First, we'll start with the mother paper:
"New Strategies for the Hofmann Reaction", J. Chem. Tech. Biotech. 59; 1994, 271
In this paper they discuss many things, including formation of the aforementioned carbamates by performing the Hofmann rearrangement in alcohol. Yields were all above 90% from amides. This will be dealt with later. For the moment, I would direct attention to page 274, the section labeled "N-Alkylation of carbamates".
In the presence of a base, R1.NHCOO.R2 can undergo elimination of OR2 to give isocyanates or N-alkylation. Hence, N-alkylation of carbamates is favored when OR2 is a poor leaving group, eg R2 = Me. The reactivity of a simple carbamate is more akin to amides than to esters and hence forcing conditions are required for these reactions. N-Monosubstituted or unsubstituted carbamates are potential nucleophiles themselves. However, they are (by analogy with amides) poor nucleophiles and only act as such when converted to anions or when the nitrogen of the carbamate is adjacent to the reactive center (neighboring group participation).
The success of this alkylation methyl-N-alkyl carbamates mainly depends on the efficient formation of the anion from corresponding carbamates, its extraction into the organic phase and subsequent reaction with alkylating agent, i.e. dimethyl sulfate (DMS).
This was achieved by employing tetrabutyl ammonium hydrogen sulfate (TBA.HSO4) as PTC, powdered NaOH and K2CO3 as the base, and toluene as the reaction medium.
The choice of base was arrived at after employing various bases generally used in the PTC reaction. Aqueous NaOH (50%) furnished only 8% of the product. The yield was drastically increased to 75% when powdered NaOH was used, further increasing to 95% with the addition of anhydrous K2CO3. Anhydrous K2CO3 may be acting not only as a base, but also as a dehydrating agent preventing the solvation of the carbamate anion and thus facilitating the alkylation.
....
general procedure for N-alkylation of carbamates:
A mixture of carbamate (0.05 mol), toluene (100 ml), powdered NaOH (0.2 mol), anhydrous K2CO3 (0.05 mol), and PTC (0.0025 mol) was stirred at room temp for 1 h. During stirring, a gelatinous mass was formed. DMS (0.06 mol) was added to the stirred mass at 30-35 C over a period of 30 min. The course of the reaction was monitored with TLC. The reaction mixture was stirred for 4 h to obtain a clear solution. Inorganics were filtered off and washed with toluene (2 x 20 ml). The combined filtrate and washings were washed with HCl (2 N, 3 x 50 ml), water (2 x 50 ml), and dried over anhydrous Na2SO4. Concentration of the solvent yielded the products.
What does this tell us? That PTC alkylation of carbamates is possible and high-yielding.
Next up, PTC alkylation of tBOC-protected guanidines. Why is this special? Because they use secondary alkyl bromides, just like our system of interest.
"Synthesis of Highly Functionalized Guanidines" JOC 2003, 2300
...Herein, we describe a relatively mild and efficient protocol for the guanidinylation of various alkyl halides in a biphasic medium containing an aqueous solution of PTC. This procedure is scaleable to muligrap quantities, yielding highly functionalyized and protected guanidines that are readily purified.
[...]
The N,N-bis-Boc-guanidine was regioselectively alkylated at one of the carbamate nitrogens. Alkylation of this substrate under phase-transfer conditions provides an alternative method for the synthesis of monosubstituted guanidines from alkyl bromides under milder conditions than previously reported. Furthermore, alkylation occurs only once even in the presence of a large excess of allyl bromide (5 equiv), with extended reaction times (24 h) or with heating (50 C). Other N1,N2-bis-Boc-N3,N3-disubstituted guanidines were allylated in high yield. The reaction is tolerant to a wide range of functional groups on the guanidine including esters, amines, ketones, alcohols, and alkenes. Competitive hydrolysis of the ethyl ester in 3e was minimized by reducing reaction time. [...] The procedure is readily adapted to larger scales, as exemplified by the allylation of tetrahydroisoquinoline-derived guanidine 3g, which was conducted on a 12 g (31.2 mmol) scale.[...]
Having demonstrated functional group tolerance in the guanidine component, the effect of variation of the electrophilic component was required. Specifically, guanidinylation of a range of electrophiles using the bis-Boc-protected model substrates 3a was examined. Saturated alkyl halides such as iodomethane and bromopropane were cleanly displaced by the guanidine nucleophile, although in the latter case, the reaction need to be heated to 50 C for 12 h. Secondary alkyl bromides could also be guanidinylated regioselectively to provide the isopropyl and cyclohexenyl guanidines in moderate yield. In contrast, secondary alkyl bromides underwent elimination using the NaH/DMF methodology, rather than alklation.
[...]
Since non-chlorinated solvents, such as toluene, are preferred industrially, the use of toluene as a cosolvent in the biphasic protocol was examined. Heating of guanidine substrate 3a with benzyl chloride in a biphasic mixture of toluene and water at 50 C for 10 h in the presence of the PTC and KOH gave the benzylated product 5r in 89% yield. The scope of the guanidinylation procedure was also extended to the use of mesylates, which are readily accessible from the corresponding alcohols. Clean alkylation of the guanidine was observed with propargyl bromide and 4-bromo-2-methyl-2-butene. Reaction at the secondary carbon of 3-bromocyclohexene, as with 2-bromopropane, was slower than the displacement at a primary carbon, and consequently, longer reaction times were required.
[...]
Other phase-transfer catalysts, such as tetrabutyl ammonium bromide and tetrabutyl ammonium chloride afforded products in yields similar to those obtained with tetrabutyl ammonium iodide.
[...]
Conclusion: An efficient method for the alkylation of N-dicarbamate-protected guanidines using a variety of alkyl halides has been established. Under this procedure, the acidic N-carbamate hydrogen is deprotonated using biphasic conditions, with a catalytic amount of tetrabutyl ammonium salt, as the phase-transfer catalyst, and then subsequently alkylated to yield highly functionalized guanidines from those currently utilized. In addition, the need for stoichiometric amounts of costly or highly reactive coupling reagents is circumvented. An attractive feature of this methodology is that few byproducts are generated and at the end of the reaction, simple aqueous workup followed by filteration through a short plug of silica gel (to remove the PTC) gives high yields of the desired products. Replacement of DCM with toluene as the organic solvent gives comparable results and is ideal for larger-scale preparation of substituted guanidines.
[...]
General procedure for PTC synthesis of guanidines
A biphasic solution of guanidine 3 (0.5 mmol), TBAI (0.05 mmol, 18 mg), and KOH (1 mmol, 56 mg) in a 1:1 mixture of DCM/H2O (5 mL) was treated with the alkyl halide or alkyl mesylate (0.6-1.0 mmol, depending on the electrophile) for 2-4 h, and then the reaction mixture was poured through H2O (25 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography through a short column of silica gel.
General procedure for deprotection of guanidines
A solution of the guanidine (0.25 mmol) in 1 M aq HCl (2 mL) was stirred at room temperature for 4 h or until all of the starting material was consumed, as monitored by TLC. The reaction was concentrated in vacuo and purified by silica gel chromatography to give the unprotected guanidine as an HCl salt.
Boc-NH-C(-NR)=N-Boc + R-X ---> Boc-N(R)-C(-NR)=N-Boc
# R-X Time(h) Temp Yield
----------------------------------------------------
1 Me.I 5 25 95 *
2 Pr.I 12 50 77 *
3 Pr.Br 12 50 81 *
4 Pr.Cl 48 50 0 *
5 iPr.Br 48 50 60 *
6 Bn.Br 4 25 95
7 Bn.Cl 12 25 88
8 Bn.OMs 16 25 92
9 HCC-CH2.Br 4 25 92
10 Me(Me)C=CHCH2.Br 4 25 99
11 3-Br cyclohexene 25 25 78 *
12 Bn=CH-CH2.Br 4 25 95
13 PhCO-CH2.Br 4 25 82
* = 2.2 equiv used, otherwise 1.2 equiv used
This is promising, because although the yields are not as high as they could be, this shows that carbamates can be PTC-alkylated with secondary bromides. Nice. Also note that they used the halide in excess and measured yield based on carbamate consumed, whereas we will be doing exactly the opposite, and probably use 2x excess carbamate.
More on the way.