Synthesis of Enantioenriched Amines by Iron-Catalysed Amination of Alcohols Employing at Least One Achiral Substrate

Article abstract of DOI:10.1002/adsc.202100231

The synthesis of a broad range of enantioenriched amines by the direct Fe-catalysed coupling of amines with alcohols through the borrowing hydrogen strategy, while at least one of these substrates is achiral is reported. When starting from α-chiral amines and achiral alcohols, a wide range of enantioenriched amine products, including N-heterocyclic moieties can be obtained with complete retention of stereochemistry and the power of this method is demonstrated in the one-step synthesis of known pharmaceuticals from commercially available, simple enantiopure primary amines and achiral alcohols. It was also found that the use of β-branched enantioenriched primary alcohols and achiral amines as reaction partners leads to a partial loss of stereochemical integrity in the final product, however, a systematic optimization enabled partial retention of enantiopurity and possible parameters effecting for racemization were identified. (Figure presented.).

Full text of DOI:10.1002/adsc.202100231

RESEARCH ARTICLE
DOI: 10.1002/adsc.202100231
Very Important Publication
Synthesis of Enantioenriched Amines by Iron-Catalysed
Amination of Alcohols Employing at Least One Achiral Substrate
Giovanni Bottari,a Anastasiia Afanasenko,a Antonio A. Castillo-Garcia,b
Ben L. Feringa,a,* and Katalin Bartaa, b,*
a
Stratingh Institute for Chemistry,
University of Groningen,
Nijenborgh 4, 9747 AG Groningen, The Netherlands
E-mail: B.L.Feringa@rug.nl
Institute of Chemistry,
b
University of Graz,
Heinrichstrasse 28, 8010 Graz, Austria
E-mail: katalin.barta@uni-graz.at
Manuscript received: May 29, 2021; Revised manuscript received: May 29, 2021;
Version of record online: ■■■, ■■■■
Dedicated to Prof. P. H. Dixneuf for his creative contributions in the field of Fe-catalysis
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100231
Abstract: The synthesis of a broad range of enantioenriched amines by the direct Fe-catalysed coupling of
amines with alcohols through the borrowing hydrogen strategy, while at least one of these substrates is achiral
is reported. When starting from α-chiral amines and achiral alcohols, a wide range of enantioenriched amine
products, including N-heterocyclic moieties can be obtained with complete retention of stereochemistry and
the power of this method is demonstrated in the one-step synthesis of known pharmaceuticals from
commercially available, simple enantiopure primary amines and achiral alcohols. It was also found that the use
of β-branched enantioenriched primary alcohols and achiral amines as reaction partners leads to a partial loss
of stereochemical integrity in the final product, however, a systematic optimization enabled partial retention of
enantiopurity and possible parameters effecting for racemization were identified.
Keywords: amination; borrowing hydrogen strategy; enantioenriched amines; homogeneous catalysis; iron
catalysis
Introduction
ever, despite remarkable progress in this field, the
development of enantioselective catalytic systems for
Enantiopure amines, particularly α-chiral amines, are the N-alkylation of amines with alcohols, that might be
key structural scaffolds in pharmaceuticals and bio- compatible with the hydrogen-transfer nature of this
logically active compounds, therefore the development method, has proven challenging and is currently under
of sustainable methods to access these moieties is of development (Scheme 1B).[5]
prime importance in catalysis research (Scheme 1A).[1]
Apart from introducing chirality during distinct
The direct coupling of alcohols with amines via the steps in the hydrogen borrowing sequence by enantio-
‘hydrogen borrowing’ methodology[2] has proven a pure auxiliaries,[6] catalyst[7] or ligands,[8] this method
highly efficient approach for the synthesis of diverse also offers the possibility of constructing chiral amines
amine products. This approach generates water as the of higher structural complexity by judicious selection
sole by-product, may utilize potentially biomass- of simple, available optically active amines and/or
derived alcohol substrates,[3] and could also be alcohols as starting materials, provided that no race-
performed applying non-noble metal catalysts.[4] How- mization occurs. Indeed, racemization of imines is a
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when enantiopure amines versus alcohols are used as
coupling partners.
Results and Discussion
We have earlier reported on the use of Knölker’s
complex (C1) in the Fe-catalysed N-alkylation of
amines with alcohols.[15] Herein, with the aim to access
chiral amine products, we examined the reaction of
(R)-phenylethylamine ((R)-PEA, 2a) with 1-pentanol
(1a) to generate chiral amine 3a using this method.
The initially applied reaction conditions with 2
equivalents of 1-pentanol (1a) and 6 mol% of C1 and
°
Me3NO, at 135 C in toluene resulted in 62% of pentyl
amine and 29% of the corresponding imine. Increasing
the amount of alcohol to 4 equivalents, an excellent
88% isolated yield of the desired amine 3a was
obtained without any loss of enantiopurity (chiral
HPLC analysis, see SI).
In further studies, the scope and limitations of the
newly established Fe-catalysed methodology were
investigated. A large variety of enantiopure benzyl-
amines and aliphatic amines were successfully con-
verted into the corresponding chiral N-pentyl substi-
tuted amines with good to excellent yield, with
complete retention of stereochemistry. Benzylamines
Scheme 1. A: Selected examples of pharmaceutically relevant
α-(first row) and β-chiral (second row) amines; B: Schematic
approach to the synthesis of chiral amines from enantiopure
amine or alcohol precursors via iron catalysis.
serious challenge, and this phenomenon is also with various meta-substituents afforded excellent iso-
industrially exploited by the formation of imines from lated yields of the target products regardless of the
chiral amines and benzaldehyde to facilitate racemiza- nature of the substituent (Scheme 2, 3b–3d, 81–86%).
tion via the formed azaenolates.[9]
Para-substituted N-alkylated phenylethylamines (3e–
The above-mentioned approach has been recog- 3g) were obtained in 62–90% isolated yields, among
nized as attractive by multiple groups: Fujita reported them using p-fluorobenzylamine as substrate gave the
the N-alkylation of chiral amines with achiral alcohols highest product yield (3g, 90%). In the latter case, the
catalysed by [Cp*IrCl2]2;[10] examples of optically reaction time was shortened to 8 h without significant
active amine substrates were employed by Williams;[11] change in yield (86% yield after 8 h vs 90% yield after
and our group demonstrated the N-alkylation of 24 h, 98% ee in both cases). Furthermore, sterically
unprotected amino acids with full retention of stereo- hindered chiral amines (3h, 3i) were smoothly
chemistry using achiral ruthenium-based catalysts.[12] converted to the desired products (87% and 79% yield,
Recently, Hultzsch[13] described the first example of respectively). Various exocyclic amines with a benzylic
using a PN3 manganese pincer complex for the chiral centre maintained their optical activity (3j, 3k);
synthesis of cinacalcet through the direct coupling of albeit slightly lower yields were obtained due to the
enantiopure naphthyl substituted amine with 3-(3- minor formation of N,N-dialkylated amines. Moderate
(trifluoromethyl)phenyl)propan-1-ol. Generally, while yields were detected employing enantiopure aliphatic
retention of chirality was observed with chiral amines, α-branched amines (3l, 3m): in these cases, the
racemization was prevalent when chiral alcohols were formation of minor amounts of the double N-alkylated
used as coupling partner with Ru and Ir based products (15-25%) was observed as well (for more
systems.[11,14] Very recently Donohoe[14d] has disclosed details, see SI, Supplementary Table 1).
an elegant iridium-catalysed annulation strategy for the
Next, aiming to obtain chiral tertiary amines, we
stereocontrolled synthesis of substituted saturated aza- investigated the effect of Lewis acid additives that can
heterocycles and observed partial racemization when be expected to enhance catalytic activity and N-
β-chiral alcohols were used as substrates.
alkylation. Previously, Zhao et.al. demonstrated that
Herein we report on the construction of a wide Lewis acids (up to 40 mol%) could improve the
variety of chiral amines, including N-heterocyclic catalytic activity of C1,[16] in the – otherwise sluggish
derivatives, and pharmacologically active compounds, – amination of secondary alcohols. In our hands, the
using a homogeneous catalyst based on non-noble addition of only 10 mol% Ni(OTf)2, directed the
metal Fe and investigate the causes of racemization reaction to the formation of N,N-dialkylated com-
pounds (3n, 3o) without loss of enantiopurity. This
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Scheme 3. Scope of N-heterocycles obtained through the reac-
tion between p-fluorophenylethylamine and selected diols.
General reaction conditions: 0.5 mmol (R)-2g, 1 mmol 4, 2 mL
°
toluene, C1 (6 mol%), Me3NO (6 mol%), 135 C, 24 h. Isolated
yields are shown. [a] 10 mol% Ni(OTf)2 was used.
such as methanol, ethanol, or cinnamyl alcohol as well
as a chiral diol as a coupling partner to benzylamine
substrates, with moderate success (see Supplementary
Information, Supplementary Table 2). Good func-
tional group tolerance was demonstrated using p-
nitrobenzyl alcohol (SI, Supplementary Table 2, en-
try 5). Moreover, a reaction between the aliphatic
pentyl amine and a chiral alcohol could be successfully
Scheme 2. N-Alkylation of α-chiral amines with 1-pentanol.
General reaction conditions: amine 2, 0.5 mmol), 1-pentanol performed, further extending the reaction scope.
(1a, 2 mmol), toluene (2 mL), C1 (6 mol%), Me3NO (6 mol%),
Next, in order to demonstrate the power and utility
of this methodology, we focused on the one-step
synthesis of pharmacologically relevant compounds
starting from simpler commercially available chiral
amines and appropriate alcohol precursors, using the
Fe-based Knölker’s complex (Scheme 4). (R)-Fendiline
[a]
°
135 C, 24 h. Isolated yields are shown.
reaction time are reported in parentheses. 10 mol% Ni(OTf)2
was used.
Results after 8 h
[b]
could be attributed to the configurational stability of is a Ca-channel blocker[18,19] that is used for the
the chiral iminium intermediate, formed in the second treatment of hypertension and coronary heart disease.
alkylation step (see also Scheme 6).
Remarkably, employing our optimized Fe-catalyzed
To further expand the scope of the reaction, we protocol, (R)-Fendiline could be afforded in 81% yield
turned our attention to the N-alkylation of (R)-p- and 99% ee (Scheme 4, left) in one step by directly
fluorophenylethylamine (2g) with potentially biomass- coupling (R)-1-phenylethylamine and 3,3-diphenylpro-
derived terminal diols, leading to the formation of pan-1-ol, which are both commercially available. The
four-, five- and six-membered N-heterocycles in good amine precursor could be also obtained by asymmetric
to excellent isolated yields (68–90%, 5a–5c, reductive amination of acetophenone with ammonia or
Scheme 3) without the loss of stereochemical integrity. its salts in presence of the ruthenium/C3-TunePhos
However, besides the target product, a minor amount
of the corresponding lactone was detected, the latter
likely originated from mono-dehydrogenation of the
diol, followed by intramolecular hemiacetal formation
and its subsequent dehydrogenation.[17] Other diols
such as 3-methylpentane-1,5-diol (4d) and 2,2’-biphe-
nyldimethanol (4e) furnished the desired products in
79% and 33% yields, respectively. The yield of the
azepane derivative (5e) could be significantly im-
proved to 80% by adding 10 mol% Ni(OTf)2 as was
discussed above.
Further investigations related to the scope of the
reactions included the use of diverse aliphatic alcohols
Scheme 4. The enantiopure amine drugs synthesized using the
Fe-based catalytic protocol (6 mol% C1, 6 mol% Me3NO,
°
0.5 mmol amine, 1.5 mmol alcohol, 2 mL toluene, 135 C,
24 h). Isolated yields are shown. The amine and the alcohol
moieties are represented in black and blue, respectively.
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Table 1. N-Alkylation of p-anisidine (6a) with (S)-2-methylbutanol (1b) under various reaction conditions.
Entry
Solvent
Temp.,
Cat.,
mol%
Additive,
mol%
Conv.,
%
7a[a],
%
8a[a],
%
ee[b],
%
°
C
1
2
3
Toluene
CPME
Octane
1,4-Dioxane
–
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
135
135
135
135
135
135
135
135
135
130
140
C1 (6), Me3NO (6)
C1 (6), Me3NO (6)
C1 (6), Me3NO (6)
C1 (6), Me3NO (6)
C1 (6), Me3NO (6)
C1 (6), Me3NO (6)
C1 (6), Me3NO (6)
C1 (10), Me3NO (10)
C2 (10)
–
–
–
–
74
60
60
42
85
99
75
93
91
86
96
37
24
30
11
68
90
48
65 (63)
60 (54)
72
37
36
30
31
17
9
27
28
31
14
41
84
70
74
46
76
6
18
80
96
96
96
4
5[c]
6
–
Ni(OTf)2 (10)
Mol. sieves
–
–
–
–
7
8
9
10
11
C2 (10)
C2 (10)
55
°
General reaction conditions: 6a (0.25 mmol), (S)-1b (1 mmol), C1 (6 mol%), Me3NO (6 mol%), solvent (1 mL), 135 C, 24 h.
[a] Determined by GC-FID.
[b] Determined by chiral HPLC.
[c] Neat (S)-2-methylbutanol (1b) was used. Isolated yields are in parentheses.
catalytic system.[20] The alcohol can be potentially suggesting a possible role of this oxidizing agent or the
synthesised through selective palladium-catalysed hy- formed Me3N in racemization.
drogenation of 3,3-diphenylallyl alcohol.[21]
Further, the scope of the reaction was extended by
One of the elegant early examples of utilizing examining various anilines as coupling partners to (S)-
hydrogen borrowing methods in the pharmaceutical 2-methylbutanol (1b) (Scheme 5). With anilines bear-
industry was the preparation of the calcimimetic agent
(R)-Cinacalcet[22] by Zentiva (Scheme 4, right), using
an iridium catalyst.[23] Applying our method, this
synthesis was successfully carried out with the iron-
catalyst C1 and (R)-Cinacalcet was obtained in good
isolated yield and excellent enantiopurity, offering a
viable non-noble metal-based alternative.
In order to determine whether racemization would
occur when a chiral alcohol is used as substrate, we
examined the model reaction between (S)-2-meth-
ylbutanol (1b) and p-anisidine (6a). This resulted in a
mixture of β-chiral amine 7a (37%) and a substantial
amount of the corresponding imine 8a (37%). Solvent
screening has not proven beneficial (Table 1, entries 1–
4). The use of Ni(OTf)2 and molecular sieves as acidic
additives improved this conversion (entries 6 and 7),
however also caused major racemization of the amine
product. Under neat reaction conditions, amine selec-
tivity increased to 68% (entry 5) and increasing the
catalyst loading to 10 mol% in toluene, the desired
amine was obtained with 63% isolated yield and 80%
ee (entry 8). Notably, a significant improvement in
terms of enantiopurity was achieved (80% ee with C1
– entry 8 vs 96% ee with C2 – entry 9) when the
acetonitrile complex C2 that does not require activa-
tion with Me3NO was used instead of Fe-catalyst C1,
Scheme 5. The N-alkylation of anilines with β-chiral alcohols.
General reaction conditions: 6 (0.25 mmol), 1 (1 mmol), C1
°
(10 mol%), Me3NO (10 mol%), solvent (1 mL), 135 C, 24 h.
a
Isolated yields and enantiomeric ratios are reported. Using C2
(10 mol%).
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ing electron-donating substituents (6a-b), including IVb)[8,14d] and/or amine to imine dehydrogenation (V to
those with bulky groups (6c), moderate to good IVa).
isolated product yields with high enantiopurity were
Aiming to shed light on the specific pathways
achieved (7a–c, 42–71%, 80–94% ee), whereas elec- responsible for the loss of chirality, isomerization of
tron-withdrawing substituents (6e) have shown a the chiral imine intermediate (Scheme 6B, IVa), and
deleterious effect on both amine selectivity and the possible dehydrogenation of the target amine
enantiomeric excess (7e, 38%, 76% ee).
product (Scheme 6B, V) were studied.
Aniline 6d afforded the corresponding N-alkylated
After the completion of the coupling reaction
amine 7d in moderate yield with almost full retention between p-anisidine (6a) with (S)-2-methylbutanol
of the streochemistry in the alcohol coupling partner. (1b) (Table 1, entry 1) sodium borohydride was added
Interestingly, 4-hydroxyaniline (6f) delivered a target to the crude mixture of corresponding amine (7a) and
amine product in good yield, however, almost full imine (8a) products and the mixture was heated for
°
racemization at the stereogenic centre was observed 24 h at 135 C; however, no changes in the enantio-
(7f, 68%, 20% ee).
meric ratio were detected. Furthermore, heating of the
Employing other β-branched chiral primary alco- isolated amine product 7a in the presence of C1 and
°
hols, the corresponding amines (7h–i) were obtained Me3NO in toluene at 135 C for 24 h did not cause any
with moderate isolated yields and good enantiopurity. racemization either, suggesting that the amine to imine
Notably, applying C2 as a catalyst, the yields obtained dehydrogenation (V to IVa) route is not likely. With
were comparable to those previously obtained with C1, regard to racemization via the imine-enamine tautome-
whereas the enantiomeric ratios were significantly rization (IVa to IVb), we investigated the reaction
higher as earlier noted (7a, 63%, 80% ee vs 54%, 96% between
ee).
p-anisidine
(6a)
with
(S)-2-meth-
°
ylbutyraldehyde in toluene at 135 C for 4 hours with
In order to rationalize the obtained experimental and without molecular sieves, respectively, and deter-
data, plausible racemization pathways during the mined the optical purity of the formed imine (Supple-
formation of the target chiral amine products synthe- mentary Note 3). Significant imine racemization was
sized from either chiral amine or alcohol are summar- observed in the presence of molecular sieves, while
ized in Scheme 6. In the case of N-alkylation of α- moderate racemization was observed in their absence.
chiral amines with achiral aliphatic alcohols, complete This may be due to the existence of the imine-enamine
retention of enantiopurity was observed in the target equilibrium, or could also originate from the configura-
amine products (Scheme 6A). This allows to rule out tional lability of the starting aldehyde. When samples
pathways potentially responsible for the loss of stereo- from such experiments were analysed at room temper-
1
chemistry with these substrates, namely amine to imine ature by H NMR spectroscopy, enamine signals could
dehydrogenation (III to IIIa)[24] and isomerization of not be confirmed under these conditions, however we
the chiral imine (IVa to IVb) formed through the cannot exclude this racemization pathway (see SI,
condensation reaction between the carbonyl compound Supplementary Note 1).
1
IIa and amine III. On the other hand, in the reaction
When the analogous H NMR experiments were
between optically active alcohols and anilines (Sche- performed by heating separately synthesised (S)-2-
me 6B), racemization occurred, which could be trig- methylbutyraldehyde[26] alone, in toluene at 135 C for
°
gered either by the tautomerization of the formed chiral 6 hours with and without molecular sieves or Me3NO,
aldehyde (IIa to IIb),[25] or imine intermediate (IVa to these experiments clearly revealed the corresponding
aldehyde/enol equilibrium (IIa to IIb tautomerization
took place) (see SI, Supplementary Note 2) in the
presence of both the studied additives.
The contribution of the in situ formed chiral
aldehyde on the racemization process (Scheme 6B,
IIa) was further evaluated by heating (S)-2-meth-
ylbutanol and C1 in presence of Me3NO, which
generated
a
small amount of (S)-2-meth-
ylbutyraldehyde in racemic form as identified by chiral
GC. The same experiment was repeated employing
C2, which does not require preliminary oxidative
activation. A 20:80 enantiomeric mixture was ob-
served, revealing the role of the additive in the
enolization of the chiral aldehyde. This last finding is
in line with the previously observed decrease in
stereoselectivity (vide supra) and 1H NMR data.
Scheme 6. The plausible mechanisms of iron-catalysed: (A)
amination of alcohols with α-chiral amines; (B) N-alkylation of
amines with chiral β-branched primary alcohols.
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times, then the amine (0.5 mmol), alcohol (4 equivalent, unless
otherwise stated in the manuscript) and degassed toluene
(2 mL) were sequentially added. The mixture was stirred at
Additionally, the effect of the molecular sieves on
enantiomeric excess of the target amine was inves-
tigated. The reaction between (R)-PEA (2a) and n-
pentanol (1a) with/without the addition of molecular
sieves furnished the mono-alkylated product with high
enantiopurity (99% ee) in both cases, whereas the
addition of the molecular sieves to the reaction
between p-anisidine (6a) and (S)-2-methylbutanol
(1b) caused major racemization. Molecular sieves
have previously shown to result in epimerization in
other reactions.[14c] The alkylation of 6a with 1b was
also monitored in time in presence/absence of molec-
ular sieves (Supplementary Figure 1) revealing sig-
nificant loss of chirality (37% ee) already after 6 h
reaction time in the presence of molecular sieves,
while minor racemization occurred without additive.
This could be explained by enolization of the config-
urationally labile intermediate chiral aldehyde, subse-
quently leading to the loss of stereochemical integrity
in the final amine product.
°
135 C (temperature of the oil bath) for the indicated time
(typically 24 h) and then cooled down to room temperature. The
solution was filtered over celite and analyzed by gas chromatog-
raphy to determine the conversion of the starting amine. The
product was isolated by column chromatography on silica gel
with pentane/ethyl acetate as eluent mixture and the enantio-
meric excess of the amine product was determined by either
chiral GC or HPLC (see details for each compound in the SI).
Acknowledgements
This work was financially supported by the People Programme
(Marie Curie Actions) of the European Union’s Seventh Frame-
work Programme FP7/2007–2013/ under REA grant agreement
no. 622724 (Asymm.Fe.Sus.Cat). K.B. is also grateful for
financial support from the European Research Council, ERC
Starting Grant 2015 (CatASus) 638076. This work is part of the
research programme Talent Scheme (Vidi) with Project Number
723.015.005, which is partly financed by The Netherlands
Organisation for Scientific Research (NWO).
Conclusion
In summary, we developed a general Fe-catalysed
method for the synthesis of enantiopure N-alkylated
amines starting from commercially available α-chiral
amines or β-chiral branched alcohols in the presence of
iron-based catalyst via the ‘hydrogen borrowing’
strategy. The described protocol was used for the
synthesis of N-heterocycles, employing biomass-de-
rived diols and applied for the synthesis of known
optically pure pharmaceuticals (Fendiline, Cinacalcet).
Notably, complete retention of stereochemistry in the
amine product was seen when starting with α-chiral
amines, whereas racemization, especially in the pres-
ence of molecular sieves, occurred when using β-chiral
alcohols as substrates. The extent of racemization was
influenced by the type of alcohol, as observed in
previous studies by Donohoe with iridium catalysis,
but could be controlled by the choice of appropriate
reaction conditions, especially by use of the
acetonitrile complex C2 as catalyst, that does not
require any activator and by avoiding molecular sieves.
To the best of our knowledge, this is the first general
Fe-catalysed method that allows constructing a wide
variety of α- and β-substituted enantioenriched higher
amines by one-step coupling of available alcohols and
amines, starting from at least one chiral substrate.
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Experimental Section
General procedure for the iron-catalyzed N-alkylation of
amines with alcohols: An oven-dried 20 mL Schlenk tube,
equipped with a stirring bar, was charged with the cyclo-
pentadienone iron complex C1 (0.03 mmol, 6 mol%) and
Me3NO (0.03 mmol, 6 mol%) or C2 (0.03 mmol, 6 mol%). The
Schlenk tube was evacuated and backfilled with argon for three
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RESEARCH ARTICLE
Synthesis of Enantioenriched Amines by Iron-Catalysed
Amination of Alcohols Employing at Least One Achiral
Substrate
Adv. Synth. Catal. 2021, 363, 1–8
G. Bottari, A. Afanasenko, A. A. Castillo-Garcia, B. L.
Feringa*, K. Barta*