Pyridin-2-yl guanidine derivatives: Conformational control induced by intramolecular hydrogen-bonding interactions

Article abstract of DOI:10.1021/jo200954c

The synthesis and conformational analysis of a series of pyridin-2-yl guanidine derivatives using NMR, X-ray crystallography, and B3LYP/6-31+G* theoretical studies are reported. A remarkable difference was observed in the ¹H NMR spectra of the guanidinium salts as compared with their N,N′-di-Boc protected and neutral analogues. This difference corresponds to a 180° change in the dihedral angle between the guanidine/ium moiety and the pyridine ring in the salts as compared to the Boc-protected derivatives, a conclusion that was supported by theoretical studies, X-ray data, and NMR analysis. Moreover, our data sustain the existence of two intramolecular hydrogen-bonding systems: (i) between the pyridine N1 atom and the guanidinium protons in the salts and (ii) within the tert-butyl carbamate groups of the Boc-protected derivatives. To verify that the observed conformational control arises from these intramolecular interactions, a new series of N-Boc-N′-propyl-substituted pyridin-2-yl guanidines were also prepared and studied.

Full text of DOI:10.1021/jo200954c

Article
pubs.acs.org/joc
Pyridin-2-yl Guanidine Derivatives: Conformational Control Induced
by Intramolecular Hydrogen-Bonding Interactions
Brendan Kelly, Daniel H. O'Donovan, John O'Brien, Thomas McCabe, Fernando Blanco,†
and Isabel Rozas*
School of Chemistry, University of Dublin, Trinity College, Dublin 2, Ireland
S
* Supporting Information
ABSTRACT: The synthesis and conformational analysis of a series of pyridin-2-
yl guanidine derivatives using NMR, X-ray crystallography, and B3LYP/6-
31+G** theoretical studies are reported. A remarkable difference was observed in
the 1H NMR spectra of the guanidinium salts as compared with their N,N′-di-Boc
protected and neutral analogues. This difference corresponds to a 180° change in
the dihedral angle between the guanidine/ium moiety and the pyridine ring in
the salts as compared to the Boc-protected derivatives, a conclusion that was
supported by theoretical studies, X-ray data, and NMR analysis. Moreover, our data sustain the existence of two intramolecular
hydrogen-bonding systems: (i) between the pyridine N1 atom and the guanidinium protons in the salts and (ii) within the tert-
butyl carbamate groups of the Boc-protected derivatives. To verify that the observed conformational control arises from these
intramolecular interactions, a new series of N-Boc-N′-propyl-substituted pyridin-2-yl guanidines were also prepared and studied.
pyridines. This topic has been thoroughly reviewed by Huc,
who found that aromatic oligoamide foldamers can be
efficiently designed, are easy to synthesize, and permit one to
obtain many different stable folded states. Furthermore, he
describes that conformational rearrangements may be induced
by changing the conformational preference of aryl−amide
bonds.19 In addition, pH-active pyridines are considered as
interesting units in molecular motion controlled by pH. Thus,
Kolomiets et al. using NMR and circular dichroism have
studied how oligopyridine carboxamide strands experience
reversible folding/unfolding when protonated.20
INTRODUCTION
■
Guanidine derivatives have a wide range of applications
throughout the field of medicinal chemistry. During the last
10 years, our group has been working on the synthesis1 and
biological evaluation of aromatic guanidine derivatives both as
α-adrenoceptor ligands for the treatment of CNS disorders2−5
and as DNA minor groove binders.6,7 The biological
importance of guanidines is highlighted by the prevalence of
guanidine-carboxylate salt bridges in protein structures, a
feature that is often closely linked to protein function.8 In
addition, aromatic guanidines have found use in a diverse range
of therapeutic and biological applications.9 Guanidines have
also proven effective as catalysts for a wide variety of organic
transformations10,11 and have been studied as ligands both in
metalloproteins12 and in synthetic metal complexes.13
In our search for new aromatic guanidine derivatives, we
present here not only the preparation of a number of novel 2-
guanidino pyridines (Figure 1) following our own synthetic
The structure of guanidine in the solid state was recently
resolved, revealing the high tendency of this molecule to form
hydrogen bond (HB) interactions.14 Tautomerism in guani-
dines has been the object of a recent 15N NMR study,15 as have
its vibrational properties, which have been the subject of a
theoretical study.16 In an attempt to elucidate their mode of
binding to biological receptors, Kleinmaier et al. have
investigated the conformational preferences of monoalkylated
acyl guanidines.17 Moreover, we have recently published a
theoretical study of the π-cation interactions in solution
between the guanidinium and simple aromatic systems.18 In
spite of all of these studies, the molecular basis for ligand−
receptor interactions in aromatic guanidines remains poorly
understood, and further knowledge of their conformational
preferences would be of great benefit in elucidating their mode
of binding to biological receptors.
Figure 1. General structures of previously prepared phenyl guanidines
and new pyridine-2-yl guanidine derivatives, indicating the numbering
scheme used throughout this work.
approach1 but also a thorough structural study at both
experimental (1H NMR and X-ray spectroscopy) and computa-
tional (density functional theory, DFT) levels.
To the best of our knowledge, these pyridin-2-yl guanidines
have not yet been studied, and only a few pyridinyl guanidine
derivatives have been reported to date. These include those in
which the pyridine and guanidine moieties are separated by a
Moreover, carbamates and amides are important building
blocks in artificially folded molecules, in conjunction with
Received: May 18, 2011
Published: October 6, 2011
© 2011 American Chemical Society
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linker, several cobalt21 and zinc22 complexes that were studied
for their potential in sensor technology and as lactide
polymerization catalysts, respectively, and a number of 2-
pyridinylguanidines prepared as urokinase inhibitors.23 Addi-
tionally, the crystal structures and conformational properties of
N,N′-diphenylguanidine and its N-methylated derivatives have
been previously investigated by X-ray crystallography and NMR
by Kagechika and co.24
using trifluoroacetic acid followed by anion exchange with
Amberlite IRA-400 resin afforded the desired guanidinium
chloride salts (3) in good to excellent overall yields (65−93%).
Significantly, in the course of the characterization of these
1
compounds, a striking difference was observed in the H NMR
chemical shifts of hydrogen H3 recorded for the neutral di-Boc-
protected compounds 2 as compared to those recorded for the
hydrochloride salts 3 (Figure 2).
This difference was preserved across a variety of R
substituents with varying electronic properties (Cl, Br, H, and
CH3), in both CDCl3 and DMSO-d6. For the sake of this
discussion, only shifts acquired in DMSO-d6 will be quoted,
unless otherwise stated. Regardless of the electronic effect
RESULTS AND DISCUSSION
■
Synthesis and Characterization of N-(Pyridin-2-yl)-
guanidinium Salts. A series of novel N-(pyridin-2-yl)-
guanidinium salts and the closely related bicyclic analogue N-
(5,6,7,8-tetrahydroquinolin-2-yl)guanidinium were synthesized
following our standard synthetic procedure for the preparation
of aromatic guanidines1 (Scheme 1).
1
induced by these R substituents, the difference in the H NMR
spectra between series 2 and 3 remained significant, thereby
indicating that this phenomenon might be the result of
conformational restraints. Considering the importance of
conformation in the potential pharmacological application of
these compounds, a complete structural study (NMR spec-
troscopy, DFT calculations, and X-ray crystallographic analysis)
of these molecules was carried out.
a
Scheme 1. General Synthetic Pathway
Theoretical Studies on Conformation and Tautomer-
ism of Aromatic Guanidines. Considering the relative
position of the guanidine/ium and pyridine moieties with
respect to the N1−C2−N1′−C2′ dihedral angle, two extreme
geometries result, which can be labeled as anti and syn
conformations (Figure 3).
a
Reagents and conditions: (i) HgCl2, Et3N, N,N′-bis(tert-butoxycar-
bonyl)-S-methylisothiourea, CH2Cl2, 0 °C to rt, 18 h. (ii) CF3CO2H,
CH2Cl2, 3 h. (iii) Amberlite IRA-400(Cl− form), H2O, 24 h.
It is known that in pyridyl guanidinium systems, the syn
conformation can be stabilized by intramolecular hydrogen-
bonding interactions (IMHB) when the guanidinium carrying
group is placed in the ortho position.26 Hence, a theoretical
DFT study at the B3LYP/6-31+G** computational level of all
possible geometries of the neutral 2-pyridinoguanidine series
(including E/Z isomers, syn/anti rotamers, and tautomers) was
Starting from commercial or synthetically prepared25 2-
aminopyridines (1), guanidylation was performed in the
presence of mercury(II) chloride using Boc-protected 2-
methyl-2-thiopseudourea to afford the corresponding N,N′-di-
Boc-protected intermediates (2). Removal of the Boc groups
Figure 2. Aromatic region of the 1H NMR spectra (DMSO-d6) of 5-methyl-2-aminopyridine 1d (bottom), 1-[2,3-di-(tert-butoxycarbonyl)-
guanidino]-5-methylpyridine 2d (middle), and N-(5-methylpyridin-2-yl)guanidinium chloride 3d (top).
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thermore, two stationary states were localized as follows: TS1,
which corresponds to the transition between the anti and the
syn minima, and TS2, which results from the transition between
the two possible degenerate anti minima (“twisted” above and
below the pyridine ring). Although the calculated barriers to the
rotation are not high enough to completely restrict the C2−N1′
rotation (36.9 and 45.7 kJ mol−1), the energetic difference
between the anti and the syn minima (34.0 kJ mol−1) suggests
an almost quantitative preference for the syn conformation.
The study of conformation and rearrangement in the Boc-
protected series 2 is considerably more complicated. In this
case, the guanidine subunit is not only triply substituted but
also neutral; therefore, the localization of the C2′N(3′,4′)
bond results in a number of tautomers. Additionally, E/Z
isomerism in the imino group, and the possible internal
rotation of the adjacent secondary amines results in further
geometries. Unlike guanidinium series 3, the combination of
these issues for the Boc-protected series 2 results in a vast array
of possible conformations/isomers/tautomers, and any a priori
prediction of geometrical preference becomes untenable. To
approach this problem in a systematic way, we have carried out
a complete screening (by means of a conformational systematic
search) of the less computationally demanding diacyl analogues
of series 2. Those structures showing total energies within a
range of 30 kJ mol−1 from the minimum were used as templates
for the di-Boc derivatives, which were then fully optimized until
a minimum energy geometry was obtained (see the Supporting
Information).
Figure 3. Anti and syn conformations available to (a) 2-
pyridinoguanidine and (b) 2-pyridinoguanidinium (series 3) via
rotation around the C2−N1′ bond.
initially performed to approach our systems. We found that, as
expected, the absolute minimum corresponds to one of the syn
geometries (Figure 3a), which is 30 kJ mol−1 more stable than
the best of the minima found in the anti conformation (for the
sake of clarity, only the most stable anti/syn minima are
shown). Thus, in 5-substituted-2-guanidinopyridines, the
stabilization induced by the IMHB through the pyridine
nitrogen [LP−NPy···H3′Gu] is considerably larger than that
through the guanidine nitrogen [LP−NGu···H3Py], in the
absence of electronic or steric secondary factors.
As mentioned before, we have experimentally observed that
the guanidinium salts showed a NMR pattern very different to
that observed in their Boc derivatives and that this could be due
to important differences in their geometries. Hence, using
B3LYP/6-31+G**, we continued with our theoretical study to
confirm this hypothesis. In the case of the protonated series 3, a
quantum theoretical intrinsic reaction coordinate (IRC) study
of the C2−N1′ rotation process27,28 was carried out (gas
phase), resulting in two energetic minima and two transition
states (Figure 4). As in the case of the neutral guanidine
(Figure 3a), the global minimum of the guanidinium series
corresponds to the syn conformation and features a coplanar
arrangement of the guanidinium and pyridine moieties
stabilized by the same type of IMHB interaction [LP−
NPy···H3′Gu]. In this case, the prevalence of the syn
conformation is also favored by steric constraints in the anti
rotamer (H3---H3′ repulsion, Figure 3b), which was also
localized as a second local minimum exhibiting a “twisted”
geometry to minimize the aforementioned repulsion. Fur-
1
The H NMR spectra of the majority of the N,N′-di-Boc-
protected phenylguanidine derivatives previously synthesized in
our group3−5 show the CH3 protons of the tert-butyl groups as
two separate signals integrating for nine protons each,
suggesting the chemical inequivalence of the two N-Boc
groups. This could be explained by the formation of two
IMHBs involving the Boc carbonyl groups and guanidine
hydrogens H1′ and H4′, which is supported by the deshielding
recorded for these two protons' signals (>10 ppm). In addition,
these two Boc groups are not equivalent because one is
connected to an amino-N and the other one is connected to an
imino-N group.
The proposed IMHB network confers rigidity to the N,N′-di-
Boc-substituted guanidine system, which could be considered
as a single “pseudo bicyclic” structure similar to that previously
described for β-diketones.29 Thus, the conformational problem
in these Boc derivatives is reduced to a simple rotation around
the C1−N1′ bond connecting the phenyl ring and the rigid
Boc-protected guanidine. Because of the symmetry of the
phenyl ring, this rotation results in a degenerate pair of
conformations stabilized by IMHBs between the guanidine N3′
and the phenyl protons H2 or H6, respectively (Figure 5a).
Figure 4. Stationary structures resulting from the IRC study at B3LYP/6-31+G** computational level of the C2−N1′ rotation in the guanidinium
derivative 3a. ΔE refers to the difference in total energy between a given state and the global energetic minimum in the gas phase, while ΔΔG is the
difference in free energy.
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subunits, strongly supporting the existence of the postulated
IMHBs (N1−C2−N1′−C2′ dihedral angle ≈ 0.0°). However,
their relative energies reveal that the tautomer 1 of the Z isomer
in its anti conformation (compound 2a antiTaut1, Figure 5b)
remains the most stable by a significant energetic margin
(>15.0 kJ mol−1). Therefore, these results strongly suggest that
compounds in series 2 should preferentially adopt the anti
conformation.
Summarizing, the Boc-protected derivatives 2 exhibit a clear
preference for the anti conformation, while the guanidinium
salts 3 and the neutral 2-pyridinylguanidine exist primarily in
the syn conformation. In addition, the energetic differences
computed between these two conformations seem large enough
to allow prediction of the predominant conformation across
series 2 and 3 under experimental conditions.
X-ray Analysis and NMR Studies of the New Pyridin-2-
yl Guanidines. Confirmation of these computational pre-
dictions was achieved with the X-ray crystal structure of some
of these pyridin-2-yl guanidine/ium derivatives (Figure 7).
Thus, slow recrystallization from a mixture of hexane/EtOAc
provided a crystal structure for the 5-chloro derivative of the di-
Boc-protected pyridin-2-yl guanidines (2b). This structure is
planar, and the N1−C2−N1′−C2′ dihedral angle is 180°, in
agreement with the predicted anti conformation (Figures 2b
and 7). This crystal structure also reveals an extensive IMHB
network involving the Boc CO and N3′ lone pairs as HB
acceptors and the H1′, H4′, and H3 as donors, as previously
described in Figure 5b. Using the same solvent system, a
second crystal structure was obtained for the di-Boc-protected
guanidine-4-ethyloxybenzene 4 (Figure 7), whose preparation
has been described by us elsewhere4 and which is structurally
related to series 2. The crystal structure obtained exhibited the
anti conformation and bears similar features to those of its
pyridine analogue 2b. A summary of the most relevant
distances and angles of these crystal structures is presented in
Table 1. The HB distances found for the O···H1′ interaction
(∼1.9 Å) in both compounds are in agreement with very strong
HBs, while those distances found for the N3′···H3(C) contacts
(∼2.3 Å) correspond to medium-weak HB interactions (see
Table 1). However, the HB formed between O···H4′ is shorter
for compound 4 than for compound 2b, indicating that even
though medium to very strong HBs are established in both
cases the one corresponding to compound 4 is stronger.
In addition, crystals for two of the 1-(pyridin-2-yl)-
guanidinium chloride salts (3d and 3e) were obtained, using
a slow diffusion of diethyl ether in a cold methanolic solution,
and resolved by X-ray crystallographic analysis (Figure 7).
These structures 3d and 3e exhibit syn conformation featuring
pyridine/guanidine coplanarity and an IMHB between the N1
Figure 5. (a) Degenerate conformations for N,N′-di-Boc substituted
phenylguanidines and (b) anti and syn conformations for Boc-
protected pyridin-2-ylguanidine 2a (Z isomer, same tautomer 1),
indicating the calculated relative energies (B3LYP/6-31+G**).
Highlighted in bold is the N1−C2−N1′−C2′ dihedral angle, and in
red is the NH···OC IMHB interaction.
This kind of C(Ar)−H···N IMHB has previously been
described for compounds such as 2,2′-bipyridine,30 1,1′-
bipyrazole,31 and 9-azaphenyl-9H-carbazoles,32 and C−H···X
(X = O, S, N) HBs have been widely discussed in the literature
by Desiraju, among others.33
Similarly, in the Boc-protected pyridin-2-yl guanidines 2, the
conformational issue could be reduced to a rotation around the
N1−C2−N1′−C2′ dihedral angle. However, in this series 2, the
resulting anti and syn conformations are no longer degenerate
(Figure 5b). In the syn conformation, a repulsive effect may
exist between the N1 and the N3′ lone pairs, while in the anti
conformation, a stabilizing IMHB involving N3′ and H3 may be
present [LP−NGu···H3Py]. B3LYP/6-31+G** calculations
performed for the Z isomer of compound 2a (same tautomer
1) confirmed that the anti conformation [(Z)-2a antiTaut1] was
30.1 kJ mol−1 more stable than the syn one [(Z)-2a synTaut1],
which shows a twisted geometry (N1−C2−N1′−C2′ dihedral
angle = 53.0°), resulting from the N1 and N3′ lone pairs
repulsion (Figure 5b).
As mentioned, the conformational analysis in series 2a was
systematically extended to all of the possible isomers/
tautomers/rotamers; hence, several reasonably stable 2a syn
minimum energy geometries were found showing at least one
of the previously described IMHBs, plus a second IMHB
involving pyridine N1 (Figure 6). These minima exhibited, in
all cases, a coplanar arrangement of the pyridine and guanidine
Figure 6. Relative energies, referred to the minimum energy structure [(Z) 2a antiTaut1 in Figure 5b] calculated at B3LYP/6-31+G** level, for the
most favorable energetic minima tautomers/rotamers selected in the syn geometry of compound 2a. Highlighted in bold is the N1−C2−N1′−C2′
dihedral angle, and in red is the NH···OC IMHB interaction.
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Figure 7. X-ray crystal structures of 2-[2,3-di-(tert-butoxycarbonyl)guanidino]-5-chloropyridine (2b), 1-[2,3-di-(tert-butoxycarbonyl)guanidino]-4-
ethoxybenzene (4), N-(5-methylpyridin-2-yl)guanidinium chloride (3d), and N-(5,6,7,8-tetrahydroquinolin-2-yl)guanidinium chloride (3e).
Curiously, in the crystal structure of N,N′-diphenylguanidine,
one of the C−N bonds connected to a phenyl ring show double
bond characteristics, while the other two (C−NH2 and C−
NHPh) appear as single bonds.24 In the case of the neutral Boc
derivatives, 2b and 4, it seems that the guanidine double bond
is localized not over the N atom attached to the pyridine/
phenyl ring but over the N atom connected to a Boc group not
involved in hydrogen bonding with N1′ (C2′−N4′). However,
in the crystal structure of N,N′-dimethyl-N,N′-diphenylguani-
dine, the CN double bond is localized over the unsubstituted
N atom,24 similar to what is observed in our neutral guanidines.
Regarding the hydrochloride salts 3d and 3e and the
hydrobromide salt of N,N′-dimethyl-N,N′-diphenylguanidine,24
very similar C−N distances are obtained for the three C−N
bonds involved in the guanidinium group (between 1.31 and
1.38 Å).
Significantly, NMR experiments in solution supported the
persistence of the conformational effects that have been
theoretically predicted (DFT calculations) and experimentally
observed in the solid state by X-ray crystallographic studies
(Table 2).
In agreement with the anti conformation, the existence of an
IMHB between N3′ and H3 in the di-Boc-protected series (2)
is strongly supported by the 1H NMR data recorded for proton
H3 (Table 2). Throughout series 2, this signal is broadened and
strongly shifted to high field (7.93−8.27 ppm). In contrast, the
H3 signal recorded for the guanidinium salt series 3
consistently appears as a sharp doublet at 6.80−7.13 ppm,
which is much closer to that observed for the corresponding
Table 1. Relevant HB Distances (Å) and Angles (°) Found in
the Crystal Structures of Compounds 4, 2b, 3d, and 3e
N3′···H3−
O···H1′−
N1′
O···H4′−
N4′
N3′···H3
C3
O···H1′
O···H4′
4
2.314
120.9
1.950
1.952
139.7
139.3
1.872
2.109
133.8
123.7
2b
2.311
119.2
C2′−N1′
C2′−N3′
C2′−N4′
N1···H3′
N1···H3′−N3′
4
1.339
1.354
1.343
1.350
1.385
1.388
1.315
1.309
1.315
1.300
1.326
1.333
2b
3d
3e
2.091
2.085
129.8
129.9
and the H3′/H4′ guanidine protons. In both compounds, the
distances observed for the N1···H3′ interaction (Table 1)
correspond to strong HBs.
Furthermore, looking at the three C−N bond distances
within the guanidine/ium moieties, it was noticed that in the
neutral Boc-protected structures (2b and 4), different values
were observed ranging from clear single C−N bonds for C2′−
N3′ to CN double bonds for C2′−N4′, while C2′−N1′ would
be slightly shorter than a single bond, indicating a degree of
delocalization. In the case of the guanidinium derivatives, 3d
and 3e, the distances found for C2′−N1′ and C2′−N4′ are
similar to the C2′−N1′ in the Boc derivatives showing
delocalization. The C2′−N3′ bond corresponding to the
N1···H3′ interaction was slightly shorter than the other two
C−N bonds due to this IMHB. The relatively longest C−N
bond corresponded, in both structures, to the C2′−N1′ bond
that connects to the pyridine system.
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a
1
Table 2. H NMR Shifts of Series 1−3 Obtained in DMSO-d6
compd
R
δH3
δH4
δH6
δH1′
δH3′
δH4′
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
H
6.41
6.45
6.42
6.37
6.20
7.33
7.39
7.49
7.18
7.03
7.88
7.88
7.94
7.72
5.85
6.14
Cl
Br
6.16
CH3
5.63
−(CH2)4−
H
5.53
8.22 (+1.81)
8.27 (+1.82)
8.22 (+1.80)
8.11 (+1.74)
7.93 (+1.73)
7.07 (+0.66)
7.13 (+0.68)
7.06 (+0.64)
6.98 (+0.61)
6.80 (+0.60)
7.87 (+0.54)
8.02 (+0.63)
8.13 (+0.64)
7.69 (+0.51)
7.53 (+0.50)
7.88 (+0.55)
7.98 (+0.59)
8.09 (+0.60)
7.71 (+0.53)
7.55 (+0.52)
8.32 (+0.44)
8.38 (+0.50)
8.44 (+0.50)
8.15 (+0.43)
11.44
11.36
11.36
11.46
11.53
11.39
11.70
11.53
11.17
11.08
10.59
10.65
10.64
10.54
10.49
Cl
Br
CH3
−(CH2)4−
H
b
b
b
b
b
8.32 (+0.44)
8.35 (+0.47)
8.43 (+0.49)
8.15 (+0.43)
8.30
Cl
8.28
8.23
8.20
8.22
Br
CH3
−(CH2)4−
a
b
The difference in chemical shift with reference to the corresponding 2-aminopyridine is shown in parentheses. H3′ and H4′ are chemically
equivalent due to free rotation around the C2′−N1′, C2′−N3′, and C2′−N4′ bonds.
series of 2-aminopyridines (1) (6.20−6.45 ppm). As shown,
this variation in the chemical shift of H3 is significant even
considering electronic effects.
The effect of the Boc-guanidine subunit upon chemical shift
generally resembles that of the guanidinium cation (Figure 8).
to the starting amine, suggesting the participation of these
protons in the HB network proposed for the anti conformation.
In the syn conformation of the guanidinium series 3, H1′ is
highly deshielded (11.08−11.70 ppm) due to its acidity
induced by the adjacent pyridine ring, while H3′ and H4′
appear as a single signal at 8.22−8.28 ppm as they are
chemically equivalent. This value is higher than the
corresponding chemical shift in nonsubstituted guanidinium
chlorides (7.07 ppm),34 and this deshielding can be explained
by the effect of the nearby pyridine nitrogen lone pair.
Nuclear Overhauser effect (NOE) experiments further
supported the postulated conformational preferences. A
through-space interaction was observed between H3 and H1′
in the N-(pyridin-2-yl)guanidinium chlorides 3, in agreement
with the syn conformation. Conversely, the absence of an NOE
signal for these same protons in the di-Boc protected series 2
suggests that they are not nearby in space, supporting the
prevalence of the anti conformation.
1
Figure 8. Average value of H NMR deshielding in aromatic protons
H3, H4, and H6 in series 2 and 3 with respect to the corresponding 2-
aminopyridine 1. E and HB indicate electronic or hydrogen-bonding
effects, respectively.
1
Moreover, variable temperature H NMR was carried out on
compounds 2d and 3d to identify if equilibrium exists between
the possible conformations in both series. Spectra were
recorded in DMSO-d6 at 10° increments from room temper-
ature to 80 °C, and a final spectrum was recorded on recooling
the sample to room temperature. Neither compound showed
significant changes, the spectra indicating in each case that in
fact a single conformer exists experimentally in solution,
confirming our predictions. The characteristic downfield shift
and broad nature of H3 in compound 2d was maintained
throughout, as was the high field shift of the NH protons at
10.5 and 11.4 ppm (see the Supporting Information). Some
degradation of the compound was observed above 70 °C. The
possibility that this was as a result of another conformation of
the same molecule was ruled out by its persistence on recooling
the compound to room temperature. For compound 3d, no
observable changes occurred on heating the solution (see the
Supporting Information). In particular, the high shift seen for
the NH signals was maintained. No degradation of the
compound was observed in this case. This leads us to conclude
that the syn conformation for compounds 3 dominates in
solution as well as in the solid state.
Focusing on the conformationally unaffected protons H4 and
H6, the average difference in chemical shift with reference to
the starting 2-aminopyridine changes little between the Boc-
guanidine and the guanidinium subunits (+0.57/+0.56 for H4
and +0.47/+0.46 for H6, respectively). However, in the case of
H3, the average change in deshielding is considerably higher for
the Boc-protected series 2 (+1.78) than for the guanidinium
series 3 (+0.64); this marked discrepancy can be explained by
the electronic effect of a IMHB interaction.
The chemical inequivalence of the Boc groups in series 2 was
confirmed by the occurrence of two separate signals for the tert-
butyl groups. The CH3 protons appeared as two singlets each
integrating for nine protons at 1.43−1.44 and at 1.44−1.51
ppm, in agreement with the rigid, “pseudo bicyclic” structure
suggested for the Boc-guanidine subunit. In the case of the Boc-
guanidine 4-ethoxybenzene derivative 4, for which a corrobo-
rating X-ray crystal structure was obtained, these signals appear
at 1.44 and 1.50 ppm.
Further evidence of the conformational arrangement was
available via the 1H NMR signals of the guanidine NH protons.
In the Boc-protected series 2, H1′ and H4′ are highly shifted
(11.36−11.53 and 10.49−10.65 ppm, respectively) with respect
On the basis of these experiments, we have calculated the
1
temperature dependence of the H NMR chemical shifts of
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those hydrogens involved in the IHMB in compounds 2d and
3d (H3 and H3′, respectively) as shown in Figure 9. It can be
Figure 9. 1H NMR chemical shifts of H3 (compound 2d, ◆) and H3′
(compound 3d, ■) as a function of temperature (°C). The
corresponding Δδ/ΔT coefficients are also shown.
observed that compound 3d experiences more internal
hydrogen bonding than 2d, and both seem to show similar
temperature dependence.
The Δδ/ΔT coefficients obtained (−0.05 for 2d and 3d) are
larger than those reported by Gellman et al. for IMHBs in
diamides35 (from −0.0025 to −0.0100), suggesting that the
IMHB formed in both cases are solvent-exposed. It can be
concluded that upon increasing the temperature the IMHBs
have been slightly distorted since a small negative shift is
observed for the corresponding signals and that this distortion
is larger for compound 2d than for 3d in agreement with the
strength of each of the IMHBs involved (C−H···N for 2d,
which is weaker than N−H···N for 3d).
Figure 10. Energetic minima calculated for (a) the best anti
conformation of N-Boc-N′-methyl-(pyridin-2-yl)guanidine 5a and
(b) the best syn conformation of the same molecule. To reduce the
computational cost of these calculations, the propyl group present in
the experimental compounds was replaced with a methyl group.
Conformational Control in N-Boc-N′-alkyl pyridin-2-yl
Guanidines. Considering the theoretical and experimental
evidence so far obtained, it was hypothesized that substitution
of one of the Boc protecting groups by an alkyl chain could
suppress the rigid IMHB network in series 2 and might thereby
induce a change from the anti to the syn conformation. Thus, a
new series of N-Boc-N′-alkyl-substituted pyridin-2-yl guanidines
(5) was studied. As for the previous series, a systematic
conformational study for 5a was performed at the B3LYP/6-
31+G** level showing that, in agreement with our hypothesis,
the syn conformation is >25.9 kJ mol−1 more stable than the
best anti one (Figure 10). However, because of the asymmetry
of this system, two different syn/anti energetic minima, 5a(i)
and 5a(ii), had to be analyzed. In the case of the syn
conformers, these minima differ by only 5.0 kJ mol−1,
suggesting the existence of two possible syn conformers
under experimental conditions.
Compounds 5b and 5d, N-Boc-N′-propylpyridin-2-yl guani-
dine-substituted analogues to 5a, were experimentally prepared
following a synthetic procedure recently developed within our
research group.36 The characterization of these compounds
confirmed the theoretical prediction that the molecules of series
5 can exist as a nearly equimolar mixture of two isomers (see
Figure 11).
In the case of compound 5b (R = Cl), a 3:4 mixture of
isomers (i) and (ii) was formed, adjudged by 1H NMR
integration. These isomers proved to be inseparable by either
column chromatography (silica gel) or by recrystallization. For
compound 5d (R = CH3), a 6:5 mixture of isomers (i) and (ii)
was obtained, and in this case, isolation of the (i) isomer was
possible using silica gel column chromatography (9:1,
hexane:EtOAc). The similar isomeric ratios found in both
compounds suggest little difference in their relative energies in
Figure 11. Isomers (i) and (ii) obtained for the N-Boc-N′-
propylpyridin-2-yl guanidines 5b and 5d. Indicated are the H NMR
shifts of protons H3, H4, and H6 in compounds 5 and 6 with respect
to the corresponding 2-aminopyridines 1. E denotes electronic effects.
1
1
agreement with our calculations. Temperature-dependent H
NMR experiments were carried out with the mixture of 5b
isomers in DMSO-d6 and heating from 20 to 100 °C. It was
observed that signals corresponding to 5b(ii) increased with
temperature (up to 75 °C) until a 50:50 proportion with those
of 5b(i), indicating that the equilibrium was reached, and
finally, the compound decomposed at 100 °C. More
1
importantly, the H NMR spectra of both isomers did not
show the H3 shift characteristic of the anti conformation but
one closer to that of the starting 2-aminopyridines (Table 3),
suggesting that it is uninvolved in IMHB interactions, in
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Table 3. 1H NMR (DMSO-d6) Shifts in Compounds 5 and 6
existence of a IMHB interaction between the pyridine nitrogen
and the guanidine protons. Moreover, the X-ray crystal
structures of the N,N′-di-Boc-protected pyridin-2-yl guanidine
2b (R = Cl) and its phenyl analogue 4 (R = OEt) confirm the
existence of an extensive IMHB network involving the
adjoining carbamate and guanidine groups.
compd
isomer δH3
δH4
δH6
δH1′
δH3′
δH4′
5b
i
6.83
7.17
6.98
6.75
7.12
7.67
7.89
7.63
7.45
7.99
8.19
8.35
8.11
7.98
8.37
12.42
7.89
9.74
R = Cl
ii
i
11.89
5d
R = CH3
11.74
10.12
10.11
8.58
1
ii
13.09
9.17
Furthermore, solution-phase H NMR, variable temperature,
6b
R = Cl
11.47
11.34
and NOE experiments confirm that the conformational
preferences suggested by our computational studies and
found in solid-state X-ray crystallographic studies are
maintained in solution.
6d
R = CH3
6.99
7.71
8.14
9.43
8.59
Finally, to verify that conformational control results from
IMHB interactions and not from electronic or steric effects, a
new series of N-Boc-N′-propyl-substituted pyridin-2-yl guani-
dines 5 has been studied. B3LYP/6-31+G** studies predicted a
shift from the anti to the syn geometry in these new derivatives.
Preparation of the corresponding derivatives 5b and 5d (R = Cl
and CH3) followed by Boc deprotection to yield the propyl
guanidinium salts (6b and 6d) allowed us to confirm the
agreement with the syn conformation. This syn conformation in
isomer (i) was further evidenced by the presence of NOE
signals between H1′ and H3 and by the high-field shift recorded
for H1′, as expected for an IMHB with a CO lone pair [5b(i),
12.42; and 5d(i), 11.74 ppm]. These NOE signals were not
observed in isomers (ii), as expected.
The prevalence of the syn conformation in compounds 5
confirms that neither the N-Boc electronic effect, the
unprotonated state of the molecules, nor the steric bulk around
the guanidine subunit are sufficient to induce the anti
conformation observed in the di-Boc derivatives 2. Thus, the
conformational control in pyridin-2-yl guanidines remains
firmly rooted in the IMHB interactions established between
the guanidine and the pyridine subunits.
1
existence of the predicted syn geometry by means of H NMR
studies. Hence, conformational control in pyridin-2-yl
guanidines seems to be entirely dependent on the IMHB
interactions within the guanidine group (in the case of the
N,N′-di-Boc derivatives) and between the guanidine and the
pyridine subunits (in the guanidinium salts).
As expected, cleavage of the Boc group in compounds 5
results in the abolition of any isomeric mixture as shown in the
1H NMR of the corresponding N-propyl 6 derivatives, which
exhibit the syn conformation (see Figure 11). It is worth noting
that the introduction of an alkyl substituent in the protonated
guanidinium 6 does not produce any significant variation in the
chemical shift of protons H3, H4, and H6 with respect to the
guanidiniums 3.
EXPERIMENTAL SECTION
■
Geometries were fully optimized at the B3LYP theoretical level with
the 6-31+G** basis set as implemented in the Gaussian03 program.37
Harmonic frequency calculations verified the nature of the stationary
points as minima (all real frequencies) or transition states (one
imaginary frequency). The scanning of the rotation was performed
using the IRC type calculation implemented in the Gaussian03
program at the same level. To reduce the computational cost, the
initial optimization of all possible tautomers, isomers, and rotamers of
the di-Boc-protected and N-Boc-N′-alkyl pyridin-2-yl guanidine
derivatives (2a and 5a, respectively) was performed using an N-acetyl
group in place of the N-Boc group. The most significant conformers
(only those structures with relative energies within 30 kJ mol−1 from
the minimum) were then optimized using the full N-Boc structure.
The complete data regarding these preliminary calculations are
available in the Supporting Information.
A suitable crystal from each compound 2b, 4, 3d, and 3e was
selected and mounted using inert oil on a 0.3 mm diameter glass fiber
tip and placed on the goniometer head in a 123 K N2 gas stream.
Nonhydrogen atoms were refined with anisotropic thermal parame-
ters. Hydrogen atoms were placed into geometrically calculated
positions and refined using a riding model. The temperature was 123
K in all cases. The agreement between the data and the model (R1) for
all structures was 5% or below.
CONCLUSIONS
■
During preparation of a new series of pyridin-2yl guanidine
derivatives following our standard synthetic method, a striking
difference between the H NMR spectra of the N,N′-di-Boc-
1
protected and guanidinium salt derivatives (series 2 and 3,
respectively) was observed. This difference remained across the
series regardless of the substituent in position 5 of the pyridine
ring; we therefore considered that this effect might result from
conformational constraints. Hence, we have carried out a
complete theoretical and experimental structural study using
B3LYP/6-31+G** calculations, NMR spectroscopy, and X-ray
crystallographic analysis.
Considering the two possible conformational extremes (anti
and syn), DFT theoretical studies yielded two main
conclusions. First, the Boc-protected derivatives 2 exhibit a
preference for the anti conformation, while the 2-pyridinogua-
nidine and the guanidinium salts 3 exist primarily in the syn
conformation. Second, the computations suggested the
formation of two IMHBs involving the Boc carbonyl groups
and guanidine hydrogens, which confer rigidity to the N,N′-di-
Boc-substituted guanidine system in series 2, and in the final
guanidinium salts (series 3), another IMHB is suggested to be
formed between the pyridine nitrogen and the protons H3′
[LP−NPy···H3′Gu] in the guanidinium moiety.
Spectra were recorded on a spectrometer operating at 600.1 MHz
for H NMR and 150.9 MHz for 13C NMR. NMR peak assignments
1
were confirmed using the following COSY and ROESY experiments:
phase-sensitive gradient enhanced (ge) 2D multiplicity-edited HSQC
using PEP and adiabatic pulses with gradients in back-inept
(hsqcedetgpsisp2), phase-sensitive ge-2D HMBC using a 2-fold low-
pass J-filter (hmbcetgpl2nd), and selective gradient enhanced 1D
ROESY (selrogp).
General Procedure for the Synthesis of Di-Boc-Protected
Guanidine Derivatives. To a solution of starting amine (1.0 equiv),
N,N′-bis-(tert-butoxycarbonyl)-S-methylisothiourea (1.1 equiv) and
triethylamine (3.5 equiv) in CH2Cl2 at 0 °C was added mercuric
chloride (1.1 equiv). The mixture was stirred for 30 min at 0 °C, then
warmed to RT, and stirred until the reaction was judged complete by
TLC analysis. The reaction mixture was diluted with EtOAc and
filtered through a pad of Celite to remove any mercury byproduct. The
filtrate was washed with brine (20 mL) and water (20 mL), dried over
X-ray crystal structures obtained for two of the 1-(pyridin-2-
yl)guanidinium chloride salts (3d and 3e) confirm the existence
of the syn conformation and demonstrate a coplanar arrange-
ment of the pyridine and guanidinium subunits, and the
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anhydrous MgSO4, and concentrated under reduced pressure to yield a
residue that was purified by silica gel column chromatography, eluting
with the appropriate hexane:EtOAc mixture.
1-[2,3-Di(tert-butoxycarbonyl)guanidino]-5,6,7,8-tetrahy-
droquinoline (2e). Brown solid (302 mg, 83%); mp 164−165 °C,
1
clean melt. H NMR (400 MHz, DMSO): δ 1.43 (s, 9H, CH3), 1.44
(s, 9H, CH3), 1.73 (m, 2H, CH2), 1.80 (m, 2H, CH2), 2.71 (m, 2H,
1-[2,3-Di(tert-butoxycarbonyl)guanidino]pyridine (2a).
Clear crystalline solid (282 mg, 79%); mp 138−140 °C, clean melt.
1H NMR (400 MHz, DMSO): δ 1.44 (s, 9H, CH3), 1.51 (s, 9H, CH3),
7.16 (app. t, 1H, J = 5.8, 5.6 Hz, Ar), 7.87 (app.t, 1H, J = 7.2, 7.7 Hz,
Ar), 8.22 (d, 1H, J = 7.9 Hz, Ar), 8.32 (d, 1H, J = 3.8 Hz, Ar), 10.59
CH2), 2.68 (m, 2H, CH2), 7.53 (d, 1H, J = 8.7 Hz, Ar), 7.93 (d, 1H, J
1
= 8.2 Hz, Ar), 10.49 (broad s, 1H, NH), 11.53 (broad s, 1H, NH). H
NMR (400 MHz, CDCl3): δ 1.52 (s, 18H, CH3),,1.78 (m, 2H, CH2),
1.84 (m, 2H, CH2), 2.70 (t, 2H, J = 6.3, 6.1 Hz, CH2), 2.78 (t, 2H, J =
6.1, 6.3 Hz, CH2), 7.35 (d, 1H, J = 8.3 Hz, Ar), 8.04 (broad s, 1H, Ar),
10.64 (broad s, 1H, NH), 11.54 (broad s, 1H, NH). 13C NMR (100
MHz, CDCl3): δ 22.7 (CH2), 22.9 (CH2t), 28.00 (CH3), 28.02 (CH2),
1
(broad s, 1H, NH), 11.44 (broad s, 1H, NH). H NMR (600 MHz,
CDCl3): δ 1.53 (s, 18H, CH3), 7.01 (app. t, 1H, J = 5.4 Hz), 7.70
(app. t, 1H, J = 7.3 Hz), 8.29 (d, 1H, J = 4.0 Hz), 8.37 (broad s, 1H),
10.89 (broad s, 1H, NH), 11.53 (broad s, 1H, NH). 13C NMR (150
MHz, CDCl3): δ 28.0 (CH3), 28.1 (CH3), 79.9 (quat. tBu), 83.9 (quat.
tBu), 116.0 (CH Ar), 119.7 (quat. Ar), 138.1 (CH Ar), 148.0 (CH
Ar), 150.6 (quat. Ar), 152.6 (quat. CO), 153.1 (quat. CO), 163.2
(quat. CN). IR (cm−1): υ 3253 (NH), 2979 (NH), 1725 (CN,
Gua), 1621 (CO, Boc), 1586, 1570, 1479, 1398, 1368, 1332, 1302,
1293, 1256, 1229, 1147, 1121, 1089, 1030, 994, 883, 848, 809, 763,
733, 710, 669. HRMS (m/z ESI+): 337.1876 calcd for C16H24N4O4
[M + H]+; found, 337.1882.
t
28.04 (CH3), 32.0 (CH2), 79.6 (quat, Bu), 83.6 (quat, Bu), 113.6
(CH Ar), 128.3 (quat. Ar), 138.7 (CH Ar), 147.6 (quat. Ar), 152.6
(quat. CO), 152.0 (quat. CO), 155.4 (quat. Ar), 163.3 (quat.
Gua). IR (cm−1): υ 3251 (NH), 2979 (NH), 1714 (CN, Gua), 1645
(CO), 1629, 1588, 1565, 1449, 1395, 1369, 1354, 1325, 1313, 1279,
1247, 1231, 1151, 1112, 1058, 1029, 996, 941, 899, 874, 864, 840, 804,
755, 713. HRMS (m/z ESI+): 391.2345 calcd for C20H30N4O4 [M +
H]+; found, 391.2342.
1-[2,3-Di(tert-butoxycarbonyl)guanidino]-4-ethoxybenzene
1
(4). White solid (330 mg, 76%); mp 118−120 °C. H NMR (400
1-[2,3-Di(tert-butoxycarbonyl)guanidino]-5-chloropyridine
MHz, CDCl3): δ 1.42 (t, 3H, J = 7.1 Hz, CH3), 1.51 (s, 9H, CH3),
1.56 (s, 9H, CH3), 4.03 (q, 2H, J = 7.1 Hz, CH2), 6.87 (d, 2H, J = 8.7
Hz, Ar), 7.47 (d, 2H, J = 8.7 Hz, Ar) 10.20 (br s, 1H, NH), 11.67 (br
s, 1H, NH). 13C NMR (100 MHz, CDCl3): δ 14.4 (CH3), 27.6 (CH3),
27.8 (CH3), 63.1 (CH2), 79.0 (CH3), 83.1 (CH3), 114.2 (CH Ar),
123.4 (CH Ar), 129.2 (quat. Ar), 152.9 (quat. Ar), 153.2 (quat. C
O), 155.7 (quat. CO), 163.2 (quat. Gua). IR (cm−1): υ 3280 (NH),
3165 (NH), 2933, 1716 (CN), 1630 (CO), 1605, 1573, 1511
(Aryl), 1390, 1345, 1227, 1155, 1117, 1057. HRMS (m/z ESI+):
380.2185 calcd for C19H29N3O5Na [M + Na]+; found, 380.2181.
General Procedure for the Synthesis of N-Boc-N′-Propyl
Guanidine Derivatives. To a solution of N-tert-butoxycarbonyl-N′-
propylthiourea (7, described below), the starting amine (1.0 equiv),
and triethylamine (3.5 equiv) in CH2Cl2 at 0 °C was added mercuric
chloride (1.2 equiv). The mixture was stirred for 30 min at 0 °C, then
warmed to RT, and stirred until reaction was adjudged complete by
TLC analysis. The reaction mixture was diluted with EtOAc and
filtered through a pad of Celite to remove any mercury byproduct. The
filtrate was washed with brine (20 mL) and water (20 mL), dried over
anhydrous MgSO4, and concentrated under reduced pressure to yield a
residue that was purified by silica gel column chromatography, eluting
with the appropriate hexane:EtOAc mixture.
1
(2b). White solid (433 mg, 75%); mp 124 °C, clean melt. H NMR
(400 MHz, DMSO): δ 1.44 (s, 9H, CH3), 1.50 (s, 9H, CH3), 8.02 (dd,
1H, J = 8.8, 2.3 Hz, Ar), 8.27 (d, 1H, J = 8.7 Hz, Ar), 8.38 (d, 1H, J =
1
2.3 Hz, Ar), 10.65 (broad s, 1H, NH), 11.36 (broad s, 1H, NH). H
NMR (400 MHz, CDCl3): δ 1.53 (s, 9H, CH3), 1.54 (s, 9H, CH3),
7.67 (dd, 1H, J = 8.9, 2.6 Hz, Ar), 8.24 (d, 1H, J = 2.6 Hz, Ar), 8.40 (d,
J = 8.9 Hz, Ar), 10.92 (broad s, 1H, NH), 11.51 (broad s, 1H, NH).
13C NMR (100 MHz, CDCl3): δ 28.0 (CH3), 28.1 (CH3), 80.1 (quat.
t
tBu), 84.1 (quat. Bu), 116.8 (CH Ar), 126.9 (quat. Ar), 137.7 (CH
Ar), 146.6 (CH Ar), 148.9 (quat. Ar), 152.6 (quat. CO), 152.9
(quat. CO), 163.0 (quat. Gua). IR (cm−1): υ 3249 (NH), 2981
(NH), 1741 (CN), 1716, 1633 (CO), 1576, 1559, 1476, 1455,
1407, 1383, 1367, 1322, 1287, 1252, 1235, 1219, 1142, 1123, 1101,
1059, 1028, 1006, 967, 917, 880, 848, 837, 801, 782, 743, 728, 685.
HRMS (m/z ESI+): 371.1486 calcd for C16H23ClN4O4 [M + H]+;
found, 371.1489.
1-[2,3-Di(tert-butoxycarbonyl)guanidino]-5-bromopyridine
1
(2c). White solid (383 mg, 80%); mp 126 °C, clean melt. H NMR
(400 MHz, DMSO): δ 1.44 (s, 9H, CH3), 1.50 (s, 9H, CH3), 8.13 (dd,
1H, J = 8.9, 1.9 Hz, Ar), 8.22 (d, 1H, J = 8.9 Hz, Ar), 8.44 (d, 1H, J =
1
1.9 Hz, Ar), 10.64 (broad s, 1H, NH), 11.36 (broad s, 1H, NH). H
NMR (400 MHz, CDCl3): δ 1.49 (s, 18H, CH3), 7.75 (dd, J = 8.7, 1.3
Hz, Ar), 8.28 (d, 1H, J = 2.1 Hz, Ar), 8.31 (d, 1H, J = 8.3 Hz, Ar),
10.86 (broad s, 1H, NH), 11.49 (broad s, 1H, NH). 13C NMR (100
N-tert-Butoxycarbonyl-N′-propylthiourea (7). To a solution
of thiourea (500 mg, 6.58 mmol) in dry THF (120 mL) at 0 °C was
added NaH (60% dispersion in mineral oil, 1184 mg, 29.60 mmol),
followed by di-tert-butyl dicarbonate (3155 mg, 14.47 mmol). After 8 h
of stirring at RT, the reaction was cooled again to 0 °C, and a second
portion of NaH (442 mg, 11.05 mmol) was added followed 1 h later
by trifluoroacetic anhydride (1.41 mL, 10.13 mmol). After 45 min, 1-
propylamine (0.83 mL, 10.13 mmol) was added neat, and the reaction
was stirred at RT for 18 h. The reaction was quenched with dropwise
H2O (20 mL) followed by extraction with EtOAc (3 × 20 mL). The
organic phase was dried over MgSO4, solvents were removed under
vacuum, and the crude product was purified by flash chromatography
(4:1 hexane:EtOAc, Rf 0.3). Recrystallization from hexanes afforded
the product as a white, crystalline solid (1019 mg, 71%); mp 58−60
°C. 1H NMR (400 MHz, CDCl3): δ 1.01 (t, 2H, J = 7.3 Hz,
CH2CH2CH3), 1.52 (s, 9H, Boc), 1.71 (q, 2H, J = 7.3 Hz,
CH2CH2CH3), 3.63 (m, 2H, CH2CH2CH3), 7.97 (br s, 1H, NH),
9.74 (br s, 1H, NH). 13C NMR (100 MHz, DMSO): δ 11.3
(CH2CH2CH3), 21.5 (CH2CH2CH3), 27.8 (CH3 Boc), 47.1
(CH2CH2CH3), 83.4 (Cq Boc), 151.8 (CO), 179.4 (CS). IR
(cm−1): υ 3245, 3175 (NH), 2961, 2934, 2875, 1720 (CO), 1523
(CN), 1243, 1206, 1142 (CS), 1073, 1008. HRMS (m/z ESI+):
219.1167 calcd for C9H19N2O2S [M + H]+; found, 219.1167.
t
MHz, CDCl3): δ 27.8 (CH3, Boc), 27.9 (CH3, Boc), 79.9 (quat. Bu),
t
83.9 (quat. Bu), 114.7 (CH Ar), 117.2 (quat. Ar), 140.3 (CH Ar),
148.6 (CH Ar), 149.1 (quat. Ar), 152.5 (quat. CO), 152.7 (quat.
CO), 162.8 (quat. Gua). IR (cm−1): υ 3247 (NH), 2980 (NH),
1715 (CN, Gua), 1632 (CO, Boc), 1593, 1553, 1453, 1404, 1367,
1324, 1287, 1252, 1232, 1148, 1129, 1101, 1057, 1028, 1004, 878, 841,
793, 745. HRMS (m/z ESI+): 415.0981 calcd for C16H23BrN4O4 [M +
H]+; found, 415.0990.
1-[2,3-Di(tert-butoxycarbonyl)guanidino]-5-methylpyridine
(2d). White crystalline solid (460 mg, 71%); mp 139 °C, clean melt.
1H NMR (400 MHz, DMSO): δ 1.44 (s, 9H, CH3), 1.51 (s, 9H, CH3),
7.69 (d, 1H, J = 8.4 Hz, Ar), 8.11 (d, 1H, J = 8.4 Hz, Ar), 8.15 (s, 1H,
1
Ar), 10.54 (broad s, 1H, NH), 11.46 (broad s, 1H, NH). H NMR
(400 MHz, CDCl3): δ 1.48 (s, 9H, CH3), 1.49 (s, 9H, CH3), 2.23 (s,
CH3), 7.45 (dd, 1H, J = 8.4, 1.9 Hz, Ar), 8.07 (d, 1H, J = 1.9 Hz, Ar),
8.20 (broad s, 1H, Ar), 10.78 (broad s, 1H, NH), 11.52 (broad s, 1H,
NH). 13C NMR (100 MHz, CDCl3): δ 17.8 (CH3), 28.0 (CH3), 28.1
(CH3), 79.7 (quat. tBu), 83.7 (quat. tBu), 115.6 (CH Ar), 129.1 (quat.
Ar), 138.6 (CH Ar), 147.9 (CH Ar), 148.4 (quat. Ar), 152.7 (quat.
CO), 153.0 (quat. CO), 163.3 (quat. CN). IR (cm−1): υ 3244
(NH), 2978 (NH), 1720 (CN), 1632 (CO), 1585, 1560, 1475,
1454, 1404, 1374, 1324, 1305, 1289, 1268, 1252, 1230, 1151, 1136,
1107, 1058, 1025, 882, 856, 838, 803, 758, 749, 709. HRMS (m/z
ESI+): 351.2032 calcd for C17H26N4O4 [M + H]+; found, 351.2036.
1-[2-(tert-Butoxycarbonyl)-3-propylguanidino]-5-chloropyri-
1
dine (5b). Clear gum (247 mg, 39%, 4:3 mixture of isomers). H
NMR (600 MHz, DMSO): δ 0.91 (m, 6H, CH3), 1.43 (s, 9H, CH3),
1.48 (s, 9H, CH3), 1.56 (m, 4H, CH2), 3.31 (m, 4H, CH2), 6.83 (d,
9224
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Article
1H, J = 8.8 Hz, Ar), 7.17 (d, 1H, J = 8.0 Hz, Ar), 7.67 (dd, 1H, J = 8.8,
2.6 Hz, Ar), 7.89 (dd, 1H, J = 8.8, 2.5 Hz, Ar), 7.89 (broad s, 1H, NH),
8.19 (d, 1H, J = 2.6 Hz, Ar), 8.35 (d, 1H, J = 2.5 Hz, Ar), 9.74 (broad
11.70 (broad s, 1H, NH). 13C NMR (150 MHz, DMSO): δ 115.0
(CH Ar), 126.6 (quat. Ar), 139.2 (CH Ar), 144.7 (CH Ar), 151.0
(quat. Ar), 155.7 (quat. CN). IR (cm−1): υ 3313 (NH), 3178 (NH),
2953, 1685 (CN), 1617, 1587, 1551, 1465, 1364, 1310, 1274, 1236,
1136, 1113, 1022, 1009, 924, 876, 828, 757, 734, 718. HRMS (m/z
ESI+): 171.0437 calcd for C6H7ClN4 [M + H]+; found, 171.0433.
Purity by HPLC: 99.0% (tR 22.68 min).
1
s, 1H, NH), 11.89 (broad s, 1H, NH), 12.42 (broad s, 1H, NH). H
NMR (600 MHz, CDCl3): δ 1.00 (m, 4H, CH3), 1.53 (s, 9H, CH3),
1.54 (s, 9H, CH3), 1.65 (app. sex, 4H, J = 7.3 Hz, CH2), 3.41 (broad s,
2H, CH2), 3.49 (m, 2H, J = 7.0, 5.5 Hz, CH2), 6.82 (d, 1H, J = 8.8 Hz,
Ar), 6.88 (broad s, 1H, Ar), 7.46 (d, 1H, J = 6.9 Hz, Ar), 7.60 (dd, 1H,
J = 8.8, 2.3 Hz, Ar), 7.87 (broad s, 1H, NH), 8.12 (broad s, 1H, Ar),
8.17 (d, 1H, J = 2.3 Hz, Ar), 9.77 (broad s, 1H, NH), 12.28 (broad s,
1H, NH), 12.62 (broad s, 1H, NH). 13C NMR (100 MHz, CDCl3): δ
N-(5-Bromopyridin-2-yl)guanidinium Chloride (3c). Oily
1
white solid (118 mg, 74%); mp 74−81 °C. H NMR (600 MHz,
DMSO): δ 7.06 (d, 1H, J = 8.8 Hz, Ar), 8.09 (dd, 1H, J = 8.8, 2.5 Hz),
8.23 (broad s, 1H, NH), 8.43 (d, 1H, J = 2.5 Hz, Ar), 11.53 (broad s,
1H, NH). 13C NMR (150 MHz, DMSO): δ 114.7 (quat. Ar), 116.1
(CH Ar), 142.9 (CH Ar), 148.1 (CH Ar), 151.7 (quat. Ar), 155.9
(quat. CN). IR (cm−1): υ 3313 (NH), 3218 (NH), 3011 (NH),
1684.0 (CN), 1618, 1582, 1551, 1465, 1360, 1308, 1275, 1234,
1137, 1094, 1006, 925, 874, 825, 732. HRMS (m/z ESI+): 214.9932
calcd for C6H7BrN4 [M + H]+; found, 214.9926. Purity by HPLC:
99.1% (tR 23.88 min).
t
22.5 (CH2), 28.2 (CH3), 28.4 (CH3), 42.6 (CH2), 78.8 (quat. Bu),
114.2 (CH Ar), 121.8 (CH Ar), 122.8 (quat. Ar), 124.9 (quat. Ar),
137.6 (CH Ar), 138.4 (CH Ar), 143.8 (CH Ar), 144.5 (CH Ar), 149.8
(quat. Ar), 151.4 (quat. Ar), 153.7 (quat. CO), 157.2 (quat. CO),
160.1 (quat. Gua), 164.4 (quat. Gua). IR (cm−1): υ 3359 (NH), 2968
(NH), 1730 (CN), 1645 (CO), 1585, 1560, 1476, 1455, 1406,
1380, 1329, 1322, 1288, 1259, 1234, 1170, 1156, 1120, 1032, 980, 832,
799, 734, 689. HRMS (m/z ESI+): 335.1251 calcd for C14H21ClN4O2
[M + Na]+; found, 335.1246.
N-(5-Methylpyridin-2-yl)guanidinium Chloride (3d). Clear
crystalline solid (94 mg, 84%); mp 188−192 °C, clean melt. 1H
NMR (600 MHz, DMSO): δ 2.27 (s, 3H, CH3), 6.98 (d, 1H, J = 8.3
Hz, Ar), 7.71 (dd, 1H, J = 8.3, 1.9 Hz, Ar), 8.15 (broad s, 1H, Ar), 8.21
(broad s, 4, NH), 11.17 (broad s, 1H, NH). 13C NMR (150 MHz,
DMSO): δ 17.1 (CH3), 112.7 (CH Ar), 128.5 (quat. Ar), 140.1 (CH
Ar), 146.1 (CH Ar), 149.7 (quat. Ar), 155.2 (quat. CN). IR (cm−1): υ
3268 (NH), 2889 (NH), 1677 (CN), 1621, 1601, 1563, 1489, 1376,
1315, 1285, 1242, 1086, 1035, 1023, 1002, 909, 873, 832, 798, 738,
718. HRMS (m/z ESI+): 151.0984 calcd for C7H10N4 [M + H]+;
found, 151.0979. Purity by HPLC: 98.3% (tR 21.57 min).
1-[2-(tert-Butoxycarbonyl)-3-propylguanidino]-5-methyl-
pyridine (5d). Column chromatography (5:1 Hexane:EtOAc) on the
mixture of isomers 5d(i) and 5d(ii), followed by recrystallization
(hexane/EtOAc) yielded 5d as a white powder (75.0 mg, 28%, single
1
isomer); mp 102−104 °C, clean melt. H NMR (400 MHz, DMSO):
δ 0.91 (t, 3H, J = 7.4 Hz, CH3), 1.42 (s, 9H, CH3), 1.54 (m, 2H, CH2),
2.24 (s, 3H, CH3), 3.31 (m, 2H, CH2), 6.98 (d, 1H, J = 8.2 Hz, Ar),
7.63 (d, 1H, J = 8.2 Hz, Ar), 8.11 (s, 1H, Ar), 10.12 (broad s, 1H,
1
NH), 11.74 (broad s, 1H, NH). H NMR (400 MHz, CDCl3): δ 0.98
(t, 3H, J = 7.4 Hz, CH3), 1.51 (s, 9H, CH3), 1.62 (app. sex, 2H, J = 7.6,
7.2 Hz, CH2), 2.24 (s, 3H, CH3), 3.46 (m, 2H, CH2), 6.72 (d, 1H, J =
8.4 Hz, Ar), 7.42 (dd, 1H, J = 8.4, 2.1 Hz, Ar), 10.17 (broad s, 1H,
NH), 11.97 (broad s, 1H, NH). 13C NMR (100 MHz, CDCl3): δ 11.5
(CH3), 17.5 (CH3), 22.5 (CH2), 28.4 (CH3), 42.4 (CH2), 78.4 (quat.
tBu), 112.7 (CH Ar), 126.7 (quat. Ar), 139.2 (CH Ar), 145.3 (CH
N-(5,6,7,8-Tetrahydroquinolin-2-yl)guanidinium Chloride
(3e). Brown solid (71 mg, 85%); mp 224−228 °C (decomposed).
1H NMR (600 MHz, DMSO): δ 1.73 (m, 2H, J = 5.8, 6.0 Hz, CH2),
1.80 (m, 2H, J = 6.1, 5.9 Hz, CH2), 2.68 (app. t, 2H, J = 6.2, 6.0 Hz,
CH2), 2.78 (app. t, 2H, J = 6.1, 6.0 Hz, CH2), 6.80 (d, 1H, J = 8.2 Hz,
Ar), 7.55 (d, 1H, J = 8.2 Hz, Ar), 8.22 (broad s, 4H, NH), 11.08
(broad s, 1H, NH). 13C NMR (150 MHz, DMSO): δ 22.1 (CH2), 22.2
(CH2), 27.2 (CH2), 31.5 (CH2), 110.5 (CH Ar), 127.3 (quat. Ar),
140.1 (CH Ar), 149.2 (quat. Ar), 154.0 (quat. Ar), 155.2 (quat. CN).
IR (cm−1): υ 3323 (NH), 3149 (NH), 2961 (NH), 1679 (CN,
Gua), 1634, 1597, 1566, 1465, 1031, 813. HRMS (m/z ESI+):
191.1297 calcd for C10H14N4 [M + H]+; found, 191.1293. Purity by
HPLC: 98.1% (tR 27.00 min).
Ar), 150.9 (quat. Ar), 157.5 (quat. CO), 164.2 (quat. Gua). IR
(cm−1): υ 3355 (NH), 2965 (NH), 2930, 2875, 1712 (CN), 1638,
1597 (CO), 1562, 1495, 1474, 1347, 1300, 1245, 1172, 1154, 1125,
1056, 1026, 961, 909, 821, 805, 774, 739, 665. HRMS (m/z ESI+):
315.1797 calcd for C15H24N4O2 [M + Na]+; found, 315.1792.
General Procedure for the Synthesis of Guanidinium
Chloride Salts. To starting 1-[2,3-di-Boc-guanidino]pyridine (1.0
equiv) was added slowly a solution of trifluoroacetic acid (TFA) in
CH2Cl2 (25.0 equiv, 25% v/v). Stirring at RT was continued until the
reaction was adjudged complete by TLC analysis (≤3 h). Solvent and
excess TFA were removed under reduced pressure to yield the
trifluoroacetate salt as an off-white solid. This was dissolved in H2O, to
which Amberlite IRA-400 resin in its chloride form (excess) was
added. The mixture was stirred for 36 h at room temperature after
which the Amberlite resin was removed by vacuum filtration. The
aqueous layer was washed with DCM and concentrated under reduced
pressure to yield an off-white solid, which was purified by small-scale
reverse-phase chromatography using C-8 silica with 100% H2O as
mobile phase. Conversion to the chloride salt was checked by 19F
NMR and if necessary stirring in Amberlite was repeated.
1-(5-Chloropyridin-2-yl)-3-propylguanidinium Chloride
(6b). Yellow crystalline solid (120 mg, 93%); mp 102−104 °C,
1
clean melt. H NMR (600 MHz, DMSO): δ 0.94 (t, 3H, J = 7.4 Hz,
CH3), 1.59 (app. sex, 2H, J = 7.2, 7.3 Hz, CH2), 3.29 (m, 2H, J = 6.7
Hz, CH2), 7.12 (s, 1H, Ar), 7.99 (dd, 1H, J = 8.8, 2.5 Hz, Ar), 8.37 (d,
1H, J = 2.5 Hz, Ar), 8.58 (broad s, 2H, NH), 9.17 (broad s, 2H, NH),
11.47 (broad s, 2H, NH).13C NMR (150 MHz, DMSO): δ 11.3
(CH3), 21.9 (CH2), 42.9 (CH2), 115.0 (CH Ar), 125.7 (quat. Ar),
139.7 (CH Ar), 145.1 (CH Ar), 154.1 (quat. Gua). IR (cm−1): υ 3268
(NH), 3097 (NH), 3059, 2958, 2931, 2875, 1673, 1646, 1629 (C
N), 1591, 1558, 1469, 1385, 1371, 1342, 1315, 1271, 1243, 1145,
1109, 1075, 1044, 1012, 966, 903, 869, 828, 772, 737, 658. HRMS (m/
z ESI−): 211.0745 calcd for C10H14N4 [M - H]−; found, 211.0750.
Purity by HPLC: 99.3% (tR 26.40 min).
N-(Pyridin-2-yl)guanidinium Chloride (3a). Orange/white
1
solid (46 mg, 81%); mp 78 °C, clean melt. H NMR (600 MHz,
1-(5-Methylpyridin-2-yl)-3-propylguanidinium Chloride
DMSO): δ 7.07 (d, 1H, J = 8.2 Hz, Ar), 7.18 (dd, 1H, J = 6.9, 5.4 Hz,
Ar), 7.88 (app t, 1 H, Ar), 8.30 (broad s, 4H, NH2), 8.32 (d, 1H, J =
4.1 Hz, Ar), 11.39 (broad s, 1H, NH). 13C NMR (150 MHz, DMSO):
δ 113.2 (CH Ar), 119.3 (quat. Ar), 139.5 (CH Ar), 146.7 (CH Ar),
151.9 (quat. Ar), 155.3 (quat. CN). IR (cm−1): υ 3312 (NH), 3180
(NH), 3130 (NH), 1679 (CN), 1622, 1596, 1561, 1462, 1416,
1319, 1274, 1244, 1154, 1054, 1020, 998, 874, 775. HRMS (m/z
ESI+): 137.0827 calcd for C6H8N4 [M + H]+; found, 137.0827. Purity
by HPLC: 97.2% (tR 16.81 min).
(6d). Yellow crystalline solid (32 mg, 90%); mp 102−104 °C, clean
1
melt. H NMR (600 MHz, DMSO): δ 0.94 (t, 3H, J = 7.5 Hz, CH3),
1.58 (app. sex, 2H, J = 7.5, 7.1 Hz, CH2), 2.25 (s, 3H, CH3), 3.29 (m,
2H, J = 6.6 Hz, CH2), 6.99 (broad s, 1H, Ar), 7.71 (dd, 1H, J = 8.4, 1.9
Hz, Ar), 8.14 (d, 1H, J = 1.9, Ar), 8.59 (broad s, 2H, NH), 9.43 (broad
s, 2H, NH), 11.34 (broad s, 2H, NH). 13C NMR (150 MHz, DMSO):
δ 11.0 (CH3), 17.2 (CH3), 21.6 (CH2), 42.5 (CH2), 112.6 (CH Ar),
128.3 (q Ar), 140.3 (CH Ar), 145.8 (CH Ar), 150.0 (q Ar), 154.1 (q,
Gua). IR (cm−1): υ 2965 (NH), 1674 (CN), 1632, 1608, 1572,
1484, 1343, 1283, 1244, 1136, 1079, 1029, 968, 831, 743. HRMS (m/z
ESI+): 193.1453 calcd for C10H17N4 [M + H]+; found, 193.1458.
Purity by HPLC: 96.9% (tR 24.57 min).
N-(5-Chloropyridin-2-yl)guanidinium Chloride (3b). Oily
1
white solid (95 mg, 85%); mp 164 °C, clean melt. H NMR (600
MHz, DMSO): δ 7.13 (d, 1H, J = 8.8 Hz, Ar), 7.98 (dd, 1H, J = 8.8,
2.6 Hz, Ar), 8.28 (broad s, 1H, NH), 8.35 (d, 1H, J = 2.6 Hz, Ar),
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Article
(11) Sohtome, Y.; Takemura, N.; Takada, K.; Takagi, R.; Iguchi, T.;
Nagasawa, K. Chem. Asian J. 2007, 2, 1150.
(12) Przybyla, A. E.; Robbins, J.; Menon, N.; Peck, H. D. Jr. FEMS
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra of all compounds described
in series 2−6; characterization data for the 2-aminopyridines
described in series 1; X-ray crystal structural data for
compounds 2b, 3d, 3e, and 4; copies of the variable
Microbiol. Rev. 1992, 88, 109.
(13) Fairlie, D. R.; Jackson, W.; Gregory, S.; Skelton, B. W.; Wen, H.;
White, A. H.; Wickramasinghe, W. A.; Woon, T. C.; Taube, H. Inorg.
Chem. 1997, 36, 1020.
1
(14) Yamada, T.; Liu, X.; Englert, U.; Yamane, H.; Dronskowski, R.
temperature H NMR spectra of compounds 2d and 3d, and
Chem.Eur. J. 2009, 15, 5651.
Cartesian coordinates of all of the structures optimized at the
B3LYP/6-31+G** level. This material is available free of charge
via the Internet at http://pubs.acs.org.
(15) Ghiviriga, I.; El-Gendy, B.; El-D., M.; Steel, P. J.; Katritzky, A. R.
Org. Biomol. Chem. 2009, 7, 4110.
(16) Todorova, T.; Krocher, O.; Delley, B. J. Mol. Struct.
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THEOCHEM 2009, 907, 16.
AUTHOR INFORMATION
(17) Kleinmaier, R.; Keller, M.; Igel, P.; Buschauer, A.; Gschwind, R.
M. J. Am. Chem. Soc. 2010, 132, 11223.
(18) Blanco, F.; Kelly, B.; Alkorta, I.; Rozas, I.; Elguero, J. Chem.
Phys. Lett. 2011, 511, 129.
(19) Huc, I. Eur. J. Org. Chem. 2004, 17.
■
Corresponding Author
*Tel: (+353)18963731. Fax: (+353)16712826. E-mail: rozasi@
tcd.ie.
Present Address
(20) Kolomiets, E.; Berl, V.; Lehn, J.-M. Chem.Eur. J. 2007, 13,
†Molecular Design Group, School of Biochemistry and
Immunology, University of Dublin, Trinity College, Dublin 2,
Ireland.
5466.
(21) Hoffmann, A.; Borner, J.; Florke, U.; Herres-Pawlis, S. Inorg.
Chim. Acta 2009, 362, 1185.
(22) Borner, J.; Florke, U.; Doring, A.; Kuckling, D.; Herres-Pawlis,
S. Chem.Eur. J. 2009, 15, 2362.
ACKNOWLEDGMENTS
■
(23) Barber, C. G.; Dickinson, R. P. Preparation of 2-
pyridinylguanidines as urokinase inhibitors. EP 1044967, Oct. 18,
2000.
This work has been funded by the SFI-RFP Grant CHE275
(F.B.), HEA-PRTLI-5 postgraduate award (B.K.), and IRCSET
postgraduate award (D.H.O.). F.B. also thanks the present
support of the European Commission (Marie-Curie Grant,
People FP7, Project Reference: 274988). We are indebted to
(24) Tanatani, A.; Yamaguchi, K.; Azumaya, I.; Fukutomi, R.; Shudo,
K.; Kagechika, H. J. Am. Chem. Soc. 1998, 120, 6433.
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1993, 58, 887.
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́
Prof. Jose Elguero for his comments and suggestions.
Calculations were performed on the IITAC cluster maintained
by the Trinity Centre for High Performance Computing and
the computer cluster maintained by Prof. Ibon Alkorta at the
́
́
́
́
Instituto de Quımica Medica (CSIC, Madrid, Spain).
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