Synthesis of arylglycines from CO2 through α-amino organomanganese species

Article abstract of DOI:10.1021/ol500701n

In the presence of three readily available chemicals, Mn powder, BF ₃·OEt₂, and LiCl, N-acyl-N,O-acetals were successfully converted into the corresponding α-amino acids (arylglycine derivatives) under 1 atm of a CO₂ atmosphere in high yields. The LiCl additive is necessary in order to increase the solubility and the nucleophilicity of an organomanganese intermediate. The products thus obtained were transformed into free α-amino acids in two steps.

Full text of DOI:10.1021/ol500701n

Letter
pubs.acs.org/OrgLett
Synthesis of Arylglycines from CO2 through α‑Amino
Organomanganese Species
Tsuyoshi Mita,*,† Jianyang Chen,† and Yoshihiro Sato*,†,‡
†Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
‡ACT-C, Japan Science and Technology Agency (JST), Sapporo 060-0812, Japan
S
* Supporting Information
ABSTRACT: In the presence of three readily available
chemicals, Mn powder, BF3·OEt2, and LiCl, N-acyl-N,O-acetals
were successfully converted into the corresponding α-amino
acids (arylglycine derivatives) under 1 atm of a CO2
atmosphere in high yields. The LiCl additive is necessary in
order to increase the solubility and the nucleophilicity of an
organomanganese intermediate. The products thus obtained were transformed into free α-amino acids in two steps.
Scheme 1. α-Amino Acid Synthesis from CO2
arbon dioxide is an ideal carbon feedstock for organic
Csynthesis due to its abundance, low cost, and low toxicity.
The reaction of carbon nucleophiles with CO2 is one of the
most efficient approaches to afford carboxylic acids and their
derivatives.1 Among the various approaches, α-amino acid
synthesis through CO2 incorporation under mild conditions is
especially attractive since α-amino acids have broad applications
in both biochemistry and organic chemistry.2 Early examples of
the synthesis of α-amino acids using CO2 were mostly
represented by the carboxylation of α-amino organolithium
compounds2g,3,4 and electrochemically promoted insertion of
CO2 into the CN bond.5 In 2011, we reported a one-pot
synthesis of N-Boc-α-amino acids from N-Boc-α-amido
sulfones by using a combination of TMS−SnBu3 and CsF
under CO2 pressure (Scheme 1, eq 1).6 It was an alternative
method for Strecker amino acid synthesis from imine
equivalents, but a toxic tin reagent was utilized.7,8 Further
investigation revealed that the use of less toxic PhMe2Si−Bpin
in combination with a catalytic amount of p-TsOH·H2O could
mediate the one-pot carboxylation more efficiently (Scheme 1,
eq 1).9 These processes avoided the use of strongly basic
organolithium reagents, which are often incompatible for many
functional groups; however, bismetal reagents, which are
relatively expensive and not so easily prepared, are necessary.
Recently, SmI2 was reported to promote the reductive coupling
of nitrones with CO2 to afford α-amino acids.10 In addition,
direct reductive carboxylation of aromatic imines with CO2
could also be realized by using Mg turnings.11 These two
transformations utilized commercially available and relatively
inexpensive reagents; however, high CO2 pressure (45−50
atm) is necessary, thus limiting their applicability to organic
synthesis.
following reduction of the resulting iminium species by a
zerovalent metal would occur to produce α-amino metals,12b−e
which would undergo carboxylation with CO2 followed by
protonation to afford the target amino acids. We report herein a
new protocol to synthesize α-amino acids based on the above
strategy using commercially available and inexpensive reagents
under mild reaction conditions (1 atm of CO2).
First, N-acyl-N,O-acetal 1a was selected as a model substrate
and treated with 3 equiv of zerovalent metal and 1.1 equiv of
AlCl3 in THF solvent at 60 °C under 1 atm of CO2 atmosphere
(balloon) (Table 1). After methyl esterification with CH2N2
With these precedents in mind, we envisioned a new strategy
for α-amino acid synthesis using N-acyl-N,O-acetals,12 which
are easily prepared from the corresponding aldehydes or acetals
(Scheme 1, eq 2).12e,13 These N,O-acetals would be converted
into iminium species in the presence of a Lewis acid. The
Received: March 6, 2014
Published: April 9, 2014
© 2014 American Chemical Society
2200
dx.doi.org/10.1021/ol500701n | Org. Lett. 2014, 16, 2200−2203

Organic Letters
Letter
Table 1. Investigation of Several Zero-Valent Metals
Table 3. Investigation of Solvents, Temperatures, and
Reagent Stoichiometry
a
yield (%)
entry
metal
2a
3a
4a
a
yield (%)
1
2
3
4
5
Mg
Mn
Zn
Fe
<1
24
2
9
44
16
22
35
45
BF3·OEt2
temp
19
22
−
−
entry
(equiv)
solvent
DMF
(°C)
2a
3a
4a
1
2
3
4
5
6
7
8
9
1.1
1.1
1.1
1.1
1.1
3
60
60
60
60
60
60
rt
26
2
−
7
58
16
28
19
27
4
−
−
CH3CN
1,4-dioxane
DME
Cu
3
12
10
6
a
Yields were determined by 1H NMR analysis using 1,1,2,2-
tetrachloroethane as an internal standard.
26
31
48
58
67
45
THF
THF
10
10
8
1
(for the determination of yields by H NMR analysis and the
3
THF
−
7
ease of further purification), the desired methyl carboxylate 2a
was obtained together with the protonated compound 3a and a
decomposed product 4a. Several basic metals including Mg,
Mn, Zn, Fe, and Cu were examined under these conditions
(entries 1−5). As a result, 2a was reasonably produced in 24%
yield only when Mn14 was used (entry 2).
We next tested Lewis acids, including AlCl3, AlEtCl2,
Al(OiPr)3, Ti(OiPr)4, Sc(OTf)3, and BF3·OEt2, in the presence
of Mn metal (Table 2), and we found that only the use of AlCl3
3
THF
0
3
THF
−10
0
7
22
b
10
5
THF
82 (80)
16
−
a
Yields were determined by 1H NMR analysis using 1,1,2,2-
tetrachloroethane as an internal standard. The value in parentheses
represents the yield of the isolated product. 4 equiv of LiCl were
b
added.
yield was observed in THF (entry 5). The yield of 2a slightly
increased to 48% by using 3 equiv of BF3·OEt2 (entry 6). A
screening of reaction temperatures (entries 6−9) revealed that
2a was obtained in 67% yield when the reaction was carried out
at 0 °C (entry 8). Eventually, by using 5 equiv of BF3·OEt2 and
4 equiv of LiCl, the highest yield (82%) was achieved (entry
10). It should be noted that this carboxylation requires Mn,
BF3·OEt2, and LiCl. Without any one of those, 2a was not
obtained at all.
Table 2. Screening of Lewis Acids with/without LiCl
a
yield (%)
With the optimal conditions in hand, we explored the scope
of this carboxylation (Figure 1). Several N-acyl-N,O-acetals
possessing electron-rich arenes (1a−1d) underwent carbox-
ylation smoothly to afford the corresponding arylglycine
derivatives in up to 80% yield. Among them, moderate
reactivity was observed for 1d, probably because the relatively
strong electron-donating effect of the methyl group on the
para-position impeded reduction of iminium species by Mn(0).
As for the electron-deficient arenes, regardless of the location of
the substituents at the para- (1e−1g) or meta-position (1h−
1j), the products were obtained in moderate to good yields.
The tolerance of the halides offered an opportunity for further
transformations, such as a transition-metal-catalyzed cross-
coupling reaction. Naphthalene substrates (1k−1l) could also
be carboxylated efficiently. Furthermore, substrates with
different protecting groups on the nitrogen atom, including
propionyl (1m), para-methoxybenzyl (PMB) (1n), allyl (1o),
and propyl groups (1p), were examined. Gratifyingly, regardless
of the structure of the protecting group, the reactions
proceeded smoothly, showing a high compatibility of N-
substitutions of N-acyl-N,O-acetals. Unfortunately, α-alkenyl
and α-alkyl N-acyl-N,O-acetals were not active in this
carboxylation.
entry
Lewis acid
LiCl (equiv)
2a
3a
4a
1
2
3
4
5
6
7
8
9
AlCl3
−
−
−
−
−
−
2
24
2
19
8
16
23
83
73
45
46
51
72
27
AlEtCl2
Al(OiPr)3
Ti(OiPr)4
Sc(OTf)3
BF3·OEt2
AlCl3
−
−
−
−
13
−
31
−
−
−
−
15
−
6
Ti(OiPr)4
2
BF3·OEt2
2
a
Yields were determined by 1H NMR analysis using 1,1,2,2-
tetrachloroethane as an internal standard.
and AlEtCl2 afforded the desired product 2a (entries 1 and 2).
In order to improve the yield, we employed LiCl as an additive
since it plays a crucial role in several transformations mediated
by Mg, Mn, Zn, and In (vide infra).15,16 The use of AlCl3
together with LiCl decreased the yield to 13% probably because
AlCl3 reacted with LiCl to generate an aluminum ate complex,
leading to a decrease in the Lewis acidity of AlCl3 (entry 7).
Although the combined use of Ti(OiPr)4 and LiCl did not
afford the desired product (entry 8), a combination of BF3·
OEt2 and LiCl actually promoted the reaction moderately and
the desired product 2a was obtained in 31% yield (entry 9),
whereas 2a was not obtained at all without LiCl (entry 6).
Next, several solvents were investigated in the presence of
Mn, BF3·OEt2, and LiCl (Table 3, entries 1−5), and the highest
Considering the synthetic utility of the products, removal of
the protecting groups on the nitrogen atom of 2n was
performed (Scheme 2). The N-PMB group was oxidatively
removed by cerium ammonium nitrate to give 5n in 73%
yield.17 The resulting monoprotected 5n was heated at 100 °C
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dx.doi.org/10.1021/ol500701n | Org. Lett. 2014, 16, 2200−2203

Organic Letters
Letter
radical, followed by the second electron transfer to afford an
RMnCl·LiCl compelx15f in the presence of an excess amount of
LiCl. It is thought that LiCl can rapidly remove the formed α-
amino organomanganese species from the metal surface by
generating a highly soluble RMnCl·LiCl complex,15 thus
allowing further carboxylation to proceed immediately and
thereby avoiding competitive deactivation of the active metal
sites. Furthermore, by forming this RMnCl·LiCl complex, the
nucleophilicity of the organomanganese intermediate might be
enhanced.16 As a result, carboxylation with CO2 would proceed
smoothly to give manganese carboxylate.20 Finally, the acid
workup affords the desired α-amino acid.
In summary, we have developed an efficient protocol for the
conversion of N-acyl-N,O-acetals to arylglycine derivatives
through CO2 incorporation. The reagents used, Mn powder,
BF3·OEt2, and LiCl, are commercially available and inexpensive.
LiCl is thought to promote generation of the organomanganese
intermediate and enhance its nucleophilicity toward CO2 by
forming an RMnCl·LiCl complex. Compared to the previous
examples, 1 atm of a CO2 atmosphere is sufficient in this
carboxylation. Studies toward an enantioselective variant of this
transformation are now ongoing.
ASSOCIATED CONTENT
* Supporting Information
■
S
Details of experimental procedures and physical properties of
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
Figure 1. Substrate scope and limitations. Isolated yields are shown.
PMB = para-methoxybenzyl.
*E-mail: tmita@pharm.hokudai.ac.jp.
*E-mail: biyo@pharm.hokudai.ac.jp.
Scheme 2. Removal of the Protecting Group
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by Grants-in-Aid for
Young Scientists (B) (No. 24750081) and for Scientific
Research (B) (No. 23390001) from JSPS and by a Grant-in-
Aid for Scientific Research on Innovative Areas “Molecular
Activation Directed toward Straightforward Synthesis (No.
25105701)” from MEXT. J.C. thanks JSPS for the fellowship
(No. 24006589).
in 6 M HCl aqueous solution for 18 h.18 After ion-exchange
column chromatography, phenylglycine (6n) was obtained in
85% yield as white solids.19
A preliminary reaction mechanism of this carboxylation is
proposed (Figure 2). Iminium formation from N-acyl-N,O-
acetal is initiated by BF3.12a,b,f The resulting iminium species is
then reduced by way of single-electron transfer, which is
analogous to Mg-mediated reductive carboxyaltion.11 The first
electron transfer would occur to generate an α-aminobenzyl
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