Preparation of heterocycle-masked β-enamino acids

Article abstract of DOI:10.1021/jo001662+

The preparation of masked N-substituted Β-enamino acid derivatives 3a-n by reaction of 2-alkyloxa(thia)zolines 2a,b with imidoylbenzotriazoles 1a-g in the presence of LDA was described.

Full text of DOI:10.1021/jo001662+

J . Org. Chem. 2001, 66, 4041-4044
4041
P r ep a r a tion of Heter ocycle-Ma sk ed â-En a m in o Acid s
Alan R. Katritzky,* Augustine Donkor, and Yunfeng Fang
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
katritzky@chem.ufl.edu
Received November 27, 2000
The preparation of masked N-substituted â-enamino acid derivatives 3a -n by reaction of 2-alkyl-
oxa(thia)zolines 2a ,b with imidoylbenzotriazoles 1a -g in the presence of LDA was described.
Sch em e 1
â-Amino acid units are important components of, and
synthetic building blocks for, natural products1a-c and are
widely used in other stereoselective syntheses,2a,b for
example, of â-lactam antibiotics,3a-c and other hetero-
cycles.4a,b The study of the synthesis and reactivity of
â-amino acids has recently intensified,2b,5 in part because
many of them are natural product metabolites.6a,b
New synthetic methodologies recently developed for
â-amino acids include (i) Michael additions of amines or
lithium amides to R,â-unsaturated esters;7a-d (ii) nucleo-
philic additions to imines;8a-e and (iii) chemoselective
reduction of â-enamino esters.9a-h
Strategy iii is a convenient and promising approach
due to the simplicity of the procedure and the availability
of the starting materials. Difficulties in selective reduc-
tion caused by the high reactivity of the ester functional-
Ta ble 1. P r ep a r a tion of Im id oylben zotr ia zoles 1a -g
product
R1
R2
method
yield (%)
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
B
A
A
A
A
A
A
97
40
50
57
39
60
40
p-Cl-C6H4
p-Br-C6H4
Ph
p-Br-C6H4
p-MeO-C6H4
p-MeO-C6H4
(1) (a) Winkler, J . D. Tetrahedron 1992, 48, 6953. (b) Sone, H.;
Nemoto, T.; Ishiwata, H.; Ojika, M.; Yamada, K. Tetrahedron Lett.
1993, 34, 8449. (c) Hashiguchi, S.; Kawada, A.; Natsugari, H. J . Chem.
Soc., Perkin Trans. 1 1991, 2435.
(2) (a) Cardillo, G.; Gentilucci, L.; Tolomelli, A.; Tomasini, C. J . Org.
Chem. 1998, 63, 3458. (b) Cardillo, G.; Tomasini, C. Chem. Soc. Rev.
1996, 117.
p-Me-C6H4
p-Me-C6H4
Ph
1g
p-Me-C6H4
(3) (a) Wang, W.-B.; Roskamp, E. J . J . Am. Chem. Soc. 1993, 115,
9417. (b) Palomo, C.; Aizpurua, J . M.; Urchegui, R.; Iturburu, M.; de
Retana, A. O.; Cuevas, C. J . Org. Chem. 1991, 56, 2244. (c) Hart, D.
J .; Ha, D.-C. Chem. Rev. 1989, 89, 1447.
(4) (a) Wamhoff, H. In Advances in Heterocyclic Chemistry; Katrit-
zky, A. R., Ed.; Academic Press: New York, 1985; Vol. 38. (b) Boger,
D. L.; Wysocki, R. J ., J r. J . Org. Chem. 1989, 54, 714.
ity toward many reducing agents were solved by Fustero
and co-workers by introducing a masked carboxylic acid
into the â-position of an enamine function.9c,d,10a,b â-E-
namino acid derivatives were prepared from 2-alkyl-2-
oxazolines and 2-alkyl-2-thiazolines by reaction with
imidoyl chlorides as electrophiles.10a Imidoyl chlorides are
generally prepared in situ by treatment of the corre-
sponding amides and cyanohydrins/ureas with phosgene,
thiophosgene, oxalyl chloride, phosphorus penta- and
trihalides, thionyl chloride, sulfuryl chloride, and halo-
gens.11 They also can be prepared from isocyanides,
nitriles, isocyanates, imines, and amines.11 Although the
preparation of imidoyl chlorides normally provides good
yields, side-reactions such as self-condensation have been
reported at elevated temperatures if R-CH groups are
present in the imidoyl chloride.12 A major disadvantage
in the use of imidoyl chlorides is their extreme lability
toward hydrolysis. Therefore, imidoyl chlorides are sel-
(5) Cole, D. C. Tetrahedron 1994, 50, 9517.
(6) (a) Schmidt, E. W.; Bewley, C. A.; Faulkner, D. J . J . Org. Chem.
1998, 63, 1254. (b) Nicolaou, K. C.; Sorensen, E. J . In Classics in Total
Synthesis; VCH: Weinheim, 1996, 655 and references therein.
(7) (a) Dumas, F.; Mezrhab, B.; d’Angelo, J .; Riche, C.; Chiaroni, A.
J . Org. Chem. 1996, 61, 2293. (b) Hawkins, J . M.; Lewis, T. A. J . Org.
Chem. 1992, 57, 2114. (c) Hawkins, J . M.; Lewis, T. A. J . Org. Chem.
1994, 59, 649. (d) Perlmutter, P. In Conjugate Addition Reactions in
Organic Synthesis; Baldwin, J . E., Magnus, P. D., Eds.; Pergamon
Press: Oxford, 1992; vol 9.
(8) (a) Kleinman, E. F. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991. (b) Kunz, H.;
Schanzenbach, D. Angew. Chem., Int. Ed. Engl. 1989, 28, 1068. (c)
Corey, E. J .; Decicco, C. P.; Newbold, R. C. Tetrahedron Lett. 1991,
32, 5287. (d) Kobayashi, S.; Araki, M.; Yasuda, M. Tetrahedron Lett.
1995, 36, 5773. (e) Loh, T.-P.; Wei, L.-L. Tetrahedron Lett. 1998, 39,
323.
(9) (a) Fustero, S.; Pina, B.; de la Torre, M. G.; Navarro, A.; de
Arellano, C. R.; Simo´n, A. Org. Lett. 1999, 1, 977. (b) Cimarelli, C.;
Palmieri, G. J . Org. Chem. 1996, 61, 5557. (c) Fustero, S.; D´ıaz, M.
D.; Navarro, A.; Salavert, E.; Aguilar, E. Tetrahedron Lett. 1999, 40,
1005. (d) Fustero, S.; D´ıaz, M. D.; Barluenga, J .; Aguilar, E. Tetra-
hedron Lett. 1992, 33, 3801. (e) Cimarelli, C.; Palmieri, G.; Bartoli, G.
Tetrahedron Asymmetry 1994, 5, 1455. (f) Lubell, W. D.; Kitamura,
M.; Noyori, R. Tetrahedron Asymmetry 1991, 2, 543. (g) Bartoli, G.;
Cimarelli, C.; Marcantoni, E.; Palmieri, G.; Petrini, M. J . Org. Chem.
1994, 59, 5328. (h) Potin, D.; Dumas, F.; d’Angelo, J . J . Am. Chem.
Soc. 1990, 112, 3483.
(10) (a) Fustero, S.; Navarro, A.; D´ıaz, D.; de la Torre, M. G.; Asensio,
A.; Sanz, F.; Gonza´lez, M. L. J . Org. Chem. 1996, 61, 8849. (b) Fustero,
S.; D´ıaz, M. D.; Asensio, A.; Navarro, A.; Kong, J . S.; Aguilar, E.
Tetrahedron 1999, 55, 2695.
(11) Kantlehner, W. K.; Mergen, W. W. In Comprehensive Organic
Functional Group Transformations; Katritzky, A. R., Meth-Cohn, O.,
Rees, C. W., Eds.; Pergamon Press: Oxford, 1995; Vol. 5.
(12) Bo¨hme, H.; Ahrens, K. H.; Drechsler, H. J .; Rumbaur, G. Z.
Naturforsch., Teil B 1978, 33, 636.
10.1021/jo001662+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/10/2001

4042 J . Org. Chem., Vol. 66, No. 11, 2001
Katritzky et al.
Sch em e 2
Ta ble 2. P r ep a r a tion of â-En a m in o Acid Der iva tives
3a -n
implying that both of these reagents could be used. The
structural assignment of compounds 3a -n was made on
the basis of their spectral and analytical data. Com-
pounds 3a -n were all isolated as enamine tautomers â,
as confirmed by their NMR spectra. The oxazolines
(3a ,c,e,g,i,k ,m ) all show a singlet around 5.00 ppm
corresponding to the vinyl proton in the HCdC group.
For the thiazolines (3b,d ,f,h ,j,l,n ) this singlet is around
5.20 ppm. A broad singlet around 10.50-11.20 ppm is
assigned to the NH proton, such a low-field chemical shift
being consistent with the formation of the intramolecular
hydrogen bond between the amino group and the sp2
nitrogen atom of the oxazoline or thiazoline ring in the
â tautomer. For thiazoline compounds, this is the only
possible conformer in which intramolecular hydrogen
bond can be formed. By analogy, we also designate the
oxazoline analogues as existing in the similar tautomeric
form. These results are consistent with those reported
by Fustero.10a
In conclusion, heterocycle masked â-enamino acids
were prepared in high yields by a modification of Fus-
tero’s method9c,d,10a starting from imidoylbenzotriazoles,
which shows advantages in stability and ease of prepara-
tion as compared to the corresponding imidoyl halides.
Hence, the present method extends those previously
reported for the synthesis of â-enamino acid derivatives
and provides an experimentally convenient general pro-
cedure for the preparation for these compounds.
compd sm 1 imine 2
X
R1
R2
yield (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
1f
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
O
S
O
S
O
S
O
S
O
S
O
S
O
S
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
85
79
87
88
89
98
82
91
96
89
84
85
85
84
p-Cl-C6H4
p-Cl-C6H4
p-Br-C6H4
p-Br-C6H4
p-Me-C6H4 Ph
p-Me-C6H4 Ph
p-Me-C6H4 p-Br-C6H4
p-Me-C6H4 p-Br-C6H4
Ph
Ph
p-MeO-C6H4
p-MeO-C6H4
1f
1g
1g
p-Me-C6H4 p-MeO-C6H4
p-Me-C6H4 p-MeO-C6H4
dom isolated or purified. Fustero’s method was also
limited because strong bases such as n-butyllithium could
not be used in this reaction due to the high reactivity of
the imidoyl halides toward nucleophiles.9d,10a
Our success in benzotriazole-mediated syntheses of
enaminones13 prompted a study of the preparation of
â-enamino acid derivatives by imidoylation of metalated
heterocyclic imines using imidoylbenzotriazoles as stable
analogues14 of imidoyl chlorides.11
P r ep a r a tion of Im id oylben zotr ia zoles 1a -g. Two
routes were used to prepare imidoylbenzotriazoles 1a -g
as shown in Scheme 1. In method A, secondary amides
were reacted with dibenzotriazolyl sulfoxide following a
literature procedure to give 1b-g in 39-60% yields
(Table 1).14 Alternatively, phenyl isocyanate was reacted
with benzoylbenzotriazole in a sealed tube according to
a general procedure reported previously15 to give 1a in
97% yield. Other routes to imidoylbenzotriazoles are also
known and include (i) reactions of amides with benzo-
triazole and phosphoryl chloride16 and (ii) from oximes
by reaction with BtTs via a Beckmann rearrangement.17
P r ep a r a tion of â-En a m in o Acid Der iva tives 3a -
n . Treatment of 2-methyl-2-oxazoline 2a or 2-methyl-2-
thiazoline 2b (1.0 equiv) with LDA (2.0 equiv) or n-BuLi
(2.0 equiv) at -78 °C in THF for 10-15 min generated a
bright yellow solution of the corresponding azaallylic
anion. THF solutions of imidoylbenzotriazoles 1a -g were
added dropwise at -78 °C, and the resulting solution was
allowed to warm to room-temperature overnight. After
standard workup, the desired products 3a -n were ob-
tained in good to excellent yields (Scheme 2, Table 2).
Both LDA and n-BuLi give essentially the same yields,
Exp er im en ta l Section
Gen er a l Com m en ts. Melting points were determined on
a hot stage apparatus and are uncorrected. 1H (300 MHz) and
13C (75 MHz) NMR spectra were recorded in CDCl3 with TMS
or CDCl3, respectively, as the internal reference. Elemental
analyses were performed on a Carlo Erba-1106 instrument.
High resolution mass spectra were measured on a Kratos/AE1-
MS 30 mass spectrometer. THF was distilled from sodium/
benzophenone under nitrogen immediately prior to use. All
reactions with air-sensitive compounds were carried out under
argon atmosphere.
N-P h en ylben zen eca r boxim id oyl-1-ben zotr ia zole (1a ):
yield 97%, yellow needles (from EtOH), mp 132-133 °C, [lit.14
1
mp 130-132 °C]; H NMR δ 6.90 (d, J ) 7.8 Hz, 2H), 7.02 (t,
J ) 7.1 Hz, 1H), 7.24 (t, J ) 7.8 Hz, 2H), 7.27-7.52 (m, 5H),
7.62 (t, J ) 7.5 Hz, 1H), 7.76 (t, J ) 7.5 Hz, 1H), 8.24 (d, J )
8.4 Hz, 1H), 8.45 (d, J ) 8.4 Hz, 1H); 13C NMR δ 115.1, 119.7,
121.0, 123.9, 125.9, 127.9, 128.7, 129.6, 129.9, 130.0, 130.4,
131.3, 145.7, 146.9, 153.8.
N-[(Z)-1H-1,2,3-Ben zotr iazol-1-yl(ph en yl)m eth yliden e]-
4-ch lor oa n ilin e (1b): yield 40%, orange needles (from EtOH/
CH2Cl2), mp 134-136 °C; 1H NMR δ 6.82 (d, J ) 8.1 Hz, 2H),
7.06 (t, J ) 7.2 Hz, 1H), 7.20-7.40 (m, 6H), 7.52 (t, J ) 8.1
Hz, 1H), 7.65 (t, J ) 7.2 Hz, 1H), 8.15 (d, J ) 8.4 Hz, 1H),
8.48 (d, J ) 8.1 Hz, 1H); 13C NMR δ 115.3, 120.0, 121.3, 124.3,
125.6, 128.5, 128.9, 129.3, 131.5, 131.8, 136.4, 146.3, 146.6,
152.5. HRMS (CI) m/z Calcd for C19H14N4Cl (M + 1): 333.0907.
Found: 333.0925.
(13) Katritzky, A. R.; Fang, Y.; Donkor, A.; Xu, J . Synthesis 2000,
2029.
(14) Katritzky, A. R.; Stevens, C. V.; Zhang, G.-F.; J iang, J .
Heterocycles 1995, 40, 231.
(15) Katritzky, A. R.; Huang, T.-B.; Voronkov, M. V. J . Org. Chem.
2001, 66(3), 1043.
(16) Katritzky, A. R.; Rachwal, S.; Offerman, R. J .; Najzarek, Z.;
Yagoub, A. K.; Zhang, Y. Chem. Ber. 1990, 123, 1545.
(17) Katritzky, A. R.; Monteux, D. A.; Tymoshenko, D. O. Org. Lett.
1999, 1, 577.
N-[(Z)-1H-1,2,3-Ben zotr iazol-1-yl(ph en yl)m eth yliden e]-
4-br om oa n ilin e (1c): yield 50%, orange needles (from EtOAc/
hexanes), mp 131-133 °C; 1H NMR δ 6.71 (d, J ) 8.4 Hz, 2H),

Heterocycle-Masked â-Enamino Acids
J . Org. Chem., Vol. 66, No. 11, 2001 4043
7.32-7.64 (m, 9H), 8.14 (d, J ) 8.1 Hz, 1H), 8.42 (d, J ) 8.1
Hz, 1H); 13C NMR δ 115.3, 117.4, 120.1, 123.3, 125.7, 128.4,
129.4, 129.9, 130.1, 130.6, 131.7, 131.9, 146.0, 146.4, 154.2.
HRMS (CI) m/z Calcd for C19H14N4Br (M + 1): 377.0402.
Found: 377.0429.
N -[(Z)-1H -1,2,3-Be n zot r ia zol-1-yl(4-m e t h ylp h e n yl)-
m eth ylid en e]a n ilin e (1d ): yield 57%, yellow needles (from
Et2O), mp 102-103 °C, [lit.14 mp 100-101 °C]; 1H NMR δ 2.35
(s, 3H), 6.85 (d, J ) 7.5 Hz, 2H), 7.03 (t, J ) 7.1 Hz, 1H), 7.14
(d, J ) 8.1 Hz, 2H), 7.23-7.36 (m, 4H), 7.49 (t, J ) 7.8 Hz,
1H), 7.61 (t, J ) 7.8 Hz, 1H), 8.15 (d, J ) 8.1 Hz, 1H), 8.44 (d,
J ) 8.3 Hz, 1H); 13C NMR δ 21.6, 115.3, 120.0, 121.5, 124.1,
125.5, 127.3, 128.9, 129.0, 129.2, 130.2, 132.1, 140.7, 146.4,
147.2, 153.9.
N -[(Z)-1H -1,2,3-Be n zot r ia zol-1-yl(4-m e t h ylp h e n yl)-
m eth yliden e]-4-br om oan ilin e (1e): yield 39%, orange prisms
(EtOAc/hexanes), mp 118-120 °C; 1H NMR δ 2.38 (s, 3H), 6.73
(d, J ) 8.4 Hz, 2H), 7.16-7.25 (m, 4H), 7.32 (d, J ) 8.7 Hz,
2H), 7.50 (t, J ) 7.5 Hz, 1H), 7.60 (t, J ) 7.8 Hz, 1H), 8.13 (d,
J ) 8.4 Hz, 1H), 8.39 (d, J ) 8.4 Hz, 1H); 13C NMR δ 21.6,
115.2, 117.3, 120.0, 123.3, 125.6, 126.9, 129.1, 129.3, 130.1,
131.9, 132.0, 141.1, 146.2, 146.4, 154.4. HRMS (CI) m/z Calcd
for C20H16N4Br (M + 1): 391.0558. Found: 391.0551.
N-[(Z)-1H-1,2,3-Ben zotr iazol-1-yl(ph en yl)m eth yliden e]-
4-m eth oxya n ilin e (1f): yield 60%, orange platelets (from
EtOAc/hexanes), mp 104-105 °C; 1H NMR δ 3.76 (s, 3H),
6.74-6.81 (m, 4H), 7.37-7.52 (m, 6H), 7.62 (t, J ) 7.2 Hz, 1H),
8.14 (d, J ) 8.4 Hz, 1H), 8.47 (d, J ) 8.4 Hz, 1H); 13C NMR δ
55.3, 114.1, 115.3, 120.0, 123.1, 125.4, 128.4, 129.1, 130.1,
130.3, 132.1, 139.8, 146.4, 153.2, 156.6. HRMS (CI) m/z Calcd
for C20H16N4O: 328.1324. Found: 328.1325.
128.3, 128.5, 128.9, 136.4, 151.8, 166.8. HRMS (CI) m/z Calcd
for C17H17N2S (M + 1): 281.1112. Found: 281.1128.
N-(4-Ch lor op h en yl)-N-[(Z)-2-(4,5-d ih yd r o-1,3-oxa zol-2-
yl)-1-p h en yleth en yl]a m in e (3c): yield 87%, yellow platelets
(from EtOAc/CH2Cl2), mp 124-126 °C; 1H NMR δ 4.00 (t, J )
9.0 Hz, 2H), 4.21 (t, J ) 9.0 Hz, 2H), 4.98 (s, 1H), 6.65 (d, J )
7.5 Hz, 2H), 6.88 (t, J ) 7.2 Hz, 1H), 7.08 (t, J ) 8.1 Hz, 2H),
7.23-7.32 (m, 4H), 10.65 (br s, 1H); 13C NMR δ 54.4, 65.8,
89.0, 121.8, 122.4, 128.6, 129.4, 134.8, 135.0, 141.0, 152.7,
166.0. Anal. Calcd for C17H15N2OCl: C, 68.34; H, 5.06; N, 9.38.
Found: C, 68.19; H, 5.39; N, 9.36.
N-(4-Ch lor op h en yl)-N-[(Z)-2-(4,5-d ih yd r o-1,3-th ia zol-2-
yl)-1-p h en yleth en yl]a m in e (3d ): yield 88%, yellow prisms
(from EtOAc/CH2Cl2), mp 138-140 °C. 1H NMR δ 3.24 (t, J )
9.0 Hz, 2H), 4.36 (t, J ) 9.0 Hz, 2H), 5.16 (s, 1H), 6.65 (d, J )
7.8 Hz, 2H), 6.88 (t, J ) 7.2 Hz, 1H), 7.08 (t, J ) 8.1 Hz, 2H),
7.22-7.31 (m, 4H), 11.21 (br s, 1H); 13C NMR δ 32.8, 64.3,
95.7, 122.0, 122.5, 128.6, 128.7, 129.5, 134.7, 134.8, 140.8,
150.5, 166.7. Anal. Calcd for C17H15N2ClS: C, 64.85; H, 4.80;
N, 8.90. Found: C, 64.82; H, 4.67; N, 8.63.
N-[(Z)-2-(4,5-Dih ydr o-1,3-oxazol-2-yl)-1-ph en yleth en yl]-
4-br om oa n ilin e (3e): yield 89%, yellow needles (from EtOAc/
1
CH2Cl2), mp 93-94 °C; H NMR δ 4.00 (t, J ) 9.0 Hz, 2H),
4.22 (t, J ) 9.0 Hz, 2H), 5.03 (s, 1H), 6.52 (d, J ) 8.7 Hz, 2H),
7.15 (d, J ) 8.7 Hz, 2H), 7.28-7.35 (m, 5H), 10.69 (br s, 1H);
13C NMR δ 54.3, 65.8, 89.5, 114.7, 123.0, 128.0, 128.5, 129.1,
131.4, 136.1, 140.4, 153.4, 166.1. Anal. Calcd for C17H15N2-
OBr: C, 59.49; H, 4.40; N, 8.16. Found: C, 59.53; H, 4.53; N,
8.00.
N-[(Z)-2-(4,5-Dih ydr o-1,3-th iazol-2-yl)-1-ph en yleth en yl]-
4-br om oa n ilin e (3f): yield 98%, orange needles (from EtOAc/
CH2Cl2), mp 139-141 °C; 1H NMR δ 3.26 (t, J ) 8.1 Hz, 2H),
4.37 (t, J ) 8.1 Hz, 2H), 5.21 (s, 1H), 6.50 (d, J ) 8.7 Hz, 2H),
7.15 (d, J ) 8.7 Hz, 2H), 7.26-7.32 (m, 5H), 11.21 (br s, 1H);
13C NMR δ 32.7, 64.3, 96.1, 114.8, 123.1, 128.1, 128.5, 129.1,
131.5, 135.9, 140.3, 151.3, 167.0. Anal. Calcd for C17H15N2-
BrS: C, 56.83; H, 4.21; N, 7.80. Found: C, 56.75; H, 3.77; N,
7.65.
N -[(Z)-1H -1,2,3-Be n zot r ia zol-1-yl(4-m e t h ylp h e n yl)-
m eth ylid en e]-4-m eth oxya n ilin e (1g): yield 40%, orange
1
prisms (from EtOAc/hexanes), mp 56-58 °C; H NMR δ 2.35
(s, 3H), 3.73 (s, 3H), 6.76 (q, J ) 8.4 Hz, 4H) 7.15 (d, J ) 8.1
Hz, 2H), 7.23 (d, J ) 8.1 Hz, 2H), 7.47 (t, J ) 7.5 Hz, 1H),
7.54 (q, J ) 7.2 Hz, 1H), 8.10 (d, J ) 8.1 Hz, 1H), 8.41 (d, J )
8.4 Hz, 1H); 13C NMR δ 21.4, 55.2, 113.9, 115.2, 119.7, 122.3,
122.9, 125.2, 127.5, 128.9, 130.0, 132.0, 139.9, 140.4, 146.2,
153.1, 156.4. HRMS (CI) m/z Calcd for C21H18N4O: 342.1481.
Found: 342.1485.
N-[(Z)-2-(4,5-Dih yd r o-1,3-oxa zol-2-yl)-1-(4-m eth ylp h en -
yl)eth en yl]a n ilin e (3g): yield 82%, orange needles (from CH2-
1
Cl2), mp 118-119 °C; H NMR δ 2.33 (s, 3H), 4.00 (t, J ) 9.0
Gen er a l P r oced u r e for th e P r ep a r a tion of Ma sk ed
â-En a m in o Acid s 3a -n . A three-necked flask equipped with
an argon inlet adapter, rubber septum, and a magnetic stirring
bar was flame dried. Diisopropylamine (2.2 mmol) was added
to the flask with THF (5 mL) and cooled to 0 °C at stirring
under argon. n-Butyllithium (2.0 mmol, hexanes solution) was
then added dropwise. After being stirred for 10 min, the
resulting solution was cooled to -78 °C and 2a ,b (1.0 mmol)
in THF (5 mL) was added. The resulting bright yellow mixture
was allowed to stir for 10-15 min at this temperature and
then the solution of imidoylbenzotriazole derivative 1a -g (1.0
mmol) in THF (5 mL) was added dropwise. The reaction
mixture was allowed to warm to room temperature while
stirring overnight. The reaction was quenched with saturated
ammonium chloride solution and extracted with EtOAc (3 ×
10 mL). The combined organic extracts were washed with brine
and dried over Na2SO4. After filtration the solvent was
removed in vacuo, and the residue was subjected to column
chromatography purification with hexanes/EtOAc to give
3a -n .
N-[(Z)-2-(4,5-Dih yd r o-1,3-oxa zol-2-yl)-1-p h en yleth en yl]-
a n ilin e (3a ): yield 85%, colorless needles (from CH2Cl2), mp
82-84 °C, [lit.9a mp 86-88 °C]; 1H NMR δ 4.01 (t, J ) 9.0 Hz,
2H), 4.22 (t, J ) 9.0 Hz, 2H), 5.00 (s, 1H), 6.65 (d, J ) 7.8 Hz,
2H), 6.85 (t, J ) 7.5 Hz, 1H), 7.06 (t, J ) 7.5 Hz, 2H), 7.25-
7.31 (m, 3H), 7.36 (d, J ) 6.0 Hz, 2H), 10.68 (br s, 1H); 13C
NMR δ 54.4, 65.7, 88.6, 121.7, 122.1, 128.1, 128.4, 128.5, 128.9,
136.6, 141.2, 154.0, 166.2.
N-[(Z)-2-(4,5-Dih ydr o-1,3-th iazol-2-yl)-1-ph en yleth en yl]-
a n ilin e (3b): yield 79%, yellow platelets (from EtOAc/CH2-
Cl2), mp 83-85 °C; 1H NMR δ 3.25 (t, J ) 9.0 Hz, 2H), 4.37 (t,
J ) 9.0 Hz, 2H), 5.19 (s, 1H), 6.65 (d, J ) 7.5 Hz, 2H), 6.86 (t,
J ) 8.7 Hz, 1H), 7.06 (t, J ) 8.1 Hz, 2H), 7.25-7.31 (m, 5H),
11.21 (br s, 1H); 13C NMR δ 32.7, 64.3, 95.4, 121.8, 122.2, 128.2,
Hz, 2H), 4.18 (t, J ) 9.0 Hz, 2H), 4.99 (s, 1H), 6.67 (d, J ) 7.5
Hz, 2H), 6.86 (t, J ) 9.0 Hz, 1H), 7.04-7.09 (m, 3H), 7.26-
7.27 (m, 3H), 10.63 (br s, 1H); 13C NMR δ 21.3, 54.4, 65.7, 88.2,
121.7, 122.0, 128.0, 128.5, 129.1, 133.6, 139.0, 141.4, 154.1,
166.2. HRMS (CI) m/z Calcd for C18H19N2O (M + 1): 279.1497.
Found: 279.1503.
N-[(Z)-2-(4,5-Dih ydr o-1,3-th iazol-2-yl)-1-(4-m eth ylph en -
yl)eth en yl]a n ilin e (3h ): yield 91%, yellow needles (from
1
EtOAc/CH2Cl2), mp 113-114 °C, H NMR δ 2.33 (s, 3H), 3.24
(t, J ) 9.0 Hz, 2H), 4.36 (t, J ) 9.0 Hz, 2H), 5.17 (s, 1H), 6.66
(d, J ) 7.8 Hz, 2H), 6.86 (t, J ) 9.0 Hz, 1H), 7.07-7.09 (m,
3H), 7.24-7.26 (m, 3H), 11.18 (br s, 1H); 13C NMR δ 21.6, 33.1,
64.6, 95.4, 122.1, 122.4, 128.4, 128.8, 129.4, 133.7, 139.2, 141.6,
152.2, 167.2. HRMS (CI) m/z Calcd for C18H19N2S (M + 1):
295.1269. Found: 295.1291.
N-[(Z)-2-(4,5-Dih yd r o-1,3-oxa zol-2-yl)-1-(4-m eth ylp h en -
yl)eth en yl]-4-br om oa n ilin e (3i): yield 96%, pale yellow
needles (from CH2Cl2), mp 136-138 °C; 1H NMR δ 2.34 (s,
3H), 3.99 (t, J ) 9.0 Hz, 2H), 4.21 (t, J ) 8.7 Hz, 2H), 5.01 (s,
1H), 6.52 (d, J ) 8.7 Hz, 2H), 7.09 (d, J ) 8.1 Hz, 2H), 7.16 (d,
J ) 8.7 Hz, 2H), 7.23 (d, J ) 8.1 Hz, 2H), 10.66 (br s, 1H); 13
C
NMR δ 21.3, 54.3, 65.7, 88.9, 114.5, 123.0, 128.0, 129.4, 131.3,
131.6, 133.1, 139.2, 140.5, 153.5, 166.1. Anal. Calcd for
C
18H17N2OBr: C, 60.52; H, 4.80; N, 7.84. Found: C, 60.53; H,
4.83; N, 7.74.
N-[(Z)-2-(4,5-Dih ydr o-1,3-th iazol-2-yl)-1-(4-m eth ylph en -
yl)eth en yl]-4-br om oa n ilin e (3j): yield 89%, pale yellow
needles (from EtOAc/CH2Cl2), mp 156-157 °C; 1H NMR δ 2.34
(s, 3H), 3.25 (t, J ) 8.1 Hz, 2H), 4.36 (t, J ) 8.1 Hz, 2H), 5.19
(s, 1H), 6.51 (d, J ) 8.7 Hz, 2H), 7.09 (d, J ) 8.1 Hz, 2H), 7.15
(d, J ) 8.7 Hz, 2H), 7.25 (t, J ) 8.1 Hz, 2H), 11.19 (br s, 1H);
13C NMR δ 21.3, 32.7, 64.3, 95.8, 114.7, 123.1, 128.0, 129.2,
131.4, 133.0, 139.2, 140.4, 151.4, 167.0. Anal. Calcd for

4044 J . Org. Chem., Vol. 66, No. 11, 2001
Katritzky et al.
C18H17N2BrS: C, 57.91; H, 4.59; N, 7.50. Found: C, 57.83; H,
4.57; N, 7.35.
needles (from EtOAc/CH2Cl2), mp 108-110 °C; 1H NMR δ 2.32
(s, 3H), 3.70 (s, 3H), 3.99 (t, J ) 9.0 Hz, 2H), 4.18 (t, J ) 9.0
Hz, 2H), 4.92 (s, 1H), 6.64 (s, 4H), 7.06 (d, J ) 8.1 Hz, 2H),
7.25 (t, J ) 8.1 Hz, 2H), 10.53 (br s, 1H); 13C NMR δ 21.3,
29.7, 55.3, 65.7, 86.5, 113.8, 123.7, 128.1, 128.9, 133.7, 134.6,
138.8, 154.9, 155.2, 166.6. HRMS (CI) m/z Calcd for C19H21N2O2
(M + 1): 309.1603. Found: 309.1583.
N-[(Z)-2-(4,5-Dih ydr o-1,3-th iazol-2-yl)-1-(4-m eth ylph en -
yl)eth en yl]-4-m eth oxya n ilin e (3n ): yield 84%, pale yellow
needles (from EtOAc/CH2Cl2), mp 133-135 °C; 1H NMR δ 2.31
(s, 3H), 3.23 (t, J ) 9.0 Hz, 2H), 3.69 (s, 3H), 4.34 (t, J ) 9.0
Hz, 2H), 5.11 (s, 1H), 6.63 (s, 4H), 7.04 (d, J ) 8.1 Hz, 2 H),
7.24 (d, J ) 8.1 Hz, 2H), 11.10 (br s, 1H); 13C NMR δ 21.3,
32.7, 55.3, 64.2, 93.6, 113.8, 123.8, 128.2, 128.9, 133.4, 134.4,
138.7, 152.8, 155.3, 166.9. Anal. Calcd for C19H20N2OS: C,
70.34; H, 6.21; N, 8.63. Found: C, 69.97; H, 6.41; N, 8.47.
N-[(Z)-2-(4,5-Dih ydr o-1,3-oxazol-2-yl)-1-ph en yleth en yl]-
1
4-m eth oxya n ilin e (3k ): yield 84%, yellow gum; H NMR δ
3.24 (t, J ) 9.0 Hz, 2H), 3.69 (s, 3H), 4.36 (t, J ) 8.1 Hz, 2H),
5.12 (s, 1H), 6.62 (s, 4H), 7.25-7.35 (m, 5H), 11.13 (br s, 1H);
13C NMR δ 32.8, 55.3, 64.3, 94.0, 113.8, 123.9, 128.2, 128.4,
128.7, 134.3, 136.4, 152.7, 155.6, 166.9. HRMS (CI) m/z Calcd
for C18H19N2O2 (M + 1): 295.1447. Found: 295.1415.
N-[(Z)-2-(4,5-Dih ydr o-1,3-th iazol-2-yl)-1-ph en yleth en yl]-
4-m eth oxya n ilin e (3l): yield 85%, orange gum; 1H NMR δ
3.25 (t, J ) 9.0 Hz, 2H), 3.70 (s, 3H), 4.36 (t, J ) 8.1 Hz, 2H),
5.12 (s, 1H), 6.63 (s, 4H), 7.26-7.35 (m, 5H), 11.13 (br s, 1H);
13C NMR δ 32.8, 55.3, 64.3, 94.0, 113.8, 123.9, 128.2, 128.4,
128.7, 134.2, 136.4, 152.7, 155.3, 166.9. HRMS (CI) m/z Calcd
for C18H19N2OS (M + 1): 311.1218. Found: 311.1215.
N-[(Z)-2-(4,5-Dih yd r o-1,3-oxa zol-2-yl)-1-(4-m eth ylp h en -
yl)eth en yl]-4-m eth oxya n ilin e (3m ): yield 85%, orange
J O001662+