Synthesis of various cyclopropyl methyl bromide and its derivatives from ketones and/or aldehydes and some β-dicarbonyl compounds in the presence of BrCN and Et3N

Article abstract of DOI:10.1007/s13738-019-01600-x

The ultimate goal in this paper has been developed for the synthesis of structurally various bromomethyl cyclopropane via an α-bromoketone and/or aldehydes with ethyl cyanoacetate or malononitrile and cyanogen bromide (BrCN) in the presence of Et₃N to give products in excellent yields within about 3?s. All structures were characterized by IR, ¹H-NMR, ¹³C-NMR, and Mass spectroscopy techniques. The reaction mechanism was discussed.

Full text of DOI:10.1007/s13738-019-01600-x

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https://doi.org/10.1007/s13738-019-01600-x
ORIGINAL PAPER
Synthesis of various cyclopropyl methyl bromide and its derivatives
from ketones and/or aldehydes and some β-dicarbonyl compounds
in the presence of BrCN and Et3N
Saeed Gholizadeh1 · Kazem D. Safa1 · Nader Noroozi Pesyan2
Received: 6 July 2018 / Accepted: 11 January 2019
© Iranian Chemical Society 2019
Abstract
The ultimate goal in this paper has been developed for the synthesis of structurally various bromomethyl cyclopropane via
an α-bromoketone and/or aldehydes with ethyl cyanoacetate or malononitrile and cyanogen bromide (BrCN) in the presence
of Et3N to give products in excellent yields within about 3 s. All structures were characterized by IR, 1H-NMR, 13C-NMR,
and Mass spectroscopy techniques. The reaction mechanism was discussed.
Keywords Ethyl cyanoacetate · One-pot reaction · 3-Alkyl-3-(bromomethyl)-1,2-dipropionylcyclopropane-
1,2-dicarbonitrile · 3-(4-(Bromomethyl)phenyl)cyclopropane-1,1,2,2-tetracarbonitrile · Cyanogen bromide ·
N-Bromosuccinimide · Photochemical · Bromonium ion
Introduction
antibacterial in many herbal compounds, in antiviral and
some enzyme inhibition activities [12, 13]. The first syn-
thesis of 1,1,2,2,3-penta-substituted cyclopropane described
by Mariella et al. [14]. In this reaction, at first, the simple
condensation reaction of aldehyde and malononitrile affords
alkylidenemalononitriles, then reaction with the second
malononitrile provides Michael adduct. Then bromination
of this product with bromine was done, and finally, intra-
molecular nucleophilic attack of a carbon atom to the other
carbon-containing bromine atom (shoving the bromide ion
out) produces penta-substituted cyclopropane [14]. There are
several routes for the synthesis of cyclopropane ring frame
in organic compounds, such as cyclopropanation of an alde-
hyde in the presence of BrCN and Et3N with β-dicarbonyl
compound as malononitrile [15], ethyl cyanoacetate [16],
Meldrum’s acid in the presence of NaOEt by ball-milling
[17], bis-spiro cyclopropanes based on Meldrum’s acid by
ball-Milling technique [18], in the presence of I2/DMAP
[19] and so on.
The α-bromination of carbonyl compounds is an important
transformation in organic synthesis chemistry [1–4]. Sev-
eral more common reagents have been already applied to
synthesis α-bromo carbonyl derivatives [4, 5]. Halogenation
of ketones has been reported widely in organic syntheses.
Therefore, many methods developed for this purpose. Clas-
sical methods for the bromination of ketones include the use
of molecular bromine [6] and copper(II) bromide [7]. The
harvests of these halogenations have long been valued as
useful synthetic intermediates [8]. For example, each year
new metabolites containing chiral halogens are isolated from
several biological sources [9, 10].
In recent years, a central purpose in organic synthe-
sis chemistry has been to develop suitable and economi-
cally competitive processes for the impressive synthesis
of biologically active compounds. The cyclopropyl group
is influential in biological systems [11], for example, as
A search in the literature found no story about cyclopro-
panation of α-bromo carbonyl compounds via ethyl cyanoac-
etate and/or malononitrile the chemical reaction route.
Owing to these concepts, in this research, we have developed
the chemical synthesis stereoselective cyclopropanation of
ethyl cyanoacetate and malononitrile in the reaction with
various α-bromo ketones and aldehydes with BrCN in the
presence of Et3N.
* Kazem D. Safa
dsafa@tabrizu.ac.ir
1
2
Organosilicon Research Laboratory, Faculty of Chemistry,
University of Tabriz, Tabriz 51666-14766, Iran
Department of Organic Chemistry, Faculty of Chemistry,
Urmia University, Urmia 57159, Iran
Vol.:(0123456789)
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resulted in diethyl 3-alkyl-3-(bromomethyl)-1,2-dicyano
cyclopropane-1,2-dicarboxylate (5a–5n) (scheme 3).
Unfortunately, all attempts failed to separate or character-
ize intermediates 3a, 3b, 4a and 4b, other evidence for the
formation and confirmation of 6 (the existence of bromine
atom in this salt structure) performed by Beilstein test and
the wet silver nitrate test (precipitate of pale yellow silver
bromide).
Results and discussion
In this article, the first goal is to synthesize α-bromination
from various ketones and aldehydes (1a–1n) with N-bro-
mosuccinimide (NBS) in the presence of UV–Vis irradia-
tion (180 nm) [20]. These substrates were converted at
30 2 °C to the corresponding α-brominated products in
excellent yields within a few minutes (Fig. 1). The results
of these studies have been summarized in (Table 1). A new
one-pot reaction of α-bromomethyl ketones and aldehydes
(2a–2r) with ethyl cyanoacetate and malononitrile in the
presence BrCN has been done to afford diethyl 3-alkyl-
1,2-dicyano-3-(bromomethyl) cyclopropane-1,2-dicarbo-
xylate and/or 3-(4-(bromomethyl)phenyl)cyclopropane-
1,1,2,2-tetra carbonitrile under Et3N in excellent yields
with short reaction time (3 s) (Scheme 1). The reaction
of aldehydes among excellent results have been reported
[15]. Instead, aliphatic ketones do not react easily due to
hindrance effect and congestion on intermediate stops
Knoevenagel condensation [20] (Scheme 2). However,
the reaction in the presence of bromine was proceeded
in the allyl position on the intermediate Knoevenagel and
the creation of intermediate bromonium ion (12z) as well
(Scheme 3). The reaction of (1) with (3) afforded (11z)
(the mixture of E and Z isomers). Previously, the reac-
tion mechanism for the formation of salts (6) [16] and (8)
[15] have been reported (Schemes 4 and 5). The salt of
(6) plays the major role and its nucleophilic attack on the
C-atom of (11z) as an α,β-unsaturated C=O compound
which afforded intermediate triethylammonium (4-bromo-
3-(bromomethyl)-4-cyano-5-ethoxy-2-(ethoxy carbonyl)-
5-oxo-3-alkyl-pent-1-en-1-ylidene)amide (14z). The (11z)
can isomerize to (12z) and (13z). Intramolecular C-attack
of the carbanion on carbon atom containing bromine atom
(path a) as an electrophile (pushing the bromide ion out)
Representatively, the reaction mechanism for the for-
mation of 5b is shown in (scheme 3). First, the reaction of
α-bromoketones with ethyl cyanoacetate 3 afforded the mix-
tures of two geometrical isomers (E) and (Z) ethyl 4-bromo-
2-cyano-3-alkyl-but-2-enoate (12b) then nucleophilic attack-
ing 6 to the β-carbon position of 12b as an α,β-unsaturated
carbonyl compound afforded intermediate triethylammo-
nium diethyl-3-alkyl-2-bromo-3-(bromomethyl)-2,4-dicy-
ano-3-pentane dioate-4-ide (14b) intermediate. Intramolecu-
lar C-attack of carbanion to carbon atom containing bromine
atom (path a) as an electrophile pushing the bromide ion
out produced diethyl-3-alkyl-3-bromomethyl-1,2-dicyano-
3-phenyl cyclopropane-1,2-dicarboxylate (5). All attempts
to separate and characterize the intermediates 12b and 14b
failed. This observation that the C-attack of 6 to C-atom in
the allyl position did not occur (path b).
As mentioned above, the reaction of 2 and 3 exclusively
also obtained the mixtures of two geometrical (E)- and (Z)-
isomers 12b in the presence of triethylamine in absence of
BrCN. It has been shown that the salt of 6 and 8 plays the
major character in these reactions. First, it is a nucleophile
in the reaction with 12b then it has an electrophilic character
(carbon atom containing bromine atom) in the intermediate
14b to form 5b (Scheme 6). On the other hand, the probable
compounds (13b), (15b), (19b) and (17b) were not created
through paths b, d, e, and f, respectively (Scheme 6). The
reaction condition, time and yields are outlined in Tables 2
and 3.
We performed the reaction of 2 with ethyl cyanoacetate 3
in the presence of BrCN following Et3N as a model reaction.
The structure of 5b characterized by IR, 1H and 13C NMR
1
spectroscopy. The H NMR spectrum of 5b consists of a
multiplet at δ 1.38, a doublet–doublet at δ 3.14, a quartet
at δ 4.32 and a quartet at δ 4.51 ppm corresponding to ali-
phatic methyls, bromomethyl and methylene protons of 5b.
13C NMR spectrum of this compound shows eleven distinct
peaks (Figs. 2, 3, respectively).
Representatively, in 1H NMR spectrum (5a) with
hydrogen in an axial position, show a doublet–doublet at
δ 3.14 ppm, and bromine atoms are in the central place
(Figs. 4, 5).
We also obtained the reaction of pentane-2,4-dione 1d
and 5,5-dimethyl cyclohexane-1,3-dione 1e with 3 in the
Fig. 1 Photograph representation of the reaction progress in the UV-
cabinet
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Table 1 The structure of ketones and aldehydes 1, brominated products 2 and reaction time
Entry
Substrate (1)
Product (2)
Time (min)
0.5
O
O
1
Br
Br
2(a)
1(a)
O
O
Br
2
3
0.5
3
1(b)
2(b)
O
O
O
Br
1(c)
2(c)
O
O
O
O
4
5
3
3
1(d)
2(d)
Br
O
O
O
Br
2(e)
1(e)
O
O
Br
Br
6
7
3
3
1(f)
2(f)
O
O
H
H
H
Br
2(g)
H
3C
1(g)
O
O
H
3C
8
3
Br
H
1(h)
2(h)
Br
CH3
O
O
9
3
3
H
H
1(i)
2(i)
10
H
H
Br
H
3C
O
O
O
O
1(j)
2(j)
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Table 1 (continued)
Entry
Substrate (1)
Product (2)
Time (min)
3
O
O
H
N
N
3C
11
H
Br
Br
H
2(k)
1(k)
CH3
O
3
O
12
13
H
H
1(l)
2(l)
3
3
H
H
Br
Br
H
3C
N
H
N
H
O
O
2(m)
1(m)
14
H
H
H
3C
S
1(n)
S
O
O
2(n)
R
Scheme 1 Representatively,
proposed afforded diethyl
3-alkyl/aryl-1,2-dicyano-
3-(bromomethyl) cyclopro-
Br
NC
CO2Et
CN
3
Br
NC
EtO2C
CN
CO2Et
+
BrCN, Et3N
CO2Et
Et3NH
EtOH
O
O
5
pane-1,2-dicarboxylate 5 and
3-(4-(bromomethyl)alkyl/
aryl)cyclopropane-1,1,2,2-
tetracarbonitrile 7 under Et3N
in excellent yields with short
reaction time
6
NBS, Et2O
UV (180 nm)
One-pot
Br
R
CH3
R
1
2
NC
CN
R
Br
CN
CN
4
Br
+
NC
NC
CN
CN
BrCN, Et3N
EtOH
Et3NH
7
8
presence of BrCN and Et3N (Scheme 7). In this feedback,
the reaction of 1d was comfortable, and the reaction of 1d
and 1e with 3 and BrCN following Et3N were furnished 5d
and 5e, respectively (Figs. 6, 7, 8 and Scheme 8).
investigate this possibility and discuss our results in future
communications. These observations were found in the
results of 1H and 13C NMR spectroscopy analysis in detail.
Experimental section
Conclusions
General
In conclusion, we have a reaction of α-bromo ketones with
ethyl cyanoacetate and cyanogen bromide in essential media
afforded stereoselectively diethyl 3-alkyl-1,2-dicyano- 3
(bromomethyl) cyclopropane-1,2-dicarboxylate in excel-
lent yields and short reaction times. Some α-bromo ketones
gave the cis and some others gave the trans cyclopropane
stereoisomer. The aliphatic ketones with any bromide atom
possessing strong electron donor and bulky hindered sub-
stituents exclusively afforded Knoevenagel adducts. We shall
ChemDraw Ultra 8.0 version software was used for the
drawing and nomenclature of compounds. Melting points
were measured with a digital melting point apparatus
(Electrothermal) and were uncorrected. IR spectra was
determined in the region 4000–400 cm−1 on a NEXUS
1
670 FT-IR spectrometer by KBr pellets. The H and 13C
NMR spectra was recorded on Bruker 300 FT-NMR at 300
and 75 MHz, respectively (Imam Khomeini International
1 3