A tandem Michael-SN2-mediated general route to six-membered heterocycles and carbocycles

Article abstract of DOI:10.1002/ejoc.201000941

A powerful, flexible, and stereoselective general strategy for the construction of chirally pure six-membered heterocycles and carbocycles by utilizing a tandem Michael-S_N2 sequence is described. The strategy avoids the tedious synthesis of sep

Full text of DOI:10.1002/ejoc.201000941

FULL PAPER
DOI: 10.1002/ejoc.201000941
A Tandem Michael–SN2-Mediated General Route to Six-Membered
Heterocycles and Carbocycles
Ananta Kumar Atta[a] and Tanmaya Pathak*[a]
Keywords: Carbocycles / Heterocycles / Sulfones / Desulfonylation / Michael addition / Nucleophilic substitution
A powerful, flexible, and stereoselective general strategy for
the construction of chirally pure six-membered heterocycles
and carbocycles by utilizing a tandem Michael–SN2 se-
quence is described. The strategy avoids the tedious synthe-
sis of separate starting materials prior to cyclization. The ex-
pedient and general strategy, which is virtually untapped un-
til now, will enrich the arsenal of synthetic chemists for the
preparation of cyclic compounds.
fones,[8] we opined that the vinyl sulfone group of an acyclic
vinyl sulfone with a properly positioned leaving group – as
in A, Scheme 1 – would react efficiently with externally de-
livered nucleophiles. The intermediate B thus formed would
displace the leaving group in an SN2 fashion to afford six-
membered heterocycles and carbocycles represented by the
general structure C.
Introduction
The importance of six-membered densely functionalized
heterocycles[1,2] and carbocycles[3] in natural products and
pharmaceuticals has led to outstanding developments in the
synthetic strategies for achieving these structures. In par-
ticular, polyhydroxylated piperidines, as well as alkyl- and/
or hydroxy-substituted carbocycles, are a common struc-
tural component in a large number of naturally occurring
and biologically active molecules.[1–3]
Tandem reactions allow several new bonds to be gener-
ated in a one-pot fashion thereby avoiding the isolation of
intermediates, minimizing the number of synthetic steps,
and eliminating the need for stepwise purification pro-
cesses.[4] The application of such strategies is therefore
highly desirable in synthetic chemistry especially for ac-
cessing heterocycles and carbocycles.[4,5]
Concomitant alkylation and Michael addition may be
considered an efficient tandem strategy for the construction
of ring structures.[6,7] However, virtually all acyclic sub-
strates used so far for such tandem reactions[6,7] have been
devoid of asymmetric centers or functional groups on the
carbon atoms connecting the Michael acceptor and the
leaving group of a substrate. It should be noted that there
have been several reports[6] on reactions involving first an
SN2 reaction followed by a Michael addition whereas the
reverse reaction pattern, that is, Michael addition followed
by SN2 reactions have rarely been reported.[7]
Scheme 1. General strategy for the synthesis of six-membered het-
erocycles and carbocycles.
However, only the isolation of appropriate intermediates
would establish the sequence of reactions delineated in
Scheme 1. We also argued that if the vinyl sulfones (like A)
are derived from inexpensive chiral pools like carbo-
hydrates, the sequence of reactions (Scheme 1) would gener-
ate compounds with well-defined chiral centers inherited
from the carbohydrates used for the synthesis of the acyclic
vinyl sulfone A. Moreover, it was necessary to design a con-
cise route for the synthesis of vinyl sulfones represented by
the general structure A in Scheme 1.
We planned to access highly functionalized and chiral
Michael acceptors having a leaving group at the δ position
from pentose and hexose sugars for tandem Michael–SN2
reactions. Thus, the known ribo-tosyl derivative 1[9] was re-
gioselectively displaced at C2 with thiocresol to provide 2
(Scheme 2). The 3,4-isopropylidine group of 2 was depro-
tected to obtain 3. Benzyl protection of 3 afforded 4, which
was ring-opened under acidic conditions. The product thus
generated was reduced to the corresponding diol 5 by using
Results and Discussion
Because carbon and other heteroatomic nucleophiles re-
act efficiently at the electrophilic β position of vinylic sul-
[a] Department of Chemistry, Indian Institute of Technology
Kharagpur,
Kharagpur 721302, India
E-mail: tpathak@chem.iitkgp.ernet.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000941.
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A General Route to Six-Membered Heterocycles and Carbocycles
NaBH4 in EtOH. The diol 5 was oxidized with magnesium
Acyclic vinyl sulfone 7 was treated with benzylamine,
monoperoxyphthalate hexahydrate (MMPP) to generate the ethylamine, isopropylamine, and an amino sugar in MeOH
sulfone derivative 6 in high yield. Mesylation of 6 and con- to produce piperidine derivatives 16–19, respectively, in
comitant elimination of one mesyl group in pyridine af- good yields (Scheme 4). Carbon nucleophiles generated
forded the required acyclic vinyl sulfone 7 (Scheme 2) in from active methylene compounds such as dimethyl or di-
good yield.
ethyl malonate using tBuOK in THF efficiently reacted
with 7 in a Michael fashion and subsequent treatment with
an additional amount of tBuOK in the same flask yielded
cyclic products 20 and 21. In addition, the potassium salt
of malononitrile efficiently reacted with 7 to afford the car-
bocycle 22 (Scheme 4). Compound 7 also readily reacted
with Na2S in MeOH at 55 °C to afford the cyclic sulfide 23.
Scheme 2. Synthesis of pentosyl acyclic vinyl sulfone modified
carbohydrates.
To synthesize the higher homologue of 7, the glucopyr-
anosyl epoxide 8[10] was treated with thiophenol in a re-
gioselective fashion to give 9 (Scheme 3). The free hydroxy
group of 9 was benzylated to yield 10. Compound 10 was
deprotected under acidic conditions to generate 11. Com-
pound 11 was converted into the vinyl sulfone 15 via inter-
mediates 12–14 following the procedure described for the
synthesis of 7.
Scheme 4. Synthesis of six-membered heterocycles and carbocycles.
The THF solution of hexosyl acyclic vinyl sulfone 15
having a leaving group at the δ position was treated with a
30% aq. ammonia solution and a 40% aq. methylamine
solution to generate cyclic derivatives 26 and 27, respec-
tively, after K2CO3 treatment in
a one-pot fashion
(Scheme 5). In addition, 15 efficiently reacted with neat
benzylamine and n-butylamine to generate the correspond-
ing cyclic derivatives 28 and 29, respectively. The potassium
salt of malononitrile added to compound 15 in a Michael
fashion to produce the mesyl derivative 32, which was sub-
sequently converted into the carbocyclic derivative 33 by
using DMSO/NaCl (Scheme 5).
It should be noted for 16–23 that the SO2Ar substituent
is the only new chiral center to be generated during the
reactions, whereas for compounds 26–29 and 33, the SO2Ar
substituent and the ring carbon connected to CH2OBn are
the two new chiral centers generated after ring closure.
However, the configuration of the ring carbon connected to
CH2OBn was easily assigned because of the SN2 nature of
the intramolecular cyclization reaction.
Scheme 3. Synthesis of hexosyl acyclic vinyl sulfone modified
carbohydrates.
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A. K. Atta, T. Pathak
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Figure 1. ORTEP diagram of compound 18.
Scheme 5. Synthesis of six-membered heterocycles and carbocycles.
The structure of 18 was unambiguously established on
Scheme 6. Formation of olefinic piperidines from selected piperi-
dine derivatives.
the basis of an X-ray analysis of its single crystal (Figure 1).
1
The H NMR spectral patterns of 16, 17, and 19 are com-
parable to that of 18, proving thereby the structural simi-
larities of these compounds. The configuration of 20 was
confirmed by COSY and NOESY experiments. The config-
urations of the sulfone-bearing carbon atom of 21 and 22
were confirmed on the basis of the 1H NMR spectra, which
are comparable to that of 20. Compound 23 was formed in
the same way and therefore was assigned the same configu-
ration. Compound 26 was treated with methyl iodide or
benzyl bromide separately to afford N-methylated 27 and
N-benzylated 28, respectively (Scheme 5). Because the con-
figuration of the sulfone-bearing C atom of 27 had been
confirmed by COSY–NOESY experiments, the configura-
tions of compounds 26 and 28 were automatically con-
firmed. The spectral pattern of 29 is comparable to that of
28, proving the structural similarities of the two com-
pounds.
On the other hand, cyclic sulfide derivative 23 was oxid-
ized to the corresponding sulfone 40 by using MMPP in
MeOH (Scheme 7). The cyclic sulfone 40 on treatment with
K2CO3/MeOH or NaOEt/EtOH underwent elimination–
addition reactions to produce 41 and 42, respectively. Sulf-
ones 41 and 42 afforded cyclopentenols 43 and 44, respec-
tively, under modified Ramberg–Baecklund conditions
(Scheme 7).[12] The configuration of 41 was confirmed by
X-ray analysis of its single crystal (Figure 2). The 1H NMR
spectral pattern of 42 was comparable to that of 41, proving
thereby the structural similarities of the two compounds
(Scheme 7). The isomers of 43 or 44 can be used for the
synthesis of several natural products and biologically active
compounds.[13]
To establish the sequence of reactions in the tandem cy-
clization delineated in Schemes 4 and 5, we isolated com-
pounds 24, 25, and 30–32. All of these compounds after
isolation and treatment with basic reagents also afforded
cyclic products. The presence of the mesyl group in 24, 25,
and 30–32 unambiguously confirmed that the Michael ad-
dition was indeed the first step in the sequence of reactions
and that ring closure occurred by intramolecular nucleo-
philic displacement reactions.
The synthetic utility of many of these compounds was
established by converting the sulfonylated piperidine deriva-
tives 16–19, 27, and 28 into functionalized olefinic piperi-
dines
34–39,
respectively,
in
moderate
yields
(Scheme 6).[1b,11]
Scheme 7. Cyclopentenol derivatives from cyclic sulfide 23.
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A General Route to Six-Membered Heterocycles and Carbocycles
(100 MHz, CDCl3): δ = 21.0, 52.9, 55.6, 62.3 (CH2), 68.4, 68.7,
100.7, 129.8, 131.1, 132.2, 137.4 ppm. HRMS (ES+): calcd. for
C13H18O4SNa [M + Na]+ 293.0824; found 293.0818.
Compound 4: Compound 3 (3.0 g, 11.11 mmol) was stirred at 0 °C
with NaH (1.09 g, 22.80 mmol) and benzyl bromide (3.8 mL,
52.20 mmol) in DMF (40 mL). The mixture was stirred at room
temperature under N2. After 4 h, the reaction mixture was poured
into an aq. saturated solution of NH4Cl and the product was ex-
tracted with EtOAc (3ϫ20 mL). The combined organic layers were
dried with anhyd. Na2SO4, filtered, and the filtrate was concen-
trated under reduced pressure to leave a residue. The residue was
purified over silica gel to afford 4 (4.10 g, 82%) as a white semi-
solid. [α]2D6 = –77.0 (c = 0.34, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 2.32 (s, 3 H), 3.39 (s, 3 H), 3.68–3.76 (m, 3 H), 3.84
(s, 2 H), 4.61–4.71 (m, 4 H), 4.80 (s, 1 H), 7.05 (d, J = 7.6 Hz, 2
H), 7.26–7.35 (m, 10 H), 7.41 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 21.0, 51.0, 55.7, 61.1, 71.8 (CH2), 72.4
(CH2), 72.9, 77.4, 100.8, 127.4, 127.5, 127.7, 127.8, 128.2, 128.3,
Figure 2. ORTEP diagram of compound 41.
Conclusions
We have described a powerful, flexible, and stereoselec- 129.5, 131.7, 132.1, 136.5, 138.2, 138.4 ppm. HRMS (ES+): calcd.
tive general strategy for the construction of chirally pure
for C27H30O4SNa [M + Na]+ 473.1757; found 473.1764.
six-membered carbocycles and heterocycles from readily
available acyclic vinyl sulfone-modified carbohydrates by
utilizing a tandem Michael–SN2 sequence. It should be re-
emphasized that the synthesis of separate starting materials,
Compound 5: A mixture of compound 4 (3.5 g, 7.78 mmol) and
80% aq. trifluoroacetic acid (20 mL) was stirred at room tempera-
ture. After 4–5 h, the reaction mixture was poured into an aq. satu-
rated solution of NaHCO3 and the product was extracted with
a common practice in the preparation of heterocycles and EtOAc (3ϫ30 mL). The combined organic layers were dried with
anhyd. Na2SO4, filtered, and the filtrate was concentrated under
reduced pressure to leave a residue. The residue was dissolved in
EtOH (40 mL) and sodium borohydride (1.16 g, 31.12 mmol) was
added at 0 °C. After being stirred for 4 h at room temperature, the
reaction mixture was concentrated under reduced pressure to leave
a residue. The residue was poured into saturated solution of
NaHCO3 and the product was extracted with EtOAC (3ϫ30 mL).
The combined organic layers were dried with anhyd. Na2SO4, fil-
tered, and the filtrate was concentrated under reduced pressure to
leave a residue. The residue was purified over silica gel to afford
compound 5 (2.31 g, 68%) as a white gum. [α]2D6 = –22.5 (c = 2.5,
carbocycles, is completely avoided in our approach. This
diversity-oriented synthetic method generates N- or S-con-
taining heterocycles as well as carbocycles by simply re-
acting easily accessible starting materials 7 or 15 with inex-
pensive reagents like carbon nucleophiles, amines, or Na2S.
Experimental Section
Compound 2: p-Thiocresol (8.66 g, 69.85 mmol) was added to a
well-stirred solution of NaOMe (2.26 g, 41.91 mmol) in DMF
(40 mL) and the mixture was stirred for 0.5 h. A solution of 1
(5.0 g, 13.97 mmol) in DMF (20 mL) was added and the reaction
mixture was heated at 120 °C. After 4 h, the mixture was cooled to
room temperature and poured into an aq. saturated solution of
NH4Cl and the product was extracted with EtOAc (3ϫ20 mL).
The combined organic layers were dried with anhyd. Na2SO4, fil-
tered, and the filtrate was concentrated under reduced pressure to
leave a residue. The residue was purified over silica gel to afford 2
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 2.21 (br. s, 2 H), 2.33
(s, 3 H), 3.59–3.63 (m, 1 H), 3.73–3.86 (m, 3 H), 3.97–4.02 (m, 2
H), 4.12–4.14 (m, 1 H), 4.36 (d, J = 11.2 Hz, 1 H), 4.58 (d, J =
11.2 Hz, 1 H), 4.75 (q, J = 11.6, 24.8 Hz, 2 H), 7.07 (d, J = 8.0 Hz,
2 H), 7.20–7.22 (m, 2 H), 7.28–7.38 (m, 10 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 21.0, 54.7, 59.6 (CH2), 63.1 (CH2), 71.9
(CH2), 74.4 (CH2), 76.6, 79.6, 127.8, 127.9 (2 C), 128.1, 128.4 (2
C), 129.8, 131.5, 131.9, 136.9, 137.6, 137.9 ppm.
1
(3.59 g, 83%) as a yellow oil. [α]2D6 = –138.9 (c = 0.4, CHCl3). H
Compound 6: Magnesium monoperoxyphthalate hexahydrate
(11.85 g, 23.97 mmol) was added to a well-stirred solution of acy-
clic sulfide 5 (3.5 g, 7.99 mmol) in dry MeOH (40 mL) and the
mixture was stirred at room temperature under N2. After 6 h, the
MeOH was evaporated to dryness under reduced pressure and the
residue was poured into an aq. saturated solution of NaHCO3 and
the product was extracted with EtOAc (3ϫ20 mL). The combined
organic layers were dried with anhyd. Na2SO4, filtered, and the
filtrate was concentrated under reduced pressure to leave a residue.
The residue was purified over silica gel to afford sulfone 6 (3.46 g,
92%) as a white semi-solid. [α]2D6 = +20.6 (c = 0.2, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 2.12 (br. s, 1 H), 2.37 (s, 3 H), 2.88
(br. s, 1 H), 3.65–3.68 (m, 1 H), 3.78 (s, 1 H), 3.85–3.87 (m, 1 H),
3.93–4.03 (m, 2 H), 4.12–4.15 (m, 1 H), 4.26–4.29 (m, 1 H), 4.51
NMR (400 MHz, CDCl3): δ = 1.38 (s, 3 H), 1.45 (s, 3 H), 2.34 (s,
3 H), 3.23 (dd, J = 2.8, 3.2 Hz, 1 H), 3.41 (s, 3 H), 3.98–4.02 (m,
2 H), 4.16–4.17 (m, 1 H), 4.27–4.31 (m, 1 H), 4.72 (d, J = 3.2 Hz,
1 H), 7.11 (d, J = 8.0 Hz, 2 H), 7.45 (d, J = 8.0 Hz, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 21.0, 26.2, 28.2, 53.1, 55.8, 58.6
(CH2), 72.8, 74.4, 100.2, 108.8, 129.5, 130.9, 133.3, 137.6 ppm.
HRMS (ES+): calcd. for C16H22O4SNa [M + Na]+ 333.1136; found
333.1136.
Compound 3: A solution of compound 2 (4.0 g, 12.90 mmol) in
80% aq. AcOH (30 mL) was stirred at room temperature. After
24 h, the acid was evaporated to dryness under reduced pressure to
leave a residue. The residue was purified over silica gel to afford 3
1
(3.13 g, 90%) as a white solid. [α]2D6 = –228.7 (c = 0.5, CHCl3). H
NMR (400 MHz, CDCl3): δ = 2.35 (s, 3 H), 2.57–2.62 (m, 1 H), (d, J = 11.2 Hz, 1 H), 4.64–4.72 (m, 3 H), 7.09–7.15 (m, 4 H), 7.25–
2.76–2.80 (m, 1 H), 3.42 (s, 3 H), 3.44–3.47 (m, 1 H), 3.83 (q, J =
7.36 (m, 8 H), 7.64 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR (100 MHz,
12.4, 36.8 Hz, 2 H), 3.96–4.00 (m, 2 H), 4.88 (d, J = 2.8 Hz, 1 H), CDCl3): δ = 21.5, 59.5 (CH2), 60.1 (CH2), 67.6, 72.1 (CH2), 74.2
7.13 (d, J = 8.0 Hz, 2 H), 7.40 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR (CH2), 75.6, 79.5, 127.7, 127.9, 128.0 (2 C), 128.2, 128.5, 129.4,
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A. K. Atta, T. Pathak
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136.9, 137.4, 137.7, 144.4 ppm. HRMS (ES+): calcd. for
amount of DCM at 0 °C under N2 atmosphere over a period of
0.5 h. The resulting solution was stirred at room temperature. After
2 h, the solution was evaporated to dryness under reduced pressure
and the residual liquid was co-evaporated twice with pyridine to
yield a syrupy compound. The resulting syrupy compound was
poured into a saturated solution of NaHCO3 (150 mL) and the
product was extracted with EtOAc (3ϫ30 mL). The combined or-
ganic layers were dried with anhyd. Na2SO4, filtered, and the fil-
trate was concentrated under reduced pressure to leave a residue.
The residue was purified over silica gel to afford compound 11
C26H30O6SNa [M + Na]+ 493.1661; found 493.1652.
Compound 7: Methanesulfonyl chloride (2.5 mL, 31.9 mmol) in
pyridine (10 mL) was added dropwise to a well-stirred solution of
acyclic sulfone 6 (3.0 g, 6.38 mmol) in pyridine (20 mL) at 0 °C
under N2. After completion of the addition, the reaction mixture
was kept at +4 °C. After 24 h (TLC), the reaction mixture was
poured into an aq. saturated solution of NaHCO3 and the product
was extracted with EtOAc (3ϫ20 mL). The combined organic lay-
ers were dried with anhyd. Na2SO4, filtered, and the filtrate was
concentrated under reduced pressure to leave a residue. The residue
was purified over silica gel to afford the required vinyl sulfone 7
(2.90 g, 86%) as a white solid; m.p. 92 °C, [α]2D6 = +39.0 (c = 0.1,
1
(2.25 g, 95%) as a yellow oil; [α]2D6 = +193.0 (c = 0.25, CHCl3). H
NMR (400 MHz, CDCl3): δ = 2.43–2.46 (m, 1 H), 3.39 (s, 3 H),
3.69 (s, 1 H), 3.79–3.99 (m, 5 H), 4.30 (d, J = 11.6 Hz, 1 H), 4.69
(d, J = 11.6 Hz, 1 H), 4.87 (s, 1 H), 7.19–7.21 (m, 2 H), 7.29–7.33
(m, 6 H), 7.38–7.43 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 48.5, 55.5, 63.0 (CH2), 64.3, 68.7, 71.2 (CH2), 76.3, 100.4, 127.8,
128.0, 128.1, 128.5, 129.3, 131.9, 134.0, 137.3 ppm. HRMS (ES+):
calcd. for C20H24O5SNa [M + Na]+ 399.1242; found 399.1262.
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 2.41 (s, 3 H), 2.87 (s, 3
H), 3.97 (d, J = 11.6 Hz, 1 H), 4.07–4.10 (m, 1 H), 4.18 (d, J =
11.6 Hz, 1 H), 4.31–4.35 (m, 2 H), 4.39–4.42 (m, 1 H), 4.49–4.56
(m, 2 H), 6.15 (s, 1 H), 6.62 (s, 1 H), 7.01–7.03 (m, 2 H), 7.24–7.35
(m, 10 H), 7.69 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.6, 37.4, 68.1 (CH2), 71.1 (CH2), 72.7 (CH2), 75.2, Compound 12: Compound 11 (2.86 g, 7.60 mmol) was converted
78.2, 127.8, 127.9, 128.1, 128.3, 128.4, 128.5 (CH2), 129.9, 135.8, into 12 (3.42 g, 81%) following the procedure described for the
136.5, 137.3, 144.9, 148.3 ppm. HRMS (ES+): calcd. for
C27H30O7S2Na [M + Na]+ 553.1325; found 553.1403.
preparation of 10. White gum, [α]2D6 = +45.1 (c = 0.29, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 3.39 (s, 3 H), 3.62 (d, J = 2.8 Hz, 1
H), 3.76–3.80 (m, 2 H), 3.85 (d, J = 2.8 Hz, 1 H), 4.00–4.04 (m, 1
H), 4.32–4.46 (m, 4 H), 4.54–4.71 (m, 3 H), 4.89 (s, 1 H), 7.18–7.37
(m, 20 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 49.7, 55.6, 67.5,
69.7 (CH2), 71.4 (CH2), 71.5 (CH2), 71.9, 73.6 (CH2), 73.9, 101.1,
127.0, 127.5, 127.6, 127.8, 128.0, 128.2, 128.4, 128.6, 129.3, 131.8,
134.6, 138.2, 138.6 ppm. HRMS (ES+): calcd. for C34H36O5SNa
[M + Na]+ 579.2181; found 579.2184.
Compound 9: Thiophenol (12.87 mL, 125.0 mmol) and tetrameth-
ylguanidine (9.4 mL, 75.0 mmol) were added to a well-stirred solu-
tion of epoxide 8 (6.60 g, 25.0 mmol) in DMF (40 mL) . The mix-
ture was heated at 90–120 °C with stirring under N2. After 4–5 h,
the reaction mixture was poured into an aq. saturated solution of
NaHCO3 and the product was extracted with EtOAc (3ϫ20 mL).
The combined organic layers were dried with anhyd. Na2SO4, fil-
tered, and the filtrate was concentrated under reduced pressure to
leave a residue. The residue was purified over silica gel to afford
Compound 13: Compound 12 (3 g, 5.40 mmol) was converted into
13 (2.02 g, 69%) following the procedure described for the prepara-
tion of 5. White semi-solid, [α]2D6 = +21.2 (c = 0.4, CHCl3). 1H
the sulfide 9 (7.29 g, 78%) as a colorless oil. [α]2D6 = +51.6 (c = 4,
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 3.14 (d, J = 7.2 Hz, 1 NMR (400 MHz, CDCl3): δ = 2.51–2.54 (m, 1 H), 2.90 (d, J =
H), 3.43 (s, 3 H), 3.66 (d, J = 2.4 Hz, 1 H), 3.88 (t, J = 10.0 Hz, 1 3.6 Hz, 1 H), 3.61–3.71 (m, 3 H), 3.74–3.81 (m, 1 H), 3.84–3.89 (m,
H), 4.12 (dd, J = 2.8, 10.0 Hz, 1 H), 4.26–4.28 (m, 2 H), 4.34–4.38
(m, 1 H), 4.89 (s, 1 H), 4.68 (s, 1 H), 7.26–7.38 (m, 6 H), 7.44–7.52 4.53–4.56 (m, 3 H), 4.63–4.69 (m, 3 H), 7.17–7.37 (m, 18 H), 7.41
(m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 51.6, 55.7, 58.6, (d, J = 7.2 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 54.1,
1 H), 4.02–4.05 (m, 1 H), 4.08–4.11 (m, 1 H), 4.22 (br. s, 1 H),
68.8, 69.1 (CH2), 76.3, 101.3, 102.2, 126.2, 127.7, 128.2, 129.1, 62.8, 71.1, 71.2 (CH2), 73.4 (CH2), 73.6 (CH2), 74.0 (CH2), 78.8,
129.4, 131.2, 133.8, 137.2 ppm. HRMS (ES+): calcd. for
C20H22O5SNa [M + Na]+ 397.1086; found 397.1084.
79.9, 126.8, 127.7 (2 C), 127.8, 127.9, 128.0, 128.3, 128.4 (2 C),
129.0, 131.2, 135.4, 137.8, 137.9, 138.0 ppm. HRMS (ES+): calcd.
for C33H36O5SNa [M + Na]+ 567.2181; found 567.2183.
Compound 10: Compound 9 (2.60 g, 6.95 mmol) was stirred at 0 °C
with NaH (0.40 g, 8.34 mmol) and benzyl bromide (1.23 mL,
10.42 mmol) in DMF (30 mL). The mixture was stirred at room
temperature under N2. After 3 h, the reaction mixture was poured
into an aq. saturated solution of NH4Cl and the product was ex-
tracted with EtOAc (3ϫ20 mL). The combined organic layers were
dried with anhyd. Na2SO4, filtered, and the filtrate was concen-
trated under reduced pressure to leave a residue. The residue was
purified over silica gel to afford 10 (2.31 g, 72%) as a yellow solid;
m.p. 118 °C, [α]2D6 = +4.6 (c = 0.1, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 3.42 (s, 3 H), 3.62 (d, J = 2.0 Hz, 1 H), 3.81 (t, J =
Compound 14: Compound 13 (2 g, 3.68 mmol) was converted into
14 (1.95 g, 92%) following the procedure described for the prepara-
tion of 6. White semi-solid, [α]2D6 = +33.9 (c = 0.6, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 2.66 (d, J = 4.8 Hz, 1 H), 2.95 (q,
J = 5.6, 8.0 Hz, 1 H), 3.50 (dd, J = 6.0, 9.6 Hz, 1 H), 3.65 (dd, J
= 2.8, 9.6 Hz, 1 H), 3.90–3.94 (m, 2 H), 4.07–4.17 (m, 2 H), 4.31–
4.32 (m, 1 H), 4.44–4.53 (m, 3 H), 4.59–4.62 (m, 2 H), 4.72 (d, J
= 11.6 Hz, 1 H), 4.83 (d, J = 11.2 Hz, 1 H), 7.10–7.12 (m, 2 H),
7.23–7.37 (m, 15 H), 7.47 (t, J = 7.6 Hz, 1 H), 7.76–7.78 (m, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 58.6 (CH2), 68.5, 70.0,
10.4 Hz, 1 H), 4.01 (s, 1 H), 4.15 (dd, J = 2.4, 9.6 Hz, 1 H), 4.32– 71.3, 73.0 (CH2), 73.3 (CH2), 73.5 (CH2), 76.2, 79.8, 127.3, 127.5,
4.36 (m, 1 H), 4.43–4.50 (m, 1 H), 4.72 (q, J = 12.8, 28.8 Hz, 2 H),
127.6, 127.8 (2 C), 127.9, 128.0, 128.1, 128.4 (2 C), 128.7, 133.0,
4.84 (s, 1 H), 5.60 (s, 1 H), 7.23–7.29 (m, 10 H), 7.37–7.38 (m, 3
137.6, 137.7, 137.8, 141.0 ppm. HRMS (ES+): calcd. for
H), 7.49–7.51 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = C33H36O7SNa [M + Na]+ 599.2079; found 599.2070.
50.8, 55.8, 58.6, 69.3 (CH2), 72.6 (CH2), 74.3, 76.8, 101.2, 102.2,
Compound 15: Compound 14 (2.50 g, 4.34 mmol) was converted
126.3, 127.3, 127.4, 127.8, 128.2 (2 C), 129.0, 129.3, 130.8, 134.2,
into 15 (2.40 g, 85%) following the procedure described for the
137.7, 138.4 ppm. HRMS (ES+): calcd. for C27H28O5SNa
preparation of 7. Colorless oil, [α]2D6 = +63.7 (c = 0.6, CHCl3). H
1
[M + Na]+ 487.1555; found 487.1564.
NMR (400 MHz, CDCl3): δ = 2.95 (s, 3 H), 3.60–3.72 (m, 2 H),
Compound 11: Acetyl chloride (0.67 mL, 9.43 mmol) was added
dropwise to a well-stirred solution of compound 10 (2.92 g,
6.29 mmol) in a mixture of dry MeOH (20 mL) and a minimum
3.97 (d, J = 12.0 Hz, 1 H), 4.03 (dd, J = 1.6, 6.8 Hz, 1 H), 4.15 (d,
J = 11.6 Hz, 1 H), 4.32 (d, J = 7.2 Hz, 1 H), 4.38–4.40 (m, 3 H),
4.49 (d, J = 11.2 Hz, 1 H), 5.12–5.13 (m, 1 H), 6.09 (s, 1 H), 6.60
6814
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6810–6819

A General Route to Six-Membered Heterocycles and Carbocycles
(s, 1 H), 7.06–7.08 (m, 2 H), 7.16–7.18 (m, 2 H), 7.25–7.35 (m, 11
11.2 Hz, 1 H), 4.91 (s, 1 H), 5.05 (d, J = 11.2 Hz, 1 H), 7.14 (d, J
= 8.4 Hz, 2 H), 7.25–7.37 (m, 10 H), 7.66 (d, J = 8.0 Hz, 2 H) ppm.
H), 7.40 (t, J = 7.6 Hz, 2 H), 7.54 (t, J = 7.6 Hz, 1 H), 7.83 (d, J
= 7.6 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 38.7, 68.8 13C NMR (100 MHz, CDCl3): δ = 21.5, 24.9, 26.4, 47.9 (CH2),
(CH2), 70.8 (CH2), 73.1 (CH2), 73.4 (CH2), 75.7, 80.3, 81.7, 127.7,
51.9 (CH2), 54.7, 60.9 (CH2), 64.9, 71.1 (CH2), 71.4, 74.0 (CH2),
127.8, 127.9 (2 C), 128.0, 128.3, 128.4 (2 C), 128.7, 128.9, 129.1, 77.8, 83.1, 84.2, 85.0, 109.3, 112.3, 127.2, 127.3, 127.6, 128.0, 128.4,
133.6, 136.5, 137.0, 137.6, 139.1, 149.0 ppm. HRMS (ES+): calcd.
for C34H36O8S2Na [M + Na]+ 659.1749; found 659.1729.
128.6, 129.5, 135.9, 137.9, 138.5, 144.4 ppm. HRMS (ES+): calcd.
for C35H44NO8S [M + H]+ 638.2813; found 638.2780.
General Procedure for the Synthesis of 16–19: The appropriate
amine (30 equiv./mmol) was added to a well-stirred solution of
compound 7 (1 mmol) in MeOH (5 mL/mmol) . After 1.5–2 h, the
MeOH was evaporated under reduced pressure and the residue was
partitioned between an aq. saturated solution of NH4Cl and
EtOAc (3ϫ15 mL). The combined organic layers were dried with
anhyd. Na2SO4, filtered, and the filtrate was concentrated under
reduced pressure to leave a residue. The residue was purified over
silica gel to afford 16–19.
General Procedure for the Synthesis of 20 and 21: Dimethyl or di-
ethyl malonate (5 equiv./mmol) was added to a well-stirred solution
of tBuOK (3 equiv./mmol) in dry THF (20 mL) and the mixture
was stirred for 0.5 h. A solution of 7 (1 mmol) in THF (10 mL)
was then added and the reaction mixture was stirred at room tem-
perature. After 2–3 h, tBuOK (2 equiv/mmol) was added to the
same flask and the mixture was stirred for an additional 15 h. Then
THF was evaporated under reduced pressure and the residue was
partitioned between an aq. saturated solution of NH4Cl and
EtOAc (3ϫ15 mL). The combined organic layers were dried with
anhyd. Na2SO4, filtered, and the filtrate was concentrated under
reduced pressure to leave a residue. The residue was purified over
silica gel to afford 20 and 21, respectively.
Compound 16: Compound 7 (0.30 g, 0.57 mmol) was converted into
16 (0.25 g, 82%) in 2 h following the general procedure. White so-
lid, m.p. 105 °C, [α]2D6 = 15.2 (c = 0.55, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 2.35 (s, 3 H), 2.46 (t, J = 10.8 Hz, 1 H),
2.58 (t, J = 11.2 Hz, 1 H), 2.79 (dd, J = 4.4, 10.8 Hz, 1 H), 2.85
(dd, J = 3.6, 10.4 Hz, 1 H), 3.18–3.21 (m, 1 H), 3.46–3.50 (m, 2
H), 3.57 (d, J = 12.8 Hz, 1 H), 4.55 (q, J = 12.0, 27.2 Hz, 2 H),
4.65 (s, 1 H), 4.74 (d, J = 11.2 Hz, 1 H), 5.04 (d, J = 10.8 Hz, 1
H),7.11 (d, J = 8.0 Hz, 2 H), 7.18 (d, J = 6.4 Hz, 2 H), 7.26–7.34
(m, 13 H), 7.61 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.5, 47.8 (CH2), 50.8 (CH2), 62.0 (CH2), 65.1, 71.1
(CH2), 71.6, 73.9 (CH2), 78.0, 127.1, 127.2, 127.3, 127.6, 127.7,
128.0, 128.3, 128.4, 128.6, 128.8, 129.4, 136.0, 137.5, 137.9, 138.6,
144.4 ppm. HRMS (ES+): calcd. for C33H35NO4SNa [M + Na]+
564.2185; found 564.2185.
Compound 20: Compound 7 (0.10 g, 0.19 mmol) was converted into
20 (0.073 g, 68%) in 18 h following the general procedure. White
gum, [α]2D6 = +173.5 (c = 0.2, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 2.25–2.35 (m, 3 H), 2.38 (s, 3 H), 2.43–2.47 (m, 1 H),
3.14–3.18 (m, 1 H), 3.37–3.39 (m, 1 H), 3.57 (s, 3 H), 3.69 (s, 3 H),
4.61–4.66 (m, 3 H), 4.78 (d, J = 11.2 Hz, 1 H), 5.03 (d, J = 10.8 Hz,
1 H), 7.20 (d, J = 8.4 Hz, 2 H), 7.23–7.37 (m, 10 H), 7.71 (d, J =
8.0 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.6, 25.9
(CH2), 30.1 (CH2), 52.9, 53.1, 53.9, 63.0, 70.6 (CH2), 71.9, 74.1
(CH2), 76.9, 127.2, 127.4, 127.7, 128.0, 128.3, 128.4, 128.6, 129.6,
135.4, 137.8, 138.4, 144.5, 170.2, 170.5 ppm. HRMS (ES+): calcd.
for C31H34O8SNa [M + Na]+ 589.1866; found 589.1874.
Compound 17: Compound 7 (0.15 g, 0.28 mmol) was converted into
17 (0.12 g, 91%) in 2 h following the general procedure. White so-
lid, m.p. 97 °C, [α]2D6 = +37.0 (c = 0.5, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 1.01 (t, J = 7.2 Hz, 3 H), 2.36 (s, 3 H), 2.43–2.50 (m,
3 H), 2.55 (t, J = 11.6 Hz, 1 H), 2.85 (dd, J = 4.0, 10.4 Hz, 2 H),
3.17–3.20 (m, 1 H), 3.51–3.54 (m, 1 H), 4.58–4.68 (m, 3 H), 4.78
(d, J = 11.2 Hz, 1 H), 5.06 (d, J = 10.8 Hz, 1 H), 7.16 (d, J =
8.4 Hz, 2 H), 7.24–7.37 (m, 10 H), 7.68 (d, J = 8.0 Hz, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 12.0, 21.5, 47.3 (CH2), 50.7
(CH2), 51.6 (CH2), 65.0, 71.1 (CH2), 71.5, 74.0 (CH2), 78.1, 127.1,
127.4, 127.6, 127.7, 128.0, 128.4, 128.5, 129.5, 136.1, 137.9, 138.6,
144.4 ppm. HRMS (ES+): calcd. for C28H34NO4S [M + H]+
480.2203; found 480.2224.
Compound 21: Compound 7 (0.07 g, 0.13 mmol) was converted into
21 (0.055 g, 70%) in 18 h following the general procedure. White
gum, [α]2D6 = +22.0 (c = 1.1, CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 1.06 (t, J = 7.2 Hz, 3 H), 1.21 (t, J = 7.2 Hz, 3 H), 2.24–2.35
(m, 3 H), 2.37 (s, 3 H), 2.44 (dd, J = 3.6, 13.2 Hz, 1 H), 3.13 (dd,
J = 4.4, 12.0 Hz, 1 H), 3.45 (dd, J = 1.6, 10.0 Hz, 1 H), 3.99–4.07
(m, 2 H), 4.12–4.17 (m, 2 H), 4.61 (s, 2 H), 4.67 (s, 1 H), 4.78 (d,
J = 10.8 Hz, 1 H), 5.04 (d, J = 10.8 Hz, 1 H), 7.20 (d, J = 7.6 Hz,
2 H), 7.23–7.37 (m, 10 H), 7.71 (d, J = 8.0 Hz, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 13.7, 13.9, 21.5, 25.9 (CH2), 30.1
(CH2), 53.9, 61.7 (CH2), 61.9 (CH2), 63.2, 70.7 (CH2), 72.0, 74.1
(CH2), 77.1, 127.1, 127.3, 127.6, 128.0, 128.4, 128.6, 129.6, 135.6,
137.9, 138.4, 144.4, 169.8, 170.0 ppm. HRMS (ES+): calcd. for
C33H38O8SNa [M + Na]+ 617.2179; found 617.2164.
Compound 18: Compound 7 (0.28 g, 0.53 mmol) was converted into
18 (0.24 g, 94%) in 1.5 h following the general procedure. White
solid, m.p. 96 °C, [α]2D6 = +31.0 (c = 2.0, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 0.99 (t, J = 6.8 Hz, 6 H), 2.39 (s, 3 H),
2.62 (t, J = 10.4 Hz, 1 H), 2.76–2.80 (m, 4 H), 3.14–3.18 (m, 1 H),
3.47–3.52 (m, 1 H), 4.58–4.68 (m, 3 H), 4.79 (d, J = 11.2 Hz, 1 H),
5.06 (d, J = 10.8 Hz, 1 H), 7.19 (d, J = 8.0 Hz, 2 H), 7.27–7.38 (m,
10 H), 7.70 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 17.9, 18.8, 21.5, 43.7, 46.4, 54.4, 65.3, 71.1, 71.7, 74.0,
78.7, 127.1, 127.3, 127.6, 127.7, 128.0, 128.2, 128.4, 128.5, 129.5,
136.2, 138.0, 138.7, 144.4 ppm. HRMS (ES+): calcd. for
C29H36NO4S [M + H]+ 494.2359; found 494.2356.
Compound 22: Malononitrile (0.03 mL, 0.47 mmol) was added to a
well-stirred solution of tBuOK (0.03 g, 0. 28 mmol) in THF
(15 mL) and the mixture was stirred for 0.5 h. A solution of 7
(0.05 g, 0.094 mmol) in THF (5 mL) was added and the reaction
mixture was stirred at room temperature. After 3 h, the THF was
evaporated under reduced pressure and the residue was partitioned
between an aq. saturated solution of NH4Cl and EtOAc
(3ϫ15 mL). The combined organic layers were dried with anhyd.
Na2SO4, filtered, and the filtrate was concentrated under reduced
pressure to leave a residue. The residue was purified over silica gel
to afford 22 (0.032 g, 68%). White gum, [α]2D6 = +37.7 (c = 0.75,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 2.30–2.33 (m, 1 H),
2.38–2.43 (m, 4 H), 2.49 (t, J = 12.0 Hz, 1 H), 2.58 (t, J = 13.2 Hz,
1 H), 3.14–3.17 (m, 1 H), 3.62–3.66 (m, 1 H), 4.64 (m, 2 H), 4.75
(s, 1 H), 4.83 (d, J = 10.4 Hz, 1 H), 4.99 (d, J = 10.4 Hz, 1 H),
7.26–7.41 (m, 12 H), 7.71 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR
Compound 19: Compound 7 (0.10 g, 0.19 mmol) was converted into
19 (0.12 g, 94%) in 2 h following the general procedure. Colorless
oil, [α]2D6 = –2.3 (c = 0.38, CHCl3). H NMR (400 MHz, CDCl3):
1
δ = 1.30 (s, 3 H), 1.46 (s, 3 H), 2.35 (s, 3 H), 2.44–2.56 (m, 2 H),
2.58–2.65 (m, 2 H), 2.82–2.90 (m, 2 H), 3.20 (s, 4 H), 3.52–3.56 (m,
1 H), 4.16 (t, J = 7.2 Hz, 1 H), 4.49–4.66 (m, 5 H), 4.75 (d, J =
Eur. J. Org. Chem. 2010, 6810–6819
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6815

A. K. Atta, T. Pathak
FULL PAPER
(100 MHz, CDCl3): δ = 21.6, 29.2 (CH2), 30.9, 32.9 (CH2), 62.0, product was extracted with EtOAc (3ϫ20 mL). The combined or-
71.0, 71.7 (CH2), 74.7 (CH2), 75.8, 114.0, 114.1, 127.5, 127.8, 128.0, ganic layers were dried with anhyd. Na2SO4 and concentrated un-
128.2, 128.3, 128.6, 128.7, 130.2, 134.4, 136.7, 137.5, 145.7 ppm.
der reduced pressure to leave a residue. The residue was purified
HRMS (ES+): calcd. for C29H28N2O4SNa [M + Na]+ 523.1661; over silica gel to afford 26 or 27, respectively.
found 523.1624.
Compound 26: Compound 15 (0.20 g, 0.308 mmol) was converted
into 26 (0.131 g, 75%) following the general procedure. White semi-
solid, [α]2D6 = –39.8 (c = 0.2, CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 2.80 (t, J = 7.2 Hz, 1 H), 2.88–2.95 (m, 1 H), 3.33 (t, J =
8.4 Hz, 1 H), 3.43–3.50 (m, 2 H), 3.76–3.83 (m, 1 H), 3.96–3.98 (m,
2 H), 4.37 (d, J = 10.8 Hz, 1 H), 4.45 (q, J = 11.6, 25.6 Hz, 2 H),
4.56 (d, J = 11.6 Hz, 1 H), 4.72 (t, J = 9.6 Hz, 2 H), 7.08–7.13 (m,
4 H), 7.24–7.36 (m, 13 H), 7.47 (t, J = 7.2 Hz, 1 H), 7.78 (d, J =
7.6 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 44.0 (CH2),
58.2, 62.7, 69.5 (CH2), 71.2 (CH2), 72.4, 73.4 (CH2), 74.6 (CH2),
80.3, 127.3, 127.5, 127.7 (2 C), 127.8, 127.9, 128.0, 128.2 (2 C),
128.4, 128.7, 132.9, 137.2, 137.7, 138.3, 141.1 ppm. HRMS (ES+):
calcd. for C33H35NO5SNa [M + Na]+ 580.2150; found 580.2143.
Compound 23: Na2S (0.27 g, 3.42 mmol) was added to a well-stirred
solution of compound 7 (0.30 g, 0.57 mmol) in MeOH (20 mL).
The mixture was heated at 55 °C with stirring under N2. After
1.5 h, the MeOH was evaporated to dryness under reduced pressure
and the residue was partitioned between an aq. saturated solution
of NaHCO3 and EtOAc (3ϫ20 mL). The combined organic layers
were dried with anhyd. Na2SO4, filtered, and the filtrate was con-
centrated under reduced pressure to leave a residue. The residue
was purified over silica gel to afford 23 (0.19 g, 72%) as a colorless
oil. [α]2D6 = +99.6 (c = 0.75, CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 2.36 (s, 3 H), 2.44–2.50 (m, 2 H), 3.07–3.14 (m, 2 H), 3.29–3.32
(m, 1 H), 3.62–3.64 (m, 1 H), 4.62–4.68 (m, 2 H), 4.73–4.78 (m, 2
H), 5.07 (d, J = 11.2 Hz, 1 H), 7.18 (d, J = 7.6 Hz, 2 H), 7.26–7.39
(m, 10 H), 7.69 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.5, 21.9 (CH2), 25.7 (CH2), 68.8, 70.9 (CH2), 72.5,
74.1 (CH2), 81.1, 127.3 (2 C), 127.5, 127.8, 128.0, 128.5, 128.7,
129.7, 135.2, 137.8, 138.3, 144.8 ppm.
Compound 27. Method A: Compound 7 (0.20 g, 0.307 mmol) was
converted into 27 (0.15 g, 85%) following the general procedure.
Colorless oil, [α]2D6 = +112.0 (c = 0.35, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 2.28 (br. s, 4 H), 2.46 (t, J = 12.0 Hz, 1
H), 3.29 (dd, J = 8.8 Hz, 1 H), 3.59–3.62 (m, 1 H), 3.89 (dd, J =
2.4, 10.8 Hz, 1 H), 4.04–4.10 (m, 2 H), 4.37 (s, 2 H), 4.41 (d, J =
11.2 Hz, 1 H), 4.60 (d, J = 11.6 Hz, 1 H), 4.37 (t, J = 9.6 Hz, 2 H),
7.08–7.13 (m, 4 H), 7.18–7.36 (m, 13 H), 7.49 (t, J = 7.6 Hz, 1 H),
7.77 (d, J = 7.6 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
42.6, 53.6 (CH2), 61.0, 64.7, 69.4 (CH2), 71.7 (CH2), 73.3 (CH2),
73.5, 75.1 (CH2), 80.4, 127.4, 127.5, 127.6, 127.7, 127.8, 128.1,
128.2, 128.3, 128.4, 128.7, 132.9, 137.1, 137.7, 138.3, 141.0 ppm.
HRMS (ES+): calcd. for C34H38NO5S [M + H]+ 572.2471; found
572.2468.
General Procedure for the Synthesis of 24 and 25: Dimethyl or di-
ethyl malonate (5 equiv./mmol) was added to a well-stirred solution
of tBuOK (3 equiv./mmol) in dry THF (20 mL) and the mixture
was stirred for 0.5 h. A solution of 7 (1 mmol) in THF (10 mL)
was added and the reaction mixture was stirred at room tempera-
ture. After 2–3 h, the THF was evaporated under reduced pressure
and the residue was partitioned between an aq. saturated solution
of NH4Cl and EtOAc (3ϫ15 mL). The combined organic layers
were dried with anhyd. Na2SO4, filtered, and the filtrate was con-
centrated under reduced pressure to leave a residue. The residue
was purified over silica gel to afford 24 and 25.
Method B: Compound 26 was stirred at 0 °C with K2CO3 and MeI
in MeOH. The mixture was stirred at room temperature under N2.
After 7 h, the reaction mixture was poured into an aq. saturated
solution of NH4Cl and the product was extracted with EtOAc. The
combined organic layers were dried with anhyd. Na2SO4, filtered,
and the filtrate was concentrated under reduced pressure to leave
a residue. The residue was purified over silica gel to afford 27.
Compound 24: Compound 7 (0.10 g, 0.20 mmol) was converted into
24 (0.09 g, 71%) following the general procedure. Colorless oil,
[α]2D6 = +35.0 (c = 0.5, CHCl3). H NMR (400 MHz, CDCl3): δ =
1
2.38 (s, 3 H), 2.45–2.51 (m, 2 H), 2.79 (s, 3 H), 3.61 (s, 6 H), 3.72–
3.75 (m, 2 H), 3.93–3.97 (m, 1 H), 4.17–4.19 (m, 1 H), 4.29 (dd, J
= 3.2, 12.0 Hz, 1 H), 4.51 (dd, J = 10.8, 24.4 Hz, 2 H), 4.63–4.71
(m, 2 H), 4.87 (d, J = 10.8 Hz, 1 H), 7.19 (d, J = 8.0 Hz, 2 H),
7.26–7.36 (m, 10 H), 7.67 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 21.5, 23.4 (CH2), 37.6, 49.1, 52.6, 62.0
(CH2), 66.9, 72.1 (CH2), 73.7, 74.3 (CH2), 77.7, 128.0, 128.2 (2 C),
128.4, 128.6, 129.8, 134.9, 137.1, 144.8, 169.1, 169.4 ppm.
General Procedure for the Synthesis of 28 and 29: A mixture of
compound 15 and the neat amine (20 equiv./mmol) was stirred at
ambient temperature. After 1–1.5 h, the residue was partitioned be-
tween an aq. saturated solution of NH4Cl and EtOAc (3ϫ15 mL).
The combined organic layers were dried with anhyd. Na2SO4, fil-
tered, and the filtrate was concentrated under reduced pressure to
leave a residue. The residue was purified over silica gel to afford 28
or 29.
Compound 25: Compound 7 (0.20 g, 0.094 mmol) was converted
into 25 (0.17 g, 62%) following the general procedure. Colorless oil,
[α]2D6 = +31.1 (c = 1.7, CHCl3). H NMR (400 MHz, CDCl3): δ =
1
Compound 28. Method A: Compound 15 (0.15 g, 0.23 mmol) was
converted into 28 (0.12 g, 76%) in 1 h following the general pro-
1.16–1.20 (m, 6 H), 2.37 (s, 3 H), 2.41–2.55 (m, 2 H), 2.79 (s, 3 H),
3.72–3.77 (m, 2 H), 3.87–3.91 (m, 1 H), 3.98–4.45 (m, 4 H), 4.18
(d, J = 8.4 Hz, 1 H), 4.28–4.32 (m, 1 H), 4.51 (dd, J = 10.4, 25.6 Hz,
2 H), 4.65–4.71 (m, 2 H), 4.88 (d, J = 10.8 Hz, 1 H), 7.18 (d, J =
8.0 Hz, 2 H), 7.29–7.38 (m, 10 H), 7.67 (d, J = 8.4 Hz, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 13.9 (2 C), 21.5, 23.4 (CH2),
37.7, 49.4, 61.5 (CH2), 61.6 (CH2), 62.1, 67.0 (CH2), 72.1 (CH2),
73.7, 74.3 (CH2), 77.8, 127.9, 128.0, 128.2, 128.3, 128.6, 129.8,
135.1, 137.1, 137.2, 144.7, 168.7, 169.0 ppm.
1
cedure. Colorless oil, [α]2D6 = +112.0 (c = 0.35, CHCl3). H NMR
(400 MHz, CDCl3): δ = 2.60 (t, J = 10.8 Hz, 1 H), 2.89 (br. s, 1
H), 3.16–3.20 (m, 1 H), 3.59–3.68 (m, 2 H), 3.74–3.84 (m, 3 H),
3.95–3.97 (m, 1 H), 4.12 (s, 1 H), 4.40–4.44 (m, 3 H), 4.57 (d, J =
11.2 Hz, 1 H), 4.66–4.75 (m, 2 H), 7.12–7.37 (m, 20 H), 7.46 (t, J
= 7.2 Hz, 1 H), 7.69 (d, J = 8.0 Hz, 2 H) ppm. HRMS (ES+): calcd.
for C40H42NO5S [M + H]+ 648.2784; found 648.2750.
Method B: Compound 26 was stirred at 0 °C with K2CO3 and BnBr
in MeOH. The mixture was stirred at room temperature under N2.
After 7 h, the reaction mixture was poured into an aq. saturated
solution of NH4Cl and the product was extracted with EtOAc. The
combined organic layers were dried with anhyd. Na2SO4, filtered,
and the filtrate was concentrated under reduced pressure to leave
a residue. The residue was purified over silica gel to afford 28.
General Procedure for the Synthesis of 26 and 27: A 30% aq. NH3
solution (5 mL) or a 40% aq. methylamine solution was added to
a well-stirred solution of compound 15 (1 equiv./mmol) in THF
(30 mL) . After 2–3 h, 3 equiv./mmol of K2CO3 was added to the
same flask. After 20 h, the THF was evaporated under reduced
pressure, an aq. saturated NaHCO3 solution was added, and the
6816
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6810–6819

A General Route to Six-Membered Heterocycles and Carbocycles
Compound 29: Compound 15 (0.15 g, 0.23 mmol) was converted
into 29 (0.13 g, 92%) in 1.5 h following the general procedure. Col-
orless oil, [α]2D6 = –14.2 (c = 0.25, CHCl3). 1H NMR (400 MHz,
H), 7.53 (t, J = 7.6 Hz, 2 H), 7.68 (t, J = 7.6 Hz, 1 H), 7.84 (d, J
= 7.6 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 26.8 (CH2),
34.1, 44.8, 61.6, 65.5 (CH2), 71.6 (CH2), 71.9, 73.2 (CH2), 75.2
CDCl3): δ = 0.87 (t, J = 7.2 Hz, 3 H), 1.15–1.24 (m, 2 H), 1.34– (CH2), 76.0, 113.3, 114.4, 126.9, 127.6 (2 C), 127.8 (2 C), 128.1,
1.38 (m, 2 H), 2.48–2.74 (m, 4 H), 3.37 (dd, J = 3.6, 12.0 Hz, 1 H),
3.47 (t, J = 8.8 Hz, 1 H), 3.59–3.62 (m, 1 H), 3.86–3.89 (m, 1 H),
3.94–3.99 (m, 1 H), 4.07 (s, 1 H), 4.35–4.42 (m, 3 H), 4.55 (d, J =
11.6 Hz, 1 H), 4.70 (t, J = 10.8 Hz, 2 H), 7.04–7.06 (m, 2 H), 7.12–
7.14 (m, 2 H), 7.21–7.35 (m, 13 H), 7.48 (t, J = 7.6 Hz, 1 H), 7.77
(d, J = 8.0 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.9,
20.5 (CH2), 26.4 (CH2), 48.9 (CH2), 52.7 (CH2), 61.0, 61.4, 68.8
(CH2), 71.5 (CH2), 73.2 (CH2), 73.9, 74.8 (CH2), 80.2, 127.3, 127.4,
127.7, 128.0 (2 C), 128.1, 128.3, 128.6, 132.8, 137.2, 37.8, 138.5,
141.1 ppm. HRMS (ES+): calcd. for C37H44NO5S [M + H]+
614.2940; found 614.2934.
128.2, 128.3 (2 C), 128.5 (2 C), 128.7, 129.6, 134.4, 136.4, 137.1,
137.2, 137.6 ppm. HRMS (ES+): calcd. for C36H34N2O5SNa [M +
Na]+ 629.2086; found 629.2090.
General Procedure for Desulfonylation: Mg turnings (15 mmol) were
added to a well-stirred solution of compound 16–19, 27 or 28 in
dry MeOH (15 mL). After 3–4 h, another portion of Mg turnings
(15 mmol) and dry MeOH (5 mL) were added. The mixture was
stirred for an additional 10 h and the reaction mixture was filtered
through Celite. The residue was washed thoroughly with MeOH.
The combined organic layers were dried with anhyd Na2SO4, fil-
tered, and the filtrate was concentrated under reduced pressure to
leave a residue. The residue was purified over silica gel to afford
34–39, respectively.
General Procedure for the Synthesis of 30 and 31: A 30% aq. NH3
solution (excess) and a 40% aq. MeNH2 solution (excess) were
separately added a well-stirred solution of compound 15 (1 mmol)
in THF (30 mL) . After 2–3 h, the THF was evaporated under re-
duced pressure, an aq. saturated NaHCO3 solution was added, and
the product was extracted with EtOAc (3ϫ20 mL). The combined
organic layers were dried with anhyd. Na2SO4, filtered, and the
filtrate was concentrated under reduced pressure to leave a residue.
The residue was purified over silica gel to afford 30 and 31, respec-
tively.
Compound 34: Compound 16 (0.20 g, 0.369 mmol) was converted
into 34 (0.07 g, 68%) following the general procedure. Yellow oil,
[α]2D6 = +57.5 (c = 0.2, CHCl3). H NMR (400 MHz, CDCl3): δ =
1
2.60 (dd, J = 6.0, 11.2 Hz, 1 H), 2.79 (dd, J = 4.4, 11.2 Hz, 1 H),
2.99 (q, J = 16.0, 25.6 Hz, 2 H), 3.63 (dd, J = 13.2, 35.2 Hz, 2 H),
4.08–4.10 (m, 1 H), 4.56 (s, 2 H), 5.85–5.91 (m, 2 H), 7.26–7.42 (m,
10 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 52.6 (CH2), 54.2
(CH2), 62.3 (CH2), 70.4 (CH2), 71.9, 126.0, 127.1, 127.4, 127.7,
128.2, 128.3, 128.9, 129.0, 137.9, 138.6 ppm. HRMS (ES+): calcd.
for C19H22NO [M + H]+ 280.1719; found 280.1698.
Compound 30: Compound 15 was converted into 30 as a mixture
of isomers following the general procedure. 1H NMR (400 MHz,
CDCl3): see the spectrum in the Supporting Information.
Compound 35: Compound 17 (0.15 g, 0.313 mmol) was converted
into 35 (0.042 g, 63%) following the general procedure. Colorless
oil, [α]2D6 = +74.4 (c = 0.75, CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 1.11 (t, J = 7.2 Hz, 3 H), 2.46–2.56 (m, 3 H), 2.81 (dd, J = 4.8,
11.2 Hz, 1 H), 2.91–2.96 (m, 2 H), 4.10 (br. s, 1 H), 4.62 (s, 2 H),
5.87–5.90 (m, 2 H), 7.26–7.37 (m, 5 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 11.9, 51.8 (CH2), 52.1 (CH2), 54.5 (CH2), 70.5 (CH2),
71.9, 126.0, 127.4, 127.7, 128.3, 128.7, 138.7 ppm. HRMS (ES+):
calcd. for C14H20NO [M + H]+ 218.1563; found 218.1539.
Compound 31: Compound 15 was converted into 31 as a single
compound following the general procedure. 1H NMR (400 MHz,
CDCl3): δ = 2.09 (s, 3 H), 2.91–3.00 (m, 4 H), 3.08–3.18 (m, 1 H),
3.50 (dd, J = 3.4, 11.2 Hz, 1 H), 3.63–3.72 (m, 2 H), 3.91–3.96 (m,
1 H), 4.27–4.28 (m, 1 H), 4.31–4.55 (m, 4 H), 4.77 (dd, J = 11.0,
24.8 Hz, 2 H), 5.10–5.14 (m, 1 H), 7.23–7.30 (m, 15 H), 7.36–7.43
(m, 2 H), 7.51–7.55 (m, 1 H), 7.76–7.77 (m, 2 H) ppm.
Compound 32: Compound 15 (0.10 g, 0.153 mmol) was converted
into 32 (0.064 g, 59%) following the procedure described for the
preparation of 24. Colorless oil, [α]2D6 = +20.2 (c = 1.75, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 2.47–2.53 (m, 1 H), 2.63–2.68
(m, 1 H), 2.97 (s, 2 H), 3.37 (dd, J = 4.8, 10.4 Hz, 1 H), 3.59–3.64
(m, 1 H), 3.75 (t, J = 6.4 Hz, 1 H), 3.79–3.81 (m, 1 H), 4.21 (d, J
= 4.8 Hz, 1 H), 4.38–4.51 (m, 5 H), 4.69 (t, J = 10.0 Hz, 2 H),
4.95–4.99 (m, 1 H), 7.25–7.26 (m, 7 H), 7.32–7.36 (m, 8 H), 7.43
(t, J = 7.6 Hz, 2 H), 7.61 (t, J = 7.2 Hz, 1 H), 7.78 (d, J = 7.6 Hz,
2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.4, 26.2 (CH2),
38.5, 61.8 (CH2), 68.1, 73.5 (CH2), 73.6 (CH2), 73.7 (CH2), 78.4,
79.1, 112.2, 112.3, 127.9, 128.2, 128.3, 128.4, 128.6 (2 C), 128.7,
128.8, 129.6, 134.5, 136.0, 136.3 (2 C), 137.0 ppm.
Compound 36: Compound 18 (0.20 g, 0.406 mmol) was converted
into 36 (0.065 g, 69%) following the general procedure. Brown oil,
[α]2D6 = 42.7 (c = 0.25, CHCl3). H NMR (400 MHz, CDCl3): δ =
1
1.05–1.08 (m, 6 H), 2.48–2.53 (m, 1 H), 2.78–2.89 (m, 2 H), 3.00–
3.10 (m, 2 H), 4.10 (br. s, 1 H), 4.59–4.65 (m, 2 H), 5.83–5.91 (m,
2 H), 7.25–7.38 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
17.9, 18.2, 48.1 (CH2), 50.2 (CH2), 53.8, 70.5 (CH2), 72.6, 126.1,
127.4, 127.7, 128.3, 129.2, 138.7 ppm. HRMS (ES+): calcd. for
C15H22NO [M + H]+ 232.1719; found 232.1691.
Compound 37: Compound 19 (0.26 g, 0.408 mmol) was converted
into 37 (0.095 g, 62%) following the general procedure. Yellow oil,
1
[α]2D6 = –14.9 (c = 0.24, CHCl3). H NMR (400 MHz, CDCl3): δ =
Compound 33: A well-stirred solution of compound 32 (0.06 g,
0.085 mmol) in DMSO (10 mL) was heated at 120–130 °C with
H2O (1 mL) and NaCl (0.025 g, 0.425 mmol). After 12 h, an aq.
saturated solution of NaHCO3 was added and the mixture was
extracted with EtOAc (3ϫ20 mL). The combined organic layers
were dried with anhyd Na2SO4, filtered, and the filtrate was con-
centrated under reduced pressure to leave a residue. The residue
was purified over silica gel to afford 33 (0.028 g, 55%) as a colorless
1.31 (s, 3 H), 1.48 (s, 3 H), 2.60 (d, J = 7.2 Hz, 2 H), 2.68–2.72 (m,
1 H), 2.79–2.83 (m, 1 H), 3.04 (q, J = 10.4, 38.0 Hz, 2 H), 3.83 (s,
3 H), 4.10 (br. s, 1 H), 4.36 (t, J = 7.2 Hz, 1 H), 4.58–4.64 (m, 3
H), 4.73 (d, J = 6.0 Hz, 1 H), 4.96 (s, 1 H), 5.85 (s, 2 H), 7.26–7.37
(m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.0, 26.4, 52.6
(CH2), 54.8, 55.2 (CH2), 60.9 (CH2), 70.4 (CH2), 71.7, 83.0, 84.3,
85.2, 109.5, 112.2, 126.0, 127.4, 127.6, 128.2, 128.5, 138.7 ppm.
HRMS (ES+): calcd. for C21H30NO5 [M + H]+ 376.2109; found
376.2119.
1
oil. [α]2D6 = 90.2 (c = 0.08, CHCl3). H NMR (400 MHz, CDCl3):
δ = 2.28 (dd, J = 3.2, 13.6 Hz, 1 H), 2.71 (t, J = 13.2 Hz, 1 H),
2.89 (t, J = 5.6 Hz, 1 H), 3.17 (dd, J = 8.4 Hz, 1 H), 3.45–3.50 (m,
Compound 38: Compound 27 (0.09 g, 0.158 mmol) was converted
1 H), 3.69–3.71 (m, 1 H), 4.02 (d, J = 11.6 Hz, 1 H), 4.28 (d, J = into 38 (0.028 g, 54%) following the general procedure. Colorless
11.6 Hz, 1 H), 4.48 (d, J = 11.2 Hz, 1 H), 4.57–4.67 (m, 3 H), 4.80
(q, J = 10.4, 28.0 Hz, 2 H), 7.21–7.31 (m, 12 H), 7.34–7.41 (m, 3
oil, [α]2D6 = +57.0 (c = 0.09, CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 2.49 (s, 3 H), 2.95 (d, J = 17.2 Hz, 1 H), 3.04 (q, J = 2.0,
Eur. J. Org. Chem. 2010, 6810–6819
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6817

A. K. Atta, T. Pathak
FULL PAPER
4.4 Hz, 1 H), 3.18 (d, J = 17.6 Hz, 1 H), 3.68–3.78 (m, 2 H), 4.11–
was purified over silica gel to afford compound 42 (0.036 g, 76%)
4.12 (m, 1 H), 4.48–4.52 (m, 2 H), 4.60 (s, 2 H), 5.79 (s, 2 H), 7.27– as a white semi-solid. [α]2D6 = –42.2 (c = 1.3, CHCl3). 1H NMR
7.35 (m, 10 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 43.0, 52.5 (400 MHz, CDCl3): δ = 1.16 (t, J = 6.8 Hz, 3 H), 3.13–3.19 (m, 1
(CH2), 61.4, 67.4 (CH2), 71.0 (CH2), 72.8, 73.3 (CH2), 125.6, 127.5,
127.7, 127.9, 128.2, 128.3 (2 C), 138.5, 138.7 ppm. HRMS (ES+):
calcd. for C21H26NO2 [M + H]+ 324.1964; found 324.1978.
H), 3.24–3.37 (m, 3 H), 3.54–3.63 (m, 2 H), 3.86–3.89 (m, 1 H),
3.96–3.97 (m, 1 H), 4.32–4.36 (m, 1 H), 4.57–4.67 (m, 3 H), 4.78 (d,
J = 12.0 Hz, 1 H), 7.30–7.37 (m, 10 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 15.0, 48.6 (CH2), 51.7 (CH2), 65.0 (CH2), 71.9 (CH2),
72.9, 73.7 (CH2), 73.8, 74.3, 127.6, 127.8, 128.0 (2 C), 128.5 (2 C),
137.4, 137.7 ppm. HRMS (ES+): calcd. for C21H26O5SNa [M +
Na]+ 413.1393; found 413.1355.
Compound 39: Compound 28 (0.08 g, 0.124 mmol) was converted
into 39 (0.03 g, 62%) following the general procedure. Yellow oil,
1
[α]2D6 = +60.2 (c = 0.3, CHCl3). H NMR (400 MHz, CDCl3): δ =
3.07 (s, 2 H), 3.52–3.56 (m, 1 H), 3.69 (dd, J = 3.6, 10.4 Hz, 1 H),
3.82–3.92 (m, 2 H), 4.03 (d, J = 13.6 Hz, 1 H), 4.31–4.32 (m, 1 H), Compound 43: CBr2F2 (1 mL) was added dropwise to a vigorously
4.49–4.57 (m, 3 H), 4.61 (d, J = 11.6 Hz, 1 H), 5.68–5.74 (m, 2 H), stirred mixture of the sulfone 41 (0.055 g, 0.146 mmol), alumina-
7.23–7.37 (m, 15 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 47.9
supported KOH (0.30 g), tBuOH (6 mL), and DCM (5 mL) kept
(CH2), 58.1, 59.7 (CH2), 65.9 (CH2), 70.7 (CH2), 73.4 (CH2), 74.1, at 5–10 °C. The reaction mixture was stirred at room temperature
126.6, 126.8, 127.2, 127.5, 127.6 (2 C), 127.7, 128.2, 128.4, 128.7,
138.5, 138.7, 139.7 ppm. HRMS (ES+): calcd. for C27H30NO2 [M
+ H]+ 400.2277; found 400.2260.
for an additional 12 h after which the solid catalyst was removed
by filtration through a Celite bed. The filtrate was evaporated to
dryness under reduced pressure. The filter cake was washed thor-
oughly with DCM and the washes were combined with the residue
from the first filtrate. The combined organic layers were dried with
anhyd. Na2SO4, filtered, and the filtrate was concentrated under
reduced pressure to leave a residue. The residue was purified over
silica gel to afford 43 (0.022 g, 49%) as a colorless oil. [α]2D6 = –306.9
(c = 0.05, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 3.44 (s, 3 H),
3.85–3.88 (m, 1 H), 4.54–4.64 (m, 5 H), 4.74 (d, J = 11.6 Hz, 1 H),
6.01–6.03 (m, 1 H), 6.09–6.11 (m, 1 H), 7.27–7.40 (m, 10 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 57.4, 70.8 (CH2), 72.0 (CH2),
78.6, 83.8, 88.0, 127.5, 127.6, 127.9, 128.3 (2 C), 131.8, 135.6, 138.1,
138.5 ppm. HRMS (ES+): calcd. for C20H22O3Na [M + Na]+
333.1467; found 333.1451.
Compound 40: Magnesium monoperoxyphthalate hexahydrate
(0.40 g, 0.96 mmol) was added to a well-stirred solution of sulfide
23 (0.15 g, 0.32 mmol) in dry MeOH (20 mL) and the mixture was
stirred at room temperature under N2. After 6 h, the MeOH was
evaporated to dryness under reduced pressure and the residue was
dissolved in an aq. saturated solution of NaHCO3 and DCM
(3ϫ15 mL). The combined organic layers were dried with anhyd.
Na2SO4, filtered, and the filtrate was concentrated under reduced
pressure to leave a residue. The residue was purified over silica gel
to afford the sulfone 40 (0.14 g, 87%) as a white solid; m.p. 206 °C,
[α]2D6 = +46.0 (c = 0.04, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
2.43 (s, 3 H), 2.99 (d, J = 13.6 Hz, 1 H), 3.18–3.21 (m, 1 H), 3.41
(d, J = 13.2 Hz, 1 H), 3.51–3.65 (m, 2 H), 3.92–3.94 (m, 1 H), 4.61–
4.68 (m, 2 H), 4.86–4.89 (m, 2 H), 5.00 (d, J = 10.8 Hz, 1 H), 7.26–
7.41 (m, 12 H), 7.71 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 21.6, 46.3 (CH2), 50.7 (CH2), 61.4, 71.2,
71.8 (CH2), 75.0 (CH2), 76.8, 127.6, 127.8, 128.0, 128.2, 128.3,
128.6, 128.7, 130.2, 134.2, 136.6, 137.3, 145.9 ppm. HRMS (ES+):
calcd. for C26H28O6S2Na [M + Na]+ 523.1219; found 523.1230.
Compound 44: Compound 42 (0.07 g, 0.179 mmol) was converted
into 44 (0.027 g, 46%) following the procedure described for the
preparation of 43. Colorless oil, [α]2D6 = –85.8 (c = 0.05, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 1.21 (t, J = 6.8 Hz, 3 H), 3.62–
3.66 (m, 2 H), 3.87 (t, J = 5.2 Hz, 1 H), 4.54 (d, J = 5.6 Hz, 1 H),
4.58 (s, 2 H), 4.62 (d, J = 12.0 Hz, 1 H), 4.68–4.69 (m, 1 H), 4.75
(d, J = 11.6 Hz, 1 H), 6.00–6.01 (m, 1 H), 6.07–6.09 (m, 1 H), 7.27–
7.39 (m, 10 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 15.6, 65.4
(CH2), 70.9 (CH2), 72.1 (CH2), 78.7, 84.2, 86.5, 127.6 (2 C), 128.0
(2 C), 128.3 (2 C), 131.6, 136.3, 138.3, 138.6 ppm. HRMS (ES+):
calcd. for C21H24O3Na [M + Na]+ 347.1623; found 347.1607.
Compound 41: Potassium carbonate (0.05 g, 0.36 mmol) was added
to a well-stirred solution of 40 (0.06 g, 0.12 mmol) in dry MeOH
(20 mL) and the mixture was stirred at room temperature under
N2. After 20 h, the MeOH was evaporated to dryness under re-
duced pressure and the residue was partitioned between an aq. sat-
urated solution of NaHCO3 and EtOAc (3ϫ15 mL). The com-
bined organic layers were dried with anhyd. Na2SO4, filtered, and
the filtrate was concentrated under reduced pressure to leave a resi-
due. The residue was purified over silica gel to afford sulfone 41
(0.045 g, 78%) as a white solid; m.p. 138 °C, [α]2D6 = –36.8 (c = 1.1,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 3.17–3.31 (m, 3 H), 3.34
(s, 3 H), 3.58 (t, J = 12.0 Hz, 1 H), 3.77–3.79 (m, 1 H), 4.00–4.01
(m, 1 H), 4.28–4.32 (m, 1 H), 4.56–4.67 (m, 3 H), 4.88 (d, J =
12.0 Hz, 1 H), 7.30–7.39 (m, 10 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 48.0 (CH2), 51.7 (CH2), 57.2, 72.0 (CH2), 73.6, 73.8
(CH2), 74.9, 127.6, 127.8, 128.0 (2 C), 128.5 (2 C), 137.4,
137.6 ppm. HRMS (ES+): calcd. for C20H24O5SNa [M + Na]+
399.1236; found 399.1294.
CCDC-752657 (for 18) and -752658 (for 41) contain the supple-
mentary crystallographic 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.
Supporting Information (see also the footnote on the first page of
this article): 1H and 13C NMR spectra for new compounds and
NOESY–COSY data for 14 and 19.
Acknowledgments
T. P. thanks the Department of Science and Technology (DST),
New Delhi for financial support. A. K. A. thanks the Council for
Scientific and Industrial Research, New Delhi for a fellowship. The
DST is also thanked for the creation of a 400 MHz NMR facility
under the IRPHA (Intensification of Research in High Priority
Areas) program and DST-FIST (Fund for Improvement of Science
and Technology Infrastructure) for a single-crystal X-ray facility.
Compound 42: NaOEt (0.025 g, 0.36 mmol) was added to a well-
stirred solution of 40 (0.06 g, 0.12 mmol) in dry EtOH (20 mL) and
the mixture was stirred at room temperature under N2. After 6 h,
EtOH was evaporated to dryness under reduced pressure and the
residue was partitioned between an aq. saturated solution of
NaHCO3 and EtOAc (3ϫ15 mL). The combined organic layers
were dried with anhyd. Na2SO4, filtered, and the filtrate was con-
centrated under reduced pressure to leave a residue. The residue
[1] For reviews on derivatives of piperidine, see: a) B. G. Davis,
Tetrahedron: Asymmetry 2009, 20, 652–671; b) K. Takasu, Syn-
lett 2009, 1905–1914; c) K. C. Majumdar, P. K. Basu, P. P. Mu-
6818
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6810–6819

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Received: July 4, 2010
Published Online: October 28, 2010
Eur. J. Org. Chem. 2010, 6810–6819
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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