Electrophilic reactivities of 1,2-diaza-1,3-dienes

Article abstract of DOI:10.1002/chem.201000828

The kinetics of the reactions of 1,2-diaza-1,3-dienes 1 with acceptor-substituted carbanions 2 have been studied at 20°C. The reactions follow a second-order rate law, and can be described by the linear free energy relationship logk(20°C)=s(N+E) [Eq. (1)]

Full text of DOI:10.1002/chem.201000828

DOI: 10.1002/chem.201000828
Electrophilic Reactivities of 1,2-Diaza-1,3-dienes
Tanja Kanzian,[a] Simona Nicolini,[b] Lucia De Crescentini,[b] Orazio A. Attanasi,*[b]
Armin R. Ofial,*[a] and Herbert Mayr[a]
Abstract: The kinetics of the reactions
of 1,2-diaza-1,3-dienes 1 with acceptor-
ꢀ15.4, the electrophilic reactivities of
1a–d are comparable to those of ben-
phines 4 agreed with those calculated
from E, N, and s, indicating the appli-
substituted carbanions
2
have been
zylidenemalononitriles, 2-benzyli
G
ACHUTNGTRENNUGcaACTHNGUTRENbUNG ility of the linear free energy rela-
studied at 208C. The reactions follow a
second-order rate law, and can be de-
scribed by the linear free energy rela-
U
tionship [Eq. (1)] for predicting poten-
tial nucleophilic reaction partners of
1,2-diaza-1,3-dienes 1. Enamines
5
tionship
logk
(208C)=s
N
react up to 102 to 103 times faster with
compounds 1 than predicted by Equa-
tion (1), indicating a change of mecha-
nism, which becomes obvious in the re-
actions of 1 with enol ethers.
[Eq. (1)]. With Equation (1) and the
known nucleophile-specific parameters
N and s for the carbanions, the electro-
philicity parameters E of the 1,2-diaza-
1,3-dienes 1 were determined. With E
parameters in the range of ꢀ13.3 to
ꢀ
Keywords: azo compounds · C C
bond formation · cycloaddition · ki-
netics · linear free energy relation-
ships
Introduction
through Michael-type addition. From these intermediates,
different intramolecular cyclizations lead to a variety of
five- and six-membered heterocycles, for example, pyrroles,
pyrazoles, imidazoles, thiazoles, selenazoles, 1,2,3-thiadia-
zoles, 1,2,3-selenadiazoles, 1,2,3-diazaphospholes, pyrid-
In recent years, 1,2-diaza-1,3-dienes 1 have become increas-
ingly important as tools for the construction of a variety of
heterocycles.[1] The electron-withdrawing effect of the azo
group in the heterodiene system controls the regioselectivity
of the nucleophilic attack at the terminal carbon. This regio-
selectivity is further enhanced by appropriate electron-with-
drawing groups at the terminal carbon and/or nitrogen atom
of the conjugated azo–ene system. As a consequence, typical
reactions of conjugated azoalkenes with a variety of carbon,
nitrogen, oxygen, phosphorus, sulfur, and selenium nucleo-
philes result in the formation of 1,4-hydrazonic adducts
AHCTUNGERTGaNNUN zines, pyrazines, 1,4-thiazines, 1,2,4-triazines, and 1,2,4-oxa-
diazines. In many cases, the 1,4-additions of nucleophiles at
1,2-diaza-1,3-dienes are accompanied by spontaneous subse-
quent formations of heterocycles. Accordingly, heterocycles
are frequently accessible by one-pot syntheses that do not
require the use of anhydrous solvents or work under an
inert atmosphere. Another advantage that makes com-
pounds 1 attractive intermediates in organic chemistry is
their good accessibility. Usually they are synthesized by the
elimination of a leaving group X in the a position of a hy-
drazone. The leaving group X can either be present in the
starting material, that is, a cyclic or acyclic carbonyl com-
pound, or be introduced in the hydrazone derivative
(Scheme 1).
[a] Dipl.-Chem. T. Kanzian, Dr. A. R. Ofial, Prof. Dr. H. Mayr
Department Chemie der Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstr. 5–13, 81377 Mꢁnchen (Germany)
Fax : (+49)89-2180-9977715
E-mail: ofial@lmu.de
In order to make the synthetic strategies that include the
use of 1 more predictable and efficient, it was our goal to
quantify the electrophilicity of different substituted 1,2-
diaza-1,3-dienes 1. We have, therefore, determined the re-
[b] Dr. S. Nicolini, Dr. L. De Crescentini, Prof. Dr. O. A. Attanasi
Istituto di Chimica Organica
Universitꢂ degli Studi di Urbino “Carlo Bo”
Via I Maggetti 24, 61029 Urbino (PU) (Italy)
Fax : (+39)0722-303441
AHCTUNGTREGaNNNU ctivities of 1 towards nucleophiles in the first step of the
E-mail: orazio.attanasi@uniurb.it
complex, sequential transformations that lead to different
products.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000828.
12008
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Chem. Eur. J. 2010, 16, 12008 – 12016

FULL PAPER
Table 1. Reference carbanions 2 used in this study, and their nucleo-
AHCTUNGTRENNUNG
N (s)[b]
2a
13.91 (0.86) in DMSO
Scheme 1. Synthetic pathways to 1,2-diaza-1,3-dienes 1.
2b
2c
16.27 (0.77) in DMSO
17.64 (0.73) in DMSO
Recently, the group of H. Mayr in Mꢁnchen has shown
that the reactions of carbocations and various electron-defi-
cient alkenes with n-, p-, and s-nucleophiles can be de-
2d
2e
18.59 (0.65) in MeOH
19.36 (0.67) in DMSO
scribed by Equation (1), in which the nuACTHNUTRGENNGUcleoCAHTUNGTRNEpNUGN hiles are char-
acterized by the parameters N and s, and the electrophiles
are characterized by the parameter E.[2] In this way, it was
possible to construct comprehensive nucleophilicity and
electrophilicity scales.[3] Reactions of carbanions with typical
[a] Counterion for 2a, 2b, 2c, and 2e: K+; counterion for 2d: Na+.
[b] Refs. [3b] and [5].
Michael acceptors, such as benzylideneACTHNUTRGNEUNGmalononitriles, ben-
zylideneindandiones, benzylidene Meldrumꢄs acids, and ben-
zylidenemalonates, have been shown to follow Equa-
tion (1).[4]
log k2ð20 ꢁCÞ ¼ sðN þ EÞ
ð1Þ
Scheme 3. Michael addition of b-dicarbonyl compounds to 1,2-diaza-1,3-
dienes 1 and subsequent cyclization.
By assuming that the reactions of 1 with carbanions can
also be described by Equation (1), we have determined the
electrophilicities of four conjugated azoalkenes (1,2-diaza-
1,3-dienes 1a–d) with ester or amido substituents at posi-
tions 1 and 4 (Scheme 2).
depend on the solvent, we repeated some of the relevant re-
actions in those solvents used for the kinetic studies in this
work, that is, DMSO or MeOH (Table 1, Scheme 4). The re-
actions of 1a with the carbanions 2c and 2e, and of 1c with
carbanion 2e, gave the expected pyrroles 2ca, 2ea, and 2ec,
whereas the reactions of 1a with 2d and of 1d with carban-
ion 2c yielded the acyclic 1,4-adducts 2da and 2cd, respec-
tively. Because the products shown in Scheme 4 accordingly
indicate initial attack of the carbanions at C4 of the diaza-
diene system, we have assumed that all other combinations
of 1a–d with 2 that were studied kinetically in this work pro-
ceed in an analogous manner.
Scheme 2. 1,2-Diaza-1,3-dienes 1a–d used in this study.
Kinetic investigations: The rates of the reactions of 1 with
the carbanions 2 were determined photometrically at 208C
by using conventional or stopped-flow UV/Vis spectrome-
ters. The carbanions 2 were used as preformed potassium
salts, or were prepared in solution by deprotonation of the
CH acids with 1.05 equiv of KOtBu (or NaOMe in the case
of 2d). The reaction progress was monitored by the decrease
of the absorbances of the electrophiles. By using the nucleo-
philes 2 in excess over the electrophiles 1, first-order condi-
tions were achieved. From the mono-exponential decays of
For this purpose, we have investigated the rates of the re-
actions of 1a–d with the carbanions 2a–e, for which the N
and s parameters are known (Table 1).[3b,5]
Results and Discussion
Reactions of 1,2-diaza-1,3-dienes 1 with carbanions 2
Product characterization: Many base-activated reactions of
1,2-diaza-1,3-dienes 1 with CH-acidic compounds, such as b-
dicarbonyl compounds, have been reported to result in the
formation of pyrroles (Scheme 3).[6]
the absorbances the first-order rate constants kobs were ob-
ꢀkobst
tained by a least-squares fit to A=A0 e
+C. Details are
given in the Supporting Information.
The reactions of 1 with the carbanion 2d were performed
in methanol, in which 2d was generated by treatment of
In previous investigations,[1,6] the majority of the reactions
between carbanions 2 and 1 were carried out in THF. As
the structure of the resulting products was reported to
ꢀ
2d H with sodium methanolate. Because ethyl cyanoacetate
ꢀ
(2d H) is only partially deprotonated by methoxide in
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A. R. Ofial, O. A. Attanasi et al.
Figure 1. Exponential decay of the absorbance at 350 nm during the reac-
tion of 1d with the anion of dimedone in DMSO at 208C ([2b]=1.43ꢅ
10ꢀ2 m; kobs =8.21ꢅ10ꢀ2 sꢀ1, counterion: K+). Insert: Determination of
the second-order rate constant k2 =5.61 mꢀ1 sꢀ1 from the slope of the cor-
relation of the first-order rate constants kobs with the concentration of 2b.
Table 2. Experimental and calculated second-order rate constants for the
reactions of 1a–d with carbanions 2a–e at 208C in DMSO.
exp
calcd
calcd
Electrophile (E)
1a (ꢀ13.28)
Nucleophile
k2
[mꢀ1 sꢀ1
k2
[mꢀ1 sꢀ1
]
k2exp/k2
[a]
G
]
E
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
2a
2b
2c
2e
1.52
3.48
0.44
2.2
2.6
4.39ꢅ102
4.02ꢅ103
2.96ꢅ103[b]
4.44ꢅ103
5.15ꢅ10ꢀ1
8.11ꢅ101
6.93ꢅ102
3.50ꢅ103[b]
2.21ꢅ103
7.98ꢅ10ꢀ2
1.88ꢅ101
3.86ꢅ101
1.64ꢅ103[b]
4.82ꢅ102
3.69ꢅ10ꢀ2
5.61
2.01ꢅ102
1.52ꢅ103
2.83ꢅ103
1.18ꢅ104
1.02
1.0
0.37
0.51
1.2
1.3
3.1
0.49
0.58
1.7
0.39
6.7
0.50
0.67
1.2
Scheme 4. Products of the reactions of 1a, 1c, and 1d with carbanions 2
(isolated yields after column chromatography).
1b (ꢀ13.90)
1c (ꢀ14.91)
1d (ꢀ15.38)
6.68ꢅ101
5.37ꢅ102
1.12ꢅ103
4.55ꢅ103
1.38ꢅ10ꢀ1
1.11ꢅ101
9.84ꢅ101
2.47ꢅ102
9.58ꢅ102
5.41ꢅ10ꢀ2
4.82
methanol, the evaluation of the kinetics of the reaction of 1
ꢀ
with 2d has to consider the acid–base equilibrium (2d Na+
ꢀ
+
ꢀ
MeOHQ2d H+MeO Na ) as well as the parallel reaction
of 1 with MeOꢀ. The actual concentrations of 2d and MeOꢀ
can be calculated by using the known equilibrium constant
K2d.[7] The independently determined second-order rate con-
stants k2,MeO for the reactions of MeOꢀ with the electro-
8.98ꢅ101
3.13ꢅ102
4.44ꢅ101
4.68ꢅ102
2.0
0.67
philes 1 were then employed to subtract k
[MeOꢀ] from
2,MeOACHTNUGTRENNUNG
kobs to get to the pseudo-first-order rate constants for the re-
action of 2d with the 1,2-diaza-1,3-dienes 1 (for details see
the Supporting Information and ref. [5]).
[a] Calculated by using Equation (1), N and s parameters from Table 1,
and E from this table. [b] Solvent: MeOH.
As exemplified in Figure 1 for the reaction of 1d with 2b,
plots of kobs (or kobsꢀk
U
quently, the electrophilicity parameters E of 1a–d could be
derived from a least-squares fit of experimental and calcu-
lated
rate
constants
by
minimization
of
D2 =
ꢀ
N
N
a
special type of the linear free energy relationship in Equa-
tion (1) avoids long-ranging extrapolations because E=ꢀN
for (logk2)/s=0, as shown graphically in Figure 2. Whereas
in most cases the calculated (from E, N, s) and experimental
rate constants agree within a factor of three (Table 2), 1c
reacts seven times faster with 2d than calculated. Because
this deviation is within the confidence limit of Equation (1),
we abstain from an interpretation of this deviation.
kobs ¼ k2½2ꢂ
Figure 2 shows linear correlations of (logk2)/s versus N
with slopes of unity, as required by Equation (1). Conse-
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Electrophilic Reactivities of 1,2-Diaza-1,3-dienes
FULL PAPER
Figure 3. Comparison of the electrophilic reactivities of 1,2-diaza-1,3-
dienes 1 with those of other classes of electrophiles (standard deviations
are given for E(1) with the number of experiments in parentheses).
Product characterization
Products of the reactions of 1 with amines 3: The reactions
of 1a,c,d with the amines 3a,c,d in MeOH furnished the ex-
pected[10] a-aminohydrazones 3aa,ac,ad,cc,dc in high yield
(Scheme 5).
Products of the reactions of 1 with triarylphosphines 4: Some
of us[11] reported previously that the reactions of 1 with tri-
phenylphosphine (4b) in ethyl acetate produced the 1,5-
zwitterions P1, which precipitated from the solvent
(Scheme 6). These intermediates undergo different hetero-
cyclization reactions depending on the nature of the solvent
used: in methanol the 1,4-adduct P1 is transformed into a
betaine intermediate I1 by intramolecular attack of the ni-
trogen at the ester group. Subsequent loss of MeOH or
EtOH yields 4-triphenylphosphoranylidene-4,5-dihydropyr-
Figure 2. Plots of (logk2)/s against the N parameters of the carbanions
2a–e for the reactions of the 1,2-diaza-1,3-dienes 1a, 1c (a), 1b, and 1d
(b) with 2a–e in DMSO at 208C (the slopes are fixed to one as required
by Equation (1); reactions of 2d in methanol).
The electrophiles 1a–d cover a reactivity range of two
orders of magnitude and can be compared to benzylidene-
malononitriles,[4a] benzylideneindandiones,[4b] benzylidene-
barbituric acids,[4c] benzylidene Meldrumꢄs acids,[4d] electron-
deficient arenes,[8] and quinone methides[3g] (Figure 3). 1,2-
Diaza-1,3-dienes are considerably more reactive than ben-
AHCTUNGTREGaNNUN zol-5-ones P2. Also in acetonitrile, the cyclic betaine inter-
mediates I1 are formed, which then cyclize to the oxaphos-
phetane intermediates I2. Finally, loss of triphenylphosphine
oxide transforms I2 into the corresponding pyrazoles P3.
Because the kinetic experiments were performed in
CH2Cl2, we also studied products of the reactions between
1a,c and 4a,b in this solvent. Scheme 7 shows the formation
of the expected phosphorus ylides 4ba, 4ac, and 4bc.[11a] In
A
N
Reactions of the 1,2-diaza-1,3-dienes 1 with other nucleo-
philes: In order to examine whether the electrophilicity pa-
rameters of 1,2-diaza-1,3-dienes 1a–d derived from the rates
of their reactions with carbanions, which are listed in
Figure 3, are suitable for the prediction of their reaction
rates with other types of nucleophiles, we studied the ki-
contrast, the reaction between 1c and tris(4-methoxyACHTUNGTRENNUNGphen-
AHCTUNGTREGyNNNU l)phosphine (4c) gave the 4-tris(4-methoxyphenyl)phos-
phoranylidene-4,5-dihydropyrazol-5-one (4cc),[11] and the re-
action between 1d and 4-tris(4-chlorophenyl)phosphine (4a)
afforded the pyrazole 4ad[11a] (Scheme 7).
ACHTUNGTRENNUNG
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A. R. Ofial, O. A. Attanasi et al.
Scheme 7. Products of the reactions of 1a, 1c, and 1d with triarylphos-
phines (4; isolated yields after column chromatography).
Scheme 5. Product studies of the reactions of 1 with amines 3 (isolated
yields).
Scheme 8. Formation of 1-aminopyrroles P4 from the reactions of 1 with
enamines 5.
5ac, respectively. The accompanying 1,4-adducts 3aa and
3ac are formed by addition of morpholine (a side product
of the formation of the pyrroles, see Scheme 8) to the elec-
trophiles 1a and 1c.[12a] In the reaction of 1a with 5d, the
loss of morpholine did not occur spontaneously, therefore
the reaction mixture in THF was heated to reflux until com-
plete conversion into pyrrole 5da was observed by TLC
analysis (Scheme 9).
Scheme 6. Mechanism of the reactions of 1 with triphenylphosphine (4b).
Products of the reactions of 1 with enamines 5: Reactions of
the conjugated azoalkenes 1 with a,b-disubstituted enamines
5 have been reported to yield 1-aminopyrroles P4 in polar
and apolar solvents. The initial attack of the nucleophilic
carbon atom of the enamine 5 at the terminal carbon atom
of the azo–ene system 1 produces hydrazonic intermediates
I3, which undergo a [3+2] cyclization to furnish the 2-
amino-substituted dihydropyrroles I4. The spontaneous sub-
sequent loss of the secondary amine results in the formation
of the 1-aminopyrrole derivatives P4 (Scheme 8).[12]
Kinetic studies: The kinetics of the reactions of 1 with
amines 3, triarylphosphines 4, and enamines 5 were deter-
mined photometrically, as described above for the reactions
of 1 with carbanions 2.
Reactions of 1 with amines 3: The reactions of 1 with
amines 3a–d were studied in different solvents. Table 3
shows that the experimental rate constants for these reac-
tions agree within a factor of seven with those calculated by
Equation (1) from the electrophilicity parameters E of 1
(Table 2) and the N and s parameters of the amines 3a–c
previously determined from the rates of their reactions with
benzhydrylium ions.[9b,d,e]
For the product investigations, we have chosen the reac-
tions between 1a,c and the 1-morpholinocycloalkenes 5a,d
in acetonitrile. The reactions of 1a and 1c with morpholino-
cyclohexene (5a) delivered the 1-aminopyrroles 5aa and
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Electrophilic Reactivities of 1,2-Diaza-1,3-dienes
FULL PAPER
1,2-Diaza-1,3-dienes
1 with
amido groups at the 1- and the
4-terminus are the least reactive
(1d and 1 f). Their reactivity in-
creases slightly when the amido
substituents at the terminal
carbon or the nitrogen atom
are replaced by the stronger
electron-withdrawing
ester
group (1d is less reactive than
1b and 1a). However, these
substituent effects are small,
and the electrophilicities of the
1,2-diaza-1,3-dienes studied in
this work cover a very narrow
reactivity range of only two
orders of magnitude.
Scheme 9. Product studies of the reactions of 1a and 1c with enamines 5 (isolated yields after chromatographic
workup).
Reactions of 1 with triarylphos-
phines 4: The rates of the reac-
tions of
1 with triarylphos-
Table 3. Experimental and calculated second-order rate constants for the reactions of 1,2-diaza-1,3-dienes 1
with amines 3 at 208C.
phines 4a–c were studied in
CH2Cl2 by following the decay
of the absorbance of the elec-
trophiles. In analogy to the re-
actions of 1 with amines, the
linearity of the kobs versus [PR3]
plots proved that second-order
rate laws were obeyed for all
studied reactions. This fact al-
lowed us to determine the
second-order rate constants for
the attack of PR3 at the C=C
double bond of 1. Comparison
of the experimentally obtained
rate constants with those pre-
dicted by Equation (1) shows
an excellent agreement of these
exp
calcd
[b]
calcd
k2exp/k2
1
Amine 3
N/s[a]
k2 [mꢀ1 sꢀ1
]
k2
[mꢀ1 sꢀ1
]
1a
1a
1a
1a
1a
1b
1b
1b
1c
1c
1c
1c
1c
1c
1d
1d
1e
1e
1 f
1 f
morpholine (3a) in MeOH
morpholine (3a) in DMSO
piperidine (3b) in MeOH
piperidine (3b) in MeCN
pyrrolidine (3c) in MeOH
morpholine (3a) in MeOH
morpholine (3a) in DMSO
piperidine (3b) in MeOH
morpholine (3a) in MeOH
morpholine (3a) in DMSO
piperidine (3b) in MeOH
piperidine (3b) in MeCN
pyrrolidine (3c) in MeOH
benzylamine (3d) in MeOH
morpholine (3a) in MeOH
piperidine (3b) in MeOH
morpholine (3a) in MeOH
piperidine (3b) in MeOH
morpholine (3a) in MeOH
piperidine (3b) in MeOH
15.40/0.64
16.96/0.67
15.63/0.64
17.35/0.68
15.97/0.63
15.40/0.64
16.96/0.67
15.63/0.64
15.40/0.64
16.96/0.67
15.63/0.64
17.35/0.68
15.97/0.63
13.46/0.62
15.40/0.64
15.63/0.64
15.40/0.64
15.63/0.64
15.40/0.64
15.63/0.64
4.72
2.27ꢅ101
2.92ꢅ102
3.19ꢅ101
5.86ꢅ102
4.95ꢅ101
9.12
0.21
0.14
0.60
0.38
0.64
1.3
1.3
2.1
1.1
0.16
3.2
0.88
3.6
1.5
1.6
3.4
–
4.12ꢅ101
1.92ꢅ101
2.22ꢅ102
3.18ꢅ101
1.15ꢅ101
1.45ꢅ102
2.63ꢅ101
2.17
1.12ꢅ102
1.28ꢅ101
2.06
3.83
9.81
2.36ꢅ101
3.11
4.00ꢅ101
1.68ꢅ101
1.91ꢅ10ꢀ1
1.69
2.89ꢅ101
4.65
1.26ꢅ10ꢀ1
1.03
4.95
1.19
4.94
1.45
–
–
–
–
–
–
8.04ꢅ10ꢀ1
2.35
values within
(Table 4).
a factor of 5
–
[a] N and s parameters of amines from refs. [9b], [9d], and [9e]. [b] Calculated by using Equation (1).
Reactions of 1 with enamines 5:
The reactions of 1 with the a,b-
The rate constants for the reactions of morpholine (3a)
and piperidine (3b) with two additional 1,2-diaza-1,3-dienes
1e and 1 f were studied in methanol. Tentative E parameters
for 1e and 1 f can be calculated by using Equation (1), from
the known N and s parameters of 3a and 3b and the
second-order rate constants listed in Table 3. The averaged
values of the electrophilicity parameters E are ꢀ14.9 for 1e
and ꢀ15.3 for 1 f.
disubstituted enamines 5a–c were studied in acetonitrile by
following the decay of the absorbance of the electrophiles.
The progress of the reaction of 1c with morpholinocyclo-
pentene (5d) can be monitored by the decrease of the ab-
sorbance of the electrophile and, additionally, by the in-
crease of the absorbance of the reaction product. From the
mono-exponential increases (as from the mono-exponential
decays) the kobs values were obtained by a least-squares fit
ꢀkobst
to the function A=(1 ꢀ A0 e
)+C. The slope of the
linear plot of kobs versus [5d] yielded the second-order rate
constants k2. Figure 4 shows the reaction progress by the
mono-exponential increase of the product and the mono-ex-
ponential decay of 1c for the same reaction ([1c]0 =2.19ꢅ
10ꢀ4 m; [5d]0 =9.40ꢅ10ꢀ4 m). The first-order rate constants
Chem. Eur. J. 2010, 16, 12008 – 12016
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A. R. Ofial, O. A. Attanasi et al.
Table 4. Experimental and calculated second-order rate constants for the reactions of 1,2-diaza-1,3-dienes 1
with phosphines 4 in CH2Cl2 at 208C.
mental rate constants are larger
than calculated; most of the re-
actions are 102–103 times faster
than derived from Equation (1),
and the strongest deviation is
found for the reactions of the
least nucleophilic enamine 5a
with the least electrophilic aza-
dienes 1c and 1d. Therefore,
one can assume that these reac-
tions experience a special accel-
exp
calcd
[b]
calcd
k2exp/k2
1
Phosphine (4)
N/s[a]
k2 [mꢀ1 sꢀ1
]
k2
[mꢀ1 sꢀ1
]
1a
1a
1a
1b
1c
1c
1c
N
12.58/0.65
14.33/0.65
16.17/0.62
14.33/0.65
12.58/0.65
14.33/0.65
16.17/0.62
3.12ꢅ10ꢀ1
6.59
3.51ꢅ10ꢀ1
4.74
0.89
1.4
1.6
0.51
3.4
4.2
1.02ꢅ102
9.63ꢅ10ꢀ1
1.05ꢅ10ꢀ1
1.73
6.19ꢅ101
1.90
3.06ꢅ10ꢀ2
4.14ꢅ10ꢀ1
6.04
2.41ꢅ101
4.0
[a] N and s parameters of triarylphosphines 4a–c from ref. [9c]. [b] Calculated by using Equation (1), N and s
parameters from ref. [9c], and the E parameters from Table 2.
eration.
As
shown
in
Scheme 10, 5 may react with
the (Z,E) conformational isomers of the diazadienes 1 to
give the zwitterions ZI1 or ZI2. Stabilization of these inter-
mediates and the preceding transition states by Coulombic
Figure 4. Exponential increase of the absorbance at 300 nm during the re-
action of 1c with morpholinocyclopentene (5d) ([5d]0 =9.40ꢅ10ꢀ4 m).
Insert: Exponential decay of the absorbance of 1c at 444 nm during the
reaction of 1c with 5d.
for the reactions of 1c with 5d obtained by the two different
methods are in fair agreement. However, because of the
high molar absorption coefficient of the product, the con-
centration of 1c had to be kept small, which resulted in a
very low absorption for 1c and a less precise kobs value de-
termined from the decay of [1c].
Scheme 10. Mechanism for the reactions of 1 with aldehyde- and ketone-
derived enamines 5.
Though some of the rate constants listed in Table 5 agree
with the calculated ones within a factor of 102, all experi-
attraction of the oppositely
charged fragments may explain
the increased reactivity of the
enamines. The observation that
the acceleration is highest for
the slowest reactions may indi-
cate that the transition state is
even stabilized by partial for-
mation of the second bond
(hatched lines in ZI1 and ZI2)
leading to the heterocycles DA
and PY, respectively.[13] In
accord with this interpretation,
Table 5. Experimental and calculated second-order rate constants for the reactions of 1,2-diaza-1,3-dienes 1
with enamines 5 in acetonitrile at 208C.
exp
calcd
[b]
calcd
k2exp/k2
1
Enamine 5
N/s[a]
k2 [mꢀ1 sꢀ1
]
k2
[mꢀ1 sꢀ1
]
1a
1a
1a
1b
1b
1b
1c
1c
1c
1c
1d
1d
1d
morpholinocyclohexene (5a)
piperidinocyclopentene (5b)
pyrrolidinocyclopentene (5c)
morpholinocyclohexene (5a)
piperidinocyclopentene (5b)
pyrrolidinocyclopentene (5c)
morpholinocyclohexene (5a)
morpholinocyclopentene (5d)
piperidinocyclopentene (5b)
pyrrolidinocyclopentene (5c)
morpholinocyclohexene (5a)
morpholinocyclopentene (5d)
piperidinocyclopentene (5b)
11.40/0.83
15.06/0.82
15.91/0.86
11.40/0.83
15.06/0.82
15.91/0.86
11.40/0.83
13.41/0.82
15.06/0.82
15.91/0.86
11.40/0.83
13.41/0.82
15.06/0.82
4.73
2.75ꢅ10ꢀ2
2.88ꢅ101
1.83ꢅ102
8.41ꢅ10ꢀ3
8.94
172
43
35
106
16
20
660
128
148
155
754
160
118
1.23ꢅ103
6.44ꢅ103
8.88ꢅ10ꢀ1
1.40ꢅ102
1.07ꢅ103
8.05ꢅ10ꢀ1
7.59[c]
5.35ꢅ101
1.22ꢅ10ꢀ3
5.89ꢅ10ꢀ2
1.33
1.96ꢅ102
1.12ꢅ103
3.75ꢅ10ꢀ1
3.89
7.24
4.97ꢅ10ꢀ4
2.42ꢅ10ꢀ2
5.47ꢅ10ꢀ1
aldehyde-derived enamines
5
6.47ꢅ101
(Rꢄ=H) have been reported to
undergo [4+2] cycloadditions
[a] N and s parameters from refs. [3a] and [9a]. [b] Calculated by using Equation (1). [c] kobs values were ob-
tained from the mono-exponential increases of the product.
with
1,2-diaza-1,3-dienes.[12d]
12014
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Chem. Eur. J. 2010, 16, 12008 – 12016

Electrophilic Reactivities of 1,2-Diaza-1,3-dienes
FULL PAPER
Possibly analogous [4+2] cycloadditions also occur with the
enamines 5a–d studied in this work. However, when Rꢄ=
alkyl, the zwitterion ZI2 is sufficiently stabilized that it can
be regenerated from the Diels–Alder adduct DA, and finally
gives the pyrrole PY as indicated in Scheme 10.
From the nucleophilicity parameters N and s for ethyl
vinyl ether (N=3.92, s=0.90), 2,3-dihydrofuran (N=4.37,
s=0.90), and cyclopentadiene (N=2.30, s=1.09),[3c] one can
derive that nucleophilic attack of these p systems at the 4-
position of the 1,2-diaza-1,3-diene 1c would occur with rate
constants between 2ꢅ10ꢀ14 and 3ꢅ10ꢀ10 mꢀ1 sꢀ1. From these
calculated rate constants one can estimate that the Diels–
Alder reactions with inverse electron demand depicted in
Scheme 11 would require 102 to 106 years at 208C (half-reac-
Figure 5. Plot of (logk2)/s for the reactions of the 1,2-diaza-1,3-diene 1c
with 2–5 at 208C against the N parameters of the carbanions 2a–e (*),
the amines 3a–c (~), the phosphines 4a–c (&, in CH2Cl2), the enamines
^
5a–c (~, in MeCN), and methanolate ( ). The linear curve refers to the
plot of (logk2)/s against the N parameters of the carbanions 2a–e, and
the slope is fixed to unity as required by Equation (1). PACTHNURTGENNUG(ani)3 =trisACHTUNGTRENNUNG(p-
anisyl)phosphine 4c.
Scheme 11. Diels–Alder reactions of 1c with ethyl vinyl ether, 2,3-dihy-
drofuran, and cyclopentadiene (at 158C, from ref. [14]).
Experimental Section
General methods and materials: 1,2-Diaza-1,3-dienes 1a–f, the potassium
salts of 2a–c and 2e, and the enamines 5a–d were synthesized by follow-
ing literature procedures.[1c,6b,15,16] Tris(4-chlorophenyl)phosphine (4a),
triphenylphosphine (4b), and tris(4-methoxyphenyl)phosphine (4c) were
purchased from ABCR (4a) and Aldrich (4b and c). Morpholine (3a),
piperidine (3b), pyrrolidine (3c), and benzylamine (3d) were purchased
and purified by distillation prior to use. 1H (400 MHz) and 13C
(100 MHz) NMR spectra were measured on a Varian Inova 400 or
Varian Mercury 400 NMR spectrometer. For details and characterization
of the products see the Supporting Information.
tion times for 1m solutions) if they proceeded stepwise
through a zwitterionic intermediate. The reported reaction
times of 1.5 to 16 h at 158C are, therefore, clear evidence
for the occurrence of concerted Diels–Alder reactions.[14]
The considerably smaller deviations between calculated
and experimental rate constants for the reactions of 1 with
enamines 5 indicate that the potentially involved initial
Diels–Alder reactions would profit much less from concert-
edness.
Reactions of 1,2-diaza-1,3-dienes 1 with carbanions 2: 1,2-Diaza-1,3-
dienes 1a,c,d (1 equiv) were added to a mixture of nucleophiles 2c,e
(1 equiv) and KOtBu (1.05 equiv) in DMSO at 208C, and the solution
was stirred until the disappearance of the starting materials (monitored
by TLC analysis), furnishing the products 2ca, 2ea, 2ec, and 2cd. Then
the reactions were quenched with water and extracted with CH2Cl2. The
combined organic layers were washed with water, dried over Na2SO4,
and the solvent was evaporated at reduced pressure. The crude products
were purified by column chromatography on silica gel. 1,2-Diaza-1,3-
diene 1a (1 equiv) was added to a stirred mixture of ethyl cyanoacetate
2d (1 equiv) and NaOMe (1.05 equiv) in MeOH at 208C. The 1,4-hydra-
zonic adduct precipitated directly from the reaction medium. After filtra-
tion and washing with diethyl ether, 2da was obtained in pure form.
Conclusion
Figure 5 illustrates that the N and s parameters for carban-
ions 2, amines 3, and phosphines 4 derived from reactions
with benzhydrylium ions also hold for their reactions with
1,2-diaza-1,3-dienes 1. Though belonging to different classes
of compounds, the deviations of these nucleophiles from the
correlation line in Figure 5 are small. The positive deviations
of enamines from this correlation line are indicative of a
mechanistic change toward concerted [4+2] cycloadditions,
which must be operating in the reactions of enol ethers with
the dienes 1, because the stepwise mechanism can be esti-
mated to require more than 102 years.
Reactions of 1,2-diaza-1,3-dienes 1 with amines 3: 1,2-Diaza-1,3-dienes
1a,c,d (1 equiv) were added to a solution of the amines 3a,c,d (1 equiv)
in MeOH at 208C, and the mixture was stirred until the disappearance of
the starting materials (monitored by TLC analysis). The products 3aa,
3ac, 3ad, and 3cc precipitated directly from the reaction medium, and
3dc was crystallized from diethyl ether/petroleum ether (40 to 608C) and
collected by filtration.
Reactions of 1,2-diaza-1,3-dienes 1 with triarylphosphines 4: 1,2-Diaza-
1,3-dienes 1a,c,d (1 equiv) were added to a stirred solution of the triaryl-
Chem. Eur. J. 2010, 16, 12008 – 12016
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12015

A. R. Ofial, O. A. Attanasi et al.
phosphines 4a–c (1 equiv) in CH2Cl2 at 208C. After the completion of
the reaction, the solvent was evaporated at reduced pressure and the
crude products 4ba, 4ac, 4bc, 4cc, and 4ad were purified by column
chromatography on silica gel.
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Reactions of 1,2-diaza-1,3-dienes 1 with enamines 5: 1,2-Diaza-1,3-dienes
1a,c (1 equiv) were added to a solution of the enamines 5a,d (1 equiv) in
acetonitrile at 208C. The solution was stirred until the disappearance of
the starting materials (monitored by TLC analysis). In the case of the re-
actions of 1a and 1c with 5a, the final products were the pyrroles 5aa
and 5ac and the a-aminohydrazones 3aa and 3ac, respectively, which
were isolated by column chromatography on silica gel. In the case of the
reaction of 1a with 5d, after the disappearance of the starting materials,
acetonitrile was evaporated at reduced pressure. The crude product mix-
ture was dissolved in THF and then heated to reflux for 16 h, to obtain
pyrrole 5da, which was purified by column chromatography on silica gel.
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Kinetics: The kinetics of the reactions of the conjugated azoalkenes 1
with the nucleophiles 2–5 were followed by UV/Vis spectroscopy by
using working stations similar to those described previously.[3a, f,17] For
slow reactions (t1/2 >10 s) the UV/Vis spectra were collected at different
times by using a J&M TIDAS diode array spectrophotometer connected
to a Hellma 661.502-QX quartz Suprasil immersion probe (5 mm light
path) by fiber-optic cables with standard SMA connectors. All kinetic
measurements were carried out in Schlenk glassware under exclusion of
moisture. The temperature of the solutions during the kinetic studies was
maintained to 20ꢃ0.18C by using circulating bath cryostats monitored
with thermo-couple probes that were inserted into the reaction mixture.
Stopped-flow spectrophotometer systems (Applied Photophysics
SX.18MV-R or Hi-Tech SF-61DX2) were used for the investigation of
fast reactions of 1,2-diaza-1,3-dienes with nucleophiles (t1/2 <10 s). The
kinetic runs were initiated by mixing equal volumes of solutions of the
1,2-diaza-1,3-dienes and the nucleophiles. Concentrations and rate con-
stants for the individual kinetic experiments are given in the Supporting
Information.
The Supporting Information provides information on preparative proce-
dures and product characterization, and details of the individual runs of
the kinetic experiments are also available.
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Acknowledgements
We are grateful to Dr. Fabio Mantellini for helpful discussions. S.N.,
L.D.C., and O.A.A. thank the Ministero dell’Istruzione, dell’Universitꢂ e
della Ricerca (MUIR)-PRIN and the Universitꢂ degli Studi di Urbino
“Carlo Bo” for financial support. T.K., A.R.O., and H.M. acknowledge
financial support by the Deutsche Forschungsgesellschaft (SFB 749).
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Received: April 1, 2010
Published online: September 10, 2010
12016
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Chem. Eur. J. 2010, 16, 12008 – 12016