Alkoxyamine-derived formamidines: Configurational control and molecular folding

Article abstract of DOI:10.1021/ol202032k

N,N'-Disubstituted formamidines, and amidines in general, have very rich configurational, conformational, and tautomeric diversities. As part of an effort to incorporate alkoxyamine-derived formamidine units into foldamers, the first evidence for the isol

Full text of DOI:10.1021/ol202032k

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5160–5163
Alkoxyamine-derived Formamidines:
Configurational Control and Molecular
Folding
Weiwen Zhao, Ruiyao Wang, Nicholas J. Mosey, and Anne Petitjean*
Department of Chemistry, Queen’s University, 90 Bader Lane, Kingston,
Ontario K7L 3N6, Canada
anne.petitjean@chem.queensu.ca
Received July 27, 2011
ABSTRACT
N,N0-Disubstituted formamidines, and amidines in general, have very rich configurational, conformational, and tautomeric diversities. As part of
an effort to incorporate alkoxyamine-derived formamidine units into foldamers, the first evidence for the isolation of the up-to-now unknown E
isomer, the conditions for its exclusive formation, its stability and self-assembly properties, and its configurational isomerization to its much more
common Z counterpart are reported. Considering the distinctly different H-bonding patterns displayed by both E and Z isomers, such
configurational control may find applications in self-assembly, molecular recognition, and biomimetic systems.
Amidines have been important units in coordination
chemistry,1 catalysis,1d,f,2 biological recognition,3 sep-
aration4 and supramolecular self-assemby.5 In all these
applications, shape and H-bonding patterns are critical
features determining the resulting properties. If N,N0-dis-
ubstituted formamidines derived from aryland alkylamines
have been well-characterized as E (trans) isomers (with one
exception6a), formamidines derived from alkoxyamines6b
(or formamidoximes) have received much less attention.
The Cambridge Crystallographic Database reports only
Z (cis) isomers rationalized by a stabilizing 5-membered
H-bonded ring which compensates for the cost of maintaining
a cis (Z) CdN double bond. With its controlled curved
structure, this motif may be valuable in the preorganization
of folded structures (foldamers).7 In our recent synthetic work
incorporating the Z-formamidine configurational codon with
the well-known pyridyl-carboxamide conformational codon,8
we observed the anticipated ZZ isomer of 1Bn2 (Figure 1a) as
the only product when trifluoroacetic acid was used in the
reaction, but the unexpected ZE isomer (∼25%) was observed
with acetic acid in the reaction medium. The configuration of
the unusual ZE isomer was confirmed in solution (see the
Supporting Information) and in the crystal (Figure 1a).9
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r
10.1021/ol202032k
Published on Web 08/26/2011
2011 American Chemical Society

E isomer: First Evidence and Properties. As indicated
above, reactions of N,N-dimethylformamidine electro-
philes such as 1 (see Figure 1 for numbering) with
alkoxyamine nucleophiles promoted by certain acids led
1
to mixtures.9 In those, two sets of H NMR signals in
CDCl3 pointed to two different isomeric structures
(Figure 2): on the one hand, the expected Z isomer is
characterized by a down-shielded H-bonded NH and an
up-shielded formamidine Hf. On the other hand, another
species is characterized by a down-shielded formamidine
Hf (∼8.5 ppm) and an up-shielded NH proton (∼7.5 ppm),
which suggests that Hf experiences an electron-rich
environment while NH is not involved in any strong
H-bond. These observations are consistent with the co-
existence of the E isomer which, up to now, has never been
clearly identified (one report10a suggests that this species may
exist based on minute amounts of a side product in a 1D 1H
NMR spectrum). To test this hypothesis, 2D NOESY
experiments were conducted on a 0.9:1.0 mixture of Z/
suspected E species (2Bn) and confirm the spacial proximity
of the OCH2 and Hf protons in the new species (Figure 2),
while no such effect is present in the Z isomer.11
Figure 1. (a) Chemical structure of the ZZ isomer, crystal
structure of the ZE species; (b) reaction studied.
To understand the conditions of the formation of the
never-before observed E configurational isomer, as well
as to explore its properties, a model reaction was studied
(Figure 1b). The present manuscript reports the sys-
tematic study of this reaction, and the first isolation of
E isomers of formamidoximes and their properties.
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Figure 2. 1H NMR of 1.0:0.9 mixture of (E)-2Bn and (Z)-2Bn;
1D (top) and 2D NOESY (bottom) spectra (CDCl3*, 500 MHz).
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The pure E isomers of alkoxylamine-derived formami-
dines (1Me, 2Me, 2Bn, 3Bn) were then isolated after
reaction under specific conditions leading to high propor-
tions or exclusive formation of the E species (as described
below). Crystallization of such species and X-ray diffrac-
tion confirmed their stereochemical identity (E), as high-
lighted below with 2Bn (Figure 3).12
In the solid state, bond lengths in the E and the Z isomers
are very similar (see the Supporting Information), indicating
that, despite the absence of an intramolecular H-bond in the
ꢀ
(11) The 1H NMR signature of the Z isomer is known based on
reactions leading to the exclusive Z species, which were characterized by
2D NMR as well as X-ray crystallography (Supporting Information).
(12) for X-ray structure of (E)-1Me, see Supporting Information.
Org. Lett., Vol. 13, No. 19, 2011
5161

carbon-based analog (Figure 3c, left; the Supporting
Information). Therefore, the E isomer can only be iso-
lated when trapped under kinetic conditions, through a
careful control of the relative kinetics of the condensa-
tion and isomerization processes, as presented below.
Conditions for Isolation of the E Isomer and E to Z Conver-
sion. The reactive N,N-dimethylformamidine electrophile is
known to be sensitized toward nucleophilic attack (e.g., by
alkoxyamines) by protonation. However, the strength and
amount of the introduced acid turn out to be critical to the
stereochemical outcome of the reaction (Table 1). For in-
stance, when N,N0-dimethyl-N-acetylformamidine 2 was con-
densed in the presence of 2 equivalents of trifluoroacetic acid
(TFA, entry 1.2a), the Z isomer was exclusively formed within
the first 10 min (see the Supporting Information). Using less
acidic conditions (e.g., only 1 equivalent of TFA, entry 1.2c, or
of a weaker acid such as AcOH, entry 1.2d), the E isomer was
formed nearly exclusively. Similar behavior was observed with
an arylamide-derived electrophile (entries 1.3a and 1.3b).
Figure 3. (a) Molecular structure of E-2Bn; (b) solid-state self-
assembly; selected bond distances (A): C9ꢀO2 1.225(2), C9ꢀN2
1.358(2), N2ꢀC8 1.380(2), C8ꢀN1 1.281(2); (c) comparison of
calculated relative energies of E and Z isomers of N-acylformami-
doxime and N-acylformamidine in CHCl3 (MP2/6-311þþG(d,p)).
E form, the CdN double-bond is still localized between the
formamidine carbon atom (C8) and the nitrogen atom of
what belonged to the alkoxyamine (N1). The molecular
structure correlates well with the 1H NMR chemical shifts
in CDCl3, with H8A in an electron-rich environment (O2,
O1), and (N)H2B exposed to the surrounding and available
to participate in intermolecular interactions.
Table 1. Effect of the Strength and Amount of Acid on the E/Z
Proportionsa
Interestingly, the solid-state self-assemby is very different
from most N,N0-disubstituted formamidines (Figure 3b):
those commonly self-assemble into dimers (through (N2)-
H2B
N1 mutual interactions).6c Importantly, in the
3 3 3 3
present case, the carbonyl oxygen is the major interaction
partner to the formamidine NH (intermolecular O2 N2:
3 3 3 3
2.780 A), with a very weak interaction between the slightly
acidic formamidine H8A proton and basic N1 nitrogen
(C8
N1 3.928 A), in a strikingly similar structure to that
3 3 303
of N,N -disubstituted ureas.13,14 In solution, dilution experi-
ments support the fact that hydrogen-bonded directed self-
assembly also takes place in CDCl3, and mostly involves the
acetyl carbonyl group, NH and formamidine protons (see the
Supporting Information for 1H NMR experimental details).14
Calculations in the gas phase and in CHCl3 also confirm
the reversed relative stabilities of the Z and E isomers of
N-acylformamidoximes and N-acylformamidines (Figure 3c,
the Supporting Information). Interestingly, the Z isomer
is as much stabilize in N-acylformamidoxime (through
intramolecular H-bonding) as it is destabilized in the
a As Determined by 1H NMR in CDCl3* after 30 min at 298 K. A
graphical representation of the kinetics for each set of conditions is given
in Supporting Information. In brackets, number of equivalents. b Com-
plement to 100% is composed of starting material.
These results suggest that the first species that is formed in
the acid-promoted condensation is the E isomer and that
when an electron-withdrawing group such as a carbonyl
function is present,15a the condensation reaction may be
rendered fast enough and isomerization to the Z isomer slow
enough for the E intermediate to be isolated. In order to
achieve those conditions, a sufficient amount of acid to
promote just the condensation step allows the analytical
and preparative isolation of the never-seen-before E isomer.
To better understand the role of acids in the subsequent
isomerization step, cascade reactions were investigated
(Figure 4). Activation of the condensation step by 1 equiva-
lent of TFA leads to immediate formation of the exclusive E
isomer, with less than 5% of the Z isomer. The dimethylam-
monium trifluoroacetate byproduct is not acidic enough to
efficiently catalyze the E to Z isomerization. However, addi-
tion of a second equivalent of TFA accelerates isomerization,
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N-acylformamidines were made unsuccessful by their difficult synthesis
and instability. See (a) Bechstein, U.; Liebscher, J. Journal f. prakt.
Chemie 1989, 1, 153–156. Supporting Information of: (b) Dıaz, D. D.;
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Org. Lett., Vol. 13, No. 19, 2011

and isomerization, similar studies were carried out with
N-aryl (4)- and N-alkyl (5)-N0,N0-dimethylformamidines. In
these cases, the condensation is slower, allowing for isomer-
ization to take place while the chemical reaction is still
occurring (see the Supporting Information). As a result,
under all conditions tested, the starting material was con-
verted to the Z isomer only (entries 1.4, 1.5a) without
detectable traces of the E isomer.
In conclusion, the present study reports, for the first
time, details on the structural, self-assembly, calculated
relative stability and preparation of the E isomer derived
from N-carbonyl-N0-substituted formamidoxime. The
carbonyl group plays a critical role in accelerating the
condensation step. Controlling the acidic conditions of
the reaction allows to prevent fast isomerization, and to
isolate the pure E isomer. Interestingly, formamidoximes
display fungicidal properties which have been tentatively
associated with the E isomer based on an analogy with
N-phenylcarbamate pesticides.10 However, the E isomer
had never been isolated to test this hypothesis prior to our
work. The methodology described herein allows easy
access to pure E isomers and should facilitate the study
of their biological properties. As a matter of fact, their mode
of self-assembly evidenced in the solid-state (Figure 3) and
in solution (see the Supporting Information) bodes well for
possible interactions with natural systems through a
combination of H-bonds. In addition to the effect of the
static E/Z stereoisomerism on biological interactions, the
present work suggests the potential use of the dynamic
pH-induced E to Z isomerization to tune the biological
properties of formamidoximes, and as a release mechan-
ism for possible applications to the pH-induced drug
delivery.16 Finally, formamidoximes of both the E and
Z forms may be interesting mimics of the amide motif in
Biomimetic Chemistry.7f,17
Figure 4. Kinetic study of the condensation and isomerization
reactions (1H NMR, CDCl3*, 500 MHz).
leading to full conversion to the Z isomer (see the Supporting
Information for NMR details on E/Z isomerization).
Looking back at the reaction of the pyridine-derived
formamidine (1), no conditions were found to exclude the
Z isomer all together. At best, 58:40 mixtures of the E and
Z isomers were isolated (AcOH 1 equiv, entry 1.1b).
Comparing with the alkyl (2)- or aryl (3)-carbonyl deri-
vatives, one may suggest that the more acidic pyridyl-
amide proton accelerates the isomerization step15b,c
through intramolecular H-transfer,6a a process which
cannot be completely prevented.
In an effort to understand the role of the carbonyl
group in influencing the relative kinetics of condensation
(15) (a) Dıaz, D. D.; Finn, M. G. Chem.;Eur. J. 2004, 10, 303–309.
´
Acknowledgment. We thank Queen’s University, the
National Science and Engineering Research Council of
Canada, the Canadian Foundation for Innovation, and
the Ontario Ministry of Research and Innovation (Early
Researcher Award) for financial support.
(b) Hegarthy, A. F.; Chandler, A. J. Chem. Soc. Chem. Commun. 1980,
131–132. (c) Hegarthy, A. F.; Cunningham, I. D. J. Chem. Soc., Perkin
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Supporting Information Available. Synthetic proce-
dures and characterizations of formamidoximes and pre-
cursors. 1H NMR and UVꢀvis kinetic studies. 1H NMR
dilution experiments for (E)-2Bn and (Z)-2Bn (CDCl3).
1H NMR details for NOESY and E to Z conversion.
Theoretical calculations for simple E and Z isomers.
Crystallographic details for (Z,E)-1Bn2 (CCDC 834517),
(E)-2Bn (CCDC 828088), (E)-1Me (CCDC 828089) and
(Z)-1Bn (CCDC 828090). This material is available free of
charge via the Internet at http://pubs.acs.org.
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2007, 36, 326–334. (b) Li, X.; Wu, Y.-D.; Yang, D. Acc. Chem. Res. 2008,
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J. Chem. Pharm. Res. 2010, 2, 197–208. (e) Boyden, T.; Niosi, M.; Vaz,
A. RSC Drug Discovery Ser. 2010, 1, 370–389. (f) Cummings, C. G.;
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