The catalytic potential of 4-guanidinylpyridines in acylation reactions

Article abstract of DOI:10.1055/s-0029-1216830

A series of 3-alkyl-4-guanidinylpyridines with variable alkylation pattern have been synthesized and characterized with respect to their catalytic potential in acylation reactions of alcohols. The ability of the substitution pattern to stabilize acylpyridinium cations, which act as critical intermediates in the catalytic cycle of pyridine-catalyzed acylation reactions, has been assessed at the MP2(FC)/6-31+G(2d,p)//B98/6-31G(d) level of theory and inclusion of solvent effects in chloroform using the PCM continuum solvation model. The most active 4-guanidinylpyridines are among those having the most electron-rich pyridine ring. The influence of the type and concentration of the auxiliary base on the catalytic activity has also been studied. While the change from triethylamine to N,N-diisopropylethylamine as the auxiliary base does not lead to a systematic increase or decrease in the catalytic rates, the complete absence of auxiliary base leads to a 27-fold reduction in reaction rate. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216830

PAPER
2267
The Catalytic Potential of 4-Guanidinylpyridines in Acylation Reactions
C
atalytic
n
P
otential of
g
4-Guanidiny
m
lpyridines inAcyla
a
tionReacti
r
Department of Chemistry and Biochemistry, LMU München, 81377 München, Germany
Fax +49(89)218077738; E-mail: zipse@cup.uni-muenchen.de
Received 3 March 2009
R2
N
R3
Abstract: A series of 3-alkyl-4-guanidinylpyridines with variable
alkylation pattern have been synthesized and characterized with re-
N
N
R4
N
N
N
N
N
spect to their catalytic potential in acylation reactions of alcohols.
The ability of the substitution pattern to stabilize acylpyridinium
cations, which act as critical intermediates in the catalytic cycle of
pyridine-catalyzed acylation reactions, has been assessed at the
MP2(FC)/6-31+G(2d,p)//B98/6-31G(d) level of theory and inclu-
sion of solvent effects in chloroform using the PCM continuum sol-
vation model. The most active 4-guanidinylpyridines are among
those having the most electron-rich pyridine ring. The influence of
the type and concentration of the auxiliary base on the catalytic ac-
tivity has also been studied. While the change from triethylamine to
N,N-diisopropylethylamine as the auxiliary base does not lead to a
systematic increase or decrease in the catalytic rates, the complete
absence of auxiliary base leads to a 27-fold reduction in reaction
rate.
R1
R5
N
N
N
N
1
2
3a
3
Figure 1
tion of alcohols12 have indicated that the structure of the
rate-limiting transition state is closely related to that of the
respective acetylpyridinium cation, and it may thus be ex-
pected that the stability values determined using the equa-
tion given in Scheme 1 are of some relevance also for the
catalytic efficiency of the pyridine catalysts in question.
We are using here results obtained from gas phase calcu-
lations at the MP2(FC)/6-31+G(2d,p)//B98/6-31G(d) lev-
el of theory, whose potential for the accurate prediction of
affinity values of neutral nucleophiles for cationic electro-
philes has recently been documented. Solvent effects in
chloroform have been quantified using the PCM continu-
um solvation model. The results obtained for a variety of
4-guanidinylpyridines are collected in Table 1 and shown
graphically in Figure 2.
Key words: esterification, Lewis bases, ab initio calculations,
kinetics
Donor-substituted pyridines are widely used as catalysts
for group-transfer reactions.1,2 Current developments
focus on enhancing the selectivity of these catalysts in
stereo- and regioselective3–7 transformations. The donor-
substituents employed in these catalysts are usually re-
stricted to dialkylamino groups, as are present in the ‘in-
dustry standard’ 4-(dimethylamino)pyridine (DMAP, 1)
as well as the more reactive 4-pyrrolidinopyridine (PPY,
2) (Figure 1). We study here the utility of guanidinyl sub-
stituents as the electron-donating motif in pyridine-based
catalysts with general structure 3. This idea had previous-
ly been explored by Hassner et al. with pyridine derivative
3a.8 The catalytic activity of 3a, as tested in the acetyla-
tion of tertiary alcohols, was found to be somewhat better
than 1, but slightly inferior to PPY (2). We show here that
this class of compounds is easily accessible through a
modular synthetic strategy and that the catalytic activity
of this class of catalysts can be tuned through proper se-
lection of the alkyl substituents R1–R5.
R
R
ΔH298
+
+
N
N
N
N
4
O
O
Ac-4
Scheme 1
Figure 2 clearly shows that guanidinyl substituents stabi-
lize acetylpyridinium cations even more strongly than di-
alkylamino substituents. Comparison of the results for
pyridines 3a, 3b, and 3c also shows that alkyl groups at-
tached to the 3-position of the pyridine ring enhance the
stability of acetylpyridinium cations with guanidinyl sub-
stituents. The length of the alkyl chain has, in comparison,
only a small effect on the stability values (3b vs 3c). The
two dimethylamino groups present in the guanidinyl sub-
stituents in 3a and 3b are twisted significantly with re-
spect to each other and it was thus anticipated that
formation of a five-membered ring as in 3d would enforce
the planarity of the guanidinyl substituent and thus en-
hance its ability to act as an electron donor. The enhanced
stability value for 3d as compared to 3a (2.6 kJ/mol)
The stability of acetylpyridinium cations as expressed
through the isodesmic equation given in Scheme 1 has
previously been used to assess the effectiveness of the
substitution pattern to stabilize the positive charge and
thus stabilize key intermediates of the catalytic cycle in
acylation reactions.9–11 Recent theoretical studies of the
complete catalytic cycle for the DMAP-catalyzed acetyla-
SYNTHESIS 2009, No. 13, pp 2267–2277
x
x.
x
x
.
2
0
0
9
Advanced online publication: 19.05.2009
DOI: 10.1055/s-0029-1216830; Art ID: Z03409SS
© Georg Thieme Verlag Stuttgart · New York

2268
I. Held et al.
PAPER
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Ph
N
N
N
N
N
N
N
3a
3b
3a
3g
3b
3e
6
–55
–65
–70
–75
–90
–95
–60
–80
–85
–100
ΔH298
[kJ mol–1
]
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Hex
Hex
N
N
N
1
5
N
N
N
N
2
3f
3d
3c
3e
Figure 2
Table 1 Reaction Enthalpies at 298 K (DH298) for the Isodesmic
Equation Given in Scheme 1 as Determined at MP2(FC)/6-
31+G(2d,p)//B98/6-31G(d) Level of Theorya
shows that this effect indeed operates, but that its magni-
tude is quite moderate. Similar conclusions can be made
for other systems as well (3b/3e and 3c/3f). Essentially the
same stability value as for 3f is obtained for chiral guanid-
inylpyridine 3g. The overall charge of the acetyl group in
acetylpyridinium adducts q(Ac) is smaller and the C–N
bond connecting the pyridine ring and the acetyl group
r(C–N) is shorter for pyridines with higher acetyl cation
affinity (Table 1). Aside from acetylation at the pyridine
nitrogen atom, it is, in principle, also possible in 4-guanid-
inylpyridines to use the connecting nitrogen atom at C4 of
the pyridine ring for acetyl group transfer. In systems con-
taining acyclic guanidinyl substituents such as 3a and 3b
the stabilities of the cations formed through acetylation of
this position are quite comparable to those obtained
through acetylation of the pyridine nitrogen. In systems
carrying cyclic guanidinyl groups, this is not the case and
we can thus assume that the pyridyl nitrogen is the lone
center of catalytic activity in these cases. Comparison of
the stability values of all guanidinylpyridines in Figure 2
with those of other known pyridine catalysts (1, 2, 5, and
6) shows that all of the guanidinylpyridines group togeth-
er in a range of less than 10 kJ/mol (67–76 kJ/mol) located
in between DMAP (1) and tricyclic system 5. In light of
the high catalytic activities of the latter compound in acy-
lation reactions, one may thus hope that practically all
guanidinylpyridine catalysts considered here have simi-
larly favorable catalytic activities.
System
DH298 (kJ/mol)
0.0
q(Ac)b,c
+0.368
+0.302
+0.295
+0.273
r(C–N)c (pm)
153.3
4
1
–61.3
148.3
2
–67.6
147.9
3a
–67.5
146.3
(–75.5)
3d
3b
–70.1
+0.270
+0.271
146.7
146.8
–73.0
(–81.0)
3c
3e
–73.8
+0.268
+0.268
146.7
146.6
–75.4
(–66.8)
3f
3g
5
–75.5
–76.0
–82.3
–85.2
+0.266
+0.266
+0.283
+0.276
146.6
146.6
147.3
147.1
6
a Solvent effects have been included through single point calculations
using the PCM/UAHF/RHF/6-31G(d) continuum solvation model.
Values in brackets indicate acetylation at the nitrogen atom in the 4-
position. The overall charge of the acetyl group in acetylpyridinium
cations q(Ac) and the distance between the pyridine nitrogen and
acetyl carbon atom r(C–N) are also given.
Catalyst Synthesis
b In units of elementary charge e.
c Charge and distance parameters are those of the energetically most
favorable conformers.
All new guanidinylpyridine catalysts described here can
be synthesized starting from pyridin-4-amine (7) as out-
lined in Scheme 2.
Synthesis 2009, No. 13, 2267–2277 © Thieme Stuttgart · New York

PAPER
Catalytic Potential of 4-Guanidinylpyridines in Acylation Reactions
2269
of column chromatography operations, typically first on
silica gel and subsequently on basic alumina. The n-hexyl
substituent present in catalysts 3c and 3f appears to reduce
the sensitivity of these compounds to the polar chroma-
tography phases and, thus, strongly facilitates chromato-
graphic purification of these catalysts. That this sequence
can, in principle, also be employed for the synthesis of
chiral guanidinyl catalysts has been demonstrated using
catalyst 3g as an example. The synthesis of catalyst 3g
starts from known proline amide 12 and involves reduc-
tion to the chiral bisamine 13, formation of the thiourea
derivative 14, and, after activation to the corresponding
Vilsmeier salt, coupling with 3-methylpyridin-4-amine
(8) (Scheme 3).15,16 The structure of 14 as determined by
N
N
N
N
N
N
N
N
N
Hex
N
N
N
Cl
Cl
N
3a
3c
3b
N
d
c
10
NH2
NH2
NH2
Hex
b
a
N
N
N
1
N
9
7
8
Cl
Cl
X-ray crystallography is fully compatible with the H
NMR spectroscopic data (see supporting material for fur-
ther information). This sequence closely parallels earlier
efforts by Ishikawa et al. in the synthesis of chiral
guanidines.17
N
g
e
f
11
N
N
N
N
N
N
N
N
N
H
N
H
N
Hex
a
Ph
Ph
N
H
N
H
O
N
N
N
3f
12
13
3d
3e
b
Scheme 2 Synthesis of 4-guanidinylpyridine catalysts. Reagents
and conditions: (a) (i) t-BuCOCl, Et3N, CH2Cl2, 5 h; (ii) BuLi, THF,
–78 to 0 °C, 3 h; (iii) MeI, THF, –78 °C to r.t., 12 h; (iv) 6 M HCl,
reflux, 12 h; 60%; (b) (i) t-BuCOCl, Et3N, CH2Cl2, 5 h; (ii) BuLi,
THF, –78 °C to r.t., 4 h; (iii) n-C6H13Br, THF, –78 °C to r.t., 16 h; (iv)
6 M HCl, reflux, 16 h; 50%; (c) 10, DIPEA, CH2Cl2, r.t., 72 h, 9.5%;
(d) 10, Et3N, CH2Cl2, r.t., 8 h, 52%; (e) 11, DIPEA, CH2Cl2, r.t., 12 h,
18%; (f) 11, DIPEA, CH2Cl2, r.t., 72 h, 18%; (g) 11, DIPEA, CH2Cl2,
r.t., 12 h, 53%.
N
N
N
N
c
N
Ph
Ph
S
N
14
3g
Scheme 3 Synthesis of chiral guanidinylpyridine catalysts 3g.
Reagents and conditions: (a) AlCl3, LiAlH4, THF, 0 °C to reflux, 12
h, quant.; (b) SCCl2, Et3N, 0 °C, 2 h, 31%; (c) (i) (COCl)2, CCl4, 60
°C, 12 h; (ii) DIPEA, 8, CH2Cl2, r.t., 12 h; 60%.
Synthesis of 3-methylpyridin-4-amine (8) involves initial
protection of the amino group in 7 by pivaloylation, ortho-
lithiation with butyllithium, reaction of the pyridyllithium
intermediate with methyl iodide, and hydrolytic removal
of the pivaloyl group.13 A similar sequence using n-hexyl
bromide as the alkylating reagent yields 3-hexylpyridin-
4-amine (9). Vilsmeier salts 10 and 11 were synthesized
following the procedure outlined by Ishikawa et al.14 Con-
densation of salt 10 with pyridin-4-amine (7) yields the
known catalyst 3a. Vilsmeier salt 10 was employed in a
completely analogous approach for the synthesis of cata-
lysts 3b (reaction with aminopyridine 8) and 3c (reaction
with aminopyridine 9). Condensation of 11 with aminopy-
ridines 7–9 yields the guanidinylpyridine catalysts 3d–f.
The yields obtained following these procedures proved
somewhat variable due to the sensitivity of 4-guanidi-
nylpyridines to hydrolytic reaction conditions as well as
the polar stationary phases used during chromatographic
purification. The washing steps with aqueous hydrochlo-
ric acid used in previous syntheses of guanidine bases14
were therefore eliminated from the workup protocol, re-
sulting in improved yields for catalysts 3c and 3f. Analyt-
ically pure samples of the catalysts suitable for subsequent
activity testing could often only be obtained after a series
Catalytic Activity
The catalytic potential of the newly synthesized 4-guanid-
inylpyridines was tested in the acetylation of 1-ethynylcy-
clohexan-1-ol (15) with acetic anhydride (16). This
reaction is performed with alcohol 15 as the limiting re-
agent, using 2.0 equivalents of acetic anhydride (16), 3.0
equivalents of triethylamine as the auxiliary base, and 0.1
equivalents of the catalysts 3a–g. The reaction is moni-
1
tored by H NMR spectroscopy and, therefore, executed
in CDCl3 as the solvent. 1,4-Dioxane was used in selected
cases as internal standard for 1H NMR measurements.
catalyst (0.1 equiv)
Et3N (3.0 equiv)
CDCl3, 23 °C
OH
O
O
O
O
+
O
16
15
Scheme 4 Benchmark reaction used for activity testing of 4-guani-
dinylpyridine catalysts.
Synthesis 2009, No. 13, 2267–2277 © Thieme Stuttgart · New York

2270
I. Held et al.
PAPER
For all catalysts studied here, essentially complete turn-
over is observed without any sign of degradation of cata-
lysts or reaction products (Figure 3). This allows for the
use of a second-order rate law for the quantitative descrip-
tion of the turnover curve and the determination of the
(synthetic) reaction half-life defined as the time required
to turn over 50% of the reactant alcohol (see supporting
material for details). The reaction half-lives obtained for
the known catalysts 1, 2, 5, and 6 in this way are slightly
smaller than those obtained earlier,18 but the second-order
function used here leads to slightly better fits and smaller
residuals for all catalysts in Table 2. The relative ordering
of the catalytic efficiency of these catalysts is, however,
not affected by this change.
Table 2 Reaction Half-Life (t1/2) for the Reaction shown in
Scheme 4 in the Presence of Triethylamine or N,N-Diisopropylethyl-
amine as the Auxiliary Base
Catalyst
Half-life t1/2 (min)
Et3N
DIPEA
3a
3d
1
295 2.1
261 3.7
151 1.7
104 0.5
101 1.4
67 0.1
63 0.1
57 0.7
44 0.5
18 0.1
15 0.1
129 0.6
–
–
3b
3g
2
–
86 0.8
–
Figure 3 Progress of the reaction shown in Scheme 4 in the
presence of guanidinylpyridine catalysts 3 and triethylamine as the
auxiliary base
3c
3e
3f
6
68 0.1
–
spond to the change in auxiliary base in a systematic
manner, showing a small acceleration in some cases and a
small deceleration in others. The largest effects are actu-
ally observed for the least active catalysts 3a, whose ac-
tivity is significantly enhanced in the presence of N,N-
diisopropylethylamine. The question whether auxiliary
bases are needed at all in acylation reactions performed in
low-polarity organic solvents has recently been raised in
several studies. Ishihara et al. found that the acetylation of
secondary alcohols can be promoted with low concentra-
tions of DMAP (1, 0.001 equiv) in heptane as solvent at
room temperature.19 The transformations were also found
to proceed more readily in the complete absence of sol-
vent. Addition of N,N-diisopropylethylamine as the auxil-
iary base accelerated the reactions, but satisfactory
turnover could also be achieved in its absence. Similar ob-
servations had earlier been made by Hassner et al. for the
acetylation of tert-butyl alcohol catalyzed by PPY (2, 0.2
equiv) in carbon tetrachloride using triethylamine as aux-
iliary base,8 and by Lamaty et al. for the acetylation of cy-
clohexanol in low polarity solvents such as dioxane,
carbon tetrachloride, and benzene.20 The reaction of cy-
clic diols with acetic anhydride as catalyzed by peptides in
toluene solution show essentially no influence through
auxiliary bases.21 This was rationalized by the low proton
basicity of the alkylimidazole active sites of the respective
78 0.7
23 0.3
18 0.1
5
The best results are obtained here for the alkyl-substituted
systems 3c, 3e, and 3f. Systems lacking alkyl groups at C3
of the pyridine ring are systematically less active.
This trend is in line with the relative stabilities calculated
for the respective acetylpyridinium cations (Figure 2).
The absolute reactivities of 3e and 3f are, however, signif-
icantly lower as compared to catalysts such as 5 and 6
based on the 4-(dialkylamino)- or 3,4-diaminopyridine
structures, in contrast to the computed stability values.
The activity of catalyst 3a originally studied by Hassner et
al. is somewhat less than that of DMAP (1). This is in con-
trast to the results obtained by Hassner et al., who found
that 3a leads to higher turnover than 1, but lower turnover
than 2, in the acetylation of 1,1-diphenylethanol in toluene
solution. Given the highly basic nature of many guanidine
bases, we anticipated that the catalytic activities deter-
mined here also depend on the nature of the auxiliary
base. Selected catalysts have therefore been studied also
in the presence of N,N-diisopropylethylamine as the aux-
iliary base. The catalysts described in Table 1 do not re-
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PAPER
Catalytic Potential of 4-Guanidinylpyridines in Acylation Reactions
2271
peptides. In order to arrive at a quantitative estimate of the Table 3 Reaction Half-Lives (t1/2) for the Reaction Shown in
Scheme 4 in the Presence of Various Amounts of Triethylamine as
the Auxiliary Base and Catalyst 3c (0.1 equiv)
influence of the auxiliary base, we have studied here the
reaction shown in Scheme 4 in the presence of various
concentrations of triethylamine as the auxiliary base and
catalyst 3c. This latter choice was made due to the good
catalytic performance of 3c and to its low sensitivity to the
type of auxiliary base. The second-order rate law used for
analysis of the reaction progress curves before can effec-
tively be used for all experiments using 1.0–4.0 equiva-
lents of triethylamine relative to the substrate alcohol 15.
In experiments with less than 1.0 equivalent of triethyl-
amine the reactions do not only become much slower, but
are also less well described by the second-order rate equa-
tion, the discrepancy being largest for the reaction lacking
any auxiliary base. Reaction half-life t1/2 has therefore
been determined using a 10th-order polynomial through
the data points for these reactions. The results are shown
in Figure 4 and Table 3.
Et3N (equiv relative to 15)
Half-life t1/2 (min)
0
1696a
313a
107a/113b
66b
0.25
0.5
1.0
2.0
2.72
3.0
3.5
4.0
63b
64b
63b
60b
66b
a Determined using a 10th-order polynomial fit of turnover to reaction
time.
b Determined using a second-order rate law.
the reaction by a factor of 27 in CDCl3 as the solvent. At
least when performed under the conditions chosen here,
we can thus clearly state that omission of the auxiliary
base in the acetylation of tertiary alcohols leads to a dra-
matic reduction in reaction rate.
With the experimentally measured reaction half-life t1/2
for a selection of pyridine-based catalysts in hand
(Table 2), it is possible to quantify the predictive value of
the theoretically calculated relative acylation enthalpies
(Table 1). Under the condition that these acylation enthal-
pies have a direct relation to the respective activation en-
thalpies, a correlation of these enthalpies with ln(1/t1/2)
must be expected (Figure 5). The correlation line shown
in Figure 5 has been derived from all data points describ-
ing acetylation at the pyridine ring and can be quantita-
tively expressed using the equation DH298 = –5.7166 ln(1/
t1/2) – 98.01 kJ/mol; R2 = 0.65.31 Closer inspection of
Figure 5 also reveals that the pyridine catalysts containing
only one nitrogen atom in the electron-donating substitu-
ents (such as DMAP, PPY, and 5) appear to deviate sys-
tematically from those containing more nitrogen atoms.
This may indicate that separate correlations of even better
fidelity exist for each of the catalyst families. The use of
relative acetylation enthalpies DH298 may thus be particu-
larly useful for the optimization of the substitution pattern
of a given catalyst family such as the guanidinylpyridines
studied here.
Figure 4 Progress of the reaction shown in Scheme 4 in the
presence of various amounts of triethylamine as the auxiliary base and
catalyst 3c (0.1 equiv)
The rate of the reaction as characterized by the reaction
half-life is essentially identical in all experiments using
1.0 or more equivalents of the auxiliary base. However,
the reaction rate drops significantly when using lower
concentrations of the auxiliary base, giving the slowest re-
action in its complete absence. Comparison of the half-life
In conclusion, a modular synthetic strategy has been de-
veloped for the preparation of selected 4-guanidinylpy-
ridines. The substitution pattern has been chosen such that
benchmark calculations on the corresponding acetylpyri-
dinium cations indicate the best possible stabilization of
positive charge. The catalytic performance of most of
these catalysts in the acetylation of a tertiary model alco-
hol is higher than those of the commercially available al-
t1/2 determined for the reaction without auxiliary base and
that in the presence of 3.0 equivalents of triethylamine
shows that the presence of the auxiliary base accelerates
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2272
I. Held et al.
PAPER
Figure 5 Correlation of relative acylation enthalpies DH298 as collected in Table 1 with relative reaction rates as defined by ln(1/t1/2
)
acetic acid in order to determine the molarity. Deuterated solvents
and Et3N were freshly distilled under N2 from CaH2. Ac2O was re-
fluxed for 5 h over coarse Mg filings, then fractionally distilled
through a short Vigreux column and stored in a Schlenk flask under
N2. All other chemicals were purchased from commercial suppliers
at the highest available grade and used as such without any further
purification.
cohols DMAP (1) and PPY (2), but not as high as those of
the previously synthesized 3,4-diaminopyridines. While
the catalytic performance of 4-guanidinylpyridines shows
little dependence on the type of auxiliary base used, the
actual omission of auxiliary bases leads to a dramatic re-
duction of catalytic activity.22,23
Kinetic Measurements; General Procedure
All Schlenk flasks used for the reactions and storage of solvents
were kept overnight in a 125 °C hot oven and were afterwards dried
again under high vacuum with a hot air blower. The flasks were
cooled under N2. 1H and 13C NMR were recorded on Varian Mercu-
ry 200 MHz, Varian 300 MHz, Varian Inova 400 MHz, and Varian
600 MHz instruments. NOESY spectra were recorded at 27 °C in
CDCl3. All 1H NMR are referenced to the respective solvent peak.
1H as well as 13C signals were successfully assigned using COSY,
NOESY, HSQC, HMBC, and DEPT NMR experiments. IR spectra
were recorded with a PerkinElmer FT-IR system Spectrum BX for
neat measurement of the sample using ATR techniques. Mass spec-
tra were recorded with a Finnigan MAT 95 using either EI (70 eV)
or CI (isobutane); ESI-MS were recorded with a Thermo Finnigan
LTQ FT instrument. Gas chromatograms were recorded on Varian
3400 using a 25 m CS Supreme-5 capillary column and the Finnigan
MAT 95 mass spectrometer as detector. HPLC spectra were record-
ed at 211 nm on Varian PrepStar model 218 using a Daicel Chiralcel
OD column together with a Daicel guard cartridge and i-PrOH–hex-
anes HPLC grade as supporting eluent at flow rates of 0.5 mL/min
or 1 mL/min. TLC were recorded on silica gel supplied by Merck
KGaA (silica gel 60 F254, 0.2 mm thickness) and basic alumina sup-
plied by Fluka (basic alumina F254, Brockmann activity 1, pH 9.5,
0.2 mm thickness). Flash chromatography was performed on Merck
KGaA silica gel 60 (particle size 0.040–0.063 mm) and Fluka basic
alumina (basic alumina, Brockmann activity 1, pH 9.5, 0.2 mm
thickness, particle size 0.05–0.15 mm) at a pressure of 1.5 bar for
silica gel and 0.5 bar for basic alumina.
Three stock solns were prepared in dry calibrated 5-mL flasks.
Stock soln A: 1.2 M in Ac2O (16, 612.5 mg) and 0.6 M in 1,4-diox-
ane. Stock soln B: 1.8 M in Et3N (910.7 mg) and 0.6 M in 1-ethy-
nylcyclohexan-1-ol (15, 372.5 mg). Stock soln C: 0.06 M in
catalyst.
An N2-flushed dry NMR tube was filled with 0.2 mL each of stock
soln A, B, and C. The NMR tube was fused with a gas burner and
immediately injected into a Varian Mercury 200 MHz NMR. FIDs
were collected in defined time intervals and the obtained multiple
FID 1H NMRs analyzed by integration of the product peaks with a
self-written subroutine using the VNMR software package. The
conversion can either be calculated directly from the intensities of
reactant and product peaks, or by using dioxane as an internal stan-
dard. The following two equations for quantifying the conversion
then apply:
with standard (Equation 1):
(IEster/3)
conversion =
⋅100%
(IDioxane/8)
Equation 1
without standard (Equation 2):
(IEster
)
⋅100%
conversion =
CH2Cl2 was stirred over concd H2SO4 for 24 h, then separated from
the inorganic phase and washed with sat. aq NaHCO3 soln (2 ×) and
distilled under N2 from CaH2. THF was distilled freshly under N2
from NaH and used directly. Toluene and CCl4 were distilled under
N2 from CaH2 and stored over 4 Å molecular sieves under N2 in a
dried Schlenk flask. BuLi, if not fresh, was titrated against diphenyl-
0.25⋅(IAc O + IHNEt OAc + IEster
)
2
3
Equation 2
The plots of conversion versus time were fitted with Equation 3:
Synthesis 2009, No. 13, 2267–2277 © Thieme Stuttgart · New York

PAPER
Catalytic Potential of 4-Guanidinylpyridines in Acylation Reactions
2273
N-(3-Hexylpyridin-4-yl)pivalamide
In a 1000-mL three-necked flask with stopcock and an addition fun-
nel was dissolved N-(pyridin-4-yl)pivalamide (20 g, 112 mmol) in
THF (500 mL) and the soln was cooled to –78 °C. To the stirred
soln was added dropwise 2.5 M BuLi in hexane (44.8 mL,
112 mmol) over a period of 0.5 h. After stirring at –78 °C for 1 h the
soln was allowed to warm up to r.t. and stirred for 4 h. The obtained
brownish slurry was cooled down again to –78 °C and hexyl bro-
mide (15.0 mL, 106 mmol) dissolved in THF (40 mL) was added
dropwise over a period of 1 h. Then the mixture was allowed to
warm up to r.t. and stirred at this temperature for 16 h. The clear
soln was transferred to a separatory funnel and quenched with ice-
H2O (50 mL). The mixture was extracted with CH2Cl2 (3 × 50 mL)
and the combined organic phases were washed with brine and then
dried (MgSO4). The solvent was distilled off under reduced pres-
sure and the yellow crude product was purified on silica gel (10%
isohexane–EtOAc) to afford the product (15.26 g, 52%) as an off-
white oil that solidified upon standing in the fridge; R =
0.28 (EtOAc–isohexane, 10:2).
1
conversion = c1⋅ 1 –
⋅100%
2exp([ROH]0k2 (t–t0) –1
Equation 3
A ‘kinetic’ half-life can be calculated with Equation 4 and a ‘syn-
thetic’ half-life can be calculated with Equation 5. The differences
between these two half-lives are, however, rather small under the
condition that a sufficiently larger number of data points are used
(see supporting material for a detailed discussion).
ln 1.5
t1/2
=
k[ROH]0
Equation 4
0.25 – c1
IR (neat): 3309 (w), 2956 (w), 2927 (m), 2858 (w), 1662 (m),
1576 (s), 1500 (vs), 1458 (sh, s), 1410 (m), 1566 (m), 1294 (m),
1224 (w), 1294 (m), 1192 (m), 1145 (m), 1059 (w), 1026 (w),
923 (w), 834 (m), 753 (w), 723 cm–1 (w).
1H NMR (600 MHz, CDCl3): d = 0.82 (t, 3J = 7.2 Hz, 3 H, H12),
1.26 [s, 9 H, C(CH3)3], 1.27 (m, 6 H, H9, H10, H11), 1.52 (t, 3J =
7.2 Hz, 2 H, H8), 2.51 (t, 3J = 7.2 Hz, 2 H, H7), 7.51 (s, 1 H, NH),
8.09 (d, 3J = 6.0 Hz, 1 H, H5), 8.29 (s, 1 H, H2), 8.30 (d, 3J = 6.0
Hz, 1 H, H6).
13C NMR (150 MHz, CDCl3): d = 14.1 (C12), 27.6 (C3¢, C4¢, C5¢),
29.3 (C7), 29.5 (C8), 22.7, 29.0, 31.7 (C9, C10, C11), 114.7 (C5),
125.4 (Cq, C3), 143.0 (Cq, C4), 149.0 (C6), 150.7 (C2), 176.9 (Cq,
C=O).
GC-MS (EI, r.t. tR = 9.30 min): m/z (%) = 263 (7), 262 (M+, 34), 219
(12), 206 (8), 205 (51), 192 (14), 177 (6), 135 (14), 133 (5), 121
(11), 108 (13), 107 (20), 85 (9), 57 (100), 41 (16).
ln
0.5 – c1
t1/2
=
ROH0k
Equation 5
Measurements with variable amounts of the auxiliary base Et3N
were also fitted with Equation 3 to obtain a second order rate con-
stant. For derivation of Equation 3 see the supporting material and
references 22 and 23.
N-(Pyridin-4-yl)pivalamide
In a 500-mL Schlenk flask was dissolved pyridin-4-amine (7,
4.50 g, 47.9 mmol) in CH2Cl2 (140 mL) and Et3N (6.29 g, 8.64 mL,
62.2 mmol). Under ice-cooling, a soln of pivaloyl chloride (6.04 g,
6.16 mL, 50.0 mmol) in CH2Cl2 (20 mL) was added dropwise over
a period of 2 h. The soln obtained was stirred at r.t. for 5 h and then
transferred to a separatory funnel and washed with sat. aq NaHCO3
(2 × 30 mL). The organic layer was dried (Na2SO4) and filtered and
the solvent was distilled off under reduced pressure to afford the
product (8.3 g, 97%) as a white solid.
HRMS (EI): m/z [M]+ calcd for C16H26N2O: 262.2045; found:
262.2032.
3-Methylpyridin-4-amine (8); Typical Procedure
1H NMR (200 MHz, CDCl3): d = 1.32 [s, 9 H, C(CH3)3], 7.53 (d,
3J = 6.4 Hz, 2 H, H3, H5), 7.55 (br, 1 H, NH), 8.47 (d, 3J = 6.4 Hz,
2 H, H2, H6). The recorded 1H NMR is in agreement with the pub-
lished data.13
A 100-mL round-bottom flask was charged with N-(3-methylpyri-
din-4-yl)pivalamide (1.01 g, 5.31 mmol) and 6 M HCl (20 mL).
The soln was refluxed for 12 h, cooled down to r.t., and then bas-
ified under ice-cooling with 20% aq NaOH to pH >12. The mother
liquor was extracted with CH2Cl2 (3 × 30 mL) and the combined or-
ganic layers were dried (MgSO4). Filtration and distillation of the
solvent via rotary evaporation afforded 8 (0.5 g, 86%) as an off-
white powder; Rf = 0.70 (basic alumina, MeOH–EtOAc, 1:3).
1H NMR (200 MHz, CDCl3): d = 2.10 (s, 3 H, H7), 4.13 (s, 2 H,
NH2), 6.49 (d, 3J = 5.4 Hz, 1 H, H5), 8.10 (s, 1 H, H2), 8.10 (d, 3J =
5.4 Hz, 1 H, H6). The recorded 1H NMR spectrum is in agreement
with published data.13
N-(3-Methylpyridin-4-yl)pivalamide
In a 500-mL 3-necked flask with addition funnel and stopcock was
dissolved N-(pyridin-4-yl)pivalamide (8.9 g, 50 mmol) in THF
(200 mL) and the soln was cooled to –78 °C. To the cooled soln was
added dropwise 2.5 M BuLi in hexane (50 mL, 125 mmol,
2.5 equiv) over a period of 1 h. Then the soln was allowed to warm
up to 0 °C and stirring was continued at this temperature for 3 h. The
obtained slightly brownish slurry was cooled down again to –78 °C
and MeI (3.45 mL, 55 mmol) was added dropwise. After the addi-
tion, the mixture was stirred overnight without cooling and the clear
orange-colored soln was then quenched slowly with demineralized
H2O (200 mL). The mixture was extracted with Et2O (3 × 50 mL)
and the combined organic phases were washed with brine and then
dried (MgSO4). The solvent was distilled off under reduced pres-
sure and the yellow crude product was purified (silica gel, acetone–
isohexane, 3:5) to afford the product (7.49 g, 72%) as a slightly yel-
low oil; R = 0.29 (acetone–isohexane, 3:5).
3-Hexylpyridin-4-amine (9)
Following the typical procedure for 8 using N-(3-hexylpyridin-4-
yl)pivalamide (1.55 g, 5.90 mmol) and 6 M HCl (25 mL) with re-
flux for 16 h afforded 9 (1.02 g, 99%) as an off-white powder.
IR (neat): 3473 (w), 3398 (w), 3123 (m), 2954 (m), 2923 (s),
1654 (s), 1560 (vs), 1565 (sh, m), 1501 (s), 1467 (m), 1434 (m),
1378 (w), 1335 (m), 1307 (w), 1290 (w), 1272 (w), 1229 (w),
1185 (s), 1050 (m), 1028 (w), 868 (m), 829 cm–1 (s).
1H NMR (600 MHz, CDCl3): d = 0.85 (t, 3J = 7.2 Hz, 3 H, H12),
1H NMR (200 MHz, CDCl3): d = 1.33 [s, 9 H, C(CH3)3], 2.22 (s, 3
H, 3-CH3), 7.46 (s, 1 H, NH), 8.04 (d, 3J = 6.0 Hz, 1 H, H5), 8.29 (s,
1 H, H2), 8.32 (d, 3J = 6.0 Hz, 1 H, H6). The recorded 1H NMR is
in agreement with published data.13
3
1.33–1.26 (m, 6 H, H9, H10, H11), 1.55 (quint, J = 7.8 Hz, 2 H,
H8), 2.42 (t, 3J = 7.8 Hz, 2 H, H7), 4.21 (s, 1 H, NH2), 6.46 (d, 3J =
5.4 Hz, 1 H, H5), 8.04 (d, 3J = 5.4 Hz, 1 H, H6), 8.05 (s, 1 H, H2).
Synthesis 2009, No. 13, 2267–2277 © Thieme Stuttgart · New York

2274
I. Held et al.
PAPER
13C NMR (150 MHz, CDCl3): d = 150.9 (Cq, C4), 150.1 (C2), 148.3
(C6), 121.4 (Cq, C3), 109.8 (C5), 31.9, 29.4, 22.8 (C9, C10, C11),
28.7 (C8), 28.4 (C7), 14.2 (C12).
1H NMR (400 MHz, CDCl3): d = 2.07 (s, 3 H, Ar-CH3), 2.69 (s, 12
H, NCH3), 6.33 (d, 3J = 5.6 Hz, 1 H, H5), 8.12 (d, 3J = 5.6 Hz, 1 H,
H6), 8.16 (s, 1 H, H2).
GC-MS (EI, r.t. tR = 9.30 min): m/z (%) = 179 (2), 178 (M+,12), 149
(2), 136 (2), 135 (4), 122 (2), 121 (11), 119 (2), 108 (13), 107 (100),
95 (3), 94 (2), 80 (5), 53 (3), 41 (2).
13C NMR (100 MHz, CDCl3): d = 15.2 (Ar-CH3), 39.5 (NCH3),
115.9 (C5), 124.7 (C3), 147.7 (C2), 150.6 (C6), 157.6 (Cq, C4),
160.1 [Cq, Ar-N=C(NMe2)2].
HRMS (EI): m/z [M]+ calcd for C11H18N2: 178.1470; found:
178.1446.
GC-MS(EI, r.t., tR = 8.15 min): m/z (%) = 207.3 (10), 206.2 (M+,
62), 205.2 (19), 192.2 (10), 191.2 (100), 162.1 (54), 148.1 (17),
135.1 (33), 119.1 (89), 100.1 (13).
[Chloro(dimethylamino)methylene]dimethylammonium Chlo-
ride (10)
HRMS (EI): m/z [M]+ calcd for C11H18N4: 206.1531; found:
206.1533.
1,1,3,3-Tetramethylthiourea (13.22 g, 100 mmol) was dissolved in
toluene (250-mL) in a 3-necked flask attached to an N2-inlet with a
stopcock, reflux condenser, and rubber septum. The mixture was
heated to 80 °C, oxalyl chloride (11 mL, 120 mmol) was slowly
added and the mixture was heated to reflux for 4 h. After 1 h, a solid
precipitate was formed and the initially yellow soln turned brown.
After 4 h the mixture was allowed to cool down to r.t. and the
formed precipitate was Schlenk filtered, washed with anhyd toluene
(10 mL) and dried in vacuo to afford 10 (11.9 g, 70%) as a faint
brown solid. Vilsmeyer salt 10 was used immediately for further re-
actions, because of its hygroscopic properties.
N-(1,3-Dimethylimidazolidin-2-ylidene)-3-methylpyridin-4-
amine (3e)
Following the typical procedure for 3b using 11 (1.00 g,
9.42 mmol), DIPEA (3.38 mL, 19.7 mmol), and CH2Cl2 (20 mL)
and 8 (1.59 g, 8.43 mmol). The soln was poured into 5% aq HCl
(100 mL) and made basic to pH 12 with 2 M NaOH. The crude
product was purified via flash chromatography (1. silica gel,
(CHCl3–MeOH–Et3N, 40:1:2; 2. basic alumina, EtOAc–MeOH,
20:1) to afford 3e (0.34 g, 18%) as a white solid; R = 0.85 (silica gel,
CHCl3–MeOH–Et3N, 40:1:2), R = 0.40 (basic alumina, EtOAc–
MeOH, 20:1).
1H NMR (200 MHz, CDCl3): d = 3.61 (s, 12 H, H4, H5). The re-
corded 1H NMR is in agreement with published data.25
IR (neat): 2941 (m), 2856 (m), 1624 (s), 1573 (s), 1534 (m),
1486 (s), 1440 (s), 1416 (s), 1391 (vs), 1324 (w), 1307 (w),
1279 (s), 1235 (s), 1187 (s), 1124 (m), 1073 (w), 1052 (w),
1034 (s), 989 (m), 970 (m), 953 (w), 921 (w), 884 (s), 805 (s),
791 (m), 764 (m), 728 (m), 690 cm–1 (m).
1H NMR (600 MHz, CDCl3): d = 2.10 (s, 3 H, CH3), 2.63 (s, 6 H,
NCH3), 3.32 (s, 4 H, H4¢, H5¢), 6.64 (d, 3J = 5.4 Hz, 1 H, H5), 8.13
(d, 3J = 5.4 Hz, 1 H, H6), 8.17 (s, 1 H, H2).
13C NMR (75 MHz, CDCl3): d = 15.8 (Ar-CH3), 35.2 (NCH3), 48.7
(C4¢, C5¢), 117.2 (C5), 125.8 (C3), 147.9 (C6), 150.8 (C2), 155.8
(Cq, C2¢), 156.5 (Cq, C4).
GC-MS (EI, r.t., tR = 8.77 min): m/z (%) = 205.2 (13), 204.2 (M+
100), 203.2 (52.5), 190.2 (10), 189.2 (79), 188.2 (4), 175.2 (3),
161.2 (6), 160.2 (5), 148.2 (6), 147.2 (4), 146.2 (8), 133.2 (4),
132.2 (8), 119.2 (9), 107.2 (5), 98.2 (18), 92.1 (4), 69.1 (10),
65.1 (6), 57.1 (4), 56.1 (6), 44.1 (6), 43.1 (4), 42.0 (13).
2-Chloro-1,3-dimethyl-4,5-dihydro-3H-imidazolium Chloride
(11)
1,3-Dimethylimidazolidin-2-one (5.19 mL, 48.0 mmol) was dis-
solved in CCl4 (30 mL) in a 3-necked flask attached to an N2-inlet
with stopcock, reflux condenser, and rubber septum. Oxalyl chlo-
ride (4.32 mL, 57.6 mmol) was added over 20 min at r.t. under vig-
orous stirring. The mixture was held overnight at 60 °C. The solid
precipitate was Schlenk filtered, washed with CCl4 (2 × 10 mL), and
dried in vacuo to afford 11 (6.10 g, 75%) as a brown solid.
Vilsmeyer salt 11 was used immediately for further reactions, be-
cause of its hygroscopic properties.
1H NMR (200 MHz, CDCl3): d = 3.33 (s, 6 H, H6, H7), 4.35 (s, 4
H, H4, H5). The recorded 1H NMR spectrum is in agreement with
published data.14
1,1,3,3-Tetramethyl-2-(3-methylpyridin-4-yl)guanidine (3b);
Typical Procedure
HRMS (EI): m/z [M]+ calcd for C11H16N4: 204.1350; found:
204.1359.
Compound 10 (1.00 g, 9.42 mmol) and DIPEA (3.38 mL,
19.7 mmol) were dissolved in CH2Cl2 (20 mL). To this soln 8
(1.59 g, 8.43 mmol) was added and the mixture was stirred at r.t. for
72 h. The brown soln turned red at this point. Afterwards the soln
was poured into 1 M HCl (100 mL) and then transferred to a sepa-
ratory funnel and extracted with CHCl3 (3 × 50 mL). The organic
phase was discarded and the aqueous phase basified to pH 11 with
2 M NaOH. The basified aqueous phase was extracted with CH2Cl2
(3 × 50 mL), the combined organic extracts were dried (Na2SO4)
and filtered, and the solvent was distilled off under reduced pres-
sure. The crude product was purified by flash chromatography (1.
silica gel, (CHCl3–MeOH–Et3N, 20:1:2; 2. basic alumina, EtOAc–
MeOH, 20:1) to afford 3b (0.14 g, 9.5%) as a faint yellow crystal-
line solid; R = 0.95 (silica gel, CHCl3–MeOH–Et3N, 20:1:2); R =
0.40 (basic alumina, EtOAc–MeOH, 20:1).
N-(1,3-Dimethylimidazolidin-2-ylidene)-3-hexylpyridin-4-
amine (3f)
In a 500-mL three-necked flask with stopcock, reflux condenser,
and addition funnel was dissolved 1,3-dimethylimidazolidin-2-one
(17.31 mL, 18.26 g, 160 mmol) in CCl4 (80 mL). To this soln was
added dropwise under ice-cooling oxalyl chloride (14.4 mL, 21.6 g,
170 mmol) over a period of 0.5 h. The ice bath was then removed
and the mixture was heated to reflux for 3 h. The mixture was
cooled to r.t. and the reflux condenser replaced by a Claisen bridge.
The excess oxalyl chloride and the solvent was distilled off under
reduced pressure. The dry orange solid in the reaction flask was tak-
en up in CH2Cl2 (100 mL) and cooled to 0 °C. To the soln was added
in this order DIPEA (27.4 mL, 20.6 g, 160 mmol) and 9 (7.13 g,
40 mmol). The purple-colored mixture was stirred at r.t. for 12 h
and then quenched with ice-H2O (20 mL). The mixture was basified
with 40% aq NaOH soln to pH >12 and then extracted with CH2Cl2
(3 × 50 mL). The combined organic layers were dried (MgSO4) and
filtered and the solvent was distilled off under reduced pressure.
The crude product obtained was purified by chromatography (1. sil-
ica gel, EtOAc–isohexanes–Et3N, 10:10:1; 2. basic alumina,
CHCl3–MeOH, 40:1) to afford 3f (5.82 g, 53%) as a slightly yellow
IR (neat): 3014 (w), 2980 (w), 2941 (m), 2876 (w), 1595 (sh),
1549 (vs, sh), 1510 (vs), 1483 (vs), 1462 (vs), 1402 (vs), 1381 (vs),
1349 (s, sh), 1305 (w), 1281 (w), 1244 (w), 1229 (m), 1190 (m),
1166 (w), 1143 (vs), 1109 (w), 1068 (m), 1055 (m), 1024 (s), 989
(s), 922 (m), 868 (m), 841 (vs), 788 (m), 771 (m), 743 (m), 695
cm–1 (m).
Synthesis 2009, No. 13, 2267–2277 © Thieme Stuttgart · New York

PAPER
Catalytic Potential of 4-Guanidinylpyridines in Acylation Reactions
2275
oil, which solidified upon standing in the freezer; Rf = 0.18 (EtOAc–
ganic phases were dried (MgSO4). After filtration the solvent was
isohexanes–Et3N, 10:10:1).
distilled off under reduced pressure and the crude product was puri-
fied by flash chromatography (silica gel, (EtOAc–Et3N, 10:1) to af-
ford 3c (2.00 g, 52%) as a faint yellow oil; Rf = 0.36 (EtOAc–Et3N,
10:1).
IR (neat): 2921 (m), 2850 (m), 1630 (s), 1572 (vs), 1537 (s),
1481 (m), 1440 (m), 1414 (m), 1395 (m), 1280 (m), 1236 (m),
1185 (s), 1074 (w), 1032 (m), 970 (m), 894 (m), 832 (m), 723 (w),
697 (m), 654 cm–1 (m).
IR (neat): 2923 (m), 2854 (w), 1598 (m), 1556 (s), 1538 (s), 1506
(s), 1480 (s), 1423 (m), 1412 (sh, m), 1378 (s), 1280 (w), 1233 (w),
1187 (w), 1138 (s), 1059 (m), 1022 (m), 923 (w), 886 (w), 870 (m),
834 (m), 772 (m), 751 (w), 723 (w), 697 cm–1 (m).
1H NMR (600 MHz, CDCl3): d = 0.80 (t, J = 7.8 Hz, 3 H, H12),
3
3
1.27–1.20 (m, 6 H, H9, H10, H11), 1.51 (quint, J = 7.2 Hz, 2 H,
H8), 2.46 (t, 3J = 7.2 Hz, 2 H, H7), 2.56 (s, 6 H, NCH3), 3.24 (s, 4
H, H4¢, H5¢), 6.54 (d, 3J = 5.4 Hz, 1 H, H5), 8.03 (d, 3J = 5.4 Hz, 1
H, H6), 8.08 (s, 1 H, H2).
3
1H NMR (600 MHz, CDCl3): d = 0.86 (t, J = 7.2 Hz, 3 H, H12),
3
1.25–1.31 (m, 6 H, H9, H10, H11), 1.57 (quint, J = 7.8 Hz, 2 H,
H8), 2.48 (t, 3J = 7.8 Hz, 2 H, H7), 2.68 [s, 12 H, N(CH3)2], 6.24 (d,
3J = 5.4 Hz, 1 H, H5), 8.09 (d, 3J = 5.4 Hz, 1 H, H6), 8.14 (s, 1 H,
H2).
13C NMR (150 MHz, CDCl3): d = 14.3 (C12), 29.1 (C7), 29.6 (C8),
31.9, 29.4, 22.8 (C9, C10, C11), 34.9 (N-CH3), 48.5 (C4¢, C5¢),
117.0 (C5), 129.9 (Cq, C3), 147.4 (C6), 150.2 (C2), 155.8 (Cq, C2¢),
155.9 (Cq, C4).
13C NMR (150 MHz, CDCl3): d = 14.0 (C12), 22.5 (C11), 28.9,
29.0, 29.2 (C7, C8, C9), 31.7 (C10), 39.5 [N(CH3)2], 115.7 (C5),
129.1 (Cq, C3), 147.3 (C6), 149.9 (C2), 156.8 (Cq, C4), 159.7 [Cq,
N=C(NMe2)2].
GC-MS(EI, r.t. tR = 10.44 min): m/z (%) = 276.3 (8), 275.3 (47),
274.3 (61), 273.3 (21), 259.3 (6), 245.3 (11), 232.2 (13),
231.2 (79), 218.2 (18), 217.2 (100), 205 (8), 204 (73), 203 (67),
202 (5), 201 (7), 190 (10), 189 (81), 188.2 (8), 187.2 (10),
174.2 (7), 160.1 (6), 98.1 (14), 58.1 (7), 56.1 (7), 42 (6).
HRMS(EI): m/z [M]+ calcd for C16H26N4: 274.2157; found:
274.2159.
GC-MS (EI, r.t., tR = 0.42 min): m/z (%) 276 (56), 275 (27), 261
(14), 233 (40), 232 (38), 219 (49), 206 (60), 205 (34), 191 (100),
189 (37), 188 (17), 176 (15), 174 (36), 162 (60), 146 (14), 145 (17),
132 (14), 131 (28), 119 (34), 118 (16), 100 (19), 92 (17), 85 (14), 71
(17), 44 (34).
N-(1,3-Dimethylimidazolidin-2-ylidene)pyridin-4-amine (3d)
1,3-Dimethylimidazolidin-2-one (1.70 g, 15 mmol) was dissolved
in CCl4 (10 mL) and oxalyl chloride (2.2 g, 1.5 mL, 17 mmol) was
added dropwise under ice-cooling within a time period of 10 min
via syringe. After 16 h reflux, the mixture was cooled down to r.t.
and the solid that precipitated filtered off under N2. The orange
powder was washed with CCl4 (5 mL) and afterwards transferred to
a 50-mL Schlenk flask. The powder was dissolved with CH2Cl2
(30 mL) and under ice-cooling DIPEA (2.5 g, 3.3 mL, 19 mmol)
was added. After stirring for 20 min, pyridin-4-amine (7, 1.41 g,
15 mmol) was added and the mixture was stirred at r.t. for 12 h. Di-
rect purification by column chromatography (silica gel, (CHCl3–
MeOH–Et3N, 40:1:2) yielded 3d (0.5 g, 18%) as a clear oil; Rf =
0.70 (CHCl3–MeOH–Et3N, 40:1:2).
HRMS (EI): m/z [M]+ calcd for C16H28N4: 276.2314; found:
276.2318.
tert-Butyl (S)-2-(Benzylcarbamoyl)pyrrolidine-1-carboxylate
L-Boc-proline (15.05 g, 70.0 mmol) was dissolved in CH2Cl2
(60 mL) and Et3N (10.0 mL, 72.2 mmol) was added. Under ice-
cooling isobutyl chloroformate (9.13 mL, 70.4 mmol) was added
dropwise. When the addition was complete, BnNH2 (7.50 g,
70.0 mmol) was added and the ice bath was removed. The reaction
was monitored by TLC (silica gel, isohexane–EtOAc–Et3N, 4:4:1,
Rf = 0.7). After termination of the reaction, the soln was transferred
to a separatory funnel, washed with 5% aq Na2CO3, and dried
(Na2SO4). Filtration of the reaction soln and removal of the solvent
under reduced pressure afforded the product (21.2 g, 99%) as a
white solid, which was used without further purification; Rf = 0.65
(EtOAc–isohexane–Et3N, 4:4:1).
IR (neat): 2941 (m, CH3), 2857 (m, CH2), 1619 (s, C=N), 1569 (s),
1485 (s), 1443 (s), 1413 (s), 1391 (s), 1324 (m), 1277 (s), 1211 (s),
1069 (m), 1031 (s), 986 (s), 967 (s), 877 (m), 838 (s), 755 (s), 731
(s), 699 (s), 650 cm–1 (s).
IR (neat): 3312 (m, br, NH), 2977 (m, Ph-H), 2872 (m, Ph-H), 1681
(s, C=O), 1652 (s, C=O/NH), 1527 (m), 1392 (s), 1370 (m), 1247
(m), 1127 (m), 1016 (s), 920 (w), 871 (s), 798 (s), 766 (m), 723 (m),
692 (m), 652 cm–1 (m).
1H NMR (400 MHz, DMSO-d6): d = 1.33 [s, 9 H, C(CH3)3], 1.79
(m, 3 H, H4, H3), 2.09 (s, 1 H, H4), 3.12 (s, 1 H, HN+-Boc), 3.34
(m, 2 H, H2), 4.24 (m, 3 H, Ph-CH2, H5), 7.27–7.18 (m, 5 H, CHAr),
8.11 (s, 1 H, CONH). The recorded 1H NMR spectrum is in agree-
ment with published data.16
1H NMR (300 MHz, CDCl3): d = 2.65 (s, 6 H, NCH3), 3.33 (s, 4 H,
H4¢, H5¢), 6.60 (d, 3J = 6.3 Hz, 2 H, H5, H3), 8.20 (d, 3J = 6.3 Hz, 2
1
H, H6, H2). The recorded H NMR spectrum compares favorably
with published data.26
13C NMR (75 MHz, CDCl3): d = 35.3 (NCH3), 48.5 (C4¢, C5¢),
117.7 (C3, C5), 149.9 (C2, C6), 157.7 (Cq, C2¢, C4).
GC-MS(EI, r.t., tR = 1.22 min): m/z (%) = 191 (11), 190 (94), 189
(100), 162 (6), 161 (9), 134 (14), 98 (14), 78 (10), 69 (13), 57 (7),
56 (6), 51 (9), 44 (6), 43 (7), 42 (16).
(S)-N-Benzylpyrrolidine-2-carboxamide (12)
tert-Butyl
(S)-2-(benzylcarbamoyl)pyrrolidine-1-carboxylate
(21.2 g, 69.7 mmol) was dissolved in CH2Cl2 (50 mL) and TFA
(20 mL, 269 mmol) was added. The soln was stirred until comple-
tion of the reaction at r.t. (TLC monitoring, isohexanes–EtOAc–
Et3N, 4:4:1). The solvent was distilled off under vacuum to afford
12 (14.2 g) as the crude product, which was used without further pu-
rification; Rf = 0.5 (EtOAc–isohexanes–Et3N, 4:4:1).
2-(3-Hexylpyridin-4-yl)-1,1,3,3-tetramethylguanidine (3c)
A 250-mL three-necked flask attached to an N2-inlet with stopcock
and reflux condenser was charged with tetramethylthiourea (7.41 g,
56.1 mmol) and toluene (40 mL). To the soln was slowly added ox-
alyl chloride (5.69 mL, 67.31 mmol) and then it was heated to re-
flux for 2 h. The solvent was then distilled off in vacuo and the
obtained yellow solid taken up in anhyd CH2Cl2 (24 mL). To the
soln was added, under ice-cooling, Et3N (9.38 mL, 67.31 mmol)
and 9 (2.5 g, 14.02 mmol). The mixture was stirred at r.t. for 8 h and
then diluted with CH2Cl2 (20 mL) and transferred to a separatory
funnel. Cold H2O (10 mL) was added and the organic phase sepa-
rated. The aqueous phase was basified with 40% aq NaOH up to
>pH 12 and extracted with CH2Cl2 (3 × 20 mL); the combined or-
+
IR (neat): 3190 (m), 3061 (m), 2832 (m, R2NH2 ), 2714 (m,
+
+
R2NH2 ), 2547 (m, R2NH2 ), 1670 (s, C=O), 1587 (m, Ph), 1563 (m,
NH), 1383 (m), 1303 (m), 1263 (m), 1231 (m), 1078 (w), 1050 (w),
1003 (w), 943 (w), 925 (w), 910 (w), 803 (m), 772 (w), 755 (s), 730
(m), 696 (s), 620 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 1.71 (m, 2 H, H3), 1.91 (m, 1 H,
H4), 2.13 (m, 1 H, H4), 2.76 (s, 1 H, NH), 2.88 (m, 1 H, H2), 3.00
Synthesis 2009, No. 13, 2267–2277 © Thieme Stuttgart · New York

2276
I. Held et al.
PAPER
(S)-N-(2-Benzylhexahydro-3H-pyrrolo[1,2-c]imidazol-3-
(m, 1 H, H2), 3.78 (m, 1 H, H5), 4.39 (d, 2 H, Ph-CH2), 7.30 (m, 5
H, HPh), 8.07 (s, 1 H, NH).
ylidene)-3-methylpyridin-4-amine (3g)
A Schlenk flask was charged with CCl4 (20 mL) and 14 (0.75 g,
3.23 mmol). The soln was cooled to 0 °C and oxalyl chloride
(0.52 g, 4.10 mmol) was added. The ice bath was removed and the
mixture was heated to 60 °C for 12 h. The mixture was then allowed
to cool to r.t. and the solvents as well as the excess oxalyl chloride
were removed under reduced pressure. The dark solid obtained was
taken up in CH2Cl2 (30 mL) and, under ice cooling, DIPEA
(1.15 mL, 6.71 mL) was added. To the soln thus obtained was add-
ed 8 (0.38 g, 3.52 mmol), the ice bath was removed and the soln was
stirred at r.t. for 12 h. The solvent then was distilled off and the
crude product was purified twice by flash chromatography (1. silica
gel, CHCl3–MeOH–Et3N, 20:1:2; 2. silica gel, CHCl3–isohexanes–
Et3N, 4:4:1) to afford 3g (0.6 g, 60%) as a slightly yellow solid;
Rf = 0.85 (CHCl3–MeOH–Et3N, 20:1:2); Rf = 0.50 (CHCl3–isohex-
anes–Et3N, 4:4:1).
13C NMR (100 MHz, CDCl3): d = 26.4 (C3), 30.9 (C4), 42.8 (C8),
47.4 (C2), 60.8 (C5), 128.0 (m, Ph), 139.3 (s, Ph), 174.9 (CONH).
GC-MS (EI, r.t., tR = 8.96 min): m/z (%) = 205.3 (1), 106.2 (3),
92.2 (1), 91.2 (12), 77.2 (1), 70.2 (100), 69.2 (1), 68.2 (4), 65.1 (2),
51.1 (1), 43.1 (1), 41.0 (3), 41.0 (1).
(S)-N-Benzylpyrrolidin-2-ylmethanamine (13)
AlCl3 (1.56 g) was added to THF (40 mL) under ice cooling. After
stirring at r.t. for 0.5 h, the suspension was cooled to 0 °C again and
LiAlH4 (0.89 g, 23.4 mmol) was added in small portions. After the
addition of 12 (2.00 g, 9.80 mmol), the ice bath was removed and
the mixture refluxed for 12 h. The mixture was then allowed to cool
down to r.t. and poured slowly into ice-H2O. The aqueous layer was
basified with 20% aq NaOH. The inorganic precipitate was filtered
off by suction and washed with CH2Cl2 (2 × 20 mL). The mother li-
quor was extracted with CH2Cl2 (3 × 30 mL), the combined organic
extracts were dried (Na2SO4), and solvent was distilled off under re-
duced pressure after filtration. The product 13 obtained (1.90 g,
100%) was used without further purification.
IR (neat): 3060 (w, Ph), 3027 (w, Ph), 2964 (w), 2940 (w), 1619 (s,
C=N), 1566 (s), 1539 (m), 1440 (m), 1276 (m), 1188 (m), 1125 (w),
1092 (w), 1075 (w), 1058 (w), 980 (w), 878 (m), 837 (m), 792 (w),
736 (w), 700 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 1.30 (m, 1 H, H7), 1.62 (m, 1 H,
H6), 1.72 (m, 1 H, H6), 1.85 (m, 1 H, H7), 2.05 (s, 3 H, 3¢-CH3),
2.68 (m, 2 H, H5), 3.09 (m, 1 H, H1), 3.37 (m, 1 H, H1), 3.73 (m, 1
H, H7a), 4.43 (m, 2 H, Ph-CH2), 6.70 (d, 3J = 5.2 Hz, 1 H, H5¢), 7.21
(m, 5 H, HPh), 8.00 (d, 3J = 5.2 Hz, 1 H, H6¢), 8.04 (s, H 1, H1¢).
13C NMR (100 MHz, CDCl3): d = 15.5 (C3¢, CH3), 26.6 (C6), 32.0
(C7), 49.2 (Ph-CH2), 49.6 (C5), 49.7 (C1), 59.4 (C7a), 116.9 (C5¢),
126.7 (C4¢), 128.2 (m, CPh), 137.2 (CPh), 147.8 (C6), 150.7 (C2¢),
156.9 (C3¢), 158.1 (N2C=N).
MS (EI) m/z (%) = 307.2 (11), 306.2 (M+, 50), 305.2 (38), 292.1
(20), 291.1 (100), 222.0 (4), 215.1 (4), 201.0 (4), 187.0 (9),
148.0 (5), 134.0 (7), 131.9 (7), 130.9 (11), 118.9 (13), 117.9 (4),
116.9 (5), 104.0 (4), 93 (5), 92.0 (9), 91.0 (38), 84 (6), 70.0 (8),
65.0 (11), 41 (7).
IR (neat): 3189 (w, Ph-H), 3062 (w, Ph-H), 2961 (w), 2833 (w,
R2N+H2), 2714 (w, R2N+H2), 2638 (w, R2N+H2), 1671 (s), 1565 (m,
NH), 1492 (w), 1453 (w), 1384 (w), 1343 (w), 1303 (w), 1263 (m),
1233 (m), 1079 (w), 755 (m), 732 (m, Ph), 696 (s, Ph), 672 cm–1 (m,
Ph).
1H NMR (600 MHz, CDCl3): d = 1.60 (m, 2 H, H3), 1.84 (m, 1 H,
H4), 2.04 (m, 1 H, H4), 2.82 (m, 4 H, H6, H2), 3.66 (m, 1 H, H5),
4.32 (m, 2 H, PhCH2), 7.19 (m, 5 H, HPh), 7.97 (s, 1 H, 7-NH).
13C NMR (150 MHz, CDCl3): d = 26.4 (C3), 31.0 (C4), 43.0 (C8),
47.4 (C6, C2), 60.7 (C5), 128.0 (CPh), 138.9 (CPh).
LC-HRMS (ESI): m/z [M + H]+ calcd for C12H19N2: 191.1543;
found: 191.1546.
(S)-2-Benzylhexahydro-3H-pyrrolo[1,2-c]imidazole-3-thione
(14)
HRMS(EI): m/z [M]+ calcd for C19H22N4: 306.1844; found:
306.1848.
Compound 13 (1.30 g, 6.84 mmol) was dissolved in CH2Cl2 and
Et3N (1.99 mL, 14.3 mmol) was added. The soln was cooled to 0 °C
and upon dropwise addition of thiophosgene (0.86 g, 7.48 mmol)
via syringe the soln turned red. The ice bath was removed and stir-
ring was continued for 2 h. The solvent was then distilled off under
reduced pressure and the crude product was purified by column
chromatography (silica gel, EtOAc–isohexane, 1:2) to afford 14 as
a slightly yellow solid. The purity of thiourea 14 can be increase by
recrystallization (MeOH or 10% MeOH–CHCl3) to give the product
(0.49 g, 31%) as a slightly yellow crystalline solid.
Computational Details
Geometry optimizations have been performed at the B98/6-31G(d)
level of theory. Thermochemical corrections to enthalpies at 298.15
K have been calculated from a harmonic vibrational frequency anal-
ysis at the same level using the rigid rotor/harmonic oscillator mod-
el. Single point energies have then been calculated at the MP2(FC)/
6-31+G(2d,p) level. Combination of these latter energies with the
thermochemical corrections from B98/6-31G(d) level yields the gas
phase H298 values cited in the manuscript. In conformationally flex-
ible systems, enthalpies have been calculated as Boltzmann-
averaged values over all available conformers. Solvent effects in
CHCl3 have been estimated using the PCM continuum solvation
model in its IEF-PCM implementation27–30 in combination with the
UAHF radii at the RHF/6-31G(d) level.31 All calculations have been
performed with the Gaussian 03 software package.24
IR (neat): 2954 (m), 2931 (m), 2891 (m), 2867 (m), 1659 (m), 1603
(w), 1491 (s), 1452 (s), 1385 (s), 1357 (m), 1302 (s), 1266 (s), 1226
(s), 1199 (s), 1099 (m), 1078 (m), 909 (m), 875 (m), 674 (m), 699
(s), 649 cm–1 (s).
1H NMR (400 MHz, CDCl3): d = 1.31 (m, 1 H, H7) 1.90 (m, 3 H,
H6, H7), 3.33 (m, 2 H, H1, H5), 3.59 (m, 1 H, H5), 3.86 (m, 1 H,
H7a), 4.05 (m, 1 H, H1), 4.78 (m, 2 H, Ph-CH2), 7.24 (m, 5 H,
CHAr).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
13C NMR (100 MHz, CDCl3): d = 186.6 (C=S), 136.8 (CPh), 127.9
(CPh), 59.8 (C7a), 51.3 (C5), 51.2 (Ph-CH2), 48.6 (C1), 31.0 (C7),
24.8 (C6).
Acknowledgment
GC-MS (EI, r.t., tR = 10.29 min): m/z (%) = 234 (5), 233 (94),
232 (100), 231 (17), 199 (10), 154 (3), 148 (3), 147 (5), 140 (20),
130 (12), 104 (7), 96 (3), 91 (3), 90 (35), 88 (3), 84 (10), 82 (6),
77 (3), 72 (5), 70 (4), 69 (7), 68 (3), 65 (9), 55 (5), 41 (11).
Financial support for this project by the Deutsche Forschungsge-
meinschaft through the focus program SPP 1179 ‘organocatalysis’
is gratefully acknowledged.
HRMS (EI): m/z [M]+ calcd for C13H16N2S: 232.1034; found:
232.1023.
Synthesis 2009, No. 13, 2267–2277 © Thieme Stuttgart · New York

PAPER
Catalytic Potential of 4-Guanidinylpyridines in Acylation Reactions
2277
(14) Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 6984.
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Synthesis 2009, No. 13, 2267–2277 © Thieme Stuttgart · New York