Synthesis of α-amino acids through samarium(II) iodide promoted reductive coupling of nitrones with CO2

Article abstract of DOI:10.1002/ejoc.201200440

Several N-benzylnitrones reacted with carbon dioxide in the presence of samarium(II) iodide leading to α-amino acids as the products of reductive C-C coupling. The best selectivities were observed at a carbon dioxide pressure of 50 bar at ambient temperature. The influences of different functional groups in the nitrone backbone and of the coordinating additives to samarium(II) iodide on the product distribution were investigated. The racemic α-amino acids were obtained in up to 70% yield based on HPLC data. A novel approach to the synthesis ofα-amino acids is disclosed, involvingC-carboxylation of nitrones by gaseous CO₂ under reductive coupling reaction conditions (SmI₂, 0.1 M in THF) at ambient temperature and 50 bar of CO ₂ pressure. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Full text of DOI:10.1002/ejoc.201200440

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200440
Synthesis of α-Amino Acids through Samarium(II) Iodide Promoted Reductive
Coupling of Nitrones with CO2
Alexander Prikhod’ko,*[a] Olaf Walter,*[a][‡] Thomas A. Zevaco[a]
Jaime Garcia-Rodriguez,[b] Omar Mouhtady,[b] and Sandrine Py*[b]
Keywords: Amino acids / Nitrones / Carbon dioxide / Samarium / High-pressure chemistry
Several N-benzylnitrones reacted with carbon dioxide in the
presence of samarium(II) iodide leading to α-amino acids as
the products of reductive C–C coupling. The best selectivities
were observed at a carbon dioxide pressure of 50 bar at am-
bient temperature. The influences of different functional
groups in the nitrone backbone and of the coordinating addi-
tives to samarium(II) iodide on the product distribution were
investigated. The racemic α-amino acids were obtained in up
to 70% yield based on HPLC data.
the reaction with CO2 would represent an ideal approach
for α-amino acid synthesis (Scheme 1). It would be the most
straightforward and atom-economic alternative to the
Strecker synthesis,[8,13] which involves nucleophilic addition
of cyanide followed by hydrolysis of the cyano group into
a carboxylic acid (the latter proceeds usually under drastic
acidic conditions).
Introduction
The use of carbon dioxide (CO2) as a carbon synthon in
organic synthesis[1] (for instance, as a C1 building block to
obtain carboxylic acids) often requires activation of this
rather inert molecule, which can be achieved through coor-
dination to an electronically rich metal center.[2] Among re-
cent advances in this field are the nickel-catalyzed carboxyl-
ation of styrenes[3] or ethylene,[4] the reaction of carbon di-
oxide with organozinc reagents,[5] and the palladium-cata-
lyzed carboxylation of aryl bromides.[6] Carboxylic acids
themselves are considered valuable synthons in organic
chemistry and exhibit a high potential as medicinally im-
portant compounds.[7] In this view, special attention is paid
to non-proteinogenic α-amino acids,[8] which are extensively
explored as promising pharmaceutics.[9]
However, synthetic approaches to α-amino acids by using
CO2 as a C1 building block are still scarce. Until recently,
these methods were mostly represented by reactions of CO2
with lithium organics,[10] with electrochemically generated
free radicals,[11] and with in situ generated stannylated
imines.[12] Formally, the umpolung of imines followed by
Scheme 1. Reductive C–C coupling of imine derivatives with CO2
(imine: X = electron pair; nitrone: X = O).
Among the reagents used in organic synthesis to mediate
umpolung of imines and nitrones[14] in reductive C–C bond
formation, samarium diiodide[15] (Kagan’s reagent, SmI2)
has emerged as one of the most versatile ones.[16] In particu-
lar, it proved to be a reagent of choice to mediate reductive
cross-coupling reactions involving nitrones and various
electrophiles.[17] Moreover, the reaction of organosamarium
intermediates derived from carbonyl compounds with CO2
was reported to yield carboxylic acids.[18] Besides this, the
reaction of bis(pentamethylcyclopentadienyl)samarium(II)
complexes with CO2 can produce oxalates[19] or N–CO2
coupled products[20] showing that electron transfer can be
also achieved from SmII to carbon dioxide.[21] With these
precedents, the work presented herein led to the first suc-
cessful SmI2-mediated reductive C–C coupling between
nitrones or aldimines and carbon dioxide to produce α-
amino acids.
[a] Karlsruhe Institute of Technology,
Institute of Catalysis Research and Technology (IKFT),
Postfach 3640, 76021 Karlsruhe, Germany
Fax: +49-721-608-22244
E-mail: alexander.prichodko@gmx.de
[b] Département de Chimie Moléculaire (SERCO) UMR 5250,
ICMG FR-2607, CNRS-Université Joseph Fourier,
Grenoble, France
Fax: +33-4-76635754
E-mail: sandrine.py@ujf-grenoble.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200440.
[‡] Current address: European Commission, Joint Research Centre,
Institute for Transuranium Elements,
Results and Discussion
Hermann-von-Helmholtz-Platz 1,
For these studies, solutions of SmI2 (0.1 m in THF) were
freshly prepared by using a fast and convenient reaction
76344 Eggenstein-Leopoldshafen, Germany
E-mail: olaf.walter@ec.europa.eu
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A. Prikhod’ko, O. Walter, S. Py et al.
SHORT COMMUNICATION
between metallic Sm and I2 in THF under ultrasonic irradi-
ation.[22] The starting SmI2 solution was found to be unre-
active towards CO2: it could be saturated with gaseous car-
bon dioxide at room temperature or treated with CO2 at
–78 °C without any noticeable changes in the initial dark-
blue color. As a consequence, the first species to be reduced
with SmI2 has to be the organic substrate – the nitrone –
leading initially to the samarium-coordinated organic
anion–radical I2SmR· (see Scheme 2).[23] Attempts to react
nitrones with CO2 “step by step” (i.e., in the presence of 1
or 2 equiv. of SmI2 under various conditions) did not result
in the isolation of intermediate C–C coupled products.
However, it was possible to obtain N-benzyl-substituted α-
amino acids by employing an excess amount of the reducing
agent (up to 10 equiv. of SmI2), which suggests three pos-
sible reaction pathways after the preliminary formation of
the I2SmR· intermediate (Scheme 2): (1) A C–C coupling
with CO2 followed by reduction with deoxygenation of ni-
trogen atom[24] leading to α-amino acid 2. (2) Further re-
duction by reaction with additional SmI2 plus proton ab-
straction from the solvent leading to amine 3. (3) Dimeriza-
tion of the radical intermediate (I2SmR·) by C–C coupling
followed by further SmI2 reduction and protonation to
yield diamines 4 and 5.
Scheme 3. Reaction conditions and successions of the reagent mix-
ing tested in experiments with nitrones, CO2, and SmI2.
acid 2a were detected, and most of the starting nitrone was
converted into reductive homocoupling product (d,l)-1,2-
diamine 4a. Isomeric meso-1,2-diamine 5a and amine 3a
were also formed.[25]
A similar distribution of the products was found when
the sequences of mixing was changed, that is, when the
solution of nitrone 1a was added dropwise to the stirred
SmI2 solution at –78 °C under CO2 (Table 1, Entry 2;
method B in Scheme 3). These results are similar to those
obtained by treatment of imines with SmI2[26] and show that
at –78 °C single-electron transfer from SmI2 to nitrone 1a
is likely to occur, and the resulting SmIII-coordinated radi-
cal anion dimerizes producing diamines 4a and 5a as the
major products (after reduction of the N–O bond of the
intermediate vicinal bishydroxylamines[24]), but the reaction
with CO2 does not proceed. Concurrently, the formation
Scheme 2. Possible pathways for the reaction of nitrones with SmI2
in presence of CO2.
The reaction was then carried out under different condi- of N-benzyl-1-(4-isopropylphenyl)methanamine (3a) results
tions (Scheme 3), which were optimized by using the reac- from simple reduction of 1a by the excess amount of SmI2.
tion of (Z)-N-(4-isopropylbenzylidene)-1-phenylmethan-
amine oxide (1a) with SmI2 and CO2 as the model reaction when the reagents were mixed at 0 °C (Table 1, Entry 3; a
(Table 1, Entries 1–4). solution of nitrone 1a was added drop by drop to the stirred
The distribution of the products changed considerably
In the first experiment, a sample of nitrone 1a was dis- SmI2 solution under CO2, method C in Scheme 3). In this
solved in THF, the solution was cooled down to –78 °C, case, the main products were 1,2-diamines 4a and 5a
and argon was replaced by gaseous CO2; the reaction (≈55%) and α-amino acid 2a (≈30%). Thus, upon increas-
Schlenk vessel was connected to a CO2 bottle at 1.1 bar ing the temperature, the reactivity of the systems becomes
(Table 1, Entry 1; method A in Scheme 3). The SmI2 solu- high enough to enable the C–C coupling reaction between
tion (7.5 equiv.) was added drop by drop to the nitrone the organosamarium radical (I2SmR·) and CO2 (see
solution at –78 °C under a CO2 atmosphere with vigorous Scheme 2). As a consequence, ≈30% of α-amino acid 2a was
stirring. After 30 min, the blue reaction mixture was slowly formed and correspondingly ≈30% less of diamines 4a and
brought to room temperature and left to stir overnight. It 5a.
was then exposed to air to oxidize the excess amount of
The yield of α-amino acid 2a was further increased up to
SmI2 and subjected to HPLC analysis. Under these condi- 70% when the reaction was carried out at ambient tempera-
tions, only trace amounts of N-benzyl-substituted α-amino ture (≈20 °C) and at elevated CO2 pressure of 50 bar
2
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Synthesis of α-Amino Acids by SmI2-Promoted Reductive Coupling
Table 1. Synthesis of amino acids by SmI2 reduction of nitrones or I2SmR· radical intermediate compared to the lifetimes of
imines in the presence of CO2.
the intermediates resulting from the SmI2-mediated re-
duction of aromatic nitrones. Accordingly, even at –78 °C
the C–C coupling reaction of nitrone 1c with CO2 yields
(Ϯ)-N-benzylvaline in yields up to 45% (Table 1, Entry 7).
In further accordance, the formation of amine 3c in the
reaction of 1c or 1d with SmI2 becomes competitive,
whereas C–C coupling side products 4c and 5c are only
formed in very small amounts (Table 1, Entries 6–9). Again,
this can be taken as a sign of enhanced reactivity, as re-
duction can be considered to proceed faster than C–C bond
formation. This could also explain why in the case of
nitrone 1c compared to its corresponding aldimine 1d the
selectivity towards α-amino acid 2c [(Ϯ)-N-benzylvaline]
decreases, because for aldimine 1d even fewer reduction
steps are needed for the formation of amine 3c. Noteworthy,
the yields of (Ϯ)-N-benzylvaline (Table 1, Entry 7,
method B; Entry 8, method D) are comparable, which indi-
cates that the positive effect of the CO2 pressure on the
formation of the α-amino acid is compensated by the in-
creased temperature.
To test the influence of various heteroatoms in the start-
ing materials on the product distribution, nitrones 1e–i
(Table 1, Entries 10–15) were treated with CO2 in the pres-
ence of SmI2 by employing method D (vide supra). It was
found that 4-fluoro- (i.e., 1e), 4-methoxy- (i.e., 1f), and 2-
methoxy-substituted aromatic nitrones (i.e., 1g) yielded the
corresponding α-amino acids as the major products in rea-
sonable yields (Table 1, Entries 10–12), and the amounts of
the corresponding byproducts varied (Table 1). An excellent
yield of α-amino acid 2h (73%) was detected from the reac-
tion involving (Z)-N-(furan-2-ylmethylene)-1-phenylmeth-
anamine oxide (1h; Table 1, Entry 13). Dimerization prod-
ucts 4h and 5h were detected in only 7% yield, in agreement
[a] Yields were determined by HPLC and NMR techniques by
with the observation that the SmI2-mediated dimerization
using N-benzylglycine as an internal standard, see the Supporting
of the corresponding imine is ineffective.[26d] This effect
could originate from the coordination of SmI2 to the oxy-
gen atom of the furanyl group, enhancing the reducing
power of the reagent.
Information for specifics. [b] The sodium salt of nitrone 1i was used
as a starting material (see text for explanation).
(Table 1, Entry 4; method D in Scheme 3). To a solution of
In contrast, the yield of the carboxylated product
nitrone 1a pressurized with 50 bar CO2 in a stainless steel dropped considerably starting from nitrone 1i containing an
autoclave (see the Supporting Information, Figure S1) the unprotected phenol functionality (Table 1, Entry 14). This
SmI2 solution (7.5 equiv.) was added by an argon overpres- suggests that the OH group in the proximity of the C=N
sure (100 bar). Simultaneous to an increase in the yield of bond leads the reaction towards 3i, probably by intramolec-
the α-amino acid, the yields of 1,2-diamines 4a and 5a de- ular proton transfer. Accordingly, a marginal increase in the
creased to below 10% in total, and the formation of 3a as yield of α-amino acid 2i was found by using the sodium salt
the simple reduction product was limited to 20% (Table 1). of nitrone 1i (Table 1, Entry 15). In addition, trace amounts
Reaction of aldimine 1b under the same conditions of 1,2-diamines 4i and 5i or other coupling products were
(Table 1, Entry 5, method D) led to a product distribution not detected, pointing out that the reduction of the interme-
similar to that obtained for nitrone 1a. Although the deoxy- diate anion–radical is favored over a dimerization due to
genation of nitrones to imines by SmI2 has not yet been steric reasons and/or delocalization of the negative charge
reported, this could be explained by assuming the reaction over the phenolate anion. To investigate further the influ-
of nitrone 1a as well as its corresponding aldimine 1b passes ence of coordination to the samarium reagent, samples of
through formation of the same intermediate.
(Z)-1-phenyl-N-(pyridin-2-ylmethylene)methanamine ox-
The reactivity of aliphatic nitrone 1c[14b] in the presence ide[27] and (Z)-1-phenyl-N-(pyridin-4-ylmethylene)methan-
of SmI2 (Table 1, Entries 6–8) seems to be higher than the amine oxide[28] were treated under conditions of method D.
reactivities of the aromatic nitrones (Table 1, Entries 1–5, Surprisingly, the reduction products N-benzyl-1-(pyridin-2-
10–15). This could be correlated to a shorter lifetime of the yl)methanamine and N-benzyl-1-(pyridin-4-yl)methan-
Eur. J. Org. Chem. 0000, 0–0
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A. Prikhod’ko, O. Walter, S. Py et al.
SHORT COMMUNICATION
amine were detected together with considerable amounts of
phenylmethanamine indicating partial decomposition. This
may be related to the nature of the pyridyl substituent lead-
ing to a stronger delocalization of the electron density in
the I2SmR· intermediate leading to a complete suppression
of any C–C coupling reaction.
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with CO2 in the presence of SmI2. Aliphatic, aromatic, and
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moderate to synthetically useful yields (up to 70% yield)
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Experimental Section
[10]
[11]
General Description of Method D:
A sample of the nitrone
(0.276 mmol) was dissolved in freshly distilled THF (15 mL) under
an atmosphere of argon and transferred into an autoclave (total
volume 170 mL). The solution was pressurized with CO2 to 50 bar
whilst stirring (about 40 mL of liquid CO2 under pressure of
200 bar). Then, a solution of SmI2 (0.1 m in THF, 20 mL,
7.5 equiv.) was injected into the autoclave under overpressure of
argon at ambient temperature (final pressure in the autoclave was
100 bar). The reaction mixture was stirred overnight (16 h), and the
pressure was then gradually decreased to atmospheric. The blue
reaction mixture was exposed to air, which resulted in a color
change to yellow. The mixture was diluted with 0.1 m CF3COOH
(30 mL), an HPLC reference was added to the clear yellow solution
[N-benzylglycine hydrochloride (Aldrich), 0.0557 g, 0.276 mmol,
1 equiv. considering the starting nitrone], and the solution was
evaporated. The residue was dried in vacuo and then dissolved in
0.1% trifluoroacetic acid (10 mL; water/acetonitrile, 1:9). The solu-
tion was then subjected to HPLC.
[12]
[13]
[14]
[15]
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures, copies of the 1H NMR and
13C NMR spectra, ESI mass spectra and HPLC traces, notes con-
cerning mechanistic investigations under influence of various addi-
tives and analytical data for N-benzyl-1-(1,2,3,4,5-pentamethylcy-
clopenta-2,4-dienyl)propan-1-amine, which was isolated when (η-
C5Me5)2Sm was used as a reducing agent.
[16]
[17]
Acknowledgments
We gratefully acknowledge financial support by the ERA-Chemis-
try program (Thematic Call 2007: “Chemical Activation of carbon
dioxide and methane”) supported by the Centre National de la
Recherche Scientifique (Institut National de Chimie) and the
Deutsche Forschungsgemeinschaft (DFG) (WA 1484/1-1).
4
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Synthesis of α-Amino Acids by SmI2-Promoted Reductive Coupling
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Received: April 5, 2012
Published Online: ᭿
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5

Job/Unit: O20440
/KAP1
Date: 11-06-12 15:54:42
Pages: 6
A. Prikhod’ko, O. Walter, S. Py et al.
SHORT COMMUNICATION
Carbon Dioxide Chemistry
A
novel approach to the synthesis of
A. Prikhod’ko,* O. Walter,* T. A. Zevaco,
J. Garcia-Rodriguez, O. Mouhtady,
S. Py* ............................................... 1–6
α-amino acids is disclosed, involving
C-carboxylation of nitrones by gaseous
CO2 under reductive coupling reaction
conditions (SmI2, 0.1 m in THF) at ambi-
ent temperature and 50 bar of CO2 press-
ure.
Synthesis of α-Amino Acids through Sam-
arium(II) Iodide Promoted Reductive
Coupling of Nitrones with CO2
Keywords: Amino acids / Nitrones / Carbon
dioxide / Samarium / High-pressure chem-
istry
6
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Eur. J. Org. Chem. 0000, 0–0