Ruthenium and Iron-Catalysed Decarboxylative N-alkylation of Cyclic Α-Amino Acids with Alcohols: Sustainable Routes to Pyrrolidine and Piperidine Derivatives

Article abstract of DOI:10.1002/cssc.201901499

A modular and waste-free strategy for constructing N-substituted cyclic amines via decarboxylative N-alkylation of α-amino acids employing ruthenium- and iron-based catalysts is presented. The reported method allows the synthesis of a wide range of five- and six-membered N-alkylated heterocycles in moderate-to-excellent yields starting from predominantly proline and a broad range of benzyl alcohols, and primary and secondary aliphatic alcohols. Examples using pipecolic acid for the construction of piperidine derivatives, as well as the one-pot synthesis of α-amino nitriles, are also shown.

Full text of DOI:10.1002/cssc.201901499

DOI: 10.1002/cssc.201901499
Full Papers
Ruthenium and Iron-Catalysed Decarboxylative N-
alkylation of Cyclic a-Amino Acids with Alcohols:
Sustainable Routes to Pyrrolidine and Piperidine
Derivatives
Anastasiia Afanasenko, Rachael Hannah, Tao Yan, Saravanakumar Elangovan, and
Katalin Barta*[a]
A modular and waste-free strategy for constructing N-substi-
tuted cyclic amines via decarboxylative N-alkylation of a-amino
acids employing ruthenium- and iron-based catalysts is pre-
sented. The reported method allows the synthesis of a wide
range of five- and six-membered N-alkylated heterocycles in
moderate-to-excellent yields starting from predominantly pro-
line and a broad range of benzyl alcohols, and primary and
secondary aliphatic alcohols. Examples using pipecolic acid for
the construction of piperidine derivatives, as well as the one-
pot synthesis of a-amino nitriles, are also shown.
Introduction
Saturated azaheterocycles, especially pyrrolidine and piperi-
dine, are ubiquitous scaffolds in biologically active com-
pounds[1] and key building blocks in diverse areas of organic
chemistry.[2] Numerous pharmaceuticals comprise five- and six-
membered azaheterocyclic moieties (Figure 1). Therefore, over
tions[3d] (Scheme 1a, pathway 2) face a number of limitations
including the use of toxic solvents and/or reagents as well as
poor atom economy.
The discovery of metal-catalysed “hydrogen borrowing”
methods for the N-alkylation of amines with alcohols[4]
(Scheme 1b, pathway 3) has led to cleaner synthesis of saturat-
ed azaheterocycles by judicious selection of appropriate com-
binations of coupling partners (e.g., benzyl amines and diols or
cyclic amines with alcohols). These methods only produce
water as a by-product, may employ bio-derived alcohol sub-
strates[5,6] and, as recently reported, can also be performed
using earth-abundant metal catalysts.[7–9]
An elegant catalytic strategy for the construction of various
cyclic amines was recently illustrated by Darcel and co-workers
(Scheme 1b, pathway 4).[10] They achieved the Fe- and Ru-
catalysed reductive amination of carbonyl compounds with w-
amino fatty acids to furnish various pyrrolidines, piperidines
and azepanes.
Figure 1. Bioactive compounds bearing N-alkylated pyrrolidine and piperi-
dine moieties.
the past decades considerable efforts have focused on the de-
velopment of novel approaches for the efficient and environ-
mentally friendly synthesis of substituted pyrrolidines and pi-
peridines, employing affordable and widely available substrates
and sustainable catalysts.
A distinctly different method for the construction of N-het-
erocycles involves the decarboxylation of amino acids already
containing such core moiety via coupling with carbonyl com-
pounds (inspired by the classical Strecker degradation[11,12]) fol-
lowed by a reaction of the formed azomethine ylides with vari-
ous non-traditional dipolarophiles[13] (Scheme 1b, pathway 5).
A highly interesting approach for the one-pot construction
of valuable N-heterocyclic scaffolds would be the combination
of the hydrogen-borrowing with the decarboxylation/azome-
thine ylide chemistry: this would enable the catalytic coupling
of naturally abundant amino acids with widely available and
potentially bio-derived alcohol substrates (Scheme 1c). In this
case, the carbonyl compounds necessary for imine formation
could be generated in situ by means of the transition-metal
catalyst while the amino acids would provide the core N-heter-
ocyclic scaffold upon decarboxylation. Surprisingly, to the best
Traditional methods for the construction of the core hetero-
cyclic centre[3a] such as the Mitsunobu[3b] and Appel-type reac-
tions[3c] (Scheme 1a, pathway 1) or classical reductive amina-
[a] A. Afanasenko, R. Hannah, Dr. T. Yan, Dr. S. Elangovan, Prof. Dr. K. Barta
Stratingh Institute for Chemistry
University of Groningen
Nijenborgh 4, 9747 AG, Groningen (The Netherlands)
E-mail: k.barta@rug.nl
Supporting Information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/cssc.201901499.
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Results and Discussion
Following our initial observations regarding the N-
alkylation of natural a-amino acids with various alco-
hols using Shvo’s complex (C1), we first selected DL-
proline (1a) and 4-methoxybenzyl alcohol (2a) as
starting materials for establishing the desired decar-
boxylative N-alkylation methodology (Table 1). The
initially selected conditions using a 1:2 molar ratio of
1a and 2a, 1 mol% C1 at 1208C delivered excellent
results. Applying these parameters, excellent (88–
99%) product (3aa) yields were detected in various
solvents such as cyclopentyl methyl ether (CPME),
toluene, 1,4-dioxane, and tert-amyl alcohol (en-
tries 4–7). In chloroform (entry 8), only traces of the
product were observed, whereas in acetonitrile mod-
erate yield was seen (52%, entry 9). While 1,4-diox-
ane furnished the highest 3aa yield, and toluene
also gave excellent results. Taking into account sol-
vent sustainability guidelines,[15] we chose toluene as
preferred solvent for further investigation; the prod-
uct yield was further improved from 90% to 94%
using 4 equiv. of 2a at 1208C (entry 4 vs entry 11).
Further decrease of reaction temperature to 1108C
negatively affected the product yield (entry 10).
Blank reactions in the absence of catalyst (entry 1) or
in the absence of alcohol (entry 2) gave no product
as expected. For comparison with our previous stud-
ies,[7e] the reaction was also conducted in trifluoroe-
thanol, indeed resulting in 90% yield of the N-alkyla-
Scheme 1. a) Classical pathways for the synthesis of the saturated azahetero-
cycles; b) catalytic and synthetic pathways for the construction of N-alkylated
heterocycles; c) Ru- and Fe-catalysed decarboxylative N-alkylation of amines
with alcohols (this work).
Table 1. Establishing the decarboxylative N-alkylation of DL-proline with
4-methoxybenzyl alcohol using iron- and ruthenium-based catalysts.[a]
of our knowledge, the first and only example for such homo-
geneously catalysed decarboxylative N-alkylation of natural a-
amino acids with alcohols has been reported by Zhao and co-
workers, employing pentamethylcyclopentadienyl iridium di-
chloride dimer ([Cp*IrCl2]2)/NaHCO3 as catalyst.[14] Despite the
potential of earth-abundant Fe- or Ru-based systems in diverse
N-alkylation reactions, no decarboxylative N-alkylation methods
have been developed yet using such catalysts. This is not sur-
prising given the highly functionalized and potentially strongly
coordinating nature of amino-acid substrates or reaction inter-
mediates.
Entry
Alcohol
[mmol]
Catalyst
[mol%]
T
[8C]
Solvent
Yield[b]
[%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14[d]
15[d]
16
2
–
1
1
1
1
1
1
1
2
2
2
2
2
2
2
–
120
120
120
120
120
120
120
120
120
110
120
120
110
110
110
120
toluene
toluene
CF3CH2OH
toluene
tert-amyl alcohol
CPME
1,4-dioxane
CHCl3
CH3CN
toluene
toluene
toluene
toluene
toluene
1,4-dioxane
1,4-dioxane
–
–
96[c]
90
88
89
99
traces
52
81
94
C1/1
C1/1
C1/1
C1/1
C1/1
C1/1
C1/1
C1/1
C1/1
C1/1
C2/4
C2/8
C2/4
C2/4
C2/4
Recently, we have shown that base-free N-alkylation of un-
protected a-amino acids[7e] with a broad range of alcohols is
feasible using Shvo’s catalyst and Knçlker’s complex and have
introduced the Fe-based catalytic N-alkylation of amines with
alcohols with a broad scope, including the construction of N-
heterocyclic scaffolds.[7d,e,8a,c] Herein, we set to establish the
first decarboxylative N-alkylation methods using these Fe- and
Ru-based half-sandwich complexes.
77
75
71
73
70
[a] General reaction conditions: 0.5 mmol of 1, 1 or 2 mmol of 2, 1 mol%
C1 or 4–8 mol% C2, 2 mL of solvent, 24 h, 100–1208C, under argon.
[b] Isolated yields. [c] N-alkylated non-decarboxylated product was ob-
served. [d] 48 h.
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tion product without decarboxylation, presumably due to the
increased acidity of the reaction medium.
Table 2. Decarboxylative N-alkylation of amino acids with primary
alcohols.[a]
Next, we turned our attention to the Fe catalyst C2.[16] Ap-
plying C2 in the model reaction at 1208C in toluene 77% yield
was achieved (entry 12) within 24 h. However, further attempts
to enhance 3aa yield either by doubling the catalyst loading
to 8 mol% or by increasing the reaction time to 48 h did not
significantly influence the yield of the reaction (75% and 71%,
entries 13 and 14, respectively). The lower yield achieved with
C2 compared to C1 could be attributed to a slower dehydro-
genation and/or a slower reduction step involved in the hydro-
gen-borrowing cycle (see also Scheme 3).
Entry
Product
Yield[b] [%]
C1
C2
1
2
3aa
3ab
94
86
77
37
75
In further studies, the scope and limitations of the newly es-
tablished Ru- and Fe-catalysed decarboxylative N-alkylation
methodologies were explored. Benzyl alcohol with electron-
donating substituents such as 4-methoxybenzyl alcohol (2a)
and 4-methylbenzyl alcohol (2b) as well as bulky substituents
(2c, 2d) were successfully coupled with 1a, furnishing the cor-
responding products (3aa, 3ab, 3ac, 3ad) with excellent iso-
lated yields (86–94%) with C1 as catalyst, whereas poorer
yields (19–77%) were obtained when applying the Fe-based
catalyst C2 (Table 2, entries 1–4). Interestingly, piperonyl alco-
hol (2e) gave excellent isolated yields (94%) of 3ae in both
systems (entry 5). With 3-pyridine methanol (2g) and 2-thio-
phene methanol (2h), moderate product yields were observed
with C1, while reactivity was completely blocked using 2g
with C2. The latter system appeared more compatible with 2h
(33% 3ah with C1 vs. 45% with C2).
When para-halide-substituted benzyl alcohols were em-
ployed, 75% of 3ai and 90% of 3aj were successfully isolated.
Moreover, desired products bearing deactivating functional
groups such as ÀCF3, ÀCN, ÀCH3COOCH3 and ÀNO2 were
formed in good-to-excellent isolated yields (65–99%, 3ak–
3an). Considerably lower yields were observed for the above-
mentioned substrates using C2 as catalyst (14–37%, 3ak–3an).
Selected aliphatic alcohols such as 2o and 2p reacted smooth-
ly with DL-proline, affording 3ao and 3ap in very good yields
(83–86%), albeit only with C1 as catalyst (entries 15 and 16).
Notably, the developed methodology could be extended to
pipecolic acid (1b) as well, and the target N-substituted piperi-
dines 3ba–3bn were obtained in 31 and 64% isolated yields,
respectively, using C1. In the case of product 3ba, the Fe-
based catalyst (C2) gave a 54% isolated yield.
3
3ac
93
4
5
6
7
8
9
3ad
3ae
3af
3ag
3ah
3ai
91
94
42
40
33
75
19
94
58
–
45
26
10
11
12
3aj
3ak
3al
90
84
83
68
37
18
13
3am
65
14
14
15
16
3an
3ao
3ap
99
traces
83[c]
86[c]
–
–
17
18
3ba
3bn
31[c]
64
54
–
Other acyclic a- and b-amino acids (glycine, DL-alanine, DL-
phenylalanine, b-alanine) as well as N-alkyl a-amino acids (N-
methyl glycine, N-isopropyl valine) were attempted to couple
with 4-methoxybenzyl alcohol (2a) under the optimized reac-
tion conditions; however, low yields were obtained in both
systems (using C1 and C2). Additionally, employing C1 as a
catalyst we examined reactions between N-methyl glycine (sar-
cosine)/N-isopropyl valine and 2a with the addition of a base
(KOtBu, KOH, K2CO3, NaHCO3) in various solvents (1,4-dioxane,
t-amyl alcohol, CPME); however, no significant improvement in
product yield could be established.
[a] General reaction conditions: 0.5 mmol of 1, 1 mmol of 2, 1 mol% C1
or 4 mol% C2, 2 mL toluene, 24 h, 1208C, under argon. [b] Isolated yields.
[c] Yields are based on 1H NMR spectroscopy, using 1,3,5-trimethoxyben-
zene as an internal standard.
system (Table 3). Cyclohexanol (2q) and 4-isopropylhexan-1-ol
(2r) smoothly reacted with 1a, providing good yields (57%
and 76%) of the corresponding products (3aq, 3ar, respective-
ly). However, no product was observed in the reaction of DL-
proline with menthol (2s), presumably due to the steric bulk
of the alcohol substrate. Similarly, other secondary alcohols
To further expand the scope of the reaction, we turned our
attention to the use of secondary and long-chain primary ali-
phatic alcohols applying the more active Ru-based catalytic
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oped methodology for the functionalization of biologically
active compounds.
Table 3. Decarboxylative N-alkylation of amino acids with secondary and
long-chain alcohols.[a]
Next, we investigated the use of mandelonitriles (4) as
unique substrates for the formation of nitriles and the possibili-
ty of accessing cyclic amino nitriles in a straightforward and
one-pot approach based on mechanistic considerations pres-
ent in literature.[17] Notably, the use of mandelonitrile (4a) and
its derivatives 4-methylmandelonitrile (4b) and 4-chloromande-
lonitrile (4c) led to the formation of products 5a, 5b and 5c
as well as their regioisomers 5’a, 5’b and 5’c in good combined
isolated yields (71–76%) when applying both catalytic systems
C1 and C2 (Table 4). A preliminary proposal for the formation
Entry
1
Product
Yield[b] [%]
57
3aq
2
3ar
76[c]
Table 4. Construction of a-amino nitriles from mandelonitrile and its de-
rivatives using an N-alkylation/decarboxylation strategy.[a]
3
4
5
3as
3at
3au
0
49
62
Entry
Major product (5)
Ratio
Yield[b] [%]
5:5’
C1
C2
6
7
8
3av
3aw
3ax
42[c]
81[d]
51[c]
1
2
3
5a+5’a
5b+5’b
5c+5’c
7:1
71
74
75
71
3:1
11:1
72
76
9
3ay
3by
54
55
[a] General reaction conditions: 1.1 mmol of 1a, 1 mmol of 4, 1 mol% C1
or 4 mol% C2, 2 mL toluene, 24 h, 1208C, under argon. [b] Reported
value refers to combined isolated yield of both regioisomers 5 and 5’.
10
[a] General reaction conditions: 0.5 mmol of 1, 1 mmol of 2, 1 mol% C1,
2 mL toluene, 24 h, 1208C, under argon. [b] Isolated yields. [c] Yields are
based on 1H NMR spectroscopy, using 1,3,5-trimethoxybenzene as an in-
ternal standard. [d] Reduced double bond in the product (note: 2 equiv.
of alcohol used).
of these regioisomers is provided (Supporting Information, Fig-
ure S5, Note 1). Basic DL-proline, used in slight excess in the
system, is assumed to play a role in a-aminonitrile isomeriza-
tion in favour of regioisomer 5 (Supporting Information, Fig-
ure S5, Note 1).[17d] This is supported by the fact that 5:5’ ratios
followed a specific trend (Table 4) related to the nature of the
substituents on the aromatic ring, where electron-withdrawing
substituents would stabilize dipoles with a partial negative
such as 2t, 2u, and 2v furnished the desired products in rea-
sonable yields. Interestingly, the use of cinnamyl alcohol 2w or
2x led to the formation of products 3aw and 3ax in good
yields, although the double bond of 3aw was found
to be reduced. Several long-chain aliphatic alcohols
were also found to react with 1a and 1b, affording
the corresponding products (3ay, 3by) in 54% and
55% isolated yields, respectively.
Encouraged by the above results showing a broad
range of alcohols suitable for the Ru-catalysed decar-
boxylative N-alkylation of a-amino acids, we investi-
gated the possibility of employing 5a-cholestan-3b-
ol as substrate for the decarboxylative N-alkylation of
DL-proline (Scheme 2). The corresponding product
was successfully obtained in 50% isolated yield,
which demonstrates the applicability of the devel-
Scheme 2. Decarboxylative N-alkylation of DL-proline with 5a-cholestan-3b-ol.
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Scheme 3. Proposed mechanism for the decarboxylative N-alkylation of a-amino acids with alcohols. Structures in boxes detected by in situ 1D and 2D NMR
spectroscopy.
charge predominantly in the benzylic position. Thus, regiose-
lectivity of the reaction could be attributed to the unlike
charge distribution of the differently substituted azomethine
ylides.[13c]
Next, 1D and 2D NMR spectroscopic investigations of a reac-
tion mixture containing 4-methoxybenzyl alcohol (2a) and 1a
in [D8]toluene at 1208C in the presence of Shvo’s catalyst (C1)
were conducted to confirm several proposed reaction inter-
mediates (Supporting Information, Figures S1–S4). These stud-
ies allowed the detection of key intermediate 4-methoxyben-
zaldehyde (III), and the ester (III’) as side product originating
from the aldehyde (Supporting Information, Figure S2). Al-
though we were not able to detect the oxazolidin-5-one deriv-
ative (IV’a) or the acyclic iminium carboxylate species (IVa), the
corresponding N-alkyl-proline (IVb) formed by hydrogenation
of (IVa)—via the metal hydride generated by dehydrogena-
tion—was observed as indirect evidence (Supporting Informa-
tion, Figure S3). The presence of the RuÀH species expected in
the catalytic cycle was also affirmed by its typical distinct
chemical shift (À9.65 ppm, Supporting Information, Figure S4).
More experiments were conducted to further elaborate on
the role of intermediate IVb. A direct decarboxylation pathway
starting from separately synthetized benzyl-pyrrolidine-2-
carboxylic acid (IVb) under the reaction conditions but in ab-
sence of C1 could be ruled out. However, excellent yield (>
99%) of the target cyclic amine (VI) was achieved starting from
(IVb) in the presence of (C1), confirming the proposed hydro-
genation/dehydrogenation equilibrium between IVa and IVb.
Indeed, C1 was previously shown to efficiently catalyse imine
hydrogenation as well as the dehydrogenation of secondary or
tertiary amines.[22,23] This result is particularly interesting, since,
to the best of our knowledge, the decarboxylation of N-alkyl
amino acids into their N-alkylamine analogues has not yet
been accomplished by using a dehydrogenation catalyst.
A plausible mechanism of the decarboxylative N-alkylation
of a-amino acids with alcohols is depicted in Scheme 3. The
proposed reaction sequence is based on control experiments
and 1D, 2D NMR spectroscopic investigations as well as earlier
literature reports[13a,14] (further specified below). The sequence
begins with the metal-catalysed dehydrogenation of an alcohol
(II) to the carbonyl compound (III), which readily undergoes
condensation with an amino acid (I; here, DL-proline). Conden-
sation and water elimination results in the formation of an oxa-
zolidin-5-one derivative (IV’a), which is in equilibrium with the
acyclic iminium carboxylate intermediate (IVa). The formation
of oxazolidones by reaction of a-amino acids with carbonyl
compounds was previously extensively investigated by Grigg
et al.[17b] and Seebach et al.[18] whereas oxazolidone/iminium
equilibria were proposed during mechanistic studies of pro-
line-mediated aldol condensation reactions.[19] Decarboxylation
of thermally labile oxazolidin-5-one derivative (IV’a) furnishes
azomethine ylides (Va and Vb) in a dipolar [3+2] cyclorever-
sion step,[20,21] as also discussed in literature for various oxazoli-
dinone derivatives.[17b,18] As a final step, the azomethine ylides
would undergo protonation and subsequent reduction by
means of the metal hydride generated during the first dehy-
drogenation step, leading to the formation of the N-alkylated
cyclic amine product (VI). The existence of a dehydrogenation
step (Scheme 3, VI to Va and Vb) through involvement of a
Ru- and Ir-based transfer hydrogenation catalyst similar to C1
was previously described in literature.[9b,c]
Further, aiming to prove that the alcohol is a genuine hydro-
gen source, 1a was allowed to react with a,a-[D2]benzyl alco-
hol (2 f–d2) under standard reaction conditions. The product
Several control experiments were conducted to confirm the
central role of the catalyst (C1) in the proposed reaction
scheme. As discussed above, no reaction occurred between
the alcohol and amino acid in the absence of C1 (entry 1,
Table 1) and C1 did not induce decarboxylation of the a-amino
acid in the absence of the alcohol (entry 2, Table 1).
1
distribution analysis employing H NMR spectroscopy (Support-
ing Information, Figure S6, Note 2) displayed deuterium incor-
poration at the 2 and 5 positions of the pyrrolidine ring as well
as at the benzylic position of the desired product, which addi-
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tionally supported the above-proposed mechanism (for discus-
sion see the Supporting Information, Note 2).
Acknowledgements
Lastly, during the 1D and 2D NMR spectroscopic investiga-
tions, where significant amount of product was detected al-
ready after 1 h reaction time, it became apparent that the reac-
tion proceeds faster than initially assumed based on our earlier
studies that frequently displayed sluggish imine hydrogenation
step.[7d,e,8a,c] Therefore we have followed the evolution of de-
tectable intermediates (III, IVb, Ru-H) and product (VI) over
time (Supplementary Figure S7, Note 3). Gratifyingly, already
after 2 h full conversion and excellent product yield was ach-
ieved, confirmed by an isolated yield of 96% for 1-(4-methoxy-
benzyl)pyrrolidine (3aa). Although certainly substrate depen-
dent, at 1208C the decarboxylation of the thermally labile oxa-
zolidin-5-one derivative to the proposed azomethine ylides is
expected to be rapid; hence, it appears that the proposed hy-
drogen transfer from the substrate alcohol to the ylides is
facile as well. This presents a unique advantage of the method
presented herein.
K.B. thanks the European Research Council, ERC Starting Grant
2015 (CatASus) 638076. This work is part of the research pro-
gramme Talent Scheme (Vidi) with project number 723.015.005
(for K.B.), which is partly financed by the Netherlands Organiza-
tion for Scientific Research (NWO).
Conflict of interest
The authors declare no conflict of interest.
Keywords: decarboxylation
heterocycles · proline
·
iron
·
N-alkylation
·
N-
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Conclusions
We have developed the decarboxylative N-alkylation of a-
amino acids with alcohols applying Ru- and Fe-based catalytic
systems for the synthesis of N-substituted cyclic amines. The
described methods demonstrate high selectivity, wide alcohol
scope and excellent functional-group tolerance, in particular
regarding the Ru-based system. Although the iron-based
method would require further optimization in terms of efficien-
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Experimental Section
General procedure for the decarboxylative N-alkylation of
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2 or 4 equiv.), Shvo’s catalyst (C1,
0.005 mmol, 1 mol%) or Knçlker’s complex (C2, 0.02 mmol,
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Manuscript received: June 4, 2019
Revised manuscript received: July 12, 2019
Version of record online: && &&, 0000
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These are not the final page numbers! ÞÞ

FULL PAPERS
A. Afanasenko, R. Hannah, T. Yan,
S. Elangovan, K. Barta*
&& – &&
Ruthenium and Iron-Catalysed
Decarboxylative N-alkylation of Cyclic
a-Amino Acids with Alcohols:
Sustainable Routes to Pyrrolidine and
Piperidine Derivatives
The best of both worlds: decarboxyla-
tive catalytic coupling of a-amino acids
and alcohols to N-heterocycles.
&
ChemSusChem 2019, 12, 1 – 8
www.chemsuschem.org
8
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!