The syntheses and structures of bis(alkylimino)isoindolines

Article abstract of DOI:10.1016/j.tetlet.2013.08.134

In this Letter, we present a synthetic and structural study into bis-imino substituted diiminoisoindolines, which can be synthesized either via CaCl ₂ mediated reaction of phthalonitrile with primary amines, or via direct reaction of these amines with unsubstituted diiminoisoindoline. The preferred synthesis does depend on the methodology, and in two cases singly substituted adducts were formed. The single crystal X-ray structures show that, with the exception of the bis-naphthyl compound, the anti conformation is preferred, and that the ionizable hydrogen atom resides on an exocyclic nitrogen rather than the central isoindoline nitrogen atom.

Full text of DOI:10.1016/j.tetlet.2013.08.134

Tetrahedron Letters 54 (2013) 6114–6117
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The syntheses and structures of bis(alkylimino)isoindolines
⇑
Ingrid-Suzy Tamgho, James T. Engle, Christopher J. Ziegler
Department of Chemistry, University of Akron, Akron, OH 44326-3601, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 July 2013
Revised 28 August 2013
Accepted 30 August 2013
Available online 10 September 2013
In this Letter, we present a synthetic and structural study into bis-imino substituted diiminoisoindolines,
which can be synthesized either via CaCl2 mediated reaction of phthalonitrile with primary amines, or via
direct reaction of these amines with unsubstituted diiminoisoindoline. The preferred synthesis does
depend on the methodology, and in two cases singly substituted adducts were formed. The single crystal
X-ray structures show that, with the exception of the bis-naphthyl compound, the anti conformation is
preferred, and that the ionizable hydrogen atom resides on an exocyclic nitrogen rather than the central
isoindoline nitrogen atom.
Keywords:
Bis(alkylimino)isoindolines
X-ray structures
Ó 2013 Elsevier Ltd. All rights reserved.
Heterocyclic compounds
Schiff bases
Introduction
merization,21,22 and metal complexes with lanthanides23,24 of
these ligands have been reported.
The chemistry of isoindolines has been the key for the develop-
mentofphthalocyaninesaswellasrelatedmacrocyclesandchelating
ligands.1–3 The synthesis of the parent isoindoline, 1,3-diiminoiso-
indoline (DII, 2) was first reported in the early 1950s.1 Compounds
derived from DII exhibit rich metal binding properties. The metal
complexes of the phthalocyanines, for example, show excellent opti-
cal properties and are used as synthetic dyes in industry or as poten-
tial photosensitizers in medicine.5,6 Additionally, the DII derived
hemiporphyrazine family of macrocycles can also bind metal ions
and have been used as components for material applications.7,8 DII
can also be used as a precursor ofisoindoline-based chelatingligands,
in particular the bis(iminopyridyl)diiminoisoindoline.7,9,10
The first examples of the products were reported following the
discovery of DII by Linstead and coworkers.11,12 These ligands are
the product of the condensation of DII and primary alkyl and aryl-
amines. Later in the 1970s, to avoid the formation of phthalocya-
nine (self-condensation of DII), CaCl2-catalyzed condensation of
phthalonitrile (precursor of DII) with primary arylamines was
employed.10 It was then found that the bis(arylimino)isoindolines
(where the aryl group is a coordinating base such as pyridine,4,10,13
imidazole,14 or thiazole15) can form N/S tridentate and pincer-like
isoindoline ligands that can coordinate to an extensive range of
transition metal cations. However studies into the reactivity of
bis(alkylimino)isoindoline were not extended. Since early work
in the 1950s only synthesis,16–20 studies on the amino/imino tauto-
In this Letter, we are revisiting the synthesis and characteriza-
tion of several bis(alkylimino)isoindolines, several of which struc-
tures were successfully elucidated. We have examined methods for
the preparation of these compounds: the direct reaction of DII with
primary amines (method A), and the reaction of primary amines
with phthalonitrile using Siegl’s conditions (method B).10 We
observed that the condensation of DII with bulky amines and cyclic
amines did not lead to high yields of products, and often afforded
only the monosubstituted adducts, regardless of reaction time or
solvent conditions. Siegl’s method, however, was shown to
produce improved yields for bulky and cyclic amines. For non-ste-
rically hindered amines, Siegl’s method did not show increased
yields. Structural elucidation of several of the reaction products
revealed that the ionizable hydrogen atoms are located at the exo-
cyclic amine position rather than on the isoindoline nitrogen. This
is in contrast with the 1H NMR spectra for these compounds, which
reveal symmetric structures in solution. In the solid state, exten-
sive hydrogen bonding was observed.
Results and discussion
A series of fifteen substituted diiminoindolines have been syn-
thesized in this study. Several of them have been previously
reported (R = methyl,11,16–18,21 ethyl,12 propyl,18 butyl,11,17,18 and
cyclohexyl16,17) but have not been fully characterized. Two meth-
ods were employed for the synthesis of the substituted isoindo-
lines. The first one was the procedure used by Linstead and
coworkers; refluxing diiminoisoindoline 2 with two equivalents
of an alkyl amine in ethanol for 24 h.4 The second method was
⇑
Corresponding author. Tel.: +1 330 972 2531; fax: +1 330 972 6085.
E-mail address: ziegler@uakron.edu (C.J. Ziegler).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.134

I.-S. Tamgho et al. / Tetrahedron Letters 54 (2013) 6114–6117
6115
Table 1
The syntheses and yields of substituted isoindolines 3–17
Compound
Name
R1
R2
Method
Yield
3
4
5
6
7
1,3-bismethyliminoisoindoline
1,3-bisethyliminoisoindoline
1-cyclopropylimino-3-iminoisoindoline
1,3-biscyclopropyliminoisoindoline
1,3-bisallyliminoisoindoline
1,3-bis-n-propyliminoisoindoline
1,3-bis-n-butyliminoisoindoline
1,3-bis-t-butyliminoisoindoline
1,3-biscyclopentyliminoisoindoline
1,3-bis-(3-pentylimino)isoindoline
1,3-bispentyliminoisoindoline
1,3-biscyclohexyliminoisoindoline
CH3
CH3
C2H5
H
A
A
A
B
A
A
A
B
B
B
A
B
B
B
B
78
75
45
69
51
68
72
77
75
68
74
75
59
45
80
C2H5
C3H5
C3H5
C3H5
C3H7
C4H9
C4H9
C5H9
C5H11
C5H11
C6H11
C10H7
C10H7
C3H5
C3H5
C3H7
C4H9
C4H9
C5H9
C5H11
C5H11
C6H11
C10H7
H
8
9
10
11
12
13
14
15
16
17
1,3-bis-
1- -naphthylimino-3-iminoisoindoline
1,3-bisadamantyliminoisoindoline
a-naphthyliminoisoindoline
a
C
10H15
C10H15
Siegl’s procedure; phthalonitrile 1 was reacted with two equiva-
lents of alkyl amine refluxing in n-butanol for 48 h, catalyzed by
CaCl2.10 In both cases, evolution of ammonia was observed.
Compound 1 also reacted with ammonia in a sodium methylate
solution to form compound 2. The bis(imino)isoindoline yields
ranged between 45% and 80% after purification either by flash
chromatography or recrystallization from various solvents. The
compounds produced in this study listed by method of preparation
and yields are shown in Table 1.
The optimal method for the syntheses of these compounds
varied based on the identity of the primary amine. For the non-ste-
rically hindered amines, such as methyl, ethyl, propyl, butyl, and
pentyl amines, direct reaction with DII afforded the desired bis-
substituted product in good yield. However, for the bulker amines
and cycloalkyl amines, Siegl’s alternative method more efficiently
produced the desired bis-substituted amines. One exception is
seen with the naphthylamine reaction, where both the bis substi-
tuted isoindoline and the monofunctionalized 1-amino-3-amino-
isoindoline are produced. Additionally, when DII is used as a
starting material for cyclopropylamine, only the monofunctional
adduct, 1-cyclopropylimino-3-iminoisoindoline, is produced. In
contrast, for the less bulky amines, Siegl’s method from phthalonit-
rile provided no advantages in yield versus direct reaction with DII.
All of the resultant compounds were fully characterized, including
by NMR spectroscopy and mass spectrometry.
We were able to structurally elucidate several of the bis-substi-
tuted isoindolines as well as two examples of the monosubstituted
compounds. The data collection and structure parameters for the
crystal structures presented in this Letter are provided in the
Supplementary Information. Figure 1 shows the structures of sev-
eral of the bis-substituted compounds (4, 6, 10, 12–15, and 17) and
Figure 2 shows the structures for two of the monofunctionalized
compounds (5 and 16). All of the compounds were isolated and
structurally characterized as neutral species with the exception
of 6, which was elucidated as the HCl salt see (Scheme 1).
For the bis-substituted isoindolines, we were able to make two
important structural observations from the single crystal data.
First, the group on the imines in these compounds can be oriented
Figure 1. Structures of bis-substituted diiminoisoindolines with 35% thermal ellipsoids. Top, left to right: 4, 6, 10, 12; Bottom, left to right 13, 14, 15, 17. Non-ionizable
hydrogen atoms have been omitted for clarity. The chloride anion for compound 6 was also omitted for clarity.

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I.-S. Tamgho et al. / Tetrahedron Letters 54 (2013) 6114–6117
depended on the method of synthesis. Method A, reaction of DII
with the amine, only resulted in the monofunctionalized product,
1-cyclopropylimino-3-iminoisoindoline. In the case of the mono-
functionalized naphthalene product, the route to the product was
slightly more complex. Initially, the bis-substituted product was
produced via Siegl’s method, however we observed the presence
of an additional equivalent of naphthylamine in the product, which
was confirmed by X-ray crystallography. When we attempted to
remove this equivalent of naphthylamine via chromatography,
we isolated 1-a-naphthylimino-3-iminoisoindoline instead.
The structures of both compounds are shown in Figure 2. Both
compounds show similar structural features. In particular, we
observe a longer bond distance to the unsubstituted exocyclic
nitrogen than in the modified one; there is some multiple bond
delocalization between the C–NH2 and C–Ncentral atoms. Addition-
ally, we located both N-bound hydrogen atoms at the terminal
unsubstituted imine nitrogen atom rather than at the central iso-
indoline nitrogen atom. This is readily confirmed via inspection
of the hydrogen bonding in the solid. Both substances form hydro-
gen bonded dimers, where one of the terminal imine hydrogen
atoms forms a complimentary hydrogen bond with the central
nitrogen atom from a neighboring equivalent. 1-Cyclopropylimi-
no-3-iminoisoindoline forms an additional hydrogen bond
between the second unsubstituted imino hydrogen atom and a
substituted imine nitrogen atom on a neighboring equivalent,
forming one dimensional hydrogen bonded chain in the solid state.
Figure 2. Structures of mono-substituted diiminoisoindolines 5 (left) and 16 (right)
with 35% thermal ellipsoids. Non-ionizable hydrogen atoms have been omitted for
clarity.
N
C
2 R-NH2
C
1
N
R
R
N
Na, NH3
NH
MeOH, 4h
N
This same interaction is not present in the 1-a-naphthylimino-3-
iminoisoindoline compound as the steric bulk of the naphthyl
group prevents the formation of a 1D hydrogen bonded network.
NH
NH
NH
3-17
2 R-NH2
2
Conclusions
R = alkyl or naphthyl
In conclusion, we have revisited the synthesis of bis-substituted
diiminoisoindolines. Both the original method developed by
Linstead and the more recent procedure presented by Siegl can
be used to generate these compounds, but for cyclic and bulky
amines, Siegl’s method provides more complete reactions and
higher yields of product. The structures of these compounds pre-
sented herein reveal the conformational and protonation states
of these substituted isoindolines. We are continuing our work on
the fundamental chemistry of diiminoisoindoline and related
compounds.
Scheme 1.
either toward the isoindoline ring (a syn conformation) or away
from the ring (an anti conformation).25,26 In all of the cases with
the exception of the bis-napthyl compound 15, the alkyl groups
adopt an anti conformation. The prevalence of this structure
results from two factors: the steric bulk of the imine substituents,
and the presence of stabilizing hydrogen bonds. A second struc-
tural aspect that can be observed in the bis substituted isoindolines
is the tautomerization of the ionizable hydrogen atom. These
compounds can tautomerize between protonation at the central
nitrogen atom position and protonation at one of the two imine
positions. Inspection of the difference map, the length of the imine
C–N bonds, and the presence of hydrogen bonding all indicate that
the protons typically reside on the external imine bond positions
rather than the central isoindoline nitrogen atom. Once again,
the only exception is observed in the bis naphthyl species, which
has the ionizable hydrogen atom on the central isoindoline nitro-
gen atom position.
Acknowledgments
We would like to thank the University of Akron for support of
this research and the National Science Foundation (CHE-
9977144) for funds used to purchase the diffractometer used in
this work.
Supplementary data
Previously, Negrebetiskii and coworkers published a study on
the E–Z isomerization of the imine bonds on the bis-methyl substi-
tuted diiminoisoindoline.21 These experiments were carried out in
3:1 chloroform/acetone using a 90 MHz NMR instrument. We
investigated the temperature dependent 1H NMR of compound 9
in two solvent systems: DMSO and 3:1 chloroform/acetone.
Although we did observe sharpening of peaks from the butyl group,
some coalescence of the phenyl AA’BB’ spin system, and downfield
shifts for the ionizable protons (see Supplementary Information),
we were not able to freeze out a proton localized form of 9. How-
ever, our observations were consistent with the room temperature
fast exchange of H+ between the nitrogen atoms in 9.
CCDC numbers 949736-949745 contain the structural data for
compounds. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via: www.ccdc.cam.-
ac.uk/data_request/cif. Supplementary data (experimental proce-
dures, characterization of the previously described compounds 3-
17, and additional X-ray crystallographic data) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2013.08.134.
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