The directing group wins over acidity: kinetically controlled regioselective lithiation for functionalization of 2-(2,4-dihalophenyl)-1,3-dithiane derivatives

Article abstract of DOI:10.1039/c5ob02172c

Regioselective lithiation followed by functionalization of 2-(2,4-dihalophenyl)-1,3-dithiane derivatives with different electrophiles was achieved in good to excellent yields. When the title compound is treated with n-butyl lithium, lithiation occurs selectively at the aromatic carbon having less acidic proton despite the presence of thermodynamically more acidic 1,3-dithiane proton in the same molecule. Computationally calculated pK_a values of the available reactive site protons and the experimental results suggest that the regioselective lithiation in 2-(2,4-dihalophenyl)-1,3-dithiane derivatives is not governed by thermodynamic acidity rather exclusively dictated by the kinetic removal of protons due to cooperative coordination (complex induced proximity effect, CIPE) and inductive effects of the 1,3-dihalo substituents present in the aromatic ring. By employing this regioselective functionalization, diverse 1,2,3,4-tetra-substituted aromatic compounds were prepared with ease.

Full text of DOI:10.1039/c5ob02172c

Organic &
Biomolecular Chemistry
View Article Online
View Journal
PAPER
The directing group wins over acidity: kinetically
controlled regioselective lithiation for
functionalization of 2-(2,4-dihalophenyl)-1,3-
dithiane derivatives†
Cite this: DOI: 10.1039/c5ob02172c
Shanmugam Sakthivel, Raveendra Babu Kothapalli and Rengarajan Balamurugan*
Regioselective lithiation followed by functionalization of 2-(2,4-dihalophenyl)-1,3-dithiane derivatives
with different electrophiles was achieved in good to excellent yields. When the title compound is treated
with n-butyl lithium, lithiation occurs selectively at the aromatic carbon having less acidic proton despite
the presence of thermodynamically more acidic 1,3-dithiane proton in the same molecule. Computation-
ally calculated pKa values of the available reactive site protons and the experimental results suggest that
the regioselective lithiation in 2-(2,4-dihalophenyl)-1,3-dithiane derivatives is not governed by thermo-
dynamic acidity rather exclusively dictated by the kinetic removal of protons due to cooperative coordi-
nation (complex induced proximity effect, CIPE) and inductive effects of the 1,3-dihalo substituents
present in the aromatic ring. By employing this regioselective functionalization, diverse 1,2,3,4-tetra-sub-
stituted aromatic compounds were prepared with ease.
Received 21st October 2015,
Accepted 11th December 2015
DOI: 10.1039/c5ob02172c
www.rsc.org/obc
metalation groups (DMGs) such as F, Cl, Br, CF3 and CN, the
inductive effect and, in the presence of an electron donating
Introduction
Achieving desired selectivity (regio, chemo and stereo) in group such as OMe, NMe2, the coordination effect influence
organic transformations is an evergreen aspect as the multi- much the deprotonation during ortho-lithiation.5,6 Also it has
step synthesis of complex natural products demands selective been demonstrated that the complexation of a directing group
functionalization. A number of factors contribute indepen- with lithium increases the kinetic acidity of the protons ortho to
dently or cooperatively to achieve the required selectivity and the directing group relative to other available protons.7 Develop-
the factors include steric, electronic, transition state stability, ment of new directing groups led to the discovery of unique syn-
reagent and reaction conditions.1 Controlling the regio- thetic methodologies.8
selectivity in organic transformation is a challenging task.2
Among the halogen directed lithiations,9,10 reactions invol-
Metalation involving directing groups for regioselective C–H ving 1,3-dichloro and 1,3-difluoro benzene derivatives are
functionalization has been drawing much attention these interesting because of the ability of these systems to direct the
days.3 Classically, in directed metalation, a strong base, gener- lithiation at the 2nd position.10 Thornton et al. reported 1,3-
ally an alkyllithium reagent, is treated with the substrate con- difluoro directed regioselective metalation in the presence of a
taining a directing group to form the lithiated species, which strong amide directing group using the “super-basic” butyl
upon treatment with an electrophile will furnish the final lithium/potassium tert-butoxide mixture.7a Knochel and co-
product. Extensive studies have been carried out by different workers reported a directed metalation of polyhaloaromatic
groups and the contributions from the research groups of compounds using TMP2Mg·2LiCl or TMPMgCl·LiCl.11
Beak and Snieckus stand remarkable.4 Directed ortho lithiation Recently, Organ and co-workers reported a regioselective
reactions are mainly driven by three factors such as the nature directed ortho-metalation (DoM) of 1,5-dichloro-2,4-dimethoxy-
of the lithium base, the ability of the directing group and the benzene where the site of metalation depends on the nature of
acidity of the proton present at the reaction site. It was estab- the solvent.12 Bradley and co-workers have reported an interest-
lished that, in the presence of electron-withdrawing directed ing observation where the relative directing abilities of two
different directing groups namely the 1,3-dichloro moiety
against the stronger amide directing group for lithiation were
School of Chemistry, University of Hyderabad, Gachibowli, Hyderabad 500046,
evaluated (Scheme 1).13 They noticed that two moderately coor-
India. E-mail: bala@uohyd.ac.in; Fax: +91-40-2301-2460
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
dinating chloro groups decided the site of metalation over the
strong carboxamide directing group. The regioselectivity was
c5ob02172c
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
Table 1 Regioselective lithiation to synthesize substituted aromatic
compounds
Entrya
1
Dithiane
Electrophile
Productb (Yield %)
Scheme 1 Unusual regioselectivity observed by Bradley and co-
workers.
2
3
4
5
6
Scheme 2 Coordination controlled regioselectivity.
attributed to the electronic or steric effects or a combination of
both. Herein, we report an interesting regioselective lithiation
of 2-(2,4-dihalophenyl)-1,3-dithiane derivatives where coordi-
nation and acidity competes with each other. It was found that
the coordinating effect clearly wins over the acidity in deciding
the regioselectivity (Scheme 2).
7
Results and discussion
8
During our endeavor in developing Brønsted acid mediated
synthesis of α-diaryl acetic esters from benzoins using in situ
formed acetals14 we attempted the synthesis of 11 to make the
corresponding benzoin derivative via deprotonation of
dithiane in 2-(2,4-dichlorophenyl)-1,3-dithiane 1a. Based on
conventional knowledge it was anticipated that n-BuLi would
abstract the acidic dithiane proton in 1a to form the corres-
ponding lithiated intermediate 10 which on reaction with
benzaldehyde would lead to the formation of product 11. To
our surprise, we observed the lithiation to occur at the arene
ring forming the compound 3a in good yield (88%). Notably,
not even a trace amount of the expected product 11 was iso-
lated in this reaction. This interesting observation of regio-
selective lithiation motivated us to investigate such behavior of
this system in detail with different dithiane derivatives and
electrophiles in order to draw a rationale for the unexpected
9
10
a Reaction conditions: 1 (1 equiv.), 2 (1.1 equiv.) and n-BuLi (1.2
equiv.) in dry THF at −78 °C for 3h. b Isolated yields.
Quenching of the lithiated species generated from 1a with
regioselectivity. To our delight, under the present reaction con- ethyl chloroformate resulted in the formation of ester 3h. In
ditions, lithiation of 1a occurred exclusively at the aromatic order to check the reactivity of the corresponding fluoro ana-
ring and furnished 3a–3h upon treatment with electrophiles logue of 1a, we reacted the lithiated 2-(2,4-difluorophenyl)-1,3-
2a–2h (Table 1, entries 1–8). The products were isolated in dithiane 1b with aromatic aldehyde 2i and isolated the alcohol
good to excellent yields (82–99%).
derivative 3i in 89% yield via regioselective lithiation at the
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
aryl carbon (Table 1, entry 9). In another experiment, reaction
of lithiated 1b with DMF 2j resulted in the aldehyde product 3j
in good yield (80%). It is therefore anticipated that the co-
operative coordination effect of the 1,3-dichloro/difluoro sub-
stituents dictate the regioselectivity of the lithiation over the
acidity of the dithiane group. Overall, 1,2,3,4-tetra substituted
phenyl derivatives can be prepared.
Since polysubstituted aromatic compounds are very useful
agrochemicals,15 the obtained dithiane compounds 3a–3d and
3i were transformed into 1,2,3,4-tetra substituted aromatic
aldehydes 4a–4d and 4i. Deprotection of dithiane in these
derivatives was achieved by treating them with the NCS/AgNO3
reagent system.14 Notably, the reactions were very clean and
high yielding (Table 2). The resulting 1,2,3,4-tetra-substituted
compounds containing hydroxy and aldehyde functional
groups could, in principle, be manipulated further.
Fig. 1 Computed pKa values of the available reactive site protons.
were also calculated. For pKa calculations, we adopted the
method established by Guo and co-workers which was also
used by Marder and co-workers for solution phase calculation
of pKa.16 This method reported pKa values using DMSO as the
solvent. But, for better correlation with our experimental con-
ditions, we used THF as the solvent. All the gas phase free
energy calculations were carried out using the standard B3LYP
method and the 6-311++G(2df, 2p) basis set in the Gaussian 09
package.17 Solvation free energy calculations were performed
To understand the underlying reason for the observed
regioselectivity, we performed pKa calculation computationally
and a few control experiments.
Computational studies
pKa values of the dithiane hydrogen Ha and aryl hydrogen Hb
present in 1a, 1b, 1c, and 1d were calculated using the DFT
technique (Fig. 1). In addition, for comparison, pKa values of using the IEF-PCM/Bondi ( f = 1.20) method and the B3LYP/6-
aryl hydrogen in 13, 14 and 15 and dithiane hydrogen in 16
311++G (2df, 2p) level.
The calculated pKa value of dithiane hydrogen in 16 was
found to be 32.8 in THF which is close to the experimental
value (pKa = 30.7 in DMSO).18 In addition to that, the calcu-
lated pKa value of the aryl hydrogen in 14 was found to be 28.0
which is in close agreement with the reported calculated pKa
value (28.7 in DMSO).16a Hence the method used for the calcu-
lation of pKa can be considered reliable for the systems
presented in this manuscript. With electron-withdrawing sub-
stituents (F and Cl) on the aryl ring, the pKa value of the
dithiane “H” reduced considerably (21.85 in 1a and 24.1 in 1b
from 32.8 in 1e). On the other hand, the pKa values of the aryl
“H” in 1a (29.58) and 1b (27.56) do not experience much
change from 13 (29.36) and 14 (28.0) respectively, due to the
attached dithiane. The dithiane substrate 1a contains two
acidic protons; one attached to dithiane carbon Ha and the
other in the aromatic ring Hb. From the experimental results,
it is clear that the lithiation took place at the aromatic ring
carbon by the deprotonation of Hb instead of at the carbon
bearing the dithiane moiety. From the calculation of pKa
values, it was found that the acidity of Ha is more than that of
Hb in both 1a and 1b. This clearly suggests that the observed
regioselectivity is not at all driven by the acidity of the dithiane
hydrogens. Therefore the coordinating ability of the 1,3-dihalo
group is believed to be responsible for the observed
regioselectivity.19
Table 2 Deprotection of dithianes to polysubstituted benzaldehydes
Entrya
1
Dithiane (3a–3d, 3i)
Productb (Yield %)
2
3
4
5
This observation is similar to that of Beak’s finding of kine-
tically controlled regioselectivity due to CIPE.20 In their work
lithiation was observed to take place at the β-position over the
more acidic α-position of carboxamides. In order to get more
insight into the relative acidities of the dithiane and arene
a Reaction conditions: 3 (1 equiv.), NCS (4 equiv.) and AgNO3 (4.5
equiv.) in CH3CN/H2O (10 : 1) at 0 °C, for 15 min. b Isolated yields.
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
protons, thermodynamic deprotonation using NaOCD3/CD3OD
was carried out. Compound 1a upon reflux with 1 equivalent
of NaOCD3 in CD3OD for 5 h resulted in 35% and 11% deuter-
ium incorporation at dithiane and arene sites respectively.
This observation corroborates with the computationally found
pKa values (Scheme 3).
Control experiments
Scheme 5 Reactions of mono chloro-substituted aromatic dithianes.
To get further insight into the proposed coordination effect in
the present lithiation reaction we designed a substrate 1c
having moderate ortho-directing methoxy groups in the place
of Cl/F in 1a/1b. It is generally considered that OMe is a better
directing group than Cl/F. If the lithiation occurs at the aryl
carbon of 1c, the predominant driving force for lithiation
should be the ‘coordination effect’ of –OMe groups as the
inductive effect of –OMe is comparatively less than that of Cl/F.
To evaluate this, lithiation of 1c followed by quenching of the
anion with 4-methyl benzaldehyde was carried out at −78 °C
(Scheme 4). The reaction resulted in 23% of 3k (product of
aryl lithiation), 13% of 16 (product of dithiane lithiation), 40%
of 17 (product of n-butyl addition in 2g) along with 56% of
unreacted 1c. Two major conclusions can be drawn from the
result of this reaction. Firstly, the substrate 1c is less reactive.
Secondly, the coordination effect of the –OMe group is slightly
more effective than the acidity of dithiane hydrogen in
directing the lithiation. The first assumption draws strong
support from the pKa calculation. Both Ha and Hb are less
acidic compared to that of 1a and 1b (Fig. 1). Hence the poor
reactivity of 1c is understandable. The poor yield of the
product of aryl lithiation (3k) compared to that obtained from
1a and 1b suggests that it is not the coordination effect alone
that decides the regioselectivity in 1a and 1b. In the case of 1a
and 1b the electron withdrawing Cl/F, by the –I effect, increase
the acidity of the arene hydrogen, where as in the case of 1c
the mesomeric effect of –OMe reduces the acidity of the arene
hydrogen. This can easily be understood from the pKa values
of the arene and dithiane protons in these substrates (Fig. 1).
Therefore the cooperative coordination effect due to 1,3-
(OMe)2 in 1c is responsible for marginal regioselectivity for
lithiation. In the case of substrate 1a and 1b the combined
effect of cooperative coordination (CIPE) and the increased
acidity of arene hydrogen due to the –I effect of 1,3-(Cl/F)2 is
responsible for the exclusive regioselectivity.
Further, to assess the crucial role of two halogens as
directing groups (cooperative coordination), lithiation was per-
formed on mono chloro derivatives 1d and 1e (Scheme 5). It
was observed that lithiation occurred exclusively at the respective
dithiane carbons as 18 and 19 were obtained upon quenching
with aldehydes 2k and 2c respectively. From the computational
studies, the acidity of the proton present on the dithiane carbon
of the substrate 1d (pKa 23.7) was found to be considerably
greater than that of the proton ortho- to chloro in the aromatic
ring (pKa 36.5) (Fig. 1). It has to be mentioned that the pKa of
the aryl H in 1d (36.5) is close to that of the aryl H in 1c (35.80).
The experimental results and the calculated pKa support the fact
that in substrate 1d the coordination effect/CIPE of one chlorine
atom in the presence of a dithiane moiety is not enough for the
kinetic removal of the aryl proton and hence, in this substrate,
lithiation occurred in accordance with the thermodynamic
acidity i.e. exclusively at the dithiane site.
Since the monochloro derivatives 1d and 1e exhibited lithia-
tion at the dithiane carbon, it gave an opportunity to check the
relative reactivity of 1a and 1d by treating an equimolar
mixture of them with 1 equivalent of n-BuLi at −78 °C. Upon
quenching with 1 equivalent of benzaldehyde, product 3a was
obtained by the lithiation of 1a at the aryl ring (Scheme 6). Not
even a trace of the product due to lithiation at the dithiane of
1d was obtained. It indicates that the cooperative coordination
Scheme 3 Thermodynamic deprotonation study.
Scheme 4 Regioselective lithiation of the substrate with two moderate
ortho-directing groups.
Scheme 6 Relative reactivities of 1a and 1d towards lithiation.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
available in the above compound for lithiation only one site
was selectively lithiated using n-BuLi at −78 °C, and quenching
the lithiated species with electrophiles resulted in 1,2,3,4-tetra
substituted aromatic compounds. The ‘inductive effect’ and
‘cooperative coordination effect’/CIPE of halogens present in
the substrate jointly contribute for the lithiation to occur regio-
selectively at the less acidic arene ring site. Upon deprotection,
these compounds can be converted into poly-substituted benz-
aldehyde derivatives.
Scheme 7 Lithiation reactions using t-BuLi.
Experimental section
General information
Chemicals and solvents were purchased from commercially
available sources. The starting materials were prepared by fol-
lowing known and standard literature procedures. Dichloro-
methane solvent was dried over CaH2 and used freshly
distilled from the still. THF was dried over sodium metal and
freshly distilled from the still before use. 1H and 13C spectra
were recorded on a 400 MHz or 500 MHz NMR spectrometer
using solutions in CDCl3 with tetramethylsilane (TMS) as
internal standard. IR spectra were recorded on a FT/IR spectro-
meter. HRMS were recorded using an ESI-Q-TOF technique.
Column chromatography was performed on silicagel
100–200 mesh, using ethyl acetate and hexanes mixture as the
eluent.
Scheme 8 Lithiation of 1a with 2.2 equivalents of n-BuLi.
effect is more prominent than thermodynamic acidity to take
the lithium reagent to the aryl site.
General procedure for the preparation of starting materials 1
In another experiment, 1a was treated with n-BuLi at −78 °C
and the reaction mixture was brought to room temperature with
the anticipation that the kinetically lithiated species would set
up equilibrium with the thermodynamically stable lithiated
species. Upon quenching with benzaldehyde at room tempera-
ture no product was obtained and only 15% of the starting
material was isolated along with decomposed products.
Interestingly, under super-basic conditions (t-BuOK/t-BuLi),
the substrate 1a showed lithiation at the dithiane carbon. In
addition to that, the displacement of either one of the aryl
The starting dithiane protected aromatic aldehydes 1 were pre-
pared from corresponding aromatic aldehydes 2, by treating
with 1,3-propanedithiol 20 under Lewis acid conditions follow-
ing the reported procedure.14 Reactions were clean, complete
in 2–3 h and resulted in dithianes 1 in good yields. The
obtained products were used as such in the next step without
any further purification step.
2-(2,4-Dichlorophenyl)-1,3-dithiane
(1a).21 Quantitative
yield; white solid; 1H NMR (400 MHz, CDCl3): δ 7.61(d, J =
8.4 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.26 (dd, J = 8.4, 2.0 Hz,
1H), 5.57 (s, 1H), 3.14–3.08 (m, 2H), 2.94–2.89 (m, 2H), 2.20–2.16
(m, 1H), 1.94–1.90 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 135.2,
134.5, 133.2, 130.5, 129.4, 127.8, 46.8, 32.2, 25.0.
chloro substituents with
a t-Bu group also occurred
(Scheme 7). The same was the result when t-BuLi alone was
used as the lithiating agent. These two reactions clearly show
there is no coordination effect with t-BuLi which generally
stays as a monomer in THF.
Finally, one more control reaction was carried out using 2.2
equivalents of n-BuLi for the lithiation of 1a. This reaction,
however, resulted in a mixture of products as given in
Scheme 8. The product of aryl lithiation was the major one.
Along with this, products 24 and 25 were also formed via
lithiation at both aryl and dithiane along with chloro
displacement.
2-(2,4-Difluorophenyl)-1,3-dithiane (1b). Quantitative yield;
white solid, mp = 85–87 °C; 1H NMR (400 MHz, CDCl3):
δ 7.62–7.56 (m, 1H), 6.91–6.86 (m, 1H), 6.83–6.77 (m, 1H), 5.48
(s, 1H), 3.14–3.07 (m, 2H), 2.93–2.88 (m, 2H), 2.19–2.15 (m,
1H), 1.97–1.91 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 162.6
(dd, J = 248.0, 12.0 Hz), 158.7 (dd, J = 249.0, 12.0 Hz),
130.6–130.5 (m, 1C), 122.4 (dd, J = 14.0, 3.0 Hz), 111.9 (dd, J =
21.0, 3.0 Hz), 103.9 (t, J = 26.0 Hz), 42.4, 32.2, 25.0; IR (KBr):
ν 3084.9, 2942.5, 2004.1, 1600.0, 1501.4, 1413.7, 1271.2, 1227.4,
1145.2, 1084.9, 964.4, 854.8, 816.4, 767.1, 668.5, 515.1; HRMS
calcd for C10H10F2NaS2 (M + H)+ 255.0090, found 255.0082.
Conclusions
2-(2,4-Dimethoxyphenyl)-1,3-dithiane
(1c).22 Quantitative
An unexpected regioselective lithiation was observed in 2-(2,4- yield; white solid, mp = 107–108 °C, 1H NMR (400 MHz,
dihalophenyl)-1,3-dithiane derivatives. Although two sites are CDCl3): δ 7.49 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 6.43
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
(s, 1H), 5.62 (s, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.13–3.07 (m, δ 162.0 (d, J = 244.0 Hz), 143.0, 137.2, 133.5, 132.5, 129.4, 127.0
2H), 2.90–2.86 (m, 2H), 2.17–2.14 (m, 1H), 1.96–1.89 (m, 1H).
(d, J = 8.0 Hz), 115.1 (d, J = 21.0 Hz), 72.1, 70.5, 37.4, 27.8, 22.4,
2-(2-Chlorophenyl)-1,3-dithiane (1d).23 Quantitative yield; 14.0; IR (KBr): ν 3545, 2937, 1610, 1512, 1440, 1221, 1054, 838,
1
white solid; H NMR (400 MHz, CDCl3): δ 7.62 (dd, J = 7.6, 1.6 772 cm−1; HRMS calcd for C17H15Cl2FNaOS2 (M + Na)+
Hz, 1H), 7.35 (dd, J = 8.0, 1.6 Hz, 1H), 7.27 (td, J = 7.6, 1.6 Hz, 410.9823, found 410.9822.
1H), 7.21 (td, J = 7.6, 1.6 Hz, 1H), 5.64 (s, 1H), 3.10 (td, J = 14.4,
(2,6-Dichloro-3-(1,3-dithian-2-yl)phenyl)(4-methoxyphenyl)-
2.4 Hz, 2H), 2.90 (dt, J = 14.4, 3.2 Hz, 2H), 2.18–2.13 (m, 1H), methanol (3d). 1.80 g, yield: 98%; gummy yellow liquid; 1H
1.97–1.87 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 136.5, 132.3, NMR (400 MHz, CDCl3): δ 7.64 (d, J = 8.4 Hz, 1H), 7.37 (d, J =
129.6, 129.5, 129.3, 127.4, 47.5, 32.2, 25.0.
8.8 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H),
2-(4-Chlorophenyl)-1,3-dithiane (1e).14 Quantitative yield; 6.65 (d, J = 9.6 Hz, 1H), 5.64 (s, 1H), 3.79 (s, 3H), 3.44 (d, J =
1
white solid, mp = 90–91 °C, H NMR (400 MHz, CDCl3): δ 7.42 10.8 Hz, 1H), 3.15–3.07 (m, 2H), 2.94–2.90 (m, 2H), 2.20–2.16
(d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.8 Hz, 2H), 5.14 (s, 1H), 3.05 (m, 1H), 1.98–1.88 (m, 1H); 13C NMR (100 MHz, CDCl3):
(dt, J = 14.4, 2.4 Hz, 2H), 2.90 (td, J = 14.4, 4.0 Hz, 2H), δ 158.7, 138.1, 136.9, 134.8, 133.4, 133.2, 129.6, 126.6, 113.6,
2.20–2.13 (m, 1H), 1.98–1.86 (m, 1H); 13C NMR (100 MHz, 72.6, 55.2, 47.6, 32.2, 24.9; IR (neat): ν 3457, 2955, 2903, 2830,
CDCl3): δ 137.6, 134.1, 129.1, 128.9, 50.5, 31.9, 24.9.
1609, 1583, 1511, 1443, 1247, 1180, 1081, 1029, 838, 776,
740 cm−1; HRMS calcd for C18H18Cl2NaO2S2 (M + Na)+
423.0023, found 423.0030.
General procedure for lithiation and synthesis of 3a–3k, 16, 18
and 1914
(2,6-Dichloro-3-(1,3-dithian-2-yl)phenyl)(m-tolyl)methanol (3e).
To a solution of dithiane 1 (1 equiv.) in dry THF, n-BuLi 1.44 g, yield: 95%; white solid, mp = 118–120 °C; 1H NMR
(1.6 M, 1.2 equiv.) was added at −78 °C. After stirring at the (400 MHz, CDCl3): δ 7.64 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.4 Hz,
same temperature for 2 h, electrophile 2 (1.1 equiv.) was added 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.11 (s, 1H), 7.07 (d, J = 8.0 Hz,
slowly and the reaction was continued. After completion of the 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.66 (s, 1H), 5.64 (s, 1H),
reaction, aqueous NH4Cl solution was added to the reaction 3.15–3.06 (m, 2H), 2.94–2.90 (m, 2H), 2.33 (s, 3H), 2.20–2.16
mixture. The solvent was evaporated and the residue was (m, 1H), 1.99–1.88 (m, 1H); 13C NMR (100 MHz, CDCl3): δ
extracted with ethyl acetate. The organic layer was dried over 141.2, 138.2, 138.0, 136.9, 134.9, 133.5, 129.7, 129.6, 128.2,
anhydrous Na2SO4, concentrated and purified by column 128.0, 126.0, 122.3, 72.8, 47.6, 32.2, 24.9, 21.5; IR (neat):
chromatography using mixtures of ethyl acetate and hexanes.
(2,6-Dichloro-3-(1,3-dithian-2-yl)phenyl)(phenyl)methanol 701 cm−1
(3a). 2.47 g, yield: 88%; white solid, mp = 149–150 °C; 1H 407.0074, found 407.0075.
NMR (400 MHz, CDCl3): δ 7.64 (d, J = 8.4 Hz, 1H), 7.36 (d, J = Benzo[d][1,3]dioxol-5-yl(2,6-dichloro-3-(1,3-dithian-2-yl)phenyl)-
8.4 Hz, 1H), 7.34–7.25 (m, 5H), 6.70 (d, J = 10.8 Hz, 1H), 5.63 methanol (3f). 0.5 g, yield: 84%; yellow solid, mp
ν 3430, 2898, 1577, 1451, 1276, 1150, 1073, 1035, 909, 750,
;
HRMS calcd for C18H18Cl2NaOS2 (M
+
Na)+
=
1
(s, 1H), 3.43 (dd, J = 10.6, 2.4 Hz, 1H), 3.14–3.05 (m, 2H), 109–110 °C; H NMR (400 MHz, CDCl3): δ 7.64 (d, J = 8.4 Hz,
2.93–2.89 (m, 2H), 2.19–2.14 (m, 1H), 1.97–1.87 (m, 1H); 13C 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.80 (s, 1H), 6.75 (d, J = 8.0 Hz,
NMR (100 MHz, CDCl3): δ 141.2, 138.1, 136.9, 134.9, 133.4, 1H), 6.67 (d, J = 8.4 Hz, 1H), 6.59 (s, 1H), 5.94 (s, 2H), 5.63 (s,
129.7, 129.6, 128.2, 127.1, 125.2, 72.7, 47.6, 32.1, 24.9; IR 1H), 3.42 (bs, 1H), 3.14–3.07 (m, 2H), 2.94–2.91 (m, 2H),
(KBr): ν 3545, 3063, 2937, 1577, 1501, 1451, 1276, 1183, 1084, 2.20–2.17 (m, 1H), 1.98–1.92 (m, 1H); 13C NMR (100 MHz,
909, 772, 700 cm−1; HRMS calcd for C17H16Cl2NaOS2 (M + Na)+ CDCl3): δ 147.8, 146.7, 138.0, 137.0, 135.2, 134.8, 133.4, 129.8,
392.9917, found 392.9918.
129.7, 118.6, 108.0, 106.3, 101.0, 72.7, 47.6, 32.2, 24.9;
(2-Chlorophenyl)(2,6-dichloro-3-(1,3-dithian-2-yl)phenyl)- IR (KBr): ν 3425, 2882, 1682, 1501, 1485, 1441, 1238, 1041, 920,
methanol (3b). 1.804 g, yield: 90%; white solid, mp = 762 cm−1; HRMS calcd for C18H16Cl2NaO3S2 (M + Na)+
64–66 °C; 1H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 8.4 Hz, 1H), 436.9816, found 436.9816.
7.59–7.57 (m, 1H), 7.36–7.33 (m, 2H), 7.28–7.22 (m, 2H), 6.76
(2,6-Dichloro-3-(1,3-dithian-2-yl)phenyl)(p-tolyl)methanol (3g).
1
(d, J = 6.4 Hz, 1H), 5.64 (s, 1H), 3.14–3.07 (m, 3H), 2.94–2.90 0.239 g, yield: 83%; yellow liquid; H NMR (400 MHz, CDCl3):
(m, 2H), 2.20–2.16 (m, 1H), 1.98–1.88 (m, 1H); 13C NMR δ 7.66 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.18 (d, J =
(100 MHz, CDCl3): δ 138.0, 136.8, 136.4, 135.3, 133.9, 132.7, 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 10.4 Hz, 1H),
129.8, 129.7, 129.2, 128.9, 126.2, 71.5, 47.7, 32.2, 24.9; IR 5.65 (s, 1H), 3.46 (dd, J = 10.4, 4.4 Hz, 1H), 3.15–3.07 (m, 2H),
(KBr): ν 3375, 2926 1572, 1451, 1380, 1274, 1188, 1079, 1035, 2.94–2.91 (m, 2H), 2.35 (s, 3H), 2.20–2.16 (m, 1H), 1.99–1.89
761 cm−1
426.9528, found 426.9528.
;
HRMS calcd for C17H15Cl3NaOS2 (M
+
Na)+ (m, 1H); 13C NMR (100 MHz, CDCl3): δ 138.2, 138.1, 136.82,
136.80, 134.8, 133.4, 129.59, 129.55, 128.9, 125.2, 72.7, 47.6,
(2,6-Dichloro-3-(1,3-dithian-2-yl)phenyl)(4-fluorophenyl)- 32.1, 24.9, 21.0; IR (neat): ν 3572, 3457, 2898, 1906, 1572, 1506,
methanol (3c). 1.92 g, yield: 99%; pale yellow solid, mp = 1440, 1276, 1079, 903, 733 cm−1
HRMS calcd for
99–100 °C; 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 8.4 Hz, C18H18NaCl2OS2 (M + Na)+ 407.0074, found 407.0074.
1H), 7.38 (d, J = 8.4 Hz, 1H), 7.27–7.22 (m, 2H), 7.02 (t, J = Ethyl 2,6-dichloro-3-(1,3-dithian-2-yl)benzoate (3h). 0.160 g,
;
1
8.4 Hz, 2H), 6.66 (d, J = 10.4 Hz, 1H), 5.64 (s, 1H), 3.40 (d, J = yield: 82%; white solid, mp = 136–138 °C, H NMR (400 MHz,
10.4 Hz, 1H), 3.16–3.08 (m, 2H), 2.95–2.92 (m, 2H), 2.22–2.18 CDCl3): δ 7.67 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 5.57
(m, 1H), 1.99–1.93 (m, 1H); 13C NMR (100 MHz, CDCl3): (s, 1H), 4.46 (q, J = 7.2 Hz, 2H), 3.13–3.07 (m, 2H), 2.93–2.89
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
(m, 2H), 2.19–2.16 (m, 1H), 1.97–1.87 (m, 1H), 1.41 (t, J = 1H), 7.44 (d, J = 6.0 Hz, 1H), 7.20 (t, J = 6.0 Hz, 1H), 7.17–7.14
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 164.4, 136.0, 134.2, (m, 1H), 7.11 (t, J = 6.0 Hz, 1H), 7.06 (t, J = 6.0 Hz, 1H), 6.72 (t,
131.2, 130.8, 129.9, 128.4, 62.3, 46.7, 32.0, 24.8, 14.0; IR (KBr): J = 7.2 Hz, 1H), 6.09 (s, 1H), 3.42 (s, 1H), 2.99–2.96 (m, 1H),
ν 2887, 1742, 1567, 1447, 1266, 1156, 1014, 904, 778 cm−1
;
2.68–2.56 (m, 3H), 1.94–1.86 (m, 1H), 1.82–1.77 (m, 1H); 13C
HRMS calcd for C13H15Cl2O2S2 (M + H)+ 336.9891, found NMR (125 MHz, CDCl3): δ 160.0 (d, J = 246.2 Hz), 135.8, 134.5,
336.9887. 133.1, 132.6, 130.0 (d, J = 2.5 Hz), 129.4 (d, J = 8.8 Hz), 129.1,
(3-(1,3-Dithian-2-yl)-2,6-difluorophenyl)(4-chlorophenyl)metha- 126.2, 124.9 (d, J = 12.5 Hz), 122.8 (d, J = 3.8 Hz), 114.6 (d, J =
nol (3i). 0.3 g, yield: 89%; yellow liquid; 1H NMR (400 MHz, 22.5 Hz), 70.6, 68.4, 27.5, 26.5, 23.3; IR (neat): ν 3436, 3058,
CDCl3): δ 7.58–7.53 (m, 1H), 7.32–7.27 (m, 4H), 6.92–6.88 (m, 2953, 2926, 1616, 1589, 1490, 1463, 1227, 1047, 751 cm−1
;
1H), 6.18 (d, J = 7.6 Hz, 1H), 5.44 (s, 1H), 3.09–3.02 (m, 2H), HRMS calcd for C17H17ClFOS2 (M + H)+ 355.0393, found
2.96 (d, J = 8.0 Hz, 1H), 2.87 (dt, J = 14.0, 3.6 Hz, 2H), 2.16–2.11 355.0393.
(m, 1H), 1.94–1.83 (m, 1H); 13C NMR (100 MHz, CDCl3):
(2-(4-Chlorophenyl)-1,3-dithian-2-yl)(4-fluorophenyl)methanol
δ 160.2 (dd, J = 250.0, 8.0 Hz), 156.8 (dd, J = 249.0, 8.0 Hz), (19).14 2.016 g, yield: 95%; white solid, mp = 94–95 °C; 1H
140.2, 133.3, 129.8(d, J = 10.0, 5.0 Hz), 128.5, 126.9, 123.1 (d, NMR (500 MHz, CDCl3): δ 7.60 (d, J = 7.5 Hz, 2H), 7.27 (d, J =
J = 15.0 Hz), 118.9 (t, J = 17.0 Hz), 112.4 (d, J = 23.0 Hz), 66.8, 9.0 Hz, 2H), 6.85–6.83 (m, 4H), 4.96 (d, J = 1.5 Hz, 1H),
42.4 (d, J = 4.0 Hz), 32.1, 24.8; IR (neat): ν 3435, 2909, 1901, 2.76–2.72 (m, 2H), 2.68–2.59 (m, 2H), 1.95–1.90 (m, 2H); 13C
1621, 1599, 1490, 1276, 1177, 1013, 777, 733 cm−1; HRMS NMR (125 MHz, CDCl3): δ 162.6 (d, J = 245.4 Hz), 136.0, 133.7,
calcd for C17H15ClF2OS2 (M + Na)+ 395.0119, found 395.0120.
132.8, 132.1, 129.8 (d, J = 8.1 Hz), 128.2, 114.0 (d, J = 21.2 Hz),
3-(1,3-Dithian-2-yl)-2,6-difluorobenzaldehyde (3j). 0.190 g, 80.2, 65.7, 27.2, 26.9, 24.6; IR (KBr): ν 3436, 2911, 1904, 1603,
1
yield: 80%; white solid, mp = 100–101 °C; H NMR (400 MHz, 1510, 1223 cm−1; C17H16ClFOS2: calcd C 57.53, H 4.54, found
CDCl3): δ 10.31 (s, 1H), 7.83 (dd, J = 14.4, 8.0 Hz, 1H), 6.99 (t, C 57.65, H 4.51.
J = 9.2 Hz, 1H), 5.48 (s, 1H), 3.13–3.06 (m, 2H) 2.91–2.88 (m,
General procedure for the deprotection of dithiane in 314
2H), 2.19–2.15 (m, 1H), 1.94–1.84 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 184.0, 162.4 (d, J = 269.0 Hz), 159.2 (d, J = 268.0 Hz), To a solution of N-chlorosuccinimide (4 equiv.) and AgNO3
136.1–135.9 (m, 1C), 123.7 (dd, J = 14.0, 4.0 Hz), 113.9–113.7 (4.5 equiv.) in acetonitrile/water (4 : 1), compound 3 (1 equiv.)
(m, 1C), 112.8 (d, J = 24.0 Hz), 41.6, 31.9, 24.6; IR (KBr): ν 2920, was added at room temperature. The reaction mixture was
2849, 2783, 1709, 1621, 1479, 1276, 1226, 1193, 1035, 920, 772, stirred at room temperature. After completion of the reaction,
712 cm−1; HRMS calcd for C11H11F2OS2 (M + H)+ 261.0219, aqueous Na2S2O3 solution was added. The crude product was
found 261.0214.
extracted with ethyl acetate, dried over Na2SO4, concentrated
(3-(1,3-Dithian-2-yl)-2,6-dimethoxyphenyl)(p-tolyl)methanol and purified by column chromatography using mixtures of
(3k). 0.69 g, yield: 23%; colorless liquid; 1H NMR (400 MHz, hexanes and ethyl acetate.
CDCl3): δ 7.57 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.10
2,4-Dichloro-3-(hydroxy(phenyl)methyl)benzaldehyde (4a).
(d, J = 8.0 Hz, 2H), 6.76 (d, J = 8.8 Hz, 1H), 6.19 (d, J = 11.2 Hz, 0.078 g, yield: 96%; colorless liquid; 1H NMR (400 MHz,
1H), 5.49 (s, 1H), 4.13 (d, J = 11.6 Hz, 1H), 3.75 (s, 3H), 3.68 (s, CDCl3): δ 10.50 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.48 (d, J =
3H), 3.14–3.07 (m, 2H), 2.92–2.88 (m, 2H), 2.32 (s, 3H), 8.4 Hz, 1H), 7.38–7.29 (m, 5H), 6.78 (d, J = 6.4 Hz, 1H), 3.48 (d,
2.20–2.16 (m, 1H), 1.98–1.88 (m, 1H); 13C NMR (100 MHz, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 189.0, 141.2,
CDCl3): δ 158.0, 155.2, 141.4, 136.2, 129.6, 128.7, 125.6, 125.5, 140.7, 139.2, 138.7, 132.2, 129.8, 129.3, 128.4, 127.4, 125.2,
125.0, 108.1, 69.0, 63.3, 55.8, 44.0, 32.5, 25.1, 21.0; IR (neat): ν 71.9; IR (neat): ν 3446, 3057, 3030, 2876, 1698, 1572, 1490,
3534, 2937, 2899, 1600, 1485, 1419, 1271, 1227, 1085, 1041, 1446, 1369, 1237, 1084, 931, 827, 695 cm−1; HRMS calcd for
740 cm−1; HRMS calcd for C20H24NaO3S2 (M + Na)+ 399.1065, C14H11Cl2O2 (M + H)+ 281.0136, found 281.0139.
found 399.1069.
2,4-Dichloro-3-((2-chlorophenyl)(hydroxy)methyl)benzaldehyde
(2-(2,4-Dimethoxyphenyl)-1,3-dithian-2-yl)(p-tolyl)methanol (4b). 0.185 g, yield: 95%; pale yellow liquid; 1H NMR
(16). 0.39 g, yield: 13%; colorless liquid; 1H NMR (400 MHz, (400 MHz, CDCl3): δ 10.5 (s, 1H), 7.87 (d, J = 8.36 Hz, 1H), 7.73
CDCl3): δ 7.47 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 8.36 Hz, 1H), 7.47 (d, J = 8.36 Hz, 1H), 7.38–7.28 (m,
(d, J = 8.0 Hz, 2H), 6.58 (d, J = 2.4 Hz, 1H), 6.36 (dd, J = 8.8, 2.4 3H), 6.82 (s, 1H), 2.96 (s, 1H); 13C NMR (100 MHz, CDCl3):
Hz, 1H), 5.53 (d, J = 3.2 Hz, 1H), 3.93 (s, 3H), 3.82 (s, 3H), 3.75 δ 189.3, 141.8, 139.3, 137.9, 137.5, 132.2, 132.1, 129.9, 129.8,
(d, J = 3.6 Hz, 1H), 3.06–3.00 (m, 1H), 2.68–2.61 (m, 3H), 2.26 129.3, 129.2, 129.1, 126.3, 70.4; IR (neat): ν 3402, 3068, 2926,
(s, 3H), 1.98–1.91 (m, 1H), 1.88–1.80 (m, 1H); 13C NMR 2876, 1693, 1577, 1435, 1380, 1238, 1089, 1029, 827, 750 cm−1
;
(100 MHz, CDCl3): δ 160.6, 158.7, 137.0, 135.2, 132.7, 127.63, HRMS calcd for C14H9Cl3NaO2 (M + Na)+ 336.9566, found
127.60, 120.4, 104.0, 100.6, 67.4, 55.9, 55.3, 27.2, 26.1, 23.8, 336.9563.
21.2; IR (neat): ν 3474, 2921, 2838, 1611, 1578, 1490, 1463,
1414, 1304, 1205, 1052, 931, 734 cm−1; HRMS calcd for (4c). 0.325 g, yield: 73%; gummy yellow solid; mp = 79–81 °C;
C20H24NaO3S2 (M + Na)+ 399.1065, found 399.1067. 1H NMR (400 MHz, CDCl3): δ 10.47 (s, 1H), 7.86 (d, J = 8.4 Hz,
2,4-Dichloro-3-((4-fluorophenyl)(hydroxy)methyl)benzaldehyde
(2-(2-Chlorophenyl)-1,3-dithian-2-yl)(2-fluorophenyl)methanol 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.49–7.25 (m, 2H), 7.03 (t, J =
(18). 0.931 g, yield: 94%; pale yellow liquid; 1H NMR 8.8 Hz, 2H), 6.73 (s, 1H), 3.44 (s, 1H); 13C NMR (100 MHz,
(500 MHz, CDCl3): δ 7.87 (d, J = 6.4 Hz, 1H), 7.64 (t, J = 6.0 Hz, CDCl3): δ 188.9, 162.1 (d, J = 245 Hz), 141.1, 138.9, 138.6,
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
136.4, 132.3, 129.9, 129.4, 127.0 (d, J = 8.0 Hz), 115.3 (d, J = 2yl)(phenyl)methanol (22). 0.312 g, yield: 70%; viscous liquid;
21.0 Hz), 71.4; IR (KBr): ν 3441, 3041, 2926, 2888, 1699, 1600, 1H NMR (500 MHz, CDCl3): δ 7.60 (d, J = 8.4 Hz, 0.49H), 7.51
1578, 1507, 1375, 1216, 1090, 838 cm−1; HRMS calcd for (d, J = 7.9 Hz, 0.46H), 7.30–7.28 (m, 2H), 7.26–7.22 (m, 5H),
C14H10Cl2FO2 (M + H)+ 299.0042, found 299.0038.
5.05 (d, J = 6.0 Hz, 0.5H), 4.9 (d, J = 7.4, 0.5H), 4.7 (s, 0.5H), 4.6
2,4-Dichloro-3-(hydroxy(4-methoxyphenyl)methyl)benzaldehyde (d, J = 7.1 Hz, 0.5H), 2.55–2.42 (m, 4H), 1.80–1.72 (m, 2H), 1.29
(4d). 0.532 g, yield: 98%; yellow liquid; 1H NMR (400 MHz, (s, 9H); 13C NMR (100 MHz, CDCl3): δ 140.5, 140.4, 136.9,
CDCl3): δ 10.5 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 135.6, 135.0, 134.0, 133.5, 131.5, 131.1, 129.0, 128.8, 128.1,
8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 128.0, 127.3, 127.2, 126.7, 126.6, 76.3, 76.0, 42.1, 31.7, 31.2,
6.71 (s, 1H), 3.80 (s, 3H), 3.42 (bs, 1H); 13C NMR (100 MHz, 31.1, 31.0, 29.7, 29.6, 27.0; IR (KBr): ν 3452, 3397, 3068, 3024,
CDCl3): δ 189.0, 158.9, 141.1, 139.2, 138.6, 132.6, 132.2, 129.8, 2958, 1772, 1462, 1046 cm−1; HRMS calcd for C21H25ClNaOS2
129.2, 126.6, 113.8, 71.7, 55.2; IR (neat): ν 3463, 2997, 2958, (M + Na)+ 415.0933, found 415.0940.
2931, 2898, 2838, 1693, 1615, 1577, 1512, 1446, 1243, 1177,
1084, 1034, 928, 843, 733 cm−1
;
HRMS calcd for
Procedure for sequential lithiation using two equivalents of
n-BuLi
C15H12Cl2NaO3 (M + Na)+ 333.0061, found 333.0033.
3-((4-Chlorophenyl)(hydroxy)methyl)-2,4-difluorobenzaldehyde
(4i). 0.079 g, yield: 97%; white solid; mp = 88–90 °C; H NMR
To a stirred solution of dithiane 1a (300 mg, 1.3 mmol) in dry
THF (5 mL), n-BuLi (1.6 M, 0.77 mL, 1.24 mmol) was added at
−78 °C. After stirring at the same temperature for 2 h, electro-
phile 2a (0.127 mL, 1.24 mmol) in 2 mL dry THF was added
slowly and the reaction was continued for 1 h. After confirming
the completion of the reaction by TLC, the second lot of
n-BuLi (1.6 M, 0.77 mL, 1.24 mmol) was added at −78 °C. After
2 h maintenance at the same temperature, electrophile 2a
(0.127 mL, 1.24 mmol) in 2 mL dry THF was added and main-
tained for another 1 h. Then aqueous NH4Cl solution was
added to the reaction mixture. The solvent was evaporated and
the residue was extracted with ethyl acetate. The organic layer
was dried over anhydrous Na2SO4, concentrated and purified
by column chromatography using mixtures of ethyl acetate
and hexanes.
1
(400 MHz, CDCl3): δ 10.22 (s, 1H), 7.84 (dd, J = 14.8, 8.4 Hz,
1H), 7.35 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H), 7.02 (t, J =
8.8 Hz, 1H), 6.26 (s, 1H), 3.13 (bs, 1H); 13C NMR (100 MHz,
CDCl3): δ 185.6 (d, J = 7.0 Hz), 164.5 (dd, J = 258.0, 9.0 Hz),
163.2 (dd, J = 261.0, 9.0 Hz), 139.7, 133.7, 129.6 (d, J = 11.0
Hz), 128.7, 126.8, 121.4 (d, J = 9.0 Hz), 120.0 (t, J = 16.0 Hz),
113.1 (d, J = 23.0 Hz), 66.4; IR (KBr): ν 3485, 3074, 2926, 1912,
1682, 1616, 1594, 1496, 1441, 1266, 1057, 1008, 816, 608 cm−1
;
HRMS calcd for C14H10ClF2O2 (M + H)+ 283.0337, found
283.0333.
Procedure for lithiation under super-basic (t-BuOK/t-BuLi)
conditions
To a stirred suspension of t-BuOK (127 mg, 1.13 mmol) in dry
THF (5 mL) at −78 °C, t-BuLi (1.6 M, 0.7 mL, 1.13 mmol) was
added and maintained for 2 h. Then 1a (300 mg, 1.13 mmol)
in dry THF (2 mL) was added slowly. After maintaining the
(2-(2-n-Butyl-4-chloro-3-(hydroxy(phenyl)methyl)phenyl)-1,3-
dithian-2-yl)(phenyl)methanol (24) and (6-n-butyl-2-chloro-3-
(2-(hydroxyl(phenyl)methyl)-1,3-dithian-2-yl)phenyl)(phenyl)-
methanol (25). 0.145 g, yield: 33%; viscous liquid; 1H NMR
(500 MHz, CDCl3): δ 7.68–7.62 (m, 1H), 7.34–7.08 (m, 11H), 6.6
(s, 0.49H), 6.70 (s, 0.42H), 5.13–5.06 (m, 1H), 4.85–4.81 (m,
1H), 3.35 (s, 1H), 2.48–2.41 (m, 6H), 1.8–1.7 (m, 2H), 1.53–1.49
(m, 2H), 1.4–1.36(m, 2H) 0.92–0.87 (m, 3H); 13C NMR
(100 MHz, CDCl3): δ 141.3, 131.0, 130.8, 129.0, 128.8, 128.3,
128.2, 128.1, 127.1, 126.6, 125.4, 125.2, 72.9, 72.8, 52.1, 31.8,
31.7, 30.8, 29.2, 22.0, 13.7; IR (KBr): ν 3567, 3408, 3024, 2958,
1446, 1188, 1024 cm−1; HRMS calcd for C28H32ClO2S2 (M + H)+
499.1532, found 499.1524.
same temperature for
1 h, electrophile 2a (0.115 mL,
1.13 mmol) in 2 mL dry THF was added and the reaction was
continued for 1 h. After completion of the reaction, aqueous
NH4Cl solution was added to the reaction mixture. The solvent
was evaporated and the residue was extracted with ethyl
acetate. The organic layer was dried over anhydrous Na2SO4,
concentrated and purified by column chromatography using
mixtures of ethyl acetate and hexanes.
Procedure for lithiation using t-BuLi
1-Phenylpentan-1-ol (23).24 0.145 g, yield: 33%; viscous
liquid; 1H NMR (400 MHz, CDCl3): δ 7.36–7.30 (m, 5H),
4.68–4.65 (m, 1H), 2.11 (s, 1H), 1.84–1.73 (m, 2H), 1.44–1.26
(m, 4H), 0.94–0.91 (m, 3H), 13C NMR (100 MHz, CDCl3):
δ 145.0, 128.4, 127.5, 127.2, 125.9, 74.7, 38.8, 28.0, 22.6, 14.0.
To a solution of dithiane 1a (300 mg, 1.13 mmol) in dry THF
(5 mL) t-BuLi (1.6 M, 0.77 mL, 1.24 mmol) was added at
−78 °C. After stirring at the same temperature for 2 h, electro-
phile 2a (0.127 mL, 1.24 mmol) in 2 mL dry THF was added
slowly and the reaction was continued for 1 h. After com-
pletion of the reaction, aqueous NH4Cl solution was added to
the reaction mixture. The solvent was evaporated and the
residue was extracted with ethyl acetate. The organic layer was
Acknowledgements
dried over anhydrous Na2SO4, concentrated and purified by We thank the SERB, India, for financial support (SB/S1/OC-51/
column chromatography using mixtures of ethyl acetate and 2013). R. B. K. and S. S. thank the Council of Scientific and
hexanes.
Industrial Research (CSIR), India, for senior research fellow-
(2-(2-(tert-Butyl)-4-chlorophenyl)-1,3-dithian-2-yl)(phenyl)- ships. The authors thank Mr Krishna Reddy for his assistance
methanol (21) and (2-(4-(tert-butyl)-2-chlorophenyl)-1,3-dithian- during DFT calculations.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
38, 1675; (f) R. Maggi and M. Schlosser, Tetrahedron Lett.,
1999, 40, 8797; (g) M. Schlosser, F. Mongin, J. Porwisiak,
W. Dmowski, H. H. Büker and N. M. M. Nibbering, Chem. –
Eur. J., 1998, 4, 1281; (h) M. Schlosser, Angew. Chem., Int.
Ed., 1998, 37, 1496; (i) S. T. Chadwick, R. A. Rennels,
J. L. Rutherford and D. B. Collum, J. Am. Chem. Soc., 2000,
122, 8640; ( j) R. A. Rennels, A. J. Maliakal and
D. B. Collum, J. Am. Chem. Soc., 1998, 120, 421;
(k) F. Gohier, A.-S. Castanet and J. Mortier, J. Org. Chem.,
2005, 70, 1501; (l) S. T. Chadwick, A. Ramirez, L. Gupta and
D. B. Collum, J. Am. Chem. Soc., 2007, 129, 2259.
8 (a) V. Snieckus, Heterocycles, 1980, 14, 1649;
(b) V. Snieckus, Lect. Heterocycl. Chem., 1984, 7, 95;
(c) N. S. Narashimhan and R. S. Mali, Top. Curr. Chem.,
1987, 138, 63; (d) V. Snieckus, Bull. Soc. Chim. Fr., 1988,
67; (e) E. Marzi, C. Bobbio, F. Cottet and M. Schlosser,
Eur. J. Org. Chem., 2005, 2116; (f) R. E. Miller,
T. Rantanen, K. A. Ogilvie, U. Groth and V. Snieckus,
Org. Lett., 2010, 12, 2198; (g) J. Morin, Y. Zhao and
Notes and references
1 (a) T. Gaich and E. Winterfeldt, Directed Selectivity in
Organic Synthesis: A Practical Guide, Wiley-VCH, Weinheim,
2014; (b) R. S. Ward, Selectivity in Organic Synthesis, Wiley,
New York, 1999.
2 For reviews on regioselective organic transformations, see:
(a) S. Saito and Y. Yamamoto, Chem. Rev., 2000, 100, 2901;
(b) A. R. Kapdi and D. Prajapati, RSC Adv., 2014, 4, 41245;
(c) A. R. Kapdi, Dalton Trans., 2014, 43, 3021; (d) D. Fujino,
H. Yorimitsu and A. Osuka, J. Am. Chem. Soc., 2014, 136,
6255; (e) D.-T. D. Tang, K. D. Collins, J. B. Ernst and
F. Glorius, Angew. Chem., Int. Ed., 2014, 53, 1809;
(f) Y. Yang and S. L. Buchwald, Angew. Chem., Int. Ed.,
2014, 53, 8677; (g) Y. Wu, Li. Linjie, Li. Hongze, L. Gao,
H. Xie, Z. Zhang, Z. Su, C. Hu and Z. Song, Org. Lett., 2014,
16, 1880.
3 For reviews on directed C–H activation, see:
(a) P. B. Arockiam, C. Bruneau and P. H. Dixneuf, Chem.
Rev., 2012, 112, 5879; (b) G. Rouquet and N. Chatani,
Angew. Chem., Int. Ed., 2013, 52, 11726; (c) A. Ros,
R. Fernández and J. M. Lassaletta, Chem. Soc. Rev., 2014,
43, 3229; (d) G. Li, L. Wan, G. Zhang, D. Leow, J. Spangler
and J.-Q. Yu, J. Am. Chem. Soc., 2015, 137, 4391; (e) J. Yang,
Org. Biomol. Chem., 2015, 13, 1930; (f) R. K. Rit,
M. R. Yadav, K. Ghosh and A. K. Sahoo, Tetrahedron, 2015,
71, 4450.
4 (a) J. Clayden, Organolithiums: Selectivity for Synthesis, Else-
vier, 2002. For reviews, see: (b) P. Beak and V. Snieckus, Acc.
Chem. Res., 1982, 15, 306; (c) P. Beak and A. I. Mayers, Acc.
Chem. Res., 1986, 19, 356; (d) V. Snieckus, Chem. Rev., 1990,
90, 879; (e) M. Schlosser, Angew. Chem., Int. Ed., 2005, 44,
376; (f) J. Epsztajn, A. Jozwiak and A. K. Szczesniak, Curr.
Org. Chem., 2006, 10, 1817; (g) K. R. Campos, Chem. Soc.
Rev., 2007, 36, 1069; (h) D. Tilly, J. Magolan and J. Mortier,
Chem. – Eur. J., 2012, 18, 3804; (i) E. Ertürk, M. A. Tezeren,
T. Atalar and T. Tilki, Tetrahedron, 2012, 68, 6463;
( j) H. J. Reich, Chem. Rev., 2013, 113, 7130.
5 (a) W. Bauer and P. v. R. Schleyer, J. Am. Chem. Soc., 1989,
111, 7191; (b) T. D. Krizan and J. C. Martin, J. Org. Chem.,
1982, 47, 2681; (c) D. A. Shirley and J. P. Hendrix, J. Organo-
met. Chem., 1968, 11, 217; (d) P. Beak, S. T. Kerrick and
D. J. Gallagher, J. Am. Chem. Soc., 1993, 115, 10628;
(e) D. R. Hay, Z. Song, S. G. Smith and P. Beak, J. Am. Chem.
Soc., 1988, 110, 8145; (f) P. Beak, A. Basu, D. J. Gallagher,
V.
Snieckus,
Org.
Lett.,
2014,
16,
2378;
(h) K. B. Jørgensen, T. Rantanen, T. Dörfler and
V. Snieckus, J. Org. Chem., 2015, 80, 9410.
9 (a) I. Haiduc and H. Gilman, J. Organomet. Chem., 1968, 12,
394; (b) M. F. Semmelhack, J. Bisaha and M. Czamy, J. Am.
Chem. Soc., 1979, 101, 768; (c) A. I. Meyers and W. Rieker,
Tetrahedron Lett., 1982, 23, 2091; (d) A. I. Meyers and
P. D. Pansegrau, Tetrahedron Lett., 1983, 24, 4935;
(e) G. W. Gribble and M. G. Saulnier, Tetrahedron Lett.,
1980, 21, 4137; (f) R. Radinov, M. Haimova and E. Simova,
Synthesis, 1986, 886; (g) A. Turck, L. Mojovic and
G. Queguiner, Synthesis, 1988, 881; (h) J. Kristensen,
M. Lysén, P. Vedsø and M. Begtrup, Org. Lett., 2001, 3,
1435; (i) A. J. Bridges, A. Lee, E. C. Maduakor and
C. E. Schwartz, Tetrahedron Lett., 1992, 33, 7495;
( j) A. J. Bridges, A. Lee, E. C. Maduakor and C. E. Schwartz,
Tetrahedron Lett., 1992, 33, 7499; (k) R. Sanz,
M. P. Castroviejo, Y. Fernández and F. J. Fañanás, J. Org.
Chem., 2005, 70, 6548; (l) V. Guilarte, M. P. Castroviejo,
P. G. García, M. A. F. Rodríguez and R. Sanz, J. Org. Chem.,
2011, 76, 3416; (m) J. A. Newby, D. W. Blaylock, P. M. Witt,
R. M. Turner, P. L. Heider, B. H. Harji, D. L. Browne and
S. V. Ley, Org. Process Res. Dev., 2014, 18, 1221;
(n) J. A. Newby, D. W. Blaylock, P. M. Witt, J. C. Pastre,
M. K. Zacharova, S. V. Ley and D. L. Browne, Org. Process
Res. Dev., 2014, 18, 1211.
Y. S. Park and S. Thayumanavan, Acc. Chem. Res., 1996, 29, 10 (a) M. D. Morrison, J. J. Hanthorn and D. A. Pratt, Org.
552.
Lett., 2009, 11, 1051; (b) L. Gupta, A. C. Hoepker,
K. J. Singh and D. B. Collum, J. Org. Chem., 2009, 74, 2231;
(c) L. Wang, Y. Wang, F. Guo, Y. Zheng, P. S. Bhadury and
Z. Sun, Tetrahedron Lett., 2013, 54, 6053; (d) Y.-H. Han,
T. Zhou, Y. Sui and R. Hua, Org. Process Res. Dev., 2014, 18,
1229; (e) T. H. Kress and M. R. Leanna, Synthesis, 1988,
803; (f) C. Heiss, E. Marzi and M. Schlosser, Eur. J. Org.
Chem., 2003, 4625.
6 (a) C. G. Hartung and V. Snieckus, in Modern Arene Chem-
istry, ed. D. Astruc, Wiley-VCH, Weinheim, Germany, 2002,
pp. 330–367.
7 (a) T. J. Thornton and M. Jarman, Synthesis, 1990, 295;
(b) R. R. Fraser, M. Bresse and T. S. Mansour, J. Am. Chem.
Soc., 1983, 105, 7790; (c) A. I. Shatenshtein, Tetrahedron,
1962, 18, 95; (d) D. A. Shirley, T. E. Harmon and
C. F. Cheng, J. Organomet. Chem., 1974, 69, 327; 11 A. Unsinn, C. J. Rohbogner and P. Knochel, Adv. Synth.
(e) D. W. Slocum and B. P. Koonsvitsky, J. Org. Chem., 1973,
Catal., 2013, 355, 1553.
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
12 J. L. Farmer, R. D. J. Froese, E. Lee-Ruff and M. G. Organ,
Chem. – Eur. J., 2015, 21, 1888.
13 M. Demas, G. J. Javadi, L. M. Bradley and D. A. Hunt,
J. Org. Chem., 2000, 65, 7201.
14 R. B. Kothapalli, R. Niddana and R. Balamurugan, Org.
Lett., 2014, 16, 1278.
15 (a) D. Lednicer and L. A. Mitscher, The Organic Chemistry of
Drug Design, Wiley-Interscience, New York, 1977, vol. 1–3;
(b) W. Sneader, Drug Discovery: The Evolution of Modern
K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar,
J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene,
J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo,
R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin,
R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin,
K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador,
J. J. Dannenberg, S. Dapprich, A. D. Daniels, Ö. Farkas,
J. B. Foresman, J. V. Ortiz, J. Cioslowski and D. J. Fox, Gaus-
sian 09, Gaussian, Inc., Wallingford CT, 2009.
Medicine, Wiley, Chichester, 1985; (c) K. C. Nicolaou and 18 F. G. Bordwell, Acc. Chem. Res., 1988, 21, 456.
T. Montagnon, Molecules that Changed the World: A Brief 19 (a) J. M. Sa, P. M. Deyii, G. A. Suiier and A. Frontera, J. Am.
History of the Art and Science of Synthesis and its Impact on
Society, Wiley-VCH, Weinheim, 2008.
16 (a) K. Shen, Y. Fu, J.-N. Li, L. Liu and Q.-X. Guo, Tetra-
hedron, 2007, 63, 1568; (b) H. Tajuddin, P. Harrisson,
Chem. Soc., 1992, 114, 9093; (b) J. C. Riggs, A. Ramirez,
M. E. Cremeens, C. G. Bashore, J. Candler, M. C. Wirtz,
J. W. Coe and D. B. Collum, J. Am. Chem. Soc., 2008, 130,
3406.
B. Bitterlich, J. C. Collings, N. Sim, A. S. Batsanov, 20 (a) P. Beak, J. E. Hunter and Y. M. Jun, J. Am. Chem. Soc.,
M. S. Cheung, S. Kawamorita, A. C. Maxwell, L. Shukla,
J. Morris, L. Lin, T. B. Marder and P. G. Steel, Chem. Sci.,
2012, 3, 3505.
1983, 105, 6350; (b) P. Beak, J. E. Hunter, Y. M. Jun and
A. P. Wallin, J. Am. Chem. Soc., 1987, 109, 5403;
(c) M. C. Whisler, S. MacNeil, V. Snieckus and P. Beak,
Angew. Chem., Int. Ed., 2004, 43, 2206.
17 J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, 21 J. Lai, W. Du, L. Tian, C. Zhao, X. She and S. Tang, Org.
B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, Lett., 2014, 16, 4396.
X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, 22 A. T. Khan, E. Mondal, S. Ghosh and S. Islam, Eur. J. Org.
J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, Chem., 2004, 2002.
J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, 23 L. Ballesteros, O. Noguez, G. Arroyo, B. Velasco, F. Delgado
H. Nakai, T. Vreven, J. A. Montgomery Jr., J. E. Peralta, and R. Miranda, J. Mex. Chem. Soc., 2005, 49, 302.
F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, 24 X.-S. Ning, X.-J. Dong, Z.-F. Xiao, C.-Z. Yao and Y.-B. Kang,
K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand,
Asian J. Org. Chem., 2015, 4, 333.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2015