A Mild and Inexpensive Procedure for the Synthesis of N,N′-Di-Boc-Protected Guanidines

Abstract

A novel and efficient synthetic procedure for converting a diverse set of amines to N,N′-di-Boc-protected guanidines is described. The methodology comprises the use of cyanuric chloride (TCT) as activating reagent for di-Boc-thiourea. The employ of inexpensive TCT instead of classical HgCl₂ eliminates the environmental hazard of heavy-metal waste without appreciable loss of yield or reactivity. This protocol provides an alternative route for the guanylation of amines from those currently employed.

cyanuric chloride - TCT - guanidine - N,N′-di-Boc-protected guanidines - guanylating reagent

References and Notes

1a Guanidines: Historical, Biological, Biochemical and Clinical Aspects of the Naturally Occurring Guanidino Compounds   Mori A. Cohen BD. Lowenthal A. Plenum Press; New York: 1985. 

1b Guanidines 2: Further Explorations of the Biological and Clinical Significance of Guanidino Compounds   Mori A. Cohen BD. Koide H. Plenum Press; New York: 1987. 

1c Feichtier K. Sings HL. Baker TJ. Matthews K. Goodman M.
J. Org. Chem.  1998,  63:  8432 

1d Le V.-D. Wong C.-H.
J. Org. Chem.  2000,  65:  2399 

1e McAlpine IJ. Armstrong RW. Tetrahedron Lett.  2000,  41:  1849 

1f De Clercq E. Nat. Rev. Drug Discovery  2006,  5:  1015 

2a Petersen MJ. Nielsen CK. Arrigoni-Martelli E.
J. Med. Chem.  1978,  21:  773 

2b Ganelin CR. Chronicles of Drug Discovery   Vol. 1:  Bindra JS. Lednicer D. Wiley; New York: 1982.  p.1-38  

2c Taniguchi K. Shigenaga S. Ogahara T. Fujitsu T. Matsno M. Chem. Pharm. Bull.  1993,  41:  301 

2d Yoshiizumi K. Seko N. Nishimura N. Ikeda S. Yoshino K. Kondo H. Tanizawa K. Bioorg. Med. Chem. Lett.  1998,  8:  3397 

3a Heys L. Moore CG. Murphy PJ. Chem. Soc. Rev.  2000,  29:  57 ; and references cited there

3b Schug KA. Lindner W. Chem. Rev.  2005,  105:  67 

4a Cotton FA. Day VW. Hazen EE. Larsen S.
J. Am. Chem. Soc.  1973,  95:  4834 

4b Schneider SE. Bishop PA. Salazar MA. Bishop OA. Anslyn EV. Tetrahedron  1998,  54:  15063 

4c Linton B. Hamilton AD. Tetrahedron  1999,  55:  6027 

4d Linton BR. Carr AJ. Orner BP. Hamilton AD. J. Org. Chem.  2000,  65:  1566 

5a Orner BP. Hamilton AD. J. Inclusion Phenom. Macrocyclic Chem.  2001,  41:  141 

5b Manimala JC. Anslyn EV. Eur. J. Org. Chem.  2002,  3909 

5c Katritzky AR. Rogovoy BV. ARKIVOC  2005,  (iv):  49 

5d Ohara K. Vasseur J.-J. Smietana M. Tetrahedron Lett.  2009,  50:  1463 

6 Schow S. Cyanamide, In Encyclopedia of Reagents for Organic Synthesis   Paquette LA. Wiley; Sussex: 1996.  p.1408-1410  

7a Bernatowicz MS. Wu Y. Matsueda GR. J. Org. Chem.  1992,  57:  2497 

7b Drake B. Patek M. Lebl M. Synthesis  1994,  579 

7c Patek M. Smrcina M. Nakanishi E. Izawa H. J. Comb. Chem.  2000,  2:  370 

7d Drager G. Solodenko W. Messinger J. Schön U. Kirschning A. Tetrahedron Lett.  2002,  43:  1401 

7e Castillo-Melendez JA. Golding BT. Synthesis  2004,  1655 

7f Solodenko W. Bröker P. Messinger J. Schön U. Kirschning A. Synthesis  2006,  461 

8 Palmer DC. O-Methylisourea, In Encyclopedia of Reagents for Organic Synthesis   Paquette LA. Wiley; Sussex: 1995.  p.3525-3526  

9 Feichtinger K. Zapf C. Sings HL. Goodman M. J. Org. Chem.  1998,  63:  3804 

10a Levallet C. Lerpiniere J. Ko SY. Tetrahedron  1997,  53:  5291 

10b Guo ZX. Cammidge AN. Horwell DC. Synth. Commun.  2000,  30:  2933 

10c Gers T. Kunce D. Markowski P. Izdebski J. Synthesis  2004,  37 

11 Yong YF. Kowalski JA. Lipton MA. J. Org. Chem.  1997,  62:  1540 

12

Many of these reagents present difficulties such as toxicity, odour, moisture-sensitivity, harsh reaction conditions, and long reaction time.

13

The application of reagents containing two urethane-type protecting groups is beneficial since two electron-withdrawing groups in positions conjugated with the reaction center increase the electrophilicity and the solubility of the guanylating agent.

14 Porcheddu A. Giacomelli G. Piredda I. J. Comb. Chem.  2009,  11:  126 

15 Porcheddu A. Giacomelli G. Chighine A. Masala S. Org. Lett.  2004,  6:  4925 

16a Falorni M. Porcheddu A. Taddei M. Tetrahedron Lett.  1999,  40:  4395 

16b Blotny G. Tetrahedron  2006,  62:  9507 ; and references cited therein

16c Giacomelli G. Porcheddu A. 1,3,5-Triazines, In Comprehensive Heterocyclic Chemistry III   Vol. 9:  Katritzky AR. Ramsden CA. Scriven EFV. Taylor RJK. Elsevier; Oxford: 2008.  p.197-290  

17

Generally, the conversion of protected thiourea into a guanidine requires initial activation.

18

In particularly, we were interested in replacing the traditional activating Mukaiyama reagent with the readily available cyanuric chloride for the guanylation of di-Boc-protected thiourea.

19

The use of NMM or Et₃N proved to be crucial to reaction success. Without a base, the reaction did not take place.

20

Adding a catalytic amount of DMAP we have detected an increased reaction rate.

21

The Boc protecting group was then removed by treatment with 3 M anhyd methanolic HCl, to yield the guanidine as the HCl salt in 96% isolated yield.

22

The ability to use only 0.33 equiv of the TCT as guanylating agent is advantageous since it minimizes reagent consumption and byproduct generation compared to the Mukaiyama reagent and S-methylisothioureas derivatives. Moreover our method does not give off toxic gaseous side product such as methyl mercaptan that is generated using N,N′′-bis-Boc-S-methylisotiourea as guanylating reagent (see ref. 10a-c).

23

Representative Procedure for the Synthesis of N , N ′′-Di-Boc-protected Guanidines: N , N ′-Bis( tert -butoxy-carbonyl)- N ′′-benzylguanidine (3a)
To a solution of cyanuric chloride (185 mg, 1.0 mmol) in dry THF (20 mL), N-methylmorpholine (303 mg, 330 µL, 3.0 mmol) was added at 0 ˚C under argon and with vigorous stirring. A white suspension was formed to which a solution of the N,N′-di-Boc-thiourea 1 (830 mg, 3.0 mmol) and N-methylmorpholine (606 mg, 660 µL) in anhydrous THF (20 mL) was added, and the stirring was continued at reflux temperature for 12 h. The slurry was cooled to r.t. and to this mixture, benzylamine 2a (482 mg, 491 µL, 4.5 mmol) and DMAP (10 mg) were added, and the stirring was run for additional 8 h at r.t. The reaction was judged to be complete by TLC analysis. After completion of the reaction, solid material was collected by suction, followed by successive washing with a minimal amount of THF, and the filtrates were combined and concentrated. The residue was dissolved in CH₂Cl₂, and the resulting solution was washed successively with H₂O, HCl (1 N), NaHCO₃ (sat. solution), and then with brine. The organic layer was dried over anhyd Na₂SO₄, passed through short a silica gel column (hexane-EtOAc = 8:2), and the solvent removed under reduced pressure to give 3a (1.0 g, 95%) pure as an off-white solid; mp 125-126 ˚C [lit.:^7b mp 126-127 ˚C]. TLC: R _f = 0.46 (hexane-EtOAc = 8:2). ^¹H NMR (300 MHz, CDCl₃): δ = 1.47 (s, 9 H), 1.51 (s, 9 H), 4.59 (d, J = 5.2 Hz, 2 H), 7.20-7.39 (m, 5 H), 8.43 (br s, 1 H), 11.41 (br s, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 27.9, 28.3, 44.9, 80.5, 82.9, 127.8, 128.2, 129.0, 137.2, 152.9, 156.4, 163.4. ESI-HRMS: m/z [M + H]⁺ calcd for C₁₈H₂₈N₃O₄: 350.2080; found: 350.2092. Anal. Calcd for C₁₈H₂₇N₃O₄: C, 61,87; H, 7,79; N, 12,03. Found: C, 61.71; H, 7.95, N, 11.92.

24 The triazine ring is weakly basic therefore a dilute acid wash is able to remove any byproduct as well as any excess reagent from the reaction mixture. Reagents for High-Throughput Solid-Phase Organic Synthesis, In Handbook of Reagents for Organic Synthesis   Wipf P. Wiley; Sussex: 1999.  p.72-74  

25

Performing the model reaction in CH₂Cl₂ we have recovered the desired protected guanidine 3a in very low yields (<5%).

26 TCT react DMF to give an insoluble Vilsmeier-Haack-type specie, which precipitates: De Luca L. Giacomelli G. Porcheddu A. Org. Lett.  2002,  4:  553 ; under these conditions, we observed a partial removal of Boc-protective group, and the formation of several side products in the crude reaction mixture.

27

Unchanged reagents were present still after 36 h at r.t.

28

All the analytical data are consistent with those described in the literature.

29 Identified by matching all the analytical data with those described in literature, see: Balakrishnan S. Zhao C. Zondlo NJ. J. Org. Chem.  2007,  72:  9834 

30

In the reaction of TCT/di-Boc-thiourea 1 with phenylalanine methyl esther 2o, we have not observed significant racemization of the stereogenic center as revealed by the optical rotation value of the products 3o if compared with that reported in the literature (ref. 29).

31a Ho K.-C. Sun C. Bioorg. Med. Chem. Lett.  1999,  9:  1517 

31b

See also ref. 5c.

32

The exact intermediates for this TCT-promoted guanylating reaction formation are unknown.