Diversity-oriented approach to novel spirocycles via 1,2,4,5-tetrakis(bromomethyl)benzene under operationally simple reaction conditions

Article abstract of DOI:10.1016/j.tet.2015.07.008

Here, we have established a simple and an efficient methodology for the synthesis of spirocyclic α-amino acids as well as spirosulfones starting with readily available active methylene compounds (AMCs). The key di-bromo building blocks were assembled by reacting various active methylene compounds with 1,2,4,5-tetrakis(bromomethyl)benzene in one step. We have also expanded this strategy to generate a variety of bis-spirocycles by treating the di-bromo intermediates with different AMCs under operationally simple reaction conditions.

Full text of DOI:10.1016/j.tet.2015.07.008

Tetrahedron 71 (2015) 6944e6955
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Diversity-oriented approach to novel spirocycles via 1,2,4,5-
tetrakis(bromomethyl)benzene under operationally simple reaction
conditions
*
Sambasivarao Kotha , Rashid Ali
Department of Chemistry, Indian Institute of Technology-Bombay, Powai, Mumbai 400076, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 May 2015
Received in revised form 22 June 2015
Accepted 3 July 2015
Available online 9 July 2015
Here, we have established a simple and an efficient methodology for the synthesis of spirocyclic a-amino
acids as well as spirosulfones starting with readily available active methylene compounds (AMCs). The
key di-bromo building blocks were assembled by reacting various active methylene compounds with
1,2,4,5-tetrakis(bromomethyl)benzene in one step. We have also expanded this strategy to generate
a variety of bis-spirocycles by treating the di-bromo intermediates with different AMCs under opera-
tionally simple reaction conditions.
Keywords:
Alkylation
Ó 2015 Elsevier Ltd. All rights reserved.
Active methylene compounds
1,2,4,5-Tetrakis(bromomethyl)benzene
Spirocycles
Spiro-a-amino acids
Spirosulfones
1. Introduction
ingestion, rapid excretion through liver and kidneys, non-
selectivity and undesirable side effects because of the interaction
In recent years, spirocycles have elevated the chemical and
pharmacological space to a higher level. There are also some other
reasons that render them unique, for example, they are the integral
parts of several natural as well as non-natural products1 and also
valuable building blocks in thermotropic liquid crystals, which in
turn are useful for optical display device.2 Due to the unique
structural and reactivity pattern a great deal of attention has been
paid to spirocycles and simple methodologies to these targets are in
high demand. Generally, design and synthesis of spirocycles is
a difficult task in preparative organic chemistry because of the
formation of a spiro-ring junction.3
of conformational flexibility of peptide(s) with a receptor.6 To ad-
dress this problem, incorporation of cyclic AAAs into a given pep-
tide chain alter the conformational rigidity and thus modulate the
pharmacological properties.7 The structures of some interesting
constrained AAAs synthesized in our laboratory are shown in Fig.1.8
The sulfone functional group is often present in ‘drug-like’ small
molecules and they are also valuable synthons for the construction
of CeC bonds.9 In addition, they are latent resource of conjugated
dienes useful for the DielseAlder (DA) chemistry.10 The
a-methy-
lene groups in sulfones can be alkylated with various electrophiles
due to the electron withdrawing nature of the sulfone moiety and
this aspect in combination with the ease of desulfonylation has
been explored in the numerous instances for assembling various
Synthesis of conformationally constrained a-amino acid (AAA)
derivatives are in great demand because they are useful for drug
discovery and development.4 Replacement of proteinogenic AAAs
biologically interesting targets.11 Furthermore,
a
-halogenated sul-
€
by cyclic
a
-imino acid derivatives or cyclic AAAs is considered to be
fones are useful precursors suitable for the RambergeBacklund
a useful tactic for the design of peptidomimetics with diverse
pharmacological profiles. Recently, usage of peptide drugs have
been expanded to a higher level.5 However, sometimes their ap-
plicability is restricted due to various factors such as instability
towards proteolytic degradation, poor absorption after oral
reaction for the generation of CeC double bonds.12
Here, we have demonstrated new strategies to various spi-
rocyclic AAAs, spirosulfone derivatives and architecturally intricate
bis-spirocyclic frameworks. Although, several methods are avail-
able for synthesis of AAAs and sulfone derivatives, most of them
involve multi-step synthetic sequences.13 Limited number of
methods are available for the synthesis of spirocyclic AAAs and
spirosulfone derivatives.14 The importance of spirocycles, cyclic
* Corresponding author. Tel.: þ91 22 2576 7160; fax: þ91 22 2572 7152; e-mail
address: srk@chem.iitb.ac.in (S. Kotha).
http://dx.doi.org/10.1016/j.tet.2015.07.008
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

S. Kotha, R. Ali / Tetrahedron 71 (2015) 6944e6955
6945
Fig. 1. Some interesting constrained AAAs synthesized in our laboratory.
AAAs as well as sulfone derivatives (Fig. 2)15 and the documented
difficulties in their synthesis prompted us to develop operationally
simple methods from the readily available starting materials. To
this end, we now report a simple route to spirocyclic AAAs and
spirosulfone derivatives including some interesting bis-spirocyclic
scaffolds. Here, the key di-bromo intermediates have been assem-
bled by partial alkylation of 1,2,4,5-tetrakis(bromomethyl)benzene
with a variety of AMCs. The structures of the AMCs used in our
strategy are shown in Fig. 3.
10aej under mild reaction conditions appears to be a good option
(Scheme 2).
To achieve this goal, we started our journey with the prepara-
tion of 1,2,4,5-tetrakis(bromomethyl)benzene 16 by using the
known procedure.17 Having the tetra-bromo derivative 16 in hand,
it was treated with various AMCs (Fig. 3) to assemble the corre-
sponding di-bromo building blocks in a single step. To this end, the
compound 10a on treatment with tetra-bromide 16 gave the de-
sired di-bromo building block 14a (39%) along with the dimeric
Fig. 2. Structures of some important bioactive AAAs, sulfones and a spirocyclic system.
2. Results and discussion
products 17a (25%) (Scheme 2, Fig. 4 and Fig. 5). Surprisingly, when
we treated the tetra-bromide 16 with indane-1,3-dione 10b, we
isolated the desired di-bromo product 14b in low yield (8%) along
with the C and O-alkylated compounds 14b0 and 17b in 30% and 18%
yields, respectively (Figs. 4 and 5).
On the other hand, we were pleased to observe that when the
tetra-bromo compound 16 was treated with 1,3-dimethylbarbituric
acid 10c the expected product 14c was obtained in respectable yield
(Fig. 4). Along similar lines, treatment of tetra-bromide 16 with 1-
indanone 10d or various tetralone derivatives 10eeg delivered
the desired products 14deg in satisfactory yields (Fig. 4). Later, this
strategy has also been extended to some interesting fluorene de-
rivatives. To this end, the compounds 10hej were treated with
tetra-bromide 16 to yield the fluorene-based di-bromo building
In view of our interest to generate new methodologies to spi-
rocycles, here we report short and operationally simple strategies.
In our earlier report,16 we have assembled various di-bromo
building blocks 14aej involving three steps: (i) propargylation of
AMCs 10aej; (ii) [2þ2þ2] cycloaddition reaction of di-
propargylated building blocks 11aej with 2-butyne-1,4-diol 12;
(iii) conversion of diols 13aej into the di-bromo building blocks
14aej via PBr3 reaction (Scheme 1). In this context, conversion of
diols into the di-bromo derivatives seems to be problem with
sensitive substrates. This aspect forced us to look for an alternate
approach. Therefore, it occurred to us that selective one side al-
kylation of 1,2,4,5-tetrakis(bromomethyl)benzene 16 with AMCs

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S. Kotha, R. Ali / Tetrahedron 71 (2015) 6944e6955
Fig. 3. Diverse active methylene compounds used in our study.
Scheme 1. Synthesis of di-bromo intermediates 14aej by earlier method.
Scheme 2. General strategy to spirosulfone derivatives. Reagents and conditions: (a) NBS, CH2Cl2, 500 W lamp, reflux, 20 h, 47%; (b) i) K2CO3, tetrabutylammonium hydrogen sulfate
(TBAHS), MeCN, rt, 8e12 h, 8e68% (compounds 14bec, 14g and 14j); ii) NaH, THF, rt, 8e24 h, 32e48% (compounds 14a, 14def and 14hei); (c) rongalite, tetrabutylammonium
bromide (TBAB), DMF, 0 ꢀC-rt, 3e6 h, 64e92%, (compounds 18aej); (d) toluene, reflux, 10e15 h 76e91%, (compounds 19aej).
Fig. 4. Diverse di-bromo building blocks assembled in our study.

S. Kotha, R. Ali / Tetrahedron 71 (2015) 6944e6955
6947
Fig. 5. Structures of bis-alkylated products isolated during the alkylation sequence.
blocks 14hej in moderate to good yields (Fig. 4). Having the di-
bromo building blocks 14aej in hand, they were successfully
transformed into the sultine derivatives 18aej by using rongalite
(Scheme 2 and Fig. 6). The sultine derivatives were then cleanly
rearranged to the sulfone derivatives 19aej under thermal reaction
conditions in good to excellent yields (Scheme 2 and Fig. 7). The
mechanism for the formation of sulfone from sultine is described in
earlier report.18
were treated with diethyl acetamidomalonate (DEAM) by using
K2CO3 as a base in MeCN at rt to deliver the spiro 1,2,3,4-
tetrahydroisoquionline-3-carboxylic acid (Tic) derivatives 20aee
in good yields (Scheme 3 and Fig. 8). Alternatively, treatment of the
di-bromo intermediates 14bec, hej with ethyl isocyanoacetate
(EICA),19 a glycine equivalent in the presence of K2CO3 gave the
isonitrile derivatives, which on hydrolysis with conc. HCl/EtOH
gave the non-protected constrained AAA derivatives 21cee in
Fig. 6. The structures of sultine derivatives assembled in our study.
Fig. 7. List of spirosulfone derivatives prepared in our strategy.
Having realized the major portion of Scheme 2, next we ex-
tended this strategy to assemble diverse spirocyclic AAA de-
rivatives. In this context, the di-bromo building blocks 14bec, hej
moderate to good yields (Scheme 3 and Fig. 9). We found that the
non-protected AAAs of the di-bromides 14b and 14c were difficult
to separate by column chromatography, therefore, we synthesized

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S. Kotha, R. Ali / Tetrahedron 71 (2015) 6944e6955
Scheme 3. General scheme to spirocyclic constrained AAAs and TIC derivatives. Reagents and conditions: (a) DEAM, K2CO3, TBAHS, MeCN, rt, 15e20 h, 37e66% (compounds 20aee);
(b) EICA, K2CO3, TBAHS, MeCN, rt, 14e17 h, 45e59% (compounds 21cee); (c) acetic anhydride (Ac2O), MeCN, 29e30 h, 39e42% (compounds 21a and 21b).
Fig. 8. List of various spirocyclic Tic derivatives assembled in our methodology.
Fig. 9. List of diverse spirocyclic constrained AAAs derivatives.
the N-acetyl AAA derivatives 21a and 21b under Ac2O/MeCN re-
action conditions (Scheme 3 and Fig. 9). To further expand the
utility of this strategy, we have also assembled some architecturally
interesting bis-spirocyclic systems 22aei and 17def by using di-
bromo building blocks 14bef, j and different AMCs 10cef under
operationally simple reaction conditions (Scheme 4, Table 1 and
Fig. 10).
3. Conclusions
In summary, we have shown that partial alkylation of 1,2,4,5-
tetrakis(bromomethyl)benzene with active methylene compounds
gave the key di-bromo building blocks in moderate to good yields.
The di-bromo intermediates were then transformed into the spiro-
amino acid derivatives as well as spirosulfones under operationally
a-
Scheme 4. General scheme for the synthesis of bis-spirocyclic compounds via alkylation route. Reagents and conditions: (a) K2CO3, TBAHS, MeCN, rt, 6e12 h, 59e78% (compounds
22a, d, h, i); (b) NaH, THF, rt, 8e20 h, 56e86% (compounds 17def and 22beg).

S. Kotha, R. Ali / Tetrahedron 71 (2015) 6944e6955
6949
Table 1
given in hertz (Hz) and chemical shifts are denoted in parts per
million (ppm) downfield from internal reference, tetramethylsilane
(TMS). The abbreviations s, d, t, q, m, dd and td, refer to singlet,
doublet, triplet, quartet, multiplet, doublet of doublet, and triplet of
doublet respectively. Yields refer to the isolated yields after column
chromatography technique. Infrared (IR) spectra were recorded on
Nicolet Impact-400 FT IR spectrometer in CHCl3. Proton nuclear
magnetic resonance (1H NMR, 400 MHz and 500 MHz) spectra and
carbon nuclear magnetic resonance (13C NMR, 100 MHz and
125 MHz) spectra were recorded on a Bruker spectrometer. The
high-resolution mass measurements were carried out by using
electrospray ionization (ESI, Q-ToF) spectrometer. Melting points
were recorded on a Veggo melting point apparatus.
Synthesis of bis-spirocycles through alkylation method
Entry
Yields
(%)a
1
2
3
4
5
6
7
8
14b
14b
14b
14c
14c
14d
14d
14d
14d
14e
14e
14e
14f
10c
10d
10f
10d
10f
10c
10d
10e
10f
10c
10d
10e
10f
10c
22a
22b
22c
22d
22e
22d
17d
22f
22g
22h
22f
17e
17f
22i
69
81
78
71
86
59
75
65
70
78
84
67
56
68
9
10
11
12
13
14
4.2. Preparation of compound 16
14j
This compound has been prepared by the known procedure and
the 1H, 13C NMR data matched with the literature reported spectral
data.15
a
Yields refers to the isolated yields after column chromatography.
Fig. 10. List of bis-spirocyclic frameworks assembled in our strategy.
simple reaction conditions. Additionally, we assebmbled diverse ar-
4.3. General procedure for the synthesis of 14bec, 14g and 14j
chitecturally interesting bis-spirocyclic systems under mild reaction
conditions. The new chemical library generated here expand the
spiro chemical space for additional studies. The unique capability of
tetra-bromo derivative 16 usage significantly increase the diversity20
of spirocyclic molecules for further studies without the involvement
of a [2þ2þ2] cycloaddition.21
To a solution of compounds 10bec, 10g or 10j, K2CO3 (5 equiv)
and TBAHS (0.5 equiv) in dry MeCN (25 mL), tetra-bromo derivative
16 (1.2 equiv) was added and the reaction mixture was stirred at rt
for 12e16 h. At the conclusion of reaction (TLC monitoring), excess
amount of K2CO3 was filtered through the sintered glass funnel and
the aqueous layer was extracted with CH2Cl2. The solvent was re-
moved under reduced pressure and the crude products were pu-
rified by silica gel column chromatography using appropriate
mixtures of EtOAc-petroleum ether to deliver the expected prod-
ucts 14b (8%, 355 mg from 1.5 g of 10b, 8 h), 14b0 (30%, 1.33 g from
1.5 g of 10b, 8 h), 14c (60%, 853 mg from 500 mg of 10c, 12 h), 14g
(68%, 404 mg from 250 mg of 10g, 8 h), and 14j (55%, 350 mg from
300 mg of 10j, 8 h), along with the dimeric products 17bec, and
17g. The 1H and 13C NMR spectra of these compounds matched
with the reported spectral data.14
4. Experimental section
4.1. General
Commercially accessible reagents were used without purifica-
tion and reactions involving air sensitive catalysts or reagents were
performed in degassed solvents. Moisture sensitive materials were
transferred by using syringe-septum techniques and the reactions
were maintained under nitrogen atmosphere. Analytical thin layer
chromatography (TLC) was performed on (7.5ꢁ2.5 cm) glass plates
coated with Acme’s silica gel GF 254 (containing 13% calcium sul-
fate as a binder) by using a suitable mixture of EtOAc and petroleum
ether for development. Column chromatography was performed by
using Acme’s silica gel (100e200 mesh) with an appropriate mix-
ture of EtOAc and petroleum ether. The coupling constants (J) are
4.4. General procedure for the synthesis of compounds 14a,
14def and 14hei
To a suspension of sodium hydride (3 equiv) in dry THF (20 mL),
compounds 10a, 10def or 10hei were added and the reaction

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S. Kotha, R. Ali / Tetrahedron 71 (2015) 6944e6955
mixture was stirred at rt for 10 min. Later, tetra-bromo compound
16 (1.2 equiv) was added and the stirring was continued at the same
temperature for 8e12 h. At the conclusion of the reaction (TLC
monitoring), the reaction mixture was quenched with EtOAc and
the solvent was removed under reduced pressure. The aqueous
layer was extracted with CH2Cl2 and the crude products were pu-
rified using appropriate mixtures of EtOAc-petroleum ether to de-
liver the expected products 14a (39%, 1.09 g from 1 g of 10a, 12 h),
14d (40%, 636 mg from 500 mg of 10d, 8 h), 14e (48%, 285 mg from
200 mg of 10e, 12 h), 14f (44%, 580 mg from 500 mg of 10f, 20 h),
14h (32%, 175 mg from 200 mg of 10h, 24 h) and 14i (36%, 204 mg
from 300 mg of 10i, 15 h), along with the dimeric products 17a and
17def products. The 1H and 13C NMR spectra of these compounds
matched with the literature reported spectral data.14b
126.88, 128.33, 128.39, 128.81, 128.87, 131.85, 133.33, 139.85, 143.41,
200.73; HRMS (ESI, Q-Tof) calculated for C30H26NaO2 [MþNa]þ
441.1825 found: 441.1827; IR (CHCl3): ymax: 1216, 1454, 1601, 1680,
2854, 2930, 3016 cmꢂ1
.
4.10. Compound 17f
White solid; yield¼7% (95 mg, starting from 500 mg of 10f);
reaction time¼20 h; mp 182e183 ꢀC; Rf¼0.50 (silica gel, 25% EtOAc-
petroleum ether); 1H NMR (500 MHz, CDCl3)
d
¼2.17 (t, J¼6.20 Hz,
4H), 2.86 (d, J¼15.16 Hz, 4H), 3.02 (t, J¼6.12 Hz, 4H), 3.43 (d,
J¼15.16 Hz, 4H), 3.86 (s, 6H), 6.69 (d, J¼2.44 Hz, 2H), 6.82 (dd,
J1¼2.52 Hz, J2¼8.76 Hz, 2H), 6.99 (s, 2H), 8.03 (d, J¼8.76 Hz, 2H); 13
C
NMR (125 MHz, CDCl3)
d
¼26.61, 34.14, 41.27, 53.74, 55.53, 112.50,
113.40, 120.90, 125.44, 130.74, 139.88, 145.83, 163.55, 199.58; HRMS
4.5. Compound 17a
(ESI, Q-Tof) calculated for C32H31O4 [MþH]þ 479.2217 found:
479.2214; IR (CHCl3): ymax: 1216, 1600, 1681, 2929, 3019 cmꢂ1
.
White solid; yield¼25% (697 mg, starting from 1 g of 10a); re-
action time¼12 h; mp 139e141 ꢀC; Rf¼0.49 (silica gel, 10% EtOAc-
4.11. Compound 17g
petroleum ether); 1H NMR (400 MHz, CDCl3)
d¼1.24 (t, J¼7.12 Hz,
12H), 3.51 (s, 8H), 4.18 (q, J1¼7.08 Hz, J2¼14.20 Hz, 8H), 7.01 (s, 2H);
White solid; yield¼15% (107 mg, starting from 250 mg of 10g);
reaction time¼8 h; mp 210e211 ꢀC; Rf¼0.59 (silica gel, 25% EtOAc-
13C NMR (100 MHz, CDCl3)
d
¼14.12, 40.15, 60.75, 61.76, 120.10,
139.01, 171.76; HRMS (ESI, Q-Tof) calculated for
C
24H30NaO8
petroleum ether); 1H NMR (500 MHz, CDCl3)
d
¼2.76 (t, J¼7.15 Hz,
[MþNa]þ 469.1833, found: 469.1835; IR (CHCl3): ymax: 1255, 1679,
4H), 3.13e3.19 (m, 8H), 3.75 (d, J¼15.45 Hz, 4H), 7.00 (s, 2H),
1730, 2983, 3054 cmꢂ1
.
7.13e3.20 (m, 8H); 13C NMR (125 MHz, CDCl3)
d
¼28.81, 37.58, 44.81,
59.42, 120.09, 126.25, 126.83, 127.50, 128.12, 135.32, 139.94, 143.30,
212.97; HRMS (ESI, Q-Tof) calculated for C30H26NaO2 [MþNa]þ
441.1825 found: 441.1828; IR (CHCl3): ymax: 665, 1265, 1706, 2856,
4.6. Compound 17b
The 1H and 13C NMR spectra matched with the reported spectral
data.14c
2932, 3033 cmꢂ1
.
4.12. Compound 18aej
4.7. Compound 17c
These compound have been prepared by the known procedure
and the 1H, 13C NMR spectra matched with the literature reported
spectral data.14
White solid; yield¼4% (56 mg, starting from 500 mg of 10c);
reaction time¼12 h; mp 157e158 ꢀC; Rf¼0.55 (silica gel, 50% EtOAc-
petroleum ether); 1H NMR (400 MHz, CDCl3)
d
¼3.28e3.36 (m,
12H), 3.58 (d, J¼7.29 Hz, 4H), 3.99 (s, 2H), 5.41 (s, 2H), 7.18 (d,
4.13. General procedure for the synthesis of sulfones 19aej
J¼7.45 Hz, 2H); 13C NMR (100 MHz, CDCl3)
¼27.37, 28.59, 29.13,
d
29.20, 43.67, 44.50, 56.25, 72.10, 89.30, 124.47, 124.58, 132.50,
138.52, 140.46, 141.41, 150.74, 151.30, 157.31, 163.56, 171.91, 172.01;
HRMS (ESI, Q-Tof) calculated for C22H22N4NaO6 [MþNa]þ 461.1432,
found: 461.1427; IR (CHCl3): ymax: 1681, 1750, 2837, 2934, 2961,
The solution of compounds 18aej in toluene (20 mL) was
refluxed for 9e14 h. At the conclusion of reaction (TLC monitoring),
the solvent was removed under reduced pressure and the crude
products were purified by silica gel column chromatography
(50e70% EtOAc-petroleum ether) to afford the sulfones 19aej.
3020 cmꢂ1
.
4.8. Compound 17d
4.14. Compound 19a
White solid; yield¼20% (295 mg, starting from 500 mg of 10d);
reaction time¼8 h; mp 230 ꢀC (decomposed); Rf¼0.51 (silica gel,
25% EtOAc-petroleum ether); 1H NMR (400 MHz, CDCl3)
White solid; yield¼78% (39 mg, starting from 50 mg of 18a);
reaction time¼12 h; mp 196e198 ꢀC; Rf¼0.66 (silica gel, 50% EtOAc-
petroleum ether); 1H NMR (400 MHz, CDCl3)
d¼1.26 (t, J¼7.12 Hz,
d
¼2.78e2.83 (m, 4H), 3.20 (d, J¼5.05 Hz, 4H), 3.44e3.49 (m, 4H),
6H), 3.57 (s, 4H), 4.21 (q, J1¼7.12 Hz, J2¼14.20 Hz, 4H), 4.31 (s, 4H),
7.06 (s, 2H), 7.39e7.46 (m, 4H), 7.63 (t, J¼7.52 Hz, 2H), 7.82 (d,
7.15 (s, 2H); 13C NMR (100 MHz, CDCl3)
d
¼14.18, 40.33, 57.02, 60.53,
J¼7.60 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d¼44.24, 44.59, 58.07,
62.11,122.10,129.94, 141.34,171.35; HRMS (ESI, Q-Tof) calculated for
120.56, 120.68, 124.49, 126.72, 127.72, 135.07, 136.40, 140.43, 152.76,
209.18; HRMS (ESI, Q-Tof) calculated for C28H22NaO2 [MþNa]þ
413.1512 found: 413.1515; IR (CHCl3): ymax: 1608, 1710, 2922, 3077,
C
17H20KO6S [MþK]þ 391.0612, found: 391.0617; IR (CHCl3): ymax
:
1603, 1732, 2854, 2936, 3033 cmꢂ1
.
3301 cmꢂ1
.
4.15. Compound 19b
4.9. Compound 17e
White solid; yield¼80% (64 mg, starting from 80 mg of 18b);
reaction time¼9 h; mp 222e224 ꢀC; Rf¼0.58 (silica gel, 50% EtOAc-
White solid; yield¼11% (63 mg, starting from 200 mg of 10e);
reaction time¼12 h; mp 171e173 ꢀC; Rf¼0.55 (silica gel, 25% EtOAc-
petroleum ether); 1H NMR (400 MHz, CDCl3)
d
¼3.35 (s, 4H), 4.36 (s,
4H), 7.18 (s, 2H), 7.91 (dd, J1¼3.08 Hz, J2¼5.68 Hz, 2H), 8.03 (dd,
petroleum ether); 1H NMR (500 MHz, CDCl3)
d
¼2.27 (t, J¼6.20 Hz,
J1¼3.12 Hz, J2¼5.64 Hz, 2H); 13C NMR (100 MHz, CDCl3)
¼40.44,
d
4H), 2.96e3.00 (m, 4H), 3.13 (t, J¼6.15 Hz, 4H), 3.47e3.52 (m, 4H),
7.07 (d, J¼7.40 Hz, 2H), 7.30e7.32 (m, 2H), 7.38 (t, J¼4.40 Hz, 2H),
7.54 (dt, J1¼1.30 Hz, J2¼7.14 Hz, 2H), 8.11e8.13 (m, 2H); 13C NMR
57.09, 58.86, 122.08, 123.98, 130.26, 136.32, 141.50, 141.68, 202.53;
HRMS (ESI, Q-Tof) calculated for C19H14NaO4S [MþNa]þ 361.0505,
found: 361.0505; IR (CHCl3): ymax: 1216, 1598, 1743, 2846, 2936,
(125 MHz, CDCl3)
d¼26.27, 34.08, 41.10, 41.19, 54.02, 120.96, 126.83,
3020 cmꢂ1
.

S. Kotha, R. Ali / Tetrahedron 71 (2015) 6944e6955
6951
4.16. Compound 19c
4.21. Compound 19h
White solid; yield¼85% (34 mg, starting from 40 mg of 18c);
reaction time¼12 h; mp 195 ꢀC (decomposed); Rf¼0.38 (silica gel,
White solid; yield¼91% (82 mg, starting from 90 mg of 18h);
reaction time¼10 h; mp 210 ꢀC (decomposed); Rf¼0.49 (silica gel,
50% EtOAc-petroleum ether); 1H NMR (400 MHz, CDCl3)
d
¼3.34 (s,
50% EtOAc-petroleum ether); 1H NMR (400 MHz, CDCl3)
d¼3.41 (s,
6H), 3.61 (s, 4H), 4.33 (s, 4H), 7.16 (s, 2H); 13C NMR (100 MHz, CDCl3)
4H), 4.41 (s, 4H), 7.21e7.24 (m, 6H), 7.36 (t, J¼6.44 Hz, 2H), 7.74 (d,
d
¼29.29, 44.14, 56.29, 57.03, 121.92, 130.47, 140.67, 151.32, 171.82;
J¼7.44 Hz, 2H); 13C NMR (100 MHz, CDCl3)
¼45.17, 57.17, 57.42,
d
HRMS (ESI, Q-Tof) calculated for C16H17N2O5S [MþH]þ 349.0858,
120.07, 122.35, 122.41, 127.75, 129.75, 139.70, 144.20, 151.74; HRMS
found: 349.0850; IR (CHCl3): ymax
:
1453, 1681, 1744, 2850,
(ESI, Q-Tof) calculated for C23H18NaO2S [MþNa]þ 381.0920, found:
2922 cmꢂ1
.
381.0919; IR (CHCl3): ymax: 1476, 1577, 2840, 2928, 3021 cmꢂ1
.
4.22. Compound 19i
4.17. Compound 19d
White solid; yield¼82% (246 mg, starting from 300 mg of 18i);
reaction time¼12 h; mp 198 ꢀC (decomposed); Rf¼0.47 (silica gel,
White solid; yield¼76% (42 mg, starting from 55 mg of 18d);
reaction time¼12 h; mp 176e178 ꢀC; Rf¼0.57 (silica gel, 50% EtOAc-
50% EtOAc-petroleum ether); 1H NMR (400 MHz, CDCl3)
d¼3.40 (s,
petroleum ether); 1H NMR (400 MHz, CDCl3)
d¼2.80 (d, J¼15.08 Hz,
4H), 4.43 (s, 4H), 7.25 (d, J¼1.52 Hz, 2H), 7.32 (d, J¼1.60 Hz, 2H), 7.48
(dd, J1¼1.72 Hz, J2¼8.12 Hz, 2H), 7.55 (d, J¼8.12 Hz, 2H); 13C NMR
2H), 3.12 (s, 2H), 3.41 (d, J¼15.81 Hz, 2H), 4.25, 4.31 (ABq,
J¼15.61 Hz, 4H), 7.10 (s, 2H), 7.34e7.39 (m, 2H), 7.57 (td, J1¼1.12 Hz,
J2¼7.52 Hz, 1H), 7.76 (d, J¼7.64 Hz, 1H); 13C NMR (100 MHz, CDCl3)
(100 MHz, CDCl3)
d
¼45.04, 57.18, 57.38,121.55,121.93,122.63,125.83,
130.28,131.18,137.74,143.16,153.67; HRMS (ESI, Q-Tof) calculated for
79
Br2NaO2S [MþNa]þ 536.9120, found: 536.9127; IR (CHCl3):
d
¼43.68, 44.57, 57.14, 57.63, 122.28, 124.64, 126.82, 127.97, 129.73,
C
H
23 16
ymax: 1216, 1449, 1522, 1600, 2846, 2927, 3019 cmꢂ1
.
135.42, 136.09, 142.92, 152.52, 208.62; HRMS (ESI, Q-Tof) calculated
for C19H16NaO3S [MþNa]þ 347.0718, found: 347.0707; IR (CHCl3):
ymax: 1216, 1602, 1701, 2846, 2926, 3020 cmꢂ1
.
4.23. Compound 19j
Orange solid; yield¼80% (32 mg, starting from 40 mg of 18j);
reaction time¼14 h; 270 ꢀC (decomposed); Rf¼0.44 (silica gel, 50%
4.18. Compound 19e
EtOAc-petroleum ether); 1H NMR (400 MHz, CDCl3)
d
¼3.53 (s, 4H),
White solid; yield¼90% (45 mg, starting from 50 mg of 18e);
reaction time¼10 h; mp 246e247 ꢀC; Rf¼0.55 (silica gel, 50% EtOAc-
4.46 (s, 4H), 7.32 (s, 2H), 7.96 (d, J¼8.40 Hz, 2H), 8.13 (s, 2H), 8.35
(dd, J1¼2.08 Hz, J2¼8.40 Hz, 2H); 13C NMR (100 MHz, CDCl3)
petroleum ether); 1H NMR (500 MHz, CDCl3)
d
¼2.37 (t, J¼6.20 Hz,
d
¼44.73, 57.13, 57.81, 118.29, 121.96, 122.87, 124.40, 130.99, 142.20,
2H), 3.11 (d, J¼16.15 Hz, 2H), 3.22 (t, J¼6.15 Hz, 2H), 3.59 (d,
J¼16.17 Hz, 2H), 4.42, 4.45 (ABq, J¼15.70 Hz, 4H), 7.25 (s, 2H), 7.40
(d, J¼3.00 Hz,1H), 7.46 (t, J¼7.55 Hz,1H), 7.63 (t, J¼7.35 Hz,1H), 8.16
143.40, 148.80, 154.46; HRMS (ESI, Q-Tof) calculated for
C
23H16N2NaO6S [MþNa]þ 471.0621, found: 471.0623; IR (CHCl3):
ymax: 1212, 1341, 1514, 1640, 2847, 2917, 3021 cmꢂ1
.
(8, J¼7.80 Hz, 1H); 13C NMR (125 MHz, CDCl3)
¼26.26, 34.08, 41.26,
d
53.79, 57.04, 122.27, 126.98, 128.31, 128.87, 129.50, 131.27, 133.61,
142.54, 143.33, 200.25; HRMS (ESI, Q-Tof) calculated for
4.24. General procedure for the synthesis of compounds
20aee
C
20H18NaO3S [MþNa]þ 361.0869, found: 361.0862; IR (CHCl3): ymax
:
1215, 1594, 1687, 2854, 2930, 3016 cmꢂ1
.
The solution of DEAM (1 equiv), TBAHS (0.25 equiv) and K2CO3
(5 equiv) in dry MeCN (10e25 mL), was stirred at rt for 15 min.
Later, compound 14bec, or 14hej was added and stirring was
continued for 15e20 h at the same temperature. At the conclusion
of the reaction (TLC monitoring), K2CO3 was filtered through the
glass sintered funnel and the solvent was removed under reduced
pressure. The crude products were purified by silica gel column
chromatography using appropriate mixtures of EtOAc-petroleum
ether to give the desired products 20aee.
4.19. Compound 19f
White solid; yield¼81% (57 mg, starting from 70 mg of 18f);
reaction time¼12 h; mp 270e271 ꢀC; Rf¼0.57 (silica gel, 50% EtOAc-
petroleum ether);1H NMR (400 MHz, CDCl3)
d
¼2.20 (t, J¼6.28 Hz,
2H), 2.95 (d, J¼16.09 Hz, 2H), 3.03 (t, J¼6.20 Hz, 2H), 3.46 (d,
J¼16.09 Hz, 2H), 3.87 (s, 3H), 4.28, 4.33 (ABq, J¼15.68 Hz, 4H), 6.71
(d, J¼2.40 Hz, 1H), 6.85 (dd, J1¼2.52 Hz, J2¼8.76 Hz, 1H), 7.12 (s, 2H),
8.01 (d, J¼8.76 Hz, 1H); 13C NMR (100 MHz, CDCl3)
¼26.69, 34.22,
d
4.25. Compound 20a
41.50, 53.58, 55.62, 57.09, 112.56, 113.64, 122.28, 124.87, 129.43,
130.81, 142.74, 145.83, 163.80, 199.16; HRMS (ESI, Q-Tof) calculated
for C21H20NaO4S [MþNa]þ 391.0975, found: 391.0975; IR (CHCl3):
White solid; yield¼66% (52 mg, starting from 70 mg of 14b);
reaction time¼16 h; mp 257e260 ꢀC; Rf¼0.31 (silica gel, 60% EtOAc-
petroleum ether); 1H NMR (400 MHz, CDCl3)
d
¼1.20 (t, J¼7.07 Hz,
ymax: 1259, 1451, 1598, 1670, 2935, 2962 cmꢂ1
.
6H), 2.29 (s, 3H), 3.31 (s, 4H), 3.41 (s, 2H), 4.18 (q, J1¼2.50 Hz,
J2¼6.92 Hz, 4H), 4.66 (s, 2H), 7.02 (s, 2H), 7.90 (dd, J1¼3.08 Hz,
J2¼5.64 Hz, 2H), 8.02 (dd, J1¼3.08 Hz, J2¼5.08 Hz, 2H); 13C NMR
4.20. Compound 19g
(100 MHz, CDCl3)
d
¼14.11, 22.59, 37.68, 40.47, 48.18, 58.95, 62.10,
White solid; yield¼90% (90 mg, starting from 100 mg of 18g);
reaction time¼12 h; mp 146e148 ꢀC; Rf¼0.52 (silica gel, 50% EtOAc-
68.22, 122.08, 123.71, 123.88, 131.55, 131.93, 136.18, 139.90, 140.35,
141.56, 168.08, 171.01, 202.84; HRMS (ESI, Q-Tof) calculated for
petroleum ether); 1H NMR (500 MHz, CDCl3)
d
¼2.77 (t, J¼7.15 Hz,
C
28H27NNaO7 [MþNa]þ 512.1680, found: 512.1678; IR (CHCl3): ymax
:
2H), 3.16e3.23 (m, 4H), 3.76 (d, J¼16.35 Hz, 2H), 4.29, 4.32 (ABq,
1415, 1654, 1709, 1742, 2252, 2944, 3121 cmꢂ1
.
J¼15.72 Hz, 4H), 7.06 (d, J¼7.65 Hz, 1H), 7.13e7.21 (m, 5H); 13C NMR
(125 MHz, CDCl3)
d
¼28.69, 37.31, 44.65, 57.06, 59.11, 121.99, 125.96,
4.26. Compound 20b
127.12, 127.49, 128.38, 129.92, 135.54, 142.14, 142.24, 212.19; HRMS
(ESI, Q-Tof) calculated for C20H18NaO3S [MþNa]þ 361.0869, found:
White solid; yield¼56% (31 mg, starting from 50 mg of 14c);
reaction time¼18 h; mp 293 ꢀC (decomposed); Rf¼0.17 (silica gel,
361.0864; IR (CHCl3): ymax: 1219, 1484, 2851, 2923, 3021 cmꢂ1
.

6952
S. Kotha, R. Ali / Tetrahedron 71 (2015) 6944e6955
60% EtOAc-petroleum ether); 1H NMR (400 MHz, CDCl3)
d
¼1.19 (t,
622.1797; IR (CHCl3): ymax: 1344, 1525, 1662, 1742, 2305, 2856,
2986, 3055 cmꢂ1
J¼7.12 Hz, 6H), 2.28 (s, 3H), 3.31 (s, 6H), 3.39 (s, 2H), 3.57 (s, 4H),
.
4.17 (q, J1¼3.52 Hz, J2¼7.04 Hz, 4H), 4.64 (s, 2H), 7.00 (d, J¼3.88 Hz,
2H); 13C NMR (100 MHz, CDCl3)
d
¼14.12, 22.61, 29.27, 37.63, 44.05,
4.31. General procedure for the synthesis of 21aee
44.19, 48.14, 56.39, 62.15, 68.20, 121.93, 123.59, 131.81, 132.15,
138.83, 139.36, 151.45, 168.07, 171.00, 172.02; HRMS (ESI, Q-Tof)
calculated for C25H30N3O8 [MþH]þ 500.2027, found: 500.2026; IR
The solution of compounds 14bec, hej, EICA (1.2 equiv), TBAHS
(0.25 equiv) and K2CO3 (5 equiv) in dry MeCN (20e25 mL) was
refluxed for 14e20 h. At the conclusion of reaction (TLC monitor-
ing), K2CO3 was filtered through glass sintered funnel and the
solvent was removed under reduced pressure. The crude products
were then dissolved in EtOH (20 mL), conc. HCl (0.50 mL) was
added slowly and the reaction was stirred at rt for 1e2 h. The re-
action mixture was made neutral by adding liq. NH3 solution. Later,
the solvent was removed under reduced pressure and the crude
products were purified by silica gel column chromatography using
appropriate mixtures of EtOAc-petroleum ether to afford the un-
protected 21cee AAAs derivatives. Later, the crude products were
dissolved in MeCN (15 mL), acetic anhydride (Ac2O, 3 mL) was
added to it and the reaction mixture was stirred at rt for 12e13 h.
The solvent was removed under the reduced pressure and the
crude products were purified by silica gel column chromatography
using (60% EtOAc-petroleum ether) to deliver the protected AAAs
derivatives 21a and 21b.
(CHCl3): ymax: 1217, 1374, 1734, 2399, 2923, 2978, 3020 cmꢂ1
.
4.27. Compound 20c
White solid; yield¼65% (110 mg, starting from 150 mg of 14h);
reaction time¼15 h; mp 215e218 ꢀC; Rf¼0.25 (silica gel, 50% EtOAc-
petroleum ether); 1H NMR (400 MHz, CDCl3)
d¼1.23 (t, J¼7.12 Hz,
6H), 2.32 (s, 3H), 3.36 (s, 4H), 3.47 (s, 2H), 4.18e4.25 (m, 4H), 4.72 (s,
2H), 7.11e7.21 (m, 6H), 7.34 (t, J¼6.96 Hz, 2H), 7.73 (d, J¼7.56 Hz,
2H); 13C NMR (100 MHz, CDCl3)
d
¼14.19, 22.64, 37.77, 45.06, 45.13,
48.31, 57.65, 62.07, 68.41, 120.03, 122.33, 122.60, 124.20, 127.62,
131.12, 131.59, 139.73, 142.49, 142.93, 152.08, 168.18, 171.06; HRMS
(ESI, Q-Tof) calculated for C32H31NNaO5 [MþNa]þ 532.2094, found:
532.2092; IR (CHCl3): ymax: 1399, 1444, 1666, 1727, 1747, 2938,
2982 cmꢂ1
.
4.28. Compound 20d
4.32. Compound 21a
White solid; yield¼37% (189 mg, starting from 470 mg of 14i);
reaction time¼20 h; mp 230e231 ꢀC; Rf¼0.22 (silica gel, 50%
White solid; yield¼42% (81 mg, starting from 200 mg of 14b);
reaction time¼(15þ2þ13) h; mp 283e285 ꢀC; Rf¼0.17 (silica gel, 60%
EtOAc-petroleum ether); 1H NMR (400 MHz, CDCl3)
d¼1.23 (t,
J¼7.16 Hz, 6H), 2.31 (s, 3H), 3.32 (s, 4H), 3.46 (s, 2H), 4.18e4.23 (m,
4H), 4.72 (s, 2H), 7.10 (s, 2H), 7.25 (d, J¼1.40 Hz, 2H), 7.45 (dd,
J1¼1.44 Hz, J2¼8.08 Hz, 2H), 7.52 (d, J¼8.10 Hz, 2H); 13C NMR
EtOAc-petroleum ether); 1H NMR (400 MHz, CDCl3)
d¼1.27 (t,
J¼7.20 Hz, 3H), 1.93 (s, 3H), 3.16e3.33 (m, 6H), 3.61 (d, J¼16.48 Hz,
2H), 4.23 (q, J1¼6.96 Hz, J2¼14.04 Hz, 2H), 6.23 (br s,1H), 7.03 (s, 2H),
7.88 (dd, J1¼2.96 Hz, J2¼5.20 Hz, 2H), 8.01 (d, J¼3.52 Hz, 2H); 13C
(100 MHz, CDCl3)
62.10, 68.26, 121.43, 121.73, 122.69, 124.23, 125.72, 130.94, 131.53,
d
¼14.20, 22.58, 37.72, 44.80, 44.85, 48.20, 57.56,
NMR (100 MHz, CDCl3)
d
¼14.29, 23.20, 40.38, 43.23, 59.28, 61.77,
131.90, 137.64, 141.32, 141.77, 153.86, 168.04, 171.05; HRMS (ESI, Q-
66.53, 120.60, 123.82, 123.86, 136.08, 136.12, 139.33, 139.58, 141.51,
141.62, 170.49, 172.90, 202.96, 203.19; HRMS (ESI, Q-Tof) calculated
for C25H23NNaO5 [MþNa]þ 440.1468, found: 440.1457; IR (CHCl3):
79
Tof) calculated for C
H
Br2NNaO5 [MþNa]þ 688.0305, found:
32 29
688.0308; IR (CHCl3): ymax
: 1660, 1737, 2265, 2851, 2927,
3051 cmꢂ1
.
ymax: 1225, 1589, 1659, 1704, 1731, 2851, 2928, 3020, 3238 cmꢂ1
.
4.29. Compounds 20d0
4.33. Compound 21b
White solid; yield¼15% (102 mg, starting from 470 mg of 14i);
reaction time¼20 h; mp 223e225 ꢀC; Rf¼0.19 (silica gel, 50% EtOAc-
White solid; yield¼39% (94 mg, starting from 250 mg of 14c);
reaction time¼(12þ2þ12) h; mp>300 ꢀC; Rf¼0.25 (silica gel, 70%
petroleum ether); 1H NMR (400 MHz, CDCl3)
d¼1.24 (t, J¼7.12 Hz,
EtOAc-petroleum ether); 1H NMR (400 MHz, CDCl3)
d¼1.24 (t,
6H), 1.28 (t, J¼7.20 Hz, 6H), 2.08 (s, 3H), 2.32 (s, 3H), 3.35 (s, 4H),
3.47 (s, 2H), 4.19e4.31 (m, 8H), 4.74 (s, 2H), 5.16 (d, J¼7.00 Hz, 1H),
6.51 (br s, 1H), 7.12 (s, 2H), 7.47 (dd, J1¼1.72 Hz, J1¼8.12 Hz, 3H). 7.55
J¼6.64 Hz, 3H), 1.88 (s, 3H), 3.14 (d, J¼16.48 Hz, 2H), 3.28e3.42 (m,
8H), 3.52e3.58 (m, 4H), 4.19 (q, J1¼6.88 Hz, J2¼14.24 Hz, 2H), 6.39
(br s, 1H), 6.99 (s, 2H); 13C NMR (100 MHz, CDCl3)
d¼14.27, 23.11,
(d, J¼8.12 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
¼14.11, 14.21, 22.58,
29.16, 29.22, 43.05, 43.16, 44.13, 56.46, 61.77, 66.47, 120.41, 138.52,
138.65, 139.41, 139.59, 151.46, 170.49, 172.17, 172.49, 172.86; HRMS
(ESI, Q-Tof) calculated for C22H25N3NaO6 [MþNa]þ 450.1636, found:
450.1634; IR (CHCl3): ymax: 1216, 1374, 1734, 2399, 2923, 2978,
22.89, 37.73, 44.83, 44.88, 48.21, 56.56, 57.59, 62.09, 62.75, 68.27,
121.44, 121.75, 122.70, 124.25, 125.74, 130.96, 131.56, 131.92, 137.67,
141.34, 141.78, 153.89, 166.54, 168.05, 169.93, 171.03; HRMS (ESI, Q-
79
Tof) calculated for C
H
Br2N2NaO10 [MþNa]þ 905.1255, found:
3020 cmꢂ1
.
41 44
905.1252; IR (CHCl3): ymax
: 1267, 1680, 1736, 2255, 2928,
3020 cmꢂ1
.
4.34. Compound 21c
4.30. Compound 20e
White solid; yield¼59% (103 mg, starting from 200 mg of 14h);
reaction time¼17 h; mp 157 ꢀC (decomposed); Rf¼0.18 (silica gel,
White solid; yield¼69% (46 mg, starting from 60 mg of 14j);
reaction time¼15 h; mp 227e230 ꢀC; Rf¼0.23 (silica gel, 50% EtOAc-
50% EtOAc-petroleum ether); 1H NMR (400 MHz, CDCl3)
d
¼1.32 (t,
J¼7.12 Hz, 3H), 1.97 (br s, 2H), 2.91 (d, J¼15.97 Hz, 2H), 3.33, 3.48
(ABq, J1¼7.78 Hz, J2¼15.64 Hz, 4H), 3.60 (d, J¼15.93 Hz, 2H), 4.26 (q,
J1¼7.00 Hz, J2¼14.12 Hz, 2H), 7.14e7.35 (m, 8H), 7.72 (d, J¼7.52 Hz,
petroleum ether); 1H NMR (400 MHz, CDCl3)
d
¼1.25 (t, J¼7.12 Hz,
6H), 2.32 (s, 3H), 3.48 (s, 4H), 3.51 (s, 2H), 4.19e4.28 (m, 4H), 4.77 (s,
2H), 7.17 (d, J¼4.36 Hz, 2H), 7.96 (d, J¼8.44 Hz, 2H), 8.10 (d,
J¼1.96 Hz, 2H), 8.33 (dd, J1¼2.04 Hz, J2¼8.40 Hz, 2H); 13C NMR
2H); 13C NMR (100 MHz, CDCl3)
d
¼14.40, 45.16, 46.04, 57.70, 61.55,
65.49, 119.89, 121.26, 122.44, 122.66, 127.42, 127.60, 127.68, 139.33,
139.64, 139.71, 141.82, 152.48, 152.87, 176.76; HRMS (ESI, Q-Tof)
calculated for C27H26NO2 [MþH]þ 396.1958, found: 396.1956; IR
(CHCl3): ymax: 1216, 1447, 1478, 1726, 2309, 2835, 2928, 3018,
(100 MHz, CDCl3)
62.24, 68.22, 118.26, 121.88, 122.88, 124.26, 124.50, 132.26, 132.52,
140.43, 140.90, 143.40, 148.73, 154.73, 168.09, 171.07; HRMS (ESI, Q-
d
¼14.21, 22.66, 37.73, 44.56, 44.63, 48.24, 58.06,
Tof) calculated for
C
32H29N3NaO9 [MþNa]þ 622.1796, found:
3373 cmꢂ1
.

S. Kotha, R. Ali / Tetrahedron 71 (2015) 6944e6955
6953
4.35. Compound 21d
4H), 3.33 (s, 6H), 3.56 (s, 4H), 7.03 (s, 2H), 7.87 (dd, J1¼3.10 Hz,
J2¼5.65 Hz, 2H), 8.01 (dd, J1¼2.60 Hz, J2¼5.65 Hz, 2H); 13C NMR
White solid; yield¼45% (57 mg, starting from 140 mg of 14i);
reaction time¼14 h; mp 270 ꢀC (decomposed); Rf¼0.16 (silica gel,
(125 MHz, CDCl3)
d¼29.25, 40.39, 43.93, 56.89, 59.36, 119.99,
123.88, 136.07, 138.76, 140.09, 141.62, 151.62, 172.16, 203.01; HRMS
(ESI, Q-Tof) calculated for C25H20KN2O5 [MþK]þ 467.1004 found:
467.1009; IR (CHCl3): ymax: 1216, 1420, 1683, 1709, 1742, 2400, 2857,
50% EtOAc-petroleum ether); 1H NMR (400 MHz, CDCl3)
d
¼1.32 (t,
J¼7.12 Hz, 3H), 2.17 (br s, 2H), 2.92 (d, J¼15.97 Hz, 2H), 3.23, 3.33
(ABq, J1¼7.78 Hz, J2¼16.01 Hz, 4H), 3.60 (d, J¼15.93 Hz, 2H), 4.26 (q,
J1¼7.08 Hz, J2¼14.20 Hz, 2H), 7.11 (s, 2H), 7.30 (d, J¼1.48 Hz, 2H),
2925, 3020 cmꢂ1
.
7.33e7.51 (m, 4H); 13C NMR (100 MHz, CDCl3)
d
¼14.36, 44.88,
4.40. Compound 22b
45.90, 57.60, 61.48, 65.44, 121.28, 121.67, 121.73, 125.69, 125.99,
130.70, 130.72, 137.45, 137.65, 139.76, 140.60, 154.12, 154.82, 176.53;
HRMS (ESI, Q-Tof) calculated for
White solid; yield¼81% (75 mg, starting from 100 mg of 14b);
reaction time¼8 h; mp 239e241 ꢀC; Rf¼0.56 (silica gel, 25% EtOAc-
C
27H23NNaO729Br2 [MþNa]þ
573.9988, found: 573.9988; IR (CHCl3): ymax: 1218, 1447, 1478, 1622,
petroleum ether); 1H NMR (500 MHz, CDCl3)
d
¼2.79 (d,
1728, 2254, 2841, 2940, 3020, 3528 cmꢂ1
.
J¼15.45 Hz, 2H), 3.19 (s, 2H), 3.32, 3.35 (ABq, J¼15.50 Hz, 4H), 3.46 (d,
J¼15.45 Hz, 2H), 7.06 (s, 2H), 7.41 (t, J¼7.45 Hz, 1H), 7.45 (d, J¼7.60 Hz,
1H), 7.62 (t, J¼7.05 Hz, 1H), 7.82 (d, J¼7.60 Hz, 1H), 7.88 (dd,
J1¼3.05 Hz, J2¼5.45 Hz, 2H), 8.02e8.04 (m, 2H); 13C NMR (125 MHz,
4.36. Compound 21e
White solid; yield¼48% (86 mg, starting from 200 mg of 14j);
reaction time¼17 h; mp 230 ꢀC (decomposed); Rf¼0.16 (silica gel,
CDCl3)
d
¼40.48, 44.22, 44.59, 58.25, 59.40, 120.38, 123.81, 123.90,
124.51, 126.82, 127.74, 135.13, 136.02, 136.08, 136.44, 139.24, 141.07,
141.60, 141.66, 152.86, 203.03, 203.34, 209.22; HRMS (ESI, Q-Tof)
calculated for C28H20NaO3 [MþNa]þ 427.1305 found: 427.1308; IR
50% EtOAc-petroleum ether); 1H NMR (400 MHz, CDCl3)
d¼1.34 (t,
J¼7.22 Hz, 3H), 1.79 (br s, 2H), 2.95 (d, J¼15.96 Hz, 2H), 3.39, 3.52
(ABq, J1¼7.89 Hz, J2¼16.08 Hz, 4H), 3.63 (d, J¼15.93 Hz, 2H), 4.29 (q,
J1¼7.08 Hz, J2¼14.20 Hz, 2H), 7.19 (s, 2H), 7.94 (dd, J1¼2.16 Hz,
J2¼8.36 Hz, 2H), 8.10 (d, J¼1.84 Hz, 1H), 8.22 (d, J¼1.80 Hz, 1H),
(CHCl3): ymax: 1276, 1465, 1596, 1701, 1735, 2854, 2918, 3013 cmꢂ1
.
4.41. Compound 22c
8.31e8.35 (m, 2H); 13C NMR (100 MHz, CDCl3)
d
¼14.42, 44.66,
46.03, 58.28, 61.62, 65.65, 118.25, 118.63, 121.57, 121.68, 121.73,
124.06, 139.78, 140.60, 143.24, 143.52, 148.76, 154.90, 155.69,
176.56; HRMS (ESI, Q-Tof) calculated for C27H24N3O6 [MþH]þ
486.1660, found: 486.1660; IR (CHCl3): ymax: 1517, 1583, 1725, 2401,
White solid; yield¼78% (80 mg, starting from 100 mg of 14b);
reaction time¼16 h; mp 252e253 ꢀC; Rf¼0.50 (silica gel, 25% EtOAc-
petroleum ether); 1H NMR (500 MHz, CDCl3)
d
¼2.14 (t, J¼6.25 Hz,
2H), 2.85 (d, J¼15.80 Hz, 2H), 2.98 (t, J¼6.20 Hz, 2H), 3.19e3.29 (m,
4H), 3.38 (d, J¼15.81 Hz, 2H), 3.81 (s, 3H), 6.65 (d, J¼2.40 Hz, 1H),
6.79 (dd, J1¼2.55 Hz, J2¼8.75 Hz, 1H), 7.25 (s, 1H), 6.97 (s, 1H),
7.81e7.85 (m, 2H), 7.96e7.99 (m, 3H); 13C NMR (125 MHz, CDCl3)
2851, 2923, 3016 cmꢂ1
.
4.37. General procedure for the synthesis of 22a, 22d, 22h and
22i
d
¼26.70, 34.21, 40.52, 41.29, 53.93, 55.61, 59.43, 112.55, 113.50,
120.51, 123.82, 123.85, 125.41, 130.83, 135.97, 136.01, 139.00, 140.79,
141.59, 141.73, 145.97, 163.63, 199.71, 203.03, 203.38; HRMS (ESI, Q-
Tof) calculated for C30H24NaO4 [MþNa]þ 471.1567 found: 471.1568;
To a solution of compound 10c, K2CO3 (5 equiv) and TBAHS
(0.5 equiv) in dry MeCN (25 mL), compounds 14a, b, e, j (1.1 equiv)
were added and stirred the reaction mixture at rt for 6e12 h. At the
conclusion of reaction (TLC monitoring), excess amount of K2CO3
was filtered through the sintered funnel and the aqueous layer was
extracted with CH2Cl2. The solvent was removed under reduced
pressure and the crude products were purified by silica gel column
chromatography using appropriate mixtures of EtOAc-petroleum
ether to deliver the products 22a, 22d, 22h and 22i (Fig. 10).
IR (CHCl3): ymax: 1598, 1681, 1706, 1737, 2852, 2924, 3016 cmꢂ1
.
4.42. Compound 22d
White solid; yield¼71% (33 mg, starting from 50 mg of 14c);
reaction time¼10 h; mp 235 ꢀC (decomposed); Rf¼0.40 (silica gel,
50% EtOAc-petroleum ether); 1H NMR (500 MHz, CDCl3)
d¼2.77 (d,
J¼15.07 Hz, 2H), 3.16 (s, 2H), 3.33 (s, 6H), 3.43 (d, J¼15.48 Hz, 2H),
3.53, 3.59 (ABq, J¼15.80 Hz, 4H), 7.03 (s, 2H), 7.39e7.44 (m, 2H),
7.59 (dt, J1¼1.05 Hz, J2¼7.55 Hz, 1H), 7.80 (d, J¼7.60 Hz, 1H); 13C
4.38. General procedure for the synthesis of 17def and 22beg
To a suspension of sodium hydride (3 equiv) in dry THF (20 mL),
was added the compounds 10bef and the reaction mixture was stir-
red at rt for 10 min. Later, compounds 14cef (1.1 equiv) were added
and the stirring was continued for 8e20 h at the same temperature. At
the conclusion of the reaction (TLC monitoring), the reaction mixture
was quenched with saturated aq NH4Cl (5 mL) solution. Aqueous layer
was then extracted with CH2Cl2 and dried over Na2SO4. The solvent
was removed under reduced pressure and the crude products were
purified by silica gel column chromatography using appropriate
mixtures of EtOAc-petroleum ether to afford the desired products 17d
(75%,104 mg from 150 mg of 14d, 6 h),17e (67%, 65 mg from 100 mg of
14e,12 h),17f (56%, 34 mg from 60 mg of 14f, 20h) and22beg (Fig.10).
The spectral data of compounds 17def prepared by this route
matched with earlier route (Scheme 2 and Fig. 5).
NMR (125 MHz, CDCl3)
d
¼29.16, 29.19, 43.99, 44.12, 44.51, 56.74,
58.12, 120.17, 124.47, 126.76, 127.72, 135.11, 136.35, 138.11, 141.23,
151.55, 152.75, 172.12, 172.33, 209.05; HRMS (ESI, Q-Tof) calculated
for C25H22N2NaO4 [MþNa]þ 437.1472 found: 437.1476; IR (CHCl3):
ymax: 1619, 1701, 1745, 2355, 3019 cmꢂ1
.
4.43. Compound 22e
White solid; yield¼86% (89 mg, starting from 100 mg of 14c);
reaction time¼20 h; mp >300 ꢀC; Rf¼0.38 (silica gel, 50% EtOAc-
petroleum ether); 1H NMR (500 MHz, CDCl3)
d¼2.15 (t, J¼6.20 Hz,
2H), 2.85 (d, J¼15.80 Hz, 2H), 2.99 (t, J¼6.15 Hz, 2H), 3.30 (d,
J¼3.55 Hz, 6H), 3.38 (d, J¼15.80 Hz, 2H), 3.54, 3.83 (ABq, J¼15.80 Hz,
4H), 3.84 (s, 3H), 6.66 (d, J¼2.15 Hz, 1H), 6.81 (dd, J1¼2.40 Hz,
J2¼8.70 Hz, 1H), 6.98 (s, 2H), 7.99 (d, J¼8.70 Hz, 1H); 13C NMR
4.39. Compound 22a
(125 MHz, CDCl3)
d
¼26.69, 29.19, 29.26, 34.22, 41.28, 44.04, 53.90,
55.61, 56.85, 112.55, 113.52, 120.43, 125.35, 130.83, 137.88, 141.02,
145.93, 151.64, 163.66, 172.10, 172.42, 199.63; HRMS (ESI, Q-Tof)
calculated for C27H26N2NaO5 [MþNa]þ 481.1734 found: 481.1735; IR
White solid; yield¼69% (68 mg, starting from 100 mg of 14b);
reaction time¼12 h; mp 290 ꢀC (decomposed); Rf¼0.46 (silica gel,
50% EtOAc-petroleum ether); 1H NMR (500 MHz, CDCl3)
d
¼3.29 (s,
(CHCl3): ymax: 1216, 1449, 1682, 1735, 2850, 2928, 3020 cmꢂ1
.

6954
S. Kotha, R. Ali / Tetrahedron 71 (2015) 6944e6955
4.44. Alternate route for the synthesis of compound 22d
8.32 (d, J¼8.40 Hz, 2H); 13C NMR (125 MHz, CDCl3)
¼29.25, 43.94,
d
44.55, 56.99, 58.30, 118.41, 120.76, 121.72, 124.08, 139.38, 140.47,
143.34, 148.73, 151.59, 155.09, 172.04; HRMS (ESI, Q-Tof) calculated
for C29H22N4KO7 [MþK]þ 577.1120 found: 577.1124; IR (CHCl3):
White solid; yield¼59% (29 mg, starting from 50 mg of 14d);
reaction time¼16 h. The 1H, 13C NMR spectra of this compound is
identical to that of the compound 22d prepared by earlier route.
ymax: 1601, 1737, 2360, 2855, 2928, 3035 cmꢂ1
.
4.45. Compound 22f
Acknowledgements
White solid; yield¼65% (112 mg, starting from 180 mg of 14d);
reaction time¼12 h; mp 210e213 ꢀC; Rf¼0.55 (silica gel, 25% EtOAc-
R. A. thanks University Grants Commission, New Delhi for the
award of research fellowship. S. K. thanks the Department of Sci-
ence and Technology for the award of a J. C. Bose fellowship. We
thank to DST-New Delhi (SR/S5/GC-11/2010) for the financial
support.
petroleum ether); 1H NMR (500 MHz, CDCl3)
d
¼2.23 (t, J¼6.24 Hz,
2H), 2.75 (d, J¼15.44 Hz, 2H), 2.92 (d, J¼15.76 Hz, 2H), 3.06 (t,
J¼6.20 Hz, 2H), 3.17 (s, 2H), 3.42e3.47 (m, 4H), 7.03 (s, 2H), 7.25 (d,
J¼2.16 Hz, 1H), 7.31 (t, J¼7.68 Hz, 1H), 7.38e7.49 (m, 3H), 7.70 (dt,
J1¼1.08 Hz, J2¼7.52 Hz, 1H), 7.81 (d, J¼7.64 Hz, 1H), 8.04 (dd,
Supplementary data
J1¼1.04 Hz, J2¼7.84 Hz, 1H); 13C NMR (125 MHz, CDCl3)
¼26.33,
d
34.29, 41.14, 44.30, 44.67, 54.01, 58.17,120.74,124.48,126.74,126.83,
126.88, 127.70, 128.39, 128.80, 131.69, 133.34, 135.04, 136.51, 140.01,
140.06, 140.28, 143.39, 152.77, 200.69, 209.13; HRMS (ESI, Q-Tof)
calculated for C29H25O2 [MþH]þ 405.1849 found: 405.1846; IR
Supplementary data (The copies of 1H and 13C NMR for all the
new compounds) related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2015.07.008.
(CHCl3): ymax: 1602, 1680, 1706, 2852, 2927, 3016 cmꢂ1
.
References and notes
4.46. Compound 22g
1. (a) Kelly, T. R.; Ohashi, N. J. Am. Chem. Soc. 1986, 108, 7100; (b) Kim, C.; Kang, S.;
Rhee, Y. H. J. Org. Chem. 2014, 79, 11119; (c) Fitjer, L.; Klages, U.; Wehle, D.;
Giersig, M.; Schormann, N.; Cleeg, W.; Stephensen, D. S.; Binsch, G. Tetrahedron
1988, 46, 416; (d) Chen, H.-J.; Wu, Y. Org. Lett. 2015, 17, 592; (e) Jiang, S.-Z.; Lei,
T.; Wei, K.; Yang, Y. R. Org. Lett. 2014, 16, 5612; (f) Kita, Y.; Iio, K.; Kawaguchi, K.-
I.; Fukuda, N.; Takeda, Y.; Ueno, H.; Okunaka, R.; Higuchi, K.; Tsujino, T.; Fujioka,
H.; Akai, S. Chem.dEur. J. 2000, 6, 3897; (g) Kita, Y.; Higuchi, K.; Yoshida, Y.; Iio,
K.; Kitagaki, S.; Akai, S.; Fujioka, H. J. Am. Chem. Soc. 2001, 123, 3214; (h) MacChi,
P.; Jing, W.; Guidetti-Grept, R.; Keese, R. Tetrahedron 2013, 69, 2479; (i) Piers, E.;
Renaud, J. J. Org. Chem. 1993, 58, 11; (j) de Meijere, A.; Kozhushkov, S. I. Chem.
Rev. 2000, 100, 93; (k) de Meijere, A.; Kozhushkov, S. I.; Schill, H. Chem. Rev.
2006, 106, 4926.
2. Feuerbacher, N.; Vogtle, R.; Windscheidt, J. P. E.; Nieger, M. Synthesis 1999, 117.
3. (a) Dushing, M. P.; Ramana, C. V. Tetrahedron Lett. 2011, 52, 4627; (b) Pradhan,
R.; Patra, M.; Behera, A. K.; Mishra, B. K.; Behera, R. K. Tetrahedron 2006, 62, 77;
(c) Kita, Y.; Higuchi, K.; Yoshida, Y.; Lio, K.; Kitagaki, S.; Shuji, A.; Fujioka, H.
Angew. Chem., Int. Ed. Engl. 1999, 38, 683; (d) Kuck, D. Chem. Ber. 1994, 127, 409;
(e) Thommen, M.; Keese, R. Synlett 1997, 231; (f) Keese, R. Chem. Rev. 2006, 106,
4787; (g) Zhao, Y.; Liu, L.; Sun, W.; Lu, J.; McEachern, D.; Li, X.; Yu, S.; Bernard,
D.; Ochsenbein, P.; Ferey, V.; Carry, J.-C.; Deschamps, J. R.; Sun, D.; Wang, S. J.
Am. Chem. Soc. 2013, 135, 7223; (h) Sannigrahi, M. Tetrahedron 1999, 55, 9007;
(i) Kotha, S.; Deb, A. C.; Lahiri, K.; Manivannan, E. Synthesis 2009, 165; (j) Kotha,
S.; Dipak, M. K.; Mobin, S. Tetrahedron 2011, 67, 2543; (k) Kotha, S.; Manivannan,
E.; Ganesh, T.; Sreenivasachary, N.; Deb, A. C. Synlett 1999, 1618; (l) Sawada, T.;
Nakada, M. Org. Lett. 2013, 15, 1004; (m) Dyakonov, V. A.; Trapeznikova, O. A.;
de Meijere, A.; Dzhemilev, U. M. Chem. Rev. 2014, 114, 5775; (n) Basavaiah, D.;
Reddy, K. R. Org. Lett. 2007, 9, 57; (o) Singh, P.; Paul, K. J. Heterocycl. Chem. 2006,
43, 607.
White solid; yield¼70% (72 mg, starting from 100 mg of 14d);
reaction time¼15 h; mp 232e233 ꢀC; Rf¼0.53 (silica gel, 25% EtOAc-
petroleum ether); 1H NMR (500 MHz, CDCl3)
d
¼2.21 (t, J¼5.85 Hz,
2H), 2.76 (d, J¼15.30 Hz, 2H), 2.91 (d, J¼15.75 Hz, 2H), 3.03 (t,
J¼5.65 Hz, 2H), 3.18 (s, 2H), 3.45 (dd, J1¼5.65 Hz, J2¼15.50 Hz, 4H),
3.86 (s, 3H), 6.70 (s, 1H), 6.84 (d, J¼7.20 Hz, 1H), 7.03 (s, 2H),
7.39e7.44 (m, 2H), 7.61 (t, J¼7.15 Hz, 1H), 7.81 (d, J¼7.45 Hz, 1H),
8.04 (d, J¼8.70 Hz, 1H); 13C NMR (125 MHz, CDCl3)
¼26.74, 34.40,
d
41.36, 44.33, 44.69, 53.78, 55.59, 58.20, 112.55, 113.45, 120.75,
124.50, 125.31, 126.75, 127.72, 130.83, 135.05, 136.54, 140.22, 145.86,
152.80, 163.60, 199.65, 209.19; HRMS (ESI, Q-Tof) calculated for
C
30H27O3 [MþH]þ 435.1955 found: 435.1952; IR (CHCl3): ymax
:
1216, 1432, 1617, 1683, 1707, 2855, 2933, 3020 cmꢂ1
.
4.47. Compound 22h
White solid; yield¼78% (77 mg, starting from 100 mg of 14e);
reaction time¼12 h; mp >300 ꢀC; Rf¼0.42 (silica gel, 50% EtOAc-
petroleum ether); 1H NMR (500 MHz, CDCl3)
d¼2.21 (t,
J¼6.20 Hz, 2H), 2.90 (d, J¼15.80 Hz, 2H), 3.05 (t, J¼6.15 Hz, 2H), 3.32
(d, J¼3.60 Hz, 6H), 3.42 (d, J¼15.85 Hz, 2H), 3.49, 3.57 (ABq,
J¼15.75 Hz, 4H), 6.99 (s, 2H), 7.24 (d, J¼7.70 Hz, 1H), 7.31 (t,
J¼7.45 Hz, 1H), 7.58 (dt, J1¼1.25 Hz, J2¼6.20 Hz, 1H), 8.03 (dd,
4. (a) Lang, K.; Chin, J. W. Chem. Rev. 2014, 114, 4764; (b) Giannis, A.; Kolter, T.
Angew. Chem., Int. Ed. 1993, 32, 1244; (c) Schiller, P. W.; Weltrowska, G.; Dung,
N. T. M.; Nguyen, C.; Lemieux, N.; Chung, N. N.; Marsden, B. J.; Wilkes, B. C. J.
Med. Chem. 1991, 34, 3125; (d) Habashita, H.; Kokubo, M.; Hamano, S.; Hama-
naka, N.; Toda, M.; Shibayama, S.; Tada, H.; Sagawa, K.; Fukushima, D.; Maeda,
K.; Mitsuya, H. J. Med. Chem. 2006, 49, 4140; (e) Zompra, A. A.; Magafa, V.;
Lamari, F. N.; Nikolopoulou, A.; Nock, B.; Maina, T.; Spyroulias, G. A.; Kar-
amanos, N. K.; Cordopatis, P. J. Pept. Res. 2006, 66, 57; (f) Etienne, M. A.; Aucoin,
J. P.; Fu, Y.; McCarley, R. L.; Hammer, R. P. J. Am. Chem. Soc. 2006, 128, 3522; (g)
J1¼0.90 Hz, J2¼7.85 Hz, 1H); 13C NMR (125 MHz, CDCl3)
¼26.29,
d
29.18, 29.25, 34.13, 41.07, 44.03, 54.13, 56.83, 120.34, 126.91, 128.39,
128.86, 131.72, 133.42, 137.96, 140.87, 143.47, 151.63, 172.09, 172.40,
200.72; HRMS (ESI, Q-Tof) calculated for C26H24N2NaO4 [MþNa]þ
451.1628 found: 451.1634; IR (CHCl3): ymax: 1216, 1452, 1621, 1680,
ꢀ
Tanaka, M. Chem. Pharm. Bull. 2007, 55, 349; (h) Arduin, M.; Spagnolo, B.; Calo,
ꢀ
G.; Guerrini, R.; Carra, G.; Fischetti, C.; Trapella, C.; Marzola, E.; McDonald, J.;
1743, 2400, 2854, 2928, 3021 cmꢂ1
.
Lambert, D. G.; Regoli, D.; Salvadori, S. Bioorg. Med. Chem. 2007, 15, 4434; (i)
Sisto, A.; Altamura, M.; Cardinali, F.; Andrea, P. D.; Rossi, C.; Fattori, D. Bioorg.
Med. Chem. Lett. 2007, 17, 4841; (j) Mishra, A.; Rastogi, N.; Batra, S. Tetrahedron
2012, 68, 2146.
4.48. Alternate route for the synthesis of compound 22f
5. (a) Fletcher, K. Pharm. Sci. Technol. Today 1998, 1, 49; (b) Pillai, O.; Panchagnula,
R. Drug Discov. Today 2001, 6, 1056; (c) Rana, S.; Kundu, B.; Durani, S. Chem.
Commun. 2004, 2462; (d) Kumar, M.; Chaturvedi, A. K.; Kavishwar, A.; Shukla,
P. K.; Kesarwani, A. P.; Kundu, B. Int. J. Antimicrob. Agents 2005, 25, 313; (e)
Duggineni, S.; Srivastava, G.; Kundu, B.; Kumar, M.; Chaturvedi, A. K.; Shukla, P.
K. Int. J. Antimicrob. Agents 2007, 29, 73.
White solid; yield¼84% (39 mg, starting from 50 mg of 14e);
reaction time¼12 h. The 1H, 13C NMR spectra of this compound is
identical to that of the compound 22f.
6. Gante, J. Angew. Chem., Int. Ed. 1994, 33, 1699.
7. (a) Liskamp, R. M. J. Angew. Chem., Int. Ed. 1994, 33, 305; (b) Kotha, S.; Lahiri, K.
Curr. Med. Chem. 2005, 12, 849.
4.49. Compound 22i
8. (a) Kotha, S.; Brahmachary, E. J. Org. Chem. 2000, 65, 1359; (b) Kotha, S.;
Brahmachary, E. Indian J. Chem. 2001, 40B, 1; (c) Kotha, S.; Ghosh, A. K. Tetra-
hedron Lett. 2004, 45, 2931.
9. (a) Chinchilla, R.; Najera, C. Recent Res. Devel. Org. Chem. 1997, 1, 437; (b) Najera,
C.; Sansano, J. M. Recent Res. Devel. Org. Chem. 1998, 2, 637; (c) Chinchilla, R.;
White solid; yield¼68% (67 mg, starting from 100 mg of 14j);
reaction time¼8 h; mp 213e215 ꢀC; Rf¼0.42 (silica gel, 50% EtOAc-
petroleum ether); 1H NMR (500 MHz, CDCl3)
d
¼3.37 (s, 6H), 3.46 (s,
ꢁ
ꢁ
4H), 3.66 (s, 4H), 7.16 (s, 2H), 7.94 (d, J¼8.40 Hz, 2H), 8.15 (s, 2H),

S. Kotha, R. Ali / Tetrahedron 71 (2015) 6944e6955
6955
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Najera, C. Chem. Rev. 2000, 100, 1891; (d) Prilezhaeva, E. N. Russ. Chem. Rev.
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2015, 71, 1597; (c) Kotha, S.; Ali, R. Heterocycles 2015, 90, 645.
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2006, 45, 4281.
18. Kotha, S.; Ghosh, A. K. Tetrahedron 2004, 60, 10833.
2001, 70, 897; (e) Back, T. G. Tetrahedron 2001, 57, 5263; (f) Sandulache, A.;
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19. For our group contribution in EICA see (a) Kotha, S.; Halder, S. Synlett 2010, 337;
(b) Kotha, S.; Mohanraja, K.; Durani, S. Chem. Commun. 2000, 1909; (c) Kotha, S.;
Brahmachary, E. Bioorg. Med. Chem. 2002, 10, 2291; (d) Kotha, S.; Brahmachary,
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machary, E. Eur. J. Org. Chem. 2001, 787; (f) Kotha, S.; Brahmachary, E.; Sree-
nivasachary, N. Tetrahedron Lett. 1998, 39, 4095; (g) Kotha, S.; Sreenivasachary,
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N. Bioorg. Med. Chem. Lett. 1998, 8, 257; (i) Kotha, S. Acc. Chem. Res. 2003, 36,
342; (j) Kotha, S.; Goyal, D.; Chavan, A. S. J. Org. Chem. 2013, 78, 12288.
20. (a) Burke, M. D.; Schreiber, S. L. Angew. Chem. 2004, 116, 48; (b) Kotha, S.; Ali, R.;
Chinnam, A. K. Tetrahedron Lett. 2014, 55, 4492; (c) Kotha, S.; Mandal, K.; Tiwari,
A.; Mobin, S. M. Chem.dEur. J. 2006, 12, 8024; (d) Tan, D. S. Nat. Chem. Biol.
2005, 1, 74.
ꢁ
11. Najera, C.; Yus, M. Tetrahedron 1999, 55, 10547.
12. (a) Paquette, L. A. Org. React. 1977, 25, 1; (b) Zhang, H.; Zhang, L.-X.; Yang, F.; Liu,
F.-L. J. Mol. Struct.: Theochem 2010, 950, 41; (c) Cooke, M. P., Jr. J. Org. Chem. 1981,
46, 1747.
13. (a) Shank, K. In The Chemistry of Sulphones and Sulphoxides; Patai, S., Rappoport,
Z., Stirling, C., Eds.; John Wiley: New York, NY, 1988; p 165; (b) Colquhoun, H.
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14. (a) Gonzalez-Vera, J. A.; Garcia-Lopez, M. T.; Herranz, R. J. Org. Chem. 2005, 70,
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Rogers-Evans, M.; Carreira, E. M. Org. Lett. 2011, 13, 6134.
15. (a) Clerc, F. F.; Guitton, J. D.; Fromage, N.; lelievre, Y.; Duchesne, M.; Tocque, B.;
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