Transition metal-free, base-promoted hydroalkoxylation: Synthesis of substituted imidazo[2,1-c][1,4]oxazines

Article abstract of DOI:10.1007/s12039-016-1045-9

An efficient, transition metal-free method to synthesize substituted imidazo[2,1-c][1,4]oxazine derivatives via hydroalkoxylation of 1,5-alkynyl alcohol has been described. The reaction proceeds regioselectively with exclusive formation of 6-exo-dig produ

Full text of DOI:10.1007/s12039-016-1045-9

J. Chem. Sci. Vol. 128, No. 3, March 2016, pp. 451–458. ꢀc Indian Academy of Sciences.
DOI 10.1007/s12039-016-1045-9
Transition metal-free, base-promoted hydroalkoxylation: Synthesis of
substituted imidazo[2,1-c][1,4]oxazines
∗
MUTHUPANDI NAGARAJ and SHANMUGAM MUTHUSUBRAMANIAN
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
e-mail: muthumanian2001@yahoo.com
MS received 11 November 2015; revised 12 January 2016; accepted 18 January 2016
Abstract. An efficient, transition metal-free method to synthesize substituted imidazo[2,1-c][1,4]oxazine
derivatives via hydroalkoxylation of 1,5-alkynyl alcohol has been described. The reaction proceeds regioselec-
tively with exclusive formation of 6-exo-dig product.
Keywords. 1,4-Oxazines; hydroalkoxylation; 6-exo-dig; regioselectivity; 1,5-alkynyl alcohol.
1
. Introduction
Nevertheless, endo mode of cyclization is also noticed
with alkynyl alcohols using metal catalysts.
12
Novel fused heterocyclic ring systems are often con-
sidered as important scaffolds in medicinal chemistry.
Synthetic and naturally occurring fused bicyclic imida-
zoles have been found to display a wide range of biolog-
2
. Experimental
1
2.1 General
ical activities, thus assuming clinical importance as
2
drugs. Obviously, efficient and combinatorial method-
1
13
Nuclear Magnetic Resonance ( H and C NMR) spec-
tra were recorded on a Bruker 300 MHz spectrometer in
CDCl using TMS as internal standard. Chemical shifts
ologies towards the convenient synthesis of fused imi-
dazole frameworks are being explored by both organic
3
and medicinal chemists. Recently, nitroimidazooxazine
are reported in parts per million (δ), coupling constants
3
(
PA-824) (figure 1) has been shown to exhibit good
(J values) are reported in Hertz (Hz). The hydroxyl
in vitro and in vivo activities against Mycobacterium
13
hydrogen signal is not visible in most of the cases. C
NMR spectra were routinely run with broadband decou-
pling. Melting points were determined on a melting
point apparatus (Inlab Pvt. Ltd., India) equipped with
a thermometer and were uncorrected. Column chro-
matography was carried out in silica gel (60–120 mesh)
using pet ether-ethyl acetate as eluent. Elemental anal-
yses were performed on a Perkin Elmer 2400 series II
Elemental CHNS analyzer.
4
tuberculosis in both active and persistent forms.
GSK588045 also exhibits outstanding profile with in
vivo activity in different animal models of anxiety and
5
depression and is being processed as a clinical candidate.
Hydroalkoxylation of alkynes is an efficient approach
to construct C–O bonds towards the synthetic interme-
6
diates of natural products. The catalytic addition of
alcohols to alkynes can be performed achieving 100%
7
atom efficiency with negligible waste formation paving
way for many useful oxygen containing organic com-
pounds. The importance of intermolecular hydroalko-
xylation in the synthesis of ethers has been widely
recognized and exploited.8
2
.2 General procedure for the preparation of aryl(4-
aryl-1-(3-arylprop-2-ynyl)-1H-imidazol-2-yl)methanol
1)
(
Metals or Lewis acids or bases have been employed
as catalysts to effect exocylic as well as endocyclic Terminal 1,5-alkyne-alcohol imidazole derivatives were
9
13a
ring formation from different starting materials. Nor- synthesized following a literature procedure. Aryl
10
mally metals catalyze the exo mode cyclization,
though bases such as sodium amide and sodium hydride nitrogen atmosphere was added with PdCl (PPh )
3 2
halide (1 equiv.) in dry acetonitrile (10 mL) under
2
have also been employed11 for this transformation. (3 mol%), CuI (6 mol%), Et N (5 equiv.) and terminal-
3
1
,5 alkyne-alcohol imidazole derivative (1.0 equiv.).
The resulting mixture was refluxed for 30 min. The
solvent was evaporated under reduced pressure and
∗
For correspondence
451

452
Muthupandi Nagaraj and Shanmugam Muthusubramanian
N
125.2, 125.3, 125.9, 126.9, 127.5, 128.4, 128.6, 128.7,
130.8, 133.3, 134.7, 139.4, 139.9, 149.0; Anal. Calcd.
%) for C H F N O: C, 72.21; H, 4.43; N, 6.48.
NH2
N
O
O
(
26
19
3
2
Found (%): C, 72.08; H, 4.36; N, 6.39.
OCF3
N
N
2.2d (1-(3-Phenylprop-2-ynyl)-4-p-tolyl-1H-imidazol-
O
2
-yl)(p-tolyl)methanol (1m): Colorless solid; M.p.
N
◦
1
1
57–159 C; H NMR (300 MHz, CDCl ) δ = 2.28
3
O N
2
O
N
(s, 3H), 2.35 (s, 3H), 4.45 (d, J = 18.0 Hz, 1H), 4.53
(
2
d, J = 18.0 Hz, 1H), 6.06 (s, 1H), 7.12 (d, J = 8.1 Hz,
N
H), 7.18 (d, J = 8.1 Hz, 2H), 7.22 (s, 1H), 7.29–7.33
PA-824
13
GSK588045
(
m, 7H), 7.64 (d, J = 8.1 Hz, 2H); C NMR (75 MHz,
CDCl ) δ = 21.1, 21.2, 36.5, 69.3, 81.8, 83.8, 115.9,
3
Figure 1. Biologically active compounds containing imi-
1
21.9, 124.7, 126.4, 128.2, 128.7, 129.3, 130.8,* 131.7,
36.4, 137.1, 137.5, 139.5, 148.6; Anal. Calcd. (%) for
dazooxazine scaffold.
1
C H N O: C, 82.62; H, 6.16; N, 7.14. Found (%):
C, 82.51; H, 6.07; N, 7.05. *Two carbon signals are
merged together.
27
24
2
the crude material was then purified by flash chro-
matography to yield non-terminal alkyne (Ethyl acetate/
petroleum ether 1:4). Terminal 1,5-alkyne-alcohol imi-
13a
dazole derivatives (1a–i) have already been reported.
2.2e (1-(3-(4-Chlorophenyl)prop-2-ynyl)-4-p-tolyl-1H-
imidazol-2-yl)(p-tolyl)methanol (1n): Colorless solid;
2
.2a Phenyl(4-phenyl-1-(3-phenylprop-2-ynyl)-1H-
◦
1
M.p. 139–141 C; H NMR (300 MHz, CDCl ) δ
3
imidazol-2-yl)methanol (1j): Colorless solid; M.p.
=
2.26 (s, 3H), 2.33 (s, 3H), 4.37 (d, J = 18.0 Hz,
◦
1
1
48–150 C; H NMR (300 MHz, CDCl ) = 4.42
3
1
H), 4.54 (d, J = 18.0 Hz, 1H), 6.11 (s, 1H), 7.08–7.14
(
(
(
d, J = 17.7 Hz, 1H), 4.51 (d, J = 17.7 Hz, 1H), 6.15
(
7
m, 3H), 7.16–7.18 (m, 4H), 7.23 (d, J = 8.4 Hz, 2H),
s, 1H), 7.22–7.23 (m, 8H), 7.32–7.44 (m, 6H), 7.73
13
.28 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 7.8 Hz, 2H); C
13
dd, J = 7.5 Hz, 1.2 Hz, 2H); C NMR (75 MHz,
NMR (75 MHz, CDCl ) δ = 21.0, 21.2, 36.3, 68.9,
3
CDCl ) δ = 36.6, 69.4, 81.8, 85.7, 116.4, 121.9,
3
8
1
1
5
3.1, 84.1, 115.8, 120.4, 124.7, 126.0, 128.5, 129.1,
29.2, 130.1, 132.9, 134.7, 136.4, 137.0, 138.7, 139.4,
48.8; Anal. Calcd. (%) for C H ClN O: C, 75.96; H,
1
24.9, 126.4, 126.9, 127.8, 128.3, 128.6, 128.6, 128.8,
31.7, 133.7, 139.6, 140.1, 148.7; Anal. Calcd. (%) for
1
27
23
2
C H N O: C, 82.39; H, 5.53; N, 7.69. Found (%): C,
8
25
20
2
.43; N, 6.56. Found (%): C, 75.82; H, 5.36; N, 6.48.
2.26; H, 5.42; N, 7.59.
2
.2f p-Tolyl(4-p-tolyl-1-(3-(3-(trifluoromethyl)phenyl)
2
.2b (1-(3-(4-Chlorophenyl)prop-2-ynyl)-4-phenyl-1H-
prop-2-ynyl)-1H-imidazol-2-yl)methanol (1o): Col-
orless solid; M.p. 126–128 C; H NMR (300 MHz,
imidazol-2-yl)(phenyl)methanol(1k): Colorless solid;
M.p. 152–154 C; H NMR (300 MHz, CDCl ) δ
◦
1
◦
1
3
CDCl ) δ = 2.24 (s, 3H), 2.34 (s, 3H), 4.37 (d, J =
3
=
4.37 (d, J = 18.0 Hz, 1H), 4.52 (d, J = 18.0 Hz, 1H),
1
7
8.0 Hz, 1H), 4.60 (d, J = 18.0 Hz, 1H), 6.13 (s, 1H),
.09–7.12 (m, 2H), 7.18 (d, J = 7.8 Hz, 2H), 7.30
6
2
2
8
1
.16 (s, 1H), 7.15–7.27 (m, 7H), 7.30 (d, J = 8.1 Hz,
H), 7.34–7.43 (m, 4H), 7.72 (dd, J = 7.8 Hz, 1.2 Hz,
(
7
(
1
1
1
7
d, J = 7.8 Hz, 2H), 7.38–7.40 (m, 2H), 7.49 (s, 1H),
13
H); C NMR (75 MHz, CDCl ) δ = 36.4, 69.1, 82.8,
13
3
.52–7.54 (m, 2H), 7.61 (d, J = 8.1 Hz, 2H); C NMR
4.2, 116.3, 120.3, 124.8, 126.1, 126.9, 127.6, 128.4,
28.5, 128.6, 132.9, 133.4, 134.8, 139.4, 139.9, 148.8;
75 MHz, CDCl ) δ = 20.7, 20.9, 36.0, 69.0, 77.2, 83.5,
3
15.6, 122.8, 124.6, 125.0, 126.0, 128.3, 128.5, 128.9,
29.0, 130.6, 131.0, 134.6, 136.3, 136.9, 137.2, 139.6,
39.9, 148.6; Anal. Calcd. (%) for C H F N O: C,
Anal. Calcd. (%) for C H ClN O: C, 75.28; H, 4.80;
N, 7.02. Found (%): C, 75.09; H, 4.72; N, 6.91.
25
19
2
28
23
3
2
3.03; H, 5.03; N, 6.08. Found (%): C, 72.94; H, 4.98;
2.2c Phenyl(4-phenyl-1-(3-(3-(trifluoromethyl)phenyl) N, 5.99.
prop-2-ynyl)-1H-imidazol-2-yl) methanol (1l): Col-
◦
1
orless solid; M.p. 124–126 C; H NMR (300 MHz,
2
.3 General procedure for the preparation of substitu-
CDCl ) δ = 4.31 (d, J = 18.0 Hz, 1H), 4.60 (d, J =
3
ted imidazo[2,1-c][1,4]oxazine (2)
1
6
7
8.0 Hz, 1H), 6.22 (s, 1H), 7.12 (s, 1H), 7.22 (d, J =
.9 Hz, 2H), 7.29–7.37 (m, 5H), 7.43–7.53 (m, 5H), Aryl(4-aryl-1-(prop-2-ynyl)-1H-imidazol-2-yl)methanol
13
.71 (d, J = 8.4 Hz, 2H); C NMR (75 MHz, CDCl ) 1 (1 mmol) was dissolved in DMF (5.0 mL) taken in
3
δ = 36.2, 68.9, 82.8, 83.6, 116.2, 121.8, 122.8, 124.8, a 10 mL microwave vial. To this, LiOtBu (7.4 mmol)

Synthesis of substituted imidazo[2,1-c][1,4]oxazines
453
was added and the reaction mixture was subjected to 2.3e 6-Methyl-2,8-dip-tolyl-8H-imidazo[2,1-c][1,4]oxazine
◦
1
microwave irradiation (CEM-DISCOVER model no. (2e): Colorless solid; M.p. 118–120 C; H NMR
◦
9
08010) at 80 C for 10 min in 120 W microwave power. (300 MHz, CDCl ) δ = 1.88 (s, 3H), 2.33 (s, 3H),
3
Completion of the reaction was confirmed by TLC. 2.34 (s, 3H), 6.22 (s, 1H), 6.34 (s, 1H), 7.11 (s, 1H),
The reaction mixture was then poured into ice-cold 7.15–7.17 (m, 4H), 7.24 (d, J = 7.8 Hz, 2H), 7.68
1
3
water and extracted with dichloromethane. The solvent (d, J = 8.1 Hz, 2H); C NMR (75 MHz, CDCl )
3
was evaporated under reduced pressure and the crude δ = 17.1, 20.9,* 75.3, 101.6, 109.8, 124.6, 126.9,
material was then purified by flash chromatography to 128.9, 129.0, 131.0, 134.5, 136.2, 138.2, 138.8, 141.7,
yield 2.
142.0; Anal. Calcd. (%) for C H N O: C, 79.72; H,
21 20 2
6
*
.37; N, 8.85. Found (%): C, 79.61; H, 6.29; N, 8.74.
Two carbons are mereged together.
2
.3a 6-Methyl-2,8-diphenyl-[2,1-c][1,4]-8H-imidazoo-
◦
1
xazine (2a): Colorless solid; M.p. 118–120 C; H
2
.3f 2,8-Bis(4-methoxyphenyl)-6-methyl-8H-imidazo
NMR (300 MHz, CDCl ) δ = 1.89 (s, 3H), 6.23
3
[
2,1-c][1,4]oxazine (2f): Colorless solid; M.p. 123–
(
s, 1H), 6.38 (s, 1H), 7.16 (s, 1H), 7.22 (t, J = 7.2 Hz,
◦
1
1
3
125 C; H NMR (300 MHz, CDCl ) δ = 1.88 (s, 3H),
3
1
H), 7.33–7.38 (m, 7H), 7.65 (d, J = 6.9 Hz, 2H); C
3
6
.78 (s, 3H), 3.81 (s, 3H), 6.24 (s, 1H), 6.30 (s, 1H),
.87 (d, J = 6.9 Hz, 2H), 6.89 (d, J = 6.9 Hz, 2H), 7.07
NMR (75 MHz, CDCl ) δ = 17.4, 75.5, 101.9, 110.5,
3
1
1
24.8, 126.8, 127.1, 128.4, 128.5, 128.7, 133.8, 137.5,
38.9, 141.7, 142.3; Anal. Calcd. (%) for C H N O:
(
s, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz,
19
16
2
13
2
7
1
3
5
H); C NMR (75 MHz, CDCl ) δ = 17.4, 55.2, 55.3,
3
C, 79.14; H, 5.59; N, 9.72. Found (%): C, 79.01; H,
5.3, 101.8, 109.4, 113.8, 113.9, 126.1, 126.8, 128.7,
29.7, 138.9, 141.6, 142.2, 158.7, 159.9; MS (M+1)
49.22; Anal. Calcd. (%) for C H N O : C, 72.40; H,
5.52; N, 9.64.
21
20
2
3
2
.3b 2,8-Bis(4-chlorophenyl)-6-methyl-8H-imidazo[2,1-c]
.79; N, 8.04. Found (%): C, 72.31; H, 5.72; N, 7.96.
◦
[
1,4]oxazine (2b): Colorless solid; M.p. 113–115 C;
1
H NMR (300 MHz, CDCl ) δ = 1.89 (s, 3H), 6.24
3
2
1
1
6
.3g 6-Methyl-2,8-di(naphthalen-2-yl)-8H-imidazo[2,
(
s, 1H), 6.30 (s, 1H), 7.13 (s, 1H), 7.25–7.32 (m, 6H),
-c][1,4]oxazine (2g): Colorless solid; M.p. 181–
13
7
.65 (d, J = 6.9 Hz, 2H); C NMR (75 MHz, CDCl ) δ
3
◦
1
83 C; H NMR (300 MHz, CDCl ) δ = 1.85 (s, 3H),
3
=
17.3, 74.8, 101.8, 110.7, 126.1, 128.5, 128.6, 128.7,
.17 (s, 1H), 6.54 (s, 1H), 7.22 (s, 1H), 7.41–7.79
1
32.2, 132.4, 134.7, 135.8, 138.6, 140.8, 147.6; Anal.
13
(
m, 13H), 8.28 (s, 1H); C NMR (75 MHz, CDCl3)
Calcd. (%) for C H Cl N O: C, 63.88; H, 3.95; N,
19
14
2
2
δ = 17.3, 75.7, 101.9, 111.1, 122.9, 123.5, 124.5,
7.84. Found (%): C, 63.72; H, 3.82; N, 7.77.
124.7, 125.4, 126.1, 126.2, 126.4, 127.6, 128.0, 128.1,
128.3, 128.5, 131.1,* 132.6,* 133.4, 133.7, 134.8,
139.1, 141.7, 142.5; Anal. Calcd. (%) for C H N O:
2
.3c 2,8-Bis(4-bromophenyl)-6-methyl-8H-imidazo[2,1-c]
27
20
2
◦
[
1,4]oxazine (2c): Colorless solid; M.p. 141–143 C;
C, 83.48; H, 5.19; N, 7.21. Found (%): C, 83.32; H,
5.11; N, 7.13. *Two carbons are merged together.
1
H NMR (300 MHz, CDCl ) δ = 1.90 (s, 3H), 6.24
3
(
s, 1H), 6.29 (s, 1H), 7.15 (s, 1H), 7.24 (d, J = 8.1 Hz,
13
2
H), 7.44–7.50 (m, 4H), 7.59 (d, J = 8.4 Hz, 2H); C
2.3h 2,8-Di(biphenyl-4-yl)-6-methyl-8H-imidazo[2,1-c]
NMR (75 MHz, CDCl ) δ = 17.3, 74.9, 101.8, 110.8,
◦
3
[
1,4]oxazine (2h): Colorless solid; M.p. 203–205 C;
120.5, 122.9, 126.4, 128.8, 131.6, 131.7, 132.7, 136.3,
1
H NMR (300 MHz, CDCl ) δ = 1.92 (s, 3H), 6.26
3
1
38.6, 140.9, 142.6; MS (M+1) 447.16; Anal. Calcd.
(
s, 1H), 6.43 (s, 1H), 7.20 (s, 1H), 7.32–7.35 (m, 3H),
(
%) for C H Br N O: C, 51.15; H, 3.16; N, 6.28.
19 14 2 2
7
7
.40 (d, J = 7.2 Hz, 2H), 7.45 (d, J = 7.8 Hz, 2H),
Found (%): C, 51.02; H, 3.08; N, 6.22.
13
.56–7.61 (m, 9H), 7.83 (d, J = 7.8 Hz, 2H); C NMR
(
75 MHz, CDCl ) δ = 17.4, 75.4, 101.9, 110.7, 125.3,
3
2
1
8
6
.3d 2,8-Bis(4-flourophenyl)-6-methyl-8H-imidazo[2, 126.8, 127.1, 127.2, 127.3, 127.5, 127.6, 128.7, 128.8,*
-c][1,4]oxazine (2d): Colorless solid; M.p. 84– 132.9, 136.5, 139.0, 139.5, 140.6, 140.9, 141.5, 141.6,
◦
1
6 C; H NMR (300 MHz, CDCl ) δ = 1.88 (s, 3H), 142.5; Anal. Calcd. (%) for C31
H N O: C, 84.52; H,
24 2
3
.24 (s, 1H), 6.30 (s, 1H), 7.01–7.10 (m, 5H), 7.35 5.49; N, 6.36. Found (%): C, 84.41; H, 5.39; N, 6.28.
1
3
(
(
t, J = 6.6 Hz, 2H), 7.68 (t, J = 6.3 Hz, 2H); C NMR *Two carbons are merged together.
75 MHz, CDCl ) δ = 17.2, 74.9, 101.8, 110.3, 115.3,
3
1
1
7
15.5, 126.4, 129.2, 129.9, 133.2, 138.7, 140.9, 142.5, 2.3i 6-Methyl-2,8-di(thiophen-2-yl)-8H-imidazo[2,1-
60.8, 164.1; Anal. Calcd. (%) for C H F N O: C, c][1,4]oxazine(2i):Viscous liquid; H NMR (300 MHz,
1
19
14
2
2
0.36; H, 4.35; N, 8.64. Found (%): C, 70.22; H, 4.23; CDCl ) δ = 1.87 (s, 3H), 6.23 (s, 1H), 6.57 (s, 1H),
3
N, 8.54.
6.91–6.93 (m, 2H), 7.00 (t, J = 5.1 Hz, 1H), 7.06

454
Muthupandi Nagaraj and Shanmugam Muthusubramanian
(
1
s, 1H), 7.17 (d, J = 5.1 Hz, 1H), 7.26 (d, J = 4.2 Hz, 138.9, 141.9, 144.8; Anal. Calcd. (%) for C H N O:
2
7
24
2
13
H), 7.30 (d, J = 4.2 Hz, 1H); C NMR (75 MHz, C, 82.62; H, 6.16; N, 7.14. Found (%): C, 82.51; H,
CDCl ) δ = 17.3, 71.2, 101.8, 110.0, 122.1, 123.3, 6.09; N, 7.08. *Two carbons are merged together.
3
1
1
4
26.6, 126.7, 126.9, 127.4, 136.8, 137.3, 138.2, 140.4,
42.2; Anal. Calcd. (%) for C H N OS : C, 59.97; H,
.03; N, 9.33; S, 21.35. Found (%): C, 59.85; H, 3.98;
15
12
2
2
2
1
1
2
6
7
3
1
1
.3n 6-(4-Chlorobenzyl)-2,8-dip-tolyl-8H-imidazo[2,
-c][1,4]oxazine (2n): Colorless solid; M.p. 126–
N, 9.27; S, 21.22.
◦
1
28 C; H NMR (300 MHz, CDCl ) δ = 2.32 (s, 3H),
3
.34 (s, 3H), 3.37 (s, 2H), 6.20 (s, 1H), 6.30 (s, 1H),
2
.3j 6-Benzyl-2,8-diphenyl-8H-imidazo[2,1-c][1,4]
.99–7.02 (m, 5H), 7.12–7.26 (m, 6H), 7.62 (d, J =
◦
1
oxazine (2j): Colorless solid; M.p. 87–89 C; H NMR
1
3
.8 Hz, 2H); C NMR (75 MHz, CDCl ) δ = 20.9,*
3
(
(
(
300 MHz, CDCl ) δ = 3.47 (s, 2H), 6.16 (s, 1H), 6.40
3
7.0, 75.4, 102.8, 110.0, 124.6, 126.7, 127.1, 128.8,
29.0, 129.4, 130.1, 130.7, 132.4, 134.3, 136.4, 138.4,
38.7,141.8, 143.9; Anal. Calcd. (%) for C H ClN O:
s, 1H), 7.14–7.17 (m, 3H), 7.25–7.39 (m, 11H), 7.76
d, J = 8.4 Hz, 2H); C NMR (75 MHz, CDCl ) δ
13
3
27
23
2
=
37.8, 75.6, 102.8, 110.6, 124.8, 126.8, 127.1, 128.3,
28.4, 128.5,* 128.6, 129.0, 133.7, 135.8, 137.2, 138.8,
C, 75.96; H, 5.43; N, 6.56. Found (%): C, 75.82; H,
.36; N, 6.48. *Two carbons are merged together.
1
1
8
5
41.8, 144.9; Anal. Calcd. (%) for C H N O: C,
25
20
2
2.39; H, 5.53; N, 7.69. Found (%): C, 82.22; H, 5.44;
N, 7.58. *Two carbons are merged together.
2.3o 2,8-Di-p-tolyl-6-(3-(trifluoromethyl)benzyl)-8H-
imidazo[2,1-c][1,4]oxazine (2o): Viscous liquid;
1
2
1
1
6
7
7
.3k 6-(4-Chlorobenzyl)-2,8-diphenyl-8H-imidazo[2,
H NMR (300 MHz, CDCl ) δ = 2.26 (s, 3H), 2.32
3
-c][1,4]oxazine (2k): Colorless solid; M.p. 140– (s, 3H), 3.42 (s, 2H), 6.24 (s, 1H), 6.30 (s, 1H), 6.94–
◦
1
42 C; H NMR (300 MHz, CDCl ) δ = 3.40 (s, 2H), 6.97 (m, 3H), 7.12–7.13 (m, 2H), 7.16 (s, 1H), 7.27
3
.22 (s, 1H), 6.36 (s, 1H), 7.01 (d, J = 8.1 Hz, 2H), (d, J = 7.8 Hz, 2H), 7.35 (s, 1H), 7.44 (d, J = 7.2 Hz,
13
.12–7.19 (m, 5H), 7.22–7.30 (m, 4H), 7.35 (d, J = 2H), 7.62 (d, J = 7.8 Hz, 2H); C NMR (75 MHz,
13
.5 Hz, 2H), 7.73 (d, J = 7.2 Hz, 2H); C NMR CDCl ) δ = 21.0, 21.1, 37.6, 75.6, 103.0, 110.2, 123.6,
3
(
1
75 MHz, CDCl ) δ = 37.2, 75.6, 102.9, 110.6, 124.8, 124.8, 125.6, 127.1, 128.7, 128.9, 129.2,* 130.8,*
3
26.9, 127.2, 128.3, 128.5, 128.7,* 130.3, 132.6, 133.6, 132.3, 133.9, 136.6, 137.1, 138.5, 138.8, 142.0, 143.5;
1
34.4, 136.9, 138.8, 141.9, 144.2; Anal. Calcd. (%) for MS (M+1) 461.37; Anal. Calcd. (%) for C H F N O:
28
23
3
2
C H ClN O: C, 75.28; H, 4.80; N, 7.02. Found (%): C, 73.03; H, 5.03; N, 6.08. Found (%): C, 72.94; H,
25
19
2
C, 75.12; H, 4.72; N, 6.93. *Two carbons are merged 4.98; N, 5.99. **Two carbons are merged together.
together.
2.4 General procedure for the preparation of 4
2.3l 2,8-Diphenyl-6-(3-(trifluoromethyl)benzyl)-8H-
imidazo[2,1-c][1,4]oxazine (2l): Viscous liquid;
Aryl halide (1 equiv.) was added to dry acetoni-
1
H NMR (300 MHz, CDCl ) δ = 3.47 (s, 2H), 6.28
3
trile (10 mL) under nitrogen atmosphere. PdCl (PPh )
2
3 2
(
s, 1H), 6.36 (s, 1H), 7.09 (d, J = 7.8 Hz, 2H), 7.16–
(
3 mol%), CuI (6 mol%), Et N (5 equiv.) and terminal-
3
7
2
.28 (m, 5H), 7.27–7.38 (m, 4H), 7.46 (d, J = 7.2 Hz,
1
,5-alkyne-carbonyl imidazole derivative (1.0 equiv.)
were added to the above solution and refluxed for
0 min. After evaporating the solvent under reduced
13
H), 7.73 (dd, J = 7.5 Hz, 1.5 Hz, 2H); C NMR
(
75 MHz, CDCl ) δ = 37.6, 75.7, 103.0, 110.7, 122.2,
3
3
123.7,* 124.9, 125.7, 126.9, 127.2, 128.3, 128.6, 128.7,
28.9, 132.3, 133.6, 136.8, 136.9, 138.8, 142.0, 143.7;
pressure, the crude material was purified by flash chro-
matography (Ethyl acetate/pet ether, 1:20).
1
Anal. Calcd. (%) for C H F N O: C, 72.21; H, 4.43;
26
19
3
2
N, 6.48. Found (%): C, 72.08; H, 4.38; N, 6.42. *Two
carbons are merged together.
2.4a (4-Chlorophenyl)(4-(4-chlorophenyl)-1-(3-phenyl-
prop-2-ynyl)-1H-imidazol-2-yl)methanone(4a): Color-
◦
1
2
.3m 6-Benzyl-2,8-dip-tolyl-8H-imidazo[2,1-c][1,4] lesssolid;M.p. 136–138 C; HNMR(300MHz, CDCl )
3
◦
1
oxazine (2m): Colorless solid; M.p. 112–114 C; H δ = 5.53 (s, 2H), 7.34–7.36 (m, 5H), 7.45–7.48 (m, 4H),
NMR (300 MHz, CDCl ) δ = 2.31 (s, 3H), 2.33 (s, 3H), 7.75 (d, J = 7.2Hz, 2H), 7.80 (s, 1H), 8.43 (d, J = 7.2 Hz,
3
13
3
4
.44 (s, 2H), 6.14 (s, 1H), 6.33 (s, 1H), 7.05–7.10 (m, 2H); C NMR (75 MHz, CDCl ) δ = 39.6, 81.8, 86.8,
3
H), 7.11–7.16 (m, 4H), 7.24–7.30 (m, 4H), 7.61 (d, J 121.0, 121.7, 126.4, 128.3, 128.4, 128.8, 129.0, 131.5,
13
=
8.1 Hz, 2H); C NMR (75 MHz, CDCl ) δ = 21.1,* 131.8, 132.6, 133.3, 135.2, 139.5, 140.7, 141.8, 182.1;
3
37.9, 75.6, 102.8, 110.1, 124.7, 126.7, 127.1, 128.4, Anal. Calcd. (%) for C H Cl N O: C, 69.62; H, 3.74;
25
16
2
2
129.0, 129.1, 129.2, 130.9, 134.3, 135.9, 136.4, 138.3, N, 6.49. Found (%): C, 69.51; H, 3.68; N, 6.41.

Synthesis of substituted imidazo[2,1-c][1,4]oxazines
455
2
.4b (4-Chlorophenyl)(4-(4-chlorophenyl)-1-(3-(4-chlo- Calcd. (%) for C H NO: C, 72.46; H, 7.43; N, 9.39.
9
11
rophenyl)prop-2-ynyl)-1H-imidazol-2-yl)methanone
Found (%): C, 72.35; H, 7.35; N, 9.28.
◦
1
(
4b): Colorless solid; M.p. 142–144 C; H NMR
(
7
2
300 MHz, CDCl ) δ = 5.55 (s, 2H), 7.32–7.47 (m,
3
2
4
.6 Preparation of 1,3-dimethyl-1H-pyrrolo[2,1-c][1,
]oxazine (6)
H), 7.62 (d, J = 7.2 Hz, 2H), 7.75 (d, J = 7.8 Hz,
13
H), 8.45 (d, J = 7.5 Hz, 2H); C NMR (75 MHz,
CDCl ) δ = 39.8, 81.6, 86.5, 121.1, 121.6, 126.5,
3
1
-(1-(Prop-2-ynyl)-1H-pyrrol-2-yl)ethanol
5
(0.1g,
1
1
28.3, 128.4, 128.9, 129.1, 131.5, 131.8, 132.7, 133.4,
35.2, 139.5, 140.5, 142.1, 182.3; Anal. Calcd. (%) for
0.67 mmol) was taken in a 10 mL microwave vial and dis-
t
solved in DMF (5.0 mL). To this, LiO Bu (0.67 mmol)
was added and the reaction mixture was subjected to
microwave irradiation at 80 C for 5 min in 120 W
C H Cl N O: C, 64.47; H, 3.25; N, 6.01. Found (%):
C, 64.36; H, 3.18; N, 5.92.
25
15
3
2
◦
microwave power. Completion of the reaction was con-
firmed by TLC. The crude material was then purified
2
1
.4c 6-Benzyl-2,8-bis(4-chlorophenyl)-8H-imidazo[2,
-c][1,4]oxazine (2p): Viscous liquid; H NMR
1
by flash chromatography (5% ethyl acetate/pet ether).
(
300 MHz, CDCl ) δ = 4.44 (s, 2H), 5.92 (s, 1H), 6.08
1
3
Viscous liquid; H NMR (300 MHz, CDCl ) δ = 1.63
3
(
s, 1H), 6.90 (s, 1H), 7.01 (d, J = 7.5 Hz, 2H), 7.12–
(
5
6
d, J = 6.3 Hz, 3H), 1.85 (s, 3H), 2.37 (t, J = 2.4 Hz, 1H),
7
2
1
1
.20 (m, 3H), 7.28–7.35 (m, 6H), 7.58 (d, J = 8.4 Hz,
.08 (q, J = 6.3 Hz, 1H), 5.89 (s, 1H), 6.14 (bs, 1H),
13
H); C NMR (75 MHz, CDCl ) δ = 36.6, 68.4, 116.4,
13
3
.21 (bs, 1H), 6.85 (bs, 1H); C NMR (75 MHz, CDCl )
3
16.6, 121.6, 125.4, 126.0, 127.4, 127.7, 128.3, 128.5,
28.6, 128.7, 131.7, 132.4, 133.6, 135.4, 138.3, 148.5;
δ = 18.3, 29.5, 69.9, 101.9, 103.7, 108.0,* 116.2,
1
7
*
40.8; Anal. Calcd. (%) for C H NO: C, 72.46; H,
.43; N, 9.39. Found (%): C, 72.32; H, 7.38; N, 9.26.
Two carbons are merged together.
9 11
Anal. Calcd. (%) for C H Cl N O: C, 69.29; H, 4.19;
N, 6.46. Found (%): C, 69.19; H, 4.11; N, 6.39.
25
18
2
2
2
.4d 6-(4-Chlorobenzyl)-2,8-bis(4-chlorophenyl)-8H-
3
. Results and Discussion
imidazo[2,1-c][1,4]oxazine (2q): Viscous liquid;
1
H NMR (300 MHz, CDCl ) δ = 4.42 (s, 2H), 5.96 We have reported the synthesis of different imidazo
3
(
2
s, 1H), 6.11 (s, 1H), 6.92 (s, 1H), 7.12 (d, J = 7.5 Hz, [1,2-x]heterocycles with a bridgehead nitrogen atom
13
H), 7.14–7.28 (m, 6H), 7.42 (d, J = 7.8 Hz, 2H), 7.62 from propargyl derivatives of imidazole. In continu-
13
(
d, J = 7.8 Hz, 2H); C NMR (75 MHz, CDCl ) ation, it has been planned to synthesize imidazo[2,1-c]
3
δ = 36.8, 68.5, 116.2, 116.5, 121.7, 125.4, 126.1, [1,4]oxazine derivatives via hydroalkoxylation of 1,5-
1
1
27.2, 127.8, 128.3, 128.5, 128.8, 128.9, 131.8, 132.4, alkynyl alcohol. Although these hydroalkoxylation re-
33.8, 135.7, 138.6, 148.3; Anal. Calcd. (%) for actions have been extensively studied by different
C H Cl N O: C, 64.19; H, 3.66; N, 5.99. Found (%): research groups, the reactions were all transition metal
25
17
3
2
C, 64.08; H, 3.62; N, 5.91.
catalyzed. The present investigation involves a metal
free, base promoted regioselective synthesis of imidazo
[
2,1-c][1,4]oxazine by exo-dig mode of addition. This
2
.5 Preparation of 1-(1-(prop-2-ynyl)-1H-pyrrol-2-yl)
core of imidazooxazine has not been reported widely
in literature with only limited references. To the best of
our knowledge, the bases like t-butoxide have not been
employed so far for the hydroalkoxylation of 1,5-alky-
nyl alcohol. The importance of this method is further
augmented by the fact that the starting materials used
ethanol (5)
The pyrrole derivative 5 was obtained by the usual
procedure of N-propargylation of 2-acetylpyrrole. The
resulting crude product was dissolved in methanol and
sodium borohydride was added slowly. After comple-
tion of the reduction, reaction mixture was poured in
to ice-cold water and extracted with dichloromethane.
The resulting crude product was purified by column
Ar
Ar
Ar
N
N
N
Ar
Ar
Ar
OH
chromatography.
N
N
+
N
1
Viscous liquid; H NMR (300 MHz, CDCl ) δ =
O
R
O
3
1
.15 (d, J = 6.0 Hz, 3H), 2.37 (t, J = 2.4 Hz, 1H), 4.72
R
R
(
(
2
3
d, J = 2.4 Hz, 1H), 4.77 (d, J = 2.4 Hz, 1H), 4.85
exo-dig
endo-dig
q, J = 6.0 Hz, 1H), 6.06–6.09 (m, 2H), 6.78 (t, J =
1
2
3
13
.4 Hz, 1H); C NMR (75 MHz, CDCl ) δ = 22.0,
3
5.8, 62.0, 73.0, 78.7, 106.2, 107.5, 121.8, 134.9; Anal.
Scheme 1. Possible modes of addition.

456
Muthupandi Nagaraj and Shanmugam Muthusubramanian
are quite common and inexpensive. For intramolecular cyclization of 1-alkynylimidazoles.15 Very recently,
hydroalkoxylations in alkynyl alcohol, two possible Wang et al., reported the synthesis of 1,4-oxazine via
products can be expected as exemplified by the exo- and sodium hydride promoted regioselective cyclization of
11c
endo-enol ether formations (scheme 1). According to 1,5-alkyne alcohol system. The chemistry described
Baldwin rule, these two products – a six membered ring in this investigation employs an alkali hydroxide as the
2
and/or a seven membered ring 3 - could be formed base and a new set of imidazooxazines – a bicyclic sys-
14
with ease.
tem with bridge head nitrogen – has been generated,
1
1c
The reaction of phenyl(4-phenyl-1-(prop-2-ynyl)- thus extending the work of Wang et al.
H-imidazol-2-yl)methanol 1 (Ar = Ph, R = H)
13a
1
The scope of the reaction was extended with various
has been tested with various bases in order to choose aryl substituted propargyl derivatives of imidazole 1
the best base for the proposed ring closure. Lithium t- under the optimized reaction condition to get 2a – 2i
butoxide has been found to be the best choice as the (table 2). The structure of 2 has been unambiguously
base for this reaction. Other organic bases, alkali hydro- assigned by spectral and analytical data, and that of 2f
xides and potassium carbonate resulted in lower yield
and after optimization, it was found that when 1 (Ar =
Table 2. Synthesis of substituted imidazo[2,1-c][1,4]oxa-
Ph, R = H) (0.4 mmol) and LiOtBu (0.4 mmol) in
◦
zine 2 (with isolated yields).
DMF was irradiated at 80 C with 120 W microwave for
Ar
Ar
1
0 minutes, 2,8-diphenyl-6-methyl-8H-imidazo[2,1-c]
N
N
t
LiO Bu/DMSO
Ar
Ar
[1,4]oxazine 2a was obtained in excellent yield after
N
N
MW/80 C/10 min
OH
O
R
purification by a short silica gel column (table 1).
It must be mentioned that, recently, related reactions
have been carried out via gold catalyzed/base-promoted
R
Cl
Br
Table 1. Screening of bases and solvents for the cycliza-
tion of 1 (Ar = Ph, R = H). All reactions were carried out
Cl
N
Br
N
N
◦
under microwaves at 80 C except entry #8.
N
N
N
Ph
O
O
Ph
O
N
N
CH3
CH3
Ph
CH3
Ph
OH
N
N
2a, 94%
2b, 92%
2
c, 94%
O
F
H3C
H CO
3
CH3
2
a
F
CH3
OCH
3
N
N
N
N
N
N
Sl No
Base
Solvent Reaction time Yield(%)
O
O
O
CH3
CH3
2f, 92%
CH
3
1
2
3
4
5
6
7
Sodium carbonate DMF
Sodium hydroxide DMF
Potassium hydroxide DMF
Lithium hydroxide DMF
2 h
1 h
1 h
Trace
26
28
25
62
78
76
40
93
81
63
25
Trace
33
86
82
87
83
2
d, 88%
2
e, 90%
S
1 h
N
N
S
N
N
Sodium hydride
Sodium hydride
Lithium t-butoxide
-
DMF
-
30 min
30 min
30 min
1 h
5 min
10 min
10 min
30 min
1 h
30 min
10 min
10 min
10 min
10 min
1 h
N
N
O
O
O
CH3
CH3
2i, 90%
CH
2h, 89%
3
8
9
1
1
1
1
1
1
1
1
1
1
2
2
*
Lithium t-butoxide DMF
Lithium t-butoxide DMF
Lithium t-butoxide DMSO
Lithium t-butoxide Dioxan
Lithium t-butoxide THF
Lithium t-butoxide Toluene
2g, 89%
0
1
2
3
4
5
6
7
8
9
0
1
N
N
N
N
N
N
O
O
O
CF3
Lithium t-butoxide CH CN
3
Cl
k, 82%
Sodium t-butoxide DMF
Sodium t-butoxide DMSO
Potassium t-butoxide DMF
Potassium t-butoxide DMSO
2j, 78%
2
2l, 87%
H C
H3C
3
H C
3
CH3
CH3
N
N
CH
3
N
N
DEA
DABCO
DMP
DME
DME
DME
Trace
18
15
N
N
O
O
1 h
1 h
O
CF3
Cl
*
The reaction in Entry 8 was carried out under thermal
2m, 85%
2n, 83%
2
o, 82%
◦
condition (80 C).

Synthesis of substituted imidazo[2,1-c][1,4]oxazines
457
has been confirmed by single crystal X-ray analysis
16
t
(
figure 2). It can be noticed that only 2 has been
LiO Bu/DMSO
CH3
CH3
N
N
formed in this manipulation with no trace of 3. It must
be mentioned that the reaction did not yield the product
quantitatively (table 1, Entry 8) under thermal condi-
tions in the absence of microwaves.
To check the validity of this reaction in non-terminal
alkynes, a set of non terminal alkynes 1 (R = Ar) has
been prepared by the Sonogashira coupling of the termi-
nal alkyne alcohol 1 (R = H) with different aryl iodides.
The reaction of these internal 1,5-alkyne alcohol - imi-
dazole derivatives has also been investigated, which
afforded the corresponding substituted imidazo[2,1-c]
MW/80ºC/10 min
O
OH
CH3
H
5
6
(
78%)
Scheme 3. Synthesis of 1,3-dimethyl-1H-pyrrolo[2,1-c]
[
1,4]oxazine.
carbon getting attacked by OH may not be electrophilic
enough when R = H.
[
(
1,4]oxazine derivatives (2j – 2o) in excellent yields
78–94%) (table 2). The reaction is not effective when
Next, the scope of the present transformation was
extended to propargyl derivative of pyrrole. The pyr-
role derivative 5, obtained by the usual procedure
of N-propaglylation of 2-acetylpyrrole followed by
sodium borohydride reduction, has been subjected to
hydroalkoxyation. As expected, the corresponding sub-
stituted pyrrolo[2,1-c][1,4]oxazine 6 was obtained in
good yield (scheme 3).
R is an alkyl group.
Encouraged by these results, we were curious to
know whether borohydride reduction can promote the
cyclization of 1,5-alkyne-carbonyl compound 4 directly
to 2. Interestingly, the reaction led to sequential reduc-
tion followed by cyclization with internal alkyne with
good yield (78–80%). However, in the case of termi-
nal alkynes, cyclization did not proceed as expected
(
scheme 2) and the reaction stopped after the initial
4
. Conclusions
reduction of carbonyl group ending up in 1. The alkyne
An effective base-promoted intramolecular hydroalko-
xylation of various 1,5-alkynyl-alcohol derivative of
imidazole leading to the regioselective synthesis of sub-
stituted imidazo[2,1-c][1,4]oxazine has ben developed.
The cyclization provided the exo-enol ethers in 78–94%
yield with complete regioselectivity.
Supporting Information (SI)
1H and 13C NMR and Mass Spectra of compounds
1
, 2, 4, 5 and 6 can be found in the Supplementary
Information available at www.ias.ac.in/chemsci.
Acknowledgements
The authors thank DST, New Delhi for assistance under
the IRHPA program for providing funds for creating
Figure 2. ORTEP diagram of 2f.
Ar
Ar
Ar
N
N
N
Ar
OH
NaBH4
NaBH4
N
Ar
Ar
N
N
methanol
When, R=Aryl
methanol
When, R=H
O
R
O
R
H
4
2
2
p, Ar= 4-Cl-Ph and R = Ph
q, Ar = R = 4-Cl-Ph
Ar = 4-Cl-Ph
R= H /Ph / 4-Cl-Ph
1
Scheme 2. Reduction of 1,5-alkyne-carbonyl system.

458
Muthupandi Nagaraj and Shanmugam Muthusubramanian
NMR facility. M.N. thanks Council of Scientific and
Industrial Research (CSIR), New Delhi for JRF.
Worby A, Zonzini L and Zucchelli V 2010 J. Med.
Chem. 53 5827
. (a) Maeda K, Shinokubo H and Oshima K 1996 J. Org.
Chem. 61 6770; (b) Hutching G J, Nicolaides C P and
Scurrel M S 1994 Catal. Today 23
6
References
7. (a) Alonso F, Beletsaya I P and Yus M 2004 Chem. Rev.
04 3079; (b) Tius M A 2004 In Modern Allene Chem-
1
1
. (a) Kim P, Kang S, Boshoff H I, Jiricek J, Collins M,
Singh R, Manjunatha U H, Niyomrattanakit P, Zhang L,
Goodwind M, Dick T, Keller T K, Dowd C S and Barry
C E 2009 J. Med. Chem. 52 1329; (b) Thompson A M,
Blasser A, Anderson R F, Shinde S S, Franzblau S G,
Ma Z, Denny W A and Palmer B D 2009 J. Med. Chem.
istry Vol. 2, N Krause and A S K Hashmi (Eds.) (Wiley-
VCH: Weinheim) pp. 834–838; (c) Tani K and Kataoka
Y 2001 In Catalytic Heterofunctionalization A Togni
and H Grutzmacher (Eds.) (Wiley-VCH: Weinheim) pp.
171–216; (d) Bartlett P A 1984 In Asymmetric Synthesis
Vol. 3 J D Morrisson (Ed.) (Academic Press: New York)
pp. 455
52 637; (c) Gehlert D R, Cippitelli A, Thorsell A, Le
A D, Hipskind P A, Hamdouchi C, Lu J, Hembre E J,
Cramer J, Song M, McKinzie D, Morin M, Ciccocioppo
R and Helig M 2007 J. Neurosci. 27 2718; (d) Miwa
S, Mizokami A, Keller E T, Taichman R, Zhang J and
Namiki M 2005 Cancer Res. 65 8818
8. (a) Wipf P and Graham T H 2003 J. Org. Chem. 68
8798; (b) Sheng Y, Musaev D G, Reddy K S, McDonald
F E and Morokuma K 2002 J. Am. Chem. Soc. 124 4149;
(c) Trost B M and Rhee Y H 2002 J. Am. Chem. Soc.
124 2528; (d) Kadota I, Lutete L M, Shibuya A and
Yamamoto Y 2001 Tetrahedron Lett. 42 6207; (e) Pale P
and Chuche J 2000 Eur. J. Org. Chem. 1019; (f) Elgafi S,
Field L D and Messerle B A 2000 J. Organomet. Chem.
607 97
2
3
4
. (a) Harrison T S and Keating G M 2005 CNS Drugs 19
6
5; (b) Basiuk V A 1997 Russ. Chem. Rev. 66 187; (c)
Ansini M, Cappelli A, Vomero S, Giorgi G, Langer T,
Bruni G, Romeo R and Basile A S 1996 J. Med. Chem.
3
9 4275; (d) Heeres J, Backx L J J, Mostmans J H and
9. Barluenga J, Dieguez A, Rodriguez F, Fananas F J,
Sordo T and Campomanes P 2005 Chem. Eur. J. 11 5735
Vancutsem J 1979 J. Med. Chem. 22 1003
. (a) Lenaerts A J, Gruppo V, Marietta K S, Johnson C M, 10. (a) Dzudza A and Marks T J 2010 Chem. Eur. J.
Driscoll D K, Tompkins N M, Rose J D, Reynolds R C
and Orme I M 2005 Antimicrob. Agents Chemother. 49
16 3403; (b) Ruettinger R, Leutzow J, Wilsdorf M,
Wilckens K and Czekelius C 2011 Org. Lett. 13 224; (c)
Praveen C, Iyyappan C and Perumal P T 2010 Tetrahe-
dron Lett. 51 4767; (d) Li H J, Guillot R and Gandon V
2010 J. Org. Chem. 75 8435
2
294; (b) Thompson A M, Blaser A, Anderson R F,
Shinde S S, Franzblau S G, Ma Z, Denny W A and
Palmer B D 2009 J. Med. Chem. 52 637
. (a) Nuermberger E, Rosenthal I, Tyagi S, Williams K 11. (a) Davies S G, Roberts P M, Pstephenson P T and
N, Almeida D, Peloquin C A, Bishai W R and Grosset
J H 2006 Antimicrob. Agents Chemother. 50 2621; (b)
Tyagi S, Nuermberger E, Yoshimatsu T, Williams K,
Rosenthal I, Lounis N, Bishai W and Grosset J 2005
Thomson J E 2009 Tetrahedron Lett. 50 3509; (b)
Pettigrew J D and Wilson P D 2006 Org. Lett. 8 1427;
(c) Vandavasi J K, Hu W P, Chen H Y, Senadi G C, Chen
C Y and Wang J J 2012 Org. Lett. 14 3134
Antimicrob. Agents Chemother. 49 2289; (c) Hu Y, 12. (a) Fernandez A V, Yebra C G, Varela J A, Esteruelas
Coates A R M and Mitchison D A 2008 Int. J. Tuberc.
Lung Dis. 12 69; (d) Nuermberger E, Tyagi S, Tasneen
R, Williams K N, Almeida D, Rosenthal I and Grosset
J H 2008 Antimicrob. Agents Chemother. 52 1522; (e)
M A and Saa C 2010 Angew. Chem. Int. Ed. 49 4278;
(b) Liu F N, Su F H, Wen T B, Sung H Y, Williams I D
and Jia G 2010 Chem. Eur. J. 16 7889; (c) Trost B M
and Rhee Y H 2003 J. Am. Chem. Soc. 125 7482
Stover C K, Warrener P, VanDevanter D R, Sherman D 13. (a) Nagaraj M, Boominathan M, Perumal D,
R, Arain T M, Langhorne M H, Anderson S W, Towell
J A, Yuan Y, McMurray D N, Krelswirth B N, Barry C E
and Baker W R 2000 Nature 405 962
Muthusubramanian S and Bhuvanesh N 2012 J. Org.
Chem. 77 6319; (b) Nagaraj M, Boominathan M,
Muthusubramanian S and Bhuvanesh N 2012 Synlett 23
1353
5
. Bromidge S M, Arban R, Bertani B, Bison S, Borriello
M, Cavanni P, Dalforno G, Difabio R, Donati D, Fontana 14. Baldwin J E 1976 J. Chem. Soc. Chem. Commun. 734
S, Gianotti M, Gordon L J, Granci E, Leslie C P, Moccia 15. Laroche C and Kerwin S M 2009 J. Org. Chem. 74 9229
L, Pasquarello A, Sartori I, Sava A, Watson J M, 16. CCDC No. 908750