[3+2] Cycloaddition-mediated synthesis of 3-methylsulfanyl-pyrrolidine-3-carboxylic acid methyl ester

Article abstract of DOI:10.1016/j.tetlet.2009.06.141

1,3-Dipolar cycloaddition reactions are fundamental processes in organic chemistry. Herein we report [3+2] annulation of thiomethylacrylate 2 and azomethine ylide precursor 3 towards the synthesis of novel 3-methylsulfanyl-pyrrolidine 5. Alternatively, we

Full text of DOI:10.1016/j.tetlet.2009.06.141

Tetrahedron Letters 50 (2009) 5315–5316
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[3+2] Cycloaddition-mediated synthesis of 3-methylsulfanyl-pyrrolidine-3-
carboxylic acid methyl ester
*
Sobhana B. Boga , Abdul-Basit Alhassan, Alan B. Cooper, Neng-Yang Shih, Ronald J. Doll
Department of Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
1,3-Dipolar cycloaddition reactions are fundamental processes in organic chemistry. Herein we report
[3+2] annulation of thiomethylacrylate 2 and azomethine ylide precursor 3 towards the synthesis of
novel 3-methylsulfanyl-pyrrolidine 5. Alternatively, we have also explored the alkylation of 7 with dim-
ethyldisulfide/LDA for the introduction of thiomethyl group towards the synthesis of 5 in moderate to
good yields. Efficacy of these two routes under various conditions/catalysts for the synthesis of 5 is
presented.
Received 12 May 2009
Revised 19 June 2009
Accepted 29 June 2009
Available online 12 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1,3-Dipolar cycloaddition reactions are fundamental processes
in organic chemistry and offer an efficient and reliable synthetic
methodology to access five-membered heterocycles, an important
building block that forms the basic frame work of many natural
products and pharmaceuticals.1 In the last two decades, extensive
studies have been performed in the area of [3+2] cycloaddition of
azomethine ylides to synthesize highly substituted pyrrolidine
moieties of their choice.2
[3+2] cycloaddition reactions which are usually carried out
using Lewis and Bronsted acids such as anhydrous AlCl3, ZnCl2,
BF3ÁOEt2, SnCl4 and TFA are among the most important reactions
in organic chemistry as they lead to C–C bond formation. It is
now well accepted that different types of clays such as Montmoril-
lonite K-10, bentonite and zeolite can catalyze various organic
transformations in an eco-friendly way. The Lewis acid properties
of Montmorillonite K-10 have been successfully utilized for many
other synthetic transformations.3
In this Letter we wish to report the synthetic application of
[3+2] cycloaddition to synthesize 3-methylsulfanyl-pyrrolidine 5
catalyzed by Montmorillonite K-10 (Scheme 1).
Methyl 2-methylthioacrylate 1 was prepared quantitatively by
chlorination of methyl 2-methylthiopropionates with sulfuryl
chloride at 0 °C followed by dehydrochlorination using refluxing
chloroform.4 The acrylate 1 was reacted with azomethine ylide
precursor 3 to give a smooth [3+2] annulation product 3-meth-
ylsulfanyl-pyrrolidine 4 (Scheme 1).
This transformation was carried out with different catalysts.
Remarkably it was observed that Montmorillonite K-10 (Mont K-
10) as an additive resulted in a significant acceleration of the reac-
tion to furnish the cycloadduct 45 in better yield in the same reac-
tion time. (Table 1, entry 7).
Efficacy of the catalyst and optimization of the reaction was
challenged by increasing the amount of the Montmorillonite K-
10 loading in the reaction, however, a slight decrease in the yield
of the product 4 was observed after the same reaction time (Table
1, entries 8–10). We found that an increase in the temperature to
50 °C decreased the yield of the product 4 (Table 1, entry 11).
Debenzylation of 1-benzyl-3-methylsulfanyl-pyrrolidine-3-car-
boxylic acid methyl ester 4 bearing thiomethyl group was not suc-
cessful under Pd/C reductions conditions due to catalyst poisoning
by the thiomethyl group. Debenzylation was finally accomplished
by heating 4 at reflux in 1,2-dichloroethane with 1 equiv of 1-chlo-
roethyl chloroformate6 for one hour resulting in the formation of
3-methylsulfanyl-pyrrolidine 57 in good yield (Scheme 1).
Alternatively, we have also explored the alkylation of 7 with
dimethyldisulfide/LDA at À78 °C that led to the introduction of
thiomethyl group to give 8 in moderate yield (Scheme 1). Depro-
tection of the BOC group was accomplished using TFA to give 3-
methylsulfanyl-pyrrolidine 5 in good yield.
Both synthetic approaches allowed the introduction of the thio-
methyl group at the 3-position of the pyrrolidine ring to give 5 and
are compared in terms of reaction viability and yields. The overall
yield of alkylation route, that is, 5 from 6 is comparable to the
cycloaddition routes 1 to 5 (Scheme 1). For the multigram prepara-
tions of 5, the cycloaddition approach is preferred over the alkyl-
ation method.
Lewis and Bronsted acid additives to assist the formation of the
[3+2] annulated product 4 were also surveyed, but upon all at-
tempts the yield of 4 was found to be significantly lower after
the same reaction time (Scheme 1, Table 1, entries 1–6).
Montmorollonite K-10 catalyzed [3+2] cycloaddition-mediated
synthesis of 3-methylsulfanyl-pyrrolidine-3-carboxylic acid
methyl ester 4 involves reaction conditions that are environmen-
tally friendly, amenable for scale-up and simple to work-up.
* Corresponding author. Tel.: +1 908 740 3484; fax: +1 908 740 7305.
E-mail address: bogababu@yahoo.com (S.B. Boga).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.141

5316
S. B. Boga et al. / Tetrahedron Letters 50 (2009) 5315–5316
(c)
MeS
(a)
(b)
MeS
MeO2C
SMe
NH
MeO2C
SMe
N
MeO2C
MeO2C
Si
N
O
5
2
4
1
3
(f)
(e)
MeS
MeO2C
(d)
N
N
CO2tBu
N
CO2tBu
HO2C
MeO2C
CO2tBu
8
6
7
Scheme 1. Reagents and conditions: (a) SO2Cl2, CHCl3, 100%; (b) catalyst, 3, conditions (see, Table 1); (c) 1-chloroethyl chloroformate, proton sponge, CH2Cl2, 86%; (d) CH2N2,
MeOH, 100%; (e) LDA, (SMe)2, THF, À78 °C, 60%; (f) TFA, CH2Cl2, 90%.
Table 1
SPRI Structural Chemistry group for providing NMR and Mass Spec-
tral support.
[3+2] cycloaddition-mediated synthesis of 1-benzyl-3-methylsulfanyl-pyrrolidine-3-
carboxylic acid methyl ester 4
No.
Catalyst
Conditions
Yield (%)
References and notes
1
2
3
4
5
6
7
8
9
(Tf)2NH
TFA
InCl3
rt, CH2Cl2, 72 h
0 °C to rt, CH2Cl2, 72 h
rt, CH2Cl2, 72 h
rt, CH2Cl2, 72 h
0 °C to rt, CH2Cl2
13
18
30
32
33
36
60
43
49
54
22
1. (a) Pandey, G.; Banerjee, P.; Smita, R. Chem. Rev. 2006, 106, 4484–4517; (b)
Pellissier, H. Tetrahedron 2007, 63, 3235; (c) Coldham, I.; Hufton, R. Chem. Rev.
2005, 105, 2765; (d) Jorgensen, K. A.; Gothelf, K. V. Chem. Rev. 1998, 98, 863.
2. (a) Tomoyuki, S.; Kimio, L.; Yukio, S. Heterocycles 1986, 24, 1331–1346; (b)
Nichols, P. J.; Demattei, J. A.; Barnett, B. R.; Lefur, N. A.; Chuang, T.-H.; Piscopio,
A. D.; Koch, K. Org. Lett. 2006, 8, 1495–1498.
3. (a) Varma, R. S. Tetrahedron 2002, 58, 1235; (b) Cornelis, A.; Gerstmans, A.;
Laszto, P.; Mathy, A.; Ziebh, I. Catal. Lett. 1990, 6, 103; (c) Clark, J. H.; Kybett, A.
P.; Macquarrie, D. J.; Barlow, S. J.; Landon, P. J. Chem. Soc., Chem. Commun. 1989,
1353.
LiBF4
BF3ÁEt2O
CSA
rt, CH2Cl2, 72 h
Mont. K-10
Mont. K-10
Mont. K-10
Mont. K-10
Mont. K-10
10% w/w, rt, CH2Cl2, 72 h
20% w/w, rt, CH2Cl2, 72 h
30% w/w, rt, CH2Cl2, 72 h
100% w/w, rt, CH2Cl2, 72 h
10% w/w, 50 °C, Cl CH2CH2Cl, 72 h
10
11
4. Iriuchijima, S.; Tanokuchi, K.; Tadokoro, K.; Tsuchihashi, G. Agric. Biol. Chem.
1976, 40, 1031.
5. General procedure for the [3+2] cycloaddition: To
a stirred solution of 2-
ethoxyacrylate 2-methylsulfanyl-acrylic acid methyl ester 2 (136 g, 1.03 mol)
and benzyl-methoxymethyl-trimethylsilanylmethyl-amine 3 (290 g, 1.22 mol)
in dichloromethane (2.7 L) was added catalyst (see Table 1 for conditions). The
resulting solution was warmed to room temperature and was stirred for 3 days.
The crude product after filtration was purified by column chromatography on
silica gel eluting with a solution of EtOAc/hexane(1:4) to give 1-benzyl-3-
methylsulfanyl-pyrrolidine-3-carboxylic acid methyl ester 4. 1H NMR d (CDCl3)
7.30 (4H, d, J 4.2 Hz), 7.26–7.22 (1H, m, 3.9 Hz), 3.74 (3H, s), 3.67 (1H, d, J 13 Hz,
6.4 Hz), 3.63 (1H, d, J 13 Hz, 6.4 Hz), 3.34 (1H, d, J 10.2 Hz), 2.79–2.74 (1H, m),
2.70–2.58 (3H, m) 2.07 (3H, s), 2.01–1.96 (1H, m). 13C NMR (CDCl3) d 173.1,
138.5, 128.5, 128.2, 127.0, 62.3, 59.7, 54.8, 52.8, 52.5, 34.7, 13.8. HRMS (ESI)
calculated for C14H20N1O2S [M+H]+: 266.12147, found 266.12126.
In summary, we have demonstrated Montmorollonite K-10 to
be an efficient catalyst for the [3+2] cycloaddition-mediated syn-
thesis of 3-methylsulfanyl-pyrrolidine-3-carboxylic acid methyl
ester 5. Further studies on the potential synthetic applications of
this novel 3-methylsulfanyl-pyrrolidine-3-carboxylic acid methyl
ester 5 in medicinal chemistry are underway and the results will
be reported in due course.
6. Olofson, R. A.; Abbott, D. E. J. Org. Chem. 1984, 49, 2795.
Acknowledgments
7. 3-Methylsulfanyl-pyrrolidine-3-carboxylic acid methyl ester 5: 1H NMR d (CDCL3)
8.77 (1H, br s), 3.88 (1H, br s), 3.80 (3H, s), 3.63 (1H, br s), 3.56 (2H br s), 2.59
(2H, br s), 2.18 (3H, s). 13C NMR (CDCl3) d 170.0, 55.0, 53.2, 51.0, 44.4, 33.3, 13.8
HRMS (ESI) calculated for C7H14N1O2S [M+H]+: 176.07452, found 176.0741.
We thank Drs. Ismail Kola and Malcom MacCoss for their strong
support at Schering-Plough Research Institute (SPRI). We thank the