Click chemistry inspired synthesis of morpholine-fused triazoles

Article abstract of DOI:10.1021/jo500890w

The synthesis of triazolyl azido alcohols from terminal alkyne via oxirane ring-opening of epichlorohydrin, followed by click reaction with alkynes, and subsequent azidation of chlorohydroxy triazoles was achieved under a one-pot methodology. The develope

Full text of DOI:10.1021/jo500890w

Subscriber access provided by UNIV OF ALABAMA BIRMINGHAM
Article
Click Chemistry Inspired Synthesis of Morpholine-Fused Triazoles
Kunj B Mishra, and Vinod Kumar Tiwari
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo500890w • Publication Date (Web): 20 May 2014
Downloaded from http://pubs.acs.org on May 27, 2014
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
Click Chemistry Inspired Synthesis of MorpholineꢀFused Triazoles
Kunj B. Mishra and Vinod K. Tiwari*
7
8
9
Department of Chemistry, Centre of Advanced Study, Faculty of Science, Banaras Hindu
University, Varanasiꢀ221005, India
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
*Corresponding author: Eꢀmail: tiwari_chem@yahoo.co.in, Tel.: +91ꢀ542ꢀ6702466; fax: +91ꢀ
542ꢀ236817
Abstract:
The synthesis of triazolyl azido alcohols from terminal alkyne via oxirane ring opening of
epichlorohydrin followed by click reaction with alkynes, and subsequent azidation of
chlorohydroxy triazoles was achieved under oneꢀpot methodology. The developed triazolyl
azido alcohols were further utilized for the synthesis of diverse range of morpholine fused
triazoles of chemotherapeutic value. Structure of all developed compounds has been elucidated
using IR, NMR, MS and elemental analysis, where four of them have been characterized by
single crystal Xꢀray analysis.
Keywords: Click Chemistry, cyclization, triazole, morpholine fused triazole, glycoconjugate
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 36
1
2
3
4
INTRODUCTION
5
6
7
8
The development of new strategies for synthesis of mediumꢀsized heterocycles found in
numerous bioactive natural products and pharmaceutical molecules, has remained a highly
attractive but challenging proposition.1 Towards this end, the triazoloꢀmorpholine skeleton
(Figure 1), a privileged bicyclic ring system in myriad compounds of chemotherapeutic values,
is significant due to wide range of enzyme inhibitory activities such as glycosidase,
galactosidase, SGLT2, gamma secretes modulators etc.2 Also, a number of molecules
possessing morpholine skeleton are the clinically approved drugs.3,4 Furthermore, the triazoloꢀ
morpholine conjugation with carbohydrates would be effectively utilized for improving the
enzyme inhibitory activities, and thus, may enhance the interaction of these ligands to
carbohydrateꢀbinding proteins.2
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Biologically active morpholineꢀfused triazoles
Nowꢀaꢀdays, Cu(I) catalyzed click reaction5,6 has emerged as an important strategy for the
discovery and optimization of lead along with its exploration as an effective drug candidate
against various therapeutic strains.7ꢀ12 Moreover, incorporation of an azide and/or an alkyne
moiety in carbohydrate scaffolds unleashes the potential to access a new dimension of structural
diversity to the molecules via click reaction.13ꢀ15 Thus, we envisioned utilizing the click
2
ACS Paragon Plus Environment

Page 3 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
chemistry for induction of bicyclic systems in biologically relevant scaffolds. Recently, a library
of triazoleꢀfused polyheterocycles via a sequential Yb(OTf)3 catalyzed intermolecular Michael
addition followed by an intramolecular azideꢀalkyne 1,3ꢀdipolar cycloaddition reaction has been
reported.1d However, method is limited to 2ꢀarylꢀethynylꢀ1Hꢀindole and related heteroaromatic
skeletons and thus need to be investigated with wide range of substrate including carbohydrates.
Recently, glycosyl 1,2 azido alcohols, obtained from 1,2ꢀanhydro sugars with the aid of
Ce(NH4)2(NO3)6 mediated azidation, has successfully been utilized for the synthesis of
structurally diverse sugar based morpholine 1,5ꢀdisubstituted triazoles.2a Despite the tremendous
biological significance of morpholineꢀfused triazoles, their heterocyclic, carbocyclic, and
carbohydrate derivatives are relatively rare. To the best of our knowledge, the oneꢀpot synthesis
of triazolyl azido alcohols via oxirane ring opening of epichlorohydrin followed by click reaction
with alkynes, and subsequent azidation of chlorohydroxy triazoles in water is not well
investigated.16 Also, the application of triazolyl azido alcohols for the development of
morpholineꢀfused triazoles by propargylation and subsequent intramolecular azideꢀalkyne
cycloaddition under oneꢀpot methodology is yet to be realized fully.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Because of an increased demand for new carbohydrate scaffolds for the numerous
pharmacological investigations17,18 and also with our previous experience,19ꢀ22 we herein
describe a novel two step protocol for an easy access to diverse range of morpholineꢀfused [5,1ꢀ
c]ꢀtriazoles from terminal glycosyl and other alkynes.
RESULTS AND DISCUSSION
Our synthetic strategy begins with orthogonally protected sugars which on propargylation under
strong basic medium in dry DMF affords good yield of glycosyl alkynes (1aꢀh).23 We further
extended our investigation with Nꢀpropargylated and other commercially available alkynes (1iꢀ
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 36
1
2
3
4
5
6
7
8
9
o), which on treatment with epichlorohydrin (a wellꢀknown versatile synthons),24 and NaN3 in
presence of CuSO4.5H2O/NaAsc in H2O at room temperature under oneꢀpot condition delivered
triazolyl azido alcohols (3aꢀo) in good yields. The regioselective ring opening of
epichlorohydrin under the influence of NaN3 resulted in the formation of azidoꢀhydroxy
chloride in situ, which further underwent Cu(I)ꢀcatalyzed 1,3ꢀdipolar cycloaddition with
terminal alkynes to afford chlorohydroxy triazoles, isolated successfully in two cases (2a and
2j). We investigated the reaction extensively and observed that the reaction of alkyne 1a,
epichlorohydrin, NaN3 in a ratio of 1:1.2:1.2 using Copper catalyst in H2O furnished 2a in 65%
yield after 5h. In reaction optimization study to measure the effect of reagent concentration and
time on product yields, we reacted 1a (1.0 eq.) with epichlorohydrin (2.0 eq), NaN3 (4.0 eq) in
presence of CuSO4.5H2O (10 mol%) and NaAsc (20 mol%) for 12h, and isolated good yields of
compound 3a (58%) along with a side product βꢀhydroxy bisꢀtriazole 5 (25%) (Scheme 1).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Model reaction of glycosyl alkyne 1a
O
O
O
O
O
O
O
O
3a (Major)
+
N
N
N
N
O
O
O
O
OH
N
N
5
(25%)
epichlorohydrin (2.0 eq)
NaN3 (4.0 eq), H2O
CuSO4.5H2O (0.1 eq)
NaAsc (0.2 eq), H2O, 12h
O
O
O
O
O
epichlorohydrin (2.0 eq)
NaN3 (4.0 eq), H2O
CuSO4.5H2O (0.1 eq)
NaAsc (0.2 eq), H2O
12h, 58%
epichlorohydrin (1.2 eq)
NaN3 (1.2 eq), H2O
CuSO4.5H2O (0.1 eq)
NaAsc (0.2 eq), H2O
5h, 65%
O
1a (1.0 eq)
O
O
O
O
O
NaN3 (2.0 eq)
O
O
O
N3
N
N
Cl
N
N
Acetone/water
8 h, 60oC, 98%
O
O
O
O
OH
OH
N
N
3a
2a
4
ACS Paragon Plus Environment

Page 5 of 36
The Journal of Organic Chemistry
1
2
3
1
In 300 MHz H NMR spectrum of compound 3a, the signal for characteristic triazoleꢀH proton
was resonated at δ 7.74. The appearance of an intense absorption band at 2105 cmꢀ1 in IR
spectrum, was identified for the azide functionality in compound 3a. Thus, under the optimized
reaction conditions, a wide range of alkynes (1aꢀo) was readily reacted with epichlorohydrin, and
NaN3 in the presence of CuSO4.5H2O and NaAsc to afford azidoꢀhydroxyl triazoles (3aꢀo) in
good yields (Scheme 2, Table 1).
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Synthesis of triazolyl azido alcohols (3aꢀ3o)
Table 1. Synthesis of various carbohydrates and other triazolyl azido alcohols (3aꢀo)
entrya
Substrate
productb
yield (%)d
time
(h)c
1
12
58
3a
1a
2
3
10
11
50
58
1b
1c
3b
3c
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 36
1
2
3
4
5
6
7
8
9
4
5
12
10
63
52
1d
3d
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1e
1f
3e
3f
6
7
12
12
56
60
1g
3g
3h
8
9
11
8
62
40
1h
1i
3i
3j
10
11
9
9
60
62
1j
1k
3k
6
ACS Paragon Plus Environment

Page 7 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
12
13
8
55
56
1l
1m
1n
3l
10
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3m
3n
14
15
10
15
45
42
3o
1o
aMolar ratios: Carbohydrate and other alkyne (1 eq), epichlorohydrin (2 eq), NaN3 (4 eq),
b
CuSO4.5H2O (10 mol%), NaAsc (20 mol%), Carbohydrate and other triazolyl azido alcohols.
cReaction time. dYield reported after purification by column chromatography.
Interestingly, the reaction of 1i with epichlorohydrin, NaN3 using CuSO4.5H2O and NaAsc in
H2O led to the formation of 5i as a major product while compound 3i only in traces. However,
the same reaction when carried out in DMF/H2O (3:1) as a molecular solvent under heating
condition furnished 3i in good yields. The reaction of aromatic acetylenes proceeded relatively
faster in compared to glycosyl alkynes. Likewise, ethisterone, a steroidal alkyne showed poor
performance, and required at least 3.0 equivalents of epichlorohydrin to afford desired steroidal
azido alcohol 3o in 42% yields.
The regioselectivity in both steps i.e. ring opening reaction of epichlorohydrin with azide
nucleophile, and the cycloaddition with alkynes was evidenced by NMR spectrum and singleꢀ
crystal Xꢀray analysis of compound 2j (see the supporting information figure S1).The Xꢀray
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 36
1
2
3
4
5
6
7
8
9
crystallographic data of compound 2j, established the presence of an intramolecular CH…N and
OH…N interactions with a measured distances of 2.648 Å and 2.473 Å, respectively. Out of the
four conformers evidenced by single crystal Xꢀray, the intermolecular interaction were observed
in between triazoleꢀCH of the one conformer to triazoleꢀN2 and oxygenꢀatom of the others, in an
alternate manner as CH…N and CH...O interactions with a measured distance of 2.530 Å, 2.537 Å
and 2.665 Å, 2.609 Å, respectively (Figure 2).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. Inter molecular and intramolecular hydrogen bonding in 2j
Regioꢀselectivity of all developed azido alcohols also supported by NMR study of the two
dissimilar regioisomers 3a and 6 synthesized by treatment of model glycosyl alkyne and two
different oxiranes via styrene oxide and epichlorohydrin individually under same reaction
1
conditions (Figure 3). Because of overlapping of peaks in H NMR spectrum of developed
13
compound, C NMR is comparatively more clear and well suited for study on regioselectivity.
C1 of 3a is appeared at δ 53.06, which is shifted to δ 65.0 in 6, indicates the presence of a upꢀ
field carbon due to CH2ꢀtriazole in 3a and favoring for predicted regioselectivity; Also a shifting
in C2 carbon peak from δ 67.3 in 6 to δ 69.4 in 3a supported to presence of secondary hydroxyl
group in 3a
.
8
ACS Paragon Plus Environment

Page 9 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. Regioselectivity of oxirane ring opening and triazole formation through 13C NMR
analysis of 3a and 6
The developed 1,2ꢀazido hydroxyl triazoles (3aꢀo) were further successfully utilized for the
synthesis of morpholine fused [5,1ꢀc]triazoles (4aꢀo) in excellent yields ranging from 65 to 90%
via Oꢀpropargylation using NaH in dry DMF at ambient temperature followed by metal free
intramolecular cyclization of intermediate azido alkynes in DMF at 1100C for 12ꢀ16 hour
(Scheme 3, Table 2). The structure of compounds 4aꢀo was deduced from their extensive spectral
studies (IR, NMR, and MS) and single crystal Xꢀray analysis.
Scheme 3. Synthesis of morpholineꢀfused [1,5ꢀc]ꢀTriazoles
Table 2: Synthesis of morpholineꢀfused Triazoles (4aꢀo)
entrya
substrate
productb
time (h)c
yield
(%)d
1
16
90
3a
4a
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 36
1
2
3
4
5
2
16
85
3b
6
7
8
9
4b
4c
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
4
15
12
80
84
3c
3d
4d
4e
5
6
7
14
16
15
82
84
85
3e
3f
4f
3g
4g
4h
8
15
88
3h
10
ACS Paragon Plus Environment

Page 11 of 36
The Journal of Organic Chemistry
1
2
3
4
5
9
14
45
3i
6
7
8
9
4i
4j
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10
11
16
14
90
82
3j
3k
4k
4l
12
13
15
15
88
86
3l
3m
4m
4n
14
15
14
16
85
67
3n
3o
4o
aMolar ratios: Carbohydrate and other azidohydroxy triazoles (1.0 eq.), Propargyl Bromide (1.2
eq.), NaH (2.0 eq.), bMorpholineꢀfused triazoles. Reaction time. Yield reported after
c
d
purification by column chromatography.
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 36
1
2
3
1
The H NMR spectrum of compound 4a exhibited two singlets one proton each observed at δ
7.58 and 7.51 were assigned for the two triazoleꢀH protons. In addition to other signals, the
appearance of two double doublets at δ 5.13 and δ 4.70 (J = 15.0 Hz) attributed for OCH2 finally
confirmed the precedence of thermal cyclization leading to the formation of morpholine fused
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
skeleton. In C NMR, two resonances observed at δ 129.6 and δ 127.8 were assigned for [1,5]
triazoleꢀC. A shifting in the signal of CH2N3 from δ 53.1 to δ 46.7 corroborated the formation of
desired cyclized morpholine 1,5ꢀtriazole. The purity of compound 4a was evidenced by HRMS
spectra which displayed a molecular ion peak at 501.2057 (M+Na+).
1
13
Using extensive spectral studies (IR, MS, H and C NMR), the structures of all the developed
compounds 4aꢀo were elucidated. Furthermore, a single crystal Xꢀray analysis evidenced the
unambiguous structure of compounds 4d, 4j and 4n (see supporting information figure S2 to S4).
Weak Interactions in crystals 4d, 4j & 4n and their role in the stabilization of geometrical
conformations
The presence of weak nonꢀbonded interactions within the molecules 4d, 4j and 4n stabilized the
conformational property. The molecules are rich in CꢀH donors and O, N and π acceptors. In
morpholine ring, methylene hydrogens besides the triazole ring and methyne hydrogen near the
ethereal oxygen act as donor. Intramolecular and intermolecular CH…X (O, N), CH…π and
OH…N interactions stabilizes the geometry of the molecules and show their effects in relative
changes in geometrical conformations of the molecules.
Role of intramolecular weak interactions
The effect of variant (alkynes) and weak interactions on structural conformation of morpholine
fused triazoles with respect to 1,4ꢀ triazole was investigated through the change of intramolecular
12
ACS Paragon Plus Environment

Page 13 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
weak interactions observed in compounds 4d, 4j and 4n. The methyne hydrogens of morpholine
ring in 4n and 4j was involved in CꢀH10…N5 and CꢀH10…N1 interactions with measured
distances of 2.822 Å and 2.716 Å, respectively, however, absent in 4d. A methylene H18B of
same ring in 4d also involves CꢀH18B…N interaction which is absent in other two, thus forces
the face of bicyclic system towards 1,4 triazole ring in 4d. In addition, the resulted conformation
of 4d was stabilized by intermolecular NꢀH hydrogen bonding CꢀH18A…N11 (2.697 Å) and Cꢀ
H15B…N12 (2.714 Å) (Figure 4).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4. Stabilization of 4d via intra and intermolecular weak interactions involving
morpholine ring hydrogens
Likewise, methylene hydrogen present between morpholine and 1,4 triazole ring facilitates Cꢀ
H…O and CH…N interactions in compound 4d (2.359 & 2.478 Å), 4j (2.601 & 2.473 Å) and 4n
(2.555 & 2.617 Å), but common hydrogen participating in both interactions was found only in
case of 4j. This observation indicated for a possible turn of triazolo morpholine skeleton in 4j in
compared to 4n and 4d. Similarly, effect of variants are appeared by CꢀH12…O8 (2.868 Å)
interaction responsible for below the plane of targeted scaffolds in 4d wherever ring hydrogen
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 36
1
2
3
4
H1 of used alkynes is taking part in CH…N interaction in 4n (2.784 Å) and 4j (2.585 Å)
5
6
responsible for rigidity of skeleton above the plane (Figure 5).
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4d
4j
4n
Figure 5. Ball stick and space fill diagram of crystals 4d, 4j and 4n having intramolecular weak
interactions. Hydrogen bonds are represented by broken light green lines. Carbon atoms are
colored red, hydrogen atoms green, oxygen atoms yellow, and nitrogen atoms blue.
Role of intermolecular weak interactions
All these crystals also show weak intermolecular interactions and hydrogen bonding with in the
crystal packing, which effect their geometrical conformations and responsible for originating the
14
ACS Paragon Plus Environment

Page 15 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
dimeric forms. The dimeric forms appeared in all of three crystals 4d, 4j and 4n are originated
from different CH…N, CH… and OH…N interactions, respectively. The 4d dimer originates
7
8
9
through CH…N (2.697 & 2.606 Å) and CH… (3.187 Å) interactions while CH… (2.828, 3.233
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Å) and OH…N (2.263 Å) interactions are involved in 4j and 4n, respectively. These
intermolecular interactions form temporary big ring systems of more than ten members (Figure
6).
4d
4j
4n
Compound 4d:
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 36
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Compound 4j:
Compound 4n:
Figure 6. Dimeric forms of 4d, 4j and 4n and their crstal packings wih weak interactions along
a,b,c axes. Hydrogen bonds are represented by broken light green lines. Carbon atoms are red
colored, hydrogen with green, oxygen with yellow, and nitrogen atoms are blue colored (see the
supporting information figure Sꢀ13 for details of intraꢀ and intermolecular interactions in
compounds 4d, 4j and 4n).
Although a detailed investigation is required to establish the concern reaction mechanism,
however we envisaged that the reaction may first involve the oxirane ring opening by azide
nucleophile followed by Cu(I) catalyzed click reaction with alkyne 1 to afford product 2 that
16
ACS Paragon Plus Environment

Page 17 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
undergoes subsequent azidation to furnish triazole linked azido alcohol 3. The base prompted
propargylation of 3 and finally the metal free thermal cycloaddition of intermediate azidoalkyne
affords 4 (Figure 7).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 7. Proposed reaction mechanism
CONCLUSION
In conclusion, we have developed a novel, short and practical methodology for the synthesis of
diverse morpholineꢀfused [5,1ꢀC]ꢀtriazolyl heterocycles containing 1,4ꢀtriazoles in conjugation
to wide range biologically relevant skeletons. The protocol exhibits a wide substrate scope, uses
cheap and readily available reagents, easy to perform, and high yielding copper free/copper
catalyst reaction that creates rare and biologically relevant heterocyclic molecules, which could
be difficult to synthesized by other ways. Furthermore, a discussion about changing in intra and
interꢀmolecular weak interactions and their effect on conformations of desired skeleton due to
changing variant (alkynes) is presented, which may be recognized as a precise tool in drug
discovery and development.
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 36
1
2
3
4
5
6
EXPERIMENTAL SECTION
General Remarks.
7
8
9
All the reactions were executed in anhydrous solvents under an argon atmosphere in one hour
oven dried glassware at 100 °C. All reagents and solvents were of pure analytical grade. Thin
layer chromatography (TLC) was performed on 60 F254 silica gel, preꢀcoated on aluminum plates
and revealed with either a UV lamp (λmax = 254 nm) or a specific colour reagent (Draggendorff
reagent or iodine vapours) or by spraying with methanolicꢀH2SO4 solution and subsequent
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
13
charring by heating at 80 °C. H and C NMR were recorded at 300 and 75 MHz, respectively.
Chemical shifts given in ppm downfield from internal TMS and J values in Hz. Infrared spectra
recorded as Nujol mulls in KBr plates. Elemental analysis was performed using a C, H, N
analyzer and results were found to be within ± 0.4% of the calculated values. Highꢀresolution
mass spectra were recorded using TofMS/ES system. Singleꢀcrystal Xꢀray data collected on
CCDꢀdiffractometer.
(A) General procedure for synthesis of glycosyl alkynes (1aꢀ1h)
A solution of orthogonally protected sugar having one free hydroxyl group (1.0 mmol) in
anhydrous DMF (10 ml) was cooled to 0 ºC and sodium hydride (3.0 mmol) was added. The
reaction mixture was stirred at 0 ºC under argon atmosphere for 20 minutes. Propargyl bromide
(1.2 mmol) was added at 0 ºC and allowed to stir for 12 hour at room temperature. Upon
completion of the reaction, remaining sodium hydride quenched by water, the solvent was
removed under reduced pressure, extracted with ethyl acetate (3 × 15 mL) and water (10 ml).
The organic layer was washed with brine solution (10 mL), dried over anhydrous Na2SO4,
filtered, concentrated under vacuum, which on flash chromatography (ethyl acetate: hexane)
afforded desired sugar based alkyne.
18
ACS Paragon Plus Environment

Page 19 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Methylꢀ3,5ꢀdiꢀOꢀbenzylꢀ2ꢀOꢀ(propꢀ2ꢀynyl)ꢀαꢀDꢀxylofuranose, 1e: Methylꢀ3,5ꢀdiꢀOꢀbenzylꢀαꢀ
Dꢀxylofuranose (0.69 g, 2.0 mmol), NaH (0.145 g, 6.0 mmol) and propargyl bromide (0.214 ml,
2.4 mmol) were reacted in DMF (15 ml) using procedure described above to afford 1e (0.6 g,
78%) as colourless liquid. 1H NMR (300 MHz, CDCl3): δ 7.32ꢀ7.30 (m, 10H), 4.88 (s, 1H), 4.68ꢀ
4.52 (m ,4H), 4.40 (m, 1H), 4.13ꢀ4.03 (m, 4H), 3.73ꢀ3.71(m, 2H), 3.41 (s, 3H), 2.46 (s, 1H); 13C
NMR (75 MHz, CDCl3): δ 138.4, 128.6, 128.5, 127.9, 108.0, 86.4, 80.9, 80.2, 75.2, 73.6, 72.3,
69.9, 57.4, 55.9 ppm; Anal. Calcd. for C23H26O5: C, 72.23; H, 6. 85; Found: C 72.41, H, 6.57.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methylꢀ3,5ꢀdiꢀOꢀbenzylꢀ2ꢀOꢀ(propꢀ2ꢀynyl)ꢀβꢀDꢀxylofuranose, 1f : Methylꢀ3,5ꢀdiꢀOꢀbenzylꢀβꢀ
Dꢀxylofuranose (0.62 g, 1.8 mmol), NaH (0.130 g, 5.4 mmol) and propargyl bromide (0.306 ml,
2.1 mmol) were reacted in DMF (15 ml) using typical procedure described above to afford 1f
(0.55 g, 80%) as colourless liquid. 1H NMR (300 MHz, CDCl3): δ 7.33ꢀ7.28 (m, 10H), 5.00 (d, J
= 2.4 Hz, 1H), 4.71ꢀ4.50 (m, 4H), 4.39ꢀ4.17 (m, 5H), 3.75ꢀ3.43 (m, 2H), 3.43 (s, 3H), 2.45 (d, J
13
= 2.1 Hz, 1H); C NMR (75 MHz, CDCl3): δ 138.1, 137.9, 128.3, 128.2, 127.7, 127.6, 127.5,
127.5, 100.3, 83.1, 81.2, 79.2, 76.0, 75.1, 73.4, 72.4, 69.2, 57.6, 55.2 ppm; Anal. Calcd. for
C23H26O5: C, 72.23; H, 6.85; Found: C 72.18, H, 6.92.
3ꢀChloroꢀ1ꢀ(4ꢀ(1,2:3,4ꢀdiꢀOꢀisopropylideneꢀ3ꢀOꢀmethyleneꢀαꢀDꢀglucofuranose)ꢀ1Hꢀ1,2,3ꢀ
triazolꢀ1ꢀyl)propanꢀ2ꢀol, 2a: A homogeneous solution of NaN3 (0.046 g, 0.72 mmol)
CuSO4.5H2O (0.016 g, 0.06 mmol) and sodium ascorbate (0.026 g, 0.13 mmol) in water (5 ml)
was added in a mixture of epichlorohydrin (0.058 ml, 0.72 mmol) and sugar alkyne (0.197 g,
0.6mmol). The resulting solution was stirred for 5 hrs at room temperature. Reaction mixture
was extracted with ethyl acetate (3 × 8ml), further purification was done by flash
chromatography to afford 2a (185 mg, 65%) as viscous liquid. 1H NMR (300 MHz, CDCl3): δ
7.81 (s, 1H), 5.87 (d, J = 3.3 Hz, 1H), 4.79ꢀ4.78 (m, 2H), 4.64ꢀ4.48 (m, 3H), 4.29 (m, 2H), 4.10ꢀ
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 36
1
2
3
4
5
6
7
8
9
3.96 (m, 4H), 3.57ꢀ3.55 (m, 2H), 1.48, 1.42, 1.36, 1.30 (each s, 12H); 13C NMR (75 MHz,
CDCl3): δ 144.7, 124.2, 111.8, 109.0, 105.1, 82.5, 81.7, 80.9, 72.2, 69.8, 67.3, 63.8, 52.8, 45.7,
26.8, 26.7, 26.1, 25.4 ppm; Anal. Calcd. for C18H28ClO7N3: C, 49.83; H, 6.50; N, 9.68; Found:
C,50.06, H, 6.33; N, 9.47.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3ꢀChloroꢀ1ꢀ(4ꢀphenylꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl)propanꢀ2ꢀol, 2j: To a stirring solution of
epichlorohydrin (0.292 mL, 3.6 mmol) in water (8.0 mL), NaN3 (0.229 g, 3.5 mmol),
CuSO4.5H2O (0.073 g, 0.3 mmol) and sodium ascorbate (0.116 g, 0.5 mmol) phenyl acetylene
(0.379 ml, 3.0 mmol) was added. The resulting solution was stirred for 5h at room temperature.
After consumption of starting material (monitored by TLC), reaction mixture was extracted with
ethyl acetate (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, and
concentrated in vacuo. The resulting residue was purified by column chromatography in Ethyl
acetate/hexane ( 2:3) and afforded 2j (0.477 g, 67%) as white solid. 1H NMR (300 MHz, CDCl3):
δ 7.79 (s, 1H), 7.63 (d, J = 6.6Hz, 2H), 7.35ꢀ7.29 (m, 3H), 4.64 (d, J = 10.2 Hz, 1H), 4.47ꢀ4.37
13
(m, 2H), 3.64ꢀ3.62 (m, 2H); C NMR (75 MHz, CDCl3): δ (ppm) 147.4, 129.8, 128.8, 128.2,
125.5, 121.4, 69.8, 53.3, 45.9 ppm.
(B) General procedure for the synthesis of triazoleꢀlinked sugar based azido alcohol
In a mixture of epichlorohydrin (2.0 mmol) and sugar alkyne (1.0 mmol), a solution of NaN3 (4.0
mmol), CuSO4.5H2O (0.1 mmol), and sodium ascorbate (0.2 mmol) in water was reacted in a
closed vessel after three subsequent flushes of argon in order to avoid the possible oxidation in
presence of molecular oxygen. The resulting solution was stirred for 10ꢀ12 h at room
temperature. After consumption of starting material (monitored by TLC), the reaction mixture
was extracted with ethyl acetate (3×15ml), combined organic layers were dried over anhydrous
20
ACS Paragon Plus Environment

Page 21 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
Na2SO4, and concentrated in vacuum. The resulting residue was purified by flash
chromatography (SiO2) using EtOAc/hexane as solvent system.
7
8
9
3ꢀAzidoꢀ1ꢀ(4ꢀ(1,2:5,6ꢀdiꢀOꢀisopropylideneꢀ3ꢀOꢀmethyleneꢀαꢀDꢀglucofuranose)ꢀ1Hꢀ1,2,3ꢀ
triazolꢀ1ꢀyl)propanꢀ2ꢀol, 3a: Compound 1a (2.63 g, 8.8 mmol), epichlorohydrin (1.4 ml, 17.6
mmol), NaN3 (2.28 g, 35.2 mmol), CuSO4.5H2O (0.22 g, 0.8 mmol) and NaAsc (0.349 g ,1.6
mmol) were reacted in water (15 ml) using procedure described above to afford 3a (2.2 g, 58%)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
as viscous; IR (KBr) cmꢀ1: 3429, 2988, 2934, 2105, 1634, 1260, 1217, 1076; H NMR (300
MHz, CDCl3): δ 7.74 (s, 1H), 5.87 (d, J = 3.0 Hz, 1H), 4.81ꢀ4.75 (m, 2H), 4.60ꢀ4.22 (m, 5H),
13
4.11ꢀ3.97 (m, 4H), 3.49ꢀ3.37 (m, 2H), 1.49, 1.42, 1.36, 1.30 (each s, 12H); C NMR (75 MHz,
CDCl3): δ 144.9, 124.2, 111.9, 109.1, 105.2, 82.6, 81.7, 80.9, 72.3, 69.3, 67.3, 63.9, 53.7, 53.0,
26.8, 26.7, 26.2, 25.4 ppm; Anal. Calcd. for C18H28O7N6: C, 49.08; H, 6.41; N, 19.08; Found: C,
49.28; H, 6.57; N, 18.69.
3ꢀAzidoꢀ1ꢀ(4ꢀ(5ꢀO–benzylꢀ3ꢀOꢀmethyleneꢀ1,2ꢀOꢀisopropylideneꢀαꢀDꢀxylofuranose)ꢀ1Hꢀ
1,2,3ꢀtriazolꢀ1ꢀyl)propanꢀ2ꢀol , 3b: Compound 1b (1.0 g, 3.1 mmol), epichlorohydrin (0.509
ml, 6.2 mmol), NaN3 (0.816 g, 12.5 mmol), CuSO4.5H2O (0.078 g, 0.3 mmol) and NaAsc (0.124
g, 0.6 mmol) were reacted in water (10 ml) procedure described above to afford 3b (0.713 g,
50%) as viscous; IR (KBr) cmꢀ1 3443, 2986, 2935 2861, 2104, 1375, 1070: 3425, 2986, 2871,
2103, 1639, 1217, 1165; 1H NMR (300 MHz, CDCl3): δ 7.59, (s, 1H), 7.31ꢀ7.27 (m, 5H), 5.88
(d, J = 3.6 Hz, 1H), 4.75ꢀ4.37 (m, 9H), 3.99 (s, 1H), 3.70ꢀ3.68 (m, 2H), 3.49 (d, J = 5.1 Hz, 1H),
13
3.33 (d, J = 5.7 Hz, 1H), 1.47, 1.30 (each s, 6H); C NMR (75 MHz, CDCl3): δ 144.2, 137.8,
128.3, 127.6, 124.2, 111.7, 104.7, 82.2, 81.6, 78.6, 73.3, 69.6, 67.1, 63.3, 53.6, 52.8, 26.5, 26.1
ppm; Anal. Calcd. for C21H28O6N6: C, 54.77; H, 6.13; N, 18.25; Found: C, 54.46; H, 6.32; N,
17.94.
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 36
1
2
3
4
5
6
7
8
9
3ꢀAzidoꢀ1ꢀ(4ꢀ(3ꢀO–benzylꢀ5ꢀOꢀmethyleneꢀ1,2ꢀOꢀisopropylideneꢀαꢀDꢀxylofuranose)ꢀ1Hꢀ
1,2,3ꢀtriazolꢀ1ꢀyl)propanꢀ2ꢀol, 3c: Compound 1c (1.5 g, 4.7 mmol), epichlorohydrin (0.738 ml,
9.4 mmol), NaN3 (1.2 g, 18.8 mmol), CuSO4.5H2O (0.117 g, 0.47 mmol) and NaAsc (0.186 g,
0.94 mmol) were reacted in water (12 ml) using procedure described above to afford 3c liquid
(1.25 g, 58%) as colorless viscous; IR (KBr) cmꢀ1: 3455, 2926, 2871, 2103, 1455, 1074; 1H NMR
(300 MHz, CDCl3): δ 7.62 (s, 1H), 7.32ꢀ7.28 (m, 5H), 5.92 (d, J = 3.0 Hz, 1H), 4.72ꢀ4.59 (m,
4H), 4.50ꢀ4.20 (m, 5H), 3.94 (d, J = 3.0 Hz, 1H), 3.79ꢀ3.77 (m, 2H), 3.45ꢀ3.30 (m, 2H), 1.47,
1.31 (each S, 6H); 13C NMR (75 MHz, CDCl3): δ 145.0, 137.4, 128.5, 127.9, 127.6, 124.1,
111.7, 105.0, 82.1, 81.7, 79.1, 71.8, 69.2, 68.2, 64.8, 53.7, 53.0, 26.7, 26.2 ppm; Anal. Calcd. for
C21H28O6N6: C, 54.77; H, 6.13; N, 18.25; Found: C, 54.65; H, 6.02; N, 17.94.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3ꢀAzidoꢀ1ꢀ(4ꢀ(methylꢀ2,3ꢀOꢀisopropylideneꢀ5ꢀOꢀmethyleneꢀβꢀDꢀribofuranose)ꢀ1Hꢀ1,2,3ꢀ
triazolꢀ1ꢀyl)propanꢀ2ꢀol, 3d: Compound 1d (1.33 g, 5.5 mmol), epichlorohydrin (0.864 ml, 11
mmol), NaN3 (1.79 g, 22 mmol), CuSO4.5H2O (0.137 g, 0.55 mmol) and NaAsc (0.218 g, 1.1
mmol) were reacted in water (10 ml) using procedure described above to afford 3d (1.32 mg,
63%) as colourless viscous ; IR (KBr) cmꢀ1: 3416, 2989, 2939, 2865, 2105, 1633, 1274, 1212,
1
1107; H NMR (300 MHz, CDCl3): δ 7.69 (s, 1H), 4.95 (s, 1H), 4.66ꢀ4.52 (m, 5H), 4.47ꢀ4.25
(m, 3H), 3.60ꢀ3.26 (m, 7H), 1.47, 1.30 (each s, 6H); 13C NMR (75 MHz, CDCl3): δ 144.7,
124.3, 112.4, 109.1, 85.0, 84.9, 81.9, 71.4, 69.1, 64.5, 54.8, 53.7, 53.2, 26.3, 24.8 ppm; Anal.
Calcd. for C15H24O6N6: C, 46.87; H, 6.29; N, 21.86; Found: C, 46.61; H, 6.11; N, 22.08.
3ꢀAzidoꢀ1ꢀ(4ꢀ( methylꢀ3,5–diꢀO–benzylꢀ2ꢀOꢀmethyleneꢀα ꢀDꢀxylofuranose)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ
1ꢀyl)propanꢀ2ꢀol, 3e: Compound 1e (0.80 g, 2 mmol), epichlorohydrin (0.339 ml, 4.1 mmol),
NaN3 (0.52 g, 8.2 mmol), CuSO4.5H2O (0.049 g, 0.2 mmol) and NaAsc (0.081 g, 0.42 mmol)
were reacted in water (8 ml) using procedure described above to afford 3e (0.569 g, 52%) as
22
ACS Paragon Plus Environment

Page 23 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
colorless viscous; IR (KBr) cmꢀ1: 3432, 2924, 2104, 1710, 1454, 1055 ; H NMR (300 MHz,
CDCl3): δ 7.58 (s, 1H), 7.32ꢀ7.30 (m, 10H), 4.88 (s, 1H), 4.63ꢀ4.35 (m, 9H), 4.15ꢀ4.00 (m, 3H),
3.76ꢀ3.67 (m, 2H), 3.40ꢀ3.31 (m, 5H); 13C NMR (75 MHz, CDCl3): δ 144.7, 138.2, 137.6,
128.4, 128.3, 127.8, 127.5, 125.9, 124.2, 107.9, 86.8, 81.1, 79.9,73.4, 72.2, 69.2, 63.3, 60.4,
55.7, 53.7, 53.0 ppm; Anal. Calcd. for C26H32O6N6: C, 59.53; H, 6.15; N, 16.02; Found: C,
59.91; H, 5.81; N, 16.29.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3ꢀAzidoꢀ1ꢀ(4ꢀ( methylꢀ3,5–diꢀO–benzyl –2ꢀmethylene ꢀβꢀꢀDꢀxylofuranose)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ
1ꢀyl)propanꢀ2ꢀol, 3f: Compound 1f (0.6 g, 1.5 mmol), epichlorohydrin (0.254 ml, 3.1 mmol),
NaN3 (0.406 g, 6.2 mmol), CuSO4.5H2O (0.039 g, 0.15 mmol) and NaAsc (0.061 g, 0.31 mmol)
were reacted in water (8 ml) using typical procedure described above to afford 3f (0.46 g, 56%)
1
as pale yellow liquid; IR (KBr) cmꢀ1 3433, 2923, 2853, 2104, 1455, 1055: H NMR (300 MHz,
CDCl3): δ 7.59 (s, 1H), 7.30ꢀ7.29 (m, 10H), 4.95 (s, 1H), 4.80ꢀ4.49 (m, 6H), 4.46ꢀ4.08 (m, 6H),
3.72ꢀ3.56 (m, 2H), 3.41ꢀ3.27 (m, 5H); 13C NMR (75 MHz, CDCl3): δ 144.7, 138.1, 137.9, 128.3,
128.0, 127.7, 127.7, 127.5, 124.4, 100.2, 83.8, 81.4, 76.0, 73.5, 72.6, 69.2, 63.8, 60.4, 55.3, 53.7,
53.0 ppm; Anal. Calcd. for C26H32O6N6: C, 59.53; H, 5.84; N, 16.02; Found: C, 59.26; H, 5.81;
N, 16.23.
3ꢀAzidoꢀ1ꢀ(4ꢀ(methyleneꢀ2,3:5,6ꢀdiꢀOꢀisopropylideneꢀβꢀDꢀmannofuranose)ꢀ1Hꢀ1,2,3ꢀ
triazolꢀ1ꢀyl)propanꢀ2ꢀol, 3g: Compound 1g (1.38 g, 4.6 mmol), epichlorohydrin (0.728 ml, 9.2
mmol), NaN3 (1.19 g, 18.4 mmol), CuSO4.5H2O (0.115 g, 0.4 mmol) and NaAsc (0.184 g, 0.9
mmol) were reacted in water (10 ml) using procedure described above to afford 3g (1.2 g, 60%)
1
as viscous; IR (KBr) cmꢀ13427, 2987, 2935, 2105, 1373, 1211, 1084: H NMR (300 MHz,
CDCl3): δ 7.66 (s, 1H), 5.12 (d, J = 7.2 Hz, 1H), 4.74ꢀ4.47 (m, 5H), 4.40ꢀ4.24 (m, 3H), 4.11ꢀ
3.76 (m, 3H), 3.50ꢀ3.34 (m, 2H), 1.45, 1.37, 1.36, 1.31 (each s, 12H); 13C NMR (75 MHz,
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 36
1
2
3
4
5
6
7
8
CDCl3): δ 144.4, 124.1, 112,6, 109.2,106.2, 84.9, 80.1, 79.4, 73.1, 69.3, 66.6, 61.4, 60.5, 53.9,
53.2 ppm; Anal. Calcd. for C18H28O7N6: C, 49.08; H, 6.41; N, 19.08; Found: C, 49.43 H, 6.67;
N, 18.79.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3ꢀAzidoꢀ1ꢀ(4ꢀ(1,2:3,4ꢀdiꢀOꢀisopropylideneꢀ5ꢀOꢀmethyleneꢀαꢀDꢀgalactopyranose)ꢀ1Hꢀ1,2,3ꢀ
triazolꢀ1ꢀyl)propanꢀ2ꢀol, 3h : Compound 1h (1.2 g, 4.0 mmol), epichlorohydrin (0.638 ml, 8.1
mmol), NaN3 (1.05 g, 16.2 mmol), CuSO4.5H2O (0.101 g, 0.4 mmol) and NaAsc (0.161 g, 0.8
mmol) were reacted in water (10 ml) using procedure described above to afford 3h (1.09 g,
62%) as viscous; IR (KBr) cmꢀ1 3345, 2988, 2924, 2105, 1383, 1069: 1H NMR (300 MHz,
CDCl3): δ 7.71 (s, 1H), 5.53 (d, J = 4.8 Hz, 1H), 4.65ꢀ4.21 (m, 8H), 3.97 (m, 1H), 3.71ꢀ3.68 (m,
2H), 3.45ꢀ3.35 (m, 2H), 1.51, 1.45, 1.43, 1.32 (each s, 12H); 13C NMR (75 MHz, CDCl3): δ
144.8, 124.3, 109.2, 108.5, 96.2, 71.1, 70.5, 70.3, 69.5, 69.1, 66.8, 64.6, 53.7, 53.2, 25.9, 25.9,
24.8, 24.3 ppm; Anal. Calcd. for C18H28O7N6: C, 49.08; H, 6.41; N, 19.08; Found: C, 48.85 H,
6.04; N, 18.75
3ꢀAzidoꢀ1ꢀ(4ꢀ(4ꢀNꢀmethyleneꢀ1ꢀNꢀphenyl piperazine)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl)propanꢀ2ꢀol, 3i:
In a solution of Nꢀpropargylated phenyl piperazine (0.56 g, 2.8 mmol), epichlorohydrin (0.46 ml,
5.6 mmol) and NaN3 (0.73 g, 11.3 mmol) in DMF (7 ml); a freshly prepared solution of
CuSO4.5H2O (0.069 g, 0.2 mmol), and sodium ascorbate (0.11 g, 0.5 mmol) in water (3 ml) was
added. The resulting solution was stirred at room temperature for 4 h and then heated at 600C
with constant stirring for next 4 h. After complete consumption of alkyne (monitored by TLC),
the solvent was evaporated and residue was extracted with water (10 ml) and ethyl acetate (3×15
ml). Organic layer was washed with 10 ml brine solution. Further purification by flash
chromatography afforded 3i (0.387 g, 40%) as white solid; IR (KBr) cmꢀ1 3368, 2923, 2884,
1
2827, 2103, 1599, 1496, 1229: H NMR (300 MHz, CDCl3): δ 767 (s, 1H), 7.24 (visualize s,
24
ACS Paragon Plus Environment

Page 25 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2H), 6.89ꢀ6.87 (m, 3H), 4.50ꢀ4.26 (m, 3H), 3.69 (s, 2H), 3.39ꢀ3.34 (m, 2H), 3.16 (visualize s,
4H), 2.66 (visualize s, 4H); 13C NMR (75 MHz, CDCl3): δ 150.9, 143.3, 129.0, 124.7, 119.9,
116.0, 69.0, 53.8, 53.3, 52.9, 52.7, 48.7 ppm; Anal. Calcd. for C16H22O1N8: C, 56.12; H, 6.48; N,
32.73; Found: C, 55.92 H, 6.86; N, 32.99.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3ꢀAzidoꢀ1ꢀ(4ꢀphenylꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl)propanꢀ2ꢀol, 3j: To a stirring solution of
epichlorohydrin (0.768 ml, 9.8 mmol) in water (6 ml), NaN3 (1.2 g, 19 mmol) CuSO4.5H2O
(0.122 g, 0.4 mmol) and sodium ascorbate (0.194 g, 0.9 mmol) phenyl acetylene (0.537 ml, 4.9
mmol) was added and stirred at room temperature for 9h. After complete consumption of
acetylene (monitored by TLC), reaction mixture were extracted with ethyl acetate (3×10 ml).
Organic layer were dried over anhydrous Na2SO4 and concentrated under reduced pressure.
Further purification by flash chromatography gave compound 3j (0.717 g, 60%) as white
crystalline solid; IR (KBr) cmꢀ1: 1H NMR (300 MHz, CDCl3): δ 7.75 (s, 1H), 7.59 (d, J = 6.6 Hz,
13
2H), 7.34ꢀ7.29 (m, 3H), 4.51 (d, J = 10.8 Hz, 1H), 4.36ꢀ4.30 (m, 2H), 3.53ꢀ3.40 (m, 2H); C
NMR (75 MHz, CDCl3): δ 147.3, 129.8, 128.8, 128.2, 125.4, 121.3, 69.1, 53.8, 53.6 ppm.
3ꢀAzidoꢀ1ꢀ(4ꢀtolueneꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl)propanꢀ2ꢀol, 3k: 4ꢀEthynyl toluene (0.545 ml, 4.3
mmol), epichlorohydrin (0.674 ml, 8.6 mmol), NaN3 (1.12 g, 17.2 mmol), CuSO4.5H2O (0.107
g, 0.4 mmol) and NaAsc (0.170mg, 0.8 mmol) were reacted in water (8 ml) using procedure
described above to afford 3k (0.689 g, 62%) as white solid ; IR (KBr) cmꢀ1:1H NMR (300 MHz,
CDCl3): δ 7.71 (s, 1H), 7.49 (d, J = 7.8 Hz,1H), 7.14 (d, J = 7.8 Hz, 1H), 4.55ꢀ4.47 (m, 2H),
13
4.34ꢀ4.31 (m, 2H), 3.50ꢀ3.42 (m, 2H), 2.36 (s, 3H); C NMR (75 MHz, CDCl3): δ 147.4, 138.1,
129.4, 127.0, 125.4, 121.0, 69.2, 53.8, 53.5, 21.2 ppm; Anal. Calcd. for C12H14O1N6: C, 55.80;
H, 5.46; N, 32.54; Found: C, 55.62; H, 5.83; N, 32.45.
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 36
1
2
3
4
5
6
7
8
9
3ꢀAzidoꢀ1ꢀ(4ꢀbutylꢀ1Hꢀ1,2,3ꢀtriazolꢀ1yl)propanꢀ2ꢀol, 3l : 1ꢀHexyne (0.696 ml, 6.0 mmol),
epichlorohydrin (0.940 ml, 12.1 mmol), NaN3 (1.58 g, 24.3 mmol), CuSO4.5H2O (0.149 g, 0.6
mmol) and NaAsc (0.237 g, 1.2 mmol) were reacted in water (10 ml) using procedure described
above to afford 3l (0.740 g, 55%) as colorless liquid; IR (KBr) cmꢀ1 3361, 2958, 2930, 2860,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2104, 1457, 1288: H NMR (300 MHz, CDCl3): δ 7.36 (s, 1H), 4.47ꢀ4.30 (m, 3H), 3.94 (s, 1H),
3.48ꢀ3.33(m, 2H), 2.66 (t, J = 7.8 Hz, 2H), 1.60 (t, J = 7.8 Hz, 2H), 1.40ꢀ1.33 (m, 2H), 0.93 (t, J
13
= 7.2 Hz, 3H); C NMR (75 MHz, CDCl3): δ 148.2, 122.2, 69.2, 53.7, 53.0, 31.3, 25.1, 22.2,
13.7 ppm; Anal. Calcd. for C9H16O1N6: C, 48.20; H, 7.19; N, 37.47; Found: C, 47.99 H, 6.88; N,
37.68.
3ꢀAzidoꢀ1ꢀ(4ꢀbenzylꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl)propanꢀ2ꢀol, 3m : 3ꢀPhenylꢀ1ꢀpropyne (0.535 ml,
4.3 mmol), epichlorohydrin (0.674 ml, 8.6 mmol), NaN3 (1.12 g, 17.2 mmol), CuSO4.5H2O
(0.107 g, 0.4 mmol) and NaAsc (0.170 g, 0.8 mmol) were reacted in water (8 ml) using
procedure described above to afford 3m (622 mg, 56%) as pale yellow liquid; IR (KBr) cmꢀ1 ꢀ
3361, 2958, 2930, 2860, 2104,: 1H NMR (300 MHz, CDCl3): δ 7.28ꢀ7.21 (m, 6H), 4.41ꢀ4.22 (m,
13
3H), 4.05ꢀ4.01 (m, 3H), 3.41ꢀ3.27 (m, 2H); C NMR (75 MHz, CDCl3) δ 147.3, 138.6, 128.6,
126.5, 123.1, 69.1, 53.7, 53.1, 32.0 ppm; Anal. Calcd. for C12H14O1N6: C, 55.80; H, 5.46; N,
32.54; Found: C 56.15, H, 5.72; N, 32.25.
3ꢀAzidoꢀ1ꢀ(4ꢀ(1ꢀcyclohexanol)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl)propanꢀ2ꢀol,
3n:
1ꢀethynylꢀ1ꢀ
cyclohexanol (0.5 g, 4.0 mmol), epichlorohydrin (0.627 ml, 8.0 mmol), NaN3 (1.04 g, 16.0
mmol), CuSO4.5H2O (0.10 mg, 0.4 mmol) and NaAsc (0.159 g, 0.8 mmol) were reacted in water
(10 ml) using procedure described above to afford 3n as viscous (0.482 g, 45%); IR (KBr) cmꢀ1
1
3383, 2934, 2857, 2104, 1707, 1447, 1061: H NMR (300 MHz, CDCl3): δ 7.54 (s, 1H), 4.95
(s,1H), 4.48ꢀ4.43 (m, 1H), 4.30ꢀ4.24 (m, 2H), 3.48ꢀ3.42 (m, 3H), 1.96ꢀ1.29 (m, 11H); 13C NMR
26
ACS Paragon Plus Environment

Page 27 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
(75 MHz, CDCl3): δ 154.5, 121.8, 69.2, 53.8, 53.6, 37.7, 37.5, 25.2, 21.9 ppm; Anal. Calcd. for
C11H18O2N6: C, 49.61; H, 6. 18; N, 31.56; Found: C 49.38, H, 5.81; N, 31.23.
7
8
9
3ꢀAzidoꢀ1ꢀ(4ꢀethisteronꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl)propanꢀ2ꢀol, 3o: Ethisteron (0.60 g, 1.9 mmol),
epichlorohydrin (0.462 ml, 5.7 mmol), NaN3 (0.617 g, 9.5 mmol), CuSO4.5H2O (0.047 g,
0.2mmol) and NaAsc (0.079 g, 0.4 mmol) were reacted in water (10 ml) using typical procedure
described above to afford 3o (0.362 g, 42%) as white solid; IR (KBr) cmꢀ1 3401, 2941, 2857,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2103, 1660, 1616: H NMR (300 MHz, CDCl3): δ 7.50 (s, 1H), 5.68 (s, 1H), 4.50ꢀ4.23 (m, 3H),
3.46ꢀ3.39 (m, 2H), 2.37ꢀ2.28 (m, 5H), 2.09ꢀ1.86 (m, 4H), 1.60ꢀ1.04 (m, 14H), 0.70 (m, 1H), 0.44
13
(m, 1H); C NMR (75 MHz, CDCl3): δ 199.6, 171.3, 153.0, 123.8, 82.1, 69.2, 53.8, 53.1, 48.9,
48.9, 46.7, 38.5, 37.6, 36.2, 35.5, 33.8, 32.7, 31.5, 29.6, 27.3, 23.5, 20.5, 17.3, 14.1ppm; Anal.
Calcd. for C24H34O3N6: C, 63.41; H, 7. 54; N, 18.49; Found: C 63.19, H, 7.92; N, 18.75.
(C) General Procedure for the synthesis of 1,2 ,3ꢀtriazolo[5,1ꢀ c]morpholines (4aꢀo)
A solution of azido alcohol (3, 1.0 mmol) in anhydrous DMF (10 ml) was cooled to 0 ºC and
NaH (2 mmol) was added portion wise. The reaction mixture was stirred at 0 ºC under argon
atmosphere for 20 minutes. Then at same temperature, propargyl bromide (1.2 mmol) was added
and reaction mixture was further stirred for 12 hour at room temperature. After disappearance of
starting materials (monitored by TLC), reaction was quenched by water and whole reaction
mixture was allowed to heat at 110 ºC with constant stirring for 3ꢀ4 hour. Upon completion of
the reaction, the solvent was removed in vacuum; the residue was mixed with water (10 mL) and
then extracted with ethyl acetate (3 × 15 mL). The combined organic extracts were washed with
brine solution (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The resulting residue was subjected to flash chromatography (silica gel 234ꢀ400 mesh,
CHCl3/CH3OH as eluent) to give title compound 4.
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 36
1
2
3
4
5
6
7
8
9
6ꢀ(4ꢀ(1,2:5,6ꢀDiꢀOꢀisopropylideneꢀ3ꢀOꢀmethyleneꢀαꢀDꢀglucofuranose)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀ
yl)ꢀ6,7ꢀdihydroꢀ4Hꢀ[1,2,3]triazolo[5,1ꢀc][1,4]oxazine, 4a: Compound 3a (1.03 g, 2.3 mmol),
NaH (0.112 g, 4.6 mmol) and propargyl bromide (0.246 ml, 2.7 mmol) were reacted in DMF (15
ml) using procedure described above to give 4a (1.0 g, 90%) as white solid; IR (KBr) cmꢀ1 3457,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3142, 2988, 2936, 1640.456, 1374, 1217, 1078: H NMR (300 MHz, CDCl3): δ 7.78 (s, 1H),
7.51 (s, 1H), 5.88 (d, J = 3.3 Hz, 1H), 5.13 (d, J = 15.0 Hz, 1H), 4.88ꢀ4.57 (m, 8H), 4.32ꢀ4.29
(m, 2H), 4.13ꢀ3.98 (m, 4H), 1.49, 1.42, 1.36, 1.30 (each s, 12H); 13C NMR (75 MHz, CDCl3): δ
144.8, 129.6, 127.8, 124.1, 111.6, 108.7, 105.0, 82.4, 81.7, 80.8, 72.1, 71.7, 67.0 , 63.7, 61.8,
51.4, 46.7, 26.6, 26.5, 25.9, 25.2 ppm. HRMS: Calcd. for C21H30N6O7 [M+Na] 501.2074; found
501.2057.
6ꢀ(4ꢀ(5ꢀO–benzylꢀ3ꢀOꢀmethyleneꢀ1,2 ꢀOꢀisopropylideneꢀαꢀDꢀxylofuranose)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ
1ꢀyl)ꢀ6,7ꢀdihydroꢀ4Hꢀ[1,2,3]triazolo[5,1ꢀc][1,4]oxazine, 4b: Compound 3b (0.20 g, 0.43
mmol), NaH (0.02 mg, 0.8 mmol) and propargyl bromide (0.046 ml, 0.5 mmol) were reacted in
DMF (6 ml) using procedure described above to give 4b (0.169 g, 85%) as white solid; IR (KBr)
cmꢀ1 3428, 2925, 2855, 1710, 1454, 1375, 1221, 1079:1H NMR (300 MHz, CDCl3): δ 7.65 (s,
1H), 7.47 (s, 1H), 7.29 (m, 5H), 5.90 (d, J =3.3 Hz, 1H), 5.05 (d, J = 15.3 Hz, 1H), 4.81ꢀ4.40
(m, 10H), 4.17 (m, 1H), 4.02ꢀ3.94 (m, 2H), 3.79ꢀ3.70 (m, 2H), 1.48, 1.30 (each s, 6H); 13C NMR
(75 MHz, CDCl3): δ (ppm) 144.7, 137.8, 129.7, 128.2, 127.9, 127.5, 124.0, 111.6, 104.7, 82,0,
81.6, 78.5, 73.2, 71.7, 67.0, 63.3, 61.8, 51.1, 46.8, 26.5, 26.0 ppm. HRMS: Calcd. for
C24H30N6O6 [M+Na] 521.2125; found 521.2123.
6ꢀ(4ꢀ(3ꢀO–benzylꢀ5ꢀOꢀmethyleneꢀ1,2 ꢀOꢀisopropylideneꢀαꢀDꢀxylofuranose)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ
1ꢀyl)ꢀ6,7ꢀdihydroꢀ4Hꢀ[1,2,3]triazolo[5,1ꢀc][1,4]oxazine, 4c: Compound 3c (0.250 g, 0.54
mmol), NaH (0.026 g, 1.08 mmol) and propargyl bromide (0.062 ml, 0.7 mmol) were reacted in
DMF (6 ml) using procedure described above to give 4c (0.215 g, 80%) as white solid; IR (KBr)
28
ACS Paragon Plus Environment

Page 29 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
cmꢀ1 3421, 3128, 2955, 2845, 1715, 1450, 1372, 1221, 1069: 1H NMR (300 MHz, CDCl3): δ
7.70 (s, 1H), 7.49 (s, 1H), 7.33ꢀ7.29 (m, 5H), 5.93 (d, J = 3.6 Hz, 1H), 5.09 (d, J = 15.0 Hz, 1H),
4.78ꢀ4.73 (m, 4H), 4.69ꢀ4.54 (m, 3H), 4.48 (d, J = 12.0Hz, 1H), 4.39 (d, J = 3.3 Hz, 1H), 4.22
9
13
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(m, 1H), 4.08ꢀ3.95 (m, 2H), 3.81ꢀ3.79 (m, 3H), 1.47, 1.31 (each s, 6H). ); C NMR (75 MHz,
CDCl3): δ 145.4, 137.3, 129.7, 128.4, 128.1, 127.8, 127.5, 124.1, 111.6, 105.0, 82.1, 81.8, 79.1,
72.0, 71.8, 68.3, 64.8, 62.0, 51.4, 47.0, 26.7, 26.2 ppm. HRMS: Calcd. for C24H30N6O6 [M+Na]
521.2125; found 521.2125.
6ꢀ(4ꢀ(Methylꢀ2,3ꢀOꢀisopropylideneꢀ5ꢀOꢀmethyleneꢀβꢀDꢀribofuranose)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl)ꢀ
6,7ꢀdihydroꢀ4Hꢀ[1,2,3]triazolo[5,1ꢀc][1,4]oxazine, 4d: Compound 3d (0.863 g, 2.2 mmol),
NaH (0.107 g, 4.4 mmol) and propargyl bromide (0.235 ml, 2.6 mmol) were reacted in DMF (10
ml) using procedure described above to give 4d (0.779 g, 84%) as white solid IR (KBr) cmꢀ1
1
3444, 3137, 2976, 2938, 2865, 1735, 1489, 1244, 1109: H NMR (300 MHz, CDCl3): δ 7.74 (s,
1H), 7.50 (s, 1H), 5.13 (d, J = 15 Hz, 1H), 4.95 ( s, 1H), 4.85ꢀ4.55 (m, 8H), 4.32ꢀ4.30 (m, 2H),
4.06 (t, J = 11.4 Hz, 1H), 3.63ꢀ3.51 (m, 2H), 3.30 (s, 3H), 1.47, 1.30 (each s, 6H); 13C NMR (75
MHz, CDCl3): δ 145.4, 129.7, 128.1, 124.1, 112.3, 109.1, 85.0, 82.0, 72.0, 71.6, 64.7, 62.1, 54.8,
54.7, 51..4, 47.0, 26.4, 26.9 ppm. HRMS: Calcd. for C18H26N6O6 [M+Na] 445.1812; found
445.1806.
6ꢀ(4ꢀ( Methylꢀ3,5–diꢀO–benzylꢀ2 ꢀOꢀmethyleneꢀαꢀDꢀxylofuranose)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl)ꢀ
6,7ꢀdihydroꢀ4Hꢀ[1,2,3]triazolo[5,1ꢀc][1,4]oxazine, 4e: Compound 3e (0.220 g, 0.4 mmol), NaH
(0.020 g, 0.8 mmol) and propargyl bromide (0.044 ml, 0.5 mmol) were reacted in DMF (6 ml)
using procedure described above to give 4e (0.193g, 82%) as viscous; IR (KBr) cmꢀ1 3439,
1
3140, 2934, 2856, 1710, 1624, 1454, 1196, 1096, 1051: H NMR (300 MHz, CDCl3): δ 7.58
(s,1H), 7.40 (s, 1H), 7.24ꢀ7.21 (m, 10H), 4.99 (d, J = 15 Hz, 1H), 4.82 (s, 1H), 4.69ꢀ4.34 (m,
11H), 4.12 (m, 1H), 3.95 (m, 3H), 3.69ꢀ3.64 (m, 2H), 3.32 (s, 3H); 13C NMR (75 MHz, CDCl3):
29
ACS Paragon Plus Environment