Chemoselective Bromination of Dienoates

Article abstract of DOI:10.1002/ejoc.202000893

A variety of tetra-, di- and monobromo derivatives of dienoates were prepared from parent polyunsaturated esters under mild conditions. According to proposed protocol the target bromoesters were easily obtained as a rule in good yields and high selectivity.

Full text of DOI:10.1002/ejoc.202000893

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Chemoselective bromination of dienoates
Authors: Valentina A. Kobelevskaya, Alexander V. Popov, Sergey V.
Zinchenko, and Alexander Rulev
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000893
Link to VoR: https://doi.org/10.1002/ejoc.202000893
01/2020

10.1002/ejoc.202000893
European Journal of Organic Chemistry
Chemoselective bromination of dienoates
Valentina A. Kobelevskaya, Alexander V. Popov, Sergey V. Zinchenko, and Alexander Yu. Rulev*
A. E. Favorsky Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 664033 Irkutsk, Russia;
e-mail: rulev@irioch.irk.ru
Abstract: A variety of tetra-, di- and monobromo derivatives of dienoates were prepared from
parent polyunsaturated esters under mild conditions. According to proposed protocol the target
bromoesters were easily obtained as a rule in good yields and high selectivity.
http://www.irkinstchem.ru
Keywords: dienoates • halogenation • selectivity
Introduction
The development of efficient and selective methods for the construction of complex molecules is
a major challenge to organic chemists and is one of the principal goals of modern organic
chemistry. The aim is no only to build the target molecule but to build it well. As is known, a
synthetic chemist having no required reagents is like an artist without paints.1 Therefore, it is an
important task for chemists to find readily available and highly functionalized starting materials
that can be easily transformed into target derivatives. Although these compounds look often
structurally quite simple, their selective synthesis sometimes remains a serious problem.
Halogenated α,β-unsaturated carbonyl bearing compounds are versatile building blocks.2-
4
Being polyfunctional substrates these compounds have found a wide range of applications in
organic synthesis. It is not surprising that very often they use as initial reagents in a one-pot
fashion cascade assembly of bioactive and pharmaceutical compounds as well as analogs of
natural substances. For example, the recently demonstrated reactivity of α-bromoenoates and
fluorinated α-bromoenones has open unusual and often unpredictable transformations. These
compounds were successfully employed as a starting material in the assembly of carbo-
(condensed and spiro) and heterocycles which are difficult or even impossible to obtain in
another way.5-8
To date the considerable attention has been focused on the α- or β-halo-α,β-unsaturated
carbonyl derivatives 1a,b – haloenals, haloenones, and haloenoates bearing only one conjugated
double bond (Scheme 1). However, the development of efficient and highly selective method for
the preparation of mono- or polyhalogenated 1,3-dienes bearing a conjugated carbonyl group 2-4
is more intriguing, and perhaps, more fundamental challenge. These conjugated 1,3-diene
patterns are regarded as principal structural units which were found in molecules of numerous
natural products and derivatives having various biological activities as well as in macrocyclic
polyenes.9,10 The behavior of simple dienes towards bromine has been extensively studied and
now this reaction has become a classical process which is discussed in University textbooks on
organic chemistry. Motivated by polyelectrophilic character of dienic systems having electron-
withdrawing group, we became interested in the development of general procedure for their
preparation. In fact, the simultaneous presence in their molecules several functional groups – two
conjugated double bonds, halogen atom and carbonyl moiety – make them attractive and useful
tools in organic synthesis. Really, they can a priori react as Michael acceptors or dienes,
dienophiles and dipolarophiles. This feature of these compounds increases their application in
synthetic and medicinal chemistry and consequently stimulates the development of efficient
methods for their selective preparation.
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10.1002/ejoc.202000893
European Journal of Organic Chemistry
The syntheses of bromoenoates described so far are based on the commonly used
methods, namely bromination – dehydrobromination of parent compounds by molecular bromine
or different organobromine compounds as halogenating reagents.11 As a continuation of our
research in this field,12 here we report an efficient synthetic procedure for the bromination of
dienoates. Depending on the reaction conditions, we prepared mono- and dibromodienoates and
their precursors in good to excellent chemo- and stereoselectivity.
Scheme 1. Halogenated unsaturated carbonyl-bearing compounds: previous and current work.
Results and discussion
Dienoates 5 can react with bromine via three different pathways: 4,5-, 2,3- or 2,5-addition modes
leading to three chemoisomers 6, 7 and 8, correspondingly (Scheme 2). The addition of the
second equivalent of bromine to enoates 6-8 must afford tetrabromoderivatives 9. It is reasonable
to assume that the result of bromination depends strongly on the nature of substituent R as well
as the reaction conditions.
Scheme 2. Possible reaction pathways.
We first focused on the transformation of 2,4-dienoates 5 into dibromo derivatives. To
evaluate the generality of this procedure and determine the influence of the structure of starting
esters on the chemo- and stereoselectivity of bromination, non-substituted (5a), alkyl (5b) and
aryl (5c) substituted dienoates were examined. We have found that the addition of bromine to
selected dienoates is a rapid reaction taking place under mild reaction conditions. Thus, when
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10.1002/ejoc.202000893
European Journal of Organic Chemistry
ethyl pentadienoate 5a was treated with one equivalent of bromine in chloroform at room
temperature, the dibromoenoate 6a was only isolated in good yield (Table 1). The structure of
synthesized dibromoester 6a was assigned based on multinuclear 1D (1H, 13C) and 2D NMR, IR
1
13
spectroscopy, mass-spectrometry and elemental analyses. Thus, both H and C NMR spectra
revealed the presence of signals of only one double bond. For example, the doublet at 5.94 ppm
(J = 15.4 Hz) and doublet of doublets at 6.75 ppm (J = 15.4, 9.4 Hz) are characteristic for trans-
1
conjugate double bond. The new signals at 3.66 (dd), 3.84 (dd), and 4.61 (ddd) ppm in the H
NMR spectra confirm the presence of a pair of the moiety CH2Br-CHBr. In the 13C NMR
spectrum only two signals in the field of olefinic carbons at 125.6 and 143.5 ppm were observed.
This result is in good agreement with the theoretical study. To understand the cause of
high chemoselectivity of bromine addition and regarding this reaction as an electrophilic process,
we carried out quantum chemical calculations of the Fukui index13,14 for pentadienoate 5a.
Previous results on structurally related electron deficient olefins have shown that, in general,
these parameters correlate well with the reactivity of similar systems.15 According to these
calculations, olefinic carbon C-2 and C-4 are the most probable centres of bromine electrophilic
attack. In an effort to explain the preferential formation of 4,5-dibromoenoate 6a, we determined
the thermodynamic characteristics of all possible chemoisomers 6a, 7a, and 8a. It was found that
the 4,5-dibromoenoate 6a is the thermodynamically most stable isomer. It is more stable than
isomeric 2,3-dibromo penten-4-oate 7a and 2,5-dibromoester 8a for 11.7 kcal/mol and 11.0
kcal/mol, correspondingly (see, SI). Taking into account that the formation of the ionic
intermediates was shown to be reversible, we concluded that the final formation of ester 6 is the
most expected process. These results clearly explain the exclusive formation of adduct 6a and
absence of its isomers 7a and 8a.
Table 1 Bromination of 5a-c.
6 (7), dr
entry dienoate brominating
reagent
solvent
conditions
products,
(yield, %)a
1
2
Br2
Br2
CHCl3
CHCl3
CHCl3
CHCl3
DCM
rt
rt
6a (59)
-
5a
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5c
6b (76) + 7b (11)
6b (67) + 7b (8)
6b (72)
23:77
23:77
24:76
33:67
33:67
40:60
0:100
0:100
11:89
0:100
0:100
(33:67)
(33:67)
3
Br2
53°C
-40°C
rt
4
Br2
5
Br2
6b (80)
6
Br2
CCl4
rt
6b (87)
7
Br2
dioxane
AcOH
TFA
10°C
rt
6b (80)
8
Br2
6b (83)
9
Br2
rt
6b (62)
10
11
12
13
14
Br2
TFE
rt
6b (51)
DPTBE
HBr/oxone
Br2
MeCN
AcOH
CHCl3
dioxane
rt
6b (20) + 7b (11)
6b (24) + 7b (7)
7c (quant)
7c (quant)
rt
-60°C
rt
Br2
5c
a Isolated yield.
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10.1002/ejoc.202000893
European Journal of Organic Chemistry
Having unambiguously established that the dibromo derivative 6a has the structure of a
4,5-addition product with E-configuration of the residual double bond (as in the starting
molecule 5a), we assumed that dienoates 5b,c react with bromine by the same pathway.
However, in contrast with non-substituted dienoate 5a, ethyl sorbate 5b reacts with an equimolar
quantity of bromine under the same conditions to give a (7:1) mixture of isomers 6b and 7b
which can be easily separated by column chromatography (Table 1, entry 2). The structure of
both isomers was undoubtedly established by 1D and 2D NMR spectra. Thus, olefinic proton
C5H= resonated as a doublet of quartets (J = 15.0 and 6.6 Hz) in the most low-frequency
magnetic field (δ = 5.89 ppm). In contrast, the methine proton C5H for isomeric derivative 6b
resonated at 4.17 – 4.38 ppm. The assignments of the configuration of the double bond and
additional arguments on stereochemistry were easily achieved by the analysis of the coupling
constants and 1H – 1H 2D homonuclear NOESY experiment (Fig. 1).
Figure 1. Main 2D correlations for compounds 6b and 7b.
The result obtained is not consistent with the previously described: the formation of
dibromo derivatives 6b and 8b was reported when ethyl sorbate 5b was treated with bromine in
CCl4 at 0°C.16 However, authors were unable to isolate adduct 8b and its structure seems to be
wrongly deduced from its dehydrobromination reaction. Moreover, the structure of 2,3-dibromo-
4-hexenoate was incorrectly determined.
When the reaction was performed at heating up to 53°C the mixture of both isomers 6b
and 7b was also obtained. The lightly decreased yields of both reaction products can be
explained by polymerization of either initial dienoate 5b or dibromoenoates 6b and 7b (Table 1,
entry 3). At the same time, when ethyl sorbate 5b was treated with bromine under low
temperature, the reaction proceeded chemoselectively and the isomer 6b was isolated only in
good yield (Table 1, entry 4). Generally, the nature of the solvent did not influence the direction
of bromine addition: in both protic and aprotic solvents bromoester 6b was the principle or even
sole product for this reaction (Table 1, entries 5-10). But it should be noted that solvent-
dependent stereochemistry of bromine addition was observed in this reaction. Thus, the reaction
of ester 5b with bromine in aprotic solvents such as DCM, chloroform, tetrachlorometane or
dioxane is not stereoselective: in these cases dibromoenoate 6b isolated as a mixture of two
diastereomers in the ratio from 23:77 to 40:60. Surprisingly, when the same reaction was
performed in acetic or trifluoroacetic acids as well as in fluorinated alcohol (such as TFE), the
dibromo derivative 6b was formed with high diastereoselectivity (up to 100%). This result can
be explained in the term of the mechanism of bromination. Though relatively few data on the
halogenation of conjugated dienes have been reported, the 1,2-addition of halogen is usually
nonstereoselective17 and strongly depend on the solvent nature.18 Taking into account that
electrophilic bromination of the double bond proceeds near exclusively as trans-addition via a
bridged-ion, we hypothesized that the charge distribution in the bromonium ion A is not
symmetric: the positive charge is preferentially located at the allylic carbon because the
conjugate enoate moiety effectively stabilizes the partial positive charge on a neighboring
carbon. This implies that the intermediate A is open to syn and anti-addition. In such cases a
solvent-dependent stereochemistry should be expected. In non-protic solvents both directions of
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10.1002/ejoc.202000893
European Journal of Organic Chemistry
nucleophilic attack of bromide anion are possible and the formation of the mixture of
diastereomers should be expected. In contrast, in organic acids and fluorinated alcohol the
bromide anion is hydrogen-bonded to the solvent. Therefore, it became less sterically accessible
and less active: as a result, the increasing of selectivity toward electrophilic center and the anti-
addition of bromine were only observed (Scheme 3). Interestingly to note that diastereomer
formed in protic solvents is slightly dominated in the mixture of diastereomers isolated in
experiments with aprotic solvents.
Scheme 3. Bromination in aprotic and protic solvents.
Other convenient brominating reagents such as 1,2-dipyridiniumditribromide-ethane
(DPTBE) or HBr in the presence of oxone were tested with ethyl sorbate. In contrast to the
experiments using molecular bromine, in these cases the formation of ethyl 4,5-
dibromohexenoate 6b as a principal reaction product was accompanied by the significant
formation of isomeric 2,3-dibromoenoate 7b: its amounts were reached by 33% (Table 1, entries
11, 12).
The preferable or exclusive bromine addition in 5,6-positions of starting dienoates 5a,b
seems to be the result of the preservation of conjugated moiety C=C˗C=O. We hypothesized that
the introduction of substituent conjugated with the γ,δ-double bond should change the reaction
course. To test this hypothesis, the phenyl group was incorporated into the molecule of ethyl
corbate 5b instead of methyl one, and ethyl 2E,4E-5-phenylpenta-2,4-dienoate 5c was reacted
with equimolar quantity of bromine. We performed the reaction under conditions that give a
higher chance to obtain both isomeric dibromoderivatives. To our delight, the steric bulk of the
aryl substituent at the remaining double bond did not prevent to the reaction. It turned out that
our hypothesis was correct: the bromine addition reaction proceeded chemoselectively in
chloroform at low temperature to give the target dibromoderivatives 7c in quantitative yield.
This result is in excellent agreement with the thermodynamic characteristics of all
chemoisomers: while non-substituted or methyl-substituted esters 6a,b are the most stable
isomers for 11.7 and 4.1 kcal/mol correspondingly, the phenyl-substituted enoates 7c is slightly
more stable (for 0.9 kcal/mol) than its isomer 6c (See SI, S.47). The same result was obtained
when the reaction was performed in dioxane as a solvent at room temperature (Table 1, entries
13, 14).
Next, we shift our focus to the preparation of tetrabromo-substituted esters 9a-c. We were
pleased to observe that the reaction of dienoates 5a-c with twofold excess of bromine was found
to be general, and tetrabromo derivatives 9a-c were obtained in all cases in good yields. The
presence or absence of any substituent at the δ-position has no significant effect on the reaction
result (Table 2). Evidently, in these reactions ethyl dienoates 5 initially provide dibromoesters 6
which subsequently transformed into tetrabromo derivatives 9 by reaction with a second
equivalent of bromine.
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10.1002/ejoc.202000893
European Journal of Organic Chemistry
It is very important to note that the bromination of dienoates 5 is highly stereoselective:
though in the molecules tetrabromoesters there are three (for 9a) or four (for 9b,c) asymmetric
centers, in the NMR spectra of the products 9a-c only one set of signals is observed. Therefore,
the bromination of each double bond occurs through the bromonium ion ensuring anti-
stereoselectivity.
Table 2. Synthesis of tetrabromoesters 9a-c.
entry dienoate
Br2
(equiv.)
2.2
2.2
2.5
conditions
products,
(yield, %)a
9a (48)b
9b (64)c
9b (77)
1
rt, 3 h
5a
2
50°C, 6 h
50°C, 6 h
rt, 16 h
5b
3
4
5b
2E,4E-5c
2.5
9c (30)
a Isolated yield.
b Dibromoenoate 6a was also isolated in 25% yield.
c Dibromoenoate 6b was also isolated in 17% yield.
To obtain mono- or dibromodienoates, di- or tetrabromoesters 6, 7 and 9 were reacted
with the organic base (TEA, DABCO or DBU). The best results were obtained with
triethylamine (for dibromo derivatives 6a,b and 7b,c) and anhydrous DABCO (for tetrabromo
derivatives 9a-c) as dehydrobromination reagent.
Thus, when dibromoenoate 6b was treated with TEA at room temperature for 2 h, the
target ethyl-4-bromosorbate 2b was isolated in excellent yield (Scheme 4). Similarly, the
treatment of ester 7b with the same base leads to the isomeric ethyl-2-bromosorbate 3b in
moderate yield. Unfortunately, the bromodienoate 3b is not quite stable and could not be isolated
in pure form. Even recording of its NMR spectra is accompanied by decomposition: the color of
the CDCl3 solution rapidly changed from light-yellow to brown and new signals appeared in the
13C NMR spectrum after the sample has been standing at room temperature for several hours.
Scheme 4. Dehydrobromination of di- and tetrabromoesters.
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10.1002/ejoc.202000893
European Journal of Organic Chemistry
Finally, we showed that tetrabromoesters 9a-c were direct precursors of tri- (10a-c) and
dibromodienoates 4a-c. Thus, when saturated ester 9b was treated with one equivalent of TEA,
tribromoester 10b was isolated in low yield. At the same time, when the same ester reacted with
2.2 equivalents of DABCO at room temperature for only one hour, the target dibromodienoate
4b was isolated in 44% yield. Note that according to the NMR spectra of the reaction mixture,
the esters 10b and 4b are really formed in high yields. Unfortunately, during their purification by
column chromatography on silica gel a particular decomposition or polymarization seems to take
place.
Interestingly, dehydrobromination leading to 2-bromoenoate 10b proceeds more rapidly
than second elimination of HBr. Most probably, the α-hydrogen in 9b is more acidic and can be
easily removed as a proton under the basic conditions leading the enoate 10b bearing a double
bond conjugated with etoxycarbonyl group. In contrast, the elimination of the proton from C-4
atom is more difficult. Thus, by the separate experiment we showed that after standing of the
solution of 6b with DABCO in THF for 2 h at room temperature, the conversion of starting ester
achieved only 20%.
Conclusion
In conclusion, we have reported an efficient method for selective bromination of alkyl
dienoates. In contrast to previously described bromination of ethyl sorbate 5b, the reaction
proceeds with the formation 4,5-dibromo enoate 6b as a principal reaction product and 2,3-
dibromoenoats (not 2,5-dibromo derivative) as a minor one. The proposed protocol is suitable for
substrates bearing terminal or internal (alkyl- and aryl-substituted) double bond, giving the
corresponding mono-, di- or tetrabrominated esters as a rule in moderate or excellent yields (up
to quantitative). Moreover, this procedure allows us to prepare the target bromine-bearing mono-
and dienic systems in a highly chemo- and stereoselective manner.
Further study addressing the extension of range of bromoderivatives of carbonyl-bearing
dienes and their utility to the synthesis of different heterocyclic systems will be explored by our
research team in the near future.
Experimental part
General Remarks.
13
1H (400.1 MHz), and C (100.6 MHz) NMR spectra were recorded on Bruker AVANCE 400
MHz spectrometer. Chemical shifts (δ) are given in ppm; the coupling constants (J) are given in
1
Hertz. The assignment of signals in the H NMR spectra was made using COSY and NOESY
1
experiments. Resonance signals of carbon atoms were assigned based on H-13C HSQC and 1H-
13C HMBC experiments. The IR spectra were recorded with an ATR/FT-IR spectrometer. The
GC/MS analyses were performed with a Shimadzu GCMS-QP5050A instrument (EI, 70 eV).
HRMS were recorded on HR-TOF-ESI-MS Agilent 6210 for solution in acetonitrile with
electrospray ionization in the positive mode. The silica gel used for column chromatography was
230-400 Mesh. All reagents were of reagent grade and were used as such or distilled prior to use.
All the solvents were dried according to standard procedures and distilled prior to use. The initial
ethyl sorbate 5b is a commercial product. Ethyl dienoates 5a,c were prepared according to
reported procedures (19 for 5a and 20 for 5c).
General procedure for synthesis of dibromoester 6a-c and 7.
Bromine (1 equiv.) in CHCl3 (5 mL for 1 mmol) was added dropwise into a stirred solution of
the enoates 5a-c (1 equiv.) in CHCl3 (2 mL for 1 mmol). During the addition the temperature
was kept at 0 ÷ 10oC. The mixture was then stirred at room temperature until disappearance of
the deep bromine coloration. The solvent was evaporated. The dibromoderivatives 6a-c and 7b,c
were isolated in pure form by column chromatography on Silica gel.
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10.1002/ejoc.202000893
European Journal of Organic Chemistry
Ethyl (E)-4,5-Dibromopent-2-enoate (6a). Yield: 169 mg (59%) (from 1 mmol of 5a);
colorless oil; TLC: Rf = 0.60 (5:1 hexane: diethyl ether). IR (KBr, ν, cm-1): 1656 (C=C), 1722
1
(C=O). H NMR (CDCl3): δ 1.30 (t, J = 7.1, 3H), 3.66 (dd, J = 10.4, 10,4, 1H), 3.84 (dd, J =
10.4, 4.3, 1H), 4.22 (q, J = 7.1, 2H), 4.61 (ddd, J = 10.4, 9.4, 4.5, 1H), 5.94 (d, J = 15.4, 1H),
6.75 (dd, J = 15.4, 9.4, 1H). 13C NMR (CDCl3): δ 14.7 (CH3), 33.8 (CH2Br), 47.2 (CHBr), 61.5
(OCH2), 125.6 (=CH), 143.5 (CH=), 165.7 (C=O). MS (EI) m/z (relative intensity): 286 (M+,
<1), 241 (9), 179 (25), 177 (25), 81 (64), 53 (100). Calcd. For C7H10Br2O2: C 29.40, H 3.52;
found C 29.55, H 3.61.
Ethyl (E)-4,5-Dibromohex-2-enoate (6b). Yield: 539 mg (72%) (from 2.5 mmol of 5b); light
yellow oil; TLC: Rf = 0.43 (10:1 hexane : diethyl ether). 1H NMR (CDCl3): major diastereomer:
δ 1.31 (t, J = 7.1, 3H), 1.89 (d, J = 6.6, 3H), 4.17-4.23 (m, 3H), 4.63 (dd, J = 9.4, 9.4, 1H), 5.99
(d, J = 15.4, 1H), 6.93 (dd, J = 15.4, 10.0, 1H); minor diastereomer (as a 0.32:1 mixture with
major diastereomer): δ 1.31 (t, J = 7.1, 3H), 1.81 (d, J = 6.8, 3H), 4.17-4.23 (m, 2H), 4.38 (dq, J
= 6.8, 3.8, 1H), 4.88 (dd, J = 9.2, 3.8, 1H), 6.08 (d, J = 15.3, 1H), 7.01 (dd, J = 15.3, 9.2, 1H).
13C NMR (CDCl3): major diastereomer: δ 14.3 (CH3), 24.8 (CH3), 49.6 (CHBrCH3), 55.1
(CHBr), 60.9 (OCH2), 124.2 (=CH), 143.9 (CH=), 165.4 (C=O); minor diastereomer (as a 0.32:1
mixture with major diastereomer): δ 14.3 (CH3), 21.2 (CH3), 49.3 (CHBrCH3), 55.6 (CHBr),
61.0 (OCH2), 125.9 (=CH), 140.9 (CH=), 165.3 (C=O). IR (KBr, ν, cm-1): 1654 (C=C), 1720
(C=O). MS (EI) m/z (relative intensity): 220 (M+ - HBr + 1, 11), 218 (15), 175 (26), 173 (17),
139 (34), 111 (100), 83 (19). Calcd. for C8H12Br2O2: C 32.03, H 4.03; found C 31.93, H 4.02.
Ethyl (E)-4,5-Dibromohex-2-enoate (7b). Yield: 84 mg (11%) (from 2.5 mmol of 5b); oil;
TLC: Rf = 0.53 (10:1 hexane : diethyl ether). 1H NMR (CDCl3): δ 1.33 (t, J = 7.1, 3H), 1.78 (d, J
= 6.6, 3H), 4.28 (q, J = 7.1, 2H), 4.39 (d, J = 11.2, 1H), 4.88 (dd, J = 10.7, 10.7, 1H), 5.55 (ddd,
J = 15.0, 10.2, 1.6, 1H), 5.89 (qd, J = 15.0, 6.6, 1H). 13C NMR (CDCl3): δ 14.0 (CH3CH2), 17.8
(CH3), 47.4 (CHBrC=O), 51.7 (CHBr), 62.6 (OCH2), 128.6 (=CH), 133.4 (CH=), 167.8 (C=O).
IR (KBr, ν, cm-1): 1630 (C=C), 1711 (C=O). MS (EI) m/z (relative intensity): 255 (M+ - OEt,
13), 227 (13), 221 (62), 219 (65), 193 (22), 191 (22), 139 (46), 111 (42), 97 (27), 95 (40), 67
(100), 66 (41), 65 (75).
Ethyl (E)-2,3-dibromo-5-phenylpent-4-enoate (7c) as a (1:2) mixture of diastereomers. Yield:
1
215 mg (99%) (from 0.6 mmol of 5c); beidge solid; without chromatographical purification. H
NMR (CDCl3): major diastereomer: δ 1.36 (t, J = 7.2, 3H), 4.33 (q, J = 7.2, 2H), 4.55 (d, J =
11.1, 1H), 5.12 (dd, J = 11.1, 10.3, 1H), 6.22 (dd, J = 10.3, 15.5, 1H), 6.74 (, J = 15.5, 1H),
7.29-7.44 (m, 5H); minor diastereomer: δ 1.31 (t, J = 7.1, 3H), 4.27 (q, J = 7.1, 2H), 4.63 (d, J =
6.6, 1H), 5.01 (ddd, J = 8.0, 6.6, 1.2, 1H), 6.65 (2, 2H), 7.29-7.44 (m, 5H). 13C NMR (CDCl3):
major diastereomer: δ 14.0 (CH3), 47.1 (CHBrC=O), 51.8 (CHBr), 62.7 (OCH2), 125.8 (=CH),
127.1 (Co), 128.8 (Cm), 128.9 (Cp), 135.3 (Ci), 136.0 (CH=), 167.7 (C=O); minor diastereomer: δ
14.1 (CH3), 48.6 (CHBrC=O), 53.0 (CHBr), 62.7 (OCH2), 125.0 (=CH), 127.2 (Co), 128.8 (Cm),
128.9 (Cp), 129.0 (Ci), 135.6 (CH=), 167.0 (C=O). IR (KBr, ν, cm-1): 1643 (C=C), 1742 (C=O).
MS (EI) m/z (relative intensity): 282 (13), 280 (12), 155 (28), 129 (100), 128 (73), 115 (12). We
had troubles obtaining suitable elemental analysis for compounds 7b,c due to their low stability
and propencity to loss HBr.
General procedure for synthesis of tetrabromoesters 9a-c.
Bromine (2.2 ÷ 2.5 equiv.) in CHCl3 (5 mL for 1 mmol) was added dropwise into a stirred
solution of the dienoates 5a-c (1 equiv.) in CHCl3 (2 mL for 1 mmol). During the addition the
temperature was kept at 0 ÷ 10oC. The mixture was then stirred under appropriates conditions (rt
(for 9a,c) or 50°C (for 9b)) until disappearance of the deep bromine coloration. After solvent
evaporation tetrabromoderivatives 9a-c were isolated by column chromatography.
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10.1002/ejoc.202000893
European Journal of Organic Chemistry
Ethyl 2,3,4,5-Tetrabromopentanoate (9a). Yield: 212 mg (48%) (from 1.0 mmol of 1a);
colorless oil; TLC: Rf = 0.8 (7:1 hexane : diethyl ether). IR (KBr, ν, cm-1): 1746 (C=O). 1H NMR
(CDCl3): δ 1.34 (t, J = 7.2, 3H), 3.83 (dd, J = 10.7, 10.4, 1H), 3.90 (dd, J = 10.4, 5.0, 1H), 4.31
(q, J = 7.2, 2H), 4.59 (d, J = 11.1, 1H), 4.74 (ddd, J = 10.7, 5.0, 1.8, 1H), 4.91 (dd, J = 11.1, 1.8,
1H). 13C NMR (CDCl3): δ 14.0 (CH3), 33.5 (CH2Br), 47.2 (CHBrCH2), 51.6 (CHBr), 52.8
(CHBrCO), 62.9 (OCH2), 167.2 (C=O). MS (EI) m/z (relative intensity): 447 (M+ +1, <1), 367,
365 (80), 339, 337 (100), 285 (39), 257 (46), 213 (69), 133, 131 (54).
Ethyl 2,3,4,5-Tetrabromohexanoate (9b). Yield: 734 mg (66%) (from 2.5 mmol of 5b); yellow
1
oil; TLC: Rf = 0.4 (20:1 hexane : diethyl ether). IR (KBr, ν, cm-1): 1747 (C=O). H NMR
(CDCl3): δ 1.34 (t, J = 7.1, 3H), 2.00 (d, J = 6.5, 3H), 4.31 (q, J = 7.2, 2H), 4.37 (dq, J = 6.5,
10.5, 1H), 4.57 (dd, J = 10.5, 1.8, 1H), 4.63 (d, J = 11, 1H), 5.13 (dd, J = 11, 1.8, 1H). 13C NMR
(CDCl3): δ 14.0 (CH2CH3), 25.9 (CH3), 47.7 (CHBr), 49.9 (CHBrC=O), 55.3 (CHBr), 59.8
(OCH2), 62.9 (CHBrCH3), 167.3 (C=O). MS (EI) m/z (relative intensity): 383 (15), 381 (46), 379
(46), 377 (15), 352 (19), 351 (19), 301 (21), 299 (42), 297 (22), 191 (27), 189 (25), 147 (25), 145
(27), 66 (100). Calcd. for C8H12Br4O2: C 20.90, H 2.63; found C 21.16, H 2.60.
Ethyl 2,3,4,5-Tetrabromo-5-phenylpentanoate (9c). Yield: 154 mg (30%) (from 1 mmol of
5c); white powder (m.p. = 107-109°C); TLC: Rf = 0.3 (20:1 hexane : diethyl ether). IR (KBr, ν,
cm-1): 1744 (C=O). 1H NMR (CDCl3): δ 1.37 (t, J = 7.1, 3H), 4.34 (q, J = 7.0, 2H), 4.70 (d, J =
11.0, 1H), 5.07 (dd, J = 11.0, 1.8, 1H), 5.24 (d, J = 11.0, 1H), 5.32 (dd, J = 11.0, 1.7, 1H), 7.35-
7.43 (m, 5H). 13C NMR (CDCl3): δ 13.6 (CH3), 47.8 (CHBrCHBrC=O), 55.0 (CHBrC=O), 55.2
(CHBrCHBrC6H5), 57.3 (CHBrC6H5), 63.0 (CH2), 128.3 (Co), 129.0(Cm), 129.4 (Cp), 139.3 (Ci),
167.3 (C=O). Calcd. for C13H14Br4O2: C 29.92, H 2.70; found C 30.23, H 2.62.
General procedure for dehydrobromination of dibromoester 6a,b or 7b,c.
The solution of triethylamine (1.1 equiv.) in THF (1 mL for 1 mmol) was added dropwise into a
stirred solution of the dibromoesters (6a,b or 7b,c) (1 equiv.) in THF (2 mL for 1 mmol). The
reaction mixture was stirred for ca 2 h, white precipitate was filtered, and residue was purified
by column chromatography to give the target monobromoenoates 2a,b or 3b,c. The following
bromoderivatives were obtained by this procedure.
Ethyl (E)-4-bromopenta-2,4-dienoate (2a). Yield: 64 mg (63%) (for 0.5 mmol of 6a); colorless
oil; TLC: Rf = 0.55 (7:1 hexane : diethyl ether). IR (KBr, ν, cm-1): 1655 (C=C), 1720 (C=O). 1H
NMR (CDCl3): δ 1.29 (t, J = 7.1, 3H), 4.21 (q, J = 7.1, 2H), 5.94 (s, 1H), 6.15 (s, 1H), 6.22 (d, J
= 14.8, 1H), 7.22 (d, J =14.8, 1H). 13C NMR (CDCl3): δ 14.3 (CH3), 60.9 (OCH2), 125.5
(=CHC=O), 127.0 (=CH2), 127.5 (CBr), 142.0 (CH=), 166.2 (C=O). Calcd. for C7H9BrO2: C
29.40, H 3.52; found C 29.55, H 3.61.
Ethyl 4-bromohexa-2,4-dienoate (2b). Mixture of two geometric isomers. Yield: 69 mg (81%)
(from 0.39 mmol of 6b); colorless oil; TLC: Rf = 0.6 (10:1 hexane : diethyl ether). Major
(2E,4E)-isomer (2b). IR (KBr, ν, cm-1): 1631 (C=C), 1718 (C=O). 1H NMR (CDCl3): δ 1.29 (t, J
= 7.1, 3H), 1.92 (d, J = 7.6, 3H), 4.21 (q, J = 7.1, 2H), 6.24 (d, J = 14.7, 1H), 6.41 (q, J = 7.6,
1H), 7.54 (d, J =14.7, 1H). 13C NMR (CDCl3): δ 14.4 (CH3CH2), 16.0 (CH3CH=), 60.8 (OCH2),
119.7 (=CBr), 124.5 (=CHCO), 136.6 (CH3CH=), 138.5 (CH=CBr), 166.7 (C=O). MS (EI) m/z
(relative intensity): 220 (M++1, 14), 218 (M+˗1, 14), 175 (20), 173 (20), 139 (34), 111 (100).
Calcd. for C8H11BrO2: C 43.86, H 5.06; found C 43.66, H 5.11. Minor (2E,4Z)-isomer (2b) as a
1
mixture with (2E,4E)-isomer (2b). H NMR (CDCl3): δ 1.30 (t, J = 7.1, 3H), 1.96 (d, J = 7.1,
3H), 4.22 (q, J = 7.1, 2H), 6.19 (d, J = 14.9, 1H), 6.43 (q, J = 7.1, 1H), 7.28 (d, J =14.9, 1H). 13C
NMR (CDCl3): δ 14.4 (CH3CH2), 18.1 (CH3CH=), 60.7 (OCH2), 121.9 (=CBr), 124.6 (=CHCO),
138.0 (CH3CH=), 143.4 (CH=CBr), 166.8 (C=O). MS (EI) m/z (relative intensity): 220 (M+ +1,
14), 218 (M+ -1, 14), 175 (20), 173 (19), 139 (34), 111 (100).
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10.1002/ejoc.202000893
European Journal of Organic Chemistry
Ethyl (Z,E)-2-Bromohexa-2,4-dienoate (3b). Yield: 141 mg (91%) (from 0.7 mmol of 7b);
light yellow oil; TLC: Rf = 0.4 (10:1 hexane : diethyl ether). IR (KBr, ν, cm-1): 1575, 1630
(C=C), 1711 (C=O). 1H NMR (CD3CN): δ 1.31 (t, J = 7.1, 3H), 1.83 (dd, J = 6.9, 1.7, 3H), 4.26
(q, J = 7.1, 2H), 6.19 (dqd, J = 15.1, 6.9, 0.8, 1H), 7.00 (ddq, J = 15.1, 11.2, 1.7, 1H), 7.18 (d, J
= 11.2, 1H). 13C NMR (CD3CN): δ 14.4 (CH3CH2), 18.9 (CH3CH=), 63.0 (OCH2), 109.6 (=CBr),
129.0 (=CH), 142.3 (CH=CBr), 146.2 (CH3CH=), 163.6 (C=O). HRMS (ES+) [M+H]+ calcd. for
C8H11BrO2 219.0021, found 219.0019.
Ethyl (2E,4E)-2-bromo-5-phenylpenta-2,4-dienoate (3c).
(2E,4E)-isomer. Yield: 33 mg (39%) (from 0.3 mmol of 7c); yellow oil; TLC: Rf = 0.4 (20:1
1
hexane : diethyl ether). IR (KBr, ν, cm-1): 1578, 1610 (C=C), 1713 (C=O). H NMR (CDCl3): δ
1.40 (t, J = 7.1, 3H), 4.33 (q, J = 7.1, 2H), 6.81 (d, J = 15.8, 1H), 7.29 (d, J = 11.6, 1H), 7.32-
7.52 (m, 5H), 7.81 (dd, J = 15.7, 11.3, 1H). 13C NMR (CDCl3): δ 14.4 (CH3), 62.4 (CH2), 111.2
(=CBr), 125.0 (=CH-), 127.6 (Co), 129.0 (Cm), 129.4 (Cp), 136.2 (Ci), 141.5 (Ph-CH=), 146.2
(CH=CBr), 163.0 (C=O). HRMS (ES+) [M+H]+ calcd. for C13H13BrO2 281.0177, found
281.0177.
(2Z,4E)-isomer. Yield: 50 mg (59%) (from 0.3 mmol of 7c); yellow oil; TLC: Rf = 0.2 (20:1
1
hexane : diethyl ether). IR (KBr, ν, cm-1): 1584, 1614 (C=C), 1715 (C=O). H NMR (CDCl3): δ
1.37 (t, J = 7.1, 3H), 4.32 (q, J = 7.1, 2H), 7.07 (d, J = 15.6, 1H), 7.17 (dd, J = 15.5, 10.3, 1H),
13
7.32-7.56 (m, 5H), 7.83 (d, J = 10.3, 1H). C NMR (CDCl3): δ 14.4 (CH3), 62.6 (CH2), 114.5
(=CBr), 125.0 (=CH-), 127.0 (Co), 129.0 (Cm), 129.7 (Cp), 136.2 (Ci), 140.1 (Ph-CH=), 142.4
(CH=CBr), 163.1 (C=O). HRMS (ES+) [M+H]+ calcd. for C13H13BrO2 281.0177, found
281.0177.
Ethyl (Z)-2,4-dibromopenta-2,4-dienoate (4a). Yield: 44 mg (62%) (from 0.25 mmol of 9a);
yellow oil; the reaction mixture was filtered through a small pad of silica gel and concentrated in
1
vacuo. H NMR (CDCl3): δ 1.36 (t, J = 7.1, 3H), 1.67 (dd, J = 7.4, 1.5, 3H), 6.06 (d, J = 2.3,
1H), 6.43 (dd, J =2.3, 1.3, 1H), 7.64 (d, J = 1.3, 1H). 13C NMR (CDCl3): δ 14.3 (CH3CH2), 63.3
(OCH2), 117.1 (=CBrCO), 122.2 (=CBr), 125.3 (CH=), 139.6 (H2C=), 162.3 (C=O).
Ethyl 2,4-dibromohexa-2,4-dienoate (4b). Yield: 68 mg (69%) (from 0.33 mmol of 9b); yellow
oil; the reaction mixture was filtered through a small pad of silica gel and concentrated in vacuo.
Major (2Z,4E)-isome (4b): 1H NMR (CDCl3): δ 1.36 (t, J = 7.1, 3H), 1.67 (dd, J = 7.4, 1.5, 3H),
4.31 (q, J = 7.1, 2H), 6.20 (dq, J =7.4, 1.3, 1H), 7.67 (m, 1H). 13C NMR (CDCl3): δ 14.2
(CH3CH2), 17.3 (CH3CH=), 63.2 (OCH2), 113.3 (=CBr), 119.3 (=CBrCO), 133.0 (CH3CH=),
138.5 (CH=CBr), 162.2 (C=O). IR (KBr, ν, cm-1): 1600, 1647 (C=C), 1726 (C=O). Minor
(2E,4Z)-isomer (4b) as a mixture with (2E,4E)-isomer (4b): 1H NMR (CDCl3): δ 1.34 (t, J = 7.1,
3H), 1.91 (dd, J = 6.7, 1.3, 3H), 4.30 (q, J = 7.1, 2H), 6.69 (d, J = 6.7, 1.2, 1H), 7.67 (m, 1H).
13C NMR (CDCl3): δ 14.3 (CH3CH2), 18.0 (CH3CH=), 63.1 (OCH2), 115.0 (=CBr), 118.5
(=CBrCO), 134.6 (CH3CH=), 140.4 (CH=CBr), 162.7 (C=O). MS (EI) m/z (relative intensity):
298 (M+, 15), 253 (6), 219 (28), 217 (27), 191 (100), 189 (98), 139 (34), 109 (8).
Ethyl (Z)-2,4,5-tribromohex-2-enoate (10b)
Yield 134 mg (22%) (from 1.6 mmol of 9b); yellow oil; TLC: Rf = 0.6 (10:1 hexane : diethyl
1
ether). IR (KBr, ν, cm-1): 1625 (C=C), 1729 (C=O). H NMR (CDCl3): δ 1.36 (t, J = 7.1, 3H),
13
1.92 (d, J = 6.6, 3H), 4.32 (m, 3H), 5.00 (dd, J = 10.1, 1H), 7.37 (d, J = 10.2, 1H). C NMR
(CDCl3): δ 14.2 (CH2CH3), 24.7 (CH3), 49.3 (CHBr), 53.4 (CH3CHBr), 63.2 (OCH2), 119.4
(CBr=), 141.5 (CH=), 161.7 (C=O).
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10.1002/ejoc.202000893
European Journal of Organic Chemistry
Acknowledgements
The authors are very thankful to Dr. Valentin Semenov for quantum chemical calculations and
fruitful discussions. The spectral and analytical data were obtained using the equipment of the
Baikal analytical center for collective use SB RAS which is gratefully acknowledged. Authors
are also grateful LIN SB RAS for shared Research Facilities for Physical and Chemical
Ultramicroanalysis.
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