Synthesis of spirocyclic thiazolidinediones using ring-closing metathesis and one-pot sequential ring-closing/cross metathesis

Article abstract of DOI:10.1039/c0ob01248c

A novel synthetic route to spirocyclic thiazolidinediones is reported by utilizing ring-closing metathesis (RCM). A selective cross metathesis (CM) of N-allyl azaspiro derivatives with different olefins has been demonstrated to prepare substituted azaspir

Full text of DOI:10.1039/c0ob01248c

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PAPER
Synthesis of spirocyclic thiazolidinediones using ring-closing metathesis and
one-pot sequential ring-closing/cross metathesis†
Kalyan Dhara, Sushovan Paladhi, Ganesh Chandra Midya and Jyotirmayee Dash*
Received 24th December 2010, Accepted 23rd February 2011
DOI: 10.1039/c0ob01248c
A novel synthetic route to spirocyclic thiazolidinediones is reported by utilizing ring-closing metathesis
(RCM). A selective cross metathesis (CM) of N-allyl azaspiro derivatives with different olefins has been
demonstrated to prepare substituted azaspiro-[4.4]nonenediones. The X-ray crystal structure of a
spirocyclic thiazolidinedione dimer is described, which has been prepared in two steps from
thiazolidinedione using a one-pot sequential ring-closing and self metathesis. Cross metathesis proceeds
smoothly with both electron rich and poor olefins. The symmetrical bis-thiazolidinedione spirocyclic
system can be used as CM coupling partner with olefins. One-pot sequential RCM-CM has been
developed for the synthesis of substituted spirocyclic compounds. The methodology allows a quick
access to thia-azaspiro-[4.4]nonene and -[4.5]decene-dione ring systems from readily available starting
materials which are not otherwise accessible.
Herein we report the RCM,7 cross metathesis (CM) and a
selective one-pot sequential RCM/CM on thiazolidinedione-
Olefin metathesis has emerged as a powerful tool for the construc-
containing substrates for the rapid construction of novel thia-
Introduction
tion of carbon–carbon double bonds.1,2 It has been extensively
azaspirocyclic ring systems (Scheme 1).
used in the areas of small molecule, natural product and polymer
synthesis.1 The commercial availability of well-defined catalysts
(Fig. 1) and their tolerance to a variety of functional groups
significantly widened the scope of olefin metathesis.1,2
Fig. 1 Metathesis catalysts.
There are numerous applications of ring-closing metathesis
(RCM) to the syntheses of heterocyclic compounds.2,3 Thiazo-
lidinediones and spirocyclic thiazolidines are potential chemother-
apeutic agents with antidiabetic, antipsychotic, sedative and
anaesthetic activities.4,5 Despite their synthetic/medicinal utility,
to the best of our knowledge only a few syntheses of 5-spirocyclic
thiazolidiones have been described in the literature5 and only
a few compounds are reported.6 Most of the applications of
thiazolidinediones are described in patents.6
Scheme 1 RCM route to spirocyclic thiazolidinediones and selective
cross metathesis (CM) and one-pot sequential RCM/CM to substituted
thiazolidinediones.
Results and discussion
In ongoing research aimed at diversity oriented synthesis8 of
functionalized thiazole derivatives,9,10 we found that treatment of
thiazolidinedione 1 with allyl bromide in the presence of K2CO3
in DMF afforded the triallyl derivative 2 in 70% yield (Scheme 2).
Initially, we examined the ability of Grubbs1 (G-I and G-II)
and Hoveyda-Grubbs1 (HG-I and HG-II) ruthenium alkylidenes
(Fig. 1) to catalyze a selective RCM of 2 (Table 1).
Indian Institute of Science Education and Research Kolkata, Mohan-
pur Campus, Mohanpur, 7412 52, Nadia, West Bengal, India. E-mail:
jyotidash@iiserkol.ac.in; Fax: +91-33-25873020
† Electronic supplementary information (ESI) available: X-Ray crystallo-
graphic data for 4 and NMR spectra of compounds. CCDC reference
number 795644. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c0ob01248c
As shown in Table 1, the best results were found using 2 mol%
of G-II or HG-II in CH2Cl2 at rt to give spirocyclopentenyl
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Table 2 RCM of thiazolidinedione derivative 7 and 8
Scheme 2 Preparation of triallyl thiazolidinedione 2.
Table 1 Optimization of RCM of 2
Entry
1
Substrate
Product
Yield (%)a
95
Entry Cat. (mol%), time Conv. (%)a Ratioa of 3 : 4 Yield (%)b 3, 4
2
3
4
5
98
80
99
81
1
2
3
4
5
6
7
8
G-I (5), 12 h
89
55
97 : 3
65c, —
39d, —
71, 17
54, 32
85, 5
83, 9
54, 35
5, 87
HG-I (5), 12 h
G-II (5), 12 h
G-II (5), 18 he
G-II (2), 8 h
83 : 17
74 : 26
60 : 40
87 : 13
85 : 15
60 : 40
10 : 90
>99
>99
>99
>99
>99
>99
9ab
HG-II (2), 8 h
HG-II (5), 12 h
HG-II (5), 18 he
a Percent conversions and E : Z ratios were determined by 1H NMR
analysis of crude reaction mixture. b Isolated yields after chromatography.
c 13% of starting material 2 left. d 41% of 2 left. e 40 ◦C.
thiazolidine 3 in high isolated yield (entries 5 and 6). Incomplete
conversion and low yields of isolated product 3 were observed
using 5 mol% of G-I or HG-I. Further optimization showed that
increasing the catalyst loading of G-II and HG-II to 5 mol%
enhanced the yield of 4 (Table 1, entries 7 and 8) derived from
homodimerization of the RCM product 3. Dimer 4 was obtained
as the sole product by using HG-II giving longer reaction times
at 40 ◦C. The structure of dimer 4 was confirmed by single crystal
X-ray analysis (Fig. 2, ESI†).11 The packing diagram of dimer 4
shows a body centered cubic arrangement in the unit cell (Fig. 2B).
a Isolated yield after chromatography. b 5 mol% of G-II, 24 h.
Fig. 2 (A) X-Ray crystal structure and (B) the packing diagram of dimer
4.
Scheme 3 Preparation of thiazolidinediones 7 and 8.
Next we examined the RCM of other thiazolidinedione sub-
strates 7 and 8 (Scheme 3, Table 2). Substrates 7 and 8 were
prepared from 1 by base mediated selective alkylation with
alkyl halides via 5 and 6 (Scheme 3). N-Alkylation of 1 was
selectively carried out using Et3N to give the corresponding
thiazolidinediones 5 in high yield.12 Alkylation at C5 of 5 and 6
was done using either K2CO3 or KOtBu depending on the alkenyl
halide (Scheme 3).
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Table 4 One-pot RCM and CM
RCM of compounds 7 and 8 using 2 mol% of G-II in
CH2Cl2 proceeded smoothly to give the corresponding spirocyclic
compounds 9 (Table 2). The yields for the RCM step ranged from
80 to 99%. Longer reaction time (24 h) and 5 mol% of G-II were
required for RCM of 7c to give compound 9a in 80% yield (entry 3).
Spirocyclic compound 9c was prepared in near quantitative yield
(entry 4). Spirocyclohexenyl derivative 9d was efficiently prepared
by RCM of 8b in 81% isolated yield (Table 2, entry 5).
Compound 9a was further functionalized to give the corre-
sponding diol 10. The diol 10 was prepared using a one-pot
two-step process involving RCM of 7a and dihydroxylation13 of
9a in 91% overall yield. A two step (RCM/hydrogenation)10c,14
one pot procedure was also developed to prepare 11, a known
compound5,15 in 93% overall yield (Scheme 4).
Entry
1
Olefin 12
Ratioa 13 : 4
Ratio 13 (E/Z)a
Yield (%)b 13
13a, 71
80 : 20
87 : 13
2
67 : 43
>99
13d, 47
Conditions: 5 equiv. of 12a and 1.5 equiv of 12d.a Determined by 1H NMR
analysis of crude reaction mixture. b Isolated yields after chromatography.
CM of 3 with 5 equiv. of 4-methylpent-1-ene 12a afforded 13a
in 78% (E/Z, 87 : 13) yield. Treatment of 3 with other olefins
12b–12e afforded 13b–13e in moderate isolated yields (53–67%,
entries 2–5).
Scheme 4 One pot RCM/dihydroxylation and RCM/hydrogenation.
Based on these successful results of selective CM with a
variety of olefins we have demonstrated one-pot sequential RCM–
CM promoted by HG-II catalyst (Table 4) for the synthesis of
substituted spirocyclic compounds 13. One-pot processes are of
considerable current interest because several chemical reactions
can be performed in only one operation avoiding the handling
and isolation of intermediates.18,19 Substrate 2 was first treated
with 2 mol% HG-II in CH2Cl2 and after completion of the RCM
step; olefin 12a or 12d was added. Spirocyclic derivatives 13a and
13d were obtained in improved yield (Table 4) compared to the
two-step procedure (66% and 45% overall yield for 13a and 13d).
In some cases (Tables 3 and 4) formation of self dimerization
product 4 was observed. Following these observations, dimer 4
was used as coupling partner with 12a (Scheme 5) in the presence
of 5 mol% HG-II in CH2Cl2 (40 ◦C) to furnish 13a in 71%
isolated yield (E/Z, 85 : 15). Use of symmetric disubstituted olefin
4 containing heteroatoms N, S and O as CM coupling partner
can find applications in the synthesis of polymers with novel
properties.20
We turned next to examine the feasibility of selective cross
metathesis of N-allyl azaspiro substrate 3 with different alkenes
(Table 3). Unlike RCM and ring-opening metathesis polymer-
ization (ROMP), cross metathesis (CM),16 is largely unexplored.
Spirocyclic compound 3 possessing a cyclic double bond can also
undergo ring-opening cross metathesis (ROCM).17 The terminal
double bond of substrate 3 was found to selectively cross with
both electron-poor and electron-rich olefins 12 to give E-selective
thiazolidinedione derivatives 13 as the major product. The reac-
tions were carried out using 3 mol% of HG-II in CH2Cl2 at 40 ◦C.
Table 3 Cross metathesis of thia-azaspirocyclic compound 3
Entry Olefin 12
Ratioa 13 : 4 Ratio 13 (E/Z)a Yield (%)b 13
1
92 : 8
83 : 17
13a, 78
2
3
100 : 0
100 : 0
85 : 15
96 : 4
13b, 67
13c, 58
Scheme 5 Cross metathesis using dimer 4.
4
5
84 : 16
90 : 10
>99
13d, 53
13e, 60d
Conclusion
c
—
In summary we have developed a general solution for the
synthesis of thia-azaspiro-[4.4]nonene and [4.5]decene-dione ring
systems from readily available starting materials which are not
otherwise accessible. This new RCM, CM and one-pot metathesis
platform will expand the scope and utility of novel spirocyclic
thiazolidinediones in materials, medicines and biology.
Conditions: 5 equiv. of 12 in entry 1, 3 equiv. in entry 2 and 5, 1.5 equiv.
in entries 3 and 4.a Determined by 1H NMR analysis of crude reaction
mixture. b Isolated yields after chromatography. c Not detected. d E only.
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anhydrous Na2SO4, filtered and concentrated in vacuo. The crude
residue was then purified by column chromatography on silica gel
with EtOAc–hexane (10/90 to 20/80) to provide compounds 5.
Experimental section
General methods
All experiments were carried out under an inert atomosphere of
argon in flame-dried flasks. Solvents were dried using standard
procedures reported in D. D. Perrin, W. L. F. Armarego, Purifi-
cation of Laboratory Chemicals, Pergamon Press, Oxford, 3rd
edn, 1988. All starting materials were obtained from commercial
suppliers and used as received. Products were purified by flash
chromatography on silica gel (100–200 mesh, Merck). Unless
otherwise stated, yields refer to analytical pure samples. Melting
3-Methylthiazolidine-2,4-dione (5a). Yield: 85%; obtained as a
colorless liquid, solidifies upon storage in refrigerator; H NMR
(400 MHz): 3.13 (2H, s), 2.07 (3H, s); 13C NMR (100 MHz):
171.7, 171.4, 33.7, 27.9; IR (KBr): 3398, 2990, 2948, 2637, 2371,
1744, 1674, 1425, 1400 cm-1; HRMS (ESI) calcd for C4H9N2O2S
[M+NH4]+: 149.0385; Found 149.0263
1
3-Benzylthiazolidine-2,4-dione (5b). Yield: 91%; colorless
solid; m.p. 61.8 ◦C;1H NMR (400 MHz): 7.45–7.41 (2H, m), 7.37–
7.31 (3H, m), 4.15 (2H, s), 3.12 (2H, s); 13C NMR (100 MHz):
171.6, 171.1, 135.0, 128.9, 128.7, 128.3, 45.3, 33.7; IR (KBr): 3210,
3082, 2950, 2325, 2126, 1421, 1255 cm-1; HRMS (ESI) calcd for
C10H10NO2S [M+H]+: 208.0424; Found 208.0762.
¨
points were measured with BUCHI Melting Point B-545 and
are uncorrected. NMR spectra were recorded in CDCl3 unless
1
otherwise stated. H NMR spectra were recorded at 500 MHz
using Bru¨ker ADVANCE 500 MHz and JEOL 400 MHz in-
struments at 278 K. Signals are quoted as d values in ppm
using residual protonated solvent signals as internal standard
(CDCl3: d 7.26 ppm). Data are reported as follows: chemical shift,
integration, multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, p = pentet, br = broad, m = multiplet), and coupling
constants (Hz). 13C NMR spectra were recorded on either a JEOL-
400 (100 MHz), or a Bru¨ker ADVANCE 500 MHz (125 MHz)
with complete proton decoupling. Chemical shifts (d) are reported
in ppm downfield from tetramethylsilane with the solvent as
the internal reference (CDCl3: d 77.23 ppm). Infrared (FTIR)
spectra were recorded on a Perkin Elmer spectrophotometer with
the KBr disk and KBr plate techniques for solid and liquid
samples, nmax cm-1. HRMS analyses were performed with Q-TOF
YA263 high resolution (Water Corporation) instruments by +ve
mode electrospray ionization. Hydrogenation was carried out with
H-Cube Hydrogenation Reactor (THALESNANO nanotechnol-
ogy). Single crystal X-ray analysis of dimer 4 was recorded on a
Brucker high resolution X-ray diffractometer instrument.
3-Allylthiazolidine-2,4-dione (5c). Yield: 86%; colorless oil; 1H
NMR (500 MHz): 5.82–5.73 (1H, m), 5.28–5.19 (2H, m), 4.19
(2H, dt, J = 6.0, 1.2 Hz), 3.95 (2H, s); 13C NMR (125 MHz):
171.1, 170.8, 129.9, 118.8, 43.7, 33.6. IR (neat): 3420, 3086, 2989,
2942, 1752, 1683, 1429, 1378, 1332 cm-1; HRMS (ESI) calcd for
C6H8NO2S [M+H]+: 158.0267; Found 158.1054.
Preparation of C5-allyl thiazolidinediones 6
General procedure. To a suspension of 2,4-thiazolidinedione 5
(1 equiv.) and K2CO3 (1 equiv.) in dry DMF (0.5 M) was added
allyl bromide (0.7 equiv.). The resulting mixture was stirred at rt for
8 h. The reaction was stopped by adding water and then the
mixture was extracted with EtOAc (3 ¥ 20 mL). The combined
organic phases were washed with brine, dried over anhydrous
Na2SO4, filtered and concentrated. The crude residue was then
purified by column chromatography on silica gel with EtOAc–
hexane (5/95 to 10/90) to give compounds 6.
Preparation of 3,5,5-triallylthiazolidine-2,4-dione (2). To a sus-
pension of 2,4-thiazolidinedione 1 (500 mg, 4.27 mmol, 1 equiv.)
and K2CO3 (2.95 g, 21.35 mmol, 5 equiv.) in dry DMF (10 mL) was
added allyl bromide (1.8 mL, 21.35 mmol, 5 equiv.). The resulting
mixture was stirred at rt for 18 h. The reaction was stopped by
adding water and then the mixture was extracted with EtOAc
(3 ¥ 20 mL). The combined organic phases were washed with
brine, dried over anhydrous Na2SO4, filtered and concentrated.
The crude residue was then purified by column chromatography on
silica gel with EtOAc–hexane (5 : 95) to give compound 2 (707 mg,
5-Allyl-3-methylthiazolidine-2,4-dione (6a). Yield: 64%; color-
less oil; 1H NMR (400 MHz): 5.45–5.32 (1H, m), 4.69 (1H, d, J =
7.6 Hz), 4.65 (1H, s), 3.52 (1H, dd, J = 11.3, 5.0 Hz), 2.04 (3H,
s), 1.90–1.83 (1H, m), 1.47–1.38 (1H, m); 13C NMR (125 MHz):
173.9, 171.0, 131.9, 119.6, 49.0, 36.5, 27.6; IR: (neat) 3813, 3417,
2921, 2352, 2328, 1682, 1416, 1367 cm-1; HRMS (ESI) calcd for
C7H10NO2S [M+H]+: 172.0424; Found 172.0497.
3,5-Diallylthiazolidine-2,4-dione (6c). Yield: 67%; colorless
oil; 1H NMR (500 MHz): 5.80–5.72 (2H, m), 5.24–5.17 (4H, m),
4.27 (1H, dd, J = 8.7, 4.0 Hz), 4.19–4.16 (2H, m), 2.94–2.90 (1H,
m), 2.64–2.58 (1H, m); 13C NMR (125 MHz): 173.5, 170.7, 131.8,
130.0, 119.9, 118.8, 49.1, 43.7, 36.6; IR (neat): 3418, 3084, 2930,
1754, 1694, 1428, 1379, 1330, 1264 cm-1; HRMS (ESI) calcd. for
C9H12NO2S [M+H]+: 198.0580; Found 198.0670.
1
70%) as colorless oil; H NMR (500 MHz): 5.76–5.66 (3H, m),
5.22–5.15 (6H, m), 4.13 (2H, dt, J = 5.9, 1.3 Hz), 2.73–2.69 (2H,
m), 2.63–2.58 (2H, m); 13C NMR (125 MHz): 175.9, 170.1, 130.7,
130.2, 121.3, 118.6, 62.9, 43.6, 42.5; IR (neat): 3417, 3083, 2983,
2917, 2352, 1748, 1732, 1694, 1682, 1434, 1378 cm-1; HRMS (ESI)
calcd for C12H16NO2S [M+H]+: 238.0893; Found 238.0965.
Preparation of thiazolidinediones 7a–b
Preparation of thiazolidinediones 5
General procedure. To a suspension of 2,4-thiazolidinedione
5a or 5b (1 equiv.) and K2CO3 (5 equiv.) in dry DMF (0.5 M)
was added allyl bromide (5 equiv.). The resulting mixture was
stirred at rt for 18 h. The reaction was stopped by adding water
and then the mixture was extracted with EtOAc (3 ¥ 20 mL).
The combined organic phases were washed with brine, dried over
anhydrous Na2SO4, filtered and concentrated. The crude residue
General procedure. MeI or BnBr or allyl bromide (3 equiv.)
was added to a solution of 2,4-thiazolidinedione 1 (1 equiv.) and
Et3N (3 equiv.) in CH2Cl2 (0.7 M) at 0 ◦C and stirred for 7 h
while warming to ambient temperature. The reaction mixture was
quenched with water and extracted with CH2Cl2 (3 ¥ 20 mL).
The combined organic phases were washed with brine, dried over
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was then purified by column chromatography on silica gel with
EtOAc–hexane (5/95 to 15/85) to give compound 7a or 7b as
colorless oils.
3,5-Diallyl-5-(but-3-enyl)thiazolidine-2,4-dione (8b). To a sus-
pension of 2,4-thiazolidinedione 6c (200 mg, 1.01 mmol, 1 equiv.)
and KOtBu (136.01 mg, 1.21 mmol, 1.2 equiv.) in dry DMF (5 mL)
was added 4-bromobut-1-ene (0.12 mL, 1.21 mmol, 1.2 equiv.).
The resulting mixture was stirred at rt for 12 h. The reaction
was stopped by adding water and then the mixture was extracted
with EtOAc (3 ¥ 20 mL). The combined organic phases were
washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated. The crude residue was then purified by column
chromatography on silica gel with EtOAc–hexane (5 : 95) to give
compound 8b (103 mg, 41%) as colorless oil; 1H NMR (400 MHz):
5.75–5.72 (3H, m), 5.30–5.18 (4H, m), 5.10–4.97 (2H, m), 4.21–
4.15 (2H, m), 2.97–2.78 (1H, m), 2.74–2.68 (1H, m), 2.66–2.59 (1H,
5,5-Diallyl-3-methylthiazolidine-2,4-dione (7a). Yield: 65%;
colorless oil; 1H NMR (500 MHz): 5.76–5.68 (2H, m), 5.21–5.17
(4H, m), 3.04 (3H, s), 2.73–2.69 (2H, m), 2.64–2.60 (2H, m); 13C
NMR (125 MHz): 176.3, 170.5, 130.7, 121.0, 63.1, 42.3, 27.5; IR
(neat): 3898, 3813, 3418, 3081, 2917, 2353, 2337, 1679, 1372 cm-1;
HRMS (ESI) calcd for C10H14NO2S [M+H]+: 212.0737; Found
212.0738.
5,5-Diallyl-3-benzylthiazolidine-2,4-dione (7b). Yield: 75%;
colorless oil; 1H NMR (500 MHz): 7.40–7.39 (2H, m), 7.37–7.32
(3H, m), 5.74–5.66 (2H, m), 5.21 (1H, dd, J = 2.8, 1.3 Hz), 5.17
(1H, dd, J = 2.8, 1.3 Hz), 5.14–5.13 (1H, m), 5.12–5.11 (1H, m),
4.77 (2H, s), 2.78–2.74 (2H, m), 2.68–2.64 (2H, m); 13C NMR
(125 MHz): 176.2, 170.4, 135.2, 130.5, 128.6, 128.4, 127.9, 121.2,
62.8, 45.1, 42.5; IR (neat): 3410, 2918, 2353, 1682, 1383, 1336 cm-1;
HRMS (ESI) calcd for C16H18NO2S [M+H]+: 288.1050; Found
288.0931.
m), 2.24–2.26 (1H, m), 2.18–2.10 (1H, m), 2.00–1.92 (1H, m); 13
C
NMR (100 MHz, CDCl3): 175.3, 169.2, 135.2, 129.6, 129.1, 120.3,
117.8, 114.9, 62.0, 42.6, 42.3, 36.3, 27.9. IR (neat): 3698, 3613,
3417, 3089, 2717, 2352, 1752, 1689, 1426, 1371 cm-1; HRMS (ESI)
calcd for C13H18NO2S [M+H]+: 252.1050; Found 252.1024.
Preparation of ring-closing metathesis products 3 and 9
General procedure. To a stirring solution of 2, 7 or 8 (1 equiv.)
in CH2Cl2 (0.05 M) was added G-II (2 mol%) and stirred for 8 h
at room temperature. The reaction mixture was then concentrated
and purified on silica gel (EtOAc–hexane, 10 : 90 to 20 : 80) to yield
products 3 and 9.
5,5-Di-(E)-but-2-enyl)-3-methylthiazolidine-2,4-dione (7c). To
a suspension of 2,4-thiazolidinedione 5a (200 mg, 1.52 mmol,
1 equiv.) and K2CO3 (1.05 g, 7.6 mmol, 5 equiv.) in dry DMF
(5 mL) was added (E)-1-bromobut-2-ene (0.62 mL, 6.08 mmol,
4 equiv.). The resulting mixture was stirred at rt for 18 h. The
reaction was stopped by adding water and then the mixture
was extracted with EtOAc (3 ¥ 20 mL). The combined organic
phases were washed with brine, dried over anhydrous Na2SO4,
filtered and concentrated. The crude residue was then purified by
column chromatography on silica gel with EtOAc–hexane (5 : 95)
3-Allyl-1-thia-3-azaspiro[4.4]non-7-ene-2,4-dione (3). Yield:
85%; colorless oil; 1H NMR (500 MHz): 5.86–5.77 (1H, m),
5.75 (2H, s), 5.25–5.24 (2H, m), 4.24 (2H, dt, J = 5.8, 1.3 Hz),
3.35–3.30 (2H, m), 2.92–2.89 (2H, m); 13C NMR (125 MHz):
177.7, 170.8, 130.2, 128.0, 118.6, 61.7, 47.9, 43.9. IR (neat): 3417,
2925, 2849, 2353, 1689, 1372, 1219 cm-1; HRMS (ESI) calcd for
C10H12NO2S [M+H]+: 210.0580; Found 210.0521.
1
to give compound 7c (257.7 mg, 71%) as colorless oil; H NMR
(400 MHz): 5.24–5.13 (2H, m), 4.90–4.80 (2H, m), 1.99 (3H, s),
1.49–1.42 (2H, m), 1.38–1.31 (2H, m), 0.26 (3H, s), 0.24 (3H, s);
13C NMR (125 MHz): 177.0, 171.2, 132.0, 64.4, 41.4, 27.5, 18.0;
IR (neat): 3898, 3813, 3417, 3081, 2917, 2352, 2336, 1679 cm-1;
HRMS (ESI) calcd for C12H18NO2S [M+H]+: 240.1050; Found
240.1295.
3-Methyl-1-thia-3-azaspiro[4.4]non-7-ene-2,4-dione
(9a).
Yield: 95%; colorless oil; 1H-NMR (500 MHz): 5.75 (2H, s),
3.37–3.30 (2H, m), 3.14 (3H, s), 2.92–2.89 (2H, m); 13C-NMR
(100 MHz): 178.2, 171.4, 128.1, 61.0, 47.9, 28.9; IR (neat): 3417,
3070, 2947, 2845, 1747, 1682, 1428, 1367, 1279 cm-1; HRMS
(ESI) calcd for C8H10NO2S [M+H]+: 184.0424; Found 184.0507.
Preparation of thiazolidinediones 8a–b
3-Benzyl-1-thia-3-azaspiro[4.4]non-7-ene-2,4-dione
(9b).
Yield: 98%; colorless oil; 1H NMR (400 MHz): 7.39–7.37
(2H, m), 7.35–7.28 (3H, m), 5.74 (2H, s), 4.79 (2H, s), 3.33–3.28
(2H, m), 2.92–2.87 (2H, m), 13C NMR: (100 MHz): 177.9, 171.0,
135.3, 128.7, 128.6, 128.1, 128.0, 61.6, 47.9, 47.3; IR (neat): 3414,
3066, 3034, 2933, 2844, 1748, 1497, 1456, 1429, 1381, 1335, 1305
cm-1; HRMS (ESI) calcd for C14H14NO2S [M+H]+, 260.0737;
Found 260.0779.
5-Allyl-3-methyl-5-(2-methylallyl)thiazolidine-2,4-dione
(8a).
To a suspension of 2,4-thiazolidinedione 10a (100 mg, 0.58 mmol,
1 equiv.) and K2CO3 (240.46 mg, 1.74 mmol, 3 equiv.) in dry
DMF (5 mL) was added 3-bromo-2-methylprop-1-ene (0.17 mL,
1.74 mmol, 3 equiv.). The resulting mixture was stirred at rt for
8 h. The reaction was stopped by adding water and then the
mixture was extracted with EtOAc (3 ¥ 20 mL). The combined
organic phases were washed with brine, dried over anhydrous
Na2SO4, filtered and concentrated. The crude residue was then
purified by column chromatography on silica gel with EtOAc-
hexane (5 : 95) to give compound 8a (128.7 mg, 99%) as colorless
oil; 1H NMR (500 MHz): 5.75–5.66 (1H, m), 5.20–5.18 (1H,
m), 5.16 (1H, m), 4.93–4.92 (1H, m), 4.80 (1H, sbr), 3.04 (3H,
s), 2.82–2.79 (1H, m), 2.72–2.67 (1H, m), 2.60–2.55 (2H, m),
1.73 (3H, s); 13C NMR (125 MHz): 176.9, 170.9, 139.4, 130.8,
121.2, 117.0, 62.9, 45.4, 43.2, 27.6, 24.2; IR (neat): 3417, 3288,
3082, 2917, 2353, 2337, 1372, 1280 cm-1; HRMS (ESI) calcd for
C11H16NO2S [M+H]+: 226.0893; Found 226.0860.
3,7-Dimethyl-1-thia-3-azaspiro[4.4]non-7-ene-2,4-dione
(9c).
1
Yield: 99%; colorless oil; H NMR (500 MHz): 5.33–5.11 (1H,
m), 3.33–3.24 (2H, m), 3.13 (3H, s), 2.86–2.82 (1H, m), 2.74–2.70
(1H, m), 1.78 (3H, s); 13C NMR (100 MHz): 178.1, 171.5, 137.9,
121.5, 62.4, 51.3, 47.9, 28.0, 16.0; IR (neat): 3614, 3170, 2945,
2744, 1645, 1582, 1427, 1360, 1271, 1204; HRMS (ESI) calcd for
C9H12NO2S [M+H]+: 198.0580; Found 198.0504.
3-Allyl-1-thia-3-azaspiro[4.5]dec-7-ene-2,4-dione (9d). Yield:
81%, colorless oil; 1H NMR (500 MHz): 5.85–5.77 (2H, m), 5.75–
5.72 (1H, m), 5.25–5.20 (2H, m), 4.22 (2H, dt, J = 5.8, 1.1 Hz),
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3.00–2.96 (1H, m), 2.39–2.25 (4H, m), 1.95–1.93 (1H, m); 13C
NMR (125 MHz): 177.4, 170.9, 130.3, 126.6, 123.5, 118.5, 58.5,
43.5, 35.9, 32.0, 22.7. IR (neat): 3415, 2924, 2363, 1689, 1376,
1260 cm-1; HRMS (ESI) calcd for C11H14NO2S [M+H]+: 224.0737;
Found 224.0828.
HRMS (ESI) calcd for C14H20NO2S [M+H]+, 266.1206; Found
266.1316.
(E)-3-(5-Bromopent-2-enyl)-1-thia-3-azaspiro[4.4]non-7-ene-
1
2,4-dione (13b). Yield: 67%; colorless oil; H NMR (400 MHz,
CDCl3): 5.80–5.66 (1H, m), 5.75 (2H, s), 5.60–5.56 (m, 1H), 4.20
(2H, d, J = 7.6 Hz), 3.37–3.30 (4H, m), 2.92–2.89 (2H, m), 2.59
(2H, q, J = 8.6 Hz); 13C NMR (125 MHz, CDCl3): 177.6, 170.8,
132.3, 128.1, 125.1, 61.7, 47.9, 43.1, 35.3, 31.6; IR (neat): 3415,
2920, 2847, 2359, 2081, 1654, 1380, 1330 cm-1; HRMS (ESI) calcd
for C12H14BrNO2SNa [M+Na]+: 337.9829; Found 337.9828.
Synthesis of diol 10. To a stirred solution of 7a (50 mg,
0.24 mmol, 1 equiv.) in CH2Cl2 (3 mL) was added G-II (4.0 mg,
2 mol%) at rt. After completion of starting material 7a (8 h, TLC
monitoring), the CH2Cl2 was concentrated and the crude product
was directly used for OsO4 dihydroxylation. The crude product
was dissolved in acetone–water (5 : 1) and N-methylmorpholine
N-oxide (NMO, 30.9 mg, 0.26 mmol, 1.1 equiv., 60 wt% in water)
and osmium tetraoxide (3.0 mg, 0.012 mmol, 0.05 equiv., 2.5 wt%
in tert-butanol) were added. The reaction mixture was stirred for
2 h at room temperature under argon and, upon completion
(TLC), was quenched with saturated sodium bisulfite, diluted
with water, and extracted with ethyl acetate. The combined
EtOAc portions were dried (Na2SO4), filtered, and concentrated.
The residue was purified by filtration through a short silica gel
column to afford the diol 10 (47.4 mg, 91%) as colorless solid
(m.p. 117.6 ◦C).
(E)-3-(4-(4-Methoxyphenyl)but-2-enyl)-1-thia-3-azaspiro[4.4]-
1
non-7-ene-2,4-dione (13c). Yield: 58%; colorless oil; H NMR
(500 MHz): 7.07–7.05 (2H, m), 6.84–6.82 (2H, m), 5.90–5.84 (1H,
m), 5.74 (2H, s), 5.54–5.47 (1H, m), 4.21 (2H, dd, J = 6.3, 1.0 Hz),
3.79 (3H, s), 3.33–3.29 (4H, m), 2.92–2.88 (2H, m); 13C NMR
(100 MHz): 177.7, 170.9, 158.1, 134.9, 131.5, 129.4, 128.0, 123.1,
113.8, 61.6, 55.2, 47.8, 43.4, 37.52; IR (neat): 3392, 2925, 2360,
1677, 1507, 1378 cm-1; HRMS (ESI) calcd for C18H19NO3SNa
[M+Na]+: 352.0986; Found 352.0953.
3-Cinnamyl-1-thia-3-azaspiro[4.4]non-7-ene-2,4-dione
(13d).
Yield: 53%; colorless oil; 1H NMR (400 MHz): 7.37–7.32 (2H, m),
7.30–7.29 (2H, m), 7.28–7.25 (1H, m), 6.69 (1H, d, J = 16.0 Hz),
6.20–6.15 (1H, m), 5.78 (2H, s), 4.39 (2H, dd, J = 5.5, 1.4 Hz),
3.35–3.30 (2H, m), 2.93–2.88 (2H, m); 13C NMR (500 MHz):
177.7, 170.9, 136.0, 135.0, 128.6, 128.1, 128.0, 126.6, 121.3, 61.7,
47.9, 43.7; IR (neat): 3404, 2924, 2855, 2356, 1751, 1679, 1424,
1379, 1330 cm-1; HRMS (ESI) calcd for C16H16NO2S [M+H]+:
286.0893; Found 286.1051.
7,8-Dihydroxy-3-methyl-1-thia-3-azaspiro[4.4]nonane-2,4-dione
(10). 1H NMR (400 MHz): 3.67–3.64 (2H, m), 2.07 (3H, s), 1.56
(1H, d, J = 7.6 Hz), 1.51(1H, d, J = 6.8 Hz), 1.08 (1H, d, J =
5.1 Hz), 1.03 (1H, d, J = 4.7 Hz); 13C-NMR (125 MHz): 178.9,
171.8, 73.7, 58.1, 45.4, 28.0; IR (neat): 3436, 2930, 2361, 1736,
1676, 1428, 1373, 1279 cm-1; HRMS (ESI) calcd for C8H12NO4S
[M+H]+: 218.0479; Found, 218.0538.
Synthesis of spirocyclopentyl thiazolidinedione 11. To a stirred
solution of 7a (30 mg, 0.14 mmol, 1 equiv.) in CH2Cl2 (3 mL) was
added G-II (2.4 mg, 2 mol%). The reaction mixture was stirred at
rt for 8 h. The CH2Cl2 was then concentrated and MeOH (5 mL)
was added. The reaction was kept in a H-Cube Hydrogenation
Reactor for 1 h. The mixture was concentrated and purified by
flash chromatography to yield (24.2 mg, 93%) of 11 as a colorless
oil, which solidifies on cooling (upon storage in refrigerator).
(E)-Methyl
4-(2,4-dioxo-1-thia-3-azaspiro[4.4]non-7-en-3-
yl)but-2-enoate (13e). Yield: 60%; colorless oil; 1H NMR
(400 MHz): 6.84–6.75 (1H, m), 5.91–5.84 (1H, m), 5.74 (2H, s),
4.36 (2H, dd, J = 6.9, 2.0 Hz), 3.71 (3H, s), 3.34–3.30 (2H, m),
2.95–2.89 (2H, m); 13C NMR (125 MHz): 177.3, 170.4, 165.8,
139.5, 128.0, 123.5, 61.8, 51.7, 47.9, 41.9; IR (neat): 3420, 2952,
2371, 1724, 1681, 1435, 1380, 1350, 1279 cm-1; HRMS (ESI) calcd
for C12H13NO4SNa [M+Na]+: 290.0465; Found 290.0463.
3-Methyl-1-thia-3-azaspiro[4.4]nonane-2,4-dione 11. 1H NMR
(400 MHz): 2.10 (3H, s), 1.28–1.18 (2H, s), 0.90–0.82 (2H, s), 0.72–
0.61 (2H, s), 0.51–0.40 (2H, s); 13C NMR (125 MHz): 178.5, 171.2,
63.6, 41.0, 28.0, 25.4; IR (neat): 3411, 2926, 2354, 1682, 1428, 1367,
1277 cm-1; HRMS (ESI) calcd for C8H12NO2S [M+H]+: 186.0580;
Found 186.0640.
General procedure for one-pot sequential metathesis of 2. To
a solution of 2 (1 equiv.) in CH2Cl2 (0.05 M) was added HG-II
(2 mol%). The mixture was stirred for 8 h at room temp. Then
olefins 12a and 12d (3 to 5 equiv.) and HG-II (3 mol%) were
added and stirred at 40 ◦C for 12 h. The reaction mixture was
concentrated and purified on silica gel (EtOAc–hexane, 5/95 to
20/80) to yield products 13a and 13d.
Preparation of cross metathesis products 13
Preparation of dimer 4. To a stirred solution of 2 (20 mg,
0.08 mmol, 1 equiv.) in CH2Cl2 (2 mL) was added HG-II (2.5 mg,
0.004 mmol, 5 mol%). The reaction mixture was heated at 40 ◦C
for 18 h. The solvent was then removed under reduced pressure,
and the residue purified by flash column chromatography on silica
gel (EtOAc–hexane, 20/80) to give 4 (27 mg, 87%) as colorless
crystal (EtOAc/hexane); m.p.148.4 ◦C. 1H NMR (500 MHz):
5.75 (4H, s), 5.74–5.73 (2H, m), 4.21–4.20(4H, m), 3.32–3.29
(4H, m), 2.92–2.89 (4H, m); 13C NMR (125 MHz): 177.5, 170.7,
128.0, 127.3, 61.6, 47.9, 42.6; IR (neat): 3397, 2945, 2362, 1750,
1673, 1432, 1389, 1356, 1322, 1244 cm-1; HRMS (ESI) calcd for
C18H19N2O4S2 [M+H]+: 391.0778; Found 391.0721; HRMS (ESI)
calcd for C18H18N2O4S2Na [M+Na]+: 413.0608; Found 413.0472.
General procedure. To a solution of 3 (1 equiv.) and olefin 13
(1.5–5 equiv.) in CH2Cl2 (0.05 M) was added HG-II (3 mol%) and
stirred at 40 ◦C for 12 h. The reaction mixture was concentrated
and purified on silica gel (EtOAc–hexane, 5/95 to 20/80) to yield
products 13.
(E)-3-(5-Methylhex-2-enyl)-1-thia-3-azaspiro[4.4]non-7-ene-
2,4-dione (13a). Yield: 78%; colorless oil; 1H NMR (500 MHz):
5.78–5.65 (1H, m), 5.74 (2H, s), 5.46–5.37 (1H, m), 4.17 (2H, d,
J = 7.9 Hz), 3.29–3.24 (2H, m), 2.91–2.87 (2H, m), 1.90 (2H, t, J =
8.7 Hz), 1.66–1.58 (1H, m), 0.86 (3H, s), 0.84 (3H, s); 13C NMR
(100 MHz): 177.7, 170.8, 135.2, 128.0, 122.9, 61.6, 47.9, 43.5, 41.4,
28.4, 22.2; IR (neat): 3400, 2956, 1683, 1428, 1379, 1335 cm-1;
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Cross metathesis of 4 with olefin 12a. To a stirred solution of 4
(20 mg, 0.05 mmol, 1 equiv) and olefin 12a (32 mL, 0.25 mmol, 5
equiv.) in CH2Cl2 (2 mL) was added HG-II (3.1 mg, 0.005 mmol,
10 mol%). The reaction mixture was heated at 40 ◦C for 18 h. The
solvent was then removed under reduced pressure, and the residue
purified by flash column chromatography on silica gel (EtOAc–
hexane, 1/99 to 5/95) to give 13a (9.2 mg, 71%) as a mixture of
E/Z in a ratio of 85 : 15.
9 (a) Z. Jin, Nat. Prod. Rep., 2006, 23, 464; (b) G. Hc¸fle, N. Bedorf,
H. Steinmetz, D. Schomburg, K. Gerth and H. Reichenbach, Angew.
Chem., Int. Ed. Engl., 1996, 35, 1567.
10 (a) J. Dash, S. Arseniyadis and J. Cossy, Adv. Synth. Catal., 2007, 349,
152; (b) T. J. Hoffman, J. Dash, J. H. Rigby, S. Arseniyadis and J. Cossy,
Org. Lett., 2009, 11, 2756; (c) J. Dash, B. Melillo, S. Arseniyadis and J.
Cossy, Tetrahedron Lett., 2011, DOI: 10.1016/j.tetlet.2011.01.027.
11 The crystal structure of 4 has been deposited at the Cambridge
Crystallographic Data Centre and allocated the deposition number
CCDC 795644†.
12 We report the preparation of 5b in improved yield: it is a known
compound see: A. Martinez, M. Alonso, A. Castro, I. Dorronsoro,
J. L. Gelp´ı, F. J. Luque, C. Pe´rez and F. J. Moreno, J. Med. Chem.,
2005, 48, 7103.
Acknowledgements
13 For one-pot RCM/dihydroxylation, see: (a) S. Beligny, S. Eibauer, S.
Maechling and S. Blechert, Angew. Chem., Int. Ed., 2006, 45, 1900;
(b) A. A. Scholte, M. H. An and M. L. Snapper, Org. Lett., 2006, 8,
4759; (c) N. M. Neisius and B. Plietker, J. Org. Chem., 2008, 73, 3218.
14 For one-pot RCM/hydrogenation, see: (a) J. Louie, C. W. Bielawski and
R. H. Grubbs, J. Am. Chem. Soc., 2001, 123, 11312; (b) S. D. Drouin,
F. Zamanian and D. E. Fogg, Organometallics, 2001, 20, 5495; (c) P.
Børsting and P. Nielsen, Chem. Commun., 2002, 2140; (d) B. Schmidt
and M. Pohler, Org. Biomol. Chem., 2003, 1, 2512; (e) A. Fu¨rstner
and A. Leitner, Angew. Chem., Int. Ed., 2003, 42, 308; (f) R. Malacea,
C. Fischmeister, C. Bruneau, J.-L. Dubois, J.-L. Couturier and P. H.
Dixneuf, Green Chem., 2009, 11, 152.
15 The NMR data of this compound are not reported in ref. 5.
16 For a review on CM: (a) S. J. Connon and S. Blechert, Angew. Chem.,
Int. Ed., 2003, 42, 1900For leading references: (b) A. K. Chatterjee,
T.-L. Choi, D. P. Sanders and R. H. Grubbs, J. Am. Chem. Soc., 2003,
125, 11360; (c) H. E. Blackwell, D. J. O’Leary, A. K. Chatterjee, R. A.
Washenfelder, D. A. Bussmann and R. H. Grubbs, J. Am. Chem. Soc.,
2000, 122, 58; (d) T. J. Donohoe and J. F. Bower, Proc. Natl. Acad. Sci.
U. S. A., 2010, 107, 3373; (e) T. J. Donohoe, N. J. Race, J. F. Bower and
C. K. A. Callens, Org. Lett., 2010, 12, 4094.
17 For specific examples of ROCM: (a) I. Ibrahem, M. Yu, R. R. Schrock
and A. H. Hoveyda, J. Am. Chem. Soc., 2009, 131, 3844; (b) M. L.
Snapper, J. A. Tallarico and M. L. Randall, J. Am. Chem. Soc., 1997,
119, 1478; (c) S. Randl, S. J. Connon and S. Blechert, Chem. Commun.,
2001, 1796; and references therein.
18 For recent reviews, see: (a) D. E. Fogg and E. N. Santos dos, Coord.
Chem. Rev., 2004, 248, 2365; (b) J. C. Wasilke, S. J. Obrey, R. T. Baker
and G. C. Bazan, Chem. Rev., 2005, 105, 1001.
19 For selective examples of ruthenium alkylidenes in tandem catalysis,
see: (a) J. Louie, C. W. Bielawski and R. H. Grubbs, J. Am. Chem. Soc.,
2001, 123, 11312; (b) B. Schmidt, Chem. Commun., 2004, 742; (c) H.-Y.
Lee, H. Y. Kim, H. Tae, B. G. Kim and J. Lee, Org. Lett., 2003, 5, 3439;
(d) S. Beligny, S. Eibauer, S. Maechling and S. Blechert, Angew. Chem.,
Int. Ed., 2006, 45, 1900.
20 (a) H. E. Blackwell, D. J. O’Leary, A. K. Chatterjee, R. A. Washenfelder,
D. A. Bussmann and R. H. Grubbs, J. Am. Chem. Soc., 2000, 122, 58;
(b) J. P. Morgan, C. Morrill and R. H. Grubbs, Org. Lett., 2002, 4, 67.
We thank DST and CSIR, India for funding. KD thanks UGC,
SP, and GCM thank CSIR for research fellowship.
Notes and references
1 (a) A. Fu¨rstner, Angew. Chem., Int. Ed., 2000, 39, 3013; (b) Y. Chauvin,
Angew. Chem., Int. Ed., 2006, 45, 3740; (c) R. R. Schrock, Angew.
Chem., Int. Ed., 2006, 45, 3748; (d) R. H. Grubbs, Angew. Chem., Int.
Ed., 2006, 45, 3760; (e) A. H. Hoveyda and A. R. Zhugralin, Nature,
2007, 450, 243.
2 (a) A. Deiters and S. F. Martin, Chem. Rev., 2004, 104, 2199; (b) J.
Cossy, Pure Appl. Chem., 2010, 82, 1365.
3 (a) J. M. Lehmann, L. B. Moore, T. A. Smith-Oliver, W. O. Wilkison, T.
M. Willson and S. A. Kliewer, J. Biol. Chem., 1995, 270, 12953; (b) A.
Zask, I. Jirkovsky, J. W. Nowicki and M. L. McCaleb, J. Med. Chem.,
1990, 1418; (c) B. Hulin, S. L. Newton, D. M. Lewis, P. E. Genereux,
E. M. Gibbs and D. A. Clark, J. Med. Chem., 1996, 39, 3897.
4 (a) J. S. New, J. P. Yevich, D. L. Temple, Jr. K. B. New, S. M. Gross,
I. R. F. Schlemmer, Jr., M. S. Eison, D. P. Taylor and L. A. Riblett,
J. Med. Chem., 1988, 31, 618; (b) W. L. Christopher, J. P. Yevich, R.
Butler, R. F. Schlemmer, Jr, C. P. VanderMaelen and J. A. Cipollinaf,
J. Med. Chem., 1989, 32, 1147.
5 E. R. H. Jones, F. A. Robinson and M. N. Strachan, J. Chem. Soc.,
1946, 91.
6 (a) Y. Kojima, I. Maruyama, F. Antoku and K. Ishizumi, Jpn. Kokai
Tokkyo Koho, 1988, p. JP 63010786; (b) F. J. Urban PCT Int. Appl.,
1992, WO 9215561; (c) D. L. Temple Jr. and R. E. Yeager, US Patent,
1984, 06/289351.
7 For a different approach using RCM on thiazolinone substrate to
prepare thiaerythrinanes, see: (a) M. Abdullah, S. Arrasate, E. Lete
and N. Sotomayor, 11th Internat. Electronic Conf. Syn. Org. Chem.
(ECSOC-11), 2007; (b) M. N. Abdullah, S. Arrasate, E. Lete and N.
Sotomayor, Tetrahedron, 2008, 64, 1323.
8 (a) M. D. Burke and S. L. Schreiber, Angew. Chem., Int. Ed., 2004,
43, 46; (b) R. J. Spandl, M. D´ıaz-Gavila´n, K. M. G. O’Connell, G. L.
Thomas and D. R. Spring, Chem. Rec., 2008, 8, 129.
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The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 3801–3807 | 3807
©