A synthesis of α-amino acids via direct reductive carboxylation of imines with carbon dioxide

Article abstract of DOI:10.1039/c3cc42057d

A method for the synthesis of α-amino acids by direct reductive carboxylation of aromatic imines with CO₂ is described. The protocol employs readily available commercial reagents and serves as a one-step alternative to the Strecker synthesis. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc42057d

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A synthesis of a-amino acids via direct reductive
carboxylation of imines with carbon dioxide†
Cite this: Chem. Commun., 2013,
49, 5040
Ajay A. Sathe, Douglas R. Hartline and Alexander T. Radosevich*
Received 21st March 2013,
Accepted 16th April 2013
DOI: 10.1039/c3cc42057d
www.rsc.org/chemcomm
A method for the synthesis of a-amino acids by direct reductive
carboxylation of aromatic imines with CO2 is described. The pro-
tocol employs readily available commercial reagents and serves as
a one-step alternative to the Strecker synthesis.
Nonnatural a-amino acids find use in a broad spectrum of applications,
including synthesis,1 catalysis,2 and enzymology.3 As a consequence,
the chemical synthesis of these valuable compounds has long been an
important area of research.4 Among the diverse approaches to the
synthesis of nonnatural a-amino acids,5 the strategic bond disconnec-
tion exemplified by the classic Strecker synthesis is appealing in its
convergency.6,7 Despite the demonstrated scope and selectivity of this
reliable protocol,8 the Strecker sequence is at root an indirect method
Fig. 1 A polarity inversion route to a-amino acids.
for the installation of the carboxyl unit that necessitates both the use carbanion equivalents. The utility of this promising methodology is
of hazardous cyanide derivatives and a subsequent hydrolysis of the mitigated only by the relatively high expense and low atom economy of
resultant nitrile in order to reveal the target a-amino acid. Alternate the demonstrated bis(metal) reagents.
approaches that capture the convergency of the Strecker synthesis, but
In this report, we describe a simple and effective method for the
result in the direct installation of the carboxyl group from a readily direct reductive carboxylation of imines with carbon dioxide that
available C1 synthon might offer an expedient complementary employs readily available and inexpensive commercial reagents. In a
route to a-amino acids.
reactivity principle drawn from the vast body of research regarding
Carbon dioxide is an ideal C1 synthon due to its low cost, low reductive transformations mediated by low-valent metals,13 we posited
toxicity, and wide availability.9 The direct use of carbon dioxide in the that reductive metallation of an imine would furnish a reactive
synthesis of a-amino acids from imines would require an inversion of (a-amino)alkyl metal intermediate or functional equivalent that could
polarity at the imine carbon, involving the intermediacy of nucleophilic be trapped with carbon dioxide to yield a-amino acids.14–16
(a-amino)alkyl anion equivalents (Fig. 1).10 Synthetically, these reactive
As an initial entry point, we investigated the simple reductive
intermediates have traditionally been accessed via directed a-metalla- carboxylation of imines using common base metal reagents (Table 1).
tion of alkylamine derivatives.11 For instance, N-acyl amine derivatives Our optimization efforts converged on the following conditions: for
may be selectively a-lithiated with sec-butyllithium at low temperature; each equivalent of imine substrate, three equivalents each of magne-
subsequent quenching with carbon dioxide then leads to a-amino sium turnings, chlorotrimethylsilane, and triethylamine in dimethyl-
acids. An alternative entry into (a-amino)alkyl metal reagents that formamide were stirred under 45 atm of carbon dioxide for 24 h
avoids the use of highly basic alkyllithium reagents was recently (entry 1).17 Following an aqueous extraction and product precipitation,
reported by Mita and Sato.12 This method employs bis(metal) reagents p-methoxyphenyl benzaldimine (1) was converted under these condi-
(i.e. silylstannanes and silylboranes) to adjust the oxidation state of the tions into N-(p-methoxy)phenyl phenylglycine (2) in 75% isolated yield.
imine substrate in situ and gain access to reactive (a-amino)alkyl The decrease or omission (entries 2–8) of any of these components
was found to negatively impact the desired reaction. For instance, a
reduction in the applied pressure of carbon dioxide from 45 atm to
1 atm (compare entries 2 through 5) was attended by a decrease
Department of Chemistry, The Pennsylvania State University, University Park,
PA 16802, USA. E-mail: radosevich@psu.edu; Tel: +1 814 867 4268
in isolated yield of a-amino acid and an increase in the formation
of C-silylated compound 3 and imine homocoupling product 4.
† Electronic supplementary information (ESI) available: Full experimental proce-
dures, characterization data, NMR spectra. See DOI: 10.1039/c3cc42057d
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5040 Chem. Commun., 2013, 49, 5040--5042
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Table 1 Conditions for reductive carboxylation
CO2
Yielda
(%)
Entry Reductant
(atm) Additive
1
2
3
4
5
6
7
8
3 equiv. Mg0 45
3 equiv. TMS–Cl; 3 equiv. Et3N 75
3 equiv. Mg0 45
3 equiv. TMS–Cl
3 equiv. TMS–Cl
3 equiv. TMS–Cl
3 equiv. TMS–Cl
1.5 equiv. TMS–Cl
None
65
3 equiv. Mg0 20
3 equiv. Mg0 10
58b
56b
35b
12
3 equiv. Mg0
1
3 equiv. Mg0 20
3 equiv. Mg0 20
N.R.
N.R.
Fig. 2 Multigram scale reductive carboxylation.
5 equiv. Zn0
1
3 equiv. TMS–Cl
a
b
Yields are for isolated product 2. See ESI for details. Compounds 3
carboxylation (5b–5d). The reaction appears to be impacted by
steric congestion about the imine center; mesityl derivative 5h
could only be obtained in low yield (20%). Attempts to extend
this reactivity to both alkyl aldimines and ketimines have not
been successful to date. However, substitution on the N-aryl
moiety was successfully tolerated, permitting the synthesis of
N-aryl phenylglycines 5m–5o.19
and 4 were also observed in this reaction.
The reductive carboxylation method is scalable to a multigram
batch without complication (Fig. 2). Specifically, reductive
carboxylation of 1 on a 25 mmol scale yields N-(p-methoxyphenyl)
phenylglycine (2) in 80% yield. This may be readily converted to
methyl phenylglycinate (7) in 53% yield via a two-step protecting
group exchange sequence.
We believe the primary function of the requisite amine base is
to buffer against adventitious HCl, although the formation of
reactive ammonium carbamates through chemisorption of CO2
cannot be excluded.18
With the reaction conditions optimized as detailed above, a
survey of substrate scope was conducted (Table 2). A diverse
panel of substituted phenylglycine derivatives could be prepared
from the corresponding benzaldimines by reductive carboxyl-
ation. Both electron-deficient (5a–5d) and electron-rich benzal-
dimines (5e–5g) underwent reaction to give the product a-amino
acids in moderate to good yields. The suite of regioisomeric
trifluoromethylated compounds (5i–5k) were all isolated in good
to moderate yield. Imine substrates with pendant nitrile, ester
and amide functionalities were found to undergo chemoselective
Given the strong reducing power of magnesium (E = À3.01 V
vs. Fc/Fc+)20 and the known reduction potentials of N-aryl
benzaldimines (E B À2.20 V vs. Fc/Fc+),14 we believe this reductive
carboxylation method is gated by one-electron reduction steps
(Fig. 3). Mechanistically, the first electron transfer event would
likely occur subsequent to an N-silylation of imine 1 with chloro-
trimethylsilane, which would lower the thermodynamic potential
for electron transfer by conversion to N-silyliminium 8.21 The
a-aminobenzyl radical intermediate 9 resulting from reduction
would be anticipated to be long-lived and largely unreactive given
the extensive delocalization and captodative stabilization of
the unpaired electron.22 Consistent with this supposition, o-allyl
benzaldimine substrate 12 was found to resist intramolecular
radical cyclization, instead undergoing reductive carboxylation to
give 13 in 64% yield (Fig. 4). We therefore believe that the
key reactive intermediate in this chemistry is a-aminobenzyl
Table 2 a-Amino acids by reductive carboxylation of imines
Entry Ar1
Ar2
Product Yielda (%)
1
2
3
4
5
6
7
8
4-FC6H4–
4-(CN)C6H4–
4-OMeC6H4– 5a
4-OMeC6H4– 5b
72
74
68
56b
50
58
63
20
69
58
48
73
62
70
60
4-[O(C2H4)2N(CQO)]C6H4– 4-OMeC6H4– 5c
4-[tBuO(CQO)]C6H4–
4-OMeC6H4–
4-MeC6H4–
4-iPrC6H4–
4-OMeC6H4 5d
4-OMeC6H4– 5e
4-OMeC6H4– 5f
4-OMeC6H4– 5g
4-OMeC6H4– 5h
4-OMeC6H4– 5i
4-OMeC6H4– 5j
4-OMeC6H4– 5k
4-OMeC6H4– 5l
2,4,6-(Me)3C6H2–
4-(CF3)C6H4–
3-(CF3)C6H4–
2-(CF3)C6H4–
b-Naphthyl
C6H5–
9
10
11
12
13
14
15
C6H5–
4-FC6H4–
4-MeC6H4–
5m
5n
5o
C6H5–
C6H5–
a
b
Yields are for isolated material. See ESI for details. Isolated as the
amino acid methyl ester.
Fig. 3 Proposed mechanistic scheme for reductive carboxylation of imines.
Chem. Commun., 2013, 49, 5040--5042 5041
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Eng. Res. Des., 2006, 84, 739; (e) W. Leitner, Coord. Chem. Rev., 1996,
153, 257; ( f ) P. G. Jessop, T. Ikariya and R. Noyori, Chem. Rev., 1995,
95, 259; (g) W. Leitner, Angew. Chem., Int. Ed. Engl., 1995, 34, 2207.
10 For a-amino acid synthesis using of formamide as C1 synthon, see:
R. Cannella, A. Clerici, W. Panzeri, N. Pastori, C. Punta and O. Porta,
J. Am. Chem. Soc., 2006, 128, 5358.
11 For selected examples, see: (a) Y. S. Park and P. Beak, J. Org. Chem.,
1997, 62, 1574; (b) D. Stead, G. Carbone, P. O’Brien, K. R. Campos,
I. Coldham and A. Sanderson, J. Am. Chem. Soc., 2010, 132, 7260;
(c) V. Coeffard, I. Beaudet, M. Evain, E. Le Grognec and
J.-P. Quintard, Eur. J. Org. Chem., 2008, 3344.
Fig. 4 Reductive carboxylation of o-allyl benzaldimine. Reagents and condi-
tions: (a) 5 equiv. Mg, 3 equiv. TMS–Cl, 3 equiv. Et3N, 45 atm CO2, DMF, rt, 24 h.
(b) TMSCHN2, MeOH–Et2O, rt, 30 min.
12 (a) T. Mita, J. Chen, M. Sugawara and Y. Sato, Angew. Chem., Int. Ed.,
2011, 50, 1393; (b) T. Mita, J. Chen, M. Sugawara and Y. Sato, Org.
Lett., 2012, 14, 6202; (c) T. Mita, Y. Higuchi and Y. Sato, Chem.–Eur.
J., 2013, 19, 1123.
13 (a) A. Fu¨rstner, Pure Appl. Chem., 1998, 70, 1071; (b) E. J. Roskamp and
S. F. Pedersen, J. Am. Chem. Soc., 1987, 109, 6551; (c) J. E. McMurry
and M. P. Fleming, J. Am. Chem. Soc., 1974, 96, 4708; (d) A. Fu¨rstner
and B. Bogdanovich, Angew. Chem., Int. Ed. Engl., 1996, 35, 2442;
(e) R. Nomura, T. Matsuno and T. Endo, J. Am. Chem. Soc., 1996,
118, 11666.
magnesium chloride 10 formed by a second electron transfer.
A competition between electrophiles in solution consumes 10;
high concentrations of CO2 result in productive carboxylation
(11, then 2), whereas at lower applied pressures undesired reaction
with either chlorotrimethylsilane to give 3,23 or another equivalent
of 1 yielding 4, become significant.
In summary, we have described a reductive carboxylation method 14 For a related electrochemical approach, see: (a) G. Silvestri and
O. Scialdone, in Carbon Dioxide as Chemical Feedstock, ed. M. Aresta,
Wiley-VCH, Weinheim, 2010; (b) N. L. Weinberg, A. Kentaro Hoffmann
and T. B. Reddy, Tetrahedron Lett., 1971, 12, 2271; (c) D. K. Root and
for the synthesis of substituted phenylglycine derivatives from
imines and CO2. The developed methodology utilizes inexpensive
and readily available starting materials and does not rely on
chromatography for the isolation of products. The further develop-
ment of both catalytic and stereoselective variants of this umpolung
Strecker-like synthesis are the focus of ongoing investigation.
We thank the Pennsylvania State University for generous
financial support of this research.
W. H. Smith, J. Electrochem. Soc., 1982, 129, 1231; (d) V. G. Koshechko,
V. E. Titov, V. N. Bondarenko and V. D. Pokhodenko, J. Fluorine Chem.,
2008, 129, 701.
15 For a related SmI2-mediated reductive carboxylation of nitrones, see:
A. Prikhod’ko, O. Walter, T. A. Zevaco, J. Garcia-Rodriguez,
O. Mouhtady and S. Py, Eur. J. Org. Chem., 2012, 3742.
16 For other carboxylations of alkylmetal species, see: (a) A. Correa and
R. Martin, Angew. Chem., Int. Ed., 2009, 48, 6201; (b) M. Shi and
K. M. Nicholas, J. Am. Chem. Soc., 1997, 119, 5057; (c) C. S. Yeung
and V. M. Dong, J. Am. Chem. Soc., 2008, 130, 7826; (d) M. Corbet and
S. Z. Zard, Org. Lett., 2008, 10, 2861; (e) H. Ohmiya, M. Tanabe
Notes and references
1 (a) M. T. Reetz, Angew. Chem., Int. Ed. Engl., 1991, 30, 1531;
(b) J. Martens, Top. Curr. Chem., 1984, 125, 165; (c) K. Drauz,
A. Kleemann and J. Martens, Angew. Chem., Int. Ed. Engl., 1982,
21, 584.
2 (a) E. R. Jarvo and S. J. Miller, Tetrahedron, 2002, 58, 2481; (b) Y. Lu,
T. C. Johnston and B. A. Arndtsen, J. Am. Chem. Soc., 2009,
131, 11284; (c) J. Paradowska, M. Stodulski and J. Mlynarski, Angew.
Chem., Int. Ed., 2009, 48, 4288; B. List, R. A. Lerner and C. F. Barbas
III, J. Am. Chem. Soc., 2000, 122, 2395; (d) K. Micskei, T. Patonay,
L. Caglioti and G. Palyi, Chem. Biodiversity, 2010, 7, 1660.
3 (a) J. Liao, Biotechnol. Prog., 2007, 23, 28; (b) C. J. Noren,
S. J. Anthony-Cahill, M. C. Griffith and P. G. Schultz, Science, 1989,
244, 182; (c) L. Wang, A. Brock, B. Herberich and P. G. Schultz,
Science, 2001, 292, 498.
´
and M. Sawamura, Org. Lett., 2011, 13, 1086; ( f ) T. Leon, A. Correa
and R. Martin, J. Am. Chem. Soc., 2013, 135, 1221.
17 For magnesium mediated reductive transformations, see:
(a) H. Maekawa, T. Murakami, T. Miyazaki and I. Nishiguchi, Chem.
Lett., 2011, 40, 368; (b) X. Zheng, X.-J. Dai, H.-Q. Yuan, C.-X. Ye, J. Ma
and P.-Q. Huang, Angew. Chem., Int. Ed., 2013, 52, 3494;
(c) N. Shohji, T. Kawaji and S. Okamoto, Org. Lett., 2011, 13, 2626;
(d) R. Nomura, T. Matsuno and T. Endo, J. Am. Chem. Soc., 1996,
118, 11666.
18 Formation of ammonium carbamate inner salts from the reaction of
tertiary amines with CO2 have been postulated in an epoxide
carboxylation reaction: M. North and R. Pasquale, Angew. Chem.,
Int. Ed., 2009, 48, 2946.
19 For an example of a medicinal chemistry application of N-aryl
arylglycines, see: V. Molteni, J. Penzotti, D. M. Wilson,
A. P. Termin, L. Mao, C. M. Crane, F. Hassman, T. Wang,
H. Wong, K. J. Miller, S. Grossman and P. D. J. Grootenhuis,
J. Med. Chem., 2004, 47, 2426.
20 Electrochemical Series, in CRC Handbook of Chemistry and Physics,
ed. W. M. Haynes, CRC Press/Taylor and Francis, Boca Raton, FL,
93rd edn, 2013.
21 In addition to this role, TMS–Cl may function to activate the
magnesium in suspension. See: T. Ohno, M. Sakai, Y. Ishino,
T. Shibata, H. Maekawa and I. Nishiguchi, Org. Lett., 2001, 3, 3439.
22 (a) A. Padwa, H. Nimmesgern and G. S. K. Wong, J. Org. Chem., 1985,
50, 5620; (b) S. F. Martin, C.-P. Yang, W. L. Laswell and H. Rueger,
Tetrahedron Lett., 1988, 29, 6685; (c) J. M. Aurrecoechea,
A. Fernandez, J. M. Gorgojo and C. Saornil, Tetrahedron, 1999,
55, 7345.
23 We confirm that C-silylated product 3 is not involved in the pathway
for carboxylation; independent synthesis of 3 and subjection to our
standard reductive carboxylation reaction conditions results in no
reaction. For comparison, see ref. 12a.
´
4 For reviews of the synthesis of amino acids, see: (a) C. Najera and
J. M. Sansano, Chem. Rev., 2007, 107, 4584; (b) R. M. Williams and
J. A. Hendrix, Chem. Rev., 1992, 92, 889; (c) R. O. Duthaler, Tetra-
hedron, 1994, 50, 1539.
5 Alternative routes to amino acids: (a) N. A. Petasis and I. A. Zavialov,
J. Am. Chem. Soc., 1997, 119, 445; (b) M. J. O’Donnell, W. D. Bennett
and S. Wu, J. Am. Chem. Soc., 1989, 111, 2353; (c) E. J. Corey, F. Xu
and M. C. Noe, J. Am. Chem. Soc., 1997, 119, 12414; (d) T. Ooi,
M. Kameda and K. Maruoka, J. Am. Chem. Soc., 1999, 121, 6519.
6 (a) A. Strecker, Ann. Chem. Pharm., 1850, 75, 27; (b) H. Groger, Chem.
Rev., 2003, 103, 2795.
7 For alternative multicomponent approaches to a-amino acids, see:
(a) A. Domling and I. Ugi, Angew. Chem., Int. Ed., 2000, 39, 3168;
(b) G. Diker, Angew. Chem., Int. Ed. Engl., 1997, 36, 1700.
8 M. Shibasaki, M. Kanai and T. Mita, Org. React., 2008, 70, 1.
9 Use of carbon dioxide as a C1 synthon: (a) M. Cokoja, C. Bruckmeier,
B. Rieger, W. A. Herrmann and F. E. Ku¨hn, Angew. Chem., Int. Ed.,
2011, 50, 8510; (b) M. Aresta and A. Dibenedetto, Dalton Trans.,
2007, 2975; (c) T. Sakakura, J.-C. Choi and H. Yasuda, Chem. Rev.,
2007, 107, 2365; (d) R. Steeneveldt, B. Berger and T. A. Torp, Chem.
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