Synthesis of substituted 4-(5-Alkyl-thiazol-2-ylmethyl)-3,4-dihydro-2H-1,4- benzoxazines and 5-(2,3-Dihydro-1,4-benzoxazin-4-ylmethyl)-4-methyl-1-phenyl-1H- pyrazol-3-ylamine

Article abstract of DOI:10.1002/jhet.10

Substituted 4-(5-alkyl-thiazol-2-ylmethyl)-3,4-dihydro-2H-1,4-benzoxazines and 5-(2,3-dihydro-1,4-benzoxazin-4-ylmethyl)-4-methyl-1-phenyl-1H-pyrazol-3- ylamines were prepared by the reaction of (2,3-dihydro-1,4-benzoxazin-4-yl)- acetic acid methyl ester

Full text of DOI:10.1002/jhet.10

January 2009
Synthesis of Substituted 4-(5-Alkyl-thiazol-2-ylmethyl)-3,4-
dihydro-2H-1,4-benzoxazines and 5-(2,3-Dihydro-1,4-benzoxazin-
4-ylmethyl)-4-methyl-1-phenyl-1H-pyrazol-3-ylamine
39
Pushpak Mizar and Bekington Myrboh*
Department of Chemistry, North Eastern Hill University, Mawlai Campus, Shillong 793022, India
*E-mail: bmyrboh@nehu.ac.in
Received December 19, 2007
DOI 10.1002/jhet.10
Published online 5 February 2009 in Wiley InterScience (www.interscience.wiley.com).
Substituted 4-(5-alkyl-thiazol-2-ylmethyl)-3,4-dihydro-2H-1,4-benzoxazines and 5-(2,3-dihydro-1,4-
benzoxazin-4-ylmethyl)-4-methyl-1-phenyl-1H-pyrazol-3-ylamines were prepared by the reaction of
(2,3-dihydro-1,4-benzoxazin-4-yl)-acetic acid methyl ester and some common reagents to provide the
product in satisfactory yields.
J. Heterocyclic Chem., 46, 39 (2009).
INTRODUCTION
tion and redox reactions. More recently, extensive stud-
ies have been focused on aryl pyrazoles for exhibiting
cyclooxygenase-2 (COX-2) and non-nucleoside HIV-1
reverse transcriptase inhibitory properties. This structure
has found applications in drug development for the
treatment of allergies, hypertension, schizophrenia,
inflammation, bacterial, and HIV7 infections. Amino-
thiazoles are known to be ligands of estrogen receptors
as well as a novel class of adenosine receptor antago-
nists, whereas other analogues are used as fungicides,
inhibiting in vivo growth of Xanthomonas and as an
ingredient of herbicides or as schistosomicidal and anti-
helmintic drugs [10–15].
Benzoxazines have been used as intermediates in the
synthesis of many heterocyclic structures of biological
importance. These derivatives have been shown to be
selective serotonin reuptake inhibitors. They have also
shown activities toward 5-HT1A receptor while the 1,4-
benzoxazine imidazole derivatives have shown in vivo
activities against a murine experimental model of candi-
diasis. Some of the benzoxazines were most effective in
promoting HUVEC apoptosis and inhibiting A549 cell
proliferation [1–4]. Some of the N-substituted benzoxa-
zines have been reported to cure thrombi-related dis-
eases, for instance, platelet aggregation, thrombosis,
myocardial infarction [5] etc. Derivatives of benzomor-
pholine have been incorporated to show hypotensive/
antihypertensive effectiveness [6] as well as potential
dopamine D3 receptor ligands and inhibitions of cardiac
phosphodiestrase (PDE) fraction in vitro and for positive
inotropic activity in vivo [7]. They also tend to inhibit
oxidative stress mediated neuronal degeneration in neu-
ronal cell cultures [8,9].
RESULTS AND DISCUSSION
As part of an ongoing program aimed at synthesizing
benzoxazine derivatives of biological interest, we
wanted to introduce different heterocyclic ring systems
on the N-atom of the benzoxazines. Our literature survey
revealed that benzoxazines-bearing pyrazole and thiazole
rings on the N-atom have not been reported in spite of
the fact that these two heterocyclic systems played an
important role in drug development.
The pyrazole and thiazole ring systems are common
structural motifs in a number of biologically active mol-
ecules. Thiazole ring systems originate in nature as a
consequence of peptide modification containing cysteine
side chain residue and are the product of cyclodehydra-
Earlier, we have reported [16] the synthesis of 3,4-
dihydro-1,4-2H-benzoxazine from 2-aminophenols and
C
V
2009 HeteroCorporation

40
P. Mizar and B. Myrboh
Vol 46
Table 1
Preparation of N-substituted 3,4-dihydro-2H-1,4-benzoxazines.
Product (2a–j)
Product (3a–j)
Entry
Yield 2a–j (%)
Yield 3a–j (%)
a
b
c
d
e
f
g
h
i
R1 ¼ H, R2 ¼ H, R3 ¼ H R4 ¼ Me
R1 ¼ H, R2 ¼ H, R3 ¼ H R4 ¼ CH2CH3
R1 ¼ H, R2 ¼ H, R3 ¼ Me, R4 ¼ Me
R1 ¼ H, R2 ¼ H, R3 ¼ Me, R4 ¼ CH2CH3
R1 ¼ H,R2 ¼ Me,R3 ¼ H, R4 ¼ CH2CH3
R1 ¼ Me, R2 ¼ H, R3 ¼ H, R4 ¼ CH2CH3
R1 ¼ H, R2 ¼ H, R3 ¼ H, R4 ¼ Ph
R1 ¼ H, R2 ¼ H, R3 ¼ Me R4 ¼ Ph
R1 ¼ H, R2 ¼ Me, R3 ¼ H R4 ¼ Ph
R1 ¼ Me, R2 ¼ H, R3 ¼ H R4 ¼ Ph
64
61
53
54
61
57
58
59
62
62
R1 ¼ H, R2 ¼ H, R3 ¼ H, R5 ¼ H
R1 ¼ H, R2 ¼ H, R3 ¼ H, R5 ¼ Me
R1 ¼ Me, R2 ¼ H, R3 ¼ H, R5 ¼ H
R1 ¼ H, R2 ¼ Me, R3 ¼ H, R5 ¼ H
R1 ¼ H, R2 ¼ F, R3 ¼ H, R5 ¼ H
R1 ¼ H, R2 ¼ CF3, R3 ¼ H, R5 ¼ H
R1 ¼ H, R2 ¼ Cl, R3 ¼ H, R5 ¼ Me
R1 ¼ H, R2 ¼ Me, R3 ¼ H, R5 ¼ Me
R1 ¼ H, R2 ¼ F, R3 ¼ H, R5 ¼ Me
R1 ¼ H, R2 ¼ H, R3 ¼ Me, R5 ¼ H
59
57
59
61
62
45
41
47
46
61
j
1,2-dibromoethane using K2CO3 in DMF, which was
then subjected to N-substitution using alkyl bromide.
Subsequent debenzylation and esterification yielded
(2,3-dihydro-1,4-benzoxazin-4-yl)-acetic acid methyl
ester 1. Here, we report the synthesis of 4-(5-alkyl-thia-
tives by passing NH3 (g) through the solution of 3 at 0–
5ꢀC and then to the corresponding thioamides using
Lawesson’s reagent (Scheme 1). Further treatment with
1-bromo-alkan-2-one in ethanol gave the desired prod-
ucts in about 53–64% yields.
zol-2-ylmethyl)-3,4-dihydro-2H-1,4-benzoxazines
and
Compounds 3a–j (Table 1) was prepared by first convert-
ing the methyl ester derivatives to the corresponding butyr-
onitrile derivatives using NaH and acetonitrile. Further
treatment with phenyl hydrazine yielded the desired prod-
ucts in 41–62% yields (Scheme 2). Catalytic amounts of
KF increased the rate of the reaction and hence the yield.
5-(2,3-dihydro-1,4-benzoxazin-4-ylmethyl)-4-methyl-1-
phenyl-1H-pyrazol-3-ylamine starting from (2,3-dihydro-
1,4-benzoxazin-4-yl)-acetic acid methyl ester.
The compounds 2a–j (Table 1) were first prepared by
converting the methyl ester derivatives to amide deriva-
Scheme 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2009 Synthesis of substituted 4-(5-alkyl-thiazol-2-ylmethyl)-3,4-dihydro-2H-1,4-benzoxazines
and 5-(2,3-Dihydro-1,4-benzoxazin-4-ylmethyl)-4-methyl-1-phenyl-1H-pyrazol-3-ylamine
41
Scheme 2
EXPERIMENTAL
Hz), 4.22 (t, 2H, J ¼ 8.9 Hz), 4.72 (s, 2H), 6.46–6.65 (m, 4H,
ArH), 7.23 (s, 1H). C13 NMR (CDCl3, 100 MHz) d ppm 14.2,
58.6, 60.2 (NCH2), 73.1 (OCH2), 113.8, 115.8, 118.3, 120.5,
130.6, 133.7, 140.1, 143.3, 165.4, m/z ¼ 247.26. Calc. for
C13H14N2OS C, 63.39; H, 5.73; N, 11.37%; observed were C,
63.41; H, 5.75; N, 11.36%.
(2c). IR (KBr) m cmꢁ1 1722 (C¼¼N stretching) H1 NMR
(CDCl3, 400 MHz) d ppm 2.32 (s, 3H), 2.47 (s, 3H), 3.84 (t,
2H, J ¼ 12.3 Hz), 4.22 (t, 2H, J ¼ 9.1 Hz), 4.76 (s, 2H),
6.46–6.65 (m, 3H, ArH), 7.31 (s, 1H). C13 NMR (CDCl3, 100
MHz) d ppm 14.5, 21.7, 58.4, 60.2 (NCH2), 74.1 (OCH2),
113.5, 115.9, 121.5, 127.1, 127.8, 133.7, 140.1, 143.3, 165.0,
m/z ¼ 247. Calc. for C14H16N2OS C, 64.58; H, 6.19; N,
10.76%; observed were C, 64.60; H, 6.20; N, 10.75%.
(2d). IR (KBr) m cmꢁ1 1721 (CAN stretching) H1 NMR
(CDCl3, 400 MHz) d ppm 1.18 (t, 3H, J ¼ 14.1 Hz), 2.31 (s,
3H), 3.29–3.39 (q, 2H, J ¼ 8.7 Hz), 3.82 (t, 2H, J ¼ 14.3 Hz),
4.27 (t, 2H, J ¼ 14.1 Hz), 5.69 (s, 2H), 6.41(s, 1H), 6.38 (d,
1H, J ¼ 7.2 Hz), 6.47 (d, 1H, J ¼ 7.2 Hz), 7.11 (s, 1H). C13
NMR (CDCl3, 100 MHz) d ppm 15.5, 21.9, 22.7, 57.7, 60.1
(NCH2), 73.3 (OCH2), 112.8, 113.3, 119.9, 127.1, 130.4,
Carbon, hydrogen, and nitrogen analysis were performed
with a Perkin-Elmer 2400 series II instrument. IR spectra were
recorded on a BOMEM DA-8 FTIR spectrophotometer. The
1H and 13C NMR spectra were recorded on a Bruker AMX
400 spectrometer. Positive-ion and negative-ion electrospray
ionization (ESI) mass spectra were measured on an ion trap
analyzer Esquire 3000 (Bruker Daltonics).
Synthesis of Substituted 4-(5-alkyl-thiazol-2-ylmethyl)-
3,4-dihydro-2H-1,4-benzoxazine. The methyl ester derivative
(1) was first dissolved in methanol, the reaction mixture was
cooled in ice, and NH3 gas was passed through it for 10 min.
The reaction mixture was stirred overnight at room tempera-
ture, resulting in separation of dirty white solids, which were
separated by filtration to yield the amide derivative. The crude
product was washed with hexane to yield the pure product. IR
(KBr) m cmꢁ1 3330 (m) and 3050 (m) (CONH2) H1 NMR
(DMSO-d6, 400 MHz) d ppm 3.3 (t, 2H, J ¼ 14.1 Hz), 4.07
(s, 2H,), 4.32 (t, 2H, J ¼ 9.1 Hz), 6.24 (b, 2H), 6.46–6.5 (m,
4H). Calc. for C10H12N2O2 C, 62.49; H, 6.29; N, 14.57%;
observed were C, 62.50; H, 6.28; N, 14.56%.
133.5, 140.2, 141.4, 166.1, m/z
C15H18N2OS C, 65.66; H, 6.61; N, 10.21%; observed were C,
65.64; H, 6.60; N, 10.22%.
¼
274.26. Calc. for
The amide derivative was then dissolved in Dry THF and
treated with Lawesson’s reagent (0.5 eq) and stirred overnight
under N2 atm. The reaction on completion was evaporated in
vacuum and extracted with ethylacetate. The complete organic
extract was dried over Na2SO4 and concentrated. The crude
product was purified by column chromatography using ethyl
acetate and hexane (1:10) as an eluent to yield the desired
product. IR (KBr) m cmꢁ1 1175. The 2-(2,3-dihydro-1,4-ben-
zoxazin-4-yl)-thioacetamide was then refluxed with 1-bromo
butan-2-one in ethanol, the reaction was monitored using TLC.
The reaction on completion was evaporated in vacuum and
extracted with DCM. The complete organic extract was dried
over Na2SO4 and concentrated. The crude product was purified
by column chromatography using ethyl acetate and hexane
(1:20) as an eluent to yield the desired product (2b). IR (KBr)
m cmꢁ1 1725 (C¼¼N stretching) H1 NMR (CDCl3, 400 MHz) d
ppm 1.17 (t, 3H, J ¼ 14.2 Hz), 3.3–3.31 (q, 2H, J ¼ 8.6 Hz),
3.82 (t, 2H, J ¼ 14.3 Hz), 4.27 (t, 2H, J ¼ 8.9 Hz), 5.72 (s,
2H), 6.46–6.65 (m, 4H), 7.04 (s, 1H). C13 NMR (CDCl3, 100
MHz) d ppm 15.6, 22.8, 57.6, 60.2 (NCH2), 73.1 (OCH2),
112.8, 116.8, 117.3, 119.5, 130.2, 133.4, 140.1, 141.3, 166.1,
m/z ¼ 261.26. Calc. for C14H16N2OS C, 64.58; H, 6.19; N,
10.76%; observed were C, 64.60; H, 6.18; N, 10.75%.
(2e). IR (KBr) m cmꢁ1 1718 (C¼¼N stretching) H1 NMR
(CDCl3, 400 MHz) d ppm 1.15 (t, 3H, J ¼ 14 Hz), 3.29–3.33
(q, 2H, J ¼ 8.7 Hz), 3.80 (t, 2H, J ¼ 14.2 Hz), 4.26 (t, 2H, J
¼ 14 Hz), 5.69 (s, 2H), 6.51–6.60 (m, 4H), 7.15 (s, 1H). C13
NMR (CDCl3, 100 MHz) d ppm 15.7, 22.9, 57.4, 60.2
(NCH2), 73.4 (OCH2), 113.1, 114.3, 118.9, 120.5, 130.9,
133.9, 140.6, 141.9, 166.3, m/z
C14H16N2OS C, 64.58; H, 6.19; N, 10.76%; observed were C,
64.60; H, 6.18; N, 10.74%.
¼
261.10. Calc. for
(2f). IR (KBr) m cmꢁ1 1719 (C¼¼N stretching) H1 NMR
(CDCl3, 100 MHz) d ppm 1.15 (t, 3H, J ¼ 14.1 Hz), 2.30 (s,
3H), 3.34–3.39 (q, 2H, J ¼ 8.9 Hz), 3.84 (t, 2H, J ¼ 14.2 Hz),
4.29 (t, 2H, J ¼ 14.0 Hz), 5.70 (s, 2H), 6.41–6.47 (m, 3H),
7.16 (s, 1H). C13 NMR (CDCl3, 400 MHz) d ppm 15.5, 16.9,
22.5, 57.5, 60.2 (NCH2), 73.6 (OCH2), 112.8, 119.9, 120.7,
127.1, 130.4, 130.9, 133.5, 141.4, 165.8, m/z ¼ 275.12. Calc.
for C15H18N2OS C, 65.66; H, 6.61; N, 10.21%; observed were
C, 65.64; H, 6.62; N, 10.20%.
(2g). IR (KBr) m cmꢁ1 1720 (C¼¼N stretching) H1 NMR
(CDCl3, 400 MHz) d ppm 3.84 (t, 2H, J ¼ 14.0 Hz), 4.20 (t,
2H, J ¼ 9.0 Hz), 4.76 (s, 2H), 6.46–6.65 (m, 4H, ArH), 7.23–
7.32 (m, 5H, ArH), 8.21 (s, 1H). C13 NMR (CDCl3, 100 MHz)
d ppm 14.5, 21.7, 58.4, 60.2 (NCH2), 74.1 (OCH2), 113.5,
(2a). IR (KBr) m cmꢁ1 1720 (C¼¼N stretching) H1 NMR
(CDCl3, 400 MHz) d ppm 2.37 (s, 3H), 3.81 (t, 2H, J ¼ 14.3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

42
P. Mizar and B. Myrboh
Vol 46
115.9, 121.5, 127.1, 127.8, 133.7, 140.1, 143.3, 165.0, m/z ¼
247. Calc. for C14H16N2OS C, 64.58; H, 6.19; N, 10.76%;
observed were C, 64.61; H, 6.21; N, 10.75%.
C19H20N4O C, 71.23; H, 6.29; N, 17.49%; observed were C,
71.25; H, 6.31; N, 17.51%.
(3c). IR (KBr) m cmꢁ1 3412 (NH stretching) H1 NMR
(DMSO-d6, 400 MHz), d ppm 2.42 (s, 3H), 3.81 (t, 2H, J ¼
9.8 Hz), 4.20 (t, 2H, J ¼ 9.0 Hz), 5.22 (s, 2H), 6.31 (s, 1H),
6.40–6.44 (m, 3H) 7.31–7.45 (m, 5H, ArH), 7.02 (b, 2H). C13
NMR (CDCl3, 100 MHz) d ppm 13.2, 50.4, 59.6 (NCH2), 73.9
(OCH2), 94.9, 112.8, 118.0, 118.6, 121.8, 126.2, 129.2, 131.1,
136.1, 136.9, 139.9, 143.1, 163.8. m/z ¼ 319. Calc. for
C19H20N4O C, 71.23; H, 6.29; N, 17.49%; observed were C,
71.24; H, 6.30; N, 17.48%.
(2i). IR (KBr) m cmꢁ1 31722 (C¼¼N stretching) H1 NMR
(CDCl3, 400 MHz) d ppm 2.34 (s, 3H), 3.80 (t, 2H, J ¼ 14
Hz), 4.32 (t, 2H, J ¼ 14.1 Hz), 5.76 (s, 2H), 6.33 (s, 1H), 6.39
(d, 1H, J ¼ 7.8 Hz), 6.47 (d, 1H, J ¼ 7.8 Hz), 7.39–7.45 (m,
5H), 7.89 (s, 1H). C13 NMR (CDCl3, 100 MHz) d ppm 23.5,
57.9, 60.7 (NCH2), 73.9 (OCH2), 112.8, 114.9, 118.7, 126.1,
128.2, 129.1, 130.3, 135.7, 133.5, 141.4, 142.8, 147.3, 166.8,
m/z ¼ 322.11. Calc. for C19H18N2OS C, 70.78; H, 5.63; N,
8.69%; observed were C, 70.77; H, 5.61; N, 8.68%.
(3d). IR (KBr) m cmꢁ1 3421 (NH stretching) H1 NMR
(DMSO-d6, 400 MHz), d ppm 2.47 (s, 3H), 3.85 (t, 2H, J ¼
9.5 Hz), 4.23 (t, 2H, J ¼ 9.1 Hz), 5.27 (s, 2H), 6.39 (s, 1H),
6.41 (s, 1H), 6.47 (d, 1H, J ¼ 7.2 Hz), 6.52 (d, 1H, J ¼ 7.2
Hz), 7.31–7.45 (m, 5H, ArH), 7.06 (b, 2H). C13 NMR (CDCl3,
100 MHz) d ppm 23.2, 32.3, 59.3 (NCH2), 74.1 (OCH2), 92.9,
113.8, 114.5, 115.1, 118.6, 126.2, 129.2, 130.1, 136.1, 137.9,
139.9, 143.1, 160.8. m/z ¼ 320.16 Calc. for C19H20N4O C,
71.23; H, 6.29; N, 17.49%; observed were C, 71.22; H, 6.30;
N, 17.47%.
(2j). IR (KBr) m cmꢁ1 1715 (C¼¼N stretching) H1 NMR
(CDCl3, 400 MHz) d ppm 2.31 (s, 3H), 3.82 (t, 2H, J ¼ 14
Hz), 4.31 (t, 2H, J ¼ 14.1 Hz), 5.79 (s, 2H), 6.43–6.49 (m,
3H), 7.36–7.42 (m, 5H), 7.91(s, 1H). C13 NMR (CDCl3, 100
MHz) d ppm 15.5, 57.9, 60.7 (NCH2), 73.9 (OCH2), 112.8,
119.9, 120.7, 126.1, 127.1, 128.2, 129.1, 130.9, 135.4, 133.5,
141.4, 147.3, 166.8, m/z ¼ 322.12. Calc. for C19H18N2OS C,
70.78; H, 5.63; N, 8.69%; observed were C, 70.76; H, 5.62; N,
8.70%.
(3e). IR (KBr) m cmꢁ1 3420 (NH stretching) H1 NMR
(DMSO-d6, 400 MHz), d ppm 2.45 (s, 3H), 3.82 (t, 2H, J ¼
9.5 Hz), 4.21 (t, 2H, J ¼ 9.1 Hz), 5.25 (s, 2H), 6.38 (s, 1H),
6.40 (s, 1H), 6.44 (d, 1H, J ¼ 7.1 Hz), 6.50 (d, 1H, J ¼ 7.1
Hz), 7.33–7.45 (m, 5H, ArH), 7.03 (b, 2H). C13 NMR (CDCl3,
100 MHz) d ppm 32.9, 59.4 (NCH2), 74.2 (OCH2), 92.9,
103.7, 105.8, 116.1, 118.6, 126.2, 129.2, 136.1, 137.9, 138.9,
146.1, 154.1, 160.8. m/z ¼ 324.16 Calc. for C18H17FN4O C,
66.65; H, 5.28; N, 17.27%; observed were C, 66.63; H, 5.30;
N, 17.26%.
(3f). IR (KBr) m cmꢁ1 3427 (NH stretching) H1 NMR
(DMSO-d6, 400 MHz), d ppm 3.86 (t, 2H, J ¼ 9.1 Hz), 4.24 (t,
2H, J ¼ 9.2 Hz), 5.28 (s, 2H), 6.41 (s, 1H), 6.74 (s, 1H), 6.79
(d, 1H, J ¼ 7.0 Hz), 6.85 (d, 1H, J ¼ 7.0 Hz), 7.36–7.45 (m,
5H, ArH), 7.23 (b, 2H). C13 NMR (CDCl3, 100 MHz) d ppm
33.1, 59.5 (NCH2), 74.4 (OCH2), 93.2, 110.5, 115.1, 116.0,
120.8, 124.1, 125.9, 129.2, 136.1, 137.9, 138.9, 144.1, 146.1,
160.8. m/z ¼ 374.26 Calc. for C19H17F3N4O C, 60.96; H, 4.58;
N, 14.97%; observed were C, 60.97; H, 4.60; N, 14.96%.
(3g). IR (KBr) m cmꢁ1 3439 (NH stretching) H1 NMR
(DMSO-d6, 400 MHz), d ppm 2.31 (s, 3H), 3.85 (t, 2H, J ¼
9.0 Hz), 4.21 (t, 2H, J ¼ 9.1 Hz), 5.30 (s, 2H), 6.39 (s, 1H),
6.54 (s, 1H), 6.69 (d, 1H, J ¼ 7.2 Hz), 6.75 (d, 1H, J ¼ 7.2
Hz), 7.45 (d, 2H, J ¼ 7.1 Hz), 7.48 (d, 2H, J ¼ 7.1 Hz), 7.18
(b, 2H). C13 NMR (CDCl3, 100 MHz) d ppm 24.1, 33.5, 59.8
(NCH2), 74.1 (OCH2), 93.7, 115.1, 116.0, 119.2, 120.8, 125.9,
129.2, 136.1, 137.2, 139.9, 144.1, 145.2, 160.8. m/z ¼ 354.16
Calc. for C19H19ClN4O C, 64.31; H, 5.40; N, 15.79%;
observed were C, 64.30; H, 5.41; N, 15.80%.
Synthesis of 5-(2,3-dihydro-1,4-benzoxazin-4-ylmethyl)-4-
methyl-1-phenyl-1H-pyrazol-3-ylamine. It involves the syn-
thesis of butyronitrile derivative from the methyl ester(1) using
acetonitrile (1.5 eq) and NaH (1.5 eq) in THF under N2 atmos-
phere. The NaH was dissolved in THF, and acetonitrile was
added drop wise at 0ꢀC. The reaction mixture was allowed to
1
stir at room temperature for = h and followed by drop wise
2
addition of (1) solution in THF at 0ꢀC. The reaction was then
stirred at room temperature for 3 h. On completion of the reac-
tion, the solvent was evaporated and work-up using ethyl ace-
tate, the complete organic extracts were dried over Na2SO4 and
evaporated to yield the crude product, which was purified by
column chromatography using ethyl acetate and hexane (1:20).
IR (KBr) m cmꢁ1 2242 (CN stretching) H1 NMR (CDCl3, 400
MHz) d ppm 3.61 (s, 2H), 3.82–3.86 (m, 2H), 4.24–4.26 (m,
2H), 4.56(s, 2H), 6.5–6.84 (m, 4H). Calc. for C12H12N2O2 C,
66.65; H, 5.59; N, 12.96%; observed were C, 66.64; H, 5.60;
N, 12.94%. The butyronitrile derivative was then refluxed with
substituted phenyl hydrazine (1.2 eq) for 4–5 h. The reaction
on completion was evaporated under vacuum and worked-up
using DCM. The complete organic was dried over Na2SO4 and
evaporated to yield the crude product, which was purified by
column chromatography using methanol and DCM (1:50) as an
eluent.
(3a). IR (KBr) m cmꢁ1 3420 (NH2 stretching) H1 NMR
(DMSO-d6, 400 MHz), d ppm 3.84–3.86 (t, 2H, J ¼ 14 Hz),
4.25–4.27 (t, 2H, J ¼ 8.9 Hz), 5.56 (s, 2H), 6.4–6.84 (m, 4H)
7.3–7.5 (m, 5H) 7.9 (s, 1H) 8.2 (b, 2H). C13 NMR (CDCl3,
100 MHz) d ppm 50.1, 60.2 (NCH2), 73.1 (OCH2), 94.8,
112.8, 116.8, 117.3, 118.8, 119.5, 126.5, 129.1, 130.2, 135.6,
139.8, 141.1, 164.3. m/z ¼ 307. Calc. for C18H18N4O C,
70.57; H, 5.92; N, 18.29%; observed were C, 70.59; H, 5.91;
N, 18.3%.
(3b). IR (KBr) m cmꢁ1 3412 (NH2 stretching) H1 NMR
(DMSO-d6, 400 MHz), d ppm 2.36 (s, 3H), 3.86 (t, 2H, J ¼
14 Hz), 4.27 (t, 2H, J ¼ 8.9 Hz), 5.42 (s, 2H), 6.35 (s, 1H),
6.48–6.64 (m, 4H) 7.35–7.51 (m, 4H, ArH), 8.12 (b, 2H). C13
NMR (CDCl3, 100 MHz) d ppm 21.2, 50.2, 59.2 (NCH2), 74.1
(OCH2), 94.8, 113.8, 115.8, 117.9, 118.3, 121.5, 129.5, 130.8,
135.2, 136.1, 136.9, 143.1, 164.1. m/z ¼ 321. Calc. for
(3h). IR (KBr) m cmꢁ1 3424 (NH stretching) H1 NMR
(DMSO-d6, 400 MHz), d ppm 2.31 (s, 3H), 2.35 (s, 3H), 3.80
(t, 2H, J ¼ 9.0 Hz), 4.23 (t, 2H, J ¼ 9.0 Hz), 5.31 (s, 2H),
6.35 (s, 1H), 6.44 (s, 1H), 6.51 (d, 1H, J ¼ 7.1 Hz), 6.59
(d, 1H, J ¼ 7.1 Hz), 7.42 (d, 2H, J ¼ 7.0 Hz), 7.49 (d, 2H, J
¼ 7.0 Hz), 7.21 (b, 2H). C13 NMR (CDCl3, 100 MHz) d ppm
24.1, 33.5, 59.8 (NCH2), 74.1 (OCH2), 93.7, 114.5,
115.5, 119.7, 120.8, 129.2, 130.3, 136.1, 137.2, 139.1, 144.1,
145.1, 160.8. m/z ¼ 335.16 Calc. for C20H22N4O C, 71.83;
H, 6.63; N, 16.75%; observed were C, 71.82; H, 6.62; N,
16.77%.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2009 Synthesis of substituted 4-(5-alkyl-thiazol-2-ylmethyl)-3,4-dihydro-2H-1,4-benzoxazines
and 5-(2,3-Dihydro-1,4-benzoxazin-4-ylmethyl)-4-methyl-1-phenyl-1H-pyrazol-3-ylamine
43
(3i). IR (KBr) m cmꢁ1 3429 (NH stretching) H1 NMR
(DMSO-d6, 400 MHz), d ppm 2.32 (s, 3H), 3.82 (t, 2H, J ¼
9.0 Hz), 4.24 (t, 2H, J ¼ 9.0 Hz), 5.32 (s, 2H), 6.41 (s, 1H),
6.56 (s, 1H), 6.70 (d, 1H, J ¼ 7.0 Hz), 6.75 (d, 1H, J ¼ 7.0
Hz), 7.45 (d, 2H, J ¼ 7.1 Hz), 7.48 (d, 2H, J ¼ 7.1 Hz), 7.23
(b, 2H). C13 NMR (CDCl3, 100 MHz) d ppm 24.3, 33.7, 59.9
(NCH2), 74.5 (OCH2), 93.4, 115.1, 116.0, 119.2, 120.8, 125.9,
129.2, 136.1, 137.2, 139.9, 145.1, 144.1, 160.8. m/z ¼ 339.16
Calc. for C19H19FN4O C, 67.44; H, 5.66; F, 5.61; N, 16.56%;
observed were C, 67.43; H, 5.60; N, 16.58%.
(3j). IR (KBr) m cmꢁ1 3422 (NH stretching) H1 NMR
(DMSO-d6, 400 MHz), d ppm 2.45 (s, 3H), 3.85 (t, 2H, J ¼
9.0 Hz), 4.28 (t, 2H, J ¼ 9.1 Hz), 5.32 (s, 2H), 6.37 (s, 1H),
6.41 (s, 1H), 6.47 (d, 1H, J ¼ 7.1 Hz), 6.52 (d, 1H, J ¼ 7.1
Hz), 7.36–7.45 (m, 5H, ArH), 7.16 (b, 2H). C13 NMR (CDCl3,
100 MHz) d ppm 23.6, 32.6, 59.5 (NCH2), 74.3 (OCH2), 92.5,
113.9, 114.5, 115.1, 118.6, 126.2, 129.2, 130.1, 136.1, 137.9,
139.9, 143.1, 160.8. m/z ¼ 321.21 Calc. for C19H20N4O C,
71.23; H, 6.29%; N, 17.49; observed were C, 71.22; H, 6.30;
N, 17.47%.
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Acknowledgments. PM thanks CSIR for the award of Junior
Research Fellowship; SAIF, NEHU Shillong, IISc Bangalore,
and CIF-IIT Guwahati for help in spectral analysis.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet