Halogenation of Electron-Deficient Vicinal Substituted Alkenes: Regio- and Stereoselectivity

Article abstract of DOI:10.1002/ejoc.202000394

The halogenation of electron-deficient vicinal substituted alkenes leads mainly to the mixture of regio- and stereoisomers of monohalogenated derivatives. Their ratio depends on the stability of the intermediate anionic complex and is determined by proper

Full text of DOI:10.1002/ejoc.202000394

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Halogenation of electron-deficient vicinal substituted alkenes:
regio- and stereoselectivity
Authors: Ilya N. Zubkov, Igor A. Ushakov, Nina N. Chipanina, and
Alexander Rulev
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0
1/2020

European Journal of Organic Chemistry
10.1002/ejoc.202000394
Halogenation of electron-deficient vicinal substituted alkenes:
regio- and stereoselectivity
Ilya N. Zubkov, Dr. Igor A. Ushakov, Dr. Nina N. Chipanina, and Dr. 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: The halogenation of electron-deficient vicinal substituted alkenes leads mainly to the
mixture of regio- and stereoisomers of monohalogenated derivatives. Their ratio depends on the
stability of the intermediate anionic complex and is determined by properties of both electron-
withdrawing groups.
http://www.irkinstchem.ru
Keywords: electron-deficient alkenes • halogenation • selectivity
Introduction
Conjugated α- or β-halogenated α,β-unsaturated carbonyl compounds (enals, enones, and
enoates) represent an important class of small building blocks which are widely used in organic
1
-3
synthesis. Their molecules contain two electrophilic centres: olefinic and carbonyl carbons. It
is not surprise that these compounds have received significant attention from synthetic and
pharmaceutical chemists as highly functionalized scaffolds for design of biologically active
molecules (namely, α- or β-amino acid derivatives) as well as for assembly of diverse carbo- and
4
heterocycles. Polyfunctionality of halogenated enals, enones and enoates allows them to be
involved in the domino reactions which offer access to a variety of complex molecules in a one-
pot fashion.
The simplest route to these derivatives is based on the halogenation –
dehydrohalogenation sequence of the parent unsaturated carbonyl-bearing compounds A and D
5
(Scheme 1).
Scheme 1. Halogenation of electron-deficient alkenes.
1
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European Journal of Organic Chemistry
10.1002/ejoc.202000394
Obviously, when dihaloderivative B is treated with any base, the only α-proton is
removed. As a result, the target compound C is formed as the sole reaction product. However, if
the second electron-withdrawing group is introduced in the vicinal position of initial electron-
deficient alkene, the problem of regioselectivity of the hydrogen halide elimination from
intermediate E arises: in this case the formation of two regioisomers F and G should be
expected. The structural elucidation of preferable formation of one or another isomer in these
cases is crucial for the control the synthesis selectivity. In continuation of our on-going research
into the application of halogenated α,β-unsaturated carbonyl compounds in organic synthesis, we
now focus on the chemistry of haloalkenes bearing more than one electron-withdrawing group.
We report here the application of NMR spectroscopy and quantum chemical calculations to
determine the selectivity in the bromination of alkenes bearing two electron-withdrawing groups
6
in vicinal position (so-called pull-pull alkenes).
Results and Discussion
Three electron-deficient alkenes bearing simultaneously two different electron-
withdrawing groups were chosen: (E)-4,4,4-trifluoro-2-butenoate (1a), ethyl (Z)-2-cyanoacrylate
(1b) and methyl (E)-4-oxo-2-pentenoate (1c). We attempted to prepare monobromoesters 3a-c
by traditional two-steps approach involving the reaction of 1a-c with bromine in anhydrous
CHCl , and subsequent dehydrobromination of the intermediates 2a-c by Et N in dry ether. We
3
3
found, that in contrast to classical alkenes, these derivatives were less active in electrophilic
reactions such as bromination due to the high electron deficiency of the double bond which was
caused by the strong electron-withdrawing property of trifluoromethyl, cyano-, and carbonyl
(
alkoxycarbonyl) groups. Thus, if the reaction of methyl (E)-4-oxo-2-pentenoate (1c) with
o
bromine was completed for less than an hour at 0 C the bromination of ethyl (E)-4,4,4-trifluoro-
-butenoate (1a) proceeded in several days at room temperature. In all cases dibromoesters 2a-c
2
were formed as a mixture of two diastereomers (Table S1, see Supporting information). Thus, in
1
the H NMR spectrum of the intermediate 2b there were two sets of methine proton signals at
1
3
4
.50-4.90 ppm in the ratio 2:1. The same ratio of signals was observed in the C NMR spectrum
of 2b: two adjacent bromine bearing carbons resonate at 26.1, 26.7 and 41.7, 42.0 ppm (see
Supporting Information). These intermediates 2a-c were used in the next step without additional
purification. All of the reactions gave the target derivatives 3 and/or 4 in moderate to good yield.
The moderate yields of bromoenoate 3a probably can be explained by the side reactions (such as
polymerization) due to the instability of these derivatives.
In the case of enoate 1 the choice between two alternative structures 3a and 4a can be
1
easy made thanks to the presence of trifluoromethyl moiety. In fact, the H NMR spectrum of the
3
compound 3a contains a quartet of olefinic proton CH= at 7.38 ppm with constant J = 7.1 Hz.
HF
1
3
In the C NMR spectrum the signal of olefinic carbon appears as a quartet at 130.3 ppm with
3
coupling constant J = 36.9 Hz. It strongly indicates that the carbon CH= is attached to the CF3
CF
group.
2
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European Journal of Organic Chemistry
10.1002/ejoc.202000394
Table 1. Bromination of enoates 1a-c.
The structural elucidation of regio- and stereoisomers of monobromoesters 3b,c and 4b,c
is not a trivial task and requires a careful analysis of 2D NMR spectra, employing NOESY and
1
3
HMBC experiments as well as the proton-coupled C NMR spectroscopy. For example, the
1
3
structures of enoate 3c is reliably confirmed by the presence in its proton-coupled C NMR
1
spectrum a doublet of olefinic carbon CH= ( J = 162.1 Hz), the both components of which are
HC
3
quartets having coupling constant J = 1.6 Hz. In contrast, for its isomer 4c there is no long-
HC
1
range couplings of olefinic carbon CH= at 128.2 ppm ( J = 165.0 Hz). These spin-spin
HC
interactions were confimed by the carefull analysis of 2D NMR (HMBC) spectra (Fig. 1).
3J
3JHC = 5.1 Hz
= 1.6 Hz
HC
H
H
Br
CO Et
H C
3
CO Me H C
CO Me
2
2
3
2
F3C
Br
O
Br
O
H
3c
3J
4c
3a
= 4.9 Hz
HC
Figure 1. Main HMBC correlations for bromoenoates 3c, 4c and 3a.
The geometry of bromoenoates 3 and 4 was established by the concerted application of
H – H 2D homonuclear experiment NOESY and especially H – C 2D heteronuclear
1
1
1
13
3
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European Journal of Organic Chemistry
10.1002/ejoc.202000394
experiment HMBC. It is well known that the vicinal C-H couplings are very useful tool to
determine the geometry of tri-substituted alkenes. Previously, this approach allowed us to
determine the correct arrangement of substituents around the double bond C=C in
7
,8
3
trifluoromethylated bromoenones. For example, the value of the vicinal coupling constant J
CH
between the carbonyl carbon of ethoxycarbonyl group and the olefinic proton CH= in the enoate
3
4
a was found to be 5.1 Hz (Figure 1). The same constant for one of the isomer of bromoenoate
c is 4.9 Hz. It was reported that this constant ranged from 0 to 6 Hz for s-cis-isomer and 9-14
9
,10
Hz for s-trans-one.
In an effort to explain the preferential formation of α- or β-bromoenoates 3 or 4, we have
determined the thermodynamic characteristics of both isomers. It was found that the calculated
values of thermodynamic parameters for bromoenoates 3 and 4 are very close and, consequently,
do not effect on the ratio of regioisomers (Table S2, see Supporting Information).
Next, we put forward a hypothesis that the reaction direction depends on the electron-
withdrawing ability of both functional groups. It is well known that the inductive and resonance
11
electronic effects of the substituents can be quantified by Hammett constants. According to this
scale, the cyano- (σ = 0.51) and trifluoromethyl (σ = 0.38) groups are the better acceptors than
I
I
alkoxycarbonyl one. In contrast, the moieties CO R and C(O)Me have approximately the same
2
electron attractive ability (σ = 0.34 and 0.33, correspondingly). At first sight, this feature of the
I
substituents is in a good accordance with the experimental data. Thus, the proton of the
CH(Br)CN moiety of dibromoderivatives 2b should be more acidic than CH(Br)CO Et one.
2
Therefore, the elimination of the former under the action of the base should be more preferable.
In fact, the ratio of regioisomers in this case was found to be 3:1. At the same time, it is difficult
to explain why the only α-bromoester 3a is isolated for substrate bearing the trifluoromethyl
group which is slightly more attractive than ester function. It was previously reported that the
1
2
bromination of 3-nitroacrylate gives exclusively β-bromoester. This result led us to the
conclusion that the regioselectivity of the dehydrobromination of the corresponding
dibromoderivative 2a depends strongly on the reaction mechanism.
A priori, the elimination of hydrogen halide from dibromoderivatives 2a-c and formation
of monobromoenoates 3 and/or 4 could be rationalized by one of the mechanisms – E1, E2 or
E1cB. The later mechanistic pathway usually occurs when compound bearing an acidic hydrogen
and electron withdrawing group attached to this carbon center is treated with a suitable base.
Thus, the formation of α-bromocyclohexenone proceeds through the bromine addition to starting
1
3
cyclic enone followed by dehydrobromination reaction according to E1cB mechanism. The
presence of two acidic hydrogens in the molecule of dibromoesters 2 favors the same
1
4
mechanistic pathway. It could be predicted that if the reaction is carried out through the anionic
complex that is formed after proton elimination, the overall selectivity of reaction is determined
by the relative stability of this intermediate. Therefore, enoates 4 bearing bromine in the β-
position with respect to the group most efficiently stabilizing the negative charge at the adjacent
carbon atom should be formed as the major reaction product. To confirm this hypothesis we
carried out the quantum chemical calculations at M06-2X/6-311G(d,p) and B3LYP/6-
3
11++G(d,p) levels of theory with full geometry optimization which provide good energy
1
5,16
characteristics for heteroatom molecules and their anions.
The results are collected in Table
2
.
4
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European Journal of Organic Chemistry
10.1002/ejoc.202000394
Table 2. M06-2X/6-311G(d,p) (normal) and B3LYP/6-311++G(d,p) (italic), relative energies
0
298
298
with ZPE correction (ΔE ), relative free energies (DG ) and formation enthalpies (DH ),
kcal/mol for anions 5,5’a-c and 6,6’a-c. Dihedral angles CCCC at the 5 and 6 orientation are 160
–
170° and at the 5’ and 6’ 50 – 60°.
o
298
298
Entry Anion
DE ,
DG ,
DH , Ratio,
kcal/mol kcal/mol kcal/mol
%
1
2
3
4
5a
5′a
6a
0
0
0
0
318.17
311.89
326.04
314.40
320.80
314.32
319.71
313.78
100
10.61
10.34
3.66
2.24
2.28
4.20
3.87
0
0
0
4
.48
2.56
.47
4.24
2
6′a
3
.90
5
6
7
8
5b
5′b
6b
0
0
0
0
309.78
304.10
319.18
311.62
317.65
310.34
316.46
310.97
25
0
9.02
.00
7.77
.10
5.96
.38
0.36
.65
0
0
7.47
4.68
7.19
5.07
5.64
5.28
6
0
6
6′b
75
5
9
5c
5′c
6c
0.09
1.27
0
322.60
314.36
321.67
311.82
323.23
316.29
323.67
316.03
10
70
10
10
1
1
0
1
2
0
1
1
1.12
.64
2.03
.87
1.06
4.07
2.22
4.30
3
6′c
3
The similar results were obtained for enoate 2b bearing cyano moiety in β-position. The
proton H of dibromoderivative 2b is the most acidic; therefore, the anion 5b is the most stable.
α
According to the calculations, the order for anionic complex stability is as followed: 5b > 6′b >
6
b > 5′b. It should be noted that the acidity of all protons of the intermediate 2b is higher than
5
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European Journal of Organic Chemistry
10.1002/ejoc.202000394
that for trifluoromethylated enoate 2a. In fact, NMR monitoring of both reactions has shown that
the transformation of dibromoderivative 2b into the corresponding bromoenoates 3b and 4b
proceeds much faster that the similar reaction for 2a. This result could lead to simultaneous
formation of anion 6′b as a kinetically formed product. The kinetic stability of this anion can
also be explained by the presence of more electron-attractive group C≡N in 2b as compared with
CF -moiety in 2a. We assumed that the dehydrobromination of 2b follows two pathways:
3
formation of enoate (E)-4b is kinetically controlled, while the formation of its isomer (Z)-3b
occurs through thermodynamically more stable anion 5b (Table 1, entry 2).
Finally, there is no a large difference in acidity of all methine protons of dibromoester 2c
(Table 2, entries 9-12). Therefore, all these protons can be successively lost to give all four
isomeric anions. At the same time, the free energy of formation of anions 5c, 5′c, 6c and 6′c
differ by only ~1 kcal/mol. However, the slightly higher acidity of H in 2c as well as the slightly
α
higher stability of anion 5′c corresponds well to the preferable formation of enoate (E)-3c in the
dehydrobromination reaction under the action of triethylamine (Table 1, entry 3). Remarkably,
the acidity of the H in 5′c is higher than that in 5′a for 4.37 kcal/mol. This feature of this anion
α
favors the formation of enoate (E)-3c.
Conclusion
In summary, we have studied the regio- and stereoselectivity of the bromination of electron poor
alkenes bearing two vicinal electron-withdrawing groups. The selectivity of HBr elimination step
can be explained by acidity of the proton in intermediate dibromoderivative and the Gibbs
energy of the corresponding anion formation and can be successfully predicted by DFT
calculation methods. The theoretical study showed a good agreement with experiments. Obtained
bromoenoates could be useful starting materials in the selective assembly of complex molecules
especially carbo- and heterocycles.
Experimental Part
General remarks.
1
13
19
H, C, and F NMR spectra were recorded on a Bruker AVANCE 400 MHz spectrometer at
00.16, 100.61, and 376.5 MHz, respectively, for solution in CDCl or CD CN. Chemical shift
4
3
3
1
13
(δ) in ppm are reported using residual chloroform (7.24 for H and 77.20 for C) or acetonitrile
1
13
(1.94 for H and 1.40, 118.60 for C) as internal reference. The coupling constants (J) are given
1
1
17
in Hertz. The concerted application of H- H 2D homonuclear experiments NOESY as well as
1
13
18
H- C 2D heteronuclear experiment HMBC were used for the distinction of the carbon and
proton resonances in all cases. The IR spectra were recorded with a Bruker Vertex 70 FT-IR
spectrometer and with a portable Varian 3100 diamond ATR/FT-IR spectrometer. The GC/MS
analyses were performed with a Shimadzu GCMS-QP5050A instrument (EI, 70 eV). 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 freshly distilled prior to use.
Computational details.
Calculations were performed by the M06-2X/6-311G(d,p) and B3LYP/6-311++G(d,p) methods
1
9
with full geometry optimization as implemented in the Gaussian09 program package.
6
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European Journal of Organic Chemistry
10.1002/ejoc.202000394
Belonging of stationary points on the potential energy surface to minima was proved by positive
eigenvalues of the corresponding Hessian matrices. The proton affinity of acid centers was
0
calculated as the enthalpy difference (D H ) between corresponding neutral and charged
acid
2
0, 21
molecules.
Bromination of alkenes (1a-c). General Procedure.
Bromine (1 equiv.) in CHCl (5 mL for 1 mmol) was added dropwise into a stirred solution of
3
the alkene (1 equiv.) in CHCl (2 mL for 1 mmol). During the addition the temperature was kept
3
o
at +10 C. The mixture was then stirred at room temperature until the orange color did not fade
away. The solvent was evaporated and crude products – dibromoderivatives 2a-c – were found
suitable for further transformation without any purification.
Triethylamine (1.1 equiv.) in anhydrous ether (10 mL for 1 mmol) was added dropwise into a
o
stirred solution of the dibromo derivative 2 in Et O (30 mL for 1 mmol) at +10 C. The mixture
2
was kept at rt overnight and filtered. After the solvent was evaporated, the target bromoenoates
3
a-c were obtained by column chromatography (Silica gel, Pentane/Et O 7:1 (for 3a),
2
Hexane/Et O 2:1 (for 3b,c)). The reactions were generally performed for 5 and 10 mmol of
2
initial enoates 1a-c.
2
2
-1
Ethyl (Z)-2-bromo-4,4,4-trifluorobuten-2-oate (Z)-3a. IR (KBr, ν, cm ): 1647 (C=C), 1738
1
13
(
C=O). H NMR (CDCl ): δ 1.34 (t, J = 7.1, 3H), 4.32 (q, J = 7.1, 2H), 7.38 (q, J = 7.1, 1H). C
3
NMR (CDCl ): δ 14.1 (CH ), 64.0 (CH ), 121.6 (q, J = 271.6, CF ), 124.7 (q, J = 5.6, =C-Br),
3
3
2
3
+
1
(
30.3 (q, J = 36.9, CH=), 161.0 (C=O). MS (EI) m/z (relative intensity): 248 (M +1, <1), 246
M -1, <1), 203 (44), 201 (47), 179 (74), 177 (66), 69 (100). C H BrF O (247.01): calcd. C
6 6 3 2
+
2
9.18, H 2.45; found C 29.22, H 2.68.
-1
Ethyl (E)-3-bromo-3-cyanopropen-2-oate (E)-4b. IR (KBr, ν, cm ): 1607 (C=C), 1726 (C=O),
1
13
2
229 (C≡N). H NMR (CDCl ): δ 1.31 (t, J = 7.4, 3H), 4.28 (q, J = 7.4, 2H), 6.93 (s, 1H). C
3
NMR (CDCl ): δ 14.1 (CH ), 62.6 (CH ), 102.8 (=CBr), 113.4 (C≡N), 138.5 (CH=), 161.4
3
3
2
+
+
(
C=O). MS (EI) m/z (relative intensity): 205 (M +1, <1), 203 (M -1, <1), 160 (79), 158 (83), 51
(
100). C H BrNO (204.02): calcd. C 35.32, H 2.96, N 6.87; found C 35.62, H 3.12, N 6.81.
6
6
2
Ethyl (Z)-2-bromo-3-cyanopropen-2-oate (Z)-3b (in the (1:1.7) mixture of isomers (Z)-3b and
-
1
1
(
=
1
E)-4b). IR (KBr, ν, cm ): 1606 (C=C), 1728 (C=O), 2228 (C≡N). H NMR (CDCl ): δ 1.33 (t, J
3
1
3
7.1, 3H), 4.32 (q, J = 7.1, 2H), 7.09 (s, 1H). C NMR (CDCl ): δ 14.0 (CH ), 64.2 (CH ),
3 3 2
13.3 (CH=), 114.8 (C≡N), 134.5 (=CBr), 160.0 (C=O). N NMR (CDCl ): δ -102.7. MS (EI)
3
m/z (relative intensity): 205 (M +1, 17), 203 (M -1, 17), 160, 158 (56), 51 (100). C H BrNO
2
1
5
+
+
6
6
(204.02): calcd. C 35.32, H 2.96, N 6.87; found C 35.21, H 2.67, N 6.75.
1
Methyl (E)-3-bromo-4-oxopenten-2-oate (E)-4c. H NMR (CDCl ): δ 2.41 (s, 3H), 3.70 (s,
3
1
3
3
1
H), 6.30 (s, 1H). C NMR (CDCl ): δ 27.3 (CH ), 52.4 (OCH ), 123.2 (=CH), 137.7 (=CBr),
3 3 3
63.9 (CO Me), 196.7 (C=O).
2
Methyl (Z)-2-bromo-4-oxopenten-2-oate (Z)-3c, methyl (Z)-3-bromo-4-oxopenten-2-oate
Z)-4c and methyl (E)-2-bromo-4-oxopenten-2-oate (E)-3c were isolated as a mixture of
(
isomers in ratio 1:1.2:2.
1
H NMR (CDCl ): (Z)-3c: δ 2.43 (s, 3H), 3.89 (s, 3H), 7.68 (s, 1H); (Z)-4c: δ 2.55 (s, 3H), 3.84
3
1
3
(s, 3H), 7.28 (s, 1H); (E)-3c: δ 2.19 (s, 3H), 3.77 (s, 3H), 6.76 (s, 1H). C NMR (CDCl ): (Z)-
3
3
4
c: δ 31.2 (CH ), 54.2 (OCH ), 138.0 (=CH), 120.3 (=CBr), 162.7 (CO Me), 197.4 (C=O); (Z)-
3 3 2
c: δ 27.2 (CH ), 52.5 (OCH ), 128.3 (=CH), 133.2 (=CBr), 162.7 (CO Me), 192.6 (C=O); (E)-
3
3
2
7
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European Journal of Organic Chemistry
10.1002/ejoc.202000394
3
c: δ 30.0 (CH ); 53.5 (OCH ); 123.6 (=CBr); 135.9 (=CH); 164.1 (CO Me); 195.1 (C=O). IR
3 3 2
-1
+
(KBr, ν, cm ): 1618 (C=C), 1723 (C=O). MS (EI) m/z (relative intensity): 208 (M +1, <1), 206
+
(M -1, <1), 193 (21), 191 (21), 177 (10), 175 (11), 43 (100). C H BrO (207.02): calcd. C 34.81,
6
7
3
H 3.41; found C 34.80, H 3.43.
Acknowledgements
The spectral and analytical data were obtained using the equipment of the Baikal analytical
center for collective use SB RAS which is acknowledged.
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Entry for the Table of Contents
Treatment with bromine solution converted electron-deficient vicinal substituted alkenes into α-
or β-bromoenoates in different regio- and stereoselectivity. The formation of these
polyfunctional isomeric esters is interpreted by DFT calculation methods.
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