Lithium bromide catalyzed Ehrlich-Sachs reactions using solvent-free conditions

Article abstract of DOI:10.1081/SCC-100104052

Lithium bromide proves to be an efficient catalyst for Ehrlich-Sachs reaction of nitroso arenes with active methylene compounds under microwave irradiation through simple solvent-free reaction conditions.

Full text of DOI:10.1081/SCC-100104052

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LITHIUM BROMIDE CATALYZED
EHRLICH-SACHS REACTIONS
USING SOLVENT-FREE
CONDITIONS
Dhrubojyoti Dey Laskar a , Dipak Prajapati a &
Jagir S. Sandhu b
a Division of Organic Chemistry , Regional
Research Laboratory , Jorhat, Assam, 785 006,
India
b Division of Organic Chemistry , Regional
Research Laboratory , Jorhat, Assam, 785 006,
India
Published online: 09 Nov 2006.
To cite this article: Dhrubojyoti Dey Laskar , Dipak Prajapati & Jagir S. Sandhu
(2001) LITHIUM BROMIDE CATALYZED EHRLICH-SACHS REACTIONS USING SOLVENT-
FREE CONDITIONS, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:9, 1427-1432, DOI: 10.1081/
SCC-100104052
To link to this article: http://dx.doi.org/10.1081/SCC-100104052
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SYNTHETIC COMMUNICATIONS, 31(9), 1427–1432 (2001)
LITHIUM BROMIDE CATALYZED
EHRLICH-SACHS REACTIONS USING
SOLVENT-FREE CONDITIONS
Dhrubojyoti Dey Laskar, Dipak Prajapati,
and Jagir S. Sandhu*
Division of Organic Chemistry, Regional Research
Laboratory, Jorhat - 785 006, Assam, India
ABSTRACT
Lithium bromide proves to be an efficient catalyst for Ehrlich-
Sachs reaction of nitroso arenes with active methylene com-
pounds under microwave irradiation through simple
solvent-free reaction conditions.
The Ehrlich-Sachs and Krohnke reactions, though first reported in the
19th century, are the important methods for the synthesis of imines and
imine oxides1,2 from arylnitroso compounds. The reaction3–5 has been
reported catalyzed by a variety of bases3–5 (NaOH, piperidine, alkoxides,
potassium cyanide, trisodium phosphate, etc.) and occurs with various
active methylene components, including arenemethyl cyanides, malonic
esters, b-keto esters, b-diketones, fluorenes, cyclopentadienes, and nuclear-
activated arenemethyl derivatives6–8 (e.g., 2,4-dinitrotoluene). In genera1,
the reaction leads to a mixture and there is limited success in predicting a
predominance of dehydration or oxidation products. Azomethine formation
* Corresponding author.
1427
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1428
LASKAR, PRAJAPATI, AND SANDHU
Scheme 1.
tends to be favored over nitrone formation when strong basic catalysts are
used to effect condensation.9 The Ehrlich-Sachs reaction is also limited in its
synthetic utility, owing to the relative inaccessibility of the nitrosoarene
starting material and the low yields due to competing nitrone formation.
In continuation of our studies on imines10–12 we report Ehrlich-Sachs reac-
tions for the synthesis of unconventional imines in near neutral solvent-free
conditions using lithium bromide under microwave activation. To our
knowledge, this is the first report that discloses lithium bromide as a new
catalyst in the said reaction under neutral conditions. The application of
microwave energy to accelerate organic reactions is a matter of increasing
interest and offers several advantages.13–18 It has been used for a variety of
organic reactions and here the reaction proceeds efficiently in excellent yield
at ambient pressure within seconds in the absence of a solvent.
Typically, N,N-dimethyl-4-nitrosoaniline, benzylcyanide, and lithium
bromide were mixed together without solvent in an Erlenmeyer flask and
irradiated for 2 min in a commercial microwave oven (operating at
2450 Mhz frequency and 70 Watts). The reaction mixture was allowed to
reach room temperature, washed with water, and extracted with dichloro-
methane. Removal of solvent and purification of the residue by column
chromatography using petroleum ether:chloroform (4:1) as eluent gave the
corresponding imines 3 (entry 1) in 90% yield, m.p. 90ꢀC (lit.19,20 m.p. 91ꢀC)
without the formation of any imine oxide 4. According to Barrow19, 20 this
reaction gives a mixture of imine and imine oxides when carried out with
30% KOH. Similarly, other substrates were used and the corresponding
imines 3 were isolated in 80–90% yields. As shown in Table 1, several
structurally varied nitrosoarenes underwent clean and remarkably fast
Ehrlich-Sachs reactions with a variety of active methylene compounds
using this procedure. Many reactions are complete within a period of
30–130 s. Interestingly, it was also observed that the presence of solvent
slowed the reaction and gave mixture of imine 3 and nitrone 4 when carried
out in ethanol; the reasons for the efficiency of the process in the solid phase
are not yet clear. Except in the case of (2-cyanomethyl)naphthalene, where

EHRLICH-SACHS REACTION
1429
Table 1. Ehrlich-Sachs Reaction Catalyzed by LiBr Under Microwave Irradiation
Product
Ar
R1
–C6H5
–C6H5
–C6H5
–CN
–CO2Et
–COPh
–CONH2
–CONHPh
–C6H4Me–p
Time M.W. (s)
Yielda (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
–C6H4NMe2–p
–C6H4NHCH3–p
–C6H5
–C6H4NMe2–p
–C6H4NMe2–p
–C6H4NMe2–p
–C6H4Nme2–p
–C6H4NMe2–p
–C6H4NMe2–p
120
125
115
30
122
126
125
123
125
90
85
85
89
85
85
85
85
80
3j
–C6H4NMe2–p
–C6H5
130
120
60
80
3k
–COOMe
aAll the yields refer to isolated chromatographically pure compounds. All the
assigned structure have been confirmed by spectroscopic data.
the yield is low presumably due to the formation of a polymeric material, the
yields in general are very high. Also when 2,4-dinitrotoluene was treated
with 4-nitrosotoluene in the presence of lithium bromide under microwave
irradiation, the imine 3 was isolated as the sole product, but literature21,22
reports suggest exclusive formation of nitrone 4 when carried out in the
presence of KOH. To check the reaction rate improvements, the thermal
reaction was also carried out without microwave energy in the solid state.
The reaction proceeds similarly, but the completion time is 25–30 min longer
and the yield is not satisfactory (see Experimental). Further, increased,
reaction time gave no significant improvement in yields; rather, decomposi-
tion of products occurred. Without lithium bromide, the reaction did not
proceed at all.
In conclusion, a new catalyst for Ehrlich-Sachs reaction under neutral
condition without solvent has been developed. It offers significant improve-
ment over the existing procedures and gives various adducts in a shorter
reaction time with good yield.
EXPERIMENTAL
M.p.s were taken in open capillary tubes on a Buchi melting point
apparatus and were uncorrected. IR spectra were recorded as KBr discs on a
Perkin-Elmer 237B IR spectrometer. Microanalyses were performed on a

1430
LASKAR, PRAJAPATI, AND SANDHU
Perkin-Elmer 240C analyser. The 1H NMR spectra were recorded at Varian
T-60 machine using tetramethylsilane (TMS) as the internal standard. The
chemical shifts are recorded as ꢀ values. All the chemicals were purified by
distillation or crystallization prior to use.
Lithium Bromide Catalyzed Condensation Between Active Methylene
Group and Aromatic Nitroso Compounds Under Thermolytic
Condition
N,N-Dimethyl-4-nitrosoaniline (1a, A ¼rC6H4NMe2-p, 1.50 g,
0.01 mol) was finely mixed with benzyl cyanide (2a, 1.17 g 0.01 mol) and
placed in a 100- mL round-bottomed flask fitted with a condenser. LiBr
was added (0.43 g 5 mmol). The reaction mixture was heated to 80ꢀ–90ꢀC
in an oil bath for 30 min. The progress of the reaction was monitored by
TLC. After completion, the reaction mixture was cooled to room tempera-
ture and washed with water. The organic layer was extracted with CH2Cl2
(2 Â 30 mL), dried over anhydrous Na2SO4, and the solvent was distilled off
to obtain crude product. Chromatography (pet. Ether/CHCl3 4:1) gives the
imine 3a in 55% yield. Other nitrosoarenes reacted similarly and the corre-
sponding imines 3b–k were obtained in 45–56% yields. All the compounds
obtained were characterized by spectroscopic data and finally by compar-
ison with authentic samples prepared by following literature procedure.
Lithium Bromide Catalyzed Condensation Between Active Methylene
Group and Aromatic Nitroso Compounds Under Microwave
Irradiation in a Solvent-Free Condition
N,N-Dimethyl-4-nitrosoaniline (1a,
A
r¼ C6H4NMe2-p, 1.50 g
0.01 mol), benzyl cyanide (2a, 1.17 g, 0:01 mol), and LiBr (0.43 g, 5 mmol)
were mixed in an Erlenmeyer flask and placed in a commercial microwave
oven (operating at 2450 MHz frequency and 70 Watt). The reaction mixture
was irradiated for 2 min, allowed to cool to room temperature, washed with
water, and extracted with CH2Cl2 (2Â34 mL). Removal of solvent and pur-
ification by column chromatography of the residue using pet.ether/CHCl3
(4:1) as eluent, afforded exclusively the imine 3a in 90% yield (entry 1)
without the formation of any N-oxide 4. Crystallization from EtOH gave
the pure imine, red crystals m.p. 90ꢀC (lit.19,20 m.p. 91ꢀC in 90%). Similar
treatment of other nitrosoarenes under identical conditions gave the corre-
sponding imines in 80–90% yields, as summarized in Table 1. All the imines
obtained were characterized by comparison with authentic samples and by

EHRLICH-SACHS REACTION
1431
spectroscopic data, which are recorded here, 3a, m.p. 90.4ꢀC lit.7 m.p. 91 ꢀC,
1H NMR 2.20 (s, 6H, NMe2), 7.02–7.32 (m, 9H, ArH). IR (KBr); 2130 cm–1.
MS m/e 249 (Mþ) Anal. calc. (found) for C16H15N3 C, 77.11(77.16); H,
6.02(6.12); N, 16.86(16.94). 3b, m.p.127ꢀC, lit.19,20 m.p. 128ꢀC, H NMR
1
2.10 (s, 3H, CH3), 7.6–7.36 (m, 10H, ArH & NH). IR (KBr): 2130 cm–1. MS
m/e 235 (Mþ). Anal. calc. (found) for C15H13N3; C, 76.59(76.64); H,
5.53(5.61); N, 17.87(17.78). 3c, m.p. 170ꢀC, lit.19,20 m.p. 170ꢀC, H NMR
1
7.10–7.42 (m, 10H, ArH). IR (KBr): 2135 cm–1. MS m/e 206 (Mþ), Anal.
calc. (found) for C14H10N2: C, 81.55(81.46); H, 4.85(4.96); N, 13.59(13.64).
3d, m.p. 162ꢀC, lit.23 m.p.. 160ꢀ–167ꢀC, 1H NMR 2.12 (s, 6H, NMe2) 7.04–
7.32 (m, 4H, ArH). IR (KBr): 2125 cm–1. MS m/e 198 (Mþ). Anal. calc.
(found) for C11H10N4; C, 66.66(66.74); H, 5.05(5.13); N, 28.28(28.19). 3e
m.p. 91ꢀC, lit.24 m.p. 91ꢀC, H NMR 2.20 (s, 6H, NMe2), 1.10 (t, 3H,
1
CH2CH3), 4.12 (q, 2H, CH2CH3,) 6.98–7.26 (m, 4H, ArH). IR (KBr):
2130 cm–1 MS m/e 245 (Mþ). Anal. calc. (found) for C13H15N3O2; C,
63.67(63.76); H, 6.12(6.24); N, 17.14(17.22). 3f m.p. 126ꢀC, lit.25 m.p.
126ꢀ–27ꢀC, H NMR 2.12 (s, 6H, NMe2), 7.02–7.36 (m, 9H, ArH). IR
1
(KBr): 2135 cm–1. MS m/e 277 (Mþ). Anal. calc. (found) for C17H15N3O;
C, 76.64(76.55); H, 5.41(5.46); N, 15.16(15.26). 3g, m.p. 223ꢀC, lit.23 m.p.
223ꢀC, H NMR 2.16 (s, 6H, NMe2), 7.10–7.42 (m, 4H, ArH). IR (KBr):
1
2130 cm–1. MS m/e 216 (Mþ). Anal. calc. (found) for C11H12N4O; C,
61.11(61.22); H, 5.55(5.63); N, 25.92(25.99). 3h, m.p. 160ꢀC, lit.23 m.p.
160ꢀC, H NMR 2.12 (s, 6H, NMe2), 7.04–7.42 (m, 10H, ArH & NH), IR
1
(KBr): 2135 cm–1. MS M/e 292 (Mþ). Anal. calc. (found) for C17H16N4O; C,
69.86(69.91); H, 5.48(5.59); N, 19.17(19.19). 3i, m.p. 148ꢀC 1H NMR 1.62 (s,
3H, CH3), 2.16 (s, 6H, NMe2) 7.12–7 45 (m, 8H, ArH). IR (KBr): 2130 cm–1.
MS m/e 263 (Mþ). Anal. calc. (found) for C17H17N3; C, 77.56(77.48); H,
6.46(6.56); N, 15.97(16.05).3j m.p. 77ꢀC, lit.27 m.p. 76ꢀ–79ꢀC. H NMR.
1
2.86 (s, 3H, CH3), 7 12–7.38 (m, 5H, ArH). IR (KBr): 2135 cm–1. MS m/e
299 (Mþ). Anal. calc. (found) for C20H17N3; C, 80.26(80.35); H, 5.68(5.73);
N, 14.04(14.18). 3k, m.p. 159ꢀC, lit.24 m.p. 159ꢀC, H NMR 2.18 (s, 6H,
1
NMe2), 7.02–7.48 (m, 12H, ArH). IR (KBr): 2130 cm–1. MS m/e 188 (Mþ).
Anal. calc. (found) for C10H8N2O2; C, 63.82(63.76); H, 4.25(4.35); N,
14.88(14.94).
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Received in the USAAugust 9, 2000