A new synthesis of cyclic α-amino acid derivatives by the intramolecular reaction of magnesium carbenoid with N-magnesio arylamine as the key reaction

Article abstract of DOI:10.1016/j.tetlet.2007.09.003

A new synthesis of pipecolic acid and homopipecolic acid derivative was accomplished from 1-chloroalkyl p-tolyl sulfoxides having a 2-aminophenyl group at the ω-position by treatment with i-PrMgCl via the intramolecular reaction of magnesium carbenoid wit

Full text of DOI:10.1016/j.tetlet.2007.09.003

Tetrahedron Letters 48 (2007) 7829–7833
A new synthesis of cyclic a-amino acid derivatives by
the intramolecular reaction of magnesium carbenoid with
N-magnesio arylamine as the key reaction
Tohru Ohbayashi, Shintaro Mitsunaga and Tsuyoshi Satoh*
Department of Chemistry, Faculty of Science, Tokyo University of Science, Ichigaya-funagawara-machi 12,
Shinjuku-ku, Tokyo 162-0826, Japan
Received 10 August 2007; revised 30 August 2007; accepted 3 September 2007
Available online 5 September 2007
Abstract—A new synthesis of pipecolic acid and homopipecolic acid derivative was accomplished from 1-chloroalkyl p-tolyl sulf-
oxides having a 2-aminophenyl group at the x-position by treatment with i-PrMgCl via the intramolecular reaction of magnesium
carbenoid with N-magnesio arylamine. In a similar way, proline and pipecolic acid derivatives were synthesized from 1-chloroalkyl
p-tolyl sulfoxides having an arylamino group at the x-position.
Ó 2007 Elsevier Ltd. All rights reserved.
a-Amino acids are the fundamental building blocks of
peptides, proteins, and many natural products and play
essential roles in living organisms. Because of the phys-
iological importance of a-amino acids, innumerable
studies regarding their chemistry and synthesis have
been published.1 Recently, cyclic a-amino acids and
their derivatives have received considerable attention.
Of particular importance are cyclic a-quaternary a-ami-
no acids, which are conformationally constrained, and
used in controlling peptide secondary structures and in
medicinal chemistry. The synthesis and chemistries of
cyclic a-amino acids have attracted much attention.2
is shown in Scheme 1. Thus, treatment of 1-chloroalkyl
p-tolyl sulfoxide having a 2-aminophenyl group at the
x-position (5) with i-PrMgCl followed by ethyl chloro-
formate gave cyclic a-amino acid derivative 7 through
a-amino-substituted alkylmagnesium intermediate 6.
On the other hand, treatment of 1-chloroalkyl p-tolyl
sulfoxide having an arylamino group at the x-position
(8) with i-PrMgCl followed by ethyl chloroformate
gave proline derivative 10 through a-amino-substituted
alkylmagnesium intermediate 9 (Scheme 1). Preliminary
results of this study are reported hereinafter.
In order to confirm the feasibility of the intramolecular
reaction, we first synthesized 1-chloropropyl p-tolyl sulf-
oxide having a 2-aminophenyl group at the 3-position
(5a) from 3,4-dihydro-2-(1H)-quinolinone 11 (Scheme 2).
Thus, quinolinone 11 was treated with MOMCl fol-
lowed by NaBH4 to afford amino alcohol 12 in high
yield.4 The amino group of 12 was protected with Boc
group and the hydroxyl group was converted to a sulfide
group to give 13. The sulfur was oxidized with mCPBA
and the resultant sulfoxide was chlorinated with NCS
to afford 14. Finally, the Boc protecting group was
removed with TFA to afford the desired compound, 1-
chloro-3-(2-methylaminophenyl)propyl p-tolyl sulfoxide
5a, in 71% overall yield from 11.
As our contribution to the synthesis of a-amino acid
derivatives, we recently reported a novel synthesis of
a-amino acid derivatives 4 based on the reaction of mag-
nesium carbenoid 2, which was derived from 1-chloro-
alkyl p-tolyl sulfoxide 1 with i-PrMgCl, with N-lithio
arylamines via N-a-magnesioalkyl arylamine 3 (Scheme
1).3 In continuation of our interest in the synthesis of a-
amino acids by this method, we recently investigated an
intramolecular version of the reaction of magnesium
carbenoids with arylamines. The essence of this study
Keywords: Cyclic a-amino acid; Magnesium carbenoid; Sulfoxide–
magnesium exchange reaction; Pipecolic acid; Proline.
*
Next, conditions for the intramolecular reaction of 5a
Corresponding author. Tel.: +81 3 5228 8272; fax: +81 3 5261
4631; e-mail: tsatoh@rs.kagu.tus.ac.jp
were investigated and the results are summarized in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.003

7830
T. Ohbayashi et al. / Tetrahedron Letters 48 (2007) 7829–7833
R
Cl
Cl
MgCl
N(Ar)R
COOEt
N(Ar)R
i-PrMgCl
LiNAr
ClCOOEt
R
R
R
R
SPh
O
MgCl
4
2
3
1
Cl
n
i-PrMgCl
ClCOOEt
STol
n
n
N
Me
NH
Me
N
Me
O
MgCl
COOEt
6
7
5
Ar
N
Ar
N
Cl
H
N
MgCl
n
i-PrMgCl
COOEt
ClCOOEt
STol
n
n
O
MeO
8
9
10
Scheme 1.
1) MOMCl / NaH
DMF / THF, 99%
1) (Boc)2O / THF, 99%
STol
OH
2) TolSSTol, nBu3P
2) NaBH4 / EtOH, 93%
NBoc
Me
N
H
NH
Me
O
THF, 89%
11
13
12
Cl
Cl
1)
mCPBA / CH2Cl2
TFA
CH2Cl2, 0 oC, 99%
STol
O
STol
O
2) NCS / CCl4
NH
Me
NBoc
Me
88% (two steps)
5a
14
Scheme 2.
Table 1. Based on our previous study,3 the hydrogen on
the nitrogen of 5a was replaced by MgCl (t-BuMgCl,
1.3 equiv) in THF at À78 °C in 5 min to give 15. To this
reaction mixture was added i-PrMgCl (2.5 equiv) and,
after 5 min, the reaction was quenched with CH3OD
(entry 1). The desired N-methyltetrahydroquinoline 17,
which was deuteriated at the a-position, was obtained,
albeit the yield was not satisfactory. In this reaction,
a-deuteriated chloroalkane 16a (see the footnote in
Table 1) was obtained in 32% yield. From this result,
it was implied that the sulfoxide–magnesium exchange
reaction took place rapidly at À78 °C; however, the
intramolecular reaction was slow at À78 °C (entry 1).
by i-PrMgCl in toluene at À40 °C and, after 5 min,
5 equiv of ethyl chloroformate was added to the reaction
mixture. The desired pipecolic acid derivative 7a was
obtained in 66% yield from 5a via the a-amino carban-
ion intermediate 6a.5
The scope and limitations of this reaction were investi-
gated using one- and two-carbon homologated sulf-
oxides (5b and 5c) and nor-compound 5d as shown in
Scheme 3. The same treatment of 5b with i-PrMgCl
followed by CH3OD gave seven-membered cyclic amine
19, which was deuteriated at the a-position in good
yield. When intermediate 18 was treated with ethyl
chloroformate, the desired homopipecolic acid deriva-
tive 7b was obtained in 68% yield. Although the syn-
thesis of six- and seven-membered cyclic a-amino acid
derivatives were successful, attempts to synthesize eight-
and five-membered cyclic a-amino acid derivatives from
5c and 5d were unsuccessful. The treatment of 5c and 5d
with i-PrMgCl followed by ethyl chloroformate under
the conditions described above afforded only olefins 20
and 21, respectively.
In fact, when the reaction was conducted in THF at
À40 °C, the yield of the desired 17 was increased to
68% (entry 2). When this reaction was conducted in
diethyl ether, the yield was decreased to 46% (entry 3).
When toluene was used as the solvent, the yield
increased to 88%; we selected the conditions in entry 4
as the optimized conditions. Combination of LDA and
i-PrMgCl as well as using only n-BuLi or i-PrMgCl were
found to be ineffective (entries 5–7).
We next investigated the intramolecular reaction of
magnesium carbenoid with N-magnesio arylamines
derived from 1-chloroalkyl p-tolyl sulfoxide having an
arylamino group at the x-position (8). Starting material
The synthesis of cyclic a-amino acid using the above-
mentioned conditions was investigated next (Scheme
3). Sulfoxide 5a was treated with t-BuMgCl followed

T. Ohbayashi et al. / Tetrahedron Letters 48 (2007) 7829–7833
7831
Table 1. Synthesis of N-methyltetrahydroquinoline 17 from 5a by the intramolecular nucleophilic reaction of the nitrogen to the magnesium
carbenoid carbon
Cl
Cl
Cl
Base
Alkylmetal
D
MgCl
STol
O
STol
O
Solvent
Temp.
N
N
Me
N
NH
Me
N
Me
MgCl
D
Me
Me
6a
5a
17
16
Solvent
15
Entry
Base (equiv)
Alkylmetal (equiv)
Temp (°C)
17
Yield (%)
D-Contenta (%)
1
2
3
4
5
6
7
t-BuMgCl (1.3)
t-BuMgCl (1.3)
t-BuMgCl (1.3)
t-BuMgCl (1.3)
LDA (1.2)
i-PrMgCl (2.5)
i-PrMgCl (2.5)
i-PrMgCl (2.5)
i-PrMgCl (2.5)
i-PrMgCl (2.5)
THF
THF
Et2O
Toluene
Toluene
Toluene
Toluene
À78
À40
À40
À40
À40
À40
À40
32b
68
46
88
Trace
Trace
22c
98
81
89
78
—
—
87
n-BuLi (3.5)
i-PrMgCl (3.5)
a The reaction was quenched with CH3OD and the deuterium content was measured by 1H NMR.
b 1-Deuteriated chloroalkane 16a (deuterium content 89%) was obtained in 32% yield.
Cl
D
NH
16a
Me
c Starting material 5a was recovered in 62% yield.
Cl
1)
2)
t-BuMgCl (1.3 eq)
ClCOOEt (5.0 eq)
STol
O
N
Me
N
Me
i-PrMgCl (2.5 eq)
COOEt
NH
Me
66%
MgCl
Toluene, -40 ˚C
7a
6a
5a
O
STol 1)
t
-BuMgCl (1.3 eq)
-PrMgCl (2.5 eq)
Toluene, -40 ˚C
CH3OD
Cl
O
2)
i
or ClCOOEt (5.0 eq)
N
N
Me
19; R=H (D), 78%,
NH
Me
R
MgCl
R
Me
5b
18
(D-content 88%)
7b; R=COOEt, 68%
1)
2)
t
-BuMgCl (1.3 eq)
STol
n
i-PrMgCl (2.5 eq)
Cl
NH
Me
NH
Me
Toluene, -40 ˚C
3) ClCOOEt
5c; n=4
5d; n=1
20; R= (CH ) CH=CH
2, 46%
2 3
21; R= CH=CH2, 83%
Scheme 3.
8a was synthesized as shown in Scheme 4. Thus, cou-
pling of 4-iodoanisole and 3-aminopropanol promoted
by L-proline gave aminoalcohol 22.6 The nitrogen of
22 was protected and the hydroxyl group was converted
to iodide to give 23 in quantitative yield. Alkylation of
the lithium a-sulfinyl carbanion of chloromethyl p-tolyl
sulfoxide7 with 23 followed by deprotection of the Boc
protecting group afforded the desired 8a in 77% overall
yield from 3-aminopropanol.
methoxyphenyl)pyrrolidine 25 in 77% yield via the intra-
molecular reaction of magnesium carbenoid 24 and
a-aminoalkylmagnesium intermediate 9a. The yield of
25 was acceptable; however, the deuterium content
was only 63%. We reinvestigated this reaction and
found that simple addition of 3.5 equiv of i-PrMgCl to
a solution of 8a in THF at À78 °C was the conditions
of choice (Scheme 5, condition 2). Generation of a-
aminoalkylmagnesium intermediate 9a using this proto-
col followed by treatment with ethyl chloroformate
gave the desired N-arylproline 10a in 59% yield from
8a.8
Treatment of 8a with the Grignard reagents as described
above (Scheme 5, condition 1) gave deuteriated N-(4-

7832
T. Ohbayashi et al. / Tetrahedron Letters 48 (2007) 7829–7833
K2CO3, CuI,
L-Proline
Boc
N
H
N
1) (Boc)2O, 99%
I
I
OH
H2N
OH
+
Ar
Ar
Cl
MeO
DMSO, 80 ˚C
84%
2) I2, Ph3P, Imid.
23
22
99%
H
N
1) TolS(O)CH(Li)Cl, 95%
2) TFA, 99%
STol
O
MeO
8a
Scheme 4.
OMe
MgCl
PMP
Cl
H
PMP
CH3OD
Conditions
N
MgCl
Cl
D
N
N
N
MgCl
STol
MeO
O
8a
25
9a
24
OMe
Conditions for the synthesis of 25 from 8a
ClCOOEt
(5.0 eq)
1 t-BuMgCl (1.2 eq), i-PrMgCl (2.5 eq), toluene, -40 ˚C, 1 min, 77% (D-content 63%).
2 i-PrMgCl (3.5 eq), THF, -78 ˚C, 1 min, 87% (D-content 90%).
59%
N
COOEt
10a
OMe
O
STol
H
N
i-PrMgCl (3.5 eq)
(5.0 eq)
ClCOOEt
N
COOEt
THF, -78~ -40 ˚C
60%
MeO
MeO
Cl
8b
10b
OMe
1)
i-PrMgCl (3.5 eq)
H
N
Cl
H
N
THF, -78 ˚C~ r.t.
+
STol
COOEt
N
2) ClCOOEt (5.0 eq)
MeO
O
26 (10%)
8c
10c (4%)
Scheme 5.
Homo- and bishomo-sulfoxides 8b and 8c were synthe-
sized in order to investigate the scope and limitations
of this reaction and the results are shown in Scheme 5.
Treatment of 8b with i-PrMgCl followed by ethyl chlo-
roformate afforded the desired N-arylpipecolic acid
ethyl ester 10b in 60% yield. Unfortunately, a similar
treatment of the one-carbon homologated sulfoxide 8c
gave a rather complex mixture from which the desired
10c (in only 4% yield) and 10% of olefin 26 were ob-
tained as the isolable products.
a-amino acid derivatives and also the chemistry of mag-
nesium carbenoids.
Acknowledgment
This work was supported by a Grant-in-Aid for Scien-
tific Research No. 19590018 from the Ministry of Edu-
cation, Culture, Sports, Science and Technology,
Japan, which is gratefully acknowledged.
In conclusion, a novel synthesis of cyclic a-amino acid
derivatives (proline, pipecolic acid,9 and homopipecolic
acid derivatives) was achieved on the bases of the intra-
molecular reaction of a magnesium carbenoid and an N-
magnesio arylamine. The results described in this paper
contribute further development of the synthesis of cyclic
References and notes
1. (a) Chemistry and Biochemistry of the Amino Acids; Barrett,
G. C., Ed.; Chapman and Hall: London, 1985; (b)
Williams, R. M. Synthesis of Optically Active a-Amino

T. Ohbayashi et al. / Tetrahedron Letters 48 (2007) 7829–7833
7833
Acids; Pergamon Press: Oxford, 1989; (c) Duthaler, R. O.
Tetrahedron 1994, 50, 1539; (d) Beller, M.; Eckert, M.
Angew. Chem., Int. Ed. 2000, 39, 1011; (e) Sano, S.; Nagao,
Y. J. Syn. Org. Chem. Jpn. 2000, 58, 756; (f) Ma, J.-A.
Angew. Chem., Int. Ed. 2003, 42, 4290; (g) Groger, H.
Chem. Rev. 2003, 103, 2795.
J = 7.6 Hz), 7.10 (1H, t, J = 7.8 Hz). Ms m/z (%) 219
(M+, 20), 146 (100), 130 (10). Calcd for C13H17NO2: M,
219.1259; Found m/z, 219.1261.
6. Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164.
7. (a) More, K. M.; Wemple, J. J. Org. Chem. 1978, 43, 2713;
(b) Satoh, T.; Kaneko, Y.; Izawa, T.; Sakata, K.; Yama-
kawa, K. Bull. Chem. Soc. Jpn. 1985, 58, 1983.
2. Some recent reviews concerning chemistry and synthesis of
cyclic a-amino acids. (a) Park, K.-H.; Kurth, M. J.
Tetrahedron 2002, 58, 8629; (b) Kotha, S. Acc. Chem.
Res. 2003, 36, 342; (c) Belvisi, L.; Colombo, L.; Manzoni,
L.; Potenza, D.; Scolastico, C. Synlett 2004, 1449; (d) Lasa,
M.; Cativiela, C. Synlett 2006, 2517.
8. 1-(4-Methoxyphenyl)pyrrolidine-2-carboxylic acid ethyl
ester (10a). To a solution of 8a (43 mg; 0.12 mmol) in
6 mL of dry THF in a flame-dried flask at À78 °C under
argon atmosphere was added a solution of i-PrMgCl (2.0 M
solution in THF, 0.213 mL; 0.43 mmol) in THF dropwise
with stirring. After 1 min, to a solution of a-aminoalkyl-
magnesium intermediate 9a was added ethyl chloroformate
(0.058 mL; 0.61 mmol) dropwise at À78 °C with stirring.
After 10 min, the reaction was quenched with satd aq
NH4Cl. The whole was extracted with CHCl3. The organic
layer was washed with satd aq NH4Cl and dried over
MgSO4. The product was purified by silica gel column
chromatography to afford 10a (18 mg; 59%) as colorless oil;
IR (neat) 2978, 2833, 1746 (CO), 1621, 1515, 1464, 1367,
3. Satoh, T.; Osawa, A.; Ohbayashi, T.; Kondo, A. Tetra-
hedron 2006, 62, 7892.
4. Wang, J.-J.; Hu, W.-P. J. Org. Chem. 1999, 64, 5725.
5. 1-Methyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl
ester (7a). To a solution of 5a (20 mg; 0.062 mmol) in 3 mL
of dry toluene in a flame-dried flask at À40 °C under argon
atmosphere was added a solution of t-BuMgCl (1.0 M
solution in THF, 0.08 mL; 0.08 mmol) dropwise with
stirring. After 5 min, a solution of i-PrMgCl (2.0 M
solution in Et2O, 0.078 mL; 0.155 mmol) was added to
the reaction mixture dropwise with stirring. After 5 min, to
a solution of a-aminoalkylmagnesium intermediate 6a was
added ethyl chloroformate (0.03 mL; 0.311 mmol) dropwise
at À40 °C with stirring. After 10 min, the reaction was
quenched with satd aq NH4Cl. The whole was extracted
with CH2Cl2. The organic layer was washed with satd aq
NH4Cl and dried over MgSO4. The product was purified by
silica gel column chromatography to afford 7a (9 mg; 66%)
as colorless oil; IR (neat) 2935, 1740 (CO), 1604, 1502,
1242, 1178, 1094, 1039, 978, 813 cmÀ1 1H NMR d 1.24
.
(3H, t, J = 7.1 Hz), 2.02–2.30 (4H, m), 3.31 (1H, q,
J = 5.7 Hz), 3.52–3.57 (1H, m), 3.74 (3H, s), 4.10–4.23
(3H, m), 6.51 (2H, d, J = 9.1 Hz), 6.82 (2H, d, J = 9.1 Hz).
Ms m/z (%) 249 (M+, 20), 176 (100). Calcd for C14H19NO3:
M, 249.1363; Found m/z, 249.1361.
9. Some selected recent papers for synthesis of pipecolic acid
derivatives. (a) Varray, S.; Gauzy, C.; Lamaty, F.; Lazaro,
R.; Martinez, J. J. Org. Chem. 2000, 65, 6787; (b) Cossy, J.;
Belotti, D. Tetrahedron Lett. 2001, 42, 2119; (c) Seitz, T.;
Baudoux, J.; Bekolo, H.; Cahard, D.; Plaquevent, J.-C.;
Lasne, M.-C.; Rouden, J. Tetrahedron 2006, 62, 6155; (d)
Jung, J.-C.; Avery, M. A. Tetrahedron: Asymmetry 2006,
17, 2479.
1374, 1336, 1185, 1102, 1038, 746 cmÀ1 1H NMR d 1.24
.
(3H, t, J = 7.1 Hz), 2.07–2.16 (1H, m), 2.26–2.32 (1H, m),
2.68–2.72 (2H, m), 2.95 (3H, s), 4.01 (1H, t, J = 4.7 Hz),
4.10–4.24 (2H, m), 6.60–6.66 (2H, m), 6.93 (1H, d,