N-Phenyl-1,2,4-triazoline-3,5-dione (PTAD) as a dienophilic dinitrogen equivalent: A simple synthesis of 3-amino-1,2,4-benzotriazines from arylcarbodiimides

Article abstract of DOI:10.1002/ejoc.200901103

N-Arylcarbodiimides react with PTAD to provide [1,2,4]triazolo[1,2-α] [l,2,4]benzotriazines by a [4+2] cycloaddition reaction. When asymmetrically substituted diarylcarbodiimides are used, the cycloaddition proceeds with total chemoselectivity because only the more electron-rich aryl nucleus is involved. This observation has been rationalized by a computational study using DFT methods that shows that, in the reaction of HTAD with arylcarbodiimides, the magnitude of the energy barriers depend on the electronic features of the substituents at the aryl nucleus; the calculations also indicate that the reaction proceeds through asynchronous states with polar characteristics. The treatment of the final cycloadducts with potassium hydroxide affords 3-aryl(alkyl)amino-l,2,4-benzotriazines.

Full text of DOI:10.1002/ejoc.200901103

FULL PAPER
DOI: 10.1002/ejoc.200901103
N-Phenyl-1,2,4-triazoline-3,5-dione (PTAD) as a Dienophilic Dinitrogen
Equivalent: A Simple Synthesis of 3-Amino-1,2,4-benzotriazines from
Arylcarbodiimides
Mateo Alajarin,*[a] Baltasar Bonillo,[a] Marta Marin-Luna,[a] Pilar Sanchez-Andrada,[a] and
Angel Vidal*[a]
Dedicated to Professor Benito Alcaide on the occasion of his 60th anniversary
Keywords: Cycloaddition / Nitrogen heterocycles / Synthetic methods / Transition states
N-Arylcarbodiimides react with PTAD to provide [1,2,4]tri-
tion of HTAD with arylcarbodiimides, the magnitude of the
azolo[1,2-a][1,2,4]benzotriazines by a [4+2] cycloaddition re- energy barriers depend on the electronic features of the sub-
action. When asymmetrically substituted diarylcarbodiimides
are used, the cycloaddition proceeds with total chemoselec-
tivity because only the more electron-rich aryl nucleus is in-
volved. This observation has been rationalized by a computa-
tional study using DFT methods that shows that, in the reac-
stituents at the aryl nucleus; the calculations also indicate
that the reaction proceeds through asynchronous states with
polar characteristics. The treatment of the final cycloadducts
with potassium hydroxide affords 3-aryl(alkyl)amino-1,2,4-
benzotriazines.
To the best of our knowledge, very few reactions between
TADs and heterocumulenes have been reported (Scheme 1).
PTAD (N-phenyl TAD) has been shown to react with the
C=C double bond of diphenyl ketene in a [2+2] fashion.[14]
We have recently shown that C-aryl ketenimines react with
two equivalents of PTAD through a Diels–Alder/ene se-
Introduction
The chemistry of the most common five-membered cyclic
azodicarbonyl
compounds,
1,2,4-triazoline-3,5-diones
(TADs), has been thoroughly reviewed.[1] These strong elec-
tron-acceptors have often been deployed in organic synthe-
sis as enophiles[2] and dienophiles,[3] affording N-substituted
urazoles (ene products) and/or [2+2] cycloadducts in their
reactions with alkenes, whereas they mainly undergo Diels–
Alder reactions with dienes.[4] As very reactive dienophiles,
TADs have found wide application in characterizing
dienes,[5] protecting diene moieties,[6] and capturing un-
stable or volatile intermediates.[7]
Our research group has a long-standing interest in ex-
ploring the chemistry of different types of heterocumulenes
such as ketenimines,[8] carbodiimides,[9] ketenes,[10] and iso-
thiocyanates;[11] we have more commonly directed our at-
tention toward their [2+2] and [4+2] cycloaddition reac-
tions.[12] In general, the cycloaddition chemistry of heteroc-
umulenes is usually dominated by the [2+2] rather than the
[4+2] mode of addition.[13]
[a] Departamento de Quimica Organica, Facultad de Quimica,
Universidad de Murcia,
Campus de Espinardo, 30100, Murcia, Spain
Fax: +34-86-8884149
E-mail: alajarin@um.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901103.
Scheme 1. Known examples of reactions of TADs with heterocu-
mulenes.[14–16]
694
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 694–704

New Dienophilic Dinitrogen Equivalent
quence to yield 1,2,4-triazolo[1,2-a]cinnolines with a pen- phorane and phenethyl isocyanate with PTAD (Scheme 3).
dant triazolidinedione group.[15] Finally, N-phenyl-NЈ-(pyr- It was found that, after the addition of two equivalents of
azol-5-yl)carbodiimide has been reacted with two different the enophile to a solution of 2a in anhydrous dichlorometh-
N-aryl TADs to give very low yields (about 10%) of the ane, and stirring at room temperature for 24 h, this carbodi-
[4+2] cycloadducts resulting from the participation of the imide was totally consumed. 9-Isopropyl-2-phenyl-5-[(2-
C4=C5 double bond of the pyrazole nucleus and its vicinal phenylethyl)amino]-1H-[1,2,4]triazolo[1,2-a][1,2,4]benzotri-
cumulated N=C bond in a reactive 2-azadiene fragment.[16] azine-1,3(2H)-dione (4a) was isolated from the reaction
Following these two latter reports, we reasoned that sim- mixture, which was easily identified from its spectroscopic
ple arylcarbodiimides could behave as reactive 2-azadienes and exact mass data. This product should reasonably result
in Diels–Alder reactions with the dienophilic N=N bond of from a sequence of two consecutive processes: a Diels–
TADs, providing that the dearomatization of the aryl ring Alder reaction of PTAD with the 2-azadiene fragment
was not too costly on energetic grounds. Here we show that formed by a cumulated N=C bond and the adjacent C=C
this new type of [4+2] cycloaddition is, in fact, easily feas- bond of its N-bonded aryl group, followed by a rapid rearo-
ible. Furthermore, differing electronic effects of the substit- matization of the intermediate cycloadduct 3 through a
uents can cause the addition to occur with complete re- prototropic equilibrium (formally
gioselectivity when diarylcarbodiimides bearing two well- Scheme 3).
differentiated aryl groups are used.
a 1,5-proton shift;
Results and Discussion
Because the reactions of carbodiimides with TADs are
almost completely unexplored, we first checked the reaction
of a simple dialkylcarbodiimide – commercially available
N,NЈ-diisopropylcarbodiimide (1) – with PTAD to evaluate
if any reaction occurred in the absence of aryl or alkenyl
substituents linked to the nitrogen atoms of the heterocu-
mulenic function, i.e. whether either a [2+2] cycloaddition
or an ene-process took place between the reagents
(Scheme 2).
Scheme 3. Reactions of N-aryl-NЈ-phenethylcarbodiimides 2 with
PTAD.
Several other aryl phenethylcarbodiimides 2b–d behaved
similarly and yielded the new triazolo-benzotriazines 4b–d
in moderate to good yields (Scheme 3, Table 1). As ex-
pected, when the aryl nucleus was ortho-monosubstituted,
as in carbodiimide 2d (entry 4), only the unsubstituted or-
tho-position was involved in the cycloaddition.
Table 1. 1H-[1,2,4]Triazolo[1,2-a][1,2,4]benzotriazine-1,3(2H)-di-
one derivatives 4.
Entry
2
R1
Yield [%] of 4
1
2
3
4
2a
2b
2c
2d
4-(CH3)2CH
4-CH3O
4-Br
50
58
48
48
2-CH3
Scheme 2. Unsuccessful reaction of N,NЈ-diisopropylcarbodiimide
(1) with PTAD.
Having thus demonstrated that both ortho-unsubstituted
Unfortunately, all the attempts at reacting PTAD with and ortho-monosubstituted N-arylcarbodiimide fragments
N,NЈ-diisopropylcarbodiimide (1) were unsuccessful; when were reactive enough to accomplish [4+2] cycloadditions
the reactions were performed in either dichloromethane or with PTAD under mild conditions, we next tested the use
acetonitrile at room temperature, compound 1 was reco- of diarylcarbodiimides to address the question of chemose-
vered unaltered. When the reaction of 1 with PTAD was lectivity in cases where asymmetrical reactants were used.
carried out in either acetonitrile or toluene at reflux, only
very complex reaction mixtures were obtained, probably as DFT methods at the B3LYP/6-31+G** theoretical level
consequence of decomposition of PTAD. with the aim of addressing this question and gaining an
Previously, we carried out a computational study using
Our second approach involved the reaction of the alkyl insight into the mechanism of the hetero-Diels–Alder reac-
arylcarbodiimide 2a [R1 = 4-(CH3)2CH], which was pre- tions of PTAD with N-arylcarbodiimides. For this study we
pared by reacting N-(4-isopropylphenyl)triphenyliminophos- selected the structurally simpler 1,2,4-triazoline-3,5-dione
Eur. J. Org. Chem. 2010, 694–704
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
695

M. Alajarin, A. Vidal et al.
FULL PAPER
(HTAD; 5) and the monoarylcarbodiimides 6a–c as reac-
tants (Scheme 4). These carbodiimides were selected to
compare the influence of electron-withdrawing and -donat-
ing substituents at the aryl nucleus on the energy barriers
associated with their hetero-Diels–Alder reactions with
HTAD.
Scheme 4. Hetero-Diels–Alder reaction of HTAD with monoaryl-
carbodiimides used in the computational study.
Figure 1 displays the calculated lowest energy transition-
states and cycloadduct structures, optimized at the B3LYP/
6-31+G** theoretical level, for the Diels–Alder reactions of
HTAD with phenylcarbodiimide (6a). Table 2 contains the
calculated low frequencies and the relative electronic and
free energies calculated at the B3LYP/6-31+G** theoretical
level for the stationary points found in the Diels–Alder re-
action of HTAD with the arylcarbodiimides 6a–c. Here, we
will comment only on the calculated electronic energies, un-
less otherwise stated.
We explored the potential energy surface of the Diels–
Alder reaction of HTAD with phenylcarbodiimide by
searching both the endo and the exo approachs. Two endo
(TSaendo-anti and TSaendo-syn) and two exo (TSaexo-anti and
TSaexo-syn) transition structures were located, which are
shown in Figure 1.
The difference between the two endo transition structures
comes from the position of the lone pair at the unsubsti-
tuted nitrogen atom of the heterocumulenic moiety. Thus,
whereas in TSaendo-anti this lone pair is positioned anti to
the adjacent C–N forming bond, in the TSaendo-syn confor-
mation it is located in the syn position. Analogously, the
difference between TSaexo-anti and TSaexo-syn also depends
on the anti or syn orientation of the lone pair at the same
Figure 1. Transition states and cycloadducts, optimized at the
B3LYP/6-31+G** theoretical level, located for the Diels–Alder re-
action of HTAD with phenylcarbodiimide (6a).
Table 2. Relative energies with zero-point vibrational energy correc-
tions, relative free energies, and low frequencies calculated at the
B3LYP/6-31+G**//B3LYP/6-31+G** theoretical level for the sta-
tionary found in the Diels–Alder reaction of HTAD (5) with aryl-
carbodiimides 6a–c.
Structure
Relative energy Relative free
Low frequencies
[cm–1]
[kcalmol–1]
energy
[kcalmol–1]
5 + 6a
0.00
21.11
26.86
25.75
33.04
–9.71
–8.09
–52.96
0.00
21.94
–9.37
–52.48
0.00
0.00
35.12
40.64
39.97
46.33
4.85
6.27
–38.44
0.00
36.04
6.24
–37.88
0.00
33.38
3.61
–38.35
139.5/54.6
–372.2
–293.6
–432.0
–339.9
54.7
42.7
46.8
139.5/45.9
–362.5
42.2
TSaendo-anti
TSaendo-syn
TSaexo-anti
TSaexo-syn
(Z)-7a
(E)-7a
8a
5 + 6b
TSbendo-anti
(Z)-7b
8b
5 + 6c
TScendo-anti
40.7
139.5/52.9
–361.7
46.3
19.26
–11.01
–52.95
nitrogen atom. In other words, two different orientations, (Z)-7c
anti and syn, are conceivable for each endo or exo mode of
8c
44.9
approach to the HTAD dienophile; one approach to each
stereoface of the diene in the axially-chiral phenylcarbodi-
imide, as depicted for the endo mode in Figure 2.
tem.[18] On the other hand, it is reasonable that the anti
The relative energies of the four transition structures are transition states are stabilized in relation to their syn analo-
shown in Table 2. Their differing values can be rationalized gous because in the latter cases the nitrogen lone pair at the
on the basis of the exo-lone-pair effect.[17] Accordingly, in unsubstituted nitrogen atom of the original carbodiimide
the exo transition structures, the lone pairs at the two function is placed synperiplanar to the adjacent forming C–
double bonded nitrogen atoms of HTAD induce a massive N bond, thus electronically disturbing its formation.[19] The
destabilizing effect by their proximity to the dienic π-sys- combination of these two stereoelectronic effects makes
696
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 694–704

New Dienophilic Dinitrogen Equivalent
bodiimide is through TSaendo-anti, for the other transforma-
tions studied (5 + 6b,cǞ7b,c), we only considered the ap-
proach through the corresponding TSb,cendo-anti transition
states (Figure 2). All these transformations were calculated
to involve exothermic processes, their reaction energies be-
ing in the range of –53.0 to –52.5 kcalmol–1, by considering
the compounds 8a–c as the final cycloadducts (Table 2).
Substitution of the hydrogen atom at the para position
of the benzene ring by either a chlorine atom or a hydroxy
group caused divergent effects in the magnitude of their re-
spective energy barriers when compared with that involving
6a. Thus, in the conversion 5 + 6bǞ(Z)-7b, the chlorine
Figure 2. The two possible endo approachs, endo–anti and endo–
syn, of HTAD to phenylcarbodiimide.
clear why the transition structure TSaendo-anti is the lowest atom provokes a slight increase in the value of the energy
in energy (21.1 kcal/mol up to reactants, or 35.1 kcal/mol barrier when compared to the unsubstituted case, 5 +
after including the entropy correction) of the four located 6aǞ(Z)-7a (21.9 vs. 21.1 kcalmol–1); the energy barrier
transition states (Table 2). The reaction of HTAD found when the arylcarbodiimide bears a hydroxy group at
with phenylcarbodiimide through either TSaendo-anti or the para position is 19.3 kcalmol–1 (see Table 2 and Fig-
TSaexo-anti leads to the cycloadduct (Z)-7a, whereas transi- ure 3).
tions structures TSaendo-syn and TSaexo-syn lead to (E)-7a.
From these calculations it is expected that electron-with-
However, because both isomeric structures are finally con- drawing groups at the aryl ring of the carbodiimide will
verted into the cycloadduct 8a as a result of hydrogen shifts, retard the Diels–Alder reaction with HTAD, whereas elec-
this aspect of the reaction was not analyzed in this study.
tron-donor substituents will accelerate it. These electronic
We have analyzed in more detail the transition structure effects are characteristic of a Diels–Alder reaction with nor-
TSaendo-anti. Concerning its geometry, it is worth pointing mal electronic demands, whereby the electron-donor sub-
out the significant twisting between the HTAD ring and the stituents at the aryl ring decrease the HOMOdiene
–
carbodiimide diene fragment in which the HTAD ring is LUMOHTAD energy gap and facilitate the electron flux
tilted 55.4° relative to the plane containing the diene frag- from the diene to HTAD. Therefore, similar chemoselective
ment.[20] This transition structure is highly asynchronous processes can be reasonably expected when using diarylcar-
because the formation of the bond between the aryl carbon bodiimide reactants whose two aryl nuclei are electronically
atom of the diene fragment and the corresponding nitrogen differentiated by appropriate substituents. We confirmed
atom (C1–N5) is notably more advanced than that between this assumption with the following experiments.
the central carbon atom of the carbodiimide and the second
A series of diarylcarbodiimides 9, prepared by treatment
nitrogen atom (C4–N6); the measured bond lengths being of N-aryltriphenyliminophosphoranes with aryl isocyan-
1.76 and 2.46 Å, respectively (see numbering in Figure 1). ates, was treated with PTAD in dicloromethane solution at
We have also computed the Wiberg bond indexes by using room temperature for 24 hours. These reactions smoothly
the NBO method, indicating that the C1–N5 bond is par- provided the 1H-[1,2,4]triazolo[1,2-a][1,2,4]benzotriazine-
tially formed; the calculated bond order value of 0.61 is 1,3(2H)-diones 10, in moderate to good yields (Scheme 5,
notably higher than that for the C4–N6 bond (0.11). We Table 3).
have also calculated a synchronicity value of 0.74 for the
As summarized in Table 3, seven symmetrically substi-
transformation 5 + 6aǞ(Z)-7a via TSaendo-anti, confirming tuted (entries 1–3, 8, 9, 12, and 13) and six asymmetrically
that this process takes place asynchronously. The natural substituted (entries 4–7, 10, and 11) diarylcarbodiimides
population analysis also allowed to us to evaluate the were assayed. In the symmetrical cases, the reactions gave
charge-transfer along this conversion. The B3LYP/6- a single product when the aryl nuclei were ortho- or para-
31+G** natural atomic charges at the transition-state monosubstituted, whereas when only one of the meta-posi-
TSaendo-anti showed that the phenylcarbodiimide is acting as tions was substituted at each moiety (entry 13) the reaction
an electron-donor and that the HTAD acts as an electron- with PTAD yielded a mixture of the two triazolo-benzotri-
acceptor as the charge-transfer fluxes from the diene to the azines 10, resulting from the occurrence of two Diels–Alder
dienophile,[21] the value of the charge transferred being reactions involving the two different ortho-positions of the
0.46e.
aryl ring participating in the cycloaddition. It is worth not-
These data clearly show that the reaction of HTAD with ing the large influence of the electronic effects of the sub-
phenylcarbodiimide can be considered to be a polar process stituents. Thus, with electron-donor groups (alkyl, alkoxy)
that is characterized by nucleophilic attack of the diene at the aryl nuclei, the reactions resulted in good yields of
fragment on the N=N double bond of HTAD.[22] This is in 10 (entries 1–3, 12, and 13), whereas an electron-with-
accord with the fact that the 1,2,4-triazolidin-3,5-diones are drawing group either considerably reduced the yield (Br, en-
among the most reactive dienophiles due to their low try 8) or even prevented the reaction (NO2, entry 9). This
LUMO energies.[1]
electronic bias perturbs the otherwise expected normal elec-
Because the calculations predict that the preferred chan- tronic demand of these HOMOdiene–LUMOPTAD Diels–
nel for the Diels–Alder reaction of HTAD with phenylcar- Alder reaction.
Eur. J. Org. Chem. 2010, 694–704
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
697

M. Alajarin, A. Vidal et al.
FULL PAPER
Figure 3. Qualitative reaction profiles of the reactions between HTAD and the arylcarbodiimides 6a–c leading to the cycloadducts 7a–
canti through transition structures TSa–cendo-anti calculated at the B3LYP/6-31+G** level.
In general, when the reactions involved an aryl fragment
that was strongly activated by a methoxy substituent, only
one equivalent of PTAD was necessary for the reactions to
go to completion (entries 3, 4, 10 and 11), while in the other
cases two equivalents of dienophile were required.
As far as the asymmetrically substituted diarylcarbodi-
imides 9 are concerned, the chemoselectivity was complete,
yielding the triazolo-benzotriazine 10 from the exclusive
participation of the more activated aryl nucleus (electron-
donor vs. electron-withdrawing groups, entries 4–7, and alk-
oxy vs. alkyl, entries 10 and 11).
Scheme 5. Reactions of diarylcarbodiimides 9 with PTAD.
Table 3. 1H-[1,2,4]Triazolo[1,2-a][1,2,4]benzotriazine-1,3(2H)-di-
one derivatives 10.
We attempted to force the reversal of such normal elec-
tronic bias by placing two methyl substituents at both ortho
positions of one ring to give an activated, but sterically con-
gested, aryl fragment, and included deactivating 4-halo sub-
stituents on the second phenyl ring, as in carbodiimides 9n
and 9o (Scheme 6). However, the reactions of these two
asymmetrically substituted carbodiimides with PTAD still
resulted in the exclusive participation of the activated 2,6-
dimethylphenyl ring. The analytical data of the products
revealed that two units of the dienophilic reactant plus a
water molecule were incorporated into the structure of the
final adducts. Following a detailed analysis of their spectro-
scopic data, these adducts were tentatively identified as spe-
cies 13, which could be formed as a result of a tandem
[4+2]/[4+2] process, leading from 9n or 9o to the first and
second cycloadducts 11 and 12, followed by the final ad-
dition of water to the 1,4-diazabutadiene fragment of 12.
This new reaction between carbodiimides and PTAD was
also applied to the preparation of a bis(triazolo-benzotri-
azine). The reaction of iminophosphorane 14 with 1,4-
Entry
9
R1
R2
Yield [%] of 10
1
2
3
4
5
6
7
8
9a
9b
9c
9d
9e
9f
4-CH3
4-CH3
4-(CH3)2CH
4-CH3O
4-Br
4-Br
4-Cl
4-NO2
4-Br
4-NO2
4-CH3
2,6-(CH3)2
2-CH3
3-CH3
93
53
75
72
63
65
67
36
0
80
61
53
51[a]
4-(CH3)2CH
4-CH3O
4-CH3O
4-(CH3)2CH
4-(CH3)2CH
4-CH3
4-Br
4-NO2
4-CH3O
4-CH3O
2-CH3
9g
9h
9i
9
10
11
12
13
9j
9k
9l
9m
3-CH3
698
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 694–704

New Dienophilic Dinitrogen Equivalent
thetic equivalent of molecular dinitrogen. We attempted a
similar degradation of the cycloadducts from the new
Diels–Alder reactions and were pleased to find that tri-
azolo-benzotriazines 4 and 10 were cleanly converted into
the respective 3-alkyl(aryl)amino-1,2,4-benzotriazines 18
upon treatment with methanolic KOH (Scheme 8, Table 4).
A simple work-up allowed the isolation of pure 18.
Scheme 6. Reactions of carbodiimides 9n and 9o with PTAD.
Scheme 8. Preparation of 3-alkyl(aryl)amino-1,2,4-benzotriazines
18.
phenylene diisocyanate 15 yielded bis(carbodiimide) 16,
which was converted into bis(triazolo-benzotriazine) 17. In
the latter compound the two [1,2,4]triazolo[1,2-a][1,2,4]-
benzotriazine-1,3-dione rings are linked through their re-
spective C4 atoms by a 1,4-diaminophenylene chain
(Scheme 7).
Table 4. 3-Alkyl(aryl)amino-1,2,4-benzotriazines 18.
Entry 18
R1
R2
Yield [%]
1
2
3
4
5
6
7
8
18a
7-CH3
4-CH3-C6H4
59
83
80
80
97
86
66
66
86
98
77
83
93
86
95
18b
18c
18d
18e
18f
18g
18h
18i
7-(CH3)2CH 4-(CH3)2CH-C6H4
7-CH3O
7-CH3O
7-(CH3)2CH 4-Br-C6H4
7-(CH3)2CH 4-Cl-C6H4
7-CH3
7-Br
7-CH3O
7-CH3O
5-CH3
7-(CH3)2CH PhCH2CH2
7-Br
4-CH3O-C6H4
4-Br-C6H4
4-NO2-C6H4
4-Br-C6H4
4-CH3-C6H4
2,6-(CH3)2-C6H3
2-CH3-C6H4
9
10
11
12
13
14
15
18j
18k
18l
18m
18n
18o
PhCH2CH2
PhCH2CH2
PhCH2CH2
5-CH3
7-CH3O
Conclusions
The sequential treatment of arylcarbodiimides with
PTAD and methanolic KOH emerges from this work as a
new and valuable synthetic approach to 3-amino-1,2,4-
benzotriazines. The global sequence can be viewed as a
[4+2] cycloaddition between the arylcarbodiimide moiety
and molecular dinitrogen, this latter, inert reactant being
contributed in a “protected” and very reactive form by the
dienophilic PTAD molecule.
Scheme 7. Preparation of bis(triazolo-benzotriazine) 17.
In the course of our previous work on the reaction of C-
aryl ketenimines with PTAD,[15] we developed a simple and
high-yielding method of removing the O=C–N(Ph)–C=O
moiety that was introduced by the PTAD molecule in the
[4+2] cycloaddition, and which finally forms part of the
fused triazolinedione ring in the resulting cycloadducts. The
removal was accomplished by treatment of the cycloadducts
with methanolic KOH at room temperature; the reaction
occurred with subsequent oxidation in situ of the remaining
cyclic system bearing the two adjacent nitrogen atoms
(cinnoline in that work). In this way, at the end of the
sequence of three consecutive chemical steps, Diels–Alder
reaction/removal of the O=C–N(Ph)–C=O fragment/oxi-
Experimental Section
General: All melting points are uncorrected. Infrared (IR) spectra
were recorded as Nujol emulsions. NMR spectra were recorded
in CD2Cl2, CDCl3, C2D2Cl4, CF3CO2D or [D6]DMSO, at 300 or
1
400 MHz for H and at 75 or 100 MHz for 13C NMR. The chemi-
cal shifts are expressed in ppm relative to Me4Si (δ = 0.00 ppm) for
1H NMR, while the chemical shifts for 13C are reported relative to
the resonance of CD2Cl2 (δ = 54.0 ppm), CDCl3 (δ = 77.1 ppm),
C2D2Cl4 (δ = 74.2 ppm), CF3CO2D (δ = 164.4, 116.5 ppm) or [D6]-
dation, the dienophilic PTAD molecule served as a syn- DMSO (δ = 39.5 ppm).
Eur. J. Org. Chem. 2010, 694–704
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
699

M. Alajarin, A. Vidal et al.
FULL PAPER
General Procedure for the Preparation of Triazolo-benzotriazine De-
rivatives 4 and 10: To a solution of the corresponding carbodiimide
2 or 9 (1 mmol) in anhydrous dichloromethane (15 mL), was added
solid PTAD (1 or 2 mmol) in several batches. The reaction mixture
was stirred at r.t. for 24 h. The precipitated solid was filtered and
air-dried for compounds 4a, 10a–d, and 10f–j. For compounds 4b–
d, 10e, and 10k–m, the solvent was removed under reduced pressure
and the resulting material was purified by column chromatography
on silica gel.
(m), 1764 (vs), 1713 (vs), 1644 (s), 1612 (s), 1561 (s), 1506 (vs),
1
1309 (s) cm–1. H NMR (300 MHz, [D6]DMSO, 100 °C): δ = 2.28
(s, 3 H, 9-CH3), 2.30 (s, 3 H, 5-NH-Ar-CH3), 6.91 (dd, J = 7.6,
1.6 Hz, 1 H, 8-H), 6.98 (d, J = 7.6 Hz, 1 H, 7-H), 7.17 (d, J =
8.8 Hz, 2 H, 5-NH-ArH), 7.47–7.62 (m, 7 H, 5-NH-ArH + 2-Ph),
7.80 (d, J = 1.6 Hz, 1 H, 10-H), 9.21 (s, 1 H, NH) ppm. 13C NMR
(75 MHz, [D6]DMSO, 100 °C): δ = 19.6, 20.1, 113.8, 120.1, 123.3,
124.8 (s), 125.6, 126.2, 128.3, 128.4, 128.7, 129.7 (s), 132.4 (s), 133.1
(s), 134.4 (s), 138.7 (s), 143.4 (s), 144.4 (s), 145.2 (s) ppm. HRMS
(ESI): calcd. for C23H20N5O2 [M + H]+ 398.1612; found 398.1595.
4a [R1 = 9-(CH3)2-CH]: Yield 50% (0.22 g); colorless prisms; m.p.
108–109 °C (diethyl ether). IR (Nujol): ν = 3340 (m), 1762 (s), 1708
˜
10b [R1 = 9-(CH3)2CH; R2 = 4-(CH3)2CH]: Yield 53% (0.24 g);
colorless prisms; m.p. 151–152 °C (dichloromethane). IR (Nujol):
ν = 2960 (vs), 1767 (vs), 1716 (vs), 1643 (vs), 1502 (vs), 1407 (vs),
˜
(vs), 1636 (s), 1598 (s), 1502 (vs), 1439 (vs), 1360 (m) cm–1. 1H
NMR (400 MHz, CD2Cl2, 25 °C): δ = 1.23 [d, J = 6.8 Hz, 6 H, 9-
CH(CH3)2], 2.88 [sept, J = 6.8 Hz, 1 H, 9-CH(CH3)2], 2.98 (t, J =
7.2 Hz, 2 H, CH2CH2Ph), 3.69–3.74 (m, 2 H, CH2CH2Ph), 6.97
(dd, J = 8.4, 2 Hz, 1 H, 8-H), 7.02 (d, J = 8.4 Hz, 1 H, 7-H), 7.22–
7.35 (m, 6 H), 7.46–7.57 (m, 5 H), 7.94 (d, J = 2 Hz, 1 H, 10-H)
ppm. 13C NMR (100 MHz, CD2Cl2, 25 °C): δ = 24.0, 34.2, 35.6,
42.5, 112.9, 124.0, 124.3, 124.8 (s), 126.6, 126.8, 128.9, 129.1, 129.4,
129.7, 130.6 (s), 131.5 (s), 139.2 (s), 142.0 (s), 143.7 (s), 145.2 (s),
145.5 (s) ppm. HRMS (ESI): calcd. for C26H26N5O2 [M + H]+
440.2086; found 440.2084.
1304 (s), 1228 (s) cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ =
1.24 [d, J = 6.8 Hz, 6 H, 9-CH(CH3)2], 1.26 [d, J = 6.8 Hz, 6 H, 5-
NH-Ar-CH(CH3)2], 2.86–2.95 [m, 2 H, 9-CH(CH3)2 + 5-NH-Ar-
CH(CH3)2], 6.98 (dd, J = 8.1, 2.1 Hz, 1 H, 8-H), 7.13 (d, J =
8.4 Hz, 1 H, 7-H), 7.23 (d, J = 8.4 Hz, 2 H, 5-NH-ArH), 7.46–7.50
(m, 1 H, 2-Ph), 7.53–7.61 (m, 6 H, 2-Ph + 5-NH-ArH), 8.01 (d, J
= 2 Hz, 1 H, 10-H), 9.34 (s, 1 H, NH) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 23.9, 24.1, 33.7, 34.0, 112.8, 120.8, 124.4, 124.7,
124.9 (s), 126.0, 127.0, 129.3, 129.5, 130.0 (s), 130.2 (s), 134.9 (s),
138.4 (s), 143.3 (s), 145.0 (s), 145.4 (s), 146.1 (s) ppm. HRMS (ESI):
calcd. for C27H28N5O2 [M + H]+ 454.2238; found 454.2228.
4b (R1 = 9-CH3O): Eluent for column chromatography: dichloro-
methane; yield 58% (0.25 g); colorless prisms; m.p. 200–201 °C (di-
ethyl ether). IR (Nujol): ν = 3337 (vs), 1769 (s), 1721 (vs), 1638
˜
10c (R1 = 9-CH3O; R2 = 4-CH3O): Yield 75% (0.32 g); colorless
(vs), 1548 (s), 1503 (vs), 1416 (vs), 1311 (vs) cm–1. 1H NMR
(300 MHz, [D6]DMSO, 25 °C): δ = 2.90 (t, J = 7.2 Hz, 2 H,
CH2CH2Ph), 3.55–3.62 (m, 2 H, CH2CH2Ph), 3.70 (s, 3 H, 9-
OCH3), 6.64 (dd, J = 8.7, 2.7 Hz, 1 H, 8-H), 6.95 (d, J = 8.7 Hz,
1 H, 7-H), 7.18–7.23 (m, 1 H), 7.27–7.33 (m, 5 H), 7.47–7.57 (m,
6 H) ppm. 13C NMR (75 MHz, [D6]DMSO, 25 °C): δ = 34.1, 41.7,
55.4, 100.4, 110.1, 124.0, 125.2 (s), 126.3, 126.6, 127.1, 128.5, 128.7,
128.9, 129.1 (s), 130.4 (s), 139.1 (s), 141.1 (s), 143.9 (s), 145.1 (s),
154.9 (s) ppm. HRMS (ESI): calcd. for C24H22N5O3 [M + H]+
428.1717; found 428.1713.
prisms; m.p. 223–225 °C (dichloromethane). IR (Nujol): ν = 3351
˜
(vs), 1767 (vs), 1706 (vs), 1638 (vs), 1596 (s), 1488 (vs), 1412 (vs),
1358 (s) cm–1. 1H NMR (300 MHz, C2D2Cl4, 25 °C): δ = 3.71 (s, 3
H), 3.75 (s, 3 H), 6.59 (dd, J = 8.7, 2.7 Hz, 1 H, 8-H), 6.83 (d, J =
9 Hz, 2 H, 5-NH-ArH), 7.02 (d, J = 8.7 Hz, 1 H, 7-H), 7.40–7.52
(m, 7 H, 2-Ph + 5-NH-ArH), 7.63 (d, J = 2.7 Hz, 1 H, 10-H), 9.02
(s, 1 H, NH) ppm. 13C NMR (75 MHz, C2D2Cl4, 25 °C): δ = 56.0,
56.1, 73.3 (s), 101.0, 112.1, 114.5, 122.5, 125.4 (s), 125.8, 126.4,
129.7, 129.9, 130.5 (s), 137.6 (s), 143.4 (s), 145.2 (s), 156.4 (s), 156.7
(s) ppm. HRMS (ESI): calcd. for C23H20N5O4 [M + H]+ 430.1515;
found 430.1505.
4c (R1 = 9-Br): Eluent for column chromatography: dichlorometh-
ane; yield 48% (0.23 g); colorless prisms; m.p. 178–180 °C (diethyl
˜
10d (R1 = 9-CH3O; R2 = 4-Br): Yield 72% (0.34 g); colorless
ether). IR (Nujol): ν = 3343 (vs), 1772 (s), 1722 (vs), 1634 (vs),
1537 (s), 1494 (vs), 1407 (s), 1303 (s) cm–1. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 2.89 (t, J = 7.2 Hz, 2 H, CH2CH2Ph), 3.65 (m,
2 H, CH2CH2Ph), 6.88 (d, J = 8.4 Hz, 1 H, 7-H), 7.11 (dd, J =
8.4, 2.4 Hz, 1 H, 8-H), 7.16–7.19 (m, 3 H), 7.24–7.27 (m, 3 H),
7.38–7.45 (m, 5 H), 8.13 (d, J = 2.4 Hz, 1 H, 10-H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 35.3, 42.4, 115.7 (s), 117.4, 125.3,
125.4 (s), 126.0, 126.8, 128.8, 129.3, 129.4, 129.5, 129.9 (s), 132.6
(s), 138.4 (s), 142.0 (s), 143.3 (s), 145.0 (s) ppm. HRMS (ESI):
calcd. for C23H19BrN5O2 [M + H]+ 476.0717; found 476.0719.
prisms; m.p. 244–246 °C (dichloromethane). IR (Nujol): ν = 1766
˜
(vs), 1715 (vs), 1642 (vs), 1601 (vs), 1552 (vs), 1505 (vs), 1411 (vs),
1
1295 (vs) cm–1. H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 3.71
(s, 3 H, 9-OCH3), 6.67 (dd, J = 8.8, 2.4 Hz, 1 H, 8-H), 7.04 (d, J
= 8.4 Hz, 1 H, 7-H), 7.49–7.56 (m, 8 H, 10-H, + 5-NH-ArH + 2-
Ph), 7.66 (d, J = 8.4 Hz, 2 H, 5-NH-ArH), 9.36 (s, 1 H, NH) ppm.
13C NMR (100 MHz, [D6]DMSO, 25 °C): δ = 55.4, 100.6, 110.2,
115.1 (s), 121.9, 125.0, 125.1 (s), 125.9 (s), 126.9, 129.1, 129.2, 130.2
(s), 131.7, 137.0 (s), 137.7 (s), 143.8 (s), 145.5 (s), 156.1 (s) ppm.
HRMS (ESI): calcd. for C22H17BrN5O3 [M + H]+ 478.0509; found
478.0497.
4d (R1 = 7-CH3): Eluent for column chromatography: dichloro-
methane; yield 48% (0.20 g); colorless prisms; m.p. 150–152 °C (di-
ethyl ether). IR (Nujol): ν = 3351 (vs), 1767 (vs), 1706 (vs), 1638
˜
10e [R1 = 9-(CH3)2CH; R2 = 4-Br]: Eluent for column chromatog-
raphy: hexanes/diethyl ether (9:1, v/v); yield 63% (0.31 g); colorless
(vs), 1596 (s), 1488 (vs), 1412 (vs), 1358 (s) cm–1. 1H NMR
(300 MHz, [D6]DMSO, 25 °C): δ = 2.27 (s, 3 H, 7-CH3), 2.91 (t, J
= 7.2 Hz, 2 H, CH2CH2Ph), 3.55–3.62 (m, 2 H, CH2CH2Ph), 6.81
(t, J = 7.5 Hz, 1 H), 6.91 (d, J = 7.5 Hz, 1 H), 7.17–7.31 (m, 5 H),
7.41–7.54 (m, 6 H), 7.71 (d, J = 8.1 Hz, 1 H) ppm. 13C NMR
(75 MHz, [D6]DMSO, 25 °C): δ = 17.1, 34.5, 42.1, 111.5, 122.1,
124.6 (s), 126.2, 126.8, 127.0, 128.4, 128.6, 128.8, 129.0, 130.5 (s),
131.1 (s), 131.5 (s), 139.1 (s), 141.7 (s), 143.8 (s), 145.1 (s) ppm.
HRMS (ESI): calcd. for C24H22N5O2 [M + H]+ 412.1768; found
412.1767.
prisms; m.p. 178–180 °C (diethyl ether). IR (Nujol): ν = 1758 (vs),
˜
1713 (vs), 1642 (vs), 1608 (vs), 1555 (vs), 1504 (vs), 1488 (s), 1310
(s) cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.22 [d, J =
7.2 Hz, 6 H, 9-CH(CH3)2], 2.29 [sept, J = 7.2 Hz, 1 H, 9-CH(CH3)
2], 6.95 (d, J = 8.4, 2 Hz, 1 H, 8-H), 6.97 (d, J = 2 Hz, 1 H, 7-H),
7.42–7.57 (m, 9 H, 2-Ph + 5-NH-ArH), 7.97 (d, J = 2 Hz, 1 H, 10-
H), 9.40 (s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3, 25 °C):
δ = 23.8, 33.9, 112.7, 116.5 (s), 121.8, 124.4, 124.7, 124.8 (s), 125.9,
129.2, 129.5, 129.7 (s), 129.8 (s), 131.9, 136.4 (s), 137.8 (s), 143.1
10a (R1 = 9-CH3; R2 = 4-CH3): Yield 93% (0.37 g); colorless (s), 145.2 (s), 146.5 (s) ppm. HRMS (ESI): calcd. for
prisms; m.p. 276–277 °C (dichloromethane). IR (Nujol): ν = 3281
C24H21BrN5O2 [M + H]+ 490.0873; found 490.0863.
˜
700
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 694–704

New Dienophilic Dinitrogen Equivalent
10f [R1 = 9-(CH3)2CH; R2 = 4-Cl]: Yield 65% (0.29 g); colorless 10l (R1 = 7-CH3; R2 = 2-CH3): Eluent for column chromatography:
prisms; m.p. 175–176 °C (dichloromethane). IR (Nujol): ν = 1759
diethyl ether/hexanes (4:1, v/v); yield 53% (0.21 g); colorless prisms;
˜
(vs), 1713 (vs), 1641 (vs), 1609 (vs), 1558 (vs), 1504 (vs), 1490 (vs),
m.p. 232–234 °C (diethyl ether). IR (Nujol): ν = 1787 (vs), 1716
˜
1
1311 (m) cm–1. H NMR (300 MHz, CDCl3, 25 °C): δ = 1.22 [d, J
(vs), 1637 (vs), 1596 (vs), 1567 (s), 1413 (vs), 1333 (s), 1268 (s) cm–1.
= 6.9 Hz, 6 H, 9-CH(CH3)2], 2.85 [sept, J = 6.9 Hz, 1 H, 9- 1H NMR (300 MHz, [D6]DMSO, 115 °C): δ = 2.26 (s, 3 H), 2.29
CH(CH3)2], 6.96 (dd, J = 8.4, 1.8 Hz, 1 H, 8-H), 7.07 (d, J = (s, 3 H), 6.89–6.97 (m, 2 H), 7.03 (td, J = 7.5, 0.9 Hz, 1 H), 7.20–
8.1 Hz, 1 H, 7-H), 7.24–7.28 (m, 2 H, 5-NH-ArH), 7.42–7.55 (m, 7.24 (m, 2 H), 7.42–7.60 (m, 5 H), 7.80 (dd, J = 8.9, 1.5 Hz, 1 H),
5 H, 2-Ph), 7.58–7.62 (m, 2 H, 5-NH-ArH), 7.96 (d, J = 1.8 Hz, 1 8.24 (d, J = 8.1 Hz, 1 H), 9.20 (s, 1 H) ppm. 13C NMR (75 MHz,
H, 10-H), 9.37 (s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3, [D6]DMSO, 115 °C): δ = 16.1, 16.4, 111.1, 121.0, 122.8, 123.2,
25 °C): δ = 23.8, 34.0, 112.8, 121.5, 124.5, 124.7, 124.8 (s), 125.9,
129.0 (s), 129.1, 129.3, 129.5, 129.8 (s), 129.9 (s), 136.0 (s), 137.9
(s), 143.1 (s), 145.2 (s), 146.5 (s) ppm. HRMS (ESI): calcd. for
C24H21ClN5O2 [M + H]+ 446.1378; found 446.1639.
124.9 (s), 125.5, 125.8 (s), 126.1, 126.4, 127.8 (s), 128.1, 128.3,
128.6, 129.5, 131.5 (s), 135.3 (s), 138.5 (s), 145.3 (s) ppm. HRMS
(ESI): calcd. for C23H20N5O2 [M + H]+ 398.1612; found 398.1612.
10m and 10mЈ (R2 = 3-CH3): Eluent for column chromatography:
hexanes/diethyl ether (4:1, v/v); yield 51% (0.20 g). IR (Nujol): ν =
˜
10g (R1 = 9-CH3; R2 = 4-NO2): Yield 67% (0.28 g); yellow prisms;
1763 (vs), 1720 (vs), 1646 (vs), 1617 (vs), 1578 (s), 1493 (vs), 1328
(s), 1287 (s) cm–1. 1H NMR (400 MHz, [D6]DMSO, 25 °C): δ =
2.24 (s, 3 H), 2.31 (s, 6 H), 2.32 (s, 3 H), 6.87 (dd, J = 8.4, 1.2 Hz,
1 H), 6.91–6.97 (m, 5 H), 7.13 (t, J = 7.6 Hz, 2 H), 7.25 (t, J =
7.6 Hz, 2 H), 7.46–7.62 (m, 13 H), 7.78 (d, J = 8 Hz, 1 H), 9.27 (s,
1 H), 9.40 (s, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO, 25 °C):
δ = 19.9, 20.4, 21.1, 133.6, 117.2, 120.5, 120.6, 121.1, 122.8 (s),
122.9 (s), 124.3, 124.4, 124.6, 124.7, 126.9, 127.0, 127.2, 127.4,
128.7, 128.8, 129.0, 129.1, 130.0 (s), 130.6 (s), 132.2 (s), 135.2 (s),
136.2 (s), 137.3 (s), 137.5 (s), 138.2 (s), 138.4 (s), 139.5 (s), 142.3
(s), 143.6 (s), 145.3 (s), 145.8 (s), 150.3 (s) ppm. HRMS (ESI):
calcd. for C23H20N5O2 [M + H]+ 398.1612; found 398.1605.
m.p. 250–252 °C (dichloromethane). IR (Nujol): ν = 1788 (vs),
˜
1757 (vs), 1716 (vs), 1646 (vs), 1582 (s), 1505 (vs), 1399 (s), 1170
1
(m) cm–1. H NMR (300 MHz, [D6]DMSO, 60 °C): δ = 2.28 (s, 3
H, 9-CH3), 6.95 (d, J = 7.8 Hz, 1 H, 8-H), 7.08 (d, J = 8.1 Hz, 1
H, 7-H), 7.45–7.60 (m, 5 H, 2-Ph), 7.78 (s, 1 H, 10-H), 7.95 (d, J
= 9 Hz, 2 H, 5-NH-ArH), 8.21 (d, J = 9 Hz, 2 H, 5-NH-ArH), 9.89
(s, 1 H, NH) ppm. 13C NMR (75 MHz, [D6]DMSO, 60 °C): δ =
20.5, 114.4, 119.4, 124.5, 125.3 (s), 126.0, 126.5, 128.7, 128.8, 129.0,
129.9 (s), 134.7 (s), 138.1 (s), 142.2 (s), 143.6 (s), 144.9 (s), 145.3
(s) ppm. HRMS (ESI): calcd. for C22H17N6O4 [M + H]+ 429.1306;
found 429.1301.
10h (R1 = 9-Br; R2 = 4-Br): Yield 36% (0.19 g); colorless prisms;
General Procedure for the Preparation of Compounds 13: To a solu-
tion of carbodiimides 9n or 9o (2 mmol) in anhydrous dichloro-
methane (15 mL), solid PTAD (0.73 g, 4.2 mmol) was added in sev-
eral batches. The reaction mixture was stirred at r.t. for 48 h. The
solvent was removed under reduced pressure and the resulting ma-
terial was purified by column chromatography on silica gel using
dichloromethane/diethyl ether (4:1, v/v) as eluent.
m.p. 283–285 °C (dichloromethane). IR (Nujol): ν = 1769 (vs),
˜
1755 (vs), 1717 (vs), 1634 (s), 1606 (s), 1554 (vs), 1488 (vs), 1301
1
(m) cm–1. H NMR (400 MHz, C2D2Cl4, 25 °C): δ = 6.98 (d, J =
8.4 Hz, 1 H, 7-H), 7.17 (dd, J = 8.4, 2 Hz, 1 H, 8-H), 7.40–7.51
(m, 9 H, 2-Ph + 5-NH-ArH), 8.13 (d, J = 1.6 Hz, 1 H, 10-H), 9.30
(s, 1 H, NH) ppm. 13C NMR (100 MHz, C2D2Cl4, 25 °C): δ =
117.4 (s), 117.6 (s), 117.7, 122.5, 125.8 (s), 126.2, 126.5, 129.6 (s),
129.8, 130.0, 131.5 (s), 132.4, 136.2 (s), 138.7 (s), 143.3 (s), 145.3
(s) ppm. HRMS (ESI): calcd. for C21H14Br2N5O2 [M + H]+
525.9509; found 525.9509.
13a (Ar = 4-Cl-C6H4): Yield 30% (0.37 g); colorless prisms; m.p.
200–202 °C (diethyl ether). IR (Nujol): ν = 3467 (m), 3302 (m),
˜
1777 (s), 1713 (vs), 1666 (s), 1606 (vs), 1559 (s), 1502 (s), 1405 (vs),
1
1329 (s) cm–1. H NMR (300 MHz, [D6]DMSO, 25 °C): δ = 1.54
10j (R1 = 9-CH3O; R2 = 4-CH3): Yield 80% (0.33 g); colorless
(s, 3 H), 1.93 (s, 3 H), 5.55 (d, J = 6 Hz, 1 H), 6.43 (d, J = 6 Hz,
1 H), 6.48 (s, 1 H), 6.64 (t, J = 6 Hz, 1 H), 7.26 (d, J = 8.4 Hz, 2
H), 7.28–7.52 (m, 10 H), 7.71 (d, J = 8.4 Hz, 2 H), 8.98 (s, 1 H)
ppm. 13C NMR (75 MHz, [D6]DMSO, 25 °C): δ = 15.5, 19.4, 54.1,
66.5 (s), 66.9 (s), 84.4 (s), 121.8, 126.4, 127.0 (s), 127.1, 127.3, 128.4,
128.7, 129.0, 129.2, 130.1 (s), 131.2 (s), 136.9 (s), 137.2, 137.8 (s),
147.2 (s), 148.7 (s), 151.2 (s), 151.3 (s) ppm. HRMS (ESI): calcd.
for C31H26ClN8O5 [M + H]+ 625.1709; found 625.1707.
prisms; m.p. 238–239 °C (dichloromethane). IR (Nujol): ν = 1763
˜
(vs), 1721 (vs), 1645 (vs), 1613 (vs), 1561 (vs), 1508 (vs), 1413 (vs),
1
1270 (vs) cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 2.30 (s, 3
H, 5-NH-ArH-CH3), 3.74 (s, 3 H, 9-OCH3), 6.61 (dd, J = 8.8,
2.8 Hz, 1 H, 8-H), 7.06 (d, J = 8.4 Hz, 1 H, 7-H), 7.11 (d, J =
8.4 Hz, 2 H, 5-NH-ArH), 7.42–7.55 (m, 7 H, 2-Ph + 5-NH-ArH),
7.70 (d, J = 2.8 Hz, 1 H, 10-H), 9.20 (s, 1 H, NH) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 20.8, 55.6, 100.4, 111.8, 120.2, 125.2
(s), 125.4 (s), 125.5, 125.8, 129.1, 129.4, 129.5, 129.9 (s), 133.5 (s),
134.7 (s), 137.1 (s), 143.0 (s), 144.9 (s), 156.5 (s) ppm. HRMS (ESI):
calcd. for C23H20N5O3 [M + H]+ 414.1561; found 414.1557.
13b (Ar = 4-Br-C6H4): Yield 30% (0.42 g); colorless prisms; m.p.
177–178 °C (diethyl ether). IR (Nujol): ν = 3469 (m), 3302 (m),
˜
1777 (s), 1765 (vs), 1714 (vs), 1668 (s), 1605 (vs), 1556 (vs), 1502
1
(vs), 1405 (vs) cm–1. H NMR (300 MHz, [D6]DMSO, 25 °C): δ =
1.57 (s, 3 H), 1.95 (s, 3 H), 5.56 (d, J = 6 Hz, 1 H), 6.45 (d, J =
6 Hz, 1 H), 6.51 (s, 1 H), 6.65 (t, J = 6 Hz, 1 H), 7.27 (d, J = 9 Hz,
2 H), 7.33–7.56 (m, 10 H), 7.67 (d, J = 9 Hz, 2 H), 9.00 (s, 1 H)
ppm. 13C NMR (75 MHz, [D6]DMSO, 25 °C): δ = 15.6, 19.6, 54.2,
66.7 (s), 67.1 (s), 84.6 (s), 115.2 (s), 122.3, 126.5, 127.2, 127.5, 128.5,
129.2, 129.4, 130.2 (s), 131.3 (s), 131.7, 137.3, 137.4 (s), 137.8 (s),
147.3 (s), 148.8 (s), 151.2 (s), 151.3 (s) ppm. HRMS (ESI): calcd.
for C31H26BrN8O5 [M + H]+ 699.1204; found 699.1193.
10k [R1
= = 2,6-(CH3)2]: Eluent for column
9-CH3O; R2
chromatography: diethyl ether/hexanes (4:1, v/v); yield 61%
(0.26 g); colorless prisms; m.p. 214–215 °C (diethyl ether). IR (Nu-
jol): ν = 3314 (vs), 1766 (vs), 1717 (vs), 1642 (vs), 1529 (vs), 1506
˜
(vs), 1411 (vs), 1306 (vs) cm–1. 1H NMR (400 MHz, CDCl3, 25 °C):
δ = 2.35 (s, 6 H, 5-NH-Ar-CH3), 3.77 (s, 3 H, 9-OCH3), 6.58 (dd,
J = 8.8, 2.8 Hz, 1 H, 8-H), 6.92 (d, J = 8.8 Hz, 1 H, 7-H), 7.10–
7.18 (m, 3 H, 5-NH-ArH), 7.44–7.48 (m, 1 H, 2-Ph), 7.52–7.60 (m,
4 H, 2-Ph), 7.76 (d, J = 2.8 Hz, 1 H, 10-H), 8.50 (s, 1 H, NH) ppm. Procedure for the Preparation of Bis(triazolo-benzotriazine) Deriva-
13C NMR (100 MHz, CDCl3, 25 °C): δ = 18.8, 55.7, 100.5, 111.8,
125.3 (s), 125.5, 126.1, 127.4, 128.4, 129.2, 129.5, 130.0 (s), 133.3
(s), 135.9 (s), 138.3 (s), 143.4 (s), 145.2 (s), 156.4 (s) ppm. HRMS
(ESI): calcd. for C24H22N5O3 [M + H]+ 428.1717; found 428.1716.
tive 17: To a solution of bis(carbodiimide) 16 (1 mmol) in anhy-
drous dichloromethane (15 mL), solid PTAD (0.38 g, 2.2 mmol)
was added. The reaction mixture was stirred at r.t. for 24 h. The
solvent was removed under reduced pressure and the resulting ma-
Eur. J. Org. Chem. 2010, 694–704
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
701

M. Alajarin, A. Vidal et al.
FULL PAPER
terial was purified by column chromatography on silica gel using
diethyl ether/dichloromethane (7:3, v/v) as eluent.
1608 (vs), 1557 (vs), 1396 (s), 1361 (s), 1289 (m), 1199 (s), 1171 (vs)
cm–1. 1H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 3.94 (s, 3 H, 7-
OCH3), 7.51 (d, J = 8.8 Hz, 2 H, 3-NH-ArH), 7.60 (dd, J = 9.2,
2.8 Hz, 1 H, 6-H), 7.68–7.72 (m, 2 H, 5-H + 8-H), 7.88 (d, J =
8.8 Hz, 2 H, 3-NH-ArH), 10.73 (s, 1 H, NH) ppm. 13C NMR
(100 MHz, [D6]DMSO, 25 °C): δ = 56.0, 106.2, 113.4 (s), 120.5,
127.8, 129.7, 131.5, 136.8 (s), 139.3 (s), 143.6 (s), 157.0 (s), 157.4
(s) ppm. HRMS (ESI): calcd. for C14H12BrN4O [M + H]+
331.0819; found 331.0185.
17: Yield 62% (0.53 g); colorless prisms; m.p. 279–280 °C (diethyl
ether). IR (Nujol): ν = 3256 (s), 1770 (vs), 1724 (vs), 1633 (vs),
˜
1592 (vs), 1504 (vs), 1403 (vs), 1300 (vs) cm–1. 1H NMR (400 MHz,
[D6]DMSO, 120 °C): δ = 0.89 (t, J = 6.8 Hz, 6 H), 1.33–1.34 (m, 8
H), 1.42–1.46 (m, 4 H), 1.69–1.76 (m, 4 H), 3.98 (t, J = 6.4 Hz, 4
H), 6.69 (dd, J = 8.4, 2.4 Hz, 2 H), 7.05 (d, J = 8.8 Hz, 2 H), 7.47–
7.61 (m, 12 H), 7.67 (m, 4 H), 9.17 (s, 2 H) ppm. 13C NMR
(100 MHz, [D6]DMSO, 120 °C): δ = 12.8, 21.1, 24.3, 28.0, 30.1,
68.0, 101.2, 111.1, 120.4, 124.2 (s), 125.2 (s), 125.4, 125.8 (s), 126.1,
128.1, 128.3, 132.9 (s), 137.6 (s), 143.4 (s), 145.0 (s), 155.1 (s) ppm.
HRMS (ESI): calcd. for C48H49N10O6 [M + H]+ 861.3831; found
861.3834.
18e [R1 = 7-(CH3)2CH; R2 = 4-Br-C6H4]: Yield 97% (0.33 g);
orange prisms; m.p. 190–191 °C (diethyl ether). IR (Nujol): ν =
˜
3256 (vs), 1610 (s), 1553 (vs), 1491 (s), 1426 (m), 1366 (m), 1241
1
(m), 1103 (s) cm–1. H NMR (300 MHz, CDCl3, 58 °C): δ = 1.38
[d, J = 6.9 Hz, 6 H, 7-CH(CH3)2], 3.12 [sept, J = 6.9 Hz, 1 H, 7-
CH(CH3)2], 7.50 (d, J = 8.7 Hz, 2 H, 3-NH-ArH), 7.67–7.78 (m, 4
H, 3-NH-ArH + 5-H + 6-H), 8.13 (s, 1 H, 8-H), 8.20 (s, 1 H, NH)
ppm. 13C NMR (75 MHz, CDCl3, 58 °C): δ = 23.6, 34.1, 115.7 (s),
120.9, 125.7, 126.9, 132.1, 136.4, 138.2 (s), 140.2 (s), 147.9 (s) ppm.
HRMS (ESI): calcd. for C16H16BrN4 [M + H]+ 343.0553; found
343.0546.
General Procedure for the Preparation of 1,2,4-Benzotriazine Deriv-
atives 18: KOH (0.56 g, 10 mmol) was dissolved in methanol
(15 mL) and either [1,2,4]triazolo[1,2-a][1,2,4]benzotriazine 4 or 10
(1 mmol) was added. The suspension was stirred at r.t. for 48 h.
For compounds 18a–l the solvent was removed under reduced pres-
sure, the solid residue was triturated with water, and the precipitate
was filtered and dried. For compounds 18m–o, the solvent was re-
moved under reduced pressure and the residue was purified by col-
umn chromatography on silica gel, using diethyl ether/hexanes (4:1,
v/v) as eluent.
18f [R1 = 7-(CH3)2CH; R2 = 4-Cl-C6H4]: Yield 86% (0.26 g);
orange prisms; m.p. 231–233 °C (diethyl ether). IR (Nujol): ν =
˜
3257 (vs), 1611 (s), 1555 (vs), 1494 (s), 1427 (m), 1241 (w), 1104
1
(m), 1092 (m) cm–1. H NMR (300 MHz, [D6]DMSO, 25 °C): δ =
18a (R1 = 7-CH3; R2 = 4-CH3-C6H4): Yield 59% (0.15 g); orange
1.29 [d, J = 6.9 Hz, 6 H, 7-CH(CH3)2], 3.10 [sept, J = 6.9 Hz, 1 H,
7-CH(CH3)2], 7.39 (d, J = 8.7 Hz, 2 H, 3-NH-ArH), 7.79 (d, J =
8.4 Hz, 1 H, 5-H or 6-H), 7.87 (d, J = 8.7 Hz, 1 H, 5-H or 6-H),
7.97 (d, J = 8.4 Hz, 2 H, 3-NH-ArH), 8.10 (s, 1 H, 8-H), 10.90 (s,
1 H, NH) ppm. 13C NMR (75 MHz, [D6]DMSO, 25 °C): δ = 23.3,
33.1, 120.2, 125.0, 125.7 (s), 126.4, 128.9, 136.3, 138.7 (s), 139.0
(s), 142.7 (s), 146.9 (s), 157.1 (s) ppm. HRMS (ESI): calcd. for
C16H16ClN4 [M + H]+ 299.1058; found 299.1054.
prisms; m.p. 230–232 °C (diethyl ether). IR (Nujol): ν = 3256 (vs),
˜
1607 (s), 1546 (vs), 1515 (vs), 1324 (s), 1241 (s), 1166 (m), 1098 (s)
cm–1. 1H NMR (300 MHz, [D6]DMSO, 25 °C): δ = 2.28 (s, 3 H, 3-
NH-ArH-CH3), 2.49 (s, 3 H, 7-CH3), 7.16 (d, J = 8.1 Hz, 2 H, 3-
NH-ArH), 7.62 (d, J = 8.7 Hz, 1 H, 5-H), 7.72 (dd, J = 8.7, 1.5 Hz,
1 H, 6-H), 7.80 (d, J = 8.1 Hz, 2 H, 3-NH-ArH), 8.05 (d, J =
1.5 Hz, 1 H, 8-H), 10.58 (s, 1 H, NH) ppm. 13C NMR (75 MHz,
[D6]DMSO, 25 °C): δ = 20.5, 20.9, 119.1, 126.2, 127.7, 129.2, 131.4
(s), 135.9 (s), 137.1 (s), 138.5, 139.1 (s), 142.5 (s), 157.5 (s) ppm.
HRMS (ESI): calcd. for C15H15N4 [M + H]+ 251.1291; found
251.1282.
18g (R1 = 7-CH3; R2 = 4-NO2-C6H4): Yield 66% (0.18 g); yellow
prisms; m.p. 286–287 °C (diethyl ether). IR (Nujol): ν = 3253 (s),
˜
1616 (s), 1584 (vs), 1562 (vs), 1542 (vs), 1504 (vs), 1334 (vs) cm–1.
1H NMR (400 MHz, CDCl3 + CF3COOD, 25 °C): δ = 2.47 (s, 3
H, 7-CH3), 7.73 (d, J = 9.2 Hz, 1 H, 5-H), 7.78–7.81 (m, 3 H, 3-
NH-ArH + 8-H), 7.96 (dd, J = 9.2, 2 Hz, 2 H, 6-H), 8.17–8.19 (m,
2 H, 3-NH-ArH) ppm. 13C NMR (100 MHz, CDCl3 + CF3COOD,
25 °C): δ = 23.5, 123.1, 127.7, 128.8, 129.3, 143.1 (s), 144.2 (s),
146.5 (s), 147.2, 150.4 (s), 150.5 (s), 153.8 (s) ppm. HRMS (ESI):
calcd. for C14H12N5O2 [M + H]+ 282.0986; found 282.0979.
18b [R1 = 7-(CH3)2CH; R2 = 4-(CH3)2CH-C6H4]: Yield 83%
(0.25 g); orange prisms; m.p. 209 °C (diethyl ether). IR (Nujol): ν
˜
= 3253 (s), 1610 (m), 1558 (vs), 1518 (m), 1464 (vs), 1377 (vs), 1105
(m), 837 (s) cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.29 [d,
J = 6.8 Hz, 6 H, 7-CH(CH3)2], 1.38 [d, J = 6.8 Hz, 6 H, 3-NH-
ArH-CH(CH3)2], 2.94 [sept, J = 6.8 Hz, 1 H, 3-NH-ArH-CH(CH3)
2], 3.11 [sept, J = 6.8 Hz, 1 H, 7-CH(CH3)2], 7.29 (d, J = 8 Hz, 2
H, 3-NH-ArH), 7.68–7.74 (m, 2 H, 5-H + 6-H), 7.81 (d, J = 8 Hz,
2 H, 3-NH-ArH), 8.12 (s, 1 H, 8-H), 8.33 (s, 1 H, NH) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 23.6, 24.2, 33.7, 33.9, 119.2,
125.5, 126.7, 127.0, 136.2, 136.5 (s), 140.3 (s), 143.5 (s), 143.9 (s),
147.1 (s), 157.5 (s) ppm. HRMS (ESI): calcd. for C19H23N4 [M +
H]+ 307.1922; found 307.1902.
18h (R1 = 7-Br; R2 = 4-Br-C6H4): Yield 66% (0.25 g); orange
prisms; m.p. 266–267 °C (diethyl ether). IR (Nujol): ν = 3254 (vs),
˜
1608 (vs), 1556 (vs), 1492 (vs), 1482 (vs), 1417 (m), 1357 (s), 1238
(s) cm–1. 1H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 7.53 (d, J =
8.8 Hz, 2 H, 3-NH-ArH), 7.69 (d, J = 8.8 Hz, 1 H, 5-H), 7.90 (d,
J = 8.8 Hz, 2 H, 3-NH-ArH), 8.00 (dd, J = 9.2, 2 Hz, 1 H, 6-H),
8.55 (d, J = 2 Hz, 1 H, 8-H), 11.11 (br. s, 1 H, NH) ppm. 13C NMR
(100 MHz, [D6]DMSO, 25 °C): δ = 114.3 (s), 118.2 (s), 120.9, 128.8,
131.2, 131.5, 138.6 (s), 139.1, 139.3 (s), 142.7 (s), 157.1 (s) ppm.
HRMS (ESI): calcd. for C13H9Br2N4 [M + H]+ 378.9188; found
378.9187.
18c (R1 = 7-CH3O; R2 = 4-CH3O-C6H4): Yield 80% (0.22 g); red
prisms; m.p. 217–219 °C (diethyl ether). IR (Nujol): ν = 3258 (vs),
˜
1602 (vs), 1556 (vs), 1500 (vs), 1401 (s), 1328 (m), 1307 (m), 1236
1
(vs) cm–1. H NMR (400 MHz, C2D2Cl4, 25 °C): δ = 3.75 (s, 3 H,
3-NH-ArH-OCH3), 3.89 (s, 3 H, 7-OCH3), 6.89 (d, J = 8.4 Hz, 2
H, 3-NH-ArH), 7.40–7.46 (m, 2 H, 6-H + 8-H), 7.58–7.64 (m, 3 H,
3-NH-ArH + 5-H), 7.80 (s, 1 H, NH) ppm. 13C NMR (100 MHz,
C2D2Cl4, 25 °C): δ = 56.0, 56.3, 106.1, 121.2, 128.2, 130.2, 132.2
(s), 138.3 (s), 144.3 (s), 155.8 (s), 157.6 (s), 157.8 (s) ppm. HRMS
(ESI): calcd. for C15H15N4O2 [M + H]+ 283.1190; found 283.1183.
18i (R1 = 7-CH3O; R2 = 4-CH3-C6H4): Yield 86% (0.23 g); orange
prisms; m.p. 206–207 °C (diethyl ether). IR (Nujol): ν = 3261 (vs),
˜
1608 (vs), 1531 (vs), 1512 (vs), 1496 (vs), 1401 (vs), 1360 (vs), 1328
(s) cm–1. 1H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 2.26 (s, 3
H, 3-NH-ArH-CH3), 3.92 (s, 3 H, 7-OCH3), 7.13 (d, J = 6 Hz, 2
H, 8-H), 7.55–7.78 (m, 5 H, 3-NH-ArH + 5-H + 6-H), 10.47 (s, 1
H, NH) ppm. 13C NMR (100 MHz, [D6]DMSO, 25 °C): δ = 20.5,
55.9, 106.2, 118.7, 127.7, 129.1, 129.4, 130.9 (s), 136.9 (s), 137.3 (s),
18d (R1 = 7-CH3O; R2 = 4-Br-C6H4): Yield 80% (0.26 g); orange
prisms; m.p. 246–247 °C (diethyl ether). IR (Nujol): ν = 3257 (vs),
˜
702
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 694–704

New Dienophilic Dinitrogen Equivalent
143.3 (s), 156.9 (s), 157.4 (s) ppm. HRMS (ESI): calcd. for
C15H15N4O [M + H]+ 267.1245; found 267.1237.
7.33 (dd, J = 9.1, 2.1 Hz, 1 H, 6-H), 7.41 (d, J = 1.7 Hz, 1 H, 8-
H), 7.46 (d, J = 9.1 Hz, 1 H, 5-H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 35.6, 42.6, 55.8, 105.9, 114.3 (s), 120.9 (s), 126.5,
127.6, 128.7, 128.9, 129.6, 139.1 (s), 156.9 (s), 159.6 (s) ppm.
HRMS (ESI): calcd. for C16H17N4O [M + H]+ 281.1397; found
281.1394.
18j [R1 = 7-CH3O; R2 = 2,6-(CH3)2-C6H3]: Yield 98% (0.27 g);
yellow prisms; m.p. 165–166 °C (diethyl ether). IR (Nujol): ν =
˜
3293 (vs), 1622 (s), 1548 (vs), 1516 (vs), 1400 (s), 1359 (vs), 1285
(s), 1202 (vs) cm–1. 1H NMR (400 MHz, [D6]DMSO, 25 °C): δ =
2.15 (s, 6 H), 3.91 (s, 3 H), 7.12 (br. s, 3 H), 7.47 (br. s, 2 H), 7.6
(s, 1 H), 9.52 (br., 1 H) ppm. 13C NMR (400 MHz, [D6]DMSO,
25 °C): δ = 18.3, 55.9, 106.0, 126.4, 127.5, 128.0, 129.5, 135.9 (s),
138.2 (s), 143.3 (s), 156.5 (s), 158.7 (s) ppm. HRMS (ESI): calcd.
for C16H17N4O [M + H]+ 281.1397; found 281.1394.
Computational Methods: All structures were optimized by using the
functional B3LYP[23] and the 6-31+G** basis set as implemented
in the Gaussian03 suite of programs.[24] Density Functional Theory
has been shown to reliably predict the results of [4+2] cycload-
ditions and other pericyclic reactions.[25] All energy minima and
transition structures were characterized by frequency analysis. The
energies reported in this work include the zero-point vibrational
energy corrections (ZPVE) and are not scaled. Wiberg bond or-
ders[26] and natural atomic charges were calculated within the natu-
ral bond orbital (NBO) analysis.[27] The synchronicity was deter-
mined by using a previously described approach.[28]
18k (R1 = 5-CH3; R2 = 2-CH3-C6H4): Yield 77% (0.19 g); orange
prisms; m.p. 202–204 °C (diethyl ether). IR (Nujol): ν = 3130 (vs),
˜
1536 (vs), 1343 (m), 1307 (m), 1254 (m), 1099 (m), 1086 (m), 957
1
(w) cm–1. H NMR (300 MHz, [D6]DMSO, 25 °C): δ = 2.30 (s, 3
H), 2.43 (s, 3 H), 7.08–7.29 (m, 1 H), 7.20–7.29 (m, 2 H), 7.42 (t,
J = 9 Hz, 1 H), 7.68–7.75 (m, 2 H), 8.09 (d, J = 8.4 Hz, 1 H), 9.86
(s, 1 H) ppm. 13C NMR (75 MHz, [D6]DMSO, 25 °C): δ = 15.5,
18.2, 124.0, 124.8, 125.3, 125.9, 126.9, 130.5, 132.0 (s), 134.4 (s),
135.1, 137.0 (s), 140.1 (s), 142.6 (s), 157.6 (s) ppm. HRMS (ESI):
calcd. for C15H15N4 [M + H]+ 251.1291; found 251.1290.
Supporting Information (see footnote on the first page of this arti-
cle): Cartesian coordinates, electronic and free energies, and low
frequencies of each stationary point optimized at the B3LYP/6-
31+G** theoretical level.
18l [R1 = 7-(CH3)2CH; R2 = C6H5-CH2CH2]: Yield 83% (0.24 g);
Acknowledgments
yellow prisms; m.p. 120–121 °C (diethyl ether). IR (Nujol): ν =
˜
3246 (vs), 1572 (vs), 1556 (vs), 1496 (m), 1333 (w), 1236 (m), 1112
1
This work was supported by the Ministerio de Ciencia e Innovación
of Spain (Project No. CTQ2008-05827/BQU), and Fundacion
Seneca-CARM (Project No. 08661/PI/08). B. B. also thanks Fun-
dacion Seneca-CARM for a fellowship.
(m), 1089 (m) cm–1. H NMR (300 MHz, CDCl3, 25 °C): δ = 1.34
[d, J = 6.9 Hz, 6 H, 7-CH(CH3)2], 3.00–3.11 [m, 3 H, CH2CH2Ph
+ 7-CH(CH3)2], 3.82–3.88 (m, 2 H, CH2CH2Ph), 5.87 (br. s, 1 H,
NH), 7.23–7.35 (m, 5 H, CH2CH2Ph), 7.56 (d, J = 9.1 Hz, 1 H, 5-
H), 7.65 (dd, J = 9.1, 1.8 Hz, 1 H, 6-H), 8.04 (s, 1 H, 8-H) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 23.5, 33.7, 35.4, 42.5,
125.4, 126.2, 126.5, 128.6, 128.8, 135.8, 138.9 (s), 141.0 (s), 143.2
(s), 146.0 (s), 159.0 (s) ppm. HRMS (ESI): calcd. for C18H21N4 [M
+ H]+ 293.1761; found 293.1760.
[1] a) C. J. Moody, Adv. Heterocycl. Chem. 1982, 30, 1–45; b) S.
Radl, Adv. Heterocycl. Chem. 1996, 67, 119–205.
[2] For recent examples of using PTAD as an enophile, see: a) O.
Acevedo, M. E. Squillacote, J. Org. Chem. 2008, 73, 912–922;
b) A. Basheer, Z. Rappoport, J. Org. Chem. 2008, 73, 184–190;
c) G. C. Vougioukalakis, M. M. Roubelakis, M. N. Alberti, M.
Orfanopoulos, Chem. Eur. J. 2008, 14, 9697–9705.
18m (R1 = 7-Br; R2 = C6H5-CH2CH2): Yield 93% (0.30 g); yellow
prisms; m.p. 156–157 °C (diethyl ether). IR (Nujol): ν = 3241 (vs),
˜
1605 (vs), 1589 (vs), 1552 (vs), 1480 (vs), 1313 (m), 1109 (m) cm–1.
1H NMR (300 MHz, CDCl3, 25 °C): δ = 2.95 (t, J = 6.9 Hz, 2 H,
CH2CH2Ph), 3.76–3.78 (m, 2 H, CH2CH2Ph), 6.03 (br. s, 1 H,
NH), 7.14–7.28 (m, 5 H, CH2CH2Ph), 7.43 (d, J = 8.9 Hz, 1 H, 5-
H), 7.69 (dd, J = 8.9, 2.1 Hz, 1 H, 6-H), 8.33 (d, J = 2.1 Hz, 1 H,
8-H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 35.4, 42.5,
117.7 (s), 126.7, 128.2, 128.8, 128.9, 131.9, 138.7 (s), 138.9, 141.1
(s), 143.2 (s), 159.4 (s) ppm. HRMS (ESI): calcd. for C15H14BrN4
[M + H]+ 329.0390; found 329.0390.
[3] For recent examples of using PTAD as a dienophile, see: a) S.
Kobayashi, T. Furuya, T. Otani, T. Saito, Tetrahedron 2008, 64,
9705–9716; b) H. W. Süennemann, M. G. Banwell, A. de Mei-
jere, Chem. Eur. J. 2008, 14, 7236–7249; c) S. Kobayashi, T.
Furuya, T. Otani, T. Saito, Tetrahedron Lett. 2008, 49, 4513–
4515; d) M. Alajarin, J. Cabrera, A. Pastor, P. Sanchez-And-
rada, D. Bautista, J. Org. Chem. 2008, 73, 963–973.
[4] For a recent insight on the mechanism of the Diels–Alder reac-
tion between PTAD and dienes, see: N. A. Alberti, M. Orfano-
poulos, Org. Lett. 2009, 11, 1659–1662.
[5] a) V. M. Kobal, D. T. Gibson, R. E. Davies, A. Garza, J. Am.
Chem. Soc. 1973, 95, 4420–4421; b) K. L. Hoffman, G. Maas,
M. Regitz, J. Org. Chem. 1987, 52, 3851–3857; c) R. Askani,
J. P. Chesick, Chem. Ber. 1973, 106, 8–19; d) T. Imagawa, N.
Sueda, M. Kawanisi, J. Chem. Soc., Chem. Commun. 1972, 388.
[6] a) D. H. R. Barton, A. A. L. Gunatilaka, T. Nakanishi, H. Pa-
tin, D. A. Widdowson, B. R. Worth, J. Chem. Soc. Perkin
Trans. 1 1976, 821–826; b) R. I. Yakhimovich, N. F. Fursaeva,
V. E. Pashinnik, Chem. Nat. Prod. 1985, 21, 98–103; c) K. Ochi,
I. Matsunaga, H. Nagano, M. Fukushima, M. Shindo, C.
Kanedo, M. Ishikawa, H. F. DeLuca, J. Chem. Soc. Perkin
Trans. 1 1979, 165–169; d) N. Bosworth, A. Emke, J. M. Midg-
ley, C. J. Moore, W. B. Whalley, G. Fergurson, W. C. Marsh, J.
Chem. Soc. Perkin Trans. 1 1977, 805–809.
[7] a) A. P. Henderson, E. Mutlu, A. Leclercq, C. Bleasdale, W.
Clegg, R. A. Henderson, B. T. Golding, Chem. Commun. 2002,
1956–1957; b) A. G. Anastassiou, E. Yakali, J. Chem. Soc.,
Chem. Commun. 1972, 92–93.
[8] a) M. Alajarin, B. Bonillo, P. Sanchez-Andrada, A. Vidal, D.
Bautista, Org. Lett. 2009, 11, 1365–1368; b) M. Alajarin, A.
18n (R1 = 5-CH3; R2 = C6H5-CH2CH2): Yield 86% (0.22 g); yellow
prisms; m.p. 145–146 °C (diethyl ether). IR (Nujol): ν = 3240 (vs),
˜
1586 (vs), 1568 (vs), 1533 (s), 1493 (s), 1344 (m), 1170 (m), 1111
1
(s) cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 2.51 (s, 3 H, 5-
CH3), 2.95 (t, J = 9.3 Hz, 2 H, CH2CH2Ph), 3.74–3.79 (m, 2 H,
CH2CH2Ph), 6.02 (s, 1 H, NH), 7.12–7.16 (m, 1 H), 7.19–7.25 (m,
5 H, CH2CH2Ph), 7.46 (d, J = 7.2 Hz, 1 H), 7.99 (d, J = 8.4 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 16.1, 35.3, 42.8,
124.6, 126.5, 127.5, 128.7, 128.9, 134.8, 135.0 (s), 139.1 (s), 141.5
(s), 143.0 (s), 159.1 (s) ppm. HRMS (ESI): calcd. for C16H17N4 [M
+ H]+ 265.1448; found 265.1437.
18o (R1 = 7-CH3O; R2 = C6H5-CH2CH2): Yield 95% (0.26 g);
orange prisms; m.p. 115 °C (diethyl ether). IR (Nujol): ν = 3233
˜
(vs), 1621 (s), 1576 (vs), 1559 (vs), 1496 (vs), 1237 (m), 1201 (s),
1
1171 (s) cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 2.94 (t, J
= 6.7 Hz, 2 H, CH2CH2Ph), 3.73–3.78 (m, 2 H, CH2CH2Ph), 3.86
(s, 3 H, 7-OCH3), 5.77 (br. s, 1 H), 7.14–7.23 (m, 5 H, CH2CH2Ph),
Eur. J. Org. Chem. 2010, 694–704
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
703

M. Alajarin, A. Vidal et al.
FULL PAPER
Vidal, M.-M. Ortin, D. Bautista, Synlett 2004, 991–994; c) M.
Alajarin, A. Vidal, M.-M. Ortin, D. Bautista, New J. Chem.
2004, 28, 570–577; d) M. Alajarin, A. Vidal, M.-M. Ortin, Org.
Biomol. Chem. 2003, 1, 4282–4292; e) M. Alajarin, A. Vidal,
M.-M. Ortin, Tetrahedron Lett. 2003, 44, 3027–3030; f) M. Ala-
jarin, A. Vidal, F. Tovar, Targets Heterocycl. Syst. 2000, 4, 293–
326; g) P. Molina, M. Alajarin, A. Vidal, J. Feneau-Dupont,
J. P. Declercq, J. Org. Chem. 1991, 56, 4008–4016.
a) M. Alajarin, B. Bonillo, A. Vidal, D. Bautista, J. Org. Chem.
2008, 73, 291–294; b) M. Alajarin, B. Bonillo, M.-M. Ortin, P.
Sanchez-Andrada, A. Vidal, Org. Lett. 2006, 8, 5645–5648; c)
P. Molina, M. Alajarin, P. Sanchez-Andrada, J. Elguero, M. L.
Jimeno, J. Org. Chem. 1994, 59, 7306–7315; d) P. Molina, M.
Alajarin, A. Vidal, J. Elguero, R. M. Claramunt, Tetrahedron
1988, 44, 2249–2259; e) P. Molina, M. Alajarin, J. R. Saez, Syn-
thesis 1984, 983–986.
a) N. A. Lisowskaya, M. Alajarin, P. Sanchez-Andrada, Eur. J.
Org. Chem. 2006, 1468–1475; b) M. Alajarin, M.-M. Ortin, P.
Sanchez-Andrada, A. Vidal, D. Bautista, Org. Lett. 2005, 7,
5281–5284; c) M. Alajarin, P. Sanchez-Andrada, F. P. Cossio,
A. Arrieta, B. Lecea, J. Org. Chem. 2001, 66, 8470–8477; d) M.
Alajarin, A. Vidal, P. Sanchez-Andrada, F. Tovar, G. Ochoa,
Org. Lett. 2000, 2, 965–968.
a) P. Molina, M. Alajarin, A. Arques, R. Benzal, H. Hernan-
dez, J. Chem. Soc. Perkin Trans. 1 1984, 1891–1897; b) P. Mol-
ina, M. Alajarin, A. Arques, Synthesis 1982, 596–597.
A. E. Pain, THEOCHEM 1991, 230, 339–347; d) A. E. Pain,
I. H. Williams, Chem. Commun. 1991, 1417–1418.
[20] We have observed a similar twisting in the Diels–Alder reaction
of HTAD with 4-alkenyl-thiazoles, see ref.[3d]
[21] The feasibility of a Diels–Alder reaction is related to the
charge-transfer along the bond-forming processes, which corre-
sponds to the more or less polar character of these reactions,
see for example: a) L. R. Domingo, M. Arno, J. Andres, J. Org.
Chem. 1999, 64, 5867–5875; b) L. R. Domingo, Tetrahedron
2002, 58, 3765–3774; c) L. R. Domingo, M. J. Aurell, P. Perez,
R. Contreras, J. Org. Chem. 2003, 68, 3884–3890.
[22] All the Diels–Alder reactions involving HTAD that have been
studied computationally – even the reaction of HTAD with
butadiene – have been calculated to occur via highly asynchro-
nous transition structures, see ref.[2c] and: a) J. S. Chen, K. N.
Houk, C. S. Foote, J. Am. Chem. Soc. 1998, 120, 12303–12309;
b) D. A. Singleton, B. E. Schulmeier, C. Hang, A. A. Thomas,
S.-W. Leung, S. R. Merrigan, Tetrahedron 2001, 57, 5149–5160;
c) A. G. Leach, K. N. Houk, Chem. Commun. 2002, 1243–
1255.
[9]
[10]
[23] a) L. J. Bartolotti, K. Fluchichk, in: Reviews in Computational
Chemistry (Eds.: K. B. Lipkowitz, D. B. Boyds), VCH Publish-
ers, New York, 1996, vol. 7, pp. 187–216; b) W. Kohn, A. D.
Becke, R. G. Parr, J. Phys. Chem. 1996, 100, 12974–12980; c)
R. G. Parr, R. G. Pearson, J. Am. Chem. Soc. 1983, 105, 7512–
7516; d) T. Ziegler, Chem. Rev. 1991, 91, 651–667.
[11]
[12]
[24] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, J. A. Montgomery Jr., T.
Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar,
J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N.
Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y.
Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P.
Hratchian, J. B. Cross, C. Adamo, J. Jaramillo, R. Gomperts,
R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pom-
elli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P.
Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich,
A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D.
Rabuck, K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui,
Baboul, A. G. Clifford, S. Cioslowski, J. Stefanov, B. B. Liu,
G. A. Liashenko, P. Piskorz, I. Martin, R. L. Komaromi, D. J.
Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara,
M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W.
Wong, C. Gonzalez, J. A. Pople, Gaussian 03, Revision B.03,
Gaussian, Inc., Pittsburgh, PA, 2003.
[25] See for example: a) E. Goldstein, B. Beno, K. N. Houk, J. Am.
Chem. Soc. 1996, 118, 6036–6043; b) O. Wiest, D. C. Montiel,
K. N. Houk, J. Phys. Chem. A 1997, 101, 8378–8388; c) J. I.
Garcia, V. Martinez-Merino, J. A. Mayoral, L. Salvatella, J.
Am. Chem. Soc. 1998, 120, 2415–2420; d) L. R. Domingo, M.
Arno, J. Andres, J. Am. Chem. Soc. 1998, 120, 1617–1618; e) J.
Liu, S. Niwayama, Y. You, K. N. Houk, J. Org. Chem. 1998,
63, 1064–1073; f) D. M. Birney, J. Am. Chem. Soc. 2000, 122,
10917–10925.
a) M. Alajarin, B. Bonillo, P. Sanchez-Andrada, A. Vidal, D.
Bautista, J. Org. Chem. 2007, 72, 5863–5866; b) M. Alajarin,
A. Vidal, F. Tovar, Tetrahedron 2005, 61, 1531–1537; c) M. Ala-
jarin, P. Sanchez-Andrada, A. Vidal, F. Tovar, Eur. J. Org.
Chem. 2004, 2636–2643; d) M. Alajarin, A. Vidal, F. Tovar,
P. Sanchez-Andrada, D. Bautista, Tetrahedron 2003, 59, 9913–
9918; e) M. Alajarin, A. Vidal, M.-M. Ortin, F. Tovar, Synthe-
sis 2002, 2393–2398; f) M. Alajarin, A. Vidal, F. Tovar, M. C.
Ramirez de Arellano, F. P. Cossio, A. Arrieta, B. Lecea, J. Org.
Chem. 2000, 65, 7512–7515; g) F. P. Cossio, A. Arrieta, B. Le-
cea, M. Alajarin, A. Vidal, F. Tovar, J. Org. Chem. 2000, 65,
3633–3642; h) M. Alajarin, A. Vidal, F. Tovar, C. Conesa, Tet-
rahedron Lett. 1999, 40, 6127–6130; i) M. Alajarin, P. Molina,
A. Vidal, Tetrahedron Lett. 1996, 37, 8945–8948.
[13]
W. M. F. Fabian, R. Janoschek, J. Am. Chem. Soc. 1997, 119,
4253–4257, and references therein.
[14] J. H. Hall, G. Krishnan, J. Org. Chem. 1984, 49, 2498–2500.
[15] a) M. Alajarin, B. Bonillo, M. Marin-Luna, A. Vidal, R.-A.
Orenes, J. Org. Chem. 2009, 74, 3558–3561; b) For a closely
related Diels–Alder reaction of a C-vinyl ketenimine with
PTAD, see: G. Barbaro, A. Battaglia, P. Giorgianni, J. Org.
Chem. 1987, 52, 3289–3296.
[16] H. Wamhoff, C. Bamberg, S. Herrmann, M. Nieger, J. Org.
Chem. 1994, 59, 3985–3993.
[17] The exo-lone-pair effect is a well known electronic effect op-
erating in hetero-Diels–Alder reactions, see: a) M. A. McCar-
rick, Y.-D. Wu, K. N. Houk, J. Am. Chem. Soc. 1992, 114,
1499–1500; b) M. A. McCarrick, Y.-D. Wu, K. N. Houk, J.
Org. Chem. 1993, 58, 3330–3343.
[18] Similar results have been reported in computational studies of
other Diels–Alder reactions involving HTAD as dienophile,
see: a) J. S. Chen, K. N. Houk, C. S. Foote, J. Am. Chem. Soc.
1998, 120, 12303–12309; b) A. G. Leach, K. N. Houk, Chem.
Commun. 2002, 1243–1255, see also ref.[3d]
[19] This stereoelectronic effect has previously been used to account
for 6π electrocyclizations of carbodiimides, as well as in hydride
transfer reactions, see: a) H. S. Rzepa, P. Molina, M. Alajarin,
A. Vidal, Tetrahedron 1992, 48, 7425–7434; b) A. E. Pain, I. H.
Williams, Chem. Commun. 1988, 1367–1368; c) I. H. Williams,
[26] K. B. Wiberg, Tetrahedron 1968, 24, 1083–1096.
[27] a) A. E. Reed, R. B. Weinstock, F. Weinhold, J. Chem. Phys.
1985, 83, 735–746; b) A. E. Reed, L. A. Curtiss, F. Weinhold,
Chem. Rev. 1988, 88, 899–926; c) A. E. Reed, P. v. R. Schleyer,
J. Am. Chem. Soc. 1990, 112, 1434–1445.
[28] a) W. T. Borden, R. J. Loncharich, K. N. Houk, Annu. Rev.
Phys. Chem. 1988, 39, 213–236; b) A. Moyano, M. A. Pericas,
E. Valenti, J. Org. Chem. 1989, 54, 573–582; c) These indexes
have also been used to characterize cycloaddition reactions
other than [4+2], see for example: B. Lecea, M. Ayerbe, A.
Arrieta, F. P. Cossio, V. Branchadell, R. M. Ortuño, A. Bacei-
redo, J. Org. Chem. 2007, 72, 357–366.
Received: September 28, 2009
Published Online: December 16, 2009
704
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 694–704