One-step synthesis of racemic α-amino acids from aldehydes, amine components, and gaseous CO2 by the aid of a bismetal reagent

Article abstract of DOI:10.1002/chem.201202332

α-Amino acids are essential resources for human life and are highly useful as building blocks for organic synthesis. The core framework of an α-amino acid can be divided into three basic components: an aldehyde, an amine, and carbon dioxide (CO₂). We report herein that a one-step synthesis of α-amino acids has been successfully achieved from these three basic and inexpensive chemicals with a single operation, in which the mixture of an aldehyde, a sulfonamide, and gaseous CO₂ was heated at 100 °C in the presence of Bu₃Sn-SnBu₃ and CsF. In this one-pot sequential protocol, two important intermediates (imine and α-amino stannane) are involved and the stannyl anion generated in situ plays a crucial role, particularly for the efficient stannylation of the imine in the presence of proton sources and for promoting retrostannylation of the undesired α-alkoxy stannane owing to its high stability and tolerance of the presence of proton sources. This methodology enabled the synthesis of a wide range of racemic arylglycine derivatives in high yields. Go retro! α-Amino acids are essential resources for human life and are highly useful as building blocks for organic synthesis. The core framework of an α-amino acid is retrosynthesized to an aldehyde, an amine, and carbon dioxide. A one-step synthesis of α-amin Copyright

Full text of DOI:10.1002/chem.201202332

FULL PAPER
DOI: 10.1002/chem.201202332
One-Step Synthesis of Racemic a-Amino Acids from Aldehydes, Amine
Components, and Gaseous CO2 by the Aid of a Bismetal Reagent
Tsuyoshi Mita,* Yuki Higuchi, and Yoshihiro Sato*[a]
Abstract: a-Amino acids are essential
resources for human life and are highly
useful as building blocks for organic
synthesis. The core framework of an a-
amino acid can be divided into three
basic components: an aldehyde, an
amine, and carbon dioxide (CO2). We
report herein that a one-step synthesis
of a-amino acids has been successfully
achieved from these three basic and in-
expensive chemicals with a single oper-
ation, in which the mixture of an alde-
hyde, a sulfonamide, and gaseous CO2
was heated at 1008C in the presence of
Bu3Sn-SnBu3 and CsF. In this one-pot
sequential protocol, two important in-
termediates (imine and a-amino stan-
nane) are involved and the stannyl
anion generated in situ plays a crucial
role, particularly for the efficient stan-
nylation of the imine in the presence of
proton sources and for promoting ret-
rostannylation of the undesired a-
alkoxy stannane owing to its high sta-
bility and tolerance of the presence of
proton sources. This methodology ena-
bled the synthesis of a wide range of
racemic arylglycine derivatives in high
yields.
Keywords: aldehydes · amino acids ·
À
carbon dioxide · C C bond forma-
tion · umpolung
Introduction
known method for the synthesis of a-amino acid derivatives
(dipeptides) from simple components is the Ugi four-compo-
nent coupling reaction.[5] Nevertheless, isocyanides, compo-
nents in this reaction, have to be prepared in advance from
the corresponding amines by multistep operations (formyla-
tion followed by dehydration).
a-Amino acids and their derivatives are essential resources
for human life and are very useful for organic synthesis as
building blocks. The practical syntheses of a-amino acids
have been seen in dozens of pieces of literature.[1] The key
steps of these transformations can be majorly classified into
1) hydrogenation of dehydroamino acid derivatives,[1a,c,d,h]
2) elongation of the side chain of glycine-derived skeletons
Our research group has already reported a novel one-pot
synthesis of a-amino acids from imine precursors, N-Boc-a-
amino sulfones (Boc=tert-butoxycarbonyl), by using TMS-
SnBu3 (TMS=trimethylsilyl) and CsF.[6] This process is effi-
cient and fascinating because three independent reactions
(imine formation, stannylation, and carboxylation) proceed
sequentially in a specific order in the same flask and CsF
plays a different role for each step (base to facilitate imine
formation, silicon activator to generate the stannyl anion,
and stannane activator to generate a fluorostannate or car-
banion). Nevertheless, substrate a-amino sulfones should be
prepared in advance from aldehydes, sodium sulfinates, and
N-Boc carbamates.[7] If aldehydes could be used directly for
this synthesis without any treatment, it would be more ele-
gant and practical. In principle, an a-amino acid can be div-
ided into three simple and commercially available compo-
nents, an aldehyde, an amine component, and a CO2 unit
(Scheme 1). CO2 is thought to be a primitive and sustainable
C1 source, the fixations of which have been intensively stud-
ied by organic chemists due to its ubiquitous, inexpensive,
and renewable properties.[8] To the best of our knowledge,
one-step chemical synthesis of a-amino acids from simple
and commercially available materials through CO2 incorpo-
ration has not been reported, and we therefore considered
the possibility that those three chemicals can be combined
with a single operation, with the aid of a stannyl anion, to
synthesize a-amino acids.
À
through C C bond formation (e.g., Michael addition and al-
kylation, etc.),[1b,c,e–h] 3) Nucleophilic substitutions of imino
esters,[1c,e,g,h] and 4) a-amination of carboxylic acid deriva-
tives.[1b,c,g,h] Although some of these methodologies were es-
tablished in respect of operational convenience[2] in addition
to high efficiency,[3] they still require multistep sequences for
the preparation of the specific substrates from commercially
available materials and/or for the conversion into the de-
sired amino acids after the key step. On the other hand, the
classical Strecker a-amino acid synthesis[1b,c,e,h] needs only a
two-step sequence from simple starting materials: cyanation
of imines derived from aldehydes and amines in situ fol-
lowed by hydrolysis of a-amino nitriles.[4] However, there is
still a disadvantage regarding the intolerability of acid-sensi-
tive functional groups because strongly acidic conditions are
often required in the final nitrile hydrolysis. Another well-
[a] Dr. T. Mita, Y. Higuchi, Prof. Dr. Y. Sato
Faculty of Pharmaceutical Sciences, Hokkaido University
Nishi 6, Kita 12, Kita-ku, Sapporo 060-0812 (Japan)
Fax : (+81)11-706-4982
E-mail: tmita@pharm.hokudai.ac.jp
biyo@pharm.hokudai.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202332.
Chem. Eur. J. 2013, 19, 1123 – 1128
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1123

sulfonamides as substrates, protonated compound 4 and sul-
finyl ester 5 were produced, the latter of which was thought
to be generated by elimination of the sulfonyl group fol-
lowed by methyl esterification (Table 1, entries 3–5). Since
eliminated products 5 derived from 2g and 2h are, however,
low-boiling-point materials, the usual workup and evapora-
tion sequence resulted in their elimination from the reaction
mixture (Table 1, entries 7 and 8). Other primary amides
and amines, such as diphenyl phosphinamide, diethyl phos-
phoramidate, tert-butylsulfinamide, acetamide, benzyl
amine, allyl amine, and aniline did not promote the desired
reaction at all, but benzaldehyde starting material 1a and/or
the corresponding imine were recovered.
Scheme 1. Division into three simple components in an a-amino acid
structure.
Results and Discussion
Given that sulfonamides are suitable for this reaction, sev-
eral silylstannanes with different sizes of silicone moieties,
such as TES-SnBu3 (TES=triethylsilyl), TIPS-SnBu3
(TIPS=triisopropylsilyl), and TBS-SnBu3 (TBS=tert-butyl-
dimethylsilyl), were prepared and subjected to the reaction
with para-toluenesulfonamide (2d; Table 2, entries 1–4). In
response to the steric bulk of the silyl groups, higher yields
First, we investigated the effect of amine components for
the synthesis of a-phenyl a-amino acid (phenylglycine;
Table 1). All reactions were carried out in the presence of
Table 1. Amide screening.
Table 2. Bismetal screening.
Entry
Amide (R2)
Yield [%][a]
3
4
5
Entry
Bismetal
Amide
Yield [%][a]
À
1
2
3
4
5
6
7
8
Boc
2a
2b
2c
2d
2e
2 f
2g
2h
13
6
33
37
40
–
3
5
–
–
3
4
5
À
Cbz
1
2
3
4
TMS SnBu3
2d (R3 =Tol)[b]
2d
2d
2d
37
39
49
51
58
64
74
32
24
16
6
2
3
25
26
26
33
31
À
SO2C6H5 (Bs)
28
32
20
–
13
22
21
25
22
–
–
–
À
À
SO2C6H4p-Me (Ts)
À
TES SnBu3
À
SO2C6H4p-OMe
À
TIPS SnBu3
À
SO2C6H4p-NO2
À
TBS SnBu3
[b]
À
SO2Me (Ms)
36
40
À
5
Bu3Sn SnBu3
2d
[b]
6
Bu3Sn SnBu3
2h (R3 =tBu)
–
–
[c]
À
SO2tBu (Bus)
À
7[d]
Bu3Sn SnBu3
2h
6
[c]
À
[a] Yields were determined by 1H NMR spectroscopic analysis by using
1,1,2,2-tetrachloroethane as an internal standard. [b] Low-boiling-point
materials.
[a] Yields were determined by 1H NMR spectroscopic analysis by using
1,1,2,2-tetrachloroethane as an internal standard. Each yield was calculat-
ed on the basis of amide 2. [b] Tol=tolyl. [c] A low-boiling-point materi-
al. [d] 1 Equivalent of benzaldehyde (1a), 1.5 equivalents of amide 2h,
and 1.5 equivalents of tin reagent were used and yields were calculated
on the basis of benzaldehyde (1a).
two equivalents of benzaldehyde (1a), one equivalent of
amine component 2, and 1.1 equivalents of TMS-SnBu3
under 1 MPa (10 atm) of CO2 pressure. Yields of the corre-
sponding carboxylic acids were determined after methyl es-
terification with TMSCHN2. Although Boc and Cbz (Cbz=
carbobenzyloxy) carbamates (2a and 2b) did not promote
the desired one-pot reaction efficiently (Table 1, entries 1
and 2), sulfonamide derivatives 2c–h, except 2 f, exhibited
moderate reactivities, in which electron-rich substitutions
(Ts, para-methoxybenzenesulfonyl) enhanced the formation
of amino acids (Table 1, entries 4 and 5), whereas electron-
withdrawing nosyl amide 2 f did not provide any products,
probably due to retardation of the condensation between
benzaldehyde (1a) and the amide 2 f (Table 1, entry 6).
Alkyl-substituted sulfonamides (2g and 2h) also displayed
similar reactivities (Table 1, entries 7 and 8). For the use of
of a-amino acid 3 were observed, with a decrease in the
amount of the protonated compound 4. Eventually, the use
of Bu3Sn–SnBu3 gave the highest yield along with a small
amount of protonated compound 4 (Table 2, entry 5). Fur-
thermore, when tert-butylsulfonamide (2h) was used instead
of 2d, the yield of a-amino acid 3 slightly increased to 64%
(Table 2, entry 6). Finally, by changing the ratio of equiva-
lents for each component to 1a/2h/Bu3Sn–SnBu3 =1:1.5:1.5,
the yield was further increased to 74% (Table 2, entry 7).[9]
Based on the results of our previous study,[6] we speculat-
ed that the reaction proceeded via imine 6 and a-amino
stannane 7. To confirm this hypothesis, Ts-protected inter-
mediates (6d and 7d) were prepared independently from
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One-Step Synthesis of Racemic a-Amino Acids
FULL PAPER
Scheme 2. Elucidation of reaction intermediates in the one-step a-amino acid synthesis. All reactions described above were conducted in autoclaves
1
filled with CO2 (1 MPa) in DMF at 1008C for 3 h. Yields were determined by H NMR spectroscopic analysis by using 1,1,2,2-tetrachloroethane as an in-
ternal standard.
benzaldehyde (1a) and para-toluenesulfonamide (2d) and
subjected to the reactions indicated in Scheme 2 (procedures
B and C). Even when the reactions were commenced at dif-
ferent stages, the target a-amino acid derivative 3d could be
obtained. However, the yield of each product (3d, 4d, and
5d) was slightly different depending on the starting material
employed. When using imine 6d, which is inherently unsta-
ble under these fluoride-mediated conditions,[6,10] the yield
of 3d decreased to 45% and 4d and 5d were obtained in 2
and 23% yields, respectively, probably because slight imine
decomposition occurred to produce benzaldehyde (1a; pro-
cedure B, Scheme 2). By comparison with procedure A,
almost the same distributions were observed when the reac-
tion began with a-amino stannane 7d by using CsF (proce-
dure C; 3d: 59; 4d: <1; 5d: 29%). These experimental re-
sults strongly suggested that this one-step reaction actually
proceeded through the proposed pathway, but a high con-
centration of imine 6d at one time gave the worse result
(procedure B). Next, to clarify the reason why the modified
reagent ratio (aldehyde 1/amide 2/Bu3Sn–SnBu3 =1:1.5:1.5)
resulted in higher yields, carboxylation of intermediate 7d
was performed in the presence of extra amide 2d and
Bu3Sn–SnBu3 [0.5 equiv each; Scheme 2, Eq. (1)]. As a
result, 3d was obtained in 75% yield with respect to 7d,
along with 4d and 5d in 15 and 50% yields, respectively.
The increase in total yield with respect to 7d to 140% was
probably due to transformation of extra 2d into 3d, 4d, and
5d during the reaction. Furthermore, carboxylation of 7d
was conducted in the presence of a different amide, such as
para-methoxybenzensulfonamide (2e), leading to the incor-
poration of these two sulfonyl groups onto the product
[Scheme 2, Eq. (2)]. This scrambling phenomenon strongly
indicated that there should be a step for the regeneration of
imine 6 during this sequential process (vide infra): N-me-
thoxybenzensulfonyl imine 6e was considered to be generat-
ed after elimination of the para-toluenesulfonyl group.
We also used a-silyloxy stannane 9 as a potential source
for producing the stannyl anion. It is known that silylstann-
naes are reacted easily with aldehydes in the presence of an
activator (cyanide, fluoride, or N-heterocyclic carbene) to
afford a-silyloxy stannane even below room temperature.[11]
This process seems to be much faster than imine formation
from the aldehyde and sulfonamide, which usually requires
azeotropic dehydration in the presence of a Lewis acid at a
high temperature.[12] If retrostannylation is more favorable
than stannylation of an aldehyde, the stannyl anion would
be regenerated. Therefore, the reaction of 9 was tested in
the presence of amide 2d, CsF, and CO2 [Scheme 2,
Eq. (3)], thus affording the desired amino acid 3d in 47%
yield, which strongly indicated that after the generation of
cesium alkoxide, retrostannylation[13] occurred to produce
benzaldehyde 1a and a stannyl anion that kept silent during
imine formation and then reacted with imine 6d as soon as
it was generated (maintaining a low concentration of the
imine).
Based on the above-described experimental results, plau-
sible reaction pathways are proposed (Scheme 3).[14] Imine 6
would be generated by the condensation of aldehyde 1 with
primary sulfonamide 2, which is stannylated by the stannyl
anion generated from a bismetal and CsF. Imine formation
is a slow equilibrium because of the low nucleophilicity of
the nitrogen atom attached to a strongly electron-withdraw-
ing sulfonyl group. However, since the corresponding amide
anion 7’ would be stabilized by the sulfonyl substitution, the
stannylation of an imine might be irreversible and the equi-
librium of imine formation eventually shifts in favor of
Chem. Eur. J. 2013, 19, 1123 – 1128
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1125

T. Mita, Y. Sato and Y. Higuchi
Scheme 3. Entire reaction processes for the one-step synthesis of a-amino acids from aldehyde 1, sulfonamide 2, and CO2 gas in the presence of a bisme-
tal reagent.
imine 6. After the protonation of amide anion 7’, either hy-
percoordinate stannate or carbanion species 7’’[6,13] would be
generated by the attack of a fluoride anion, which exhibits
nucleophilic character at the a-position of amines (umpo-
lung reactivity[15]). Then this species undergoes the desired
carboxylation to afford a-amino acid 3 by nucleophilic addi-
tion to CO2. At the same time, the undesired protodestanny-
lation caused by proton sources, such as sulfonamide 2 and
H2O, generated during imine formation, as well as elimina-
tion of the sulfony group, somewhat proceeds to afford
benzyl amine derivative 4 and sulfinic acid 5, respectively.
During the elimination step, NH-imine 6’ is generated, and
part of it might be hydrolyzed to aldehyde 1. Both 6’ and
the regenerated 1 could react with sulfonamide 2 to repro-
duce N-sulfonyl imine 6 to participate in the reaction se-
quence. Meanwhile, the stannyl anion can react with alde-
hyde 1.[11] However, although a-alkoxy stannane 9’ is gener-
ated, retrostannylation would be favorable [Scheme 2,
Eq. (3)]. Therefore, aldehyde 1 and the stannyl anion are re-
generated, the latter of which should be consumed for stan-
nylation of imines. When other bismetal reagents, such as
25.0, respectively,[16] which support the proposed stability of
the stannyl anion, especially towards H2O generated during
imine formation (H2O: pKa =32.0 in DMSO; MsNH2 (2g):
pKa =17.5 in DMSO).
The decrease in the yield of the benzylamine derivative 4
in response to the steric bulk of the silicone moiety
(Table 2) might be attributed to the speed of generation of
the stannyl anion. If stannyl anion formation is fast in the
case of sterically smaller silylstannanes, the stannyl anion
can be partly protonated during slow imine formation, pro-
ducing HSnBu3, which might reduce sulfonyl imine 6 to
afford 4 through hydrostannylation [Scheme 3, Eq. (4)]. On
the other hand, when the formation of the stannyl anion is
slow and it is gradually produced in the case of sterically
bulkier silylstannanes and ditin reagents, the generated
stannyl anion would be adjusted to react with imine 6
before its protonation. We consider that 4 could be generat-
ed through two pathways (protodestannylation of 7[6,13] and
hydrostannylation of 6) and that the hydrostannylation is
the main pathway when using sterically smaller silylstan-
nanes that are more susceptible to a fluoride source. To con-
firm this hypothesis, 6d and 1a were treated with commer-
cially available HSnBu3 in DMF at 1008C (Scheme 4). As a
result, without any activators or catalysts, hydrostannylation
of 6d was completed within 1 h to afford 4d in 98% yield
[Scheme 4, Eq. (5)]. However, the reaction of 1a with
HSnBu3 was slower and benzyl alcohol (10) was obtained in
only 30% yield even after 3 h [Scheme 4, Eq. (6)]. The re-
sults of this study indicate the possibility that HSnBu3 gener-
ated in situ can reduce imine 6 efficiently and preferentially.
Next, under the optimal conditions, substrate scope was
examined by using the optimal amide 2h (Scheme 5). To
À
À
Si B and Si Si were employed for the purpose of the gener-
ation of the silyl anion, both benzyl alcohol and pinacol de-
rivatives were observed as major products,[9] which indicates
that the silylation of aldehyde 1 actually proceeded, but the
desilylation by fluoride was much faster than the retrosilyla-
tion. It is notable that this a-amino acid synthesis takes ad-
vantage of the properties of the stannyl anion being relative-
ly stable in the presence of proton sources, leading to the
enhancement of retrostannylation from the undesired a-
alkoxy stannane 9’. The reported pKa values of HSnMe3 in
DMSO and HSnBu3 in 1,2-dimethoxyethane were 23.4 and
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One-Step Synthesis of Racemic a-Amino Acids
FULL PAPER
hydes possessing electron-withdrawing groups on the aro-
matic ring (1a–h) were applicable and afforded the corre-
sponding a-amino acid derivatives 3 in up to 88% yield. It
is noteworthy that cyano functionality, which is not tolerated
under the conventional Strecker synthesis, remained intact
in this sequence (3gh). In addition, the ester moiety could
survive even though the stannyl anion was generated in situ
(3hh).[10] Moreover, aldehydes possessing electron-rich
arenes (1i–k) were also suitable candidates. Both 1- and 2-
naphthaldehydes (1l and 1m), as well as heteroaromatic al-
dehydes possessing 2-furyl, 2-thienyl, and 2-benzofuryl
groups (1n–p), were all active under these conditions. A
larger-scale reaction (1 mmol scale) proceeded without any
problems, giving 3ah with an identical yield (71%). Al-
though these amino acids were obtained as the racemic
form and only limited to arylglycine derivatives,[17] it is note-
worthy that only a single operation enables their syntheses
with high efficiency.
Scheme 4. Hydrostannylation reactions of imine 6d and benzaldehyde
(1a).
remove organotin residues and neutral compound 4, the
crude mixture was treated with an excess amount of
tBuNH2 to convert it into its stable tBuNH3 salt.[3] After fine
solids had been washed with hexane to completely remove
those materials,[13] pure methyl N-sulfonylamino carboxy-
lates 3 could be obtained through acid treatment followed
by methyl esterification with TMSCHN2. A variety of alde-
Finally, considering the utility of the products, removal of
the tert-butylsulfonyl group in 3ah and 3gh was demonstrat-
ed (Scheme 6). By following the Endersꢁ procedure[18] with a
Scheme 6. Removal of the tert-butylsulfonyl group.
different quenching method, the tert-butylsulfonyl group was
cleaved in the presence of AlCl3 and anisole, affording the
corresponding free amines 11a and 11g in 82 and 72%
yield, respectively. Notably, the free amino ester 11g pos-
sessing a cyano moiety, which cannot be synthesized by the
conventional Strecker method, could be accessed by this
protocol. The use of tert-butylsulfonamide (2h) has a great
advantage for deprotection of the tert-butylsulfonyl group of
the product under mild conditions owing to the facile gener-
ation of the tert-butyl carbocation in the presence of a Lewis
acid.
Conclusion
We have developed a one-step convergent synthesis of a-
amino acids from aldehydes, sulfonamides, and gaseous
CO2. This new method is quite efficient and the correspond-
ing a-amino acids were obtained in moderate-to-high yields
with a single operation (up to 88% yield). This sequential
reaction proceeds via two intermediates, an imine and an a-
amino stannane. The use of a stannyl anion is key because it
is relatively stable against proton sources such as sulfona-
mides and H2O that exist in the reaction and because it fa-
cilitates the retrostannylation of the undesired a-alkoxy
stannanes. This novel method proposes a new strategy for
Scheme 5. Substrate scope for the one-step a-amino acid synthesis from
aldehydes 1, tert-butylsulfonamide (2h), and CO2. Yields of the isolated
products are shown. All reactions were performed by using 0.1 mmol of
1. [a] 1 mmol of 1a was used (10-times larger scale).
Chem. Eur. J. 2013, 19, 1123 – 1128
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T. Mita, Y. Sato and Y. Higuchi
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b) J. Busch-Petersen, Y. Bo, E. J. Corey, Tetrahedron Lett. 1999, 40,
2065; c) R. Blanc, L. Commeiras, J.-L. Parrain, Adv. Synth. Catal.
2010, 352, 661.
[12] W. R. McKay, G. R. Proctor, J. Chem. Soc. Perkin Trans. 1 1981,
2435.
[13] T. Mita, M. Sugawara, H. Hasegawa, Y. Sato, J. Org. Chem. 2012,
77, 2159.
[14] The one-step reaction of 1a and 2h in the presence of a radical scav-
enger, 3,5-di-tert-butyl-4-hydroxytoluene (BHT), proceeded to
afford the desired a-amino acid 3ah in 47% yield along with 4ah in
35% yield, which indicates exclusion of the radical process. Since
BHT also worked as a proton source, the yield of 4ah might be in-
creased. See the Supporting Information for details.
Preparative scale (1mmol) procedure for the one-step synthesis of 3ah:
Dry CsF (760 mg, 5.0 mmol, 5 equiv), which was preheated for 10 min by
a heat gun under vacuum before use (<5 mmHg at ca. 4008C), was
quickly mixed with tert-butylsulfonamide (2h; 206 mg, 1.5 mmol,
1.5 equiv). After addition of dry DMF (3.0 mL), benzaldehyde (1a;
102 mL, 1.0 mmol) was added, followed by hexabutylditin (758 mL,
1.5 mmol, 1.5 equiv). The mixture was placed inside an autoclave and
sealed tightly. CO2 gas was introduced into the autoclave (1 MPa), which
was heated at 1008C for 5 h. After the mixture had cooled to room tem-
perature, water and Et2O were added, and the pH of the mixture was ad-
justed to 2 by using 1m HCl. The organic layer was extracted with Et2O,
washed with brine, and dried over Na2SO4. The solvent was removed
under reduced pressure, and the residue was diluted with Et2O (ca.
2 mL) followed by treatment with an excess of tert-butylamine (ca.
500 mL). After 20 min, hexane was added, and the resultant solids were
filtrated and washed with hexane. The solids were placed into water fol-
lowed by addition of AcOEt, and the pH of the mixture was adjusted to
2 by using 1m HCl. The organic layer was extracted with AcOEt and
dried over Na2SO4. The solvent was removed under reduced pressure,
and the residue was diluted with Et2O/MeOH=4:1 (ca. 4 mL) followed
by treatment with TMSCHN2 (2m in Et2O). After 1 h, the mixture was
directly concentrated under high vacuum to afford the crude product.
The crude product was then purified by silica gel column chromatogra-
phy (hexane/AcOEt, 3:1), affording methyl 2-(1,1-dimethylethylsulfona-
mido)-2-phenylacetate (3ah; 203 mg, 0.71 mmol) in 71% yield as a white
solid.
Removal of the tert-butylsulfonyl group: In a drying tube, the a-amino
acid derivative 3ah (57.1 mg, 0.20 mmol) was dissolved in dry dichloro-
methane (5.0 mL). Anisole (45.3 mL. 0.40 mmol, 2.0 equiv) and aluminum
chloride (93.3 mg, 0.70 mmol, 3.5 equiv) were added successively in one
portion to the reaction mixture. After stirring for 1 h at room tempera-
ture, the resulting yellow solution was diluted with dichloromethane
(16 mL) and 30% ammonia solution (14 mL). The organic layer was ex-
tracted six times with dichloromethane. The combined organic layers
were dried over Na2SO4 and the solvent was removed under reduced
pressure. The crude product was then purified by silica gel column chro-
matography (dichloromethane-MeOH, 97:3), affording methyl 2-amino-
2-phenylacetate (11a; 27.1 mg, 0.16 mmol) in 82% yield as a yellow oil.
Acknowledgements
[15] a) D. Seebach, D. Enders, Angew. Chem. 1975, 87, 1; Angew. Chem.
Int. Ed. Engl. 1975, 14, 15; b) P. Beak, D. B. Reitz, Chem. Rev. 1978,
78, 275.
[16] E. S. Petrov, M. I. Terekhova, R. G. Mirskov, M. G. Voronkov, A. I.
Shatenshtein, Dokl. Chem. 1975, 221, 193 (English Translation).
[17] The reactions of alkenyl, alkynyl, and alkyl aldehydes under these
conditions did not give the desired amino acids, but resulted in the
observation of several unidentified compounds.
This work was financially supported by Grants-in-Aid for Young Scien-
tists (B; no. 24750081) and for Scientific Research (B) (no. 23390001)
from the Japan Society for the Promotion of Science (JSPS), by a Grant-
in-Aid for Scientific Research on Innovative Areas “Molecular Activa-
tion Directed toward Straightforward Synthesis (no. 23105501)” from the
Ministry of Education, Culture, Sports, Science and Technology, Japan,
and by the Uehara Memorial Foundation.
[18] a) D. Enders, M. Seppelt, T. Beck, Adv. Synth. Catal. 2010, 352,
1413; for the original procedure, see: b) P. Sun, S. M. Weinreb, J.
Org. Chem. 1997, 62, 8604.
[1] For representative reviews, see: a) W. S. Knowles, Acc. Chem. Res.
1983, 16, 106; b) R. M. Williams, J. A. Hendrix, Chem. Rev. 1992, 92,
889; c) R. O. Duthaler, Tetrahedron 1994, 50, 1539; d) H. J. Kreuz-
Received: June 30, 2012
Revised: October 2, 2012
Published online: November 26, 2012
1128
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