Synthesis of 2,8-disubstituted analogues of Troeger's base

Article abstract of DOI:10.1055/s-2004-829117

Starting from the 2,8-dibromo- and the 2,8-diiodo-substituted Troeger's base analogues 1 and 2, several new symmetrically disubstituted derivatives 4, 5, and 7-17 could be obtained by transition metal-catalyzed cross-coupling reactions or other functional

Full text of DOI:10.1055/s-2004-829117

PAPER
1687
Synthesis of 2,8-Disubstituted Analogues of Troeger’s Base
S
ynthesis of 2,8-D
l
isubstit
f
uted
A
nalogue
K
s
of Troeger’s Bas
i
e
ehne, Arne Lützen*
University of Oldenburg, Institute of Pure And Applied Chemistry, P. O. Box 2503, 26111 Oldenburg, Germany
Fax +49(441)7983329; E-mail: arne.luetzen@uni-oldenburg.de
Received 17 March 2004
reaction generally works best with 4-halo-2-methyl-
anilines because the electron-donating character of the
methyl group facilitates the electrophilic aromatic substi-
tution being part of the formation mechanism.8
Abstract: Starting from the 2,8-dibromo- and the 2,8-diiodo-sub-
stituted Troeger’s base analogues 1 and 2, several new symmetrical-
ly disubstituted derivatives 4, 5, and 7–17 could be obtained by
transition metal-catalyzed cross-coupling reactions or other func-
tionalizations like borylation or protecting group operations. For the
first time, conditions for a highly efficient Suzuki cross-coupling re-
action involving the Troeger’s base core were established.
Within the course of our studies concerning the formation
of self-assembled supramolecular receptors11,12 the 2,8-di-
bromo- and 2,8-diiodo analogues 1 and 2 (Figure 2) of
Troeger’s base attracted our interest and prompted us to
evaluate the possibilities to apply them as substrates in a
number of transition-metal catalyzed cross-coupling
reactions13 and some other transformations in order to get
access to versatile difunctionalized rigid molecules with
extended V-shaped cores. This paper describes the syn-
thesis of a number of racemic 2,8-disubstituted deriva-
tives of Troeger’s Base (Table 1) that were prepared from
1 and 2 in Ullmann, Sonogashira, and Suzuki cross-coup-
ling reactions as well as by some further functionaliza-
tions like borylation or protecting group operations.
Key words: Troeger’s base, cross-coupling reactions, Suzuki reac-
tion
Troeger’s base (Figure 1) was first synthesized more than
hundred years ago in 1887.1 However, its structure was
not eludicated until 1935.2 Due to the rigid shape of the
molecule, both N-atoms are sterically fixed. Thus, the
molecule is dissymmetric and therefore chiral.
N
19
1
12
N
X
11
N
14
15
2
10
17
16
9
Figure 1 Troeger’s base
13
3
N
5
4
8
1: X = Br
2: X = I
X
7
6
Besides this special stereochemical situation that made
this molecule become one of the textbook examples for
explaining dissymmetry,3 it is the unique V-shaped struc-
ture of the compound that has attracted the interest of
many chemists, since its rigid conformation makes it an
almost ideal building block to introduce curvature into
larger molecules. This is, of course, of major importance
in supramolecular chemistry, e.g. in order to achieve con-
cave structures of receptor molecules.4–6
18
Figure 2 2,8-Dibromo-4,10-dimethyl-6H,12H-5,11-methanodiben-
zo[b,f]diazocine (1), 2,8-diiodo-4,10-dimethyl-6H,12H-5,11-me-
thanodibenzo[b,f]diazocine (2)
The dimethoxy derivative 3 could already be synthesized
by Wilcox in 1988 by condensation of 4-methoxy-2-
methylaniline and formaline in acidic ethanol solution,
but the yield was only 14%.14 Treatment of 2 with sodium
methoxide under Ullmann conditions gave 3 in almost
quantitative yield. Subsequent deprotection of 3 with bo-
ron tribromide gave the 2,8-dihydroxy derivative 4
(Scheme 1).
Troeger’s base derivatives are usually formed by reaction
of an aniline, formaldehyde, and a strong acid.7 This con-
densation has been limited to electron-rich anilines for a
long time. Only recently, however, Wärnmark and co-
workers succeeded in the synthesis of halo-substituted an-
alogues of Troeger’s base using paraformaldehyde, tri-
fluoroacetic acid, and the corresponding aniline.8
Although they showed that the formation is very sensitive
to the reaction conditions, especially the scale,9 this meth-
od allows easy access to symmetrically dihalogen-substi-
tuted analogues in almost any position in each of the two
aromatic rings.10 Independent of the scale, however, the
The dialkyne 6, which contains two ethynyl groups in the
2- and 8-positions of Troeger’s base and, therefore, is a
very interesting compound with regard to its possible ap-
plication in building up larger supramolecular aggregates,
has already been synthesized through a Corriu–Kumada
reaction of 2 and ethynylmagnesium bromide.8 An alter-
native route to this molecule is a Sonogashira reaction of
1 or 2 with trimethylsilylacetylene followed by deprotec-
tion of the TMS group. This approach offers the possibili-
ty to further elaborate the core prior to deprotection or to
deprotect the initial Sonogashira product in a stepwise
manner in order to differentiate the two terminal groups
SYNTHESIS 2004, No. 10, pp 1687–1695
x
x.
x
x
.
2
0
0
4
Advanced online publication: 23.06.2004
DOI: 10.1055/s-2004-829117; Art ID: Z05804SS
© Georg Thieme Verlag Stuttgart · New York

1688
U. Kiehne, A. Lützen
PAPER
Table 1 2,8-Disubstituted Analogues of Troeger’s Base Derived by
Transition Metal-Catalyzed Cross-Couplings and Further Functional-
izations
I
N
N
N
N
R
I
N
2
3
4
NaOCH3, CuCl,
MeOH/DMF, ∆
N
R
98%
O
Entry
R
Product
1
2
3
4
5
OCH3
OH
3
4
5
6
7
N
O
C≡CTMS
C≡CH
BBr3, CH2Cl2
–78 °C
94%
OH
6
8
N
HO
Scheme 1 Ullmann methoxylation of 2 followed by demethylation.
7
8
9
through further functionalization. Recently, a general pro-
tocol for the use of 2 in Sonogashira reactions based on a
protocol of Fu15 has been established to introduce several
alkyne moieties into the Troeger’s base skeleton.16 Reac-
tions were carried out at room temperature using the high-
ly reactive catalytic system [Pd(Pt-Bu3)2], which we were
already able to use in other cross-couplings17 and which is
necessary due to the relatively electron-rich character of
the benzene rings of the Troeger’s base core. We have also
applied these conditions to the synthesis of 5, which could
be obtained from both 1 at 60 °C and 2 at room tempera-
ture in good to excellent yields. Finally, complete depro-
tection with cesium fluoride yielded 6 (Scheme 2).
Cl
O
O
10
9
10
11
12
13
11
12
13
14
15
O
NH2
CN
Due to the air and moisture stabilty of boronic acids and
their derivatives, the palladium-catalyzed Suzuki reaction
is a very versatile and powerful method to form C–C
bonds, especially aryl–aryl bonds.13 So far, there has not
been any existing protocol for the Suzuki reaction involv-
ing analogues of Troeger’s base. The successful Sono-
gashira cross-couplings of ethynyl derivatives and
Troeger’s base halides, however, led us to use the same
palladium phoshane complex, i.e. [Pd(Pt-Bu3)2], in the
Suzuki reaction. Thus, a general protocol from Fu and co-
workers which also included the use of potassium fluoride
as a base and THF as solvent was adapted18 and first ap-
plied to 1, which we expected to react more reluctantly
than 2 due to the much higher reacitivity of iodine com-
pared to bromine in cross-coupling reactions.19 Com-
pounds 7 and 8 were synthesized this way in good to
excellent yields (Table 2).
OH
OTf
14
15
B(OH)2
16
17
O
B
O
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PAPER
Synthesis of 2,8-Disubstituted Analogues of Troeger’s Base
1689
Since [Pd(Pt-Bu3)2] is rather expensive it should be men-
tioned that we also tested a more conventional and cheap-
er catalytic system consisting of [Pd(PPh3)4] and
potassium phosphate in DMF in the synthesis of 8, but
even after two days of refluxing no conversion could be
detected. The next logical step was the use of boronic ac-
ids substituted with different functional groups.
X
N
N
X
1, 2
[Pd(Pt-Bu3)2], CuI, iPr2NH,
TMSC≡CH, Dioxane,
conditions for 1: 60 °C, 48 h, 83%
conditions for 2: r.t., 24 h, 93%
With respect to the aim to integrate the Troeger’s base
core into larger (supra)molecular structures, the use of
para-substituted arylboronic acids is of great interest be-
cause a potential p-phenylene spacer for larger structures
is provided by this strategy. Therefore, our attention was
especially turned to the synthesis of p-bromo- and p-chlo-
rophenyl substituted analogues of Troegers base 18 and 9,
which provide a promising basis for further cross-coup-
ling reactions. Following the protocol for the synthesis of
7 and 8, the diiodo derivative 2 was chosen as reactant in-
stead of 1 for reactivity reasons. After one day at 60 °C,
however, no conversion could be detected in both reac-
tions. Thus, the reaction mixtures were refluxed for anoth-
er day, which unfortunately led to a complicated mixture
of multi-coupling products in case of the 4-bromophenyl-
boronic acid. Nevertheless, 9 could be isolated in 53%
yield at least. This result encouraged us to optimize the re-
TMS
N
N
5
TMS
CsF,
MeOH/THF 1:1
79%
N
N
6
Scheme 2 Sonogashira reaction of 1 and 2 with TMSC≡CH and de-
protection of 5 with CsF.
Table 2 Introduction of Substituted Aryl Moieties into the Troeger’s Base Core via Suzuki Reactions
X
N
N
X
R2
R1
R2
a, b
R1
(RO)2B
R2
N
R = H, Alkyl
R2
R2
N
7-12, 18
R1
kk
a) 4 mol% [Pd(Pt-Bu3)2] , 6.6 equiv CsF, THF, 40 °C (optimized)
b) 4 mol% [Pd(Pt-Bu3)2] , 6.6 equiv KF, THF, 40-60 °C
R2
Entry
X
Br
Br
I
R1
H
R2
H
Method
Product
Yield (%)
1
2
3
4
5
6
7
b
b
a
a
a
a
a
7
90
65
97
85
93
–
H
CH3
H
8
Cl
9
I
CO2CH3
OCH3
Br
H
10
11
18
12
I
H
I
H
I
NH2
H
–
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1690
U. Kiehne, A. Lützen
PAPER
action conditions. Eventually, the change from potassium
fluoride to the stronger base cesium fluoride turned out to
be very efficient because 9 could now be synthesized in a
very smooth reaction at 40 °C in 97% yield (Table 2). Un-
fortunately, the same polymeric products were obtained
again when applying the optimized protocol for the syn-
thesis of 18 probably due to the highly active [Pd(Pt-
Bu3)2]. Also, the introduction of a p-aminophenyl group
failed: even after refluxing for 2 days, no conversion
could be detected. However, using the same protocol, 4-
(methoxycarbonyl)phenyl 10 and 4-methoxyphenyl 11
moieties could be introduced into the Troeger’s base core
in excellent yields (Table 2).
Triflates do have about the same reactivity as bromides in
cross-coupling reactions.13 Thus, we tried to get access to
the corresponding ditriflate as a substitute for the dibro-
mide 18 by deprotection of 11 with boron tribromide to
yield 14 and subsequent reaction of the diol with trifluo-
romethanesulfonic acid anhydride (Tf2O) (Scheme 3).
Following this approach 14 was synthesized in a similiar
way as 4 and could be obtained in a quantitative yield
from 11. Surprisingly, the formation of the ditriflate 15
turned out to be problematic since the desired product
could only be obtained in a moderate yield of 45%.
Scheme 4 Bromine–lithium exchange and Suzuki cross-coupling
mized Suzuki protocol for the reaction with 4-iodoaniline
(Scheme 4).
Since we succeeded to synthesize the diamine 12 by first
generating a diboronic acid derivative, the next step was
to isolate such a derivative which can be used as a sub-
strate for any of the performed and listed Suzuki cross-
couplings. Thus, we performed the bromine–lithium ex-
change again and the resulting mixture was either hydro-
lyzed to yield the diboronic acid 16 or concentrated in
vacuo followed by heating to reflux in a toluene/glycol
mixture (3:1)21 to give the corresponding diboronic acid
ester 17. The diboronic acid ester 17 was then tested as a
substrate in an exemplary Suzuki reaction using the opti-
mized protocol and 4-iodobenzonitrile to obtain 13 in a
good yield of 70% (Scheme 5), which proved the princi-
pal applicability of 17 in Suzuki reactions.
O
N
11
N
BBr3, CH2Cl2
–78 °C
OH
O
99%
N
14
N
In conclusion, we have demonstrated that the dibromo (1)
and the diiodo (2) derivatives of Troeger’s base are very
versatile starting materials for the preparation of elaborat-
ed derivatives of Troeger’s base. Using cross-coupling
conditions, like Ullmann, Sonogashira, or Suzuki-reac-
tions allowed the synthesis of a number of new 2,8-disub-
stituted analogues and has improved the synthesis of
previously known derivatives like 3 and development of
an alternative route to diethynylated compound 6. Fur-
thermore we could show that 1 and 2 as well as some of
the cross coupling products could be used for further
transfomations involving, for example, the formation of
valuable ditriflate 15 and bis(boronic acid) derivatives 16
and 17. Except for the formation of ditriflate 15 all of
these reactions could be performed in very good to excel-
lent yields. These compounds do represent versatile deriv-
atives of Troeger’s base that in most cases have elongated
rigid V-shaped structures bearing functional groups use-
ful for further elaborations and we are currently trying to
use them for the synthesis of ditopic ligands that are
thought to form dinuclear helicates.
Tf2O, CH2Cl2,
Et3N, –30 °C
45%
OTf
HO
N
15
N
TfO
Scheme 3 Two-step synthesis of the diftriflate 15 from the dime-
thoxy derivative 11
Because the optimized protocol for the Suzuki reaction
did not give access to the dianiline analogue 12, we decid-
ed to synthesize it by lithiation of 1 using a published pro-
cedure,20 then forming a diboronic acid derivative in situ
by adding trimethyl borate, and finally applying the opti-
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Synthesis of 2,8-Disubstituted Analogues of Troeger’s Base
1691
dine.22 All chemicals were used as received from commercial sourc-
es. 1,8 2,8 [Pd(Pt-Bu3)2]23 and [Pd(PPh3)4]24 were prepared
according to published procedures.
Br
N
N
2,8-Dimethoxy-4,10-dimethyl-6H,12H-5,11-methanodiben-
zo[b,f]diazocine (3)14
Br
1
Compound 2 (500 mg, 1.0 mmol), NaOMe (290 mg, 5.4 mmol), and
CuCl (27 mg, 0.27 mmol) were suspended in a mixture of MeOH (5
mL) and DMF (3 mL) and heated at 80 °C. After 16 h, the suspen-
sion was slowly cooled down and a mixture of diisopropyl ether (7
mL), H2O (15 mL), and 5% aq NH4Cl solution (10 mL) were added
and the resulting solution was stirred at r.t. After 5 h, the solution
was filtered over Celite and the filtrate was extracted with CH2Cl2
(4 ×). The combined organic layers were washed with aq 5 N NaOH
and dried (Na2SO4). Concentration in vacuo gave 309 mg (99%) of
3 as a brown solid; mp 129–131 °C (Lit.14 mp 127–131 °C).
1) n-BuLi, THF, –78 °C
then B(OMe)3
2) hydrolysis
1) n-BuLi, THF,
–78 °C, then
B(OMe)3
2) ethylene
glycol/toluene
(1:3), ∆
90% (over both steps)
OH
B
N
OH
87% (over both
steps)
HO
B
N
1H and 13C NMR data were in accordance with the literature,14
where no assignments had been given.
O
16
OH
B
1H NMR (500.1 MHz, CDCl3): d = 2.38 (s, 6 H, H-18, H-19), 3.69
(6 H, OCH3), 3.90 (d, 2 H, H-6endo, H-12endo, 2J = –16.5 Hz), 4.30
(s, 2 H, H-13), 4.53 (d, 2 H, H-6exo, H-12exo, 2J = –16.5 Hz), 6.29
(d, 2 H, H-1, H-7, 4J = 2.8 Hz), 6.63 (d, 2 H, H-3, H-9, 4J = 2.8 Hz).
O
N
N
O
B
17
13C NMR (125.8 MHz, CDCl3): d = 17.2 (C-18, C-19), 55.3
(OCH3), 55.5 (C-6, C-12), 68.0 (C-13), 108.4 (C-1, C-7), 115.3
(C-3, C-9), 128.8 (C-14, C-16), 134.3 (C-4, C-10), 139.0 (C-15,
C-17), 155.8 (C-2, C-8).
O
4-iodobenzonitrile, CsF
[Pd(Pt-Bu3)2], THF, 60 °C
CN
70%
MS (CI, i-butane): m/z = 311.2 ([C19H23N2O2]+, 100).
N
2,8-Dihydroxy-4,10-dimethyl-6H,12H-5,11-methanodiben-
zo[b,f]diazocine (4)
Compound 3 (100 mg, 0.32 mmol) was dissolved in CH2Cl2 (7 mL)
and cooled to –78 °C. After addition of 1 M BBr3 solution in CH2Cl2
(1.3 mL, 1.3 mmol) at this temperature, the reaction mixture was al-
lowed to come to r.t. and stirred for 5 h. Aq 2 N NaOH was added
until the excess of BBr3 had been completely hydrolyzed. After ad-
dition of EtOAc (10 mL), the solution was neutralized using 6 N
HCl and extracted with EtOAc (3 ×). Concentration in vacuo gave
85 mg (94%) of 4 as a yellow solid; mp >300 °C.
N
13
NC
Scheme 5 Synthesis of 16 and 17, two substrates for Suzuki cross-
couplings as demonstrated exemplarily for the formation of 13.
1H NMR (500.1 MHz, DMSO-d6): d = 2.42 (s, 6 H, H-18, H-19),
2
All reactions except the synthesis of 6 were performed under argon
using standard Schlenk techniques and oven-dried glassware prior
to use. TLC was performed on aluminum TLC plates silica gel 60
F254 from Merck. Detection was done by UV-light (254 and 366
nm). Products were purified by column chromatography on silica
gel 60 (70–230 mesh) from Merck. 1H and 13C NMR spectra were
recorded on a Bruker DRX 500 spectrometer at 300 K at 500.1 and
125.8 MHz, respectively. 19F NMR spectra were recorded on a
3.72 (d, 2 H, H-6endo, H-12endo, J = –16.5 Hz), 4.10 (s, 2 H,
H-13), 4.37 (d, 2 H, H-6exo, H-12exo, 2J = –16.5 Hz), 6.16 (d, 2 H,
H-1, H-7, 4J = 2.8 Hz), 6.44 (d, 2 H, H-3, H-9, 4J = 2.8 Hz), 8.86 (s,
2 H, OH).
13C NMR (125.8 MHz, DMSO-d6): d = 16.7 (C-18, C-19), 54.8
(C-6, C-12), 67.5 (C-13), 109.9 (C-1, C-7), 115.6 (C-3, C-9), 128.9
(C-14, C-16), 133.2 (C-4, C-10), 137.4 (C-15, C-17), 152.9 (C-2,
C-8).
1
Bruker DPX 300 spectrometer at 300 K at 282.4 MHz. H NMR
MS (CI, i-butane): m/z = 283.1 ([C17H19N2O2]+, 100).
chemical shifts are reported on the d-scale (ppm) relative to residual
nondeuterated solvent as internal standard. 13C NMR chemical
shifts are reported on the d-scale relative to deuterated solvent as in-
ternal standard. 19F NMR chemical shifts are reported on the d-scale
relative to CCl3F as external standard. Signals were assigned on the
HRMS (EI): m/z calcd for C17H18N2O2: 282.1369; found: 282.1368.
4,10-Dimethyl-2,8-bis[(trimethylsilyl)ethynyl]-6H,12H-5,11-
methanodibenzo[b,f]diazocine (5)
1
basis of H, 13C, H,H-COSY, HMQC, and HMBC NMR experi-
Compound 2 (500 mg, 1.0 mmol), [Pd(Pt-Bu3)2] (6 mol%, 30.7 mg),
and CuI (7.6 mg, 4 mol%) were dissolved in 1,4-dioxane (5 mL). To
this solution were added trimethylsilylacetylene (0.56 mL, 4.0
mmol) and i-Pr2NH (0.34 mL, 2.4 mmol). After 20 h, the reaction
mixture was quenched with sat. aq NaCl (5 mL) and filtered over
Celite. The residue was extracted with CH2Cl2. The filtrate was
washed with aq sat. NaHCO3 (2 ×), dried (Na2SO4), and concentrat-
ed in vacuo. Purification by column chromatography (toluene–
EtOAc, 20:1 + 0.5% Et3N, Rf = 0.58) gave 410 mg (93%) of 5 as a
yellow solid; mp 67–69 °C.
ments. Numbering of the 1H and 13C nuclei was done according to
the one shown in Figure 2. Mass spectra were taken on a Finnigan
MAT 212 with data system MMS–ICIS (EI, CI, i-butane, NH3) or a
Finnigan MAT 95 with data system DEC-Station 5000 (CI, i-butane
or NH3; HiRes-CI, i-butane or NH3; FD). Mps were measured with
a hot-stage microscope SM-Lux from Leitz and are not corrected.
Elemental analyses were carried out with a Fisons Instrument
EA1108.
Most solvents were dried, distilled and stored over argon according
to standard procedures. n-BuLi solutions were purchased from
Merck and were titrated prior to use against N-pivaloyl-o-tolui-
1H NMR (500.1 MHz, CDCl3): d = 0.19 [s, 18 H, Si(CH3)3], 2.33 (s,
6 H, H-18, H-19), 3.91 (d, 2 H, H-6endo, H-12endo, 2J = –17.0 Hz),
Synthesis 2004, No. 10, 1687–1695 © Thieme Stuttgart · New York

1692
U. Kiehne, A. Lützen
PAPER
4.27 (s, 2 H, H-13), 4.50 (d, 2 H, H-6exo, H-12exo, 2J = –17.0 Hz),
6.89 (d, 2 H, H-1, H-7, 4J = 1.1 Hz), 7.15 (m, 2 H, H-3, H-9).
4,10-Dimethyl-2,8-bis(3,5-dimethylphenyl)-6H,12H-5,11-meth-
anodibenzo[b,f]diazocine (8)
Following the general procedure, compound 1 (200 mg, 0.49
mmol), KF (188 mg, 3.23 mmol), [Pd(t-Bu3P)2] (10 mg), and 3,5-
dimethylphenylboronic acid (177 mg, 1.18 mmol) in THF were
heated for 48 h at 60 °C. Column chromatography (toluene–EtOAc
20:1 + 0.5% Et3N, Rf = 0.37) gave 147 mg (65%) of 8 as a yellowish
solid; mp 85 °C.
1H NMR (500.1 MHz, CDCl3): d = 2.35 [s, 12 H, ArMe2], 2.49 (s,
6 H, H-18, H-19), 4.12 (d, 2 H, H-6endo, H-12endo, 2J = –16.5 Hz),
4.41 (s, 2 H, H-13), 4.69 (d, 2 H, H-6exo, H-12exo, 2J = –16.5 Hz),
6.94 (s, 2 H, H-4Ph), 7.01 (d, 2 H, H-1, H-7¢, 4J = 1.7 Hz), 7.12 (4 H,
H-2Ph, H-6Ph), 7.29 (d, 2 H, H-3, H-9, 4J = 1.7 Hz).
13C NMR (125.8 MHz, CDCl3): d = 0.0 [Si(CH3)3], 16.9 (C-18,
C-19), 54.8 (C-6, C-12), 67.5 (C-13), 93.1 (C≡CTMS), 105.0
(C≡CTMS), 118.3, (C-2, C-8), 127.8 (C-14, C-16), 128.1 (C-1,
C-7), 132.5 (C-3, C-9), 132.8 (C-4, C-10), 146.3 (C-15, C-17).
MS (CI, i-butane): m/z = 443.2 ([C27H35N2Si2]+, 100).
HRMS (CI, i-butane): m/z calcd for [C27H35N2Si2]+: 443.2345;
found: 443.2338.
2,8-Diethynyl-4,10-dimethyl-6H,12H-5,11-methanodiben-
zo[b,f]diazocine (6)8
Compound 5 (200 mg, 0.45 mmol) and CsF (275 mg, 1.8 mmol)
were dissolved in MeOH (15 mL) and THF (15 mL). After 16 h, the
solution was concentrated in vacuo and the crude product purified
by column chromatography (toluene–EtOAc, 20:1 + 0.5% Et3N,
Rf = 0.42) to give 106 mg (79%) of 6; mp 173–175 °C (Lit.8 mp
174 °C).
13C NMR (125.8 MHz, CDCl3): d = 17.3 (C-18, C-19), 21.4
(ArMe2), 55.2 (C-6, C-12), 67.7 (C-13), 123.1 (C-1, C-7), 124.8
(C-2Ph, C-6Ph), 127.9 (C-3, C-9), 128.1 (C-14, C-16), 128.5 (C-4Ph),
133.1 (C-4, C-10), 137.0 (C-2, C-8), 138.1 (C-3Ph, C-5Ph), 140.9
(C-1Ph), 145.2 (C-15, C-17).
MS (CI, i-butane): m/z = 459.4 ([C33H35N2]+, 100).
1H and 13C NMR data were in accordance with the literature,8 where
no assignments had been given to the quaternary carbons.
HRMS (EI): m/z calcd for C33H34N2: 458.2724; found: 458.2721.
13C NMR (125.8 MHz, CDCl3): d = 16.9 (C-18, C-19), 54.7 (C-6,
C-12), 67.3 (C-13), 76.2 (C≡CH), 83.5 (C≡CH), 117.3, (C-2, C-8),
128.0 (C-14, C-16), 128.3 (C-1, C-7), 132.6 (C-3, C-9), 133.1 (C-4,
C-10), 146.7 (C-15, C-17).
Anal. Calcd for C33H34N2·2/3H2O: C, 84.26; H, 7.43; N 6.02.
Found: C, 83.96; H, 7.71; N, 5.63.
2,8-Bis(4-chlorophenyl)-4,10-dimethyl-6H,12H-5,11-methano-
dibenzo[b,f]diazocine (9)
MS (EI): m/z = 298.1 ([C21H18N2]+, 100).
Following the general procedure, compound 2 (200 mg, 0.40
mmol), CsF (400 mg, 2.63 mmol), Pd(Pt-Bu3)2 (8.5 mg), and 4-
chlorophenylboronic acid (149.5 mg, 0.96 mmol) were heated for
12 h at 40 °C. Column chromatography (toluene–EtOAc, 20:1 +
0.5% Et3N, Rf = 0.38) gave 185 mg (97%) of 9 as a white solid; mp
205–206 °C.
2,8-Disubstituted Analogues of Troeger’s Base Obtained by Su-
zuki Cross-Coupling Reactions; General Procedure
To a stirred mixture of either 1 or 2 (1 equiv), KF or CsF (6.6 equiv),
[Pd(Pt-Bu3)2] (4 mol%), and the corresponding boronic acid deriv-
ative (2.4 equiv) was added THF (10 mL) with a syringe. The result-
ing solution was heated (40–80 °C) and the stirring was continued.
After 6–48 h, CH2Cl2 was added and the mixture was washed with
aq sat. solution of Na2CO3 (2 ×). The combined aqueous layers
were extracted with CH2Cl2 (3 ×), and the combined CH2Cl2 layers
were washed with brine, dried (Na2SO4), concentrated in vacuo, and
purified by column chromatography.
1H NMR (500.1 MHz, CDCl3): d = 2.49 (s, 6 H, H-18, H-19), 4.10
2
(d, 2 H, H-6endo, H-12endo, J = –17.0 Hz), 4.39 (s, 2 H, H-13),
4.68 (d, 2 H, H-6exo, H-12exo, 2J = –17.0 Hz), 6.97 (d, 2 H, H-1,
H-7, 4J = 1.7 Hz), 7.25 (m, 2 H, H-3, H-9), 7.33 (dd, 4 H, H-3Ph,
H-5Ph, 3J = 6.9 Hz, 4J = 2.2 Hz), 7.40 (dd, 4 H, H-2Ph, H-6Ph, 3J = 6.9
Hz, 4J = 2.2 Hz).
13C NMR (125.8 MHz, CDCl3): d = 17.3 (C-18, C-19), 55.2 (C-6,
C-12), 67.7 (C-13), 122.9 (C-1, C-7), 127.7 (C-3, C-9), 128.0
(C-2Ph, C-6Ph), 128.3 (C-14, C-16), 128.8 (C-3Ph, C-5Ph), 133.0
(C-4Ph), 133.5 (C-4, C-10), 135.6 (C-2, C-8), 139.2 (C-1Ph), 145.5
(C-15, C-17).
4,10-Dimethyl-2,8-diphenyl-6H,12H-5,11-methanodiben-
zo[b,f]diazocine (7)
Following the general procedure compound 1 (200 mg, 0.49 mmol),
KF (188 mg, 3.23 mmol), [Pd(Pt-Bu3)2] (10 mg), and phenylboronic
acid (143 mg, 1.18 mmol) in THF were heated for 24 h at 40 °C.
Column chromatography (toluene–EtOAc, 5:1 + 0.5% Et3N, Rf =
0.63) gave 180 mg (91%) of 7 as a white solid; mp 181–183 °C.
MS (CI, i-butane): m/z (%) = 471.1 ([C29H2535Cl2N2]+, 100), 473.1
([C29H2535Cl37ClN2]+, 65).
HRMS (CI, i-butane): m/z calcd for [C29H25Cl2N2]+, 471.1393
1H NMR (500.1 MHz, CDCl3): d = 2.49 (s, 6 H, H-18, H-19), 4.12
(35Cl); found: 471.1394 (35Cl).
2
(d, 2 H, H-6endo, H-12endo, J = –17.0 Hz), 4.41 (s, 2 H, H-13),
4.69 (d, 2 H, H-6exo, H-12exo, 2J = –17.0 Hz), 7.02 (d, 2 H, H-1,
Anal. Calcd for C29H24Cl2N2·2H2O·toluene: C, 72.11; H, 6.05; N
4.67. Found: C, 71.85; H, 6.06; N, 4.91.
4
3
4
H-7, J = 1.6 Hz), 7.27 (dd, 2 H, H-4Ph, J = 8.2 Hz, J = 1.1 Hz),
4
7.30 (d, 2 H, H-3, H-9, J = 1.6 Hz), 7.37 (dd, 4 H, H-3Ph, H-5Ph,
3J = 7.7 Hz, 3J = 8.2 Hz), 7.48 (dd, 4 H, H-2Ph, H-6Ph, 3J = 7.7 Hz,
2,8-Bis[4-(methoxycarbonyl)phenyl]-4,10-dimethyl-6H,12H-
5,11-methanodibenzo[b,f]diazocine (10)
4J = 1.1 Hz).
13C NMR (125.8 MHz, CDCl3): d = 17.3 (C-18, C-19), 55.2 (C-6,
C-12), 67.7 (C-13), 123.1 (C-1, C-7), 126.8 (C-3Ph, C-5Ph,), 126.9
(C-4Ph)*, 127.9 (C-3, C-9), 128.6 (C-14, C-16, C-2Ph, C-6Ph,), 133.3
(C-4, C-10), 136.9 (C-2, C-8)*, 140.8 (C-15, C-17, C-1Ph);
(*assignment not confirmed).
MS (CI, i-butane): m/z = 403.3 ([C29H27N2]+, 100).
HRMS (CI, i-butane): m/z calcd for [C29H27N2]+: 403.2168; found:
Following the general procedure, compound 2 (246 mg, 0.49
mmol), CsF (493 mg, 2.63 mmol), [Pd(Pt-Bu3)2] (12 mg), and 4-
(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)benzoate (308 mg,
1.18 mmol) were heated for 24 h at 40 °C. Filtration over a short
column of silica gel 60 (toluene + 0.5% Et3N, Rf = 0.02) gave 217
mg (85%) of 10 as a yellow solid; mp 240–241 °C.
1H NMR (500.1 MHz, CDCl3): d = 2.49 (s, 6 H, H-18, H-19), 3.91
(s, 6 H, CO2CH3), 4.12 (d, 2 H, H-6endo, H-12endo, 2J = –17.0 Hz),
4.39 (s, 2 H, H-13), 4.69 (d, 2 H, H-6exo, H-12exo, 2J = –17.0 Hz),
7.06 (d, 2 H, H-1, H-7, 4J = 1.1 Hz), 7.33 (d, 2 H, H-3, H-9, 4J = 1.1
Hz), 7.55 (dd, 4 H, H-2Ph, H-6Ph, 3J = 7.4 Hz, 4J = 1.6 Hz), 8.03 (dd,
4 H, H-3Ph, H-5Ph, 3J = 7.4 Hz, 4J = 1.6 Hz).
403.2174.
Anal. Calcd for C29H26N2·2/3 n-hexane: C, 86.17; H, 7.74; N 6.09.
Found: C, 86.47; H, 7.63; N, 5.81.
Synthesis 2004, No. 10, 1687–1695 © Thieme Stuttgart · New York

PAPER
Synthesis of 2,8-Disubstituted Analogues of Troeger’s Base
1693
13C NMR (125.8 MHz, CDCl3): d = 17.3 (C-18, C-19), 52.0
(CO2CH3), 55.2 (C-6, C-12), 67.7 (C-13), 123.3 (C-1, C-7), 126.6
(C-2Ph, C-6Ph), 128.0 (C-3, C-9), 128.4 (C-14, C-16), 128.5 (C-4Ph),
130.0 (4C, C-3Ph, C-5Ph), 133.5 (C-4, C-10), 135.4 (C-2, C-8), 145.2
(C-1Ph), 146.2 (C-15, C-17), 167.0 (CO2Me).
Anal. Calcd for C29H28N4·3/4 EtOAc: C, 77.08; H, 6.87; N 11.24.
Found: C, 76.69; H, 6.87; N, 11.12.
2,8-Bis(4-cyanophenyl)-4,10-dimethyl-6H,12H-5,11-methano-
dibenzo[b,f]diazocine (13)
Compound 17 (200 mg, 0.51 mmol), CsF (514 mg, 3.4 mmol),
[Pd(Pt-Bu3)2] (10.5 mg, 4 mol%), and 4-iodobenzonitrile (282 mg)
were dissolved in THF (10 mL) and the resulting solution was re-
fluxed for 20 h. CH2Cl2 was added and the reaction mixture was
washed with aq sat. solution of Na2CO3 (2 ×). The combined organ-
ic layers were extracted with CH2Cl2 (3 ×), washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
column chromatography (toluene–EtOAc, 20:1 + 0.5% Et3N, Rf =
0.12) to give 162 mg (70%) of 13 as a white solid; mp 248–250 °C.
MS (CI, i-butane): m/z = 519.2 ([C33H31N2O4]+, 100).
HRMS (CI, i-butane): m/z calcd for [C33H31N2O4]+: 519.2294;
found: 519.2283.
Anal. Calcd for C33H30N2O4·3/4 H2O: C, 74.49; H, 5.97; N 5.26.
Found: C, 74.77; H, 6.13; N, 5.13.
2,8-Bis(4-methoxyphenyl)-4,10-dimethyl-6H,12H-5,11-metha-
nodibenzo[b,f]diazocine (11)
1H NMR (500.1 MHz, CDCl3): d = 2.49 (s, 6 H, H-18, H-19), 4.11
Following the general procedure, compound 2 (400 mg, 0.80
mmol), CsF (798 mg, 5.26 mmol), [Pd(Pt-Bu3)2] (17 mg), and 4-
methoxyphenylboronic acid (290.5 mg; 1.91 mmol) in THF were
heated for 6 h at 40 °C. Filtration over a short column of silica gel
60 (toluene + 0.5% Et3N, Rf = 0.02) gave 340 mg (92%) of 11 as a
white solid; mp 183–184 °C.
2
(d, 2 H, H-6endo, H-12endo, J = –17.0 Hz), 4.38 (s, 2 H, H-13),
4.69 (d, 2 H, H-6exo, H-12exo, 2J = –17.0 Hz), 7.02 (d, 2 H, H-1,
H-7, 4J = 1.6 Hz), 7.30 (d, 2 H, H-3, H-9, 4J = 1.6 Hz), 7.57 (dd, 4
3
4
H, H-2Ph, H-6Ph, J = 7.7 Hz, J = 2.2 Hz), 7.64 (dd, 4H, H-3Ph,
H-5Ph, 3J = 7.7 Hz, 4J = 2.2 Hz).
1H NMR (500.1 MHz, CDCl3): d = 2.48 (s, 6 H, H-18, H-19), 3.81
(s, 6 H, OCH3), 4.09 (d, 2 H, H-6endo, H-12endo, 2J = –17.0 Hz),
4.39 (s, 2 H, H-13), 4.67 (d, 2 H, H-6exo, H-12exo, 2J = –17.0 Hz),
6.91 (dd, 4 H, H-3Ph, H-5Ph, 3J = 6.9 Hz, 4J = 1.6 Hz), 6.96 (d, 2 H,
13C NMR (125.8 MHz, CDCl3): d = 17.3 (C-18, C-19), 55.1 (C-6,
C-12), 67.6 (C-13), 110.5 (C-4Ph), 118.9 (CN), 123.3 (C-1, C-7),
127.3 (C-2Ph, C-6Ph), 127.9 (C-3, C-9), 128.6 (C-14, C-16), 132.5
(C-3Ph, C-5Ph,), 133.8 (C-4, C-10), 134.6 (2 C-2, C-8), 145.2
(C-1Ph), 146.7 (C-15, C-17).
MS (CI, i-butane): m/z = 453.2 ([C31H25N4]+, 100).
HRMS (CI, i-butane): m/z calcd for [C31H25N4]+: 453.2097; found:
4
4
H-1, H-7, J = 1.1 Hz), 7.25 (d, 2 H, H-3, H-9, J = 1.1 Hz), 7.41
(dd, 4H, H-2Ph, H-6Ph, 3J = 6.9 Hz, 4J = 1.6 Hz).
13C NMR (125.8 MHz, CDCl3): d = 17.3 (C-18, C-19), 55.2 (C-6,
C-12), 55.3 (OCH3), 67.7 (C-13), 114.4 (C-3Ph, C-5Ph), 122.6 (C-1,
C-7), 127.5 (C-3, C-9), 127.8 (C-2Ph, C-6Ph), 128.2 (C-14, C-16),
133.2 (C-4, C-10)*, 133.5 (C-1Ph)*, 136.4 (C-2, C-8), 144.8 (C-15,
C-17), 158.9 (C-4Ph) (*assignment not confirmed).
453.2079.
Anal. Calcd for C31H24N4·1/4 H2O: C, 81.46; H, 5.40; N 12.26.
Found: C, 81.44; H, 5.48; N, 11.89.
MS (CI, i-butane): m/z = 463.3 ([C31H31N2O2]+, 100).
HRMS (CI, i-butane): m/z calcd for [C31H31N2O2]+: 463.2384;
2,8-Bis(4-hydroxyphenyl)-4,10-dimethyl-6H,12H-5,11-metha-
nodibenzo[b,f]diazocine (14)
found: 463.2385.
Compound 11 (300 mg, 0.65 mmol) was dissolved in CH2Cl2 (10
mL) and cooled to –78 °C. After addition of a 1 M BBr3 solution in
CH2Cl2 (2.6 mL, 2.6 mmol) at this temperature, the reaction mixture
was allowed to come to r.t. and stirred for 16 h. Aq 2 N NaOH was
added until the excess of BBr3 had been completely hydrolyzed. Af-
ter addition of EtOAc (10 mL), the solution was neutralized using 6
N HCl and extracted with EtOAc (3 ×). Concentration in vacuo
gave 275 mg (99%) of 14 as a brown solid, mp 148–149 °C.
.
Anal. Calcd for C31H30N2O2 1/4 H2O: C, 79.71; H, 6.58; N 6.00.
Found: C, 79.51; H, 6.75; N, 5.83.
2,8-Bis(4-aminophenyl)-4,10-dimethyl-6H,12H-5,11-methano-
dibenzo[b,f]diazocine (12)
A solution of compound 1 (300 mg, 0.74 mmol) in THF (5 mL) was
cooled to –78 °C. At this temperature, n-BuLi (1.10 mL of a 1.6 M
solution in n-hexane, 1.77 mmol) was added dropwise within 5 min.
After stirring for 5 min, trimethylborate (0.25 mL, 2.21 mmol) was
added instantly and the reaction mixture was allowed to come to r.t.
and stirred for another 15 min. This mixture was then added to a so-
lution of 4-iodoaniline (354 mg, 1.62 mmol), CsF (737 mg, 4.85
mmol) and [Pd(Pt-Bu3)2] (15 mg) in THF (5 mL). The resulting re-
action mixture was refluxed for 48 h. Column chromatography (n-
hexane–EtOAc, 1:2 + 0.5% Et3N, Rf = 0.36) gave 280 mg (88%) of
12 as a brown solid; mp 98–100 °C.
1H NMR (500.1 MHz, DMSO-d6): d = 2.39 (s, 6 H, H-18, H-19),
2
4.03 (d, 2 H, H-6endo, H-12endo, J = –17.0 Hz), 4.26 (s, 2 H,
H-13), 4.54 (d, 2 H, H-6exo, H-12exo, 2J = –17.0 Hz), 6.77 (d, 4 H,
3
4
H-3Ph, H-5Ph, J = 8.2 Hz,), 6.99 (d, 2 H, H-1, H-7, J = 1.6 Hz),
3
7.23 (m, 2 H, H-3, H-9), 7.35 (d, 4 H, H-2Ph, H-6Ph, J = 8.2 Hz),
9.40 (s, 2 H, OH).
13C NMR (125.8 MHz, DMSO-d6): d = 17.4 (C-18, C-19), 55.1
(C-6, C-12), 67.7 (C-13), 116.0 (C-3Ph, C-5Ph,), 122.4 (C-1, C-7),
126.8 (C-3, C-9), 127.8 (C-2Ph, C-6Ph,), 128.8 (C-14, C-16), 131.3
(C-1Ph), 132.9 (C-4, C-10), 135.7 (C-2, C-8), 144.8 (C-15, C-17),
157.1 (C-4Ph).
MS (CI, i-butane): m/z = 435.2 ([C29H27N2O2]+, 100).
HRMS (CI, i-butane): m/z calcd for [C29H27N2O2]+: 435.2081;
1H NMR (500.1 MHz, DMSO-d6): d = 2.39 (s, 6 H, H-18, H-19),
2
4.01 (d, 2 H, H-6endo, H-12endo, J = –17.0 Hz), 4.25 (s, 2 H,
H-13), 4.53 (d, 2 H, H-6exo, H-12exo, 2J = –17.0 Hz), 5.09 (s, 4 H,
NH2), 6.57 (d, 4 H, H-3Ph, H-5Ph, 3J = 8.2 Hz), 6.95 (s, 2 H, H-1,
H-7), 7.20 (s, 2 H, H-3, H-9), 7.23 (dd, 4 H, H-2Ph, H-6Ph, 3J = 8.2
Hz).
found: 435.2072.
13C NMR (125.8 MHz, DMSO-d6): d = 17.4 (C-18, C-19), 55.1
(C-6, C-12), 67.7 (C-13), 114.6 (C-3Ph, C-5Ph,), 121.7 (C-1, C-7),
126.2 (C-3, C-9), 127.2 (C-2Ph, C-6Ph,), 127.9 (C-1Ph), 128.7 (C-14,
C-16), 132.7 (C-4, C-10), 136.2 (C-2, C-8), 144.3 (C-15, C-17),
148.3 (C-4Ph).
Anal. Calcd for C29H26N2O2·5/4 EtOAc: C, 74.98; H, 6.66; N 5.14.
Found: C, 74.98; H, 6.41; N, 5.58.
2,8-Bis(4-trifluoromethanesulfoxyphenyl)-4,10-dimethyl-
6H,12H-5,11-methanodibenzo[b,f]diazocine (15)
Et3N (1.00 mL) was added to a solution of 14 (500 mg, 1.15 mmol)
in CH2Cl2 (50 mL) and cooled to – 30 °C. At this temperature, a so-
lution of trifluoromethanesulfonic acid anyhydride (0.78 mL, 4.60
MS (CI, i-butane): m/z = 433.2 ([C29H29N4]+, 100).
HRMS (EI): m/z calcd for C29H28N4: 432.2308; found: 432.2313.
Synthesis 2004, No. 10, 1687–1695 © Thieme Stuttgart · New York

1694
U. Kiehne, A. Lützen
PAPER
mmol) and CH2Cl2 (10 mL) was added dropwise and the resulting
reaction mixture was stirred for another hour, then allowed to come
to r.t. and stirred for 16 h. This solution was poured into cold H2O,
extracted with CH2Cl2 (5 ×), washed with aq sat. solution of
NaHCO3, and dried (Na2SO4). The crude product was purified by
column chromatography (toluene + 0.5% Et3N, Rf = 0.09) to give
350 mg (45%) of 15 as a white solid; mp 129–131 °C.
1H NMR (500.1 MHz, CDCl3): d = 2.39 (s, 6 H, H-18, H-19), 4.03
(d, 2 H, H-6endo, H-12endo, 2J = –16.5 Hz), 4.30 (s, 8H,
OCH2CH2O), 4.32 (s, 2 H, H-13), 4.59 (d, 2 H, H-6exo, H-12exo,
2J = –16.5 Hz), 7.23 (s, 2 H, H-1, H-7), 7.48 (s, 2 H, H-3, H-9).
13C NMR (125.8 MHz, CDCl3): d = 17.0 (C-18, C-19), 54.8 (C-6,
C-12), 65.9 (OCH2CH2O), 67.7 (C-13), 122.3 (C-2, C-8), 127.3
(C-14, C-16), 131.4 (C-1, C-7), 132.2 (C-4, C-10), 135.5 (C-3,
C-9), 149.2 (C-15, C-17)
1H NMR (500.1 MHz, CDCl3): d = 2.49 (s, 6 H, H-18, H-19), 4.10
2
(d, 2 H, H-6endo, H-12endo, J = –17.0 Hz), 4.39 (s, 2 H, H-13),
MS (CI, i-butane): m/z = 391.2 ([C21H25B2N2O4]+, 100).
HRMS (CI, i-butane): m/z calcd for [C21H25B2N2O4]+: 391.2000;
4.69 (d, 2 H, H-6exo, H-12exo, 2J = –17.0 Hz), 6.98 (d, 2 H, H-1,
H-7, 4J = 1.1 Hz), 7.26 (m, 2 H, H-3, H-9), 7.27 (dd, 4 H, H-3Ph,
H-5Ph, 3J = 9.0 Hz, 4J = 2.2 Hz), 7.52 (dd, 4 H, H-2Ph, H-6Ph, 3J = 9.0
Hz, 4J = 2.2 Hz).
found: 391.2007.
Anal. Calcd for C21H24B2N2O4·1/4 toluene: C, 66.15; H, 6.35; N
6.78. Found: C, 65.71; H, 6.58; N, 7.13.
13C NMR (125.8 MHz, CDCl3): d = 17.3 (C-18, C-19), 55.1 (C-6,
C-12), 67.6 (C-13), 118.8 [CF3, 1J (C,F) = 322 Hz], 121.5 (C-3Ph,
C-5Ph), 123.2 (C-1, C-7), 127.9 (C-3, C-9), 128.4 (C-14, C-16),
128.5 (C-2Ph, C-6Ph), 133.7 (C-4, C-10), 134.9 (C-2, C-8), 141.3
(C-1Ph), 146.0 (C-15, C-17), 148.7 (C-4Ph).
19F (282.4 MHz, CDCl3): d = –72.8 (CF3).
MS (CI, i-butane): m/z = 699.1 ([C31H25F6N2O6S2]+, 100).
Acknowledgment
We thank Prof. Dr. P. Köll for providing us with excellent working
conditions. Financial support from the DFG (SPP 1118, LU 803/3-
1) and the Fonds der Chemischen Industrie is gratefully acknowled-
ged.
HRMS (EI): m/z calcd for C31H24F6N2O6S2: 698.0989; found:
698.0979.
References
Anal. Calcd for C31H24F6N2O6S2: C, 53.29; H, 3.46; N 4.01. Found:
C, 53.36; H, 3.95; N, 3.96.
(1) (a) Tröger, J. J. Prakt. Chem. 1887, 36, 227. (b) To be exact
the name should be spelled ‘Tröger’s base’ (Ref.1).
However, we used the commonly used ‘international’
spelling ‘Troeger’ throughout this paper in order to avoid
misunderstandings.
(2) Spielman, M. A. J. Am. Chem. Soc. 1935, 57, 583.
(3) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic
Compounds; Wiley: New York, 1994.
(4) Demeunynck, M.; Tatibouët, A. In Progress in Heterocyclic
Chemistry, Vol. 11; Gribble, G. W.; Gilchrist, T. L., Eds.;
Pergamon: Oxford, 1999, 1–20.
(5) Mas, T.; Pardo, C.; Salort, F.; Elguero, J.; Rosario Torres, M.
Eur. J. Org. Chem. 2004, 1097.
(6) Klärner, F.-G.; Kahlert, B. Acc. Chem. Res. 2003, 36, 919.
(7) (a) Wagner, E. C. J. Am. Chem. Soc. 1935, 57, 1296.
(b) Wagner, E. C. J. Org. Chem. 1954, 19, 1862.
(8) Jensen, J.; Wärnmark, K. Synthesis 2001, 1873.
(9) Jensen, J.; Strozyk, M.; Wärnmark, K. J. Heterocycl. Chem.
2003, 40, 373.
(10) Hansson, A.; Jensen, J.; Wendt, O. F.; Wärnmark, K. Eur. J.
Org. Chem. 2003, 3179.
(11) Lützen, A.; Hapke, M.; Griep-Raming, J.; Haase, D.; Saak,
W. Angew. Chem. Int. Ed. 2002, 41, 2086; Angew. Chem.
2002, 114, 2190.
2,8-(4,10-Dimethyl-6H,12H-5,11-methanodibenzo[b,f]diazo-
cineylene)diboronic Acid (16)
A solution of 1 (1 g, 2.45 mmol) in THF (10 mL) was cooled to
–78 °C. At this temperature, n-BuLi (3.65 mL of a 1.6 M solution in
n-hexane, 5.87 mmol) was added dropwise within 5 min. After stir-
ring for 5 min, trimethylborate (0.83 mL, 7.35 mmol) was added in-
stantly and the reaction mixture was allowed to come to r.t. and
stirred for another 15 min. H2O (15 mL) was added and after extrac-
tion with CH2Cl2, the aqueous solution was extracted with EtOAc
(3 ×) and dried (Na2SO4). Concentration in vacuo gave 750 mg
(90%) of 16 as a white solid. If necessary, 16 can be recrystallized
from acetone; mp >300 °C.
1H NMR (500.1 MHz, DMSO-d6): d = 2.33 (s, 6 H, H-18, H-19),
2
3.93 (d, 2 H, H-6endo, H-12endo, J = –17.0 Hz), 4.24 (s, 2 H,
H-13), 4.51 (d, 2 H, H-6exo, H-12exo, 2J = –17.0 Hz), 7.19 (s, 2 H,
H-1, H-7), 7.44 (s, 2 H, H-3, H-9), 7.74 (s, 4 H, OH).
13C NMR (125.8 MHz, DMSO-d6): d = 17.3 (C-18, C-19), 54.9
(C-6, C-12), 67.5 (C-13), 127.2 (C-14, C-16), 129.0 (C-2, C-8),
131.0 (C-1, C-7), 131.1 (C-4, C-10), 135.0 (C-3, C-9), 148.1 (C-15,
C-17).
MS (CI, i-butane): m/z = 339.2 ([C17H21B2N2O4]+, 100).
(12) Schalley, C. A.; Lützen, A.; Albrecht, M. Chem.–Eur. J.
2004, 10, 1072.
HRMS (CI, ammonia): m/z calcd for [C17H21B2N2O4]+: 356.1971;
found: 356.1953.
(13) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(b) Metal-Catalyzed Cross-Coupling Reactions; Diederich,
F.; Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998.
(c) Cross-Coupling Reactions: A Practical Guide; Miyaura,
N., Ed.; Springer-Verlag: Berlin, 2002. (d) 30 Years of the
Cross-Coupling Reaction, Vol. 653; Tamao, K.; Hiyama, T.;
Negishi, E., Eds.; J. Organomet. Chem. Elsevier:
Amsterdam, 2002, 1–301.
(14) Sucholeiki, I.; Lynch, V.; Phan, L.; Wilcox, C. S. J. Org.
Chem. 1988, 53, 98.
(15) Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C.
Org. Lett. 2000, 2, 1729.
Anal. Calcd for C17H20B2N2O4·4/3 H2O: C, 56.40; H, 6.31; N 7.74.
Found: C, 56.52; H, 6.06; N, 7.62.
2,8-Bis[1,3]dioxa[2]borolane-2-yl-4,10-dimethyl-6H,12H-5,11-
methanodibenzo[b,f][1,5]diazocine (17)
A solution of 1 (1 g, 2.45 mmol) in THF (10 mL) was cooled to
–78 °C. At this temperature n-BuLi (3.65 mL of a 1.6 M solution in
n-hexane, 5.87 mmol) was added dropwise within 5 min. After stir-
ring for 5 min, trimethylborate (0.83 mL, 7.35 mmol) was added in-
stantly and the reaction mixture was allowed to come to r.t. and
stirred for another 15 min. After concentration in vacuo, the residue
was dissolved in a mixture of ethylene glycol (10 mL) and toluene
(30 mL) and refluxed for 16 h. The toluene layer was separated and
concentrated in vacuo to give 830 mg (87%) of 17 as a white solid;
mp 183–185 °C.
(16) Jensen, J.; Strozyk, M.; Wärnmark, K. Synthesis 2002, 2761.
(17) (a) Lützen, A.; Hapke, M. Eur. J. Org. Chem. 2002, 2292.
(b) Lützen, A.; Hapke, M.; Staats, H.; Bunzen, J. Eur. J. Org.
Chem. 2003, 3948.
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1695
(18) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122,
(21) Wong, K.; Chen, Y.; Liao, Y.; Lin, C.; Chou, M.; Leung, M.
4020.
J. Org. Chem. 2002, 67, 1041.
(19) Grushin, V. V.; Alper, H. Chem. Rev. 1994, 94, 1047.
(20) Jensen, J.; Tejler, J.; Wärnmark, K. J. Org. Chem. 2002, 67,
6008.
(22) Suffert, J. J. Org. Chem. 1989, 54, 509.
(23) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719.
(24) Coulson, D. R. Inorg. Synth. 1990, 28, 107.
Synthesis 2004, No. 10, 1687–1695 © Thieme Stuttgart · New York