Reactivity of bispropargyl sulfones under basic conditions: Interplay between Garratt-Braverman and Schmittel/Myers-Saito cyclization pathway

Article abstract of DOI:10.1002/asia.201100903

The preference for Garratt-Braverman (GB) over Myers-Saito (MS) and Schmittel (SCM) cyclizations has recently been demonstrated in sulfones capable of undergoing all three of the processes. As the GB cyclization is a self-quenching process, there is a nee

Full text of DOI:10.1002/asia.201100903

DOI: 10.1002/asia.201100903
Reactivity of Bispropargyl Sulfones under Basic Conditions: Interplay
Between Garratt–Braverman and Schmittel/Myers–Saito Cyclization
Pathway
Raja Mukherjee,[a] Sayantan Mondal,[a] Amit Basak,*[a] Dibyendu Mallick,[b] and
Eluvathingal D. Jemmis*[b, c]
Abstract: The preference for Garratt–
Braverman (GB) over Myers–Saito
(MS) and Schmittel (SCM) cyclizations
has recently been demonstrated in sul-
fones capable of undergoing all three
of the processes. As the GB cyclization
is a self-quenching process, there is a
need to change the selectivity to the
non-self-quenching MS or SCM path-
way so as to enhance the DNA-cleav-
ing efficiency that operates through the
radical-mediated process. Herein we
computations (M06-2X/6-31+G*) to
switch the selectivity from GB to MS/
SCM pathway which also results in
greater DNA-cleavage activity. The
preference for GB could be brought
back by easing the constraint with the
help of spacers.
report
a conformational constraint-
based strategy developed by using
Keywords: antibiotics · cyclization ·
DNA cleavage · enediyne · sulfones
Introduction
sallenes have a self-quenching mechanism; therefore chan-
ces of interaction of the diradicals with external sources are
greatly reduced. Although the DNA cleavage exhibited by
these molecules may also involve Michael addition of DNA
base followed by Maxam–Gilbert-type cleavage,[10] the
cleaving efficiency of these molecules is generally much
less[11] than molecules that undergo BC or MSC. The effi-
ciency of hydrogen abstraction by a diradical is of utmost
importance from a medicinal chemistry standpoint because
that will finally decide the potential of the diradical-generat-
ing molecule as an antitumor agent. Recently[11] we have
shown the complete preference for GB over MS/SCM in
bispropargyl sulfones, which have the possibility to undergo
all three processes under basic conditions. This preference
for GB makes these molecules less efficient as DNA-cleav-
ing agents. It would be better if it were possible to reverse
the preference for the cyclization processes. In this paper,
we demonstrate a conformational constraint-based strategy
by which one can completely shift the preference of cycloar-
omatization from GB to the MS or SCM pathway in bispro-
pargyl sulfones. We have also demonstrated that the prefer-
ence for GB could be brought back through incorporation
of spacers to lessen the constraint.
The discovery of naturally occurring and highly potent anti-
cancer agents collectively called enediyne antibiotics[1] in the
1980s triggered the search for ways to spontaneously gener-
ate diradicals.[2] Since then, the role of the diradicals in or-
ganic synthesis,[3] in the preparation of new materials,[4] and
especially in pharmacology[5] has become a major topic of
research interest. The conditions to generate diradicals and
their efficiency of hydrogen abstraction vary widely. Diradi-
cals that do not have any mechanism to self-quench become
diamagnetic by means of abstraction of atoms from external
sources. Bergman cyclization (BC)[6] and related reactions
like Myers–Saito (MS)[7] and Schmittel (SCM)[8] belong to
this category (Scheme 1). On the other hand, cyclizations
like Garratt–Braverman (GB)[9] that involve conjugated bi-
[a] R. Mukherjee, S. Mondal, Dr. A. Basak
Department of Chemistry,
Indian Institute of Technology
Kharagpur 721 302 (India)
E-mail: absk@chem.iitkgp.ernet.in
[b] D. Mallick, Dr. E. D. Jemmis
Department of Inorganic and Physical Chemistry
Indian Institute of Science
Results and Discussion
Bangalore 560 012 (India)
Experimental Studies
[c] Dr. E. D. Jemmis
Indian Institute of Science Education and
Research Thiruvananthapuram, CET Campus
Thiruvananthapuram, 695016, Kerala (India)
E-mail: jemmis@iisertvm.ac.in
Initially, we had two strategies in mind to switch the prefer-
ence. Both strategies aimed to prevent the molecule from
adapting the conformation suitable for the GB pathway,
either by steric effects or through geometric constraints. In
the first strategy, we argued that the intermediates for GB
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100903.
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adical over MS biradical and
the intramolecular self-quench-
ing nature of the GB pathway
remain the main reasons for
this preference (see the Sup-
porting Information for a de-
tailed discussion).
The second strategy involved
tying up the two ends of the
alkyne by oxidative coupling. If
the compound has to undergo
GB cyclization, it has to
Scheme 1. Various cyclization pathways in the presence of hydrogen donors.
adapt the conformation
M
(Scheme 3), which is 12.0 kcal
molꢀ1 higher in energy at the M06-2X/6-31+G* level of
theory[20] than the initial conformation required for MS or
SCM cyclization. The conformation for the diradical is then
best represented by N. In comparison to the diradical P
formed by the MS pathway, N is 3.6 kcalmolꢀ1 less stable
and also not in a position to un-
cyclization, namely 3 and 5, will be destabilized by possible
steric repulsions as shown in Scheme 2. Moreover, phenyl-
substituted eneyne allenes are known[12] to undergo SCM
cyclization because of the extra stability of the benzylidene
radical 4 (Scheme 2). However, when the phenyl-substituted
dergo the self-quenching pro-
cess that is essential to lead to
the finally stable GB product.
The conformation O, through
which self-quenching can occur,
is extremely distorted and
could not be obtained as sta-
tionary point computationally.
However, alternate MS or SCM
cyclization pathways were cal-
culated to be feasible (see
below).
With this idea in mind, we
proceeded with the synthesis of
the target sulfones 7 and 8. The
key steps involved are the CuI-
catalyzed modified Glaser cou-
pling[13] of the terminal alkynes
10 and 15 followed by intramo-
Scheme 2. The proposed steric crowding for the GBC intermediates and reactivity of sulfone 1. Reaction con-
dition a) dry Et3N, 45 min.
lecular cyclic sulfide formation.
Oxidation with meta-chloroper-
oxybenzoic acid (m-CPBA) fi-
bispropargyl sulfone 1 (for its synthesis, see the Supporting
Information) was treated with a base, the only product iso-
nally led to the starting sulfones 7 and 8 (Schemes 4 and 5).
The experiment was first carried out with the aromatic sul-
fone 7. Thus the compound dissolved in CHCl3 was treated
with triethylamine (TEA, 1 equiv) and 1,4-cyclohexadiene
lated, in
a very high yield, was the GB product 6
(Scheme 2). Thus, neither the expected steric crowding as in
3 and 5 nor the extra stability
of biradical
4 changed the
course of the reaction. Compu-
tational studies, described later,
at the B3LYP/6-31G* level indi-
cated the preference of GB
product, as has also been ob-
served earlier.[11] Like the previ-
ously reported sulfones, the
higher thermodynamic stability
of the initially formed GB bir- Scheme 3. The possible intermediates for GBC from a conformationally constrained sulfone.
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Bispropargyl Sulfones
80–110 ppm. The spectral data
also completely matched with
what has been reported in the
literature.[16] The formation of
21 can be explained through
formation of monoallene fol-
lowed by MS cyclization and
quenching by H from 1,4-CHD
and repetition of the same se-
quence. The alternative possi-
bility of involvement of a bisal-
lene can be ruled out because
that would involve a tetraradi-
cal.[17] The minor product could
have originated through the
attack of the benzene radical
formed in the MSC to a ben-
zene molecule. Semmelhack
et al.[18] had previously reported
the formation of a product that
arose out of similar trapping
with a phenyl radical.
Scheme 4. Synthesis and reactivity of sulfone 7. Reaction conditions: a) KF, dry MeOH, 4 h (95 %); b) DBU,
CuBr, O2, dry pyridine, 4 h (78 %); c) PPTS, EtOH, 558C, 5 h; MsCl, Et3N, 0 8C, 10 min; LiBr, dry THF, 6 h
(91 %); d) Na2S, TBAB, THF/H2O, 0 8C, 30 min (82 %); e) mCPBA, dry DCM, rt, 1h (89 %); f) 1,4-CHD,
Et3N, 24 h (32 %). DBU=1,8-diazabicycloACTHNUTRGNEUNG[5.4.0]undec-7-ene.
Now that we were able to
switch the preference from GB
to SCM or MS, these sulfones
were expected to show better
DNA-cleavage activity than
that for earlier reported[11] simi-
lar compounds that undergo
GB cyclization. Thus the sul-
fones 7 and 8 were incubated
with pBR322 DNA at pH 8.5.
Aliquots were taken at 12, 24,
and 48 hours and subjected to
agarose gel electrophoresis. The
results demonstrated that both
sulfones have cleavage activity
Scheme 5. Synthesis and reactivity of sulfone 8. Reaction conditions: a) KF, dry MeOH, 4 h (91 %); b) DBU,
CuBr, O2, dry pyridine, 4 h (71 %); c) PPTS, EtOH, 558C, 5 h (92 %); d) MsCl, Et3N, 0 8C, 10 min; LiBr, dry
THF, 6 h (81 %); e) Na2S, TBAB, THF/H2O, 0 8C, 30 min (72 %); f) mCPBA, dry DCM, rt, 1 h (90 %);
g) 1,4-CHD, Et3N, dry benzene, 24 h
(1,4-CHD, 10 equiv).[14] Within 1 hour, the substrate com-
pletely disappeared and from the reaction mixture only a
single product could be isolated, the structure of which was
found to be 20 by NMR spectroscopy and mass spectromet-
ric data. The structure was further confirmed by single-crys-
tal X-ray analysis (ORTEP diagram shown in Figure 1).[15]
As expected, no GB product could be isolated from the re-
action mixture. The formation of 20 can only be explained
by the initial isomerization to the monoallene followed by
Schmittel cyclization (Scheme 4). The low yield of 20 (only
32%) was due to extensive polymerization of the intermedi-
ate biradicals.
The aliphatic sulfone 8, on the other hand, upon similar
base treatment produced two products (one major 21 along
with the minor product 22) identified by NMR spectroscopy
and mass spectral data. In the major product 21, the
1H NMR spectrum shows only one singlet for the two meth-
ylenes, thus indicating the symmetrical nature of the struc-
ture. In addition, the 13C NMR spectrum showed a complete
absence of the acetylenic carbon atoms in the range of d=
(Figure 2). Although the cleavage efficiency of the aromatic
sulfone 7 did not improve much, the aliphatic sulfone 8
showed much stronger DNA-cleaving activity (72% at
20 mm relative to 10% at 1 mm for acyclic sulfones as al-
ready reported[11]).
To lend further support to the fact that conformational
constraints play a major role in the above switch from GB
to MSC or SCM, we prepared a series of sulfones 30a–d
with increasing degrees of constraints from n=4 to n=1.
This was done by varying the length of the spacer between
the acetylenic carbon atoms to alter the steric constraint.
When these sulfones were separately treated with Et3N in
CDCl3, compounds 30a–c with spacers of n=4, 3, and 2
gave exclusively GB products, whereas for compound 30d
with spacer n=1, we could not isolate any well-defined
1
product (Scheme 6). However, the H NMR spectrum of the
crude reaction mixture ruled out the formation of any GB
product. The results showed that once the steric strain was
removed as in compounds 30a–c, the preference to undergo
GBC was brought back. For compound 30d, because of the
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Figure 2. DNA-cleavage studies with the sulfones at 378C: a) lane 1:
DNA (7 mL) in tris(hydroxymethyl)aminomethane (Tris)-acetate buffer
containing ethylenediaminetetraacetic acid (EDTA; TAE buffer, pH 8.5,
5 mL) and DMSO (5 mL); lanes 3–5: DNA (7 mL) in TAE buffer (5 mL) +
sulfone 7 in DMSO (20 mm) after incubation for 12, 24, and 48 h, respec-
tively. Cleavage as determined by densitometric analysis: lane 1: 4%,
lane 3: 31%, lane 4: 32%, lane 5: 35%. b) lane 1: DNA (7 mL) in TAE
buffer (5 mL) + DMSO (5 mL); lanes 3–5: DNA (7 mL) in TAE buffer
(5 mL) + sulfone 8 in DMSO (20 mm) after incubation for 12, 24, and
48 h, respectively. Cleavage as determined by densitometric analysis:
lane 1: 3%, lane 3: 58%, lane 4: 67%, lane 5: 72%. The upper band in
both gels corresponds to supercoiled DNA, while the lower band corre-
sponds to nicked DNA. Lanes 2, blank.
short spacer length, the steric strain for attaining the confor-
mation for BC prevented the molecules from undergoing
such a process. Computational exercises (discussed later)
also supported such results. The structures of the GB prod-
ucts were characterized by NMR spectroscopy and mass
spectroscopy, and from the X-ray crystal structure of one of
the products (Figure 1).
Figure 1. X-ray structures of a) 20 and b) 32a.
Scheme 6. Synthesis and reactivity of sulfones 30a–d. Reaction conditions: a) K2CO3, DMF (>90 %); b) PPTS, EtOH, 508C (>85 %); c) MsCl, Et3N,
DCM, 08C (>95 %); d) LiBr, THF (>90 %); e) Na2S, THF/H2O (>75 %), TBAB, 08C!rt (>90 %); f) mCPBA, DCM, 08C!R.T. (72 %); g) Et3N,
CDCl3 (>90 %); h) Et3N, 1,4-CHD, CDCl3 (>90 %).
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Bispropargyl Sulfones
more feasible. To understand the solvent effects on the reac-
tion rates and selectivities, we have carried out the calcula-
tions in CHCl3. We have found that the increase in the free-
energy difference (DDG°) between the two transition states
(TS1-MS and TS1-SCM) from 1.5 kcalmolꢀ1 in the gas
phase to 2.0 kcalmolꢀ1 in CHCl3 makes the formation of the
MS1 biradical more favorable. We have not observed any
other significant changes in the relative free energies of the
different species involved in the reactions in CHCl3 from
their gas-phase values (Figure 3). After the formation of the
biradical, it abstracts hydrogen from 1,4-CHD, which is pres-
ent in the reaction medium. The activation energy for the
first hydrogen-abstraction step for the MS pathway is
4.6 kcalmolꢀ1, whereas that of the SCM pathway is 8.0 kcal
molꢀ1 (Schemes S3 and S4 in the Supporting Information).
This implies that, after the formation of biradical MS1, it is
readily converted to the single cyclization product MS2. We
have found a very high thermodynamic stability of the hy-
Computational Study
The strategy based on conformational constraints to switch
the preference from GB cyclization to the MS or SCM
mode was computationally analyzed.[19–23] As we mentioned
earlier, the non-occurrence of GB cyclization for one of the
conformationally constrained molecule 7 is due to the insta-
bility of the initial biradical M compared to that of MS or
SCM biradical (MS-DR and SCM-DR), and more impor-
tantly, because of its inability to undergo self-quenching pro-
cess due to the geometrical constraints. After successfully
explaining the non-occurrence of the GB reaction for the
geometrically constrained sulfone 7, we searched for an ex-
planation for the double occurrence of the MS pathway for
aliphatic sulfone 8 as opposed to the occurrence of an SCM
pathway for the corresponding aromatic sulfone 7. The reac-
tion profile for the aliphatic sulfone 8 was studied in detail
at the M06-2X/6-31+G* level of theory[20,22] by using the
Gaussian 09 package[19] (Figure 3). We took bisallenic sul-
fone (SM1) as a starting material, which can be obtained by
the isomerization of sulfone 8 under basic conditions. This
bisallenic sulfone can undergo either MS cyclization or SCM
cyclization or both. There is a slight difference in energy be-
tween the initial biradicals (MS1 and SCM1) for the two re-
actions (DGMS1ꢀSCM1 =ꢀ0.7 kcalmolꢀ1). The activation
energy required for the formation of the MS1 biradical is
26.1 kcalmolꢀ1, whereas that for the formation of SCM1 is
27.6 kcalmolꢀ1. Hence the biradical MS1 is thermodynami-
cally slightly more stable and its formation is also kinetically
drogen-quenched species MS2 over SCM2 (DGMS2ꢀSCM2
=
ꢀ28.4 kcalmolꢀ1), and this can be attributed to the aromatic
stabilization gained by the formation of a phenyl ring in the
case of MS2. So for the aliphatic sulfone, MS cyclization is
preferred due to the lower kinetic barrier for the formation
of the initial biradical and its facile conversion to the prod-
uct with lower hydrogen abstraction barrier than those of
the SCM pathway.
We also chose a bisallenic sulfone as the starting material
for aromatic sulfone 7. For 7, the preference for SCM cycli-
zation over MS cyclization happens on account of the higher
kinetic and thermodynamic sta-
bility of the Schmittel biradical
(SCM-DR) over the Myer–
Saito
biradical
(MS-DR,
Figure 4). The biradical SCM-
DR is 1.8 kcalmolꢀ1 more
stable than the diradical MS-
DR. The activation energy bar-
rier for the biradical generation
process is less (35.8 kcalmolꢀ1)
for the Schmittel reaction than
that of the MS reaction
(37.7 kcalmolꢀ1). Hence the bir-
adical SCM-DR is thermody-
namically and kinetically more
stable than the MS-DR biradi-
cal, which in turn causes the
preference for SCM over MS.
Then
the
biradicals
are
quenched by abstracting hydro-
gen from 1,4-CHD, and finally
they isomerize to the final
products. Unlike the aliphatic
sulfone for which we have ob-
served double cyclization, the
aromatic sulfone shows only
single cyclization. This may be
due to the fact that the SCM
Figure 3. Comparison between Myer–Saito (MS) and Schmittel (SCM) reaction pathways for aliphatic systems.
The relative free energies (DG298K) in the gas phase were calculated at the M06-2X/6-31+G* level of theory
(values within square brackets were calculated in CHCl3) for different species involved in the reaction path-
way.
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Conclusion
In conclusion, we have been
successful in executing a strat-
egy to interchange the prefer-
ence of cyclization of suitably
substituted bispropargyl sul-
fones between the diradical
self-quenching GB mode and
the externally quenched MS or
SCM pathway by incorporation
of a steric constraint of varying
degree. The experimental re-
sults also fit nicely with the the-
oretical calculations. The find-
ings should provide a new twist
in the design of radical mediat-
ed DNA-cleaving agents and
also in synthesis.
Experimental Section
Figure 4. Comparison between Myer–Saito (MS) and Schmittel (SCM) reaction pathways for aromatic systems.
The relative free energies (DG298K) in the gas phase were calculated at the M06-2X/6-31+G* level of theory
(values within square brackets were calculated in CHCl3) for different species involved in the reaction path-
way.
Computational Details
All the computations were performed
with the Gaussian 09 software pack-
age.[19] Optimization of all ground-
state geometries except phenyl-substi-
tuted systems were done using the M06-2X functional,[20] which accounts
for the dispersive interaction. Like the previously reported work,[11] the
B3LYP functional[21,22] was used for the phenyl-substituted system. The 6-
31+G* basis set was used for all the calculations. The stability of the
wave function was checked for all the species. A restricted approach was
used in the computational analysis for the closed-shell structures, whereas
an unrestricted broken-spin symmetry approach (BS-UM06-2X) was
used for the open-shell singlet-state transition states and intermediates.
The broken-spin symmetry solutions were achieved by feeding the SCF
computation with a 50:50 mix (singlet/triplet) initial guess of the HOMO
and LUMO orbitals.[23a] This approach worked acceptably well for the
biradical intermediates and the transition states of GB reaction. But for
the MS biradicals this approach is problematic, because the HOMO and
LUMO for these biradicals do not correspond to the orbitals required for
proper mixing. In these cases we used PO-DFT, suggested by Cremer
and co-workers,[24] to calculate the open-shell singlet state. The nature of
stationary points was characterized by vibrational frequency calculation.
biradical produced after the first cyclization cannot be stabi-
lized through extended conjugation, which is lost after the
first cyclization.
We have also calculated the activation energies and the
reaction free energies for Garratt–Braverman and Myer–
Saito reactions for different spacer lengths (n=3, 2, 1). To
reduce the computational cost, we have replaced the nosyl
(Ns) group with hydrogen in all these species. For all the
cases, the initial conformations for the GB pathway are
found to be more stable than that for the MS pathway
(Table 1). The free-energy differences (DGGBꢀMS) between
the initial conformations for GB and MS reactions are ꢀ6.4,
ꢀ5.0, and ꢀ3.0 kcalmolꢀ1 for n=3, 2, and 1, respectively.
From Table 1 it is evident that as the spacer length increases,
the GB cyclization becomes more and more favorable
(along with an increase in the reaction rate) to the MS cycli-
zation. These results are highly consistent with the experi-
mentally observed data.
Characterization
All 1H and 13C NMR spectra were respectively recorded at 400 and
100 MHz in CDCl3 unless mentioned otherwise. The X-ray crystal data
was recorded with a Bruker AXS Smart Apex-II. ESI-MS and HRMS
were taken with a Waters LCT mass spectrometer; the solutions of the
compounds were injected directly into the spectrometer by means of a
Rheodyne injector equipped with 10 mL loop. A Phoenix 20 micro LC sy-
ringe pump delivered the solution to the vaporization nozzle of the elec-
trospray ion source at a flow rate of 3 mLminꢀ1. Nitrogen was used both
as a drying gas and for nebulization with flow rates of approximately
3 Lminꢀ1 and 100 mLminꢀ1, respectively. Pressure in the analyzer region
was usually about 3ꢁ10ꢀ5 torr.
Table 1. Computed activation and reaction free energies [kcalmolꢀ1] for
Garratt–Braverman and Myer–Saito reactions at the M06-2X/6-31+G*
level of theory for different spacer lengths (Scheme 5).
[a]
Spacer length DGGBꢀMS
Garratt–Braverman
cyclization
Myer–Saito cycliza-
tion
D°G298K
DG298K
D°G298K
DG298K
General Procedure for the Glaser Coupling
n=3
n=2
n=1
ꢀ6.4
ꢀ5.0
ꢀ3.0
25.8
22.8
22.2
ꢀ3.9
ꢀ4.8
ꢀ4.5
32.2
24.3
24.6
8.9
ꢀ0.5
The terminal alkyne (2 mmol) was dissolved in dry pyridine (15 mL) and
1,8-diazabicycloACTHNUTRGNEU[GN 5.4.0]undec-7-ene (DBU) and CuBr (5 mol% of each)
ꢀ0.6
[a] Free-energy difference between the initial conformations for GB and
MS reactions.
were added to it. Then oxygen gas was slowly and continuously bubbled
through the reaction for 4 h. The reaction mixture was then poured into
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ice-cold 3n HCl (25 mL) and was extracted with CH2Cl2 (3ꢁ25 mL). The
combined organic layers were dried over anhydrous sodium sulfate and
CH2Cl2 was evaporated under vacuum. The coupling product was puri-
fied by column filtration with ethyl acetate/petroleum ether as eluent.
Aromatic Sulfide 13
Brown sticky mass; yield: 79%; 1H NMR (200 MHz): d=7.50–7.43 (m,
4H), 7.33–7.29 (m, 4H), 3.78 ppm (s, 4H); 13C NMR (50 MHz): d=131.2,
130.2, 128.9, 128.8, 128.0, 125.7, 90.5, 83.4, 81.5, 79.1, 19.7 ppm; MS: m/z:
309 [M+H+]; HRMS: m/z calcd for C22H12S+H+: 309.0735; found:
309.0741.
General Procedure for THP Deprotection
The THP-protected alkynyl compound (1 mmol) and a catalytic amount
of pyridinium p-toluenesulfonate (PPTS; 5 mol%) was stirred in ethanol
(10 mL) at 558C for 6 h. Ethanol was removed, and the crude mixture
was directly subjected to column chromatography for purification.
Aromatic Sulfone 7
1
Yellow solid; yield: 89%; H NMR: d=7.59 (app d, J=8.8 Hz, 2H), 7.49
(app d, J=8.8 Hz, 2H), 7.40–7.37 (m, 4H), 4.40 ppm (s, 4H); 13C NMR:
d=132.0, 130.1, 129.0, 128.7, 127.2, 125.7, 85.4, 83.4, 81.2, 79.2, 44.0 ppm;
MS: m/z: 341 [M+H+]; HRMS: m/z calcd for C22H12O2S+H+: 341.063;
found: 341.0639.
General Procedure for Mesylation and Bromide Formation Reaction
The alcohol (0.4 mmol) was treated with triethylamine (2 equiv) and
mesyl chloride (2 equiv) in dry dichloromethane (5 mL) at 08C under an
argon atmosphere until TLC showed the disappearance of the starting
material. The reaction was quenched by the addition of brine and ex-
tracted with CH2Cl2 (20 mL). The organic layer was dried with anhydrous
sodium sulfate. The solvent was evaporated, and the product, mesylate,
was vacuum-dried. LiBr (2 equiv) was added to the crude mesylate
(0.3 mmol) in dry THF (5 mL) and stirred for 2 h after the completion of
the reaction. Removal of solvent followed by silica gel column filtration
with ethyl acetate/hexane afforded the pure bromide.
Indenyl Sulfone 20
White solid; yield: 32%; 1H NMR (CD3COCD3): d=7.79 (d, J=7.2 Hz,
1H), 7.64–7.62 (m, 1H), 7.54–7.47 (m, 3H), 7.37 (d, J=6.8 Hz, 1H), 7.30
(t, J=7.2 Hz, 1H), 7.26–7.21 (m, 2H), 7.15 (s, 1H), 5.33 (s, 2H),
4.46 ppm (s, 2H); 13C NMR: d=140.1, 139.8, 137.0, 132.5, 130.6, 129.0,
128.9, 128.8, 126.6, 126.3, 124.1, 123.3, 121.6, 107.3, 101.1, 91.0, 87.7, 82.1,
48.6, 46.5 ppm; MS: m/z: 343 [M+H+]; HRMS: m/z calcd for
C22H14O2S+H+: 343.0789; found: 343.0782.
General Procedure for the Synthesis of SulfideMethod A for the Cyclic
Sulfide
AHCTUNGTERG(NNUN 4Z,10Z)-1,14-Bis(tetrahydro-2H-pyran-2-yloxy)tetradeca-4,10-dien-
2,6,8,12-tetrayne (16)
The cyclic sulfide was synthesized according to a high-dilution technique.
The bromide (0.1 mmol) was dissolved in THF (34 mL) and stirred at
08C. Sodium sulfide (0.5 equiv) was added, followed by catalytic amount
of tetrabutylammonium bromide (TBAB, 2 mol%) and water (0.5 mL).
The reaction mixture was stirred at room temperature until TLC showed
disappearance of the bromide. The reaction mixture was then partitioned
between EtOAc and water. The organic layer was dried over anhydrous
sodium sulfate. The solvent was evaporated under vacuum and the prod-
uct was purified by silica gel column chromatography with hexane/ethyl
acetate as eluent.
White gummy liquid; yield: 91%; 1H NMR (200 MHz): d=6.00 (app d,
J=12.4 Hz, 2H), 5.90 ( d, J=10.8 Hz, 2H), 4.89 (app d, J=3.4 Hz, 2H),
4.48 (d, J=1.6 Hz, 2H), 3.92–3.80 (m, 2H), 3.60–3.50 (m, 2H), 1.83–
1.54 ppm (m, 12H); 13C NMR (50 MHz): d=122.6, 118.2, 96.8, 94.9, 83.1,
81.1, 80.7, 62.2, 54.6, 30.3, 25.4, 19.1 ppm; MS: m/z: 379 [M+H+];
HRMS: m/z calcd for C24H26O4+H+: 379.1902; found: 379.1908
AHCTUNGERTG(NNUN 4Z,10Z)-Tetradeca-4,10-dien-2,6,8,12-tetrayne-1,14-diol (17)
White sticky mass; yield: 91%; 1H NMR (200 MHz): d=5.99 (app d, J=
12.2 Hz, 2H), 5.89 (d, J=10.8 Hz, 2H), 4.46 (s, 4H), 2.81 ppm (brs, 2H);
13C NMR (50 MHz): d=123.0, 118.5, 97.2, 82.9, 81.4, 80.9, 51.5 ppm; MS:
m/z: 211 [M+H+]; HRMS: m/z calcd for C14H10O2+H+: 211.0756;
found: 211.0751
Method B for the Open-Chain Sulfide
The bromide (0.1 mmol) was dissolved in dry methanol (5 mL) and
stirred at 08C. Sodium sulfide (0.5 equiv) was added. The reaction mix-
ture was allowed to stir at room temperature until TLC showed disap-
pearance of the bromide. Methanol was evaporated off. The crude was
subjected to silica gel column chromatography for isolation.
AHCTUNGERTG(NNUN 4Z,10Z)-1,14-Dibromotetradeca-4,10-dien-2,6,8,12-tetrayne (18)
Yellow liquid; yield: 90%; 1H NMR (200 MHz): d=6.00 (s, 4H),
4.15 ppm (s, 4H); 13C NMR (50 MHz): d=122.3, 119.7, 93.6, 83.7, 81.4,
15.0 ppm.
General Procedure for Oxidation of Sulfide to Sulfone
m-CPBA (2 equiv) was added to an ice-cold solution of the sulfide
(0.1 mmol) in dry CH2Cl2 (5 mL) and stirred overnight under an argon
atmosphere. The organic layer was diluted with CH2Cl2 (15 mL) and
washed with aqueous saturated solutions (15 mL) of sodium bicarbonate,
sodium sulfite, and sodium carbonate to make the solution free from m-
CPBA and m-chlorobenzoic acid. The combined organic layer was dried
over anhydrous sodium sulfate, which was then removed by filtration.
The solvent was removed and the crude mass was purified by column fil-
tration.
Aliphatic Sulfide 19
Brown liquid; yield: 88%; 1H NMR: d=6.16 (app d, J=4.4 Hz, 1H),
6.14 (app d, J=4.4 Hz, 1H), 5.98 (d, J=10 Hz, 2H), 3.65 ppm (d, J=
2 Hz, 4H); 13C NMR (50 MHz): d=126.2, 120.5, 95.8, 85.1, 82.7, 81.3,
20.1 ppm; MS: m/z: 209 [M+H+]; HRMS: m/z calcd for C14H8S+H+:
209.0423; found: 209.0429.
Aliphatic Sulfone 8
Brown sticky liquid; yield: 74%; 1H NMR: d=6.28 (d, J=10 Hz, 2H),
6.16 (d, J=10 Hz, 2H), 4.22 ppm (d, J=2 Hz, 4H); 13C NMR: d=125.4,
122.6, 86.1 85.7, 85.0, 83.4, 44.7 ppm; MS: m/z: 241 [M+H+]; HRMS: m/
z calcd for C14H8O2S+H+: 241.0321; found: 241.0331.
General Procedure for Base-Catalyzed Cyclization
The respective sulfone (0.05 mmol) was treated with dry triethylamine
(1 equiv) and an excess amount of 1,4-CHD (10 equiv) in CDCl3
(0.5 mL) (for the aromatic sulfones) and in dry benzene (0.5 mL) (for the
aliphatic sulfone) for 24 h (unless mentioned). After the completion of
the reaction (either monitored by NMR spectroscopy or TLC), the crude
product was subjected to flash column chromatography. The product was
further purified by HPLC.
Dibenz-1,1-dioxothiapane 21
White liquid; yield: 28%; 1H NMR: d=7.51–7.49 (m, 8H), 4.02 ppm (s,
4H); 13C NMR: d=140.0, 130.9, 129.6, 129.5, 129.1, 128.2, 57.4 ppm; MS:
m/z: 245 [M+H+]; HRMS: m/z calcd for C14H12O2S+H+: 245.0633;
found: 245.0641.
1,4-Bis[2-(3-bromoprop-1-ynyl)phenyl]buta-1,3-diyne (12)
Yellow oil; yield: 91%; 1H NMR (200 MHz): d=7.53–7.49 (m, 2H),
7.45–7.40 (m, 2H), 7.32–7.27 (m, 4H, m), 4.22 ppm (s, 4H); 13C NMR
(50 MHz): d=133.0, 132.3, 129.0, 128.6, 125.6, 124.6, 88.8, 84.7, 81.0,
15.2 ppm.
Phenyl Dibenz-1,1-dioxothiapane 22
White liquid; yield: 4%; 1H NMR (CD3COCD3): d=7.60–7.55 (m, 4H),
7.35–7.31 (m, 1H), 7.20 (brs, 3H), 7.09 (brs, 3H), 6.81 (d, J=7.2 Hz,
Chem. Asian J. 2012, 7, 957 – 965
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www.chemasianj.org
963

Amit Basak, Eluvathingal D. Jemmis et al.
FULL PAPERS
1H), 4.31, 4.28 (AB q, J=14 Hz, 2ꢁ1H), 4.18 (d, J=14.4 Hz, 1H),
3.83 ppm (d, J=13.6 Hz, 1H); MS: m/z: 321 [M+H+]; HRMS: m/z calcd
for C20H16O2S+H+: 321.0945; found: 321.0941.
m/z: 597 [M+H+]; HRMS: m/z calcd for C32H25N2O6S2+H+: 597.1154;
found: 597.1153.
Acyclic Sulfone 1
White sticky mass; yield: 94%; 1H NMR: d=7.59–7.57 (m, 4H), 7.54 (d,
J=7.6 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H), 7.36–7.33 (m, 4H), 7.29–7.26 (m,
6H), 4.37 ppm (s, 4H); 13C NMR: d=132.5, 132.1, 131.8, 128.9, 128.6,
128.3, 128.0, 126.1, 123.7, 122.6, 93.6, 87.5, 86.4, 80.0, 44.0 ppm; MS: m/z:
495 [M+H+]; HRMS: m/z calcd for C34H22O2S+H+: 495.1413; found:
495.1411
Acknowledgements
D.M. and E.D.J. thank SERC, IISc, and CMSD, University of Hyderabad
for computational resources. DST is acknowledged for the J.C. Bose Fel-
lowship grant to E.D.J and for an SERC grant to A.B. that supported this
research. R.M. and S.M. are grateful to CSIR, Government of India, for
a research fellowship. The NMR spectroscopy and X-ray facility were
provided at IIT, Kharagpur by DST under the IRPHA and FIST pro-
grammes, respectively. We would also like to thank Mr. L. K. Rajput and
Mr. M. K. Sarkar for their help in solving the X-ray structure and to Ms.
S. Datta for the densitometric studies.
Sulfolene 6
Yellow liquid; yield: 96%; 1H NMR: d=8.48 (s, 1H), 7.80 (d, J=6.8 Hz,
1H), 7.74–7.72 (m, 1H), 7.67–7.65 (m, 2H), 7.51–7.48 (m, 4H), 7.42–7.36
(m, 5H), 7.31 (dd, J=3.6, 1.6 Hz, 1H), 7.20–7.13 (m, 3H), 4.65 (s, 2H),
4.44, 4.16 ppm (AB q, J=16.4 Hz, 2H); 13C NMR: d=139.4, 136.9, 132.9,
132.6, 131.8, 131.6, 131.2, 131.1, 129.9, 129.3, 129.2, 128.7, 128.6, 128.5,
128.4, 128.3, 128.1, 126.9, 126.3, 123.4, 123.2, 122.8, 122.3, 121.0, 94.8,
93.2, 87.1, 86.9, 57.2, 56.1 ppm; MS: m/z: 495 [M+H+]; HRMS: m/z
calcd for C34H22O2S+H+: 495.1413; found: 495.1419.
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Garratt–Braverman (GB) Product 32a
Colorless solid; yield: 73%; 1H NMR: d=8.31 (s, 1H), 8.06 (d, J=
8.4 Hz, 2H), 7.66 (d, J=8.4 Hz, 2H), 7.56–7.50 (m, 2H), 7.46 (d, J=
7.2 Hz, 1H), 7.43–7.37 (m, 1H), 7.26–7.22 (m, 4H), 7.00 (d, J=8.4 Hz,
1H), 4.58, 4.52 (AB q, J=16.0 Hz, 2H), 4.25, 3.75 (AB q, J=16.4 Hz,
2H), 3.70, 3.63 (AB q, J=18.4 Hz, 2H), 2.69–2.33 (m, 4H), 2.04–1.96 (m,
2H), 1.78–1.68 ppm (m, 2H); 13C NMR: d=149.5, 144.7, 140.5, 136.3,
133.9, 132.8, 132.0, 129.3, 129.2, 128.9, 128.7, 127.8, 127.4, 126.4, 125.3,
123.6, 123.5, 122.7, 122.2, 104.1, 86.1, 82.8, 81.6, 57.2, 55.6, 49.4, 38.5, 30.2,
27.1, 20.3 ppm; MS: m/z: 611 [M+H+]; HRMS: m/z calcd for
C33H27N2O6S2+H+: 611.1311; found: 611.1306.
GB Product 31a
Colorless gummy mass; yield: 25%; 1H NMR: d=8.41 (d, J=8.8 Hz,
2H), 8.33 (s, 1H), 8.00 (d, J=8.8 Hz, 2H), 7.61–7.55 (m, 3H), 7.51–7.49
(m, 1H), 7.47–7.41 (m, 2H), 7.37–7.32 (m, 2H), 4.69, 4.60 (AB q, J=
16.0 Hz, 2H), 4.32, 3.99 (AB q, J=16.4 Hz, 2H), 3.30, 3.16 (AB q, J=
16.8 Hz, 2H), 3.10–3.03 (m, 1H), 3.00–2.94 (m, 1H), 1.85–1.80 (m, 1H),
1.50–1.39 (m, 3H), 0.79–0.75 (m, 1H), 0.26–0.22 ppm (m, 1H); 13C NMR:
d=150.3, 143.9, 140.7, 138.0, 134.1, 133.3, 131.7, 130.3, 130.0, 129.0, 128.8,
128.6, 128.2, 127.7, 126.3, 125.3, 124.7, 123.0, 120.2, 95.5, 92.9, 86.9, 78.3,
57.5, 56.1, 49.8, 41.9, 31.4, 26.4, 19.1 ppm; MS: m/z: 611 [M+H+];
HRMS: m/z calcd for C33H27N2O6S2+H+: 611.1311; found: 611.1319.
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GB Product 32b
Colorless viscous liquid; yield: 57%; 1H NMR: d=8.19 (s, 1H), 8.16 (d,
J=8.8 Hz, 2H), 7.78 (d, J=8.8 Hz, 2H), 7.58–7.52 (m, 2H), 7.44–7.37 (m,
2H), 7.28–7.20 (m, 3H), 7.10 (d, J=8.4 Hz, 1H), 4.54, 4.50 (AB q, J=
15.6 Hz, 2H), 4.30, 3.97 (AB q, J=16.4 Hz, 2H), 3.81, 3.53 (AB q, J=
18.4 Hz, 2H), 2.83–2.75 (m, 1H), 2.59–2.43 (m, 3H), 2.06–1.99 (m, 1H),
1.71–1.66 ppm (m, 1H); 13C NMR: d=149.9, 144.9, 140.6, 136.0, 134.3,
133.5, 132.3, 129.4, 129.2, 128.6, 128.5, 127.6, 126.7, 126.5, 125.6, 123.8,
123.3, 123.1, 122.6. 107.3, 87.2, 85.8, 81.5, 57.2, 55.5, 46.7, 37.4, 30.1,
17.8 ppm; MS: m/z: 597 [M+H+]; HRMS: m/z calcd for
C32H25N2O6S2+H+: 597.1154; found: 597.1143
GB Product 31b
Colorless liquid; yield: 38%; 1H NMR: d=8.36 (d, J=8.4 Hz, 2H), 8.32
(s, 1H), 8.16 (d, J=7.6 Hz, 2H), 7.61 (d, J=8.4 Hz, 1H), 7.50 (d, J=
6.8 Hz, 1H), 7.45–7.30 (m, 4H), 7.30–7.25 (m, 3H), 4.76, 4.67 (AB q, J=
16.0 Hz, 2H), 4.44, 4.27 (AB q, J=17.6 Hz, 2H), 4.28, 4.16 (AB q, J=
16.0 Hz, 2H), 3.07–2.99 (m, 1H), 1.54–1.04 (m, 1H), 0.96–0.86 ppm (m,
1H); 13C NMR: d=150.1, 145.1, 141.0, 137.7, 134.2, 133.8, 131.6, 130.3,
129.1, 128.6, 128.5, 128.3, 128.1, 127.2, 126.8, 126.2, 125.1, 124.5, 123.6,
121.2, 97.6, 93.7, 88.9, 78.1, 57.2, 55.8, 53.4, 49.8, 41.3, 29.9, 16.8 ppm; MS:
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964
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Bispropargyl Sulfones
[14] The absence of 1,4-CHD led to the decomposition of starting mate-
rial. However, no GB product could be isolated.
[15] CCDC 776535 and CCDC 826450 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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[17] The formation of product 21 could also be explained by stepwise
double Bergman cyclization (BC). However, because of the large
ring size (15-membered before cyclization and 11-membered after
first BC) and also the requirement of basic conditions to carry out
the cyclization, such a process can be ruled out.
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[19] a) All computations were performed using the Gaussian 09 package.
The nature of the stationary points was characterized by vibrational
frequency calculations; b) Gaussian 09, Revision A.02, M. J. Frisch
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Received: November 3, 2011
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Published online: March 7, 2012
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