Facile synthesis of β-anilinopropionates from Lewis acid-induced N-methyleneanilines with ketene acetals

Article abstract of DOI:10.1081/SCC-120004138

A facile synthesis of β-anilinopropionates was achieved from the reaction of N-methyleneanilines derived from 1,3,5-triphenylhexahydro-1,3,5-triazines with ketene acetals in the presence of Lewis acid.

Full text of DOI:10.1081/SCC-120004138

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
FACILE SYNTHESIS OF β-ANILINOPROPIONATES
FROM LEWIS ACID-INDUCED N-
METHYLENEANILINES WITH KETENE ACETALS*
Hyun-Joon Ha , Chang-Ju Choi & Won Koo Lee
To cite this article: Hyun-Joon Ha , Chang-Ju Choi & Won Koo Lee (2002) FACILE SYNTHESIS OF
β-ANILINOPROPIONATES FROM LEWIS ACID-INDUCED N-METHYLENEANILINES WITH KETENE
ACETALS*, Synthetic Communications, 32:10, 1495-1500, DOI: 10.1081/SCC-120004138
To link to this article: http://dx.doi.org/10.1081/SCC-120004138
Published online: 12 Dec 2006.
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SYNTHETIC COMMUNICATIONS, 32(10), 1495–1500 (2002)
FACILE SYNTHESIS OF
b-ANILINOPROPIONATES FROM
LEWIS ACID-INDUCED
N-METHYLENEANILINES WITH
KETENE ACETALS*
Hyun-Joon Ha,1,y Chang-Ju Choi,1 and
Won Koo Lee2,y
1Department of Chemistry, Hankuk University of
Foreign Studies, Yongin, Kyunggi-Do 449-791, Korea
2Department of Chemistry, Sogang University,
Seoul, 121-742, Korea
ABSTRACT
A facile synthesis of b-anilinopropionates was achieved from
the reaction of N-methyleneanilines derived from 1,3,5-
triphenylhexahydro-1,3,5-triazines with ketene acetals in the
presence of Lewis acid.
*This paper is part 15 in the series of ‘‘Lewis acid induced synthetic equivalents
of imines and iminium ions’’. For part 14 see, Ha., H.-J.; Ahn, Y.-G.; Woo, J.-S.;
Lee, G.-S.; Lee, W.K. Bull. Chem. Soc. Jpn. 2001, 74, 1667.
yCorresponding authors. Fax: (þ82)-31-3331696; E-mail: hjha@hufs.ac.kr or Fax:
(182)-2-7010967; E-mail: wonkoo@sogang.ac.kr
1495
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1496
HA, CHOI, AND LEE
During last few years in our laboratory, we have developed methods
for the generation and utilization of N-methyleneamine equivalents from
hexahydro-1,3,5-triazine.1 N-Methyleneamine equivalents, as shown by 2
and 3 in Scheme 1 with characteristics of imine and iminium ions, were
used for aminomethylation reaction with various nucleophiles at the a-posi-
tion of amines.2 N-Methyleneanilines were also reacted with olefins to pro-
vide 1,2,3,4-tetrahydroquinolines, whose mechanism is suggested by either a
step-wise Mannich type reaction3 or by [4p þ 2p] cycloaddition.4 Our
recent success supports the possible route of [4p þ 2p] cycloaddition for
the preparation of 2a,8b-bistrimethylsilyloxy-1,2,2a,3,4,8b-hexahydrocyclo-
buta[c]-quinolines from N-methyleneaniline with 1,2-bistrimethylsilyloxy-
cyclobutene in the presence of TMSCl.5 These results suggest the possible
dual roles of N-methyleneanilines as Mannich bases or azadienes depending
on the characteristics of nucleophiles as shown in Scheme 1. In this report is
described the reaction with electron-rich olefins of ketene acetals with
N-methyleneaniline in the presence of Lewis acid to yield synthetically
valuable b-anilinopropionates.6
The reaction of N-methyleneaniline (2,3) generated from 1,3,5-tri-
phenylhexahydro-1,3,5-triazine (1) with methyl trimethylsily dimethylketene
acetal (4a) was carried out with 1 mol equiv. of various Lewis acid with
careful analysis of products (table). With all the Lewis acids we tested, such
as BF3ÁOEt2, SnCl4, TMSCl, TMSOTf, and AlCl3, all were obtained only as
Scheme 1.

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b-ANILINOPROPIONATES
1497
Scheme 2.
aminomethylated product (5a) in 80, 60, 45, 82 and 71% yield, respectively,
without any trace of cycloaddition products (Entries 1–5). This reaction can
be explained with the cationic intermediate by the addition of N-methylene-
amine as a Mannich base to ketene acetal and the subsequent desilylation.7
This result suggests N-methyleneaniline serves as only Mannich base. The
role of N-methyleneaniline either as a Mannich base or a azadienes may
depend on the characteristics of reacting olefins. Reactions of 1,3,5-tri-
phenylhexahydro-1,3,5-triazine (1) with ketene acetal (4a) in the presence
of TMSOTf afforded a facile synthetic route toward b-anilinopropionate
(5a) which is known to be an important backbone in various biologically
important molecules.6
Under these conditions, the reaction proceeded well with 1,3,5-tri-
phenylhexahydro-1,3,5-triazines with various substituents (Table 1) on the
benzene ring, such as p-methoxy, o-methyl and p-nitro (1b–d), to afford the
corresponding products (5b–d) in respective yields of 78, 52 and 60%
regardless of the electronic characteristics of the aromatic ring (Entries 6–
8). Furthermore the scope of this reaction was expanded with various ketene
acetals including methyl and t-butyl trimethylsilyl 2-methoxylketene acetal
(4b–c) to yield b-anilino-a-methoxypropionate (5e–f) in 45 and 58% yield
(Entries 9and 10). The same reaction was performed with 3,4-dihydro-6-
(trimethylsilyloxy)-2H-pyran (4d) to yield 3-anilinomethyltetrahydropyran-
2-one (5g) in 14% isolated yield (Entry 11).
In conclusion a facile synthesis of b-anilinopropionates was achieved
from the reaction of N-methyleneanilines derived from 1,3,5-triphenyl-
hexahydro-1,3,5-triazines with ketene acetal in the presence of TMSOTf
in high yields.
EXPERIMENTAL
1
General: H NMR and 13C NMR spectra were recorded on a Varian
1
200 (200 MHz for H and 50.3 MHz for 13C). Chemical shifts were given in
ppm using TMS as internal standard. IR spectrum was obtained using

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1498
HA, CHOI, AND LEE
Table. b-Anilinopropionate (5) Prepared from the Reaction of 1,3,5-Triphenyl-
hexahydro-1,3,5-triazines (1) with Ketene Acetals (4) in the Presence of Lewis Acids
Lewis
Acid
Yield
(%)
Entry
1
1 (Ar)
1a (C6H5)
4
4a (R1, R2 ¼ Me,
R3 ¼ Me)
BF3ÁOEt2
SnCl4
5a (80)
5a (60)
5a (45)
5a (82)
5a (71)
5b (78)
5c (52)
5d (60)
5e (45)
5f (58)
5g (14)
2
3
1a (C6H5)
4a (R1, R2 ¼ Me,
R3 ¼ Me)
1a (C6H5)
4a (R1, R2 ¼ Me,
R3 ¼ Me)
TMSCl
4
1a (C6H5)
4a (R1, R2 ¼ Me,
R3 ¼ Me)
TMSOTf
AlCl3
5
1a (C6H5)
4a (R1, R2 ¼ Me,
R3 ¼ Me)
6
1b (4-MeOC6H4)
1c (2-MeC6H4)
1d (4-NO2C6H4)
1a (C6H5)
4a (R1, R2 ¼ Me,
R3 ¼ Me)
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
7
4a (R1, R2 ¼ Me,
R3 ¼ Me)
8
4a (R1, R2 ¼ Me,
R3 ¼ Me)
9
4b (R1 ¼ H, R2 ¼ OMe,
R3 ¼ Me)
10
11
1a (C6H5)
4c (R1 ¼ H, R2 ¼ OMe,
R3 ¼ t-Bu)
1a (C6H5)
4d (R1 ¼ H, R2,
R3 ¼ -CH2CH2CH2-)
Perkin-Elmer System 2000 FT-IR spectrophotometer. Elemental analysis
was taken on a Perkin-Elmer 240 DS elemental analyzer. The silica gel
used for column chromatography was Merck 200–230 mesh. Thin layer
chromatography was carried out with Merck 60F-254 plates with 0.25 mm
thickness.
General procedure for b-anilinopropionates (5): To a stirred solution of
1,3,5-triphenylhexahydro-1,3,5-triazine8 (0.63 mmol) in CH2Cl2 (15 ml) was
slowly added TMSOTf (0.14 ml, 0.63 mmol) at 0ꢀC. After stirring for 5 min,
ketene acetal (1.90 mmol) was added. The resulting solution was stirred at
0ꢀC until all of the starting materials had disappeared on TLC. The reaction
mixture was then poured into ice-water. The resulting solution was neutral-
ized with cold sat. NaHCO3 solution. The reaction product was extrac-
ted twice with CH2Cl2 (50 ml). The organic layer was washed successively
with water (50 ml) and brine, dried over anhydrous Na2SO4, filtered, and

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b-ANILINOPROPIONATES
1499
concentrated under reduced pressure. The crude product was further puri-
fied by flash chromatography to yield b-anilinopropionate.
5a: 1H NMR d 1.36 (s, 6H, 2 ꢁ CH3), 3.32 (s, 2H, -CH2-), 3.74 (s, 3H,
OCH3), 4.07 (brs, 1H, -NH), 6.69–6.81 (m, 3H, ArH), 7.25 (t, 2H,
J ¼ 7.4 Hz, ArH); 13C NMR d 23.3, 43.4, 51.8, 52.3, 112.6, 117.0, 128.9, 148.2,
177.2. Anal. calcd for C12H17NO2: C, 69.5; H, 8.27; N, 6.76. Found: C, 69.4;
H, 8.31; N, 6.59.
5b: 1H NMR d 1.19(s, 6H), 3.10 (s, 2H), 3.59(s, 3H), 3.65 (s, 3H), 6.53
(d, 2H, J ¼ 7.6 Hz), 6.67 (d, 2H, J ¼ 7.6 Hz); 13C NMR d 23.5, 43.5, 51.9,
53.9, 55.7, 114.2, 114.7, 142.6, 151.9, 177.4. Anal. calcd for C13H19NO3: C,
65.8; H, 8.07; N, 5.90. Found: C, 65.9; H, 8.13; N, 5.94.
5c: 1H NMR d 1.29(s, 6H), 2.15 (s, 3H), 3.26 (s, 2H), 3.70 (s, 3H), 6.66
(t, 2H, J ¼ 7.3 Hz), 7.05–7.26 (m, 2H); 13C NMR d 17.4, 23.6, 43.3, 52.0, 52.5,
109.6, 116.8, 122.0, 127.0, 130.1, 146.3, 177.5, Anal. calcd for C13H19NO2:
C, 70.6; H, 8.65; N, 6.33. Found: C, 70.3; H, 8.81; N, 6.52.
1
5d: H NMR d 1.27 (s, 6H), 3.33 (s, 2H), 3.69(s, 3H), 5.00 (brs, 1H),
6.55 (d, 2H, J ¼ 7.4 Hz), 8.05 (d, 2H, J ¼ 7.4 Hz); 13C NMR d 23.4, 43.7,
51.4, 52.3, 111.1, 126.4, 137.8, 153.5, 177.1. Anal. calcd for C12H16N2O4: C,
57.1; H, 6.39; N, 11.1. Found: C, 57.0; H, 6.62; N, 11.0.
5e: 1H NMR d 3.39 (s, 3H), 3.40–3.46 (m, 2H), 3.70 (s, 3H), 3.96–3.99
(m, 1H), 4.46 (brs, 1H), 6.60 (d, 2H, J ¼ 7.4 Hz), 6.67 (t, 1H, J ¼ 7.4 Hz),
7.12 (t, 2H, J ¼ 7.4 Hz); 13C NMR d 45.9, 52.2, 58.6, 78.9, 113.4, 118.1,
129.3, 147.4, 171.6. Anal. calcd for C11H15NO3: C, 63.1; H, 7.23; N, 6.69.
Found: C, 62.9; H, 7.11; N, 6.78.
1
5f: H NMR d 1.48 (s, 9H), 3.35 (s, 2H), 3.45 (s, 3H), 3.92–3.98 (m,
1H), 4.06 (brs, 1H), 6.63–6.73 (m, 3H), 7.71 (t, 2H, J ¼ 7.4 Hz); 13C NMR d
28.0, 45.9, 58.3, 79.2, 82.0, 113.3, 117.8, 129.2, 147.6, 170.2. Anal. calcd for
C14H21NO3: C, 66.9; H, 8.42; N, 5.57. Found: C, 66.7; H, 8.28; N, 5.54.
5g: IR (neat) 3389, 2945, 1724, 1603, 1508, 1257, 1159, 751; 1H NMR d
1.35–1.94 (m, 4H), 2.46–2.58 (m, 1H), 3.06–3.31 (m, 2H), 4.06 (t, 2H,
J ¼ 5.8 Hz), 4.14 (t, 1H, J ¼ 5.2 Hz), 6.39–6.53 (m, 3H), 6.96 (t, 2H,
J ¼ 7.4 Hz); 13C NMR d 21.6, 22.6, 38.8, 44.5, 68.2, 112.8, 117.5, 129.2,
147.4, 174.2. Anal. calcd for C12H15NO2: C, 70.2; H, 7.37; N, 6.82.
Found: C, 70.1; H, 7.49; N, 6.59.
ACKNOWLEDGMENTS
This work was supported by HUFS and Korea Science and Engi-
neering Foundation (2000-1-12300-002-5 to HJH and 1999-1-123-001-5
to WKL).

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1500
HA, CHOI, AND LEE
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Received in the UK December 19, 2000