Hitchhiker's Guide to Reductive Amination

Article abstract of DOI:10.1055/s-0037-1611788

A comparative study of various widely used methods of reductive amination is reported. Specifically, such reducing agents as H ₂, Pd/C, hydride reagents [NaBH ₄, NaBH ₃ CN, NaBH(OAc) ₃ ], and CO/Rh ₂ (OAc) ₄ system were considered. For understanding the selectivity and activity of the reducing agents reviewed herein, different classes of starting materials were tested, including aliphatic and aromatic amines, as well as aliphatic and aromatic aldehydes and ketones. Most important advantages and drawbacks of the methods, such as selectivity of the target amine formation and toxicity of the reducing agents were compared. Methods were also considered from the viewpoint of green chemistry.

Full text of DOI:10.1055/s-0037-1611788

SYNTHESIS
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Georg Thieme Verlag Stuttgart · New York
2019, 51, A–K
special topic
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de
Synthesis
E. Podyacheva et al.
Special Topic
Hitchhiker’s Guide to Reductive Amination
Evgeniya Podyachevaa
Oleg I. Afanasyeva
Alexey A. Tsygankova
Maria Makarovaa,b
Denis Chusov*a,c,d
a
Nesmeyanov Institute of Organoelement Compounds of the
Russian Academy of Sciences, Vavilova 28, Moscow 119991,
Russian Federation
Dmitry Mendeleev University of Chemical Technology of Russia,
b
Miusskaya sq. 9, Moscow 125047, Russian Federation
Peoples’ Friendship University of Russia, 6 Miklukho-Maklaya
c
Street, Moscow 117198, Russian Federation
denis.chusov@gmail.com
Moscow Institute of Physics and Technology, 9 Institutskiy per.,
d
Dolgoprudny, Moscow Region, 141700, Russian Federation
Published as part of the Special Topic Amination Reactions in
Organic Synthesis
Received: 14.02.2019
Accepted after revision: 12.03.2019
Published online: 17.04.2019
tures of these reducing agents both for laboratory practice
and industry. The convenience of NaBH , NaBH(OAc) , and
4
3
DOI: 10.1055/s-0037-1611788; Art ID: ss-2019-c0097-st
NaBH CN is in their physical solid state, these reagents are
3
relatively easy to handle and very convenient for small-
Abstract A comparative study of various widely used methods of re-
ductive amination is reported. Specifically, such reducing agents as H2,
scale laboratory synthesis. In comparison to NaBH , less ac-
4
tive NaBH(OAc) and NaBH CN are known to be much more
3
3
Pd/C, hydride reagents [NaBH4, NaBH CN, NaBH(OAc)3], and
3
selective and tolerant to potentially reducible functional
groups, which make the use of them very attractive for the
CO/Rh (OAc) system were considered. For understanding the selectivi-
2
4
ty and activity of the reducing agents reviewed herein, different classes
of starting materials were tested, including aliphatic and aromatic
amines, as well as aliphatic and aromatic aldehydes and ketones. Most
important advantages and drawbacks of the methods, such as selectivi-
ty of the target amine formation and toxicity of the reducing agents
were compared. Methods were also considered from the viewpoint of
green chemistry.
late-stage modification of complex molecules. According to
common belief given in the textbooks9 mild reagents
NaBH CN and NaBH(OAc)3 reduce rapidly iminium ions
3
while carbonyl compounds are not affected (Scheme 1).
However, possible releasing of boranes and hydrogen and
sensitivity to moisture and air are shortcomings of
NaBH(OAc) , NaBH CN, and NaBH . Moreover, sodium
Key words reductive amination, selectivity, atom efficiency, boro-
hydride, hydrogen, palladium, carbon monoxide
3
3
4
cyanoborohydride reductions require specialized disposal
of highly toxic reaction by-products, for example, HCN.
The important value for chemical industry is the con-
cept of atom economy10 and minimization of material and
energy wastes. In an ideal chemical process, all atoms of the
starting material are converted into the atoms of the target
products. In this context, borohydrides are far from ideal re-
Introduction
Reductive amination is one of the most versatile and
useful approaches for the preparation of amines in chemi-
cal and biological systems. The present work focuses on
comparison of the most widespread and powerful reducing
1
,2
3–5
agents such as H /Pd, NaBH , NaBH CN, NaBH(OAc) , and
ducing agents, while reductions with H gas clearly fit atom
2
4
3
3
2
6–8
CO/Rh system. Here we consider important chemical fea-
economical principle. But, H has another problem – low
2
R1 CH2OH
R1 CHO
Expectation
Ref. 9
NaBH3CN
R2
+
+
R1
N
R2 NH2
NaBH(OAc)3
H
?
Reality
Scheme 1 Reductive amination with mild reducing agents
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B
Synthesis
E. Podyacheva et al.
Special Topic
selectivity. System H , Pd/C can launch side reductions of
Results and Discussion
2
other reducible functional groups and hydrogenolysis in
addition to reductive amination. Besides, with regard to for-
mation of wastes, it is necessary to consider the handling of
not only the reaction itself but also the production of the
Although there are plenty of works in which reductions
there is no unified re-
ductive amination procedure for all types of carbonyl com-
with chosen agents are reported,1
3–15
1
6–21
pounds and amines. Conditions such as solvent,
tem-
can vary. Besides, some
additives are sometimes used in the processes: titanium
perature,2
2,23
and reaction time
24–26
reducing agents. In the case of H , steam methane reform-
2
ing is used to produce it from natural gas, which requires
two steps, high temperatures (750–800 °C), and separation
of gas mixture. Borohydride-based reducing agents require
even more labor-intensive manufacturing, which produces
lots of wastes.
2
7,28
isopropoxide and other Lewis acids for NaBH ,
AcOH, 3Å
HCl and CF3-
4
2
4,29,30
and 4Å molecular sieves for NaBH(OAc) ,
3
4,5,31
17
CO H for NaBH CN,
and AcOH for H /Pd. Thus, the first
2
3
2
goal of this work is to investigate the applicability of equal
conditions for reductive amination of different challenging
substrates for every chosen reducing agent and identify the
problems that will appear. Results are shown in Table 2. The
second aim is to point out possible ways to optimize reac-
tion conditions for those compounds, which would not be
obtained in more than 60% yield (Table 3).
Carbon monoxide is a waste of metallurgy,11,12 so it has
very low prime cost, although it requires separation of gas
mixture and additional purification. The main advantage of
CO/Rh system is lack of external hydrogen source, which
provides unique selectivity for this approach. CO promoted
by Rh-catalyst works both as a reducing agent and scaven-
ger of the oxygen atom. In this case, the only by-product is
carbon dioxide. Thus, after releasing of gases, almost no pu-
rification might be needed. The large drawback of carbon
monoxide is toxicity and flammability of this agent. How-
ever, toxicity of CO is not as high as it is generally thought.
Important physical and chemical characteristics of the re-
ducing agents are set out in Table 1.
Reductive Amination with H /Pd
2
In the case of reduction with H /Pd, several factors
2
made it impossible to obtain most of the target amines in
good yields. First, there is a side reduction of starting car-
bonyl compounds. Second, reduction of potentially reduc-
ible functional groups, for example, NO and Cl, proceeded.
2
Table 1 Physical and Chemical Characteristics of Reducing Agents
[
H]
H
2
/Pd
NaBH
4
NaBH(OAc)
3
NaBH
3
CN
CO/Rh
High Activity
Selectivity
Atom economy
Workup
Solid wastes
Solid wastes
Solid wastes
Extraction is needed
Extraction is needed
Extraction is needed
Flammability
Sensitivity to H
2
O and O
2
Toxicity
Low toxicityf
374
Cost, $/mol producti
1264
78
327
479
a
b
c
d
e
f
Extraction causes additional wastes of organic solvents.
Sigma-Aldrich, Safety Data Sheet.
Reducing agent does not react with water.
NaBH , NaBH(OAc) , and NaBH CN are decomposed in contact with large amounts of H O.
4 3 3 2
LD50 (Oral-Rat) = 162 mg/kg. Sigma-Aldrich, Material Safety Data Sheet, Mutagenic activity of emitted product B
LD50 (Oral-Rat) = 2000.0 mg/kg. Sigma-Aldrich, Safety Data Sheet.
Toxic compound, but no available LD50 data. Sigma-Aldrich, Safety Data Sheet.
LC50 (Inhalation-Rat) = 3760 ppm/h. Treatment continued for 14 h. Linde Gas North America LLC, Material Safety Data Sheet.
The price of the reagent/catalyst per mol product in case of 100% yield. For details, see Supporting Information.
2 6
H .
g
h
i
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E. Podyacheva et al.
Special Topic
Third, hydrogenolysis of compounds with Bn and Cbz
H for possible formation of Schiff base. Addition of H after
2
2
groups occurred under H , Pd/C system. Thus, aromatic al-
dehydes might be a problem for reductive amination pro-
preparation of imine should cause its reduction. Besides we
decreased the process temperature down to room tempera-
ture to reduce probability of other side reactions. After this
optimization, we obtained products 2, 3, and 8 in 40–48%
2
cess using H /Pd.
2
Though H , Pd/C showed the worst efficiency and selec-
2
tivity for selected substrates even at room temperature and
low pressure, it is notable that the reaction between 3-
phenylpropanal and anisidine proceeded better (61%) than
with other reducing agents. Similar result was obtained for
yields (Table 3). However, NO group was reduced again in
the reaction of 3-nitrobenzaldehyde with aniline. Besides,
the yields of products 6 and 10 decreased under mild condi-
2
tions. Selectivity of reductive amination with H could be
2
32
4-methoxybenzaldehyde and piperidine (64%). Other com-
improved through use of poisoned Pd/CaCO
catalyst or
3
other more selective catalysts,3
3,34
but our aim was to carry
pounds were prepared in 0–11% yields (Table 2). To prevent
the problem of reduction of starting material, we decided
first to mix carbonyl compounds, amines, and Pd/C without
out reductive amination by means of the simplest, commer-
cially available reagents.
Table 2 Reductive Amination Using Unified Procedure for Every Reducing Agent
R3
R4
O
H
N
reducing agent
N
+
R1
R2
R3
R4
R1
R2
c
CNd
H
2
/Pde
Product
Rh/COa
94%
NaBH b
4
NaBH(OAc)
99%
3
NaBH
3
O
N
H
94%
96%
92%
93%
82%
92%
0%
0%
Cl
1
O
N
H
84%
89%
93%
83%
HO
2
O
N
H
11%
N
3
O2N
Ph
N
H
8
6%
10%
32%
75%
>99%
23%
0%
0%
4
N
H
58–74%f
85%
5
O
2
1–25%f
27%
0%
52–66%f
33%
0%
61%
0%
Ph
N
H
6
H
N
8%
0%
O
7
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Synthesis
E. Podyacheva et al.
Special Topic
Table 2 (continued)
c
CNd
H
2
/Pde
Product
Rh/COa
NaBH b
4
NaBH(OAc)
13%
3
NaBH
3
Ph
N
>99%
0%
6%
0%
0%
0%
8
9
N
18%
<1%
14%
29%
84%
N
98%
57%
64%
0%
O
1
0
NHCBz
87–92%f
N
60%
40%
60%
H
1
1
a
Amine (1.2 equiv), carbonyl compound (1 equiv), Rh
Amine (1 equiv), carbonyl compound (1.2 equiv), and MeOH were refluxed for 2 h. Then 2 equiv of NaBH
2
(OAc)
4
(0.7 mol%), THF, 120 °C, 22 h, 50 atm.
b
4
were added and the reaction mixture was stirred at
c
3
(1.4 equiv), and DCE were stirred at r.t. for 18 h under argon.
Amine (1 equiv), AcOH (1 equiv), and MeOH were stirred. Then, carbonyl compound (1 equiv) and NaBH CN (2 equiv) in MeOH (1 mL) were added and the
3
reaction mixture was stirred for 24 h.
e
Amine (1 equiv), carbonyl compound (1 equiv), 10% Pd/C (5 mol%), EtOH, 40 °C, 24 h, 5 atm H
2
.
f
The range of yields is pointed out for several experiments.
Table 3 Optimization of Reductive Amination
R3
R1
R4
R2
O
H
N
reducing agent
solvent
N
+
R1
R2
R3
R4
yields were more than 60% in table 2
Rh/COa,b,c
NaBH
+ Ti(Oi-Pr)
d
or TiCl
e
NaBH(OAc)
+ AcOH or Ti(Oi-Pr)
f
d
NaBH
CN + Ti(Oi-Pr)
d
H
2
/Pdg
Product
4
4
4
3
4
3
4
O
N
H
0
%g
Cl
1
O
48%g
N
H
HO
2
O
41%g
N
H
N
3
O2N
Ph
N
H
7%d
0%g
7
4
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E. Podyacheva et al.
Special Topic
Table 3 (continued)
Rh/COa,b,c
NaBH
+ Ti(Oi-Pr)
d
or TiCl
e
NaBH(OAc)
+ AcOH or Ti(Oi-Pr)
f
d
NaBH
CN + Ti(Oi-Pr)
d
H
2
/Pdg
Product
4
4
4
3
4
3
4
N
H
>99%d
69%f
65%d
0%g
5
O
4
0%a
>99%d
>99%d
Ph
N
H
6
H
0%f
N
9%b
0%d
0%d
0%g
6
d
0%
O
7
8
9
Ph
N
%e
54%h
71%d
40%g
8
N
3%c
16%e
60–71%i
27%d
17%g
6
N
3
0%d
79%d
O
1
0
NHCBz
N
40%
4%g
H
1
1
a
b
c
Two equiv of p-anisidine were added. Reaction conditions: 160 °C for 22 h in toluene.
Reaction conditions: 160 °C for 48 h in THF.
Five equiv of i-Pr
2
NH were added. Reaction conditions: 140 °C for 2 h in THF.
Carbonyl compound, amine, and Ti(Oi-Pr) and anhydrous THF were placed in a dry Schlenk glassware under argon and stirred for 3 h. Then, THF was evaporat-
, NaBH(OAc) , or NaBH CN was added with the same solvent as in the unified procedure.
Same time and temperature for reduction were used as in the unified procedure for every reducing agent.
d
4
ed under reduced pressure and the corresponding reducing agent NaBH
4
3
3
e
Under these conditions instead of 2 equiv of Ti(Oi-Pr)
One equiv of AcOH was added to amine, carbonyl compound, and NaBH(OAc)
4
, 0.5 equiv of TiCl
4
was used in comparison to the procedure given in footnote d.
. Reaction time: 22 h.
f
3
g
2
Carbonyl compound, amine, and 1% of (10% Pd/C) were premixed and stirred overnight. Then, H (3 atm) was charged and the reaction mixture was stirred for
2
4 h.
h
Preparation of this substrate was conducted according to the unified procedure but over 48 h.
i
3
Preparation of this substrate was conducted at r.t. for 8 h using 10 mmol of reagents and 14 mmol of NaBH(OAc) .
Reductive Amination with NaBH4
confirmed by good to excellent yields (77–99%) of 4, 5, and
NaBH allows to afford high efficiency (93–96%) of re-
6 (Table 3). TiCl appeared to be more active in cases of 8
4
4
ductive amination between aromatic aldehydes with elec-
tron-withdrawing or electron-donating groups. However,
and 9. The yields of 8 and 9 with TiCl appeared to be 8–
4
16%, whereas Ti(Oi-Pr) was totally powerless in these cas-
4
the main drawback of reductive amination using NaBH is
es.
4
side reduction of starting carbonyl compounds. It was con-
firmed by several of our experiments (Table 2). According to
Interestingly, low efficiency of the reaction between 4-
methoxybenzaldehyde and piperidine (30%) even after ad-
dition of Ti(Oi-Pr)4 points out to difficulties in reductive
amination of secondary amines with aldehydes and ke-
tones. According to literature data, reductive amination
products between secondary amines and aldehydes or ke-
literature data, combination of NaBH and Ti(Oi-Pr)427 or
4
28
TiCl4 allows to improve the efficiency of reductive amina-
tion, thanks to preliminary formation of a Schiff base that is
subsequently reduced. Promoting ability of Ti(Oi-Pr) was
4
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F
Synthesis
E. Podyacheva et al.
Special Topic
tones with NaBH4 can be obtained in good yields using
more complicated methods. Process should be conducted in
the presence of silica gel-supported sulfuric acid, silica-
ments constituted 60–71%. Besides, we managed to in-
crease the yield of 8 up to 54% thanks to prolonged reaction
times. Similar to NaBH CN, in the case of NaBH(OAc) we
observed that it can reduce carbonyl compounds. We found
the corresponding alcohols in the reaction mixtures (Table
2, 6, 9).
35
3
3
3
6
37
supported boron sulfonic acid, or silica chloride. Effi-
ciency of the reaction can be improved also by using 2,2,2-
38
39
trifluoroethanol or ionic liquid as solvent. The literature
data showed possibility to carry out the reaction using
40
NaBH4 with Ti(Oi-Pr)4 between aromatic aldehyde and
secondary amine in good yield (82%).
Reductive Amination with NaBH CN
3
Five substrates were obtained in 57–99% yields using
the unified procedure with NaBH CN. Despite the softness
3
of NaBH CN, it did not afford to obtain all the substrates us-
3
ing the procedure without modifications. Necessity to carry
out the reaction in the presence of AcOH provokes side
aldol condensation particularly for 3-phenylpropanal. As in
the case of sodium borohydride, Ti(Oi-Pr) can be used to
increase yields for some substrates (Table 3). We decided to
4
Figure 1 Number of products synthesized using unified procedure
try it for reductive amination with NaBH CN. It was con-
3
firmed by increasing of the process efficiency for 5 (from
Reductive Amination with CO/Rh (OAc)
2
4
2
1
3% to 65%), 6 (from 33% to >99%), 8 (from 6% to 71%), and
0 (from 57% to 79%) (Table 3). This means that sodium cya-
Despite the fact that there are many protocols for reduc-
tive amination with CO, we chose Rh (OAc) as it is com-
2
4
noborohydride is an effective reducing agent in reductive
amination, however, its drawbacks make it necessary to
conduct the reactions in a certain pH interval with require-
ment of specialized disposal of highly toxic reaction by-
products such as HCN. It is commonly believed that
mercially available and most versatile.7 Eight substrates
were obtained in 60–99% yields using unified procedure
with CO/Rh (OAc) (Figure 1). Optimization was conducted
2
4
for reductive amination products 6, 7, and 9. While other
reducing agents turned out to be completely useless in the
synthesis of product 7 from camphor and anisidine, use of
CO/Rh (OAc) allowed us to obtain this product in 8% using
NaBH CN does not reduce carbonyl compounds under con-
ditions of reductive amination, but our experimental re-
3
2
4
sults showed that NaBH CN is able to reduce carbonyl com-
pounds.
unified conditions. At higher temperature and prolonged
reaction times the outcome increased up to 69%. It is worth
to mention that only exo-diastereomer of the product is
formed. In addition, we managed to increase outcome of
product 6 from 21–25% to 40% and product 9 from 18% to
63%, although, multiple aldol condensations appeared to be
a side processes in the case of 6. It is worth noting that
there are other catalysts for conducting process with car-
3
Reductive Amination with NaBH(OAc)3
Six substrates were obtained in 52–99% yields (Table 2)
using unified procedure with NaBH(OAc) (Figure 1). The
3
24
described method with AcOH led to an increase of the
yield of 5 up to 69% during 22 hours, while according to au-
thors’ data the outcome of the same compound comprises
41
bon monoxide such as Rh on Carbon Matrix, [(C Et )Rh(p-
4
4
8
42
43
5
5% for 10 days. The opposite scenario was obtained for 9.
xylene)]PF , anthracene rhodium complexes, and RuCl3,
6
24
In literature data, the yield of this compound was 88%, al-
though no precise protocol for this product was described.
In our hands, an average outcome of four equal experi-
which might provide such transformations. However, as for
H /Pd we did not try any other catalysts.
2
R1 CH2OH
R1 CHO
Expectation
Ref. 9
NaBH3CN
R2
+
+
R1
N
R2 NH2
NaBH(OAc)3
H
R1 CH2OH
Reality
Ref. 3,4,24 and this work
Scheme 2 Formation of alcohols under reductive amination conditions
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

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Synthesis
E. Podyacheva et al.
Special Topic
Table 4 Reaction Mass Efficiency (RME, %)
R3
R4
O
H
N
N
reducing
agent
+
+
+
solvent
+
by-products
R1
R2
R3
R4
R1
R2
Product
Rh/CO
NaBH
4
NaBH(OAc)
3
NaBH
3
CN
H
2
/Pd
0%
O
N
H
77%
75%
67%
63%
64%
62%
44%
39%
34%
51%
44%
47%
Cl
1
O
42%a
34%a
N
H
HO
2
O
N
H
N
3
O2N
Ph
N
H
21%b
24%b
6
7%
34%
23%
55%
0%
0%
4
N
H
15%b
72%
5
O
1
6
7
9%
5%
6%
26%b
23%
25%
39%
0%
Ph
N
H
6
H
N
0%
0%
0%
O
7
8
9
Ph
N
12%b
17%b
0%
34%
N
7
5%
7%
9%
0%
33%
29%
6%b
38%
3%a
N
4
13%b
O
1
0
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Synthesis
E. Podyacheva et al.
Special Topic
Table 4 (continued)
Product
Rh/CO
61%
NaBH
4
NaBH(OAc)
3
NaBH
3
CN
H
2
/Pd
0%
NHCBz
N
30%
31%
55%
H
1
1
Average RME
64%
27%
25%
31%
17%
Generalized RMEc
14.3%
0.55%
4.11%
0.99%
0.78%
a
2
Reaction conditions: 10% Pd/C (1%), 5 atm H , r.t.
Procedure with Ti(Oi-Pr) .
4
Solvents are taken into account in the calculation.
b
c
Functional Group Tolerance
Obviously, according to our results H /Pd showed the
duces lots of waste (low RME) or it is ecologically friendly
and usage of all the reagents is reasonable (high RME). RME
is an actually illustrative green chemistry metric because it
takes into account the yield of a product, which means that
it shows overall efficiency of the method. It is obvious from
Table 4 that using the hydride reagents, even if they furnish
the desired amines in good to excellent yields in many cas-
es, it still means producing solid wastes and average reac-
tion mass efficiencies of 25–31%. CO/Rh system showed the
highest average RME (64%), because it does not produce any
solid wastes and allows to obtain most of the desired prod-
2
worst tolerance to potentially reducible functional groups.
Nitro group was reduced by this agent, cleavage of C–N
bond in Cbz-protected amine as well as N-benzyl contain-
ing products was observed. Aldehydes and ketones were re-
duced to the corresponding alcohols. Notably, no reducing
agent was tolerant to starting carbonyl compounds. Return-
ing to Scheme 1, it can be said that in spite of statements in
textbooks that NaBH CN and NaBH(OAc) cannot reduce
3
3
carbonyl compounds, our experiments (Table 2, 6, 9) and
4,13,24
other literature data
pointed out the presence of the
ucts in good to excellent yields. Notably, H /Pd system
2
corresponding alcohols in reaction mixtures (Scheme 2).
However, sterically hindered ketones like camphor were
not reduced by tested reducing agents. Surprisingly, C–N
showed not as low RMEs as we could expect (17% average,
42% the highest), because despite its low selectivity to-
wards most of the reported reductive aminations, reduc-
bond in Cbz-protected amine was cleaved by NaBH , but ni-
tions by H are almost zero-waste. Significantly, when the
4
2
tro group persisted under reductive amination conditions
RMEs are counted taking into account the amounts of sol-
vents (Generalized RME, for more details see Supporting In-
formation), the values significantly decrease, which points
at the necessity of using less solvents in the reactions.
using NaBH , although according to literature data the re-
4
44
duction of NO group is possible. Such functional groups
2
as halogen, OH, pyridine fragments are resistant under used
conditions.
To sum up our results, several recommendations can be
given. First, for aromatic aldehydes and amines without po-
tentially reducible functional groups any of standard meth-
Conclusions
We have conducted a comparative study of five power-
ful methods of reductive amination. Various types of
amines were synthesized using these protocols, and com-
parison of the corresponding yields of the products allowed
us to evaluate the effectiveness and selectivity of each
method. We showed that hydride reducing agents, which
are thought to be the most selective towards reductive ami-
nation are indeed effective in many cases, however, they are
not always as perfect as it seems. In spite of common view-
ods except for H /Pd can be used. Second, if such groups, for
2
example, NO and Cl, are present in molecules, it is worth to
2
use more soft and selective NaBH CN, NaBH(OAc) , or
3
3
CO/Rh system. Third, to prevent side reduction of carbonyl
compounds, aldol condensation and also to increase reac-
tivity of ketones, additives such as Ti(Oi-Pr) or TiCl can be
4
4
used. Finally, for the synthesis of sterically hindered amines
by reductive amination CO/Rh system is more suitable.
point, we found that soft and selective NaBH CN and
3
NaBH(OAc) are able to reduce aldehydes, which was con-
3
Green Chemistry Metrics
firmed by analysis of literature data.3 Moreover, in cases
where sterically hindered substrate such as camphor is
used, CO/Rh system appeared to be the only effective reduc-
ing agent. Molecular hydrogen on Pd, being one of the most
atom-economical reducing agents, showed low selectivity
and is only effective in two cases reviewed herein. To con-
–5
To prove the efficiency and purity of the described
methods from the ecological point, we decided to count a
green chemistry metric for all of them, namely reaction
45
mass efficiency (RME). RME is the ratio of the mass of a
product to the mass of reagents. It shows if a method pro-
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

I
Synthesis
E. Podyacheva et al.
Special Topic
clude, we hope that this paper will be useful for under-
standing which method of reductive amination a chemist
should choose in different cases.
tion completion, the mixture was diluted with H O, and the product
2
extracted with CH Cl . The organic layer was dried (anhydrous
2
2
Na SO ), filtered, and evaporated. The yield of product was deter-
2
4
1
mined by H NMR with an internal standard.
General Procedure for Reductive Amination with H /Pd
2
Unless otherwise stated, all reagents were purchased from commer-
cial suppliers and used without further purification, THF was distilled
A glass vial in a 10 mL stainless autoclave was charged with 10% Pd/C
(5 mol %), amine (0.2 mmol), carbonyl compound (0.2 mmol), and a
over Na/benzophenone. CO of >98% purity was obtained from NII KM
Moscow, Russia). 1H and C spectra were recorded in CDCl3 and
13
magnetic stir bar. EtOH (0.5 mL) was added and the autoclave was
(
sealed and charged with 5 atm H at 40 °C. After heating for 24 h, the
2
DMSO-d on Bruker Avance 300, Bruker Avance 400, Varian Inova 400
6
reactor was cooled to r.t. and depressurized. The reaction mixture was
transferred to a flask and the autoclave was washed with CH Cl . The
spectrometers. Chemical shifts  are reported in ppm relative to the
solvent resonance signal as an internal standard. Standard abbrevia-
tions were used to designate chemical shift multiplicities. Coupling
constants are given in hertz (Hz).
2
2
combined solvents were removed on a rotary evaporator. The yield of
1
product was determined by H NMR with an internal standard.
General Procedures Under Optimized Conditions
Unified General Procedures
We consider that determining the yields by NMR with internal stan-
dard is highly reliable for comparing different protocols and gives less
error of measuring than isolated yields.
General Procedure for Reductive Amination with CO/Rh
The optimized conditions differ from unified ones by temperatures,
reaction times, solvents, and equivalents of reagents. Details are set
out in Supporting Information.
General Procedure for Reductive Amination with CO/Rh
A glass vial in a 10 mL stainless autoclave was charged with Rh (OAc)4
2
General Procedure for Reductive Amination with NaBH and
Ti(Oi-Pr)4
4
(0.7 mol%), amine (1.98 mmol), and carbonyl compound (1.65 mmol).
anhydrous THF (0.7 mL) was added and the autoclave was sealed,
flushed three times with 3 atm of CO, and then charged with 50 atm
CO. The reactor was placed in an oil bath preheated to 120 °C. After
heating for 22 h, the reactor was cooled to r.t. and depressurized. The
reaction mixture was transferred to a flask and the autoclave was
washed with CH Cl . The filtrate was passed through a small pad of
After removing traces of moisture and oxygen of air from the Schlenk
glassware, it was charged with carbonyl compound (0.24 mmol),
amine (0.2 mmol), Ti(Oi-Pr)4 (0.4 mmol), and anhydrous THF (1.5
mL). The reaction mixture was stirred at r.t. for 3 h under argon. Then,
THF was evaporated under reduced pressure. NaBH (0.4 mmol) and
4
2
2
MeOH (2 mL) were added and the reaction mixture was refluxed for 4
silica gel in order to remove the catalyst and the solvents were re-
moved on a rotary evaporator. The yield of product was determined
h. After reaction completion, the mixture was diluted with H O, and
2
1
the product extracted with CH Cl . The organic layer was dried (anhy-
by H NMR with an internal standard.
2 2
drous Na SO ), filtered, and evaporated. The yield of product was de-
2
4
1
termined by H NMR with an internal standard.
General Procedure for Reductive Amination with NaBH4
A 10 mL round-bottomed flask was charged with carbonyl compound
General Procedure for Reductive Amination with NaBH and TiCl
4
4
(0.24 mmol), amine (0.2 mmol), and MeOH (2 mL) and the mixture
After removing traces of moisture and oxygen of air from the Schlenk
glassware, it was charged with carbonyl compound (0.24 mmol),
was refluxed for 2 h. NaBH4 (0.4 mmol) was added to the reaction
mixture and the suspension was stirred at r.t. overnight. Then, the
mixture was refluxed for an additional 2 h. After reaction completion,
amine (0.2 mmol), TiCl (0.1 mmol), and anhydrous THF (1.5 mL). The
4
reaction mixture was stirred at r.t. for 3 h under argon. Then, THF was
the mixture was diluted with H O, and the product extracted with
2
evaporated under reduced pressure. NaBH (0.4 mmol) and MeOH (2
EtOAc. The organic layer was dried (anhydrous Na SO ), filtered, and
4
2
4
1
mL) were added and refluxed for 4 h. After reaction completion, the
evaporated. The yield of product was determined by H NMR with an
internal standard.
mixture was diluted with H O, and the product extracted with CH Cl .
2
2
2
The organic layer was dried (anhydrous Na SO ), filtered, and evapo-
2
4
1
rated. The yield of product was determined by H NMR with an inter-
nal standard.
General Procedure for Reductive Amination with NaBH(OAc)3
A 10 mL round-bottomed flask with an inlet for argon was charged
with carbonyl compound (0.2 mmol), amine (0.2 mmol), and 1,2-di-
chloroethane (0.7 mL). The mixture was stirred at r.t. under argon at-
General Procedure for Reductive Amination with NaBH(OAc) and
3
AcOH
mosphere for 15 min. NaBH(OAc) (0.28 mmol) was added to the mix-
3
A 10 mL round-bottomd flask with an inlet for argon was charged
with carbonyl compound (0.2 mmol), amine (0.2 mmol), glacial AcOH
ture and the suspension was stirred at r.t. under argon atmosphere for
1
8 h. The reaction mixture was quenched by adding sat. aq NaHCO3,
and the product extracted with EtOAc. The organic layer was dried
anhydrous Na SO ), filtered, and evaporated. The yield of product
(0.2 mmol), and 1,2-dichloroethane (0.7 mL). The mixture was stirred
at r.t. under argon atmosphere for 15 min. NaBH(OAc) (0.28 mmol)
(
3
2
4
1
was added to the reaction mixture. The suspension was stirred at r.t.
under argon atmosphere for 22 h. The mixture was quenched by add-
was determined by H NMR with an internal standard.
ing sat. aq NaHCO , and the product extracted with EtOAc. The organ-
3
General Procedure for Reductive Amination with NaBH CN
3
ic layer was dried (anhydrous Na SO ), filtered, and evaporated. The
2
4
1
A penicillin vial was charged with amine (0.2 mmol), glacial AcOH
yield of product was determined by H NMR with an internal stan-
dard.
(0.2 mmol), and MeOH (2 mL). After that, carbonyl compound (0.2
mmol) and a solution of NaBH CN (0.4 mmol) in MeOH (1 mL) were
3
added. The reaction mixture was stirred at r.t. overnight. After reac-
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

J
Synthesis
E. Podyacheva et al.
Special Topic
General Procedure for Reductive Amination with NaBH(OAc) and
Ti(Oi-Pr)4
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(
6) Ambrosi, A.; Denmark, S. E. Angew. Chem. Int. Ed. 2016, 26,
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2
4
1
yield of product was determined by H NMR with an internal stan-
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(
(
13) Abdel-Magid, A. F.; Mehrman, S. J. Org. Process Res. Dev. 2006,
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44, 1037.
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(
(
(
(
2
THF was evaporated under reduced pressure. NaBH CN (0.4 mmol)
3
and MeOH (2 mL) were added and stirred at r.t. overnight. After reac-
tion completion, the mixture was diluted with H O, and the product
2
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2
2010035166, 2010, 66.
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4
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mined by H NMR with an internal standard.
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General Procedure for Reductive Amination with H /Pd
2
A glass vial in a 10 mL stainless autoclave was charged with 10% Pd/C
(
1 mol %), amine (0.2 mmol), carbonyl compound (0.2 mmol), and a
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magnetic stir bar. EtOH (0.5 mL) was added and the autoclave was
sealed. The reaction mixture was stirred overnight at r.t. Then auto-
clave was charged with 3 atm H and the contents were stirred at r.t.
2
for 15 h. After reaction completion, the reactor was depressurized.
The mixture was transferred to a flask and the autoclave was washed
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Funding Information
This work was supported by the RFBR (grant numbers 18-33-20065,
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18-03-00839) and the Council of the President of the Russian Federa-
tion (Grant for Young Scientists No. MK- 1736.2019.3). D.C. is grateful
to the generous support of RUDN "5-100" program.
R
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n
F
o
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n
d
ati
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for
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asi
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(18-33-2
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5)R
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for
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(18-03-0
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8
3
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©
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