Scope and limitations of reductive amination catalyzed by half-sandwich iridium complexes under mild reaction conditions

Article abstract of DOI:10.1016/j.tetlet.2020.152196

The conversion of aldehydes and ketones to 1° amines could be promoted by half-sandwich iridium complexes using ammonium formate as both the nitrogen and hydride source. To optimize this method for green chemical synthesis, we tested various carbonyl substrates in common polar solvents at physiological temperature (37 °C) and ambient pressure. We found that in methanol, excellent selectivity for the amine over alcohol/amide products could be achieved for a broad assortment of carbonyl-containing compounds. In aqueous media, selective reduction of carbonyls to 1° amines was achieved in the absence of acids. Unfortunately, at Ir catalyst concentrations of <1 mM in water, reductive amination efficiency dropped significantly, which suggest that this catalytic methodology might be not suitable for aqueous applications where very low catalyst concentration is required (e.g., inside living cells).

Full text of DOI:10.1016/j.tetlet.2020.152196

Journal Pre-proofs
Scope and Limitations of Reductive Amination Catalyzed by Half-Sandwich
Iridium Complexes Under Mild Reaction Conditions
Dat P. Nguyen, Rudolph N. Sladek, Loi H. Do
PII:
S0040-4039(20)30661-4
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152196
TETL 152196
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
25 May 2020
22 June 2020
29 June 2020
Please cite this article as: Nguyen, D.P., Sladek, R.N., Do, L.H., Scope and Limitations of Reductive Amination
Catalyzed by Half-Sandwich Iridium Complexes Under Mild Reaction Conditions, Tetrahedron Letters (2020),
doi: https://doi.org/10.1016/j.tetlet.2020.152196
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover
page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version
will undergo additional copyediting, typesetting and review before it is published in its final form, but we are
providing this version to give early visibility of the article. Please note that, during the production process, errors
may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2020 Elsevier Ltd. All rights reserved.

1
Scope and Limitations of Reductive
Amination Catalyzed by Half-Sandwich
Iridium Complexes Under Mild Reaction
Conditions
Leave this area blank for abstract info.
Dat P. Nguyen, Rudolph N. Sladek, and Loi H. Do*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Scope and Limitations of Reductive Amination Catalyzed by Half-Sandwich Iridium
Complexes Under Mild Reaction Conditions
Dat P. Nguyen, Rudolph N. Sladek, and Loi H. Do*
aDepartment of Chemistry, University of Houston, Houston, Texas 77004, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The conversion of aldehydes and ketones to 1° amines could be promoted by half-sandwich
iridium complexes using ammonium formate as both the nitrogen and hydride source. To
optimize this method for green chemical synthesis, we tested various carbonyl substrates in
common polar solvents at physiological temperature (37 °C) and ambient pressure. We found
that in methanol, excellent selectivity for the amine over alcohol/amide products could be
achieved for a broad assortment of carbonyl-containing compounds. In aqueous media, selective
reduction of carbonyls to 1° amines was achieved in the absence of acids. Unfortunately, at Ir
catalyst concentrations of <1 mM in water, reductive amination efficiency dropped significantly,
which suggest that this catalytic methodology might be not suitable for aqueous applications
where very low catalyst concentration is required (e.g., inside living cells).
Available online
Keywords:
Reductive Amination
Green Chemistry
Transfer Hydrogenation
Iridium
Half-Sandwich Complexes

2
Introduction
Primary amines are ubiquitous in nature (e.g., in amino acids, nucleic acids, and alkaloids) and are key
components in numerous synthetic products such as dyes, pharmaceuticals, and agrochemicals.1-4 Because of
their central importance to both life and industry, the synthesis of 1° amines is a major focus in modern organic
chemistry. Conventional methods for the synthesis of 1° amines include reduction of nitrile/amide/nitro groups,5
alkylation of ammonia,6 and hydroamination of alkenes.7 One of the most attractive methods to prepare 1°
amines is reductive amination (RA) of aldehydes and ketones because it can be performed under mild reaction
conditions and tolerates a broad range of functional groups (Scheme 1).8 The RA process involves condensation
between carbonyl compounds with ammonia to generate imine intermediates that are subsequently reduced using
a hydride donor. Unfortunately, a common competing side reaction is the reduction of the starting carbonyl
compound to the corresponding alcohol.
The selection of suitable hydride reagents and reaction conditions are important factors in determining the
efficiency and selectivity of RA reactions. The most common reductants used for this application are sodium
cyanoborohydride (NaBH3CN),9 sodium triacetoxyborohydride (NaBH(OAc)3),10 organosilanes,11,12 and other
similar reagents (Scheme 2).13-15 Such reagents, however, can give poor chemoselectivity and generate
potentially non-innocent byproducts (e.g., cyanide and boron-containing species are toxic to cells in biological
applications). RA of aldehydes/ketones could also be achieved using metal catalysts in the presence of alkyl
amines and hydrogen gas to give 2° amines (hydrogenation)16,17 or ammonium formate to give 1° amines
(Leuckart-Wallach reaction).18 A disadvantage of the former is the use of flammable gas and a disadvantage of
the latter is the requirement for high temperatures (>120 °C).
One of the earliest examples of using organometallic catalysts for transfer hydrogenative reductive amination
was reported by Ogo/Watanabe and co-workers in 2001, who used pentamethylcyclopentadienyl (Cp*) iridium
catalysts and ammonium formate in water to convert aldehydes and ketones to 1° amines.19 Ogo and Fukuzumi
also discovered that Cp*Ir complexes were capable of furnishing α-amino acids from α-keto acids using excess
ammonium formate (20 equiv. relative to substrate) in aqueous solutions (pH = 5.0-6.5) at 80 °C.20 In 2002,
Kitamura and co-workers showed that [Cp*RhCl2]2 in combination with HCOONH4 was highly effective for the
chemoselective synthesis of 1° amines from ketones in methanol.21 In 2003, Kadyrov and co-worker achieved the
asymmetric RA of aromatic ketones by taking advantage of ruthenium catalysts in the presence of chiral ligands
and ammonium formate in ammonia/methanol solutions.22 Lastly, Xiao and co-workers developed
cyclometallated Cp*Ir complexes that efficiently provided 2° or 3° amines from ketones, 1° or 2° amines, and
azeotropic mixtures of formic acid/triethylamine.23 The synthesis of 1° amines was also achieved.24 Although the
examples above demonstrate the remarkable progress made in catalytic amine synthesis in recent years, some of
the methods required high temperatures (≥ 80 °C) and have poor chemoselectivity in water. RA in aqueous
solutions is particularly challenging because water is unfavorable for the formation of imines, which are key
reaction intermediates (Scheme 1).25
Because our research group is interested in biocompatible chemistry, we were intrigued by the prospect of
applying transfer hydrogenative RA in biological systems.26-28 A seminal report by McFarland and Francis in
2005 showed that lysozymes could be alkylated via reductive amination between lysine side chains and carbonyl
containing substrates using [Cp*Ir(bipyridine)OH2]2+ catalysts in the presence of sodium formate.29 This example
was noteworthy because the reactions were carried out under physiologically relevant conditions (pH 7.4
aqueous buffer, 37 °C) and were as efficient as classical protein conjugation methods such as lysine acylation or
reductive amination using sodium cyanoborohydride. Given our previous success in demonstrating that
[Cp*Ir(N-phenyl-2-
pyridinecarboxamidate)Cl] (Ir1) is capable of
promoting
intracellular
transfer
hydrogenation,30 we wanted to assess whether
such complexes could also mediate transfer
hydrogenative RA to afford 1° amines under
mild reaction conditions. Recently, Kuwata,
Watanabe, and co-workers reported a study
showing that Ir1 and related complexes could
Scheme 2. Methods for conversion of carbonyls to amines
be used with very low catalyst loading (e.g., substrate/catalyst ratio of up to 20,000) to achieve efficient transfer
hydrogenative RA.31 Unfortunately, these reactions were performed at temperatures ≥ 60 °C in methanol, which
are not suitable conditions for biological environments. In the present work, we report on the scope and
limitations of transfer hydrogenative reductive amination using organoiridium complexes in both methanol and
water at 37 °C. Our studies showed that
iridium-catalyzed RA reactions could
Scheme 1. Reductive amination (RA) of carbonyl compounds to give 1° amines

3
proceed with excellent selectivity for a variety of carbonyl substrates in polar organic solvents; however, catalyst
loading below 1.0 mM is not sufficient to achieve appreciable reaction rates for practical synthesis in aqueous
media.
Results and Discussion
Catalyst Screening. Pentamethylcyclopentadienyl iridium complexes are attractive catalysts because they are
air and water stable, can be easily prepared, and show excellent transfer hydrogenation activity.19,26,32 To
determine whether such catalysts could be employed for synthetically challenging applications, such as in
reactions involving thermally sensitive substrates or inside living environments, we evaluated a series of Ir
complexes in open air and mild temperatures. Our studies focused primarily on Cp*Ir N-heterocyclic-
carboxamidate complexes (Ir1-Ir9, Chart 1) because of their demonstrated ability to catalyze RA at ultra low
catalyst loading.31 For comparison, we also screened reactions using [Cp*Ir(N-tosylethylenediamine)Cl] (Ir10),27
[Cp*Ir(bipyridine)Cl]Cl (Ir11),33 and [Cp*Ir(PPh3)Cl2)] (Ir12)34 as examples of other common half-sandwich
complexes. All of these Ir complexes were synthesized according to reported procedures.
Table 1. Comparison of catalyst efficiency and chemoselectivitya
Temp. Conv.
2a
3a
4a
Entry
Cat.
Solvent
(°C)
25
37
37
37
37
37
37
37
37
37
37
37
37
37
37
37
37
37
37
(%)b
40
(%)b
(%)b
(%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14c
15c
16c
17c
18c
19
Ir1
Ir1
Ir2
Ir3
Ir4
Ir5
Ir6
Ir7
Ir8
Ir9
Ir10
Ir11
Ir12
Ir1
Ir1
Ir1
Ir1
Ir1
none
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
28
93
95
92
98
95
90
93
96
96
12
11
21
81
52
62
10
96
<1
12
7
5
4
2
5
10
7
4
4
67
59
29
<1
<1
<1
25
4
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
18
48
38
<1
<1
<1
>99
>99
96
>99
>99
>99
>99
>99
>99
80
71
50
>99
>99
>99
35
iPrOH
THF
MeCN
>99
<1
MeOH
<1
b
1
aReagents and conditions: 1a (100 µmol), Ir1 (1.0 µmol), HCOONH4 (200 µmol), solvent (0.5 mL), 15 h. Determined by H NMR
spectroscopy using 1,3,5-trimethoxybenzene as an internal standard. c10 equiv. of HCOONH4 was used.
Our initial studies were conducted in
methanol because it provided the best
solubility for the catalysts and reagents
(Table 1). At 25 °C, reaction of
benzaldehyde (1a) with
2
equiv. of
HCOONH4 using Ir1 gave only about 40%
conversion (Entry 1). The product
selectivity was poor, showing 28%
benzylamine (2a, product of reductive
amination) and 12% benzyl alcohol (3a,
product of direct reduction). Only trace
amounts of N-benzylformamide (4a) was
Chart 1. Organoiridium complexes tested in this study.

4
detected, which is presumably obtained from the condensation of benzylamine with formate. When the reaction
temperature was increased to 37 °C (Entries 2-10), complexes Ir1-Ir9 all gave excellent yield and selectivity for
benzylamine (> 90%) over benzyl alcohol (< 10%). The complex containing an electron-donating dimethylamino
group (Ir6, Entry 7) gave slightly more benzyl alcohol than the one containing an electron-withdrawing
trifluoromethyl group (Ir8, Entry 9). This result is consistent with our previous study,26,27 which found that
electron rich Ir6 was faster at reducing carbonyls than electron poor Ir8. Because reductive amination is a two-
step process (Scheme 1), the faster transfer hydrogenation catalyst Ir6 is actually less ideal for RA because it
could reduce carbonyl groups to alcohols before they undergo imine condensation. We found that when the
amount of HCOONH4 was increased to 10 equiv., relative to substrate, the formation of 3a by Ir1 in various
alcohol solvents was suppressed but significant quantities of 4a were obtained (Entries 14-16). When the solvent
was changed to either THF (Entry 17) or acetonitrile (Entry 18), formation of 4a was significantly reduced but
various amounts of 3a were observed (25% and 4%, respectively). These results indicate that the
chemoselectivity of the Ir catalysts is strongly influenced by their reaction conditions.
Interestingly, complexes Ir10-Ir12 showed moderate activity (< 80% conversion) and gave more alcohol than
amine products (Table 1, Entries 11-13), which demonstrated that Cp*Ir pyridinecarboxamidate complexes are
more efficient RA catalysts than other typical Ir half-sandwich complexes.
Table 2. Reductive amination of benzaldehydesa
Entry
Aldehyde
1a R = H
2 (%)b
81 (72c)
79 (92c)
87 (73c)
72 (84c)
97 (89c)
98 (90c)
48
3 (%)b
4 (%)b
18
21
11
21
<1
<1
26
9
1
2
<1
<1
2
1b R = p-OMe
1c R = p-Br
1d R = m-Br
1e R = o-Br
1f R = p-Cl
1g R = p-F
3
4
7
5
3
6
<1
26
4
7
8
1h R = p-NO2
1i R = m-NO2
1j R = o-NO2
1k R = p-CN
87 (81c)
9
86
4
10
21
28
10
11
71
8
63
9
aReagents and conditions: aldehyde (100 µmol), Ir1 (1.0 µmol), HCOONH4 (1.0 mmol), CH3OH (0.5 mL), 37 °C, 15 h. bDetermined
by 1H NMR with 1,3,5-trimethoxybenzene as internal standard, each experiment was performed in triplicate and the average yield was
c
calculated. Isolated yield. Some isolated yields of 2 were higher than their NMR yields because compound 4 was hydrolyzed to 2
during the workup step.
Benzaldehyde Substrate Scope. Using an excess of HCOONH4 to maximize the yield of 2/4, we examined
the benzaldehyde substrate scope using Ir1 (Table 2). The reaction of benzaldehyde with HCOONH4 (10 equiv.)
in methanol at 37 °C for 15 h led to complete consumption of starting material. High chemoselectivity of 2 over
3 was achieved in reactions with benzaldehyde (1a, Entry 1), p-methoxybenzaldehyde (1b, Entry 2), and p-
chlorobenzaldehyde (1f, Entry 6). Compounds containing bromo (1c-1e, Entries 3-5), nitro (1h-1j, Entries 8-10),
and nitrile (1k, Entry 11) groups gave minor amounts of alcohol in addition to the major amine product. Notably,
4-fluorobenzaldehyde (1g, Entry 7) was converted to significantly larger amounts of alcohol (26%) in
comparison to other aldehydes (<10%). The amine/alcohol product ratios for ortho-, meta-, and para-substituted
isomers (1c–1e and 1h-1j) varied but with no obvious trend. In most reactions, formamide by-products (4) were
detected in different amounts. Because formamide can be hydrolyzed to the free amine during the workup step,
its formation is not a major concern from a practical standpoint. Overall, our results suggest that RA of
benzaldehyde and its functionalized analogues (except for those bearing fluoro substituents) by Ir catalysts is
highly efficient in methanol.
Aromatic Ketone Substrate Scope. Kuwata, Watanabe, and co-workers demonstrated that high yields of
amines could be obtained from reactions of ketones and HCOONH4 promoted by Cp*Ir pyridinecarboxamidate

5
complexes at 60-80 °C.31 Using our standard reaction conditions, we screened a variety of aromatic ketones as
substrates (Table 3). We observed that most reactions produced exclusively RA products (i.e., amine 6 and
formamide 8), with almost no trace of alcohol 7. Only 4-acetylbenzonitrile 5h gave a minor amount of 7h in
addition to 6h (Entry 8). The high selectivity for amines over alcohol products is attributed to the reduced
electrophilicity and increased steric bulk of the C=O moieties in ketones compared to those in aldehydes.
Furthermore, we have demonstrated previously that reduction of ketones to alcohols by Ir catalysts/formate does
not occur readily.26
Table 3. Reductive amination of aromatic ketonesa
Conv.
6
(%)b
99
7
8
Entry
Ketone
R = Ph
R’ = Me
R = p-OMePh
R’ = Me
R = p-OHPh
R’ = Me
R = p-BrPh
R’ = Me
R = p-FPh
R’ = Me
R = p-NO2Ph
R’ = Me
R = m-NO2Ph
R’ = Me
R = p-CNPh
R’ = Me
(%)b
(%)b
(%)b
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
>99
>99
>99
>99
81
<1
<1
<1
<1
<1
<1
<1
4
<1
<1
<1
13
2
(96c)
>99
(93c)
>99
87
(82c)
79
92
>99
>99
>99
>99
8
(87c)
5g
5h
5i
>99
96
<1
<1
<1
R = Ph
R’ = CF3
O
98
<1
O
10
11
5j
>99
86
99
81
<1
<1
<1
<1
O
S
5k
O
12
5l
20
20
63
<1
<1
N
H
O
64
13
14
5m
5n
<1
0
<1
0
(>99d)
(70c,d
)
O
O
<1
0
aReagents and conditions: ketone (100 µmol), Ir1 (1.0 µmol), HCOONH4 (1.0 mmol), CH3OH (0.5 mL), 37 °C, 15 h. bDetermined by
1H NMR with 1,3,5-trimethoxybenzene as an internal standard. Each experiment was performed in triplicate and the average yield was
calculated. cIsolated yield. dReaction was run for 24 h.
In contrast to the acetophenone substrates that gave high conversion (Table 3, Entries 1-9), other aromatic
ketones were not as easily converted to amines. Although 2-acetylfuran 5j (Entry 10) gave quantitative yield of
amine, 2-acetylthiophene 5k (Entry 11) and 3-acetylindole 5l (Entry 12) exhibited only 86 and 20% conversion,
respectively. We hypothesized that the reduced yields of the latter substrates might be due to their metal
coordinating abilities, which may poison the iridium catalyst. The sterically congested ketone 9-fluorenone 5m
was successfully converted to the corresponding amine in 70% yield after 24 h (Entry 13). Although it has a
similar structure to that of 9-fluorenone, xanthone 5n did not undergo reductive amination (Entry 14).
Benzophenone 5o produced an unexpected product 6o (Scheme 3). This species most likely formed from imine
condensation between 5o and an in situ generated amine product. Because 6o has low solubility in methanol, it
readily precipitated out of solution and was isolated in 97% yield.

6
Ketoacid Substrate Scope. To explore further the versatility of transfer hydrogenative RA, we targeted a
variety of ketoacid substrates. Because the RA products of α-ketoacids are α-amino acids, this method could
provide easy access to both natural and unnatural polypeptide building blocks. In addition, α-amino acids are
important precursors for various pharmaceuticals, such as ampicillin,35 amoxicillin,36 resorcinomycin,37 and
pheganomycin.37
In the presence of Ir1 and HCOONH4 (10 equiv.) at 37 °C for 6 h, a wide range of ketoacids were converted to
the desired amino acids (Scheme 4 and Table S1). The natural α-amino acids glycine (10a), alanine (10b), and
Scheme 3. Reductive amination of benzophenone 5o.
Scheme 4. Reductive amination of ketoacids. Reagents and conditions: ketoacid (100 µmol), Ir1 (1.0 µmol), HCOONH4 (1.0 mmol),
CH3OH (0.5 mL), 37 °C, 6 h. Reactions were performed in triplicate and the average yields are shown above. Products were
quantified by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard. Isolated yields are shown with an asterisk
(*).
tyrosine (10d) were obtained in >90% yield, whereas phenylalanine (10c) and DOPA (10f) were obtained in 62
and 82% yield, respectively. The lower yields of the latter two compounds were attributed to product lost from
washing with methanol in the workup step. The unnatural α-amino acids, such as tert-leucine (10e),
phenylglycine (10g), 4-methylphenylglycine (10h), 4-methoxyphenylglycine (10i), and N-methyl-3-
indoleglycine (10j) were produced in ≥ 95% yield. Several other γ-ketoacids (10k, 10l) and δ-ketoacids (10m,
10n) were also converted into the corresponding amino acids with high efficiency (94–97% yield). Our results
were consistent with those reported by Kuwata, Watanabe, and co-workers, who showed that structurally diverse
amino acids could be obtained from transfer hydrogenation RA of ketoacids by Ir catalysts and HCOONH4.31
However, since the present studies were performed at 37 °C rather than under reflux, our reaction conditions are
more compatible with applications involving thermally sensitive molecules or biological environments.
Reactions in Aqueous Media and Possible Biological Relevance. Although the results above showed that
polar organic solvents (e.g., alcohol or acetonitrile) promoted selective transfer hydrogenative RA, the use of
water is preferred in terms of green chemistry38 and biological compatibility.28 However, examples of aqueous
RA are still relatively rare,20,32,39,40 particularly those that employ reaction temperatures below 80 °C.41,42 To
explore the feasibility of carrying out aqueous RA under physiological conditions, we conducted reactions using
Ir1 with formate/formic acid and pyruvic acid (9b) in water at 37 °C. Consistent with other reports,20,32 we found
that product selectivity was highly dependent on acid concentration. For example, reaction of Ir1 with pyruvic
acid and HCOONH4 produced a mixture containing 58% of alanine (10b) and 42% of lactic acid (11b) (Fig. S2).

7
In contrast, when sodium pyruvate was used instead of pyruvic acid, about 95% of the α-amino acid product was
obtained (Fig. S3). Importantly, in pH 7.4 aqueous solutions, such as phosphate buffered saline (PBS) or cell
growth media RPMI-1640, > 90% yield of alanine was achieved (Table S2). These results were surprising given
that other researchers reported transfer hydrogenative RA was most efficient at ~pH 5.20,32 However, we have not
yet conducted a detailed pH dependence study so we cannot comment on the optimal pH range of Ir1 at this
time.
Another important point to consider in terms of possible biological relevance is whether the iridium catalysts
could operate at appreciable rates in dilute solutions. For example, it is generally recommended that use of metal
catalysts inside living cells be restricted to concentrations as low as possible to minimize any potential
cytotoxicity issues.28 In these experiments, we kept the stoichiometry of Ir1, HCOONH4, and sodium pyruvate
constant in all reactions but only varied their concentrations (Table S3). We observed ≥ 80% reaction conversion
after 15 h at 37 °C when the concentration of Ir1 was 2.5 and 1.0 mM. Unfortunately, at 0.5, 0.2, and 0.1 mM
catalyst loading, the conversion dropped to 41, 12, and <1%, respectively (Fig. 1). These results were not entirely
surprising given we had found in prior work that the overall rate law for transfer hydrogenation was first-order in
the Ir1 complex.27 Additionally, because the IC50 (half maximal inhibitory concentration) of Ir1 in NIH-3T3
mouse fibroblast cells is about 0.1 mM,30 our data suggest that keeping Ir1 below its toxic threshold might not be
sufficient to enable fast catalysis inside cells. However, due to the complexity of cellular environments, such as
the possibility of catalyst aggregation within specific organelles,43 further biological studies are needed to assess
the capability of Ir1 to promote intracellular RA reactions.
Conclusion
In summary, we have shown that [Cp*Ir(N-phenyl-2-pyridinecarboxamidate)Cl] and related complexes are
excellent catalysts for converting aldehydes and ketones to 1° amines using HCOONH4 as both the hydride and
nitrogen donor. This work has expanded upon other studies by demonstrating that aqueous transfer
hydrogenative RA could be carried out at mild temperatures (37 °C) and in many cases, with excellent selectivity
of amine over alcohol products. A broad range of substrates was tolerated, including ketoacids and sterically
Figure 1. Comparison of reaction efficiency as a function of catalyst concentration. Reaction conditions: Ir1, HCOONH4, and sodium
pyruvate in 0.5 mL of H2O at 37 °C for 15 h. See Table S3 for more details.
hindered carbonyls. Product selectivity in water was highly pH dependent, in which neutral and pH 7.4 buffered
solutions gave appreciable yields of the desired amine product. A limitation of these Ir complexes is that they are
not efficient catalysts at concentrations below 1 mM in water, which may be problematic for applications
requiring low catalyst loading. For intracellular reactions, this problems could perhaps be mitigated by taking
advantage of polymeric vesicles44 or other delivery systems to increase catalyst and substrate accumulation inside
cells.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could
have appeared to influence the work reported in this paper.
Acknowledgements
We are extremely grateful to the Welch Foundation (Grant No. E-1894) and National Institute of General
Medical Science of the NIH (Grant No. R01GM129276) for financial support.

8
Appendix A. Supplementary data
Supplementary data to this article can be found online at https:///
References
(1) Henkel, T.; Brunne, R. M.; Müller, H.; Reichel, F. Angew. Chem. Int. Ed. 1999, 38, 643-647.
(2) Berger, M.; Albrecht, B.; Berces, A.; Ettmayer, P.; Neruda, W.; Woisetschläger, M. J. Med. Chem. 2001, 44,
3031-3038.
(3) Salvatore, R. N.; Yoon, C. H.; Jung, K. W. Tetrahedron 2001, 57, 7785-7811.
(4) Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Keßeler, M.; Stürmer, R.; Zelinski, T. Angew. Chem. Int. Ed.
2004, 43, 788-824.
(5) Satoh, T.; Suzuki, S.; Suzuki, Y.; Miyaji, Y.; Imai, Z. Tetrahedron Lett. 1969, 10, 4555-4558.
(6) Fujita, K.-i.; Furukawa, S.; Morishima, N.; Shimizu, M.; Yamaguchi, R. ChemCatChem 2018, 10, 1993-1997.
(7) Müller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675-704.
(8) Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451-3479.
(9) Barney, C. L.; Huber, E. V.; McCarthy, J. R. Tetrahedron Lett. 1990, 31, 5547-5550.
(10) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849-
3862.
(11) Apodaca, R.; Xiao, W. Org. Lett. 2001, 3, 1745-1748.
(12) Patel, J. P.; Li, A.-H.; Dong, H.; Korlipara, V. L.; Mulvihill, M. J. Tetrahedron Lett. 2009, 50, 5975-5977.
(13) Ranu, B. C.; Majee, A.; Sarkar, A. J. Org. Chem. 1998, 63, 370-373.
(14) Kim, S.; Oh, C. H.; Ko, J. S.; Ahn, K. H.; Kim, Y. J. J. Org. Chem. 1985, 50, 1927-1932.
(15) Grenga, P. N.; Sumbler, B. L.; Beland, F.; Priefer, R. Tetrahedron Lett. 2009, 50, 6658-6660.
(16) Werkmeister, S.; Junge, K.; Beller, M. Green Chem. 2012, 14, 2371-2374.
(17) Bhor, M. D.; Bhanushali, M. J.; Nandurkar, N. S.; Bhanage, B. M. Tetrahedron Lett. 2008, 49, 965-969.
(18) Alexander, E. R.; Wildman, R. B. J. Am. Chem. Soc. 1948, 70, 1187-1189.
(19) Ogo, S.; Makihara, N.; Kaneko, Y.; Watanabe, Y. Organometallics 2001, 20, 4903-4910.
(20) Ogo, S.; Uehara, K.; Abura, T.; Fukuzumi, S. J. Am. Chem. Soc. 2004, 126, 3020-3021.
(21) Kitamura, M.; Lee, D.; Hayashi, S.; Tanaka, S.; Yoshimura, M. J. Org. Chem. 2002, 67, 8685-8687.
(22) Kadyrov, R.; Riermeier, T. H. Angew. Chem. Int. Ed. 2003, 42, 5472-5474.
(23) Wang, C.; Pettman, A.; Bacsa, J.; Xiao, J. Angew. Chem. Int. Ed. 2010, 49, 7548-7552.
(24) Talwar, D.; Salguero, N. P.; Robertson, C. M.; Xiao, J. Chem. Eur. J. 2014, 20, 245-252.
(25) Wei, Y.; Wu, X.; Wang, C.; Xiao, J. Catal. Today 2015, 247, 104-116.
(26) Ngo, A. H.; Ibañez, M.; Do, L. H. ACS Catal. 2016, 6, 2637-2641.
(27) Ngo, A. H.; Do, L. H. Inorg. Chem. Front. 2020, 7, 583-591.
(28) Ngo, A. H.; Bose, S.; Do, L. H. Chem. Eur. J. 2018, 24, 10584-10594.
(29) McFarland, J. M.; Francis, M. B. J. Am. Chem. Soc. 2005, 127, 13490-13491.
(30) Bose, S.; Ngo, A. H.; Do, L. H. J. Am. Chem. Soc. 2017, 139, 8792-8795.
(31) Tanaka, K.; Miki, T.; Murata, K.; Yamaguchi, A.; Kayaki, Y.; Kuwata, S.; Ikariya, T.; Watanabe, M. J. Org.
Chem. 2019, 84, 10962-10977.
(32) Lei, Q.; Wei, Y.; Talwar, D.; Wang, C.; Xue, D.; Xiao, J. Chem. Eur. J. 2013, 19, 4021-4029.
(33) Youinou, M.-T.; Ziessel, R. J. Organomet. Chem. 1989, 363, 197-208.
(34) Kang, J. W.; Moseley, K.; Maitlis, P. M. J. Am. Chem. Soc. 1969, 91, 5970-5977.
(35) Rafailidis, P. I.; Ioannidou, E. N.; Falagas, M. E. Drugs 2007, 67, 1829-1849.
(36) Todd, P. A.; Benfield, P. Drugs 1990, 39, 264-307.
(37) Ogasawara, Y.; Ooya, K.; Fujimori, M.; Noike, M.; Dairi, T. J. Antibiot. 2016, 69, 119-120.
(38) Simon, M.-O.; Li, C.-J. Chem. Soc. Rev. 2012, 41, 1415-1427.
(39) Wei, Y.; Wang, C.; Jiang, X.; Xue, D.; Li, J.; Xiao, J. Chem. Commun. 2013, 49, 5408-5410.
(40) Wang, S.; Huang, H.; Bruneau, C.; Fischmeister, C. Catal. Sci. Technol. 2019, 9, 4077-4082.
(41) Gülcemal, D.; Gülcemal, S.; Robertson, C. M.; Xiao, J. Organometallics 2015, 34, 4394-4400.
(42) Özbozkurt, İ. K.; Gülcemal, D.; Günnaz, S.; Gökçe, A. G.; Çetinkaya, B.; Gülcemal, S. ChemCatChem 2018, 10,
3593-3604.
(43) Conesa, J. J.; Carrasco, A. C.; Rodríguez-Fanjul, V.; Yang, Y.; Carrascosa, J. L.; Cloetens, P.; Pereiro, E.;
Pizarro, A. M. Angew. Chem. Int. Ed. 2019, 59, 1270-1278.
(44) Soussan, E.; Cassel, S.; Blanzat, M.; Rico-Lattes, I. Angew. Chem. Int. Ed. 2009, 48, 274-288.

Declaration of interests

9
X The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be
considered as potential competing interests:


Highlights
 Half-sandwich Ir complexes show excellent chemoselectivity under optimized
reaction conditions.
 Reactions could be performed at 37 °C under air.
 A variety of natural and unnatural amino acids could be synthesized.