Direct Catalytic N-Alkylation of α-Amino Acid Esters and Amides Using Alcohols with High Retention of Stereochemistry

Article abstract of DOI:10.1002/cssc.202100373

The direct functionalization of naturally abundant chiral scaffolds such as α-amino acid esters or amides with widely abundant alcohols, without any racemization, is a demanding transformation that is of central importance for the synthesis of bio-active compounds. Herein a robust and general method was developed for the direct N-alkylation of α-amino acid esters and amides with alcohols. This powerful ruthenium-catalyzed methodology is atom-economic, base-free, and allowed for excellent retention of stereochemical integrity. The use of diphenylphosphate as additive was crucial for significantly enhancing reactivity and product selectivity. Notably, the only by-product was water and both substrates could be potentially derived from renewable resources.

Full text of DOI:10.1002/cssc.202100373

Communications
doi.org/10.1002/cssc.202100373
ChemSusChem
Direct Catalytic N-Alkylation of α-Amino Acid Esters
and Amides Using Alcohols with High Retention of
Stereochemistry
Tao Yan,[a] Ben L. Feringa,[a] and Katalin Barta*[a, b]
The direct functionalization of naturally abundant chiral scaf-
folds such as α-amino acid esters or amides with widely
abundant alcohols, without any racemization, is a demanding
transformation that is of central importance for the synthesis of
bio-active compounds. Herein a robust and general method
was developed for the direct N-alkylation of α-amino acid esters
and amides with alcohols. This powerful ruthenium-catalyzed
methodology is atom-economic, base-free, and allowed for
excellent retention of stereochemical integrity. The use of
Figure 1. Important pharmaceutically active compounds containing a chiral
N-alkyl amino acid ester or amide moiety.
diphenylphosphate as additive was crucial for significantly
enhancing reactivity and product selectivity. Notably, the only
by-product was water and both substrates could be potentially
derived from renewable resources.
N-alkyl amino acid esters and amides are frequently encoun-
tered chiral moieties in bioactive compounds (Figure 1). For
example, Cilazapril[1a] and Enalapril[1b] are enzyme inhibitors,
while Ximelagatran is an anticoagulant that has been inves-
tigated as an alternative for warfarin therapy.[1c] Furthermore,
Lidocaine and Bupivacaine are well-known and widely used
drug molecules that are included in the World Health Organ-
ization (WHO) list of essential medicines.[2] Traditional pathways
to obtain N-alkyl amino acid esters commonly include reductive
amination of aldehydes or nucleophilic substitution with alkyl
halides (Scheme 1A).[3] While the former pathway[3b,c] may be
limited by the availability and stability of the aldehyde
substrates as well as the formation of side products, the latter
pathway[3d,e] generally suffers from poor selectivity and atom
economy due to the formation of stoichiometric amount of
undesired halogen-containing salts.
Scheme 1. Synthesis of functionalized N-alkyl amino esters and amides via
N-alkylation of amino acids and/or esters.
[a] T. Yan, Prof. B. L. Feringa, Prof. K. Barta
Stratingh Institute for Chemistry
University of Groningen
Nijenborgh 4, 9747 AG Groningen (The Netherlands)
E-mail: k.barta@rug.nl
[b] Prof. K. Barta
Alcohols are vastly abundant substrates[4] and would be
optimal alkylation agents and excellent alternatives to the
commonly used alkyl-halogenides or aldehydes. Despite tre-
mendous developments in catalytic borrowing hydrogen
strategies[5,6] the direct N-alkylation of natural amino acid esters
via this methodology has remained largely unaddressed and
there is lack of general methods that would allow for preserving
the valuable chiral information in the amino acid backbone.
While there are a number of examples that involve the use of
chiral substrates,[6f] to the best of our knowledge, only one
example for the N-alkylation of an unnatural amino acid ester
has been reported employing an Ir-based homogeneous
Institute for Chemistry
University of Graz
Heinrichstrasse 28/II, 8010, Graz (Austria)
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catalytic system and 1,5-pentane-diol, which was limited to
using NaHCO3 as base and a substrate that comprised a
quaternary stereocenter (Scheme 1B).[7] Indeed, most of the
borrowing hydrogen methodologies rely on the use of a base
for activation of the catalyst or substrates.[6] Considering the use
of natural amino acid esters as substrates, the chiral α-carbon
would be sensitive to racemization due to its acidic proton in
the presence of a base, as previously described.[8]
In order to accomplish the challenging N-alkylation of
natural or synthetic amino acid esters with alcohols without
racemization on α-carbon, a robust, base-free catalyst system is
needed. Importantly such catalyst should be tolerant to strong
chelating coordination of the highly functionalized amino acid
ester or amide substrates or derived reaction intermediates
(Scheme 1C) that may block important coordination sites and
thus might slow or shut down catalysis.[9]
well as the direct amination of β-hydroxyl acid esters[13] and the
decarboxylative N-alkylation of cyclic amino acids with
alcohols[14] using the Ru-based Shvo’s catalyst[15] (Cat 1). These
findings serve as excellent starting point for establishing a novel
catalytic methodology for the direct coupling of amino acid
amides and esters with alcohols (Scheme 1). Initial study
revealed that amino acid esters behave differently from
unprotected amino acids, since the lack of free carboxylic acid
moiety may influence the imine formation or reduction rates
and transesterification may also occur at higher temperatures.
The method requires unique reaction conditions (temperature,
catalyst loading, potential additives) to allow for sufficiently
facile imine formation and reduction without competing side
reactions (i.e., transesterification, dialkylation) and avoiding
racemization (Scheme 2).
To establish suitable conditions for the selective N-alkylation
of amino acid esters, we have selected phenylalanine pentyl
ester (1a) and 4-methylbenzyl alcohol (2a) as substrates and
We have previously introduced the first homogeneous Fe-
catalyzed direct N-alkylation of amines with alcohols (with
Knölker’s complex)[10] without any addition of base.[11] Next, we
have also developed a powerful, base-free method for the
direct coupling of unprotected amino acids with alcohols[12] as
°
toluene as the solvent. The use of 0.5 mol% Cat 1, at 120 C for
18 h, gave full conversion of 1a, but only 55% selectivity of the
desired mono-alkylation product 3a (Table 1, entry 1) due to
the formation of 35% alkylated transesterification side product,
as expected. With the benzyl ester of phenylalanine (1b) the
reaction was more sluggish, displaying only 69% conversion
°
(Table 1, entry 2). Lowering the reaction temperature to 90 C
with phenylalanine pentyl ester (1a) gave minimal (<5%)
conversion (Table 1, entry 3), but no transesterification was
seen.
Realizing that at lower temperatures the competing trans-
esterification step is much less pronounced, we have searched
°
for alternative ways to enhance reactivity at 90 C, by employing
an appropriate Brønsted acid co-catalyst. Previous studies have
described cooperative catalysis in ruthenium-catalyzed imine
Scheme 2. Reaction scheme of mono N-alkylation of amino acid esters:
desired product and possible side reactions.
Table 1. Direct N-alkylation of l-phenylalanine ester with 4-methylbenzyl alcohol.[a]
Entry
R2/1
2a
[equiv.]
solvent
co-cat.
T
Conv. 1
[%]
Sel. 3
[%]
°
[ C]
1
2
n-pentyl/1a
Bn/1b
1.5
1.5
2
2
2
2
2
2
2
toluene
toluene
toluene
toluene
toluene
toluene
CPME
–
–
–
120
120
90
>99
69
<5
23
14
–
26
18
34
3a
3b
3a
3a
3a
3a
3a
3a
3a
3a
3a
55[b]
60
–
22
13
–
23
10
3[c]
4[c]
5[c]
6[c,d]
7
n-pentyl/1a
n-pentyl/1a
n-pentyl/1a
n-pentyl/1a
n-pentyl/1a
n-pentyl/1a
n-pentyl/1a
n-pentyl/1a
n-pentyl/1a
A1
A2
A3
A1
A1
A1
A1
A1
90
90
90
100
100
100
100
100
8
9
10
11
THF
heptane
toluene
toluene
32
62
2
4
63
>99
93 (86), 96% ee
[a] General reaction conditions: general procedure (see the Supporting Information, page S2), 0.5 mmol 1, 1.5–4 equiv. 2a, 0.5 mol% Cat 1, 2 mL solvent, 18 h,
°
90–120 C, isolated yield in parentheses, unless otherwise specified. Conversion and selectivity were determined by GC-FID based on the integration ratio
among amino acid contained moieties. [b] 35% Alkylated transesterification side-product was observed. [c] 24 h. [d] Decomposition of ester 1a was
observed.
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hydrogenation using chiral or achiral Brønsted acids,[16] and we
have earlier reported the enhancement of both the imine
formation as well as the imine reduction step involved in the
hydrogen borrowing sequence during the amination of β-
hydroxy acids employing the same Ru catalyst.[13] Indeed, both
the conversion of 1a (23%) and 3a selectivity (22%) improved
upon addition of 4 mol% of diphenyl phosphate (A1) (Table 1,
entry 4). The use of other Brønsted acids [p-toluenesulfonic acid
(A2) and benzoic acid (A3)] resulted only in moderate improve-
ment (Table 1, entries 5 and 6) and screening a range of
Next, the reaction scope was explored with selected
examples of methyl-, ethyl-, isopropyl-, and pentyl esters of
diverse amino acids including phenylalanine (Phe), alanine
(Ala), valine (Val), leucine (Leu), proline (Pro) and glutamic acid
(Glu) (Scheme 3, details in the Supporting Information Ta-
ble S2). Various esters of phenylalanine (Ph) were efficiently N-
alkylated with substituted benzyl alcohols (2a, 2b, 2d) or
pentanol (2c) with excellent selectivity, high isolated yields, and
high retention of ee in the corresponding products 3c–3f
(Table S2, entries 1–4). The functionalization of the alanine (Ala)
backbone was evaluated using isopropyl and pentyl esters
(Table S2, entries 6–9). Gratifyingly, the pentyl esters resulted in
the formation of the corresponding mono-alkylated products
(3i–3k) in 66–79% isolated yields and 92–97% ee retention.
Interestingly, slight racemization was observed for the isopropyl
ester 3h (83% ee). Next, the pentyl ester of valine (Val) was
subjected to this optimized N-alkylation protocol with benzyl
alcohols (2a, 2b, 2e) affording the corresponding N-alkyl
analogues (3m–3o) with 82–87% isolated yield and outstand-
ing ee (99%), while also the pentyl analogue 3l was obtained in
86% isolated yield (Table S2, entries 10–13). Similarly, the ethyl
°
solvents at 100 C with A1 also showed poor results (Table 1,
entries 7–9). Therefore, further optimization of reaction temper-
ature and 2a amount in toluene was carried out, while keeping
A1 as the co-catalyst in toluene (Table 1, entries 10 and 11). The
°
best result was obtained at 100 C, leading to full conversion of
1a, and 93% selectivity (86% isolated yield) of the desired
product 3a with and 96% retention of enantiomeric excess (ee;
Table 1, entry 11). The positive results with diphenyl phosphate
(A1) are likely due to the enhancement of imine formation[17] as
well as imine reduction[16] steps involved in the hydrogen
borrowing cycle.[13]
Scheme 3. Direct N-alkylation of l-amino acid ester with alcohols.
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ester of leucine (Leu) provided the desired products 3p and 3q
with 96 and 94% ee, respectively (Table S2, entries 14 and 15).
Interestingly, the reaction of 4-methyl-benzyl alcohol (2a)
with glutamic acid (Glu) diethyl ester (1i) lead to the formation
of the cyclic 2-pyrrolidinone derivative 3r with excellent stereo-
selectivity (99% ee) albeit moderate isolated yield (35%), due to
an intramolecular amide formation (Table S2, entry 16). Finally,
when the pentyl ester of proline (Pro) was selected to react
with alcohol 2a, the corresponding product 3t was obtained
with 42% isolated yield and 70% retention of ee (Table S3,
entry 1).
We also performed a specific comparison between our Ru-
based catalytic system with the previously described Ir-based
system shown on Scheme 1B (Table S2, entry 17 vs. entry 18), in
the direct alkylation of phenylalanine ethyl ester (1d) with 1,5-
pentanediol (2f). While our base-free system (comprising Cat 1
and A1) resulted in 3s in 48% yield and 89% ee, the base-
containing Ir system displayed lower conversion and significant
racemization (16% 3s yield, 35% ee).
Next, we addressed challenging examples of direct alkyla-
tion of amino acid amides with alcohols (Scheme 4). Gratify-
ingly, when prolinamide (1k) and 4-methylbenzyl alcohol (2a)
were selected as substrates (Scheme 4A), 83% isolated yield of
the desired N-alkylation product N-(4-methyl)-benzyl prolina-
mide (3u) was obtained, with as low as 0.5 mol% Cat 1 and
4 mol% A1 (Table S3, entry 5). Unfortunately, only 59% ee was
obtained in this case, which indicates easier racemization of
amino amides than esters in the working condition. Interest-
ingly, when the Fe-based Cat 2 (Knölker’s complex),[10] pre-
viously applied in N-alkylation by our group,[11] was used in the
same reaction, the cyclic product 4-imidazonone 3w was
obtained instead, via intramolecular nucleophilic attack of the
iminium intermediate by the amide group (Scheme 4A), likely
due to the sluggish iminium reduction step. This underscores
the efficiency of our Ru-based, base free method and the
advantages of using the acid co-catalyst A1 expected to
facilitate the important reduction step.
Finally, to demonstrate the versatility of our methodology,
we turned our attention to the straightforward synthesis of the
pharmaceutical compound Ropivacaine (3v).[18] Previously,
Leonard et al.[7] attempted the direct Ru-catalyzed N-alkylation
of the specific amino amide 1l with n-propanol to access
Ropivacaine (3v); however, the imidazolidinone derivative (3x)
was obtained instead, similarly to what we observed with Cat 2
in the case of 3w (Scheme 4A). Gratifyingly, with our catalytic
system, quantitative yield of Ropivacaine (3v) was obtained
with 90% ee when the N-alkylation of amino-amide 1l was
°
performed in neat n-propanol at 90 C, using 1 mol% Cat 1 and
4 mol% A1 (Scheme 4C; Table S3, entry 6). This demonstrates
the superior performance of our newly developed Ru-catalyzed
method for preparing pharmaceutically relevant N-alkyl amino
amides.
In summary, this study demonstrates an efficient method
(0.5–1 mol% Ru loading) for the direct selective mono-N-
alkylation of natural amino acid esters and amides with
alcohols, with good to excellent yields and retention of the
stereochemical integrity. This provides an excellent opportunity
for the direct coupling of naturally abundant amino acid
derivatives with widely accessible and potentially bio-based
alcohols. Moreover, this method allowed for the challenging
direct N-alkylation of amino-acid amides, while taking advant-
age of the facile iminium reduction step, thus overcoming a
common cyclization side reaction. The successful synthesis of
Ropivacaine, which was prepared in quantitative yield and
excellent ee retention, underscores the power of this method-
ology.
Scheme 4. Comparison of product outcomes in the direct N-alkylation of amino amides with alcohols.
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[9] O. Yamauchi, A. Odani, M. Takani, J. Chem. Soc. Dalton Trans. 2002,
Conflict of Interest
3411–3421.
[10] H.-J. Knölker, E. Baum, H. Goesmann, R. Klaus, Angew. Chem. Int. Ed.
The authors declare no conflict of interest.
1999, 38, 2064–2066; Angew. Chem. 1999, 111, 2196–2199.
[11] T. Yan, B. L. Feringa, K. Barta, Nat. Commun. 2014, 5, 5602.
[12] T. Yan, B. L. Feringa, K. Barta, Sci. Adv. 2017, 3, eaao6494.
[13] A. Afanasenko, T. Yan, K. Barta, Commun. Chem. 2019, 2, 127.
[14] A. Afanasenko, R. Hannah, T. Yan, S. Elangovan, K. Barta, ChemSusChem
2019, 12, 3801–3807.
Keywords: amino acid esters · borrowing hydrogen · chirality ·
N-alkylation · Ru catalysis
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Manuscript received: February 20, 2021
Revised manuscript received: April 25, 2021
Version of record online: ■■■, ■■■■
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N-alkylation: An efficient method for
the base-free N-alkylation of amino
acid esters and amides with easily ac-
cessible alcohols is presented. Ropi-
vacaine is synthesized in high yield
and excellent retention of the stereo-
chemical integrity.
T. Yan, Prof. B. L. Feringa, Prof. K.
Barta*
1 – 6
Direct Catalytic N-Alkylation of α-
Amino Acid Esters and Amides
Using Alcohols with High Retention
of Stereochemistry