A Highly Stereocontrolled Intramolecular Cycloaddition Reaction of Azomethine Ylide Activated by a Pyrimidine Ring: Access to Novel Tricyclic Hexahydro-1H-pyrrolo[2′,3′:4,5]pyrido[2,3-d]pyrimidines

Abstract

A pyrimidine ring was discovered to aid formation of an azomethine ylide undergoing intramolecular cycloaddition reactions. This method enabled efficient synthesis of a novel tricyclic pyrimidine-piperidine-pyrrolidine scaffold from various pyri­midinemethyl amines and aldehydes in complete stereocontrol and could be rationalized by an S-shaped azomethine ylide intermediate.

1,3-Dipolar cycloaddition of azomethine ylide is one of the most efficient approaches to prepare pyrrolidine derivatives and has been extensively used in the synthesis of natural products and biologically active molecules. [¹] Intramolecular azomethine ylide reactions can provide direct access to polycyclic scaffolds of considerable complexity with high to complete stereocontrol. [²] Azomethine ylides are often generated from a secondary amine and an aldehyde, [²a] however the amine usually must contain an electron-withdrawing group [¹] [²a] [³] which serves dual purposes: increasing the acidity of the α-proton to promote formation of the azomethine ylide and stabilizing the resulting negatively charged carbon. Thus far, only a couple of cases of azomethine ylide reactions involving cyclic amines with an aromatic ring that may serve as the direct facilitating group have been reported. [4]

Pyrimidine is a well-known electron-deficient heterocycle and has been widely utilized in the design of biologically active agents, [5] while pyrrolidine is frequently present among natural products and pharmacologically active molecules. [6] Therefore, development of methodologies for the synthesis of novel polycyclic scaffolds containing both pyrimidine and pyrrolidine moieties should be of interest to synthetic and medicinal chemists. In this context, we envisaged a synthetic strategy to create novel tricyclic pyrimidine-piperidine-pyrrolidine system via an intramolecular 1,3-dipolar cycloaddition of azomethine ylides (Scheme  [¹] ). In the outlined strategy, the pyrimidine ring could play the dual roles of electron withdrawing and charge delocalization to facilitate the formation of azomethine ylide and enable the subsequent productive 1,3-dipolar cycloaddition reactions. [7] In this case, the pyrimidine ring acts both as a linker between the eventually formed azomethine ylide and the dienophile, and as the activating group without metal coordination through a nitrogen atom as reported. [8] This reaction should produce tricyclic compounds with several stereogenic centers in highly controlled manners. Herein, the preliminary results of the investigation are reported.

A series of pyrimidines 4-10 were prepared in a four-step sequence in 30-64% overall yields as depicted in Scheme  [²] . For detailed reactions conditions please consult the Supporting Information.

Treatment of 4 with benzaldehyde (1.2 equiv) for four hours in refluxing toluene with removal of water using a Dean-Stark trap yielded the desired product 11a in 89% yield (entry 1, Table  [¹] ). [9] Product 11a was characterized as configured with phenyl and the two bridgehead hydrogen atoms on the same side of the newly formed pyrrolidine ring based on ^¹H NMR spectrum (J _3a,_9b = 3.6 Hz) and X-ray analysis. [¹0] Pyrimidine 4 (R^¹ = n-Bu) reacted with various aldehydes to produce exclusively analogously configured products 11 as determined by comparison of their ^¹H NMR spectra (Table  [¹] ).

In general, aromatic aldehydes (including heterocyclic and α,β-unsaturated aldehydes) participated in the current reaction effectively to produce the desired products in good to excellent yields (entries 1-13, Table  [¹] ). Both electron-rich and electron-deficient aldehydes gave excellent yields, suggesting that the current reaction is less sensitive to electronic factors on the aromatic aldehydes. On the other hand, 2-methoxybenzaldehyde gave lower yield (entry 10, Table  [¹] ) compared to other benzaldehydes, suggesting potential steric hindrance. In contrast, aliphatic ­aldehydes failed in the current reaction with only cyclohexanecarbaldehyde producing the desired product 11p in 51% yield (entry 16, Table  [¹] ). Ready enamine formation for butyraldehyde might explain its failure to produce any desired product, [²a] while pivalaldehyde might be just too hindered sterically for the cycloaddition.

Table 1 Cycloadditions of 4 via Pyrimidine-Stabilized Azomethine Ylide

Entry	R5	Time (h)	11	Yield (%)
1	Ph	4	11a	89
2	4-O2NC6H4	4	11b	95
3	4-ClC6H4	6.5	11c	86
4	3-ClC6H4	1	11d	93
5	2-ClC6H4	4	11e	97
6	4-MeC6H4	4	11f	85
7	3-MeC6H4	4	11g	97
8	2-MeC6H4	7	11h	97
9	4-MeOC6H4	5.5	11i	83
10	2-MeOC6H4	36	11j	66
11	2-furanyl	5	11k	88
12	2-thienyl	4	11l	83
13	(E)-2-phenylethenyl	3	11m	95
14	n-Pr	12	11n	0a
15	t-Bu	9	11o	0a
16	c-Hex	48	11p	51
a Starting material 4 was recovered.

This new intramolecular [3+2]-cycloaddition reaction was further explored by varying the substituents in the substrates (Table  [²] ). Both aliphatic and aromatic groups were suitable as R^¹ for the cycloaddition (entries 1-3, Table  [²] ). However, the reaction proceeded very slowly when R^¹ was an aromatic group (entry 3, Table  [²] ). This was very likely due to the difficulty in forming the iminium ion between a secondary aromatic amine and an aldehyde. The reaction seemed very sensitive to R^³ since no product 11t was formed when R^³ was a methyl group (entry 4, Table  [²] ), while product 11u was obtained in a 46% yield when R^³ was a phenyl group (entry 5, Table  [²] ). It is interesting that the Baylis-Hillman adduct 10 could also react with benzaldehyde to give the desired product 11v in 41% yield (entry 6, Table  [²] ), which indicated that the orientation of R^³ group in substrate dictated the one of R^³ in product 11. The product structures of 11q and 11v were unambiguously determined by X-ray crystal structure analysis [¹0] and the rest by ^¹H NMR spectra in comparison.

The stereoselectivity of products 11 suggested that the ­cycloaddition reaction proceeded exclusively via an S-shaped azomethine ylide 12 as depicted in Scheme  [³] . The results of entries 4 and 5 in Table  [²] could be easily explained by the transition states shown in Scheme  [³] .

Transition state 12t (R^³ = Me) is disfavored due to the repulsion between the methyl of E-type dipolarophile and the phenyl of azomethine ylide while 12u (R^³ = Ph) is favored because of the π-π interaction between two phenyls. [³c] Therefore, the reaction of phenyl substrate 9 yielded the desired product 11u in a 46% yield while the one of methyl substrate 8 failed. The stereochemical outcome of product 11v is also consistent with the S-shaped azomethine ylide.

In conclusion, pyrimidine was demonstrated as an effective azomethine ylide stabilizing group, which led to the development of an intramolecular [3+2]-cycloaddition reaction of pyrimidine-activated azomethine ylide. This new method proved to be an efficient way to access novel and complex tricyclic pyrimidine-piperidine-pyrrolidine scaffolds in a highly stereocontrolled fashion. The stereo­chemical outcome of this reaction is rationalized by an S-shaped azomethine ylide intermediate. The sensitivity of the reaction towards the substituent R^³ could be explained by interactions between R^³ and R⁵ of the aldehyde. This reaction yields a novel scaffold for studies in chemical biology and drug discovery.

Supporting Information for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synlett.

Table 2 Azomethine Ylide Cycloadditions of Pyrimidines 5-10

Entry	5-10	R¹	R²	R³	R4	Time (h)	11	Yield (%)
1	5	Me	H	H	H	1	11q	75
2	6	i-Pr	H	H	H	23	11r	59
3	7	Ph	H	H	H	60	11s	32a
4	8	Me	H	Me	H	1	11t	0b
5	9	Me	H	Ph	H	1.5	11u	46
6	10	Me	CO2Me	H	Ph	1.5	11v	41
a Starting material 7 (43%) was recovered. b Starting material 8 decomposed.

Acknowledgment

This work was supported by a Seed research grant from Jilin University, the Science and Technology Development Plan of Jilin ­Province of China (No. 20106039), and Changchun Discovery Sciences, Ltd. Junting Jiang helped in performing several reactions.

References and Notes

• For recent reviews about 1,3-dipolar cycloaddition reactions of azomethine ylides, see:
• 1a Nájera C. Sansano JM. Curr. Org. Chem.  2003,  7:  1105 
  Search in Google Scholar
• 1b Pandey G. Banerjee P. Gadre SR. Chem. Rev.  2006,  106:  4484 
  Search in Google Scholar
• 1c Pellissier H. Tetrahedron  2007,  63:  3235 
  Search in Google Scholar
• 1d Stanley LM. Sibi MP. Chem. Rev.  2008,  108:  2887 
  Search in Google Scholar
• 1e Álvarez-Corral M. Muñoz-Dorado M. Rodríguez-García I. Chem. Rev.  2008,  108:  3174 
  Search in Google Scholar
• 1f Burrell AJM. Coldham I. Curr. Org. Synth.  2010,  7:  312 
  Search in Google Scholar
• 1g Adrio J. Carretero JC. Chem. Commun.  2011,  47:  6784 
  Search in Google Scholar
• For one review and recent reports about intramolecular 1,3-dipolar cycloaddition reactions of azomethine ylides, see:
• 2a Coldham I. Hufton R. Chem. Rev.  2005,  105:  2765 
  Search in Google Scholar
• 2b Burrell AJM. Coldham I. Watson L. Oram N. Pilgram CD. Martin NG. J. Org. Chem.  2009,  74:  2290 
  Search in Google Scholar
• 2c Kathiravan S. Ramesh E. Raghunathan R. Tetrahedron Lett.  2009,  50:  2389 
  Search in Google Scholar
• 2d Bakthadoss M. Sivakumar N. Synlett  2009,  1014 
• 2e Pankova AS. Voronin VV. Kuznetsov MA. Tetrahedron Lett.  2009,  50:  5990 
  Search in Google Scholar
• 2f Pandey G. Gupta NR. Pimpalpalle TM. Org. Lett.  2009,  11:  2547 
  Search in Google Scholar
• 2g Bélanger G. Darsigny V. Doré M. Lévesque F. Org. Lett.  2010,  12:  1396 
  Search in Google Scholar
• 2h Kathiravan S. Vijayarajan D. Raghunathan R. Tetrahedron Lett.  2010,  51:  3065 
  Search in Google Scholar
• 2i Sirisha N. Raghunathan R. Tetrahedron Lett.  2010,  51:  2515 
  Search in Google Scholar
• 2j Purushothaman S. Prasanna R. Niranjana P. Raghunathan R. Nagaraj S. Rengasamy R. Bioorg. Med. Chem. Lett.  2010,  20:  7288 
  Search in Google Scholar
• 2k Kathiravan S. Raghunathan R. Synlett  2010,  952 
• 2l Burrell AJM. Watson L. Martin NG. Oram N. Coldham I. Org. Biomol. Chem.  2010,  8:  4530 
  Search in Google Scholar
• 2m Coldham I. Burrell AJM. Guerrand HDS. Oram N. Org. Lett.  2011,  13:  1267 
  Search in Google Scholar
• 3a Martin SF. Cheavens TH. Tetrahedron Lett.  1989,  30:  7017 
  Search in Google Scholar
• 3b Grigg R. Sridharan V. Thornton-Pett M. Wang J. Xu J. Zhang J. Tetrahedron  2002,  58:  2627 
  Search in Google Scholar
• 3c Pospíšil J. Potáček M. Tetrahedron  2007,  63:  337 
  Search in Google Scholar
• 4a Ardill H. Fontaine XLR. Grigg R. Henderson D. Montgomery J. Sridharan V. Surendrakumar S. Tetrahedron  1990,  46:  6449 
  Search in Google Scholar
• 4b Wang B. Mertes MP. Mertes KB. Takusagawa F. Tetrahedron Lett.  1990,  31:  5543 
  Search in Google Scholar
• 4c Deb I. Das D. Seidel D. Org. Lett.  2011,  13:  812 
  Search in Google Scholar
• For examples, see:
• 5a Jang M. Lin Y. Jonghe SD. Gao L. Vanderhoydonck B. Froeyen M. Rozenski J. Herman J. Louat T. Belle KV. Waer M. Herdewijn P. J. Med. Chem.  2011,  54:  655 
  Search in Google Scholar
• 5b Saravanan K. Barlow HC. Barton M. Calvert AH. Golding BT. Newell DR. Northen JS. Curtin NJ. Thomas HD. Griffin RJ. J. Med. Chem.  2011,  54:  1847 
  Search in Google Scholar
• 5c Jorda R. Havlíček L. McNae IW. Walkinshaw MD. Voller J. Šturc A. Navrátilová J. Kuzma M. Mistrik M. Bártek J. Strnad M. Kryštof V. J. Med. Chem.  2011,  54:  2980 
  Search in Google Scholar
• 5d Maruoka H. Jayasekara MPS. Barrett MO. Franklin DA. Castro SD. Kim N. Costanzi S. Harden TK. Jacobson KA. J. Med. Chem.  2011,  54:  4018 
  Search in Google Scholar
• For examples, see:
• 6a Merritt JR. Liu J. Quadros E. Morris ML. Liu R. Zhang R. Jacob B. Postelnek J. Hicks CM. Chen W. Kimble EF. Rogers WL. O’Brien L. White N. Desai H. Bansal S. King G. Ohlmeyer MJ. Appell KC. Webb ML. J. Med. Chem.  2009,  52:  1295 
  Search in Google Scholar
• 6b Ueda J. Takagi M. Shin-ya K. J. Nat. Prod.  2009,  72:  2181 
  Search in Google Scholar
• 6c Vartak AP. Nickell JR. Chagkutip J. Dwoskin LP. Crooks PA. J. Med. Chem.  2009,  52:  7878 
  Search in Google Scholar
• 6d Xue F. Kraus JM. Labby KJ. Ji H. Mataka J. Xia G. Li H. Delker SL. Roman LJ. Martásek P. Poulos TL. Silverman RB. J. Med. Chem.  2011,  54:  6399 
  Search in Google Scholar
• 7 During the preparation of this manuscript, we noticed a recent report on an intermolecular reaction of 4,6-dimethylpyrimidine-activated secondary amines with different aryl/heteroaryl and N-methylmaleimide or maleimide by: Elboray EE. Grigg R. Fishwick CWG. Kilner C. Sarker MAB. Aly MF. Abbas-Temirek HH. Tetrahedron  2011,  67:  5700 
  Search in Google Scholar
• 8a Stohler R. Wahl F. Pfaltz A. Synthesis  2005,  1431 
• 8b Grigg R. Sarker MAB. Tetrahedron  2006,  62:  10332 
  Search in Google Scholar
• 8c Padilla S. Tejero R. Adrio J. Carretero JC. Org. Lett.  2010,  12:  5608 
  Search in Google Scholar
• 9 Confalone PN. Huie EM. J. Am. Chem. Soc.  1984,  106:  7175 
  Search in Google Scholar

CCDC 848492 (11a), CCDC 848493 (11q) and CCDC 848494 (11v) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

References and Notes

• For recent reviews about 1,3-dipolar cycloaddition reactions of azomethine ylides, see:
• 1a Nájera C. Sansano JM. Curr. Org. Chem.  2003,  7:  1105 
  Search in Google Scholar
• 1b Pandey G. Banerjee P. Gadre SR. Chem. Rev.  2006,  106:  4484 
  Search in Google Scholar
• 1c Pellissier H. Tetrahedron  2007,  63:  3235 
  Search in Google Scholar
• 1d Stanley LM. Sibi MP. Chem. Rev.  2008,  108:  2887 
  Search in Google Scholar
• 1e Álvarez-Corral M. Muñoz-Dorado M. Rodríguez-García I. Chem. Rev.  2008,  108:  3174 
  Search in Google Scholar
• 1f Burrell AJM. Coldham I. Curr. Org. Synth.  2010,  7:  312 
  Search in Google Scholar
• 1g Adrio J. Carretero JC. Chem. Commun.  2011,  47:  6784 
  Search in Google Scholar
• For one review and recent reports about intramolecular 1,3-dipolar cycloaddition reactions of azomethine ylides, see:
• 2a Coldham I. Hufton R. Chem. Rev.  2005,  105:  2765 
  Search in Google Scholar
• 2b Burrell AJM. Coldham I. Watson L. Oram N. Pilgram CD. Martin NG. J. Org. Chem.  2009,  74:  2290 
  Search in Google Scholar
• 2c Kathiravan S. Ramesh E. Raghunathan R. Tetrahedron Lett.  2009,  50:  2389 
  Search in Google Scholar
• 2d Bakthadoss M. Sivakumar N. Synlett  2009,  1014 
• 2e Pankova AS. Voronin VV. Kuznetsov MA. Tetrahedron Lett.  2009,  50:  5990 
  Search in Google Scholar
• 2f Pandey G. Gupta NR. Pimpalpalle TM. Org. Lett.  2009,  11:  2547 
  Search in Google Scholar
• 2g Bélanger G. Darsigny V. Doré M. Lévesque F. Org. Lett.  2010,  12:  1396 
  Search in Google Scholar
• 2h Kathiravan S. Vijayarajan D. Raghunathan R. Tetrahedron Lett.  2010,  51:  3065 
  Search in Google Scholar
• 2i Sirisha N. Raghunathan R. Tetrahedron Lett.  2010,  51:  2515 
  Search in Google Scholar
• 2j Purushothaman S. Prasanna R. Niranjana P. Raghunathan R. Nagaraj S. Rengasamy R. Bioorg. Med. Chem. Lett.  2010,  20:  7288 
  Search in Google Scholar
• 2k Kathiravan S. Raghunathan R. Synlett  2010,  952 
• 2l Burrell AJM. Watson L. Martin NG. Oram N. Coldham I. Org. Biomol. Chem.  2010,  8:  4530 
  Search in Google Scholar
• 2m Coldham I. Burrell AJM. Guerrand HDS. Oram N. Org. Lett.  2011,  13:  1267 
  Search in Google Scholar
• 3a Martin SF. Cheavens TH. Tetrahedron Lett.  1989,  30:  7017 
  Search in Google Scholar
• 3b Grigg R. Sridharan V. Thornton-Pett M. Wang J. Xu J. Zhang J. Tetrahedron  2002,  58:  2627 
  Search in Google Scholar
• 3c Pospíšil J. Potáček M. Tetrahedron  2007,  63:  337 
  Search in Google Scholar
• 4a Ardill H. Fontaine XLR. Grigg R. Henderson D. Montgomery J. Sridharan V. Surendrakumar S. Tetrahedron  1990,  46:  6449 
  Search in Google Scholar
• 4b Wang B. Mertes MP. Mertes KB. Takusagawa F. Tetrahedron Lett.  1990,  31:  5543 
  Search in Google Scholar
• 4c Deb I. Das D. Seidel D. Org. Lett.  2011,  13:  812 
  Search in Google Scholar
• For examples, see:
• 5a Jang M. Lin Y. Jonghe SD. Gao L. Vanderhoydonck B. Froeyen M. Rozenski J. Herman J. Louat T. Belle KV. Waer M. Herdewijn P. J. Med. Chem.  2011,  54:  655 
  Search in Google Scholar
• 5b Saravanan K. Barlow HC. Barton M. Calvert AH. Golding BT. Newell DR. Northen JS. Curtin NJ. Thomas HD. Griffin RJ. J. Med. Chem.  2011,  54:  1847 
  Search in Google Scholar
• 5c Jorda R. Havlíček L. McNae IW. Walkinshaw MD. Voller J. Šturc A. Navrátilová J. Kuzma M. Mistrik M. Bártek J. Strnad M. Kryštof V. J. Med. Chem.  2011,  54:  2980 
  Search in Google Scholar
• 5d Maruoka H. Jayasekara MPS. Barrett MO. Franklin DA. Castro SD. Kim N. Costanzi S. Harden TK. Jacobson KA. J. Med. Chem.  2011,  54:  4018 
  Search in Google Scholar
• For examples, see:
• 6a Merritt JR. Liu J. Quadros E. Morris ML. Liu R. Zhang R. Jacob B. Postelnek J. Hicks CM. Chen W. Kimble EF. Rogers WL. O’Brien L. White N. Desai H. Bansal S. King G. Ohlmeyer MJ. Appell KC. Webb ML. J. Med. Chem.  2009,  52:  1295 
  Search in Google Scholar
• 6b Ueda J. Takagi M. Shin-ya K. J. Nat. Prod.  2009,  72:  2181 
  Search in Google Scholar
• 6c Vartak AP. Nickell JR. Chagkutip J. Dwoskin LP. Crooks PA. J. Med. Chem.  2009,  52:  7878 
  Search in Google Scholar
• 6d Xue F. Kraus JM. Labby KJ. Ji H. Mataka J. Xia G. Li H. Delker SL. Roman LJ. Martásek P. Poulos TL. Silverman RB. J. Med. Chem.  2011,  54:  6399 
  Search in Google Scholar
• 7 During the preparation of this manuscript, we noticed a recent report on an intermolecular reaction of 4,6-dimethylpyrimidine-activated secondary amines with different aryl/heteroaryl and N-methylmaleimide or maleimide by: Elboray EE. Grigg R. Fishwick CWG. Kilner C. Sarker MAB. Aly MF. Abbas-Temirek HH. Tetrahedron  2011,  67:  5700 
  Search in Google Scholar
• 8a Stohler R. Wahl F. Pfaltz A. Synthesis  2005,  1431 
• 8b Grigg R. Sarker MAB. Tetrahedron  2006,  62:  10332 
  Search in Google Scholar
• 8c Padilla S. Tejero R. Adrio J. Carretero JC. Org. Lett.  2010,  12:  5608 
  Search in Google Scholar
• 9 Confalone PN. Huie EM. J. Am. Chem. Soc.  1984,  106:  7175 
  Search in Google Scholar

CCDC 848492 (11a), CCDC 848493 (11q) and CCDC 848494 (11v) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

• Supplementary Material