Alkylhalovinylboranes: a new class of Diels-Alder dienophiles

Article abstract of DOI:10.1039/C8RA07089J

The Diels-Alder reactions of alkylhalovinylboranes have been investigated theoretically and experimentally. Alkylhalovinylboranes presented higher reactivity than the corresponding dialkylvinylboranes. Although endo/exo selectivities were high for the reactions with cyclopentadiene, facial selectivities for the chiral analogues were low. Our results demonstrate that the replacement of an alkyl group on the boron atom by a halogen increases the dienophilicity considerably.

Full text of DOI:10.1039/C8RA07089J

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Alkylhalovinylboranes: a new class of Diels–Alder
dienophiles†
Cite this: RSC Adv., 2018, 8, 33864
*
Pablo L. Pisano
and Silvina C. Pellegrinet
The Diels–Alder reactions of alkylhalovinylboranes have been investigated theoretically and experimentally.
Alkylhalovinylboranes presented higher reactivity than the corresponding dialkylvinylboranes. Although
endo/exo selectivities were high for the reactions with cyclopentadiene, facial selectivities for the chiral
analogues were low. Our results demonstrate that the replacement of an alkyl group on the boron atom
by a halogen increases the dienophilicity considerably.
Received 24th August 2018
Accepted 19th September 2018
DOI: 10.1039/c8ra07089j
rsc.li/rsc-advances
Singleton for (+)-camphene (Scheme 1),8 consisting of
hydroboration, transmetallation, Diels–Alder reaction and
Introduction
oxidation. In situ preparation of intermediates 7, 2 and 8
under inert atmosphere would avoid the manipulation of the
labile boranes. Unfortunately, although numerous reactions
were tested for the three chiral terpenes with different
reagents and reaction conditions, we failed to detect the
presence of the desired products.22 By monitoring the reac-
tion by 1H NMR under inert atmosphere we observed that,
although the hydroboration step occurred efficiently, trans-
metallation of the dialkylhaloboranes did not go to comple-
tion. We managed to avoid this difficulty by generating the
monohaloborane free of dimethylsulde in situ with triha-
loborane and triethylsilane.23 Nevertheless, when using this
method we could not detect the formation of product 9
either, possibly due to the competitive dimerization of the
vinylboranes6 and the protodeboronation of the
cycloadducts.
In the past decades, Singleton and others have extensively
explored the synthetic utility of alkenyl-, alkynyl- and dienylbor-
anes in Diels–Alder reactions.1–18 Given that many variations of
the Diels–Alder reaction of vinylboranes have been developed, it
is surprising that there is only one precedent in the use of chiral
vinylboranes in asymmetric [4 + 2] cycloaddition reactions. This
Diels–Alder reaction was based on the use of dialkylvinylborane
1, derived from (+)-camphene, with 2-phenyl-1,3-butadiene
(Scheme 1).8 However, although the yield of the oxidized prod-
ucts and the para regioselectivity were high, the enantiomeric
excess of the major regioisomer was lower than 10%.
One of the main goals of our group is to develop new chiral
unsaturated boron compounds that exhibit high reactivity and
selectivity as dienophiles in Diels–Alder reactions. Such
compounds have a tremendous potential as precursors of chiral
building blocks in asymmetric synthesis.
Alternative use of cyclohexene as an achiral model of starting
alkene, to generate dicyclohexylvinylborane (10), also gave
negative results. These initial results demonstrated that dia-
lkylvinylboranes with secondary carbons attached to the boron
atom, such as 2–4 and 10, are highly congested, which
complicates their synthesis and the course of their Diels–Alder
reactions.19
Initially, we thought that dialkylvinylboranes 2–6 shown
in Scheme 2 would be good candidates because the stereo-
centers are directly bonded to the boron atom, and therefore
closer to the prochiral olen than in the derivative of
(+)-camphene (1).19 Furthermore, compounds 2–4 could be
readily synthesized from commercial optically pure terpenes
(+)-a-pinene, (+)-2-carene and (+)-3-carene.20,21 For that
purpose, we tested the reaction sequence shown in Scheme 3
for (+)-a-pinene, analogous to that developed previously by
´
´
Instituto de Quımica Rosario (CONICET), Facultad de Ciencias Bioquımicas
y
´
Farmaceuticas, Universidad Nacional de Rosario, Suipacha 531, Rosario (2000),
Argentina. E-mail: pellegrinet@iquir-conicet.gov.ar
† Electronic supplementary information (ESI) available: Experimental section,
NMR spectra, computational methods, FMOs and global and local reactivity
indices of reactants, optimized geometries of the transition structures (TSs) not
included in the paper and charge transfer (GEDT) of TSs, cartesian coordinates,
absolute energies including zero-point energy corrections, free energies and
number of imaginary frequencies of all the stationary points reported in the
paper and values of imaginary frequencies of all transition structures. See DOI:
10.1039/c8ra07089j
Scheme
lkylvinylborane 1.
1 Synthesis and Diels–Alder reaction of chiral dia-
33864 | RSC Adv., 2018, 8, 33864–33871
This journal is © The Royal Society of Chemistry 2018

View Article Online
Paper
RSC Advances
reactive and easily accessible diene, with theoretical methods.
Due to the absence of chiral centres in the alkyl moiety, only
endo and exo attacks should be considered, which, in turn,
would give rise to diastereomeric products as racemic mixtures.
Aer oxidation, racemic endo and exo alcohols 9 might arise.
All calculations were performed with the Gaussian 09
package.25 We carried out thorough conformational analyses to
locate the lowest energy geometry for all the structures under
study. Final geometry optimizations were carried out using the
B3LYP hybrid functional together with the 6-31G* basis set. The
selection of this level of theory was based on existing records in
the literature for the modelling of Diels–Alder reactions.19,26–32
Additionally, solvent effects in dichloromethane (3 ¼ 8.93) and
heptane (3 ¼ 1.91) were calculated for the most stable geome-
tries of reagents, transition structures (TSs), and products using
the Polarized Continuum Model of Self-Consistent Reaction
Field method (PCM method).33,34 Furthermore, the molecular
orbitals (MOs) of reagents were calculated to analyse the Fron-
tier molecular orbital interactions and Natural Bond Orbitals
(NBOs) analysis of TSs were performed using Wiberg bond
indices for interpreting most relevant electronic interac-
tions.35–38 Finally, we performed Intrinsic Reaction Coordinate
calculations (IRC) to verify if the TSs were directly connected to
the reactants and the products.
Scheme
attached to boron.
2 Chiral dialkylvinylboranes with secondary carbons
Scheme 3 One-pot synthesis of chiral dialkylvinylborane 2, followed
by Diels–Alder reaction and oxidation. The same procedure was tested
for (+)-2-carene and (+)-3-carene and cyclohexene.
To circumvent these problems, it occurred to us that alkyl-
halovinylboranes would represent an interesting alternative to
dialkylvinylboranes because the boron atom would be less
sterically hindered and more electron decient, which should
ultimately increase the reactivity in Diels–Alder reactions
(Fig. 1).24 In this paper, we present the results of a theoretical
study of the Diels–Alder reactions of a number of alkylhalovi-
nylboranes with cyclopentadiene, together with the experi-
mental development of a one-pot procedure that includes the
synthesis of the dienophiles, the Diels–Alder reaction and the
oxidation of the products.
Fig. 2 shows the correlation diagrams for the Diels–Alder
reactions of vinylboranes 10, 11a, and 11b with cyclo-
pentadiene. Analysis of MOs of the reagents shows that all
Diels–Alder reactions under study are of normal electron-
demand dominated by the HOMOdiene–LUMOdienophile interac-
tion. As expected, the LUMOs of the vinylboranes have large
Results and discussion
Model studies with cyclohexene vinylborane derivatives
To validate our hypothesis, we rst performed a comparative
study of the reactivity of dicyclohexylvinylborane (10), chlor-
ocyclohexylvinylborane (11a) and bromocyclohexylvinylborane
(11b), derived from cyclohexene as achiral models of the dien-
ophiles. Initially, we investigated the Diels–Alder reactions of
vinylboranes 10, 11a and 11b with cyclopentadiene, a highly
Fig. 2 Correlation diagrams for the Diels–Alder reaction of vinyl-
boranes 10, 11a, and 11b with cyclopentadiene. Energy gaps are shown
in red and blue.
Fig. 1 Dialkylvinylboranes and alkylhalovinylboranes.
This journal is © The Royal Society of Chemistry 2018
RSC Adv., 2018, 8, 33864–33871 | 33865

View Article Online
RSC Advances
Paper
Table 1 Calculated activation free energies and endo/exo selectivities
for the Diels–Alder reaction of vinylboranes 10, 11a, and 11b with
cyclopentadiene. Relative activation free energies are shown in
parenthesis
coefficients on the two carbon atoms of the carbon–carbon
double bond of the vinyl group, and also on the boron atoms.
This feature promotes the non-classical [4 + 3] secondary orbital
interaction (SOI) between the boron atom of vinylboranes and
C1 of the diene, resulting in an increase in the observed endo-
selectivity. Both FMOs of haloalkylvinylboranes 11a and 11b
also show important coefficients in the halogen atoms too. The
presence of the halogen attached to the boron atom lowers the
LUMO energy signicantly (ca. 0.5 eV) and, therefore, the energy
gap for the HOMOdiene–LUMOdienophile interaction of 11a and
11b is lower than the value obtained for 10, which suggests
greater reactivity for alkylhalovinylboranes with respect to the
corresponding dialkylvinylborane.39
DG‡, kcal molꢀ1 (DGr‡el
)
Vinylborane
endo
exo
endo/exo
Gas phase
Heptane
10
32.28 (0.00)
30.10 (0.00)
27.22 (0.00)
16.52 (0.00)
12.71 (0.00)
10.62 (0.00)
32.39 (0.12)
30.22 (0.12)
27.34 (0.12)
16.73 (0.21)
13.25 (0.54)
11.01 (0.38)
55 : 45
55 : 45
55 : 45
59 : 41
71 : 29
65 : 35
11a
11b
10
11a
11b
Fig. 3 shows the optimized geometries of the most stable
conformers for the TSs for the Diels–Alder reaction of vinyl-
boranes 10, 11a, and 11b with cyclopentadiene, with the
cyclohexyl group and the double bond is eclipsed with the
boron–halogen bond. Table 1 shows the activation free energies
(DG‡) calculated in the gas phase and heptane of the three
systems derived from cyclohexene. As expected, the relative
energies of the TSs in the gas phase are considerable higher
than in solution. However, in both cases the reactions of 11a
and 11b have lower activation free energies than those for 10,
which in principle indicates higher reactivity for the alkylhalo-
vinylborane compounds relative to the dialkylvinylborane
counterpart. Also, endo TSs were computed to be more stable
than the exo isomers for all systems. Selectivity calculations
were performed at 298 K using the Boltzmann equation with the
activation free energies calculated for the TSs. The selectivity
values obtained for 10, 11a and 11b are shown in Table 1. For
alkylhalovinylboranes 11a and 11b, the endo/exo selectivity is
signicantly higher in solution than the gas phase. The
computed energies of the products also suggested that the
reactions under study are exergonic (see the ESI†).
˚
carbon–carbon and C6–B bond distances (in A) and Wiberg
bond indices in parentheses. C6–B distances are approximately
˚
3.1 A and NBOs of 0.08 and 0.06 indicating that the SOI [4 + 3]
are weak. In the IRC studies no intermediate structures between
reagents and TSs and between TSs and products were found,
conrming that the Diels–Alder reactions under study are
concerted. Although in these reactions all bonds are formed
and broken in a single stage, all TSs are asynchronous with
˚
carbon–carbon distances approximately of 2.0 A for C2–C3 and
2.6 A for C1–C6.40,41 As shown in Fig. 3, the dienophile portion of
˚
the structures corresponding to 11a and 11b adopts the same
conformation in all TSs, the halogen attached to the boron atom
is anti relative to the adjacent axial hydrogen atom of the
Encouraged by these promising results, we then studied and
optimised the reaction sequence shown in Scheme 4. Many
experiments were performed using different reaction times and
temperatures, as well as number of equivalents and modes of
addition of reagents. Fortunately, our hypothesis, which was
supported by the calculations, proved to be correct and we
managed to obtain the expected products. Initial reaction of
trichloroborane with one equivalent of triethylsilane in the
presence of 1.1 equivalents of cyclohexene readily gave
dichloroborane, which subsequently hydroborated the starting
Fig. 3 Optimized geometries of the TSs for the Diels–Alder reaction
of vinylboranes 10, 11a, and 11b with cyclopentadiene, with carbon–
carbon and C6–B bond distances (in A˚) and Wiberg bond indices in Scheme 4 One-pot synthesis of chlorocyclohexylvinylborane (11a),
parentheses.
followed by Diels–Alder reaction and oxidation.
33866 | RSC Adv., 2018, 8, 33864–33871
This journal is © The Royal Society of Chemistry 2018

View Article Online
Paper
RSC Advances
Fig. 4 11B NMR of the consecutive steps of the synthetic sequence.
alkene, giving rise to dichlorocyclohexylborane (12). Simulta-
neous addition of one equivalent of tributylvinyltin and three
equivalents of cyclopentadiene successively generated the
desired dienophile 11a and cycloadduct (11a+cp). Final oxida-
tion of the reaction mixture conducted to 5-norbornen-2-ol (9)
in 48% global yield with 80 : 20 endo/exo selectivity. The
consecutive steps of the synthetic sequence were monitored by
11B NMR under inert atmosphere (Fig. 4), which allowed the
optimization of the reaction conditions.
Scheme 5 Diels–Alder reactions of chiral alkylhalovinylboranes 16–
22 with cyclopentadiene.
As an example, the optimized geometries of the most stable
conformers for the TSs for the Diels–Alder reaction of vinyl-
borane 16a with cyclopentadiene are depicted in Fig. 5. Tables 2
and 3 present the activation free energies (DG‡) and the ster-
eoselectivities calculated in the gas phase and heptane for the
Diels–Alder reactions of chiral alkylhalovinylboranes. In general
terms, all [4 + 2] cycloadditions of chiral alkylhalovinylboranes
present the same features as the reactions of cyclo-
hexylhaloboranes 11a and 11b:
Studies with chiral terpene vinylborane derivatives
-
Normal electron demand Diels–Alder reactions
Having accomplished the proof of concept with the achiral
models, we then turned our attention to the Diels–Alder reac-
tions of chiral alkylhalovinylboranes derived from (ꢀ)-a-pinene,
(+)-2-carene, (+)-3-carene as starting alkenes. To increase the
structural diversity of the ligands, we also included (ꢀ)-myrte-
nol, which has the same carbon skeleton as (ꢀ)-a-pinene and
allows the preparation synthetic derivatives 13–15 due to the
presence of the hydroxymethyl group (for synthetic procedures
see the ESI†). We gured that the presence of a heteroatom or
an aromatic ring in the side chain of the dienophile would
introduce further steric and electronic features, which in turn
might contribute to reduce the conformational exibility and,
therefore, increase the stereoselectivity of the cycloaddition.
(HOMOdiene–LUMOdienophile ꢁ4 eV).
- LUMOs of the dienophiles show high coefficients on the
C–C double bond, the boron and the halogen atoms.
- Concerted reactions with asynchronous TSs with classical [4
+ 2] character and weak C–B [4 + 3] SOI (C2–C3, C1–C6 and C6–B
˚
distances 2.0, 2.6, and 3.0 A respectively).
- DG‡ in heptane 13–15 kcal molꢀ1 for chloroalkylboranes
and 11 kcal molꢀ1 for bromoalkylboranes.
The Diels–Alder reactions of the resulting alkylhalovi-
nylboranes 16–22 with cyclopentadiene were rst studied
theoretically (Scheme 5). In these cases, four diasteromeric
Diels–Alder cycloadducts might arise from the endo and exo
attacks of the diene to both faces of the double bond of the
chiral alkylhalovinylborane (Re and Si). Upon oxidation such
compounds would be converted into two diasteromeric pairs of
enantiomers.
Fig. 5 Optimized geometries of the TSs for the Diels–Alder reaction
of vinylboranes 16a with cyclopentadiene with the carbon–carbon and
C6–B bond distances (in A˚) and Wiberg bond indices in parentheses.
This journal is © The Royal Society of Chemistry 2018
RSC Adv., 2018, 8, 33864–33871 | 33867

View Article Online
RSC Advances
Paper
Table 2 Calculated activation free energies for the Diels–Alder reaction of alkylhalovinylboranes 16–22 with cyclopentadiene. Relative acti-
vation free energies are shown in parenthesis
DG‡, kcal molꢀ1 (DG‡
)
rel
Vinylborane
Re endo
Re exo
Si endo
Si exo
Gas phase
16a
16b
17a
17b
18a
18b
19a
20a
21a
22a
16a
16b
17a
17b
18a
18b
19a
20a
21a
22a
29.89(0.78)
27.32(0.42)
30.09(0.51)
28.40(1.04)
29.18(0.00)
27.31(0.30)
30.80(2.03)
29.97(0.00)
31.64(0.69)
29.30(0.74)
13.43(0.46)
11.46(0.50)
13.56(0.23)
11.65(0.27)
12.99(0.00)
10.86(0.00)
13.71(0.83)
15.40(1.38)
16.00(0.92)
14.67(1.10)
29.79(0.68)
27.43(0.52)
30.37(0.78)
27.72(0.35)
29.44(0.26)
27.02(0.00)
28.76(0.00)
30.64(0.67)
31.56(0.60)
29.37(0.81)
14.07(1.11)
11.67(0.71)
13.97(0.63)
11.53(0.15)
13.50(0.51)
11.14(0.28)
12.88(0.00)
14.02(0.00)
16.54(1.47)
15.15(1.59)
29.23(0.12)
26.90(0.00)
29.58(0.00)
27.50(0.13)
30.36(1.18)
27.71(0.69)
30.25(1.49)
30.58(0.61)
31.17(0.22)
28.56(0.00)
12.96(0.00)
10.96(0.00)
13.34(0.00)
11.40(0.02)
13.16(0.16)
11.26(0.40)
13.79(0.91)
14.02(0.00)
15.08(0.00)
13.56(0.00)
29.11(0.00)
26.91(0.01)
29.68(0.10)
27.37(0.00)
30.05(0.87)
27.54(0.53)
29.78(1.02)
30.78(0.80)
30.95(0.00)
28.87(0.31)
13.48(0.52)
11.20(0.24)
13.72(0.38)
11.38(0.00)
13.57(0.58)
11.06(0.21)
13.82(0.93)
14.48(0.46)
15.69(0.61)
14.07(0.51)
Heptane
Table 3 Calculated stereoselectivities for the Diels–Alder reaction of
alkylhalovinylboranes 16–22 with cyclopentadiene
reactivities and selectivities. As found before, in all TSs the
vinylborane portion adopts the same conformation in which the
halogen attached to the boron atom and the hydrogen of the
vicinal carbon adopt a antiperiplanar relationship and the
double bond is eclipsed with the boron–halogen bond.
As a consequence the substituents of the carbon backbone
(for instance, methyls for 16–18) block preferentially one face of
the dienophile and the attack of the diene occurs from the other
face.
As an example, in the TSs of the vinylborane derived from
(ꢀ)-a-pinene (16a), the methyl shields the Re face, making the Si
endo approximation more favourable (Fig. 5). The same situa-
tion is observed for the derivatives of (+)-2-carene (17), while for
the (+)-3-carene counterparts (18) the facial selectivity is
reversed because the methyl group is on the other side of the
molecule and, therefore, steric clashes would make the attack of
the Si face more difficult. The synthetic analogues derived from
(ꢀ)-myrtenol 21a and 22a were predicted to give the highest
endo/exo and Re/Si facial stereoselectivities.
Since the reactions conditions had already been optimised
using cyclohexene as the starting alkene (Scheme 4), we next
investigated the use of the chiral terpenes and synthetic deriv-
atives as staring materials. The reaction sequences were rst
investigated using (+)-3-carene and different reagents as the
boron source: BCl3 (1 M in hexanes), BBr3 and HBBr2$SMe2 (1 M
in CH2Cl2). The reoptimised reaction conditions for the
consecutive steps of the synthetic sequences were then used
with the chiral terpenes and derivatives (Table 4).
(+)-Longifolene and (ꢀ)-camphene with exocyclic double
bonds, which generate primary alkylhalovinylboranes 23 and 24
respectively, were also included in the experimental study
(Scheme 6).
Vinylborane endo/exo endo Re/Si exo Re/Si Re/Si
Gas phase 16a
45 : 55
51 : 49
56 : 44
38 : 62
57 : 43
39 : 61
9 : 91
70 : 30
42 : 58
60 : 40
72 : 28
59 : 41
66 : 34
47 : 53
68 : 32
53 : 47
28 : 72
43 : 57
73 : 27
70 : 30
25 : 75
33 : 67
30 : 70
18 : 82
88 : 12
66 : 34
29 : 71
74 : 26
31 : 69
23 : 77
31 : 69
30 : 70
41 : 59
40 : 60
57 : 43
66 : 34
53 : 47
9 : 91
24 : 76
29 : 71
24 : 76
36 : 64
73 : 27
71 : 29
85 : 15
56 : 44
27 : 73
30 : 70
27 : 73
31 : 69
40 : 60
44 : 56
53 : 47
47 : 53
83 : 17
68 : 32
19 : 81
14 : 86
25 : 75
31 : 69
27 : 73
29 : 71
82 : 18
69 : 31
80 : 20
68 : 32
29 : 71
26 : 74
30 : 70
31 : 69
40 : 60
42 : 58
56 : 44
57 : 43
74 : 26
43 : 57
18 : 82
14 : 86
16b
17a
17b
18a
18b
19a
20a
21a
22a
Heptane
16a
16b
17a
17b
18a
18b
19a
20a
21a
22a
18 : 82
14 : 86
Computed endo/exo stereoselectivities are higher for the
chloro analogues than for the bromo counterparts and vary
considerably (from 28 : 72 to 72 : 28 in heptane). Likewise, Re/Si
facial selectivities are variable, ranging from 74 : 26 for 19a to
14 : 86 for 22a. Since the free energies of the four TSs are within
1 kcal molꢀ1 for most systems, none of the approximations
would be clearly favoured and all cycloadducts would be
formed, albeit in different amounts. Both electronic, steric and
stereoelectronic effects seem to contribute to give the computed
33868 | RSC Adv., 2018, 8, 33864–33871
This journal is © The Royal Society of Chemistry 2018

View Article Online
Paper
RSC Advances
Table 4 Experimental results for the tandem hydroboration, transmetallation, Diels–Alder reaction with cyclopentadiene and oxidation for chiral
terpenes and synthetic derivatives
endo Re/Si
(R/S)
exo Re/Si
(R/S)
Terpene/vinylborane
Methoda
Global yield (%)
endo/exo
Re/Si
(+)-a-Pinene/160ab
(+)-(2)-Carene/17a
(+)-(3)-Carene/18a
(ꢀ)-Myrtenol/19a
13/20a
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
C
C
51
34
54
21
27
24
26
42
41
36
35
32
27
30
32
28
10
23
80 : 20
76 : 24
79 : 21
76 : 24
78 : 22
79 : 21
78 : 22
79 : 21
78 : 22
90 : 10
91 : 9
93 : 7
86 : 14
96 : 4
91 : 9
93 : 7
53 : 47
30 : 70
62 : 38
48 : 52
47 : 53
45 : 55
47 : 53
44 : 56
48 : 52
50 : 50
49 : 51
48 : 52
48 : 52
45 : 55
47 : 53
50 : 50
45 : 55
50 : 50
50 : 50
48 : 52
48 : 52
50 : 50
44 : 56
45 : 55
50 : 50
50 : 50
52 : 48
50 : 50
50 : 50
50 : 50
50 : 50
50 : 50
50 : 50
50 : 50
50 : 50
49 : 51
51 : 49
39 : 61
55 : 45
49 : 51
46 : 54
45 : 55
49 : 51
47 : 53
50 : 50
50 : 50
50 : 50
49 : 51
49 : 51
48 : 52
49 : 51
50 : 50
48 : 52
50 : 50
14/21a
15/22a
(+)-Longifolene/23a
(ꢀ)-Camphene/24a
(+)-a-Pinene/160bb
(+)-(2)-Carene/17b
(+)-(3)-Carene/18b
13/20b
15/22b
(+)-Longifolene/23b
(ꢀ)-Camphene/24b
(+)-(2)-Carene/17b
(+)-(3)-Carene/18b
60 : 40
74 : 26
a
Method A: (1) BCl3 (1 M in hexanes, 1 mL), Et3SiH (1 equiv.), alkene (1.1 equiv.), ꢀ10 ꢂC to RT, 1 h; (2) tributilvinylstannane (1 equiv.),
cyclopentadiene (5 equiv.), 0 ꢂC to RT, 3 h; (3) THF (3 mL), Et3N (1 mL), NaOH 3 N (3 mL), H2O2 30% (3 mL), 0 ꢂC to RT, 15 h. Method B: (1)
CH2Cl2 (1 mL), BBr3 (1 mmol), Et3SiH (1 equiv.), alkene (1.1 equiv.), ꢀ40 ꢂC to RT, 2 h; (2) same as Method A, 5 h; (3) same as Method A.
Method C: (1) HBBr2$SMe2 (1 M in CH2Cl2, 1 mL), alkene (1.1 equiv.), ꢀ10 ꢂC to reux, 2 h; (2) tributilvinylstannane (1 equiv.), cyclopentadiene
(5 equiv.), 0 ꢂC to reux, 5 h, then RT, 15 h; (3) same as Method A, 4 h. b Compounds 160a and 160b are the enantiomers of 16a and 16b, respectively.
Based on the literature, and the results of our theoretical
In general, global yields for chiral terpenes and synthetic
calculations, we assumed that different reactivities would be derivatives were comparable to those previously obtained with
observed for boron trichloride and tribromide (Methods A and achiral cyclohexene, although much lower numbers were ob-
B). However, only differences in reactivity were observed in the tained for HBBr2$SMe2 and consequently only (+)-(2)- and
ꢂ
initial steps, which had to be initiated at ꢀ40 C for boron tri- (+)-(3)-carene were tested with Method C.
bromide to avoid that temperatures increased and secondary
Facial selectivities (Re/Si) and resulting enantiomeric ratios
reactions took place. 11B NMR indicated that transmetallation and absolute congurations (R/S) of the products of oxidation
and Diels–Alder reactions occurred at similar rates. On the other (endo- and exo-5-norbornen-2-ol, 9) were determined by 1H NMR
hand, when HBBr2$SMe2 was used (Method C), much lower using a methodology developed in our group that involves the
reactivity was observed, probably due to the lower electron de- use of (S)-(+)-O-acetylmandelic acid as chiral derivatising
ciency on boron of the dimethyl sulde complexes of the reacting agent.42,43 Endo-selectivities were good to excellent. In partic-
species in the studied sequence. As a consequence, reaction ular, bromovinylboranes obtained with BBr3 (Method B) gave
times and temperatures had to be increased and yields dropped endo/exo ratios higher than 86 : 14, with vinylborane 22b
considerably perhaps as a result of secondary reactions.
derived from synthetic analogue 15 displaying the best endo-
selectivity (endo/exo 96 : 4). When BCl3 was used, (+)-a-pinene-
derived vinylborane 160a showed the highest endo-selectivity
(endo/exo 80 : 20). Disappointingly, facial selectivities were low.
The chlorovinylborane derived from (+)-2-carene 17a exhibited
the highest chiral induction (Re/Si 30/70 for the major endo
diastereoisomer). Although we hoped to get better enantiomeric
ratios, such value is considerably higher than those obtained for
other Diels–Alder reactions of boron-substituted dienophiles
Scheme 6 (+)-Longifolene and (ꢀ)-camphene and derived alkylha-
lovinylboranes 23 and 24.
This journal is © The Royal Society of Chemistry 2018
RSC Adv., 2018, 8, 33864–33871 | 33869

View Article Online
RSC Advances
Paper
dialkylvinylboranes by a halogen on the boron atom of the
dienophile increases the reactivity of the vinylborane signi-
cantly. Overall, experimental results were in line with those
predicted by theoretical calculations. Alkylhalovinylboranes
displayed high endo/exo selectivities, in particular for bromo-
vinylboranes. Unfortunately, in general enantioselectivities ob-
tained for the oxidized products were low. However, the highest
value obtained with (+)-2-carene-derived chlorovinylborane
(17a) was much higher than those described in the literature for
Diels–Alder reactions of other boron-substituted dienophiles.
This work contributes to a little-explored area of study, as is the
use of chiral vinylboranes in asymmetric cycloaddition reac-
tions. Finally, this novel example of the use of alkylhalovi-
Scheme 7 Diels–Alder reactions of alkylchlorovinylboranes 160a–18a nylboranes in synthesis highlights the practical potential of
with other dienes.
such organoboron species, which may be applied to other
transformations.
(ee < 10%), such as the one of dialkylvinylborane 1, derived from
(+)-camphene, with 2-phenyl-1,3-butadiene (Scheme 1).8,44,45
Conflicts of interest
As can be observed in Tables 3 and 4, experimental endo-
selectivities for the Diels–Alder reactions of chlorovinylboranes
were correctly predicted by the theoretical calculations. In
There are no conicts to declare.
contrast, computed endo-selectivities for bromovinylboranes
were lower than those for chlorovinylboranes and than the
experimental values. In general, experimental facial selectivities
We thank CONICET, ANPCyT and Universidad Nacional de
were in accordance to the ones computed in the theoretical
Acknowledgements
Rosario for nancial support.
study. In addition, the calculations predicted that activation
free energies for bromovinylboranes would be 2 kcal molꢀ1
lower than those for the chloro counterparts. However, experi-
mental yields were comparable, and in some cases lower to
Notes and references
those obtained with chlorovinylboranes. We believe that this is
caused by the great reactivity of BBr3, which decomposes rapidly
during manipulation and generates experimental difficulties.
To determine the scope of the studied reactions, we per-
formed preliminary experiments for the Diels–Alder reactions
of alkylchlorovinylboranes 160a–18a with other dienes (1,3-
cyclohexene, isoprene and trans,trans-1,4-diphenyl-1,3-
butadiene) (Scheme 7).
1 G. Hilt and P. Bolze, Synthesis, 2005, 2091–2115.
2 D. G. Hall, Boronic Acids: Preparation and Applications in
Organic Synthesis and Medicine, Wiley-VCH Verlag GmbH,
Weinheim, 2005.
3 D. A. Singleton and J. P. Martinez, J. Am. Chem. Soc., 1990,
112, 7423–7424.
4 D. A. Singleton and J. P. Martinez, Tetrahedron Lett., 1991, 32,
7365–7368.
Reaction conditions were the same as for cyclopentadiene
(Method A, Table 4), except that the transmetallation-Diels–
Alder reaction step was carried out at reux for 5 h (Method A0).
Global yields for 1,3-cyclohexene and isoprene were lower than
those obtained with cyclopentadiene (16–34%) and poor for
trans,trans-1,4-diphenyl-1,3-butadiene. Furthermore, the endo/
exo selectivity for 1,3-cyclohexene was excellent (endo/exo 98 : 2),
while the para/meta regioselectivity for isoprene above 60 : 40.
In general, enantiomeric excesses for both dienes were <10%,
except for the reaction of isoprene with the chlorovinylborane
derived form (+)-(2)-carene 17a (R/S para 36 : 64). This indicates
that more experiments should be performed to optimise the
reaction conditions.
5 D. A. Singleton, J. P. Martinez and J. V. Watson, Tetrahedron
Lett., 1992, 33, 1017–1020.
6 D. A. Singleton, J. P. Martinez, J. V. Watson and G. M. Ndip,
Tetrahedron, 1992, 48, 5831–5838.
7 D. A. Singleton and S. W. Leung, J. Org. Chem., 1992, 57,
4796–4797.
8 D. A. Singleton, J. P. Martinez and G. M. Ndip, J. Org. Chem.,
1992, 57, 5768–5771.
9 D. A. Singleton, K. Kim and J. P. Martinez, Tetrahedron Lett.,
1993, 34, 3071–3074.
10 J.-M. Jego, B. Carboni, A. Yousso and M. Vaultier, Synlett,
1993, 595, 597.
11 D. A. Singleton and A. M. Redman, Tetrahedron Lett., 1994,
35, 509–512.
12 D. A. Singleton and Y. K. Lee, Tetrahedron Lett., 1995, 36,
3473–3476.
Conclusions
In this investigation we explored the synthesis and the Diels– 13 D. A. Singleton, S. W. Leung, J. P. Martinez and Y. K. Lee,
Alder reactivity of alkylhalovinylboranes with computational Tetrahedron Lett., 1997, 38, 3163–3166.
and experimental methods. We veried the viability of our 14 D. A. Singleton and S. W. Leung, J. Organomet. Chem., 1997,
initial postulate that the replacement of an alkyl group in
544, 157–161.
33870 | RSC Adv., 2018, 8, 33864–33871
This journal is © The Royal Society of Chemistry 2018

View Article Online
Paper
RSC Advances
15 Y.-K. Lee and D. A. Singleton, J. Org. Chem., 1997, 62, 2255– 30 M. A. Silva, S. C. Pellegrinet and J. M. Goodman, J. Org.
2258. Chem., 2003, 68, 4059–4066.
16 N. Noiret, A. Yousso, B. Carboni and M. Vaultier, J. Chem. 31 D. Hallooman, D. Cudian, M. Rıos-Gutierrez, L. Rhyman,
´
´
Soc., Chem. Commun., 1992, 1105–1107.
17 R. A. Batey, D. Lin, A. Wong and C. L. S. Hayhoe, Tetrahedron
Lett., 1997, 38, 3699–3702.
I. A. Alswaidan, M. I. Elzagheid, L. R. Domingo and
P. Ramasami, ChemistrySelect, 2017, 2, 9736–9743.
32 A. Atalay and R. Abbasoglu, J. Phys. Org. Chem., 2018, e3893,
DOI: 10.1002/poc.3893.
´
18 M. Zaidlewicz, J. R. Binkul and W. Sokoł, J. Organomet.
Chem., 1999, 580, 354–362.
19 S. C. Pellegrinet, M. A. Silva and J. M. Goodman, J. Comput.-
Aided Mol. Des., 2004, 18, 209–214.
20 H. C. Brown and P. K. Jadhav, J. Org. Chem., 1984, 49, 4089–
4091.
21 U. S. Racherla, Y. Liao and H. C. Brown, J. Org. Chem., 1992,
57, 6614–6617.
33 B. Mennucci and J. Tomasi, J. Chem. Phys., 1996, 106, 5151–
5158.
34 J. Tomasi, B. Mennucci and R. Cammi, Chem. Rev., 2005,
105, 2999–3094.
35 J. P. Foster and F. Weinhold, J. Am. Chem. Soc., 1980, 102,
7211–7218.
36 A. E. Reed and F. Weinhold, J. Chem. Phys., 1983, 78, 4066–
4073.
22 S. C. Pellegrinet, unpublished results.
23 U. P. Dhokte, R. Soundararajan, P. V. Ramachandran and 37 A. E. Reed, L. A. Curtiss and F. Weinhold, Chem. Rev., 1988,
H. C. Brown, Tetrahedron Lett., 1996, 37, 8345–8348. 88, 899–926.
24 To the best of our knowledge, the only example of 38 F. Weinhold and C. R. Landis, Valency and Bonding: a Natural
alkylhalovinylboranes that has been described to date is
Bond Orbital Donor-Acceptor Perspective, Cambridge
chloromethylvinylborane, but its reactivity as Diels–Alder
University Press, Cambridge, UK, New York, 2005.
dienophile has not been investigated. C. D. Good and 39 Analysis of the computed global and local reactivity indices
D. M. Ritter, J. Am. Chem. Soc., 1962, 84, 1162–1166. of the reactants is in line with FMO results (see the ESI†).
25 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, 40 The Diels–Alder reactions can take place by different
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone,
B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato,
X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng,
J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota,
R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery Jr,
J. E. Peralta, F. Ogliaro, M. J. Bearpark, J. Heyd,
E. N. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi,
J. Normand, K. Raghavachari, A. P. Rendell, J. C. Burant,
S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, N. J. Millam,
M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo,
J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev,
A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski,
R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth,
mechanisms: synchronical mechanism, biradicaloidal one
step-mechanism, stepwise biradical mechanism (non-polar
mechanisms) or one step-two stage mechanism, stepwise
zwitterionic mechanism (polar mechanisms). The Diels–
Alder reactions under study can be classied as one step-
´
two stage reactions. For example see:(a) R. Jasinski, React.
Kinet., Mech. Catal., 2016, 119, 49–57; (b) D. A. Singleton,
B. E. Schulmeier, C. Hang, A. A. Thomas, S.-W. Leung and
S. R. Merrigan, Tetrahedron, 2001, 57, 5149–5160; (c)
´
R. Jasinski, M. Kubik, A. Łapczuk-Krygier, A. K˛acka,
E. Dresler and A. Boguszewska-Czubara, React. Kinet.,
´
Mech. Catal., 2014, 113, 333–345; (d) R. Jasinski, Comput.
´
Theor. Chem., 2014, 1046, 93–98; (e) R. Jasinski, J. Fluorine
Chem., 2018, 206, 1–7.
P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, 41 The computed values of electron density transfer (GEDT) for
¨
O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski and
the TSs (see the ESI†) also suggested that the Diels–Alder
reactions under study can be classied as polar Diels–
Alder reactions (P-DA).
D. J. Fox, Gaussian 09W, Gaussian, Inc., 2009.
26 S. C. Pellegrinet, M. A. Silva and J. M. Goodman, J. Am. Chem.
Soc., 2001, 123, 8832–8837.
42 P. L. Pisano, A. M. Sarotti and S. C. Pellegrinet, Tetrahedron
Lett., 2009, 50, 6121–6125.
´
27 A. Rastelli, R. Gandol, M. Sarzi-Amade and B. Carboni, J.
Org. Chem., 2001, 66, 2449–2458.
28 M. A. Silva, S. C. Pellegrinet and J. M. Goodman, J. Org.
Chem., 2002, 67, 8203–8209.
29 M. A. Silva, S. C. Pellegrinet and J. M. Goodman, Arkivoc,
2003, 2003, 556–565.
43 A. M. Sarotti, P. L. Pisano and S. C. Pellegrinet, Arkivoc, 2011,
2011, 343–357.
44 J. D. Bonk and M. A. Avery, Tetrahedron: Asymmetry, 1997, 8,
1149–1152.
45 N. Grimblat, A. M. Sarotti, P. L. Pisano and S. C. Pellegrinet,
New J. Chem., 2016, 40, 1966–1969.
This journal is © The Royal Society of Chemistry 2018
RSC Adv., 2018, 8, 33864–33871 | 33871