Design and synthesis of carbohydrate based medium sized sulfur containing benzannulated macrocycles: Applications of Sonogashira and Heck coupling

Article abstract of DOI:10.1016/j.tet.2013.04.090

Palladium catalyzed intramolecular Sonogashira and Heck coupling reactions have been applied for diversity-oriented synthesis of sulfur containing carbohydrate based medium sized ring macrocycles. The process involves design and synthesis of building bloc

Full text of DOI:10.1016/j.tet.2013.04.090

Tetrahedron 69 (2013) 5517e5524
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Design and synthesis of carbohydrate based medium sized sulfur
containing benzannulated macrocycles: applications of Sonogashira
and Heck coupling
,
,
,b
Altaf Hussain a b, Syed Khalid Yousuf b, Deepak K. Sharma a b, L. Mallikharjuna Rao a
,
Baldev Singh b, Debaraj Mukherjee a
,
b
, ,
y
*
a Academy of Scientific and Innovative Research (AcSIR), NPC (Microbes), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, J & K,
180001, India
b CSIR-IIIM (Indian Institute of Integrative Medicine), Medicinal Chemistry Division, Sanat Nagar, Srinagar, J & K, 190005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 March 2013
Received in revised form 31 March 2013
Accepted 18 April 2013
Available online 25 April 2013
Palladium catalyzed intramolecular Sonogashira and Heck coupling reactions have been applied for di-
versity-oriented synthesis of sulfur containing carbohydrate based medium sized ring macrocycles. The
process involves design and synthesis of building blocks with predisposed functional units prerequisite
for CeC coupling. Both cis- and trans-fused benzannulated medium sized macrocyles with different ring
sizes (8e13-membered) fused at different positions of furannose and pyranose moiety have been
achieved.
Keywords:
Medium sized sulfur containing
macrocycles
Ó 2013 Elsevier Ltd. All rights reserved.
Sonogashira coupling
Heck coupling
Carbohydrate
Protection and deprotection
1. Introduction
transannular interactions. Very recently, Daniel Werz et al., reported
Pd-catalyzed ring annulations using monosaccharides for the con-
Discovery and progress in cross coupling reactions have opened
a new paradigm in synthetic chemistry.1 Especially palladium cat-
alyzed CeC bond forming coupling reactions have enabled con-
siderably the prowess of synthetic chemist to take new challenges
for the generation of new structural frameworks.2 Sonogashira and
Heck coupling are among the most important and widely used
sp2esp and sp2esp2 CeC bond forming reactions, respectively.
These are frequently employed in the synthesis of natural products,
biologically active molecules, heterocycles, molecular electronics,
dendrimers and conjugated polymers or nanostructures.3,4
Carbohydrate fused bi-cyclic systems containing medium to large
sized heterocyclic rings are encountered in innumerable number of
biologically active natural products.5 The possible role of these me-
dium sized ring macrocycles in antibiotics has always drawn the at-
tention of synthetic chemists to synthesize oxygen and nitrogen
containing benzannulated medium sized rings fused with carbohy-
drates,6,7 which are difficult to prepare owing to the ring strain and
struction of small sized oxygen and nitrogen containing bi-cyclic and
tri-cyclic benzannulated molecular systems.8 Despite these applica-
tions, there is no report of palladium catalyzed CeC bond forming
intramolecular coupling reactions in the construction of rigid me-
dium sized sulfur containing carbohydrate based macrocycles with
defined stereochemistry. The sulfurcontaining products are attaining
a legal superiority in the gamete of modern world bioactives.9 For
example, the versatility of sulfur has been exploited significantly in
drug discoveryefforts, as evidenced by the fact that several of the 200
top-selling pharmaceutical agents in 201010 contain sulfur and, in
manycases, the sulfur atom is contained in a ring. Withour interest in
the synthesis of benzannulated medium sized macrocycles from
carbohydrates,11 hereinwe want to report the design and synthesis of
medium sized sulfur containing benzannulated macrocycles using
carbohydrate as chiral pool. The facile variation of the carbohydrate
part leads to a high degree of structural diversity.
2. Results and discussions
* Corresponding author. Tel.: þ91 191 2569000; fax: þ91 191 2569111; e-mail
Our approach was designed to mirror our route to the formation
of oxygen-containing macrocycles.9 Thus, we designed two types of
addresses: dmukherjee@iiim.ac.in, debarajrrl@gmail.com (D. Mukherjee).
y
CSIR-IIIM Pub. No-IIIM/1509/2012.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.090

5518
A. Hussain et al. / Tetrahedron 69 (2013) 5517e5524
scaffolds (A) and (B) (Fig. 1) keeping in view the basic requirements
for Sonogashira and Heck coupling under the concept of build/
couple/pair strategy.12 In order to synthesize medium sized sulfur
macrocycles with particular ring size, we designed different scaf-
folds (Fig. 2), which could be synthesized from carbohydrates either
involving 1,2-OH or 3,5,6-OH so that remaining hydroxyl groups
after deprotection can be utilized. All the newly designed furan
With all building blocks for Sonogashira and Heck coupling re-
actions in hand, I was selected as model substrate for coupling
reaction. Thus, the scaffold I was allowed to undergo intra-
molecular Sonogashira reaction using the heterogeneous catalyst
developed in our lab (Scheme 4).6 It was found that the reaction
proceeds smoothly leading to the generation of sulfur containing
medium sized benzannulated ring Ia in 86% yield. The structure of
Ia was confirmed through various spectroscopic techniques. The
based scaffolds were prepared from 1,2,5,6-di-O-acetonide-a-D-
glucofuranose (1) by the strategic installation of functional groups
as discussed in Scheme 1. In general the synthesis involves aceto-
nide deprotection, alkylation/arylation, epoxidation, epoxide
opening, sugar aldehyde generation and glycosylation reactions. It
is noteworthy that using glycosylation reactions we managed to
create both cis- and trans-stereochemistry (relative to 2-OH),
which enable us to generate cis/trans-fused benzannulated mac-
rocycles present in natural products. The allose derivative II was
prepared by 3-OH oxidation of 1 with PDC followed by NaBH4 re-
duction to get the inversion product.
disappearance of acetylene peak (
appearance of a new quaternary carbon (
d
¼2.5 ppm) in the 1H NMR and
d
¼75 ppm) in 13C NMR of
Ia was in full agreement with the assigned structure. Encouraged by
the results, all the furan based building blocks (II, IV, VI, VII and X)
with terminal alkyne group and aryl halide group were subjected to
intramolecular CeC bond formation under standardized reaction
conditions to yield the corresponding medium sized macrocycles in
good to excellent yields (Table 1, entries 1e6). The scope of the
reagent system was explored by extending the study to pyran based
scaffolds (XI, XIII, XV, XVI, XVII and XVIII). In all the cases the
macrocycle formed smoothly in good to excellent yield (Table 1,
entries 7e12).
After obtaining the satisfactory results in Sonogashira reaction,
next we attempted Heck coupling with substrate III. Thus, in our
initial experiment III was allowed to undergo intramolecular Heck
coupling (Scheme 5) using different Pd catalysts (Table 2, entries
1e10). We observed that Pd(OAC)2 in presence of Cs2CO3 is the
appropriate catalyst for this purpose (59%, Table 2, entry 7). Having
optimized the reaction conditions for Heck coupling, all the furan
based building units were subjected to same reaction conditions
O
O
n
n
OPG
OPG
n = 1 or 2
B
A
Br
Br
For Heck coupling
n = 1 or 2
For Sonogashira
coupling
Fig. 1. General structure of chiral scaffolds for Sonogashira and Heck coupling
reactions.
Scaffolds for
Scaffolds for
Scaffolds for
Scaffolds for
Scaffolds for
8-membered rings
9-membered rings
10-membered rings
11-membered rings 13-membered rings
Br
Br
Br
O
O
S
O
Br
S
S
OH
O
S
O
O
O
S
O
MeO
OMe
BnO
IV
O
O
O
O
BnO
O
OMe
XV
S
Br
O
O
V
O
Br
O
O
BnO
BnO
I
BnO
Br
S
X
O
O
S
O
S
Br
O
Br
BnO
BnO
O
VI
BnO
OBn
O
BnO
VIII
OBn
OH
OBn
OH
XVI
O
S
O
O
O
S
S
S
Br
Br
O
Br
Br
O
O
O
IIO
O
Br
O
O
BnO
O
III
O
S
VII
IX
MeO
O
S
OMe
O
S
BnO
BnO
BnO
OMe
Br
XVII
Br
BnO
O
O
OBn
OBn
O
Br
XII
XI
O
O
S
O
S
S
BnO
BnO
BnO
BnO
Br
BnO
Br
OBn
O
O
OBn
OBn
OBn
XVIII
XIV
XIII
Fig. 2. Designed furan and pyran building blocks for the synthesis of 8e13-membered rings by Sonogashira and Heck coupling.
Further, in order to synthesize pyran based building blocks XI
and XIII, -glucal (18) was subjected to benzylation, oxidation using
m-CPBA followed by glycosylation using suitably substituted bro-
mothiophenol and finally alkylation (Scheme 2).
(Table 3, entries 1e4) to derive the corresponding cyclized prod-
D
ucts. Similarly, pyran based building blocks 34 and 36 also yielded
the desired medium sized macrocycle in moderate yield (Table 3,
entries 5 and 6).
To investigate the possibility of macrocyclization between 6-O-
propargyl and aryl bromide derived from anomeric position 1,2,3,4-
Some of the products synthesized above can be utilized for the
synthesis of conformationally locked nucleosides, e.g., the iso-
propylidene unit of the product Xa has been de-protected followed
by acetylation gives anomeric mixture (ab) of diacetate Xab, which
di-O-acetonide-
a-D-galactopyranoside (22) was utilized to obtain
bridgehead building blocks XVeXVIII as depicted in Scheme 3.

A. Hussain et al. / Tetrahedron 69 (2013) 5517e5524
5519
HO
O
O
i. TsCl, Py,
O
O
HO
O
O
O
O
R-Br, DCM:NaOH
O
R = Bn (8)
70% AcOH in H O
78%
R = Propargyl (9)
R = Allyl (10)
ii. NaOMe, MeOH
75% over 2 steps
TBAB rt, 3-5 h, 80%
O
O
O
O
RO
O
RO
HO
O
O
RO
O
1
R = Bn(5)
R = Bn (2)
R = Propargy (6)
R = Allyl (7)
R = Propargyl (3)
R = Allyl (4)
Et N
2-bromothiophenol
75%
OH
i. 70% AcOH in H O, 78%
Br
S
ii. Silica supported NaIO , DCM, 95%
iii. NaBH , MeOH, 0°C, 90%
O
S
iv. benzylbromide, TBAB, DCM-NaOH, 80%
OR
O
Br
RO
O
O
R-Br, DCM:NaOH
R = Bn (11)
R = Propargyl (IV)
R = Allyl (V)
R = Propargyl (I)
R = Allyl (III)
TBAB rt, 3-5 h, 80%
O
BnO
O
BnO
BnO
BnO
BnO
i. Resin IR-120 H form
O
S
O
2-bromothiophenol
O
O
S
OAc
CH CN, reflux,
+
, DCM, 0°C
.
BF
OEt
90%
O
ii. Ac O, Py
70% over 2 steps
BnO
BnO
OAc
15
BnO
O
BnO
OAc
BnO
OAc
Br
Br
14
12
13
R-Br, DCM:NaOH
R-Br, DCM:NaOH
TBAB rt, 3-5 h, 80%
TBAB rt, 3-5 h, 80%
BnO
BnO
O
S
O
70% AcOH
in H O
S
Br
S
OR
Br
BnO
OR
Br
R = Propargyl (VII)
R = Allyl (IX)
R = Propargyl (VI)
R = Allyl (VIII)
OHC
O
HO
HO
O
S
O
Silica supported
2-bromothiophenol
O
.
O
O
BF
NaIO , DCM, 95%
OEt ,
CHCl , 0°C
O
O
Br
RO
O
X
O
O
16
90%
17
Scheme 1. Synthetic strategies applied for the synthesis of furan based building blocks.
OH
OH
O
O
S
S
Cl
Sonogashira Coupling
O
O
O
O
Br
OR
O
Heterogeneous catalyst (R)
O
O
O
2-bromothiophenol
HO
HO
BnO
i. NaH, DMF, BnBr 0 °C, 83%
ii. m-CPBA, CHCl , rt, 40%
Ia, 86%
I
.
BF
0°C, 88%
OEt ,
O
BnO
OH
Scheme 4. Cyclization of substrate I by Sonogashira coupling.
OH
OBn
19
18
O
S
BnO
BnO
can be converted to nucleoside using literature procedure.13 Since
the CeC triple bond is not common in biologically active macro-
cycles, Xa has also been subjected to PdeC/H2 hydrogenation giving
the product Xac (Scheme 6).
Br
OR
O
S
OBn
BnO
BnO
R-Br, DCM:NaOH
XI.R = Propargyl
XII.R = Allyl
Br
TBAB, rt, 3-5 h, 80%
OH
+
O
OBn
21
20,
S
BnO
BnO
3. Conclusion
Br
OR
OBn
Design and synthesis of diversity oriented medium sized sulfur
containing carbohydrate fused benzannulated macrocycles (8e13-
membered) have been achieved using Pd-catalyzed CeC bond
coupling. Both cis- and trans-fused medium sized rings have been
generated taking advantage of glycosylation reaction. The down-
stream products originated will be used to generate targeted nat-
ural product analogues.
XIII.R = Propargyl
XIV.R = Allyl
Scheme 2. Synthesis of pyran based building blocks using 1,2-position of sugar moiety.
i. 2-bromothiophenol
.
BF OEt ,
0°C, 90%
4. Experimental section
4.1. General information
i. Propargyl bromide, TBAB
DCM:NaOH, rt, 3-5 h, 80%
O
ii. NaOMe, MeOH
O
O
HO
O
OAc
OAc
O
iii. MeI, NaH, THF, 0 C
OR
ii. TFA, 0 °C, stir
iii. Ac O, Py
60% over 2 steps (i & ii)
O
AcO
O
iv. BnBr, NaH, THF, 0 C.
OAc
23
22
81% over 2 steps
Proton NMR spectra and carbon-13 NMR spectra were recorded
on Bruker 200, 400 and 500 MHz spectrometers (Model No. D 205/
52-2382, Avance 500) with TMS as the internal standard. Chemical
shifts are expressed in parts per million (ppm). MS were recorded
on Waters LC Mass spectrometer (Model No. Symapt MS). Silica gel
coated aluminium plates were used for TLC. Elemental analyses
were performed on Vario Elementar, Model No. EL-III (installed at
CSIR-IIIM, Jammu, India). Reagents and solvents used were mostly
of LR grade.
Br
Br
O
O
O
S
O
S
+
RO
RO
OR
OR
OR
OR
XVII.R = Me
XV.R = Me
XVIII.R = Bn
XVI.R = Bn
Scheme 3. Synthesis of pyran based building blocks using 1,6-position of sugar moiety.

5520
A. Hussain et al. / Tetrahedron 69 (2013) 5517e5524
Table 1 (continued)
Table 1
Synthesis of carbohydrate based medium sized oxo-sulfur benzannulated macro-
cycles using Sonogashira reaction
S no.
Substratea
Productb
Time (h)
Yieldc (%)
S no.
Substratea
Productb
Time (h)
Yieldc (%)
OAc
O
S
O
O
11
XVII
19
82
S
1
I
20
86
O
O
O
MeO
OMe
OMe
Ia
XVIIa
OH
O
S
2
3
II
20
20
86
85
O
O
O
12
XVIII
20
83
IIa
XVIIIa
O
a
Reaction conditions: substrate (100 mg, 0.25 mmol), CuI (0.0125 mg, 5 mol %),
4.7 wt % heterogeneous catalyst R (100 mg), THF (2 mL), rt.
O
S
b
IV
Characterized through spectroscopic analysis.
Isolated yield after column chromatography.
O
BnO
O
c
IVa
BnO
BnO
OH
OH
O
O
S
S
O
4
5
VI
19
24
88
88
S
Heck Coupling
O
BnO
BnO
O
O
O
Br
O
VIa
O
O
III
IIIa
59%
S
O
Scheme 5. Cyclization of substrate III by Heck coupling.
VII
O
VIIa
Table 2
Comparative study of different commercially available catalysts for Heck reaction
Br
Catalysta,b
Base
Solvent
Temp (ꢁC)
Yield (%)
S
Entry
S
O
1
2
3
4
5
6
7
8
9
R
R
R
R
No ext. base
No ext. base
No ext. base
No ext. base
Et2NH
Et3N
Cs2CO3
KCO3
(i-Pr)2NH
(i-Pr)2NH
DMF
THF
DMF
THF
DMF
DMF
DMF
DMF
DMF
THF
rt
rt
02
02
02
02
50
50
59
57
58
58
6
X
24
90
O
O
O
100
100
100
100
100
100
100
100
Xa
Pd(PPh3)2Cl2
Pd(PPh3)Cl2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd(PPh3)4
S
O
BnO
BnO
7
8
XI
23
21
81
82
10
O
OBn
R
(heterogeneous catalyst)¼bis(
m-chloro) bis[2-(di-tert-butylphosphino)-2-
XIa
methylpropyl]dipalladium (C24H52Cl2P2Pd2).
a
Reaction conditions: for entries 1e4: substrate (III) (200 mg, 0.28 mmol),
4.7 wt
environment.
%
heterogeneous catalyst (R) (200 mg),6 solvent (2 mL), under N2
S
O
BnO
BnO
b
Reaction conditions: for entries 5e10: substrate (III) (100 mg, 0.25 mmol),
XIII
homogeneous Pd catalyst (10 mol %), base (2.75 equiv), TBAB (1 equiv), solvent
(3 mL), 100 ꢁC under N2 environment.
O
OBn
XIIIa
4.2. Typical procedure (1) for cyclization via intramolecular
Sonogashira reaction
O
S
O
To a solution of I (100 mg, 0.25 mmol) in dry THF (2.0 mL) was
added 4.7 wt % heterogeneous palladium catalyst (100 mg) de-
veloped by our own lab9 and co-catalyst CuI (0.0125 mg, 5 mol %).
The reaction mixture was allowed to stir at room temperature for
20 h under nitrogen atmosphere. After ascertaining completion of
the reaction by TLC, the mixture was filtered and the solvent was
evaporated under vacuum. The product was extracted with ethyl
acetate, dried over anhydrous Na2SO4 and purified by column
chromatography on silica gel using petroleum ether/ethyl acetate
as the eluent to yield Ia (83.85 mg, 86%). Rf (35% EtOAc/hexane)
0.45; IR (CHCl3) 2850, 2210, 1734 cmꢀ1; H NMR (500 MHz, CDCl3):
9
XV
22
81
MeO
OMe
OMe
XVa
O
S
O
10
XVI
20
83
BnO
OBn
OBn
XVIa

A. Hussain et al. / Tetrahedron 69 (2013) 5517e5524
5521
Table 3
Ar), 7.34e7.55 (m, 1H, Ar), 7.66 (d, J¼11.9 Hz, 1H, Ar), 7.64 (dd, J¼1.2,
7.6 Hz, 1H, Ar), 8.05 (dd, J¼1.2, 7.6 Hz, 1H, Ar); C NMR (500 MHz,
Synthesis of carbohydrate based medium sized oxo-sulfur benzannulated macro-
cycles using Heck reaction
CDCl3): d 20.8, 26.4, 26.8, 35.0, 57.5, 68.8, 70.8, 74.8, 79.3, 80.8, 81.4,
S no.
Substratea
Productb
Time (h)
Yieldc (%)
105.2, 112.3, 124.5, 127.0, 127.8, 128.6, 129.6, 137.5, 169.7; ESI MS (m/
z): 390 [MþNa]þ. Anal. Calcd for C20H22O6S: C, 61.52; H, 5.68.
Found: C, 61.40; H, 5.59.
OH
S
O
1
III
12
59
O
4.3. Typical procedure (2) for cyclization via intramolecular
Heck reaction
O
O
IIIa
To a solution of III (0.28 mmol, 100 mg) in dry DMF (3 mL) were
added Pd(OAc)2 (0.028 mg, 10 mol %), Cs2CO3 (251 mg, 2.75 equiv)
and tetrabutylammonium bromide (74.00 mg, 1 equiv). The re-
action mixture was stirred at 100 ꢁC for 12 h. After completion of
the reaction as monitored through TLC, the reaction was quenched
by addition of solution of ammonium chloride. The product was
extracted with ethyl acetate, dried over anhydrous Na2SO4 and
purified by column chromatography on silica gel using petroleum
ether/ethyl acetate as the eluent to yield IIIa (57.82 mg, 59%). Rf
(50% EtOAc/hexane 0.50); IR (CHCl3) 3500e3300 (br), 2985, 2931,
O
O
S
2
V
8
57
O
BnO
O
Va
BnO
O
S
1645 cmꢀ1 1H NMR (400 MHz, CDCl3):
; d 1.32 (s, 3H), 1.48 (s, 3H),
3
4
5
VIII
10
12
58
59
BnO
O
2.75 (d, J¼5.2 Hz, 1H), 3.06 (dd, J¼8.4, 14.0 Hz, 1H), 3.45 (dd, J¼2.8,
13.6 Hz, 1H), 4.10e4.20 (m, 4H), 4.56 (d, J¼3.6 Hz, 1H), 5.21 (dd,
J¼1.6, 10.4 Hz, 1H), 5.28 (dd, J¼1.6, 14.0 Hz, 1H), 5.91 (d, J¼7.2 Hz,
1H), 7.05 (dd, J¼1.2, 7.6 Hz, 1H, Ar), 7.27 (m, 1H, Ar), 7.40 (m, 1H, Ar),
VIIIa
BnO
O
O
7.54 (dd, J¼1.2, 8.0 Hz, 1H, Ar); 13C NMR (500 MHz, CDCl3):
d
26.2,
S
26.8, 38.5, 67.3, 71.2, 81.6, 82.3, 105.1, 111.8, 118.2, 123.89, 126.9,
127.9, 133.0, 133.6, 136.9, 148.5; ESI MS (m/z): 350 [MþNa]þ. Anal.
Calcd for C18H22O5S: C, 61.69; H, 6.33. Found: C, 61.60; H, 5.99.
IX
BnO
XIa
4.4. Preparation and spectral analysis of IIa
S
O
BnO
Prepared by following the typical procedure for Sonogashira
reaction (1) by using II (100 mg, 0.23 mmol) to yield the desired
product IIa as a semi-solid (68.80 mg, 86%). Rf (50% EtOAc/hexane
XII
8
58
58
BnO
O
OBn
XIIa
0.5); IR (CHCl3) 3600e3200 (br), 2920, 2850, 2214 cmꢀ1 1H NMR
;
(400 MHz, CDCl3):
d
1.36 (s, 3H),1.57 (s, 3H), 3.09 (dd, J¼9.6,14.0 Hz,
S
O
BnO
BnO
1H), 3.23 (dd, J¼3.6, 14.0 Hz, 1H), 4.01 (m, 1H), 4.10 (dd, J¼3.6,
7.6 Hz, 1H), 4.24 (dd, J¼4.4, 8.8 Hz, 1H), 4.31 (d, J¼16.4 Hz, 1H), 4.47
(d, J¼16.8 Hz, 1H), 4.68 (t, J¼4, 1H), 5.79 (d, J¼3.6 Hz, 1H), 7.07 (m,
1H, Ar), 7.26 (m, 1H, Ar), 7.36 (d, J¼7.6 Hz, 1H, Ar), 7.55 (m, 1H, Ar);
6
XIV
12
O
OBn
XIVa
13C NMR (500 MHz, CDCl3):
d 26.6, 26.8, 36.2, 57.7, 68.9, 71.5, 75.2,
a
Reaction conditions: substrate (100 mg, 0.28 mmol), Pd(OAc)2 (0.028 mg,
76.4, 77.3, 79.9, 104.2, 113.4, 124.3, 127.2, 128.1, 132.1, 133.1, 136.8;
ESI MS (m/z): 348 [MþNa]þ. Anal. Calcd for C18H20O5S: C, 62.05; H,
5.79. Found: C, 62.00; H, 5.68.
10 mol %), Cs2CO3 (251 mg, 2.75 equiv), TBAB (92 mg, 1 equiv), DMF (3 mL), 100 ꢁ
under N2 environment.
C
b
Identified through 1H NMR and 13C NMR.
Isolated yield after column chromatography.
c
4.5. Preparation and spectral analysis of IVa
S(o-C6H4Br)
S
Prepared by following the typical procedure for Sonogashira re-
action (1) by using IV (100 mg, 0.19 mmol) to yield the desired
product IVa as a semi-solid (70.74 mg, 85%). Rf (35% EtOAc/hexane
0.48); IR (CHCl3) 2919, 2850, 2210 cmꢀ1; 1H NMR (400 MHz, CDCl3):
i. Acidic resin IR 120
O
OAc
Synthetic
Nucleosides
Br
S
ii. Ac2O, Py
70% over 2 steps
O
OAc
Xab
S
O
d
1.31 (s, 3H),1.48 (s, 3H), 3.14 (dd, J¼4.6,12.8 Hz,1H), 3.51 (dd, J¼2.8,
O
SPh
12.8 Hz, 1H), 4.08e4.14 (m, 2H), 4.17 (d, J¼16.0 Hz, 1H), 4.30 (dd,
J¼2.8, 9.2 Hz,1H), 4.37 (d, J¼16.0 Hz,1H), 4.58 (d, J¼11.6 Hz,1H), 4.60
(d, J¼4.0 Hz, 1H), 4.65 (d, J¼11.6 Hz, 1H), 5.89 (d, J¼3.6 Hz, 1H), 6.99
(d, J¼1.2 Hz, 1H, Ar), 7.23e7.45 (m, 6H, Ar), 7.51 (d, J¼1.2 Hz, 1H, Ar);
O
O
O
S
Xa
iii. H2 /Pd/C, 78%
O
O
O
13C NMR (500 MHz, CDCl3):
d 26.4, 26.9, 35.7, 58.7, 70.6, 72.0, 74.8,
Xac
Scheme 6. Probable application of benzannulated macrocycles in the synthesis of
conformationally locked synthetic nucleosides.
75.4, 80.5, 81.5, 81.9,105.1,112.1,123.5,126.5,127.7,127.7,127.8,128.4,
128.5, 128.5, 132.9, 134.6, 137.3, 137.9; ESI MS (m/z): 438 [MþNa]þ.
Anal. Calcd for C25H26O5S: C, 68.47; H, 5.98. Found: C, 68.42; H, 5.97.
d
1.33 (s, 3H), 1.50 (s, 3H), 1.93 (s, 3H), 3.19 (dd, J¼6.3, 4.5 Hz, 1H),
4.6. Preparation and spectral analysis of VIa
3.58 (dd, J¼2.9, 5.4 Hz, 1H), 3.92e4.13 (m, 1H), 4.23e4.29 (m, 2H),
4.51(dd, J¼3.2, 3.0 Hz, 1H), 4.57 (d, J¼3.6 Hz, 1H), 5.90 (d, J¼3.7 Hz,
1H), 5.95 (d, J¼3.6 Hz, 1H), 7.03e7.10 (m, 1H, Ar), 7.26e7.27 (m, 1H,
Prepared by the typical procedure (1) for Sonogashira reaction
by using VI (100 mg, 0.18 mmol) to yield the desired product IVa as

5522
A. Hussain et al. / Tetrahedron 69 (2013) 5517e5524
a semi-solid (72.55 mg, 88%). Rf (35% EtOAc/hexane) 0.48; IR
(CHCl3) 2919, 2210 cmꢀ1 1H NMR (400 MHz, CDCl3):
3.69 (dd,
4.47e4.51 (m, 3H), 4.58 (d, J¼12.0 Hz, 1H), 4.81 (dd, J¼10.8, 14.8 Hz,
2H), 4.95 (d, J¼10.8 Hz,1H), 5.91 (d, J¼5.5 Hz,1H), 7.04 (dt J¼1.6, 7.6,
9.2 Hz, 1H, Ar), 7.13e7.16(m, 2H, Ar), 7.19 (dd J¼1.2, 14.8 Hz, 1H, Ar),
7.25e7.38 (m, 13H, Ar), 7.53 (dd J¼1.2, 8.0 Hz,1H, Ar), 7.60 (dd J¼1.6,
;
d
J¼5.2, 10.0 Hz, 1H), 3.79 (dd, J¼5.6, 10.0 Hz, 1H), 4.18 (dd, J¼2.4,
4.4 Hz, 1H), 4.40 (d, J¼4.0 Hz, 1H), 4.46 (dd, J¼2.4, 5.2 Hz, 1H), 4.51
(d, J¼12.0 Hz, 1H), 4.53e4.63 (m, 4H), 4.68 (d, J¼12 Hz, 1H), 5.82 (d,
J¼5.2 Hz, 1H), 7.15e7.35(m, 14H, Ar); 13C NMR (400 MHz, CDCl3):
8.0 Hz, 1H, Ar); 13C NMR (400 MHz, CDCl3):
d 58.5, 68.4, 71.1, 71.6,
73.4, 75.1, 75.2, 75.7, 77.4, 79.2, 82.4, 85.3, 126.1, 127.7, 127.8, 127.9,
127.9, 127.9, 127.9, 127.9, 128.2, 128.3, 128.3, 128.3, 128.3, 128.4,
128.5, 128.5, 128.5, 128.5, 132.6, 133.1, 135.0, 138.0, 138.5, 139; ESI
MS (m/z): 578 [MþNa]þ. Anal. Calcd for C36H34O5S: C, 74.71; H, 5.92.
Found: C, 74.65; H, 5.85.
d
58.9, 67.8, 71.3, 72.4, 73.4, 75.2, 78.4, 81.7, 83.9, 88.4, 125.3, 127.6,
127.6, 127.7, 127.8, 127.8, 128.1, 128.4, 128.5, 128.5, 131.9, 132.1, 132.2,
132.9, 136.5, 137.5, 138.2; ESI MS (m/z): 458 [MþNa]þ. Anal. Calcd
for C28H26O4S: C, 73.34; H, 5.71. Found: C, 73.29; H, 5.60.
4.7. Preparation and spectral analysis of VIIa
4.11. Preparation and spectral analysis of XVa
Prepared by the typical procedure for Sonogashira reaction (1)
by using VII (100 mg, 0.18 mmol) to yield the desired product VIIa
as a semi-solid (70.07 mg, 85%). Rf (35% EtOAc/hexane) 0.48;
Prepared by the typical procedure for Sonogashira reaction (1)
by using XV (100 mg, 0.23 mmol) to yield the desired product XVa
as a semi-solid (65.21 mg, 81%). Rf (35% EtOAc/hexane) 0.45; IR
(CHCl3) 2919, 2210 cmꢀ1; H NMR (400 MHz, CDCl3):
d
3.80 (m, 2H),
(CHCl3) 2920, 2810, 2210 cmꢀ1 1H NMR (400 MHz, CDCl3):
; d 3.45
4.06 (dd, J¼1.6, 5.2 Hz, 1H), 4.16 (s, 2H), 4.31 (t, J¼2.4 Hz, 1H), 4.35
(dd, J¼5.2, 11.2 Hz, 1H), 4.60e4.52 (m, 3H), 4.69 (dd, J¼5.2, 12.0 Hz,
1H), 5.37 (d, J¼2.8 Hz, 1H), 7.03e7.04 (m, 1H, Ar), 7.06e7.33 (m, 11H,
Ar), 7.64 (dd, J¼1.2, 7.6 Hz, 1H, Ar), 7.66 (dd, J¼1.6, 8.0 Hz, 1H, Ar);
(s, 3H), 3.46 (s, 3H), 3.52 (s, 3H), 3.55e3.65 (m, 1H), 3.83 (dd, J¼3.2,
7.2 Hz, 2H), 3.88 (t, J¼2.8 Hz, 2H), 4.10 (dd, J¼2.0, 4.4 Hz, 2H), 4.24
(dd, J¼3.2, 7.2 Hz, 1H), 5.63 (d, J¼2.4 Hz, 1H), 7.10 (dd, J¼1.2, 7.6 Hz,
1H, Ar), 7.24e7.26 (m, 2H), 7.22e7.38 (m, 1H, Ar), 7.55 (dd, J¼1.2,
8.0 Hz, 1H, Ar), 7.64 (dd, J¼1.2, 8.0 Hz, 1H, Ar); 13C NMR (400 MHz,
13C NMR (400 MHz, CDCl3):
d 58.1, 68.6, 71.0, 72.2, 73.5, 75.0, 80.9,
81.5, 86.8, 88.6, 124.3, 127.6, 127.7, 127.7, 127.8, 127.8, 127.8, 127.9,
128.0, 128.3, 128.3, 128.5, 128.5, 130.9, 132.8, 137.1, 137.5, 138.2; ESI
MS (m/z): 458 [MþNa]þ. Anal. Calcd for C28H26O4S: C, 73.34; H, 5.71.
Found: C, 73.25; H, 5.61.
CDCl3): d 58.3, 59.3, 61.3, 61.4, 67.8, 72.1, 74.8, 74.9, 77.1, 79.0, 85.8,
86.2, 124.0, 127.5, 127.9, 130.6, 132.8, 136.4; ESI MS (m/z): 350
[MþNa]þ. Anal. Calcd for C18H22O5S: C, 61.69; H, 6.33. Found: C,
61.63; H, 6.28.
4.8. Preparation and spectral analysis of Xa
4.12. Preparation and spectral analysis of XVIa
Prepared by the typical procedure for Sonogashira reaction (1)
by using X (100 mg, 0.17 mmol) to yield the desired product Xa as
a semi-solid (77.27 mg, 90%). Rf (20% EtOAc/hexane) 0.6; IR (CHCl3)
Prepared by the typical procedure for Sonogashira reaction (1)
by using XVI (100 mg, 0.15 mmol) to yield the desired product XVIa
as a semi-solid (71.96 mg, 83%). Rf (35% EtOAc/hexane) 0.48; IR
2920, 2850, 2210 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
1.31 (s, 3H),
(CHCl3) 2919, 2210 cmꢀ1 1H NMR (400 MHz, CDCl3):
; d 3.57e3.67
1.45 (s, 3H), 4.15 (d, J¼12.4 Hz, 1H), 4.21 (s, 1H), 4.24 (d, J¼12.4 Hz,
1H), 4.45 (dd, J¼2.8, 9.6 Hz, 1H), 4.67 (d, J¼3.6 Hz, 1H), 5.06 (d,
J¼9.6 Hz, 1H), 5.95 (d, J¼3.6 Hz, 1H), 7.07 (m, 1H, Ar), 7.24 (m, 2H,
Ar), 7.44 (m, 1H, Ar), 7.54 (m, 2H, Ar), 7.64 (dd, J¼1.2, 7.6 Hz, 1H, Ar),
(m, 4H), 3.96 (d, J¼2.6 Hz, 1H), 4.05 (t, J¼9.3 Hz, 1H), 4.12 (d,
J¼7.8 Hz, 2H), 4.66 (d, J¼11.4 Hz, 1H), 4.71 (dd, J¼9.8, 4.4 Hz, 2H),
4.76 (s, 2H), 4.82 (d, J¼10.0 Hz,1H), 4.99 (d, J¼11.4 Hz,1H), 7.01 (ddt,
J¼22.8, 7.5, 1.5 Hz, 2H), 7.22e7.38 (m, 14H), 7.40 (dd, J¼7.8, 1.6 Hz,
2H), 7.50 (dd, J¼7.8, 1.5 Hz, 1H), 7.69 (dd, J¼7.8, 1.6 Hz, 1H); 13C NMR
8.05 (dd, J¼1.2, 7.6 Hz, 1H, Ar); 13C NMR (500 MHz, CDCl3):
d 26.3,
26.8, 54.6, 58.6, 70.9, 74.9 81.5, 81.9, 82.6, 105.1, 112.1, 118.2, 124.8,
126.4, 127.9,128.6,128.9,129.5,130.1,132.9, 133.1, 133.4,134.7,135.1,
138.1; ESI MS (m/z): 505 [MþNa]þ. Anal. Calcd for C23H21BrO4S2: C,
54.65; H, 4.19. Found: C, 54.60; H, 4.11.
(400 MHz, CDCl3): d 59.1, 68.7, 72.1, 73.2, 73.3, 74.5, 75.7, 75.8, 76.8,
77.2, 83.9, 86.3, 127.3, 127.4, 127.5, 127.6, 127.6, 127.7, 127.8, 127.8,
127.9, 128.1, 128.1, 128.2, 128.3, 128.3, 128.3, 128.4, 128.4, 128.5,
128.5, 128.6, 128.7, 130.7, 132.8, 138.1; ESI MS (m/z): 578 [MþNa]þ.
Anal. Calcd for C36H34O5S: C, 74.71; H, 5.92. Found: C, 74.63; H, 5.85.
4.9. Preparation and spectral analysis of XIa
4.13. Preparation and spectral analysis of XVIIa
Prepared by the typical procedure for Sonogashira reaction (1)
by using XI (100 mg, 0.15 mmol) to yield the desired product XIa as
a semi-solid (70.23 mg, 81%). Rf (35% EtOAc/hexane) 0.45; IR
Prepared by the typical procedure for Sonogashira reaction (1)
by using XVII (100 mg, 0.23 mmol) to yield the desired product
XVIIa as a semi-solid (66.01 mg, 82%). Rf (35% EtOAc/hexane) 0.43;
(CHCl3) 2919, 2210 cmꢀ1 1H NMR (400 MHz, CDCl3):
; d 3.53e3.56
(m, 2H), 3.59e3.69 (m, 3H), 3.75 (dd, J¼1.6, 10.8 Hz, 1H), 4.48e4.61
(m, 4H), 4.67 (d, J¼10.0 Hz, 1H), 4.74 (d, J¼9.6 Hz, 1H), 4.82 (dd,
J¼3.6, 10.8 Hz, 2H), 4.95 (d, J¼10.8 Hz, 1H), 7.18e7.69 (m, 19H, Ar);
IR (CHCl3) 2919, 2810, 2210 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d 3.24
(dd, J¼2.8, 9.2 Hz, 1H), 3.35e3.40 (m, 1H), 3.54e3.56 (m, 1H), 3.56
(s, 3H), 3.60 (s, 3H), 3.61 (s, 3H), 3.73e3.81 (m, 3H), 4.12 (dd, J¼2.4,
10.0 Hz, 2H), 4.59 (d, J¼9.6 Hz, 1H), 7.04e7.06 (m, 1H, Ar), 7.25 (dd,
J¼1.2, 8.0 Hz, 1H, Ar), 7.52 (dd, J¼1.2, 8.0 Hz, 1H, Ar), 7.59 (dd, J¼1.2,
13C NMR (400 MHz, CDCl3):
d 60.7, 69.0, 73.5, 75.1, 75.9, 77.6, 79.2,
80.5, 86.0, 86.3, 124.5, 127.6, 127.7, 127.8, 127.8, 127.9, 128.0, 128.2,
128.2, 128.3, 128.4, 128.5, 128.6, 130.9, 131.9, 132.0, 132.1, 132.2,
132.9, 133.1, 136.0, 138.0, 138.2; ESI MS (m/z): 578 [MþNa]þ. Anal.
Calcd for C36H34O5S: C, 74.71; H, 5.92. Found: C, 74.67; H, 5.83.
8.0 Hz, 1H, Ar); 13C NMR (400 MHz, CDCl3):
d 58.3, 59.3, 61.3, 61.4,
67.8, 72.1, 74.8, 74.9, 77.1, 79.0, 85.8, 86.04, 124.0, 127.5, 127.9, 130.6,
132.8, 136.4; ESI MS (m/z): 350 [MþNa]þ. Anal. Calcd for C18H22O5S:
C, 61.69; H, 6.33. Found: C, 61.64; H, 6.29.
4.10. Preparation and spectral analysis of XIIIa
4.14. Preparation and spectral analysis of XVIIIa
Prepared by the typical procedure for Sonogashira reaction (1)
by using XIII (100 mg, 0.15 mmol) to yield the desired product XIIIa
as a semi-solid (71.09 mg, 82%). Rf (35% EtOAc/hexane) 0.43; IR
Prepared by the typical procedure for Sonogashira reaction (1)
by using XVIII (100 mg, 0.15 mmol) to yield the desired product
XVIIIa as a semi-solid (71.09 mg, 82%). Rf (35% EtOAc/hexane) 0.45;
(CHCl3) 2919, 2210 cmꢀ1 1H NMR (400 MHz, CDCl3):
; d 3.58 (dd,
J¼1.6, 10.8 Hz, 1H), 3.75 (m, 2H), 3.90 (t, 9.2 Hz, 1H), 4.07 (dd, J¼5.6,
IR (CHCl3) 2920, 2210 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
3.62e3.71
9.6 Hz, 1H), 4.28 (dd, J¼1.6, 10.0 Hz, 1H), 4.40 (d, J¼12.0 Hz, 1H),
(m, 2H), 3.76 (dd, J¼8.8, 5.5 Hz, 1H), 4.06e4.11 (m, 1H), 4.14 (dd,

A. Hussain et al. / Tetrahedron 69 (2013) 5517e5524
5523
J¼8.9, 3.1 Hz, 3H), 4.28e4.33 (m, 1H), 4.35 (d, J¼3.2 Hz, 1H), 4.47
(dd, J¼13.9, 2.1 Hz, 3H), 4.52 (d, J¼3.3 Hz, 1H), 4.63e4.71 (m, 2H),
7.06 (dt, J¼7.7,1.5 Hz,1H), 7.20e7.40 (m,16H), 7.54 (dd, J¼7.9,1.2 Hz,
(CHCl3) 2985, 2931, 1645 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
3.57
(d, J¼10.7 Hz, 1H), 3.67e3.81 (m, 2H), 3.91e3.94 (m, 2H), 4.14 (d,
J¼5.5 Hz, 1H), 4.20 (d, J¼5.8 Hz, 1H), 4.27e4.61 (m, 4H), 4.83 (t,
J¼11.0 Hz, 2H), 5.02 (d, J¼10.7 Hz, 1H), 5.22 (d, J¼11.2 Hz, 1H), 5.33
(d, J¼11.2 Hz, 1H), 5.86 (d, 3.6 Hz, 1H), 7.08e7.36 (m, 17H, Ar),
1H), 7.61 (dd, J¼7.9, 1.4 Hz, 1H); 13C NMR (400 MHz, CDCl3):
d 59.1,
68.7, 72.1, 73.2, 73.3, 74.5, 75.7, 75.8, 76.8, 77.2, 83.9, 86.9, 127.3,
127.4, 127.5, 127.6, 127.6, 127.7, 127.8, 127.8, 127.9, 128.1, 128.1, 128.2,
128.3, 128.3, 128.3, 128.4, 128.4, 128.5, 128.5, 128.6, 128.7, 130.7,
132.8, 138.1; ESI MS (m/z): 578 [MþNa]þ. Anal. Calcd for C36H34O5S:
C, 74.71; H, 5.92. Found: C, 74.61; H, 5.81.
7.05e7.09 (m, 2H, Ar); 13C NMR (400 MHz, CDCl3):
d 68.4, 71.5, 71.6,
73.4, 75.1, 75.8, 77.2, 79.5, 82.5, 85.3, 118.0, 126.1, 127.6, 127.6, 127.7,
127.7, 127.7, 127.7, 127.8, 127.8, 127.9, 127.9, 128.0, 128.0, 128.0, 128.1,
128.3, 128.4, 128.4, 132.7, 133.1, 134.4, 135.5, 138.0, 138.5, 139.0,
148.8; ESI MS (m/z): 580 [MþNa]þ. Anal. Calcd for C36H36O5S: C,
74.46; H, 6.25. Found: C, 74.34; H, 6.12.
4.15. Preparation and spectral analysis of Va
Prepared by the typical procedure for Heck reaction (2) by using
the substrate V (100 mg, 0.19 mmol) to yield the desired product Va
as a semi-solid (47.65 mg, 57%). Rf (35% EtOAc/hexane) 0.5; IR
4.19. Preparation and spectral analysis of XIVa
Prepared by the typical procedure for Heck reaction (2) by using
the substrate XIV (100 mg, 0.15 mmol) to yield the desired product
XIVa as a semi-solid (50.46 mg, 58). Rf (30% EtOAc/hexane) 0.41; IR
(CHCl3) 2985, 2931, 1645 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d 1.32 (s,
3H), 1.49 (s, 3H), 2.15 (dd, J¼6.8, 13.6 Hz, 1H), 3.54 (dd, J¼2.8,
13.6 Hz, 1H), 3.94 (dd, J¼5.6, 12.4 Hz, 1H), 4.03e4.06 (m, 1H), 4.07
(dd, J¼2.8, 9.2 Hz, 1H), 4.21 (dd, J¼5.612.4 Hz, 1H), 4.31 (dd, J¼3.2,
8.8 Hz, 1H), 4.54 (d, J¼11.6 Hz, 1H), 4.61 (d, J¼3.6 Hz, 1H), 4.67 (d,
J¼11.6 Hz, 1H), 5.06 (dd, J¼1.6, 10.4 Hz, 1H), 5.18 (dd, J¼1.6, 17.2 Hz,
1H), 5.91 (d, J¼4.0 Hz, 1H), 6.96e6.98 (m, 1H, Ar), 6.99e7.35 (m, 6H,
Ar), 7.39 (dd, J¼1.2, 8.0 Hz, 1H), 7.52 (dd, J¼1.2, 8.0 Hz, 1H); 13C NMR
(CHCl3) 2985, 2931, 1645 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
3.44e3.78 (m, 6H), 4.21e4.30 (m, 1H), 4.39 (d J¼5.8 Hz, 1H), 4.45
(d, J¼5.7 Hz,1H), 4.53e4.60 (m, 2H), 4.7 (d, J¼9.7 Hz,1H), 4.82e4.96
(m, 3H), 5.18 (d, J¼10.0 Hz, 1H), 5.27 (d, J¼10.0 Hz, 1H), 7.02e7.33
(m, 17H), 7.53 (d, J¼7.7 Hz, 1H), 7.63 (d J¼7.8 Hz, 1H, Ar); 13C NMR
(400 MHz, CDCl3): d 69.0, 73.4, 74.4, 75.1, 75.9, 77.6, 79.2, 80.5, 86.3,
(500 MHz, CDCl3):
d
26.4, 26.8, 36.1, 71.9, 71.9, 74.8, 80.9, 81.7, 81.9,
86.7, 117.8, 124.1, 127.5, 127.5, 127.6, 127.6, 127.7, 127.7, 127.8, 127.8,
127.8, 127.9, 127.9, 127.9, 127.9, 128.3, 128.4, 128.4, 128.5, 132.8,
134.5, 137.0, 138.5, 138.7, 138.9, 147.1; ESI MS (m/z): 580 [MþNa]þ.
Anal. Calcd for C36H36O5S: C, 74.46; H, 6.25. Found: C, 74.37; H, 6.10.
105.1, 111.9, 116.8, 123.4, 126.3, 127.6, 127.7, 127.9, 128.4, 128.5, 128.5,
132.8, 134.6, 137.4, 138.5, 148.2; ESI MS (m/z): 440 [MþNa]þ. Anal.
Calcd for C25H28O5S: C, 68.16; H, 6.41. Found: C, 68.11; H, 6.39.
4.16. Preparation and spectral analysis of VIIIa
4.20. Spectral analysis of Xab
Prepared by the typical procedure for Heck reaction (2) by using
the substrate VIII (100 mg, 0.18 mmol) to yield the desired product
VIIIa as a semi-solid (48.02 mg, 58%). Rf (35% EtOAc/hexane) 0.48;
Rf (40% EtOAc/hexane) 0.45; IR (CHCl3) 2214, 1732 cmꢀ1
NMR (400 MHz, CDCl3):
;
1H
d
1.99 (s, 3H), 2.03 (s, 3H), 4.03 (d, J¼7.3 Hz
1H), 4.02 (d, J¼8.5 Hz, 1H), 4.11 (d, J¼7.1 Hz, 1H), 4.62 (t, J¼5.8 Hz,
1H), 4.90 (d, J¼5.7 Hz, 1H), 5.23 (s, 1H), 5.99 (d, J¼7.1 Hz, 1H), 6.40
(d, J¼4.3 Hz, 1H), 6.98e7.05 (m, 3H, Ar), 7.14e7.20 (m, 3H, Ar),
IR (CHCl3) 2985, 2931, 1645 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d 3.71
(dd, J¼5.6, 10.0 Hz, 1H), 3.81 (dd, J¼6.0, 10.0 Hz, 1H), 4.06e4.14 (m,
3H), 4.24 (dd, J¼2.4, 6.8 Hz, 1H), 4.51e4.65 (m, 4H), 4.74 (d,
J¼14.0 Hz, 1H), 5.29 (dd, J¼1.6, 10.5 Hz, 1H), 5.32 (dd, J¼1.6, 17.2 Hz,
1H), 5.83 (d, J¼4.8 Hz, 1H), 7.03e7.05(m, 1H, Ar), 7.24e7.33 (m, 11H,
Ar), 7.54 (dd, J¼1.2, 8.0 Hz, 1H), 7.60 (dd, J¼1.2, 7.6 Hz, 1H); 13C NMR
7.43e7.51 (m, 2H, Ar); 13C NMR (500 MHz, CDCl3):
d 20.5, 20.9, 56.6,
58.9, 70.9, 74.9, 75.9, 80.5, 80.8, 93.9, 99.0, 119.9, 126.9, 127.8, 128.0,
128.9, 133.1, 133.1133.2, 133.5, 133.7, 135.2, 169.1, 169.6; ESI MS (m/
z): 549 [MþNa]þ. Anal. Calcd for C24H21BrO6S2: C, 52.46; H, 3.85.
Found: C, 52.41; H, 3.79.
(500 MHz, CDCl3): d 67.6, 72.3, 72.4, 73.4, 78.4, 81.6, 83.8, 88.5, 118.1,
124.9, 127.5, 127.6, 127.7, 127.8, 127.9, 127.9, 128.3, 128.5, 131.6, 132.6,
132.7, 132.8, 133.9, 137.7, 138.2, 148.1; ESI MS (m/z): 460 [MþNa]þ.
Anal. Calcd for C28H28O4S: C, 73.02; H, 6.13. Found: C, 72.98; H, 6.10.
4.21. Spectral analysis of Xac
Rf (35% EtOAc/hexane) 0.6; IR (CHCl3) 2890, 2850 cmꢀ1; 1H NMR
4.17. Preparation and spectral analysis of IXa
(400 MHz, CDCl3): d 0.83e0.95 (m,1H),1.14e1.19 (m,1H),1.31 (s, 3H),
1.40 (d, J¼2.7 Hz, 2H), 1.46 (s, 3H), 3.18e3.28 (m, 1H), 3.45e3.59 (m,
1H), 4.04 (d, J¼3.3 Hz,1H), 4.42 (dd, J¼9.6, 2.9 Hz,1H), 4.54 (dd, J¼6.1,
2.6 Hz, 1H), 5.03e5.08 (m, 1H), 5.95 (d, J¼3.6 Hz, 1H), 7.03e7.11 (m,
1H), 7.22e7.25 (m, 3H), 7.32e7.33 (m, 1H), 7.42e7.45 (m, 1H),
7.49e7.55 (m, 2H), 7.58e7.66 (m, 1H); 13C NMR (500 MHz, CDCl3):
Prepared by the typical procedure for Heck reaction (2) by using
the substrate IX (100 mg, 0.18 mmol) to yield the desired product
IXa as a semi-solid (48.85 mg, 59%). Rf (35% EtOAc/hexane) 0.44; IR
(CHCl3) 2985, 2931, 1642 cmꢀ1 1H NMR (400 MHz, CDCl3):
; d 3.80
(dd, J¼6.4, 10.8 Hz, 1H), 3.85 (dd, J¼5.6, 10.0 Hz, 1H), 4.01e4.06 (m,
3H), 4.17e4.18 (m, 1H), 4.14 (dd, J¼10.4, 11.2 Hz, 1H), 4.52 (d,
J¼3.6 Hz, 1H), 4.55 (d, J¼3.6 Hz, 1H), 4.59 (d, J¼12.0 Hz, 1H), 4.68 (d,
J¼12.0 Hz, 1H), 5.20 (d, J¼12.0 Hz,1H), 5.26 (d, J¼16 Hz,1H), 5.40 (d,
J¼2.8 Hz,1H), 7.04e7.05(m,1H, Ar), 7.26e7.35 (m,10H, Ar), 7.53 (dd,
J¼1.2, 11.6 Hz, 2H), 7.68 (dd, J¼1.2, 12.0 Hz, 1H); 13C NMR (500 MHz,
d 25.93, 26.37, 26.82, 29.67, 53.46, 70.48, 81.31, 81.82, 82.44, 105.19,
111.92, 125.93, 127.56, 127.77, 128.63, 128.90, 132.38, 133.08, 134.36,
134.71, 135.23, 135.54, 135.99; ESI MS (m/z): 430 [MþNa]þ. Anal.
Calcd for C23H26O4S2: C, 64.16; H, 14.86. Found: C, 63.99; H, 14.81.
Acknowledgements
CDCl3):
d 67.6, 72.3, 72.4, 73.4, 78.4, 81.6, 83.8, 88.5, 118.1, 124.9,
127.5, 127.6, 127.7, 127.8, 127.9, 127.9, 128.3, 128.5, 131.6, 132.6, 132.7,
132.8, 133.9, 137.7, 138.2, 148.1; ESI MS (m/z): 460 [MþNa]þ. Anal.
Calcd for C28H28O4S: C, 73.02; H, 6.13. Found: C, 72.95; H, 6.07.
Authors are highly thankful to the Director IIIM Jammu for the
support. A.H. and S.K.Y. acknowledge UGC (SRF) and DST for fel-
lowship (INSPIRE Faculty, IFCH-18) and DST for funding under the
project GAP-1145.
4.18. Preparation and spectral analysis of XIIa
Supplementary material
Prepared by the typical procedure for Heck reaction (2) by using
the substrate XII (100 mg, 0.15 mmol) to yield the desired product
XIIa as a semi-solid (50.46 mg, 58%). Rf (30% EtOAc/hexane) 0.45; IR
General procedures, spectral data of starting materials and
copies of 1H NMR and 13C NMR spectra of final products.

5524
A. Hussain et al. / Tetrahedron 69 (2013) 5517e5524
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