Modular design of pyridine-based acyl-transfer catalysts

Article abstract of DOI:10.1055/s-2007-965973

Derivatives of 3,4-diaminopyridine have been synthesized and studied as catalysts for acyl-transfer reactions. The design of these catalysts is guided by the stability of their acetyl intermediates as determined through theoretical calculations at the B3LYP/6-311 + G(d,p)//B3LYP/6-31G(d) level of theory. The most promising catalysts have been synthesized through a three- to five-step synthesis starting from 3,4-diaminopyridine. The catalytic activity has been determined for the acylation of 1-ethynylcyclohexanol with acetic anhydride at 23°C and with isobutyric anhydride at 40°C. For both reactions, the catalytic activity depends dramatically on the substitution pattern of the diaminopyridines. Best results are obtained with catalysts containing alkyl substituents at both amine nitrogens. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-965973

PAPER
1185
Modular Design of Pyridine-Based Acyl-Transfer Catalysts
3
, 4-Diam
n
inopyridine
g
as
H
ighly A
m
ctive
A
cylation Ca
a
Department Chemie und Biochemie, LMU München, Butenandtstraße 5-13, 81377 München, Germany
Fax +49(89)218077738; E-mail: zipse@cup.uni-muenchen.de
Received 24 January 2007
However, experimentation has so far concentrated mainly
on maximizing the success of stereodifferentiating pro-
cesses, and it has therefore remained unclear in how far
the variation of the substituents attached to the C3 posi-
Abstract: Derivatives of 3,4-diaminopyridine have been synthe-
sized and studied as catalysts for acyl-transfer reactions. The design
of these catalysts is guided by the stability of their acetyl intermedi-
ates as determined through theoretical calculations at the B3LYP/6-
311 + G(d,p)//B3LYP/6-31G(d) level of theory. The most promis- tion of pyridines affect the catalytic activity in absolute
ing catalysts have been synthesized through a three- to five-step
rate terms. Very recently Han and co-workers have de-
synthesis starting from 3,4-diaminopyridine. The catalytic activity
scribed highly active catalysts based on the 3,4-diami-
has been determined for the acylation of 1-ethynylcyclohexanol
nopyridine skeleton 3,10 (Figure 1) prompting us to
with acetic anhydride at 23 °C and with isobutyric anhydride at
describe our own results on this class of compounds.
40 °C. For both reactions, the catalytic activity depends dramatical-
ly on the substitution pattern of the diaminopyridines. Best results
are obtained with catalysts containing alkyl substituents at both
amine nitrogens.
R1
R2
N
N
N
R3
N
Key words: catalysis, nucleophilic pyridines, acylation, alcohols
R4
N
N
N
Donor-substituted pyridines play an important role as nu-
cleophilic catalysts for a variety of synthetically important
transformations such as the acylation of alcohols, amines,
and enolates.1,2 More recently major advances have been
made in kinetic resolution experiments using appropriate-
ly substituted derivatives of DMAP [(4-dimethylami-
no)pyridine, 1] or PPY [(4-pyrrolidino)pyridine, 2].2–8
Despite these efforts, the current status of the field is
somewhat uneven, providing multiple effective solutions
for some problems (e.g., the kinetic resolution of second-
ary alcohols), but leaving other synthetic problems un-
solved (e.g., the kinetic resolution of primary or tertiary
alcohols). In this situation, the development of a modular
concept for the design of new catalysts is highly desirable,
because it allows for the broad variation of the catalyst
structure within one synthetic strategy. Solutions to this
problem have recently been provided by Miller et al. in
the development of peptide-based catalysts with imida-
zole as the active nucleophilic center.2d,9 Peptides are also
the variable component in modified versions of PPY (2)
developed by Kawabata et al. and by Campbell et al.3,4 In
all of these cases the peptide side chain influences the
course of the reaction through making additional contacts
to the substrates in the rate-limiting step of the catalytic
cycle. However, the character of the nucleophilic center
remains largely unaffected by these side chain variations.
The modular design of 3-substituted derivatives of 1 and
2 (Figure 1) by several groups has the potential to modify
both the nucleophilicity of the pyridine nucleus as well as
the asymmetry of the two faces of the pyridine ring.4–8
1
2
3
Figure 1 Aminopyridines 1–3
Theoretical Considerations
Earlier studies on the catalytic potential of donor-substi-
tuted pyridines in acylation reactions have highlighted the
relative stability of acylpyridinium cations as a qualitative
criterion for catalyst activity.11,12 The design of catalysts
based on the 3,4-diaminopyridine motif was therefore
guided by the theoretical assessment of the stability of the
respective acetyl intermediates, as expressed through the
reaction enthalpy of the homodesmic acetyl-transfer reac-
tion shown in Equation 1.
R
R
∆H298
+
+
+N
N
N
+N
4
O
O
4Ac
Equation 1
The reaction enthalpies for a variety of 3,4-diaminopy-
ridines have been collected in Table 1 together with the
values for pyridine derivatives, whose catalytic potential
is well known from earlier studies, such as pyridine (4),
DMAP (1), PPY (2), and tricyclic DMAP-derivative 5. A
graphical representation of the results is given in Figure 2.
The structurally least complex 3,4-diaminopyridine con-
sidered here is 6, which is based on the tetrahydropyri-
do[3,4-b]pyrazine skeleton. The stability of the
SYNTHESIS 2007, No. 8, pp 1185–1196
x
x
.
x
x
.2
0
0
7
Advanced online publication: 28.02.2007
DOI: 10.1055/s-2007-965973; Art ID: Z02207SS
© Georg Thieme Verlag Stuttgart · New York

1186
I. Held et al.
PAPER
O
O
Ph
O
Ph
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
O
N
N
10
N
N
298
∆Hrxn
11
14
17
19
20
13
1
2
[kJ mol–1
]
–30
–40
–50
–60
–80
–90
–100
–130
–70
–110
–120
O
O
O
N
N
N
N
N
N
N
N
N
N
N
N
N
O
N
N
5
O
O
O
N
N
N
N
N
12
7
N
N
8
16
18
N
N
N
15
N
N
N
O
N
21
6
9
Figure 2 Structures of 3,4-diaminopyridines 6–21 together with their respective reaction enthalpies for the acetyl-transfer reaction defined in
Equation 1. Data for 4-aminopyridines 1, 2, and 5 are also shown.
corresponding acetyl intermediate 6Ac is close to that of
the highly catalytically active 5.
Table 1 Reaction Enthalpies at 298.15 K for the Acetyl-Transfer
Reaction Shown in Equation 1 as Calculated at the B3LYP/6-311 +
G(d,p)// B3LYP/6-31G(d) Level of Theory (in kJ mol–1)
Replacement of the two methyl groups in 6 by one (as in
7 and 21) or by two (as in 8) acetyl groups is found to de-
crease the electron density in the pyridine ring and thus
the stability of the corresponding cations 7Ac and 8Ac
quite significantly. The stability difference between 6Ac
and 21Ac (19.5 kJ mol–1) and that between 6Ac and 7Ac
(37.9 kJ mol–1) indicates that the nitrogen atom at C4 is
much more sensitive to changes in the substituent pattern
as compared to the nitrogen atom at C3. The combined ef-
fect of both substituents as in 8 (56.3 kJ mol–1 relative to
6) is practically identical to the sum of the two individual
substitutions (57.4 kJ mol–1). Replacement of the methyl
substituents in 6 by ethyl groups enhances the stability of
the acetyl intermediate by 10 kJ mol–1. Annulation of a
saturated alkyl ring to system 6 in either a cis-fashion
(yielding 9) or trans-fashion (as in 10) also enhances their
stability of the acetyl intermediates by approximately 15
kJ mol–1. The stability of the acetylpyridinium cations de-
rived from the tricyclic systems 9 and 10 depends on the
N-substituents in much the same way as already found for
bicyclic system 6. Introduction of two N-ethyl substitu-
ents thus leads to the most stable acetyl intermediates
11Ac and 15Ac. Finally the introduction of aryl substitu-
ents as in 19 also stabilizes the corresponding cationic in-
termediate (relative 6Ac), most likely through inductive
electron donation to the 3,4-diamino nitrogen atoms. The
stability values of the acetyl intermediates of the com-
pounds shown in Figure 2 cover a range of almost 90 kJ
mol–1. Perusal of the charge and C–N distance data in
Table 1 also shows that larger thermochemical stability
correlates with shorter C–N bond distances and smaller
acetyl group charges.
System DHrxn (298) [kJ mol–1] q (Ac)a,b
r (C–N)b [pm]
4
18
14
8
0.0
–39.0
+0.366
+0.318
+0.321
+0.324
+0.294
+0.310
+0.305
+0.299
+0.298
+0.301
+0.291
+0.291
+0.284
+0.279
+0.278
+0.274
+0.277
+0.277
+0.274
+0.272
153.4
149.7
149.9
150.1
148.7
149.3
149.0
148.7
148.2
148.6
147.9
148.2
147.7
147.1
147.3
147.2
147.5
147.3
147.1
147.1
–46.2
–48.7
17
7
–57.3
–67.1
13
16
1
–73.1
–82.0
–82.1
21
2
–85.5
–93.1
12
6
–103.2
–105.0
–108.9
–115.5
–116.5
–117.9
–119.2
–122.2
–127.1
5
20
19
10
9
15
11
a In units of elemental charge e.
b Charge and distance parameters of the most favorable conformer.
Synthesis 2007, No. 8, 1185–1196 © Thieme Stuttgart · New York

PAPER
3,4-Diaminopyridines as Highly Active Acylation Catalysts
1187
two steps in 37% yield. The cis-annulated diamine 27 is
available from 24 through selective reduction with
Synthesis of 3,4-Diaminopyridines
Some of the compounds shown in Figure 2 can efficiently NaBH4/BH3/H2NCH2CH2OH in 74% yield17 or through
be synthesized from 3,4-diaminopyridine (22) in a three- reduction with LiAlH4 at –40 °C in 90% yield. Applica-
or four-step sequence (Scheme 1). Condensation of 22 tion of the simpler reduction conditions used for 26 leads
with glyoxal, 1,2-cyclohexadione or benzil leads to the di- to a mixture of cis- and trans-annulated diaminopyridines.
imines 23–25 in good yields.13 Pyridopyrazine 23 (R = H) Use of a milder acylation procedure for the acetylation of
was subsequently reduced14 to the tetrahydro derivative 27 shows the C4-amino group to be significantly more re-
26 and bis-methylated under Eschweiler–Clark conditions active than the amino group at C3, yielding amide 28 as
to yield compound 6.15 The introduction of longer alkyl the sole product. Reduction of the amide as before to the
chains proves more efficient through a two-step sequence corresponding amine and acetylation of the remaining
involving initial bis-acylation, followed by reduction of amino group at C3 thus provides a strategy for the synthe-
the amide groups to the corresponding amines.16 Starting sis of catalysts with two donor substituents of variable
from 26, the bis-ethylated compound 20 can be synthe- strength. The influence of aryl substituents in the bridge
sized in this fashion in 48% yield. A similar approach has connecting the two amino substituents on the catalytic
been taken for the synthesis of the cyclohexyl-annulated properties was explored with compound 34. While reduc-
system 11, which is available from the free amine 27 in tion of the corresponding pyridopyrazine 25 proceeds
R
NH2
R
N
HN
N
NH2
a
b
c
N
NH
N
R = H
N
N
N
N
22
23, R = H
26
6
24, R = -(CH2)-
25, R = Ph
R = Ph
Ph
d
l
R = -(CH2)-
f
HN
N
O
Ph
N
N
N
N
HN
N
e
N
N
NH
NH
O
31
27
8
20
g
m
i
Ph
O
O
Ph
HN
N
N
N
N
N
N
N
N
h
N
N
NH
O
32
28
14
11
j
n
Ph
Ph
Ph
Ph
N
O
N
N
N
N
N
N
N
NH
N
o
k
O
N
N
33
34
29
30
Scheme 1 Synthesis of catalysts based on the 3,4-diaminopyridine motif. Reagents and conditions: a) glyoxal, 1,2-cyclohexadienone, or
benzil, EtOH, 70 °C, 5 h, 90–98%; b) powdered NaBH4, EtOH, 40 °C, 24 h, 50%; c) CH2O (200 equiv, 37% in H2O), HCO2H (100 equiv),
110 °C, 48 h, 57%; d) Ac2O, pyridine, 100 °C, 24 h, 80%; e) LiAlH4 (4.2 equiv), AlCl3 (2.6 equiv), MTBE, 0 °C, 1 h, then reflux, 8 h, 60%; f)
LiAlH4, THF, –40 °C to r.t., 32 h, 90%; g) Ac2O, 25 mol% PPY, pyridine, 100 °C, 48 h, 68%; h) LiAlH4 (4.2 equiv), AlCl3 (2.6 equiv), MTBE,
0 °C, 1 h, then reflux, 8 h, 55%; i) Ac2O (1.1 equiv), 2 (0.2 equiv), Et3N, CH2Cl2, r.t., 3 h, 82%; j) LiAlH4 (2.2 equiv), AlCl3 (1.3 equiv), MTBE,
0 °C, 1 h, then reflux, 8 h, 65%; k) 1. n-BuLi (1 equiv), THF, –78 °C, 1 h, then 0 °C, 1 h, 2. AcCl (1.1 equiv), THF, –78 °C to r.t., 1 h, 16%; l)
powdered NaBH4, EtOH, 40 °C, 48 h, 74%; m) CH2O (88 equiv, 37% in H2O), HCO2H (200 equiv), 110 °C, 48 h, 90%; n) 1. n-BuLi (1 equiv),
MTBE, –78 °C, 1 h, then 0 °C, 1 h; 2. AcCl (1.1 equiv), MTBE, –78 to 0 °C, 1 h, 36%; o) LiAlH4 (2.2 equiv), AlCl3 (1.3 equiv), THF, 0 °C, 1
h, then reflux, 18 h, 53%.
Synthesis 2007, No. 8, 1185–1196 © Thieme Stuttgart · New York

1188
I. Held et al.
PAPER
well under the conditions used before for the synthesis of
26,14 the N-methylation under Eschweiler–Clark condi-
tions stops at the stage of singly methylated compound 32.
Acetylation of this latter compound proved surprisingly
difficult under all conditions used previously, but could fi-
nally be accomplished through initial deprotonation of the
amino substituent at C4 with n-BuLi, trapping of the
amide anion with AcCl, and subsequent reduction with
LiAlH4/AlCl3 yielding 34 as the final product. Compound
5 was synthesized following a slightly modified version of
the procedure described by Sakamoto et al.18
H
Ha
He
H
N
N
CH2
H
H3C
N
N
NH
N
11
29
H
H
H
H
O
CH2
H
H
The composition of all compounds shown in Scheme 1 is
supported by high-resolution mass spectra. The integrity
of the pyridine ring can in all compounds be inferred di-
rectly from the presence of three signals (one singlet, two
doublets) in the appropriate range (6.5–8 ppm) of the 1H
NMR spectra. This leaves us with the question of the ste-
reochemical assignment of the cyclohexane annulation in
compounds 11, 14, and 27–30, as well as the question of
regiochemical control in the N-alkylation and N-acylation
H3C
N
N
N
N
H
N
N
CH3
CH3
H
H
12
31
Figure 3 Arrows indicate observed NOE enhancements
1
reactions. The H NMR signals for the neighboring pro-
tons Ha and He in structure 11 (see Figure 3) exhibit a cou-
pling constant of 3JH,H = 2.8 Hz and show a positive NOE
enhancement signal, in line with either an axial–equatorial
or an equatorial–equatorial orientation of the respective
protons.19 An equatorial–equatorial orientation of the two
protons can be excluded since the 3,4-diaminopyridine
moiety cannot possibly be connected to the cyclohexane
ring through diaxial annulation. The regioselectivity of
the acetylation of 27 to give 28 could not be determined
directly, since the spectroscopic properties of 28 proved
inconclusive in this respect. After reduction of 28 to 29
NOE enhancements could be detected between the ethyl
substituent and the hydrogen at the C5 position of the py-
ridine ring, in support of the structure shown in Scheme 1.
The regiochemistry of the N-methylation of 31 to yield 32
could be determined through detection of NOE enhance-
ments between the signals for the methyl group protons
(2.85 ppm) and those for the proton at C1 of the pyridine
ring (7.82 ppm) as well as one of the benzylic protons
(4.44 ppm). That this regioselectivity is ultimately con-
served in the doubly alkylated product 34 could unequiv-
ocally be verified through the X-ray crystal structure
analysis of this compound (as crystallized from isohex-
ane–dichloromethane, Figure 4).
Figure 4 X-ray crystal structures of 34 and 5
tion of 10% (relative to 35). The reaction half-life t1/2, de-
termined through integration of the reactant and product
signals in the 1H NMR spectrum, is taken here as a mea-
sure of catalyst activity. Reaction B involves the same al-
cohol, but isobutyric anhydride (38) as the acylation
reagent. This is an intrinsically slower reaction and the re-
action temperature (40 °C) has therefore been chosen
such that the absolute reaction half-lives are roughly com-
parable for both reactions. Based on recent mechanistic
studies of DMAP-catalyzed acylation reactions,20,21 the
following minimal reaction mechanism can be assumed to
be valid for both anhydrides in apolar solution
(Scheme 3). Anhydride and the pyridine catalyst react in
Catalytic Properties
The catalytic potential of pyridines 1, 2, 5, 6, 8, 11, 20 and
34 was tested in the two acylation reactions A and B
shown in Scheme 2. Tertiary alcohol 35 has already been
used in the past as a benchmark substrate in acylation re-
actions due to its very low rate of acylation under uncata-
lyzed conditions.11 Acetylation of 35 with acetic
anhydride (36) in the presence of triethylamine as the aux-
iliary base (reaction A) proceeds quantitatively, provided
a catalyst as reactive as DMAP (1) is used in a concentra-
Synthesis 2007, No. 8, 1185–1196 © Thieme Stuttgart · New York

PAPER
3,4-Diaminopyridines as Highly Active Acylation Catalysts
1189
a first (usually rapid) preequilibrium step to form a com-
plex of acylpyridinium cation and carboxylate anion. This
complex is not detected by 1H NMR spectroscopy under
the conditions used here and we can therefore assume the
equilibrium constant K to be small for both reactions stud-
ied here. Reaction of the acylpridinium cation then occurs
in the rate-limiting step with alcohol 35, generating the es-
ter products together with the deactivated catalyst. Regen-
eration of the latter requires the presence of the auxiliary
base Et3N.
Table 2 Reaction Half-Lives for Benchmark Reactions A and B
Catalyst
A t1/2 (min)
>38000a
166
B t1/2 (min)
>100000a
304
8
1 (DMAP)
34
144
269
30
138b
112
2 (PPY)
75
171
6
20
11
5
56
129
A
B
53
91
O
O
O
O
24 (37)c
21 (29)c
63 (81)c
67 (86)c
O
O
OH
36
38
a See ref. 22.
b See ref. 23.
CDCl3, 40 °C
cat. (10 mol%)
Et3N
CDCl3, 23 °C
cat. (10 mol%)
Et3N
35
c Results in parentheses were obtained using Hünig’s base
[EtN(i-Pr)2] as the auxiliary base
measurements. Still, even for the most active catalysts it
is not necessary to perform the reactivity measurements
under strictly anaerobic conditions. The reactivity data for
catalysts 6, 11, and 20 in Table 2 show that alkyl-substi-
tuted 3,4-diaminopyridines are more reactive than 4-ami-
nopyridines such as DMAP or PPY.
O
O
O
O
37
39
Scheme 2
The best results have been obtained with compound 11,
whose catalytic performance is comparable to that of car-
bacyclic compound 5. Comparison of the results for 20
and 11 shows a strong influence of the donor ability of the
bridge on the catalytic performance, while the presence of
N-methyl or N-ethyl substituents (20 vs. 6) appears to be
slightly less relevant. While this trend is in line with the
stability values reported in Table 1 and Figure 2, the cata-
lytic performance of 34 is too low, considering the rela-
tively stable acetyl intermediate formed by system 19.
The catalytic performance is reduced through introduc-
tion of acceptor substituents as documented by the catalyt-
ic activity of 30 (as compared to 11), as well as the
exceedingly slow reactions observed for the N-acetylated
compound 8. While this had to be expected from the low
stability of the corresponding acetyl intermediate, we
have to acknowledge that the stability scale reported in
Figure 2 is not in line with the reactivities reported in
Table 2 in all cases. That the latter will also depend on the
substrates as well as the temperature chosen for a particu-
lar experiment is borne out by comparison of the results
for reactions A and B. The reactivity ratio for the most ac-
tive diaminopyridine 11 and DMAP amounts to 7.0 for re-
action A and to 4.8 for reaction B. A similar result can be
found for carbacyclic catalyst 5 with reactivity ratios of
7.9 and 4.5. The choice of the auxiliary base represents
one additional experimental variable, which was again ex-
plored for catalysts 5 and 11. It was surprisingly found
that use of a stronger, sterically hindered base such as
EtN(i-Pr)2 (Hünig’s base) leads to uniformly slower reac-
tions as compared to those with Et3N as the auxiliary base.
R'
R
R'
K
–O
O
O
O
+
R
N
+
R
O
R
N
O
OH
R'
kcat
R
–O
O
O
O
R
+
+
N
H
Scheme 3
The reaction half-lives t1/2 measured here (Table 2) reflect
the influence of the catalyst substitution pattern on both of
these steps. A clear correlation of t1/2 with the stability
values determined computationally for the acetylpyridini-
um cations before (Table 1) can thus only be expected, if
the substituent effects on K are larger than those on kcat.
The reactivity data shown in Table 2 for compounds 1, 2,
and 5 are slightly different from those reported earlier for
the same reaction under identical conditions.11 This is due,
in part, to small differences in the NMR procedure em-
ployed for following the course of the reaction (see exper-
imental details). It was additionally found that results for
the more active catalysts such as 5 could only be repro-
duced if exceedingly pure samples are used for NMR
Synthesis 2007, No. 8, 1185–1196 © Thieme Stuttgart · New York

1190
I. Held et al.
PAPER
Reactivity Studies Using Reactions A and B; General Procedure
CDCl3, Et3N and Hünig’s base were freshly distilled under N2 from
CaH2 before use. All kinetic measurements were recorded at a con-
stant temperature of 23 °C for reaction A and 40 °C for reaction B
on a Varian Mercury 200 spectrometer. The following solutions
were prepared in CDCl3 in three dry, calibrated 5 mL flasks:
In conclusion we have found that alkyl-substituted 3,4-di-
aminopyridines represent a potent new class of catalysts
for the acylation of alcohols. The catalytic efficiency of
these catalysts can be varied broadly through variation of
the nitrogen substituents within one synthetic approach.
The catalytic efficiencies of the best of these catalysts are
comparable to the best carbacyclic derivatives of DMAP
reported before. In contrast to these latter compounds, the
most active 3,4-diaminopyridine catalysts are synthetical-
ly accessible through a flexible three- or four-step proce-
dure, which can easily be modified to allow for further
structural variation.
A: 1.2 M in Ac2O or isobutyric anhydride, and 0.3 M in anhyd di-
oxane;
B: 0.6 M in ethynylcyclohexanol and 1.8 M in Et3N or Hünig’s
base;
C: 0.06 M in catalyst.
Sample Preparation and Kinetic Measurements for Reaction A
In an NMR tube, 200 mL each of the above mentioned standardized
solutions were added using an Eppendorf pipette. The reaction so-
lution was mixed and immediately inserted into the NMR spectrom-
eter. The reaction was monitored by recording NMR spectra within
a defined time interval until full conversion.
Reactions which require anhydrous conditions were carried out un-
der N2 in absolute solvents in oven- and hot-air-blower-dried glass-
ware using syringe and Schlenk techniques. THF was distilled
under N2 from NaH. MTBE, pyridine, Et3N and CDCl3 were dis-
tilled under N2 from CaH2. Ac2O and isobutyric anhydride were dis-
tilled under reduced pressure from P4O10 on anhyd K2CO3, filtered
and fractionally distilled under reduced pressure. Both anhydrides
were kept over 4 Å molecular sieves. EtOH, CH2Cl2, EtOAc and
MeOH were distilled via rotary evaporation. n-BuLi was standard-
ized by titration with diphenylacetic acid. Other reagents, unless
otherwise mentioned, were purchased at the highest available com-
mercial quality and used without further purification. TLC was per-
formed on Merck KGaA precoated plates (silica gel 60 F254, layer
thickness 0.2 mm) and on Fluka precoated plates (basic alumina
F254, Brockmann activity 1, pH 9.5, layer thickness 0.2 mm). Flash
chromatography was performed with Merck KGaA silica gel 60
(0.040–0.063 mm) and Fluka basic alumina (Brockman activity 1,
pH 9.5, 0.05–0.15 mm) with a N2 pressure of 1.5 bar for silica gel
and 0.5 bar for basic alumina. 1H and 13C NMR spectra were record-
ed on Varian Mercury 200, Varian 300, Varian INOVA 400 and
Varian 600 instruments. NOE measurements were performed in
CDCl3 at 27 °C. Chemical shifts are reported in ppm and referenced
to the solvent peak.24 Peaks in the 1H and 13C NMR were assigned
by DQCOSY, NOESY, HSQC, HMBC and DEPT experiments. 1H
NMR spectra for kinetic experiments were analyzed with the
VNMR 4.3 Rev. G0194 program package. Integrals were recorded
using a self-written subroutine using MAGICAL™ II Program-
ming. IR spectra were recorded with a PerkinElmer 1420 IR spec-
trometer using KBr pellets as sample holder and PerkinElmer FT-
IR system Spectrum BX for neat measurement of the sample using
ATR techniques. Peaks are listed as vs = very strong, s = strong,
m = medium and w = weak. Mass spectra were recorded with a
Finnigan MAT 95 using either electron impact ionization (EI, 70
eV) or chemical ionization (CI, isobutane). Electro spray injection
mass spectra were recorded with Thermo Finnigan LTQ FT instru-
ment. 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. In the case of the electron-rich py-
ridines 11, 5, 6, 20 and 32, the solvent was removed after column
chromatography via rotary evaporation under reduced pressure,
leaking a constant stream of N2 into the rotavapor.
Sample Preparation and Kinetic Measurements for Reaction B
The reagents were added to the NMR tube in the same way as de-
scribed above for reaction A. In order to prevent evaporation of the
solvent at higher reaction temperatures, the NMR tube was then
flame-sealed under N2.
Determination of Half-Life Times for Reaction A
All signals in the 1H NMR spectrum related to the acetyl group hy-
drogen atoms were integrated automatically during the course of the
reaction (the Ac2O integral with boundaries of 8 Hz, the ester in-
tegral with boundaries of 2 Hz and the triethylammonium acetate
integral with boundaries of 6 Hz). The conversion was calculated
from these integrals using Equation 2. The time course of the reac-
tion was fitted until self-consistency with Equation 4. The reaction
half-life was calculated using function 4 at 50% conversion.
Determination of Half-Life Times for Reaction B
All signals in the 1H NMR spectrum related to the isobutyrate group
as well as the internal standard dioxane were integrated automati-
cally during the course of the reaction (the dioxane integral with
boundaries of 2 Hz and isobutyric anhydride integral with bound-
aries of 2 Hz). The conversion was calculated from these integrals
using Equation 3. The time course of the reaction was fitted until
self-consistency with Equation 4. The reaction half-life was calcu-
lated using function 4 at 50% conversion.
Iester
x 100%
conversion =
–
+
0.25 (I
+ Iester + I
AC2O
E3t NH AcO
Equation 2
Ianhydride
3(Iester
conversion =
x 200%
1 –
Geometry optimizations have been performed using the
Becke3LYP hybrid functional in combination with the 6-31G(d)
basis set. Thermochemical corrections to enthalpies at 298.15 K
have been calculated from a harmonic vibrational frequency analy-
sis at this same level. Single point energies have then been calculat-
ed at the Becke3LYP/6-311 + G(d,p) level. Combination of these
latter energies with thermochemical corrections from the
Becke3LYP/6-31G(d) level yield the H298 values cited in the text.
All calculations have been performed with Gaussian 03.25
)
Equation 3
x–x0
t0
–
y = A exp
+ const.
Equation 4
Synthesis 2007, No. 8, 1185–1196 © Thieme Stuttgart · New York

PAPER
3,4-Diaminopyridines as Highly Active Acylation Catalysts
1191
Pyrido[3,4-b]pyrazine (23)
1H NMR (400 MHz, CDCl3): d = 2.25 (s, 3 H, CH3), 2.31 (s, 3 H,
CH3), 3.90 (ddd, J = 12, J = 4, J = 4 Hz, 2 H, CH2), 3.94 (ddd,
2J = 12, 3J = 4, 3J = 4 Hz, 2 H, CH2), 7.67 (s, 1 H, H-5), 7.87 (br s,
1 H, H-5), 8.32 (d, 3J = 4 Hz, 1 H, H-7), 8.46 (m, 1 H, H-8).
13C NMR (100 MHz, CDCl3): d = 22.3, 22.8 (CH3), 42.1, 46.5
(CH2), 117.4 (C-5), 128.2 (Cq), 139.0 (Cq), 145.7 (C-7), 146.9 (C-
8), 168.6 (C=O).
GC-MS (EI): tR = 9.66 min; m/z (%) = 220 (14), 219 (M+, 81), 178
(11), 177 (M+ – AcO, 100), 176 (10), 162 (3), 159 (2), 136 (7), 135
(78), 134 (M+ – 2 AcO, 99), 133 (8), 132 (9), 120 (4), 119 (2), 107
(5), 105 (2), 93 (3), 80 (2), 79 (4), 78 (4), 52 (2), 51 (2), 43 (AcO+,
20).
2
3
3
To a solution of glyoxal (40 wt% in H2O, 2.82 mL, 62.48 mmol) in
EtOH (30 mL) was added 3,4-diaminopyridine (22; 2.00 g,
18.33 mmol). The mixture was kept at 70 °C oil bath temperature
for 5 h. After cooling to r.t., the solvent was distilled off by rotary
evaporation. The crude product was purified by flash chromatogra-
phy (isohexane–EtOAc, 1:9) to afford 2.35 g (98%) of a white solid;
Rf = 0.27 (isohexane–EtOAc, 1:9).
IR (KBr): 3435 (vs), 3092 (w), 3023 (m), 1969 (w), 1758 (w), 1631
(w), 1598 (vs), 1562 (m), 1536 (w), 1488 (s), 1436 (vs), 1416 (m),
1381 (m), 1351 (w), 1290 (w), 1279 (m), 1212 (m), 1201 (m), 1148
(w), 1033 (s), 1014 (s), 972 (w), 959 (vs), 931 (m), 881 (vs), 838
(m), 824 (s), 773 (w), 651 (s), 623 (m), 546 (w), 524 (w), 457 cm–1
(s).
1H NMR (200 MHz, CDCl3): d = 7.94 (dd, J = 5.8, J = 0.6 Hz, 1
H, H-7), 8.83 (d, 3J = 5.8 Hz, 1 H, H-8), 8.96 (d, 3J = 1.6 Hz, 1 H,
H-3), 9.02 (d, 3J = 1.6 Hz, 1 H, H-2), 9.56 (d, 4J = 0.6 Hz, 1 H, H-5).
13C NMR (100 MHz, CDCl3): d = 121.6 (CH-7), 138.0 (Cq), 145.3
(Cq), 147.3 (CH-8), 146.5 (CH-3), 149.2 (CH-2), 154.8 (CH-5).
GC-MS (EI): tR = 5.45 min; m/z (%) = 132 (8), 131 (M+, 100), 104
(25), 77 (13), 50 (10).
HRMS (EI): m/z calcd for C11H13N3O2 [M+]: 219.1008; found:
219.0995.
3
4
1,4-Diethyl-1,2,3,4-tetrahydropyrido[3,4-b]pyrazine (20)
AlCl3 (1.56 g, 11.69 mmol) was suspended in MTBE (60 mL) at r.t.
After stirring for 45 min, the mixture was cooled to 0 °C and
LiAlH4 (1.32 g, 34.65 mmol) was added in small portions. The mix-
ture was stirred for 15 min, and then compound 8 was added. The
mixture was stirred for 1 h at 0 °C and then refluxed for 8 h. It was
then allowed to cool down to r.t. and poured into ice water. The in-
organic precipitate was filtered off and washed with CH2Cl2 (2 × 30
mL). The aqueous layer was basified with aq NaOH (30%) to pH 12
and extracted with CH2Cl2 (3 × 40 mL). The combined organic ex-
tracts were dried (Na2SO4) and the solvent was distilled off via ro-
tary evaporation. The crude material obtained was purified with
flash chromatography (EtOAc–MeOH–Et3N, 10:0.5:1) to afford
0.52 g (60%) of a colorless liquid, which solidified in the freezer;
Rf = 0.47 (EtOAc–MeOH–Et3N, 10:0.5:1).
1,2,3,4-Tetrahydropyrido[3,4-b]pyrazine (26)
To a solution of quinoxaline 23 (2.90 g, 0.022 mol) in anhyd EtOH
(100 mL), was added powdered NaBH4 (2.90 g, 0.076 mol). The
mixture was kept at 40 °C for 24 h. After completion of the reaction,
the mixture was cooled to r.t.; H2O (3 mL) was added, and the inor-
ganic precipitate was filtered off and washed with CH2Cl2 (2 × 20
mL). The organic solvent was dried (Na2SO4) and distilled off via
rotary evaporation. The crude material was purified by flash chro-
matography (basic alumina, EtOAc–MeOH, 10:1) to afford 1.49 g
(50%) of a white solid; Rf = 0.15 (basic alumina, CH2Cl2–MeOH,
20:1).
IR (KBr): 3436 (s), 3112 (w), 3019 (w), 2964 (w), 1661 (s), 1686
(vs), 1583 (m), 1497 (m), 1409 (s), 1363 (w), 1332 (m), 1311 (s),
1260 (m), 1249 (w), 1232 (m), 1220 (m), 1180 (m), 1150 (w), 1119
(m), 1064 (w), 1035 (m), 985 (m), 970 (m), 886 (s), 858 (m), 847
(m), 802 (m), 765 (w), 740 (w), 704 (w), 647 (w), 614 (w), 592 (w),
577(m), 570 (m), 507 cm–1 (w).
IR (KBr): 3349 (m), 2859 (m), 1593 (s), 1534 (s), 1474 (s), 1344 (s),
1311 (s), 1281 (s), 1256 (w), 1228 (m), 1182 (m), 1102 (m), 1051
(w), 1038 (m), 893 (m), 862 (m), 824 (s), 772 cm–1 (m).
3
1H NMR (400 MHz, CDCl3): d = 1.15 (q, J = 14 Hz, 6 H, CH3),
1H NMR (200 MHz, CDCl3): d = 3.37 (d, J = 5.8 Hz, 1 H, H-3),
3
3
2
3.22 (m, J = 6 Hz, 2 H, H-3), 3.23 (m, J = 14 Hz, 4 H, CH2),
3
3
3.38 (d, J = 5.8 Hz, 1 H, H-2), 6.29 (d, J = 5.4 Hz, 1 H, H-8),
3
3.42 (m, J = 6 Hz, 2 H, H-2), 6.34 (d, 3J = 5.2 Hz, 1 H, H-8),
7.67 (d, 3J = 5.4 Hz, 1 H, H-7), 7.67 (s, 1 H, H-5).
7.69 (s, 1 H, H-5), 7.75 (d, 3J = 5.2 Hz, 1 H, H-7).
13C NMR (100 MHz, CDCl3): d = 40.1 (CH2), 41.0 (CH2),
107.8 (C-5), 129.6 (Cq), 135.3 (CH-7), 140.1 (Cq), 141.1 (CH-5).
GC-MS (EI): tR = 8.09 min; m/z (%) = 136 (8), 135 (M+, 79), 134
(M+ – H+, 100), 133 (10), 132 (7), 131 (2), 120 (4), 107 (7), 105 (4),
94 (2), 93 (7), 80 (2), 79 (3), 78 (4), 67 (4), 66 (2), 53 (2), 52 (2), 52
(3), 51 (2).
13C NMR (100 MHz, CDCl3): d = 10.1, 10.4 (CH3), 44.6, 46.5
(CH2-2,3), 44.9, 45.0 (CH2), 104.0 (C-8), 130.5, 130.1 (Cq), 131.8
(C-5), 140.7 (C-7).
GC-MS (EI): tR = 8.63 min; m/z (%) = 192 (10), 191 (M+, 100), 190
(4), 177 (8), 176 (95), 175 (5), 162 (11), 161 (8), 160 (5), 148 (13),
147 (10), 146 (8), 135 (2), 134 (9), 133 (6), 131 (8), 121 (2), 119 (4),
118 (3), 107 (3), 104 (2), 92 (2), 91 (2), 80 (8), 77 (4).
HRMS (EI): m/z calcd for C7H8N3 (M – H+): 134.0718; found:
134.0709.
HRMS (EI): m/z calcd for C11H17N3 [M+]: 191.1422; found:
191.1430.
1-(4-Acetyl-3,4-dihydro-2H-pyrido[3,4-b]pyrazin-1-yl)ethan-
one (8)
1,4-Dimethyl-1,2,3,4-tetrahydropyrido[3,4-b]pyrazine (6)
Under ice cooling, formic acid (35 mL) was added slowly to dihyd-
roquinoxaline 26 (1.26 g, 9.32 mmol). Aq formaldehyde (12 mL,
<37% in H2O) was then added and the mixture was kept at 110 °C
for 48 h. The mixture was allowed to cool down to r.t., and under
ice cooling approximately 20% aq NaOH (150 mL) was added in
such a way that the solution had a pH of 12. The mother liquor was
extracted with CH2Cl2 (250 mL) overnight using a continuous liq-
uid/liquid extractor. The organic phase was dried (Na2SO4) and the
solvent was removed by rotary evaporation. The crude product was
purified twice by flash chromatography (silica gel, EtOAc–MeOH–
Et3N, 10:1:1) and (basic alumina, EtOAc–MeOH, 10:1) to afford 6
(0.849 mg, 57%) as a faint yellow solid; Rf = 0.56 (basic alumina,
EtOAc–MeOH, 10:1).
To a solution of dihydroquinoxaline 26 (1.49 g, 0.011 mol) in pyri-
dine (60 mL), was added Ac2O (23 mL, 24.71 g, 24.20 mol) at 0 °C.
The mixture was heated up to 100 °C and kept at that temperature
for 48 h. After cooling to r.t., the solvent was distilled off under vac-
uum and the yellow crude product was purified by flash chromatog-
raphy (EtOAc–MeOH, 10:3) to afford 1.93 g (80%) of a faint
yellow solid; Rf = 0.28 (EtOAc–MeOH, 10:3).
IR (neat): 2960 (w), 1684 (s), 1654 (vs), 1582 (m), 1494 (s), 1407
(vs), 1330 (m), 1320 (vs), 1277 (m), 1259 (s), 1248 (m), 1217 (s),
1248 (s), 1217 (s), 1179 (m), 1150 (w), 1118 (m), 1064 (m), 1033
(s), 969 (s), 886 (w), 857 (m), 846 (s), 799 (s), 764 (w), 749 (w), 704
cm–1 (w).
Synthesis 2007, No. 8, 1185–1196 © Thieme Stuttgart · New York

1192
I. Held et al.
PAPER
IR (neat): 3378 (w), 3035 (w), 2979 (w), 2873 (m), 2826 (s), 2792
(w), 1581 (s), 1519 (s), 1466 (s), 1454 (s), 1435 (m), 1416 (m), 1380
(w), 1335 (vs), 1290 (s), 1250 (w), 1235 (vs), 1214 (m), 1172 (s),
1114 (s), 1099 (s), 1069 (s), 1030 (m), 936 (w), 911 (w), 883 (s),
815 (s), 800 (s), 783 (s), 746 (m), 709 (m), 622 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 2.77 (s, 3 H, CH3), 2.82 (s, 3 H,
CH3), 3.12 (m, 2 H, CH2-2), 3.37 (m, 2 H, CH2-3), 6.21 (d,
3J = 5.6 Hz, 1 H, H-7), 7.56 (s, 1 H, H-5), 7.74 (d, 3J = 5.6 Hz, 1 H,
H-8).
13C NMR (75 MHz, CDCl3): d = 38.0 (N-1-CH3), 39.1 (N-4-CH3),
48.8 (C-3), 49.6 (C-2), 104.0 (C-7), 131.2 (C-5), 132.3 (C-4a),
141.6 (C-7), 142.2 (C-8a).
GC-MS (EI): tR = 8.05 min; m/z (%) = 164 (8), 163 (M+, 100), 162
(21), 161 (5), 149 (4), 148 (40), 147 (9), 146 (8), 134 (8), 133 (11),
132 (6), 121 (4), 120 (2), 119 (6), 107 (3), 105 (2), 93 (2), 92 (4), 81
(6), 80 (4), 79 (2), 78 (4), 66 (3), 51 (2), 42 (4).
1269 (s), 1240 (m), 1206 (s), 1175 (s), 1087 (m), 1052 (m), 1003
(m), 938 (m), 884 (m), 810 (vs), 725 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 1.32–1.40 (m, 3 H), 1.56–1.75 (m,
5 H), 3.41 (m, 1 H), 3.46 (s, 1 H, NH), 3.51 (m, 1 H), 4.20 (s, 1 H,
3
NH), 6.29 (d, 1 H, J = 5.4 Hz, H-3), 7.65 (d, 1 H, 3J = 5.4 Hz, H-
4), 7.68 (s, 1 H, H-1).
13C NMR (75 MHz, CDCl3): d = 22.0, 22.2 (C-7,8), 30.4,
30.8 (CH2-6,9), 49.2 (CH-5a), 50.1 (CH-9a), 107.7 (C-4),
128.8 (Cq-10a), 134.8 (C-3), 139.2 (Cq-4a), 140.7 (C-4).
GC-MS (EI): tR = 10.06 min; m/z (%) = 190 (13), 189 (M+, 99), 188
(9), 187 (3), 185 (10), 184 (4), 170 (4), 160 (10), 159 (3), 158 (5),
148 (2), 147 (16), 146 (100), 145 (2), 134 (13), 133 (17), 132 (15),
120 (10), 119 (3), 105 (2), 94 (3), 93 (2), 78 (3), 66 (2), 40 (2).
HRMS (EI): m/z calcd for C11H15N3 [M+]: 189.1266, found:
189.1259.
The reaction can also be performed in 74% yield following the pro-
tocol by Opatz et al. with NaBH4/BH3/H2NCH2CH2OH as the re-
ducing agent.17
HRMS (EI): m/z calcd for C9H13N3 [M+]: 163.1109; found:
163.1089.
6,7,8,9-Tetrahydropyrido[3,4-b]quinoxaline (24)
1-(10-Acetyl-6,7,8,9,9a,10-hexahydro-5aH-pyrido[3,4-b]quin-
oxalin-5-yl)ethanone (14)
To a suspension of 3,4-diaminopyridine (22; 5 g, 45.81 mmol) in
EtOH (100 mL) was added 1,2-cyclohexanedione (5.13 g,
45.81 mmol). The flask was immersed in an oil bath and kept at
70 °C oil bath temperature for 5 h. After cooling the mixture to r.t.,
the solvent was distilled off by rotary evaporation. The solid crude
product was purified by flash chromatography with EtOAc as eluent
to afford 7.69 g (90%) as a white powder. The product should be
used within 48 h and should be kept cool in the refrigerator. Upon
standing in an open flask in the sunlight, the compound turned grey-
green; Rf = 0.25 (EtOAc–hexane, 20:1).
In a 250 mL round-bottomed flask, were added under ice cooling 27
(1.20 g, 6.34 mmol), pyridine (40 mL), Ac2O (30 mL, 32.36 g,
317 mmol), and PPY (0.234 g, 25 mol%). The mixture was heated
to 100 °C and kept at that temperature for 48 h. The reaction can be
monitored by TLC on basic alumina (EtOAc–MeOH, 10:1). After
cooling to r.t., the solvent was distilled off and the brown crude
product obtained was purified with flash chromatography on basic
alumina (EtOAc–MeOH, 10:1); Rf = 0.45 (EtOAc–MeOH, 10:1).
IR (neat): 2940 (m), 1660 (vs), 1587 (m), 1559 (w), 1498 (s), 1448
(w), 1427 (w), 1388 (m), 1353 (w), 1337 (m), 1289 (s), 1270 (s),
1248 (s), 1248 (m), 1220 (w), 1183 (w), 1102 (w), 1036 (m), 978
(m), 857 (w), 839 (w), 777 cm–1 (w).
1H NMR (400 MHz, CDCl3): d = 1.34 (m, 4 H), 1.60 (m, 4 H),
2.23 (s, 3 H, H3CCON), 2.27 (s, 3 H, H3CCON), 4.74 (m, 1 H), 4.85
(m, 1 H), 7.25 (d, 3J = 5.6 Hz, 1 H, H-4), 8.41 (d, 3J = 5.6 Hz, H-3),
8.49 (s, 1 H, H-1).
13C NMR (75 MHz, CDCl3): d = 21.7, 21.9 (C-7,8), 23.1,
23.6 (H3CCON), 28.4, 28.5 (C-6,9), 55.2, 56.0 (CH-5a,9a),
119.6 (C-4), 130.8 (Cq-10a), 141.6 (Cq-4a), 147.1, 147.2 (C-1, C-
3), 169.1, 169.2 (C=O).
GC-MS (EI): tR = 10.45 min; m/z (%) = 274 (13), 273 (M+, 58), 232
(15), 231 (100), 230 (42), 216 (5), 214 (5), 213 (5), 203 (3), 202 (4),
190 (13), 189 (84), 188 (45), 173 (5), 172 (6), 160 (7), 159 (5), 158
(5), 147 (8), 146 (40), 134 (6), 133 (13), 132 (15), 120 (7), 43 (9).
IR (KBr): 3435 (vs), 2947 (s), 2864 (m), 1594 (s), 1557 (w), 1461
(w), 1421 (m), 1385 (s), 1365 (w), 1330 (w), 1297 (m), 1211 (m),
1140 (w), 979 (m), 949 (w), 901 (m), 849 (m), 679 (w), 629 (w), 570
(w), 412 cm–1 (w).
1H NMR (200 MHz, CDCl3): d = 2.05 (m, 4 H, H-7,8), 3.18 (m, 4
3
3
H, H-6,9), 7.79 (d, J = 5.8 Hz, 1 H), 8.72 (d, J = 5.8 Hz, 1 H),
9.38 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 22.8 (CH2, C-7,8), 33.7 (CH2, C-
6,9), 121.2 (CH), 136.9 (Cq), 144.1 (Cq), 146.8 (CH), 153.9 (CH),
156.8 (Cq), 159.9 (Cq).
GC-MS (EI): tR = 8.44 min; m/z (%) = 186 (11), 185 (M+, 100), 184
(39), 183 (3), 182 (3), 171 (2), 170 (21), 169 (4), 158 (2), 157 (5),
156 (5), 131 (2), 104 (2), 103 (4), 78 (3), 76 (4), 67 (2), 64 (2), 51
(2), 50 (6).
HRMS (EI): m/z calcd for C11H11N3 [M+]: 185.0953; found:
185.0935.
HRMS (EI): m/z calcd for C11H15N3 [M+]: 273.1477; found:
273.1482.
5,5a,6,7,8,9a,10-Octahydropyrido[3,4-b]quinoxaline (27)
Compound 24 (6.13 g, 33.09 mmol) was dissolved in anhyd THF
(100 mL) in a 250 mL Schlenk-flask. The solution was cooled to
–40 °C and LiAlH4 (3.09 g, 81.42 mmol, 2.5 equiv) was added in
small portions. The mixture was allowed to warm to r.t. and stirred
at that temperature for 32 h. Afterwards, the mixture was poured
into ice water. The aqueous layer was basified with sat. aq K2CO3
to pH 12 and the inorganic precipitate was filtered off and was
washed with CH2Cl2 (2 × 50 mL). The mother liquor was extracted
with CH2Cl2 (250 mL) for 8 h using a continuous liquid/liquid ex-
tractor. The organic layer was separated and dried (Na2SO4). Flash
chromatography on silica gel (EtOAc–MeOH–Et3N, 10:1:1) afford-
ed 5.63 g (90%) of a white foam; Rf = 0.36 (EtOAc–MeOH–Et3N,
10:1:1).
5,10-Diethyl-5,5a,6,7,8,9,9a,10-octahydropyrido[3,4-b]quinoxa-
line (11)
AlCl3 (3.98 g, 29.9 mmol) was suspended in THF (60 mL) at r.t. Af-
ter stirring for 45 min, the mixture was cooled to 0 °C and LiAlH4
(1.92 g, 50.62 mmol) was added in small portions. The mixture was
stirred for 15 min, and then compound 14 (3.15 g, 11.5 mmol) was
added. The mixture was stirred for 1 h at 0 °C and then refluxed for
8 h. It was then allowed to cool down to r.t. and then poured into ice
water. The inorganic precipitate was filtered off and washed with
CH2Cl2 (2 × 30 mL). The aqueous layer was basified with aq NaOH
(30%) to pH 12 and extracted with CH2Cl2 (3 × 40 mL). The com-
bined organic extracts were dried (Na2SO4) and the solvent was dis-
tilled off by rotary evaporation. The crude product was distilled
with a Kugelrohr-distillation setup at 160 °C/0.4 mbar and after-
wards further purified by chromatography on basic alumina with
IR (neat): 3220 (s), 2927 (s), 2852 (s), 2354 (m), 1725 (w), 1595
(vs), 1523 (vs), 1456 (w), 1443 (m), 1403 (w), 1362 (s), 1294 (s),
Synthesis 2007, No. 8, 1185–1196 © Thieme Stuttgart · New York

PAPER
3,4-Diaminopyridines as Highly Active Acylation Catalysts
1193
EtOAc–MeOH (10:1) as eluent to afford 1.85 g (66%) of a slight
yellow oil which solidified in the freezer; Rf = 0.32 (basic alumina,
EtOAc–MeOH, 10:1).
phy on silica gel (EtOAc–Et3N, 10:1) to afford 0.430 mg (55%) of
a white foam; Rf = 0.24 (EtOAc–Et3N, 10:1).
IR (neat): 3212 (m), 3093 (w), 2971 (w), 2928 (s), 2851 (s), 1589
(s), 1560 (m), 1505 (vs), 1470 (w), 1442 (m), 1419 (m), 1363 (s),
1280 (vs), 1244 (s), 1210 (m), 1194 (s), 1177 (m), 1108 (m), 1072
(m), 1039 (m), 1007 (w), 968 (w), 897 (w), 886 (w), 795 (s),
740 cm–1 (m).
IR (neat): 3436 (s), 2970 (m), 2860 (vs), 2860 (s), 1628 (w), 1576
(vs), 1513 (vs), 1473 (w), 1447 (m), 1348 (s), 1317 (w), 1267 (s),
1211 (s), 1167 (w), 1125 (w), 1107 (w), 1077 (w), 1059 (w), 1040
(w), 920 (w), 798 (s), 777 (m), 746 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 1.11, 1.13 (t, 3J = 7.2 Hz,
1H NMR (300 MHz, CDCl3): d = 1.06 (t, 3J = 7.2 Hz, 3 H,
H3CCH2N-5), 1.25 (m, 2 H), 1.54 (m, 5 H), 1.78 (m, 1 H), 3.20 (m,
4 H), 3.79 (s, 1 H, NH), 6.21 (d, 3J = 5.7 Hz, 1 H, H-4), 7.57 (s, 1 H,
H-1), 7.65 (d, 3J = 5.7 Hz, 1 H, H-3).
13C NMR (75 MHz, CDCl3): d = 12.1 (H3CCH2N-5), 19.3 (C-7),
24.8 (C-8), 26.8 (C-6), 30.9 (C-9), 42.8 (H3CCH2N-5), 47.8 (C-5a),
58.4 (C-9a), 103.9 (C-4), 129.8 (Cq-10a), 133.4 (C-1), 138.4 (Cq-
4a), 140.9 (C-3).
GC-MS (EI): tR = 10.58 min; m/z (%) = 218 (17), 217 (M+, 100),
216 (7), 215 (7), 213 (5), 203 (5), 202 (51), 186 (17), 185 (5), 174
(12), 162 (6), 161 (8), 160 (9), 158 (7), 148 (5); 148 (5), 146 (16),
145 (7), 134 (8), 133 (9), 132 (25), 120 (14), 78 (4).
3
H3CCH2N-5, J = 7.2 Hz, H3CCH2N-10, 6-H), 1.37 (m, 2 H, H-
3
3
7,8), 1.56 (m, Ja,a = 6.8, Je,e = 3.2 Hz, 4 H, H-6, H-9, H-7, H-8),
1.76 (m, 3Ja,e = 3.2 Hz, 1 H, H-9), 1.89 (m, 3Ja,e = 3.2 Hz, 1 H), 3.18
3
2
(dq, J = 7.2, J = 14.4 Hz, 2 H, H3CCHABN-5, H3CCHABN-10),
3
3
3
3.23 (ddd, Ja,e = 2.8, Ja,e = 3.2, Ja,a = 6.8 Hz, 1 H, H-5a),
3.34 (ddd, Ja,e = 2.8, Ja,e = 3.2, Ja,e = 3.2 Hz, H-1, H-9a),
3.43 (dq, J = 7.2, J = 14.4 Hz, H3CCHABN-5, H3CCHABN-10, 2
H, H-1), 6.33 (d, 3J = 5.6 Hz, 1 H, H-4), 7.67 (s, 1 H, H-1), 7.72 (d,
3J = 5.6 Hz, 1 H, H-3).
3
3
3
3
2
13C NMR (100 MHz, CDCl3): d = 10.8 (H3CCH2N-5), 11.8
(H3CCH2N-10), 21.7 (C-7), 22.9 (C-8), 27.3 (C-6), 27.8 (C-9),
40.4 (H3CCH2N-5), 41.7 (H3CCH2N-10), 52.8 (C-9a), 56.4 (C-5a),
104.3 (C-4), 130.6 (C-10a, C-1), 139.4 (C-3), 141.2 (C-4a).
MS (EI): m/z (%) = 246 (18), 245 (M+, 100), 231 (9), 230 (57), 217
(7), 216 (44), 207 (6), 186 (7), 174 (15), 162 (6), 160 (16), 158 (6),
148 (12), 146 (6), 132 (8).
HRMS (EI): m/z calcd for C13H19N3 [M+]: 217.1579; found:
215.1573.
1-(5-Ethyl-5a,6,7,8,9,9a-hexahydro-5H-pyrido[3,4-b]quinoxa-
lin-10-yl)ethanone (30)
HRMS (EI): m/z calcd for C15H23N3 [M+]: 245.1892; found:
245.1889.
Compound 29 (0.250 g, 1.15 mmol) was dissolved in THF (10 mL)
THF in a 100 mL Schlenk-flask. The solution was cooled to –78 °C
and then n-BuLi (0.51 mL, 1.27 mmol, 1.1 equiv, 2.5 M in hexane)
was added and the mixture was stirred for 30 min without cooling.
After 30 min, the mixture was cooled again to –78 °C and AcCl
(0.09 mL, 0.109 g, 1.4 mmol) was added and then allowed to stir for
1 h without cooling. Afterwards, the mixture was quenched with
H2O (4 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined
organic phases were dried (Na2SO4) and the solvent was distilled off
by rotary evaporation. The crude product was purified by flash
chromatography on silica gel (EtOAc–MeOH, 10:2) to yield 16%
(48 mg) of pure 30; Rf = 0.16 (EtOAc–Et3N, 10:1).
1-(6,7,8,9,9a,10-Hexahydro-5aH-pyrido[3,4-b]quinoxalin-5-
yl)ethanone (28)
In
a 100 mL round-bottomed flask, compound 27 (1.0 g,
5.28 mmol) was dissolved in CH2Cl2 (20 mL), and Et3N (2.20 mL,
15.84 mmol) and PPY (39 mg, 0.264 mmol, 5 mol%) were added.
Afterwards, Ac2O (0.54 mL, 5.81 mmol) was added and the mix-
ture was stirred for 30 min. After 30 min, the reaction was quenched
by addition of MeOH (2 mL), and after stirring for 10 min, the sol-
vent was distilled off by rotary evaporation. The crude product ob-
tained was purified by flash chromatography on silica gel (EtOAc–
Et3N–MeOH, 10:1:1) to afford 1 g (82%) of 28. The product ob-
tained in this way still contained traces of PPY and was used as such
without further purification; Rf = 0.44 (EtOAc–Et3N–MeOH,
10:1:1).
1H NMR (300 MHz, CDCl3): d = 1.44 (m, 5 H), 1.76 (m, 3 H),
2.29 (s, 3 H, H3CCON), 3.59 (m, 1 H), 4.07 (m, 1 H), 7.08 (br s, 1
H, H-4), 7.85 (d, 3J = 5.4 Hz, 1 H, H-3), 7.98 (s, 1 H, H-1).
13C NMR (75 MHz, CDCl3): d = 18.5 (CH2), 23.5 (H3CCON), 24.8,
25.4 (CH2), 31.08 (CH2), 48.9 (C-9a), 118.1 (Cq-4a), 127.9 (Cq-
10a), 132.2 (C-4), 136.6 (C-1), 138.0 (C-3), 169.0 (C=O).
IR (neat): 3398 (s), 2933 (s), 2863 (m), 1731 (m), 1637 (vs), 1595
(vs), 1512 (s), 1546 (w), 1449 (m), 1397 (s), 1365 (s), 1334 (m),
1285 (s), 1239 (m), 1198 (m), 1168 (vs), 1123 (w), 1067 (w), 1068
(w), 1016 (w), 802 (vs), 718 (w), 668 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 1.19 (t, 3J = 7.2 Hz, 3 H,
H3CCH2N-5), 1.24 (m, 2 H), 1.45 (m, 2 H), 1.58 (m, 2 H), 1.74 (m,
1 H), 2.18 (m, 1 H), 3.34 (m, 2J = 14.4, 3J = 7.2 Hz, 1 H,
H3CCHABN-5), 3.53 (m, 1 H, CH), 3.57 (m, 2J = 15.2, 3J = 7.2 Hz,
1 H, H3CCHABN-5), 4.90 (br s, 1 H, CH), 6.62 (d, 3J = 5.6 Hz, 1 H,
H-4), 8.12 (s, 1 H, H-1), 8.08 (d, 3J = 5.6 Hz, 1 H, H-3).
13C NMR (100 MHz, CDCl3): d = 12.4 (H3CCH2N-5), 18.9 (C-7),
HRMS (EI): m/z calcd for C13H17N3O [M+]: 231.1372; found:
22.8 (H3CCON-10),
24.7 (C-8),
25.8 (C-6),
28.5 (C-9),
231.1368.
40.0 (H3CCH2N-5), 48.7 (C-9a), 53.7 (C-5a), 106.4 (C-4),
120.1 (Cq-10a), 145.1, 145.2 (C-1, Cq-4a), 147.1 (C-3),
167.1 (C=O).
GC-MS (EI): tR = 10.39 min; m/z (%) = 260 (11), 259 (M+, 100),
230 (8), 218 (9), 217 (79), 216 (40), 203 (4), 202 (23), 203 (3), 202
(23), 201 (4), 189 (6), 188 (31), 187 (4), 186 (3), 174 (11), 162 (4),
161 (6), 160 (5), 158 (4), 148 (5), 146 (6), 136 (3), 132 (4),
131 (12), 120 (6), 43 (3).
5-Ethyl-5,5a,6,7,8,9a,10-octahydropyrido[3,4-b]quinoxaline
(29)
AlCl3 (0.619 g, 4.64 mmol) was suspended in THF (30 mL) at r.t.
After stirring for 45 min, the mixture was cooled to 0 °C and
LiAlH4 (0.300 g, 7.91 mmol) was added in small portions. The mix-
ture was stirred for 15 min and then compound 28 (0.832 g,
3.59 mmol) was added. The mixture was stirred for 1 h at 0 °C and
then refluxed for 8 h. It was then allowed to cool down to r.t. and
then poured into ice water (30 mL). The inorganic precipitate was
filtered off and washed with CH2Cl2 (2 × 30 mL). The aqueous layer
was basified with aq NaOH (30%) to pH 12 and extracted with
CH2Cl2 (3 × 40 mL). The combined organic extracts were dried
(Na2SO4) and the solvent was distilled off by rotary evaporation.
The crude material obtained was purified with flash chromatogra-
HRMS (EI): m/z calcd for C15H21N3O [M+]: 259.1685; found:
259.1687.
2,3-Diphenylpyrido[3,4-b]quinoxaline (25)
Modified Procedure from Ref. 14: To a suspension of 3,4-diami-
nopyridine (2.86 g, 0.026 mol) in EtOH (50 mL) was added benzil
(5.51 g, 0.026 mol). The flask was immersed in an oil bath and kept
Synthesis 2007, No. 8, 1185–1196 © Thieme Stuttgart · New York

1194
I. Held et al.
PAPER
at 70 °C oil bath temperature for 6 h. After cooling to r.t., the yellow
precipitate (ice cooling may be useful) was collected by filtration
and recrystallized from EtOH to afford 6.91 g (94%) of 25 as a faint
yellow solid.
crude product was purified by flash chromatography (CHCl3–iso-
hexane–Et3N, 10:2:1) to afford (0.564 g, 90%) of a faint yellow sol-
id; Rf = 0.40 (CHCl3–isohexane–Et3N, 10:2:1).
IR (neat): 3200 (w), 3158 (w), 3029 (w), 2948 (w), 2881 (w), 2824
(w), 1578 (s), 1516 (vs), 1491 (m), 1452 (m), 1421 (m), 1374 (w),
1353 (w), 1326 (w), 1294 (w), 1256 (m), 1235 (m), 1199 (w), 1157
(m), 1131 (m), 1103 (w), 1073 (m), 1054 (m), 1031 (m), 1013 (m),
969 (w), 922 (w), 842 (w), 810 (s), 766 (s), 755 (m), 733 (m),
641 cm–1 (vs).
1H NMR (400 MHz, CDCl3): d = 2.85 (s, 3 H, CH3), 4.42 (s, 1 H,
NH), 4.44 (d, 3J = 3.6 Hz, 1 H, H-3), 4.95 (d, 3J = 3.6 Hz, 1 H, H-
2), 6.50 (d, 3J = 5.2 Hz, 1 H, H-8), 6.64 (dd, 4J = 2.8, 3J = 9.2 Hz, 2
H, 2,6-CH, C6H5), 6.90 (m, 2 H, 2,6-CH, C6H5), 7.05 (m, 2 H, CH,
C6H5), 7.16 (m, 4 H, CH, C6H5), 7.82 (s, 1 H, H-5), 7.84 (d,
3J = 5.2 Hz, 1 H, H-7).
13C NMR (75 MHz, CDCl3): d = 37.2 (CH3), 57.8 (C-3), 67.9 (C-
2), 107.6 (C-8), 127.4–128.5 (CH, C6H5), 131.3 (C-5), 131.6 (Cq,
C-4a), 137.4, 138.8 (Cq, C6H5), 139.9 (C-7, C-8a).
MS (EI): m/z (%) = 302 (22), 301 (M+, 100), 300 (5), 286 (5), 224
(10), 222 (4), 211 (13), 210 (87), 209 (3), 208 (6), 195 (11), 181 (6),
179 (3), 178 (3), 178 (3), 150 (7), 132 (3), 127 (3), 120 (3), 104 (4);
92 (3), 91 (31), 85 (4), 83 (6), 78 (4), 77 (5).
IR (neat): 3061 (w), 1589 (m), 1577 (w), 1538 (w), 1492 (w), 1443
(m), 1419 (w), 1379 (s), 1346 (w), 1326 (m), 1315 (m), 1288 (w),
1211 (m), 1244 (w), 1227 (m), 1212 (w), 1180 (w), 1075 (m), 1058
(m), 1020 (m), 1001 (w), 976 (s), 921 (w), 892 (m), 892 (m),
830 (m), 819 (w), 811 (m), 763 (s), 735 (m), 708 (vs), 629 (s),
615 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 7.32–7.42 (m, 6 H, 3,4,5-CH,
C6H5), 7.54–7.51 (m, 4 H, 2,6-CH, C6H5), 7.98 (dd, 3J = 6,
4J = 0.8 Hz, 1 H, 7-H), 8.82 (d, 3J = 6 Hz, 1 H, 8-H), 9.59 (d,
4J = 0.8 Hz, 1 H, 5-H).
13C NMR (100 MHz, CDCl3): d = 121.3 (C-7), 128.4, 129.4–
129.9 (CH, C6H5), 136.3 (Cq-4a), 143.5 (Cq-8a), 147.3 (C-8),
154.5 (C-5), 155.3, 157.9 (Cq, C6H5).
GC-MS (EI): tR = 12.34 min; m/z (%) = 285 (3), 284 (M+ + H, 22),
283 (M+, 100), 282 (46), 206 (2), 181 (3), 180 (25), 179 (17), 154
(3), 153 (5), 152 (3), 142 (1), 141 (8), 140 (4), 127 (2), 104 (3), 103
(14), 102 (3), 78 (2), 77 (5), 76 (4), 51 (2), 50 (9).
2,3-Diphenyl-1,2,3,4-tetrahydropyrido[3,4-b]pyrazine (31)
To a solution of 25 (6.25 g, 22.05 mmol) in EtOH (200 mL) in a
500 mL flask, was added powdered NaBH4 (6.25 g, 165.20 mmol).
The mixture was kept at 40 °C for 48 h, cooled to r.t. and quenched
with cold H2O (10 mL). After stirring for 10 min, the mixture was
extracted with CH2Cl2 (2 × 100 mL). The combined organic phases
were dried (Na2SO4) and the solvent was removed by rotary evapo-
ration. The crude product obtained was purified with flash chroma-
tography on silica gel (EtOAc–Et3N, 10:1) to afford (4.70 g, 74%)
of a faint yellow solid; Rf = 0.23 (EtOAc–Et3N, 10:1).
HRMS (EI): m/z calcd for C20H19N3 [M+]: 301.1574; found:
301.1559.
4-(Methyl-2,3-diphenyl-1,2,3,4-tetrahydropyrido[3,4-b]pyr-
azin-1-yl)ethanone (33)
In a 250 mL Schlenk-flask, compound 32 (2.90 g, 9.62 mmol) was
dissolved in MTBE (100 mL). The solution was cooled to –78 °C
and n-BuLi (4.62 mL, 11.50 mmol, 1.1 equiv, 2.5 M in hexane) was
added over 10 min. The mixture was stirred without cooling for
30 min, then cooled down again to –78 °C and AcCl (1.0 mL,
0.96 g, 12.55 mmol) was added. The mixture was allowed to warm
up to r.t. and stirred for 30 min at that temperature. After quenching
the reaction with H2O (10 mL), the mixture was extracted with
CH2Cl2 (3 × 50 mL). The combined organic phases were dried
(Na2SO4) and the solvent was distilled off by rotary evaporation.
The crude product can either be purified by recrystallization from
EtOAc or purified by flash chromatography on silica gel (CHCl3–
isohexane–Et3N) to afford 1.2 g (36%) of a white solid.
IR (neat): 3215 (w), 2830 (w), 1596 (s), 1519 (s), 1493 (w), 1466
(w), 1452 (s), 1360 (m), 1290 (s), 1250 (m), 1231 (m), 1174 (s),
1120 (m), 1072 (m), 1050 (w), 1029 (w), 1005 (w), 989 (w), 950
(w), 905 (w), 844 (w), 810 (m), 770 (m), 723 (m), 675 (vs),
668 (w), 645 (w), 618 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 3.99 (s, 1 H, NH), 4.59 (s, 2 H,
2,3-H), 4.62 (s, 1 H, NH), 6.39 (d, 3J = 5.4 Hz, 1 H, 8-H), 6.80 (dd,
4J = 1.2, 3J = 9.3 Hz, 2 H, 2,6-CH, C6H5), 6.84 (dd, 4J = 1.2,
3J = 9.3 Hz, 2 H, 2,6-CH, C6H5), 7.12 (m, 6 H, 3,4,5-CH, C6H5).
13C NMR (75 MHz, CDCl3): d = 58.6, 60.1 (C-2,3), 108.0 (C-8),
127.9–128.4 (CH, C6H5), 129.8 (C-4a), 139.8 (Cq, C6H5),
140.0 (Cq-8a), 134.9 (C-5), 141.3 (C-7).
MS (EI): m/z (%) = 288 (22), 287 (M+, 100), 286 (24), 285 (7), 284
(6), 283 (8), 282 (5), 211 (13), 210 (78), 209 (5), 208 (13), 197 (4),
196 (26), 181 (13), 179 (3), 127 (4), 104 (7), 92 (3), 91 (32), 77 (5).
IR (neat): 2428 (m), 2039 (w), 1688 (s), 1613 (w), 1534 (s), 1492
(m), 1454 (w), 1388 (m), 1364 (m), 1345 (m), 1317 (w), 1292 (w),
1292 (w), 1272 (w), 1227 (vs), 1209 (vs), 1122 (w), 1103 (w), 1078
(m), 1028 (m), 998 (m), 822 (s), 799 (m), 768 (m), 704 (m),
691 (m), 638 cm–1 (w).
1H NMR (600 MHz, CDCl3): d = 2.40 (s, 3 H, H3CCON), 2.86 (s, 3
3
H, CH3), 4.99 (m, 1 H, H-3), 5.35 (d, J = 4.2 Hz, 1 H, H-2), 6.53
(d, 3J = 7.8 Hz, 2 H, 2,6-CH, C6H5), 6.80 (br s, 2 H, 2,6-CH, C6H5),
7.08 (t, 3J = 7.2 Hz, 2 H, CH, C6H5), 7.17 (t, 3J = 6.0 Hz, 2 H, CH,
C6H5), 7.22 (t, 3J = 6.0 Hz, 1 H, CH, C6H5), 7.25 (t, 3J = 6.0 Hz, 1
HRMS (EI): m/z calcd for C19H17N3 [M+]: 287.1422; found:
287.1402.
3
H, CH, C6H5), 8.03 (d, J = 6.6 Hz, 1 H, H-8), 8.17 (s, 1 H, H-5),
8.41 (d, 3J = 6.6 Hz, 1 H, H-7).
4-Methyl-2,3-diphenyl-1,2,3,4-tetrahydropyrido[3,4-b]pyr-
azine (32)
13C NMR (150 MHz, CDCl3): d = 24.60 (H3CCON), 36.9 (H3C),
61.8 (C-3), 63.8 (C-2), 116.9 (C-8), 124.6 (C-5), 128.4–128.9 (CH,
C6H5), 134.7 (Cq-8a), 138.7 (Cq-4a), 171.0 (C=O).
GC-MS (EI): tR = 1.22 min; m/z (%) = 345 (3), 344 (27), 343 (M+,
100), 315 (6), 302 (7), 301 (41), 300 (84), 224 (6), 223 (4), 222 (5),
211 (4), 210 (27), 208 (9), 195 (6), 181 (9), 179 (4), 178 (4), 146 (4),
118 (15), 104 (5), 92 (9), 91 (94), 78 (4), 77 (4), 43 (6).
In a 100 mL round-bottomed flask was dissolved under ice cooling
compound 31 (0.600 g, 2.08 mmol) in formic acid (15.5 mL,
417.6 mmol), and aq formaldehyde solution (5.1 mL;
183.6 mmol, 37% in H2O) was added. After addition, the ice bath
was removed and the mixture was heated at 120 °C oil bath temper-
ature for 48 h. The mixture was then cooled to r.t., and under ice
cooling aq NaOH (50%) was added dropwise until the pH of the re-
action mixture had reached a value of 12. The mixture was extracted
with CH2Cl2 (3 × 50 mL), the combined organic phases were dried
(Na2SO4), and the solvent was removed by rotary evaporation. The
HRMS (EI): m/z calcd for C22H23N3O [M+]: 343.1685; found:
343.1699.
Synthesis 2007, No. 8, 1185–1196 © Thieme Stuttgart · New York

PAPER
3,4-Diaminopyridines as Highly Active Acylation Catalysts
1195
1-Ethyl-4-methyl-2,3-diphenyl-1,2,3,4-tetrahydropyr-
ido[3,4-b]pyrazine (34)
K2CO3 (50 mL) and CHCl3 (25 mL). The aqueous phase was ex-
tracted with CHCl3 (3 × 100 mL). The combined organic phases
were dried (MgSO4) and the solvent was removed by rotary evapo-
ration to afford a low melting solid. The crude product was purified
on silica gel by chromatography (30:1, CHCl3–MeOH) to give
1.60 g (52%) of a brown solid.
AlCl3 (0.575 g, 4.320 mmol) was suspended in THF (20 mL) at r.t.
After stirring for 45 min, the mixture was cooled to 0 °C and
LiAlH4 (0.277 g, 7.290 mmol) was added in small portions. The
mixture was then stirred for 15 min and compound 33 (1.00 g,
3.32 mmol) was added. The mixture was stirred at 0 °C for further
60 min and then refluxed for 12 h. Afterwards, the mixture was
cooled to r.t. and poured into ice water. The precipitate was collect-
ed by filtration and the mother liquor was extracted with CH2Cl2.
The combined organic phases were dried (Na2SO4) and the solvent
was removed by rotary evaporation. The crude product was purified
by flash chromatography (EtOAc–MeOH–Et3N, 10:1:0.5) to afford
0.580 g (53%) of a faint yellow solid; Rf = 0.57 (EtOAc–MeOH–
Et3N, 10:1:0.5).
(E)-3-(1,6-Naphthyridin-8-yl)acrylate Ethyl Ester (42)
A 100 mL sealed tube equipped with a magnetic stirrer was dried,
purged with N2 and charged with Pd(OAc)2 (30 mg, 0.11 mmol, 2.6
mol%), (tol)3P (80.9 mg, 0.27 mmol), Et3N (0.88 mL, 6.29 mmol),
ethyl acrylate (1.75 mL, 16.08 mmol), 41 (1.98 g, 9.47 mmol) and
MeCN (6 mL). The sealed tube was immersed in a silicon oil bath
heated to 120 °C for 16 h. The mixture was diluted with H2O (10
mL) and extracted with CHCl3 (3 × 35 mL). After extracting the
combined organic layers with 2 M aq HCl (3 × 25 mL), the aqueous
phases were combined and made basic by the addition of K2CO3.
The cloudy aqueous phase was then extracted with CH2Cl2 (4 × 35
mL) and the combined organic phases were dried (Na2SO4). Evap-
oration of the solvent, followed by flash chromatography of the res-
idue on silica gel using 10% isohexane–EtOAc as the eluent,
furnished 1.83 g (85%) of 42 as a faint yellow solid.
IR (neat): 2965 (w), 2818 (w), 1578 (s), 1518 (vs), 1492 (m), 1452
(s), 1430 (w), 1371 (m), 1356 (m), 1308 (m), 1286 (m), 1266 (s),
1241 (s), 1215 (vs), 1165 (m), 1119 (m), 1067 (s), 1023 (s), 884 (w),
867 (w), 828 (w), 810 (s), 764 (s), 749 (m), 705 (vs), 660 (w),
615 cm–1 (w).
1H NMR (400 MHz, CDCl3): d = 1.05 (t, 3J = 7.2 Hz, 3 H,
2
3
H3CCH2N), 2.71 (s, 3 H, H3C), 3.17 (qd, J = 14.8, J = 7.2 Hz, 1
H, CH3CHABN), 3.38 (qd, 2J = 14.8, 3J = 7.2 Hz, 1 H, CH3CHABN),
4.40 (d, 3J = 3.6 Hz, 1 H, H-3), 4.55 (d, 3J = 3.6 Hz, 1 H, H-2), 6.52
(d, 3J = 5.6 Hz, 1 H, H-8), 6.73 (m, 4 H, CH, C6H5), 7.07 (t,
4,5,9,10-Tetrahydro-8H-pyrido[3,2,1-ij][1,6]naphthyridine-6-
one (43)
A 250 mL three-necked round-bottomed flask equipped with a mag-
netic stirrer and a three-way stopcock attached to a N2 and H2 inlet
was charged with a solution of 42 (4.12 g, 18 mmol) in anhyd EtOH
(120 mL) and Pd on activated carbon (10% Pd, 992 mg). The system
was purged with N2 and then purged with H2. The reaction was
monitored by 1H NMR and was complete after the 1H-signals for the
olefinic and aromatic protons in the 2-, 3- and 4- position were no
longer detected. The mixture was filtered through Celite and the sol-
vent was removed by rotary evaporation. The crude product was pu-
rified on silica gel by column chromatography (40:1, CHCl3–
MeOH, 5.0% Et3N) to afford a white solid (2.97 g, 87%).
3
3J = 7.2 Hz, 2 H, CH, C6H5), 7.11 (t, J = 8 Hz, 2 H, CH, C6H5),
7.16 (m, 2 H, CH, C6H5), 7.92 (s, 1 H, H-5), 7.96 (d, 3J = 5.6 Hz, 1
H, H-7).
13C NMR (100 MHz, CDCl3): d = 11.1 (H3CCH2N), 37.1 (H3CN),
43.3 (H3CCH2N), 65.7 (C-2), 66.0 (C-3), 104.3 (C-8), 127.7–129.3
(CH, C6H5), 133.0 (C-5), 133.3 (Cq-8a), 137.8, 138.6 (Cq, C6H5),
140.8 (Cq-8a), 141.0 (C-7).
LC-HRMS (ESI): tR = 0.53–1.43 min; m/z calcd for C44H47N6
[2 M+ + H]: 659.3862; found: 659.3823; m/z calcd for C22H24N3
[M+ + H]: 330.1970; found: 330.1940.
5,6,9,10-Tetrahydro-4H,8H-pyrido[3,2,1-ij][1,6]naphthyridine
(5)18
1,6-Naphthyridine (40)
A 1000 mL three-necked round-bottomed flask fitted with a reflux
condenser was charged with fresh fuming H2SO4 (50 mL,
648 mmol, 20% free SO3) and nitrobenzene (18.4 mL, 178 mmol).
The flask was immersed in an oil bath and kept at 70 °C for 8 h. Af-
ter cooling to r.t., the mixture was cooled in an ice bath, while slow-
ly glycerin (19.9 mL, 272 mmol) and 4-aminopyridine (7.5 g,
80 mmol) were added. Afterwards demineralized H2O (40 mL) was
added and the mixture was stirred until a homogenous mixture was
obtained. The ice bath was removed and the mixture was heated to
130 °C in an oil bath for 5 h. The mixture was allowed to cool to r.t.
and then cooled in an ice bath, while slowly adding aqueous NaOH
(20%, approx. 400 mL) up to pH 12. The solid precipitate was fil-
tered off by suction and washed with CHCl3 (250 mL). The aqueous
phase was extracted with CHCl3 (750 mL) and the combined organ-
ic phases were dried (NaSO4). The solvent was distilled off by rota-
ry evaporation and the crude product obtained was used without
further purification: 5.10 g (49% yield) of an brown oil which solid-
ified upon standing in the fridge (5.10 g).
A 250 mL Schlenk flask equipped with a magnetic stirrer, reflux
condenser, and N2 inlet was dried, purged with N2 and charged with
THF (120 mL) and AlCl3 (5.33 g, 39 mmol). After the solution was
made homogeneous by stirring, LiAlH4 (4.55 g, 120 mmol) and a
solution of 43 (2.97 g, 120 mmol) in THF (50 mL) were added. The
flask was immersed in an oil bath and the mixture was refluxed for
20 h. After cooling to r.t., the mixture was poured into ice water.
The aqueous phase was made basic by adding aq sat. K2CO3 solu-
tion (30 mL). The aqueous phase was extracted with CH2Cl2 (3 × 30
mL). The combined organic extracts were dried (Na2SO4) and the
solvent was removed by rotary evaporation. The crude product was
purified on silica gel by column chromatography (CHCl3–MeOH,
10:1, 2.5% Et3N) to provide 2.05 g (74%) of a white solid.
Crystals of 34 and 5 suitable for single crystal X-ray diffraction
studies could be obtained from CH2Cl2–hexane mixtures at 5 °C.
Data describing the solid state strutcure of 34 and 5 have been de-
posited in the Cambridge Crystallographic Data Center with depo-
sition number CCDC 622355 for 34 and CCDC 633500 for 5.
8-Bromo-1,6-naphthyridine (41)
A 250 mL three-necked round-bottomed flask equipped with a mag-
netic stirrer, reflux condenser and addition funnel was charged with
anhyd AcOH (100 mL) and 1,6-naphthyridine (40; 1.92 g,
14.8 mmol). Br2 (0.86 mL, 16.3 mmol) was added slowly over a pe-
riod of 30 min and afterwards the flask was immersed in an oil bath
and heated to 80 °C for 12 h. The AcOH was removed by vacuum
distillation and the remaining residue was diluted in ice-cold aq sat.
Acknowledgment
This work has been financially supported by the Deutsche For-
schungsgemeinschaft (DFG) under the focus program ‘organocata-
lysis’. We thank Herbert Mayr and Wolfgang Steglich for
stimulating discussions.
Synthesis 2007, No. 8, 1185–1196 © Thieme Stuttgart · New York

1196
I. Held et al.
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Synthesis 2007, No. 8, 1185–1196 © Thieme Stuttgart · New York