Synthesis of Chromen[4,3-b]pyrrolidines by Intramolecular 1,3-Dipolar Cycloadditions of Azomethine Ylides: An Experimental and Computational Assessment of the Origin of Stereocontrol

Article abstract of DOI:10.1002/ejoc.201500434

Azomethine ylides, generated from imine-derived O-cinnamyl or O-crotonyl salicylaldeyde and α-amino acids, undergo intramolecular 1,3-dipolar cycloaddition, leading to chromene[4,3-b]pyrrolidines. Two reaction conditions are used: (a) microwave-assisted heating (200 W, 185 °C) of a neat mixture of reagents, and (b) conventional heating (170 °C) in PEG-400 as solvent. In both cases, a mixture of two epimers at the α-position of the nitrogen atom in the pyrrolidine nucleus was formed through the less energetic endo-approach (B/C ring fusion). In many cases, the formation of the stereoisomer bearing a trans-arrangement into the B/C ring fusion was observed in high proportions. Comprehensive computational and kinetic simulation studies are detailed. An analysis of the stability of transient 1,3-dipoles, followed by an assessment of the intramolecular pathways and kinetics are also reported. The two-component synthesis of chromene[4,3-b]pyrrolidines has been achieved under two different conditions. The strategy was used to obtain N-sulfonylated adducts with interesting biological activity. Calculations show that formation of W and S′ 1,3-dipoles determines the stereochemical outcome of the reaction, which involves asynchronous transition structures.

Full text of DOI:10.1002/ejoc.201500434

FULL PAPER
DOI: 10.1002/ejoc.201500434
Synthesis of Chromen[4,3-b]pyrrolidines by Intramolecular 1,3-Dipolar
Cycloadditions of Azomethine Ylides: An Experimental and Computational
Assessment of the Origin of Stereocontrol
Paulo R. R. Costa,[a] José M. Sansano,*[b] Unai Cossío,[c] Julio C. F. Barcellos,[a]
Ayres G. Dias,*[d] Carmen Nájera,[b] Ana Arrieta,[c] Abel de Cózar,[c,e] and
Fernando P. Cossío*[c]
Dedicated to the memory of Dr. Jean-Paul Picard
Keywords: Cycloaddition / Azomethine ylides / Kinetics / Reaction mechanisms / Transition states
Azomethine ylides, generated from imine-derived O-cinna-
myl or O-crotonyl salicylaldeyde and α-amino acids, undergo
intramolecular 1,3-dipolar cycloaddition, leading to
chromene[4,3-b]pyrrolidines. Two reaction conditions are
used: (a) microwave-assisted heating (200 W, 185 °C) of a
neat mixture of reagents, and (b) conventional heating
(170 °C) in PEG-400 as solvent. In both cases, a mixture of
rolidine nucleus was formed through the less energetic endo-
approach (B/C ring fusion). In many cases, the formation of
the stereoisomer bearing a trans-arrangement into the B/C
ring fusion was observed in high proportions. Comprehen-
sive computational and kinetic simulation studies are de-
tailed. An analysis of the stability of transient 1,3-dipoles, fol-
lowed by an assessment of the intramolecular pathways and
two epimers at the α-position of the nitrogen atom in the pyr- kinetics are also reported.
compound 1,[3] and constrained analogues 2,[4] which are
Introduction
antagonists of muscarinic acetylcholine receptors (mAChR)
and displayed potent activity against four selected bacterial
pathogens. The diazo derivative 3[5] is a key precursor in
the preparation of new amino azachromenes that display
photochromic properties (Figure 1). The chromene moiety
The chromene[4,3-b]pyrrolidine moiety is present in
many compounds exhibiting remarkable physiological
properties (Figure 1). This structural motif[1,2] is present in
[a] Laboratório de Química Biorgânica, Núcleo de Pesquisas de
Produtos Naturais, Centro de Ciencias da Saúde, Universidade
Federal do Rio de Janeiro,
Cidade Universitária, 21941-590 Rio de Janeiro, Brazil
http://www.nppn.ufrj.br
[b] Departamento de Química Orgánica, Instituto de Síntesis
Orgánica (ISO), and Centro de Innovación en Química
Avanzada (ORFEO-CINQA), Universidad de Alicante,
Apdo. 99, 03080 Alicante, Spain
E-mail: jmsansano@ua.es
http://dqorg.ua.es/es/curriculum-vitae.html
[c] Departmento de Química Orgánica I, Facultad de Química,
and Centro de Innovación en Química Avanzada (ORFEO
CINQA), Universidad del País Vasco/Euskal Herriko
Unibertsitatea (UPV/EHU), and Donostia International
Physics Center (DIPC),
Manuel Lardizábal 3, 20018 San Sebastián, Spain
E-mail: fp.cossio@ehu.es
http://www.ehu.eus/es/web/qbmm/hasiera
[d] Instituto de Química Universidade do Estado do Rio de
Janeiro - UERJ,
Rua São Francisco Xavier 524, PHLC, 3° andar, 20550-900 Rio
de Janeiro-RJ, Brazil
E-mail: ayres.dias@gmail.com
http://www.iq.uerj.br/principal.html
[e] IKERBASQUE, Basque Foundation for Science,
48011 Bilbao, Spain
Figure 1. Selected bioactive compounds bearing the chromene[4,3-
b]pyrrolidine moiety.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500434.
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FULL PAPER
is also present in a new class of modified isoflavonoids was also considered. In addition, the preparation of N–H
LQB-226 (4; Figure 1), which present antineoplastic and derivatives makes the synthesis more attractive because it
antiparasitary properties.[6] Encouraged by these properties, allows additional substitution at the nitrogen atom. A com-
we proposed the synthesis of related compounds 5 to study putational study of the simplest skeleton was also under-
their bifunctional biological activity.[7]
taken to determine a reasonable course for the reaction of
The most accessible routes to these fused chromene–pyr- the azomethine ylide on an electron-rich olefin, which is
rolidine skeletons involve intramolecular 1,3-dipolar cyclo- very difficult to achieve in an intermolecular version.
addition (1,3-DC) between azomethine ylides and alkenes
as a key step.[8] The 1,3-dipolar reaction between azome-
thine ylides and alkenes leads to the efficient regio- and
stereocontrolled synthesis of pyrrolidines,[9,10] the relevance
of which in biological chemistry[11] and materials science[12]
is well known. The synthesis of these particular polycyclic
compounds (with a core pyrrolidine ring)[13] has been
achieved through this intramolecular reaction onto imines
8[14–17] or iminium salts 10, which were prepared in situ by
reaction of O-allylated salicylaldehydes 6 with amino esters
7 or N-alkyl amino esters 9, respectively (Scheme 1).[18–20]
Imines 8 (R1 = Ph) do not react under thermal conditions,
so the use of the more reactive iminium cations of type 10
is recommended in this case.[21–26]
Results and Discussion
Synthesis of Compounds 5 by Intramolecular 1,3-DC
Compounds 6a and 6b were prepared by O-alkylation of
salicylaldehyde 12 with cinnamyl bromides 13 according to
standard procedures (Scheme 2), in good yields (70 and
73%, respectively). p-Nitrocinnamyl bromide 13b was pre-
pared from the corresponding alcohol in 73% overall yield.
Several attempts to prepare p-methoxycinnamyl derivative
6 (R1 = OMe) were unsuccessful.
Scheme 2. Synthesis of aldehydes 6.
Scheme 1. Synthetic strategies for the synthesis of 11 using either
imines 8 or iminium salts 10.
With compounds 6 in hand, we attempted the two-com-
ponent reactions in the presence of the corresponding
amino acid alkyl ester hydrochloride 7; this means that im-
ine formation and cyclization takes place in a one-pot pro-
cess, either under microwave-assisted heating or by using
conventional heating. After the optimization process, the
best reaction conditions were found to be: Method A: neat,
185 °C, 200 W microwave irradiation and Method B: poly-
ethylene glycol (PEG-400) at 170 °C.
The condensation of diethyl aminomalonate hydrochlo-
ride (7a) with aldehyde 6a followed by intramolecular 1,3-
DC was successfully performed by following Method A
(Table 1, entry 1). In this case, Method B afforded lower
yield of the product in a very complex reaction mixture. To
our knowledge, this is the first time that freshly generated
imino ester 8aa has undergone an intramolecular 1,3-DC
with R1 = Ph. When glycine hydrochloride derivative 7b
was tested, Method A was found to be the most appropri-
ate, giving a 45% yield of a mixture of three diastereoiso-
mers 14ab, 15ab, and 16ab (Table 1, entries 2 and 3). The
employment of natural α-substituted amino ester hydro-
chlorides also required the use of Method A to achieve bet-
ter chemical yields and higher diastereoselectivities for
products 14ac and 14ad (Table 1, entries 4–7).
Considering both strategies, there are two difficulties to
overcome. In the first route, the resulting imine 8 is, in some
cases, unstable, and in the second route, N-alkyl amino es-
ters 9 have to be prepared. To increase the efficiency of
the last process to ultimately synthesize compounds 5, we
investigated the two-component [3+2] cycloaddition in
which the imines were prepared in situ from 6 and 7 (Fig-
ure 2). The effect of microwave irradiation on the overall
course of the reaction as well as the identification of all
detected stereoisomers from the crude reaction mixtures
Figure 2. Salicylaldehydes and amino acid derivatives used in this
study.
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Synthesis of Chromen[4,3-b]pyrrolidines
Table 1. Intramolecular two component 1,3-DC between 6 and 7.[a] tion involving 6c and phenylalanine methyl ester hydro-
chloride 7d. Here, polycycle 14cd was the major stereoiso-
mer, which was isolated (70:30 dr) in 68% combined yield
(Table 1, entry 17). Unfortunately, the reaction performed
with the allylic system 6d failed under both Methods A and
B.
The presence of mixtures of cycloadducts 14 and 15 in
different proportions is consistent with previous re-
ports.[14–20] However, the isolation of 16 as a third stereoiso-
mer in high percentages was unexpected. To establish the
relative configuration, single-crystal X-ray diffraction and a
range of NMR experiments were combined. The absence of
a third chiral center (at the α-position) simplified the analy-
sis of the stereochemical outcome of the chromene-pyrroli-
Entry R1
R2
R3 Method Time (14/15/16)[b]
Yield
[%][c]
[min]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-NO2Ph
p-NO2Ph Me
p-NO2Ph Bn
CO2Me CO2Et Et
CO2Me
CO2Me
CO2Me Me
CO2Me Me
CO2Me Bn
CO2Me Bn
CO2Et Et
A
A
B
A
B
60
20
90
20
60
aa (90:0:10)
ab (65:24:11)
ab (50:30:20)
ac (83:0:17)
ac (70:0:30)
83
45
15
77
51
79
22
96
74
92
50
50
45
50
64
68
45
H
Me
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bn
Bn
H
A
B
120 ad (68:22:10)
150 ad (64:36:0)
20
20
A
A
A
A
A
B
A
B
A
B
bb (55:26:19)
bc (80:0:20)
9
10
11
12
13
14
15
16
17
120 bd (54:38:8)
60
20
20
20
20
ca (50:0:50)
cb (60:0:40)
cb (60:0:40)
cc (60:0:40)
cc (80:0:20)
H
H
Me
Me
Me
Me
Me
Me
120 cd (70:0:30)
60 cd (66:0:34)
[a] Method A: MW (200 W), 185 °C. Method B: PEG-400, 170 °C.
[b] Determined by CG-MS and 1H NMR analyses of the crude
product. The same ratio of products was obtained after purifica-
tion. [c] Yield of the mixture obtained after flash chromatography.
The influence of the electronic nature of the group in
the allyl ether precursor 6 was then surveyed. For electron-
deficient arenes (R1 = p-NO2C6H4), the reaction worked
in short reaction times, giving adducts 14bb–bd as major
diastereoisomers (Table 1, entries 8–10). In the series of
electron-withdrawing groups such as R1 = CO2Me, both
methods were found to be satisfactory in terms of the over-
all yield (Table 1, entries 11–17). The diastereoselectivity
was also always clearly in favor of compound 14 when the
glycine-derived amino ester hydrochloride 7b was employed
(Table 1, entries 12 and 13). However, diethyl aminomalon-
ate furnished a 1:1 mixture of epimers 14ca and 16ca
(Table 1, entry 11). The reaction of α-alkyl-substituted
amino esters 7c and 7d was much more stereoselective, and
only small amounts of trans-fused isomers were observed in
the crude product mixture. Thus, when alanine methyl ester
hydrochloride 7c was allowed to react with 6c, Method B
afforded the highest chemical yield and the best 14cc/16cc
diastereomeric ratio (80:20) (Table 1, entries 14 and 15). In
Figure 3. MM3 (CHCl3) minimized structures, NOESY contacts
observed in compounds 14ac, 14ad, and 16cc, and relative configu-
ration of racemic compounds 17. Distances are given in Å. Ball
and stick structures correspond to the minimum energy conformers
after Monte–Carlo simulations. The remaining ten structures for
compounds 14ac, 14ad, and 16cc correspond to conformers within
3–2 kcalmol–1 with respect to the respective conformational min-
contrast, Method A was the most appropriate in the reac- ima.
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dine fusion. Based on the NMR analysis of the major endo pending on the substitution pattern, the [3+2]-thermal cy-
adducts 14 (coupling constants and NOESY studies) it was cloaddition between NH- and N-metallated azomethine
not possible to determine unambiguously the relative con- ylides can take place through concerted [π4s+π2s] path-
figuration. Fortunately, the relative configuration of struc- ways[30] or through a stepwise mechanism involving zwitter-
ture 14ac was established by X-ray diffraction analysis[27] ionic intermediates.[31] However, the intramolecular version
(see the Supporting Information). An identical protocol for of the reaction between azomethine ylides and alkenes has
separated/isolated compounds 15ab and 16bb, bc, cb, and been less studied.[32] In particular, to our knowledge, the
cd was followed, but it was not possible to obtain either concerted or stepwise nature of the mechanism of this par-
appropriate crystals or consistent X-ray diffraction patterns. ticular transformation has not been assessed. One impor-
The cis-configuration could be assigned to the ring junc- tant feature of intramolecular 1,3-DC is the possibility of
tion of all the cycloadducts by comparison of the coupling generating fused or bridged regioisomers (Scheme 4). In ge-
constant of compounds 14ac (unequivocally characterized neral, the restricted conformational freedom imposed by
by crystal X-ray diffraction analysis) and 14ad. The stereo- the spacer connecting the dipole and the dipolarophile moi-
chemistry could also be analyzed by 2D nuclear Overhauser eties results in high levels of regiocontrol, except when the
effect spectroscopy (NOESY) of 14ac and 14ad. These spacer is large enough.[33] If the spacer (denoted as Σ in
NOESY contacts were found to be compatible with the cor- Scheme 4) connects the alkene and one of the carbon atoms
responding MM3-minimized structures, in which Monte of the azomethine ylide (I), both fused and bridged cycload-
Carlo simulations in CHCl3 showed quite rigid AB scaffolds ducts (IIF and IIB, respectively) can be formed. In contrast,
with conformationally flexible pyrrolidinyl, methoxycarb- when the spacer links the olefinic moiety with the central
onyl, methyl, and benzyl groups (Figure 3).
N-atom of the dipole, only bridged [3+2] cycloadducts can
The trans arrangement in molecules 16 was deduced be formed (compounds IVB and IVBЈ). Here, we will focus
from analysis of the coupling constants and all the infor- on the origins of the stereocontrol in several IǞIIF cyclo-
mation supplied by NOESY experiments (see the Support- additions.
ing Information) and by comparison with the coupling con-
stants reported previously.[15] Our MM3 (CHCl3) Monte
Carlo simulations show that the tricyclic scaffold in 16cc is
more rigid than those computed for diastereomers 14 (see
Figure 3). On the other hand, the presence of stereoisomer
17 (Figure 3) can be discounted.
The transformation of major compounds 14 into the cor-
responding bioactive tosylamides 5 was then carried out by
following standard procedures (Scheme 3). In addition, the
relative configuration of 5ab derived from 14ab was con-
firmed by X-ray diffraction analysis (see the Supporting In-
formation).[28]
Scheme 4. Fused (F) and bridged (B) regioisomers in intramolecu-
lar [3+2] cycloadditions between azomethine ylides and alkenes.
The specific intramolecular process addressed in this work is high-
lighted.
The stereochemistry of these reactions is, in principle,
complex because two diastereoisomers and up to four chiral
centers can be formed in one preparative step, thus giving
4
rise to a maximum of 2ϫVR2 = 32 possible isomeric cy-
cloadducts, which can be reduced to 16 racemic diastereo-
isomers. As far as the possible configurations of azomethine
ylides I are concerned, at least four possible conformers can
be envisaged. These conformers are denoted as IW, IS, ISЈ,
and IU depending upon the relative positions of the substit-
uents at the terminal carbon atoms of the 1,3-dipole
(Scheme 5). In general, X can be H, alkyl, or a metal with
Scheme 3. Preparation of N-tosyl derivatives 5ab–ad.
Computational Studies
General Considerations
The mechanism of 1,3-dipolar cycloadditions has been
studied in detail[29] and it has been concluded that, de- Scheme 5. Possible geometries of azomethine ylides I.
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Synthesis of Chromen[4,3-b]pyrrolidines
different ligands, and B is an electron-withdrawing group
such as methoxycarbonyl.
Reactive intermediates I can, in turn, react intramolecu-
larly with an alkene to yield, for a given regioisomer, two
possible racemic pairs of diastereoisomers. For instance, in
Scheme 6 we have depicted the four possible pyrrolidine ra-
cemic cycloadducts corresponding to the [3+2] cycload-
dition between NH-azomethines of W and SЈ configuration
(X = H, B = CO2Me) and a trans-alkene. We denote endo-
cycloadducts as those in which the R and A substituents
are cis to each other, and the alternative exo-pyrrolidines
IIF possessing these substituents in a trans relative stereo-
chemistry.
Scheme 7. Reaction profiles associated with the thermal formation
of azomethine ylides 8Wab and 8SЈab. Numbers below the com-
pounds and arrows corresponds to the relative and activation ener-
gies respectively. The corresponding Gibbs energies are in parenthe-
ses. Values computed at 298.15 K are in grey. Values computed at
460.15 K are in italics, between brackets. All the results were com-
puted at the M06-2X(PCM,toluene)/def2-TZVPP//B3LYP-
(PCM,toluene)/6-31G* level of theory and are given in kcalmol–1.
Scheme 6. Pyrrolidine cycloadducts associated with the [3+2] cyclo-
addition between (E)-olefins and azomethine ylides IW[a] and
1SЈ[a]. [a] Only one enantiomer and regioisomer is represented in
each case.
Given that in the considered reaction the initial reactants
imines 8b are generated in situ (Scheme 1), the actual steps
leading to cycloadducts 14ab–17ab involve (1) generation of
the 1,3-dipoles, and (2) intramolecular (3+2) cycload-
ditions. Our computational results on both steps will be
presented and discussed in the following subsections.
Figure 4. The main geometric features of transition structures asso-
ciated with the formation of azomethine ylides 8Wab and 8SЈab
computed at the B3LYP(PCM,toluene)/6-31G* level of theory. Dis-
tances and angles are in Å and deg respectively.
Generation of 1,3-Dipoles
We first analyzed computationally the generation of azo-
methine ylides 8Wab and 8SЈab. This process can be formally
considered as a 1,2-prototropy, in which an acidic proton
Our calculations show that the initial enolization of 8ab
on the α-position of the methoxycarbonyl group migrates is a highly endothermic process. Therefore, iminoenol 8Јab
to the iminic nitrogen (Scheme 7). In a previous work,[31c] will be in low concentration in the reaction media. Once
we have demonstrated that the only energetically feasible the transient enol 8Јab is formed, it can easily rearrange
pathway to generate azomethine ylides W consists of an through a [1,5]-hydrogen shift to yield azomethine ylide
enolization of the initial imino ester followed by a pseudo- 8Wab. The activation barrier associated with this process is
pericyclic [1,5]-prototropy (see below). On the other hand, approximately 8 kcalmol–1 at both temperatures. This low
azomethine ylides SЈ can be generated by cis–trans isomer- value and the planar geometry of the system (see Figure 4)
ization of the former azomethineylide. To reproduce the are compatible with the pseudoperyciclic nature of TS0.[34]
harsh conditions required experimentally (namely high tem- Moreover, formation of 8Wab is thermodynamically favored
peratures and/or microwave irradiation, see above) both with respect to 8Јab.
298 K and 460 K temperatures were considered in our
On the other hand, azomethine ylide 8SЈab can be formed
study. The obtained reaction profiles and the main geomet- through rotation about the N(d)–C(c) bond in 8Wab. No-
ric features of the computed transition structures associated tably, the computed activation barrier associated with this
with the formation of ylides 8Wab and 8SЈab are gathered in step depends strongly on the temperature considered. Our
Scheme 7 and Figure 4, respectively.
results show that the isomerization process is favored at
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high temperatures (ca. 6 kcalmol–1 lower than at room tem-
perature), thus showing the importance of the entropic con-
tribution to the Gibbs free activation barrier in this isomer-
ization step. Moreover, formation of 8SЈab is a thermody-
namically unfavored process because the hydrogen bond be-
tween the NH and carboxy moieties present in azomethine
ylide 8Wab is stronger than the hydrogen bond between the
arylidene CH and carboxy groups in 8SЈab (Scheme 7).
Intramolecular [3+2]Cycloadditions
Once we had calculated the reaction coordinates leading
to azomethine ylides 8SЈab and 8Wab, we analyzed the dif-
ferent intramolecular [3+2] pathways leading to tricyclic
pyrrolidines 14ab–17ab shown in Table 1. In these com-
pounds, the double bond (namely the dipolarophile moiety)
is not attached to an electron-withdrawing group. There-
fore, the expected two-electron interactions required for the
electronic circulation of pericyclic [3+2]-cycloadditions
would be less favored than those found for other di-
polarophiles such as β-nitrostyrenes.[31c] The analysis of the
frontier orbitals of azomethine ylides 8SЈab and 8Wab shows
that in the latter case the main two-electron interactions
correspond to the HOMO–1/LUMO and HOMO/
LUMO+1 pairs (see the Supporting Information). Accord-
ing to this interaction scheme, the less energetic saddle
point endo-TSW should be the most synchronous (Fig-
ure 5). In contrast, intramolecular cyclization of 8SЈab in-
volves HOMO/LUMO and HOMO–1/LUMO+1 two-elec-
tron interactions thus leading to quite asynchronous, but
still concerted, transition structures.
The computed energetic profiles corresponding to the
[3+2] cycloaddition as well as the chief geometric features
of the corresponding transition structures are gathered in
Scheme 8 and Figure 5, respectively.
According to our calculations, the endo-approaches pres-
ent lower activation barriers than their exo analogues.
Moreover, azomethine ylide 8SЈab was found to be more
reactive than its isomer 8Wab, with endo-TSSЈ being the sad-
dle point with the lowest activation barrier. On the other
hand, endo cycloadducts 14ab and 15ab are more stable
than exo-tricyclic pyrrolidines 16ab and 17ab, so an in-
Scheme 8. Reaction profiles associated with the intramolecular
[3+2] cyclization of azomethine ylides 8Wab and 8SЈab. Numbers
below the compounds and arrows correspond to the relative and
activation energies, respectively. The corresponding Gibbs energies
are in parentheses. Values computed at 298.15 K are in grey. Values
computed at 460.15 K are in italics, between brackets. All the re-
sults were computed at the M06–2X(PCM,toluene)/def2-TZVPP//
B3LYP(PCM,toluene)/6-31G* level of theory and are given in
kcalmol–1.
Figure 5. Main geometric features of transition structures associated with the intramolecular [3+2] cyclization of azomethine ylides 8Wab
and 8SЈab. See caption of Figure 4 for further details.
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Synthesis of Chromen[4,3-b]pyrrolidines
d/dt [14ab] = kN,M [8Wab]
d/dt [17ab] = kX,M [8Wab]
d/dt [15ab] = kN,SЈ [8SЈab]
d/dt [16ab] = kX,SЈ [8SЈab]
(1)
(2)
(3)
(4)
crement of the temperature using harsh conditions favored
them. Therefore, formation of 14ab and 15ab are both ther-
modynamically and kinetically favored compared with their
counterparts 16ab and 17ab. According to the Curtin–
Hammett principle, the isomerization step is kinetically cru-
cial to determine the distribution of the different isomeric
cycloadducts. Thus, formation of 15 depends strongly on
the previous isomerization step because all the activation
barriers computed for the [3+2] cycloaddition steps were
found to be quite similar in magnitude within the uncer-
tainty inherent to our theoretical level. However, we can
assume that the magnitude of the possible deviations must
be similar for related stationary points. This approach is
assumed in almost any calculation involving selectivity is-
sues. In addition, it must be taken into account that the
actual isomeric ratio between the two possible 1,3-dipoles
can vary depending upon the substitution pattern being
considered (see Table 1).
The concentration of azomethine ylides 8Wab and 8SЈab
are described by Equations (5) and (6).
d/dt [8Wab] = k0 [8Јab] + k–1 [8SЈab] – (k1 + kX,W + kN,W) [8Wab]
(5)
d/dt [8SЈab] = k1 [8Wab] – (k–1 + kX,SЈ + kN,SЈ) [8SЈab]
(6)
Notably, when higher temperatures were considered in
the calculations, the Gibbs activation barriers associated
with the [3+2] cycloadditions increased substantially. This
thermal effect can be ascribed to a lower contribution of
the entropic factor of this step compared with the previous
isomerization process.
In Equations (1)–(6), the meaning of the kinetic con-
stants associated with the different elementary steps is that
indicated in Figure 6. From the information contained in
this Figure it is clear that formation of cycloadducts 14ab–
17ab depends only on the concentration of the azomethine
ylides 8Wab and 8SЈab. On the other hand, 8Wab can be
generated from iminoenol 8Јab, whereas 8SЈab can only be
formed through isomerization of 8Wab. This situation leads
to a complex kinetic scheme in which kinetic constant k1
acts as a threshold that controls the formation of cycload-
ducts 15ab and 16ab.
The analysis of the geometries of the computed transi-
tion structures showed that these intramolecular [3+2] cy-
cloaddition reactions consist of concerted but quite asyn-
chronous processes. Notably, our calculations show that in
these saddle points, C(e)–C(a) distances are shorter than
the C(c)–C(b) distances, which is contrary to that found for
intermolecular [3+2] cycloadditions involving π-deficient al-
kenes.[9d,29a,31c] Moreover, the lower activation barrier com-
puted for endo-cycloadditions can be ascribed to the pres-
ence of stabilizing electrostatic interactions between the NH
and the alkoxy moieties, which cannot occur along the exo
reaction paths (Figure 5). It is interesting to note that in the
exo-saddle points, the 3,4-dihydro-2H-pyranyl ring of the
chromane moiety being formed adopts a stable half-chair
conformation, whereas in the case of the endo transition
structures the O···H–N interaction leads to an unexpected
boat conformation for this six-membered ring.
Kinetic Simulations
Our computed reaction paths involve complex profiles
including enolization, pseudopericyclic, torsional, and per-
icyclc elementary steps, many of them being significantly
temperature dependent. As a consequence, the stereochemi-
cal outcome for the whole process could not be deduced
directly from the ensemble of activation energies. Therefore,
we decided to perform kinetic simulations on the computed
reaction profiles at both the standard temperature of 298 K
Figure 6. Qualitative diagram showing the different reaction paths
and kinetic constants in the formation of cycloadducts 14ab–17ab.
We estimated the kinetic constants gathered in Figure 6
and at 460 K, the temperature at which the experimental by means of the Eyring equation.[35] The values for these
studies were carried out (see above).
constants can be found in the Supporting Information. By
Given that the final steps leading to the [3+2] cycload- using these values, we performed Runge–Kutta numerical
ducts can be considered to be irreversible, the formation of integration of the kinetic equations associated with the pro-
14ab–17ab can be described by Equations (1), (2), (3), and cesses shown in Scheme 7 and Scheme 8. The outcome of
(4).
these simulations is show in Figure 7.
Eur. J. Org. Chem. 2015, 4689–4698
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4695

J. M. Sansano, A. G. Dias, F. P. Cossío et al.
FULL PAPER
cloadducts 14ab and 15ab at high temperatures, with the
former coming from the W 1,3-dipole and the latter from
the corresponding SЈ analogue.
Experimental Section
General Method for [3+2] Cycloaddition to O-Alkylated Salicylalde-
hydes Using Microwave Irradiation: To a solution of the corre-
sponding O-alkylated salicylaldehyde 6 (0.1 mmol) in toluene
(0.7 mL) in
a Pyrex test tube, amino ester hydrochloride
(0.12 mmol), and triethylamine (0.5 mmol), were added in se-
quence. The mixture was submitted to 200 W microwave irradiation
at 185 °C (see Table 1 for reaction times). For the 4-nitrocinnamyl
analogues 6b, the reactions are performed in anhydrous toluene.
After cooling, ethyl acetate was added and the mixture was washed
three times with brine, then Na2SO4 was added, filtered, and the
organic phase was evaporated. The crude reaction mixture was
purified by flash column chromatography on silica gel to provide
Figure 7. Simulated stereochemical outcome associated with the in-
tramolecular [3+2] cyclization of azomethine ylides 8Wab and 8SЈab
at (A) 298 K and (B) 460 K.
Our kinetic simulations show that the product ratio de-
pends on the temperature considered in the calculations. At the cycloadducts 14, 15, and 16 as viscous oils. Yields, dia-
stereomeric ratio and other details are described in Table 1, for
characterization material, see the Supporting Information.
298 K, the cycloadducts that come from azomethine ylide
8Wab are the major products, thus showing that no azome-
thine ylide isomerization occurs at this and lower tempera-
tures. In this case, the simulated outcome shows a 14ab/
16ab product ratio of 73:37. However, at high temperatures,
the stereochemical outcome is qualitatively different; in this
case, 14ab remains the major product, but formation of
15ab is now possible because of the partial isomerization
of 1,3-dipole 8Wab to 8SЈab. Thus, at 460 K, our numerical
simulations yield a 14ab/15ab/16ab ratio of 75:17:8, which
is in nice agreement with the experimentally found ratio of
65:24:11 (Table 1, entry 2).
General Method for [3+2] Cycloaddition to O-Alkylated Salicylalde-
hydes in PEG-400: To a solution of the corresponding O-alkylated
salicylaldehyde 6 (0.1 mmol) in PEG (1.0 mL) in a Pyrex test tube,
the amino ester hydrochloride (0.12 mmol), and triethylamine
(0.5 mmol), were added in sequence. The mixture was heated at
170 °C (see Table 1 for reaction times). After cooling, ethyl acetate
was added and the mixture was washed three times with brine, then
Na2SO4 was added, filtered, and the organic phase was evaporated.
The crude reaction mixture was purified by flash column
chromatography on silica gel to provide the cycloadducts 14, 15,
and 16 as viscous oils. Yields, diastereomeric ratio and other details
are described in Table 1, for characterization material, see the Sup-
porting Information.
Conclusions
General Method for the Synthesis of Sulfonamides 5: To a solution
of cycloadduct 14 (0.1 mmol) in anhydrous pyridine (0.8 mL), tosyl
chloride (0.25 mmol) was added. The reaction was heated at 80 °C
for 15 h, then the mixture was cooled to room temperature, the
pyridine was removed under vacuo, and warm methanol was added
until the crude material was dissolved. Water was added and the
precipitation of sulfonamide occurred. The mixture was centrifuged
and the aqueous layers were separated, giving pure sulfonamide 5
as a single diastereoisomer. Yield, temperature and other physical
data are described in Scheme 3 and in the Supporting Information.
By using this two-component synthesis employing two
different reaction conditions, the preparation of
chromene[4,3-b]pyrrolidines can be easily achieved. This is
the first time that freshly generated imino ester promoted
an intramolecular 1,3-dipolar cycloaddition from 6a with
R1 = Ph. When R1 = Ar, Method A (MW, 200 W) gave
compounds 14 as major stereoisomers in shorter reaction
times, rather than Method B (PEG-400, 170 °C). Mixtures
of 14, 15, and 16 were detected in variable proportions.
When R1 = CO2Me, Methods A and B gave similar results
in most cases, furnishing molecules 14 as major stereoiso-
mers together with cycloadducts 16. It is noticeable that, in
these examples, compounds 15 were not identified in the
Computational Methods: Conformational analyses were carried out
with the MM3 force field[36] in CHCl3 as implemented in Macro-
Model.[37] Conformational searches were performed by means of
Monte Carlo simulations.[38] All the computational mechanistic
studies were carried out with the Gaussian 09[39] suite of programs.
crude reaction material. This strategy is the key to ob- Density Functional Theory[40] (DFT) geometry optimizations and
taining adducts 16 after purification. Computational analy-
sis of these [3+2] intramolecular cycloaddition reactions
harmonic analyses were performed with the B3LYP[41] functional.
Relative energies were computed by means of single-point calcula-
tions on the optimized geometries with the M06-2X[42] functional.
show that formation of W and SЈ 1,3-dipoles determines the
This M06-2X//B3LYP hybrid theoretical level was chosen because
stereochemical outcome of the reaction. The latter reactive
it is known that B3LYP and M06-2X produce similar optimized
species require higher temperatures to be formed from the
geometries.[43] We tested this statement by means of a benchmark-
ing test, which is described in the Supporting Information. More-
corresponding imines. Intramolecular 1,3-dipolar reactions
take place via relatively asynchronous transition structures,
over, the latter highly parameterized M06-2X method is well suited
with the endo-geometries being the less energetic. The ki-
for the treatment of nonbonding interactions and dispersion forces,
which can be relevant in densely substituted interacting systems.[44]
netic profile obtained from these computational studies are
compatible with the preferential formation of major cy- The 6-31G* and def2-TZVPP basis sets were used. Solvent effects
4696 Eur. J. Org. Chem. 2015, 4689–4698
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Synthesis of Chromen[4,3-b]pyrrolidines
were computed with the PCM method using toluene as solvent.[45]
All the stationary points were characterized by harmonic analysis.
Reactants, intermediates and products showed positive definite
Hessians. Transition structures (TSs) showed one and only one
imaginary frequency associated with nuclear motion along the
chemical transformation under study. Free energies at 298.15 and
460.15 K were calculated by including the corresponding thermal
corrections to Gibbs free energies (TCGE). Figures including opti-
mized structures were made with Maestro[46] and CYL-view pro-
grams.[47] Orbital interaction diagrams were prepared by using the
Gauss-view interface.[48]
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Acknowledgments
Financial support was provided by the Brasilian Universiade Fed-
eral do Rio de Janeiro (UFRJ), the Fundação de Amparo à Pes-
quisa do Estado do Rio de Janeiro (FAPERJ) and the Coord-
enação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES),
by the Spanish Ministerio de Ciencia e Innovación (MICINN)
(projects CTQ2010-20387, Consolider Ingenio 2010, CSD2007-
00006), the Spanish Ministerio de Economía y Competitividad
(MINECO) (projects CTQ2013-43446-P, CTQ2014-51912-REDC,
and CTQ2013-45415-P), the Fondos Europeos para el Desarrollo
Regional (FEDER), the Generalitat Valenciana (PROMETEO
2009/039 and PROMETEOII/2014/017), the Basque Government
(GV/EJ, grant IT-324-07), and the Universities of Alicante and of
the Basque Country (UPV/EHU) (UFI11/22 QOSYC). The au-
thors thank the SGI/IZO-SGIker UPV/EHU and the DIPC for
generous allocation of computational and analytical resources.
Technical and human support provided by SGIker (UPV/EHU,
MINECO, GV/EJ, ESF) is gratefully acknowledged.
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Received: April 4, 2015
Published Online: June 10, 2015
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