Synthesis of fused nine-membered rings: A simple protocol for synthesis of [1,2,3]-triazolo-[1,4]-benzoxazonine frameworks from the Baylis-Hillman acetates

Article abstract of DOI:10.1016/j.tet.2013.09.056

A simple and facile protocol for synthesis of tricyclic [1,2,3]-triazolo-[1,4]-benzoxazonine derivatives has been developed from the Baylis-Hillman acetates by treatment with sodium azide followed by heating the resulting azido-alkyne in toluene under ref

Full text of DOI:10.1016/j.tet.2013.09.056

Accepted Manuscript
Synthesis of fused nine membered rings: A simple protocol for synthesis of [1,2,3]-
triazolo-[1,4]-benzoxazonine frameworks from the Baylis-Hillman acetates
Deevi Basavaiah, Bhavanam Sekhara Reddy, Harathi Lingam
PII:
S0040-4020(13)01478-6
10.1016/j.tet.2013.09.056
TET 24831
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 August 2013
Revised Date: 15 September 2013
Accepted Date: 18 September 2013
Please cite this article as: Basavaiah D, Reddy BS, Lingam H, Synthesis of fused nine membered rings:
A simple protocol for synthesis of [1,2,3]-triazolo-[1,4]-benzoxazonine frameworks from the Baylis-
Hillman acetates, Tetrahedron (2013), doi: 10.1016/j.tet.2013.09.056.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Synthesis of fused nine membered rings :
A simple protocol for synthesis of [1,2,3]-triazolo-
[1,4]-benzoxazonine frameworks from the
Baylis-Hillman acetates
Leave this area blank for abstract info.
CO2R2
OAc
O
CO2R2
i) DMSO, rt, 3-10 h
R1
9
NaN3
N
N
+
R1
Deevi Basavaiah*, Bhavanam Sekhara Reddy
ii) Aqueous work-up
iii) Toluene, 110 oC, 4-5 h
N
O
and Harathi Lingam
6a-i
57-72% for overall two steps
4a-i
School of Chemistry, University of Hyderabad
Hyderabad-500 046, India

ACCEPTED MANUSCRIPT
1
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of fused nine membered rings: A simple protocol for synthesis of [1,2,3]-
triazolo-[1,4]-benzoxazonine frameworks from the Baylis-Hillman acetates@
Deevi Basavaiah*, Bhavanam Sekhara Reddy and Harathi Lingam
School of Chemistry, University of Hyderabad, Central University (PO), Gachibowli, Hyderabad 500 046, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple and facile protocol for synthesis of tricyclic [1,2,3]-triazolo-[1,4]-benzoxazonine
derivatives has been developed from the Baylis-Hillman acetates by treatment with sodium
azide followed by heating the resulting azido-alkyne in toluene under reflux [Huisgen reaction
(click reaction)] in the absence of any copper salts.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Baylis-Hillman reaction
Azido-alkyne
Click reaction
[1,2,3]-Triazolo-[1,4]-benzoxazonines
1. Introduction
construction of 9-membered rings i.e. [1,4]-oxazonine ring.
Accordingly we herein report a one-pot facile protocol for
synthesis of tricyclic triazolo-[1,4]-benzoxazonine frameworks
from the Baylis-Hillman acetates.
Development of efficient and simple protocols for obtaining
medium sized rings (particularly eight and nine membered rings)
still continues to be one of the fascinating endeavors in organic
chemistry because of challenges involved in their synthesis.1
1,4-Oxazonine framework is one such skeleton which has
attracted the attention of synthetic chemists in recent years.2
[1,2,3]-Triazole framework is medicinally important structural
organization present in many bioactive molecules showing
various activities like anti-HIV (1a),3a anti-allergic (1b),3b anti-
bacterial (1c3c&1d3d) and antimicrobial (1e)3e (Figure 1).
Therefore there has been increasing interest in the synthesis of
diverse classes of [1,2,3]-triazole frameworks.4 Also there has
been growing interest in [1,2,3]-triazole frameworks fused with
various other moieties, particularly [1,4]-oxaza cyclic units
containing 6/7/8-membered rings (A, B, C) (Figure 2) because
of their biological properties.5 In most of these protocols the key
step is the formation of [1,2,3]-triazole unit via the well known
click reaction (Huisgen cycloaddition reaction).4 In continuation
of our interest in the development of different aspects of the
Baylis-Hillman reaction and its applications in synthesis of
various carbocyclic and heterocyclic compounds,6 we became
interested in triazolo-[1,4]-oxazonine system D (Figure 2)
because of two main reasons: 1) there is not much literature
available on this framework 2) due to the challenges in the
N
O
H
N
N
O
Si
H2N
O
CONMe2
N
N
N
MeSO2O
O
R
R = H, Me
O
O
OSi
S
1b
O
1a
S
O
H2N
N
N
N
NH
O
S
N
NC
N
NH
N
O
N
MeO
N
S
S
F
N
O
CO2H
1d
1c
NHAc
NH3
O
O
H3N
N
N
N
N
N
N
O
O
1e
NH3
H3N
*
Corresponding author. Tel.: +91 040 23134812; fax: +91 40
Figure 1 Bioactive molecules containing [1,2,3]-triazole framework.
23012460.E-mail address: dbsc@uohyd.ernet.in (D. Basavaiah).

ACCEPTED MANUSCRIPT
2
Tetrahedron
2. Results and discussion
when the reaction was performed in DMSO as a solvent at room
temperature (entry 6, Table 1). Thus the treatment of B-H acetate
(4a) (1.0 mmol) with sodium azide (1.5 mmol), in DMSO at
room temperature for 3 h provided methyl (E)-2-(azidomethyl)-3-
[2-(prop-2-ynyloxy)phenyl]prop-2-enoate (5a), in 85% isolated
yield.
Functional group transformation is one of the most important
operations in organic synthesis and therefore preparation of
molecules containing several functional groups is considered to
be a challenging and attractive endeavor in organic chemistry.
The Baylis-Hillman reaction is one such synthetic tool which
provides densely functionalized molecules via the reaction of
activated alkenes with electrophiles in the presence of a suitable
catalyst.7,8 These densely functionalized molecules have been
Table 1
Optimization: Synthesis of azido alkyne 5aa,b
OAc
CO2Me
+
CO2Me
N3
reaction conditions
NaN3
O
8
O
O
9
R
R
R
O
O
R
O
7
6
4a
N
N
N
5a
N
N
N
N
N
N
N
N
N
A
B
D
C
Entry
Conditions
Yield(%)c
1
2
3
4
5
6
7
Toluene, rt, 1 day
Toluene-H2O, rt, 1 day
THF-H2O (1:1), rt, 1 day
DMSO-H2O, rt, 12 h
DMSO, rt, 2 h
-
Figure 2
11
-
meticulously and systematically employed in various organic
transformations including in the synthesis of molecules of
medicinal relevance. In the literature there are some reports9 on
the utility of the Baylis-Hillman acetates for preparation of
triazole derivatives,9c,d triazole-fused bi/ tricyclic systems such
as triazolo-1,4-oxazepines5d triazolodiazepines9b and triazolo-
benzazepines9e,f via Huisgen (click) reaction of azido-alkyne
units as the key step. However there are no reports available in
the literature on synthesis of triazolo-[1,4]-benzo-xazonine
framework from the BH adducts / acetates. Attracted by the
challenges involved in obtaining oxazonine (nine membered
23
65
85
73
DMSO, rt, 3 h
DMSO, rt, 12 h
aAll reactions were carried out on a 1.0 mmol scale of B-H acetate (4a) with
sodium azide (1.5 eq.) at room temperature.
bFully characterized.
cYields were based on B-H acetate 4a.
ring)
skeleton we have directed our studies towards
transformation of BH acetates into [1,2,3]-triazolo-[1,4]-
benzoxazonine derivatives according to the retro-synthetic
sequence shown in Scheme 1.
After having azido-alkyne (5a) in hand, we tried for
intramolecular [3+2] Huisgen cyclization under usual conditions
using Cu(0)/CuSO4 as a catalytic system (entry 1, Table 2). The
desired triazole was obtained in low yield. In order to increase
the yield of the desired triazolo-[1,4]-benzoxazonine, we have
examined this reaction under different conditions and observed
that just refluxing in toluene provided better yields (Entry 4,
Table 2). Thus heating methyl 2-(azidomethyl)-3-[2-(prop-2-
ynyloxy)phenyl]propenoate (5a) (1 mmol) in refluxing toluene
for 4 h provided 10-methoxycarbonyl-2-oxa-6,7,8-triazatricyclo-
[10.4.0.04,8]hexadeca-1(12),4,6,10,13,15-hexaene (6a) in 80%
isolated yield. We have also obtained single crystal for this
compound and further confirmed the structure of molecule 6a by
single crystal X-ray data analysis (Figure 3).11
CO2R2
CO2R2
Click
reaction
R1
R1
N
N
O
N3
N
O
5
6
Azide formation
OH
O
OAc
O
CO2R2
CO2R2
R1
Acetylation
R1
BH alcohol
BH acetate
3
4
Table 2
Optimization: Synthesis of triazolo-[1,4]-benzoxazonine 6aa,b
BH reaction
CO2Me
CO2Me
CHO
Reaction conditions
CO2R2
R1
9
N
N
N
+
O
N3
O
O
2
6a
5a
Entry
Conditions
Yield(%)c
Scheme 1. Retro-Synthetic strategy
1
2
3
4
Cu/CuSO4, EtOH, reflux, 4 h
DMSO, reflux, 4 h
30
67
59
80
Accordingly we have first selected methyl 3-acetoxy-2-
methylene-3-[2-(prop-2-ynyloxy)phenyl]propanoate (4a), the
Baylis-Hillman acetate, which was obtained via the acetylation
of B-H alcohol, methyl 3-hydroxy-2-methylene-3-[2-(prop-2-
ynyloxy)phenyl]propanoate (3a), [which was in turn derived via
the coupling of 2-(prop-2-ynyloxy)benzaldehyde (2a) with
methyl acrylate in the presence of DABCO]10 as a substrate for
reaction with sodium azide. We have carried out this reaction
under different conditions and the best results were obtained
Toluene, reflux, 2 h
Toluene, reflux, 4 h
aAll reactions were carried out on a 1 mmol scale of azido-alkyne (5a)
bFully characterized
cYields were based on azido-alkyne 5a.

ACCEPTED MANUSCRIPT
3
Table 3
Synthesis of BH alcohols (3a-i)a and BH acetates (4a-i)b
O
OH
O
OAc
O
DABCO
CO2R2
CO2R2
CO2R2
Acetyl chloride
(0.5-1.0 eq.)
R1
+
R1
R1
Silica gel, 7-20 d
r.t.
Pyridine
CH2Cl2, r.t., 2 h
O
2a-e
3a-i
4a-i
30-87%
85-92%
Entry
R1
H
R2
Aldehyde
BH alcoholc
Yield(%)d
BH acetatec
Yield(%)e
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Et
2a
2b
2c
2d
2e
2a
2b
2c
2d
3a
3b
3cf
3d
3e
3f
70
57
30
83
65
81
71
41
87
4a
4b
4c
4d
4e
4f
85
90
85
90
91
88
86
87
92
3-OMe
4-OMe
5-Br
5-Cl
H
3-OMe
4-OMe
5-Br
Et
3g
3hf
3i
4g
4h
4i
Et
Et
a All reactions were carried out on a 20 mmol scale of aldehydes (2a-e) with 30 mmol of alkyl acrylates, under the influence of DABCO (50 mol%) in the silica
gel-solid phase medium (mesh >200-400) at room temperature for 7-14 days (see experimental).
bAll reactions were carried out on a 10 mmol scale of Baylis-Hillman alcohols (3a-i) with acetyl chloride, in the presence of pyridine at room temperature for 2 h
(see experimental).
cThe molecules 3a-i and 4a-i are fully characterized (see experimental).
dYields are based on aldehydes (2a-e).
eYields are based on B-H alcohols (3a-i).
fThese reactions were carried out under influence of 1 eq. of DABCO for 20 days.
Encouraged by the success in obtaining [1,2,3]-triazolo-[1,4]-
benzoxazonine 6a in reasonably high yields we turned our
attention to achieve [1,2,3]-triazolo-[1,4]-benzoxazonine without
purifying the intermediate azido-alkyne 5a in a one-pot reaction.
In this direction we have treated the Baylis-Hillman acetate 4a
with sodium azide in DMSO for 3 h at room temperature and
o
then heated the resulting mixture for 2 h at 110 C in the same
solvent to provide 10-methoxycarbonyl-2-oxa-6,7,8-triazatri-
cyclo[10.4.0.04,8]hexadeca-1(12),4,6,10,13,15-hexaene (6a) in
overall 55% isolated yield (Scheme 2).
CO2Me
OAc
CO2Me
N3
11
12
10
CO2Me
+
13
16
110 oC, 2 h
9
DMSO
rt, 3 h
14
15
7
8
O
N
N
NaN
3
1
O
4
N
6
O
2
Figure 3. ORTEP diagram of compound 6a
3
5
5a
4a
6a
not isolated
55% for overall two steps
4,6,10,13,15-hexaene (6a), in 72% overall isolated yield for two
steps (Scheme 3). We were indeed pleased to see the better yield
of 6a in this two-step process.
Scheme 2. One-pot synthesis of 6a
Since in the two pot operation process, second step using
toluene as a solvent (under reflux) gave high yields (entry 4,
Table 2) we have treated methyl 3-acetoxy-2-methylene-3-[2-
(prop-2-ynyloxy)phenyl]propanoate (4a) with sodium azide in
DMSO for 3 h at room temperature. Then the resulting crude
compound methyl 2-(azidomethyl)-3-[2-(prop-2-ynyloxy)phe-
nyl]propenoate (5a), obtained after aqueous work-up (after
removing DMSO), without further purification was heated in
toluene under reflux for 4 h at 110 oC to provide 10-metho-
xycarbonyl-2-oxa-6,7,8-triazatricyclo[10.4.0.04,8]hexadeca-1(12)-
OAc
O
CO2Me
CO2Me
iii) Toluene
110 oC, 4 h
i) DMSO
rt, 3 h
CO2Me
N3
+
NaN3
9
N
N
ii) Aqueous
work-up
O
N
O
4a
6a
72% for overall two steps
not purified/isolated
5a
Scheme 3.
Synthesis of 6a without isolating 5a

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4
Tetrahedron
With a view to understand the generality of this reaction
the copper free click reactions for intramolecular azide-alkyne
cyclization,4e, 5d,9b,e,f for substrates containing electron-deficient
alkynes13a and strained units like octynes13b-f & benzynes.13g
sequence and to obtain different triazolo-[1,4]-benzoxazonine
derivatives we have prepared various Baylis-Hillman acetates
(4b-i) from the BH adducts [which were in turn obtained from
2-(prop-2-ynyloxy)arylaldehydes (2b-e) and alkyl acrylates] by
acetylation (Table 3). BH acetates 4b-i were successfully
converted into the desired triazolo-[1,4]-benzoxazonine
derivatives (6b-i) in 57-71% isolated yields (for two steps) via
the treatment with sodium azide in DMSO and then heating the
resulting crude azides (after aqueous work-up) in toluene under
reflux (Table 4).
Mechanism for the formation of triazolo-[1,4]-benzoxazonine
derivatives from the Baylis-Hillman acetates is presented in
Scheme 4 by taking reaction between methyl 3-acetoxy-2-
methylene-3-[2-(prop-2-ynyloxy)phenyl]propanoate (4a) and
NaN3 as a model case. Treatment of 4a with NaN3 provided
alkynyl-azide 5a intermediate, which would then undergo
intramolecular [3+2] cycloaddition reaction leading to the
formation of the triazole derivative 6a.
3. Conclusion
Table 4
Synthesis of triazolo-[1,4]-benzoxazonine derivatives (6a-i)a
In conclusion we have developed a facile strategy for
synthesis of tricyclic [1,2,3]-triazolo-[1,4]-benzoxazonine
frameworks from the Baylis-Hillman acetates by treatment with
sodium azide and subsequent [3+2] cyclization of the resulting
crude azido-alkyne in refluxing toluene. It needs to be mentioned
here that [1,2,3]-triazolo-[1,4]-oxazonine framework is an
interesting structural moiety that is not well studied in the
literature and is believed to be very useful in the medicinal
chemistry point of view. This methodology demonstrates the
applicability of Baylis-Hillman adducts for synthesis of nine
membered rings containing [1,4]-benzoxazonine framework
fused with [1,2,3]-triazole skeleton.
CO2R2
OAc
11
CO2R2
13
16
9
i) DMSO, rt, 3-10 h
14
R1
10
8
R1
NaN3
12
+
N
N
7
ii) Aqueous work-up
iii) Toluene, 110 oC, 4-5 h
O
N
15
1
O
2
6
4
3
5
6a-i
4a-i
57-72% for overall two steps
Entry
BH acetate
R1
H
R2
Productb,c Yield(%)d
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
Me
6ae
6b
6c
6d
6e
6f
72
68
63
57
62
58
65
68
71
3-OMe
4-OMe
Me
Me
Me
Me
Et
OAc
5-Br
5-Cl
CO2Me
CO2Me
-NaOAc
+
N
N N Na
O
O
N3
H
4g
4h
4i
3-OMe
4-OMe
5-Br
Et
6g
6h
6i
4a
5a
Et
no catalyst
CO2Me
Et
aAll reactions were carried out on 1.0 mmol scale of B-H acetate (4a-i) with
sodium azide (1.5 mmol) in DMSO (2 mL) for 3-10 h at room temperature
followed by aqueous work-up and heating the resulting crude in toluene (2
mL) for 4-5 h under reflux (see experimental).
CO2Me
9
N
N
O
N
N
N
N
O
bThese compounds are fully characterized (see experimental).
6a
c (E)-Stereochemistry of the double bond for the compounds 6a-i at C-10 is
H
confirmed by 1H NMR spectral analysis.12
Scheme 4. Plausible
mechanism
dYields are based on B-H acetates (4a-i).
e
Structure and double bond stereochemistry were further confirmed by
single crystal X-ray data analysis11 of 6a.
4. Experimental section
4.1. General remarks
It is interesting to note the easy formation of even nine
membered rings in the click reaction without using any copper
catalyst in all our reactions. From these results it may be possible
to understand that intramolecular version of click reaction
provides an easy access to the formation of nine-membered rings
(otherwise difficult to prepare)1 even in the absence of any
copper catalyst. It is appropriate to mention here that Lee and
coworkers reported copper free Huisgen intramolecular
cyclization of azido-alkyne systems, obtained from Baylis-
Melting points were recorded on a Superfit (India) capillary
melting point apparatus and were uncorrected. IR spectra were
recorded on a JASCO FT / IR-5300 spectrophotometer, solid
samples were recorded as KBr wafers and liquid samples as thin
1
film between NaCl plates. H NMR (400 MHz) and 13C NMR
(100 MHz) spectra were recorded on a Bruker-AVANCE-400
spectrometer in deuterochloroform (CDCl3) with tetramethyl-
silane (TMS, δ = 0) as an internal standard for 1H NMR and
chloroform-d middle peak of the triplet (δ = 77.10 ppm) as an
Hillman acetates, to provide triazolo-benzazepines9e,f
in
internal standard for 13C NMR spectra. HRMS spectra were
recorded on Bruker maXis ESI-TOF spectrometer. The X-ray
diffraction measurements were carried out at 298 K on a Bruker
SMART APEX CCD area detector system equipped with a
graphite-monochromated Mo-Kα radiation with the wavelength
of 0.71073 Å.
refluxing THF9e and also in refluxing toluene.9f Lamaty9b and
Batra5d reported respectively synthesis of triazolo-diazepines9b
and triazolo-1,4-oxazepines5d via copper free intra-molecular
click reaction of azido-alkyne systems obtained from the Baylis-
Hillman adducts/ acetates, in toluene. In recent years, copper
free click reactions has attracted the attention of synthetic
chemists. There has been in fact, some interesting reports on
4.2. Representative procedure

ACCEPTED MANUSCRIPT
5
4.2.1 All the aldehydes 2a-e were prepared by treating propargyl
bromide with corresponding 2-hydroxyarylaldehyde in the presence
of K2CO3 following the literature procedure.14
52.05, 56.25, 67.23, 76.10, 77.95, 113.94, 114.25, 126.63,
130.68, 131.42, 132.26, 140.59, 153.51, 166.89; HRMS (ESI)
exact mass calc’d for C14H13BrO4+Na (M+Na)+: 346.9895, found:
346.9891.
4.2.2. Methyl 3-hydroxy-2-methylene-3-[2-(prop-2-ynyloxy)-
phenyl]propanoate (3a): To
a
solution of 2-(prop-2-
4.2.6. Methyl 3-[5-chloro-2-(prop-2-ynyloxy)phenyl]-3-hydroxy-
2-methylenepropanoate (3e). Reaction time: 14 days; yield: 65%;
Rf (20% EtOAc in hexanes) 0.51; pale yellow viscous liquid; IR
(neat): ν 3470, 3294, 2953, 2121, 1718, 1631 cm-1; 1H NMR (400
MHz): δ 2.51 (t, 1H, J = 2.4 Hz), 3.34 (d, 1H, J = 5.6 Hz), 3.77
(s, 3H), 4.69 (d, 2H, J = 2.4 Hz), 5.71 (s, 1H), 5.85 (d, 1H, J =
5.6 Hz), 6.33 (s, 1H), 6.92 (d, 1H, J = 8.8 Hz), 7.24 (dd, 1H, J =
2.8 & 8.8 Hz), 7.42 (d, 1H, J = 2.8 Hz); 13C NMR (100 MHz): δ
52.01, 56.32, 67.20, 76.05, 78.00, 113.50, 126.56, 126.80,
127.78, 128.40, 131.92, 140.63, 152.99, 166.87; HRMS (ESI)
exact mass calc’d for C14H13ClO4+Na (M+Na)+: 303.0400, found:
303.0397.
ynyloxy)benzaldehyde (2a) (20 mmol, 3.20 g) in methyl acrylate
(30 mmol, 2.58 g, 2.7 mL) was added DABCO (10 mmol, 1.12 g)
at room temperature. Then silica gel (mesh >200-400) was added
and thoroughly mixed. After keeping the resulting solid at room
temperature for 7 days, the reaction mixture was washed with
ethyl acetate (3 X 20 mL). Combined organic layer was washed
successively, with 2N HCl (15 mL), saturated NaHCO3 solution
(15 mL), water (15 mL) and then dried over anhydrous Na2SO4.
Solvent was evaporated and the crude thus obtained was purified
by column chromatography to provide the title compound in 70%
(3.44 g) isolated yield.
Rf (20% EtOAc in hexanes) 0.46; pale yellow viscous liquid; IR
(neat): ν 3466, 3287, 2953, 2121, 1712, 1631 cm-1; 1H NMR (400
MHz): δ 2.50 (t, 1H, J = 2.4 Hz), 3.36 (d, 1H, J = 6.0 Hz), 3.74,
(s, 3H), 4.72 (d, 2H, J = 2.4 Hz), 5.75 (s, 1H), 5.89 (d, 1H, J =
6.4 Hz), 6.32 (s, 1H), 6.95-7.06 (m, 2H), 7.27-7.31 (m, 1H), 7.41
(d, 1H, J = 7.2 Hz); 13C NMR (100 MHz): δ 51.67, 55.87, 67.33,
75.62, 78.36, 112.04, 121.45, 125.78, 127.59, 128.55, 129.94,
141.24, 154.42, 166.81; HRMS (ESI) exact mass calc’d for
C14H14O4+Na (M+Na)+: 269.0790, found: 269.0794.
4.2.7.
Ethyl
3-hydroxy-2-methylene-3-[2-(prop-2-ynyloxy)-
phenyl]propanoate (3f). Reaction time: 7 days; yield: 81%; Rf
(20% EtOAc in hexanes) 0.50; pale yellow viscous liquid; IR
(neat): ν 3468, 3288, 2984, 2121, 1712, 1631 cm-1; 1H NMR (400
MHz): δ 1.26 (t, 3H, J = 7.2 Hz), 2.50 (t, 1H, J = 2.4 Hz), 3.40
(d, 1H, J = 6.4 Hz), 4.19 (q, 2H, J = 7.2 Hz), 4.71 (d, 2H, J = 2.4
Hz), 5.74 (s, 1H), 5.89 (d, 1H, J = 6.0 Hz), 6.32 (s, 1H), 6.96-
7.05 (m, 2H), 7.24-7.31 (m, 1H), 7.41 (dd, 1H, J = 1.2 & 7.6
Hz); 13C NMR (100 MHz): δ 13.96, 56.00, 60.72, 67.66, 75.64,
78.42, 112.11, 121.56, 125.61, 127.77, 128.64, 130.06, 141.48,
154.56, 166.51; HRMS (ESI) exact mass calc’d for C15H16O4+Na
(M+Na)+: 283.0946, found: 283.0946.
Similar procedure was followed for preparation of compounds
3b-e, via the reaction between the corresponding aldehyde (2a-e)
with methyl acrylate in the presence of DABCO. The compounds
3f-i were synthesized by treatment of arylaldehyde (2a-d)with
ethyl acrylate in presence of DABCO. For synthesis of
compounds 3c and 3h, 1 equivalent of DABCO was used.
4.2.8. Ethyl 3-hydroxy-3-[3-methoxy-2-(prop-2-ynyloxy)phenyl]-
2-methylenepropanoate (3g). Reaction time: 14 days; yield: 71%;
Rf (20% EtOAc in hexanes) 0.45; pale yellow viscous liquid; IR
(neat): ν 3489, 3287, 2939, 2119, 1714, 1631 cm-1; 1H NMR (400
MHz): δ 1.24 (t, 3H, J = 7.2 Hz), 2.51 (t, 1H, J = 2.4 Hz), 3.27
(d, 1H, J = 5.6 Hz), 3.86 (s, 3H), 4.13-4.22 (m, 2H), 4.75 & 4.81
(dABq, 2H, J = 2.4 & 17.6 Hz), 5.85 (s, 1H), 6.01 (d, 1H, J = 5.6
Hz), 6.35 (s, 1H), 6.87 (d, 1H, J = 8.0 Hz), 6.98 (d, 1H, J = 7.6
Hz), 7.05-7.13 (m, 1H); 13C NMR (100 MHz): δ 14.01, 55.73,
59.89, 60.71, 67.66, 75.42, 79.57, 111.88, 119.36, 124.59,
125.67, 135.68, 141.67, 144.02, 152.22, 166.35; HRMS (ESI)
exact mass calc’d for C16H18O5+Na (M+Na)+: 313.1052, found:
313.1057.
4.2.3.
Methyl
3-hydroxy-3-[3-methoxy-2-(prop-2-ynyloxy)-
phenyl]-2-methylenepropanoate (3b). Reaction time: 14 days;
yield 57%; Rf (20% EtOAc in hexanes) 0.38; colorless viscous
1
liquid; IR (neat): ν 3489, 3287, 2951, 2123, 1716, 1631 cm-1; H
NMR (400 MHz): δ 2.51 (t, 1H, J = 2.4 Hz), 3.23 (d, 1H, J = 5.2
Hz), 3.72 (s, 3H), 3.86 (s, 3H), 4.74 & 4.82 (dABq, 2H, J = 2.4
& 15.2 Hz), 5.85-5.89 (m, 1H), 6.01 (d, 1H, J = 5.6 Hz), 6.36 (s,
1H), 6.87 (dd, 1H, J = 1.6 & 8.0 Hz), 6.97 (dd, 1H, J = 1.6 & 8.0
Hz), 7.05-7.12 (m, 1H); 13C NMR (100 MHz): δ 51.84, 55.75,
59.91, 67.64, 75.46, 79.56, 111.94, 119.33, 124.64, 126.01,
135.58, 141.41, 144.01, 152.25, 166.81; HRMS (ESI) exact mass
calc’d for C15H16O5+Na (M+Na)+: 299.0895, found: 299.0891.
4.2.9. Ethyl 3-hydroxy-3-[4-methoxy-2-(prop-2-ynyloxy)phenyl]-
2-methylenepropanoate (3h). Reaction time: 20 days; yield: 41%;
Rf (20% EtOAc in hexanes) 0.37; pale yellow viscous liquid; IR
(neat): ν 3477, 3287, 2982, 2121, 1711, 1612 cm-1; 1H NMR (400
MHz): δ 1.26 (t, 3H, J = 7.2 Hz), 2.52 (t, 1H, J = 2.4 Hz), 3.25 (b
s, 1H), 3.80 (s, 3H), 4.18 (q, 2H, J = 7.2 Hz), 4.69 (d, 2H, J = 2.4
Hz), 5.77 (s, 1H), 5.83 (s, 1H), 6.31 (s, 1H), 6.53 (dd, 1H, J = 2.0
4.2.4.
Methyl
3-hydroxy-3-[4-methoxy-2-(prop-2-ynyloxy)-
phenyl]-2-methylenepropanoate (3c). Reaction time: 20 days;
yield: 30%; Rf (20% EtOAc in hexanes) 0.30; colorless viscous
1
liquid; IR (neat): ν 3493, 3287, 2953, 2121, 1722, 1612 cm-1; H
NMR (400 MHz): δ 2.52 (t, 1H, J = 2.4 Hz), 3.25 (d, 1H, J = 6.0
Hz), 3.73 (s, 3H), 3.80 (s, 3H), 4.69 (d, 2H, J = 2.0 Hz), 5.78 (s,
1H), 5.82 (d, 1H, J = 6.0 Hz), 6.31 (s, 1H), 6.53 (dd, 1H, J = 2.4
& 8.4 Hz), 6.57 (d, 1H, J = 2.4 Hz), 7.28 (d, 1H, J = 8.4 Hz); 13
C
NMR (100 MHz): δ 13.97, 55.25, 56.05, 60.65, 67.29, 75.78,
78.29, 99.91, 105.35, 122.53, 125.21, 128.44, 141.72, 155.60,
160.12, 166.51; HRMS (ESI) exact mass calc’d for C16H18O5+Na
(M+Na)+: 313.1052, found: 313.1049.
& 8.8 Hz), 6.57 (d, 1H, J = 2.4 Hz), 7.27 (d, 1H, J = 8.8 Hz); 13
C
NMR (100 MHz): δ 51.77, 55.26, 56.06, 67.32, 75.81, 78.28,
99.96, 105.39, 122.43, 125.57, 128.42, 141.44, 155.59, 160.16,
166.95; HRMS (ESI) exact mass calc’d for C15H16O5+Na (M+Na)+:
299.0895, found: 299.0893.
4.2.10. Ethyl 3-[5-bromo-2-(prop-2-ynyloxy)phenyl]-3-hydroxy-
2-methylenepropanoate (3i). Reaction time: 14 days; yield: 87%;
Rf (20% EtOAc in hexanes) 0.54; pale yellow viscous liquid; IR
(neat): ν 3460, 3294, 2982, 2121, 1709, 1630 cm-1; 1H NMR (400
MHz): δ 1.29 (t, 3H, J = 7.2 Hz), 2.51 (t, 1H, J = 2.4 Hz), 3.37
(d, 1H, J = 5.6 Hz), 4.22 (q, 2H, J = 7.2 Hz), 4.69 (d, 2H, J = 2.4
Hz), 5.70 (s, 1H), 5.84 (d, 1H, J = 5.6 Hz), 6.33 (s, 1H), 6.87 (d,
1H, J = 8.8 Hz), 7.38 (dd, 1H, J = 2.4 & 8.8 Hz), 7.56 (d, 1H, J =
2.4 Hz); 13C NMR (100 MHz): δ 14.09, 56.27, 61.03, 67.36,
76.09, 77.96, 113.92, 114.22, 126.34, 130.76, 131.38, 132.33,
4.2.5. Methyl 3-[5-bromo-2-(prop-2-ynyloxy)phenyl]-3-hydroxy-
2-methylenepropanoate (3d). Reaction time: 14 days; yield: 83%;
Rf (20% EtOAc in hexanes) 0.53; pale yellow viscous liquid; IR
(neat): ν 3466, 3292, 2953, 2121, 1716, 1631 cm-1; 1H NMR (400
MHz): δ 2.51 (t, 1H, J = 2.4 Hz), 3.33 (d, 1H, J = 5.6 Hz), 3.77
(s, 3H), 4.69 (d, 2H, J = 2.0 Hz), 5.71 (s, 1H), 5.85 (d, 1H, J =
6.0 Hz), 6.33 (s, 1H), 6.87 (d, 1H, J = 8.8 Hz), 7.38 (dd, 1H, J =
2.4 & 8.8 Hz), 7.55 (d, 1H, J = 2.4 Hz); 13C NMR (100 MHz): δ

ACCEPTED MANUSCRIPT
6
Tetrahedron
140.82, 153.55, 166.46; HRMS (ESI) exact mass calc’d for
(20% EtOAc in hexanes) 0.48; colorless viscous liquid; IR (neat):
ν 3292, 2953, 2123, 1743, 1728, 1635 cm-1; 1H NMR (400 MHz):
δ 2.12 (s, 3H), 2.49 (s, 1H), 3.75 (s, 3H), 4.71 (s, 2H), 5.69 (s,
1H), 6.43 (s, 1H), 6.94-7.00 (m, 2H), 7.23-7.29 (m, 2H); 13C
NMR (100 MHz): δ 20.95, 52.04, 56.43, 67.45, 75.98, 78.00,
113.91, 126.54, 127.66, 127.86, 128.74, 129.12, 138.37, 153.39,
165.38, 169.25. HRMS (ESI) exact mass calc’d for C16H15ClO5+Na
(M+Na)+: 345.0506, found: 345.0510.
C15H15BrO4+Na (M+Na)+: 361.0051, found: 361.0056.
4.2.11. Methyl 3-acetoxy-2-methylene-3-[2-(prop-2-ynyloxy)-
phenyl]propanoate (4a). To a stirring solution of methyl 3-
hydroxy-2-methylene-3-[2-(prop-2-ynyloxy)phenyl]propanoate
(3a) (10 mmol, 2.46 g) in dichloromethane (10 mL) was added
pyridine (20 mmol, 1.58 g, 1.62 mL) followed by acetyl chloride
(20 mmol, 1.57 g, 1.42 mL) at 0 oC. After stirring at room
temperature for 2 h, reaction mixture was diluted with diethyl
ether (20 mL) and 2N HCl (15 mL). Organic layer was separated
and was washed successively with saturated aq. NaHCO3
solution, water and dried over anhydrous Na2SO4. Crude product
thus obtained after solvent evaporation, was purified by column
chromatography (5% EtOAc in hexanes) to provide the desired
product as a colorless viscous liquid in 85% (2.46 g) isolated
yield.
4.2.16. Ethyl 3-acetoxy-2-methylene-3-[2-(prop-2-ynyloxy)-
phenyl]propanoate (4f). Reaction time: 2 h; yield: 88%; Rf (20%
EtOAc in hexanes) 0.50; pale yellow viscous liquid; IR (neat): ν
3287, 2984, 2121, 1743, 1720, 1637 cm-1; 1H NMR (400 MHz): δ
1.23 (t, 3H, J = 7.2 Hz), 2.11 (s, 3H), 2.48 (s, 1H), 4.18 (q, 2H, J
= 7.2 Hz), 4.73 (s, 2H), 5.64 (s, 1H), 6.40 (s, 1H), 6.93-7.07 (m,
3H), 7.22-7.34 (m, 2H); 13C NMR (100 MHz): δ 13.98, 20.93,
56.08, 60.77, 67.98, 75.52, 78.44, 112.44, 121.34, 126.77,
126.82, 127.91, 129.34, 139.13, 154.89 165.14, 169.30. HRMS
(ESI) exact mass calc’d for C17H18O5+Na (M+Na)+: 325.1052,
found: 325.1050.
Rf (20% EtOAc in hexanes) 0.49; colorless viscous liquid; IR
(neat): ν 3287, 2955, 2121, 1739, 1728, 1635 cm-1; 1H NMR (400
MHz): δ 2.11 (s, 3H), 2.48 (t, 1H, J = 2.4 Hz), 3.73 (s, 3H), 4.72
(d, 2H, J = 2.4 Hz), 5.67 (s, 1H), 6.41 (s, 1H), 6.97-7.06 (m, 3H),
7.27-7.34 (m, 2H); 13C NMR (100 MHz): δ 20.86, 51.84, 56.00,
67.90, 75.52, 78.38, 112.41, 121.30, 126.63, 127.11, 127.78,
129.34, 138.80, 154.81, 165.53, 169.26; HRMS (ESI) exact mass
calc’d for C16H16O5+Na (M+Na)+: 311.0895, found: 311.0898.
4.2.17. Ethyl 3-acetoxy-3-[3-methoxy-2-(prop-2-ynyloxy)phenyl]-
2-methylenepropanoate (4g). Reaction time: 2 h; yield: 86%; Rf
(20% EtOAc in hexanes) 0.45; pale yellow viscous liquid; IR
(neat): ν 3285, 2982, 2945, 2125, 1743, 1722, 1637 cm-1; 1H
NMR (400 MHz): δ 1.24 (t, 3H, J = 7.2 Hz), 2.10 (s, 3H), 2.49 (t,
1H, J = 2.4 Hz), 3.86 (s, 3H), 4.18 (q, 2H, J = 7.2 Hz), 4.74 &
4.81 (dABq, 2H, J = 2.4 & 15.2 Hz), 5.66 (s, 1H), 6.41 (s, 1H),
6.89 (s, 1H) 6.91 (s, 1H), 7.03-7.10 (m, 2H); 13C NMR (100
MHz): δ 14.09, 21.10, 55.84, 60.06, 60.87, 68.67, 75.17, 79.32,
112.51, 119.72, 124.45, 127.04, 132.09, 139.28, 144.71, 152.57,
165.15, 169.34. HRMS (ESI) exact mass calc’d for C18H20O6+Na
(M+Na)+: 355.1158, found: 355.1164.
Similar procedure was followed for synthesis of Baylis-Hilman
acetates 4b-i.
4.2.12. Methyl 3-acetoxy-3-[3-methoxy-2-(prop-2-ynyloxy)-
phenyl]-2-methylenepropanoate (4b). Reaction time: 2 h; yield:
90%; Rf (20% EtOAc in hexanes) 0.40; pale yellow viscous
liquid; IR (neat): ν 3288, 2951, 2125, 1736, 1720, 1635 cm-1; H
1
NMR (400 MHz): δ 2.10 (s, 3H), 2.49 (t, 1H, J = 2.4 Hz), 3.73 (s,
3H), 3.86 (s, 3H), 4.75 & 4.81 (dABq, 2H, J = 2.4 & 14.8 Hz),
5.70 (d, 1H, J = 0.8 Hz), 6.42 (s, 1H), 6.87-6.92 (m, 2H), 7.03-
7.10 (m, 2H); 13C NMR (100 MHz): δ 20.91, 51.82, 55.69, 59.88,
68.44, 75.13, 79.15, 112.46, 119.50, 124.33, 127.08, 131.82,
138.90, 144.54, 152.45, 165.42, 169.17; HRMS (ESI) exact mass
calc’d for C17H18O6+Na (M+Na)+: 341.1001, found: 341.0998.
4.2.18. Ethyl 3-acetoxy-3-[4-methoxy-2-(prop-2-ynyloxy)phenyl]-
2-methylenepropanoate (4h). Reaction time: 2 h; yield: 87%; Rf
(20% EtOAc in hexanes) 0.41; pale yellow viscous liquid; IR
(neat): ν 3283, 2982, 2123, 1743, 1724, 1612 cm-1; 1H NMR (400
MHz): δ 1.23 (t, 3H, J = 7.2 Hz), 2.09 (s, 3H), 2.50 (t, 1H, J = 2.0
Hz), 3.80 (s, 3H), 4.16 (q, 2H, J = 7.2 Hz), 4.71 (d, 2H, J = 1.6
Hz), 5.68 (s, 1H), 6.40 (s, 1H), 6.51 (dd, 1H, J = 2.4 & 8.4 Hz),
6.61 (d, 1H, J = 2.0 Hz), 6.97 (s, 1H), 7.17 (d, 1H, J = 8.4 Hz);
13C NMR (100 MHz): δ 13.90, 20.84, 55.19, 56.07, 60.64, 67.78,
75.64, 78.26, 100.02, 105.36, 118.95, 126.00, 128.81, 139.26,
156.01, 160.70, 165.06, 169.25; HRMS (ESI) exact mass calc’d for
C18H20O6+Na (M+Na)+: 355.1158, found: 355.1160.
4.2.13. Methyl 3-acetoxy-3-[4-methoxy-2-(prop-2-ynyloxy)-
phenyl]-2-methylenepropanoate (4c). Reaction time: 2 h; yield:
85%; Rf (20% EtOAc in hexanes) 0.38; pale yellow viscous
1
liquid; IR (neat): ν 3285, 2955, 2121, 1739, 1728, 1614 cm-1; H
NMR (400 MHz): δ 2.09 (s, 3H), 2.50 (t, 1H, J = 2.0 Hz.), 3.72
(s, 3H), 3.80 (s, 3H), 4.70 (d, 2H, J = 2.0 Hz), 5.71 (d, 1H, J =
0.8 Hz), 6.40 (s, 1H), 6.51 (dd, 1H, J = 2.0 & 8.4 Hz), 6.60 (d,
1H, J = 2.0 Hz), 6.96 (s, 1H), 7.17 (d, 1H, J = 8.4 Hz); 13C NMR
(100 MHz): δ 20.88, 51.81, 55.24, 56.11, 67.81, 75.65, 78.28,
100.11, 105.42, 118.92, 126.40, 128.80, 138.99, 156.04, 160.76,
165.56, 169.32; HRMS (ESI) exact mass calc’d for C17H18O6+Na
(M+Na)+: 341.1001, found: 341.1006.
4.2.19. Ethyl 3-acetoxy-3-[5-bromo-2-(prop-2-ynyloxy)phenyl]-
2-methylenepropanoate (4i). Reaction time: 2 h; yield: 92%; Rf
(20% EtOAc in hexanes) 0.50; pale yellow viscous liquid; IR
(neat): ν 3292, 2984, 2123, 1745, 1722, 1635 cm-1; 1H NMR (400
MHz): δ 1.25 (t, 3H, J = 7.2 Hz), 2.12 (s, 3H), 2.49 (t, 1H, J = 2.0
Hz), 4.19 (q, 2H, J = 7.2 Hz), 4.71 (d, 2H, J = 1.6 Hz), 5.66 (s,
1H), 6.43 (s, 1H), 6.91 (d, 1H, J = 8.0 Hz), 6.97 (s, 1H), 7.37-
7.44 (m, 2H); 13C NMR (100 MHz): δ 14.04, 20.96, 56.36, 60.95,
67.44, 76.02, 77.94, 113.83, 114.31, 127.37, 129.19, 130.81,
132.04, 138.59, 153.92, 164.90, 169.20; HRMS (ESI) exact mass
calc’d for C17H17BrO5+Na (M+Na)+: 403.0157, found: 403.0158.
4.2.14. Methyl 3-acetoxy-3-[5-bromo-2-(prop-2-ynyloxy)phenyl]-
2-methylenepropanoate (4d). Reaction time: 2 h; yield: 90%; Rf
(20% EtOAc in hexanes) 0.45; pale yellow viscous liquid; IR
(neat): ν 3292, 2953, 2123, 1743, 1732, 1635 cm-1; 1H NMR (400
MHz): δ 2.12 (s, 3H), 2.49 (s, 1H)*, 3.75 (s, 3H), 4.71 (s, 2H),
4.2.20.
Methyl
(E)-2-(azidomethyl)-3-[2-(prop-2-ynyloxy)-
5.69 (s, 1H), 6.43 (s, 1H), 6.92 (d, 1H, J = 8.4 Hz), 6.97 (s, 1H),
phenyl]prop-2-enoate (5a). To a stirring solution of methyl 3-
acetoxy-2-methylene-3-[2-(prop-2-ynyloxy)phenyl]propanoate
(4a) (5 mmol, 1.44 g) in DMSO (10 mL) was added sodium
azide (7.5 mmol, 0.48 g) and stirred for 3 h at room temperature.
Then the reaction mixture was diluted with ethyl acetate (50 mL)
and washed with water (3 X 10 mL) (to remove DMSO). Organic
layer was dried over anhydrous Na2SO4. The solvent was
removed in vacuo. Residue thus obtained was purified by column
*
7.36-7.44 (m, 2H); unresolved triplet. 13C NMR (100 MHz): δ
20.93, 52.02, 56.34, 67.34, 76.01, 77.92, 113.83, 114.34, 127.63,
129.12, 130.70, 132.08, 138.34, 153.88, 165.33, 169.20; HRMS
(ESI) exact mass calc’d for C16H15BrO5+Na (M+Na)+: 389.0001,
found: 388.9999.
4.2.15. Methyl 3-acetoxy-3-[5-chloro-2-(prop-2-ynyloxy)phenyl]-
2-methylenepropanoate (4e). Reaction time: 2 h; yield: 91%; Rf

ACCEPTED MANUSCRIPT
7
chromatography (10% ethyl acetate in hexanes) on silica gel to
4.2.22. 16-Methoxy-10-methoxycarbonyl-2-oxa-6,7,8-triazatri-
afford 85% (1.160 g) of the title compound as a colorless viscous
liquid. (optimization for obtaining 5a from 4a was performed on
1.0 mmol scale of 4a).
cyclo[10.4.0.04,8]hexadeca-1(12),4,6,10,13,15-hexaene
(6b).
Reaction time: 3 h + 4 h; yield: 68%; Rf (50% EtOAc in hexanes)
0.16; colorless solid; mp: 185-188 C; IR (KBr): ν 1709, 1631 cm-1;
o
1H NMR (400 MHz): δ 3.88 (s, 3H), 3.94 (s, 3H), 5.28 (s, 4H), 6.81-
6.86 (m, 1H), 6.98 (dd, 1H, J = 1.2 & 8.0 Hz), 7.10-7.17 (m, 1H),
7.57 (s, 1H), 7.77 (s, 1H); 13C NMR (100 MHz): δ 46.04, 52.42,
55.86, 64.38, 113.22, 122.20, 124.64, 126.95, 127.24, 132.09,
134.84, 140.37, 145.29, 152.47, 166.21; HRMS (ESI) exact mass
calc’d for C15H15N3O4+Na (M+Na)+: 324.0960, found: 324.0956.
Rf (20% EtOAc in hexanes) 0.52; colorless viscous liquid; IR
(neat): ν 3292, 2951, 2094, 1714, 1633 cm-1; 1H NMR (400
MHz): δ 2.53 (t, 1H, J = 2.4 Hz), 3.89 (s, 3H), 4.15 (s, 2H), 4.76
(d, 2H, J = 2.4 Hz), 7.02-7.11 (m, 2H), 7.35-7.43 (m, 2H), 8.11
(s, 1H); 13C NMR (100 MHz): δ 47.48, 52.34, 56.04, 76.09,
78.12, 112.26, 121.51, 123.81, 126.84, 130.36, 131.03, 140.27,
155.67, 167.45; HRMS (ESI) exact mass calc’d for C14H13N3O3+Na
(M+Na)+: 294.0855, found: 294.0858.
4.2.23. 15-Methoxy-10-methoxycarbonyl-2-oxa-6,7,8-triazatri-
cyclo[10.4.0.04,8]hexadeca-1(12),4,6,10,13,15-hexaene
(6c).
Reaction time: 4 h + 4 h; yield: 63%; Rf (50% EtOAc in hexanes)
4.2.21.
10-Methoxycarbonyl-2-oxa-6,7,8-triazatricyclo-
o
0.18; colorless solid; mp: 145-148 C; IR (KBr): ν 1714, 1632 cm-1;
[10.4.0.04,8]hexadeca-1(12),4,6,10,13,15-hexaene (6a).
1H NMR (400 MHz): δ 3.83 (s, 3H), 3.85 (s, 3H), 5.26 (s, 2H), 5.43
(s, 2H), 6.70 (d, 1H, J = 2.4 Hz), 6.74 (dd, 1H, J = 2.8 & 8.8 Hz),
7.25 (d, 1H, J = 8.8 Hz, [one of the peak of the doublet merges with
[CDCl3] CHCl3 peak], 7.58 (s, 1H), 7.86 (s, 1H), 13C NMR (100
MHz): δ 46.36, 52.41, 55.51, 64.65, 107.10, 110.41, 116.91, 123.14,
131.92, 133.01, 134.65, 141.41, 158.69, 162.17, 166.61; HRMS
(ESI) exact mass calc’d for C15H15N3O4+Na (M+Na)+: 324.0960,
found: 324.0967.
Method A: To a stirring solution of methyl 2-(azidomethyl)-3-
[2-(prop-2-ynyloxy)phenyl]prop-2-enoate (5a) (1 mmol, 0.271 g)
in toluene (2 ml) was heated under reflux for 4 h (reaction
monitered by TLC) and reaction mixture was cooled to room
temperature. Solvent was removed in vacuo and purification of
the residue by column chromatography (60% ethyl acetate in
hexanes) on silica gel afforded 0.217 g (80%) of the title
compound as a colorless solid.
4.2.24.
14-Bromo-10-methoxycarbonyl-2-oxa-6,7,8-triazatri-
(6d).
cyclo[10.4.0.04,8]hexadeca-1(12),4,6,10,13,15-hexaene
Rf (50% EtOAc in hexanes) 0.30; colorless solid; mp: 148-150 oC;
IR (KBr): ν 1714, 1628 cm-1; H NMR (400 MHz): δ 3.86 (s, 3H),
1
Reaction time: 3 h + 5 h; yield: 57%; Rf (50% EtOAc in hexanes)
o
0.30; colorless solid; mp: 212-214 C; IR (KBr): ν 1711, 1631 cm-1;
5.29 (s, 2H), 5.38 (s, 2H), 7.16-7.22 (m, 2H), 7.29-7.34 (m, 1H),
7.37-7.45 (m, 1H), 7.58 (s, 1H), 7.87 (s, 1H); 13C NMR (100 MHz):
δ 46.46, 52.65, 64.87, 121.44, 124.29, 124.87, 125.93, 131.60,
132.09, 132.68, 133.65, 140.96, 157.16, 166.38; HRMS (ESI) exact
mass calc’d for C14H13N3O3+H (M+H)+: 272.1035, found: 272.1035.
1H NMR (400 MHz): δ 3.86 (s, 3H), 5.27 (s, 2H), 5.36 (s, 2H), 7.06
(d, 1H, J = 8.4 Hz), 7.43 (d, 1H, J = 2.4 Hz), 7.50 (dd, 1H, J = 2.8 &
8.4 Hz), 7.58 (s, 1H), 7.76 (s, 1H); 13C NMR (100 MHz): δ 46.40,
52.82, 65.01, 116.88, 123.20, 126.97, 127.24, 132.28, 133.45,
134.31, 134.84, 139.15, 156.15, 166.01; HRMS (ESI) exact mass
calc’d for C14H12BrN3O3+Na (M+Na)+: 371.9960, found: 371.9959.
Crystal data for 6a: Empirical formula, C14H13N3O3; Formula
weight, 271.27; crystal color, colorless; habit, block; crystal
dimensions, 0.52 x 0.48 x 0.40 mm3; crystal system, monoclinic;
lattice type, C centered; lattice parameters, a = 19.4754(15) Å, b
= 10.3699(8) Å, c = 15.3638(12) Å, α = 90.00, β = 125.1930(10),
4.2.25.
14-Chloro-10-methoxycarbonyl-2-oxa-6,7,8-triazatri-
(6e).
cyclo[10.4.0.04,8]hexadeca-1(12),4,6,10,13,15-hexaene
Reaction time: 3 h + 4 h; yield: 62%; Rf (50% EtOAc in hexanes)
o
0.28; colorless solid; mp: 204-206 C; IR (KBr): ν 1711, 1633 cm-1;
γ = 90.00; V = 2535.7(3) Å3; space group, C2/c; Z = 8; Dcald
=
1H NMR (400 MHz): δ 3.86 (s, 3H), 5.27 (s, 2H), 5.36 (s, 2H), 7.12
(d, 1H, J = 8.4 Hz), 7.28 (d, 1H, J = 2.8 Hz), 7.35 (dd, 1H, J = 2.8 &
8.4 Hz), 7.58 (s, 1H), 7.76 (s, 1H); 13C NMR (100 MHz): δ 46.33,
52.74, 65.00, 122.80, 126.50, 127.20, 129.38, 131.30, 131.76,
132.19, 133.48, 139.14, 155.53, 165.97; HRMS (ESI) exact mass
calc’d for C14H12ClN3O3+Na (M+Na)+: 328.0465, found: 328.0475.
1.421 g / cm3; F000 = 1136; λ (Mo-Kα) = 0.71073 Å; R(I≥2σ1) =
0.0384, wR2 = 0.0958. Detailed X-ray crystallographic data is
available from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK (for compound 6a CCDC
# 956293).
Method B: (From methyl 3-acetoxy-2-methylene-3-[2-(prop-2-
4.2.26. 10-Ethoxycarbonyl-2-oxa-6,7,8-triazatricyclo-[10.4.0.-
04,8]hexadeca-1(12),4,6,10,13,15-hexaene (6f). Reaction time: 4 h
+ 4 h; yield: 58%; Rf (50% EtOAc in hexanes) 0.26; colorless solid;
ynyloxy)phenyl]propanoate (4a) without isolating azido-alkyne
5a)
mp: 88-89 C; IR (KBr): ν 1709, 1639 cm-1; 1H NMR (400 MHz): δ
To a stirring solution of methyl 3-acetoxy-2-methylene-3-[2-
(prop-2-ynyloxy)phenyl]propanoate (4a) (1.0 mmol, 0.288 g) in
DMSO (2 mL) was added sodium azide (1.5 mmol, 0.096 g) and
stirred for 3 h at room temperature. Then the reaction mixture
was diluted with ethyl acetate (15 mL) and washed with water (3
X 2 mL) (to remove the DMSO). Organic layer was dried over
anhydrous Na2SO4. The solvent was removed in vacuo. The
crude azido-alkyne 5a was dissolved in toluene (2 ml) and
refluxed for 4 h and reaction mixture was cooled to room
temperature and solvent was removed in vacuo and purification
of the residue by column chromatography (60% ethyl acetate in
hexanes) on silica gel afforded 0.195 g (72%) of the title
compound as a colorless solid for overall two steps from methyl
3-acetoxy-2-methylene-3-[2-(prop-2-ynyloxy)phenyl]propaneate
o
1.35 (t, 3H, J = 7.2 Hz), 4.30 (q, 2H, J = 7.2 Hz), 5.29 (s, 2H), 5.39
(s, 2H), 7.15-7.22 (m, 2H), 7.31 (d, 1H, J = 7.2 Hz), 7.37-7.43 (m,
1H), 7.57 (s, 1H), 7.86 (s, 1H); 13C NMR (100 MHz): δ 14.20, 46.51,
61.80, 64.88, 121.51, 124.32, 124.93, 126.19, 131.55, 132.11,
132.78, 133.60, 140.67, 157.20, 165.93; HRMS (ESI) exact mass
calc’d for C15H15N3O3+Na (M+Na)+: 308.1011, found: 308.1017.
4.2.27.
10-Ethoxycarbonyl-16-methoxy-2-oxa-6,7,8-triazatri-
(6g).
cyclo[10.4.0.04,8]hexadeca-1(12),4,6,10,13,15-hexaene
Reaction time: 3 h + 4 h; yield: 65%; Rf (50% EtOAc in hexanes)
o
0.21; colorless solid; mp: 160-162 C; IR (KBr): ν 1705, 1633 cm-1;
1H NMR (400 MHz): δ 1.37 (t, 3H, J = 7.2 Hz), 3.94 (s, 3H), 4.33 (q,
2H, J = 7.2 Hz), 5.277 (s, 2H), 5.284 (s, 2H), 6.81-6.86 (m, 1H), 6.98
(dd, 1H, J = 1.2 & 8.0 Hz), 7.10-7.16 (m, 1H), 7.56 (s, 1H), 7.76 (s,
1H); 13C NMR (100 MHz): δ 14.10, 46.10, 55.90, 61.54, 64.39,
113.20, 122.32, 124.64, 127.08, 127.56, 132.11, 134.78, 139.98,
145.34, 152.52, 165.75; HRMS (ESI) exact mass calc’d for
C16H17N3O4+Na (M+Na)+: 338.1117, found: 338.1114.
1
(4a). Mp, spectral data (IR, HNMR, 13CNMR, HRMS) data of
this compound are in complete agreement with the data of the
compound prepared via method A.
Compounds 6b-i were prepared following the procedure as in
Method B.

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8
Tetrahedron
10994−10997; (c) Reddy, M. N.; Kumara Swamy, K. C. Eur. J. Org.
4.2.28. 10-Ethoxycarbonyl-15-methoxy-2-oxa-6,7,8-triazatri-
cyclo[10.4.0.04,8]hexadeca-1(12),4,6,10,13,15-hexaene
(6h).
Chem. 2012, 2013-2022; (d) Hu, Y-Y.; Hu, J.; Wang, X-C.; Guo, L-
N.; Shu, X-Z.; Niu, Y-N.; Liang, Y-M. Tetrahedron 2010, 66, 80–
86; (e) Li, R.; Jansen, D. J.; Datta, A. Org. Biomol. Chem. 2009, 7,
1921–1930; (f) Klemm, C. M.; Berthelmann, A.; Neubacher, S.;
Arenz, C. Eur. J. Org. Chem. 2009, 2788–2794; (g) Jin, S.;
Choudhary, G.; Cheng, Y.; Dai, C.; Li, M.; Wang, B. Chem.
Commun. 2009, 5251–5253; (h) Meldal, M.; Tornøe, C. W. Chem.
Rev. 2008, 108, 2952–3015; (i) Moses, J. E.; Moorhouse, A. D.
Chem. Soc. Rev. 2007, 36, 1249–1262; (j) Huisgen, R. Proceedings
of the Chemical Society 1961, 357- 396.
Reaction time: 10 h + 4 h; yield: 68%; Rf (50% EtOAc in hexanes)
0.27; colorless solid; mp: 140-142 oC; IR (KBr): ν 1703, 1610 cm-1;
1H NMR (400 MHz): δ 1.33 (t, 3H, J = 7.2 Hz), 3.85 (s, 3H), 4.27 (q,
2H, J = 7.2 Hz), 5.26 (s, 2H), 5.44 (s, 2H), 6.69 (d, 1H, J = 2.4 Hz),
6.74 (dd, 1H, J = 2.4 & 8.8 Hz), 7.25 (d, 1H, J = 8.4 Hz), 7.57 (s,
1H), 7.84 (s, 1H); 13C NMR (100 MHz): δ 14.20, 46.53, 55.63,
61.63, 64.78, 107.27, 110.55, 117.07, 123.57, 132.07, 132.98,
134.86, 141.21, 158.86, 162.23, 166.25; HRMS (ESI) exact mass
calc’d for C16H17N3O4+Na (M+Na)+: 338.1117, found: 338.1119.
5. (a) Oliva, A. I.; Christmann, U.; Font, D.; Cuevas, F.; Ballester, P.;
Buschmann, H.; Torrens, A.; Yenes, S.; Pericas, M. A. Org. Lett.
2008, 10, 1617-1619; (b) Chandrasekhar, S.; Seenaiah, M.; Kumar, A.;
Reddy, C. R.; Mamidyala, S. K.; Kumar, C. G.; Balasubramanian, S.
Tetrahedron Lett. 2011, 52, 806-808; (c) Hotha, S.; Anegundi, R. I.;
Natu, A. A. Tetrahedron Lett. 2005, 46, 4585-4588;(d) Mishra, A.;
Hutait, S.; Bhowmik, S.; Rastogi, N.; Roy, R.; Batra, S. Synthesis
2010, 2731–2748.
4.2.29. 14-Bromo-10-ethoxycarbonyl-2-oxa-6,7,8-triazatricyclo-
[10.4.0.04,8]hexadeca-1(12),4,6,10,13,15-hexaene (6i). Reaction
time: 3 h + 4 h; yield: 71%; Rf (50% EtOAc in hexanes) 0.23;
colorless solid; mp: 166-169 C; IR (KBr): ν 1712, 1630 cm-1; H
NMR (400 MHz): δ 1.35 (t, 3H, J = 7.2 Hz), 4.30 (q, 2H, J = 7.2
Hz), 5.27 (s, 2H), 5.36 (s, 2H), 7.06 (d, 1H, J = 8.8 Hz), 7.44 (d, 1H
J = 2.0 Hz), 7.48 (dd, 1H, J = 2.4 & 8.8 Hz), 7.57 (s, 1H), 7.75 (s,
1H); 13C NMR (100 MHz): δ 14.25, 46.48, 62.06, 65.05, 116.96,
123.30, 127.05, 127.53, 132.36, 133.34, 134.29, 135.02, 138.86,
156.22, 165.57; HRMS (ESI) exact mass calc’d for
C15H14N3O3Br+Na (M+Na)+: 386.0116, found: 386.0112.
o
1
6. (a) Basavaiah, D.; Badsara, S. S.; Sahu, B. C. Chem. Eur. J. 2013,
19, 2961-2965; (b) Basavaiah, D.; Kumar, K. S.; Aravindu, K.;
Lingaiah, B. RSC Adv, 2013, 3, 9629-9632. (c) Basavaiah, D.;
Badsara, S. S.; Veeraraghavaiah, G. Tetrahedron 2013, 69, 7995-
8001; (d) Basavaiah, D.; Reddy, D. M. Org. Biomol. Chem. 2012, 10,
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Acknowledgement: We thank DST (New Delhi) for funding this
project. BSR thanks CSIR and DST (New Delhi) for research
fellowships. HL thanks CSIR for her research fellowship. We
thank UGC (New Delhi) for support and for providing some
instrumental facilities. We thank the National Single-Crystal X-
ray facility funded by DST. We also thank Professor S. Pal,
School of Chemistry, University of Hyderabad, for helpful
discussions regarding X-ray data analysis.
7. For reviews see (a) Basavaiah, D.; Sahu, B. C. Chimia 2013, 67, 8-16;
(b) Wei, Y.; Shi, M. Chem. Rev. 2013, 113, 6659-6690; (c) Liu, T. Y.;
Xie, M.; Chen, Y. C. Chem. Soc. Rev. 2012, 41, 4101-4112; (d)
Basavaiah, D.; Veeraraghavaiah, G. Chem. Soc. Rev. 2012, 41, 68-78;
(e) Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Chem. Rev. 2010, 110,
5447-5674; (f) Wei, Y.; Shi, M. Acc. Chem. Res. 2010, 43, 1005-
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(i) Masson, G.; Housseman, C.; Zhu, J. Angew. Chem. Int. Ed. 2007,
46, 4614-4628; (j) Basavaiah, D.; Rao, K. V.; Reddy, R. J. Chem. Soc.
Rev. 2007, 36, 1581-1588; (k) Basavaiah, D.; Rao, A. J.;
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1996, 52, 8001-8062; (o) Drewes, S. E.; Roos, G. H. P. Tetrehedron
1988, 44, 4653-4670.
References and notes
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trisubstituted alkenes the olefinic proton cis to the ester group
appears downfield in comparison with that of the olefinic protons
trans to ester group. (E)-Stereochemistry of C10-C11- double bond
in the compounds 6a-i is assigned on the basis of chemical shift
values (δ 7.75-7.87) of olefinic proton at C-11 carbon. (ref.
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crystal X-ray data analysis.11
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Supporting Information
Synthesis of fused nine membered rings: A simple protocol for synthesis
of [1,2,3]-triazolo-[1,4]-benzoxazonine frameworks from the Baylis-
Hillman acetates
Deevi Basavaiah*, Bhavanam Sekhara Reddy and Harathi Lingam
School Of Chemistry, University Of Hyderabad
Central University (PO), Gachibowli, Hyderabad 500 046, India
dbsc@uohyd.ernet.in, Fax +91 40 23012460
CONTENTS
1.
2.
ORTEP diagram of compound 6a
S2
1H and 13C NMR Spectra for the compounds 6a-6i
S3-S20
S1

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Crystal data for 6a: Empirical formula, C14H13N3O3; Formula weight, 271.27; crystal color,
colorless; habit, block; crystal dimensions, 0.52 x 0.48 x 0.40 mm3; crystal system, monoclinic;
lattice type, C centered; lattice parameters, a = 19.4754(15) Å, b = 10.3699(8) Å, c = 15.3638(12)
Å, α = 90.00, β = 125.1930(10), γ = 90.00; V = 2535.7(3) Å3; space group, C2/c; Z = 8; Dcald
=
1.421 g / cm3; F000 = 1136; λ (Mo-Kα) = 0.71073 Å; R(I≥2σ1) = 0.0384, wR2 = 0.0958. Detailed
X-ray crystallographic data is available from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK (for compound 6a CCDC # 956293).
Figure 1. ORTEP diagrams of compound 6a
S2

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