Hetero-Diels-Alder reaction of aromatic aldehydes catalyzed by titanium tetrachloride: Computational and experimental results

Article abstract of DOI:10.1016/j.tet.2013.11.077

Computational calculations of the hetero-Diels-Alder (HDA) reactions of benzaldehyde with 2,3-dimethyl-1,3-butadiene (DMB) catalyzed by BF₃, EtAlCl₂ or TiCl₄ at the density functional theory (DFT) (B3LYP/6-31G(d,p)) level

Full text of DOI:10.1016/j.tet.2013.11.077

Tetrahedron 70 (2014) 735e741
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Hetero-DielseAlder reaction of aromatic aldehydes catalyzed by
titanium tetrachloride: computational and experimental results
*
Nidhi Sogani, Pragya Sinha, Raj K. Bansal
Department of Chemistry, The IIS University, Jaipur 302020, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 August 2013
Received in revised form 16 November 2013
Accepted 21 November 2013
Available online 28 November 2013
Computational calculations of the hetero-DielseAlder (HDA) reactions of benzaldehyde with 2,3-
dimethyl-1,3-butadiene (DMB) catalyzed by BF3, EtAlCl2 or TiCl4 at the density functional theory (DFT)
(B3LYP/6-31G(d,p)) level reveal that the reactions involve activation energy barriers of 14.59, 14.34, and
17.44 kcal molꢀ1, respectively. In the first two cases, reaction occurs through a concerted mechanism,
whereas in the presence of TiCl4, stepwise mechanism involving zwitterionic intermediate is followed.
The reaction with isoprene proceeds with complete regioselectivity leading to the expected regioisomer
having O/Me in 1:4 positions. The computational results have been verified experimentally when aro-
matic aldehydes react with 1,3-dienes in the presence of a catalyst to give 3,6-dihydro-2H-pyran de-
rivatives in high yields.
Keywords:
Hetero-DielseAlder reaction
Aldehydes
Homogeneous catalysis
Density functional calculations
Stepwise mechanism
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
HDA reaction of unactivated aldehydes with simple dienes was
achieved in the presence of Pdþ2 catalyst9a or a mixture of AlCl3 or
Since its discovery in 1928, the DielseAlder (DA) reaction1 has
witnessed many path-breaking developments2 resulting in in-
numerable elegantly planned applications in the construction of
many complex organic molecules.3 The scope of the DA reaction
was greatly broadened by using hetero-dienes and hetero-
dienophiles facilitating the synthesis of many heterocycles and
complex natural products.4 Hetero-DielseAlder (HDA) reaction
using carbonyl compounds as hetero-dienophiles or hetero-dienes
has made a wide variety of substituted dihydropyrans accessible,
which occur as structural motifs in many biologically active natural
products.4,5 However, carbonyl compounds as dienophiles are
much less reactive and the HDA reaction between aldehydes and
dienes has been limited either to the reaction of highly electron-
rich dienes (such as Danishefsky’s diene) with simple aldehydes
or to the reaction of highly activated aldehydes (such as chloral and
glyoxalates) with simple dienes.6 In view of this, the HDA reaction
of the carbonyl compounds often requires a Lewis acid as catalyst.
For example, aldehydes underwent HDA reaction with Dani-
shefsky’s diene in the presence of Lewis acid catalysts.7 The HDA
reaction of simple dienes, such as cyclohexadiene and dime-
thylbutadiene (DMB) have been accomplished with alkyl glyox-
alates in the presence of cationic copper-Lewis acid catalyst.8 The
SnCl4 with nitroalkane as catalyst.9b Similarly in other cases, strong
€
Bronsted acid was used as catalyst, which caused side reactions or
gave poor yields.9c,d
The experimental results of the DA reactions, particularly the
observed stereo- and regio-selectivities, have been often rational-
ized on the basis of computational calculations.10 Likewise, theo-
retical studies of the HDA reactions have been carried out, though to
a lesser extent, to investigate their mechanism and mode of action of
the catalyst.11 For example, in a study on the mechanism of the HDA
reactions with Danishefsky’s diene at the semiempirical (AM1) and
ab initio (HF/6-31G) levels, the uncatalyzed reaction was found to
proceed through a concerted mechanism involving an asynchro-
nous transition state, whereas, in the presence of (MeO)2AlMe as
catalyst, the reaction occurred via a stepwise mechanism involving
a zwitterionic intermediate.11a Theoretical study of the mechanism
of the HDA reaction of butadiene with benzaldehyde catalyzed by
chiral N,N0-dioxide/In(OTf)3 complex by using DFT method in-
dicated that the catalyzed reaction proceeded through a concerted
mechanism via a highly zwitterionic transition state and the lowest
energy barrier was 11.8 kJ molꢀ1, 63.0 kJ molꢀ1 lower than that of the
uncatalyzed reaction. Furthermore, the endo approach was found to
be preferred over the exo approach, because the latter suffered from
more steric hindrance.12 In another theoretical investigation at the
DFT level, intramolecular HDA reaction of cyclic benzylidene sulf-
oxides was predicted to give endo products stereoselectively, which
accorded well with the experimental results.11c The
* Corresponding author. Tel.: þ91 141 240 0160; fax: þ91 141 239 5494; e-mail
addresses: bansal56@gmail.com, bansalrk43@yahoo.com (R.K. Bansal).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.077

736
N. Sogani et al. / Tetrahedron 70 (2014) 735e741
stereoselectivity in the HDA reaction of ortho-xylylenes with acet-
aldehydes was investigated theoretically with the B3LYP and MP2
functionals and the observed high endo selectivity was shown to
In a theoretical study of the complexes of formaldehyde with
titanium tetrachloride at the ab initio level, formation of the 1:1
and 2:1 complexes was detected and the latter was found to be
energetically preferred.14 In view of this, we also optimized 1:1 and
2:1 complexes of benzaldehyde with titanium tetrachloride and
determined their energies. It is found that the 2:1 complex is more
stable than the 1:1 complex by ca. 11 kcal molꢀ1. For the purpose of
the calculation of the activation enthalpies, however,1:1 complexes
were taken into account. Furthermore, on attempting to optimize
the transition structures corresponding to the endo and the exo
approaches in the HDA reaction of benzaldehydeeTiCl4 complex
with DMB, only the former was optimized, whereas the transition
structure for the exo approach suffered from the steric hindrance
between the diene moiety and TiCl4 and optimization could not be
completed. This observation is similar to the one reported for the
HDA reaction of benzaldehyde with butadiene catalyzed by In(III)
complex.12 In view of this, in other cases, the transition structures
for the endo approach only were investigated.
result from the CHep interactions between the alkyl groups of the
aldehyde and the aromatic ring in the transition state.13
We undertook a systematic theoretical and experimental in-
vestigation of the HDA reactions of aromatic aldehydes with simple
dienes, namely DMB and isoprene; the results are presented here.
2. Results and discussion
2.1. Computational results
To investigate the mechanisms of the HDA reactions of the ar-
omatic aldehydes in the absence of the catalyst and also in the
presence of three catalysts, we computed fifteen model reactions
(Scheme 1 and Table 1) at the DFT level.
Z
R2
R3
2.1.1. Geometries. The B3LYP/6-31G(d,p) optimized geometries of
the transition structures, TS1e6 involved in the uncatalyzed HDA
reaction nos. 1e7 are shown (Fig. 1).
Z
O
C
O
R2
R3
H
H
+
TS
In accordance with the earlier report,10a uncatalyzed HDA re-
actions in the present case also follow pericyclic mechanism in-
volving concerted transition structures that are, however,
asynchronous, formation of the CeC bond (WBI¼0.45e0.48) being
more advanced than the CeO bond (WBI¼0.33e0.36), in the endo
approach of the diene. Asynchronous transition structures have
been located in the dimerization of methacrolein, which have been
attributed to the merging of [4þ2] and [2þ2] mechanisms.15 It is
noteworthy that the asynchronicity is reduced in the exo approach
and the transition structure, TS1 exo becomes almost synchronous
(WBI, CeC¼0.36, CeO¼0.35).
R1
3a-n
2a,b
1a-e
R1
R1
3
Z
R2
R3
R2
R3
1
R1
Z
2
a
H
Cl
H
NIL
NIL
NIL
NIL
NIL
NIL
BF3
Me
Me
H
Me
H
Me
Me
Me
Me
Me
H
Me
H
Me
Me
Me
Me
Me
H
a
b
c
d
e
f
H
Cl
H
H
H
Cl
NIL
NIL
BF3
EtAlCl2
TiCl4
TiCl4
a
b
Me
Me
Me
H
b
c
d
e
f
H
Cl
Cl
H
g
h
i
H
H
Cl
H
H
Cl
Cl
EtAlCl2 Me
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
Me
Me
H
Me
H
Me
In the reaction of benzaldehyde with isoprene, the transition
structures resulting from the para approach of the diene (O/Me,
1:4) are comparatively more asynchronous (WBI, CeC¼ca. 0.46,
CeO¼0.33) than the transition structures obtained from the meta
approach (O/Me, 1:3) (WBI, CeC¼ca. 0.45, CeO¼ca. 0.36).
The HDA reactions of benzaldehyde in the presence of ethyl-
aluminium dichloride and boron trifluoride as catalysts are also
j
k
l
m
n
Me
H
Scheme 1. Computed model DA reactions of aromatic aldehydes.
Table 1
Computed reactions of aromatic aldehydes with 1,3-diene in the absence of the catalyst and in the presence of a catalyst (Scheme 1)
Reac. no.
Z
R1R2R3
Approach of the diene
TS
Relative energy (kcal molꢀ1
Hs Hꢁ
D
)
D
1
2
3
4
5
6
7
8
Nil
Nil
Nil
Nil
Nil
Nil
Nil
BF3
EtAlCl2
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
H Me Me
H Me Me
Cl Me Me
H H Me
H Me H
Cl H Me
Cl Me H
H Me Me
H Me Me
H Me Me
Cl Me Me
H H Me
H Me H
Cl H Me
Cl H H
endo
exo
endo
endo (O/Me, para)
endo (O/Me, meta)
endo (O/Me, para)
endo (O/Me, meta)
endo
endo
endo
endo
endo (O/Me, para)
endo (O/Me, meta)
endo (O/Me, para)
endo (O/Me, meta)
TS1 (endo)
TS1 (exo)
TS2
TS3
TS4
TS5
TS6
TS7
TS8
29.72 (30.47)
30.19 (30.89)
28.88 (29.39)
29.33 (30.10)
31.30 (32.15)
28.54 (29.12)
30.59 (31.23)
14.59 (14.24)
14.34 (14.71)
17.44 (15.29)
17.05 (14.84)
17.62 (15.41)
23.24 (21.31)
17.27 (14.92)
22.59 (20.39)
ꢀ9.71 (ꢀ8.45)
ꢀ12.53 (ꢀ11.21)
ꢀ10.29 (ꢀ9.18)
ꢀ9.14 (ꢀ7.82)
ꢀ9.19 (ꢀ7.86)
ꢀ9.71 (ꢀ8.59)
ꢀ9.83 (ꢀ8.70)
ꢀ12.29 (ꢀ9.48)
ꢀ4.63 (ꢀ2.67)
ꢀ2.50 (ꢀ0.54)
ꢀ3.39 (ꢀ1.56)
ꢀ4.76 (ꢀ2.62)
ꢀ4.72 (ꢀ2.53)
ꢀ5.41 (ꢀ3.48)
ꢀ5.45 (ꢀ3.49)
9
10
11
12
13
14
15
TS9
TS10
TS11
TS12
TS13
TS14
Relative energy values for the solvent phase (toluene) are given in parentheses.
The HDA reactions of benzaldehyde with DMB have been com-
puted involving the endo as well as the exo approaches of the diene.
As reported in other HDA reactions of the aldehydes,12,13 the endo
approach in the present case also has preference over the exo ap-
found to involve concerted, but asynchronous transition structures
(Fig. 2). Earlier attempts10a to locate a concerted transition state in
the HDA reaction of benzaldehyde with Danishefsky’s diene in the
presence of (MeO)2AlMe as catalyst failed. The asynchronicity in
these cases increases further and these reactions in fact lie on the
proach by ca. 0.5 kcal molꢀ1
.

N. Sogani et al. / Tetrahedron 70 (2014) 735e741
737
The HDA reaction of benzaldehydes with DMB in the presence of
Ti(IV) chloride occurs in two steps, the first step leading to the
zwitterionic intermediate being rate determining. The optimized
geometries of the first and the second transition structures (TS9i
and TS9ii, respectively) along with that of the intermediate in-
volved in the HDA reaction of benzaldehyde with DMB in the
presence of TiCl4 are shown (Fig. 3).
Fig. 3. B3LYP/6-31G(d,p) optimized geometries of the first and the second transition
structures (TS9i and TS9ii, respectively) and the zwitterionic intermediate (Int9) in-
volved in the HDA reaction of benzaldehyde with 2,3-dimethyl-1,3-butadiene cata-
lyzed by TiCl4.
It may be noted that formation of the CeC bond in the first
transition structure, TS9i is quite advanced (occupancy, 1.70e; bond
distance, 1.855 A; WBI, 0.59) and approaches the reaction in-
Fig. 1. B3LYP/6-31G(d,p) optimized geometries of the transition structures in the un-
catalyzed HDA reactions along with the bond distances (in A) and Wiberg bond index
ꢀ
ꢀ
(WBI) in parentheses.
termediate, Int9. The second transition state, TS9ii is not much
different from the intermediate, i.e., it is reached quite early. The
LUMOs of benzaldehyde (1) and of its complexes with BF3 (2),
EtAlCl2 (3), and TiCl4 (4) and the HOMOs of DMB (5) and isoprene
(6) are shown (Fig. 4).
It is noteworthy that polarization of the LUMO centered on the
carbonyl group of benzaldehyde is not much altered on its com-
plexation with BF3 and EtAlCl2, although their energies are lowered.
It explains the involvement of a concerted transition state in all the
three cases, and the reaction becoming faster in the presence of BF3
or EtAlCl2. However, on complexation with TiCl4, polarization of the
LUMO on the carbonyl group changes remarkably, the lobe on the
carbonyl oxygen merging with the d orbital of the titanium atom
due to dp/pp bonding. Due to this reason, carbonyl carbon be-
comes significantly positively charged, thus inducing a stepwise
ionic mechanism.
Fig. 2. B3LYP/6-31G(d,p) optimized geometries of the transition structures in the HDA
reactions catalyzed by BF3 and by EtAlCl2 along with the bond distances (in A) and
ꢀ
2.1.2. Energetics. Thermodynamic data of the calculated model
HDA reactions are given in the Supplementary data TS2. All the
reactions are exothermic, but as expected, the entropy of the re-
action decreases substantially. Thus it is the activation enthalpy
Wiberg bond index in parentheses.
border-line between two distinct types of mechanisms, namely the
pericyclic mechanism and the stepwise ionic mechanism. The latter
type of mechanism is found to operate in the presence of TiCl4 as
catalyst, discussed later.
(DH
s), which plays the main role in the occurrence of the reaction.
The activation enthalpy of the uncatalyzed HDA reaction of
benzaldehyde with DMB in the gas phase (
D
Hs¼29.72 kcal molꢀ1
)

738
N. Sogani et al. / Tetrahedron 70 (2014) 735e741
Fig. 4. LUMOs of benzaldehyde (1) and its complexes with BF3 (2), EtAlCl2 (3), and
TiCl4 (4) and the HOMOs of DMB (5) and isoprene (6) along with their energies.
Fig. 5. Relative activation enthalpies for the reaction of benzaldehyde with 2,3-
dimethyl-1,3-butadiene without catalyst and in the presence of various catalysts.
is quite high, which increases further by ca. 1 kcal molꢀ1 in toluene.
The presence of an electron-withdrawing group (EWG) like chlo-
rine in the phenyl ring is also not much effective, as it brings down
as catalyst. Encouraged by these results, we investigated the HDA
reactions of four aromatic aldehydes (1aed) with DMB and isoprene.
DH
s only marginally, just by ca. 1 kcal molꢀ1 in the gas phase or in
solution. It explains the inertness of aromatic aldehydes towards
HDA reaction under uncatalyzed conditions.
2.2. Experimental results
The presence of BF3 or EtAlCl2 as catalyst brings down the D
Hs
in the gas phase substantially (ca. 15 kcal molꢀ1), which is further
reduced marginally in toluene. It indicates that the HDA reaction of
aromatic aldehydes with DMB should be possible in the presence of
any of these catalysts. As described later, the HDA reaction of m-
nitrobenzaldehyde with DMB could be accomplished successfully
in the presence of EtAlCl2. The use of TiCl4 as catalyst not only
Aromatic aldehydes (1) on reacting with 1,3-diene (2) in the
presence of a catalyst in toluene at room temperature afford 3,6-
dihydro-2H-pyran derivatives (3) (Scheme 2).
The reaction is complete in ca. 1e2 h at room temperature. The
presence of EWG (Table 2, entries 1, 2, 5, 6, 7) makes the reaction
lowers the
D
Hs by ca. 12 kcal molꢀ1 in the gas phase, which is
further reduced in the solvent by 2 kcal molꢀ1, it also changes the
mechanism of the reaction from pericyclic to the stepwise ionic.
Now the reaction occurs in two steps, the first step being rate de-
termining. Although it has been possible to locate the second
transition state, it is very similar to the intermediate and is only
0.11 kcal molꢀ1 higher in energy than the intermediate in the gas
phase (0.46 kcal molꢀ1 in the solvent). The presence of chlorine
atom in the phenyl ring is not of much consequence and there is no
HE
HD
R2
6
3
O
C
O
5
4
1
2
HA
1'
6'
3'
Me
R2
15% Catalyst
Toluene, r.t.
5'
H
Me
+
HB
HC
2'
4'
R1
R1
2
1b,g-i
3b,o-s
significant change in the DH
s value for the TiCl4 catalyzed reaction.
As regards the regioselectivity of the reaction with isoprene in the
R1
R1
4-Cl
3-NO2 Me
2-OMe Me
2,5-(OMe)2 Me
4-Cl
3-NO2
R2
Me
1
3
presence of TiCl4 catalyst, the path leading to the para regioisomer
4-Cl
3-NO2
2-OMe
b
g
h
i
b
o
p
q
r
(O/Me, 1:4) has D
Hs lower than the path giving meta regioisomer
(O/Me,1:3) by ca. 6 kcal molꢀ1. The activation enthalpies of the HDA
reactions under different conditions are depicted graphically
(Fig. 5).
2,5-(OMe)2
H
H
s
It may be inferred from the above theoretical results that the
HDA reactions of benzaldehydes with simple dienes, such as DMB
or isoprene should be possible only in the presence of a Lewis acid
Scheme 2. HDA reaction of aromatic aldehyde with 1,3-diene in the presence of
catalyst.

N. Sogani et al. / Tetrahedron 70 (2014) 735e741
739
Table 2
The HDA reactions of aromatic aldehydes in the presence of a catalyst
4. Computational methods
In a number of investigations of the DA and HDA reactions, the
activation barriers calculated at the DFT level using the B3LYP hy-
brid functional18,19 have been found in good agreement with the
experimental results. In the present study therefore all geometries
of the reactants, cycloadducts, and the corresponding transition
structures were optimized in the gas phase at the B3LYP/
6ꢀ31G(d,p) level of theory using Gaussian 03 suite of program,20
generating basis sets for Ti at the 6-31G(d,p) level.
Entry
R1
R2
Catalyst (mol %)
Yield (%)
Time (h)
1
2
3
4
5
6
7
4-Cl
Me
Me
Me
Me
Me
H
TiCl4 (15)
TiCl4 (15)
TiCl4 (15)
TiCl4 (15)
EtAlCl2 (15)
TiCl4 (15)
TiCl4 (15)
74
84
56
52
79
70
72
1.50
1.25
2.50
2.00
1.00
1.75
1.50
3-NO2
2-OMe
2,5-(OMe)2
3-NO2
4-Cl
3-NO2
H
Frequency calculations were done at the same level to de-
termine zero-point correction energies and to characterize the
transition structure by the presence of one and only one imaginary
frequency corresponding to the movement of the atoms in the di-
rection of the bond formation. The intrinsic reaction coordinate
(IRC)21,22 calculations starting at the respective transition structure
were carried out at the B3LYP/6ꢀ31G(d,p) level to confirm its
connection with the corresponding reactants and the cycloadducts.
The natural bond orbital (NBO) analysis23 was employed for the
evaluation of the forming bonds. Following the reports of the other
research groups24e27 on the use of the self-consistent reaction field
polarizable continuum model (SCRF-PCM)28,29 for studying the
solvent effect, we also used this model and calculated single point
energy of the B3LYP/6ꢀ31G(d,p) gas phase optimized stationary
points at the same level using SCRF method based on Tomasi’s
polarizable continuum model (PCM).30 FMOs were generated by
using Chemcraft software.31
faster. As described earlier, the relative activation energy barrier
for the HDA reaction in the presence of EtAlCl2 is smaller than in
the presence of TiCl4; it is supported by the experimental results,
as the HDA reaction of 1b with DMB in the presence of EtAlCl2
(Table 2, entry 5) is complete sooner than in the presence of TiCl4
(Table 2, entry 2). All the reactions occur with complete stereo-
selectivity, only one product (in fact a racemic mixture of two
enantiomers) being formed in the reaction with DMB. As regards
the regioselectivity, experimental results are in complete agree-
ment with the theoretical results; the reaction of p-chlor-
obenzaldehyde (1b) with isoprene in the presence of TiCl4
(15 mol %) gives only the regioisomer having O/Me in the 1:4-
positions.
On using less than 15 mol % of the catalyst, unreacted aldehyde
is detected (TLC). Furthermore, if the reaction mixture is not
quenched just after completion, aldehyde is regenerated. Similar
observations have been made earlier.16,17
5. Experimental section
All the products are pale yellow to orangish-yellow syrupy mass,
which have been characterized on the basis of IR spectra, 1H and
13C NMR spectra and elemental analysis. In the IR spectra, an in-
Commercially available aldehydes, DMB, and isoprene were
used without further purification. TiCl4 (1.0 M solution in CH2Cl2)
and EtAlCl2 (1.8 M solution in toluene) were purchased from Sig-
maeAldrich. Solvents were freshly dried and distilled.
IR spectra were recorded on NaCl plate on Perkin Elmer Pre-
cisely FT-IR spectrometer. NMR spectra were recorded on Bruker-
DPX-300 MHz spectrometer: 1H NMR at a frequency of 300.13 MHz
and 13C NMR at a frequency of 75.48 MHz using TMS as the internal
reference. The C, H, N elemental analyses were done on FLASH Ea
1112 series CHN analyzer at the School of Chemistry, University of
Hyderabad, Hyderabad, India.
tense absorption band in the region n
1099e1090 cmꢀ1 results due
to CeO stretching vibrations. In the 1H NMR spectra, protons
HB and HC (at C3) are diastereotopic and they constitute an
ABC spin system with the proton HA (at C2): proton HA gives
a double doublet (dd) at
d
4.49e4.91 ppm (3JHA,HB¼9.0e10.5 Hz,
3JHA,HC¼3.6e6.0 Hz), HB
a
dd at
d
2.11e2.91 ppm
3
(2JHB,HC¼14.1e16.8 Hz, JHA,HB¼9.0e10.5 Hz) and HC a dd at
3
d
2.11e3.06 ppm (2JHB,HC¼14.1e16.8 Hz, JHA,HC¼3.6e6.0 Hz). Like-
wise, protons HD and HE at C6 are diastereotopic forming an AB spin
system and each gives
a
doublet at
d
4.18e4.35 ppm
(2JHD,HE¼9.0e9.9 Hz) and at
d
4.05e4.35 ppm (2JHD,HE¼9.0e9.9 Hz),
5.1. General procedure for the TiCl4 and EtAlCl2 catalyzed HDA
reaction (3b,oes)
respectively. The methyl groups at C4 and C5 give singlets in the
region
gions. In the 13C NMR spectrum, the carbon atoms C2 and C6 absorb
typically at 70.6e75.4 and 66.4e70.1 ppm, respectively. The
d 1.57e1.79 ppm. Other protons absorb in the expected re-
Aldehyde 1 (3 mmol) was dissolved in toluene (20 mL) taken in
a 100 mL R.B. flask at room temperature (w25 ꢁC). To this solution
was added the solution of TiCl4 (0.45 mmol, 0.45 mL 1 M solution in
CH2Cl2) or EtAlCl2 (0.45 mmol, 0.25 mL 1.8 M solution in toluene)
when yellow to orangish brown color developed. After stirring the
resulting turbid solution at room temperature for about 30 min,
two-fold excess of the diene 2 (6 mmol) was added dropwise and
the reaction mixture was stirred at room temperature for 1e2.5 h,
progress of the reaction being monitored by TLC (solvent: pet. ether
60e80 ꢁC/EtOAc: 80:20 v/v %). After completion of the reaction, the
reaction mixture was quenched with water (10 mL) and the organic
layer was separated. The aqueous layer was extracted with toluene
(2ꢂ2 mL). The combined extracts were dried over anhydrous so-
dium sulfate and the solution was concentrated to ca. 2e3 mL. The
crude product was purified by column chromatography over silica
gel (eluent; pet. ether 60e80 ꢁC/EtOAc: 98:2 v/v%). A viscous oil 3
was obtained.
d
d
other carbon atoms give signals in the expected regions.
3. Conclusion
We have demonstrated theoretically that the HDA reactions of
the aromatic aldehydes with simple dienes, such as DMB or iso-
prene can be catalyzed by Lewis acid, namely BF3, EtAlCl2 or TiCl4.
In the case of the first two catalysts, the reaction follows a con-
certed mechanism with the asynchronous transition states, but
TiCl4 catalyzed reaction occurs through a stepwise ionic mecha-
nism involving a zwitterionic intermediate. The reaction with iso-
prene is expected to take place with complete regioselectivity to
give the regioisomer having O/Me in the 1:4 positions. These results
have been verified experimentally, when HDA reactions of aromatic
aldehydes with DMB and with isoprene have been accomplished
successfully in the presence of 15 mol % TiCl4 to give 3,6-dihydro-
2H-pyran derivatives in high yields. That EtAlCl2 can be used as
catalyst in place of TiCl4, has been demonstrated for the HDA re-
action of m-nitrobenzaldehyde with DMB.
5.1.1. 3,6-Dihydro-4,5-dimethyl-2-(40-chlorophenyl)-2H-pyran
3b. From 4-chlorobenzaldehyde (421 mg, 3 mmol) and DMB
(493 mg, 6 mmol, 0.68 mL) 3b (490 mg, 74%) was obtained as

740
N. Sogani et al. / Tetrahedron 70 (2014) 735e741
a colorless viscous oil; [found: C, 70.25; H, 6.85. C13H15OCl requires
C, 70.11; H, 6.79%]; Rf (25% EtOAc/pet. ether) 0.59; nmax (NaCl plate)
5.50 (s, 1H, 5-H), 4.51 (dd, 3JHAHB¼10.5 Hz, 3JHAHC¼3.6 Hz, 1H, 2-HA),
4.31 (s, 2H, 6-HD, 6-HE), 2.32e2.12 (m, 2H, 3-HB, 3-HC), 1.79 ppm (s,
3H, 4-Me).
2956, 2922, 2868, 1491, 1449, 1405, 1382, 1090, 1014, 821 cmꢀ1
;
dH
3
(CDCl3, 25 ꢁC) 7.78 (d, JHH¼6.6 Hz, 2H, H20, H60), 7.47 (d,
3JHH¼6.6 Hz, 2H, H30, H50), 4.49 (dd, 3JHAHB¼10.5 Hz, 3JHAHC¼3.9 Hz,
5.1.6. 3,6-Dihydro-4-methyl-2-(30-nitrophenyl)-2H-pyran 3s. From
3-nitrobenzaldehyde (453 mg, 3 mmol) and isoprene (408 mg,
6 mmol, 0.60 mL) 3s (475 mg, 72%) was obtained as a yellow viscous
oil. [Found: C, 65.86; H, 5.91; N, 6.28. C12H13NO3 requires C, 65.74;
H, 5.98; N 6.39]; Rf (10% EtOAc/pet. ether) 0.67; nmax (NaCl plate)
2
1H, 2-HA), 4.18 (d, JHDHE¼15.6 Hz, 1H, 6-HD), 4.08 (d,
2JHDHE¼15.6 Hz, 1H, 6-HE), 2.26e2.17 (m, 2H, 3-HB, 3-HC), 1.67 (s,
3H, 5-Me), 1.57 ppm (s, 3H, 4-Me); dC (CDCl3, 25 ꢁC): 141.2, 132.9,
128.0, 126.9, 124.5, 123.5, 75.4 (2-C), 70.7 (6-C), 38.5 (3-C), 18.8,
13.8 ppm.
2929, 1531, 1481, 1446, 1348, 1122, 1095, 1044, 813 cmꢀ1
; dH (CDCl3,
4
3
25 ꢁC) 8.27 (d, JHH¼1.5 Hz, 1H, H20), 8.14 (dd, JHH¼8.1 Hz,
3
5.1.2. 3,6-Dihydro-4,5-dimethyl-2-(30-nitrophenyl)-2H-pyran
4JHH¼1.5 Hz, 1H, H40), 7.73 (d, JHH¼7.8 Hz, 1H, H60), 7.52 (t,
3
3o. From 3-nitrobenzaldehyde (453 mg,
3
mmol) and DMB
3JHH¼7.8 Hz, JHH¼8.1 Hz, 1H, H50), 5.53 (s, 1H, H5), 4.64 (dd,
3
(493 mg, 6 mmol, 0.68 mL) 3o (590 mg, 84%) was obtained as
a yellow viscous oil; [found: C, 66.85; H, 6.54; N, 6.12. C13H15NO3
requires C, 66.94; H, 6.48; N, 6.00%]; Rf (10% EtOAc/pet. ether) 0.67;
3JHAHB¼9.6 Hz, JHAHC¼4.2 Hz, 1H, 2-HA), 4.35 (d, 2J¼2.1 Hz, 2H, 6-
2
3
HD, 6-HE), 2.28 (dd, JHBHC¼16.8 Hz, JHAHB¼9.6 Hz, 1H, 3-HB), 2.18
2
3
(dd, JHBHC¼16.8 Hz, JHAHC¼4.2 Hz, 1H, 3-HC), 1.77 ppm (s, 3H, 4-
Me); dC (CDCl3, 25 ꢁC) 148.3, 144.9, 131.9, 131.4, 129.3, 122.3,
120.9, 119.9, 74.5 (2-C), 66.4 (6-C), 37.5 (3-C), 22.9 (5-Me) ppm.
nmax (NaCl plate) 2958, 2868, 1531, 1454, 1350, 1099, 805 cmꢀ1
; dH
(CDCl3, 25 ꢁC)¼8.26 (d, 4JHH¼1.8 Hz, 1H, H20), 8.21 (dd, 3JHH¼8.1 Hz,
3
4JHH¼1.8 Hz, 1H, H40), 7.72 (d, JHH¼7.8 Hz, 1H, H60), 7.52 (t,
3
3
3JHH¼7.8 Hz, JHH¼8.1 Hz, 1H, H50), 4.65 (dd, JHAHB¼9.9 Hz,
3JHAHC¼6.0 Hz,1H, 2-HA), 4.23 (d, 2JHDHE¼15.6 Hz,1H, 6-HD), 4.18 (d,
2JHDHE¼15.6 Hz, 1H, 6-HE), 3.06 (dd, 2JHBHC¼15.6 Hz, 3JHAHC¼6.0 Hz,
Acknowledgements
Thanks are due to Therachem, Jaipur (India) for instrumental
facilities. N.S. thanks the UGC, New Delhi for a fellowship.
2
3
1H, 3-HC), 2.63 (dd, JHBHC¼15.6 Hz, JHAHB¼9.9 Hz, 1H, 3-HB), 1.70
(s, 3H, 5-Me), 1.60 ppm (s, 3H, 4-Me); dC (CDCl3, 25 ꢁC) 148.3, 144.9,
132.0, 129.3, 124.7, 123.2, 122.4, 121.0, 75.0 (2-C), 70.2 (6-C), 38.3 (3-
C), 18.3, 13.9 ppm.
Supplementary data
Total energies of reactants, transition structures, intermediates
and cycloadducts in gas phase and in toluene (Table S1), standard
and activation enthalpies, entropies and Gibbs free energies of the
computed reactions, 1e15 at the B3LYP/6-31G(d,p)level (Table S2)
and Cartesian coordinates of the geometries optimized at B3LYP/6-
31G** (generated basis sets) level (Table S3). Supplementary data
related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2013.11.077.
5.1.3. 3,6-Dihydro-4,5-dimethyl-2-(20-methoxyphenyl)-2H-pyran
3p. From 2-methoxybenzaldehyde (408 mg, 3 mmol) and DMB
(493 mg, 6 mmol, 0.68 mL) 3p (370 mg, 56%) was obtained as an
orange viscous oil. [found: C, 77.19; H 8.42 requires C, 77.03; H,
8.31]; Rf (15% EtOAc/pet. ether) 0.80; nmax (NaCl plate) 2923, 2837,
1588, 1493, 1463, 1438, 1244, 1099, 1050, 1029, 753 cmꢀ1
; dH (CDCl3,
4
3
25 ꢁC) 7.47 (d, JHH¼7.5 Hz, 1H, 60-H), 7.26 (t, JHH¼8.1 Hz,
3JHH¼7.5 Hz, 1H, H40), 6.98 (t, JHH¼3JHH¼7.5 Hz, 1H, H50), 6.85 (d,
3
3JHH¼8.1 Hz, 1H, H30), 4.91 (dd, 3JHAHB¼9.0 Hz, 3JHAHC¼5.1 Hz, 1H, 2-
HA), 4.18 (d, 2JHDHE¼11.1 Hz, 1H, 6-HD), 4.05 (d, 2JHDHE¼11.1 Hz, 1H,
6-HE), 3.82 (s, 3H, 20-OMe), 2.91 (dd, 2JHBHC¼14.7 Hz, 3JHAHB¼9.0 Hz,
References and notes
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2
3
1H, 3-HB), 2.74 (dd, JHBHC¼14.7 Hz, JHAHC¼5.1 Hz, 1H, 3-HC), 1.67
(s, 3H, 5-Me), 1.58 ppm (s, 3H, 4-Me); dC (CDCl3, 25 ꢁC) 155.8, 129.3,
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1049, 799 cmꢀ1
;
dH (CDCl3, 25 ꢁC) 7.08 (s, 1H, H60), 6.79 (d,
3
3JHH¼6.3 Hz, 1H, H30), 6.75 (d, JHH¼6.3 Hz, 1H, H40), 4.88 (dd,
3JHAHB¼9.6 Hz, 3JHAHC¼4.5 Hz, 1H, 2-HA), 4.21 (d, 2JHDHE¼9.9 Hz, 1H,
2
6-HD), 4.07 (d, JHDHE¼9.9 Hz, 1H, 6-HE), 3.80 (s, 6H, 20-OMe, 50-
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1.59 ppm (s, 3H, 4-Me); dC (CDCl3, 25 ꢁC) 153.9, 150.0, 132.2, 124.3,
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