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Knoevenagel condensation of aromatic bisulfite adducts with 2,4-thiazolidinedione in the presence of Lewis acid catalysts
Tetrahedron Letters xxx (2015) xxx–xxx
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Knoevenagel condensation of aromatic bisulfite adducts with 2,4-thiazolidinedione in the presence of Lewis acid catalysts Sandeep Mohanty a,b,⇑, Amrendra Kumar Roy a, G. Sandeep Reddy a, K. P. Vinay Kumar a, B. RamaDevi b, G. Bhargavi c, Arun Chandra Karmakar d 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, Andhra Pradesh, India b Centre for Environment, Institute of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500072, Andhra Pradesh, India c School of Chemistry, University of Hyderabad, Hyderabad 500 046, India d Shasun Pharmaceuticals Limited, Shasun Road, Periakalapet, Pondicherry 605014, India
a r t i c l e
i n f o
Article history: Received 4 February 2015 Revised 23 March 2015 Accepted 25 March 2015 Available online xxxx Keywords: Bisulfite adduct Lewis acid Knoevenagel condensation Thiazolidinedione
a b s t r a c t Several commercial Lewis acids, specifically TiCl4, were able to promote the condensation reaction between aromatic bisulfite adducts and 2,4-thiazolidinedione to produce 5-arylidene derivatives. The product distribution was not affected by the equivalents of TiCl4 used, but was dependent on temperature and the nature of the solvent medium. In all cases, the reaction required activation of the aromatic bisulfite adducts by Lewis acids, followed by the loss of SO2 and subsequent regeneration of the parent aldehyde. The in situ formed aldehyde ultimately underwent acid-catalyzed carbon–carbon bond formation to give 5-arylidene derivatives. The reaction with TiCl4 afforded the products from aromatic and aliphatic bisulfite adducts in moderate to good yields. When hydrated Lewis acids were used, in addition to 5-arylidenes, the in situ formed aldehyde underwent a disproportionation reaction to give a carboxylic acid as a by-product. Ó 2015 Elsevier Ltd. All rights reserved.
Introduction The synthesis of 5-arylidene-2,4-thiazolidinediones is of great interest because of their important applications in the pharmaceutical industry.1 These molecules are particularly fascinating because of the diversity of synthetic procedures that can be used for their synthesis.2 Given their medicinal as well as synthetic interest, 5-arylidenes are of significant importance in the area of heterocyclic chemistry. Extensive effort has been expended in the search for efficient processes to synthesize these compounds. The most common methodology adopted for the synthesis of 5-arylidene-2,4-thiazolidinediones is the condensation of aromatic aldehydes with active methylene groups such as 2,4-thiazolidinedione in a single step. Above base-promoted condensation, leading to carbon-carbon bond formation is the key step in this reaction. In general, these reactions are catalyzed by bases, but there are reports of Knoevenagel condensations promoted by Lewis acids.3 In most of these cases, the Lewis acid was used in a quantity greater than the stoichiometric amount and aldehydes were used as the starting material. The use of aldehydes on a commercial scale has several disadvantages owing to their inherent instability. ⇑ Corresponding author.
Therefore, bisulfite adducts can be the preferred intermediates for many commercially manufactured aldehydes as these adducts are usually crystalline and stable, thus making their handling and storage more suitable. Unlike other reactions between aldehydes and active methylene groups, the bisulfite adduct has rarely been used for direct carbon–carbon bond formation. Therefore, our main effort was directed toward exploring the possibility of using bisulfite adducts for condensation reactions in the presence of various catalysts, without the need for deprotection of the bisulfite adducts to its parent aldehyde. Herein, we report our preliminary results on this subject. In our attempt to use bisulfite adduct in condensation reactions, we have shown previously that the condensation of bisulfite adducts with 2,4-thiazolidinedione was feasible in the presence of acetic anhydride4 and POCl35 resulting in 5-arylidene-2,4-thiazolidinediones in good yields along with unprecedented high level of (Z)-isomer selectivity. We speculated that in addition to acetic anhydride and POCl3, various other catalysts could not only help the formation of the corresponding aldehyde but also promote Knoevenagel-type reactions between 2,4-thiazolidinedione and an in situ formed aldehyde. A model condensation reaction between a bisulfite adduct (1a) and 2,4-thiazolidinedione (2) was selected for this investigation
http://dx.doi.org/10.1016/j.tetlet.2015.03.117 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Mohanty, S.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.03.117
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S. Mohanty et al. / Tetrahedron Letters xxx (2015) xxx–xxx H N
O OH R
1a
Lewis Acid
SO 3Na Solvent, heat
R CHO 3a
2
Table 2 Screening of solvents for the TiCl4-mediated condensation of 1a and 2
O O
S R o
130 C
NH
S 4a O
R=4-OEt-C6 H4
Scheme 1. Synthesis of thiazolidinedione 4a using Lewis acids.
(Scheme 1). As a first step, various Lewis acids were screened (Table 1) to find a suitable catalyst.6 Based on prior experience,5 all screening experiments were performed using toluene as the solvent at 110 °C with 2.0 equiv of Lewis acids as reported (Table 1). Product conversion in the reaction mass was determined by HPLC (area%). As evident from Table 1, all Lewis acids that were screened, afforded a mixture of unreacted 2, in situ released parent aldehyde 3a, and the desired product 4a in different ratios. It is evident from Table 1 that the conversion of product 4a varied significantly among the Lewis acids and their hydrated salts (MLnXH2O). Lewis acids such as TiCl4, AlCl3, and SnCl4 were the most effective, displaying 58–69% conversion of bisulfite adduct 1a. On the other hand, all the hydrated Lewis acids (MLnXH2O; X = 1 7) resulted in poor yields and an unknown impurity (0.5 37% in HPLC) at RRT 0.86 (Table 1; entries 3–7); this is discussed later. No product formation was observed with BaCl22H2O, NiCl26H2O, CuCl22H2O, and PdCl22H2O (not shown in Table 1). The most promising results were obtained with TiCl4 and SnCl4; in particular, the reaction with TiCl4 was completed within 30 min of heating, that is, the reaction was found to be complete before the reaction temperature reached 110 °C. The course of the reaction was monitored using HPLC and LC–MS; the reaction was found to proceed via the in situ generation of aldehyde 3a (Scheme 1). Inspired by this success, we then focused on solvent screening. The preferred choice of Lewis acid for our subsequent study was TiCl4. For comparison, the reaction (Scheme 1) was performed with solvents (bp ranging from 39 °C to 130 °C) at reflux temperature (Table 2). The results of the TiCl4-mediated (2.0 equiv) reaction carried out with different solvents are summarized in Table 2. It appears that any solvent with a bp greater than 60 °C is sufficient for conversion to product 4a; however, with CH2Cl2, there was no product formation (40 °C). In the case of cyclohexane, the conversion to the product was low (13.2%) because of the poor solubility of 1a and 2. The best conversions were obtained in high boiling non-polar solvents, such as o-xylene and chlorobenzene (Table 2; entries 6 and 7). o-Xylene was selected for further optimization, as it is a common industrial solvent that can be recovered and recycled easily. Last phase of the optimization was to study the effect of different equivalents of TiCl4 on the conversion. Literature search showed that Titanium chloride ((Ti(IV)-base)) has been well documented to facilitate carbon-carbon bond formation reactions.7
Entry
Solvent
T (°C)
Time (h)
TiCl4 (equiv)
Product
% area
1 2 3 4 5 6 7
CH2Cl2 CHCl3 Cy(C6H5) Benzene Toluene o-Xylene Cl-C6H5
40 60 80 80 105 130 130
8.0 6.0 4.0 1.5 1.5 1 0.5
2.0 2.0 2.0 2.0 2.0 2.0 2.0
4a 4a 4a 4a 4a 4a 4a
— 72.8 13.2 58.0 69.7 83.5 86.6
There are instances where Ti(IV)-derivatives, in combination with organic bases (TiCl4/Et3N,8 Ti(O-i-Pr)4,9 TiCl4/pyridine,10 TiCl4/N-methyl morphorine,11 and TiCl4–Et3N,12), have been used to promote Knoevenagel condensations; but, in such cases, they have been used in stoichiometric amounts and the ratio of TiCl4 to base used was 1:1. In order to find the optimized equivalent of TiCl4 required for maximizing the conversion, reactions were conducted with different equivalents of TiCl4 and the conversion to product 4a with respect to yield and purity was monitored (Table 3).13 It is apparent that the reaction involves two chemical step (Scheme 1), first step involves insitu deprotection of bisulfite adduct 1a to parent aldehyde 3a and this deprotection was found to be instantaneous in the presence of a Lewis acid and heat. The second step is the condensation of insitu generated aldehyde with thiazolidine-2,4-dione 2 in the presence of Lewis acid catalyst. Moreover, Knoevenagel condensation is a net dehydration reaction and water is a by-product. Therefore, we envisioned that a minimum of 1 equiv or more of TiCl4 would be required for the transformation of 1a to 4a; surprisingly, however, only 0.5 to 1.0 equiv of TiCl4 led to the product 4a with good yield (Table 3; entries 4 and 5). The reaction proceeded with even 0.1 equiv of TiCl4; however, an optimal yield was obtained with 0.5–1.0 equiv of TiCl4. To our delight, the reaction proceeded directly from bisulfite adduct 1a with only a less than stoichiometric amount of TiCl4.
Table 3 Study of different equivalents of TiCl4 on conversion of 1a to 4a Entry
TiCl4 (equiv)
Adduct 1a (g)
T (°C)
Product 4a (g)
Yield (%)
Purity
1 2 3 4 5 6 7
0.1 0.2 0.3 0.5 1.0 1.5 2.0
5.0 5.0 5.0 5.0 5.0 5.0 5.0
110 110 110 110 110 110 110
1.1 2.7 3.6 4.4 4.0 3.5 2.5
24.3 56.8 75.0 91.1 83.0 71.9 52.6
68.1 97.9 84.7 91.8 96.4 96.4 97.9
O MLn R
H 2O
OH R
Entry
Lewis acid
TiCl4 (equiv)
Time (h)
T (°C)
Product
% area
1 2 3 4 5 6 7 8
TiCl4 AlCl3 SnCl4 LiCl.H2O ZnBr2.2H2O CrCl3.6H2O MgCl2.6H2O CeCl3.7H2O
2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0
0.5 6.0 2.0 8.0 8.0 8.0 6.0 6.0
110 110 110 110 110 110 110 110
4a 4a 4a 4a 4a 4a 4a 4a
69.7 58.3 68.0 12.6 28.1 8.7 3.0 2.9
H 5
S
S
NH
S 6
Table 1 Lewis acid screening for the condensation of 1a and 2
O R
O
4a
O MLn
OH
O S O O- + Na 1a
O
ML n
O
NH O
S O ML n
R
NH
MLn, heat H O SO2
S R 3a
NH +
2
NH O
H
O 7
Scheme 2. MLn-mediated condensation of 2 with bisulfite adduct 1a.
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S. Mohanty et al. / Tetrahedron Letters xxx (2015) xxx–xxx H N
O
O
S 2 + OH R
1a
O OH
MLn.XH 2 O; X = 1-7 R S 4a
o-xylene, reflux
NH +
O
R 8
O
SO 3Na
7.3 to 38%
Scheme 3. Lewis acid mediated disproportionation reaction of 3a.
Table 4 TiCl4-catalysis reaction of bisulfite adducts with 2 Entry
Product
TiCl4 (equiv)
Time (h)
Yield (%)
Purity
1 2 3 4 5
4a 4b 4c 4d 4e
0.5-0.75 0.5-0.75 0.5-0.75 0.5-0.75 0.5-0.75
3.0 3.5 3.0 3.0 3.0
86.73 81.79 81.79 94.26 81.63
99.54 95.91 94.90 95.62 98.80
O
OH Et
SO 3Na N
NH
+ S
O 9
2O
TiCl 4 (0.5 equiv), o-xylene, 130 o C, 3 h
Yield: 92% Purity: 93.2 O
Et N
O 4f
S
NH O
Scheme 4. Synthesis of pioglitazone intermediate 4f.
OH SO3 Na
+
11
OH
10b
COOEt
COOEt
10a
SO3 Na
COOEt TiCl4 (0.5 equiv), o-xylene, 60 o C, 2 h
+
COOEt 12a
COOEt TiCl4 (0.5 equiv), o-xylene, 60 oC, 2 h COOEt 11
COOEt COOEt 12b
Scheme 5. Condensation of aliphatic bisulfite adducts 10(a–b) with diethyl malonate 11.
In order to ascertain the effect of TiCl4, two-control condensation reaction of 2 was performed using free aldehyde 3a and its bisulfite adduct 1a (Scheme 2). Firstly, the reactions with 1a/3a were performed in the presence of 0.5 equiv of TiCl4 with 1.1 equiv of 2, and 5.0-volume o-xylene at 130 °C. Irrespective of
3
the starting material (1a or 3a) the reaction proceeded to afford product 4a. However, aldehyde 3a resulted in 62.3% conversion whereas bisulfite adduct 1a gave a conversion of 85%. Secondly, the reaction conversions were investigated in the absence of TiCl4. In the absence of TiCl4, the aldehyde 3a showed a conversion of only 2.9%, whereas bisulfite adduct 1a resulted in a conversion of only 14%. These results further confirm the essential role of TiCl4 in the transformation of 1a ? 4a (Scheme 2). Based on the above observation, we proposed a reaction mechanism wherein Lewis acid is acting as a catalyst (Scheme 2). In addition to an effective Knoevenagel reaction of 1a ? 3a ? 4a with catalytic TiCl4 we also observed, some unknown impurities at RRTs; 0.86. These impurities were monitored using LC–MS/MS and had m/z 167.0705 (M+1) with MS/MS fragment ions of 149.0592 and 121.0275. For example, when hydrated Lewis acids (ZnBr22H2O, CeCl37H2O, CrCl36H2O, LiClH2O, and MgCl26H2O) were used, the carboxylic acid (8)14 corresponding to parent aldehyde 3a as the major product was observed (7.3% to 38%; Table 5 in the Supporting information). Carboxylic acid (8) was isolated using preparative HPLC and the structure was established.15 Interestingly, our investigation of the Lewis acid-mediated synthesis of 4a revealed an important synthetic aspect of the reaction, wherein an in situ formed aldehyde might undergo a disproportionation reaction to give a carboxylic acid as a by-product. A full investigation into this disproportionation reaction is underway (Scheme 3). Having recognized the catalytic role of TiCl4, we tested this reaction using a diverse range of bisulfite adducts 1a–e that contain various functional groups, such as 4b: 4-OMe-C6H4, 4c: 4-Cl-C6H4, and 4d: 2-Cl-C6H4, as well as the bisulfite adduct of benzaldehyde (4e: C6H5), for which the data is captured in Table 4. It is evident from Table 2 and Table 4 that the yields and purity of products 4a–4e were much better with catalytic amount of TiCl4.16 Inspired by these results, we carried out a reaction between pio-adduct 9, isolated from a pharmaceutically important aryl intermediate of pioglitazone, and 0.5 equiv of TiCl4 in o-xylene to afford 5-arylidene 4f in good yields (Scheme 4). In addition to the catalytic nature of the present methodology, other advantages include rapid product 4f isolation, a cleaner reaction, and better operational efficiency.17 To demonstrate the utility, aliphatic bisulfite adducts 10(a–b) with active methylene groups such as diethylmalonate 11 were examined with TiCl4. Aliphatic aldehyde bisulfite adducts 10(a–b) with catalytic TiCl4 (0.5 equiv) gave product 12(a–b) under mild condition in prolonged reaction time (Scheme 5).18,19 The Z-configurations of 4a–f were determined by 1H NMR. The 1H NMR spectra of all the compounds (4a–f) were very similar to those of our previously isolated 5-arylidene-2,4-thiazolidinediones obtained using acetic anhydride. The methine protons of compounds 4a–f appeared between d 7.90 and 7.74. This result suggests that this proton in each of the compounds is on the same side as the carbonyl group at the 4-position of the thiazolidinedione ring.
Figure 1. X-ray structure (ORTEP) of 4a.
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S. Mohanty et al. / Tetrahedron Letters xxx (2015) xxx–xxx
Unequivocal evidence for the structure of 4a was also obtained from single crystal X-ray analysis. The structure deduced from the crystallographic data shows that product 4a is the Z-isomer. The ORTEP diagram is shown in Figure 1.20 In summary, the TiCl4-mediated Knoevenagel condensation affords the condensation product directly from the bisulfite adduct. The use of hydrated Lewis acids should be avoided for optimal yield. This methodology could help in handling unstable aldehydes on a commercial scale in their stable bisulfite adduct form. There is no need to deprotect the bisulfite adducts to the parent aldehydes prior to the reaction because, in the present case, both deprotection and subsequent condensation occur in a single pot.
7.
8. 9. 10. 11. 12. 13.
Acknowledgment We are grateful to the management of Dr. Reddy’s Laboratories Limited for the support to carry out this work. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.03. 117.
14. 15.
References and notes 16. 1. Wang, Z.; Liu, Z.; Lee, W.; Kim, S.-N.; Yoon, G.; Cheon, S. H. Bioorg. Med. Chem. Lett. 2014, 24, 3337. 2. (a) Pratap, U. R.; Jawale, D. V.; Waghmare, R. A.; Lingampalle, D. L.; Mane, R. A. New J. Chem. 2011, 35, 49; (b) Khazaei, A.; Veisi, H.; Safaei, M.; Ahmadian, H. J. Sulfur Chem. 2014, 35, 270; (c) Shah, S.; Singh, B. Bioorg. Med. Chem. Lett. 2012, 22, 5388. 3. (a) Leelavathi, P.; Ramesh Kumar, S. J. Mol. Catal. A: Chem. 2005, 240, 99; (b) Narasiah, A. V.; Nagaih, K. Synth. Commun. 2003, 33, 3825; (c) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L. Chem. Rev. 2002, 102, 2227; (d) Malona, J. A.; Colbourne, J. M.; Frontier, A. J. Org. Lett. 2006, 8, 5661; (e) Pridgen, L. N.; Huang, K.; Shilcrat, S.; Tickner-Eldridge, A.; DeBrosse, C.; Haltiwanger, R. C. Synlett 1999, 1612; (f) Forsberg, J. H.; Spaziano, V. T.; Balasubramanian, T. M.; Liu, G. K.; Kinsley, S. A.; Duckworth, C. A.; Poteruca, J. J.; Brown, P. S.; Miller, J. L. J. Org. Chem. 1987, 52, 1017; (g) Kumar, D.; Kumar, A.; Qadri, M. M.; Ansari, Md. I.; Gautam, A.; Chakraborti, A. K. RSC Adv. 2015, 5, 2920; (h) Attanasi, O.; Fillippone, P.; Mei, A. Synth. Commun. 1983, 13, 1203; (i) Khan, R. H.; Mathur, R. K.; Ghosh, A. C. Synth. Commun. 1996, 26, 683; (j) Prajapati, D.; Sandhu, J. S. J. Chem. Soc., Perkin Trans. 1 1993, 739; (k) Bennazha, J.; Zahouily, M.; Sebti, S.; Boukhari, A.; Holt, E. M. Catal. Commun. 2001, 2, 101; (l) Abaee, M. S.; Mojtahedi, M. M.; Zahedi, M. M.; Khanalizadeh, G. Arkivoc 2006, xv, 48; (m) Cabello, J. A.; Campelo, J. M.; Garcia, A.; Luna, D.; Marinas, J. M. J. Org. Chem. 1984, 49, 5195; (n) Zhang, Y.; Dou, Q.; Dai, L.; Wang, X.; Chen, Y. RSC Adv. 2012, 2, 8979; (o) Zhang, Y.; Xia, C. Appl. Catal., A 2009, 366, 141; (p) Vijender, M.; Kishore, P.; Satyanarayana, B. Arkivoc 2008, xiii, 122; (q) Ilangovan, A.; Muralidharan, S.; Maruthamuthu, S. J. Korean Chem. Soc. 2011, 55, 1000. 4. Mohanty, S.; Roy, A. K.; Kumar, V. K. P.; Reddy, G. S.; Karmakar, A. C. Tetrahedron Lett. 2014, 55, 4585–4589. 5. Mohanty, S.; Reddy, G. S.; Karmakar, A. C. Lett. Org. Chem. 2014, 11, 197–202. 6. Reaction monitoring by HPLC: Lewis acids (2.0 equiv) were added into a round bottom flask containing 1a in 5.0 mL of toluene and 1.1 equiv of 2 at 25 °C (Scheme 1). The temperature of the reaction mixture was gradually raised to 110 °C. Prior to the reaction, the retention time (RT) and relative retention time (RRT) of aldehyde 3a, adduct 4a, thiazolidine-2,4-dione 2, and product 4a were established by HPLC co-injection. HPLC analysis was performed using a Waters 2690 HPLC system. The reaction mass sampling for HPLC was carried out using a pipette under a N2 atmosphere. The sample was transferred to a 50 mL round bottom flask, and the reaction mass was concentrated by evaporation (using N2 pressure). The resulting dry sample (20 mg) was removed and transferred to a 10.0 mL volumetric flask. Then, the freshly prepared diluted sample was transferred to an injection loop for analysis (5 mL diluted sample). The HPLC conditions to monitor the progress of the reaction were: column: Kromasil, Altima C18, 150 4.6, 3 lm; kmax: 245 nm; flow rate: 1.0 mL/min; run time:
17.
18.
19.
20.
30 min; and solvent for dilution: DMSO. Chromatograms of the samples were recorded during the reaction. The percentage conversion was determined by HPLC, as shown in Table 1. (a) Lehnert, W. Tetrahedron Lett. 1970, 4723; (b) Lehnert, W. Tetrahedron 1972, 28, 663; (c) Lehnert, W. Tetrahedron 1973, 29, 635; (d) Lehnert, W. Tetrahedron 1974, 30, 301; (e) Reetz, M. T.; Von Itzstein, M. J. Organomet. Chem. 1987, 334, 85; (f) Reetz, M. T.; Peter, R.; Von Itzstein, M. Chem. Ber. 1987, 120, 121. Renzetti, A.; Dardennes, E.; Fontana, A.; De Maria, P.; Sapi, J.; Gérard, S. J. Org. Chem. 2008, 73, 6824. Yamashita, K.; Tanaka, T.; Hayashi, M. Tetrahedron 2005, 61, 7981. Green, B.; Crane, R. I.; Khaidem, I. S.; Leighton, R. S.; Newaz, S. S.; Smyser, T. E. J. Org. Chem. 1985, 50, 640. Zhang, X.-R.; Chao, W.; Chuai, Y.-T.; Ma, Y.; Hao, R.; Zou, D.-C.; Wei, Y.-G.; Wang, Y. Org Lett. 2006, 8, 2563. Marrone, A.; Renzetti, A.; De Maria, P.; Gérard, S.; Sapi, J.; Fontana, A.; Re, N. Chem. –Eur. J. 2009, 15, 11537. A slurry of bisulfite adduct 1a (5 g) with TZD 2 (2.5 g), was prepared in oxylene (25 mL) in a 100 mL round bottom flask. TiCl4 was added in one portion at 25 °C. The reaction temperature was gradually raised to 130 °C, and the reaction mass temperature was maintained for 1 h. After the visual absence of aldehyde in TLC, the reaction mass was slowly quenched by adding ice-cold water at 10 °C, and the biphasic slurry was stirred below 20 °C for 10 min. The resulting bright yellow crystalline material was separated from the liquid layer by filtering the slurry mass using a Buchner funnel in a vacuum of 650 mm Hg. The wet cake obtained was washed with 2 5 mL o-xylene at 25 °C and dried in vacuum at 50 °C to afford product 4a. Brewster, T. P.; Ou, W. C.; Tran, J. C.; Goldberg, K. I.; Hanson, S. K.; Cundari, T. R.; Heinekey, D. M. ACS Catal. 2014, 4, 3034. 4-Ethoxybenzoic acid: 1H NMR (400 MHz, DMSO-d6): d 7.8 (d, 2H), 7.0 (d, 2H), 4.1 (q, 2H), 1.3 (t, 3H) ppm; 13C NMR (400 MHz, DMSO-d6): d 167.048, 162.075, 131.315, 122.928, 114.128, 63.401, 14.492 ppm; MS: calcd for C9H10O3 166.06, found 167.0419 (M+H+); IR (KBr) 3436 (acid O–H), 2985 (aromatic CH), 1677, 1610 (C@O), 1175 (C–O) cm 1. 1a: 1H NMR (400 MHz, DMSO-d6): d 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, DMSO-d6): d 167.9, 167.3, 160.0, 132.1, 131.8, 129.5, 125.2, 120.0, 115.2, 63.4, 14.4 ppm; ESI-MS: m/z 248.3 (M1). 1b: 1H NMR (400 MHz, DMSO-d6): d 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, DMSO-d6): d 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). 1c: 1H NMR (400 MHz, DMSO-d6): d 12.66 (s, 1H), 7.78 (s, 1H), 7.63–7.58 (m, 4H) ppm; 13C NMR (400 MHz, DMSO-d6): d 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 (M-1). 1d: 1H NMR (400 MHz, DMSO-d6): d 12.70 (br s, 1H), 7.90 (s, 1H), 7.45 (m, 4H) ppm; 13C NMR (100 MHz, DMSO-d6): d 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). 1e: 1H NMR (400 MHz, DMSO-d6): d 12.65 (br s, 1H), 7.78 (s, 1H), 7.60–7.45 (m, 5H) ppm; 13C NMR (100 MHz, DMSO-d6): d 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). 4f: 1H NMR (400 MHz, DMSO-d6): 12.5 (s, 1H), 8.3–7.0 (m, 7H), 4.40 (t, J = 6.8 Hz, 2H), 3.20 (t, J = 6.8 Hz, 2H), 2.60 (q, J = 7.4 Hz, 2H), 1.20 (d, J = 7.5 Hz, 3H) ppm; 13C NMR (100 MHz, DMSO d6): 167.9, 167.4, 160.1, 155.1, 148.5, 136.7, 135.7, 132, 131, 125, 123, 120, 115.3, 67, 36.5, 24.9, 15.3 ppm; ESI-MS: m/z 355.1 (M+1). 12(a–b). A slurry of bisulfite adduct 10(a–b) (5.0 g) with 11 (8.50 g), was prepared in o-xylene (25 mL) in a 100 mL round bottom flask. TiCl4 (2.50 g) was added in one portion at 25 °C. The reaction temperature was gradually raised to 60 °C, and the reaction mass temperature was maintained for 2 h. The reaction mass was slowly quenched by adding ice-cold water at 10 °C. The product was extracted in to o-xylene (2 10 mL) and then evaporated under reduced pressure to give crude product 12(a–b) 5.5 g (91.0% yield). Crude product 12(a–b) on purification by column chromatography afforded product as a colourless oil (silica gel, 95:05 pet ether/ethyl acetate). (12a; 2.10 g, 35%): (12b; 2.28 g, 38%). 12a: 1H NMR (400 MHz, DMSO-d6): d 6.92 (t, J = 8 Hz, 1H), 4.2 (m, 4H), 2.15 (t, J = 6.4 Hz, 2H), 1.8 (m, 1H), 1.2–1.4 (m, 6H), 0.88 (d, J = 6.4 Hz, 6H) ppm; 13C NMR (100 MHz, DMSO-d6): d 167.7, 164.7, 147.4, 129, 60.9, 27.4, 22.1, 21.8, 13.8 ppm; ESI-MS: m/z 229 (M+1). 12b: 1H NMR (400 MHz, DMSO-d6): d 6.92 (t, J = 8 Hz, 1H), 4.1 (m, 4H), 2.2 (q, J = 7.6 Hz, 2H), 1.2–1.4 (m, 10H), 0.8 (t, J = 7.6 Hz, 6H) ppm; 13C NMR (100 MHz, DMSO-d6): d 167.7, 163.2, 148.7, 128.3, 60, 29.6, 28.7, 21.6, 13.9, 13.4 ppm; ESI-MS: m/z 229 (M+1). 0.5 g of 4a was dissolved in 3 mL THF and the crystals were isolated by a slow evaporation process. The crystals were characterized using single crystal X-ray diffraction analysis. Deposition number: CCDC 1046394; formula: C12H11N1O3S1; unit cell parameters: a 6.8871(5), b 9.0708(5), c 19.0615(13), P21/n.
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Knoevenagel condensation of aromatic bisulfite adducts with 2,4-thiazolidinedione in the presence of Lewis acid catalysts Sandeep Mohanty a,b,⇑, Amrendra Kumar Roy a, G. Sandeep Reddy a, K. P. Vinay Kumar a, B. RamaDevi b, G. Bhargavi c, Arun Chandra Karmakar d 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, Andhra Pradesh, India b Centre for Environment, Institute of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500072, Andhra Pradesh, India c School of Chemistry, University of Hyderabad, Hyderabad 500 046, India d Shasun Pharmaceuticals Limited, Shasun Road, Periakalapet, Pondicherry 605014, India
a r t i c l e
i n f o
Article history: Received 4 February 2015 Revised 23 March 2015 Accepted 25 March 2015 Available online xxxx Keywords: Bisulfite adduct Lewis acid Knoevenagel condensation Thiazolidinedione
a b s t r a c t Several commercial Lewis acids, specifically TiCl4, were able to promote the condensation reaction between aromatic bisulfite adducts and 2,4-thiazolidinedione to produce 5-arylidene derivatives. The product distribution was not affected by the equivalents of TiCl4 used, but was dependent on temperature and the nature of the solvent medium. In all cases, the reaction required activation of the aromatic bisulfite adducts by Lewis acids, followed by the loss of SO2 and subsequent regeneration of the parent aldehyde. The in situ formed aldehyde ultimately underwent acid-catalyzed carbon–carbon bond formation to give 5-arylidene derivatives. The reaction with TiCl4 afforded the products from aromatic and aliphatic bisulfite adducts in moderate to good yields. When hydrated Lewis acids were used, in addition to 5-arylidenes, the in situ formed aldehyde underwent a disproportionation reaction to give a carboxylic acid as a by-product. Ó 2015 Elsevier Ltd. All rights reserved.
Introduction The synthesis of 5-arylidene-2,4-thiazolidinediones is of great interest because of their important applications in the pharmaceutical industry.1 These molecules are particularly fascinating because of the diversity of synthetic procedures that can be used for their synthesis.2 Given their medicinal as well as synthetic interest, 5-arylidenes are of significant importance in the area of heterocyclic chemistry. Extensive effort has been expended in the search for efficient processes to synthesize these compounds. The most common methodology adopted for the synthesis of 5-arylidene-2,4-thiazolidinediones is the condensation of aromatic aldehydes with active methylene groups such as 2,4-thiazolidinedione in a single step. Above base-promoted condensation, leading to carbon-carbon bond formation is the key step in this reaction. In general, these reactions are catalyzed by bases, but there are reports of Knoevenagel condensations promoted by Lewis acids.3 In most of these cases, the Lewis acid was used in a quantity greater than the stoichiometric amount and aldehydes were used as the starting material. The use of aldehydes on a commercial scale has several disadvantages owing to their inherent instability. ⇑ Corresponding author.
Therefore, bisulfite adducts can be the preferred intermediates for many commercially manufactured aldehydes as these adducts are usually crystalline and stable, thus making their handling and storage more suitable. Unlike other reactions between aldehydes and active methylene groups, the bisulfite adduct has rarely been used for direct carbon–carbon bond formation. Therefore, our main effort was directed toward exploring the possibility of using bisulfite adducts for condensation reactions in the presence of various catalysts, without the need for deprotection of the bisulfite adducts to its parent aldehyde. Herein, we report our preliminary results on this subject. In our attempt to use bisulfite adduct in condensation reactions, we have shown previously that the condensation of bisulfite adducts with 2,4-thiazolidinedione was feasible in the presence of acetic anhydride4 and POCl35 resulting in 5-arylidene-2,4-thiazolidinediones in good yields along with unprecedented high level of (Z)-isomer selectivity. We speculated that in addition to acetic anhydride and POCl3, various other catalysts could not only help the formation of the corresponding aldehyde but also promote Knoevenagel-type reactions between 2,4-thiazolidinedione and an in situ formed aldehyde. A model condensation reaction between a bisulfite adduct (1a) and 2,4-thiazolidinedione (2) was selected for this investigation
http://dx.doi.org/10.1016/j.tetlet.2015.03.117 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
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2
S. Mohanty et al. / Tetrahedron Letters xxx (2015) xxx–xxx H N
O OH R
1a
Lewis Acid
SO 3Na Solvent, heat
R CHO 3a
2
Table 2 Screening of solvents for the TiCl4-mediated condensation of 1a and 2
O O
S R o
130 C
NH
S 4a O
R=4-OEt-C6 H4
Scheme 1. Synthesis of thiazolidinedione 4a using Lewis acids.
(Scheme 1). As a first step, various Lewis acids were screened (Table 1) to find a suitable catalyst.6 Based on prior experience,5 all screening experiments were performed using toluene as the solvent at 110 °C with 2.0 equiv of Lewis acids as reported (Table 1). Product conversion in the reaction mass was determined by HPLC (area%). As evident from Table 1, all Lewis acids that were screened, afforded a mixture of unreacted 2, in situ released parent aldehyde 3a, and the desired product 4a in different ratios. It is evident from Table 1 that the conversion of product 4a varied significantly among the Lewis acids and their hydrated salts (MLnXH2O). Lewis acids such as TiCl4, AlCl3, and SnCl4 were the most effective, displaying 58–69% conversion of bisulfite adduct 1a. On the other hand, all the hydrated Lewis acids (MLnXH2O; X = 1 7) resulted in poor yields and an unknown impurity (0.5 37% in HPLC) at RRT 0.86 (Table 1; entries 3–7); this is discussed later. No product formation was observed with BaCl22H2O, NiCl26H2O, CuCl22H2O, and PdCl22H2O (not shown in Table 1). The most promising results were obtained with TiCl4 and SnCl4; in particular, the reaction with TiCl4 was completed within 30 min of heating, that is, the reaction was found to be complete before the reaction temperature reached 110 °C. The course of the reaction was monitored using HPLC and LC–MS; the reaction was found to proceed via the in situ generation of aldehyde 3a (Scheme 1). Inspired by this success, we then focused on solvent screening. The preferred choice of Lewis acid for our subsequent study was TiCl4. For comparison, the reaction (Scheme 1) was performed with solvents (bp ranging from 39 °C to 130 °C) at reflux temperature (Table 2). The results of the TiCl4-mediated (2.0 equiv) reaction carried out with different solvents are summarized in Table 2. It appears that any solvent with a bp greater than 60 °C is sufficient for conversion to product 4a; however, with CH2Cl2, there was no product formation (40 °C). In the case of cyclohexane, the conversion to the product was low (13.2%) because of the poor solubility of 1a and 2. The best conversions were obtained in high boiling non-polar solvents, such as o-xylene and chlorobenzene (Table 2; entries 6 and 7). o-Xylene was selected for further optimization, as it is a common industrial solvent that can be recovered and recycled easily. Last phase of the optimization was to study the effect of different equivalents of TiCl4 on the conversion. Literature search showed that Titanium chloride ((Ti(IV)-base)) has been well documented to facilitate carbon-carbon bond formation reactions.7
Entry
Solvent
T (°C)
Time (h)
TiCl4 (equiv)
Product
% area
1 2 3 4 5 6 7
CH2Cl2 CHCl3 Cy(C6H5) Benzene Toluene o-Xylene Cl-C6H5
40 60 80 80 105 130 130
8.0 6.0 4.0 1.5 1.5 1 0.5
2.0 2.0 2.0 2.0 2.0 2.0 2.0
4a 4a 4a 4a 4a 4a 4a
— 72.8 13.2 58.0 69.7 83.5 86.6
There are instances where Ti(IV)-derivatives, in combination with organic bases (TiCl4/Et3N,8 Ti(O-i-Pr)4,9 TiCl4/pyridine,10 TiCl4/N-methyl morphorine,11 and TiCl4–Et3N,12), have been used to promote Knoevenagel condensations; but, in such cases, they have been used in stoichiometric amounts and the ratio of TiCl4 to base used was 1:1. In order to find the optimized equivalent of TiCl4 required for maximizing the conversion, reactions were conducted with different equivalents of TiCl4 and the conversion to product 4a with respect to yield and purity was monitored (Table 3).13 It is apparent that the reaction involves two chemical step (Scheme 1), first step involves insitu deprotection of bisulfite adduct 1a to parent aldehyde 3a and this deprotection was found to be instantaneous in the presence of a Lewis acid and heat. The second step is the condensation of insitu generated aldehyde with thiazolidine-2,4-dione 2 in the presence of Lewis acid catalyst. Moreover, Knoevenagel condensation is a net dehydration reaction and water is a by-product. Therefore, we envisioned that a minimum of 1 equiv or more of TiCl4 would be required for the transformation of 1a to 4a; surprisingly, however, only 0.5 to 1.0 equiv of TiCl4 led to the product 4a with good yield (Table 3; entries 4 and 5). The reaction proceeded with even 0.1 equiv of TiCl4; however, an optimal yield was obtained with 0.5–1.0 equiv of TiCl4. To our delight, the reaction proceeded directly from bisulfite adduct 1a with only a less than stoichiometric amount of TiCl4.
Table 3 Study of different equivalents of TiCl4 on conversion of 1a to 4a Entry
TiCl4 (equiv)
Adduct 1a (g)
T (°C)
Product 4a (g)
Yield (%)
Purity
1 2 3 4 5 6 7
0.1 0.2 0.3 0.5 1.0 1.5 2.0
5.0 5.0 5.0 5.0 5.0 5.0 5.0
110 110 110 110 110 110 110
1.1 2.7 3.6 4.4 4.0 3.5 2.5
24.3 56.8 75.0 91.1 83.0 71.9 52.6
68.1 97.9 84.7 91.8 96.4 96.4 97.9
O MLn R
H 2O
OH R
Entry
Lewis acid
TiCl4 (equiv)
Time (h)
T (°C)
Product
% area
1 2 3 4 5 6 7 8
TiCl4 AlCl3 SnCl4 LiCl.H2O ZnBr2.2H2O CrCl3.6H2O MgCl2.6H2O CeCl3.7H2O
2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0
0.5 6.0 2.0 8.0 8.0 8.0 6.0 6.0
110 110 110 110 110 110 110 110
4a 4a 4a 4a 4a 4a 4a 4a
69.7 58.3 68.0 12.6 28.1 8.7 3.0 2.9
H 5
S
S
NH
S 6
Table 1 Lewis acid screening for the condensation of 1a and 2
O R
O
4a
O MLn
OH
O S O O- + Na 1a
O
ML n
O
NH O
S O ML n
R
NH
MLn, heat H O SO2
S R 3a
NH +
2
NH O
H
O 7
Scheme 2. MLn-mediated condensation of 2 with bisulfite adduct 1a.
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S. Mohanty et al. / Tetrahedron Letters xxx (2015) xxx–xxx H N
O
O
S 2 + OH R
1a
O OH
MLn.XH 2 O; X = 1-7 R S 4a
o-xylene, reflux
NH +
O
R 8
O
SO 3Na
7.3 to 38%
Scheme 3. Lewis acid mediated disproportionation reaction of 3a.
Table 4 TiCl4-catalysis reaction of bisulfite adducts with 2 Entry
Product
TiCl4 (equiv)
Time (h)
Yield (%)
Purity
1 2 3 4 5
4a 4b 4c 4d 4e
0.5-0.75 0.5-0.75 0.5-0.75 0.5-0.75 0.5-0.75
3.0 3.5 3.0 3.0 3.0
86.73 81.79 81.79 94.26 81.63
99.54 95.91 94.90 95.62 98.80
O
OH Et
SO 3Na N
NH
+ S
O 9
2O
TiCl 4 (0.5 equiv), o-xylene, 130 o C, 3 h
Yield: 92% Purity: 93.2 O
Et N
O 4f
S
NH O
Scheme 4. Synthesis of pioglitazone intermediate 4f.
OH SO3 Na
+
11
OH
10b
COOEt
COOEt
10a
SO3 Na
COOEt TiCl4 (0.5 equiv), o-xylene, 60 o C, 2 h
+
COOEt 12a
COOEt TiCl4 (0.5 equiv), o-xylene, 60 oC, 2 h COOEt 11
COOEt COOEt 12b
Scheme 5. Condensation of aliphatic bisulfite adducts 10(a–b) with diethyl malonate 11.
In order to ascertain the effect of TiCl4, two-control condensation reaction of 2 was performed using free aldehyde 3a and its bisulfite adduct 1a (Scheme 2). Firstly, the reactions with 1a/3a were performed in the presence of 0.5 equiv of TiCl4 with 1.1 equiv of 2, and 5.0-volume o-xylene at 130 °C. Irrespective of
3
the starting material (1a or 3a) the reaction proceeded to afford product 4a. However, aldehyde 3a resulted in 62.3% conversion whereas bisulfite adduct 1a gave a conversion of 85%. Secondly, the reaction conversions were investigated in the absence of TiCl4. In the absence of TiCl4, the aldehyde 3a showed a conversion of only 2.9%, whereas bisulfite adduct 1a resulted in a conversion of only 14%. These results further confirm the essential role of TiCl4 in the transformation of 1a ? 4a (Scheme 2). Based on the above observation, we proposed a reaction mechanism wherein Lewis acid is acting as a catalyst (Scheme 2). In addition to an effective Knoevenagel reaction of 1a ? 3a ? 4a with catalytic TiCl4 we also observed, some unknown impurities at RRTs; 0.86. These impurities were monitored using LC–MS/MS and had m/z 167.0705 (M+1) with MS/MS fragment ions of 149.0592 and 121.0275. For example, when hydrated Lewis acids (ZnBr22H2O, CeCl37H2O, CrCl36H2O, LiClH2O, and MgCl26H2O) were used, the carboxylic acid (8)14 corresponding to parent aldehyde 3a as the major product was observed (7.3% to 38%; Table 5 in the Supporting information). Carboxylic acid (8) was isolated using preparative HPLC and the structure was established.15 Interestingly, our investigation of the Lewis acid-mediated synthesis of 4a revealed an important synthetic aspect of the reaction, wherein an in situ formed aldehyde might undergo a disproportionation reaction to give a carboxylic acid as a by-product. A full investigation into this disproportionation reaction is underway (Scheme 3). Having recognized the catalytic role of TiCl4, we tested this reaction using a diverse range of bisulfite adducts 1a–e that contain various functional groups, such as 4b: 4-OMe-C6H4, 4c: 4-Cl-C6H4, and 4d: 2-Cl-C6H4, as well as the bisulfite adduct of benzaldehyde (4e: C6H5), for which the data is captured in Table 4. It is evident from Table 2 and Table 4 that the yields and purity of products 4a–4e were much better with catalytic amount of TiCl4.16 Inspired by these results, we carried out a reaction between pio-adduct 9, isolated from a pharmaceutically important aryl intermediate of pioglitazone, and 0.5 equiv of TiCl4 in o-xylene to afford 5-arylidene 4f in good yields (Scheme 4). In addition to the catalytic nature of the present methodology, other advantages include rapid product 4f isolation, a cleaner reaction, and better operational efficiency.17 To demonstrate the utility, aliphatic bisulfite adducts 10(a–b) with active methylene groups such as diethylmalonate 11 were examined with TiCl4. Aliphatic aldehyde bisulfite adducts 10(a–b) with catalytic TiCl4 (0.5 equiv) gave product 12(a–b) under mild condition in prolonged reaction time (Scheme 5).18,19 The Z-configurations of 4a–f were determined by 1H NMR. The 1H NMR spectra of all the compounds (4a–f) were very similar to those of our previously isolated 5-arylidene-2,4-thiazolidinediones obtained using acetic anhydride. The methine protons of compounds 4a–f appeared between d 7.90 and 7.74. This result suggests that this proton in each of the compounds is on the same side as the carbonyl group at the 4-position of the thiazolidinedione ring.
Figure 1. X-ray structure (ORTEP) of 4a.
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S. Mohanty et al. / Tetrahedron Letters xxx (2015) xxx–xxx
Unequivocal evidence for the structure of 4a was also obtained from single crystal X-ray analysis. The structure deduced from the crystallographic data shows that product 4a is the Z-isomer. The ORTEP diagram is shown in Figure 1.20 In summary, the TiCl4-mediated Knoevenagel condensation affords the condensation product directly from the bisulfite adduct. The use of hydrated Lewis acids should be avoided for optimal yield. This methodology could help in handling unstable aldehydes on a commercial scale in their stable bisulfite adduct form. There is no need to deprotect the bisulfite adducts to the parent aldehydes prior to the reaction because, in the present case, both deprotection and subsequent condensation occur in a single pot.
7.
8. 9. 10. 11. 12. 13.
Acknowledgment We are grateful to the management of Dr. Reddy’s Laboratories Limited for the support to carry out this work. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.03. 117.
14. 15.
References and notes 16. 1. Wang, Z.; Liu, Z.; Lee, W.; Kim, S.-N.; Yoon, G.; Cheon, S. H. Bioorg. Med. Chem. Lett. 2014, 24, 3337. 2. (a) Pratap, U. R.; Jawale, D. V.; Waghmare, R. A.; Lingampalle, D. L.; Mane, R. A. New J. Chem. 2011, 35, 49; (b) Khazaei, A.; Veisi, H.; Safaei, M.; Ahmadian, H. J. Sulfur Chem. 2014, 35, 270; (c) Shah, S.; Singh, B. Bioorg. Med. Chem. Lett. 2012, 22, 5388. 3. (a) Leelavathi, P.; Ramesh Kumar, S. J. Mol. Catal. A: Chem. 2005, 240, 99; (b) Narasiah, A. V.; Nagaih, K. Synth. Commun. 2003, 33, 3825; (c) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L. Chem. Rev. 2002, 102, 2227; (d) Malona, J. A.; Colbourne, J. M.; Frontier, A. J. Org. Lett. 2006, 8, 5661; (e) Pridgen, L. N.; Huang, K.; Shilcrat, S.; Tickner-Eldridge, A.; DeBrosse, C.; Haltiwanger, R. C. Synlett 1999, 1612; (f) Forsberg, J. H.; Spaziano, V. T.; Balasubramanian, T. M.; Liu, G. K.; Kinsley, S. A.; Duckworth, C. A.; Poteruca, J. J.; Brown, P. S.; Miller, J. L. J. Org. Chem. 1987, 52, 1017; (g) Kumar, D.; Kumar, A.; Qadri, M. M.; Ansari, Md. I.; Gautam, A.; Chakraborti, A. K. RSC Adv. 2015, 5, 2920; (h) Attanasi, O.; Fillippone, P.; Mei, A. Synth. Commun. 1983, 13, 1203; (i) Khan, R. H.; Mathur, R. K.; Ghosh, A. C. Synth. Commun. 1996, 26, 683; (j) Prajapati, D.; Sandhu, J. S. J. Chem. Soc., Perkin Trans. 1 1993, 739; (k) Bennazha, J.; Zahouily, M.; Sebti, S.; Boukhari, A.; Holt, E. M. Catal. Commun. 2001, 2, 101; (l) Abaee, M. S.; Mojtahedi, M. M.; Zahedi, M. M.; Khanalizadeh, G. Arkivoc 2006, xv, 48; (m) Cabello, J. A.; Campelo, J. M.; Garcia, A.; Luna, D.; Marinas, J. M. J. Org. Chem. 1984, 49, 5195; (n) Zhang, Y.; Dou, Q.; Dai, L.; Wang, X.; Chen, Y. RSC Adv. 2012, 2, 8979; (o) Zhang, Y.; Xia, C. Appl. Catal., A 2009, 366, 141; (p) Vijender, M.; Kishore, P.; Satyanarayana, B. Arkivoc 2008, xiii, 122; (q) Ilangovan, A.; Muralidharan, S.; Maruthamuthu, S. J. Korean Chem. Soc. 2011, 55, 1000. 4. Mohanty, S.; Roy, A. K.; Kumar, V. K. P.; Reddy, G. S.; Karmakar, A. C. Tetrahedron Lett. 2014, 55, 4585–4589. 5. Mohanty, S.; Reddy, G. S.; Karmakar, A. C. Lett. Org. Chem. 2014, 11, 197–202. 6. Reaction monitoring by HPLC: Lewis acids (2.0 equiv) were added into a round bottom flask containing 1a in 5.0 mL of toluene and 1.1 equiv of 2 at 25 °C (Scheme 1). The temperature of the reaction mixture was gradually raised to 110 °C. Prior to the reaction, the retention time (RT) and relative retention time (RRT) of aldehyde 3a, adduct 4a, thiazolidine-2,4-dione 2, and product 4a were established by HPLC co-injection. HPLC analysis was performed using a Waters 2690 HPLC system. The reaction mass sampling for HPLC was carried out using a pipette under a N2 atmosphere. The sample was transferred to a 50 mL round bottom flask, and the reaction mass was concentrated by evaporation (using N2 pressure). The resulting dry sample (20 mg) was removed and transferred to a 10.0 mL volumetric flask. Then, the freshly prepared diluted sample was transferred to an injection loop for analysis (5 mL diluted sample). The HPLC conditions to monitor the progress of the reaction were: column: Kromasil, Altima C18, 150 4.6, 3 lm; kmax: 245 nm; flow rate: 1.0 mL/min; run time:
17.
18.
19.
20.
30 min; and solvent for dilution: DMSO. Chromatograms of the samples were recorded during the reaction. The percentage conversion was determined by HPLC, as shown in Table 1. (a) Lehnert, W. Tetrahedron Lett. 1970, 4723; (b) Lehnert, W. Tetrahedron 1972, 28, 663; (c) Lehnert, W. Tetrahedron 1973, 29, 635; (d) Lehnert, W. Tetrahedron 1974, 30, 301; (e) Reetz, M. T.; Von Itzstein, M. J. Organomet. Chem. 1987, 334, 85; (f) Reetz, M. T.; Peter, R.; Von Itzstein, M. Chem. Ber. 1987, 120, 121. Renzetti, A.; Dardennes, E.; Fontana, A.; De Maria, P.; Sapi, J.; Gérard, S. J. Org. Chem. 2008, 73, 6824. Yamashita, K.; Tanaka, T.; Hayashi, M. Tetrahedron 2005, 61, 7981. Green, B.; Crane, R. I.; Khaidem, I. S.; Leighton, R. S.; Newaz, S. S.; Smyser, T. E. J. Org. Chem. 1985, 50, 640. Zhang, X.-R.; Chao, W.; Chuai, Y.-T.; Ma, Y.; Hao, R.; Zou, D.-C.; Wei, Y.-G.; Wang, Y. Org Lett. 2006, 8, 2563. Marrone, A.; Renzetti, A.; De Maria, P.; Gérard, S.; Sapi, J.; Fontana, A.; Re, N. Chem. –Eur. J. 2009, 15, 11537. A slurry of bisulfite adduct 1a (5 g) with TZD 2 (2.5 g), was prepared in oxylene (25 mL) in a 100 mL round bottom flask. TiCl4 was added in one portion at 25 °C. The reaction temperature was gradually raised to 130 °C, and the reaction mass temperature was maintained for 1 h. After the visual absence of aldehyde in TLC, the reaction mass was slowly quenched by adding ice-cold water at 10 °C, and the biphasic slurry was stirred below 20 °C for 10 min. The resulting bright yellow crystalline material was separated from the liquid layer by filtering the slurry mass using a Buchner funnel in a vacuum of 650 mm Hg. The wet cake obtained was washed with 2 5 mL o-xylene at 25 °C and dried in vacuum at 50 °C to afford product 4a. Brewster, T. P.; Ou, W. C.; Tran, J. C.; Goldberg, K. I.; Hanson, S. K.; Cundari, T. R.; Heinekey, D. M. ACS Catal. 2014, 4, 3034. 4-Ethoxybenzoic acid: 1H NMR (400 MHz, DMSO-d6): d 7.8 (d, 2H), 7.0 (d, 2H), 4.1 (q, 2H), 1.3 (t, 3H) ppm; 13C NMR (400 MHz, DMSO-d6): d 167.048, 162.075, 131.315, 122.928, 114.128, 63.401, 14.492 ppm; MS: calcd for C9H10O3 166.06, found 167.0419 (M+H+); IR (KBr) 3436 (acid O–H), 2985 (aromatic CH), 1677, 1610 (C@O), 1175 (C–O) cm 1. 1a: 1H NMR (400 MHz, DMSO-d6): d 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, DMSO-d6): d 167.9, 167.3, 160.0, 132.1, 131.8, 129.5, 125.2, 120.0, 115.2, 63.4, 14.4 ppm; ESI-MS: m/z 248.3 (M1). 1b: 1H NMR (400 MHz, DMSO-d6): d 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, DMSO-d6): d 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). 1c: 1H NMR (400 MHz, DMSO-d6): d 12.66 (s, 1H), 7.78 (s, 1H), 7.63–7.58 (m, 4H) ppm; 13C NMR (400 MHz, DMSO-d6): d 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 (M-1). 1d: 1H NMR (400 MHz, DMSO-d6): d 12.70 (br s, 1H), 7.90 (s, 1H), 7.45 (m, 4H) ppm; 13C NMR (100 MHz, DMSO-d6): d 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). 1e: 1H NMR (400 MHz, DMSO-d6): d 12.65 (br s, 1H), 7.78 (s, 1H), 7.60–7.45 (m, 5H) ppm; 13C NMR (100 MHz, DMSO-d6): d 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). 4f: 1H NMR (400 MHz, DMSO-d6): 12.5 (s, 1H), 8.3–7.0 (m, 7H), 4.40 (t, J = 6.8 Hz, 2H), 3.20 (t, J = 6.8 Hz, 2H), 2.60 (q, J = 7.4 Hz, 2H), 1.20 (d, J = 7.5 Hz, 3H) ppm; 13C NMR (100 MHz, DMSO d6): 167.9, 167.4, 160.1, 155.1, 148.5, 136.7, 135.7, 132, 131, 125, 123, 120, 115.3, 67, 36.5, 24.9, 15.3 ppm; ESI-MS: m/z 355.1 (M+1). 12(a–b). A slurry of bisulfite adduct 10(a–b) (5.0 g) with 11 (8.50 g), was prepared in o-xylene (25 mL) in a 100 mL round bottom flask. TiCl4 (2.50 g) was added in one portion at 25 °C. The reaction temperature was gradually raised to 60 °C, and the reaction mass temperature was maintained for 2 h. The reaction mass was slowly quenched by adding ice-cold water at 10 °C. The product was extracted in to o-xylene (2 10 mL) and then evaporated under reduced pressure to give crude product 12(a–b) 5.5 g (91.0% yield). Crude product 12(a–b) on purification by column chromatography afforded product as a colourless oil (silica gel, 95:05 pet ether/ethyl acetate). (12a; 2.10 g, 35%): (12b; 2.28 g, 38%). 12a: 1H NMR (400 MHz, DMSO-d6): d 6.92 (t, J = 8 Hz, 1H), 4.2 (m, 4H), 2.15 (t, J = 6.4 Hz, 2H), 1.8 (m, 1H), 1.2–1.4 (m, 6H), 0.88 (d, J = 6.4 Hz, 6H) ppm; 13C NMR (100 MHz, DMSO-d6): d 167.7, 164.7, 147.4, 129, 60.9, 27.4, 22.1, 21.8, 13.8 ppm; ESI-MS: m/z 229 (M+1). 12b: 1H NMR (400 MHz, DMSO-d6): d 6.92 (t, J = 8 Hz, 1H), 4.1 (m, 4H), 2.2 (q, J = 7.6 Hz, 2H), 1.2–1.4 (m, 10H), 0.8 (t, J = 7.6 Hz, 6H) ppm; 13C NMR (100 MHz, DMSO-d6): d 167.7, 163.2, 148.7, 128.3, 60, 29.6, 28.7, 21.6, 13.9, 13.4 ppm; ESI-MS: m/z 229 (M+1). 0.5 g of 4a was dissolved in 3 mL THF and the crystals were isolated by a slow evaporation process. The crystals were characterized using single crystal X-ray diffraction analysis. Deposition number: CCDC 1046394; formula: C12H11N1O3S1; unit cell parameters: a 6.8871(5), b 9.0708(5), c 19.0615(13), P21/n.
Please cite this article in press as: Mohanty, S.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.03.117