Preparation of (Cyanomethylene)tributylphosphorane: A New Mitsunobu-Type Reagent

Abstract

The Mitsunobu reaction is a well-established fundamental reaction and has been applied widely in organic synthesis. In the Mitsunobu reaction, a unique dehydration occurs between alcohols and various Brønsted-Lowry acids (HA) utilizing the combination of diethyl azodicarboxylate and triphenylphosphine ( Fig. 1). 1,2) However, the reaction has a serious limitation (so-called the restriction of pK a ); the acidic hydrogen in HA has to have pK a of less than 11 for the reaction to proceed satisfactorily. If HA has pK a of higher than 11, the yield of RA is considerably lower, and with HA having pK a of higher than 13, the desired reaction does not occur. In order to overcome the restriction of pK a and expand the versatility of the original Mitsunobu reaction, 3-7) stabilized trialkylphosphoranes such as (cyanomethylene)tributylphosphorane (CMBP) 8) and (cyanomethylene)trimethylphosphorane (CMMP) 9,10) have been developed to replace the DEAD-TPP system.It was noted that CMBP was the only reagent that can be effectively applied to the Mitsunobu reaction of N-nonsubstituted sulfonamides such as p-toluenesulfonamide (1) (Fig. 2). The sulfonamide was unfortunately converted to phosphine sulfonimide 3 without any desired N-alkylated product 2 when using the traditional reagent DEAD-TPP or new reagents (TMAD-PBu 3 , 7) CMMP, etc.). 11)Thus, CMBP can not only promote the reaction of nucleophiles with pK a of higher than 13, but can be also utilized for synthesis of primary amines via Mitsunobu alkylation of sulfonamides.CMBP is now commercially available. However, many inquiries about the stability and handling of CMBP have been received. The reason is that we have not reported the procedure for the preparation of CMBP in detail, yet. In this paper, we would like to describe the experimental details for the preparation of this reagent and some important findings related to the handling. Furthermore, it is important to establish a facile procedure for CMBP preparation without further purification, especially when the Mitsunobu reaction is to be carried out on a large scale.Preparation of CMBP via (Cyanomethyl)tributylphosphonium Chloride (4) CMBP could be synthesized in two steps starting from chloroacetonitrile (Fig. 3). As the first step, tributylphosphine reacted with chloroacetonitrile in nitromethane to afford phosphonium salts 4 as colorless needles in 91% yield. The process was highly exothermic, and the addition rate of chloroacetonitrile was adjusted to be maintained at below 50°C. Since the salts 4 were hygroscopic, quick operation and storage in a desiccator were needed to prevent moisture from condensing on the product. The salts 4 were converted to CMBP by treatment with 0.95 equivalent of n-butyllithium in hexane at 0°C. It is important to note that the yield of CMBP decreased dramatically, when excess base (Ͼ1.0 eq) was used. So, a fresh n-butyllithium solution, of which the concentration is determined by titration, should be used.Furthermore, the Mitsunobu reaction could not unfortunately proceed effective...

Solvent-Dependent Switch of Helical Main-Chain Chirality in Sergeants-and-Soldiers-Type Poly(quinoxaline-2,3-diyl)s: Effect of the Position and Structures of the “Sergeant” Chiral Units on the Screw-Sense Induction

“…THF and toluene were dried and deoxygenized using an alumina/catalyst column system (Glass 3 Contour Co.). 4,7-dibromo-5,6-bis(bromomethyl)benzo[c][1,2,5]thiadiazole 5 , 2,3-Bis(bromomethyl)-1,4-dimethylbenzene 6 , acetic formic anhydride (AFA), 3,6-dimethyl-4,5-dinitrobenzene-1,2-diol 9 , cyanomethylenetributylphosphorane (CMBP), ( S )-1-bromo-2-methylbutane, monomers 1 , 2a , ( S )- 2a , 2e , and o -TolNiCl(PMe 3 ), were prepared according to the reported procedure. Other chemical reagents were purchased from the commercial sources and were used without further purification.…”

“…The dimethoxy compound was nitrated under acidic conditions and then deprotected by treatment with BBr 3 to give compound 9 . Monomer 2f was prepared from 9 by Mitsunobu reaction mediated by a phosphorane reagent. , …”

Synthesis of β-Hydroxy-α,α-difluorosulfonamides from Carbanions of Difluoromethanesulfonamides

“…44 Fortunately, 34 can be alkylated using cyanomethyltributylphosphorane (CMBP) to give 35 in 64% yield. 45 Despite an excess of CMBP, double alkylation was not observed under these conditions. This represents an overall 32% yield of 35 over 10 steps from 26.…”

“…This is likely due to the formation of a triphenylphosphine sulfonimide, which is a known side reaction of primary sulfonamides . Fortunately, 34 can be alkylated using cyanomethyltributylphosphorane (CMBP) to give 35 in 64% yield . Despite an excess of CMBP, double alkylation was not observed under these conditions.…”

2-(1,3-Dioxan-2-yl)ethylsulfonyl Group: A New Versatile Protecting and Activating Group for Amine Synthesis

“…These problems were overcome by using new Mitsunobu reagents developed by our group . The reagents satisfactorily mediated the alkylation reaction of various nucleophiles with a p K a of 11−23, such as N -methyltosylamide (p K a = 11.7),10a geranyl phenyl sulfone (p K a = 22.5 in DMSO),10b and others. 10c-e In addition, the alkylation of tosylamide 1 was found to proceed smoothly with the use of only (cyanomethylene)tributylphosphorane (CMBP), 10a, one of the phosphorane types of new Mitsunobu reagents, to give the desired N-monosubstituted sulfonamides 3 in excellent yields (Scheme 1), establishing a new facile synthetic method to primary amines 10f …”