1,1′-(ETHANE-1,2-DIYL)DIPYRIDINIUM BIS(TRIBROMIDE) 1

1,1′′′-(Ethane-1,2-diyl)dipyridiniumBis(tribromide)1

NN

2 Br3

1

[854029-41-7] C12H14Br6N2 (MW 665.68)InChI = 1/C12H14N2.2Br2.2BrH/c1-3-7-13(8-4-1)11-12-14-9-5

-2-6-10-14;2*1-2;;/h1-10H,11-12H2;;;2*1H/q+2;;;;/p-2/fC12H14N2.2Br2.2Br/h;;;2*1h/qm;;;2*-1

InChIKey = YBFZTDCXNZECEN-BWJFIAIJCY

(recyclable brominating1 and acylating reagent,2 and reagent fordithiin and benzothiin formation,3 solvent-free brominations)

Alternate Name: 1,1′-ethylenedipyridinium bis(tribromide).Physical Data: solid, mp 136–138 ◦C.Solubility: sol acetonitrile, DMSO, DMF; sparingly soluble in

methanol, ethanol, and acetic acid.Analysis of Reagent Purity: 1H NMR, 13C NMR, UV (CH3CN)

267 nm, IR, microanalysis.Preparative Methods: refluxing 1,2-dibromoethane in pyridine

results in the formation of solid 1,1′-ethylenedipyridinium di-bromide, which, upon treatment with KBr followed by oxida-tion with aqueous Oxone©R , gives the solid bis(tribromide) 1 in88% yield (eq 1).1

NN

2Br3

BrCH2CH2Br1. pyridine, ∆

2. KBr3. aq. Oxone

(1)

1

Handling, Storage, and Precautions: stable at room temperaturefor several months.

1,1′-Ethylenedipyridinium bis(tribromide) is similar to othertribromide reagents developed for bromination reactions.4–6

Use of this reagent for acylation,2 and in the condensation of1,2-dithiols with ketones to give dithiins and benzothiins3 hasalso been reported. The higher water solubility of the dibromideby-product (itself the precursor of 1) facilitates product recoveryby simple aqueous workup. The 1,1′-ethylenedipyridiniumdibromide by-product can be easily recovered from the aqueouslayer for reuse.

Bromination. Highly regioselective brominations of substi-tuted aromatic rings, alkenes, alkynes, and acetyl groups using1 under solvent-free conditions have been reported.1 Reactionof acetanilide (5 mmol) with 1 (2.5 mmol) in acetonitrile gaveexclusively p-bromoacetanilde in 95% yield (eq 2). A similarreaction conducted in the absence of solvent by grinding thereagents together with a mortar and pestle at room temperaturegave p-bromoacetanilde in similar yield (eq 2). The solvent-freereaction of aromatic phenols and amines with 1 liberates acidicfumes, but this can be prevented by addition of solid NaHCO3

(2 equiv) with no effect on regioselectivity. In the presence oftwo o, p-directing groups in an aromatic ring, the substituent with

the higher o,p-directing power forces the incoming bromo groupto its p-position. If the p-position is blocked, then brominationtakes place at the o-position, as shown in eq 3. As expected, inthe presence of m- and o,p-directing groups in the same aromaticring, the o,p-directing groups control the regioselectivity of thereaction (eq 4). Regioselective bromination of aromatic rings inthe presence of various functional groups such as benzoyl andbenzyloxycarbonyl groups has also been reported.1

AcHN AcHN

Br1

acetonitrile: 95%no solvent: 95%

(2)

HO

OMe

HO

OMeBr

92%

(3)1

HO

CN

HO

CNBr

93%

(4)1

Solvent-free reaction of 1,1-diphenylethene (1.0 equiv) with1 (0.5 equiv) gave the trans-dibromo product (eq 5). Similarly,bromination of acetophenone gave bromoacetophenone in 85%yield (eq 6). Bromination of a terminal alkyne with 0.5 equiv of1 gave a mixture of trans and cis products in a ratio of 80:20 ingood yield as shown in eq 7.

Ph Ph Ph Ph

Br

Br

(5)

87%

1

O

Br

O

85%

(6)1

Br

H

Br

trans:cis (80:20)84%

(7)1

Acylation. Reaction of structurally diverse alcohols, amines,phenols, and thiols with various aliphatic and aromatic anhy-drides in the presence of 0.05 equiv of 1 in acetone gave acylatedproducts with good yields as shown in Table 1. 2 It is believedthat the reaction of acetone with catalytic 1 gives bromoacetoneand HBr. This in situ-generated anhydrous HBr catalyzes theacylation reaction. Consumption of 1 by acetone also preventsunwanted substrate bromination. In the case of thiols, acetonitrilewas used as the solvent.

Synthesis of 1,4-Dithiins and 1,4-Benzothiins. The acidicnature of 1 enables its application to the synthesis of 1,4-dithiins

Avoid Skin Contact with All Reagents

2 1,1′-(ETHANE-1,2-DIYL)DIPYRIDINIUM BIS(TRIBROMIDE)

Table 1 Acylation of alcohols, phenols, amines, and thiols with catalytic 1Substrate Product Time (min) Yield (%)

CH3(CH2)8CH2OH CH3(CH2)8CH2OAc 5 92Ph-CH(CH3)OH Ph-CH(CH3)OAc 15 92Ph-CH=CH-CH2OH Ph-CH=CH-CH2OAc 5 892-HO-C6H4-OH 2-AcO-C6H4-OAc 300 782-F-C6H4-NH2 2-F-C6H4-NHAc 5 90CH3(CH2)10CH2SH CH3(CH2)10CH2SC(=O)Et 60 72Ph(CH2)2CH2OH Ph(CH2)2CH2OC(=O)iPr 20 92PhCH2NH2 PhCH2NHC(=O)tBu 15 884-OH-C6H4-CH2CH2OH 4-OH-C6H4-CH2CH2OC(=O)C6H5 120 80

Table 1 Formation of 1,4-dithiins and 1,4-benzothiinsSubstrate Product Time (min) Yield (%)

O

S

S

15 85

HO

O

S

SS

S

25 50

O

S

S40 62

O

S

S90 70

O S

S

60 67

and 1,4-benzothiins from 1,2-dithiols and enolizable ketones.3

Reaction of acetophenone (5 mmol) with 1,2-ethanedithiol(5.5 mmol) in acetonitrile using catalytic quantity of 1 (0.5 mmol)gives 1,4-dithiins product as shown in Table 2. The formationof 1,4-dithiins and 1,4-benzothiins is highly dependent onsubstituent present on the aromatic ring as well as the amount of1 employed. Under the above reaction conditions, 4-hydroxyacetophenone gives 1,2,5,6-tetrathiocane as themajor product (Table 2). Similarly, the reaction of cyclohexanoneand 1,2-ethanedithiol in the presence of 0.6 equiv of 1 gives1,4-dithiin as the major product while employment of 1.6 equivof 1 gives 1,4-benzothiin as the major product (Table 2).

1. Kavala, V.; Naik, S.; Patel, B. K., J. Org. Chem. 2005, 70, 4267.

2. Naik, S.; Kavala, V.; Gopinath, R.; Patel, B. K., ARKIVOC 2006, 11, 21.

3. Murru, S.; Kavala, V.; Singh, C. B.; Patel, B. K., Tetrahedron Lett. 2007,48, 1007.

4. Bora, U.; Bose, G.; Chaudhuri, M. K.; Dhar, S. S.; Gopinath, R.; Khan,A. T.; Patel, B. K., Org. Lett. 2000, 2, 247.

5. Salazar, J.; Dorta, R., Synlett 2004, 1318.

6. Muathen, H. A., J. Org. Chem. 1992, 57, 2740.

Mitesh PatelSigma-Aldrich, Milwaukee, WI, USA

A list of General Abbreviations appears on the front Endpapers