Facile approach to natural or non-natural amino acid derivatives: Me 3SiCl-promoted coupling reaction of organozinc compounds with N,O-acetals

Article abstract of DOI:10.1002/ejoc.200801107

We have developed a Me₃SiCl-promoted coupling reaction of aryl- and alkylzinc compounds, in-situ generated either by transmetalation of the corresponding organometallic reagents or by insertion of zinc metal into organic halides, with several N

Full text of DOI:10.1002/ejoc.200801107

FULL PAPER
DOI: 10.1002/ejoc.200801107
Facile Approach to Natural or Non-Natural Amino Acid Derivatives: Me3SiCl-
Promoted Coupling Reaction of Organozinc Compounds with N,O-Acetals
Norio Sakai,*[a] Junichi Asano,[a] Yuki Kawada,[a] and Takeo Konakahara[a]
Keywords: Amino acids / Acetals / Zinc / Arylation / Alkylation
We have developed a Me3SiCl-promoted coupling reaction
of aryl- and alkylzinc compounds, in-situ generated either by
transmetalation of the corresponding organometallic rea-
gents or by insertion of zinc metal into organic halides, with
several N,O-acetals, which leads to the preparation of a vari-
ety of natural and non-natural amino acid derivatives.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
drawing groups, such as ketones, aldehydes, nitriles, and es-
ters.[6] In addition, organozinc compounds can be easily
prepared either by transmetalation of organolithium rea-
gents or Grignard reagents or by insertion of zinc metal
into organic halides. Consequently, the coupling reaction of
such arylzinc compounds with N,O-acetals, activated by a
proper catalyst, would be suitable for the preparation of α-
aryl amino acid derivatives having electron-deficient groups
(Scheme 1).[7,8]
Introduction
α-Aryl amino acid derivatives are important and indis-
pensable materials for the maintenance of human life.[1] Ap-
proaches that employ Friedel–Crafts-type reactions of aro-
matics with imine (iminoesters),[2] N,O-acetals,[3] and N,N-
acetals[4] as glycine cation equivalents are among the most
useful and representative tools for the preparation of these
α-aromatic amino acid derivatives. In this type of reaction,
aromatic compounds with electron-donating groups, such
as an alkyl or alkoxy group and an amino group, and elec-
tron-rich heterocycles, such as indole, pyrrole, and furan,
have generally been utilized. However, reactions in which
less-activated aryl compounds, such as benzene and tolu-
ene, and aromatic compounds with an electron-withdrawing
group, such as a halogen substituent and an ester group, are
used have been unsuccessful due to lower nucleophilicity. A
Hf(OTf)4-doped Me3SiCl catalytic system was also found
to effectively catalyze the aminomethylation of electron-rich
arenes with several N,O-acetals, which led to the production
of α-aryl amino acid derivatives.[5] Unfortunately, amino-
methylation with the use of aromatic compounds with elec-
tron-deficient substituents was entirely unproductive. Thus,
it was necessary to focus on the development of an efficient
process, which could undertake the aminomethylation of
aromatic compounds having an electron-withdrawing group
with N,O-acetals.
Scheme 1. Metal-promoted coupling reaction of arylzinc com-
pounds with N,O-acetals 1 as a glycine moiety precursor.
In this paper, the authors report a Me3SiCl-promoted
coupling reaction of arylzinc compounds, prepared by
transmetalation of the corresponding aryllithium com-
pounds having electron-deficient groups, with N,O-acetals
as a glycine cation equivalent, leading to the synthesis of a
variety of α-arylglycine derivatives. The authors also dem-
onstrate that this method can be applied to the coupling
reaction of benzyl- and alkylzinc species with N,O-acetals,
which leads to the preparation of standard amino acid de-
rivatives such as glycine, phenylalanine, aspartic acid, val-
ine, and leucine.
Organozinc reagents, which are tolerant for a variety of
functional groups, generally show lower reactivity to typical
organic electrophiles than the corresponding organolithium
compounds and Grignard reagents. However, these reagents
display a potential advantage for carbon–carbon bond for-
mation with organic compounds having electron-with-
Results and Discussion
[a] Department of Pure and Applied Chemistry, Faculty of Science
and Technology, Tokyo University of Science (RIKADAI),
Noda, Chiba 278-8510, Japan
On the basis of previous studies, when the reaction of in
situ generated phenylzinc bromide with N,O-acetal[9] 1a was
initially performed with the use of Hf(OTf)4 (5 mol-%) and
Fax: +81-4-7123-9890
E-mail: sakachem@rs.noda.tus.ac.jp
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N. Sakai, J. Asano, Y. Kawada, T. Konakahara
FULL PAPER
chlorotrimethylsilane (Me3SiCl, 1.2 equiv.), the desired ami- Table 2. Synthesis of α-arylglycine derivatives.[a]
nomethylated product 2a was obtained in 95% yield
(Table 1, run 1). When the reaction was attempted without
the hafnium catalyst, the same result was obtained (Table 1,
run 2); moreover, without the addition of hafnium and
Me3SiCl, starting N,O-acetal 1a was recovered (Table 1,
run 3). Consequently, it was found that Me3SiCl activates
the N,O-acetal, to make up for the low nucleophilicity of
the arylzinc reagent, and promotes the coupling reaction.
In order to better adjust the reaction conditions, a
counteranion exchange on a silicon catalyst was carried out,
which resulted in a decreased yield (Table 1, runs 4 and 5).
In contrast, the use of chlorobenzene instead of the bro-
mide resulted in the recovery of the starting acetal. In the
case of iodobenzene, the yield decreased slightly (Table 1,
runs 6 and 7).
Table 1. Optimization of reaction conditions.
Run
Ph–X
Me3Si–Y
Time [h]
Yield [%][a]
1
2
3
4
5
6
7
PhBr
PhBr
PhBr
PhBr
PhBr
PhCl
PhI
Me3SiCl
Me3SiCl
none
1
1
1
1.5
1
1
95[b]
93
NR
ND
33
[a] Isolated yield.
Me3SiI
Me3SiOTf
Me3SiCl
Me3SiCl
3a,b were obtained in 96 and 61% yield, respectively. The
reactions with substrates having an electron-withdrawing
group, such as an ester group or a bromine substituent,
were also successful and produced expected phenylalanine
derivatives 3c,d in good yields.
NR
77
0.5
[a] Isolated yield. [b] Reaction was carried out in the presence of
Hf(OTf)4 (5 mol-%).
Preparation of a variety of α-arylglycine derivatives with
several N,O-acetals was then examined, and the results are
summarized in Table 2. The reaction can be successfully
adapted to aryl bromides with either an electron-donating
or an electron-withdrawing group, as well as to a heterocy-
cle such as 2-bromothiophene. It was particularly successful
in the one-pot synthesis of arylglycine derivatives 2d,e hav-
ing an electron-withdrawing group as a fluorine substituent.
The location of a methyl group on the benzene ring did
not affect the reactivity, and the corresponding amino acid
derivative 2f was produced in good yield. The use of N,O-
acetal 1c markedly decreased the yield of 2i. Me3SiCl seems
to prefer to coordinate to the N-phenylpiperazine rather
than to serve as an activator for the methoxy substituent.
The reaction of N,O-acetals with benzyl halide deriva-
tives instead of aryl bromide derivatives was the carried out
for the preparation of phenylalanine derivatives, and the re-
sults are shown in Table 3. The reaction with benzyl bro-
mide did not need the generation of the corresponding ben-
zyl anion from the halide with nBuLi and proceeded
through a standard Reformatsky-type reaction with me-
Table 3. Synthesis of phenylalanine derivatives.[a]
[a] Isolated yield.
The present method was used to prepare several amino
tallic zinc to produce expected phenylalanine derivatives 3. acid derivatives with aliphatic chains, as shown in Table 4.
For example, when the reaction with benzyl bromide and For example, with the use of nBuLi in the presence of
3-methylbenzyl bromide was carried out in the presence of ZnBr2 the reaction proceeded to give desired amino acid 4a
granular zinc, the corresponding phenylalanine derivatives in 84% yield. Similar cases in which isopropyl or sec-butyl
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Facile Approach to Natural or Non-Natural Amino Acid Derivatives
Grignard reagents were used were also successful in produc- lylamino group and deprotection of the diallylamino group
ing valine derivative 4b and leucine derivative 4c in practical in product 3e with the method described by Guibé or Tsu-
yields.
kamoto[10] successfully produced N-unsubstituted phenyl-
alanine derivative 6.
Table 4. Synthesis of amino acid derivatives 4 having an alkyl
chain.[a]
Conclusions
In summary, this study demonstrated the Me3SiCl-pro-
moted coupling reaction of aryl- and alkylzinc compounds,
which were generated either by transmetalation of the cor-
responding organometallic reagents or by insertion of zinc
metal into organic halides, with several N,O-acetals as a
glycine cation equivalent, which led to the preparation of a
variety of natural and non-natural amino acid derivatives
involving standard amino acids, such as glycine, phenylala-
nine, aspartic acid, valine, and leucine.
[a] Isolated yield.
Experimental Section
Moreover, as shown in Table 5, the reaction of N,O-ace-
tals 1a,d with methyl bromoacetate in the presence of met-
allic zinc and Me3SiCl produced novel aspartic acid deriva-
tives 5a,b in 99 and 70% yield, respectively. When the reac-
tion was performed with bromoacetonitrile and propargyl
bromide, the corresponding amino acid derivatives 5c,d
were obtained in good yields.
General Methods: Column chromatography was performed by
using silica gel. THF and Et2O were distilled from sodium–benzo-
phenone and dried with 4Å MS. MeOH was distilled from Mg/I2
and dried with 3Å MS. Secondary amines (piperidine, etc.) were
commercially available and distilled prior to use. All reactions were
carried out under a nitrogen atmosphere, unless otherwise noted.
1H NMR spectra were measured at 500 (or 300) MHz by using
tetramethylsilane as an internal standard. 13C NMR spectra were
measured at 125 (or 75) MHz by using TMS or a center peak of
chloroform (δ =77.0 ppm) as an internal standard. High-resolution
mass spectra were measured by using NBA (3-nitrobenzylalcohol)
as a matrix. Methyl 2-bromo-2-methoxyacetate was prepared ac-
cording to the literature.[5a]
Table 5. Synthesis of various amino acid derivatives.[a]
General Procedure for the Synthesis of N,O-Acetals 1a–d: To a
freshly distilled THF (100 mL) was successively added the corre-
sponding secondary amine (24 mmol), triethylamine (24 mmol),
and methyl 2-bromo-2-methoxyacetate (20 mmol), and the solution
was stirred at room temperature. After 2 h, the reaction was
quenched by adding
a saturated aqueous solution Na2CO3
(2.0 mL). The aqueous layer was extracted with CHCl3, and the
organic phase was combined, dried with anhydrous Na2CO3, fil-
tered, and evaporated under reduced pressure. The crude product
was distilled (Kugelrohr) to give the corresponding N,O-acetals.
[a] Isolated yield.
Finally, to prepare an N-underivatized amino acid deriv-
ative, deprotection of the diallylamino group was performed
(Scheme 2). It was demonstrated that a sequential pro-
1a:[5a] B.p. 71–72 °C/5 Torr (colorless oil). 1H NMR (300 MHz,
CDCl3): δ = 1.3–1.4 (m, 2 H, N-CH2-CH2-CH2), 1.5–1.6 (m, 4 H,
N-CH2-CH2), 2.5–2.8 (m, 4 H, N-CH2), 3.39 (s, 3 H, O-CH3), 3.77
cedure consisting of a Me3SiCl-catalyzed coupling reaction (s, 3 H, CO2-CH3), 4.23 (s, 1 H, C-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 24.2, 25.8, 48.4, 51.4, 55.5, 94.0, 168.7 ppm.
of benzylzinc bromide with N,O-acetal 1b having a dial-
1b:[5a] B.p. 69–70 °C/5 Torr (colorless oil). 1H NMR (300 MHz,
CDCl3): δ = 3.2–3.3 (m, 4 H, N-CH2-CH=CH2), 3.36 (s, 3 H, O-
CH3), 3.76 (s, 3 H, CO2-CH3), 4.45 (s, 1 H, C-H), 5.1–5.2 (m, 4 H,
N-CH2-CH=CH2), 5.7–5.8 (m, 2 H, N-CH2-CH=CH2) ppm. 13C
NMR (75 MHz, CDCl3): δ = 51.8, 52.1, 55.5, 89.8, 117.5, 135.7,
169.7 ppm. MS (ESI): m/z = 222 [M + Na]. HRMS (ESI): calcd
for C10H17NNaO3 222.1106; found 222.1095.
1c:[5a] B.p. 148–150 °C/5 Torr (brown oil). 1H NMR (500 MHz,
CDCl3): δ = 2.76 (t, J = 5.5 Hz, 2 H, CH-N-CH2-CH2-N-Ph), 2.92
(t, J = 5.5 Hz, 2 H, CH-N-CH2-CH2-N-Ph), 3.17 (t, J = 5.5 Hz, 4
H, CH-N-CH2-CH2-N-Ph), 3.42 (s, 3 H, O-CH3), 3.78 (s, 3 H,
CO2-CH3), 4.32 (s, 1 H, C-H), 6.83 (t, J = 7.5 Hz, 1 H, Ar-H), 6.91
Scheme 2. Synthesis of N-underivatized phenylalanine derivative 6.
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N. Sakai, J. Asano, Y. Kawada, T. Konakahara
FULL PAPER
(d, J = 7.5 Hz, 2 H, Ar-H), 7.23 (t, J = 7.5 Hz, 2 H, Ar-H) ppm.
172.4 ppm. MS (FA): m/z (%) = 264 (80) [M + H], 192 (100) [M –
13C NMR (125 MHz, CDCl3): δ = 47.3, 49.3, 51.6, 55.8, 93.2, CO2Me]. HRMS (FAB): calcd. for C15H19NO2F 264.1400; found
116.1, 119.7, 128.9, 151.2, 168.3 ppm.
264.1410.
2f: Yield: 105.0 mg, 81% (colorless oil). 1H NMR (300 MHz,
CDCl3): δ = 2.40 (s, 3 H, Ar-CH3), 3.16 (m, 2 H, N-CH2-
CH=CH2), 3.30 (m, 2 H, N-CH2-CH=CH2), 3.69 (s, 3 H, CO2-
CH3), 4.79 (s, 1 H, C-H), 5.0–5.2 (m, 4 H, N-CH2-CH=CH2), 5.7–
5.8 (m, 2 H, N-CH2-CH=CH2), 7.14 (m, 3 H, Ar-H), 7.24 (m, 1
H, Ar-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.3, 51.3, 53.2,
64.5, 64.5, 117.2, 125.7, 127.8, 128.3, 130.7, 134.9, 135.9, 137.8,
172.9 ppm. MS (FA): m/z (%) = 260 (5) [M + H], 200 (100) [M –
CO2Me]. HRMS (FAB): calcd. for C16H22NO2 260.1651; found
260.1668.
1d:[5] B.p. 84–86 °C/5 Torr (colorless oil). 1H NMR (300 MHz,
CDCl3): δ = 2.6–2.8 (m, 4 H, N-CH2-CH2-O), 3.42 (s, 3 H, O-
CH3), 3.6–3.7 (m, 4 H, N-CH2-CH2-O), 3.79 (s, 3 H, CO2-CH3),
4.23 (s, 1 H, C-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 47.6,
51.7, 55.8, 66.9, 93.4, 168.2 ppm.
General Procedure for the Synthesis of Amino Acid Derivatives 2a–
i: Aryl bromide (0.75 mmol) and n-butyllithium (1.6  in hexane,
0.50 mL, 0.80 mmol) were successively mixed in Et2O at room tem-
perature by stirring. After 0.2 h, ZnBr2 (0.75 mmol) was added,
and the suspension was stirred for 0.5 h at room temperature. N,O-
Acetal 1a (0.50 mmol) and freshly distilled Me3SiCl (0.60 mmol)
were then added, and the mixture was stirred until the reaction
reached completion, as shown by TLC (SiO2; hexane/AcOEt, 2:1).
The reaction was quenched with a saturated aqueous solution of
Na2CO3 (2 mL). The combined organic layer was dried with anhy-
drous Na2CO3 and evaporated under reduced pressure. The crude
product was purified by silica gel column chromatography (hexane/
AcOEt) to afford amino acid derivative 2.
2a:[11] Yield: 108.3 mg, 93% (colorless oil). 1H NMR (300 MHz,
CDCl3): δ = 1.4–1.5 (m, 2 H, N-CH2-CH2-CH2), 1.5–1.6 (m, 4 H,
N-CH2-CH2), 2.3–2.4 (m, 4 H, N-CH2), 3.67 (s, 3 H, CO2-CH3),
3.97 (s, 1 H, C-H), 7.2–7.3 (m, 3 H, Ar-H), 7.3–7.4 (m, 2 H, Ar-
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 24.2, 25.7, 51.8, 52.3,
128.0, 128.3, 128.7, 136.1, 172.2 ppm. MS (FA): m/z (%) = 234
(63) [M + H], 174 (100) [M – CO2Me]. HRMS (FAB): calcd. for
C14H20NO2 234.1494; found 234.1504.
1
2g: Yield: 89.7 mg, 75% (red oil). H NMR (500 MHz, CDCl3): δ
= 1.4–1.5 (m, 2 H, N-CH2-CH2-CH2), 1.5–1.6 (m, 4 H, N-CH2-
CH2), 2.4–2.5 (m, 4 H, N-CH2), 3.74 (s, 3 H, CO2-CH3), 4.36 (s, 1
H, C-H), 6.94 (t, J = 4.0 Hz, 1 H, Ar-H), 7.02 (d, J = 4.0 Hz, 1 H,
Ar-H), 7.28 (d, J = 4.0 Hz, 1 H, Ar-H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 24.2, 25.8, 51.9, 52.0, 69.4, 126.1, 126.2, 127.0, 139.0,
171.1 ppm. MS (FA): m/z (%) = 240 (42) [M + H], 180 (100) [M –
CO2Me]. HRMS (FAB): calcd. for C12H18NO2S 240.1058; found
240.1051.
2h: Yield: 106.8 mg, 85% (brown oil). 1H NMR (300 MHz,
CDCl3): δ = 3.2–3.3 (m, 4 H, N-CH2-CH=CH2), 3.76 (s, 3 H, CO2-
CH3), 4.86 (s, 1 H, C-H), 5.1–5.3 (m, 4 H, N-CH2-CH=CH2), 5.8–
5.9 (m, 2 H, N-CH2-CH=CH2), 6.94 (m, 2 H, Ar-H), 7.26 (m, 1
H, Ar-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 51.6, 53.2, 62.2,
117.5, 125.7, 126.3, 126.4, 135.6, 139.9, 171.3 ppm. MS (FA): m/z
(%) = 252 (100) [M + H], 192 (75) [M – CO2Me]. HRMS (FAB):
calcd. for C13H18NO2S 252.1058; found 252.1059.
2b: Yield: 110.0 mg, 89% (colorless oil). 1H NMR (300 MHz,
CDCl3): δ = 1.4–1.5 (m, 2 H, N-CH2-CH2-CH2), 1.5–1.6 (m, 4 H,
N-CH2-CH2), 2.3–2.4 (m, 7 H, N-CH2, Ar-CH3), 3.66 (s, 3 H, CO2-
CH3), 3.93 (s, 1 H, C-H), 7.12 (d, J = 8.5 Hz, 2 H, Ar-H), 7.30 (d,
J = 8.5 Hz, 2 H, Ar-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
21.0, 24.2, 25.7, 51.7, 52.3, 128.6, 129.0, 133.1, 137.8, 172.4 ppm.
MS (FA): m/z (%) = 188 (80) [M + H], 248 (100) [M – CO2Me].
HRMS (FAB): calcd. for C15H22NO2 248.1651; found 248.1628.
2c: Yield: 106.5 mg, 81% (colorless oil). 1H NMR (500 MHz,
CDCl3): δ = 1.4–1.5 (m, 2 H, N-CH2-CH2-CH2), 1.5–1.6 (m, 4 H,
N-CH2-CH2), 2.3–2.4 (m, 4 H, N-CH2), 3.67 (s, 3 H, O-CH3), 3.79
(s, 3 H, CO2-CH3), 3.90 (s, 1 H, C-H), 6.85 (d, J = 8.5 Hz, 2 H,
Ar-H), 7.34 (d, J = 8.5 Hz, 2 H, Ar-H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 24.3, 25.6, 51.8, 52.3, 55.1, 113.7, 128.1, 129.8, 159.4,
172.5 ppm. MS (FA): m/z (%) = 264 (100) [M + H], 204 (85) [M –
CO2Me]. HRMS (FAB): calcd. for C15H22NO3 264.1600; found
264.1589.
2d: Yield: 90.5 mg, 72% (yellow oil). 1H NMR (500 MHz, CDCl3):
δ = 1.4–1.5 (m, 2 H, N-CH2-CH2-CH2), 1.5–1.6 (m, 4 H, N-CH2-
CH2), 2.3–2.4 (m, 4 H, N-CH2), 3.68 (s, 3 H, CO2-CH3), 3.95 (s, 1
H, C-H), 7.00 (t, J = 8.5 Hz, 2 H, Ar-H), 7.40 (t, J = 8.5 Hz, 2 H,
Ar-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 24.2, 25.7, 51.8,
52.2, 74.0, 115.2, 115.3, 130.3, 130.4, 131.9, 132.0, 161.5, 163.5,
172.1 ppm. MS (FA): m/z (%) = 252 (100) [M + H], 192 (82) [M –
CO2Me]. HRMS (FAB): calcd. for C14H19NO2F 252.1400; found
252.1402.
2e: Yield: 93.5 mg, 71% (yellow oil). 1H NMR (500 MHz, CDCl3):
δ = 3.18 (m, 4 H, N-CH2-CH=CH2), 3.71 (s, 3 H, CO2-CH3), 4.50
(s, 1 H, C-H), 5.1–5.2 (m, 4 H, N-CH2-CH=CH2), 5.8–5.9 (m, 2
H, N-CH2-CH=CH2), 7.00 (m, 2 H, Ar-H), 7.34 (m, 2 H, Ar-H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 51.6, 53.0, 53.3, 66.9,
115.1, 115.3, 117.6, 130.2, 130.3, 131.8, 132.3, 135.3, 161.4, 163.3,
2i: Yield: 49.6 mg, 32% (colorless oil). 1H NMR (300 MHz,
CDCl3): δ = 2.60 (t, J = 5.0 Hz, 4 H, CH-N-CH2-CH2-N-Ph), 3.20
(t, J = 5.0 Hz, 4 H, CH-N-CH2-CH2-N-Ph), 3.70 (s, 3 H, CO2-
CH3), 4.05 (s, 1 H, C-H), 6.82 (t, J = 7.0 Hz, 1 H, Ar-H), 6.88 (d,
J = 7.0 Hz, 2 H, Ar-H), 7.22 (t, J = 7.0 Hz, 2 H, Ar-H), 7.34 (m,
3 H, Ar-H), 7.45 (m, 2 H, Ar-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 48.9, 51.1, 52.0, 74.1, 116.0, 119.7, 127.1, 128.6, 128.8,
129.0, 135.5, 151.1, 171.8 ppm. MS (FA): m/z (%) = 311 (100) [M +
H], 251 (93) [M – CO2Me]. HRMS (FAB): calcd. for C19H23N2O2
311.1760; found 311.1744.
General Procedure for Phenylalanine Derivatives 3: Freshly distilled
THF (3 mL) and benzyl bromide (0.75 mmol) were successively
added to a glass vessel (20 mL) containing Zn dust (1.0 mmol) un-
der a nitrogen atmosphere, and the suspension was stirred at room
temperature for 0.5 h. N,O-Acetal (0.50 mmol) and Me3SiCl
(0.6 mmol) were then added, and the mixture was stirred at room
temperature. The reaction was quenched with saturated aqueous
NaHCO3 and extracted with CHCl3. The organic layer was dried
with anhydrous Na2CO3 and the solvent removed. The product was
isolated by flash chromatography (hexane/AcOEt) and charac-
terized by using spectroscopic techniques.
3a:[12] Yield: 118.7 mg, 96% (yellow oil). 1H NMR (500 MHz,
CDCl3): δ = 1.2–1.3 (m, 2 H, N-CH2-CH2-CH2), 1.3–1.5 (m, 4 H,
N-CH2-CH2), 2.3–2.5 (m, 4 H, N-CH2), 2.76 (m, 1 H, Ar-CH2-
CH), 2.88 (m, 1 H, Ar-CH2-CH), 3.23 (m, 1 H, C-H), 3.41 (s, 3 H,
CO2-CH3), 7.0–7.2 (m, 5 H, Ar-H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 24.4, 26.3, 35.6, 50.7, 50.9, 70.3, 126.2, 128.1, 129.0,
138.3, 171.7 ppm. MS (FA): m/z (%) = 248 (95) [M + H], 188 (100)
[M – CO2Me]. HRMS (FAB): calcd. for C15H22NO2 248.1651;
found 248.1637.
3b: Yield: 80.3 mg, 61% (yellow oil). 1H NMR (500 MHz, CDCl3):
δ = 2.31 (s, 3 H, Ar-CH3), 2.6–2.7 (m, 4 H, N-CH2-CH2-O), 2.91
920
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Facile Approach to Natural or Non-Natural Amino Acid Derivatives
(m, 1 H, Ar-CH2-CH), 3.01 (m, 1 H, Ar-CH2-CH), 3.38 (m, 1 H,
= 6.0 Hz, 3 H, CH-CH-(CH3)2], 1.3–1.5 (m, 6 H, N-CH2-CH2-
C-H), 3.60 (s, 3 H, CO2-CH3), 3.6–3.8 (m, 4 H, N-CH2-CH2-O), CH2), 2.00 [dd, J = 6.0, 10.5 Hz, 1 H, CH-CH-(CH3)2], 2.33 (m, 2
6.9–7.0 (m, 3 H, Ar-H), 7.16 (t, J = 8.0 Hz, 1 H, Ar-H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 21.3, 35.2, 50.2, 51.0, 67.2, 69.9,
H, N-CH2), 2.48 (m, 2 H, N-CH2), 2.65 [d, J = 10.5 Hz, 1 H, CH-
CH-(CH3)2], 3.65 (s, 3 H, CO2-CH3) ppm. 13C NMR (125 MHz,
126.0, 127.2, 128.2, 129.8, 137.6, 137.8, 171.5 ppm. MS (FA): m/z CDCl3): δ = 19.1, 19.7, 24.7, 26.5, 26.6, 50.3, 50.7, 75.1, 172.2 ppm.
(%) = 264 (100) [M + H], 204 (96) [M – CO2Me]. HRMS (FAB):
MS (FA): m/z (%) = 200 (100) [M + H], 139 (75) [M – CO2Me].
calcd. for C15H22NO3 264.1600; found 264.1610.
HRMS (FAB): calcd. for C11H22NO2 200.1651; found 200.1641.
3c: Yield: 125.3 mg, 79% (colorless oil). 1H NMR (500 MHz,
CDCl3): δ = 2.94 (m, 1 H, Ar-CH2-CH), 3.05 (m, 3 H, Ar-CH2-
CH, N-CH2-CH=CH2), 3.34 (m, 2 H, N-CH2-CH=CH2), 3.65 (s,
3 H, CH-CO2-CH3), 3.72 (t, J = 7.5 Hz, 1 H, C-H), 3.90 (s, 3 H,
Ar-CO2-CH3), 5.0–5.2 (m, 4 H, N-CH2-CH=CH2), 5.6–5.7 (m, 2
H, N-CH2-CH=CH2), 7.23 (d, J = 8.0 Hz, 2 H, Ar-H), 7.93 (d, J
= 8.0 Hz, 2 H, Ar-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 35.6,
51.1, 51.9, 53.3, 63.2, 117.2, 128.1, 129.3, 129.4, 136.0, 144.1, 167.0,
172.6 ppm. MS (FA): m/z (%) = 318 (100) [M + H], 258 (98) [M –
CO2Me]. HRMS (FAB): calcd. for C18H24NO4 318.1705; found
318.1718.
3d: Yield: 128.5 mg, 76% (colorless oil). 1H NMR (500 MHz,
CDCl3): δ = 2.81 (m, 1 H, Ar-CH2-CH), 2.97 (m, 1 H, Ar-CH2-
CH), 3.02 (m, 2 H, N-CH2-CH=CH2), 3.33 (m, 2 H, N-CH2-
CH=CH2), 3.65 (s, 3 H, CO2-CH3), 3.69 (t, J = 7.5 Hz, 1 H, C-
H), 5.0–5.2 (m, 4 H, N-CH2-CH=CH2), 5.6–5.7 (m, 2 H, N-CH2-
CH=CH2), 7.03 (d, J = 8.0 Hz, 2 H, Ar-H), 7.37 (d, J = 8.0 Hz, 2
H, Ar-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 35.1, 51.1, 53.4,
63.4, 117.2, 120.0, 131.0, 131.1, 136.1, 137.5, 172.7 ppm. MS (FA):
m/z (%) = 338 (35) [M + H], 278 (100) [M – CO2Me]. HRMS
(FAB): calcd. for C16H22BrNO2 338.0756; found 338.0736.
3e: Yield: 116.6 mg, 90% (yellow oil). 1H NMR (500 MHz,
CDCl3): δ = 2.86 (m, 1 H, Ar-CH2-CH), 3.0–3.1 (m, 3 H, Ar-CH2-
CH, N-CH2-CH=CH2), 3.34 (m, 2 H, N-CH2-CH=CH2), 3.62 (s,
3 H, CO2-CH3), 3.69 (t, J = 7.5 Hz, 1 H, C-H), 5.0–5.2 (m, 4 H,
N-CH2-CH=CH2), 5.6–5.7 (m, 2 H, N-CH2-CH=CH2), 7.1–7.2 (m,
3 H, Ar-H), 7.2–7.3 (m, 2 H, Ar-H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 35.7, 50.9, 53.4, 63.8, 117.0, 126.1, 128.0, 129.2, 136.2,
138.4, 172.9 ppm. MS (FA): m/z (%) = 260 (93) [M + H], 200 (100)
[M – CO2Me]. HRMS (FAB): calcd. for C16H22NO2 260.1651;
found 260.1656.
4c: Yield: 81.0 mg, 76% (colorless oil). 1H NMR (500 MHz,
CDCl3): δ = 0.84 [d, J = 6.0 Hz, 3 H, CH-CH2-CH-(CH3)2], 0.87
[d, J = 6.0 Hz, 3 H, CH-CH2-CH-(CH3)2], 1.37 (m, 2 H, N-CH2-
CH2-CH2), 1.4–1.6 [m, 7 H, CH-CH2-CH-(CH3)2, N-CH2-CH2-
CH2], 2.42 (m, 2 H, N-CH2), 2.52 (m, 2 H, N-CH2), 3.17 [m, 1
H, CH-CH2-CH-(CH3)2], 3.64 (s, 3 H, CO2-CH3) ppm. 13C NMR
(125 MHz, CDCl3): δ = 22.5, 22.6, 24.6, 25.1, 26.4, 38.2, 50.7, 50.8,
66.3, 173.0 ppm. MS (FA): m/z (%) = 214 (100) [M + H], 153 (75)
[M – CO2Me]. HRMS (FAB): calcd. for C12H24NO2 214.1807;
found 214.1815.
General Procedure for Amino Acids 5: Freshly distilled THF (3 mL)
and the corresponding alkyl bromide (0.75 mmol) were successively
added to a glass vessel (20 mL) containing Zn dust (1.0 mmol) un-
der a nitrogen atmosphere, and the suspension was stirred at room
temperature for 0.5 h. N,O-Acetal (0.50 mmol) and Me3SiCl
(0.6 mmol) were then added, and the mixture was stirred at room
temperature. The reaction was quenched with a saturated aqueous
solution of Na2CO3 (2 mL) and extracted with CHCl3. The organic
layer was dried with anhydrous Na2CO3, and the solvent was re-
moved under reduced pressure. The product was isolated by flash
chromatography (hexane/AcOEt) and characterized by using spec-
troscopic techniques.
5a:[14] Yield: 113.4 mg, 99% (colorless oil). 1H NMR (500 MHz,
CDCl3): δ = 1.3–1.4 (m, 2 H, N-CH2-CH2-CH2), 1.4–1.5 (m, 4 H,
N-CH2-CH2), 2.3–2.4 (m, 2 H, N-CH2), 2.5–2.6 (m, 3 H, CH2-
CO2-CH3, N-CH2), 2.78 (m, 1 H, CH-CH2-CO2-CH3), 3.63 (s, 3
H, CO2-CH3), 3.6–3.7 (m, 1 H, C-H), 3.74 (s, 3 H, CO2-CH3) ppm.
13C NMR (125 MHz, CDCl3): δ = 24.2, 26.3, 34.0, 50.8, 51.2, 51.6,
64.1, 171.2, 171.9 ppm. MS (FA): m/z (%) = 230 (100) [M + H],
170 (100) [M – CO2Me]. HRMS (FAB): calcd. for C11H20NO4
230.1392; found 230.1414.
General Procedure for the Synthesis of Amino Acid Derivatives 4:
Alkyl bromide (1.0 mmol) and Mg turnings (2.0 mmol) were suc-
cessively mixed in THF (2 mL) at room temperature with vigorous
stirring. After 0.5 h, ZnBr2 (1.0 mmol) was added, and the suspen-
5b:[15] Yield: 80.9 mg, 70% (yellow oil). 1H NMR (500 MHz,
CDCl3): δ = 2.51 (m, 2 H, N-CH2-CH2-O), 2.62 (m, 1 H, CH-CH2-
CO2-CH3), 2.66 (m, 2 H, N-CH2-CH2-O), 2.86 (m, 1 H, CH-CH2-
CO2-CH3), 3.6–3.7 (m, 4 H, N-CH2-CH2-O), 3.67 (s, 3 H, CO2-
CH3), 3.72 (m, 1 H, C-H), 3.75 (s, 3 H, CO2-CH3) ppm. 13C NMR
(125 MHz, CDCl3): δ = 33.9, 49.8, 49.9, 51.4, 51.7, 63.6, 67.2,
170.8, 171.5 ppm. MS (FA): m/z (%) = 232 (100) [M + H], 172
(98) [M – CO2Me]. HRMS (FAB): calcd. for C10H18NO5 232.1185;
found 232.1214.
sion was stirred 0.5 h at room temperature. N,O-Acetal
1
(0.50 mmol) and freshly distilled Me3SiCl (0.60 mmol) were then
added, and the mixture was stirred until the reaction reached com-
pletion, as shown by TLC (SiO2; hexane/AcOEt, 2:1). The reaction
was quenched with a saturated aqueous solution of Na2CO3
(2 mL). The combined organic layer was dried with anhydrous
Na2CO3 and evaporated under reduced pressure. The crude prod-
uct was purified by silica gel column chromatography (hexane/Ac-
OEt) to afford derivative 4. In case of 4a, nBuLi (1.5 mmol) was
used instead of the corresponding Grignard reagent.
4a:[13] Yield: 89.5 mg, 84% (colorless oil). 1H NMR (300 MHz,
CDCl3): δ = 0.81 (t, J = 7.0 Hz, 3 H, CH-CH2-CH2-CH2-CH3),
1.1–1.7 (m, 12 H, CH-CH2-CH2-CH2-CH3, N-CH2-CH2-CH2),
2.4–2.5 (m, 4 H, N-CH2), 3.08 (t, J = 7.0 Hz, 1 H, C-H), 3.64 (s, 3
H, CO2-CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.8, 22.5,
24.5, 26.3, 28.4, 29.1, 50.7, 50.8, 68.4, 172.9 ppm. MS (FA): m/z
(%) = 214 (100) [M + H], 154 (65) [M – CO2Me]. HRMS (FAB):
calcd. for C12H24NO2 214.1807; found 214.1814.
5c: Yield: 96.8 mg, 93% (colorless oil). 1H NMR (500 MHz,
CDCl3): δ = 2.62 (m, 2 H, CH-CH2-CN), 3.04 (m, 2 H, N-CH2-
CH=CH2), 3.23 (m, 2 H, N-CH2-CH=CH2), 3.71 (s, 3 H, CO2-
CH3), 3.81 (m, 1 H, C-H), 5.1–5.3 (m, 4 H, N-CH2-CH=CH2),
5.7–5.8 (m, 2 H, N-CH2-CH=CH2) ppm. 13C NMR (125 MHz,
CDCl3): δ = 19.2, 51.8, 53.6, 57.9, 117.5, 118.0, 135.3, 170.6 ppm.
MS (FA): m/z (%) = 209 (100) [M + H], 149 (98) [M – CO2Me].
HRMS (FAB): calcd. for C11H17N2O2 209.1290; found 209.1270.
5d: Yield: 83.9 mg, 81% (yellow oil). 1H NMR (500 MHz, CDCl3):
δ = 1.94 (s, 1 H, CCH), 2.43 (m, 1 H, CH2-CCH), 2.60 (m, 1 H,
CH2-CCH), 3.03 (m, 2 H, N-CH2-CH=CH2), 3.24 (m, 2 H, N-
CH2-CH=CH2), 3.65 (m, 1 H, C-H), 3.69 (s, 3 H, CO2-CH3), 5.0–
5.2 (m, 4 H, N-CH2-CH=CH2), 5.7–5.8 (m, 2 H, N-CH2-CH=CH2)
4b: Yield: 65.7 mg, 66% (colorless oil). 1H NMR (500 MHz,
CDCl3): δ = 0.80 [d, J = 6.0 Hz, 3 H, CH-CH-(CH3)2], 0.91 [d, J ppm. 13C NMR (125 MHz, CDCl3): δ = 19.7, 51.3, 53.6, 61.0, 69.8,
Eur. J. Org. Chem. 2009, 917–922
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
921

N. Sakai, J. Asano, Y. Kawada, T. Konakahara
FULL PAPER
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80.9, 117.3, 136.0, 171.9 ppm. MS (FA): m/z (%) = 208 (100) [M +
H], 168 (86) [M – CO2Me]. HRMS (FAB): calcd. for C12H18NO2
208.1338; found 208.1341.
6:[16] Glycine derivative 3e (0.50 mmol), 1,3-dimethylbarbituric acid
(1.0 mmol), and Pd(PPh3)4 (0.025 mmol) were successively mixed
together in MeOH (5 mL) at room temperature by stirring. After
3 h, the reaction was quenched with 1  HCl (3 mL). The aqueous
layer was washed by CHCl3 (3ϫ5 mL). A saturated aqueous solu-
tion of Na2CO3 (10.0 mL) was then added to the resulting CHCl3
solution. The separated organic layer was dried with sodium car-
bonate and evaporated under reduced pressure to afford product
1
6, which was almost pure. Yield: 62.7 mg, 70% (colorless oil). H
[7]
NMR (500 MHz, CDCl3): δ = 1.49 (br., 2 H, NH2), 2.8–3.0 (m, 2
H, Ar-CH2-), 3.69 (s, 3 H, CO2-CH3), 3.70 (m, 1 H, C-H), 7.1–7.3
(m, 5 H, Ar-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 41.0, 51.8,
55.7, 126.7, 128.4, 129.1, 137.1, 175.2 ppm. MS (FA): m/z (%) =
180 (48) [M + H], 120 (100) [M – CO2Me].
Acknowledgments
This work was partially supported by a fund for the “High-Tech
Research Center” Project for Private Universities: a matching fund
subsidy from MEXT (2000–2004 and 2005–2007).
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Received: November 9, 2008
Published Online: January 2, 2009
922
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 917–922