Synthesis of 3,4-benzo-7-hydroxy-2,9-diazabicyclo[3.3.1]non-7-enes by cyclization of 1,3-bis(silyl enol ethers) with quinazolines

Article abstract of DOI:10.1039/b803141j

A variety of functionalized 3,4-benzo-7-hydroxy-2,9-diazabicyclo[3.3.1]non- 7-enes were prepared by one-pot cyclizations of 1,3-bis(silyl enol ethers) with quinazolines. The mechanism of the cyclization was studied by B3LYP/6-31G(d) density functional theory computations. The products could be functionalized by Suzuki cross-coupling reactions. The reaction of 1,3-bis(silyl enol ethers) with phthalazine afforded open-chain rather than cyclization products. The Royal Society of Chemistry.

Full text of DOI:10.1039/b803141j

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Synthesis of 3,4-benzo-7-hydroxy-2,9-diazabicyclo[3.3.1]non-7-enes by
cyclization of 1,3-bis(silyl enol ethers) with quinazolines†
Vahuni Karapetyan,a Satenik Mkrtchyan,a Andreas Schmidt,a Jo¨rg-Peter Gu¨tlein,a Alexander Villinger,a
Helmut Reinke,a Haijun Jiao,b Christine Fischerb and Peter Langer*a,b
Received 22nd February 2008, Accepted 16th May 2008
First published as an Advance Article on the web 21st June 2008
DOI: 10.1039/b803141j
A variety of functionalized 3,4-benzo-7-hydroxy-2,9-diazabicyclo[3.3.1]non-7-enes were prepared by
one-pot cyclizations of 1,3-bis(silyl enol ethers) with quinazolines. The mechanism of the cyclization
was studied by B3LYP/6-31G(d) density functional theory computations. The products could be
functionalized by Suzuki cross-coupling reactions. The reaction of 1,3-bis(silyl enol ethers) with
phthalazine afforded open-chain rather than cyclization products.
antiviral activity has been reported.9 Chlorinated 1,2,4-triazolo-
Introduction
[1,5-c]quinazolines and the isomeric 1,2,4-triazolo[4,3-c]quina-
Iminium salts represent important synthetic building blocks.1
In recent years, cyclocondensation reactions of iminium salts
with bis(silyl enol ethers) have been reported, which al-
low for a convenient synthesis of various bridged and non-
bridged N-heterocycles.2 Recently, we reported3 the cyclization
of 1,3-bis(trimethylsilyloxy)-1,3-butadienes4 with quinazolines.
These one-pot reactions allow for the synthesis of densely
functionalized 3,4-benzo-7-hydroxy-2,9-diazabicyclo[3.3.1]non-7-
enes, which can be regarded as bridged quinazoline derivatives.
Herein, we report the full details of this reaction and a com-
prehensive study related to the preparative scope. A number of
novel quinazolines were prepared for the first time and successfully
employed in our cyclization reaction. This includes, for example,
derivatives containing an annulated ring or a lipophilic side-
chain (hexyl group). It has been shown that the products can be
functionalized by Suzuki cross-coupling reactions. In addition, we
studied the mechanism of the cyclization by DFT computations.
We also studied the reaction of 1,3-bis(silyl enol ethers) with
phthalazine. These reactions afforded open-chain rather than
cyclization products.
zolines exhibit antiinflammatory and sedative activity.10
Results and discussion
Parent quinazoline (3a), 7-bromoquinazoline (3b) and 6-methyl
quinazoline (3c) are commercially available. These substrates were
used in our preliminary studies. The novel quinanzolines 3d–i
were prepared in two steps according to a procedure reported by
Chilin and coworkers (Table 1).11 Anilines 1a–f were transformed
into the carbamates 2a–f. Reflux of 2a–f in the presence of
hexamethylenetetramine (HMTA, urotropine) and trifluoroacetic
acid (TFA) and subsequent reflux in the presence KOH (EtOH–
H2O 1 : 1) and K3Fe(CN)6 afforded the novel quinazolines 3d–i
Table 1 Synthesis of quinazolines 3d–i
Quinazoline derivatives are of considerable pharmacological
importance and occur in a number of natural products (e.g.
tetrodotoxin, febrifugine, glomerine, or peganine). For example,
1,2,4-triazolo[5,1-b]quinazolines show antihypertonic activity.5
Antirheumatic and antianaphylactic activity has been recog-
nized for 3-heteroaryl-1,2,4-triazolo[5,1-b]quinazolines.6 1,2,4-
Triazolo[1,5-c]quinazolines possess antiasthmatic, tranquilizing
and neuro-stimulating activity.7 Aryl- and heteroaryl substituted
derivatives have been shown to possess benzodiazepine bind-
ing activity.8 In addition, antiinflammatory, antihypertonic and
Reagents and conditions: i, 1a–f (1.0 equiv.), NEt3 (2.0 equiv.),
ClCO2Et (2.0 equiv.), THF, 20 ◦C, 1 h; ii, (a) 2a–f (1.0 equiv.),
HMTA (7.0 equiv.), TFA, reflux, 1 h (b) 10% KOH
(EtOH–H2O = 1 : 1), K3Fe(CN)6 (7.6 equiv.), reflux, 4 h
1
3
R1
R2
%(3)a
aInstitut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059
Rostock, Germany. E-mail: peter.langer@uni-rostock.de; Fax: 00 49 381
49864112; Tel: 0049 381 4986410
a
b
c
d
e
f
d
e
f
g
h
i
Et
iPr
tBu
nHex
–(CH2)3–
Me
H
H
H
H
21
35
30
30
54
35
bLeibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-
Einstein-Str. 29a, 18059 Rostock, Germany
† Electronic supplementary information (ESI) available: Experimental
and computational details. CCDC reference numbers 676867–676869 and
677226. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/b803141j
Me
a Isolated yields (based on 1).
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Table 2 Cyclization of 1,3-bis(silyl enol ethers) 4a–g with 3a–i
of only 3.0 (rather than 4.0) equivalents of methyl chloroformate
resulted in a decrease of the yield. Methyl or benzyl chloroformate
was used as the activating agent. The employment of methyl iodide
or TFA resulted in the formation of complex mixtures. Optimal
yields were obtained when the reaction mixture was directly
purified by chromatography (without aqueous work-up) and when
the reaction was carried out at room temperature. The formation
of the products can be explained by the formation of an iminium
salt by reaction of 3a with methyl chloroformate, and subsequent
regioselective attack of the terminal carbon atom of the 1,3-
bis(silyl enol ether) onto carbon atom C-4 of the quinazoline. The
reaction of the second nitrogen atom with methyl chloroformate
again afforded an iminium ion, which is attacked by the central
carbon atom of the 1,3-dicarbonyl unit.
The cyclization of 3a with 4d, derived from acetyl acetone,
gave the acetyl-substituted diazabicyclo[3.3.1]nonene 5d. The
cyclization of 3a with 4d, in the presence of benzyl chloroformate,
afforded product 5dꢀ. However, all attempts to induce a reductive
cleavage of the protective group failed. The reaction of 3a with 2,4-
bis(trimethylsilyloxy)-5,5-dimethylhexane-1,3-diene (4e) afforded
a separable mixture of diazabicyclo[3.3.1]nonene 5e and an open-
chain product. Due to the difficult separation, 5e could be
isolated in only low yield. The reaction of 3a with 1-phenyl-1,3-
bis(trimethylsilyloxy)buta-1,3-diene (4f) resulted in the formation
of a complex mixture. The cyclization of 1,3-bis(silyloxy)-1,3-
butadienes with the substituted quinazolines 3b–i afforded the
diazabicyclo[3.3.1]nonenes 5g–z. The deprotection of 5a and 5d
failed under various conditions (decomposition).
Reagents and conditions: i, 3a–i (1.0 equiv.), 4a–g (1.4 equiv.), ClR4
(4.0 equiv.), CH2Cl2, 0 ◦C, 2 h, 20 ◦C, 12 h
3
4
5
R1
R2
R3
% (5)a
a
a
a
a
a
a
b
b
c
c
d
d
d
e
e
e
f
a
b
c
d
e
f
c
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
OMe
OEt
O(CH2)2OMe
Me
tBu
Ph
O(CH2)2OMe
Me
OMe
Me
OMe
OEt
Me
OMe
OEt
Me
OMe
O(CH2)2OMe
OiBu
Me
OMe
Me
OMe
Me
OMe
Me
H
H
H
H
H
H
Br
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Et
Et
Et
iPr
iPr
iPr
tBu
tBu
tBu
tBu
nHex
nHex
52
46
53
63b
12
0
The cyclization of 3a with 1,3-bis(silyl enol ethers) 4h and
4i, containing an ethyl group attached to carbon atom C-4,
afforded products 5aa and 5ab as mixtures of diastereomers
(dr = 7 : 3 and 2 : 1, respectively) (Table 3). The cyclization of
23
37
43
31
43
37
26
44
44
38
50
38
54
44
37
53
51
53
46
48
d
a
d
a
b
d
a
b
d
a
c
g
d
a
d
a
d
a
d
Table 3 Cyclization of 1,3-bis(silyl enol ethers) 4h–j with 3a
H
H
H
H
H
H
f
f
f
s
t
g
g
h
h
i
u
v
w
x
y
z
–(CH2)3–
–(CH2)3–
Me
Me
Me
i
Me
a Yields of isolated products; all products were isolated as racemates.
b Product 5dꢀ was isolated in 38% yield when benzyl chloroformate (R4 =
CO2Bn) was used.
Reagents and conditions: i, 3a (1.0 equiv.), 4h–j (1.4 equiv.),
in 21–54% yields. The best yield was obtained for the tricyclic
quinazoline 3h.
ClR3 (4.0 equiv.), CH2Cl2, 0 ◦C, 2 h, 20 ◦C, 12 h
4
5
R1
R2
% (5)a
drb
1,3-Bis(trimethylsilyloxy)-1,3-butadienes 4a–c and 4g–j were
prepared from the corresponding b-ketoesters in two steps.12
Dienes 4d–f are available from the corresponding 1,3-diketones
in one step.13 The cyclization of parent quinazoline (3a) with
1,3-bis(trimethylsilyloxy)-1,3-butadienes 4a–c, in the presence of
methyl chloroformate (4.0 equiv.), afforded the 3,4-benzo-7-
hydroxy-2,9-diazabicyclo[3.3.1]non-7-enes 5a–c (Table 2). The use
h
i
j
aa
ab
ac
OMe
OEt
Et
Et
Et
Me
43
50
75
7 : 3
2 : 1
6 : 1
a Yield of isolated products; all products were isolated as racemates.
b Diastereomeric ratio trans : cis (by 1H NMR); the assignment is arbitrary.
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3a with 4j, prepared from heptane-3,5-dione, gave product 5ac
with good diastereoselectivity (dr = 6 : 1). The diastereomeric
mixtures of 5aa, 5ab and 5ac could not be separated. Extension of
the reaction times did not result in a change in the selectivity
or epimerization. Therefore, the diastereomeric mixtures are
presumably kinetic products.
The configurations of the 3,4-benzo-7-hydroxy-2,9-diaza-
bicyclo[3.3.1]non-7-enes 5 were elucidated by NMR spectroscopy
(HMBC, COSY, NOESY). For example, in the COSY spectrum
of 5b, correlations were observed between the hydrogen atoms
of the NCHCH2 moiety. In addition, NOE effects between
the hydrogen atoms of the ring -CH2- group and an aromatic
hydrogen atom and the OH-proton were found. The HMBC
spectrum showed correlations between the ring-CH2 group and
the NCH, NCHCAr, COH and COHCCO groups. The relative
configurations of 5aa, 5ab and 5ac could not be unambiguously
assigned. Due to the hindered rotation of the carbamate moieties,
a fine splitting of many of the signals of 5a–ac was observed in
their 1H and 13C NMR spectra. The structures of 5n, 5q, 5w, and 5y
were independently confirmed by X-ray crystal structure analyses
(Fig. 1–4)†.14
Fig. 2 Molecular structure of 5q in the crystal form (ORTEP plot, 50%
probability level, only one position of the disordered atoms is shown).
Fig. 1 Molecular structure of 5n in the crystal form (ORTEP plot, 50%
probability level, only one of the two symmetry independent molecules is
shown).
Fig. 3 Molecular structure of 5w in the crystal form (ORTEP plot, 50%
probability level, only one position of the disordered atoms is shown).
3,4-Benzo-7-hydroxy-2,9-diazabicyclo[3.3.1]non-7-ene 5d was
transformed into its triflate 6. The Suzuki cross-coupling reaction
of 6 with phenyl- and 3,5-dimethylphenylboronic acid afforded
products 7a and 7b, respectively (Scheme 1).
The reaction of 1,3-bis(silyl enol ethers) 4c and 4f with phtha-
lazine (8), in the presence of methyl chloroformate (4.0 equiv.),
afforded the condensation products 9a and 9b, respectively, rather
than the cyclization products 10a,b (Scheme 2). All attempts to in-
duce a cyclization, by treatment of 9a,b with methyl chloroformate
or with acid (TFA), failed. In all experiments, the starting material
was recovered. This might be explained by the steric effect of the
carbamate moiety. In addition, the basicity of the imino group
of 9a,b is considerably reduced, due to the electron-withdrawing
effect of the neighboring carbamate nitrogen. Although a number
of reactions of iminium salts of phthalazine with nucleophiles have
been reported,15 double functionalizations are very rare.
Along with our synthetic efforts, we have carried out B3LYP/6-
31G(d) density functional theory computations on the cyclization
of 1,3-bis(silyl enol ethers) with quinazolines in order to get some
mechanistic insight. The reaction of the unsubstituted reactants
3a and 4a was studied in detail. At B3LYP/6-31(d), 3a has a
planar structure as the energy minimum (Fig. 5). Since the two
nitrogen atoms in 3a are non-equivalent, its reaction with methyl
chloroformate can result in the formation of two different iminium
ions, i.e. 3a+R1and 3a+R3. It is found that 3a+R3 is more stable
than 3a+R1 by 5.69 kcal mol−1 in Gibbs free energy. Therefore,
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Fig.
5
Reaction free energies (DGr) and relative free energies
(B3LYP/6-31G(d) at 298K).
Fig. 4 Molecular structure of 5y in the crystal form (ORTEP plot, 50%
probability level, only one position of the disordered atoms is shown).
butadiene moieties. The latter is more stable by 1.55 kcal mol−1
and the expected equilibrium ratio of 4a-cis to 4a-trans should be
93% to 7%. The computed rotation free energy barriers between
4a-cis and 4a-trans are in the range of 4.32–4.71 kcal mol−1. On
the basis of this equilibrium, we have considered for comparison
the cyclization of 4a-cis and 4a-trans with 3a+R3.
The reaction of 3a+R3 with 4a-cis or 4a-trans results in
the formation of a racemic mixture. We have calculated the
intermediates derived from the R-enantiomer. The reaction maps
are shown in Fig. 6 along with the reaction free energies (DGr) and
relative free energies. Upon orientation of the butadiene moiety of
4a-cis and 4a-trans with the six-membered ring in 3a+R3 there are
two competitive allylic intermediates for each: allyl-cis-endo/allyl-
cis-exo, and allyl-trans-endo/allyl-trans-exo. It is found that allyl-
trans-endo is the most stable intermediate, while allyl-cis-endo and
allyl-cis-exo are higher in free energy by 3.07 and 4.31 kcal mol−1,
respectively. The large energy differences reveal that the addition
of 4a-cis to 3a+R3 is not competitive, as compared to that of
4a-trans. Thus, we have paid our attention to the addition of 4a-
trans to 3a+R3 (right side of Fig. 6). However, the data for the
addition of 4a-cis to 3a+R3 are shown for comparison (left side of
Fig. 6). Allyl-trans-endo and allyl-trans-exo are close in free energy
(1.29 kcal mol−1), and the expected ratio should be 89% to 11%. For
the neutral intermediates, formed by removing Me3Si+, A-trans-
endo is more stable than A-trans-exo by 3.32 kcal mol−1, and the ex-
pected ratio should be larger than 99% to 1%. Further nucleophilic
addition of +CO2Me results in B-trans-endo and B-trans-exo, and
the former is more stable than the latter by 1.08 kcal mol−1. On
the basis of all these energetic differences, one would expect that
B-trans-endo should be the principal intermediate.
Scheme 1 Synthesis of 7a,b: i, Tf2O, pyridine, −78 → 20 ◦C, 4 h;
ii, 6 (1.0 equiv.), ArB(OH)2 (1.3 equiv.), K3PO4 (1.6 equiv.), Pd(PPh3)4
(0.03 equiv.), 1,4-dioxane, reflux, 20 h.
Scheme 2 Synthesis of 9a,b: i, 8 (1.0 equiv.), 4c,f (1.4 equiv.), ClCO2Me
The next step is the intramolecular electrophilic substitution to
(4.0 equiv.), CH2Cl2, 0 ◦C, 2 h, 20 ◦C, 12 h.
=
form the products. Due to the proper orientation of the C C
double bond, the expected product of B-trans-endo is 5a-exo-
=
3a+R3 should be the only product. It should also be noted that
3a+R3 has a rotamer of the carbamate group, which is higher in
energy by less than 1.00 kcal mol−1, and the computed rotation free
energy barrier is 8.7 kcal mol−1. In addition, we have found two
conformers of 4a which possess s-trans (4a-trans) and s-cis (4a-cis)
ketone, formed when the cation attacks the C C double bond
along with the extrusion of Me3Si+. Due to the orientation of the
Me3SiO group, the expected product of B-trans-exo is 5a-pyran-cis,
formed when the cation attacks the oxygen atom along with the
extrusion of Me3Si+. It has been found that 5a-exo-ketone is more
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Fig. 6 Reaction free energies (DGr) and relative free energies (B3LYP/6-31G(d) at 298K), R = CO2Me.
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stable than 5a-pyran-cis by 10.59 kcal mol−1. Therefore, 5a-exo-
ketone is the only product. We have also calculated the transition
state for the ring closure of B-trans-endo; the activation barrier is
27.62 kcal mol−1. In addition, we have calculated the enol form
of the final product (5a-enol), which is more stable than 5a-exo-
ketone by 0.96 kcal mol−1. The expected ratio should be 86% to
14%. This result agrees reasonably with the experimental findings.
It can be concluded that the addition reaction takes place
through the allyl-trans-endo intermediate, formed by the reaction
of 3a+R3 with 4a-trans. The total reaction free energy from 3a +
4a-trans + 2 ClCO2Me to give 5a-enol + 2 Me3SiCl is highly
exergonic, by 50.50 kcal mol−1 at the B3LYP/6-31G(d) level, and
this should be the driving force for the complete reaction.
at geometrically calculated positions and refined using a riding
model.
General procedure for the synthesis of the substituted quinazolines
3. To a solution of aniline 1 (10.0 mmol) in THF (100 mL)
were added triethylamine (20.0 mmol) and ethyl chloroformate
(20.0 mmol). The solution was stirred for 1 h at 20 ◦C, filtered
and concentrated in vacuo. To the residue was added ethyl acetate
(100 mL) and the solution was washed with water (2 × 100 mL).
The combined organic layers were dried (Na2SO4), filtered and
concentrated in vacuo. To the residue was added TFA (70 mL).
Hexamethylenetetramine (HMTA) (9.800 g, 70.0 mmol) was
added and the solution was heated under reflux for 1 h. To the
solution was added hydrochloric acid (4 M, 400 mL) and the
solution was filtered and concentrated in vacuo. To the residue
was added a 1 : 1 mixture of water and ethanol (600 mL). To the
solution was added KOH (66.60 g) and K3Fe(CN)6 (25.00 g) and
the solution was heated under reflux for 4 h. Water (600 mL)
was added and the solution was extracted with toluene (5 ×
100 mL). The combined organic layers were dried (Na2SO4),
filtered and concentrated in vacuo. The residue was purified by
column chromatography (silica gel, heptane → heptane–EtOAc =
2 : 1).
Conclusions
In conclusion, we have reported the synthesis of a variety of
functionalized 3,4-benzo-7-hydroxy-2,9-diazabicyclo[3.3.1]non-7-
enes by the one-pot cyclization of 1,3-bis(silyl enol ethers) with
quinazolines. In addition, B3LYP/6-31G(d) density functional
theory computations have been performed to get some insight
into the reaction mechanism. It is worth noting that the reaction
of 1,3-bis(silyl enol ethers) with phthalazine afforded open-chain
rather than cyclization products, which can be explained by steric
and electronic reasons.
General procedure for the reaction of the 1,3-bis(silyl enol ethers)
with quinazolines. To a solution of quinazoline 3 (4.0 mmol)
in CH2Cl2 (40 mL) were added at 0 ◦C the 1,3-bis(silyl enol
ether) (5.6 mmol) and the chloroformate (16.0 mmol). The
solution was stirred for 2 h at 0 ◦C and for 12 h at 20 ◦C. The
solvent was removed in vacuo. The residue was purified by
column chromatography (silica gel, heptane → heptane–EtOAc =
2 : 1).
Experimental section
Computational details. All structures were optimized at the
B3LYP/6-31G(d)16 level of density functional theory. All opti-
mized structures were characterized by frequency calculations as
energy minima without imaginary frequencies (NImag = 0) or
transition states with only one imaginary frequency (NImag =
1) at the same level of theory.17 The thermal corrections to
the Gibbs free energies at 298 K at B3LYP/6-31G* from the
frequency calculations were added to the total electronic energies
for analyzing the selectivity, which was estimated on the basis of the
relationship of DDG = −RTlnK, in which DDG is the difference in
the Gibbs free energy, and K presents the considered equilibrium
constant of the two competing reactions. All calculations were
carried out by using the Gaussian 03 program package.18
11-Hydroxy-8,13-diaza-tricyclo[7.3.1.02,7 ]trideca-2(7),3,5,10-
tetraene-8,10,13-tricarboxylic acid trimethyl ester (5a). Start-
ing with quinazoline 3a (0.521 g, 4.0 mmol), 1-methoxy-1,3-
bis(trimethylsilyloxy)-buta-1,3-diene 4a (1.460 g, 5.6 mmol) and
methyl chloroformate (1.512 g, 16.0 mmol) in CH2Cl2 (40 mL), 5a
was obtained as a colorless solid (0.750 g, 52%); mp 133–135 ◦C.
2
3
1H NMR (250 MHz, CDCl3): d = 2.41 (dd, J = 17.5 Hz, J =
1.5 Hz, 1H, CH2), 2.99 (br dd, 1H, CH2), 3.76, 3.80 (2 s, 6H,
OCH3), 3.87 (s, 3H, OCH3), 5.40 (br, 1H, NCHCH2), 7.03–7.13
(m, 2H, Ar), 7.20–7.26 (m, 1H, Ar), 7.38 (br, 1H, NCHN), 7.75
(br, 1H, Ar), 12.26 (s, 1H, OH). 13C NMR (75.5 MHz, CDCl3):
d = 38.0 (CH2), 48.7 (br, NCHCH2), 52.0, 53.2, 53.3 (OCH3),
58.9 (NCH), 98.0 (CCO2CH3), 124.2, 124.4, 126.8, 127.6 (CHAr),
126.3, 134.4 (br) (CAr), 153.4, 154.0 (NCOO), 170.6 (COO), 173.2
(br, COH). IR (Nujol, cm−1): m = 3080 (w), 1707 (s), 1652 (m),
1613 (m), 1494 (m), 1335 (m), 1287 (s), 1263 (m), 1230 (s), 1196
(m), 1142 (m), 1111 (m), 1064 (m), 1039 (m), 1008 (m), 778
(m). MS (EI, 70 eV): m/z (%) = 362 (M+, 10), 303 (100), 271
(36), 212 (23), 180 (21), 239 (13). Anal. calcd for C17H18N2O7
(362.33): C, 56.35; H, 5.01; N, 7.73. Found: C, 56.35; H, 5.13;
N, 7.46.
General. Chemical shifts of the 1H and 13C NMR are reported
in parts per million using the solvent as the internal standard
(chloroform, 7.26 and 77.0 ppm, respectively). Infrared spectra
were recorded on a FTIR spectrometer. Mass spectrometric
data (MS) were obtained by electron ionization (EI, 70 eV),
chemical ionization (CI, isobutane) or electrospray ionization
(ESI). Melting points are uncorrected. Analytical thin layer
˚
chromatography was performed on 0.20 mm 60 A silica gel plates.
˚
Column chromatography was performed using 60 A silica gel (60–
200 mesh). All cyclization reactions were carried out in Schlenk
tubes under an argon atmosphere. The bis(silyl enol ethers) were
prepared as described in the literature. Crystallographic data
were collected on a Bruker X8Apex with MoKa radiation (k =
Preparation of 10-acetyl-11-trifluoromethanesulfonyloxy-8,13-
diaza-tricyclo[7.3.1.02,7]trideca-2(7),3,5,10-tetraene-8,13-dicarbox-
ylic acid dimethyl ester (6). To a CH2Cl2 solution (21 mL) of 5f
(0.723 g, 2.1 mmol) and pyridine (0.331 g, 4.2 mmol) was added
trifluoromethanesulfonic acid anhydride (0.708 g, 2.5 mmol)
dropwise at −78 ◦C. The solution was allowed to warm up to
˚
0.71073 A). The structures were solved by direct methods using
SHELXS-97 and refined against F2 on all data by fullmatrix least-
squares with SHELXL-97. All non-hydrogen atoms were refined
anisotropically. All hydrogen atoms were refined in the model
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20 ◦C within 4 h and was then concentrated in vacuo. The residue
was purified by column chromatography (silica gel, heptane →
heptane–ethyl acetate = 2 : 1) to give 6 as a yellowish oil (0.570 g,
(250 MHz, CDCl3): d = 2.31 (br m, 1H, NCHCH2, enol), 2.59
(br m, 1H, NCHCH2, enol), 2.82 (dd, 2J = 16.3 Hz, 3J = 4.4 Hz,
2
3
1H, NCHCH2, keto), 3.03 (dd, J = 16.3 Hz, J = 8.7 Hz, 1H,
1
2
57%). H NMR (250 MHz, CDCl3): d = 2.36 (s, 3H, COCH3),
NCHCH2, keto), 3.32 (d, J = 15.7 Hz, 1H, COCH2CO), 3.33
2
3
2.53 (dd, J = 17.7 Hz, J = 1.53 Hz, 1H, CH2), 3.21 (br dd,
(s, 3H, CH2OCH3), 3.45 (d, 2J = 15.7 Hz, 1H, COCH2CO),
3.55 (m, 2H, CH2OCH3), 3.89 (s, 3H, COOCH3), 4.21 (m, 2H,
COOCH2), 4.83 (s, 1H, COCHCOH, enol), 6.00 (dd, 2J =
8.4 Hz, 3J = 4.4 Hz, 1H, NCHCH2), 7.14–7.46 (m, 4H, Ar), 7.70
(s, 1H, NCONCH). 13C NMR (75.5 MHz, CDCl3): d = 39.7
(NCHCH2), 47.3 (COCH2CO, rotamers), 49.2 (CH2OCH3), 49.5
(COCH2CO, rotamers), 54.0 (NCHCH2), 58.9, 59.0 (COOCH3),
63.1 (CH2OCH3, enol), 64.3 (CH2OCH3, keto), 70.1, 70.3
(COOCH2, rotamers), 92.0 (COCHCOH, enol), 123.3, 123.4
(CAr, rotamers), 125.9, 126.0, 126.2, 126.9, 128.1, 128.7, 129.0,
131.8, 132.0, 132.3 (CHAr, keto, enol, rotamers), 132.7 (CAr), 143.2
(NCONCH), 154.3 (NCOO), 166.6 (COOCH2), 172.0, 173.0
(COH, enol, rotamers), 199.0 (CH2COCH2). IR (neat, cm−1): m =
2955 (m), 2932 (m), 2894 (m), 2821 (w), 1742 (s), 1711 (s), 1655
(m), 1566 (m), 1445 (s), 1379 (s), 1321 (s), 1197 (s), 1157 (s), 1128
(s), 1099 (m), 1040 (m), 983 (w), 924 (m), 847 (w), 766 (m), 551
(m), 531 (m). MS (EI, 70 eV): m/z (%) = 348 (M+, 3), 289 (9), 203
(20), 189 (100), 145 (84), 130 (26), 117 (13), 76 (8). Anal. calcd.
for C17H20N2O6 (348.35): C, 58.61; H, 5.79; N, 8.04. Found: C,
58.42; H, 5.93; N, 7.84.
3
2J = 17.7 Hz, J = 5.2 Hz, 1H, CH2), 3.78 (s, 3H, COOCH3),
3.87 (s, 3H, COOCH3), 5.46 (br, 1H, NCHCH2), 7.08–7.19 (m,
2H, Ar), 7.28 (m, 1H, Ar), 7.52 (br, 1H, NCHN), 7.70 (br m,
1H, Ar). 13C NMR (75.5 MHz, CDCl3): d = 30.7 (COCH3),
37.5 (CH2), 49.4 (br, NCHCH2), 53.6, 53.9 (COOCH3), 60.4
(NCHN), 118.1 (q, 1J = 320.4 Hz, CF3), 124.2, 125.0, 126.4,
128.5 (CHAr), 125.6, 128.8, 134.0 (CAr, CCO), 150.8 (br, COS),
153.3, 153.8 (NCOO), 194.8 (CCOCH3). 19F NMR (235 MHz,
CDCl3): d = −117.6 (CF3). MS (EI, 70 eV): m/z (%) = 478
(M+, 34), 345 (22), 269 (100), 251 (17), 211 (8), 117 (5), 63 (23).
HRMS (EI): calcd for C18H17F3N2O8S (M+) 478.06522, found
478.064923.
General procedure for the synthesis of 7a,b. To a solution of
triflate 6 (1.00 mmol) in 1,4-dioxane (2.5 ml) at 20 ◦C were added
boronic acid (1.30 mmol), potassium phosphate (1.60 mmol)
and tetrakis(triphenylphosphine)palladium(0) (0.03 mmol). The
solution was refluxed for 20 h. After cooling to 20 ◦C a saturated
aqueous solution of ammonium chloride (3 ml) was added. The
solution was diluted with CH2Cl2 (15 ml). The phases were
separated and the aqueous phase was extracted with CH2Cl2
(20 ml). The collected organic phases were dried (Na2SO4), filtered
and concentrated in vacuo. The residue was purified by column
chromatography (silica gel, heptane → heptane–ethyl acetate =
2 : 1).
Acknowledgements
Financial support by the state of Mecklenburg-Vorpommern
(Landesgraduiertenstipendium for A. S. and V. K.) and by the
DAAD (scholarship for S. M.) is gratefully acknowledged.
10-Acetyl-11-phenyl-8,13-diaza-tricyclo[7.3.1.02,7]trideca-2(7),3,
5,10-tetraene-8,13-dicarboxylic acid dimethyl ester (7a). Starting
with 6 (0.546 g, 1.14 mmol), phenyl boronic acid (0.181 g,
1.48 mmol), potassium phosphate (0.387 g, 1.82 mmol and
tetrakis(triphenylphosphine)palladium(0) (0.040 g, 0.03 mmol) in
1,4-dioxane (3 ml),◦ 7a was obtained as a yellow solid (0.303 g,
65%); mp 130–131 C. 1H NMR (250 MHz, CDCl3): d = 1.51 (s,
Notes and references
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2
3
3H, COCH3), 2.66 (dd, J = 18.3 Hz, J = 1.5 Hz, 1H, CH2),
2
3
2.97 (dd, J = 18.3 Hz, J = 1.2 Hz, 1H, CH2, rotamers), 2.99
(dd, 2J = 18.3 Hz, 3J = 1.2 Hz, 1H, CH2, rotamers), 3.77 (s, 3H,
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NCHN). 13C NMR (75.5 MHz, CDCl3): d = 30.8 (COCH3), 40.4
(CH2), 49.1 (NCHCH2), 53.1, 53.5 (NCOOCH3), 60.4 (NCHN),
123.7, 124.3, 124.3, 126.1, 127.3, 127.6, 127.8, 128.7, 129.1 (CHAr,
rotamers), 134.9, 134.9, 135.1, 138.9 (CAr, NCHCCO), 143.5 (br,
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m = 3027 (w), 2955 (w), 2927 (w), 2853 (w), 1717 (s), 1491 (m),
1448 (s), 1413 (m), 1374 (m), 1332 (m), 1273 (s), 1222 (m),
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(5). HRMS (EI): calcd for C23H22N2O5 (M+) 406.15232, found
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1
was isolated as a yellow, viscous oil (0.775 g, 56%). H NMR
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2968 | Org. Biomol. Chem., 2008, 6, 2961–2968
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The Royal Society of Chemistry 2008
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