Experimental and theoretical studies of the [3,3]-sigmatropic rearrangement of prenyl azides

Article abstract of DOI:10.1039/c7ra09759j

[3,3]-Sigmatropic rearrangement of isoprenyl azides has been extensively investigated in an experimental and theoretical level. Prenylazides with different chain lengths and phenyl prenylazide have been synthesized. NMR analysis of each azide has been made to determine the equilibrium composition, showing the predominance of primary allyl azides over the tertiary ones and E over Z isomer, regardless of the chain length, temperature, solvent or the regiochemistry of the precursor isoprenyl alcohol. It was determined that phenyl prenylazides do not experience [3,3]-sigmatropic rearrangement. In order to rationalize the experimental results and to gain insight in the mechanism of the [3,3]-sigmatropic rearrangement of prenylazides a theoretical study was performed using density functional theory and the QTAIM approach.

Full text of DOI:10.1039/c7ra09759j

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Experimental and theoretical studies of the [3,3]-
sigmatropic rearrangement of prenyl azides†
Cite this: RSC Adv., 2017, 7, 47527
a
Exequiel O. J. Porta,a Margarita M. Vallejos,b Andrea B. J. Bracca
ac
*
and Guillermo R. Labadie
[3,3]-Sigmatropic rearrangement of isoprenyl azides has been extensively investigated in an experimental
and theoretical level. Prenylazides with different chain lengths and phenyl prenylazide have been
synthesized. NMR analysis of each azide has been made to determine the equilibrium composition,
showing the predominance of primary allyl azides over the tertiary ones and E over Z isomer, regardless
of the chain length, temperature, solvent or the regiochemistry of the precursor isoprenyl alcohol. It was
determined that phenyl prenylazides do not experience [3,3]-sigmatropic rearrangement. In order to
rationalize the experimental results and to gain insight in the mechanism of the [3,3]-sigmatropic
rearrangement of prenylazides a theoretical study was performed using density functional theory and the
QTAIM approach.
Received 2nd September 2017
Accepted 3rd October 2017
DOI: 10.1039/c7ra09759j
rsc.li/rsc-advances
temperature. Lately, VanderWerf and Heasley found that
tertiary and secondary allylic azides rearrange faster than the
primary ones7 with the regioisomer with the most substituted
alkene being thermodynamically favoured. The effective appli-
cation of this reaction in synthetic schemes has been difficult
due to the spontaneous rearrangement. It is necessary to
control the thermodynamic ratio of the regioisomeric azides in
order to be synthetically useful and that generally depends on
the substrate.8
Introduction
In this century, an amazing increase in the number of appli-
cations of organic azide derivatives have been reported. Azides
and alkynes chemical orthogonality has allowed unique appli-
cations in different elds including bioconjugation,1 material
sciences,2 organic chemistry and medicinal chemistry.3 1,2,3-
Triazoles synthesis became very valuable aer the independent
discoveries of Meldal's4 and Sharpless'5 groups that introduced
Isoprenylazides have been used for protein labelling9 and to
prepare 1,2,3-triazole libraries, generating phenyl triazoles 1 as
antibiolm,10 steryl derivatives 2 as antiparasites,11 bisphosph-
onates 3 as geranylgeranyl transferase II inhibitors12 and b-
lactones 4 as fatty acid synthase inhibitors (Fig. 2).13 In those
reports, prenyl azides in equilibrium reacted with alkynes to
produce 1,2,3-triazoles as a mixture of regioisomers. Recently,
our group has successfully prepared and chromatographically
separated different regioisomers derived from prenyl-1,2,3-
triazoles. The activity of those compounds is hardly depen-
dent on the regiochemistry of the rst isoprenic unit, playing an
important role on the modulation of the activity between
trypanosomatids.14
¨
the copper(I) accelerated Huisgen 1,3-dipolar cycloaddition of
alkynes and azides (CuAAC). That completely regioselective
reaction has become one of the most commonly used organic
synthesis.
Allylic azides are versatile building blocks for the synthesis of
natural products and nitrogen-containing heterocycles of
pharmacological relevance. However, they undergo a sponta-
neous dynamic rearrangement at ambient temperature (Fig. 1).
In 1960 Young and co-workers reported the study of [3,3]-
sigmatropic rearrangement of allylic azides (known as Win-
stein's rearrangement).6 They observed that allylic azide exists
as a regioisomeric mixture that interconverts rapidly at room
a
´
Instituto de Quımica Rosario, UNR, CONICET, Suipacha 531, S2002LRK, Rosario,
Argentina. E-mail: labadie@iquir-conicet.gov.ar; Fax: +54-341-4370477 ext. 112;
Tel: +54-341-4370477 ext. 108
b
´
´
Laboratorio de Quımica Organica, IQUIBA-NEA, Universidad Nacional del Nordeste,
CONICET, FACENA, Av. Libertad 5460, Corrientes 3400, Argentina
cDepartamento de Quımica Organica, Facultad de Ciencias Bioquımicas
y
´
´
´
´
Farmaceuticas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK, Rosario,
Argentina
† Electronic supplementary information (ESI) available: NMR spectra of all
synthesized compounds. Distances, topological properties and electron
population along the Cartesian coordinates of the stationary points under
study. See DOI: 10.1039/c7ra09759j
Fig. 1 [3,3]-Sigmatropic rearrangement of allyl azides.
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Scheme 1 Synthesis of prenyl azides 6a–e from the corresponding
alcohols (prenol, geraniol, farnesol, geranylgeraniol and phytol,
respectively).
similarity of the products. To rationalize these likeness, the
physicochemical properties were calculated in silico using the
Molinspiration soware.26 As was expected, there are no
substantial differences on the more relevant parameters of the
isomers (log P, volume and TPSA), explaining the impossibility
of the experimental products separation. As an example, in the
case of the mixture 6b: geranyl azide (6b-E), neryl azide (6b-Z)
and linaloyl azide (6b–t) log P values, calculated as a lip-
ophilicity parameter, were 4.54, 4.54 and 4.55, respectively.
Those similarities, combined with the rapid interconversion at
room temperature, made impossible to isolate any isomer.
Fig. 2 Bioactive prenyl 1,2,3-triazole derivatives.
Besides the utility of this important scaffold, a complete
study of the isoprenylazides equilibrium has not been con-
ducted. That information will contribute to nd factors that rule
the equilibrium and the reactivity of this synthetically useful
compounds. Therefore, in this paper we report a detailed
experimental and theoretical study of isoprenylazides and their
[3,3]-sigmatropic rearrangement.
Computational methods
The geometries of the reactants, the transition structures (TSs)
and the products were optimized using MPWB1K27 global hybrid
meta-GGA functional together with 6-311++G(d,p) basis set. The
MPWB1K has shown to be appropriate to obtain reliable geom-
etries and for describing kinetics of organic reactions. Solvent
effects in toluene (solvent used experimentally) were taken into
account through full optimizations using the SMD continuum
solvation method.28 Frequency calculations were computed to
verify the nature of the stationary points as true minima or as rst
order transition structure (TS) and to evaluate the thermal
corrections. Free energies were calculated at 298.15 K and 1 atm
in toluene. Intrinsic reaction coordinate (IRC) paths were traced
using the Hessian-based predictor corrector (HPC)29,30 algorithm
to verify the connectivity of the TSs with reactants and products.
All calculations were performed with the Gaussian 09 package.31
The topological properties in the framework of the QTAIM theory
were calculated using the AIMALL program.32
Results and discussion
Chemistry
Synthesis. In recent years, numerous methods for the prep-
aration of allylic azides by substitution reactions from allylic
halides or (homo)allylic alcohols and metal-catalysed azidation
have been reported.15–23 However, allylic halides are very reactive
species and are prone to decomposition. On the other hand,
metal-catalysed reactions are very expensive. To avoid this
problem, isoprenyl azides 6a–e were conveniently prepared
from the corresponding isoprenyl alcohols 5a–e following the
one-pot modied Mitsunobu procedure (Thompson's reaction),
using diphenylphosphorylazide (DPPA) as azide donor and 1,8-
diazabicycloundec-7-ene (DBU) as a non-nucleophilic base.24,25
Aer 8 hours reaction, the allylic azide mixture are obtained
Equilibrium composition studies
with an average yield of 87% aer purication (Scheme 1). This Given the limited precedents of the equilibrium for this system,
one-pot procedure enabled a clean and rapid preparation of the a complete study was necessary. These analyzes included the
products due to the high lipophilicity of the product mixture, nature of the substrates (number of isoprene units and unsa-
compared to the reagents.
turations), regiochemistry of the starting alcohol, solvent and
All the attempts to obtain a single isomer from this mixture temperature. The composition of each mixture at room
was doomed due to the dynamic interconversion. Presumably, temperature was determined by 1H NMR spectra. First,
the physicochemical properties are an additional factor that a detailed analysis of the composition at the equilibrium of the
difficulted the separation based on their low polarity and mixture was carried out identifying the signals corresponding to
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Fig. 3 Left: 1H NMR spectrum of the double bond section of the mixture 6b. Right: nOe experiment.
each component of the mixture. In the case of 6b (6b-E, 6b-Z Independently, nerol (5b-Z) and linalool (5b–t) were reacted
and 6b–t) the solution 1H NMR in CDCl3 (Fig. 3), shows under Thompson's conditions, providing the products with
a multiplet at 5.09 ppm assignable to the common olenic similar yield than that for geraniol (5b-E). In those cases,
proton H-6 (pink) shared by all the isomers, being taken as a similar isomeric ratio was obtained regardless the precursor
a reference. A double doublet at 5.78 ppm is observed for the alcohol. Geranyl azide (6b-E), neryl azide (6b-Z), linalooyl azide
olenic proton H-2 (yellow) of linaloyl azide 6b–t. This azide is (6b–t) were obtained in a 54 : 33 : 13 ratio, respectively (Scheme
in a 13% in the mixture, as was expected, since it is the less 2). Also, in different reported procedures to generate 6b the
substituted alkene. Finally, to calculate the E : Z ratio of the same regioisomer proportions were obtained, regardless of
primary azides, nOe experiments selectively irradiating the reaction conditions used (temperature, solvents, reagents,
triplet present at 5.33 ppm, which corresponds to the olenic catalysts).16,21,33,34 These results demonstrate that isoprenyl
proton H-2 (blue) shown positive effect on the singlet present at azides cannot be obtained as pure isomer and consequently not
1.79 ppm. This signal is assigned to the methyl group of the Z requiring regiopure isoprenols for their preparation, which
isomer (6b-Z), providing a ratio E : Z of 5 : 3.
results in a signicant cost reduction. The relative tertiary azide
The NMR analysis of the other mixtures (6a, 6c, 6d and 6e) in proportion increases 15% (Fig. 4, from 11.2% to 13.2%).
CDCl3 have shown that the azide composition remains constant
regardless the number of isoprenyl units or (un)saturation
grade, suggesting that increasing the number of isoprene units
does not inuence the equilibrium. It was noticed that primary
allyl-azides are the major compounds present in the mixture
(87%), while tertiary allyl-azides represent only 13% at room
temperature. Concerning the composition of primary allyl-
azides, the E- and Z-isomers correspond to 54% and 33% of
the mixture, respectively.
To corroborate that the equilibrium composition is inde-
pendent of the regiochemistry and the degree of substitution of
the starting isoprenol, a set of reactions were conducted.
Scheme 2 Synthesis of the azide mixture from nerol, geraniol and Fig. 4 Dependence of tertiary azide population vs. temperature (T)
linalool.
(blue ¼ experimental, red ¼ calculated).
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Then, the temperature effect on the system was examined. compounds one methyl group was replaced by an aromatic ring,
NMR experiments were conducted in CD2Cl2 from ꢀ55 ꢁC to keeping the other methyl group in one analog or being replace
25 ꢁC acquiring spectra every 10 ꢁC. In that 80 degrees window, by a hydrogen (Fig. 5).
however, in the same experiment the primary regioisomer
To prepare the phenyl substituted allylic azide 8, cinnamyl
population composition change (6b-E and 6b-Z) is less appre- alcohol 7 was transformed into the corresponding azide by
ciable (E-isomer increases only 7% at the same range of Thompson's reaction with DPPA and DBU in toluene providing
temperature, see ESI†). The same tendency was observed when the expected product with 78% yield aer purication (Scheme
the proportion of the tertiary azide on the equilibrium was 3). Cinnamylazide 8 was obtained as the only product, main-
analyzed theoretically (Fig. 4).
taining the same regiochemistry of the starting material. This
Strikingly, when the same experiment was conducted on was conrmed by 1H NMR visualization of the signal corre-
ꢁ
DMSO-d6 to increase the temperature beyond 80 C, the integ- sponding to the olenic proton adjacent to the aromatic ring at
rity of the compound was affected based on the wide change on 6.66 ppm with a J ¼ 15.8 Hz, distinctive for the E-isomer. The
the 1H NMR spectra. The decomposition of the azide was other olenic signal appears at 6.25 ppm as a double triplet (J ¼
conrmed by the disappearance of the characteristic azide 15.8 and 6.6 Hz).
stretching band at 2200 to 2100 cmꢀ1 in the IR spectrum. That
Srinu et al. have obtained cinnamyl azide 8 from vinylbenzyl
unexpected reaction avoids expanding the equilibrium shi alcohol 9 using BF3$Et2O and TMSN3 without isolating the ex-
beyond that temperature.
pected product 11.39 These authors proposed a SN20 with the
The next step was to determine how the solvent polarity azide attacking the terminal olenic carbon and releasing
affects the equilibrium. 1% v/v solution of the 6b in different a TMSO as possible mechanism for that reaction. Different
deuterated solvents, including non-polar (benzene, toluene, authors have also reported the same results using substituted
chloroform), polar aprotic (THF, acetone, DCM, DMSO) and phenyl propenols,16,21,23,40 and different reagents and reaction
a protic solvent (MeOH). Those solvents cover a wide spectrum conditions. The reaction of homoallylic alcohols using TMSN3
of dielectric constant (from 2.27 for benzene to 46.83 for under PdCl2 catalysis also produced the conjugated products.41
DMSO). The analysis of the spectra revealed that the nature of
In order to synthesize the isomeric mixture 16, acetophe-
solvents does not appreciably affect the azide population. The none 12 was submitted to a Horner–Wadsworth–Emmons
proportion of tertiary azide goes from 12.5% in chloroform to reaction with triethylphosphonoacetate providing the a,b-
13.7% in methanol, having a distribution between those values
for the rest of the solvents. The theoretical calculations agree
with the experimental results showing a small population
difference among the solvents, demonstrating the low effect of
the type of solvent on the population distribution.
It has previously been reported for other allyl azides systems
that solvent exchange and temperature can be used to control
the equilibrium composition. Thevenet et al. efficiently modu-
lated the reactivity of allylazides controlling the [3,3]-
sigmatropic rearrangement changing the solvent and the
temperature of the reaction.35 Our results showed that prenyl
azides are insensitive to those changes, leaving equilibrium
distribution solely dependent on the substrate structure.
Finally, to study how the structure affects the equilibrium,
a set of new analogues were proposed. The methyl group should
be exchange by a phenyl group (changing electronic and steric
factors). Aromatic compounds containing isoprenyl substitu-
ents have interesting pharmacological proles including anti-
microbial, antifungal, anti-carcinogenic and anti-HIV
activities.36–38 The proposed phenyl derivatives 8 and 15,
inspired by prenyl azide mixtures 6a were prepared. In both
Scheme 3 Reagents and conditions: (a) DPPA, DBU, toluene, 12 h,
0
ꢁC / rt, 78%; (b) BF3$Et2O, TMSN3, DCM (ref. 39); (c) triethylphos-
phonoacetate, NaH, dimethoxyethane, 3 h, r.t., 60%; (d) LiAlH4, THF,
1 h, rt, 80%; (d) DPPA, DBU, toluene, 12 h, 0 ꢁC / r.t., 91%. In dotted
lines, the synthetic routes developed in the present work.
Fig. 5 Phenyl prenylazides proposed.
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unsaturated ester 13 in 3 hours with 60% yield (E : Z, 92 : 8,
Scheme 3).
Several topological properties evaluated at a bond critical
point (bcp) are used to characterize the nature of a bonding
The ester was reduced with LiAlH4 in THF in 1 hour, to get interaction (calculated properties at the bcp are labelled with
the alcohol 14 (80% yield). In this step, the E-isomer was the subscript “b”).
separated by chromatography. Lastly, the alcohol was trans-
formed into azide 16 by reaction with DPPA and DBU in toluene Laplacian, V2rb gives information about the local charge
with 91% yield.
concentration (V2rb < 0) or depletion (V2rb > 0).44,45 The ellip-
The charge density, rb, reects the bond strength and its
The 1H NMR spectrum of product 16 shows a triplet at ticity, 3, provides information about the charge distribution
5.88 ppm with a J ¼ 6.7 Hz for the olenic proton coupled with around the bond path and can be used to determine the bond
the protons of the allylic methylene of 3.99 ppm (J ¼ 6.7 Hz). stability and its p character.46 The total energy density, Hb, (Hb
These signals are a clear indication that only one isomer has ¼ Gb + Vb, being Gb and Vb the potential and the kinetic energy
been formed without experiencing the [3,3]-sigmatropic rear- densities at the bcp, respectively), which designs the density of
rangement. Those results are also in agreement with the work the total electronic energy at a bcp, is used to analyse the
reported by Srinu et al. where only the primary azide 16 was covalent character of an interaction.47 Also, the delocalization
obtained starting from the alcohol 14 or an isomeric alcohol index, DI, is an important parameter that indicates the amount
1539 (Scheme 3).
of the electron pairs number shared by two atoms.48,49
In summary, our results and the literature precedents clearly
The molecular graphs of the TSs under study are shown in
showed that, in any case starting from conjugated allylic alco- Fig. 7 and the topological properties evaluated at the selected
hols or their isomers phenethyl vinyl alcohols, only one conju- bcps are listed in Table 1 along with the bond distances (such
gated product is obtained.
properties for another bcps are given in the ESI†).
Products from the reactions with cinnamyl alcohol 7 and its
The molecular graphs of TSs show the bcps associated with
methyl substituted derivative 14 retain their regiochemistry forming C1–N1 and breaking C3–N3 bonds and a ring critical
demonstrating that the presence of the aromatic ring disfavours point (rcp) related to a half-chair cyclic structure.
the [3,3]-sigmatropic rearrangement due to stereoelectronic and
In TS-6a, the values at the C1–N1 bcp of rb (0.058 au.), V2rb
inductive effects.
(0.091 au.), and DI (0.32) are slightly lower than these calculated
To rationalize the experimental evidences that showed at the C3–N3 bcp (rb ¼ 0.059 au., V2rb ¼ 0.095 au., and DI ¼
a high dependency of the double bond substitution on the 0.37). In contrast, in TS-8 and TS-16, the values of rb and DI at
equilibrium of allylic alcohols, a theoretical study was per- C1–N1 bcp are slightly higher than these calculated at the C3–
formed. In contrast to the large number of experimental and N3 bcp (except DI in TS-16, that in both bcps take the same
theoretical investigations aimed to understand sigmatropic value). Therefore, in TSs with aromatic ring substituent, the
rearrangements of different systems,35,42,43 azides has received formation/rupture of C1–N1/C3–N3 bonds are more advanced
scarce attention, especially from the theoretical point of view. In than in TS with methyl substituents. These facts are also re-
addition, an analysis based on the quantum theory of atoms in ected toward the bond distances.
molecules (QTAIM)44,45 was performed. Such studies provide
information of the electron charge distribution involved in the bcps (see the ESI†) indicate that these bonds have an interme-
[3,3]-sigmatropic rearrangements of 6a, and 12. That diate character between single and double covalent bond, due
The topological properties evaluated at C1–C2 and C2–C3
8
approach is based on the topological analysis of the electron to the delocalization of the “p” electrons upon the C1–C2–C3
charge density allowing a clear insight into structure and the fragment. The double bond character is higher for the C2–C3
stability of a chemical species.
bond, being more notable in TS-8 and TS-16.
The distances and topological properties of N1–N2 and N2–
N3 bonds are quite similar, however, these show that the “p”
electron density is slightly more localized on the N2–N3 bond
Theoretical studies of 6a, 8 and 16
Energetic, structural and electron charge density analysis. particularly in TS-8 and TS-16. The geometric and topological
The free energy proles for the [3,3]-sigmatropic rearrange- results support the existence of p-electron delocalization in the
ment of 6a, 8 and 12 showing the located stationary points TSs and strongly suggest that the effect of the aromatic
with their corresponding relative free energies are displayed substituent is strictly electronic, thus the contribution of steric
in Fig. 6. TS-6a (DG# ¼ 26.0 kcal molꢀ1) has lower free acti- factor to the stability of the systems must be scarce or null.
vation energy than TS-8 and TS-16 (by 3.7 and 3.1 kcal molꢀ1
,
In addition, an analysis of the variation of the topological
respectively). The aromatic ring disfavours the stability of properties at the selected bcps (C1–N1, C3–N3, C1–C2, C2–C3,
TS-8 and TS-16, increasing the activation energies. The N1–N2, N2–N3) along the reaction courses was carried out (see
former is slightly less stable than the second one, which is the ESI†). Such analysis has been successfully applied to ratio-
attributed to the absence of methyl group. The [3,3]- nalize the mechanism of a wide variety of chemical trans-
sigmatropic rearrangement of 6a is endergonic (DG ¼ formations.46,50–58 The proles of topological properties
1.8 kcal molꢀ1) and the endothermicity increases for the evaluated at the selected bcps showed similar patterns for all
aromatic systems 8 and 16 by 4.6 and 4.0 kcal molꢀ1
respectively. Again, the presence of methyl group slightly of the pairs of bcps C1–N1 and C3–N3, C1–C2 and C2–C3, and
,
reaction pathways. The evolution of the topological properties
favours the stability of the system.
N1–N2 and N2–N3, are complementary demonstrating that
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Fig. 6 MPWB1K/6-311++G(d,p) free energy profiles for the [3,3]-sigmatropic rearrangement of allylic azides 6a, 8 and 16. Relative free energies
in toluene are in kcal molꢀ1. The optimized geometries (in 3D) for the transition structures are showed.
Table 1 Bond distances and topological properties for selected bcps
a continuous electron transfer occurs. These results reinforce
the fact that the effect of the aromatic substituent is strictly
calculated at the TSs under studya,b
electronic.
Species
TS-6a
TS-8
Bonds
R
rb
V2rb
3
Hb
DI
Atomic properties analysis. The analysis of the changes in
atomic populations N(U), and atomic energies E(U) is carried
out to know the distribution of the electron charge density and
to pinpoint the atoms or group of atoms that undergo the
greatest changes in their atomic properties in achieving the
TSs.44,59–63
C1–N1
C3–N3
C1–N1
C3–N3
C1–N1
C3–N3
2.14
2.11
2.08
2.15
2.13
2.17
0.058
0.059
0.063
0.054
0.059
0.052
0.091
0.095
0.092
0.096
0.089
0.095
0.142
0.104
0.133
0.120
0.138
0.123
ꢀ0.072
ꢀ0.009
ꢀ0.011
ꢀ0.007
ꢀ0.009
ꢀ0.006
0.32
0.37
0.37
0.34
0.33
0.33
TS-16
Fig. 8 displays the changes in atomic population DN(U) and
atomic energy DE(U) in the TSs respect to the corresponding
reactants (6a, 8 and 16). The changes in such properties in the
group of atoms, R1 and R2 that form the substituent fragments
are also included. The net charges calculated for selected atoms
in the TSs and azides 6a, 8 and 16 are showed in Table 2.
The atoms in TSs whose atomic population and atomic
energy were signicantly affected respect to the reactant 6a, 8
and 16 (i.e., |DN(U)| > 0.02 e, and |DE(U)| > 20 kcal molꢀ1) are
N1, N3 and C3. The C1 atom shows a considerable variation in
its atomic energy, however, the change in its atomic population
is less important. Thus, the largest changes of atomic properties
to reach the TSs occur in the atoms involved in the forming and
breaking bonds, particularly in the latter one.
a
2
˚
Bond distances (R) in A; rb, V rb, Hb in au. 3 and DI are dimensionless.
b
To identify the atoms, see Fig. 7.
destabilized (except N2, which increases its electron population
and is stabilized, and C2 in TS-6a, which decreases its atomic
energy).
N(U) of C1 atom decrease taking its net charge values posi-
tive, +0.031, +0.022 and +0.027 e for TS-6a, TS-8 and TS-16,
respectively (Table 2). The destabilization of C1 increases in the
order TS-8 (19 kcal molꢀ1) < TS-6a (25 kcal molꢀ1) < TS-16
(30 kcal molꢀ1). The decrease of N(U) and the destabilization of
C1 are related with the loss of “s” character.
Because of the C3–N3 bond is breaking, an increase of “s”
over “p” character in C3 occurs and in consequence, it gains
electron population. The largest amount of electron population
The atomic properties of the remaining atoms and the group
of atoms, R1 and R2, show relative lower changes in achieving
the TSs. Overall, these atoms lose electron population and are
Fig. 7 Molecular graphs of the TSs corresponding to [3,3]-sigmatropic rearrangement of allylic azides 6a, 8 and 12.
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Fig. 8 Variation of (a) electron population, DN(U), and (b) energy, DE(U), for atoms and atom groups at the TSs with respect to the corresponding
reactants. DN(U) < 0 and DN(U) > 0 indicate that the atom loses and gains electron population. DE(U) < 0 and DE(U) > 0 indicate that the atom is
stabilized and destabilized at TS regarding to the corresponding reactants, respectively. R1 ¼ Me, H, Me and R2 ¼ Me, Ph, Ph in TS-6a, TS-8 and
TS-16, respectively. See Fig. 7 to identify atoms label.
gained by C3 comes mainly from all atoms of allylic fragment destabilized due to the loss of a great amount of electron pop-
and R1 and R2 groups, which lose electron population. The p- ulation in achieving the TSs. The increase of DE(N3) follows the
electrons of aromatic substituent in TS-8 and TS-16 may be order TS-16 (170 kcal molꢀ1) > TS-8 (166 kcal molꢀ1) > TS-6a
better delocalized than the electrons donated by the methyl (151 kcal molꢀ1), which is in line with the increase of free
group in TS-6a, and the electron transfer toward C3 may occur activation energy calculated. Accordingly, a strong linear
due to the delocalization of the charge density of the double dependence of DE(N3) on DG# is established (R2 ¼ 0.994, see the
bond C1–C2. Consequently, the C3 atom in TS-8 (0.37 e) and TS- ESI†). These results clearly demonstrate that the relatively high
16 (0.36 e) gains a slightly greater electron population than in free activation energy for the [3,3]-sigmatropic rearrangement
TS-6a (0.35 e), and it is more stabilized in the former TSs under study come from the great destabilization of N3.
(DE(C3) ¼ ꢀ140 and ꢀ138 kcal molꢀ1 for TS-8 and TS-16, and
In a related reaction, the Cope rearrangement of 1,5-hex-
ꢀ131 kcal molꢀ1 for TS-6a). In addition, a good linear correla- adiene, the great destabilization of two ethylenic terminal
tion between DN(C3), DE(C3) and DG#(R2 ¼ 0.891 and 0.995, carbons (C1 and C6) was considered as the “source” of the high
respectively) is obtained (see the ESI†). Thus, DN(C3) reects the barrier for this reaction. In the case of the sigmatropic rear-
effect of the different substituents upon the electron delocal- rangement of isoprenylazides, the particular redistribution of
ization but the stabilization of C3 is inverse to the values of DG#, the electron charge density which makes the destabilization of
and therefore does not explain the high energy barriers.
N3, is attributed to the singular electronic characteristic of the
The loss of electron population of N3 increases in the order azide group.
TS-6a (ꢀ0.27 e) > TS-16 (ꢀ0.30 e) > TS-8 (ꢀ0.31 e), and its net
The charge loss by N3 achieving the TSs is mainly transferred
charge becomes less negative (Table 2) due to the partial to N1, which increased its electron and is stabilized, but less
breaking of C3–N3 bond. This trend is contrary to the increase than C3. The stabilization of the N1 and C3 atoms in the TSs
of electron population of C3, and reects the effect of the contributes to lowering the energy barrier although the desta-
substituents. In addition, a good linear correlation between bilization of N3 is more relevant.
DN(N3) and DG# (R2 ¼ 0.921), is obtained (see the ESI†). N3 is
Additionally, an analysis of the evolution of DN(U) and DE(U)
along the course of reaction was performed (see the ESI†). Such
analysis demonstrates that the atomic properties of C1, C3, N1
and N3 are signicantly affected along the reaction pathways.
Interestingly, the proles of DE(N3) have a similar pattern but
show larger differences in quantitative sense which is in
agreement with the energy barriers of the reaction under study.
Table 2 Atomic net charges (in e) for selected atoms in the azides 6a,
8 and 12 and the in TSs under study
Species
q(C1)
q(C2)
q(C3)
q(N1)
q(N2)
q(N3)
6a
TS-6a
8
TS-8
16
TS-16
ꢀ0.012
+0.031
ꢀ0.022
+0.022
ꢀ0.010
+0.027
ꢀ0.035
+0.012
ꢀ0.045
+0.019
ꢀ0.038
+0.017
+0.352
ꢀ0.004
+0.374
ꢀ0.003
+0.359
ꢀ0.010
+0.124
ꢀ0.134
0.138
ꢀ0.129
+0.136
ꢀ0.131
ꢀ0.213
ꢀ0.219
ꢀ0.211
ꢀ0.220
ꢀ0.213
ꢀ0.226
ꢀ0.402
ꢀ0.127
ꢀ0.420
ꢀ0.105
ꢀ0.414
ꢀ0.112
Conclusions
Since the advent of click chemistry, azides play a key role in the
synthesis of 1,2,3-triazoles. Isoprenyl azides can be considered
an important synthetic intermediate to generate new
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chemotherapeutic entities. Their use has been disfavoured Atmospheric Pressure Chemical Ionization High-resolution
since they tend to produce Winstein's rearrangements, mass spectra (ESI-HRMS, APCI-HRMS) were recorded on a Bru-
producing
regioisomers.
a
mixture of chromatographically inseparable kerMicroTOF II with lock spray source. IR spectra were obtained
using an FTIR Shimadzu spectrometer and only partial spectral
In this work, isoprenylic azides were synthesized, using NMR data are listed. Chemical reagents were purchased from
spectroscopy to identify the regioisomers' ratio. It was observed commercial suppliers and used without further purication,
that the ratio remains unchanged at room temperature unless otherwise noted. Solvents were analytical grade or were
regardless the number of isoprene units, regiochemistry and puried by standard procedures prior to use. Yields were
the substitution of the starting isoprenol. Additionally, when calculated for material judged homogeneous by thin layer
isoprene double bond was decorated with aromatic rings, the chromatography (TLC) and nuclear magnetic resonance (1H-
azide do not experiment the [3,3]-sigmatropic rearrangement. NMR). All reactions were monitored by thin layer chromatog-
The equilibrium composition dependence with the temperature raphy performed on silica gel 60 F254 pre-coated aluminum
and the solvent were also analysed. From ꢀ55 to 25 ꢁC, the sheets, visualized by a 254 nm UV lamp, and stained with an
tertiary azide proportion increases only 15% (11.2% to 13.2%). ethanolic solution of 4-anisaldehyde. Column ash chroma-
The study curry out on eight different solvents showed that the tography was performed using silica gel 60 (230–400 mesh).
equilibrium is not appreciably affected. Those results were
conrmed by theoretical calculation where the energy differ-
ence for the isomers on different solvents has low impact on the
General procedure for prenyl azides synthesis
equilibrium population distribution. Together, those results One equivalent of the prenyl alcohol substrate was dissolved in
ꢁ
proved that isoprenyl azides cannot be experimentally obtained anhydrous toluene at 0 C. Then, 1.3 equivalents of diphenyl-
as pure isomer.
phosphorylazide (DPPA) were added followed by the addition of
To rationalize the experimental results, theoretical studies 1.3 equivalents of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
were performed using density functional theory and the QTAIM Aer 2 h of continuous stirring at 0 ꢁC, the reaction was warmed
approach. The free energy barrier and the endothermicity of the to room temperature. Finally, the mixture of reaction was
reaction involving aromatic azides were higher than that of quenched with water. The aqueous layer was extracted 3 times
methyl azides. Thus, Winstein' rearrangement of aromatic with ethyl acetate and the combined organic layers concen-
systems is kinetically and thermodynamically disfavoured trated under vacuum. The residue was puried on a silica gel
which is in agreement with the experimental results. The column (hexane).
topological analysis of the electron charge density revealed that
Synthesis of mixture of allylazides from the prenol: 1-azido-
the rearrangement takes place via a concerted mechanism 3-methylbut-2-ene (6a) and 3-azido-3-methylbut-1-ene (6a
involving a half-chair TS in which a signicant redistribution of rearr). Following the general reaction conditions for the prenyl
the charge density occurs. Additionally, it was demonstrated azides synthesis, 3-methylbut-2-en-1-ol 5a (100 mg; 1.16 mmol)
that the effect of the aromatic substituent is purely electronic.
was dissolved in anhydrous toluene (2.5 mL). Then, DPPA was
The analysis of atomic properties allowed pinpoint the slowly added (400 mg, 1.51 mmol) followed by the addition of
atoms or region that experience the greatest changes in electron DBU (232 mg; 1.51 mmol). Aer 8 h of continuous stirring at
population and energy in achieving the TSs. Although the effect room temperature, the reaction was worked up and puried to
of the substituent affects the properties of the whole systems, it afford 108 mg of the product as a colourless oil (isolated yield:
was found that the destabilization of N3 plays a key role in the 84%).1H NMR (CDCl3): d 5.94 ppm (dd, 0.16H, 3JH2–H1 ¼ 17.3 Hz
larger energy barrier, and clearly reects the degree of electron and 3JH2–H1 ¼ 10.7 Hz, C2t–H); 5.41 (tt, 1H, 3JH2–H1 ¼ 7.5 Hz and
delocalization caused by the substituent effect.
4JH2–H4 ¼ 1.4 Hz, C2P–H); 5.31 (d, 0.16H, 3JH1–H2 ¼ 17.3 Hz, C1T–
3
Therefore, the formation of the tertiary regioisomers H); 5.24 (d, 0.16H, JH1–H2 ¼ 10.7 Hz, C1T–H); 3.83 (d,
through [3,3]-sigmatropic rearrangement may be controlled by 2.06H,3JH1–H2 ¼ 7.3 Hz, C1P–H); 1.89 (s, 3.15H, C5P–H); 1.79 (s,
modifying the electronic structure of isoprenylazides.
3.15H, C4P–H) and 1.43 (s, 1.15H, C4T–H and C5T–H). 13C NMR
(CDCl3): d 141.2 ppm (CT2, CH); 139.6 (CP3, quaternary); 117.4
(CP2, CH); 113.9 (CT1, CH2); 49.6 (CT3, quaternary); 48.2 (CP1,
CH2); 26.1 (CT4 and CT5, CH3); 25.7 (CP4, CH3) and 18.1 (CP5,
CH3).
Experimental
General information
1H and 13C NMR spectra were acquired on a BrukerAvance II 300
Synthesis of mixture of allyl azides from the geraniol: (E)-1-
MHz (75.13 MHz) using CDCl3 as solvent. Chemical shis (d) azido-3,7-dimethylocta-2,6-diene
(6b-E);
(Z)-1-azido-3,7-
were reported in ppm downeld from tetramethylsilane (TMS) dimethylocta-2,6-diene (6b-Z) and 3-azido-3,7-dimethylocta-
at 0 ppm as internal standard and coupling constants (J) are in 1,6-diene (6b–t). Following the general reaction conditions for
hertz (Hz). Chemical shis for carbon nuclear magnetic reso- the prenyl azides synthesis, geraniol 5b-E (600 mg; 3.90 mmol)
nance (13C NMR) spectra are reported in parts per million was dissolved in anhydrous toluene (8 mL). Then, DPPA was
relative to the center line of the CDCl3 triplet at 76.9 ppm. The slowly added (1320 mg, 5.00 mmol) followed by the addition of
following abbreviations are used to indicate NMR signal DBU (770 mg; 5.00 mmol). Aer 8 h of continuous stirring at
multiplicities: s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, p room temperature, the reaction was worked up and puried to
¼ pentuplet, m ¼ multiplet, br ¼ broad signal. Electrospray and afford 608 mg of colourless oil (isolated yield: 87%).1H NMR
47534 | RSC Adv., 2017, 7, 47527–47538
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(CDCl3): d 5.78 ppm (dd, 0.12H, 3JH2–H1 trans ¼ 17.3 Hz and 3JH2– 0.12H, 3JH1 trans–H2 ¼ 17.3 Hz, C1T–H); 5.21 (d, 0.12H, 3JH1–H2
¼
¼ 10.7 Hz, C2T–H); 5.33 (t, 0.88H, 3JH2–H1 ¼ 7.3 Hz, C2E–H 10.7 Hz, C1T–H); 5.09 (m, 2H, C7–H and C12–H); 3.77 (d, 1.77H,
H1 cis
and C2Z–H); 5.23 (d, 0.14H, 3JH1 trans–H2 ¼ 17.3 Hz, C1T–H); 5.20 3JH1–H2 ¼ 7.3 Hz, C1E–H and C1Z–H); 2.11 (m, 8H, C5–H, C6–H,
3
(d, 0.14H, JH1 trans–H2 ¼ 10.7 Hz, C1T–H); 5.09 (m, 1H, C7–H); C10–H, C11–H); 1.80 (s, 1.05H, C4Z–H); 1.71 (s, 2.01H, C4E–H);
3.75 (dd, 1.85H,3 JH1–H2 ¼ 7.2 Hz, C1E–H and C1Z–H); 2.10 (bs, 1.68 (s, 3H, C15–H); 1.61 (s, 6H, C9–H and C14–H); 1.55 (s,
3.67H, C5–H and C6–H); 1.79 (s, 1.07H, C4Z–H); 1.70 (s, 1.87H, 0.40H, C9T–H) and 1.35 (s, 0.40H, C4T–H). 13C NMR (CDCl3):
C4E–H); 1.68 (s, 3H, C10–H), 1.61 (s, 3H, C9–H) and 1.35 (s, d 143.1 (CE3, quaternary); 143.0 (CZ3, quaternary); 140.1 (CT2,
0.41H, C4T–H). 13C NMR (CDCl3): d 143.1 ppm (CE3, quater- CH); 135.9 (CZ8, quaternary); 135.7 (CT8, quaternary); 135.6
nary); 143.0 (CZ3, quaternary); 140.1 (CT2, quaternary); 132.3 (CE8, quaternary); 131.3 and 131.2 (CE13, CZ13 and CT13,
(CZ8, quaternary); 132.1 (CT8, quaternary); 131.9 (CE8, quater- quaternary); 124.3 (CE12, CZ12 and CT12, CH); 123.5 (CE7, CH);
nary); 123.6 (CE7, CH); 123.5 (CT7, CH); 123.4 (CZ7, CH); 117.9 123.4 (CT7, CH); 123.3 (CZ7, CH); 117.9 (CZ2, CH); 117.1 (CE2,
(CZ2, CH); 117.0 (CE2, CH); 114.6 (CT1, CH2); 64.9 (CT3, CH); 114.6 (CT1, CH2); 64.9 (CT3, quaternary); 48.0 (CE1 and CZ1,
quaternary); 48.0 (CE1, CH2); 47.9 (CZ1, CH2); 40.1 (CT5, CH2); CH2); 40.1 (CT5, CH2); 39.7 (CT10, CH2); 39.5 (CE5, CH2); 32.1
39.5 (CE5, CH2); 32.1 (CZ5, CH2); 26.7 (CZ6, CH2); 26.4 (CE6, (CZ5, CH2); 26.7 (CE6, CZ6, CZ10, CE10, CH2); 25.6 (C14, CH3);
CH2); 25.6 (CZ10, CE10, CH3); 23.3 (CZ4, CH3); 23.1 (CT4, CH3); 23.3 (CT4, CH3); 23.1 (CE4, CH3); 22.7 (CT6, CH2); 17.6 (C15,
22.8 (CT6, CH2); 17.7 (CT9, CH3); 17.6 (CE9, CH3); 17.6 (CZ9, CH3) CH3); 16.4 (CE4, CH3); 16.0 (C9, CH3) and 15.9 (CZ4, CH3). HRMS
and 16.4 (CE4, CH3). HRMS (APCI): calculated mass for (APCI): mass calculated for
10H18Nꢀ 152.14447; found 152.14438. IR (lm): ymax (cmꢀ1 220.21291. IR (lm): ymax (cmꢀ1) 2968 (]CH–), 2926 (–CH2–),
2969 (]CH–), 2928 (–CH2–), 2884 (–CH2–C–N–), 2098 (–N3), 2856 (–CH2–C–N–), 2097 (–N3), 1665 (–C]C–).
C
15H26Nꢀ 220.20707, found
C
)
1664 (–C]C–).
Synthesis of mixture of allylazides from the geranylgeraniol:
Synthesis of mixture of allylazides from the nerol: (E)-1- (2E,6E,10E)-1-azido-3,7,11,15-tetramethylhexadeca-2,6,10,14-
azido-3,7-dimethylocta-2,6-diene
(6b-E);
(Z)-1-azido-3,7- tetraene
(6d-E);
(2Z,6E,10E)-1-azido-3,7,11,15-tetramethyl-
dimethylocta-2,6-diene (6b-Z) and 3-azido-3,7-dimethylocta- hexadeca-2,6,10,14-tetraene (6d-Z) and (6E,10E)-3-azido-3,7,11,15-
1,6-diene (6b–t). Following the general reaction conditions for tetramethylhexadeca-1,6,10,14-tetraene (6d–t). Following the
the prenylazides synthesis, nerol 5b-Z (100 mg; 0.65 mmol) was general reaction conditions for the prenylazides synthesis, ger-
dissolved in anhydrous toluene (2 mL). Then, DPPA was slowly anylgeraniol 5d (50 mg; 0.17 mmol) was dissolved in anhydrous
added (220 mg, 0.83 mmol) followed by the addition of DBU toluene (1 mL). Then, DPPA was slowly added (58 mg, 0.22 mmol)
(129 mg; 0.83 mmol). Aer 8 h of continuous stirring at room followed by the addition of DBU (34 mg; 0.22 mmol). Aer 8 h of
temperature, the reaction was worked up and puried to afford continuous stirring at room temperature, the reaction was worked
104 mg of colourless oil (isolated yield: 89%). The spectra of 1H up and puried to afford 49 mg of colorless oil (isolated yield:
3
and 13C coincident with spectra obtained of mixture of allylic 92%). 1H NMR (CDCl3): d 5.79 ppm (dd, 0.12H, JH2–H1 trans
azides from the geraniol.
¼
17.3 Hz and 3JH2–H1 cis ¼ 10.7 Hz, C2T–H); 5.34 (t, 0.93H, 3JH2–H1
¼
Synthesis of mixture of allyl azides from the linalool: (E)-1- 7.3 Hz, C2E–H and C2Z–H); 5.23 (d, 0.14H, 3JH1 trans–H2 ¼ 17.3 Hz,
3
azido-3,7-dimethylocta-2,6-diene
(6b-E);
(Z)-1-azido-3,7- C1T–H); 5.20 (d, 0.14H, JH1–H2 ¼ 10.7 Hz, C1T–H); 5.10 (m, 3H,
dimethylocta-2,6-diene (6b-Z) and 3-azido-3,7-dimethylocta- C7–H, C12–H and C17–H); 3.78 (d, 1.78H, 3JH1–H2 ¼ 7.3 Hz, C1E–
1,6-diene (6b–t). Following the general reaction conditions for H); 3.76 (d, 1.78H, 3JH1–H2 ¼ 7.3 Hz, C1Z–H); 2.05 (m, 12H, C5–H,
the prenyl azides synthesis, linalool 5b–t (100 mg; 0.65 mmol) C6–H, C10–H, C11–H, C15–H and C16–H); 1.80 (s, 1.07H, C4Z–H);
was dissolved in anhydrous toluene (2 mL). Then, DPPA was 1.71 (s, 3H, C4E–H); 1.68 (s, 3H, C15–H); 1.61 (s, 9H, C9–H, C14–H
slowly added (220 mg, 0.83 mmol) followed by the addition of and C19–H); 1.55 (s, 3H, C20–H) and 1.35 (s, 0.45H, C4T–H). 13
C
DBU (129 mg; 0.83 mmol). Aer 8 h of continuous stirring at NMR (CDCl3): d 143.2 ppm (CE3, quaternary); 143.1 (CZ3, quater-
room temperature, the reaction was worked up and puried to nary); 140.1 (CT2, quaternary); 136.0 (CZ8, quaternary and CT8,
afford 99 mg of colourless oil (isolated yield: 85%).
The spectra of 1H and 13C coincide with spectra obtained of 131.3 (C18, quaternary); 124.4 (C17, CH); 124.2 (CZ12, CH); 124.2
mixture of allylic azides from the geraniol. (CT12, CH); 124.1 (CE12, CH); 123.5 (CE7, CH); 123.5 (CT7, CH);
quaternary); 135.6 (CE8, quaternary); 135.0 (C13, quaternary);
Synthesis of mixture of allylazides from the farnesol: (2E,6E)- 123.3 (CZ7, CH); 117.9 (CZ2, CH); 117.0 (CE2, CH); 117.0 (CT1, CH2);
1-azido-3,7,11-trimethyldodeca-2,6,10-triene (6c-E); (2Z,6E)-1- 64.9 (CT3, quaternary); 48.1 (CE1, CH2); 48.0 (CZ1, CH2); 40.1 (CT5,
azido-3,7,11-trimethyldodeca-2,6,10-triene (6c-Z) and (E)-3- CH2); 39.7 (C11, CH2); 39.7 (C16, CH2); 39.5 (CE5, CH2); 32.1 (CZ5,
azido-3,7,11-trimethyldodeca-1,6,10-triene (6c–t). Following the CH2); 26.8 (C16, CH2); 26.6 (C10, CH2); 26.4 (CE6 and CZ6, CH2);
general reaction conditions for the prenylazides synthesis, far- 25.7 (C20, CH3); 23.4 (CE4, CH3); 23.2 (CT4, CH3); 22.7 (CT6, CH2);
nesol 5c (300 mg; 1.35 mmol) was dissolved in anhydrous 17.7 (C19, CH3); 16.4 (C14, CH3); 16.0 (CZ4, CH3) and 16.0 (C9,
toluene (4 mL). Then, DPPA was slowly added (355 mg, 1.75 CH3). IR (lm): ymax (cmꢀ1) 2967 (]CH–), 2928 (–CH2–), 2882
mmol) followed by the addition of DBU (270 mg; 1.75 mmol). (–CH2–C–N–), 2096 (–N3), 1660 (–C]C–).
Aer 8 h of continuous stirring at room temperature, the reac-
Synthesis of mixture of allylazides from the phytol: (E)-1-
tion was worked up and puried to afford 284 mg of colourless azido-3,7,11,15-tetramethylhexadec-2-ene (6e-E); (Z)-1-azido-
oil (isolated yield: 85%). 1H NMR (CDCl3): d 5.79 ppm (dd, 3,7,11,15-tetramethylhexadec-2-ene (6e-Z) and (3R)-3-azido-
0.12H, 3JH2–H1 trans ¼ 17.3 Hz and 3JH2–H1 cis ¼ 10.7 Hz, C2T–H); 3,7,11,15-tetramethylhexadec-1-ene (6e–t). Following the
3
5.34 (t, 0.87H, JH2–H1 ¼ 7.3 Hz, C2E–H and C2Z–H); 5.24 (d, general reaction conditions for the prenylazides synthesis,
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(Z)-Ethyl 3-phenylbut-2-enoate (13Z). 1HNMR (CDCl3):
d 7.47 ppm (m, 2H, meta aromatics, C3–H and C5–H); 7.37 (m,
3H, ortho and para aromatics, C2–H, C4–H and C6–H); 5.91 (dd,
1H, olenic, C8–H); 4.00 (q, 2H, 3JH11–H12 ¼ 7.1 Hz, C11–H); 2.18
phytol 5e (300 mg; 1.01 mmol) was dissolved in anhydrous
toluene (4 mL). Then, DPPA was slowly added (270 mg, 1.33
mmol) followed by the addition of DBU (205 mg; 1.33 mmol).
Aer 8 h of continuous stirring at room temperature, the reac-
tion was worked up and puried to afford 282 mg of colourless
oil (isolated yield: 87%). 1H NMR (CDCl3): d 5.78 ppm (dd,
0.13H, 3JH2–H1 trans ¼ 17.3 Hz and 3JH2–H1 cis ¼ 10.7 Hz, C2T–H);
5.34 (tq, 0.92H,3JH2–H1 ¼ 7.5 Hz, C2E–H and C2Z–H); 5.24 (dd,
4
3
(d, 3H, JH10–H8 ¼ 1.2 Hz, C10–H) and 1.08 (t, 3H, JH12–H11
¼
7.1 Hz, C12–H). 13C NMR (CDCl3): d 166.9 ppm (C9, carbonyl);
155.3 (C7, quaternary olenic); 142.3 (C1, ipso aromatic); 128.0
(C3 and C5, meta aromatics); 127.8 (C4, para aromatic); 126.9
(C2 and C6, ortho aromatic); 117.9 (C8, CH, olenic); 59.8 (C11,
O–CH2–); 29.6 (C10, CH3) and 14.3 (C12, CH3). HRMS (ESI):
0.12H, 3JH1 trans–H2 ¼ 17.3 Hz, C1T–H); 5.19 (d, 0.12H, 3JH1–H2
¼
3
10.7 Hz, C1T–H); 3.78 (d, 1.93H, JH1–H2 ¼ 7.3 Hz, C1E–H and
C1Z–H); 2.05 (m, 2H, C5E–H and C5Z–H); 1.78 (s, 3H, C4Z–H);
1.70 (s, 3H, C4E–H); 1.54 to 1.15 (m, 19H, CH2 and CH) and 0.88
to 0.83 (m, 12H, CH3). 13C NMR (CDCl3): d 143.7 ppm (CE3 and
CZ3, quaternary); 140.3 (CT2, quaternary); 117.5 (CZ2, CH); 116.8
(CE2, CH); 114.5 (CT1, CH2); 65.2 (CT3, quaternary); 48.1 (CE1,
CH2); 47.9 (CZ1, CH2); 40.5 (CT5, CH2); 39.5 (CE5, CH2); 39.4
(C17, CH2); 28.0 (C18; CH) and 16.4 (CE4, CH3).
calculated mass for C12H15O2 (M + H+), 191.10666; found,
+
191.10670. IR (lm): ymax (cmꢀ1) 2978 (]CH–), 2926 (–CH2–),
1713 (C]O), 1628 (C]C).
Synthesis of (E)-3-phenylbut-2-en-1-ol (14). 1 equivalent of
compound 10 (50 mg, 0.21 mmol) was dissolved in 2 mL of
anhydrous tetrahydrofuran at room temperature and inert
atmosphere. Then, 2.5 equivalents of LiAlH4 (20 mg, 0.50 mmol)
were slowly added. Aer 1 h of vigorous stirring, the reaction
was quenched with a mixture methanol : water (90 : 10), fol-
lowed by the addition of 5 mL of a NH4Cl solution (10% w/w). A
partial evaporation of the mixture is performed to remove
interfering solvent. The inorganic phase was extracted 3 times
(3 ꢂ 15 mL) with ethyl ether and the combined organic layers
concentrated under vacuum. The residue was puried on
a silica gel column (hexane : ethyl acetate) to afford 34 mg of
colourless oil (isolated yield: 80%). 1H NMR (CDCl3): d 7.42 ppm
(m, 2H, meta aromatic, C3–H and C5–H); 7.37 (t, 2H, ortho
aromatics, C2–H and C6–H); 7.21 (d, 1H, para aromatic, C4–H);
5.98 (dt, 1H, 3JH8–H9 ¼ 6.7 Hz, 4JH8–H10 trans ¼ 1.3 Hz, C8–H); 4.37
Synthesis of (E)-(3-azidoprop-1-en-1-yl) benzene (8).
Following the general reaction conditions for the prenylazides
synthesis, cinnamyl alcohol 7 (50 mg; 0.37 mmol) was dissolved
in anhydrous toluene (2 mL). Then, DPPA was slowly added
(126 mg, 0.48 mmol) followed by the addition of DBU (74 mg;
0.48 mmol). Aer 8 h of continuous stirring at room tempera-
ture, the reaction was worked up and puried to afford 47 mg of
colorless oil (isolated yield: 78%).1H NMR (CDCl3): d 7.36 ppm
(m, 5H, aromatics); 6.67 (bd, 1H, 3JH7–H8 trans ¼ 15.8 Hz, C7–H);
6.27 (dt, 1H, 3JH8–H7 trans ¼ 15.7 Hz, 3JH8–H9 ¼ 6.6 Hz, C8–H) and
3.96 (bd; 2H, 3JH9–H8 ¼ 6.5 Hz, C9–H). 13C NMR (CDCl3): d 136.1
(C1, ipso aromatic); 134.6 (C7, quaternary olenic); 128.7 (C3
and C5, meta aromatics); 128.2 (C4, para aromatic); 126.7 (C2
and C6, ortho aromatics); 122.5 (C8, CH olenic) and 53.0 (C9,
N–CH2–).
3
4
(q, 2H, JH9–H8 ¼ 6.7 Hz, C9–H) and 2.09 (d, 3H, JH10–H8
¼
1.3 Hz, C10–H). 13C NMR (CDCl3): d 142.9 ppm (C1, ipso
aromatic); 128.5 (C7, quaternary olenic); 128.3 (C3 and C5,
meta aromatics); 127.0 (C4, para aromatic); 125.8 (C2 and C6,
ortho aromatics); 60.0 (C9, O–CH2–) and 16.0 (C10, CH3). HRMS
(ESI): mass calculated for C10H13O+ (M + H+), 149.09609; found,
149.09610. IR (lm): ymax (cmꢀ1) ¼ 3402 (O–H), 2969 (]CH–),
2921 (–CH2–).
Synthesis of (E)-ethyl 3-phenylbut-2-enoate (13E). 1.1 equiv-
alents of sodium hydride (55.2 mg, 2.3 mmol) were dissolved in
4 mL of anhydrous dimethoxy ethane at room temperature and
inert atmosphere. Then, 1.1 equivalents of triethylphospho-
noacetate (TEPA, 517 mg, 2.3 mmol) were added followed by the
slowly addition of 1 equivalent of acetophenone (250 mg, 2.1
mmol). Aer 3 h of continuous stirring, the reaction was
quenched with water. The inorganic phase was extracted 3
times (3 ꢂ 30 mL) with ethyl ether and the combined organic
layers concentrated under vacuum. The residue was puried on
a silica gel column (hexane : ethyl acetate) to afford 205 mg of
colourless oil (isolated yield: 60%, ratio E/Z 92 : 8). 1H NMR
(CDCl3): d 7.47 ppm (m, 2H, meta aromatics, C3–H and C5–H);
7.37 (m, 3H, ortho and para aromatics, C2–H, C4–H and C6–H);
Synthesis of (E)-(4-azido-but-2-en-2-yl) benzene (16).
Following the general reaction conditions for the prenyl azides
synthesis, compound 5 (34 mg; 0.23 mmol) was dissolved in
anhydrous toluene (1 mL). Then, DPPA was slowly added
(79 mg, 0.30 mmol) followed by the addition of DBU (46 mg;
0.30 mmol). Aer 8 h of continuous stirring at room tempera-
ture, the reaction was worked up and puried to afford 36 mg of
colourless oil (isolated yield: 91%). 1H NMR (CDCl3): d 7.42 ppm
(m, 2H, meta aromatics, C3–H and C5–H); 7.32 (m, 3H, ortho
and para aromatics, C2–H, C4–H and C6–H); 5.88 (dt, 1H, 3JH8–
4
6.14 (dd, 1H, olenic, C8–H, JH8–H10 ¼ 1.3 Hz); 4.22 (q, 2H,
3JH11–H12 ¼ 7.1 Hz, C11–H); 2.58 (d, 3H, 4JH10–H8 ¼ 1.2 Hz, C10–
H) and 1.32 (t, 3H, 3JH12–H11 ¼ 7.1 Hz, C12–H). 13C NMR (CDCl3):
d 166.9 (C9, carbonyl); 155.5 (C7, quaternary olenic); 142.3 (C1,
ipso aromatic); 129.0 (C4, para aromatic); 128.5 (C3 and C5, meta
aromatics); 126.3 (C2 and C6, ortho aromatics); 117.2 (C8, CH,
¼ 6.7 Hz and 4JH8–H10 trans ¼ 1.3 Hz, C8–H); 3.99 (d, 2H, 3JH9–
H9
¼ 6.7 Hz, C9–H) and 2.12 (d, 3H, 4JH10–H8 ¼ 1.3 Hz, C10–H).
H8
13C NMR (CDCl3): d 142.4 ppm (C1, ipso aromatic); 141.4 (C7,
quaternary olenic); 128.4 (C3 and C5, meta aromatics); 127.7
(C4, para aromatic); 125.9 (C2 and C6, ortho aromatics); 120.2
(C8, CH olenic); 48.6 (C9, N–CH2–) and 16.3 (C10, CH3). IR
(lm): ymax (cmꢀ1) 2976 (cCH–), 2928 (–CH2–), 2095 (–N3), 1623
(C]C).
olenic); 59.8 (C11, O–CH2–); 17.9 (C10, CH3) and 14.3 (C12,
+
CH3). HRMS: mass calculated for C12H15O2 (M
+
H+),
191.10666; found, 191.10670. IR (lm): ymax (cmꢀ1) 2978 (]CH–
), 2926 (–CH2–), 1713 (C]O), 1628 (C]C).
47536 | RSC Adv., 2017, 7, 47527–47538
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RSC Advances
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Conflicts of interest
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Y. Nagao, Tetrahedron Lett., 1987, 28, 6289–6292.
19 S. Murahashi, Y. Taniguchi, Y. Imada and Y. Tanigawa, J.
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There are no conicts to declare.
Acknowledgements
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E. Alvarez, R. Alvarez-Manzaneda, A. Haidour and
J. M. Ramos Lopez, Tetrahedron Lett., 2005, 46, 3755–3579.
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The authors wish to express their gratitude to UNR (Universidad
´
Nacional de Rosario), Fundacion Josena Prats, CONICET
´
´
(Consejo Nacional de Investigaciones Cientıcas y Tecnicas, PIP
2009-11/0796 and PIP 2012-14/0448), Agencia Nacional de
´
´
´
Promocion Cientıca y Tecnologica (PICT-2011-0589). MMV
thanks UNNE, SECYT-UNNE (PI F005-2013), and ANPCyT (PICT-
2015-2635). This investigation also received nancial support
(through GRL) from the UNICEF/UNDP/WORLD BANK/WHO
Special Programme for Research and Training in Tropical
Diseases (TDR). GRL, MMV and ABJB are members of the
Research Career of CONICET. EOJP thanks CONICET for the
award of a Fellowship.
25 G. R. Labadie, R. Viswanathan and C. D. Poulter, J. Org.
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26 Molinspiration chemoinformatics.
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47538 | RSC Adv., 2017, 7, 47527–47538
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