylbenzamide,

which underwent the C−N bond cleavage to produce benzyl

alcohol in 98% yield (entry 1). N,N-Diethylbenzamide and N,N-

diethyl-m-toluamide aﬀorded the corresponding benzyl amines

in 80 and 99% isolated yields, respectively (entries 2 and 3).

Even sterically hindered amides, such as N,N-diisopropylbenza-

mide, were rapidly reduced to N,N-diisopropylbenzyl amine in

99% yield (entry 4). The unsymmetrical N-methyl-N-

propylbenzylamine was isolated from the reduction of N-

methyl-N-propylbenzamide in 92% yield (entry 5). Benzamides

with electron-withdrawing groups, such as bromo or triﬂuor-

omethyl substituents, were successfully reduced (entries 6 and

7).

Aliphatic tertiary amides and lactams were also reduced

eﬃciently by (iBu)₂AlBH₄to the corresponding amines in very

6213

https://doi.org/10.1021/acs.joc.0c03062

J. Org. Chem. 2021, 86, 6207−6227

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

a

Table 3. Reduction of Aryl Nitriles by (iBu)₂AlBH₄

a

Reaction conditions with (iBu)₂AlBH₄: nitrile substrate (1 equiv), (iBu)₂AlBH₄(1 equiv), anhydrous THF, 25 °C, 1 h, under an argon

b

c

atmosphere. Reductions were all essentially complete. Moderate yields observed were an artifact of the isolation procedure. Isolated yield. Yield

based on H NMR, only the starting material was present in addition to the product.

1

good yields (Table 9, entries 1−3). Lactams can be reduced

either to acyclic amino alcohol or to a cyclic amine.²⁴Reduction

of lactams by BMS^3b,23aﬀorded the cyclic amine, but the

reactions required heating to achieve reduction. When lactams

were reduced using DIBAL, a mixture of the amino-alcohol and

cyclic amine products were observed.^9dSimilar to BMS,

(iBu)₂AlBH₄was reduced 1-octyl-2-pyrrolidone to 1-octylpyr-

rolidine in a 87% isolated yield (entry 4). Most notably, 1-

phenyl-2-pyrrolidone was reduced to 1-phenylpyrrolidine in a

71% isolated yield (entry 5). Reduction of this lactam with other

reducing agents typically gave the ring-opened product, 4-

(phenylamino)butan-1-ol.²⁴It was predicted that reductions of

lactams using (iBu)₂AlBH₄go through an imine intermediate,

leading to the cyclic amine product. N-Methyl-2-piperidone and

N-methylcaprolactam were reduced to give the 1-methylpiper-

6214

https://doi.org/10.1021/acs.joc.0c03062

J. Org. Chem. 2021, 86, 6207−6227

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

a

Table 4. Reduction of Benzylic Nitriles to Amines Using (iBu)₂AlBH₄

a

Reaction conditions with (iBu)₂AlBH₄: nitrile substrate (1 equiv), (iBu)₂AlBH₄(1 equiv), anhydrous THF, 25 °C, 1 h, under an argon

atmosphere. Reductions were all essentially complete. Moderate yields observed were an artifact of the isolation procedure. Isolated yield.

idine-borane complex and 1-methylazepane-borane complex,

respectively (entries 6 and 7).

because it has a wider solvent compatibility, as it is soluble in

both ethereal and hydrocarbon solvents. Overall, our mixed

metal hydride can be selective for aldehydes and ketones when

in the presence of nitriles or esters.

Chemoselective Reactions. As described above,

(iBu)₂AlBH₄will reduce a wide range of functionalities, but

the hallmark of a useful reducing agent is its ability to reduce a

speciﬁc functional group in a multifunctional compound.

Consequently, we examined whether (iBu)₂AlBH₄would

selectively reduce an aldehyde or ketone in the presence of a

nitrile or ester. The reaction of (iBu)₂AlBH₄and 4-

cyanobenzaldehyde (1) illustrated the selective reduction of

the aldehyde to benzyl alcohol at 0 °C without reducing the

nitrile group (Scheme 8). It is important to note that this

selectivity occurs at 0 °C. When the reaction was performed at

room temperature, the nitrile was partially reduced (Table S1).

BMS showed a similar selectivity, but the reaction produced

lower yields and required an additional hour of reaction time.

With DIBAL, both functionalities reduced, thus oﬀering no

functional group selectivity. Similar results were observed for 4-

cyanoacetophenone (2) and 4-cyanobenzophenone (3) with

(iBu)₂AlBH₄at 0 °C.

We then tested the selectivity of (iBu)₂AlBH₄with

compounds containing an ester and an aldehyde or ketone

substituent (Scheme 9). These reactions have to be conducted

at −78 °C to obtain the selective reduction of the aldehyde or

ketone.

For many of these multifunctional compound reductions,

NaBH₄can be used to achieve similar selectivity as that of

(iBu)₂AlBH₄. However, NaBH₄is soluble only in alcohol

solvents and undergo solvolytic decomposition to produce H₂

gas. Diisobutylaluminum borohydride is more advantageous

One of the beneﬁts of (iBu)₂AlBH₄is its ability to reduce

tertiary amides and nitriles in an eﬃcient manner. However, the

question remains if (iBu)₂AlBH₄has a preference to react with

one of these nitrogen compounds over the other. The results of

the competitive reaction between 4-tolunitrile and N,N-diethyl-

m-toluamide with (iBu)₂AlBH₄are reported in Scheme 10.

Individually, each substrate would require one equivalence of

(iBu)₂AlBH₄, and thus, a 1:1:1 ratio of the two substrates to

(iBu)₂AlBH₄was used to identify which functionality

(iBu)₂AlBH₄would favor. When the reaction mixture was

cooled to −78 °C, clear selectivity for the reduction of the nitrile

was achieved, producing the primary amine in good yields.

CONCLUSIONS

■

In summary, this work explored the reductive scope of

diisobutylaluminum borohydride [i(Bu)₂AlBH₄]. In a 1:1 ratio

of BMS and DIBAL, i(Bu)₂AlBH₄was generated and it was

stable under ambient conditions. To make the binary hydride

more accessible, it was possible to synthesize it from sodium

borohydride and diisobutylaluminum chloride in a THF/

tetraglyme mixture. Under ambient conditions, i(Bu)₂AlBH₄

eﬀectively and eﬃciently reduced aldehydes, ketones, carboxylic

acids, and esters to the corresponding alcohols. It was found that

the reduction of unsymmetrical epoxides favored the production

of the more substituted alcohol. Additionally, i(Bu)₂AlBH₄

reduced tertiary amides and nitriles to amines under ambient

6215

https://doi.org/10.1021/acs.joc.0c03062

J. Org. Chem. 2021, 86, 6207−6227

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

a

Table 5. Reduction of Epoxides by (iBu)₂AlBH₄

a

Reaction conditions: epoxide substrate (1 equiv), (iBu)₂AlBH₄(0.5 equiv), anhydrous THF, 1 h, under an argon atmosphere. Reductions were all

b

c

1

essentially complete. Moderate yields observed were an artifact of the technique employed. Ratio based on H NMR. Isolated yield.

conditions. The hydride was shown to be selective toward

aldehydes and ketones when in the presence of nitriles or esters.

In a competitive reaction between a nitrile and a tertiary amide,

the nitrile was preferentially reduced. While many of these

functionalities can be reduced with DIBAL or BMS, extreme

temperatures, excess reagent, or removal of byproducts are

required to achieve results that i(Bu)₂AlBH₄can accomplish

under ambient conditions. Overall, this unique binary reducing

agent is an attractive alternative to other more pyrophoric or

degradable hydrides, such as LiAlH₄or BH₃·THF. It is a

relatively safe reducing agent that can reduce a wide variety of

Scheme 6. Possible Mechanism for the Reduction of Epoxides

by (iBu)₂AlBH₄

Scheme 7. Reduction of Benzoic Acid Using BMS, DIBAL, and (iBu)₂AlBH₄

a

b

c

Isolated yield. Reference 24. References 1b and 1c.

6216

https://doi.org/10.1021/acs.joc.0c03062

J. Org. Chem. 2021, 86, 6207−6227

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

a

Table 6. Reduction of Carboxylic Acids by (iBu)₂AlBH₄

a

Reaction conditions: carboxylic acid (1 equiv), (iBu)₂AlBH₄(1.1 equiv), anhydrous THF, 1 h, under an argon atmosphere. Reductions were all

b

c

essentially complete. Moderate yields observed were an artifact of the technique employed. Isolated yield. Reaction performed for 3 h.

room temperature. Anhydrous THF (7.96 mL) was added to make a

0.25 M solution. (iBu)₂AlBH₄(0.25 M) was used without puriﬁcation.

¹¹B NMR (500 MHz): δ −36 (quintet, J = 83 Hz)

functionalities, and product isolation does not require column

chromatography.

Representative Procedure for the Reduction of Aldehydes

Using (iBu)₂AlBH₄. In an Ar-purged 100 mL round bottom ﬂask ﬁtted

with a rubber septum, aldehyde (5 mmol, 1 equiv) and anhydrous THF

(5 mL) were combined. (iBu)₂AlBH₄(2.5 mmol, 0.5 equiv) was added

dropwise. Once (iBu)₂AlBH₄was added, the reaction mixture was

allowed to stir for 1 h at room temperature. The reaction mixture was

quenched with methanol (5 mL) and deionized H₂O (5 mL) (caution:

H₂evolution!). A gel formed with the addition of methanol. The

resulting reaction mixture was ﬁltered, and the ﬁltrate was acidiﬁed with

concentrated HCl (12 M, 1 mL). The product was extracted with

diethyl ether (3 × 10 mL), and the combined organic extracts were

dried (MgSO₄) and concentrated to aﬀord the alcohol.

EXPERIMENTAL SECTION

■

General Information. All reagents were purchased from Sigma-

Aldrich, except for DIBAL, which was purchased from Acros. High

purity dry argon (Ar) was used during synthesis, storage, and use. THF

was dried by reﬂuxing it with Na° and benzophenone and distilling oﬀ

the dried THF. The products were conﬁrmed by nuclear magnetic

resonance (NMR) spectroscopy and measured in ppm. ¹H NMR

spectra were recorded on a Bruker 500 MHz spectrometer at 297 K and

calibrated using the residual CDCl₃(δ = 7.26 ppm) as an internal

standard. The ¹³C NMR spectra were analyzed at 125.7 MHz (297 K)

and calibrated using CDCl₃(δ = 77.0 ppm) as an internal standard.

Coupling constants (J) are given in hertz (Hz), and signal multiplicities

are abbreviated as s = singlet, d = doublet, t = triplet, m = multiplet, and

br = broad. ¹¹B NMR spectra were recorded at 80.25 MHz, and

chemical shifts were reported relative to the external standard, BF₃/

OEt₂(δ = 0 ppm).

Synthesis of Diisobutylaluminum Borohydride [(iBu)₂AlBH₄]

(1). In an argon-purged 100 mL round bottom ﬂask, DIBAL (1.2 M in

toluene, 4.6 mL, 5 mmol, 1 equiv) was added. BMS (10.6 M, 0.47 mL, 5

mmol, 1 equiv) was added dropwise. The reaction mixture was allowed

to stir for 1 h at room temperature. (iBu)₂AlBH₄(1 M) was used

without puriﬁcation and stored under Ar at room temperature in an

ampule. The hydride reagent was found to be stable for at least 3

months at 25 °C under an inert atmosphere. ¹¹B NMR (500 MHz): δ

−36 (quintet, J = 83 Hz).

Benzyl Alcohol (2, Scheme 3).^25aBenzaldehyde (0.5 mL, 5 mmol)

was reacted with (iBu)₂AlBH₄(2.3 mL, 2.5 mmol) in THF (5 mL) for 1

h. The product was isolated as a colorless oil via the abovementioned

1

procedure (0.494 g, 93%): H NMR (500 MHz, chloroform-d): δ

7.38−7.30 (m, 5H), 4.63 (s, 2H), 2.64 (br s, 1H). ¹³C {¹H} NMR (126

MHz, chloroform-d): δ 140.9, 128.5, 127.6, 127.0, 65.1.

Cyclohexanemethanol (3, Table 1, Entry 1).^25bCyclohexanecar-

boxaldehyde (0.61 mL, 5 mmol) was reacted with (iBu)₂AlBH₄(2.3

mL, 2.5 mmol) in THF (5 mL) for 1 h. The product was isolated as a

1

colorless oil via the abovementioned procedure (0.406 g, 71%): H

NMR (500 MHz, chloroform-d): δ 4.72 (s, 1H), 3.41 (s, 2H), 1.72 (s,

5H), 1.45 (s, 1H), 1.20 (d, J = 46.3 Hz, 3H), 0.91 (d, J = 9.8 Hz, 2H);

¹³C {¹H} NMR (126 MHz, chloroform-d): δ 68.8, 40.5, 29.6, 26.7, 25.9.

2-Methylbenzyl Alcohol (4, Table 1, Entry 2).^25c2-Tolualdehyde

(0.35 mL, 3 mmol) was reacted with (iBu)₂AlBH₄(1.9 mL, 1.5 mmol)

in THF (3 mL) for 1 h. The product was isolated as a white solid via the

Alternative Synthesis of Diisobutylaluminum Borohydride

[(iBu)₂AlBH₄] (1). In an Ar-purged 100 mL round bottom ﬂask, NaBH₄

(0.078 g, 2 mmol, 1 equiv) and tetraglyme (2 mL) were allowed to stir

until a homogenous solution was formed. To that solution,

diisobutylaluminum chloride (1 M in hexanes, 0.49 mL, 2 mmol, 1

equiv) was added. The reaction mixture was allowed to stir for 1 h at

1

abovementioned procedure (0.483 g, 98%): H NMR (500 MHz,

chloroform-d): δ 7.38 (d, J = 9.0 Hz, 1H), 7.26 (d, J = 11.8 Hz, 2H),

7.23 (d, J = 2.9 Hz, 1H), 4.66 (s, 2H), 2.75 (s, 1H), 2.38 (s, 3H); ¹³C

6217

https://doi.org/10.1021/acs.joc.0c03062

J. Org. Chem. 2021, 86, 6207−6227

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

a

Table 7. Reduction of Esters by (iBu)₂AlBH₄

a

Reaction conditions: ester (1 equiv), (iBu)₂AlBH₄(1 equiv), anhydrous THF, 3 h, under an argon atmosphere. Reductions were all essentially

b

c

1

complete. Moderate yields observed were an artifact of the technique employed. Isolated yield. Yield based on H NMR; only the starting

material was present in addition to the product. Reaction performed for 24 h.

d

1

{¹H} NMR (126 MHz, chloroform-d): δ 138.7, 136.0, 130.2, 127.6,

127.5, 126.0, 63.1, 18.6.

via the abovementioned procedure (0.396 g, 93%): H NMR (500

MHz, chloroform-d): δ 7.33 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 8.5 Hz,

2H), 4.67 (s, 2H), 1.72 (s, 1H); ¹³C{¹H} NMR (126 MHz, chloroform-

d): δ 139.2, 133.3, 128.6, 128.2, 64.5.

3-Methylbenzyl Alcohol (5, Table 1, Entry 3).^25c,d3-Tolualdehyde

(0.35 mL, 3 mmol) was reacted with (iBu)₂AlBH₄(1.9 mL, 1.5 mmol)

in THF (3 mL) for 1 h. The product was isolated as a colorless oil via

the abovementioned procedure (0.358 g, 98%): ¹H NMR (500 MHz,

chloroform-d): δ 7.13 (t, J = 7.5 Hz, 1H), 7.04 (s, 1H), 7.00 (dd, J =

14.5, 7.7 Hz, 2H), 4.48 (s, 2H), 2.77 (s, 1H), 2.24 (s, 3H); ¹³C {¹H}

NMR (126 MHz, chloroform-d): δ 140.8, 138.1, 128.4, 128.3, 127.8,

124.0, 65.1, 21.4.

2-Fluorobenzyl Alcohol (8, Table 1, Entry 6).^25b2-Fluorobenzalde-

hyde (0.3 mL, 3 mmol) was reacted with (iBu)₂AlBH₄(2.78 mL, 3

mmol) in THF (3 mL) for 1 h. The product was isolated as a yellow oil

1

via the abovementioned procedure (0.288 g, 76%): H NMR (500

MHz, chloroform-d): δ 7.32 (t, J = 7.6 Hz, 1H), 7.18 (q, J = 7.0, 6.6 Hz,

1H), 7.05 (t, J = 7.5 Hz, 1H), 6.98−6.92 (m, 1H), 4.65 (s, 2H), 2.23 (s,

1H); ¹³C{¹H} NMR (126 MHz, chloroform-d): δ 161.5, 159.6, 129.3,

127.8, 127.7, 124.2 (d, J = 3.6 Hz), 115.3, 115.1, 59.2 (d, J = 4.4 Hz).

2-Chloro-5-nitrobenzyl Alcohol (9, Table 1, Entry 7).^25f2-Chloro-

5-nitrobenzaldehyde (0.47 g, 2.5 mmol) was reacted with (iBu)₂AlBH₄

(1.17 mL, 1.26 mmol) in THF (2.5 mL) for 1 h. The product was

isolated as a solid via the abovementioned procedure (0.37 g, 79%): ¹H

NMR (500 MHz, chloroform-d): δ 8.46 (d, J = 2.7 Hz, 1H), 8.11 (dd, J

= 8.7, 2.7 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 4.87 (d, J = 4.5 Hz, 2H),

1.56 (s, 1H); ¹³C{¹H} NMR (126 MHz, chloroform-d): δ 140.4, 138.8,

130.1, 128.5, 126.6, 123.4, 123.0, 61.8.

4-Methylbenzyl Alcohol (6, Table 1, Entry 4).^25e4-Tolualdehyde

(0.24 mL, 2 mmol) was reacted with (iBu)₂AlBH₄(0.93 mL, 1 mmol)

in THF (2 mL) for 1 h. The product was isolated as a white solid via the

1

abovementioned procedure (0.201 g, 82%): H NMR (500 MHz,

chloroform-d): δ 7.27 (d, 2H), 7.18 (d, 2H), 4.65 (s, 2H), 2.35 (s, 3H),

1.56 (br s, 1H); ¹³C{¹H} NMR (500 MHz, chloroform-d): δ 137.9,

137.4, 129.3, 127.1, 65.3, 21.2.

4-Chlorobenzyl Alcohol (7, Table 1, Entry 5).^25a4-Chlorobenzal-

dehyde (0.420 g, 3 mmol) was reacted with (iBu)₂AlBH₄(1.9 mL, 1.5

mmol) in THF (3 mL) for 1 h. The product was isolated as a white solid

6218

https://doi.org/10.1021/acs.joc.0c03062

J. Org. Chem. 2021, 86, 6207−6227

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

a

Table 8. Reduction of Aromatic Tertiary Amides Using iBu₂AlBH₄

a

Reaction conditions: amide (1 equiv), (iBu)₂AlBH₄(1.1 equiv), and anhydrous THF were combined at 0 °C. Once all the hydride was added, the

ice bath was removed and the reaction mixture continued to stir for 1 h, under an argon atmosphere. Reductions were all essentially complete.

Moderate yields observed were an artifact of the technique employed. Isolated yield.

b

5-Chloro-2-nitrobenzyl Alcohol (10, Table 1, Entry 8).^25g5-

Chloro-2-nitrobenzaldehyde (0.557 g, 3 mmol) was reacted with

(iBu)₂AlBH₄(1.9 mL, 1.5 mmol) in THF (3 mL) for 1 h. The product

was isolated as a yellow solid via the abovementioned procedure (0.496

NMR (500 MHz, chloroform-d): δ 7.39 (d, J = 7.5 Hz, 2H), 7.31−7.27

(m, 3H), 3.73 (d, J = 7.5 Hz, 2H), 2.98 (h, J = 7.0 Hz, 1H), 1.89 (s, 1H),

1.33 (d, J = 7.1 Hz, 3H). ¹³C{¹H} NMR (126 MHz, chloroform-d): δ

143.9, 128.6, 127.5, 126.6, 68.6, 42.4, 17.7.

Furan-3-Methanol (13, Table 1, Entry 11).^25b3-Furancarboxalde-

hyde (0.418 mL, 5 mmol) was reacted with (iBu)₂AlBH₄(2.3 mL, 2.5

mmol) in THF (5 mL) for 1 h. The product was isolated as a yellow oil

1

g, 88%): H NMR (500 MHz, chloroform-d): δ 8.09 (d, J = 8.7 Hz,

1H), 7.82 (s, 1H), 7.43 (d, J = 9.5 Hz, 1H), 5.02 (s, 2H), 2.17 (s, 1H);

¹³C{¹H} NMR (126 MHz, chloroform-d): δ 140.9, 139.1, 129.4, 128.3,

126.5, 62.0.

1

via the abovementioned procedure (0.361 g, 74%): H NMR (500

4-Bromo-3-nitrobenzyl Alcohol (11, Table 1, Entry 9).^25h4-Bromo-

3-nitrobenzaldehyde (0.400 g, 1.74 mmol) was reacted with

(iBu)₂AlBH₄(0.81 mL, 0.87 mmol) in THF (2 mL) for 1 h. The

product was isolated as a yellow solid via the abovementioned

procedure (0.363 g, 90%): ¹H NMR (500 MHz, chloroform-d): δ 7.86

(d, J = 2.2 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.43 (dd, J = 8.3, 1.9 Hz,

1H), 4.76 (s, 2H); ¹³C{¹H} NMR (126 MHz, chloroform-d): δ 142.0,

135.0, 131.0, 123.4, 112.9, 63.3.

MHz, chloroform-d): δ 7.37 (s, 2H), 6.39 (s, 1H), 4.48 (s, 2H), 2.70 (s,

1H); ¹³C{¹H} NMR (126 MHz, chloroform-d): δ 143.3, 139.8, 125.1,

109.8, 56.3.

Representative Procedure for the Reduction of Ketones

Using (iBu)₂AlBH₄. In an Ar-purged 100 mL round bottom ﬂask,

ketone (5 mmol, 1 equiv) and anhydrous THF (5 mL) were combined.

(iBu)₂AlBH₄(2.5 mmol, 0.5 equiv) was added dropwise. Once all

(iBu)₂AlBH₄was added, the reaction mixture was allowed to stir for 1 h

at room temperature. The reaction mixture was quenched with

methanol (7 mL) and deionized H₂O (5 mL) (Caution! Hydrogen

evolution). A gel formed with the addition of methanol. The resulting

reaction mixture was ﬁltered, and the ﬁltrate was acidiﬁed with

2-Phenyl-1-propanol (12, Table 1, Entry 10).²⁵ⁱ2-Phenylpropio-

naldehyde (0.66 mL, 5 mmol) was reacted with (iBu)₂AlBH₄(2.3 mL,

2.5 mmol) in THF (5 mL) for 1 h. The product was isolated as a

1

colorless oil via the abovementioned procedure (0.552 g, 81%): H

6219

https://doi.org/10.1021/acs.joc.0c03062

J. Org. Chem. 2021, 86, 6207−6227

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

a

Table 9. Reduction of Aliphatic Amides and Lactams Using (iBu)₂AlBH4

a

Reaction conditions: amide (1 equiv), (iBu)₂AlBH₄(1.1 equiv), and anhydrous THF were combined at 0 °C. Once all the hydride was added, the

ice bath was removed and the reaction mixture continued to stir for 1 h, under an argon atmosphere. Reductions were all essentially complete.

Moderate yields observed were an artifact of the technique employed. Isolated yield.

b

Scheme 8. Chemoselective Reductions of Aldehydes and Ketones with (iBu)₂AlBH₄

Scheme 9. Chemoselective Reduction of Aromatic Esters with (iBu)₂AlBH₄

concentrated HCl (12 M, 1 mL). The product was extracted with

diethyl ether (3 × 10 mL), and the combined organic extracts were

dried (MgSO₄) and concentrated to aﬀord an alcohol.

1-Phenylethanol (14, Scheme 4).^26aAcetophenone (0.585 mL, 5

mmol) was reacted with (iBu)₂AlBH₄(2.3 mL, 2.5 mmol) in THF (5

mL) for 1 h. The product was isolated as a colorless oil via the

6220

https://doi.org/10.1021/acs.joc.0c03062

J. Org. Chem. 2021, 86, 6207−6227

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Scheme 10. Chemoselective Reduction of 4-Tolunitrile with (iBu)₂AlBH₄

1

abovementioned procedure (0.598 g, 98%): H NMR (500 MHz,

chloroform-d): δ 7.33 (s, 4H), 7.28−7.24 (m, 1H), 4.83 (q, J = 6.5 Hz,

1H), 2.72 (s, 1H), 1.46 (d, J = 5.0 Hz, 3H). ¹³C{¹H} NMR (126 MHz,

chloroform-d): δ 145.8, 128.5, 127.4, 125.3, 70.4, 25.1.

3H). ¹³C{¹H} NMR (126 MHz, chloroform-d): δ 139.6, 128.6, 128.5,

126.7, 79.2, 58.4, 22.7.

2-Bromo-1-(4-methoxyphenyl)ethanol (22, Table 2, Entry 8).^26g

2-Bromo-4-methoxyacetophenone (0.043 mL, 0.188 mmol) was

reacted with (iBu)₂AlBH₄(0.17 mL, 0.188 mmol) in THF (0.2 mL)

for 7 h. The product was isolated as a colorless oil via the

2-Octanol (15, Table 2, Entry 1).^26b2-Octanone (0.785 mL, 5

mmol) was reacted with (iBu)₂AlBH₄(2.31 mL, 2.5 mmol) in THF (5

mL) for 1 h. The product was isolated as a colorless oil via the

1

abovementioned procedure (0.036 g, 84%): H NMR (500 MHz,

1

abovementioned procedure (0.683 g, 99%): H NMR (500 MHz,

chloroform-d): δ 7.30 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 4.87

(dd, J = 8.9, 3.5 Hz, 1H), 3.81 (s, 3H), 3.61−3.50 (m, 2H), 2.65 (s, 1H).

¹³C{¹H} NMR (126 MHz, chloroform-d): δ 159.6, 132.4, 127.2, 114.0,

chloroform-d): δ 3.77 (sextet, J = 6.2 Hz, 1H), 2.69 (br s, 1H), 1.49−

1.35 (m, 3H), 1.26 (s, 7H), 1.16 (d, J = 6.2 Hz, 3H), 0.87−0.84 (m,

3H). ¹³C{¹H} NMR (126 MHz, chloroform-d): δ 68.1, 39.3, 31.8, 29.3,

25.7, 23.4, 22.6, 14.0.

73.4, 55.3, 40.2.

Representative Procedure for the Reduction of Nitriles

Using (iBu)₂AlBH₄. In an Ar-purged 100 mL round bottom ﬂask, the

nitrile (5 mmol, 1 equiv) and anhydrous THF (5 mL) were combined.

(iBu)₂AlBH₄(5 mmol, 1 equiv) was added dropwise. Once all

(iBu)₂AlBH₄was added, the reaction mixture was allowed to stir for 1 h

at room temperature. The reaction mixture was quenched with

methanol (5 mL) and deionized H₂O (5 mL) (Caution! Hydrogen

evolution). A gel formed with the addition of methanol. The resulting

reaction mixture was ﬁltered, and the ﬁltrate was acidiﬁed with

concentrated HCl (12 M, 1 mL). The reaction mixture was reﬂuxed for

1 h. The reaction mixture was extracted with diethyl ether (3 × 10 mL),

and the combined aqueous extracts were basiﬁed with NaOH_(s)(pH ∼

12). The product was then extracted with diethyl ether (3 × 10 mL).

The product was extracted with diethyl ether (3 × 10 mL), and the

combined organic extracts were dried (MgSO₄) and concentrated to

aﬀord the amine.

5-Nonanol (16, Table 2, Entry 2).^26c5-nonanone (0.711 g, 5 mmol)

was reacted with (iBu)₂AlBH₄(2.3 mL, 2.5 mmol) in THF (5 mL) for 1

h. The product was isolated as an oil via the abovementioned procedure

1

(0.640 g, 89%): H NMR (500 MHz, chloroform-d): δ 3.59 (s, 1H),

1.42 (m, 13H), 0.91 (s, 6H). ¹³C{¹H} NMR (126 MHz, chloroform-d):

δ 71.8, 37.1, 27.8, 22.7, 14.0.

1-(2-Bromophenyl)ethanol (17, Table 2, Entry 3).^26d2-Bromo-

acetophenone (0.67 mL, 5 mmol) was reacted with (iBu)₂AlBH₄(3.1

mL, 3.3 mmol) in THF (5 mL) for 1 h. The product was isolated as a

1

colorless oil via the abovementioned procedure (0.858 g, 86%): H

NMR (500 MHz, chloroform-d): δ 7.56 (d, J = 7.7 Hz, 1H), 7.49 (d, J =

7.9 Hz, 1H), 7.32 (t, J = 7.3 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 5.20 (q, J

= 6.4 Hz, 1H), 1.45 (d, J = 6.5 Hz, 3H). ¹³C{¹H} NMR (126 MHz,

chloroform-d): δ 144.7, 132.6, 128.7, 127.8, 126.7, 121.6, 69.1, 23.6.

1-(2-Methoxyphenyl)ethanol (18, Table 2, Entry 4).^25d2-Methoxy-

acetophenone (0.413 mL, 3 mmol) was reacted with (iBu)₂AlBH₄(1.9

mL, 1.5 mmol) in THF (3 mL) for 1 h. The product was isolated as an

oil via the abovementioned procedure (0.239 g, 69%): ¹H NMR (500

MHz, chloroform-d): δ 7.35 (d, J = 7.5 Hz, 1H), 7.27−7.23 (m, 1H),

6.97 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 5.10 (q, J = 6.5 Hz,

1H), 3.86 (s, 3H), 2.54 (s, 1H), 1.51 (d, J = 6.5 Hz, 3H). ¹³C{¹H} NMR

(126 MHz, chloroform-d): δ 156.5, 133.4, 128.3, 126.1, 120.8, 110.4,

66.5, 55.2, 22.8.

Benzylamine (23, Scheme 5).^3aBenzonitrile (0.408 mL, 4 mmol)

was reacted with (iBu)₂AlBH₄(3.7 mL, 4 mmol) in THF (4 mL) for 1

h. The product was isolated as a yellow oil via the abovementioned

procedure (0.425 g, 99%). ¹H NMR (500 MHz, chloroform-d): δ 7.20

(d, J = 19.8 Hz, 4H), 7.12 (s, 1H), 3.72 (s, 2H), 1.45 (s, 2H). ¹³C{¹H}

NMR (126 MHz, chloroform-d): δ 143.4, 140.4, 128.5, 127.0, 126.7,

46.5.

4-Methylbenzyl Amine (24, Table 3, Entry 1).^3a4-Methylbenzoni-

trile (0.470 g, 4 mmol) was reacted with (iBu)₂AlBH₄(3.7 mL, 4

mmol) in THF (5 mL) for 1 h. The product was isolated as an oil via the

abovementioned procedure (0.459 g, 94%). ¹H NMR (500 MHz,

chloroform-d): δ 7.21 (d, J = 7.8 Hz, 2H), 7.15 (d, J = 7.9 Hz, 2H), 3.83

(s, 2H), 2.35 (s, 3H), 1.36 (s, 2H). ¹³C{¹H} NMR (126 MHz,

chloroform-d): δ 140.4, 136.3, 129.2, 127.0, 46.2, 21.0.

1-(2-Naphthyl)ethanol (19, Table 2, Entry 5).^26d2-Acetonaph-

thone (0.851 mL, 5 mmol) was reacted with (iBu)₂AlBH₄(2.3 mL, 2.5

mmol) in THF (5 mL) for 1 h. The product was isolated as a white solid

1

via the abovementioned procedure (0.879 g, 99%): H NMR (500

MHz, chloroform-d): δ 7.86−7.80 (m, 4H), 7.52−7.46 (m, 3H), 5.06

(q, J = 6.5 Hz, 1H), 2.09 (br s, 1H), 1.59 (d, J = 6.5 Hz, 3H). ¹³C{¹H}

NMR (126 MHz, chloroform-d): δ 143.1, 133.3, 132.9, 128.3, 127.9,

127.6, 126.1, 125.8, 123.8, 70.5, 25.1.

3-Bromobenzyl Amine (25, Table 3, Entry 2).^3a3-Bromobenzoni-

trile (0.546 g, 3 mmol) was reacted with (iBu)₂AlBH₄(2.8 mL, 3

mmol) in THF (3 mL) for 1 h. The product was isolated as a yellow oil

1-(3-Thienyl)ethanol (20, Table 2, Entry 6).^26e3-Acetylthiophene

(0.25 g, 2 mmol) was reacted with (iBu)₂AlBH₄(0.93 mL, 1 mmol) in

THF (2 mL) for 5 h. The product was isolated as a clear oil via the

1

via the abovementioned procedure (0.399 g, 72%). H NMR (500

1

MHz, chloroform-d): δ 7.46 (s, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.22 (d, J

= 7.6 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 3.83 (s, 2H), 1.42 (s, 2H).

¹³C{¹H} NMR (126 MHz, chloroform-d): δ 145.6, 130.1, 130.0, 129.8,

125.6, 122.6, 45.9.

abovementioned procedure (0.219 g, 86%): H NMR (500 MHz,

chloroform-d): δ 7.29 (d, J = 8.1 Hz, 1H), 7.17 (s, 1H), 7.09 (d, J = 5.0

Hz, 1H), 4.94 (q, J = 6.5 Hz, 1H), 2.29 (s, 1H), 1.51 (d, J = 6.5 Hz, 3H).

¹³C{¹H} NMR (126 MHz, chloroform-d): δ 147.3, 126.1, 125.6, 120.1,

4-Chlorobenzylamine (26, Table 3, Entry 3).^27a4-Chlorobenzoni-

trile (0.691 g, 5 mmol) was reacted with (iBu)₂AlBH₄(4.6 mL, 5

mmol) in THF (5 mL) for 1 h. The product was isolated as a colorless

oil via the abovementioned procedure (0.604 g, 85%). ¹H NMR (500

MHz, chloroform-d): δ 7.29 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.4 Hz,

2H), 3.83 (s, 2H), 1.51 (s, 2H). ¹³C{¹H} NMR (126 MHz, chloroform-

d): δ 141.6, 132.4, 128.6, 128.4, 45.7.

66.5, 24.4.

(1S*,2R*)-2-Bromo-1-phenyl-1-propan-1-ol (21, Table 2, Entry

7).^26f2-Bromopropiophenone (0.45 mL, 3 mmol) was reacted with

(iBu)₂AlBH₄(1.9 mL, 1.5 mmol) in THF (3 mL) for 1 h. The product

was isolated as an oil via the abovementioned procedure (0.385 g,

60%): ¹H NMR (500 MHz, chloroform-d): δ 7.37 (m, 5H), 4.62 (d, J =

6.8 Hz, 1H), 4.37−4.32 (quintet, J = 6.8 Hz, 1H), 1.57 (d, J = 6.8 Hz,

6221

https://doi.org/10.1021/acs.joc.0c03062

J. Org. Chem. 2021, 86, 6207−6227

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

4-Nitrobenzyl Amine (27, Table 3, Entry 4).^27b4-Nitrobenzonitrile

(0.086 g, 0.58 mmol) was reacted with (iBu)₂AlBH₄(0.54 mL, 0.58

mmol) in THF (1 mL) for 1 h. The product was isolated as a yellow oil

via the abovementioned procedure (0.87 g, 98%). ¹H NMR (500 MHz,

chloroform-d): δ 8.20 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 3.49

(s, 2H), 1.59 (s, 2H). ¹³C{¹H} NMR (126 MHz, chloroform-d): δ

147.4, 128.6, 123.7, 115.0, 52.4.

Representative Procedure for the Reduction of Epoxides

Using (iBu)₂AlBH₄. In an Ar-purged 100 mL round bottom ﬂask, the

epoxide (5 mmol, 1 equiv) and anhydrous THF (5 mL) were

combined. The ﬂask was placed in an ice bath and cooled to 0 °C before

(iBu)₂AlBH₄(2.5 mmol, 0.5 equiv) was added dropwise. Once all

(iBu)₂AlBH₄was added, the reaction mixture was allowed to stir for 1 h

under the ice bath. The reaction mixture was quenched with methanol

(7 mL) and deionized H₂O (5 mL) (Caution! Hydrogen evolution). A gel

formed with the addition of methanol. The resulting reaction mixture

was ﬁltered, and the ﬁltrate was acidiﬁed with concentrated HCl (12 M,

1 mL). The product was then extracted with diethyl ether (3 × 10 mL).

The product was extracted with diethyl ether (3 × 10 mL), and the

combined organic extracts were dried (MgSO₄) and concentrated to

aﬀord the alcohol.

2,4-Dichlorobenzyl Amine (28, Table 3, Entry 5).^3a2,4-Dichlor-

obenzonitrile (0.860 g, 5 mmol) was reacted with (iBu)₂AlBH₄(4.6

mL, 5 mmol) in THF (5 mL) for 1 h. The product was isolated as a

yellow oil via the abovementioned procedure (0.833 g, 94%). ¹H NMR

(500 MHz, chloroform-d): δ 7.26−7.22 (m, 2H), 7.13 (dd, J = 8.3, 2.1

Hz, 1H), 3.80 (s, 2H), 1.40 (s, 2H). ¹³C{¹H} NMR (126 MHz,

chloroform-d): δ 137.0, 135.7, 131.7, 129.5, 129.4 (d, J = 6.8 Hz),

129.3, 129.1, 127.4, 43.7.

Cyclohexanol (36, Table 5, Entry 1).^28aCyclohexene oxide (0.5 mL,

5 mmol) was reacted with (iBu)₂AlBH₄(2.3 mL, 2.5 mmol) in THF (5

mL) for 1 h. The product was isolated as a colorless oil via the

abovementioned procedure (0.42 g, 84%). ¹H NMR (500 MHz,

chloroform-d): δ 3.57 (dp, J = 8.6, 4.2 Hz, 1H), 1.89 (d, J = 23.7 Hz,

3H), 1.70 (s, 2H), 1.51 (d, J = 12.3 Hz, 1H), 1.24 (d, J = 8.1 Hz, 4H),

1.14 (d, J = 2.9 Hz, 1H). ¹³C{¹H} NMR (126 MHz, chloroform-d): δ

70.3, 35.5, 25.5, 24.2.

2,6-Dichlorobenzyl Amine (29, Table 3, Entry 6).^3a2,6-Dichlor-

obenzonitrile (0.860 g, 5 mmol) was reacted with (iBu)₂AlBH₄(4.6

mL, 5 mmol) in THF (5 mL) for 1 h. The product was isolated as a

yellow oil via the abovementioned procedure (0.236, 27%). ¹H NMR

(500 MHz, chloroform-d): δ 7.21 (d, J = 8.0 Hz, 2H), 7.04 (t, J = 7.9 Hz,

1H), 4.02 (s, 2H), 1.75 (s, 2H). ¹³C{¹H} NMR (126 MHz, chloroform-

d): δ 138.7, 135.1, 128.9, 128.5, 128.4, 41.9.

2-Hexanol (37, Table 5, Entry 3).^28b1,2-Epoxy hexane (0.6 mL, 5

mmol) was reacted with (iBu)₂AlBH₄(2.3 mL, 2.5 mmol) in THF (5

mL) for 1 h. The product was isolated as a colorless oil via the

abovementioned procedure (0.356 g, 70%). ¹H NMR (500 MHz,

chloroform-d): δ 3.74 (dq, J = 11.8, 6.2 Hz, 1H), 2.23 (br s, 1H), 1.43

(m, 6H), 1.14 (d, J = 6.2 Hz, 3H), 0.86 (d, J = 7.2 Hz, 3H). ¹³C{¹H}

NMR (126 MHz, chloroform-d): δ 68.2, 39.0, 27.9, 23.4, 22.7, 14.0.

1-Biphenyl2-yloxypropan-2-ol (39, Table 5, Entry 4).^28c2-

Biphenylyl glycidyl ether (0.452 g, 2 mmol) was reacted with

(iBu)₂AlBH₄(0.93 mL, 1 mmol) in THF (2 mL) for 1 h. The product

was isolated as an oil via the abovementioned procedure (0.41 g, 90%).

¹H NMR (500 MHz, chloroform-d): δ 7.55 (d, J = 6.9 Hz, 2H), 7.44 (t,

2-Chloro-6-ﬂuorobenzyl Amine (30, Table 3, Entry 7).^3a2-Chloro-

6-ﬂuorobenzonitrile (0.780 g, 5 mmol) was reacted with (iBu)₂AlBH₄

(4.6 mL, 5 mmol) in THF (5 mL) for 1 h. The product was isolated as a

yellow oil via the abovementioned procedure (0.129 g, 16%). ¹H NMR

(500 MHz, chloroform-d): δ 7.16 (m, J = 2.8, 2.4 Hz, 2H), 7.00−6.96

(m, 1H), 3.99 (d, J = 1.9 Hz, 2H), 1.55 (s, 2H). ¹³C{¹H} NMR (126

MHz, chloroform-d): δ 162.0, 129.0, 128.8, 125.4, 114.3, 114.2, 37.2.

4-(4-Methyl-5-thiazolyl)benzenemethanamine (31, Table 3,

Entry 8).¹⁸4-(4-Methyl-5-thiazolyl)benzonitrile (0.111 g, 0.554

mmol) was reacted with (iBu)₂AlBH₄(0.52 mL, 0.554 mmol) in

THF (1 mL) for 1 h. The product was isolated as a yellow oil via the

abovementioned procedure (0.11 g, 90%). ¹H NMR (500 MHz,

chloroform-d): δ 8.67 (s, 1H), 7.42 (s, 4H), 3.88 (s, 2H), 2.54 (s, 3H),

1.70 (s, 2H). ¹³C{¹H} NMR (126 MHz, chloroform-d): δ 161.4, 150.2,

148.4, 130.9, 129.3, 128.6, 52.4, 16.1.

J = 7.6 Hz, 2H), 7.38−7.32 (m, 3H), 7.10 (t, J = 7.5 Hz, 1H), 7.01 (d, J =

8.2 Hz, 1H), 4.10−4.04 (m, 1H), 3.98 (d, J = 9.2 Hz, 1H), 3.78 (dd, J =

9.2, 7.6 Hz, 1H), 2.21 (d, J = 3.7 Hz, 1H), 1.21 (d, J = 6.4 Hz, 3H).

¹³C{¹H} NMR (126 MHz, chloroform-d): δ 155.4, 138.4, 131.4, 130.9,

2-(4-Methoxyphenyl)ethanamine (32, Table 4, Entry 1).^3a4-

Methoxyphenylacetonitrile (0.4 mL, 3 mmol) was reacted with

(iBu)₂AlBH₄(2.8 mL, 3 mmol) in THF (3 mL) for 1 h. The product

was isolated as a yellow oil via the abovementioned procedure (0.214 g,

47%). ¹H NMR (500 MHz, chloroform-d): δ 7.11 (d, J = 8.6 Hz, 2H),

6.84 (d, J = 8.7 Hz, 2H), 3.78 (s, 3H), 2.92 (t, J = 6.9 Hz, 2H), 2.68 (t, J

= 6.9 Hz, 2H), 1.41 (br s, 2H). ¹³C{¹H} NMR (126 MHz, chloroform-

d): δ 158.0, 131.8, 129.7, 113.8, 55.2, 43.6, 39.1.

129.4, 128.7, 128.1, 127.0, 121.6, 113.3, 74.3, 66.2, 18.6.

Representative Procedure for the Reduction of Carboxylic

Acids Using (iBu)₂AlBH₄. In an Ar-purged 100 mL round bottom

ﬂask, the carboxylic acid (5 mmol, 1 equiv) and anhydrous THF (5 mL)

were combined. (iBu)₂AlBH₄(5.5 mmol, 1.1 equiv) was added

dropwise, and once all (iBu)₂AlBH₄was added, the reaction mixture

was allowed to stir for 1 h at room temperature. The reaction mixture

was quenched with methanol (7 mL) and deionized H₂O (5 mL)

(Caution! Hydrogen evolution). A gel formed with the addition of

methanol. The resulting reaction mixture was ﬁltered, and the ﬁltrate

was acidiﬁed with concentrated HCl (12 M, 1 mL). The product was

extracted with diethyl ether (3 × 10 mL), and the combined organic

extracts were dried (MgSO₄) and concentrated to aﬀord the alcohol.

Benzyl Alcohol (2, Scheme 7).^25aBenzoic acid (0.491 g, 4 mmol)

was reacted with (iBu)₂AlBH₄(3.7 mL, 4 mmol) in THF (4 mL) for 1

h. The product was isolated as an oil via the abovementioned procedure

(0.43 g, 99%). ¹H NMR (500 MHz, CDCl₃): δ 7.37−7.36 (m, 5H, J =

4.4 Hz), 4.68 (s, 2H), 1.85 (s, 1H). ¹³C{¹H} NMR (151 MHz, CDCl₃):

δ 140.8, 128.4, 127.4, 127.0, 64.7.

2-Bromophenethylamine (33, Table 4, Entry 2).^3a2-Bromophe-

nylacetonitrile (0.39 mL, 3 mmol) was reacted with (iBu)₂AlBH₄(2.8

mL, 3 mmol) in THF (3 mL) for 1 h. The product was isolated as a

yellow oil via the abovementioned procedure (0.446 g, 74%). ¹H NMR

(500 MHz, chloroform-d): δ 7.51 (d, J = 8.0 Hz, 1H), 7.20 (s, 2H), 7.05

(s, 1H), 2.94 (t, J = 7.0 Hz, 2H), 2.87 (t, J = 6.9 Hz, 2H), 1.77 (s, 2H).

¹³C{¹H} NMR (126 MHz, chloroform-d): δ 139.1, 132.9, 130.8, 127.9,

127.4, 124.6, 42.0, 40.3.

4-Triﬂuoromethylphenethylamine (34, Table 4, Entry 3).^2b4-

(Triﬂuoromethyl)phenylacetonitrile (0.377 g, 2 mmol) was reacted

with (iBu)₂AlBH₄(1.9 mL, 2 mmol) in THF (2 mL) for 1 h. The

product was isolated as an oil via the abovementioned procedure (0.283

g, 74%). ¹H NMR (500 MHz, chloroform-d): δ 7.54 (d, J = 8.0 Hz, 2H),

7.30 (d, J = 7.9 Hz, 2H), 2.97 (t, J = 6.9 Hz, 2H), 2.79 (t, J = 6.9 Hz,

2H). ¹³C{¹H} NMR (126 MHz, chloroform-d): δ 142.2, 130.5, 129.5,

1.29.2, 125.4, 40.3, 35.4.

3,5-Dimethylbenzene Methanol (40, Table 6, Entry 1).^25c3,5-

Dimethylbenzoic acid (0.303 g, 2 mmol) was reacted with (iBu)₂AlBH₄

(1.9 mL, 2 mmol) in THF (2 mL) for 1 h. The product was isolated as a

yellow oil via the abovementioned procedure (0.122 g, 44%). ¹H NMR

(500 MHz, chloroform-d): δ 6.82 (s, 2H), 6.80 (s, 1H), 4.42 (s, 2H),

2.83 (s, 1H), 2.19 (s, 6H). ¹³C{¹H} NMR (126 MHz, chloroform-d): δ

140.8, 138.1, 129.2, 124.8, 65.3, 21.2.

2-Thiophen-3-ylethanamine (35, Table 4, Entry 4).^11b3-

Thiopheneacetonitrile (0.570 mL, 5 mmol) was reacted with

(iBu)₂AlBH₄(4.6 mL, 5 mmol) in THF (5 mL) for 1 h. The product

was isolated as an oil via the abovementioned procedure (0.451 g, 71%).

¹H NMR (500 MHz, chloroform-d): δ 7.19−7.16 (m, 1H), 6.91 (s,

1H), 6.86 (d, J = 5.1 Hz, 1H), 2.87 (t, J = 6.9 Hz, 2H), 2.71 (t, J = 6.9

Hz, 2H), 2.14 (s, 2H). ¹³C{¹H} NMR (126 MHz, chloroform-d): δ

140.0, 128.1, 125.6, 121.0, 42.6, 34.3.

4-(Chloromethyl)-benzene Methanol (41), (Table 6, Entry 2).^29a4-

(Chloromethyl)benzoic acid (0.689 g, 4 mmol) was reacted with

(iBu)₂AlBH₄(4.1 mL, 4.4 mmol) in THF (4 mL) for 1 h. The product

was isolated as a white solid via the abovementioned procedure (0.597

g, 95%). ¹H NMR (500 MHz, chloroform-d): δ 7.36 (d, J = 8.2 Hz, 2H),

7.31 (d, J = 8.0 Hz, 2H), 4.62 (s, 2H), 4.57 (s, 2H), 2.64 (s, 1H).

6222

https://doi.org/10.1021/acs.joc.0c03062

J. Org. Chem. 2021, 86, 6207−6227

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

¹³C{¹H} NMR (126 MHz, chloroform-d): δ 141.2, 136.8, 128.8, 127.2,

64.7, 46.0.

General Procedure for the Reduction of Amides Using

(iBu)₂AlBH₄. The following procedure for the reduction of N,N-

diethylbenzamide by (iBu)₂AlBH₄is representative of the amide

reductions. An oven-dried 50 mL round-bottom ﬂask equipped with a

magnetic stir bar was 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 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 min with stirring. Upon the completion of the

addition of (iBu)₂AlBH₄, the ice bath was removed and the reaction

mixture was allowed to stir at 25 °C for 1 h. The reaction mixture was

then concentrated under reduced pressure, and the reaction ﬂask was

recapped with a septum. Methanol (15 mL) was added slowly to the

residue (Caution! Hydrogen evolution) and was and stirred for 1 h at 25

°C. The reaction mixture was concentrated under reduced pressure to

give a white solid. Methanol (15 mL) followed by conc. HCl (12 M, 1

mL) was added, and the reaction reﬂuxed for 1 h using a heating mantle.

The reaction was ﬁltered and concentrated. Pentane (10 mL) and

deionized water (5 mL) were added to the ﬁltrate. The layers were

separated, and the aqueous layer was neutralized using NaOH_(s)until

the pH of the aqueous layer becomes 10. The aqueous layer was then

extracted with diethyl ether (3 × 10 mL). The combined organic layers

were dried with anhydrous MgSO₄, ﬁltered, and concentrated to aﬀord

the amine (0.653 g, 80%).

4-Methoxybeznene Methanol (42, Table 6, Entry 3).^25a4-

Methoxybenzoic acid (0.610 g, 4 mmol) was reacted with (iBu)₂AlBH₄

(4.1 mL, 4.4 mmol) in THF (4 mL) for 1 h. The product was isolated as

1

a colorless oil via the abovementioned procedure (0.657 g, 98%). H

NMR (500 MHz, chloroform-d): δ 7.31 (d, J = 8.1 Hz, 2H), 6.92 (d, J =

8.5 Hz, 2H), 4.91 (s, 1H), 4.63 (s, 1H), 3.83 (d, J = 1.7 Hz, 3H).

¹³C{¹H} NMR (126 MHz, chloroform-d): δ 159.2, 128.6, 113.9, 64.9,

55.3.

2-Bromobenzene Ethanol (43, Table 6, Entry 4).^29b2-Bromophe-

nylacetic acid (0.862 g, 4 mmol) was reacted with (iBu)₂AlBH₄(4.1

mL, 4.4 mmol) in THF (4 mL) for 1 h. The product was isolated as a

1

colorless oil via the abovementioned procedure (0.639 g, 79%). H

NMR (500 MHz, chloroform-d): δ 7.56 (d, J = 7.9 Hz, 1H), 7.28−7.25

(m, 2H), 7.12−7.08 (m, 1H), 3.89 (t, J = 6.7 Hz, 2H), 3.03 (t, J = 6.7

Hz, 2H), 1.62 (s, 1H). ¹³C{¹H} NMR (126 MHz, chloroform-d): δ

137.8, 132.9, 131.2, 128.2, 127.4, 124.7, 62.0, 39.3.

Representative Procedure for the Reduction of Esters Using

(iBu)₂AlBH₄. In an Ar-purged 100 mL round bottom ﬂask, the ester (5

mmol, 1 equiv) and anhydrous THF (5 mL) were combined.

(iBu)₂AlBH₄(5 mmol, 1 equiv) was added dropwise, and once all

(iBu)₂AlBH₄was added, the reaction mixture was allowed to stir for 3 h

at room temperature. The reaction mixture was quenched with

methanol (7 mL) and deionized H₂O (5 mL) (Caution! Hydrogen

evolution). A gel formed with the addition of methanol. The resulting

reaction mixture was ﬁltered, and the ﬁltrate was acidiﬁed with

concentrated HCl (12 M, 1 mL). The product was extracted with

diethyl ether (3 × 10 mL), and the combined organic extracts were

dried (MgSO₄) and concentrated to aﬀord the alcohol.

Benzyl Alcohol (2, Table 8, Entry 1).^25aColorless oil (0.530 g, 98%

yield) ¹H NMR (500 MHz, CDCl₃): δ 7.37−7.36 (m, 5H, J = 4.4 Hz),

4.68 (s, 2H), 1.85 (s, 1H); ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 140.8,

128.4, 127.4, 127.0, 64.7.

N,N-Diethylbenzylamine (49, Table 8, Entry 2).^31aColorless oil

(0.653 g, 80% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.35−7.31 (m,

5H), 3.58 (s, 2H), 2.53 (q, 4H, J = 5 Hz), 1.05 (t, 6H, J = 5 Hz);

¹³C{¹H} NMR (126 MHz, CDCl₃): δ 140.0, 129.1, 128.3, 126.9, 57.7,

Benzyl Alcohol (2, Table 7, Entry 1).^25aMethyl benzoate (0.328 mL,

3 mmol) was reacted with (iBu)₂AlBH₄(2.8 mL, 3 mmol) in THF (3

mL) for 1 h. The product was isolated as a colorless oil via the

abovementioned procedure (0.239 g, 74%). ¹H NMR (500 MHz,

chloroform-d): δ 7.40−7.29 (m, 5H), 4.60 (s, 2H), 3.17 (s, 1H).

¹³C{¹H} NMR (126 MHz, chloroform-d): δ 140.9, 128.5, 127.5, 127.0,

46.9, 11.9.

N,N-Diethyl-(3-methylbenzyl)amine (50, Table 8, Entry 3).^31b

Colorless oil (0.878 g, 99% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.21

(s, 1H), 7.17 (d, 1H, J = 7.4 Hz), 7.09 (d, 2H, J = 7.4 Hz), 3.58 (s, 2H),

2.57 (q, 4H, J = 7.1 Hz), 2.38 (s, 3H), 1.09 (q, 6H, J = 7.1 Hz); ¹³C{¹H}

NMR (151 MHz, CDCl₃): δ 139.5, 137.9, 130.0, 128.2, 127.8, 126.4,

57.6, 46.8, 21.6, 11.7.

64.9.

2-Bromo-benzene Methanol (44, Table 7, Entry 2).^30aMethyl 2-

bromobenzoate (0.42 mL, 3 mmol) was reacted with (iBu)₂AlBH₄(2.8

mL, 3 mmol) in THF (3 mL) for 1 h. The product was isolated as a

white solid via the abovementioned procedure (0.52 g, 93%). ¹H NMR

(500 MHz, chloroform-d): δ 7.55 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 7.6

Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 4.76 (s, 2H),

1.69 (br s, 1H). ¹³C{¹H} NMR (126 MHz, chloroform-d): δ 139.7,

132.6, 129.1, 128.9, 127.6, 122.6, 65.1.

N,N-Diisopropylbenzylamine (51, Table 8, Entry 4).^31aColorless

oil (0.947 g, 99% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.44 (d, 2H, J

= 7.4 Hz), 7.34 (d, 2H, J = 7.4 Hz), 7.24 (t, 1H, J = 7.4 Hz), 3.70 (s,

2H), 3.08 (dt, 2H, J = 12.9, 6.5 Hz), 1.09 (d, 12H, J = 6.5 Hz); ¹³C{¹H}

NMR (151 MHz, CDCl₃): δ 143.2, 128.0, 127.9, 126.1, 48.9, 47.8, 20.8.

N-Benzyl-N-methylpropan-1-amine (52, Table 8, Entry 5).^31c

2-Fluorobenzyl Alcohol (8, Table 7, Entry 3).^25bMethyl 2-

ﬂuorobenzoate (0.637 mL, 5 mmol) was reacted with (iBu)₂AlBH₄

(4.6 mL, 5 mmol) in THF (5 mL) for 1 h. The product was isolated as a

yellow oil via the abovementioned procedure (0.563 g, 89%). ¹H NMR

(500 MHz, chloroform-d): δ 7.45 (s, 1H), 7.31−7.28 (m, 1H), 7.17 (t, J

= 7.8 Hz, 1H), 7.07 (s, 1H), 5.08 (s, 1H), 4.78 (s, 2H). ¹³C{¹H} NMR

(126 MHz, chloroform-d): δ 161.5, 159.6, 129.2, 127.8, 124.2, 115.2,

58.9.

1

Colorless oil (0.750 g, 92% yield). H NMR (600 MHz, CDCl₃): δ

7.32−7.30 (m, 4H), 7.25−7.21 (m, 1H) 3.47 (s, 2H), 2.32 (d, 2H, J =

7.6 Hz), 2.18 (s, 3H), 1.53 (h, 2H, J = 7.4 Hz), 0.90 (t, 3H, J = 7.4 Hz);

¹³C{¹H} NMR (151 MHz, CDCl₃): δ 139.4, 129.2, 128.3, 127.0, 62.5,

59.7, 42.4, 20.7, 12.1.

1-(3-Bromo-4-methylbenzyl)pyrrolidine (53, Table 8, Entry 6).^31c

Colorless oil (1.131 g, 89% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.49

(s, 1H), 7.14 (m, 2H), 3.52 (s, 2H), 2.47 (m, 4H), 2.35 (s, 3H), 1.76−

1.74 (m, 4H); ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 139.0, 136.4,

132.7, 130.7, 128.0, 124.9, 59.9, 54.3, 23.6, 22.7.

4-(Bromomethyl)benzene Methanol (45, Table 7, Entry 4).^30b

Methyl 4-(bromomethyl)benzoate (0.688 g, 3 mmol) was reacted with

(iBu)₂AlBH₄(2.8 mL, 3 mmol) in THF (3 mL) for 1 h. The product

was isolated as a white solid via the abovementioned procedure (0.505

g, 84%). ¹H NMR (500 MHz, chloroform-d): δ 7.39 (d, J = 8.0 Hz, 2H),

7.35 (d, J = 8.2 Hz, 2H), 4.70 (s, 2H), 4.50 (s, 2H), 1.67 (s, 1H).

¹³C{¹H} NMR (126 MHz, chloroform-d): δ 141.1, 137.2, 129.2, 127.3,

64.9, 33.2.

1-(4-(Triﬂuoromethyl)benzyl)pyrrolidine (54, Table 8, Entry 7).^31d

Colorless oil (0.962 g, 84% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.49

(d, 2H, J = 8 Hz), 7.39 (d, 2H, J = 8 Hz), 3.61 (s, 2H), 2.47−2.44 (m,

4H, J = 6.6 Hz), 1.75−1.72 (m, 4H); ¹³C{¹H} NMR (126 MHz,

CDCl₃): δ 143.8, 129.1, 127.6, 125.3 (q, J_CF= 3.9 Hz), 60.3, 54.4, 23.7;

¹⁹F NMR (470 MHz, CDCl₃): δ −64.44.

3-Phenyl-1-propanol (46, Table 7, Entry 7).^30cEthyl 3-phenyl-

propionate (0.479 mL, 4.5 mmol) was reacted with (iBu)₂AlBH₄(4.6

mL, 4.95 mmol) in THF (4.5 mL) for 1 h. The product was isolated as a

N,N-Dimethylhexan-1-amine (55, Table 9, Entry 1).^31eColorless

oil (0.542 g, 84% yield). ¹H NMR (500 MHz, CDCl₃): δ 2.21−2.17 (m,

2H), 2.15 (s, 6H), 1.42−1.36 (m, 2H), 1.26−1.21 (m, 6H), 0.82 (t, 3H,

J = 6.8 Hz); ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 59.7, 45.1, 31.7, 27.3,

27.0, 22.4, 13.8.

1

colorless oil via the abovementioned procedure (0.558 g, 91%). H

NMR (500 MHz, chloroform-d): δ 7.25 (t, J = 7.6 Hz, 2H), 7.17 (d, J =

7.7 Hz, 3H), 3.60 (t, J = 6.5 Hz, 2H), 2.66 (t, J = 7.8 Hz, 2H), 2.41 (br s,

1H), 1.87−1.82 (m, 2H). ¹³C{¹H} NMR (126 MHz, chloroform-d): δ

141.8, 128.4, 125.8, 62.2, 34.2, 32.1.

1-Hexylpyrrolidine (56, Table 9, Entry 2).^31fColorless oil (0.683 g,

88% yield). ¹H NMR (500 MHz, CDCl₃): δ 2.42 (m, 4H, J = 5.6 Hz),

2.35−2.32 (m, 2H), 1.70 (q, 4H, J = 3.1 Hz), 1.47−1.40 (m, 2H), 1.22

6223

https://doi.org/10.1021/acs.joc.0c03062

J. Org. Chem. 2021, 86, 6207−6227

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(s, 6H), 0.85−0.79 (m, 3H); ¹³C{¹H} NMR (126 MHz, CDCl₃): δ

68.2, 62.2, 56.6, 54.1, 31.7, 28.9, 27.3, 23.2, 22.5, 13.9.

(0.492 g, 3 mmol, 1 equiv) and anhydrous THF (3 mL) were

combined. (iBu)₂AlBH₄(1.08 M, 2.8 mL, 3 mmol, 1 equiv) was added

dropwise, and once all the (iBu)₂AlBH₄was added, the reaction mixture

was allowed to stir for 5 h at −78 °C. The reaction mixture was

quenched with methanol (5 mL) (Caution! Hydrogen evolution). The

reaction mixture was evaporated followed by the addition of pentanes

(5 mL) and deionized H₂O (5 mL). The reaction mixture was ﬁltered,

and the ﬁltrate was acidiﬁed with HCl (1 M) to achieve pH ∼ 2. The

product was extracted with diethyl ether (3 × 10 mL). The combined

organic extracts were dried (MgSO₄) and concentrated to aﬀord the

alcohol as a white solid (0.272 g, 55%).

1-(2-Bromophenethyl)pyrrolidine (57, Table 9, Entry 3).^31g

1

Colorless oil (1.055 g, 83% yield). H NMR (500 MHz, CDCl₃): δ

7.47 (d, 1H, J = 8 Hz), 7.22−7.16 (m, 2H, J = 7.4 Hz), 7.00 (t, 1H, J =

8.4 Hz), 2.93 (dd, 2H, J = 9.8, 6.8 Hz), 2.66−2.62 (m, 2H), 2.57 (s,

4H), 1.77 (s, 4H); ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 139.9, 132.9,

130.8, 127.9, 127.6, 124.6, 56.5, 54.2, 36.0, 23.7.

1-Octylpyrrolidine (58, Table 9, Entry 4).^31hColorless oil (0.797 g,

87% yield). ¹H NMR (500 MHz, CDCl₃): δ 2.40 (app. t, 4H, J = 5.2

Hz), 2.34−2.31 (m, 2H), 1.68 (app. s, 4H), 1.20−1.19 (m, 12H), 0.79

(t, 3H, J = 7.0 Hz); ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 56.7, 54.1,

31.8, 29.5, 29.2, 29.0, 27.7, 23.3, 22.6, 14.0.

Methyl 4-(Hydroxymethyl)benzoate (63, Scheme 9).^25b¹H NMR

(500 MHz, chloroform-d): δ 8.02 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.0

Hz, 2H), 4.76 (s, 2H), 3.91 (s, 3H), 1.79 (s, 1H). ¹³C{¹H} NMR (126

MHz, chloroform-d): δ 166.9, 145.9, 129.8, 129.3, 126.4, 64.6, 52.1.

Reduction of Methyl-4-acetylbenzoate with (iBu)₂AlBH₄. In

an Ar-purged 100 mL round bottom ﬂask, methyl-4-acetylbenzoate

(0.530 g, 3 mmol, 1 equiv) and anhydrous THF (3 mL) were