A novel synthesis of cyclic α-amino aldehydes, amino alcohols, and α-amino acid methyl esters from cyclic ketones through sulfinylaziridines

Article abstract of DOI:10.1016/j.tetlet.2004.03.124

Treatment of 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from cyclic ketones and chloromethyl p-tolyl sulfoxide in three steps in good yields, with N-lithio arylamines gave sulfinylaziridines in high yields. On treatment with N-lithio aniline

Full text of DOI:10.1016/j.tetlet.2004.03.124

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3903–3907
A novel synthesis of cyclic a-amino aldehydes, amino alcohols,
and a-amino acid methyl esters from cyclic ketones through
sulfinylaziridines
Hiroyuki Ota, Toshio Chyouma, Shuyu Iso and Tsuyoshi Satoh*
Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Received 13 February 2004; revised 10 March 2004; accepted 19 March 2004
Abstract—Treatment of 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from cyclic ketones and chloromethyl p-tolyl
sulfoxide in three steps in good yields, with N-lithio arylamines gave sulfinylaziridines in high yields. On treatment with N-lithio
aniline or N-lithio p-chloroaniline, the sulfinylaziridines gave a-amino aldehydes in high yields. The a-amino aldehydes were
converted to amino alcohols and a-amino acid methyl esters in moderate to good yields. This procedure offers an efficient method
for synthesis of cyclic a-quaternary a-amino aldehydes, amino alcohols, and a-amino acid derivatives from cyclic ketones.
Ó 2004Elsevier Ltd. All rights reserved.
Amino acids are the fundamental building blocks of
peptides and proteins and play essential roles in living
organisms.1 Because of the physiological importance of
a-amino acids, innumerable studies for their chemistry
and synthesis have been published.2 Recently, quater-
nary a-amino acids3 and b-amino acids4 have received
considerable attention. Especially, the cyclic a-quater-
nary a-amino acids are conformationally constrained,
they are used in controlling peptide secondary structures
and in drug design and development.5 The synthesis and
chemistries of cyclic a-quaternary a-amino acids have
attracted great attention these days.6 On the other hand,
a-amino aldehydes and amino alcohols are also quite
important and interesting compounds in organic chem-
istry.7
acid methyl esters 5 from the 1-chlorovinyl p-tolyl sulf-
oxide 2 via the sulfinylaziridines 3 (Scheme 1).
First, 1-chlorovinyl p-tolyl sulfoxide 69 was treated with
1.2 equiv of N-lithio aniline in THF at 0 °C for 30 min.
Quite clean reaction took place and sulfinylaziridine 7c 10
was obtained in 92% yield (Scheme 2). It is interesting to
note that the product 7c is a single isomer though it has
two stereogenic centers. On the other hand, when this
reaction was conducted with excess N-lithio aniline at
room temperature, a-amino aldehyde 8c11 was obtained
in 90% yield.
A plausible mechanism of this very interesting reaction
is as follows (Scheme 3). Conjugate addition of N-lithio
aniline to the 1-chlorovinyl p-tolyl sulfoxide 6 gave the
adduct 9, which affords a-sulfinyl carbenoid 10 with
elimination of LiCl. N–H insertion reaction, then, took
place to give the sulfinylaziridine 7c. Another plausible
path for the formation of 7c is thought to be the sub-
stitution of the chloride by nitrogen via 11.
We have reported some new synthetic methods starting
from 1-chlorovinyl p-tolyl sulfoxides 2,8 which were
synthesized easily from aldehydes and ketones 1, and
chloromethyl p-tolyl sulfoxide. In continuation of our
study concerning the use of 1-chlorovinyl p-tolyl sulf-
oxides in the development of new synthetic methods,
herein we report our recent results for a novel synthesis
of cyclic a-quaternary a-amino aldehydes 4 and a-amino
The mechanism for the formation of the a-amino alde-
hyde 8c by treatment of 6 with excess N-lithio aniline
was confirmed to be as follows. The sulfinylaziridine 7c
is attacked by the anilide to give ring-opened adduct 12.
The sulfinyl group in 12 is eliminated via 13 to give
imine 14, which is hydrolyzed in the work-up process to
give the a-amino aldehyde 8c. In fact, treatment of the
sulfinylaziridine 7c with excess N-lithio aniline at room
Keywords: Sulfoxides; Sulfinylaziridine; Amination; Cyclic a-amino
aldehyde; Cyclic a-amino acid.
* Corresponding author. Tel.: +3-5228-8272; fax: +3-3235-2214;
e-mail: tsatoh@ch.kagu.tus.ac.jp
0040-4039/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.124

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H. Ota et al. / Tetrahedron Letters 45 (2004) 3903–3907
O
Ar
R N
TolSCH2Cl
R
R
ArNHLi
H
R
R
S(O)Tol
Cl
O
S(O)Tol
R
1
3
2
X
NHLi
R
R
R
R
NHAr
CHO
NH2
COOCH3
X=H, Cl
4
5
Scheme 1.
The results for a trial to synthesize the a-amino alde-
hydes 8 directly from 6 are summarized in Table 2. The
reaction was conducted with large excess of various
N-lithio arylamines at room temperature. As shown in
Table 2, very limited arylamines gave the desired
a-amino aldehyde 8 (entries 3 and 4). It is interesting to
note that o-methoxy and p-methoxy aniline gave a
mixture of the aldehyde 8 and imine 14 (entries 1 and 2).
From these results, we concluded that there is little
prospect for the synthesis of a-amino aldehydes by this
direct procedure.
Ph
N
O
PhNHLi (1.2 equiv.)
O
O
S(O)Tol
Cl
H
S(O)Tol
THF, 0 °C, 30 min
92%
O
6
7c
O
O
NHPh
CHO
PhNHLi (5.0 equiv.)
THF, 0 °C - room temp., 1 h
90%
8c
Scheme 2.
Next, we investigated the reaction of the sulfinyl azir-
idine 7 with various N-lithio arylamines and found that
N-lithio aniline and N-lithio p-chloroaniline gave good
to high yields of the desired a-amino aldehyde 8 (Table
3). As can be expected, this reaction with N-lithio
4-methoxyaniline gave a mixture of the aldehyde 8 and
the imine 14.
temperature resulted in the formation of a-amino alde-
hyde 8c in high yield (vide infra, Table 3, entry 4).
In order to know what kind of amines afford the sulf-
inylaziridine 7, the vinyl sulfoxide 6 was treated with
various N-lithio arylamines and N-lithio alkylamines,
and the results are summarized in Table 1. As shown in
Table 1, arylamines gave sulfinylaziridine 7 in good to
high yields (entries 1–5), except p-nitroaniline (entry 6).
Quite interestingly, no alkylamine gave the desired sul-
finyl aziridine 7. The reaction with about 2 equiv of
N-lithio alkylamines did not proceed; however, with
large excess of N-lithio alkylamines, the reaction only
resulted in decomposition of 6 (entries 7–9).
Finally, the a-amino aldehyde 8a (the product in Table
3, entry 1) was converted to cyclic a-quaternary a-amino
acid methyl ester 16 (Scheme 4). Because highly oxi-
dizable nitrogen is present in 8a, a mild oxidizing re-
agent for the conversion of aldehyde to carboxylic acid
must be selected. We found that iodine and a base in
methanol were the reagent of choice.12 The a-amino
Scheme 3. A plausible mechanism for the formation of sulfinylaziridine 7c and a-amino aldehyde 8c.

H. Ota et al. / Tetrahedron Letters 45 (2004) 3903–3907
3905
Table 1. Synthesis of sulfinylaziridine 7 from 1-chlorovinyl p-tolyl sulfoxide 6 with various N-lithio amines
R
O
O
O
O
N
S(O)Tol
Cl
H
RNHLi
S(O)Tol
THF
6
7
Entry
RNHLi
Temperature °C
7 Yield %
R
(Equivalents)
1
2
3
4
5
6
7
8
9
o-MeOC6H4
p-MeOC6H4
C6H5
(2.1)
(1.3)
(1.2)
(1.7)
(2.3)
(1.7)
(5.3)
(5.2)
(2.2)
0
7a 80
7b 90
7c 92
7d 93
7e 84
––a
0
0
p-ClC6H4
p-CNC6H4
p-NO2C6H4
0
0
0 to rt
CH2@CHCH2
CH3(CH2)5
PhCH2
0
0
0
––b
––b
––b
a No reaction.
b A complex mixture.
Table 2. Synthesis of a-amino aldehyde 8 from 1-chlorovinyl p-tolyl sulfoxide 6 with various N-lithio arylamines
O
O
NHAr
CHO
NHAr
S(O)Tol
Cl
ArNHLi
+
THF
CH=NAr
room temp.
6
8
14
8 Yield %
Entry
ArNHLi
14 Yield %
Ar
(Equivalents)
1
2
3
4
5
o-MeOC6H4
p-MeOC6H4
C6H5
(12.4)
(7.5)
(4.0)
(8.3)
(6.2)
8a ––a
8b ––b
8c 90
8d 80
0c
14a ––a
14b ––b
0
0
0
p-ClC6H4
p-CNC6H4
a An inseparable mixture of a-amino aldehyde 8a and imine 14a; 84% yield.
b An inseparable mixture of a-amino aldehyde 8b and imine 14b; 40% yield.
c The product of this reaction was the sulfinylaziridine 7e (Table 1, entry 5; yield 75%).
Table 3. Synthesis of a-amino aldehyde 8 from sulfinylaziridine 7
Ar
O
O
N
O
NHAr
CHO
Ar'NHLi
H
S(O)Tol
THF
room temp., 4 h
O
8
7
Entry
Ar
Ar0
(Equivalents)a
8 Yield %
1
2
3
4
5
6
o-MeOC6H4
p-MeOC6H4
p-MeOC6H4
C6H5
C6H5
C6H5
(5.5)
(4.0)
(5.5)
(4.0)
(4.5)
(8.5)
8a 90
8b 76
8b 91
8c 94
8d 90
0b
p-ClC6H4
C6H5
p-ClC6H4
p-CNC6H4
p-ClC6H4
C6H5
a Use of less amount of aniline or p-chloroaniline gave incomplete reaction.
b A complex mixture.
aldehyde 8a was treated with a solution of iodine and
KOH in methanol to give the methyl ester 15 in 84%
yield. Finally, the methyl ester 15 was treated with celic
ammonium nitrate (CAN).13 This reaction gave the
desired free amine 16 in moderate yield. Reduction of
the aldehyde 8a with NaBH4 in ethanol gave the desired

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H. Ota et al. / Tetrahedron Letters 45 (2004) 3903–3907
OCH3
OCH3
O
O
NH2
NH
I2
O
O
NH
CAN
KOH
COOCH3
CH3CN-H2O
0 °C
CHO
COOCH3
OCH3
CH3OH
8a
16
room temp.
15
54%
84%
O
NH
NaBH4
CH2OH
O
EtOH, 0 °C
99%
17
Scheme 4.
Ar
o-MeOC6H4NHLi
C6H5NHLi
N
H
Cl
THF, room temp.
88%
THF, 0 °C, 1 h
72%
S(O)Tol
S(O)Tol
19
18
OCH3
NH
OCH3
I2
NH
CAN
NH2
KOH
COOCH3
CHO
CH3CN-THF-H2O
COOCH3
21
CH3OH-THF
room temp.
0 °C
40%
20
22
85%
Scheme 5.
amino alcohol 17 in a quantitative yield without any
problem.
of Japan to promote multi-disciplinary research project,
which is gratefully acknowledged.
To investigate the generality of these reactions, we fur-
ther studied this procedure starting from 1-chlorovinyl
p-tolyl sulfoxide 18 derived from cyclopentadecanone9
(Scheme 5). The reaction of 1-chlorovinyl p-tolyl sulf-
oxide 18 with N-lithio 2-methoxyaniline gave the desired
sulfinylaziridine 19 in somewhat lower yield (72%)
compared with the examples in Table 1. The amino
aldehyde 20 was obtained from 19 by treatment with N-
lithio aniline in 88% yield. Oxidation of the aldehyde
group to a methoxycarbonyl group was successful by the
oxidation with iodine to afford the amino acid methyl
ester 21 in 85% yield. Finally, the methoxyphenyl group
was eliminated with CAN as above to give the cyclic
amino acid methyl ester having a large carbon ring 22 in
moderate yield.
References and notes
1. Chemistry and Biochemistry of the Amino Acids; Barrett,
G. C., Ed.; Chapman and Hall: London, 1985.
2. (a) Williams, R. M. Synthesis of Optically Active a-Amino
Acids; Pergamon: Oxford, 1989; (b) Duthaler, R. O.
Tetrahedron 1994, 50, 1539; (c) Beller, M.; Eckert, M..
Angew. Chem., Int. Ed. 2000, 39, 1011.
3. (a) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron:
Asymmetry 1998, 9, 3517; (b) Cativiela, C.; Diaz-de-
Villegas, M. D. Tetrahedron: Asymmetry 2000, 11, 645; (c)
Sano, S.; Nagao, Y. J. Synth. Org. Chem. Jpn. 2000, 58,
756; (d) Tanaka, M. J. Synth. Org. Chem. Jpn. 2002, 60,
125.
4. (a) Cole, D. C. Tetrahedron 1994, 50, 9517; (b) Juaristi, E.;
Quintana, D.; Escalante, J. Aldrichimica Acta 1994, 27, 3;
(c) Enantioselective Synthesis of b-Amino Acids; Juaristi,
E., Ed.; Wiley-VCH: New York, 1997; (d) Davies, S. G.;
Ichihara, O. J. Synth. Org. Chem. Jpn. 1997, 55, 26; (e)
Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M.
Synlett 2001, 1813; (f) Liu, M.; Sibi, M. P. Tetrahedron
2002, 58, 7991.
We are continuing to study the scope and limitation of
this procedure and extension of this reaction to the
asymmetric synthesis of cyclic and acyclic a-quaternary
a-amino aldehydes, amino alcohols, and amino acid
derivatives.
5. Park, K.-H.; Kurth, M. J. Tetrahedron 2002, 58, 8629.
6. Some recent reviews and papers concerning cyclic amino
acids. (a) Czombos, J.; Aelterman, W.; Tkachev, A.;
Martins, J. C.; Tourwe, D.; Peter, A.; Toth, G.; Fulop, F.;
Kimpe, N. D. J. Org. Chem. 2000, 65, 5469; (b) Kabalka,
G. W.; Das, B. C.; Das, S. Tetrahedron Lett. 2001, 42,
Acknowledgements
This work was supported by a grant from the Ministry
of Education, Culture, Sports, Science and Technology

H. Ota et al. / Tetrahedron Letters 45 (2004) 3903–3907
3907
7145; (c) Volk, F.-J.; Wagner, M.; Frahm, A. W. Tetra-
hedron: Asymmetry 2003, 14, 497; (d) Truong, M.;
Lecornue, F.; Fadel, A. Tetrahedron: Asymmetry 2003,
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Andrei, M.; Undheim, K. Tetrahedron: Asymmetry 2004,
15, 53.
(39), 158 (100). Calcd for C22H25NO3S: 383.1555. Found:
m=z 383.1545.
11. n-BuLi (0.5 mmol) was added dropwise to a solution of
aniline (0.5 mmol) in 1 mL of dry THF at 0 °C with
stirring. The solution was stirred at 0 °C for 10 min. To
this solution was added a solution of 6 (33 mg; 0.1 mmol)
in 0.5 mL of THF. The cooling bath was removed and the
reaction mixture was stirred at room temperature for 1 h.
The reaction was quenched by adding saturated aq NH4Cl
and the whole was extracted with AcOEt. The product was
purified by silica gel column chromatography to give the
cyclic amino aldehyde 8c (23.5 mg; 90%) as colorless
crystals; mp 92–94 °C (AcOEt–hexane). IR (KBr) 3392
(NH), 1711 (CO), 1600, 1091/cm; 1H NMR d 1.74(4H, m),
1.95 (2H, m), 2.05 (2H, m), 3.95 (4H, m), 6.56 (2H, m),
6.74(1H, m), 7.19 (2H, m), 9.64(1H, s, CHO). MS m=z
(%) 261 (Mþ, 6), 232 (100), 170 (32). Calcd for
C15H19NO3: 261.1364. Found: m=z 261.1367.
7. Jurczak, J.; Golebiowski, A. Chem. Rev. 1989, 89, 149.
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Satoh, T.; Ota, H. Tetrahedron 2000, 56, 5113; (c) Satoh,
T.; Yoshida, M.; Ota, H. Tetrahedron Lett. 2001, 42, 9241;
(d) Satoh, T.; Sakamoto, T.; Watanabe, M. Tetrahedron
Lett. 2002, 43, 2043; (e) Satoh, T.; Sugiyama, S.; Ota, H.
Tetrahedron Lett. 2002, 43, 3033; (f) Satoh, T.; Yoshida,
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14, 281; (g) Satoh, T.; Sugiyama, S.; Kamide, Y.; Ota, H.
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10. Compound 7c: Colorless crystals; mp 151–154 °C (AcOEt–
hexane). IR (KBr) 1595, 1492, 1397, 1272, 1080, 1048,
1
1030 (SO)/cm; H NMR d 1.12, 1.42, 1.63 (each 1H, m),
1.75 (2H, m), 1.97, 2.20, 2.27 (each 1H, m), 2.45 (3H, s),
3.26 (1H, s), 3.95 (4H, m), 6.89 (2H, d, J ¼ 7 Hz), 6.99
(1H, t, J ¼ 7 Hz), 7.19 (2H, t, J ¼ 8 Hz), 7.39, 7.69 (each
2H, d, J ¼ 8 Hz); MS m=z (%) 383 (Mþ, trace), 367 (2), 244