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Acetic anhydride-promoted one-pot condensation of 2,4-thiazolidinedione with bisulfite adducts of aldehydes
Accepted Manuscript Acetic anhydride-promoted one-pot condensation of 2,4-thiazolidinedione with bisulfite adducts of aldehydes Sandeep Mohanty, Amrendra Kumar Roy, Vinay K.P. Kumar, Sandeep G. Reddy, Arun Chandra Karmakar PII: DOI: Reference:
S0040-4039(14)01084-3 http://dx.doi.org/10.1016/j.tetlet.2014.06.082 TETL 44806
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
24 April 2014 19 June 2014 20 June 2014
Please cite this article as: Mohanty, S., Roy, A.K., Kumar, V.K.P., Reddy, S.G., Karmakar, A.C., Acetic anhydridepromoted one-pot condensation of 2,4-thiazolidinedione with bisulfite adducts of aldehydes, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.06.082
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Graphical Abstract
Acetic anhydride-promoted one-pot condensation of 2,4-thiazolidinedione with bisulfite adducts of aldehydes
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Sandeep Mohanty, Amrendra Kumar Roy, Vinay K. P. Kumar, Sandeep G. Reddy and Arun Chandra Karmakar
1
Tetrahedron Letters jo u r n a l h o m e p a g e : w w w .e ls e v ie r .c o m
Acetic anhydride-promoted one-pot condensation of 2,4-thiazolidinedione with bisulfite adducts of aldehydes Sandeep Mohantya,*, Amrendra Kumar Roya, Vinay K. P. Kumara, Sandeep G. Reddya and Arun Chandra Karmakarb a
Dr. Reddy’s Laboratories Limited, Process Research and Development, API Plant, Bollaram-III, Plot No’s 116, 126C, Survey No.157, S.V. Co-operative Industrial Estate, IDA Bollaram, Jinnaram Mandal, Medak District, Hyderabad 502325, Andra Pradesh, India b Shasun Pharmaceuticals Limited, Shasun Road, Periakalapet, Pondicherry 605014, India
A R T IC LE IN F O
A B S TR A C T
Article history: Received Received in revised form Accepted Available online
We describe a simple and efficient one-pot method for condensing bisulfite adducts of aromatic aldehydes directly with 2,4-thiazolidinedione catalyzed by acetic anhydride. The t wo main highlights of this study are the one-pot condensation of bisulfite adducts with 2,4thiazolidinedione in non-aqueous media and the use of Design of Experiment to understand and optimize the reaction conditions. This methodology was then generalized using other active methylene compounds, such as malononitrile.
Key words: Acetic anhydride Aromatic bisulfite adducts Analysis of variance (ANOVA) Regression analysis
Substituted olefins obtained from the classical Knoevenagel condensation,1 form the basic building blocks of many pharmacologically important molecules. Examples of aldehydes used in the production of such olefins include 4fluorobenzaldehyde in atorvastatin2 and in rosiglitazone3, 4hydroxybenzaldehyde in pioglitazone,4 4-chlorobenzaldehyde in lumefantrine, 5 and 3,4-dihydroxy-5-nitrobenzaldehyde in entacapone6. Another very important class of Knoevenagel products is 5-benzylidenethiazolidine-2,4-diones obtained from the condensation of aldehydes with 2,4-thiazolidinediones. These compounds form an integral part of many biologically active compounds such as antidiabetic, anticancer, anti-HIV, antihistamine, anti-ischemic, anticonvulsant, antihistaminic, antimicrobial, and anti-inflammatory agents, as well as aldose reductase inhibitors, inhibitors of MurD ligase, etc.7-16 The major hurdle faced by the pharmaceutical industry in performing largescale Knoevenagel condensations is the instability of aldehydes during storage and transportation.17-19 To overcome this instability, two major approaches have been employed: (a) distillation of aldehydes prior to use, and (b) conversion of aldehydes into bisulfite adducts. The use of bisulfite adducts is preferred commercially because these adducts are usually stable crystalline solids, which makes handling and storage more convenient, and these adducts can easily be hydrolysed back to the pure aldehyde whenever required.20 Our idea was to use these stable bisulfite adducts directly in the condensation reactions, eliminating the need for a separate ——— *
2009 Elsevier Ltd. All rights reserved.
deprotection unit operation in the plant in a biphasic media. Moreover, we proposed deprotecting the bisulfite adduct to form the aldehyde in situ and performing the subsequent reaction in the same pot. This method would not only save time, but would also reduce effluent load.21 A Scifinder® search showed only a few cases in which bisulfite adducts were used directly in organic synthesis.22-23 One such study was carried out by Kjell et al., in which the aldehydes were regenerated from the bisulfite adducts in a non-aqueous medium (Scheme 1). 24
Scheme 1. Balanced chemical equation proposed by Kjell et al.24 for the regeneration of aldehydes from bisulfite adducts using trimethylsilyl chloride (TMS-Cl) The key advantage of the above reported procedure is the deprotection of the bisulfite adducts in an organic solvent instead of in a biphasic system, which is commonly employed in industry. The organic solvent contains the free aldehyde after deprotection (as described by Kjell et al.24) and could be used in situ for a subsequent Knoevenagel condensation if the reaction by-products are altered appropriately. Herein, we report the
Corresponding author: Tel.: +91 08458 279485; Fax: +91 08458 279619; Hand phone: +91 9989997191; E-mail: [email protected], [email protected]; Dr. Reddy’s Laboratories Limited communication number: IPDO IPM-00403
2
Tetrahedron Letters
optimized conditions for the acetic anhydride-promoted condensation of a bisulfite adduct with 2,4-thiazolidinedione to give substituted 5-benzylidenethiazolidine-2,4-diones in a single pot, utilizing a single solvent. This method provides a promising solution to the challenges faced by industry on the commercial scale. 24
The utility of the methodology described by Kjell et al. (Scheme 1) can be extended by optimizing the reaction conditions so that subsequent reactions can be carried out in the same pot. We focused on altering the in situ generated byproducts (NaCl and HCl) of the aldehyde regeneration reaction appropriately so that they could facilitate the subsequent condensation reaction. We focused on NaCl particularly, which being a neutral salt could not act as a base for the condensation reaction. If the chloride ion is replaced with an acetate ion then the resulting sodium acetate could act as a base for the condensation reaction. However, for the condensation reaction to proceed with sodium acetate, a weaker acid than HCl needs to be generated as a by-product, in order to arrest the back conversion of CH3COONa into CH3COOH. The most suitable alternative reagent to trimethylsilyl chloride (TMS-Cl) is acetic anhydride. The use of this reagent would generate acetic acid in the system, along with the desired sodium acetate, which in turn could facilitate the condensation of the aldehyde with 2,4thiazolidinedione as shown in Scheme 2.
Scheme 2. Envisaged one-pot condensation of bisulfite adducts with 2,4-thiazolidinedione in the presence of Ac2O
common industrial solvent that can be recovered and recycled easily.
Table 1. Screening of solvents for the preparation of 5-(4ethoxybenzylidene)thiazolidine-2,4-dione (6) Entry
Solvent
% conversion (6)
1
Acetonitrile
53.7
2
Propionitrile
73.4
3
Tetrahydrofuran
65.8
4
Dichloromethane
9.3
5
Chloroform
55.6
6
Toluene
77.4
7
Chlorobenzene
76.2
8
o-Xylene
71.4
It is envisaged that this condensation goes through an in situ generated aldehyde (1). If this is the case then this is the first report of acetic anhydride-mediated deprotection of bisulfite adducts and subsequent condensation with active methylene compounds in non-aqueous media. In order to understand the reaction and identify any reaction intermediates, the bisulfite adduct (Table 1, entry 6) was monitored by proton nuclear magnetic resonance (1H NMR) spectroscopy at different temperatures during the heating of the reaction. The stacked plot of the 1H NMR study (Figure 1) shows that bisulfite adduct 2 was consumed immediately at 65 ºC (disappearance of Ar-H proton at ~7.33 and ~6.78 ppm of 2a), with simultaneous formation of aldehyde 1 (appearance of aldehydic proton at ~9.9 ppm and Ar-H proton at ~7.87 and ~7.12 ppm of 1) and product 6 (appearance of =CH- proton at ~7.25 ppm). Hence, the reaction is considered to proceed via the aldehyde intermediate.
The balanced equation proposed by Kjell et al.24 (Scheme 1) using TMS-Cl was the basis for the conversion of the bisulfite adduct (2) to 5-(4-ethoxybenzylidene)thiazolidine-2,4-dione (6) in the presence of two equivalents of acetic anhydride as shown in Scheme 2. All bisulfite adducts (2) were prepared as per the reported procedure.25 However, the adducts were found to be contaminated with traces of the parent aldehyde (1) as shown by infrared (IR) analysis. With a little optimization (the precipitated adduct 2a was washed with n-hexane after isolation), adduct 2 was synthesized without any traces of 1 with our reported procedure.26 This purified material was required to establish whether the reaction went through an aldehyde intermediate. A proof of concept, reaction was planned as per Scheme 2 involving bisulfite adduct 2, 2,4-thiazolidinedione (3) and two equivalents of acetic anhydride in acetonitrile. No reaction occurred at room temperature, but as the reaction temperature reached ~85 °C, a new spot was observed by thin layer chromatography (TLC27). This new spot was consistent with the reference product (6), but the reaction was slow and showed only a moderate conversion of 53.7% after 12 h. The success of the reaction prompted us to screen for a suitable solvent for optimal yield. Various solvents that were screened are summarized in Table 1. Interestingly, the conversions obtained in high boiling non-polar solvents (Table 1; entry 6, 7, and 8) were promising. From these solvents, toluene was selected (Table 1; entry 6) for further optimization as conversion was good and it is also a
Figure 1. Characteristic 1H NMR signals of aldehyde 1, adduct 2, and product 6 at various time intervals during the reaction
The above experiment was conducted based on the work of Kjell et al.24 and accordingly, two equivalents of acetic anhydride were used for the initial screening reaction. The first equivalent of acetic anhydride was thought to regenerate the aldehyde, and the second equivalent to consume the water formed during the condensation reaction. In order to optimize and understand the effect of the various reaction parameters, this reaction was studied using Design of Experiments (DoE),28 utilizing a full factorial design of 23, i.e., eight experiments. Table 2 shows the three factors that were considered for optimization and Table 3
3
shows the results of the corresponding 23 full factorial experiments. The analysis of variance (ANOVA, Table 4) showed that the conversion was affected only by the reaction time and the equivalents of 2,4-thiazolidinedione, but surprisingly the equivalents of acetic anhydride (2–4) did not affect the conversion.29
Table 2. Reaction variables (factors) considered for optimization Factor
Name
Units
Minimum (−1)
Maximum (+1)
A
Time
Time (h)
6
12
B
Ac2O
Equivalents
2
4
C
(3)
Equivalents
1
2
Figure 2. Contour plot of % conversion with 1.0 equivalent of 2,4thiazolidinedione. Please use
R1, R2… below
Table 3. 23 full factorial design (8 experiments) and corresponding % product formation Experiment Number
Reaction time (h)
Ac2O equivalents
2,4Thiazolidinedione (3) equivalents
Product (6) (%)
1
6
1
1
72.15
2
12
1
1
85.04
3
6
2
1
58.86
4
12
2
1
73.89
5
6
1
2
36.6
6
12
1
2
50.37
7
6
2
2
31.58
8
12
2
2
58.6
The relationship between the conversion and the two significant reaction variables is given by the regression equation (1) and the relationship has been depicted by a 3D contour plot in Figure 2. Figure 3: Proposed reaction mechanism for the one-pot condensation of bisulfite adducts with 2,4-thiazolidinedione in the presence of Ac2O.
% Conversion = 74.91 + 2.86×ReactionTime - 28.19×2,4-thiazolidinedione
(1)
Table 4. ANOVA Table a
a
Df
Mean square
F Values
p-value (Prob > F)
2180.33
2
1090.16
25.04
0.0025
590.13
1
590.13
13.55
0.0143
C- 2,4Thiazolidinedione
1590.19
1
1590.19
36.53
0.0018
Residual
217.64
5
43.52
Cor Total
2397.97
7
Source
Sum of squares
Model
A-Time
p-value less than 0.05 indicates the variable is significant
The negative relationship between 2,4-thiazolidinedione equivalents and conversion could be explained by the increased formation of impurities when more 2,4-thiazolidinedione is available. Surprisingly, ANOVA and the regression analysis did not contain acetic anhydride.29 This could only be explained if <2 equivalents of acetic anhydride are required, as this was the lower limit taken for the study (Table 2). This means that acetic anhydride may act as a catalyst as shown in the reaction scheme proposed in Figure 3.
In order to check the validity of ANOVA and the regression analysis, and to ascertain whether acetic anhydride is acting as a catalyst, three reactions were planned with various equivalents of acetic anhydride and the results are shown in Table 5. Interestingly, even with 0.5 equivalents of acetic anhydride the same conversion to product was observed for the condensation reactions. Hence, we were successful in demonstrating the direct condensation reaction of bisulfite adduct 2 with 3, through in situ generation of aldehyde 1, in a single pot catalyzed by acetic anhydride. This procedure worked for bisulfite adducts of aromatic or aliphatic aldehydes, but only moderate yields were obtained with the aliphatic aldehydes (Table 6). In addition, the isolation process is quite simple with excellent purity and good yields.
Table 5. The effect of acetic anhydride equivalents on the yield of 6 Entry
Time (h)
T (ºC)
Ac2O equivalents
% conversion (6)
1
15
110
1.5
83
2
15
110
1.0
82.3
3
15
110
0.5
83.8
In principle, two geometrical isomers, namely E and Z, are possible for all the products isolated according to Scheme 2; it is well known that E and Z isomers can be distinguished by the 1H
4
Tetrahedron Letters
NMR spectral characteristics.30 The methine proton for the benzylidene compounds (6a–h) appears between 7.74 and 8.2 ppm and for the alkylidene compounds (6i–j) appears between 6.92 and 6.91 ppm (Table 6). This indicates that the methine proton in compounds 6a–j is on the same side as that of the carbonyl group (4-position) of the 2,4-thiazolidinedione ring and, hence the products obtained are Z isomers. Encouraged by the above results, this methodology was extended to other active methylene compounds, such as malononitrile (see Scheme 3 and the experimental section). This reaction proceeded with moderate yield and 2-(4ethoxybenzylidene)malononitrile 7 was isolated as the product after column chromatography.
acetic anhydride that make the process not only environmental friendly, but also eliminates the need for either aldehyde distillation or a biphasic system for the deprotection of bisulfite adducts on an industrial scale. Interestingly, the synthetic route using 0.5 equivalents of Ac2 O produced an array of benzylidene and, alkylidene compounds with low-levels of impurities. Although not all impurities were identified, as an exemplar of the generalized one-pot condensation of aromatic bisulfite adduct 2a with 2,4thiazolidinedione 3 using catalytic amounts of acetic anhydride in the nonpolar solvent system, the improved purity (Table 6, HPLC purity of 98.6%) and improved colour of the product 6a with this optimized process is shown in Figure 4 (HPLC purity of 96.7% with 2.0 equivalent acetic anhydride).
Scheme 3. Synthesis of 2-(4-ethoxybenzylidene)malononitrile (7). In summary, we have developed a generalized one-pot condensation of aromatic or aliphatic bisulfite adducts with 2,4thiazolidinedione using catalytic amounts of acetic anhydride in a nonpolar solvent system, such as toluene. This methodology was also extended to the condensation of other active methylene compounds, such as malononitrile. The highlight of this methodology is the use of a single solvent and 0.5 equivalents of
Figure 4. Physical appearance of product 6a isolated with 2.0 and 0.5 equivalents of acetic anhydride.
Table 6. Representative examples of products prepared by the current methodology Compound
Structure
Spectral data 1 H NMR (400 MHz, CDCl3 ): δ 12.50 (s, 1H), 7.74 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 4.10 (q, J = 6.8 Hz, 2H), 1.3–1.36 (t, J = 6.8 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): 167.9, 167.3, 160.0, 132.1, 131.8, 125.2, 120.0, 129.5, 115.2, 63.4, 14.4 ppm; ESI-MS: m/z 248.3 (M1).
6a
Yield, Physical appearance, HPLC purity 80%, Yellow solid, 98.6%
1
6b
H NMR (400 MHz, CDCl3 ): δ 12.50 (s, 1H), 7.75 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): 167.9, 167.4, 160.9, 132.0, 131.8, 131.7, 125.5, 120.3, 114.8, 55.5 ppm; ESI-MS: m/z 234.0 (M-1).
6c
1 H NMR (400 MHz, DMSO-d6): δ 12.66 (s, 1H), 7.78 (s, 1H), 7.63–7.58 (m, 4H) ppm; 13C NMR (400 MHz, DMSO-d6): 172.11, 170.10, 134.11, 132.8, 131.27 (2C), 129.17, 128.27, 127.52, 127.46 ppm; ESI-MS: m/z 238.4 (M1).
80.8%, Light brown solid, 99.26%
1 H NMR (400 MHz, CDCl3 ): δ 12.70 (brs, 1H), 7.90 (s, 1H), 7.45 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3): 173.8, 166.9, 134.4, 131.8, 131.0, 130.3, 128.8, 127.2 ppm; ESI-MS: m/z 237.7 (M-1).
78.6%, Pale yellow solid, 99.85%
1 H NMR (400 MHz, CDCl3 ): δ 12.82 (s, 1H), 7.86 (s, 1H), 8.30–8.40 (d, J = 8.6 Hz, 2H), 7.60–7.80 (d, J = 8.6 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): 167.3, 167.0, 147.4, 139.3, 130.9, 129.1, 124.2, 116.2 ppm; ESIMS: m/z 249.0 (M-1).
81.7%, Yellow solid, 97.15%
1 H NMR (400 MHz, CDCl3 ): δ 12.65 (brs, 1H), 7.78 (s, 1H), 7.60–7.45 (m, 5H) ppm; 13 C NMR (100 MHz, CDCl 3): δ 167.8, 167.2, 133.0, 131.7, 130.3, 129.9, 129.2, 123.5 ppm; ESI-MS: m/z 204.1 (M-1).
64%, Off-white solid, 99.50%
1 H NMR (400 MHz, CDCl3 ): δ 12.65 (s, 1H), 8.20 (s, 1H), 8.08–7.94 (m, 4H), 7.74–7.56 (m, 3H) ppm; 13C NMR (100 MHz, CDCl 3): δ 167.9, 167.3, 133.2, 132.7, 131.7, 130.8, 130.6, 128.9, 128.6, 127.9, 127.6, 127.1, 125.9, 123.7 ppm; ESI-MS: m/z 254.4 (M-1).
82.8%, Yellow solid, 91.26%
O (Z)
NH
6d Cl
S
77%, Yellow solid, 99.03%
O
6e
6f
6h
5
1
H NMR (400 MHz, DMSO-d6): δ 12.37 (s, 1H), 6.92–6.88 (t, J = 7.3, 1H), 2.09–2.03 (m, 2H), 1.94–1.82 (m, 1H), 0.91–0.90 (d, J = 6.4, 6H) ppm; 13C NMR (400 MHz, DMSO-d6): 167.63, 165.92, 136.06, 126.04, 70.89, 40.24, 27.55, 25.50 (2C) ppm; ESI-MS: m/z 186.05 (M+1).
6i31
50.0%, Pale yellow liquid, 94.32%
1
6j
H NMR (400 MHz, DMSO-d6): δ 12.36 (s, 1H), 6.91–6.87 (t, J = 7.3, 1H), 2.10 (m, 2H), 1.22–1.40 (m, 2H), 1.12–1.20 (m, 2H), 0.90 (t, J = 7.4, 3H) ppm; 13C NMR (400 MHz, DMSO-d6 ): 167.59, 165.97, 137.3, 127.79, 40.0, 30.90, 21.74, 13.59 ppm; ESI-MS: m/z 186.99 (M+1).
7
1 H NMR (400 MHz, DMSO-d6): δ 8.39 (s, 1H), 7.98–7.96 (d, J = 8.8, 2H), 7.18–7.16 (d, J = 8.8, 2H), 4.18–4.16 (m, 2H), 1.37–1.34 (t, J = 7.4, 3H) ppm; 13C NMR (400 MHz, DMSO-d6 ): 163.68, 160.43, 133 (2C), 123.95, 115.5, 76.63, 64.04, 14.34 ppm; ESI-MS: m/z 217 (M+19).
31
Acknowledgements We are thankful to the management of Dr. Reddy’s Laboratories Ltd., for giving support to carry out our work. We are also thankful to our colleagues in analytical and process research for their collaboration. References and notes 1. 2. 3. 4. 5. 6. 7.
8. 9.
10. 11. 12.
13. 14. 15. 16. 17.
18. 19. 20. 21.
Ricardo, M. In Green Chemistry – Environmentally Benign Approaches; Kidwai, M., Ed.; InTech: Shanghai, 2012, pp 13-32. Harrington, P. J. Pharmaceutical Process Chemistry for Synthesis: Rethinking the Routes to Scale-Up, John Wiley & Sons: Hoboken, 2011. Krishna, S. R.; Rao, M. V. N. B.; Raju, T. S.; Himabindu, V.; Reddy, G. M. E-J. Chem. 2008, 5, 562-566. Madivada, L. R.; Anumala, R. R.; Gilla, G.; Alla, S.; Charagondla, K.; Kagga, M.; Bhattacharya, A.; Bandichhor, R.; Org. Progress Res. Dev. 2009, 13, 1190-1194. Beutler, U.; Fuenfschilling, P. C.; Steinkemper, A. Org. Process Res. Dev. 2007, 11, 341–345. Mukarram, S. M. J.; Khan, R. A. R.; Yadav, R. P. U.S. Patent 2007/0004, 935, 2007. (a) Jain, V. S.; Vora, D. K.; Ramaa, C. S. Bioorg. Med. Chem. 2013, 21, 1599-1620. (b) Chen, H.; Fan, Y.-H.; Natarajan, A.; Guo, Y.; Iyasere, J.; Harbinski, F.; Luus, L.; Christ, W.; Aktas, H.; Halperin, J. A. Bioorg. Med. Chem. Lett. 2004, 14, 5401-5405. Oguchi, M.; Wada, K.; Honma, H.; Tanaka, A.; Kaneko, T.; Sakakibara, S.; Ohsumi, J.; Serizawa, N.; Fujiwara, T.; Horikoshi, H.; Fujita, R. J. Med. Chem. 2000, 43, 3052–3066. Ma, L.; Xie, C.; Ma, Y.; Liu, J.; Xian, M.; Ye, X.; Zheng, H.; Chen, Z.; Xu, Q.; Chen, T.; Chen, J.; Yang, J.; Qiu, N.; Wang, G.; Liang, X.; Peng, A.; Yang, S.; Wei, Y.; Chen, L. J. Med. Chem. 2011, 54, 2060–2068. Wu, Y.; Karna, S.; Choi, C. H.; Tong, M.; Tai, H.-H.; Na, D. H.; Jang, C. H.; Cho, H. J. Med. Chem. 2011, 54, 5260–5264. Hulin, B.; Clark, D. A.; Goldstein, S. W.; McDermott, R. E.; Dambek, P. J.; Kappeler, W. H.; Lamphere, C. H.; Lewis, D. M.; Rizzi, J. P. J. Med. Chem. 1992, 35, 1853–1864. Zidar, N.; Tomašić, T.; Šink, R.; Rupnik, V.; Kovač, A.; Turk, S.; Patin, D.; Blanot, D.; Martel, C. C.; Dessen, A.; Premru, M. M.; Zega, A.; Gobec, S.; Mašič, P.; Kikelj, D. J. Med. Chem. 2010, 53, 6584–6594. Rawal, R. K.; Prabhakar, Y. S.; Katti, S. B.; De Clercq, E. Bioorg. Med. Chem. 2005, 13, 6771-6776. Suster, D. C.; Feyns, L. V.; Ciustea, G.; Botez, G.; Dobre, V.; Bick, R.; Niculescu-Duvaz, I. J. Med. Chem. 1974, 17, 758–760. Das, J.; Floyd, D. M.; Kimball, S. D.; Duff, K. J.; Lago, M. W.; Krapcho, J.; White, R. E.; Ridgewell, R. E.; Obermeier, M. T. J. Med. Chem. 1992, 35, 2610–2617. Somu, R. V.; Boshoff, H.; Qiao, C.; Bennett, E. M.; Barry, C. E., III; Aldrich C. C. J. Med. Chem. 2006, 49, 31–34. (a) Bekbölet, M.; Getoff, N. Int. J. Photoenergy 2002, 4, 133-139. (b) van der Beek P. A. A. Recl. Trav. Chim. Pays-Bas 1928, 47, 286–300. (c) Bawn, C. E. H.; Jolley, J. E. Proc. R. Soc. Lond. Ser. A 1956, 237, 297-312. Jones, C. W. Applications of Hydrogen Peroxide and Derivatives, Royal Society of Chemistry: Cambridge, 1999. Liu, Q.; Perreault, S.; Rovis, T. J. Am. Chem. Soc. 2008, 130, 14066-14067. March, J. Advanced Organic Chemistry, 4th ed., John Wiley & Sons (Asia): Singapore, 2005. Spent aqueous acid or base used for deprotection would go to an effluent treatment plant before being discharged.
50.0%, Yellow liquid, 90.53%
57.7%, Off-white solid, 97.61%
22. Ragan, J. A.; am Ende, D. J.; Brenek, S. J.; Eisenbeis, S. A.; Singer, R. A.; Tickner, D. L.; Teixeira, J. T., Jr.; Vanderplas, B. C.; Weston, N. Org. Process Res. Dev. 2003, 7, 155−160. 23. A Scifinder® search from 1886 to present-day showed 114 articles on the various roles of the bisulfite adduct of benzaldehyde; only two of those articles were on carbon-carbon bond formation. 24. Kjell, D. P.; Slattery, B. J.; Semo, M. J. J. Org. Chem. 1999, 64, 5722-5724. 25. Cong, C.; Wang, H.; Hu, Y.; Liu, C.; Ma, S.; Li, X.; Ma, S. Eur. J. Med. Chem. 2011, 46, 3105-3111. 26. Mohanty, S.; Reddy, S. G.; Karmakar, A. C. Lett. Org. Chem. 2014, 11, 197–202. 27. Mobile phase: ethyl acetate and petroleum ether (3:7). Sample preparation: take reaction mass and dilute with diluents methanol and dichloromethane (1:1). 28. Montgomery, D. C. Design and Analysis of Experiments: 7th ed., John Wiley & Sons: Hoboken, 2009. 29. Significant variables will have p-values <0.05 at the 95% confidence interval. 30. (a) Momose, Y.; Meguro, K.; Ikeda, H.; Hatanaka, C.; Oi, S.; Sodha, T. Chem. Pharm. Bull. 1991, 39, 1440–1445. (b) Pratap, U. R.; Jawale, D. V.; Waghmare, R. A.; Lingampalle, D. L.; Mane, R. A. New J. Chem. 2011, 35, 49–51. (c) Pascual, C.; Meier, J.; Simon, W. Helv. Chim. Acta 1966, 49, 164–168. 31. General procedure for the condensation of the aliphatic bisulfite adduct of aldehydes with 2,4-thiazolidinedione. The bisulfite adduct of aliphatic aldehydes such as sodium 1-hydroxy-4methylpentane-1-sulfonate/sodium 1-hydroxypentane-1-sulfonate was taken with active methylene compounds such as 2,4thiazolidinedione/malononitrile as described in the experimental section to afford compounds 6i–j and 7. Purified through column by using silica gel (Mesh 100–200, eluting with 5%, 10%, and 15% ethyl acetate in hexane) to obtain title compounds. 32. General procedure for the condensation of the bisulfite adduct of aldehydes with 2,4-thiazolidinedione. The bisulfite adduct of aromatic aldehydes (2a–h,33 39.40 mmol) was taken with 2,4thiazolidinedione (3, 39.30 mmol) in toluene (50 mL) in a 100 mL round bottom flask. Ac2 O (2.0 g, 0.5 equiv.) was then added in one portion at 55 ºC. The reaction temperature was gradually raised to 110 ºC and was maintained for 12 h. After the completion of the reaction, it was slowly quenched into ice water. The biphasic slurry was allowed to stir below 20 ºC for 10 min and the precipitated product was filtered using a Buchner funnel. The wet cake was washed with 2 × 10 mL toluene at 25 ºC and dried under vacuum at 50 ºC to afford the desired benzylidene-2,4thiazolidinedione (6) in good yields. 33. R2CHO, 2a–h (R2 = 4-EtO-C6 H5, 4-MeO-C6 H5 , 4-Cl-C6H5, 2-ClC6H5, 4-NO2-C6 H5, C6H5, naphthyl)
S0040-4039(14)01084-3 http://dx.doi.org/10.1016/j.tetlet.2014.06.082 TETL 44806
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
24 April 2014 19 June 2014 20 June 2014
Please cite this article as: Mohanty, S., Roy, A.K., Kumar, V.K.P., Reddy, S.G., Karmakar, A.C., Acetic anhydridepromoted one-pot condensation of 2,4-thiazolidinedione with bisulfite adducts of aldehydes, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.06.082
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Graphical Abstract
Acetic anhydride-promoted one-pot condensation of 2,4-thiazolidinedione with bisulfite adducts of aldehydes
Leave this area blank for abstract info.
Sandeep Mohanty, Amrendra Kumar Roy, Vinay K. P. Kumar, Sandeep G. Reddy and Arun Chandra Karmakar
1
Tetrahedron Letters jo u r n a l h o m e p a g e : w w w .e ls e v ie r .c o m
Acetic anhydride-promoted one-pot condensation of 2,4-thiazolidinedione with bisulfite adducts of aldehydes Sandeep Mohantya,*, Amrendra Kumar Roya, Vinay K. P. Kumara, Sandeep G. Reddya and Arun Chandra Karmakarb a
Dr. Reddy’s Laboratories Limited, Process Research and Development, API Plant, Bollaram-III, Plot No’s 116, 126C, Survey No.157, S.V. Co-operative Industrial Estate, IDA Bollaram, Jinnaram Mandal, Medak District, Hyderabad 502325, Andra Pradesh, India b Shasun Pharmaceuticals Limited, Shasun Road, Periakalapet, Pondicherry 605014, India
A R T IC LE IN F O
A B S TR A C T
Article history: Received Received in revised form Accepted Available online
We describe a simple and efficient one-pot method for condensing bisulfite adducts of aromatic aldehydes directly with 2,4-thiazolidinedione catalyzed by acetic anhydride. The t wo main highlights of this study are the one-pot condensation of bisulfite adducts with 2,4thiazolidinedione in non-aqueous media and the use of Design of Experiment to understand and optimize the reaction conditions. This methodology was then generalized using other active methylene compounds, such as malononitrile.
Key words: Acetic anhydride Aromatic bisulfite adducts Analysis of variance (ANOVA) Regression analysis
Substituted olefins obtained from the classical Knoevenagel condensation,1 form the basic building blocks of many pharmacologically important molecules. Examples of aldehydes used in the production of such olefins include 4fluorobenzaldehyde in atorvastatin2 and in rosiglitazone3, 4hydroxybenzaldehyde in pioglitazone,4 4-chlorobenzaldehyde in lumefantrine, 5 and 3,4-dihydroxy-5-nitrobenzaldehyde in entacapone6. Another very important class of Knoevenagel products is 5-benzylidenethiazolidine-2,4-diones obtained from the condensation of aldehydes with 2,4-thiazolidinediones. These compounds form an integral part of many biologically active compounds such as antidiabetic, anticancer, anti-HIV, antihistamine, anti-ischemic, anticonvulsant, antihistaminic, antimicrobial, and anti-inflammatory agents, as well as aldose reductase inhibitors, inhibitors of MurD ligase, etc.7-16 The major hurdle faced by the pharmaceutical industry in performing largescale Knoevenagel condensations is the instability of aldehydes during storage and transportation.17-19 To overcome this instability, two major approaches have been employed: (a) distillation of aldehydes prior to use, and (b) conversion of aldehydes into bisulfite adducts. The use of bisulfite adducts is preferred commercially because these adducts are usually stable crystalline solids, which makes handling and storage more convenient, and these adducts can easily be hydrolysed back to the pure aldehyde whenever required.20 Our idea was to use these stable bisulfite adducts directly in the condensation reactions, eliminating the need for a separate ——— *
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deprotection unit operation in the plant in a biphasic media. Moreover, we proposed deprotecting the bisulfite adduct to form the aldehyde in situ and performing the subsequent reaction in the same pot. This method would not only save time, but would also reduce effluent load.21 A Scifinder® search showed only a few cases in which bisulfite adducts were used directly in organic synthesis.22-23 One such study was carried out by Kjell et al., in which the aldehydes were regenerated from the bisulfite adducts in a non-aqueous medium (Scheme 1). 24
Scheme 1. Balanced chemical equation proposed by Kjell et al.24 for the regeneration of aldehydes from bisulfite adducts using trimethylsilyl chloride (TMS-Cl) The key advantage of the above reported procedure is the deprotection of the bisulfite adducts in an organic solvent instead of in a biphasic system, which is commonly employed in industry. The organic solvent contains the free aldehyde after deprotection (as described by Kjell et al.24) and could be used in situ for a subsequent Knoevenagel condensation if the reaction by-products are altered appropriately. Herein, we report the
Corresponding author: Tel.: +91 08458 279485; Fax: +91 08458 279619; Hand phone: +91 9989997191; E-mail: [email protected], [email protected]; Dr. Reddy’s Laboratories Limited communication number: IPDO IPM-00403
2
Tetrahedron Letters
optimized conditions for the acetic anhydride-promoted condensation of a bisulfite adduct with 2,4-thiazolidinedione to give substituted 5-benzylidenethiazolidine-2,4-diones in a single pot, utilizing a single solvent. This method provides a promising solution to the challenges faced by industry on the commercial scale. 24
The utility of the methodology described by Kjell et al. (Scheme 1) can be extended by optimizing the reaction conditions so that subsequent reactions can be carried out in the same pot. We focused on altering the in situ generated byproducts (NaCl and HCl) of the aldehyde regeneration reaction appropriately so that they could facilitate the subsequent condensation reaction. We focused on NaCl particularly, which being a neutral salt could not act as a base for the condensation reaction. If the chloride ion is replaced with an acetate ion then the resulting sodium acetate could act as a base for the condensation reaction. However, for the condensation reaction to proceed with sodium acetate, a weaker acid than HCl needs to be generated as a by-product, in order to arrest the back conversion of CH3COONa into CH3COOH. The most suitable alternative reagent to trimethylsilyl chloride (TMS-Cl) is acetic anhydride. The use of this reagent would generate acetic acid in the system, along with the desired sodium acetate, which in turn could facilitate the condensation of the aldehyde with 2,4thiazolidinedione as shown in Scheme 2.
Scheme 2. Envisaged one-pot condensation of bisulfite adducts with 2,4-thiazolidinedione in the presence of Ac2O
common industrial solvent that can be recovered and recycled easily.
Table 1. Screening of solvents for the preparation of 5-(4ethoxybenzylidene)thiazolidine-2,4-dione (6) Entry
Solvent
% conversion (6)
1
Acetonitrile
53.7
2
Propionitrile
73.4
3
Tetrahydrofuran
65.8
4
Dichloromethane
9.3
5
Chloroform
55.6
6
Toluene
77.4
7
Chlorobenzene
76.2
8
o-Xylene
71.4
It is envisaged that this condensation goes through an in situ generated aldehyde (1). If this is the case then this is the first report of acetic anhydride-mediated deprotection of bisulfite adducts and subsequent condensation with active methylene compounds in non-aqueous media. In order to understand the reaction and identify any reaction intermediates, the bisulfite adduct (Table 1, entry 6) was monitored by proton nuclear magnetic resonance (1H NMR) spectroscopy at different temperatures during the heating of the reaction. The stacked plot of the 1H NMR study (Figure 1) shows that bisulfite adduct 2 was consumed immediately at 65 ºC (disappearance of Ar-H proton at ~7.33 and ~6.78 ppm of 2a), with simultaneous formation of aldehyde 1 (appearance of aldehydic proton at ~9.9 ppm and Ar-H proton at ~7.87 and ~7.12 ppm of 1) and product 6 (appearance of =CH- proton at ~7.25 ppm). Hence, the reaction is considered to proceed via the aldehyde intermediate.
The balanced equation proposed by Kjell et al.24 (Scheme 1) using TMS-Cl was the basis for the conversion of the bisulfite adduct (2) to 5-(4-ethoxybenzylidene)thiazolidine-2,4-dione (6) in the presence of two equivalents of acetic anhydride as shown in Scheme 2. All bisulfite adducts (2) were prepared as per the reported procedure.25 However, the adducts were found to be contaminated with traces of the parent aldehyde (1) as shown by infrared (IR) analysis. With a little optimization (the precipitated adduct 2a was washed with n-hexane after isolation), adduct 2 was synthesized without any traces of 1 with our reported procedure.26 This purified material was required to establish whether the reaction went through an aldehyde intermediate. A proof of concept, reaction was planned as per Scheme 2 involving bisulfite adduct 2, 2,4-thiazolidinedione (3) and two equivalents of acetic anhydride in acetonitrile. No reaction occurred at room temperature, but as the reaction temperature reached ~85 °C, a new spot was observed by thin layer chromatography (TLC27). This new spot was consistent with the reference product (6), but the reaction was slow and showed only a moderate conversion of 53.7% after 12 h. The success of the reaction prompted us to screen for a suitable solvent for optimal yield. Various solvents that were screened are summarized in Table 1. Interestingly, the conversions obtained in high boiling non-polar solvents (Table 1; entry 6, 7, and 8) were promising. From these solvents, toluene was selected (Table 1; entry 6) for further optimization as conversion was good and it is also a
Figure 1. Characteristic 1H NMR signals of aldehyde 1, adduct 2, and product 6 at various time intervals during the reaction
The above experiment was conducted based on the work of Kjell et al.24 and accordingly, two equivalents of acetic anhydride were used for the initial screening reaction. The first equivalent of acetic anhydride was thought to regenerate the aldehyde, and the second equivalent to consume the water formed during the condensation reaction. In order to optimize and understand the effect of the various reaction parameters, this reaction was studied using Design of Experiments (DoE),28 utilizing a full factorial design of 23, i.e., eight experiments. Table 2 shows the three factors that were considered for optimization and Table 3
3
shows the results of the corresponding 23 full factorial experiments. The analysis of variance (ANOVA, Table 4) showed that the conversion was affected only by the reaction time and the equivalents of 2,4-thiazolidinedione, but surprisingly the equivalents of acetic anhydride (2–4) did not affect the conversion.29
Table 2. Reaction variables (factors) considered for optimization Factor
Name
Units
Minimum (−1)
Maximum (+1)
A
Time
Time (h)
6
12
B
Ac2O
Equivalents
2
4
C
(3)
Equivalents
1
2
Figure 2. Contour plot of % conversion with 1.0 equivalent of 2,4thiazolidinedione. Please use
R1, R2… below
Table 3. 23 full factorial design (8 experiments) and corresponding % product formation Experiment Number
Reaction time (h)
Ac2O equivalents
2,4Thiazolidinedione (3) equivalents
Product (6) (%)
1
6
1
1
72.15
2
12
1
1
85.04
3
6
2
1
58.86
4
12
2
1
73.89
5
6
1
2
36.6
6
12
1
2
50.37
7
6
2
2
31.58
8
12
2
2
58.6
The relationship between the conversion and the two significant reaction variables is given by the regression equation (1) and the relationship has been depicted by a 3D contour plot in Figure 2. Figure 3: Proposed reaction mechanism for the one-pot condensation of bisulfite adducts with 2,4-thiazolidinedione in the presence of Ac2O.
% Conversion = 74.91 + 2.86×ReactionTime - 28.19×2,4-thiazolidinedione
(1)
Table 4. ANOVA Table a
a
Df
Mean square
F Values
p-value (Prob > F)
2180.33
2
1090.16
25.04
0.0025
590.13
1
590.13
13.55
0.0143
C- 2,4Thiazolidinedione
1590.19
1
1590.19
36.53
0.0018
Residual
217.64
5
43.52
Cor Total
2397.97
7
Source
Sum of squares
Model
A-Time
p-value less than 0.05 indicates the variable is significant
The negative relationship between 2,4-thiazolidinedione equivalents and conversion could be explained by the increased formation of impurities when more 2,4-thiazolidinedione is available. Surprisingly, ANOVA and the regression analysis did not contain acetic anhydride.29 This could only be explained if <2 equivalents of acetic anhydride are required, as this was the lower limit taken for the study (Table 2). This means that acetic anhydride may act as a catalyst as shown in the reaction scheme proposed in Figure 3.
In order to check the validity of ANOVA and the regression analysis, and to ascertain whether acetic anhydride is acting as a catalyst, three reactions were planned with various equivalents of acetic anhydride and the results are shown in Table 5. Interestingly, even with 0.5 equivalents of acetic anhydride the same conversion to product was observed for the condensation reactions. Hence, we were successful in demonstrating the direct condensation reaction of bisulfite adduct 2 with 3, through in situ generation of aldehyde 1, in a single pot catalyzed by acetic anhydride. This procedure worked for bisulfite adducts of aromatic or aliphatic aldehydes, but only moderate yields were obtained with the aliphatic aldehydes (Table 6). In addition, the isolation process is quite simple with excellent purity and good yields.
Table 5. The effect of acetic anhydride equivalents on the yield of 6 Entry
Time (h)
T (ºC)
Ac2O equivalents
% conversion (6)
1
15
110
1.5
83
2
15
110
1.0
82.3
3
15
110
0.5
83.8
In principle, two geometrical isomers, namely E and Z, are possible for all the products isolated according to Scheme 2; it is well known that E and Z isomers can be distinguished by the 1H
4
Tetrahedron Letters
NMR spectral characteristics.30 The methine proton for the benzylidene compounds (6a–h) appears between 7.74 and 8.2 ppm and for the alkylidene compounds (6i–j) appears between 6.92 and 6.91 ppm (Table 6). This indicates that the methine proton in compounds 6a–j is on the same side as that of the carbonyl group (4-position) of the 2,4-thiazolidinedione ring and, hence the products obtained are Z isomers. Encouraged by the above results, this methodology was extended to other active methylene compounds, such as malononitrile (see Scheme 3 and the experimental section). This reaction proceeded with moderate yield and 2-(4ethoxybenzylidene)malononitrile 7 was isolated as the product after column chromatography.
acetic anhydride that make the process not only environmental friendly, but also eliminates the need for either aldehyde distillation or a biphasic system for the deprotection of bisulfite adducts on an industrial scale. Interestingly, the synthetic route using 0.5 equivalents of Ac2 O produced an array of benzylidene and, alkylidene compounds with low-levels of impurities. Although not all impurities were identified, as an exemplar of the generalized one-pot condensation of aromatic bisulfite adduct 2a with 2,4thiazolidinedione 3 using catalytic amounts of acetic anhydride in the nonpolar solvent system, the improved purity (Table 6, HPLC purity of 98.6%) and improved colour of the product 6a with this optimized process is shown in Figure 4 (HPLC purity of 96.7% with 2.0 equivalent acetic anhydride).
Scheme 3. Synthesis of 2-(4-ethoxybenzylidene)malononitrile (7). In summary, we have developed a generalized one-pot condensation of aromatic or aliphatic bisulfite adducts with 2,4thiazolidinedione using catalytic amounts of acetic anhydride in a nonpolar solvent system, such as toluene. This methodology was also extended to the condensation of other active methylene compounds, such as malononitrile. The highlight of this methodology is the use of a single solvent and 0.5 equivalents of
Figure 4. Physical appearance of product 6a isolated with 2.0 and 0.5 equivalents of acetic anhydride.
Table 6. Representative examples of products prepared by the current methodology Compound
Structure
Spectral data 1 H NMR (400 MHz, CDCl3 ): δ 12.50 (s, 1H), 7.74 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 4.10 (q, J = 6.8 Hz, 2H), 1.3–1.36 (t, J = 6.8 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): 167.9, 167.3, 160.0, 132.1, 131.8, 125.2, 120.0, 129.5, 115.2, 63.4, 14.4 ppm; ESI-MS: m/z 248.3 (M1).
6a
Yield, Physical appearance, HPLC purity 80%, Yellow solid, 98.6%
1
6b
H NMR (400 MHz, CDCl3 ): δ 12.50 (s, 1H), 7.75 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): 167.9, 167.4, 160.9, 132.0, 131.8, 131.7, 125.5, 120.3, 114.8, 55.5 ppm; ESI-MS: m/z 234.0 (M-1).
6c
1 H NMR (400 MHz, DMSO-d6): δ 12.66 (s, 1H), 7.78 (s, 1H), 7.63–7.58 (m, 4H) ppm; 13C NMR (400 MHz, DMSO-d6): 172.11, 170.10, 134.11, 132.8, 131.27 (2C), 129.17, 128.27, 127.52, 127.46 ppm; ESI-MS: m/z 238.4 (M1).
80.8%, Light brown solid, 99.26%
1 H NMR (400 MHz, CDCl3 ): δ 12.70 (brs, 1H), 7.90 (s, 1H), 7.45 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3): 173.8, 166.9, 134.4, 131.8, 131.0, 130.3, 128.8, 127.2 ppm; ESI-MS: m/z 237.7 (M-1).
78.6%, Pale yellow solid, 99.85%
1 H NMR (400 MHz, CDCl3 ): δ 12.82 (s, 1H), 7.86 (s, 1H), 8.30–8.40 (d, J = 8.6 Hz, 2H), 7.60–7.80 (d, J = 8.6 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): 167.3, 167.0, 147.4, 139.3, 130.9, 129.1, 124.2, 116.2 ppm; ESIMS: m/z 249.0 (M-1).
81.7%, Yellow solid, 97.15%
1 H NMR (400 MHz, CDCl3 ): δ 12.65 (brs, 1H), 7.78 (s, 1H), 7.60–7.45 (m, 5H) ppm; 13 C NMR (100 MHz, CDCl 3): δ 167.8, 167.2, 133.0, 131.7, 130.3, 129.9, 129.2, 123.5 ppm; ESI-MS: m/z 204.1 (M-1).
64%, Off-white solid, 99.50%
1 H NMR (400 MHz, CDCl3 ): δ 12.65 (s, 1H), 8.20 (s, 1H), 8.08–7.94 (m, 4H), 7.74–7.56 (m, 3H) ppm; 13C NMR (100 MHz, CDCl 3): δ 167.9, 167.3, 133.2, 132.7, 131.7, 130.8, 130.6, 128.9, 128.6, 127.9, 127.6, 127.1, 125.9, 123.7 ppm; ESI-MS: m/z 254.4 (M-1).
82.8%, Yellow solid, 91.26%
O (Z)
NH
6d Cl
S
77%, Yellow solid, 99.03%
O
6e
6f
6h
5
1
H NMR (400 MHz, DMSO-d6): δ 12.37 (s, 1H), 6.92–6.88 (t, J = 7.3, 1H), 2.09–2.03 (m, 2H), 1.94–1.82 (m, 1H), 0.91–0.90 (d, J = 6.4, 6H) ppm; 13C NMR (400 MHz, DMSO-d6): 167.63, 165.92, 136.06, 126.04, 70.89, 40.24, 27.55, 25.50 (2C) ppm; ESI-MS: m/z 186.05 (M+1).
6i31
50.0%, Pale yellow liquid, 94.32%
1
6j
H NMR (400 MHz, DMSO-d6): δ 12.36 (s, 1H), 6.91–6.87 (t, J = 7.3, 1H), 2.10 (m, 2H), 1.22–1.40 (m, 2H), 1.12–1.20 (m, 2H), 0.90 (t, J = 7.4, 3H) ppm; 13C NMR (400 MHz, DMSO-d6 ): 167.59, 165.97, 137.3, 127.79, 40.0, 30.90, 21.74, 13.59 ppm; ESI-MS: m/z 186.99 (M+1).
7
1 H NMR (400 MHz, DMSO-d6): δ 8.39 (s, 1H), 7.98–7.96 (d, J = 8.8, 2H), 7.18–7.16 (d, J = 8.8, 2H), 4.18–4.16 (m, 2H), 1.37–1.34 (t, J = 7.4, 3H) ppm; 13C NMR (400 MHz, DMSO-d6 ): 163.68, 160.43, 133 (2C), 123.95, 115.5, 76.63, 64.04, 14.34 ppm; ESI-MS: m/z 217 (M+19).
31
Acknowledgements We are thankful to the management of Dr. Reddy’s Laboratories Ltd., for giving support to carry out our work. We are also thankful to our colleagues in analytical and process research for their collaboration. References and notes 1. 2. 3. 4. 5. 6. 7.
8. 9.
10. 11. 12.
13. 14. 15. 16. 17.
18. 19. 20. 21.
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50.0%, Yellow liquid, 90.53%
57.7%, Off-white solid, 97.61%
22. Ragan, J. A.; am Ende, D. J.; Brenek, S. J.; Eisenbeis, S. A.; Singer, R. A.; Tickner, D. L.; Teixeira, J. T., Jr.; Vanderplas, B. C.; Weston, N. Org. Process Res. Dev. 2003, 7, 155−160. 23. A Scifinder® search from 1886 to present-day showed 114 articles on the various roles of the bisulfite adduct of benzaldehyde; only two of those articles were on carbon-carbon bond formation. 24. Kjell, D. P.; Slattery, B. J.; Semo, M. J. J. Org. Chem. 1999, 64, 5722-5724. 25. Cong, C.; Wang, H.; Hu, Y.; Liu, C.; Ma, S.; Li, X.; Ma, S. Eur. J. Med. Chem. 2011, 46, 3105-3111. 26. Mohanty, S.; Reddy, S. G.; Karmakar, A. C. Lett. Org. Chem. 2014, 11, 197–202. 27. Mobile phase: ethyl acetate and petroleum ether (3:7). Sample preparation: take reaction mass and dilute with diluents methanol and dichloromethane (1:1). 28. Montgomery, D. C. Design and Analysis of Experiments: 7th ed., John Wiley & Sons: Hoboken, 2009. 29. Significant variables will have p-values <0.05 at the 95% confidence interval. 30. (a) Momose, Y.; Meguro, K.; Ikeda, H.; Hatanaka, C.; Oi, S.; Sodha, T. Chem. Pharm. Bull. 1991, 39, 1440–1445. (b) Pratap, U. R.; Jawale, D. V.; Waghmare, R. A.; Lingampalle, D. L.; Mane, R. A. New J. Chem. 2011, 35, 49–51. (c) Pascual, C.; Meier, J.; Simon, W. Helv. Chim. Acta 1966, 49, 164–168. 31. General procedure for the condensation of the aliphatic bisulfite adduct of aldehydes with 2,4-thiazolidinedione. The bisulfite adduct of aliphatic aldehydes such as sodium 1-hydroxy-4methylpentane-1-sulfonate/sodium 1-hydroxypentane-1-sulfonate was taken with active methylene compounds such as 2,4thiazolidinedione/malononitrile as described in the experimental section to afford compounds 6i–j and 7. Purified through column by using silica gel (Mesh 100–200, eluting with 5%, 10%, and 15% ethyl acetate in hexane) to obtain title compounds. 32. General procedure for the condensation of the bisulfite adduct of aldehydes with 2,4-thiazolidinedione. The bisulfite adduct of aromatic aldehydes (2a–h,33 39.40 mmol) was taken with 2,4thiazolidinedione (3, 39.30 mmol) in toluene (50 mL) in a 100 mL round bottom flask. Ac2 O (2.0 g, 0.5 equiv.) was then added in one portion at 55 ºC. The reaction temperature was gradually raised to 110 ºC and was maintained for 12 h. After the completion of the reaction, it was slowly quenched into ice water. The biphasic slurry was allowed to stir below 20 ºC for 10 min and the precipitated product was filtered using a Buchner funnel. The wet cake was washed with 2 × 10 mL toluene at 25 ºC and dried under vacuum at 50 ºC to afford the desired benzylidene-2,4thiazolidinedione (6) in good yields. 33. R2CHO, 2a–h (R2 = 4-EtO-C6 H5, 4-MeO-C6 H5 , 4-Cl-C6H5, 2-ClC6H5, 4-NO2-C6 H5, C6H5, naphthyl)