An efficient approach to α-aryl β-amino esters through 1,2-aryl migration of p-toluenesulfonic acid mediated diazo decomposition

Article abstract of DOI:10.1055/s-2002-19354

A new method for the synthesis of α-aryl β-amino esters has been developed. The key step in this preparation is the chemoselective 1,2-aryl migration of diazo carbonyl compounds catalyzed by TsOH.

Full text of DOI:10.1055/s-2002-19354

LETTER
149
An Efficient Approach to -Aryl -Amino Esters through 1,2-Aryl Migration
of p-Toluenesulfonic Acid Mediated Diazo Decomposition
N-Aryl- -enamino
a
Esters Syn
nthesis Jiang, Jianbo Wang*
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College
of Chemistry, Peking University, Beijing 100871, China
Fax +86(10)62751708; E-mail: wangjb@pku.edu.cn
Received 5 October 2001
a. Ar = Ph, 72 %
Ts
Abstract: A new method for the synthesis of -aryl -amino esters
b. Ar = p-MeOC6H4, 84 %
c. Ar = p-PhC6H4, 78 %
d. Ar = p-FC6H4, 63 %
e. Ar = m-CF3C6H4, 72 %
f. Ar =
H
NTs O
DBU (10 %)
N
has been developed. The key step in this preparation is the chemose-
lective 1,2-aryl migration of diazo carbonyl compounds catalyzed
by TsOH.
Ar
OEt
Ar
H
N2CHCO2Et
CH2Cl2, r.t.
H
N2
1
4
79 %
Key words: diazo compounds, 1,2-aryl migration, amino acids, hy-
O
drogenations -aryl -amino esters
Scheme 2
Considerable efforts have been directed to the synthesis of
In our previous investigation, the -diazo carbonyl com-
-amino acids and their derivatives in recent years, be- pounds are decomposed with Rh(II) or copper catalysts to
cause of their occurrence in biologically active natural give -aryl- -enamino esters (Scheme 3).8
products, such as alkaloids and antibiotics.1 -Amino ac-
ids also find application in the synthesis of -lactams,2 pi-
peridines,3 indolizidines,4 and -peptides.5 -Aryl
HNTs
H
HNTsO
NTs O
Ar
TsOH (1 mol %)
CH2Cl2, 0 °C
-
H
+
H
OEt
Ar
OEt
H
Ar
amino acids have been found in some biologically impor-
tant products. For example, (S)-3-Amino-2-phenylpropi-
onic acid is the side chain of penicillin betacine, and its
ethyl ester derivatives has neurological activity.6 The syn-
thesis of -aryl -amino acids and their derivatives are
particularly challenging and there are only few methods
now available.7 In this communication, we report an effi-
cient approach to the synthesis of this type of -amino
acid derivatives through p-toluenesulfonic acid (TsOH)
catalyzed 1,2-aryl migration of -diazo carbonyl com-
pounds, as shown in Scheme 1.
N2
O
OEt
5
6
4
Scheme 3
Table TsOH-Catalyzed Diazo Decomposition of 4a– f
Entry
Substrate
Product ratio (5:6)a
71:29
Yield (5)b
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
89
90
95
87
85
79
62:38
78:22
1) N2CHCO2Et
Base
O
HNTs
Ts
H
O
[H]
H
TsN
N
OEt
H
OEt
>95:5
2) H+
Ar
Ar
Ar
75:25
3
1
2
70:30
Scheme 1
a Product ratio was determined by 1H NMR (400 MHz).
b Yields after column chromatography.
We have recently reported that the -diazo carbonyl com-
pounds 4a–f can be prepared by nucleophilic addition of
diazo ethylacetate (EDA) anion to the N-tosyl protected
imine 1.8 The EDA anion was generated through deproto-
nation by lithium diisopropylamide (LDA) or NaH. In the
later investigation, we find that this nucleophilic addition
can be promoted by 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) under catalytic condition. The reaction condition
is milder and the yields are moderate to good (Scheme 2).
We now find that the -diazo carbonyl compounds, which
are in general quite stable at room temperature, can be ef-
ficiently decomposed at 0 °C with catalytic TsOH ( 1
mol%).9 As in the reaction with Rh(II) or copper catalysts,
the 1,2-aryl products are predominate in all cases (Table).
However, in Rh(II) or Cu(I) catalyzed reaction, trans -
aryl- -enamino esters are predominant, while the TsOH
promoted reaction gave predominately cis products. The
cis isomer is more stable than the trans isomer because of
the intramolecular hydrogen bonding. We have observed
Synlett 2002, No. 1, 28 12 2001. Article Identifier:
1437-2096,E;2002,0,01,0149,0151,ftx,en;Y20601ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

150
N. Jiang, J. Wang
LETTER
that trans products could isomerize to their cis isomer in
silica gel column. Therefore it is likely that the predomi-
nant formation of the cis products under TsOH catalysis
condition is due to the acid-catalyzed isomerization dur-
ing the reaction.9 To test this point, the diazo decomposi-
tion of 4a was carried out with 10% TsOH at room
temperature. As expected, the ratio of the cis to trans in-
creased from 71:29 to 95:5.
References
(1) For reviews, see: (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) Juaristi, E.; Lopez-Ruiz, H. Current
Medical Chemistry 1999, 6, 983.
(2) For example, see: Kim, S.; Lee, P. H.; Lee, T. A. J. Chem.
Soc., Chem. Commun. 1988, 1242.
-Enamino esters are reported to be easily reduced to the
corresponding -amino esters with NaBH(OAc)3.10 How-
ever, the -aryl- -enamino esters obtained in our investi-
gation did not react with NaBH(OAc)3 under identical
condition. On the other hand, the cis and trans mixture of
-aryl- -enamino esters 5a–f and 6a–f can be easily con-
verted to -aryl -amino esters by hydrogenation with 1
atm H2 and 10% Pd/C as the catalyst (Scheme 4).11,12
(3) For example, see: Jefford, C. W.; Wang, J. B. Tetrahedron
Lett. 1993, 34, 2911.
(4) For example, see: Jefford, C. W.; Wang, J. B. Tetrahedron
Lett. 1993, 34, 3119.
(5) For a review on -peptides, see: Gellman, S. H. Acc. Chem.
Res. 1998, 31, 173.
(6) Leonard, F.; Wajngurt, A.; Klein, M.; Smith, C. M. J. Org.
Chem. 1961, 26, 4062.
(7) Arvanitis, E.; Ernst, H.; Ludwig, A. L.; Robinson, A. J.;
Wyatt, P. B. J. Chem. Soc. Perkin Trans. 1 1998, 521.
(8) Jiang, N.; Qu, Z.; Wang, J. Org. Lett. 2001, 3, 2989.
(9) General procedure for the TsOH catalyzed diazo
decomposition: To a solution of TsOH (1 mg) in anhydrous
CH2Cl2 (20 mL) at 0 °C under N2, was added dropwise a
solution of diazo compound in anhydrous CH2Cl2 (5 mL).
The reaction was complete within 30 min as indicated by
TLC check. Solvent was removed by evaporation, and the
residue was purified by flash column chromatography to
give cis and trans -aryl- -enamino esters as a mixture.
(10) Cimarelli, C.; Palmieri, G. J. Org. Chem. 1996, 61, 5557.
(11) General procedure for the hydrogenation of -aryl- -
enamino esters: To a solution of -aryl- -enamino esters
(50 mg, cis and trans mixture) in absolute MeOH (25 mL)
was added 10% Pd/C catalyst (10 mg). The reaction mixture
was stirred for 10 h under 1 atm hydrogen atmosphere. Then
catalyst was removed by filtration and solvent was
evaporated to give a residue, which was purified by flash
column chromatography.
For the acid catalyzed 1,2-aryl migration, we can propose
a possible reaction mechanism. The diazo compound was
first protonated at the negatively polarized carbon to
which the diazo group is attached, following the extrusion
of N2 to give a highly reactive -carbonyl cation. The
neighboring phenyl group migrates through a bridged
phenylium ion (Scheme 5).
In summary, we have developed an efficient route to the
synthesis of -aryl- -amino esters. Efforts toward the
synthesis of enantiomerically pure -aryl- -amino esters
by asymmetric hydrogenation is currently under the way
and the results will be report in due course.
Acknowledgement
The project is generously supported by Natural Science Foundation
of China (Grant No. 29972002)
3a: 1H NMR (200 MHz, CDCl3): 1.13 (t, 3 H), 2.36 (s, 3
H), 3.19–352 (m, 2 H), 3.79–3.86 (q, 1 H), 4.04–4.17 (m, 2
H), 5.13 (t, 1 H), 7.13 (m, 7 H), 7.72 (d, 2 H); 13C NMR (50
MHz, CDCl3): 13.88, 21.42, 45.62, 51.72, 61.27, 126.91,
a. Ar = Ph, 95 %
b. Ar = p-MeOC6H4, 88 %
c. Ar = p-PhC6H4, 95 %
d. Ar = p-FC6H4, 96 %
e. Ar = m-CF3C6H4, 85 %
f. Ar =
O
HNTs
HNTsO
10 % Pd/C
MeOH, r.t.
Ar
H
TsN
H
OEt
+
H
OEt
Ar
Ar
O
OEt
5
3
6
94 %
O
Scheme 4
H
NTsO
HNTs O
H
H
NTsO
NTsO
H+
OEt
OEt
H
H
OEt
OEt
H
H
H
H
N
N
N
N
N
N
4a
7
8
O
H
H
O
H
H
O
OEt
- H+
TsN
H
TsN
OEt
H
TsN
OEt
H
H
Ph
Ph
10
9
2
Scheme 5
Synlett 2002, No. 1, 149–151 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
-Aryl- -enamino Esters Synthesis
151
127.82, 127.84, 128.88, 129.68, 135.63, 136.86, 143.40,
3.20–3.55 (m, 2 H), 3.87–3.94 (q, 1 H), 4.04–4.17 (m, 2 H),
5.13 (t, 1 H), 7.29 (m, 2 H), 7.31–7.56 (m, 4 H), 7.70 (m, 2
H); 13C NMR (50 MHz, CDCl3): 13.84, 21.42, 45.44,
51.55, 61.61, 124.74, 124.81, 126.91, 129.42, 131.44,
136.68, 136.78, 143.62, 171.70. m/z (relative intensity): 415
(M+, 8%) 184 (100%).
172.34; MS m/z (relative intensity): 347 (M+, 17%), 118
(100%).
3b: 1H NMR (200 MHz, CDCl3) 1.18 (t, 3H), 2.42 (s, 3 H),
3.16–3.50 (m, 2H), 3.77–3.81 (m, 1 H), 3.79 (s, 3H), 4.04–
4.17 (m, 2 H), 5.07 (t, 1 H), 6.83 (d, 2 H), 7.06 (d, 2 H), 7.29
(d, 2 H), 7.72 (d, 2 H); 13C NMR (50 MHz, CDCl3): 13.90,
21.41, 45.67, 50.82, 55.14, 61.18, 114.25, 126.91, 127.60,
128.90, 129.65, 136.90, 143.36, 159.14, 172.56; MS m/z
(relative intensity): 377 (M+, 10%), 194 (100%).
3f: 1H NMR (200 MHz, CDCl3) 1.22 (t, 3 H), 1.97 (m, 2
H), 2.39 (s, 3 H), 2.83 (t, 2 H), 3.89 (d, 2 H), 4.02–4.20 (m,
4 H), 5.15 (t, 1 H), 7.23 (d, 2 H), 7.68 (d, 2 H); 13C NMR (50
MHz, CDCl3): 14.32, 21.40, 23.74, 31.15, 39.35, 59.84,
72.16, 76.36, 76.99, 77.63, 98.03, 127.10, 129.11, 137.59,
142.79, 167.55, 173.76. m/z (relative intensity): 339 (M+,
14%), 184 (100%).
3c: 1H NMR (200 MHz, CDCl3) 1.19 (t, 3 H), 2.39 (s, 3 H),
3.21–3.55 (m, 2 H), 3.84–3.91(q, 1 H), 4.04–4.20 (m, 2 H),
5.07 (t, 1 H), 7.20–7.57 (m, 1 1H), 7.71 (d, 2 H); 13C NMR
(50 MHz, CDCl3): 13.96, 21.45, 45.65, 51.40, 61.39,
126.95, 127.45, 127.60, 128.30, 129.71, 134.60, 136.89,
140.26, 140.82, 143.45, 172.36. m/z (relative intensity): 423
(M+, 11%), 240 (100%).
(12) For the -aryl- -enamino esters 5f and 6f, the hydrogenation
gave a product with the furanyl moiety being partially
hydrogenated. The structure of the 3f (Figure) is as follows.
3d: 1H NMR (200 MHz, CDCl3) 1.17 (t, 3 H), 2.42 (s, 3 H),
3.15–3.50 (m, 2 H), 3.78–3.85 (q, 1 H), 4.04–4.18 (m, 2 H),
5.20 (t, 1 H), 6.92–7.30 (m, 6 H), 7.70 (d, 2 H); 13C NMR (50
MHz, CDCl3): 13.87, 21.41, 45.57, 50.92, 61.37, 115.55,
115.98, 126.89, 129.44, 129.60, 129.69, 136.79, 143.47,
172.19. m/z (relative intensity): 365 (M+, 24%), 182 (100%).
3e: 1H NMR (200 MHz, CDCl3) 1.18 (t, 3 H), 2.42 (s, 3 H),
O
H
OEt
TsN
O
3f
Figure
Synlett 2002, No. 1, 149–151 ISSN 0936-5214 © Thieme Stuttgart · New York