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.

Key words

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

References and Notes

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• 31b

  See also ref. 5c.

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.

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.

25

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

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.

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).

32

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