A novel method for synthesis of tetrahydro-2H-oxazolo[2,3-a]isoquinolines

Article abstract of DOI:10.14233/ajchem.2019.21673

An efficient and direct method for the synthesis of tetrahydro-2H-oxazolo[2,3-a]isoquinolines is reported. This novel method involves 3P mediated in situ oxidation of benzyl alcohols to aldehyde followed by acetic acid mediated [3+2] cycloaddition reaction to afford tetrahydro-2H-oxazolo[2,3-a]isoquinolines in one-pot operation with good to excellent yields. Heterocyclic alcohols also underwent the reaction with tetrahydroquinolines at room temperature.

Full text of DOI:10.14233/ajchem.2019.21673

Asian Journal of Chemistry; Vol. 31, No. 2 (2019), 403-409
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2019.21673
A Novel Method for Synthesis of Tetrahydro-2H-oxazolo[2,3-a]isoquinolines
1
2
1,*
H.E. DINESHA , N.C. SANDHYA and K. MANTELINGU
1
2
Department of Chemistry, Manasagangotri, University of Mysore, Mysuru-570 006, India
Department of Studies in Chemistry, P.G. Centre, St. Philomena's College, Mysuru-570 015, India
Corresponding author: E-mail: kmlingu@gmail.com
Received: 24 August 2018; Accepted: 16 October 2018;
*
Published online: 31 December 2018;
AJC-19217
An efficient and direct method for the synthesis of tetrahydro-2H-oxazolo[2,3-a]isoquinolines is reported. This novel method involves
®
T3P mediated in situ oxidation of benzyl alcohols to aldehyde followed by acetic acid mediated [3+2] cycloaddition reaction to afford
tetrahydro-2H-oxazolo[2,3-a]isoquinolines in one-pot operation with good to excellent yields. Heterocyclic alcohols also underwent the
reaction with tetrahydroquinolines at room temperature.
®
Keywords: C-H functionalization, T3P, [3+2] cycloaddition, Isoquinolines.
addition reaction between aldehyde and in situ generated azome-
thine ylide from L-proline through decarboxylation method
INTRODUCTION
1
,3-Oxazolidine core structure is present in a large number
[
9,10]. A diastereoselective synthesis of pyrrolidinooxazoli-
of drugs, synthetic complex compounds, natural products, dyes
and agrochemicals [1]. These are building blocks for the asse-
mbly of nitrogen-containing heterocycles that constituted incre-
dible class of biologically active compounds [2]. Furthermore,
they are useful not only as intermediates in organic synthesis
but also as effective ligands for metal-catalyzed asymmetric
synthesis [3]. Many organic compounds containing 1,3-oxazo-
lidine core showed various biological activities like antitumor,
cytotoxic, anti-inflammatory, analgesic properties, etc. [4]. They
also act as anticonvulsant antibiotic, antibacterial, antifouling,
cystic fibrosis transmembrane conductance regulator (CFTR)
inhibitor [5], etc. Synoxazolidione C extracted from marine
organism Synocium pulmonaria was found to be antifouling
agent against marine bacteria and algae [6]. Linezolid showed
antibacterial activity against gram-positive, drug-resistant
bacterial infections [7]. Quinocarcin and its analogues are poly-
cyclic tetrahydroisoquinoline alkaloids with remarkable activities
against several tumor cell lines [8].
dines was achieved by Rahman et al. [11] under microwave
condition (Scheme-I). Alladoum et al. [2] demonstrated that
unsaturated amino alcohols possessing a dialkylamino function
cyclize in the presence of Pd(II) catalyst to afford bicyclic oxazo-
lidines (Scheme-II). But all these methods have limitations
like use of metal catalyst, low yield, high temperature and drastic
conditions.
H
O
Toluene
O
N
H
KOAc (20 mol%)
+
N
o
MW, 180 C
H
H
Scheme-I
OH
NH
PdCl (10 mol)
O H
2
CuCl2, O2
As a consequence, substantial attention has been paid to
develop efficient methods for their syntheses. Recently, Ghosal
et al. [4] reported metal catalyzed conversion of aziridines to
oxazolidines through geminal difunctionalization of vinyl
arenes. Pyrrolidinooxazolidines were synthesized by cyclo-
Ph
N
Ph
THF, 5 h
OMe
R
R
OMe
Scheme-II
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(

404 Dinesha et al.
Asian J. Chem.
(
d, J = 8.4 Hz, 1H), 3.88 (d, J = 8.0 Hz, 1H), 2.99 (s, 12H), 2.94-
EXPERIMENTAL
General synthesis of 3a-3q: To a solution of alcohol (2
mmol) in DMSO (2 mL), was added at 0 ºC T3P (1.0 mmol,
0 % solution in ethyl acetate) and the resulting reaction mixture
13
2
.89 (m, 2H), 2.58-2.55 (m, 2H). C NMR (100 MHz, CDCl
δ 135.1, 130.0, 128.8, 128.5, 128.1, 127.8, 126.8, 126.3, 125.6,
25.0, 112.1, 90.3, 85.1, 70.07, 45.7, 41.8, 29.4. m/z (ESI-
3
):
1
5
+
MS) [M + H] calcd (found): 401.2389 (401.2381).
was stirred at room temperature for 1-2 h under nitrogen atmos-
phere. The reaction was monitored by TLC, after the completion
of the reaction, the solvent was removed under reduced pressure.
The crude product was taken in toluene, was added 3 Å molecular
sieves (200 mg), amine 1 (1.0 mmol) acetic acid (0.5 equiv)
was added and stirred further for 1-2 h. After completion of
the reaction, the mixture was diluted with water (20 mL) and
Compound 3e: Colourless solid; yield 60 %; (R = 0.55
f
in hexanes/EtOAc 85:15 v/v). m.p. 114-116 ºC; IR (KBr, νmax
,
-1
1
cm ): 3015, 2915, 1668, 1629, 1622, 107. H NMR (400 MHz,
CDCl ): δ 7.49 (t, J = 4.0 Hz, 1H), 7.35-7.29 (m, 2H), 7.25 (d,
J = 8 Hz, 6H), 7.22-7.18 (m, 1H), 7.16 (d, J = 8 Hz, 1H), 5.8
s, 1H), 4.76 (d, J = 7.6 Hz, 1H), 3.87 (d, J = 7.2 Hz, 1H), 3.10-
3
(
3
13
.04 (m, 2H), 2.93- 2.81 (m, 2H). C NMR (100 MHz, CDCl
3
):
neutralized with 10 % NaHCO solution. The product was
3
δ 147.9, 147.7, 147.2, 146.9, 135.4, 134.1. 133.5, 133.1, 128.6,
extracted with ethyl acetate (10 mL) and the combined organic
phase was washed with water (10 mL) and brine solution. The
1
1
28.5, 128.2, 126.5, 122.1, 120.4, 109.4, 108.1, 107.3, 106.6,
+
01.0, 100.9, 90.0, 87.3, 75.6, 46.3, 29.0. m/z (ESI-MS [M + H]
organic phase was dried over anhydrous Na
was dried under reduced pressure to afford a crude product,
3a-3q) which was purified on silica gel using ethyl acetate and
2
SO
4
. The solvent
calcd (found): 402.1263 (402.1259).
Compound 3f: Colourless solid; yield 80 %; (R = 0.55
f
(
in hexanes/EtOAc 95:05 v/v). m.p. 140-142 ºC; IR (KBr, νmax
,
petroleum ether.
-1
1
cm ): 3012, 2852, 1667, 1648, 1633, 1079, 790. H NMR
(400 MHz, CDCl ): δ 7.28-7.23 (m, 2H), 7.19-7.16 (m, 2H),
.09 (s, 1H), 6.92 (s, 1H), 6.82-6.71 (comp, 3H); 6.68 (d, J =
.2 Hz, 1H), 5.94 (s, 4H), 5.76 (s, 1H), 4.71 (d, J = 7.6 Hz,
Characterization data
3
7
3
Compound 3a: Colourless solid; yield 68 %; (R = 0.8 in
f
hexanes/EtOAc 95:05 v/v). m.p. 142-144 ºC; IR (KBr, νmax
,
-1
1
1H), 3.82 (d, J = 7.6 Hz, 1H), 3.08 (t, J = 6.0, 1H), 2.89-2.84
cm ): 3010, 2850, 1670, 1639, 1608, 1070. H NMR (400
MHz, CDCl ): δ 7.42 (dd, J = 1.6 Hz, 8.8 Hz, 1H), 7.27-7.23
comp, 3H), 7.21-7.12 (comp, 9H), 7.11-7.08 (m, 1H), 5.72
s, 1H), 4.77 (d, J = 8.0 Hz, 1H), 3.90 (d, J = 6.8 Hz, 1H),
1
3
(
1
1
m, 2H), 2,74-2.73 (m, 1H). C NMR (100 MHz, CDCl
3
): δ
38.4, 137.7, 135.4, 133.7, 133.3, 133.2, 128.9, 128.7, 128.6,
28.4, 128.1, 128.0, 127.4, 126.6, 90.4, 86.6, 75.6, 46.4, 28.0;
3
(
(
3
+
1
3
m/z (ESI-MS) [M + H] calcd (found): 396.0844 (396.0846).
Compound 3g: Colourless solid; yield 65 %; (R = 0.50
in hexanes/EtOAc 95:05 v/v). m.p. 132-134 ºC; IR (KBr, νmax
cm ): 3012, 2895, 1680, 1619, 1611, 1110. H NMR (400
MHz, CDCl ): δ 7.22 (dd, J = 0.8 Hz, 8.8 Hz, 2H), 7.22-7.18
m, 4H), 7.12-6.98 (m, 3H), 6.95-6.86 (m, 4H), 5.73 (s, 1H),
.06-2.97 (m, 2H), 2.85-2.82 (m, 1H), 2.76-2.71 (m, 1H). C
): δ 140.5, 139.6, 135.6, 133.3, 128.8,
28.5, 128.3, 127.7, 127.46. 127.43, 126.9, 126.65, 126.60,
f
NMR (100 MHz, CDCl
1
9
3
,
-1
1
+
0.4, 87.1, 76.3, 46.7, 28.4; m/z (ESI-MS) [M + H] Calcd
3
(
found): 328.1623 (328.1688).
(
4
Compound 3b: Colourless solid; yield 64 %; (R = 0.86
f
.65 (d, J = 7.6Hz, 1H), 3.80 (d, J = 7.6 Hz, 1H), 3.02-2.99
in hexanes/EtOAc 80:20 v/v). m.p. 138-140 ºC; IR (KBr, νmax
,
13
-1
1
(m, 2H), 2.82-2.73 (m, 2H). C NMR (100 MHz CDCl ): δ
3
cm ): 3018, 2915, 1670, 1629, 1599. H NMR (400 MHz,
CDCl ): δ 7.49 (d, J = 5.2 Hz, 1H), 7.32-7.26 (m, 2H), 7.22-
.17 (comp, 2H), 7.15-7.10 (m, 5H), 7.06 (d, J = 5.2 Hz, 2H),
1
1
1
63.6 (d, JC-F = 72.8 Hz, 1C),161.1 (d, JC-F = 469.6 Hz, 1C),
35.5, 135.4, 134.8, 133.3, 128.8, 128.4, 128.4, 128.1, 128.09,
3
7
5
3
28.02, 115.6, 115.5, 115.38, 115.31, 90.3, 86.9, 75.5, 46.4, 27.9.
.78 (s, 1H), 4.81 (d, J = 7.6 Hz, 1H), 3.92 (d, J = 7.2 Hz, 1H),
.13-3.05 (m, 2H), 3.02-2.80 (m, 2H), 2.34 (s, 3H), 2.30 (s, 3H).
C NMR (100 MHz, CDCl3): δ 137.5, 137.4, 136.9, 136.6,
35.6, 133.5, 129.1, 129.0, 128.6, 127.9, 127.0, 126.7, 126.4,
+
m/z (ESI-MS) [M + H] calcd (found): 364.1935 ( 364.1929.
13
Compound 3h: Colourless solid; yield 83 %; (R = 0.68
f
in hexanes/EtOAc 90:10 v/v). m.p. 100-102 ºC; IR (KBr, νmax
,
1
1
-1
1
+
cm ): 3018, 2912, 1671, 1629, 1611, 1070, 990, 1118. H
NMR (400 MHz, CDCl ): δ 7.62 (d, J = 8.0 Hz, 2H), 7.56 (d,
J = 8.1 Hz, 2H), 7.51 (d, J = 4.4 Hz, 1H), 7.46 (d, J = 8.4 Hz,
H), 7.37- 7.31 (m, 4H), 7.24-7.21 (m, 1H), 5.84 (s, 1H), 4.87
(d, J = 7.2 Hz, 1H), 3.0 (d, J = 7.0. Hz, 1H), 3.12-3.09 (m,
26.1, 90.2, 87.2, 75.9, 46.5, 28.3, 21.0; m/z (ESI-MS) [M + H]
3
Calcd (found): 356.1936 (356.1956).
Compound 3c: Colourless solid; yield 70 %; (R = 0.88
f
2
in hexanes/EtOAc 80:20 v/v). m.p. 148-150 ºC; IR (KBr, νmax
,
-1
1
cm ): 3018, 2902, 2898, 2853, 1673, 1648, 1621, 1070. H
NMR (400 MHz, CDCl ): δ 7.50-7.48 (m, 1H), 7.39-7.33 (m,
H), 7.13 (d, J = 7.2 Hz, 4H), 7.28-7.23 (m, 4H), 7.20 7.16 (m,
13
2
H), 3.00 2.92 (m, 1H), 2.88-2.83 (m, 1H). C NMR (100 MHz,
3
3
CDCl ): δ144.0, 143.2, 135.3, 132.7, 130.4, 130.1, 128.5, 128.3,
2
1
1
1
1
1
1
1
28.1, 127.4, 126.9, 126.6, 126.2, 125.6, 125.5, 125.3, 122.7,
H), 5.76 (s, 1H), 4.86 (d, J = 7.6 Hz, 1H), 4.02 (d, J = 7.2 Hz,
+
22.6, 90.7, 86.3, 76.0, 46.6, 28.1. m/z (ESI-MS) [M + H]
H), 3.22-3.17 (m, 1H), 3.09-2.95 (m, 2H), 2.87-2.80 (m, 1H),
13
calcd (found): 464.1371 (464.1381).
.32 (s, 9H), 1.29 (s, 9H). C NMR (100 MHz, CDCl ): δ150.6,
3
Compound 3i: Colourless solid; yield 82 %; (R
f
= 0.58
50.0, 138.3, 138.0, 136.8, 135.6, 133.2, 128.8, 127.9, 126.5,
in hexanes/EtOAc 85:15 v/v). m.p. 136-138 ºC; IR (KBr, νmax
,
26.3, 126.0, 125.4, 125.3, 90.3, 86.8, 75.8, 46.9, 31.3, 28.8; m/
-1
1
+
cm ): 3012, 2912, 1684, 1643, 1611, 1530, 1311, 1180. H
NMR (400 MHz, CDCl ): δ 8.22 (d, J = 8.4 Hz, 2H), 8.16 (d,
z (ESI-MS) [M + H] Calcd (found): 440.2875 (440.2897).
3
Compound 3d: Colourless solid; yield 60 %; (R
f
= 0.65
J = 8.4 Hz, 2H), 7.50 (t, J = 7.6 Hz, 3H), 7.41 (d, J = 8.20 Hz,
2H), 7.33 (t, J = 4.4 Hz, 2H), 7.24- 7.22 (m, 1H), 5.84 (s, 1H),
in hexanes/EtOAc 80:20 v/v). m.p. 124-126 ºC; IR (KBr, νmax
,
-1
1
cm ): 3018, 2850, 1640, 1639, 1622, 1079. H NMR (400
MHz, CDCl ): δ 7.51 (d, J = 8.0 Hz, 1H), 7.26-7.13 (comp, 6H),
.07-7.05 (m, 2H), 6.79 (t, J = 6.8 Hz, 2H), 4.92 (s, 1H), 4.62
4
(
.89 (d, J = 7.6 Hz, 1H), 4.04 (d, J = 6.8 Hz, 1H), 3.12-3.08
3
13
m, 2H), 3.00-2.84 (m, 2H). C NMR (100 MHz, CDCl ): δ
3
7

Vol. 31, No. 2 (2019)
A Novel Method for Synthesis of Tetrahydro-2H-oxazolo[2,3-a]isoquinolines 405
1
1
4
47.8, 147.7, 147.2, 146.3, 135.2, 132.3, 128.5, 128.4, 128.1,
1H), 3.9 (d, J = 12, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 3.05-3.0
13
27.90, 127.92, 127.4, 126.8, 124.0, 123.9, 91.0, 85.8, 76.0,
(m, 2H), 2.94-2.84 (m, 2H), 1.07 (s, 3H). C NMR (100 MHz,
CDCl ): δ 139.6, 138.8, 136.4, 135.7, 134.4, 134.2, 127.9,
+
6.8, 28.2. m/z (ESI-MS) [M + H] calcd (found): 418.1325
3
(
418.1333).
Compound 3j: Colourless solid; yield 78 %; (R
in hexanes/EtOAc 95:05 v/v). m.p. 138-140 ºC; IR (KBr, νmax
127.7, 127.6, 127.4, 127.1, 127.0, 126.4, 125.6, 90.4, 86.6,
75.6, 55.3, 46.9, 28.5, 21.2. m/z (ESI-MS) [M + H] calcd
(found): 467.1420 (468.1413).
+
f
= 0.85
,
-1
1
cm ): 3014, 2910, 1658, 1612, 1112. 710, 738. H NMR (400
MHz, CDCl ): δ 7.83 (d, J = 7.2 Hz, 1H), 7.55-7.51 (m, 3H),
.44 (d, J = 8 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.33-7.28 (m,
Compound 3o: Colourless solid; yield 65 %; (R
f
= 0.36
3
in hexanes/EtOAc 80:20 v/v). m.p. 144-146 ºC; IR (KBr, νmax
,
-1
1
7
2
7
cm ): 3358, 3018, 2912, 1660, 1638, 1621, 1078. H NMR
(400 MHz, CDCl ): δ 8.53 (s, 1H), 7.58 (d, J = 7.6 Hz, 1H),
H), 7.26-7.18 (m, 2H), 7.14 (t, J = 7.6 Hz, 1H), 7.08 (t, J =
.2 Hz, 1H), 5.92 (s, 1H), 5.45 (d, J = 6.4 Hz, 1H), 4.64 (d, J
3
7.38-7.28 (m, 7H), 7.25-7.14 (m, 6H), 7.12-7.09 (m, 1H), 7.01
(dd, J = 2.0 Hz, 8 Hz, 1H), 6.22 (s, 1H), 5.01 (d, J = 7.6 Hz,
1H), 4.02 (d, J = 8.2 Hz, 1H), 3.24 (q, J = 4.4 Hz, 2H) 2.88-
=
6.4 Hz, 1H), 3.19-3.07 (m, 1H), 2.91-2.87 (m, 1H), 2.83 (t,
13
J = 3.2 Hz, 1H), 2.79 (t, J = 3.6 Hz, 1H). C NMR (100 MHz,
CDCl3): δ 139.5, 135.4, 132.96, 132.90, 132.5, 129.0, 128.9,
13
2.86 (m, 1H), 2.68-2.64 (m, 1H). C NMR (100 MHz, CDCl ):
3
1
1
28.8, 128.6, 128.4, 128.1, 128.0, 127.7, 127.6, 126.5, 124.8,
22.8, 90.5, 83.5, 74.9, 46.9, 28.6. m/z (ESI-MS) [M + H]
δ 138.8, 137.9, 136.6, 131.9, 128.6, 128.3, 128.0, 127.9, 127.2,
127.1, 126.8, 126.6, 126.59, 126.54, 122.5, 119.6, 119.5,
118.9, 111.4, 109.8, 88.5, 86.8, 71.4, 43.9, 29.7. m/z (ESI-MS)
+
calcd (found): 472.9735 (472.9727).
+
Compound 3k: Colourless solid; yield 69 %; (R
f
= 0.66
[M + H] calcd (found): 367.1732 (367.1748).
in hexanes/EtOAc 80:20 v/v). m.p. 134-136 ºC; IR (KBr, νmax
,
Compound 3p: Colourless solid; yield 73 %; (R
in hexanes/EtOAc 80:20 v/v). m.p. 154-156 ºC; IR (KBr, νmax
cm ): 3348, 3010, 2914, 1674, 1645, 1621, 1514, 1318, 1079.
f
= 0.36
-1
1
cm ): 3018, 2902, 1658, 1659, 1090, 690. H NMR (400 MHz,
CDCl ): δ 7.79 (d, J = 2 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.48-
.46 (m, 1H), 7.33-7.25 (m, 4H), 7.21-7.19 (m, 1H), 6.66 (d,
,
-1
3
1
7
H NMR (400 MHz, CDCl ): δ 8.36 (br s, 1H), 8.22 (d, J = 8.8
3
J = 8.4 Hz, 2H), 5.66 (s, 1H), 5.15 (d, J = 6.8 Hz, 1H), 4.36 (d,
J = 7.2 Hz, 1H), 3.53 (s, 3H), 3.44 (s, 3H), 3.22-3.19 (m, 1H),
Hz, 2H), 8.03 (d, J =8.4 Hz, 2H), 7.55 (d, J = 8.0 Hz, 1H), 7.48-
7.39 (m, 3H), 7.29- 7.24 (m, 1H), 7.16 (t, J = 8.0 Hz, 1H),
7.10 (d, J = 8.8 Hz, 1H), 4.99 (d, J = 7.6 Hz, 1H), 4.06 (d, J =
5.6 Hz, 1H), 3.28-3.23 (m, 1H), 3.16-3.13 (m, 1H), 2.88-2.80
13
3
.05-3.02 (m, 2H), 2.84- 2.80 (m, 1H). C NMR (100 MHz,
CDCl ): δ156.3, 156.2, 135.7, 132.3, 131.0, 130.6, 130.3, 130.2,
30.1, 128.9, 128.2, 128.0, 126.3, 112.99, 112.97, 111.8, 111.6,
0.1, 79.2, 70.5, 55.3, 54.9, 47.4, 29.6. m/z (ESI-MS) [M +
3
13
1
9
(m, 1H), 2.72-2.68 (m, 1H). C NMR (100 MHz, CDCl ): δ
3
148.0, 147.8, 145.5, 144.7, 136.8, 130.6, 128.7, 128.4, 128.2,
127.3, 126.5, 126.2, 124.1, 123.7, 123.2, 120.0, 119.1, 111.5,
+
H] calcd (found): 546.0024 (546.0018).
+
Compound 3l: Yellow solid; yield 63 %; (R
f
= 0.75 in
86.9, 71.0, 44.13, 29.6. m/z (ESI-MS) [M + H] calcd (found):
hexanes/EtOAc 80:20 v/v). m.p. 120-122 ºC; IR (KBr, νmax
,
406.1199 (406.1191).
-1
1
cm ): 3014, 2912, 1668, 1638, 1612, 1080. H NMR (400 MHz,
CDCl ): δ 7.37 (d, J = 8.8 Hz, 1H), 7.21-7.13 (m, 4H), 7.12-
.08 (m, 1H), 6.95 (d, J = 3.2 Hz, 1H), 6.90 (m, 1H), 6.85 (t,
Compound 3q: Colourless solid; yield 74 %; (R
f
= 0.30
3
in hexanes/EtOAc 80:20 v/v). m.p. 152-154 ºC; IR (KBr, νmax
,
-1
7
cm ): 3340, 3014, 2914, 1659, 1657, 1622, 1110, 680, 710.
1
J = 4.8 Hz, 2H), 5.66 (s, 1H), 5.14 (d, J = 6.8 Hz, 1H), 4.30 (d,
J = 6.4 Hz, 1H), 3.20-3.13 (m , 1H), 3.08-3.03 (m ,1H), 2.95-
H NMR (400 MHz, CDCl ): δ 8.36 (s 1H), 7.89 (d, J = 7.6
3
Hz, 1H), 7.59 (d, J = 8 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.43-
7.37 (m, 3H), 7.26 (t, J = 10.4 Hz, 2H), 7.18-7.22 (m, 3H), 7.04
(t, J = 8.0 Hz, 1H), 6.23 (s, 1H), 5.52 (d, J = 7.2 Hz, 1H), 4.66
(d, J = 7.2 Hz, 1H), 3.25-3.21 (m, 1H), 3.15-3.12 (m, 1H),
1
3
2
.87 (m, 1H), 2.78-2.72 (m, 1H). C NMR (100 MHz, CDCl
δ 142.8, 135.5, 132.4, 128.9, 128.7, 128.1, 127.9, 127.3, 126.3,
25.7, 125.4, 124.6, 124.0, 123.9, 90.3, 83.0, 72.9, 47.0, 28.7.
3
):
1
+
13
m/z (ESI-MS) [M + H] calcd (found): 340.0752 (340.0750).
Compound 3m: Colourless solid; yield 71 %; (R = 0.40
in hexanes/EtOAc 90:10 v/v). m.p. 162-164 ºC; IR (KBr, νmax
cm ): 3021, 2918, 1670, 1648, 1621, 1070, 658, 748. H NMR
400 MHz, CDCl ): δ 7.52-7.50 (m, 2H), 7.46- 7.41 (m, 3H),
.35-7.29 (m, 5H), 7.11 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 6.4,
1.2 Hz, 1H), 6.82 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 2.8 Hz, 1H),
.99 (d, J = 8.8 Hz 1H), 3.84 (dd, J = 8.1 Hz, 1H), 3.84 (s,
H), 3.15-3.09 (m, 1H), 2.87-2.78 (m, 2H), 2.59-2.53 (m, 1H).
2.93-2.86 (m, 1H), 2.70-2.69 (m, 1H). C NMR (100 MHz,
f
CDCl ): δ138.1, 132.8, 132.4, 131.4, 129.4, 129.2, 128.9, 127.8,
3
,
127.7, 125.2, 122.9, 122.6, 119.6, 119.1, 111.4, 110.5, 86.8, 85.5,
69.3, 44.3, 29.6, 18.0. m/z (ESI-MS) [M + H] calcd (found):
524.9922 (524.9914).
-1
1
+
(
3
7
1
4
3
RESULTS AND DISCUSSION
®
Propylphosphonic anhydride ( T3P) has received increased
attention as a coupling agent and dehydrating agent, offering
several advantages such as high yields, purity, low toxicity,
broad functional group tolerance and easy work-up when com-
pared to traditional reagents [12-14]. In continuation of our
13
C NMR (100 MHz, CDCl ): δ 158.7, 146.0, 137.7, 136.3,
3
1
1
7
5
35.3, 131.7, 131.2,130.4, 130.3, 130.2, 129.8, 129.0, 128.3,
27.8, 127.7, 121.9, 121.8, 113.3, 112.2, 112.1, 96.1, 87.0,
+
®
2.2, 55.2, 41.1, 29.6; m/z (ESI-MS) [M + H] calcd (found):
work on synthetic applications of ( T3P) in heterocyclic comp-
92.0232 (592.0236).
ounds and development of the useful synthetic methodologies
[12,15-20], herein we report novel, tandem approach for the
synthesis of tetrahydro-2H-oxazolo[2,3-a]isoquinoline and its
analogues. The tandem process involves DMSO mediated oxid-
ation of alcohols followed by intermolecular [3 + 2] cycloaddi-
tions of azomethineylides under mild conditions (Scheme-III).
Compound 3n: Colourless solid; yield 45 %; (R
f
= 0.40
in hexanes/EtOAc 80:20 v/v). m.p. 104-106 ºC; IR (KBr, νmax
,
-1
1
cm ): 3394, 2998, 2934, 1685, 1604, 1054. H NMR (400 MHz,
CDCl ): δ 7.24-7.14 (m, 6H), 7.11-7.08 (m, 1H), 7.05 (d, J =
.4 Hz, 1H), 6.96 (s, 1H), 6.84 (s, 1H), 4.85 (d, J = 12.4 Hz,
3
8

406 Dinesha et al.
Asian J. Chem.
Br
H
Further increase in the amount of acetic acid to 1.0 and
1.5 equiv, no significant improvement in the yield was observed
N
1. ®T3P(2.0 equiv)/
DMSO
OH
Br
H
(
Table-1, entries 7 and 8). The effect of temperature was also
O
H
Br
tested, when temperature was increased to 40 , 50 and 60 ºC,
no significant improvement in the yields were observed (Table-
1, entries 9-11). Later we screened a number of solvents viz.,
NH
2
. CH COOH/Toluene
3
1
3
2
THF, EtOAc, DMF, ethanol and CH CN found that toluene
3
Scheme-III
was preferred as a solvent. We also screened other molecular
sieves like 3 and 4 Å but no significant difference was observed
finally, it was found that the reactions with aldehyde (crude)
Initially, 2-bromobenzyl alcohol was oxidized to 2-bromo-
®
benzaldehyde using T3P and DMSO at room temperature [15].
The reaction of 2-bromobenzaldehyde (crude) was carried out
with tetrahydroisoquinoline (THIQ) in the absence of acetic
acid and toluene as a solvent, the desired product 3was obtained
in trace amount (Table 1, entry 1). Later we carried out the reaction
of aldehyde (crude) with THIQ in the presence of 10 mol %
acetic acid, product 3 was obtained in 35 % yield (Table-1,
entry 2). Upon increasing the amount of acetic acid 20, 30, 40
and 50 mol % the yield of products 3 were increased (Table-1,
entries 3-6).
(
1.0 mmol) and tetrahydroisoquinoline (1.0 mmol) in the presence
of acetic acid at room temperature for 6 h was ideal (Table-1,
entry 5). Under the above optimized reaction conditions, the
efficiency and versatility of this newly developed methodology,
reactions of THIQs with a range of benzaldehyde derived from
differently substituted benzylalcohol were evaluated (Scheme-
IV). In all cases, products (3a-3q) were obtained in good yields
at room temperature.
R
H
N
1
. ®T3P(2.0 equiv)/
TABLE-1
R1
R2
O
H
DMSO
OPTIMIZATION OF REACTION CONDITIONS
R
OH
NH + R2
2. CH3COOH/Toluene
CH COOH
Temp.
(°C)
Yield
(%)
3
No.
Solvent
Time (h)
(mol %)
R1
2
R2
1
3(a-q)
1
2
3
4
5
6
7
8
9
–
10
20
30
40
50
100
150
50
50
50
50
50
50
50
50
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
24
24
24
12
6
6
6
6
6
Reflux
RT
RT
RT
RT
RT
RT
RT
40
Trace
35
37
54
63
81
77
74
67
66
66
35
25
55
10
48
Scheme-IV
Using optimized reaction conditions we studied the general
substrate scope of the reaction (Table-2). A number of benzal-
dehyde derived from benzyl alcohols efficiently reacted with
THIQs to afford the corresponding products under the opti-
mized reaction conditions (3a-3q). Benzyl alcohols bearing
halogens such as -F, -Cl, -Br, CF and a strong electron with-
drawing group like -NO were underwent the title reaction to
form desired products in good yields (3f-3j). Even disubstituted
benzyl alcohols successfully formed the product without dimin-
ishing the yield compound 3k. Piperonal and heterocyclic
benzyl alcohol like thiophen-2-yl-methanol also underwent
10
11
12
13
14
15
16
6
6
50
60
3
2
24
24
24
24
24
RT
RT
RT
RT
RT
EtOAc
DMF
Ethanol
CH CN
3
TABLE-2
SUBSTRATE SCOPE FOR THE [3 + 2] CYCLOADDITION REACTION
Entry
Substrate 1 Substrate 2 Product 3
Yield (%)
68
OH
N
H
1
2
NH
NH
O
H
2
a
2
1
1
a
3a
OH
N
H
64
70
O
b
H
a
a
3
b
OH
N
3
NH
H
O
2
c
1
H
3c

Vol. 31, No. 2 (2019)
A Novel Method for Synthesis of Tetrahydro-2H-oxazolo[2,3-a]isoquinolines 407
N
OH
4
NH
NH
N
61
63
H
O
N
O
2
d
1
1
a
a
H
N
3
d
O
O
OH
N
5
H
O
H O
2
2
e
H
O
3
e
O
Cl
OH
N
6
7
NH
NH
80
65
83
H
Cl
F
H
O
f
1
1
a
a
H
Cl
3
f
F
OH
N
H
H O
2
g
H
F
3
g
CF3
OH
N
8
9
NH
H
F3C
H
O
2
h
1
a
H
CF3
3h
NO2
OH
N
NH
NH
82
78
H
O N
2
H O
2
i
1
1
a
a
H
NO2
3i
Br
Br
N
OH
H
1
0
1
H O
H
2
j
3j Br
Br
OMe
OH
N
1
NH
NH
69
63
H
OMe
Br
H
O
1
1
a
a
H
Br
S
2k
3k
MeO
S
N
O
H
12
OH
H
2
l
S
3l

408 Dinesha et al.
Asian J. Chem.
Br
MeO
OH
MeO
N
NH
1
1
3
4
H
H
71
Ph
Br
Cl
O
2
m
Ph
H
H
Br
3
m
1
1
b
c
Cl
MeO
MeO
OH
MeO
MeO
NH
NH
N
45
65
72
O
2
n
Cl
3n
OH
N
1
1
1
5
6
7
N
H
H
N
H H
O
2
a
3
o H
1
1
1
d
NO
2
NH
NH
OH
N
N
H
H
N
O N
2
H H O
2
i
3
p H
NO
2
d
Br
N
OH
N
H
Br
N
H
74
H
H
O
H
2
j
d
3q
Br
the reaction to give the desired products 3e and 3l, respectively
in good yields. The scope of the reaction was successfully
extended to other substrates such as trypoline and sterically
demanding 1-alkyl THIQ, 1-aryl THIQ and 1-aryl-trypoline
which also underwent the title reaction under equally mild
conditions (3m-3q).
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