Synthesis of novel glycosyl-1,2,3-1H-triazolyl methyl quinazolin-4(3H)-ones and their effect on GLUT4 translocation

Article abstract of DOI:10.1016/j.tet.2016.11.074

Cu(OTf)₂catalyzed synthesis of propargylated 2,3-dihydroquinazolin-4(1H)-ones has been accomplished from 2-amino-N-propargyl benzamides and aromatic aldehydes under MW irradiation. Next, a series of novel glycosyl triazolyl methyl quinazolin-4(

Full text of DOI:10.1016/j.tet.2016.11.074

Accepted Manuscript
Synthesis of novel glycosyl-1,2,3-1H-triazolyl methyl quinazolin-4(3H)-ones and their
effect on GLUT4 translocation
K. Kumar G. Ramakrishna, Ravi Kumar Thakur, Venkata Reddy Pasam, Jyotsana
Pandey, Rohit Mahar, Sanjeev K. Shukla, Akhilesh K. Tamrakar, Rama Pati Tripathi
PII:
S0040-4020(16)31254-6
10.1016/j.tet.2016.11.074
TET 28288
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 June 2016
Revised Date: 22 November 2016
Accepted Date: 29 November 2016
Please cite this article as: Ramakrishna KKG, Thakur RK, Pasam VR, Pandey J, Mahar R, Shukla SK,
Tamrakar AK, Tripathi RP, Synthesis of novel glycosyl-1,2,3-1H-triazolyl methyl quinazolin-4(3H)-ones
and their effect on GLUT4 translocation, Tetrahedron (2016), doi: 10.1016/j.tet.2016.11.074.
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Graphical Abstract:
Synthesis of novel glycosyl-1,2,3-1H-triazolyl
methyl quinazolin-4(3H)-ones and their effect
on GLUT4 translocation
Leave this area blank for abstract info.
K. Kumar G. Ramakrishna, Ravi Kumar Thakur, Venkata Reddy Pasam, Jyotsana Pandey,
Rohit Mahar, Sanjeev K. Shukla, Akhilesh K. Tamrakar and Rama Pati Tripathi*
1

ACCEPTED MANUSCRIPT
Synthesis of novel glycosyl-1,2,3-1H-triazolyl methyl quinazolin-4(3H)-ones and their effect
on GLUT4 translocation
a
a
a
b
K. Kumar G. Ramakrishna, Ravi Kumar Thakur, Venkata Reddy Pasam, Jyotsana Pandey,
c
c,d
b,d
a,d,
Rohit Mahar, Sanjeev K. Shukla, Akhilesh K. Tamrakar and Rama Pati Tripathi *
a
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow-
2
26031, India.
b
Biochemistry Division, CSIR-Central Drug Research Institute, Lucknow-226031, India.
c
Sophisticated Analytical Instrument Facility, CSIR-Central Drug Research Institute, Lucknow
2
26031, India.
d
Academy of Scientific & Innovative Research (AcSIR), New Delhi, India.
*
Corresponding author.
E-mail address: rp_tripathi@cdri.res.in; rpt.cdri@gmail.com (Rama.P. Tripathi)
Tel.: +91-0522-2772450 Extn: 4755
Fax: +91 522 2623405/ 2623938/ 2629504.
Abstract:
Cu(OTf) catalyzed synthesis of propargylated 2,3-dihydroquinazolin-4(1H)-ones has been
2
accomplished from 2-amino-N-propargyl benzamides and aromatic aldehydes under MW
irradiation. Next, a series of novel glycosyl triazolyl methyl quinazolin-4(3H)-ones have been
synthesized by CuAAC reaction of propargylated 2,3-dihydroquinazolin-4(1H)-ones with
glycosyl azides followed by iodine mediated oxidation. In this series, six compounds showed
promising to significant GLUT4 translocation activity comparable to rosiglitazone.
2

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Keywords: Copper(II) triflate, 2,3-Dihydroquinazolin-4(1H)-ones, Glycosyl quinazolin-4(3H)-
ones, GLUT4 translocation activity
1
. Introduction
Quinazolinones, a class of nitrogen heterocycle are assigned as privileged structures in drug
1
discovery due to their important roles as key building blocks in the synthesis of a many drugs.
This class is associated with diverse range of pharmacological activities such as
2
3
4
5
6
7
antihypertensive, antibacterial, anti-inflammatory, anticancer, analgesic, antituberculosis,
8
9
10
11
12
antidefibrillatory, antihistamine, diuretic, CNS stimulant, tranquilizer, vasodilating
1
3
14
15
agent, antianxietic, and antidepressant activities. The quinazolinone ring is also a ubiquitous
1
6
pharmacophore in many biologically active natural products like Rutaecarpine (1),
1
7
18
19
19
Bouchardatine (2), Luotonine A (3), Febrifugine (4), Methaqualone (5) and 2-(4-
2
0
21
Hydroxybutyl)-4(3H)-quinazolinone (6) as shown in Figure 1. Balaglitazone (7),
a
quinazolinone analogue of thiazolidinedione has excellent antidiabetic and hypolipidemic
properties with less adipogenic activity (Figure 1).
Figure 1. Natural and synthetic examples of bioactive quinazolinones
3

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1
,2,3-Triazoles are also important scaffold in drug discovery and development as several
2
2
molecules with this moiety exhibited important biological activities such as antitubercular,
2
3
24
25
26
27
28
anticancer, anti-HIV, antibacterial, antiviral, antialzheimer, antimycobacterial and
2
9
glycosidase inhibitors.
Most of the biologically active compounds incorporating glycosyl motifs coupled with
3
0
heterocycles exhibit potent biological activities. Glycosylation of biomolecules offers better
pharmacokinetic parameters to the bioactive molecules, and also helps in creating molecular
3
1
diversity. Skeletal muscle is the major depot for postprandial glucose utilization and disposal.
Insulin stimulates glucose uptake in skeletal muscle is characterized by enhancing translocation
and redistribution of insulin sensitive glucose transporter-4 (GLUT-4) from the intracellular
3
2
compartment to the plasma membrane. Under diabetic condition insulin stimulated
3
3
translocation of GLUT4 gets impaired, leading to decreased uptake of glucose inside the tissue.
Thus interventions with ability to enhance the rate of GLUT4 translocation might be useful for
the treatment of diabetes. Quinazolinones have been reported to possess GLUT4 translocation
3
4
enhancing activity.
Keeping in mind the above facts we were prompted to synthesize a new series of hybrid
molecules, consisting of quinazolinones, triazole and sugars and investigate their GLUT4
translocation enhancing activity in a quest for new antidiabetic agents (Figure 2).
4

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Figure 2. Designing the structure for novel glycosyl quinazolinones
Due to medicinal importance of quinazolinone scaffolds various synthetic methods have been
3
5
explored.
2,3-Dihydroquinazolin-4(1H)-ones have been accessed by reaction of 2-
aminobenzamides and aldehydes under the influence of different catalysts such as chiral
3
6
37
38
39
40
phosphoric acid, Sc(III)-inda-pybox, TiCl /Zn, cyanuric chloride, ionic liquid/water,
4
4
1
42
43
44
45
gallium(III) triflate, AcOH, iodine, silica sulfuric acid, montmorillonite K-10, [Zn-
4
6
47
48
49
50
51
(
PFO) ], KAl(SO ) ·12H O, MCM-41-SO H, Al(H PO ) , [bmim]BF , sulfamic acid,
2 4 2 2 3 2 4 3 4
5
2
53
54
55
56
β-cyclodextrin, cellulose-SO H, ammonium chloride, Cu-CNTs, p-TsOH, tartaric acid-
3
5
7
58
SDS, and CuO nanoparticles. Few of the reported methods suffer from drawbacks such as
low yields, long reaction time, strongly acidic conditions and use of expensive reagents.
2
,3-Dihydroquinazolin-4(1H)-ones derivatives have been synthesized from 2-aminobenzamides
or 3,1-Benzoxazine-2,4(1H)-diones (isatoic anhydrides), in the presence of Cu salt as catalyst.
Only one example of a three-component reaction of isatoic anhydrides with amines and ketones
5
9
in the presence of Cu(OTf) is known till date. Herein, we describe a novel and simple method
2
to access a diverse range of 2,3-dihydroquinazolin-4(1H)-ones via one-pot two-component
5

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condensation of substituted 2-aminobenzamides with various aldehydes in the presence of
Cu(OTf) under microwave irradiation.
2
2
2
2
2
. Results and discussion
.1.Chemistry
.1.1. Synthesis of 2,3-dihydroquinazolin-4(1H)-ones
-Amino-N-propargyl benzamides (9a and 9b) were prepared from commercially available
anthranilic acid (8a) and 2-amino-4-chloro-benzoic acid (8b) following earlier reported
6
0
protocols as shown in Scheme 1. The structures were established on the basis of their
6
1
spectroscopic data.
Scheme 1. Synthesis of 2-amino-N-propargyl benzamide derivatives
To optimize reaction condition for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones initially
we carried out the reaction of 2-amino-N-propargyl benzamide (9a) with benzaldehyde as model
substrate to get 2-phenyl-3-propargyl-2,3-dihydroquinazolin-4(1H)-one (10a) under the
influence of various reaction conditions and the results are summarized in Table 1. Using of 20
mol% of CuCl in refluxing ethanol and 20 mol% InCl in acetonitrile at room temperature
2
3
offered 62% and 65% yields of 2,3-dihydroquinazolin-4(1H)-one 10a (entries 1 and 2)
6

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respectively. Next, Cu(OTf)
2
(20 mol%) in toluene at room temperature gave an increased yield
7
6% of the compound 10a (entry 3). However, utilizing the same catalyst Cu(OTf) under
2
refluxing and ultrasonic bath in toluene decreased the yield of the compound 10a (entry 4 and 5).
Table 1. Optimization of the reaction conditions for the synthesis of 2,3-dihydroquinazolin-
a
4
(1H)-one 10a
b
Entry
Catalyst
CuCl (20 mol%)
InCl (20 mol%)
Cu(OTf) (20 mol%) toluene
Solvent
Conditions
reflux, 4 h
rt,15 h
Yield (%)
1
2
2
EtOH
62
65
76
60
35
93
75
3
3
CH CN
3
4
5
6
7
8
9
2
rt, 36 h
Cu(OTf) (20 mol%) toluene
reflux, 8 h
2
Cu(OTf) (20 mol%) toluene
ultrasonic, 5 h
2
c
Cu(OTf) (20 mol%) toluene MW, 110 °C, High, 30 min
2
c
Cu(OTf) (10 mol%) toluene MW, 110 °C, High, 30 min
2
c
Cu(OTf) (20 mol%)
EtOH
toluene
toluene
MW, 110 °C, High, 30 min
no reaction
no reaction
no reaction
2
p-TsOH
rt, 36 h
rt, 48 h
1
0
Amberlyst-15
a
All reactions were performed with 9a (1.0 mmol), benzaldehyde (1.1 mmol), catalyst, solvent (5
b
mL); in microwave vial (5-10 mL) sealed and placed in microwave reactor (400 W); Isolated
c
yield as pure product; High-absorption condition
7

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Interestingly, with 20 mol% of Cu(OTf) in the microwave (MW, 400W) at 110 °C for 30 min in
2
toluene, the yield of the compound 10a increased to 93% (entry 6). Apart from increased yield,
shorter reaction times and reduction of the byproducts with controlled heating were also
observed on employing the microwave irradiation. Further changing the catalyst Cu(OTf)2
loading to 10 mol%, the yield of the desired product 10a was decreased (entry 7). However,
2
Cu(OTf) (20 mol%) in the microwave (MW) at 110 °C for 30 min in EtOH did not give the
desired product 10a (entry 8). Notably, the combination of p-TsOH or Amberlyst-15 did not
produce the cyclized product 10a at room temperature (entry 9 and 10). The structural
elucidation of known compound 10a was carried out on the basis of its MS and NMR data. The
6
2
2
,3-dihydroquinazolin-4(1H)-one (10a) was identical in all respects to those reported earlier.
In order to assess the scope of this methodology, further reactions of 2-amino-N-propargyl
benzamide derivatives (9a and 9b) with various aldehydes were examined. These
transformations were carried out in the presence of 20 mol% of Cu(OTf)
2
and toluene in MW for
3
0-40 min using the optimized conditions found in the case of compound 10a (Table 1). The
results are summarized in Scheme 2. The direct two-component reactions worked well with a
variety of aldehydes. Reactions between 2-amino-N-propargyl benzamide (9a) with
benzaldehyde, 4-methoxybenzaldehyde and 4-nitrobenzaldehyde afforded products 10a-c in 93,
8
9 and 86% yield, respectively. Similarly, reactions of 2-amino-4-chloro-N-propargyl benzamide
9b) with benzaldehyde, 4-methoxybenzaldehyde and 4-nitrobenzaldehyde produced the desired
products 10d-f in 88, 85 and 82% yield, respectively (Scheme 2).
(
8

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Scheme 2. Synthesis of 2,3-dihydroquinazolin-4(1H)-ones
2
.1.2. Synthesis of glycosyl triazolyl quinazolin-4(3H)-ones
The glycosyl azides (I and II) were prepared from commercially available glucose and galactose
6
3
following the methods already reported in the literature as shown in Scheme 3. The structures
were established on the basis of their spectroscopic data. These were identical in all respects to
6
4
those reported earlier.
Scheme 3. Synthesis of the glycosyl azides
The strategy for the synthesis of glycosyl triazolyl quinazolin-4(3H)-ones is depicted in Scheme
4
. Having the 2-phenyl-3-propargyl-2,3-dihydroquinazolin-4(1H)-ones (10a-f) and glycosyl
9

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2
azides (I and II) in our hand the CuAAC reactions were performed in t-BuOH/H O (1:1) using
equimolar quantities of the reagents, CuSO .5H O (10 mol%) and sodium ascorbate (20 mol%)
4
2
at ambient temperature to afford epimeric mixtures of peracetyl glycosyl-triazolyl 2,3-
dihydroquinazolin-4(1H)-ones (11a-l) in good yields (Scheme 4, Table 2). Propargyl
quinazolinones and glycosyl azides selectively gave only one regioisomer, 1,4-disubstituted
triazole via 1,3-dipolar cycloaddition reaction.
The above glycosyl triazolyl 2,3-dihydroquinazolin-4(1H)-ones (11a-l) were treated with 1.5 eq.
6
5
of I
peracetylated glycosyl triazolyl quinazolin-4(3H)-ones (12a-l) in good yields (Scheme 4, Table
).
2
in ethanol at refluxing conditions which led to the formation of corresponding
2
Scheme 4. Synthesis of glycosyl quinazolin-4(3H)-ones
The final products were purified by column chromatography and the structures were established
on the basis of NMR data. One of the prototype compound 12a showed all the glycosyl protons
10

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between 5.8 and 3.9 ppm apart from the anomeric proton (H-1'') which was shifted to 5.81 ppm in
1
its H NMR spectrum. The triazolyl proton (H-5') was observed as a singlet at δ 7.85 ppm. The
protons of the methylene group adjacent to triazolyl ring were located as singlet at 5.29 ppm. In
1
3
C NMR spectrum, the position of the anomeric carbon was assigned at 86.0 ppm. The peak at δ
1
62.5 ppm accounted for the amide group carbon (N-CO), quite distinct from the ester acetyl
carbon signals at δ 170.7, 170.1, 169.4 and 168.9 ppm. The 1,4-regioselectivity during
cycloaddition reaction was evidenced on the basis of chemical shifts of the triazolyl carbon signals
1
which were visible at δ 143.9 ppm (C-4') and 122.6 ppm (C-5'), a characteristic feature of the H
1
3
66
and C NMR spectra of 1,4-regioisomers as reported earlier in literature. while the methylene
carbon was observed at δ 42.1 ppm along with other usual signals.
Figure 3. Relevant nOe and HMBC correlations in compound 12a
Further the 1,4-regioselectivity of cycloaddition product 12a was confirmed by 2D NMR
1
13
experiments. The H and C NMR signal assignments and connectivity between quinazolin-4-
3H)-one ring and glucose to 1,4-disubstituted triazole were determined with the help of various
D and 2D NMR experiments (Figure 3). COSY and TOCSY correlations established the coupled
(
1
11

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systems of glucose sugar, H-7 to H-10 of quinazolin-4-(3H)-one ring and a phenyl moiety. HMBC
correlation of CH -6′ to C-2 and C-4 supported that connectivity of CH -6′ to quinazolin-4-(3H)-
2
2
one was through N-3. H-1′′ showed HMBC correlation with C5′ of triazole and confirmed the
connectivity of glucose sugar with triazole through N-1′. HMBC correlation of CH -6′ to C-4′ and
2
C-5′ established the connectivity of CH -6′ with triazole through C-4′. These HMBC correlations
2
established the 1,4-disubstituted regioselectivity of the product. Important nOe correlations
2
between CH -6′ and H-1′′ to H-5′ showed the proximity of protons in the space and supported the
formation of 1,4-disubstituted regioisomer (Figure 3).
Table 2. Peracetylated glycosyl triazolyl quinazolin-4(3H)-ones (12a-12l) from glycosyl azides
and 2,3-dihydroquinazolin-4(1H)-ones
Entry 2,3-Dihydro Glycosyl
quinazolin- azide
Cyclo adduct
Peracetylated glycosyl Yield
a
quinazolin-4(3H)-one
(%)
4(1H)-ones
1
2
3
10a
I
80
1
1a
12a
12b
12c
10a
10b
II
I
78
77
11b
1
1c
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4
5
6
7
8
9
10b
10c
10c
10d
10d
10e
10e
II
75
73
71
79
76
74
73
1
1d
12d
12e
12f
I
II
I
1
1e
1
1f
1
1g
1
2g
II
I
11h
1
2h
1
1i
1
2i
1
0
II
1
1j
1
2j
13

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1
1
1
2
10f
10f
I
72
70
11k
1
2k
II
1
1l
1
2l
a
Isolated yield as pure product
The unsubstituted phenyl containing peracetylated glycosyl triazolyl 2,3-dihydroquinazolin-
(1H)-ones (11a, 11b, 11g and 11h) gave the desired oxidation to furnish the peracetylated
glycosyl triazolyl quinazolin-4(3H)-ones (12a, 12b, 12g and 12h) respectively in good yields
76-80%). Similarly, p-methoxy substituted phenyl containing peracetylated glycosyl triazolyl
,3-dihydroquinazolin-4(1H)-ones (11c, 11d and 11i) underwent smooth oxidation to furnish the
4
(
2
peracetylated glycosyl triazolyl quinazolin-4(3H)-ones (12c, 12d and 12i) in 74-77% yield.
However, p-nitro substituted phenyl containing peracetylated glycosyl triazolyl 2,3-
dihydroquinazolin-4(1H)-ones (11e, 11f, 11j, 11k and 11l) gave a somewhat lower yield (70-
7
3%) of the corresponding peracetylated glycosyl triazolyl quinazolin-4(3H)-ones (12e, 12f, 12j,
2k and 12l) compared to the other peracetylated glycosyl triazolyl quinazolin-4(3H)-one
1
derivatives.
The Zemplen deacetylation of the above peracetylated glycosyl triazolyl quinazolin-4(3H)-ones
(12a-l) with NaOMe/MeOH at room temperature led to the formation of the deacetylated
glycosyl triazolyl quinazolin-4(3H)-ones (13a-l) respectively in good yields (Scheme 4, Table 3).
14

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Table 3: Synthesized deacetylated compounds 13a-l from peracetylated glycosyl triazolyl
quinazolin-4(3H)-ones (12a-l)
a
Entry
Peracetylated
substrates
Deacetylated products
Yield (%)
1
12a
12b
12c
12d
12e
12f
94
1
3a
2
3
4
5
6
92
93
91
92
90
13b
1
3c
13d
1
3e
1
3f
15

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7
8
9
12g
12h
12i
92
91
91
89
90
89
1
3g
13h
1
3i
1
0
1
2
12j
12k
12l
1
3j
1
1
13k
1
3l
a
Isolated yield as pure product
2
2
.2.Biology
.2.1. In vitro GLUT4 translocation activity
We initially performed bioevalution of 2,3-dihydroquinazolin-4(1H)-ones (10a-f) for their in
16

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vitro GLUT4 translocation activity using L-6 muscle cell lines and the results are shown in Table
4
. All the 2,3-dihydroquinazolin-4(1H)-ones (10a-f) showed promising to significant GLUT4
translocation activity with 1.06-1.27 fold stimulation at 10 µM (Table 4). In this series, the p-
methoxy phenyl substituted 2,3-dihydroquinazolin-4(1H)-ones 10b and 10e displayed the most
promising GLUT4 translocation activity with 1.27 and 1.24 fold stimulation at 10 µM in L-6
muscle cell lines, respectively. Other phenyl substituted 2,3-dihydroquinazolin-4(1H)-ones (10a,
1
0c, 10d and 10f) showed significant GLUT4 translocation activity at 10 µM in L-6 muscle cell
lines.
Table 4. In vitro GLUT4 translocation activity (10 µM) of glycosyl quinazolin-4(3H)-ones
S. No
Compound
GLUT4 translocation (Fold Stimulation)
1
2
3
4
5
6
7
8
9
10a
10b
10c
10d
10e
10f
1.06
1.27
1.22
1.16
1.24
1.21
0.60
0.57
Nil
12a
12b
12c
12d
12e
1
1
0
1
1.18
0.51
17

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1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
12f
12g
12h
12i
1.08
0.40
0.87
ND
12j
12k
12l
ND
0.84
1.09
0.55
0.54
0.52
1.18
0.73
1.09
0.59
0.57
0.79
ND
13a
13b
13c
13d
13e
13f
13g
13h
13i
13j
13k
13l
ND
1.35
1.31
Rosiglitazone (Std)
Nil – ≤ 0.2 fold response comparison to control, ND – Not determined
18

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The glycosyl 1,2,3-1H-triazolyl quinazolin-4(3H)-one derivatives (12a-l and 13a-l) were also
screened for their in vitro GLUT4 translocation activity using rosiglitazone (A thiazolidinedione
antidiabetic agent, a key underlying metabolic abnormality in most patients with type 2 diabetes
mellitus, improves insulin resistance) as standard (Table 4). As evident in Table 4, most of the
galactosyl triazolyl quinazolin-4(3H)-ones showed better GLUT4 translocation activity as
compared to the glucosyl triazolyl quinazolin-4(3H)-ones. Out of all the compounds screened for
GLUT4 translocation activity, 6 compounds (12d, 12f, 12l, 13d, 13f and 13l) exhibited
promising to significant GLUT4 translocation activity with 1.08-1.35 fold stimulation at a
concentration of 10 µM in L-6 muscle cell lines (Table 4). In this series, the p-nitro phenyl
substituted hydroxy galactosyl triazolyl chloro quinazolin-4(3H)-one 13l (1.35 fold stimulation)
exhibited the most promising GLUT4 translocation activity as compared to its peracetylated
analogue 12l (1.09 fold stimulation) at 10 µM in L-6 muscle cell lines. The p-methoxy phenyl
substituted hydroxy galactosyl triazolyl quinazolin-4(3H)-one 13d (1.18 fold stimulation) and
peracetylated galactosyl triazolyl quinazolin-4(3H)-one 12d (1.18 fold stimulation) showed good
GLUT4 translocation activity as compared to 13l. Another p-nitro phenyl substituted hydroxy
galactosyl triazolyl quinazolin-4(3H)-one 13f (1.09 fold stimulation) and peracetylated
galactosyl triazolyl quinazolin-4(3H)-one 12f (1.08 fold stimulation) showed moderate GLUT4
translocation activity at 10 µM concentration. Other compounds belonging to glycosyl 1,2,3-1H-
triazolyl quinazolin-4(3H)-one showed less GLUT4 translocation activity compared to standard
drug rosiglitazone.
3
. Conclusion
19

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In conclusion, we have developed an efficient method for the synthesis of 3-propynyl-2,3-
dihydroquinazolin-4(1H)-ones in high yields. The reaction involves the cyclization of anthranyl
derivatives with aromatic aldehydes using Cu(OTf) as catalyst under microwave irradiation with
2
short reaction time, simple work-up, and mild reaction conditions. Further subjected to CuAAc
reaction of glycosyl azides with these propargylated dihydroquinazolinones through Click
reaction afforded the glycosyl triazolyl 2,3-dihydroquinazolin-4(1H)-one derivatives in excellent
yields. The latter on iodine catalyzed oxidation resulted in a series of novel glycosyl 1,2,3-1H-
triazolyl quinazolin-4(3H)-one derivatives. 24 compounds were screened against in vitro GLUT4
translocation activity, six compounds 12d, 12f, 12l, 13d, 13f and 13l showed promising GLUT4
translocation activity (fold stimulation). While the deacetylated galactosyl 1,2,3-1H-triazolyl
quinazolin-4(3H)-one derivative 13l exhibited the most promising GLUT4 translocation activity
with 1.35-fold stimulation at the concentration of 10 µM in L-6 muscle cell lines.
4
4
. Experimental section
.1. General methods
Commercially available reagent grade chemicals were used as received. All reactions were
monitored by TLC on E. Merck Kieselgel 60 F254, with detection in UV light (254 nm),
spraying 20% aq KMnO
4
2 4
solution and/or spraying 4% ethanolic H SO . Column
chromatography was performed on Silica Gel (60-120 mesh, E. Merck). IR spectra were
-1
recorded as thin films with a Perkin-Elmer Spectrometer RX-1 (4000–450 cm )
1
13
spectrophotometer. H and C NMR spectra were recorded on Bruker AV III HD 400 MHz and
5
00 MHz instruments, respectively, in CDCl and DMSO-d . Chemical shift values are reported
3
6
in ppm relative to TMS (tetramethylsilane) as the internal reference, unless otherwise stated; s
20

ACCEPTED MANUSCRIPT
(singlet), d (doublet), t (triplet), dd (doublet of doublets), m (multiplet); Coupling constants
n
(
patterns) J are expressed (given) in Hertz (Hz). HRMS spectra were taken under ESI-Q-TOF
H,H
conditions. Optical rotations were measured in a 1.0-dm tube with a Rudolf Autopol III polari
meter in CHCl and MeOH. Microwave mediated reactions were performed in commercial
3
microwave system [maximum output power 400W, built-in magnetic stirrer (300-900 rpm) and
an IR temperature sensor (40-250 °C)].
4
.2. General procedure for the preparation of N-propargyl benzamides (9a and 9b)
Anthranilic or 2-amino-4-chlorobenzoic acid (8, 1 mmol) was dissolved in dry DMF (20 mL),
resulted solution was degassed with N then cooled at 0 °C and 1-Hydroxybenzotriazole (Bt-OH,
2
1
mmol), 4-Dimethylaminopyridine (DMAP, 1 mmol) were added to the reaction mixture. N,N'-
Diisopropylcarbodiimide (DIPC, 1 mmol) was added dropwise to the stirring reaction mixture.
After 10 mins, propargyl amine (1.1 mmol) was added to the reaction mixture and stirred
overnight at ambient temperature. The crude mixture was taken up with water (50 mL) and
extracted with ethyl acetate (3 × 40 mL). The combined organic extracts were washed with brine
(50 mL), dried over sodium sulfate, filtered, concentrated, and purified by column
chromatography (20% EtOAc:Hexane) to afford desired compounds 9a and 9b.
6
1a
4
.3. 2-Amino-N-(prop-2-yn-1-yl)benzamide (9a)
A mixture of anthranilic acid 8a (5.0 g, 36.49 mmol), HOBt (4.92 g, 36.49 mmol), DMAP (4.45
g, 36.49 mmol), DIPC (5.67 mL, 36.49 mmol) and propargyl amine (2.56 mL, 40.14 mmol) in
dry DMF (20 mL) was stirred under nitrogen atmosphere at room temperature for 10 h. The
reaction mixture was extracted with ethyl acetate and the solvent evaporated in vacuo to give the
21

ACCEPTED MANUSCRIPT
crude product, which was purified by column chromatography (20% EtOAc/Hexane) to give the
title compound 9a (5.65 g, 89%) as a white solid; R (20% EtOAc/Hexane) 0.50; mp 86-88 °C;
f
-1
IR (νmax): 3372, 3019, 1648, 1586, 1403, 1215, 757 cm ; δ (400 MHz, CDCl +CCl ) 7.24 (1H,
H
3
4
m, Ar-H), 7.12 (1H, m, Ar-H), 6.57 (2H, m, Ar-H), 6.25 (1H, bs, -NH), 5.43 (2H, bs, -NH ), 4.10
2
1
3
(
2H, m, -CH ), 2.16 (1H, m, -CH); δ C NMR (100 MHz, CDCl +CCl ) 168.8 (C=O), 148.9
2 C 3 4
(Ar-C), 132.6 (Ar-C), 127.2 (Ar-C), 117.3 (Ar-C), 116.5 (Ar-C), 114.9 (Ar-C), 79.7, 71.7 (-CH),
+
2
9.4 (-CH
2
); HRMS: [M+H] , found 175.0874. C10
H
11
N
2
O requires 175.0866.
6
1b
4
.4. 2-Amino-4-chloro-N-(prop-2-yn-1-yl)benzamide (9b)
A mixture of 2-amino-4-chloro-benzoic acid 8b (5.0 g, 29.23 mmol), HOBt (3.94 g, 29.23
mmol), DMAP (3.56 g, 29.23 mmol), DIPC (4.54 mL, 29.23 mmol) and propargyl amine (2.05
mL, 32.16 mmol) in dry DMF (20 mL) was stirred under nitrogen atmosphere at room
temperature for 12 h. The reaction mixture was extracted with ethyl acetate and the solvent
evaporated in vacuo to give the crude product, which was purified by column chromatography
(20% EtOAc/Hexane) to give the title compound 9b (5.35 g, 88%) as a light yellow solid; R
f
-1
(
20% EtOAc/Hexane) 0.51; mp 112-114 °C; IR (νmax): 3391, 3019, 1650, 1385, 1215, 758 cm ;
δ (400 MHz, CDCl +CCl ) 7.25 (1H, m, Ar-H), 6.65 (1H, m, Ar-H), 6.59 (1H, m, Ar-H), 6.15
H
3
4
(
1H, bs, -NH), 5.66 (2H, bs, -NH ), 4.18 (2H, m, -CH ), 2.26 (1H, m, -CH); δ (100 MHz,
2 2 C
CDCl +CCl ): 168.0 (C=O), 150.0 (Ar-C), 138.5 (Ar-C), 128.3 (Ar-C), 116.6 (2 × Ar-C), 113.1
3
4
+
(
Ar-C), 79.4, 71.9 (-CH), 29.4 (-CH ); HRMS: [M+H] , found 209.0477. C H ClN O requires
2 10 10 2
2
09.0476.
4
.5. General procedure for the compounds 10a-f
22

ACCEPTED MANUSCRIPT
An oven-dried 5 mL microwave reaction vessel containing a stir bar was charged with 2-amino-
N-(prop-2-yn-1-yl)benzamide derivative 9 (1.0 mmol), aldehyde (1.1 mmol) and Cu(OTf) (20
2
mol%) to this, 5 mL toluene was added and the vessel was sealed with a plastic microwave
septum. The vessel was placed into the CEM Discover SP system under the following
conditions: pre-stirring 30 s, stirring was set high (absorption). Maximum power and maximum
pressure were set 450 Wand 450 psi respectively, with a set temperature of 110 °C for 30-40 min
(
hold time). After microwave irradiation was complete, the mixture was cooled to room
temperature and then diluted with ethyl acetate and water. The organic layer was separated and
dried with anhyd. Na SO and evaporated under reduced pressure to give the crude mass, which
2
4
was purified by column chromatography on silica gel (60-120 mesh) using 20% EtOAc/ hexane
to give desired products 10a-f.
6
2
4
.6. 2-Phenyl-3-(prop-2-yn-1-yl)-2,3-dihydroquinazolin-4(1H)-one (10a)
A mixture of 2-amino-N-(prop-2-yn-1-yl)benzamide 9a (1.0 g, 5.74 mmol), benzaldehyde (0.64
mL, 6.32 mmol) and Cu(OTf) (0.41 g, 1.14 mmol) in toluene (5 mL) was stirred under
2
microwave irradiation at 110 °C temperature for 30 min. The reaction mixture was extracted
with ethyl acetate and the solvent evaporated in vacuo to give the crude product, which was
purified by column chromatography (20% EtOAc/Hexane) to give the title compound 10a (1.40
g, 93%) as a white solid; R (20% EtOAc/Hexane) 0.62; mp 141-143 °C; IR (νmax): 3400, 3019,
f
-1
1
647, 1403, 1215, 757 cm ; δ (500 MHz, CDCl ) 7.97 (1H, d, J 8.0 Hz, Ar-H), 7.49 (2H, m,
H 3
Ar-H), 7.39 (3H, m, Ar-H), 7.29 (1H, m, Ar-H), 6.86 (1H, t, J 8.0 Hz, Ar-H), 6.57 (1H, d, J 8.0
Hz, Ar-H), 6.04 (1H, s, -CH), 5.00 (1H, dd, J 17.5 Hz, J 2.3 Hz), 4.55 (1H, bs, -NH), 3.31 (1H,
dd, J 17.5 Hz, J 2.3 Hz), 2.18 (1H, s, -CH); δ (125 MHz, CDCl ) 163.2 (C=O), 145.6 (Ar-C),
1
2
1
2
C
3
23

ACCEPTED MANUSCRIPT
1
1
2
38.5 (Ar-C), 133.9 (Ar-C), 129.7 (Ar-C), 129.0 (2 × Ar-C), 128.9 (Ar-C), 127.2 (2 × Ar-C),
+
19.2 (Ar-C), 115.2 (Ar-C), 114.1 (Ar-C), 78.3, 72.0, 71.7, 32.6 (-CH ); HRMS: [M+H] , found
2
63.1185. C H N O requires 263.1179.
17
15
2
4
.7. 2-(4-Methoxyphenyl)-3-(prop-2-yn-1-yl)-2,3-dihydroquinazolin-4(1H)-one (10b)
mixture of 2-amino-N-(prop-2-yn-1-yl)benzamide 9a (1.0 g, 5.74 mmol), 4-
methoxybenzaldehyde (0.76 mL, 6.32 mmol) and Cu(OTf) (0.41 g, 1.14 mmol) in toluene (5
A
2
mL) was stirred under microwave irradiation at 110 °C temperature for 30 min. The reaction
mixture was extracted with ethyl acetate and the solvent evaporated in vacuo to give the crude
product, which was purified by column chromatography (20% EtOAc/Hexane) to give the title
compound 10b (1.49 g, 89%) as a white solid; R (20% EtOAc/Hexane) 0.63; mp 138-140 °C; IR
f
-1
(
νmax): 3399, 3019, 1638, 1403, 1216, 770 cm ; δ (400 MHz, CDCl ) 7.97 (1H, d, J 6.8 Hz, Ar-
C 3
H), 7.44 (2H, m, Ar-H), 7.30 (1H, m, Ar-H), 6.91 (2H, m, Ar-H), 6.88 (1H, m, Ar-H), 6.58 (1H,
d, J 8.0 Hz, Ar-H), 5.99 (1H, s, -CH), 4.96 (1H, dd, J 17.5 Hz, J 2.6 Hz), 4.48 (1H, bs, -NH),
1
2
3
.81 (3H, s, -OCH
3 1 2 C
), 3.29 (1H, dd, J 17.4 Hz, J 2.3 Hz), 2.17 (1H, t, J 2.4 Hz, -CH). δ (100
MHz, CDCl ) 163.4 (C=O), 160.6 (Ar-C), 145.8 (Ar-C), 133.8 (Ar-C), 130.4 (Ar-C), 128.9 (Ar-
3
C), 128.7 (2 × Ar-C), 119.1 (Ar-C), 115.3 (Ar-C), 114.3 (2 × Ar-C), 114.1 (Ar-C), 78.4, 71.7,
+
7
2
1.5, 55.3 (-OCH ), 32.4 (-CH ); HRMS: [M+H] , found 293.1291. C H N O requires
3
2
18 17
2
2
93.1285.
4
.8. 2-(4-Nitrophenyl)-3-(prop-2-yn-1-yl)-2,3-dihydroquinazolin-4(1H)-one (10c)
A mixture of 2-amino-N-(prop-2-yn-1-yl)benzamide 9a (1.0 g, 5.74 mmol), 4-nitrobenzaldehyde
0.95 g, 6.32 mmol) and Cu(OTf) (0.41 g, 1.14 mmol) in toluene (5 mL) was stirred under
(
2
24

ACCEPTED MANUSCRIPT
microwave irradiation at 110 °C temperature for 40 min. The reaction mixture was extracted
with ethyl acetate and the solvent evaporated in vacuo to give the crude product, which was
purified by column chromatography (20% EtOAc/Hexane) to give the title compound 10c (1.51
g, 86%) as a yellow solid; R (20% EtOAc/Hexane) 0.39; mp 136-138 °C; IR (νmax): 3398, 3019,
f
-1
1
644, 1403, 1215, 757 cm ; δ (400 MHz, CDCl +CCl ) 8.21 (2H, m, Ar-H), 7.95 (1H, m, Ar-
H 3 4
H), 7.64 (2H, m, Ar-H), 7.33 (1H, m, Ar-H), 6.90 (1H, m, Ar-H), 6.63 (1H, d, J 8.0 Hz, Ar-H),
.16 (1H, s, -CH), 5.01 (1H, dd, J 17.7 Hz, J 2.6 Hz), 4.82 (1H, bs, -NH), 3.51 (1H, dd, J 17.7
Hz, J 2.4 Hz), 2.25 (1H, t, J 2.5 Hz, -CH); δ (100 MHz, CDCl +CCl ) 162.6 (C=O), 148.5 (Ar-
6
1
2
1
2
C
3
4
C), 145.7 (Ar-C), 144.7 (Ar-C), 134.2 (Ar-C), 128.9 (Ar-C), 127.9 (2 × Ar-C), 124.2 (2 × Ar-C),
+
1
3
19.9 (Ar-C), 115.4 (Ar-C), 114.7 (Ar-C), 77.6, 73.2, 70.3, 33.1 (-CH ); HRMS: [M+H] , found
2
08.1015. C H N O requires 308.1030.
17
14
3
3
4
.9. 7-Chloro-2-phenyl-3-(prop-2-yn-1-yl)-2,3-dihydroquinazolin-4(1H)-one (10d)
A mixture of 2-amino-7-chloro-N-(prop-2-yn-1-yl)benzamide 9b (1.0 g, 4.80 mmol),
benzaldehyde (0.53 mL, 5.28 mmol) and Cu(OTf) (0.34 g, 0.96 mmol) in toluene (5 mL) was
2
stirred under microwave irradiation at 110 °C temperature for 30 min. The reaction mixture was
extracted with ethyl acetate and the solvent evaporated in vacuo to give the crude product, which
was purified by column chromatography (20% EtOAc/Hexane) to give the title compound 10d
(
1.25 g, 88%) as a white solid; R (20% EtOAc/Hexane) 0.60; mp 160-162 °C; IR (νmax): 3399,
f
-
1
3
7
019, 1638, 1402, 1215, 757 cm ; δ (400 MHz, CDCl +CCl ) 7.85 (1H, d, J 8.3 Hz, Ar-H),
H 3 4
.46 (2H, m, Ar-H), 7.39 (3H, m, Ar-H), 6.79 (1H, m, Ar-H), 6.56 (1H, m, Ar-H), 6.02 (1H, s, -
17.5 Hz, J 2.5 Hz), 4.74 (1H, bs, -NH), 3.27 (1H, dd, J 17.5 Hz, J 2.4
Hz), 2.17 (1H, t, J 2.4 Hz, -CH); δ (100 MHz, CDCl +CCl ) 162.2 (C=O), 146.3 (Ar-C), 139.8
CH), 4.97 (1H, dd, J
1
2
1
2
C
3
4
25

ACCEPTED MANUSCRIPT
(Ar-C), 138.3 (Ar-C), 130.4 (Ar-C), 129.8 (Ar-C), 129.1 (2 × Ar-C), 127.0 (2 × Ar-C), 119.5
+
(
Ar-C), 113.8 (Ar-C), 113.5 (Ar-C), 78.0, 72.2, 71.5, 32.5 (-CH ); HRMS: [M+H] , found
2
2
97.0799. C H ClN O requires 297.0789.
17 14 2
4
.10. 7-Chloro-2-(4-methoxyphenyl)-3-(prop-2-yn-1-yl)-2,3-dihydroquinazolin-4(1H)-one
10e)
A mixture of 2-amino-7-chloro-N-(prop-2-yn-1-yl)benzamide 9b (1.0 g, 4.80 mmol), 4-
methoxybenzaldehyde (0.64 mL, 5.28 mmol) and Cu(OTf) (0.34 g, 0.96 mmol) in toluene (5
(
2
mL) was stirred under microwave irradiation at 110 °C temperature for 30 min. The reaction
mixture was extracted with ethyl acetate and the solvent evaporated in vacuo to give the crude
product, which was purified by column chromatography (20% EtOAc/Hexane) to give the title
compound 10e (1.33 g, 85%) as a light yellow solid; R (20% EtOAc/Hexane) 0.64; mp 150-152
f
-1
°
C; IR (νmax): 3399, 3019, 1638, 1403, 1215, 769 cm ; δ (400 MHz, CDCl +CCl ) 7.86 (1H, d,
H 3 4
J 8.3 Hz, Ar-H), 7.40 (2H, m, Ar-H), 6.89 (2H, m, Ar-H), 6.79 (1H, m, Ar-H), 6.56 (1H, m, Ar-
H), 5.97 (1H, s, -CH), 4.94 (1H, dd, J 17.3 Hz, J 2.4 Hz), 4.58 (1H, bs, -NH), 3.81 (3H, s, -
OCH ), 3.24 (1H, dd, J 17.5 Hz, J 2.4 Hz), 2.15 (1H, t, J 2.4 Hz, -CH). δ (100 MHz,
CDCl +CCl ) 162.5 (C=O), 160.7 (Ar-C), 146.5 (Ar-C), 139.8 (Ar-C), 130.4 (Ar-C), 130.1 (Ar-
1
2
3
1
2
C
3
4
C), 128.6 (2 × Ar-C), 119.4 (Ar-C), 114.3 (2 × Ar-C), 113.7 (Ar-C), 113.5 (Ar-C), 78.2, 72.0,
+
7
3
1.3, 55.2 (-OCH ), 32.4 (-CH ); HRMS: [M+H] , found 327.0885. C H ClN O requires
3
2
18 16
2
2
27.0895.
4
.11. 7-Chloro-2-(4-nitrophenyl)-3-(prop-2-yn-1-yl)-2,3-dihydroquinazolin-4(1H)-one
10f)
(
26

ACCEPTED MANUSCRIPT
A mixture of 2-amino-7-chloro-N-(prop-2-yn-1-yl)benzamide 9b (1.0 g, 4.80 mmol), 4-
nitrobenzaldehyde (0.79 g, 5.28 mmol) and Cu(OTf) (0.34 g, 0.96 mmol) in toluene (5 mL) was
2
stirred under microwave irradiation at 110 °C temperature for 40 min. The reaction mixture was
extracted with ethyl acetate and the solvent evaporated in vacuo to give the crude product, which
was purified by column chromatography (20% EtOAc/Hexane) to give the title compound 10f
(
1.34 g, 82%) as a light yellow solid; R (20% EtOAc/Hexane) 0.38; mp 204-206 °C; IR (νmax):
f
-
1
3
398, 3019, 1637, 1403, 1215, 769 cm ; δ
.72 (1H, m, Ar-H), 7.66 (3H, m, Ar-H, -NH), 6.70 (2H, m, Ar-H), 6.17 (1H, s, -CH), 4.80 (1H,
17.6 Hz, J 2.3 Hz), 3.73 (1H, dd, J 17.6 Hz, J 2.3 Hz), 2.80 (1H, t, J 2.4 Hz, -CH); δ
100 MHz, CDCl +DMSO-d ) 161.6 (C=O), 148.1 (Ar-C), 147.1 (Ar-C), 146.9 (Ar-C), 139.3
H 3 6
(400 MHz, CDCl +DMSO-d ) 8.22 (2H, m, Ar-H),
7
dd, J
1
2
1
2
C
(
3
6
(Ar-C), 129.9 (Ar-C), 127.9 (2 × Ar-C), 124.0 (2 × Ar-C), 118.1 (Ar-C), 114.1 (Ar-C), 112.8
+
(
Ar-C), 78.2, 74.6, 69.7, 33.6 (-CH ); HRMS: [M+H] , found 342.0760. C H ClN O requires
2
17 13
3
3
3
42.0640.
4
.12. General Procedure for the synthesis of 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl
azide (I)
To a stirring suspension of sodium acetate (9 g, 111.11 mmol) in acetic anhydride (105 ml,
111.11 mmol) was added glucose (10 g, 55.55 mmol). The reaction mixture was heated at 90
C for 4 hours. After completion of the reaction (on TLC), the reaction mixture was immediately
1
°
transferred into ice-water mixture and stirred vigorously until the white solid precipitates. The
white solid is filtered and dried completely on vacuo.
To a solution of glucosyl peracetate (5.0 g, 12.82 mmol) in anhydrous dichloromethane was
added trimethylsilyl azide (2.21 mL, 16.66 mmol), followed by 1.0 M solution of Stannic
27

ACCEPTED MANUSCRIPT
chloride (0.75 mL, 6.41 mmol). The resulting solution was stirred at room temperature for 12
hours under inert atmosphere. After the completion of the reaction (on TLC), the reaction
mixture was diluted with dichloromethane, washed with saturated aqueous solution of sodium
bicarbonate, dried over Na SO , filtered and concentrated in vacuo to give the crude product,
2
4
which was purified by recrystallization (hexane/dichloromethane) to give the title compound I
4.6 g, 96%) as a white solid; R (50% EtOAc/Hexane) 0.70; The melting point and the spectral
(
f
1
13
64
data (IR, H, and C NMR) were identical to those previously reported. mp 130-132 °C, lit mp
1
31-135 ºC.
4
.13. General Procedure for the synthesis of 2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl
azide (II)
To a stirring suspension of sodium acetate (9 g, 111.11 mmol) in acetic anhydride (105 ml,
111.11 mmol) was added galactose (10 g, 55.55 mmol). The reaction mixture was heated at 90
C for 4 hours. After completion of the reaction (on TLC), the reaction mixture was immediately
1
°
transferred into ice-water mixture and stirred vigorously until the white solid precipitates. The
white solid is filtered and dried completely on vacuo.
To a solution of galactosyl peracetate (5.0 g, 12.82 mmol) in anhydrous dichloromethane was
added trimethylsilyl azide (2.21 mL, 16.66 mmol), followed by 1.0 M solution of Stannic
chloride (0.75 mL, 6.41 mmol). The resulting solution was stirred at room temperature for 12
hours under inert atmosphere. After the completion of the reaction (on TLC), the reaction
mixture was diluted with dichloromethane, washed with saturated aqueous solution of sodium
bicarbonate, water, dried over Na SO , filtered and concentrated in vacuo to give the crude
2
4
28

ACCEPTED MANUSCRIPT
product, which was purified by recrystallization (hexane/dichloromethane) to give the title
compound II (4.3 g, 89%) as a white solid; R (50% EtOAc/Hexane) 0.69; The melting point and
f
1
13
64
the spectral data (IR, H, and C NMR) were identical to those previously reported. mp 93-95
°
C, lit mp 90-92 ºC.
4
.14. General procedure for the synthesis of peracetylated compounds 11a-l
2
-phenyl-3-(prop-2-yn-1-yl)-2,3-dihydroquinazolin-4(1H)-ones 10a-f (1 mmol) and glycosyl
azide (1 mmol) were suspended in a mixture of 1:1 tert-butanol:water (20 mL) and kept for
stirring at room temperature. To the stirring reaction mixture freshly prepared solution of sodium
ascorbate (20 mol%) in 500 ꢀL and freshly prepared solution of CuSO .5H O (10 mol%) in 200
4
2
ꢀ
L water were sequentially added. The reaction mixture was stirred at ambient temperature for 8-
0 h. The reaction mixture was extracted with ethyl acetate and washed with water. The organic
layer was dried over anhydrous Na SO and evaporated under reduced pressure to give a white
1
2
4
crude product. The latter was purified by silica gel (60-120 mesh) column chromatography to
give the cycloaddition product 11a-l.
4
.15. 2-Phenyl-3-[{1′-(1′′-deoxy-2′′,3′′,4′′,6′′-tetra-O-acetyl-β-
′,2′,3′-triazol-4′-yl}methyl]-2,3-dihydroquinazolin-4(1H)-one (11a)
A mixture of 10a (0.49 g, 1.87 mmol), glycosyl azide I (0.70 g, 1.87 mmol), CuSO .5H O (0.046
D-glucopyranos-1′′-yl)-1′H-
1
4
2
g, 0.18 mmol) and sodium ascorbate (0.074 g, 0.37 mmol) in 1:1 tert-Butanol:water (40 mL) was
stirred at room temperature for 8 h. The reaction mixture was extracted with ethyl acetate and the
solvent evaporated in vacuo to give the crude product, which was purified by column
chromatography (50% EtOAc/Hexane) to give the title compound 11a (1.08 g, 91%) as a white
29