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Ketones as Electrophiles in Two Component Baylis-Hillman Reaction: A Facile One-Pot Synthesis of Substituted Indolizines Deevi Basavaiah,* Gorre Veeraraghavaiah and Satpal Singh Badsara 5
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Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x 2-Alkanoyl(aroyl)-pyridines have been successfully used for coupling with alkyl vinyl ketones under the influence of TMSOTf providing a facile protocol for synthesis of substituted indolizines, thus demonstrating the applications of ketones as electrophiles in a two component BH reaction. The Baylis-Hillman (BH) reaction1,2 is an interesting three component reaction essentially involving the coupling of αposition of activated alkenes (first component) with electrophiles (second component) under the influence of a catalyst (reaction initiator) (third component) providing diverse classes of useful compounds of high synthetic potential. This reaction has already attained the status of highly popular and useful tool in synthetic, mechanistic, and medicinal chemistry and in fact, also offers many challenges and attractions which need to be addressed systematically.1d,i Two such challenges are: Number one: although aldehydes have been extensively used as electrophiles in various kinds of Baylis-Hillman reactions, ketones are known to be very weak electrophiles for coupling with activated alkenes. Ketones (except very reactive ketones like isatins,3a-c 1,2diketones3d-g, α-keto-esters3h-k, fluoro ketones3i,l-n) require high pressure conditions3o for coupling with activated alkenes in the presence of appropriate catalysts.1e,j There are only a few reports in recent years employing ketones as electrophiles in certain intramolecular Baylis-Hillman reactions.4 The second one- is the development of two-component BaylisHillman reactions. Two component BH reactions in principle can be performed in three different ways i) intramolecular (BH) cyclization of substrates containing both activated alkene and electrophile components under the influence of a catalyst1d,e,i,j,4 ii) coupling of substrates containing electrophilic and catalytic sites with activated alkenes5a and iii) coupling of substrates containing activated alkene and catalytic sites with electrophiles.3e,5b,c The first category is well known intramolecular Baylis-Hillman reaction. 1d,e,i,j,4 However, the real challenge lies in the develop-
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a
School of Chemistry, University of Hyderabad, Hyderabad, 500 046, India.; Fax: (+91) 40-23012460; Tel: (+91) 40-23134812; E-mail: [email protected], [email protected]
† Electronic Supplementary Information (ESI) available: [representative experimental procedure and 1H and 13C NMR spectra of 3a-j, 4a–f, 4h, 6a–f, 8 and 9. Crystal data and ORTEP diagrams of 3f, 4f, 3h, 4h and 9.]. See DOI: 10.1039/b000000x/
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ment of other two categories and there are very few reports in the literature.3e,5 We have focused to address simultaneously the challenge number #1 and also the category # ii in the second challenge as a part of our ongoing long term research program on BH reaction. Accordingly we herein report a facile two component BH reaction involving the coupling of 2alkanoyl(aroyl) pyridines [as the source of two components, pyridine-nitrogen (acts as initiator site) induces the reaction while the keto group works as an electrophile] with alkyl vinyl ketones under the influence of TMSOTf leading to the synthesis of substituted indolizine derivatives, thus demonstrating the applications of ketones as electrophiles and also providing an example for two component BH reaction. A few years ago we have reported coupling of pyridine-2carboxaldehyde with alkyl vinyl ketones under the influence of TMSOTf thus providing a facile methodology for obtaining indolizine derivatives.5a In this strategy pyridine-nitrogen (acts as initiator site) induces the reaction while the aldehyde group works as an electrophile. Although this is an interesting study, unfortunately we did not then attempt the possible application of 2-alkanoyl(aroyl) pyridines for coupling with alkyl vinyl ketones with a wrong assumption that ketones may not work as they are less reactive electrophiles. Very recently we examined these reactions and were pleased to see that they work reasonably well. These results are presented here in this communication. We have first selected 2-acetylpyridine for coupling with methyl vinyl ketone (MVK) under the influence of appropriate Lewis acid catalyst. On the basis of our earlier experience we have treated 2-acetylpyridine (1a) with methyl vinyl ketone (MVK) (2a) under the influence of TMSOTf in CH3CN (containing 1% water, v/v) at room temperature for 12 h which provided the desired 8-acetyl-1-aza-7-methylbicyclo[4.3.0]nona2,4,6,8-tetraene (3a) in 24% yield. We also noticed the formation of 8-acetyl-1-aza-7-methyl-9-(3-oxobutyl)bicyclo[4.3.0]nona2,4,6,8-tetraene (4a) (MVK addition product of 3a) in 8% yield. For optimization of this coupling strategy we have examined the same reaction under different Lewis acids and conditions (Table 1). Best result was obtained when 1a was treated with 2a in the presence of TMSOTf at reflux temperature in acetonitrile (containing 1% water, v/v) for 12 h thus providing the desired indolizine derivative 3a in 62% yield along with the side product 4a (MVK addition product of 3a) in 20% yield (Table 1, entry 7) [journal], [year], [vol], 00–00 | 1
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DOI: 10.1039/C3OB42064G
(combined yield 82%).This result indeed is very encouraging. Table 1 Optimization of reaction conditionsa
O
N
2a
O
1a
N
Lewis acid, CH3CN
+
N
+
temperature, time
O
O
3a
4a minor
O
major
Entry
10
Lewis Acid
Temperature (°C)
Product 3ab Yield (%)c
Time (h)
Product 4ab Yield (%)c
3+4 Yield (%)c
1d TiCl4 rt 12 2e TMSOTf rt 12 24 8 32 3f TMSOTf reflux 12 17 3 20 4g TMSOTf reflux 12 8 0 8 5 TMSOTf rt 12 54 23 77 6 TMSOTf rt 24 55 21 76 7 TMSOTf reflux 12 62 20 82 8 Zn(OTf)2 rt 12 45 13 58 9 Sc(OTf)3 rt 12 51 16 67 10 Sc(OTf)3 reflux 12 56 19 75 a All reactions were carried out on a 1.0 mmol scale of 2-acetylpyridine with 2.0 mmol of methyl vinyl ketone under the influence of various Lewis acids (1.0 mmol) in acetonitrile (containing 1% H2O, v/v) (2 mL). b Compounds 3a and 4a were fully characterized (see: ESI). cActual yields of the products obtained based on 2-acetylpyridine (1.0 mmol) (1a). d Reaction was not clean. eReaction was carried out on a 1.0 mmol scale of 2-acetylpyridine with 1.0 mmol of methyl vinyl ketone. f Reaction was carried out with catalytic amount of TMSOTf (10 mol%) in acetonitrile (containing 1% H2O, v/v) (2 mL). g Reaction was carried out in dry acetonitrile using TMSOTf (1.0 mmol).
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In order to understand the generality of this strategy we have treated various 2-alkanoyl(aroyl) pyridines (1a-f) with MVK (2a) and ethyl vinyl ketone (2b) under similar conditions which provided indolizine derivatives 3a-j in 23–62% yields along with the side products 4a-j in 0–46% yields (Table 2). With a view to
further expand the scope of this strategy we also used isoquinolin-1-yl phenyl ketone (7) for coupling with MVK (2a) which furnished 12-acetyl-1-aza-11-phenyltricyclo-[8.3.0.04,9]trideca-2,4(9),5,7,10,12-hexaene (8) as a solid in 55% yield (Eq. 1).6 We did not observe formation of any side product here.
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Table 2 Synthesis of indolizines 3 and 4 via treatment of 2-alkanoyl(aroyl) pyridines 1 with methyl(ethyl) vinyl ketones 2 under optimized conditions a,b 4 4
3
3
R
O R
R
N 1
R
+
O
2
TMSOTf, CH3CN reflux, 12 h
2
R1
N 1
7 9
35
R1
R2
Productc
R1
8
9
O R
2
major
R
+
O R
Entry
7
N 1
8
3
30
6 2
6 2
1
5
R
5
R2
2
O
Yield (%)d
4
minor
Productc
Yield (%)d
3+4 Yield (%)d
1 H Me (1a) Me (2a) 62 20 82 3a 4a 2 H Me (1a) Et (2b) 37 13 50 3b 4b 3 H Et (1b) Me (2a) 57 23 80 3c 4c 4 H Et (1b) Et (2b) 23 14 37 3d 4d 5 4-Me Me (1c) Me (2a) 33 46 79 3e 4e 6 6-MeO Me (1d) Me (2a) 3fe 59 4fe 13 72 7 6-MeO Me (1d) Et (2b) 41 41 3g 4g 8 H Ph (1e) Me (2a) 3he 49 4he 11 60 Me (2a) 31 31 9 H Pyrid-2-yl (1f) 3i 4i 10 H Pyrid-2-yl (1f) Et (2b) 27 27 3j 4j a All reactions were carried out on a 1.0 mmol scale of 2-alkanoyl(aroyl) pyridines (1) with 2.0 mmol of activated alkene (2) in the presence of TMSOTf (1.0 mmol) in acetonitrile (containing 1% H2O, v/v) (2 mL). b In most of the cases [except in the cases of 3a (4a), 3c (4c), 3e (4e) and 3f (4f) considerable amounts of starting ketones remained intact. c Compounds 3a-d, 4a-d, and 3i were obtained as viscous liquids while the remaining were obtained as solids. All these compounds were fully characterized (see: ESI). d Actual yields of the products obtained based on 2-alkanoyl(aroyl) pyridines (1.0 mmol) (1). eStructure of these molecules were further confirmed by single crystal X-ray data analysis (see:ESI).7
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O TMSOTf, CH3CN
+
N
2a
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O
5
10
13
(1)
12
Ph 11
8
7
10 N 1
9
8
Ph
2 50
7
reflux, 12 h
3
4
6
O
55%
Next we have directed our efforts towards understanding the application of cyclic activated alkenes 5a & 5b in this methodology. Thus coupling of 5a and 5b with selected 2alkanoyl(aroyl) pyridines 1a,b,e,f under similar conditions provided indolizine derivatives 6a-f in 10–60% yields (Table 3). Similar coupling of isoquinolin-1-yl phenyl ketone (7) with cyclohex-2-enone (5a) also gave the desired product 2-aza-14oxo-12-phenyltetracyclo[11.4.0.02,11,05,10]heptdeca-1(13),3,5(10), -6,8,11-hexaene (9)7 as a solid in 45% yield (Eq. 2).6 We have also found that methyl acrylate fails to undergo reaction with 2acetylpyridine.8
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for obtaining indolizine framewoks.3b,5a,11 Because of the importance of indolizine derivatives there has been increasing interest in the development of useful strategies for synthesis of diverse classes of such framework.3b,5,9a-c,e,g,i,j,k,m,11,12 In this context it is certainly appropriate to say that this present work also shows significant relevance as a strategy, in obtaining such useful derivatives. A plausible mechanism has been described for the reaction of 2-acetylpyridine (1a) and MVK (2a) as a model case in Scheme 1. The first step involves the initial Michael addition of pyridylnitrogen onto MVK leading to the formation of silyl enolate (A) followed by intramolecular aldol addition of (A) to carbonyl of Me3Si O
11 12
N 1
+ O R3 = H R3
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R3
TMSOTf, CH3 CN
13 1
reflux, 12 h
R3 5a
8 R1
2
7 4
R3 5 3 6 R
= Me 5b
Entry
R1
R3
1
Me (1a)
H (5a)
6
35
Me (1a)
Me (5b)
6b
31
Et (1b)
H (5a)
6c
26
4
Ph (1e)
H (5a)
6d
35
5
Ph (1e)
Me (5b)
6e
10
6
70
Pyrid-2-yl (1f)
H (5a)
6f
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All reactions were carried out on a 1.0 mmol scale of 2-alkanoyl(aroyl) pyridines (1) with 1.0 mmol of cyclic activated alkene (5) in the presence of TMSOTf (1.0 mmol) in acetonitrile (containing 1% H2O, v/v) (2 mL). b In all the cases considerable amounts of starting ketones remained intact. c All compounds were obtained as solids and fully characterized (see: ESI). d Actual yields of the products obtained based on 2-alkanoyl(aroyl) pyridines (1.0 mmol) (1).
TMSOTf, CH3CN
+
reflux, 12 h O
Ph 7
40
45
5a
8 9
9
H
–TfOH
OTf
–H2O
N 3a
N O major
O
O
O Me3Si
N
–TMSOTf H O SiMe3
N
O major
OTf
65 Me Si OTf 3
O
4a minor
O
Yield(%)d
2
N
SiMe3
H OH
addition
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5
O
O
6a
6
N
OTf
Productc
7
N
–Me3SiOH
second Michael
3
O
N
H
Me3SiO
O
a
30
O
enol (B)
N
3
OTf
silyl enolate (A) O
O
aldol reaction
2a
1a
10 9
R1
Me3SiO intramolecular
N
addition
+
N
Table 3 Synthesis of indolizines 6 via the treatment of 2-alkanoyl(aroyl) pyridines 1 with cyclic activated alkenes 5 under optimized conditiona,b O
O Michael
H
15
OTf
O
4
Ph 45%
80
3
11 N2 1 10 12
75
17
13
O
14
16
(2)
Scheme 1 Plausible mechanism
acetyl group. Subsequent removal of trimethylsilyloxy group (as silanol or its ether) and TfOH followed by neutralization of positive charge on the nitrogen provided the desired product 3a (major). The minor compound 4a was formed via the Michael addition of indolizine 3a onto MVK as shown in Scheme 1 under the influence of TMSOTf. In conclusion, we have developed a facile strategy for coupling of 2-alkanoyl(aroyl) pyridines with representative alkyl vinyl ketones under the influence of TMSOTf leading to the formation of indolizine derivatives. This methodology clearly demonstrates the applications of certain ketones as good electrophiles in BH reaction and also opens up the ground for the design of appropriate substrates for two component Baylis-Hillman reactions.
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It is very appropriate to mention here the importance of indolizine framework.9 Several natural products such as (–)swainsonine9d,e, slaframine9f,g, castanospermine9h,i, cryptaustoline9j, 219F9k, camptothecin9l,m contain the indolizine structural unit. Also good number of compounds having indolizine framework exhibit various biological activities such as antibacterial activity against mycobacterium tuberculosis10a, antioxidant10b, inhibitors of phosphatase10c and aromatase10d, antidepressant10e, antileukemic10f, and calcium entry blocker activities10g etc. It is also worth mentioning here that the BaylisHillman adducts have already been employed as useful synthons This journal is © The Royal Society of Chemistry [year]
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Acknowledgments We thank DST (New Delhi) for funding this project. GV and SSB thank CSIR and DST (New Delhi) for their research fellowships. We thank UGC for support and providing some instrumental facilities. We thank the national single crystal X-ray and HRMS facility funded by DST. We also thank Professor S. Pal, School of Chemistry, University of Hyderabad, for helpful discussions regarding X-ray data analysis.
Notes and references 1 95
For leading reviews see: (a) Y. Wei and M. Shi, Chem. Rev., 2013, 113, 6659; (b) D. Basavaiah and B. C. Sahu, Chimia, 2013, 67, 8; (c) T. Y. Liu, M. Xie and Y. C. Chen, Chem. Soc. Rev., 2012, 41, 4101;
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(d) D. Basavaiah and G. Veeraraghavaiah, Chem. Soc. Rev., 2012, 41, 68; (e) D. Basavaiah, B. S. Reddy and S. S. Badsara, Chem. Rev., 2010, 110, 5447; (f) V. Declerck, J. Martinez and F. Lamaty, Chem. Rev., 2009, 109, 1; (g) G.-N. Ma, J.-J. Jiang, M. Shi and Y. Wei, Chem. Commun. 2009, 5496; (h) V. Singh and S. Batra, Tetrahedron, 2008, 64, 4511; (i) D. Basavaiah, K. V. Rao and R. J. Reddy, Chem. Soc. Rev., 2007, 36, 1581; (j) D. Basavaiah, A. J. Rao and T. Satyanarayana, Chem. Rev., 2003, 103, 811; (k) E. Ciganek, Org. React., 1997, 51, 201; (l) D. Basavaiah, P. D. Rao and R. S. Hyma, Tetrahedron, 1996, 52, 8001; (m) S. E. Drewes and G. H. P. Roos, Tetrahedron, 1988, 44, 4653. For recent publications on the Baylis-Hillman reaction see: (a) D. Basavaiah, S. S. Badsara and B. C. Sahu, Chem. Eur. J., 2013, 19, 2961; (b) F.-L. Hu, Y. Wei, M. Shi, S. Pindi and G. Li, Org. Biomol. Chem., 2013, 11, 1921; (c) J. W. Lim, K. H. Kim, S. H. Kim and J. N. Kim, Tetrahedron Lett., 2013, 54, 2595; (d) X. Huang, J. Peng, L. Dong and Y.-C. Chen, Chem. Commun., 2012, 48, 2439; (e) D. Basavaiah and D. M. Reddy, Org. Biomol. Chem., 2012, 10, 8774; (f) W. Yang, D. Tan, L. Li, Z. Han, L. Yan, K.-W. Huang, C.-H. Tan and Z. Jiang, J. Org. Chem., 2012, 77, 6600; (g) L. Huang and M. Shi, Chem. Commun., 2012, 48, 4501; (h) H. Batchu, S. Bhattacharyya and S. Batra, Org. Lett., 2012, 14, 6330; (i) M. S. Santos and F. Coelho, RSC Adv., 2012, 2, 3237; (j) J. C. Gomes, M. T. Rodrigues Jr., A. Moyano and F. Coelho, Eur. J. Org. Chem., 2012, 6861; (k) B. Tan, N. R. Candeias and C. F. Barbas III, J. Am. Chem. Soc., 2011, 133, 4672; (l) D. Basavaiah, B. Devendar, K. Aravindu and A. Veerendhar, Chem. Eur. J., 2010, 16, 2031; (m) H.H. Kuan, R. J. Reddy and K. Chen, Tetrehedron, 2010, 66, 9875; (n) D. Basavaiah, K. Aravindu, K. S. Kumar and K. R. Reddy, Eur. J. Org. Chem., 2010, 1843; (o) A. Arfaoui and H. Amri, Tetrahedron, 2009, 65, 4904; (p) E. L. Myers, J. G. de Vries and V. K. Aggarwal, Angew. Chem. Int. Ed., 2007, 46, 1893; (q) M. E. Krafft, T. F. N. Haxell, K. A. Seibert and K. A. Abboud, J. Am. Chem. Soc., 2006, 128, 4174; (r) M. J. Lee, K. Y. Lee, J. Y. Lee and J. N. Kim, Org. Lett., 2004, 6, 3313; (s) G. W. Kabalka, B. Venkataiah and G. Dong, Org. Lett., 2003, 5, 3803. (a) S. J. Garden and J. M. S. Skakle, Tetrahedron Lett., 2002, 43, 1969; (b) D. Basavaiah and A. J. Rao, Tetrahedron Lett., 2003, 44, 4365; (c) Y.-L. Liu, B.-L. Wang, J.-J. Cao, L. Chen, Y.-X. Zhang, C.Wang and J. Zhou, J. Am. Chem. Soc., 2010, 132, 15176; (d) D. Basavaiah, S. Roy and U. Das, Tetrahedron, 2010, 66, 5612; (e) T. Kataoka, H. Kinoshita, S. Kinoshita and T. Iwamura, J. Chem. Soc. Perkin Trans. 1, 2002, 2043; (f) D. Basavaiah, B. Sreenivasulu and J. S. Rao, Tetrahedron Lett., 2001, 42, 1147; (g) G. M. Strunz, R. Bethell, G. Sampson and P. White, Can. J. Chem. 1995, 73, 1666; (h) I. Deb, P. Shanbhag, S. M. Mobin and I. N. N. Namboothiri, Eur. J. Org. Chem., 2009, 4091; (i) D. Basavaiah, B. Sreenivasulu, R. M. Reddy and K. Muthukumaran, Synth. Commun., 2001, 31, 2987; (j) D. Basavaiah, K. Muthukumaran and B. Sreenivasulu, Synlett, 1999, 1249; (k) D. Basavaiah, T. K. Bharathi and V. V. L. Gowriswari, Tetrahedron Lett., 1987, 28, 4351; (l) M. V. R. Reddy, M. T. Rudd and P. V. Ramachandran J. Org. Chem., 2002, 67, 5382; (m) P. V. Ramachandran, M. V. R. Reddy and M. T. Rudd, Chem. Commun. 2001, 757; (n) A. S. Golubev, M. V. Galakhov, A. F. Kolomiets and A. V. Fokin, Bull. Russ. Acad. Sci., 1992, 41, 2193; (o) J. S. Hill and N. S. Isaacs, Tetrahedron Lett., 1986, 27, 5007. (a) K. Tong, J. Tu, X. Qi, M. Wang, Y. Wang, H. Fu, C. U. Pittman Jr. and A. Zhou, Tetrahedron, 2013, 69, 2369; (b) B. Ressault, A. Jaunet, P. Geoffroy, S. Goudedranche and M. Miesch, Org. Lett., 2012, 14, 366 (c) L. R. Reddy, P. Saravanan and E. J. Corey, J. Am. Chem. Soc., 2004, 126, 6230. (a) D. Basavaiah and A. J. Rao, Chem. Commun., 2003, 604; (b) T. Kataoka, S. Kinoshita, H. Kinoshita, M. Fujita, T. Iwamura and S-I Watanabe Chem. Commun., 2001, 1958; (c) T. Kataoka, H. Kinoshita, S. Kinoshita and T. Iwamura, Tetrahedron Lett., 2002, 43, 7039. Reasonable amounts of isoquinolin-1-yl phenyl ketone (7) remained intact in the cases of 8 and 9. Structure of these molecules were further confirmed by single crystal X-ray data analysis (see:ESI). For compound 3f (CCDC # 950620),
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3h (CCDC # 950387), 4f (CCDC # 950621), 4h (CCDC # 950388) and 9 (CCDC # 950389). 8 Methyl acrylate fails to react with 2-acetylpyridine in the presence of TMSOTf (one equivalent) even after heating under reflux for 48 hours in acetonitrile (containing 1% H2O, v/v). Most of the 2acetylpyridine remained intact. 9 (a) G. S. Singh and E. E. Mmatli, Eur. J. Med. Chem., 2011, 46, 5237; (b) B. Liu, Z. Wang, N. Wu, M. Li, J. You and J. Lan, Chem. Eur. J., 2012, 18, 1599; (c) J. P. Michael, Nat. Prod. Rep., 2008, 25, 139; (d) R. J. Molyneux and L. F. James, Science, 1982, 216, 190; (e) J. Louvel, F. Chemla, E. Demont, F. Ferreira and A. Perez-Luna, Org. Lett., 2011, 13, 6452; (f) R. A. Gardiner, K. L. Rinehart Jr., J. J. Snyder and H. P. Broquist, J. Am. Chem. Soc., 1968, 90, 5639; (g) M. P. Sibi and J. W. Christensen, J. Org. Chem., 1999, 64, 6434; (h) L. D. Hohenschutz, E. A. Bell, P. J. Jewess, D. P. Leworthy, R. J. Pryce, E. Arnold and J. Clardy, Phytochemistry, 1981, 20, 811; (i) T. Machan, A. S. Davis, B. Liawruangrath and S. G. Pyne, Tetrahedron, 2008, 64, 2725; (j) A. I. Meyers, T. M. Sielecki, D. C. Crans, R. W. Marshman and T. H. Nguyen, J. Am. Chem. Soc., 1992, 114, 8483; (k) N. Toyooka, D. Zhou, H. Nemoto, H. M. Garraffo, T. F. Spande and J. W. Daly, Beil. J. Org. Chem., 2007, 3, doi:10.1186/1860-53973-29; (l) M. E. Wall, M. C. Wani, C. E. Cook, K. H. Palmer, A. T. McPhail and G. A. Sim, J. Am. Chem. Soc., 1966, 88, 3888; (m) D. P. Curran, S-B Ko and H. Josien, Angew. Chem. Int. Ed., 1996, 34, 2683. 10 (a) L. L. Gundersen, C. Charnock, A. H. Negussie, F. Rise and S. Teklu, Eur. J. Pharm. Sci., 2007, 30, 26; (b) O. B. Ostby, B. Dalhus, L. L. Gundersen, F. Rise, A. Bast and G. R. M. M. Haenen, Eur. J. Org. Chem., 2000, 3763; (c) T. Wiede, L. Arve, H. Prinz, H. Waldmann and H. Kessler, Bioorg. Med. Chem. Lett., 2006, 16, 59; (d) P. Sonnet, P. Dallemagne, J. Guillon, C. Enguehard, S. Stiebing, J. Tanguy, R. Bureau, S. Rault, P. Auvray, S. Moslemi, P. Sourdaine and G. E. Seralini, Bioorg. Med. Chem., 2000, 8, 945; (e) B. E. Maryanoff, J. L. Vaught, R. P. Shank, D. F. McComsey, M. J. Costanzo and S. O. Nortey, J. Med. Chem., 1990, 33, 2793; (f) W. K. Anderson, A. R. Heider, N. Raju and J. A. Yucht, J. Med. Chem., 1988, 31, 2097; (g) J. Gubin, H. D. Vogelaer, H. Inion, C. Houben, J. Lucchetti, J. Mahaux, G. Rosseels, M. Peiren, M. Clinet, P. Polster and P. Chatelain, J. Med. Chem., 1993, 36, 1425. 11 (a) D. Basavaiah, B. Devendar, D. V. Lenin and T. Satyanarayana, Synlett, 2009, 411; (b) M. L. Bode and P. T. Kaye J. Chem. Soc. Perkin Trans. 1, 1993, 1809; (c) M. L. Bode and P. T. Kaye J. Chem. Soc. Perkin Trans. 1, 1990, 2612. 12 (a) H. Huang, X. Ji, W. Wu and H. Jiang, Chem. Commun., 2013, 49, 3351; (b) M. J. Albaladejo, F. Alonso and M. Yus, Chem. Eur. J., 2013, 19, 5242; (c) M. Kucukdisli and T. Opatz, J. Org. Chem., 2013, 78, 6670; (d) Z. Li, D. Chernyak and V. Gevorgyan, Org. Lett., 2012, 14, 6056 (e) P. P. Lange, A. R. Bogdan and K. James, Adv. Synth. Cat., 2012, 354, 2373; (f) Y. Yang, C. Xie, Y. Xie and Y. Zhang, Org. Lett., 2012, 14, 957; (g) L. Albrecht, A. Albrecht, L. K. Ransborg and K. A. Jorgensen, Chem. Sci., 2011, 2, 1273; (h) J. Barluenga, G. Lonzi, L. Riesgo, L. A. Lopez and M. Tomas, J. Am. Chem. Soc., 2010, 132, 13200.
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Ketones as Electrophiles in Two Component Baylis-Hillman Reaction: A Facile One-Pot Synthesis of Substituted Indolizines Deevi Basavaiah,* Gorre Veeraraghavaiah and Satpal Singh Badsara 5
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Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x 2-Alkanoyl(aroyl)-pyridines have been successfully used for coupling with alkyl vinyl ketones under the influence of TMSOTf providing a facile protocol for synthesis of substituted indolizines, thus demonstrating the applications of ketones as electrophiles in a two component BH reaction. The Baylis-Hillman (BH) reaction1,2 is an interesting three component reaction essentially involving the coupling of αposition of activated alkenes (first component) with electrophiles (second component) under the influence of a catalyst (reaction initiator) (third component) providing diverse classes of useful compounds of high synthetic potential. This reaction has already attained the status of highly popular and useful tool in synthetic, mechanistic, and medicinal chemistry and in fact, also offers many challenges and attractions which need to be addressed systematically.1d,i Two such challenges are: Number one: although aldehydes have been extensively used as electrophiles in various kinds of Baylis-Hillman reactions, ketones are known to be very weak electrophiles for coupling with activated alkenes. Ketones (except very reactive ketones like isatins,3a-c 1,2diketones3d-g, α-keto-esters3h-k, fluoro ketones3i,l-n) require high pressure conditions3o for coupling with activated alkenes in the presence of appropriate catalysts.1e,j There are only a few reports in recent years employing ketones as electrophiles in certain intramolecular Baylis-Hillman reactions.4 The second one- is the development of two-component BaylisHillman reactions. Two component BH reactions in principle can be performed in three different ways i) intramolecular (BH) cyclization of substrates containing both activated alkene and electrophile components under the influence of a catalyst1d,e,i,j,4 ii) coupling of substrates containing electrophilic and catalytic sites with activated alkenes5a and iii) coupling of substrates containing activated alkene and catalytic sites with electrophiles.3e,5b,c The first category is well known intramolecular Baylis-Hillman reaction. 1d,e,i,j,4 However, the real challenge lies in the develop-
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School of Chemistry, University of Hyderabad, Hyderabad, 500 046, India.; Fax: (+91) 40-23012460; Tel: (+91) 40-23134812; E-mail: [email protected], [email protected]
† Electronic Supplementary Information (ESI) available: [representative experimental procedure and 1H and 13C NMR spectra of 3a-j, 4a–f, 4h, 6a–f, 8 and 9. Crystal data and ORTEP diagrams of 3f, 4f, 3h, 4h and 9.]. See DOI: 10.1039/b000000x/
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ment of other two categories and there are very few reports in the literature.3e,5 We have focused to address simultaneously the challenge number #1 and also the category # ii in the second challenge as a part of our ongoing long term research program on BH reaction. Accordingly we herein report a facile two component BH reaction involving the coupling of 2alkanoyl(aroyl) pyridines [as the source of two components, pyridine-nitrogen (acts as initiator site) induces the reaction while the keto group works as an electrophile] with alkyl vinyl ketones under the influence of TMSOTf leading to the synthesis of substituted indolizine derivatives, thus demonstrating the applications of ketones as electrophiles and also providing an example for two component BH reaction. A few years ago we have reported coupling of pyridine-2carboxaldehyde with alkyl vinyl ketones under the influence of TMSOTf thus providing a facile methodology for obtaining indolizine derivatives.5a In this strategy pyridine-nitrogen (acts as initiator site) induces the reaction while the aldehyde group works as an electrophile. Although this is an interesting study, unfortunately we did not then attempt the possible application of 2-alkanoyl(aroyl) pyridines for coupling with alkyl vinyl ketones with a wrong assumption that ketones may not work as they are less reactive electrophiles. Very recently we examined these reactions and were pleased to see that they work reasonably well. These results are presented here in this communication. We have first selected 2-acetylpyridine for coupling with methyl vinyl ketone (MVK) under the influence of appropriate Lewis acid catalyst. On the basis of our earlier experience we have treated 2-acetylpyridine (1a) with methyl vinyl ketone (MVK) (2a) under the influence of TMSOTf in CH3CN (containing 1% water, v/v) at room temperature for 12 h which provided the desired 8-acetyl-1-aza-7-methylbicyclo[4.3.0]nona2,4,6,8-tetraene (3a) in 24% yield. We also noticed the formation of 8-acetyl-1-aza-7-methyl-9-(3-oxobutyl)bicyclo[4.3.0]nona2,4,6,8-tetraene (4a) (MVK addition product of 3a) in 8% yield. For optimization of this coupling strategy we have examined the same reaction under different Lewis acids and conditions (Table 1). Best result was obtained when 1a was treated with 2a in the presence of TMSOTf at reflux temperature in acetonitrile (containing 1% water, v/v) for 12 h thus providing the desired indolizine derivative 3a in 62% yield along with the side product 4a (MVK addition product of 3a) in 20% yield (Table 1, entry 7) [journal], [year], [vol], 00–00 | 1
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(combined yield 82%).This result indeed is very encouraging. Table 1 Optimization of reaction conditionsa
O
N
2a
O
1a
N
Lewis acid, CH3CN
+
N
+
temperature, time
O
O
3a
4a minor
O
major
Entry
10
Lewis Acid
Temperature (°C)
Product 3ab Yield (%)c
Time (h)
Product 4ab Yield (%)c
3+4 Yield (%)c
1d TiCl4 rt 12 2e TMSOTf rt 12 24 8 32 3f TMSOTf reflux 12 17 3 20 4g TMSOTf reflux 12 8 0 8 5 TMSOTf rt 12 54 23 77 6 TMSOTf rt 24 55 21 76 7 TMSOTf reflux 12 62 20 82 8 Zn(OTf)2 rt 12 45 13 58 9 Sc(OTf)3 rt 12 51 16 67 10 Sc(OTf)3 reflux 12 56 19 75 a All reactions were carried out on a 1.0 mmol scale of 2-acetylpyridine with 2.0 mmol of methyl vinyl ketone under the influence of various Lewis acids (1.0 mmol) in acetonitrile (containing 1% H2O, v/v) (2 mL). b Compounds 3a and 4a were fully characterized (see: ESI). cActual yields of the products obtained based on 2-acetylpyridine (1.0 mmol) (1a). d Reaction was not clean. eReaction was carried out on a 1.0 mmol scale of 2-acetylpyridine with 1.0 mmol of methyl vinyl ketone. f Reaction was carried out with catalytic amount of TMSOTf (10 mol%) in acetonitrile (containing 1% H2O, v/v) (2 mL). g Reaction was carried out in dry acetonitrile using TMSOTf (1.0 mmol).
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In order to understand the generality of this strategy we have treated various 2-alkanoyl(aroyl) pyridines (1a-f) with MVK (2a) and ethyl vinyl ketone (2b) under similar conditions which provided indolizine derivatives 3a-j in 23–62% yields along with the side products 4a-j in 0–46% yields (Table 2). With a view to
further expand the scope of this strategy we also used isoquinolin-1-yl phenyl ketone (7) for coupling with MVK (2a) which furnished 12-acetyl-1-aza-11-phenyltricyclo-[8.3.0.04,9]trideca-2,4(9),5,7,10,12-hexaene (8) as a solid in 55% yield (Eq. 1).6 We did not observe formation of any side product here.
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Table 2 Synthesis of indolizines 3 and 4 via treatment of 2-alkanoyl(aroyl) pyridines 1 with methyl(ethyl) vinyl ketones 2 under optimized conditions a,b 4 4
3
3
R
O R
R
N 1
R
+
O
2
TMSOTf, CH3CN reflux, 12 h
2
R1
N 1
7 9
35
R1
R2
Productc
R1
8
9
O R
2
major
R
+
O R
Entry
7
N 1
8
3
30
6 2
6 2
1
5
R
5
R2
2
O
Yield (%)d
4
minor
Productc
Yield (%)d
3+4 Yield (%)d
1 H Me (1a) Me (2a) 62 20 82 3a 4a 2 H Me (1a) Et (2b) 37 13 50 3b 4b 3 H Et (1b) Me (2a) 57 23 80 3c 4c 4 H Et (1b) Et (2b) 23 14 37 3d 4d 5 4-Me Me (1c) Me (2a) 33 46 79 3e 4e 6 6-MeO Me (1d) Me (2a) 3fe 59 4fe 13 72 7 6-MeO Me (1d) Et (2b) 41 41 3g 4g 8 H Ph (1e) Me (2a) 3he 49 4he 11 60 Me (2a) 31 31 9 H Pyrid-2-yl (1f) 3i 4i 10 H Pyrid-2-yl (1f) Et (2b) 27 27 3j 4j a All reactions were carried out on a 1.0 mmol scale of 2-alkanoyl(aroyl) pyridines (1) with 2.0 mmol of activated alkene (2) in the presence of TMSOTf (1.0 mmol) in acetonitrile (containing 1% H2O, v/v) (2 mL). b In most of the cases [except in the cases of 3a (4a), 3c (4c), 3e (4e) and 3f (4f) considerable amounts of starting ketones remained intact. c Compounds 3a-d, 4a-d, and 3i were obtained as viscous liquids while the remaining were obtained as solids. All these compounds were fully characterized (see: ESI). d Actual yields of the products obtained based on 2-alkanoyl(aroyl) pyridines (1.0 mmol) (1). eStructure of these molecules were further confirmed by single crystal X-ray data analysis (see:ESI).7
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(1)
12
Ph 11
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9
8
Ph
2 50
7
reflux, 12 h
3
4
6
O
55%
Next we have directed our efforts towards understanding the application of cyclic activated alkenes 5a & 5b in this methodology. Thus coupling of 5a and 5b with selected 2alkanoyl(aroyl) pyridines 1a,b,e,f under similar conditions provided indolizine derivatives 6a-f in 10–60% yields (Table 3). Similar coupling of isoquinolin-1-yl phenyl ketone (7) with cyclohex-2-enone (5a) also gave the desired product 2-aza-14oxo-12-phenyltetracyclo[11.4.0.02,11,05,10]heptdeca-1(13),3,5(10), -6,8,11-hexaene (9)7 as a solid in 45% yield (Eq. 2).6 We have also found that methyl acrylate fails to undergo reaction with 2acetylpyridine.8
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for obtaining indolizine framewoks.3b,5a,11 Because of the importance of indolizine derivatives there has been increasing interest in the development of useful strategies for synthesis of diverse classes of such framework.3b,5,9a-c,e,g,i,j,k,m,11,12 In this context it is certainly appropriate to say that this present work also shows significant relevance as a strategy, in obtaining such useful derivatives. A plausible mechanism has been described for the reaction of 2-acetylpyridine (1a) and MVK (2a) as a model case in Scheme 1. The first step involves the initial Michael addition of pyridylnitrogen onto MVK leading to the formation of silyl enolate (A) followed by intramolecular aldol addition of (A) to carbonyl of Me3Si O
11 12
N 1
+ O R3 = H R3
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R3
TMSOTf, CH3 CN
13 1
reflux, 12 h
R3 5a
8 R1
2
7 4
R3 5 3 6 R
= Me 5b
Entry
R1
R3
1
Me (1a)
H (5a)
6
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Me (1a)
Me (5b)
6b
31
Et (1b)
H (5a)
6c
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4
Ph (1e)
H (5a)
6d
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5
Ph (1e)
Me (5b)
6e
10
6
70
Pyrid-2-yl (1f)
H (5a)
6f
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All reactions were carried out on a 1.0 mmol scale of 2-alkanoyl(aroyl) pyridines (1) with 1.0 mmol of cyclic activated alkene (5) in the presence of TMSOTf (1.0 mmol) in acetonitrile (containing 1% H2O, v/v) (2 mL). b In all the cases considerable amounts of starting ketones remained intact. c All compounds were obtained as solids and fully characterized (see: ESI). d Actual yields of the products obtained based on 2-alkanoyl(aroyl) pyridines (1.0 mmol) (1).
TMSOTf, CH3CN
+
reflux, 12 h O
Ph 7
40
45
5a
8 9
9
H
–TfOH
OTf
–H2O
N 3a
N O major
O
O
O Me3Si
N
–TMSOTf H O SiMe3
N
O major
OTf
65 Me Si OTf 3
O
4a minor
O
Yield(%)d
2
N
SiMe3
H OH
addition
60
5
O
O
6a
6
N
OTf
Productc
7
N
–Me3SiOH
second Michael
3
O
N
H
Me3SiO
O
a
30
O
enol (B)
N
3
OTf
silyl enolate (A) O
O
aldol reaction
2a
1a
10 9
R1
Me3SiO intramolecular
N
addition
+
N
Table 3 Synthesis of indolizines 6 via the treatment of 2-alkanoyl(aroyl) pyridines 1 with cyclic activated alkenes 5 under optimized conditiona,b O
O Michael
H
15
OTf
O
4
Ph 45%
80
3
11 N2 1 10 12
75
17
13
O
14
16
(2)
Scheme 1 Plausible mechanism
acetyl group. Subsequent removal of trimethylsilyloxy group (as silanol or its ether) and TfOH followed by neutralization of positive charge on the nitrogen provided the desired product 3a (major). The minor compound 4a was formed via the Michael addition of indolizine 3a onto MVK as shown in Scheme 1 under the influence of TMSOTf. In conclusion, we have developed a facile strategy for coupling of 2-alkanoyl(aroyl) pyridines with representative alkyl vinyl ketones under the influence of TMSOTf leading to the formation of indolizine derivatives. This methodology clearly demonstrates the applications of certain ketones as good electrophiles in BH reaction and also opens up the ground for the design of appropriate substrates for two component Baylis-Hillman reactions.
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It is very appropriate to mention here the importance of indolizine framework.9 Several natural products such as (–)swainsonine9d,e, slaframine9f,g, castanospermine9h,i, cryptaustoline9j, 219F9k, camptothecin9l,m contain the indolizine structural unit. Also good number of compounds having indolizine framework exhibit various biological activities such as antibacterial activity against mycobacterium tuberculosis10a, antioxidant10b, inhibitors of phosphatase10c and aromatase10d, antidepressant10e, antileukemic10f, and calcium entry blocker activities10g etc. It is also worth mentioning here that the BaylisHillman adducts have already been employed as useful synthons This journal is © The Royal Society of Chemistry [year]
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Acknowledgments We thank DST (New Delhi) for funding this project. GV and SSB thank CSIR and DST (New Delhi) for their research fellowships. We thank UGC for support and providing some instrumental facilities. We thank the national single crystal X-ray and HRMS facility funded by DST. We also thank Professor S. Pal, School of Chemistry, University of Hyderabad, for helpful discussions regarding X-ray data analysis.
Notes and references 1 95
For leading reviews see: (a) Y. Wei and M. Shi, Chem. Rev., 2013, 113, 6659; (b) D. Basavaiah and B. C. Sahu, Chimia, 2013, 67, 8; (c) T. Y. Liu, M. Xie and Y. C. Chen, Chem. Soc. Rev., 2012, 41, 4101;
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Organic & Biomolecular Chemistry Accepted Manuscript
DOI: 10.1039/C3OB42064G
