Direct synthesis of butadiynyl-substituted pyrroles under solvent- and transition metal-free conditions

Abstract

The work describes a convenient and highly efficient C-H butadiynylation of substituted pyrroles with the use of 1halobutadiynes. The method requires only a simple grinding of substrates in a mortar under mild, solvent-and transition metal-free conditions and constitutes the first example of pyrrole butadiynylation via cross-coupling reaction with the use of 1-halobutadiynes. The scope of this mechanochemical approach covers 4,5,6,7-tetrahydro-1H-indole, its N-substituted derivatives and 2-phenylpyrrole and on the other hand ester and phenyl end-capped 1-halobutadiynes including chlorides, bromides and iodides. Interestingly, the method has proven effective also for weak electron withdrawing aryl substituted 1-halobutadiynes what has not been yet achieved for 1-haloacetylenes. Such reactivity was unexpected in the view of the literature data and opened a gate to the plethora of substrates for organic synthesis including syntheses of pharmaceuticals. An X-ray analysis of two coupling products is also presented.A butadiyne (1 equivalent) was dissolved in acetonitrile (20 mL) in a Schlenk flask under N 2 atmosphere. Next H 2 O (2 eqivalents), N-halosuccinimide (1.2 equivalents) and AgNO 3 (0.3 equivalents)/KF(1.0 equivalent) or AgF (1.0 equivalent) were added. Flask was wrapped in aluminum foil and the reaction mixture was stirred for 3-24 h. Next the solvent was removed under reduced pressure and the product was purified by passing through short silica gel plug (hexanes/DCM, 1/2, v/v) yielding pure 1-halobutadiyne. Ethyl 5-chloropenta-2,4-diynoate (2b-Cl) Yellow oil (51 mg, 0.33 mmol), yield: 20%. 1 H NMR (500 MHz, CDCl 3 ): δ H 4.25 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H). 13 C NMR (126 MHz, CDCl 3 ): δ C 152.6, 70.4, 64.8, 64.5, 62.8, 54.0, 14.1. HRMS(ESI): m/z calcd for 157.0051; C 7 H 6 ClO 2 : [M+H + ]; found: 157.0051. Methyl 5-bromopenta-2,4-diynoate (2a-Br) Yellow crystals, yield: 71 mg (0.28 mmol), 56%; mp 69.2 -71.5 o C. 1 H NMR (CDCl 3 , 500 MHz): δ H 6.86 (dd, J = 16.0, 9.3 Hz, 1H), 6.57 (s, 1H), 5.38 (dd, J = 16.0, 1.2 Hz, 1H), 4.94 (dd, J = 9.3, 1.2 Hz, 1H), 3.80 (s, 3H), 2.64-2.62 (m, 2H), 2.48-2.45

Reactivity of 3-halopropynols: X-ray crystallographic analysis of 1,1-dihalocumulenes and 2+2 cycloaddition products

“…28 Therefore, we assume that the precursor of 14 are both compounds that underwent reaction according to the proposed mechanism (Scheme 4). We decided to look closer at the 13 C NMR spectra of allenes 10 and 13 (see Figure 1). The chemical shifts of signals of the three allenic carbon atoms of 10 and 13 are given in Table 1.…”

“…The chemical shifts of signals of the three allenic carbon atoms of 10 and 13 are given in Table 1. 13 C NMR spectrum of 13 is a standard spectrum of allene with slightly upfield shifted signal of C1 (54.4 ppm). The situation for 10 is different and the carbon signal derived from C1 atom is extremely strongly shifted upfield (-46.4 ppm) which is considerably outside the typical chemical shift range used for 13 C NMR measurements.…”

“…13 C NMR spectrum of 13 is a standard spectrum of allene with slightly upfield shifted signal of C1 (54.4 ppm). The situation for 10 is different and the carbon signal derived from C1 atom is extremely strongly shifted upfield (-46.4 ppm) which is considerably outside the typical chemical shift range used for 13 C NMR measurements. The examples of 1,1-diiodoallenes are very rare in the literature and the majority of them were obtained in pre- 13 C NMR era.…”

“…1,1-Dibromo-or 1,1-diiodo-cumulenes have a significant potential as building blocks for more complex, all-carbon scaffolds and may be obtained from 1-halobutadiynes. In our group, we have been conducting continuous studies on the syntheses and reactivity of 1-haloalkynes and 1-halopolyynes [11][12][13][14][15][16] and we attempted to use them as precursors of 1,1-dihalocumulenes. On the other hand, (2+2) cycloaddition of allenes has been intensively explored for many years.…”

One-step synthesis of conjugated enynenitriles from bromocyanoacetylene

“…7 Inspired by this work, we wondered whether the smaller homologous counterpart bromocyanoacetylene BrC 3 N 2 could react the same way or would lead to a more standard reactivity such as a Cadiot-Chodkiewicz coupling as does the corresponding ester. 8 If the reactivity would be the same as BrC 5 N, BrC 3 N should be a precursor of conjugated enynenitriles (Scheme 1b). Surprisingly, to the best of our knowledge, the chemical reactivity of BrC 3 N in solution has never been investigated whereas its halogen-free counterpart HC 3 N has largely been documented.…”