Synthesis of symmetrical amino and aminomethyl derivatives of Tro?ger's base via Pd-catalyzed C-C and C-N bond formation

Article abstract of DOI:10.1016/j.tet.2007.02.032

In this paper, we report the synthesis of amino and aminomethyl derivatives of Tr?ger's base (±)-1 and (±)-2. The key steps in the synthesis of (±)-1 and (±)-2 are Pd-catalyzed amination and cyanation, respectively, of the easily accessible dihalo derivat

Full text of DOI:10.1016/j.tet.2007.02.032

Tetrahedron 63 (2007) 3864–3869
Synthesis of symmetrical amino and aminomethyl derivatives of
€
Troger’s base via Pd-catalyzed C–C and C–N bond formation
*
Delphine Didier and Sergey Sergeyev
´
Universite Libre de Bruxelles, Laboratoire de Chimie des Polymeres, CP 206/01, Boulevard du Triomphe, 1050 Bruxelles, Belgium
ꢀ
Received 10 January 2007; revised 5 February 2007; accepted 8 February 2007
Available online 13 February 2007
€
Abstract—In this paper, we report the synthesis of amino and aminomethyl derivatives of Troger’s base (ꢀ)-1 and (ꢀ)-2. The key steps in the
synthesis of (ꢀ)-1 and (ꢀ)-2 are Pd-catalyzed amination and cyanation, respectively, of the easily accessible dihalo derivatives (ꢀ)-3. These
compounds are important intermediates in the synthesis of new ligands and building blocks for H-bonded supramolecular architectures.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
All these molecular designs require the introduction of
specific functional groups in certain positions of the rigid
€
€
Troger’s base, (ꢀ)-2,8-dimethyl-6H,12H-5,11-methano-
dibenzo[b,f][1,5]diazocine (Fig. 1), was first synthesized
in 1887 by the condensation of para-methylaniline with
skeleton of Troger’s base. This can be achieved either by
the condensation of the suitable aniline derivatives bearing
the necessary functional groups with formaldehyde or its
synthetic equivalent2,3 or, alternatively, via the sequential
build-up of functionality to create complex linked aniline de-
€
formaldehyde. Troger’s base is a chiral diamine with two
stereogenic bridge-head nitrogen atoms. The unique set of
structural features (C2-symmetry and a rigid V-shape geom-
etry with the two aromatic rings nearly perpendicular to each
€
rivatives that are finally transformed into an intact Troger’s
base skeleton.4
€
other) makes derivatives of Troger’s base very attractive for
the application in supramolecular chemistry and molecular
In the course of our own studies on ligands for H-bonded su-
pramolecular architectures, we became interested in the de-
1
€
recognition. In particular, the rigid scaffold of Troger’s
€
rivatives of Troger’s base bearing amide, urea, and similar
H-bond donor groups connected by a s-bond or by a CH2
base has been used in the design of synthetic receptors for
recognition of adenine, pyrimidine, biotin derivatives,2 and
dicarboxylic acids,3 in the ‘molecular torsion balance’ for
the quantification of weak interactions,4 and in the templated
synthesis of functional fullerene derivatives with precisely
defined geometry.5,6 Very recently, a-amino acid conjugates
spacer to the various positions of the heterocyclic system.
€
Amino and aminomethyl derivatives of Troger’s base are
evident but not easily accessible intermediates for these
molecules. Here, we report the synthesis of 6H,12H-5,11-
methanodibenzo[b,f][1,5]diazocine derivatives (ꢀ)-1 and
(ꢀ)-2 bearing NH2 and CH2NH2 groups via Pd-catalyzed
cross-coupling reactions followed by common transforma-
tions of functional groups.
€
of Troger’s base were suggested as novel conformationally
restricted scaffolds inducing ca. 90ꢁ turn in non-natural
proteins.7
2. Results and discussion
€
The most practical and general synthesis of Troger’s base
derivatives is the condensation of anilines with formalde-
hyde or its synthetic equivalent. The amino derivatives of
€
Troger’s base are not accessible by this route since the re-
€
Figure 1. Troger’s base: structural formula (left) and optimized geometry of
(S,S)-enantiomer (right).
action of diaminobenzenes with formaldehyde will obvi-
ously afford polymeric products. Hence, another synthetic
methodology is required in order to access these amino com-
pounds. At this point halogen-substituted derivatives of
€
Troger’s base seemed to be a very attractive solution for
two reasons. On the one hand, they can easily be prepared
€
Keywords: Troger’s base; Cross coupling; Amination; Cyanation.
* Corresponding author. Tel.: +32 2 6505392; fax: +32 2 6505410; e-mail:
sserguee@ulb.ac.be
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.032

D. Didier, S. Sergeyev / Tetrahedron 63 (2007) 3864–3869
3865
starting from the corresponding halo anilines.6,8 On the other
hand, they are versatile intermediates for many metal-cata-
lyzed cross-coupling reactions, which have already shown
acidic–basic work up allowed to remove the catalyst and
other impurities, and afforded diamines (ꢀ)-1a,b that were
sufficiently pure for the subsequent synthesis. The analyti-
cally pure products were isolated by column chromato-
graphy on SiO2.
their efficiency in the preparation of symmetric acetylenic
€
9,10
and biaryl derivatives of Troger’s base.
We decided to
investigate the possibility of the catalytic amination of
4,10-dibromo ((ꢀ)-3a) and 2,8-diiodo ((ꢀ)-3b) derivatives
of 6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine.
In the recent years, the aromatic amination catalyzed by
transition metal complexes became a powerful tool in or-
ganic synthesis.11 Although direct coupling of aryl halides
with NH3 is not synthetically feasible, other nitrogen
derivatives such as amines, imines, or carbamates can be
successfully used as a ‘masked ammonia’.12,13 An interest-
€
ing example reported on Troger’s base derivatives is the
Cu-catalyzed coupling of diiodide (ꢀ)-3b with BocNH2
(Boc¼tert-butoxycarbonyl).10 This reaction could be of in-
€
terest for the synthesis of amino derivatives of Troger’s
base since N-Boc group is easily cleavable upon the action
of acids. However, this reaction produced only the product
of the single halogen substitution in moderate yield.
Although this method provides access to otherwise hardly
€
available unsymmetrical derivatives of Troger’s base, it is
clearly unsuitable for the synthesis of symmetrical deriv-
atives. It also became obvious that a careful choice of the
catalytic system is necessary for the double substitution
of halogen in the deactivated aromatic rings of 6H,12H-
5,11-methanodibenzo[b,f][1,5]diazocine.
We have chosen the benzophenone imine (Ph2C]NH) as
a synthetic equivalent of NH3 for Pd-catalyzed amination.
Earlier, Buchwald and co-workers have reported the applica-
tionofthisreagentinthe Pd-catalyzedcouplingofvariousaryl
halides including deactivated methoxy-substituted bromo-
and iodobenzenes.13 This methodology is quite appealing
since benzophenone imine is more reactive compared to
amines or carbamates, it is commercially available, and fi-
nally, the product of the cross-coupling can be conveniently
isolatedandtransformedintoafreeaminebyvariousmethods.
€
Scheme 1. Synthesis of amino derivatives of Troger’s base (ꢀ)-1a,b;
dba¼dibenzylideneacetone, BINAP¼(ꢀ)-2,20-bis(diphenylphosphino)-1,10-
binaphthalene.
€
The di(aminomethyl) derivative of Troger’s base (ꢀ)-2b was
synthesized earlier in moderate yield (33%) via the conden-
sation of the phthalimide derivative of 4-aminobenzylamine
with formaldehyde followed by deprotection with N2H4.14
A
more general and rapid access to variety of aminomethyl de-
rivatives such as (ꢀ)-2a,b could be granted by the reduction
of the corresponding dinitriles (ꢀ)-5a,b. Unfortunately, di-
We have found that the treatment of (ꢀ)-3a or (ꢀ)-3b
with Ph2C]NH in the presence of [Pd2(dba)3] (dba¼
dibenzylideneacetone), (ꢀ)-2,20-bis(diphenylphosphino)-
1,10-binaphthalene (BINAP), and tBuONa at 80 ꢁC smoothly
afforded symmetrical coupling products (ꢀ)-4a and (ꢀ)-4b,
respectively (Scheme 1). TLC and 1H NMR spectra of reac-
tion mixture confirmed complete conversion of the starting
dihalides. Crude diimines (ꢀ)-4a,b can be purified by col-
umn chromatography on SiO2. However, this purification
appeared to be cumbersome and resulted in a considerable
loss of product, presumably, due to the lability of imine
groups upon contact with the slightly acidic surface of
SiO2. Fortunately, we found that the thorough purification
of diimines (ꢀ)-4a,b was not necessary. Instead, crude inter-
mediates were subjected to the mild acidic cleavage (HCl in
THF/H2O at pH¼2) to give the diamines (ꢀ)-1a and (ꢀ)-1b
in a yield of 69 and 86%, respectively. The given yields cor-
respond to the total of two steps starting from dihalides (ꢀ)-
3a,b. The slightly lower yield of (ꢀ)-1a compared to (ꢀ)-1b
can probably be explained by a better reactivity of the iodine
derivative (ꢀ)-3b in the Pd-catalyzed cross-coupling step
compared to the bromo analog (ꢀ)-3a. Notably, a simple
€
cyano derivatives of Troger’s base are in general not acces-
sible via direct condensation of amino nitriles because of the
strong electron-withdrawing nature of the CN group. The
only reported exception is an unusual reaction of 4-cyano-
aniline with DMSO as a formaldehyde equivalent in rela-
tively drastic conditions upon the action of the gaseous
HCl to give dinitrile (ꢀ)-5b in low yield (21%).15
At the same time, the reaction of metal cyanides with aryl
halides is a well-known method for the synthesis of aromatic
nitriles.16 Classically known as the Rosenmund–von Braun
reaction, this useful transformation was greatly improved
by application of transition metal complexes as catalysts.17
Therefore, we developed a synthesis of dinitriles (ꢀ)-5a,b
based on a double displacement of halogen by CNꢂ in dihalo
derivatives (ꢀ)-3a,b. The Pd-catalyzed cyanation of (ꢀ)-3b
was attempted earlier.10 However, similar to the above dis-
cussed amination, it only gave a product of a single halogen
substitution in moderate yield. The Cu-mediated cyanation
catalyzed by chelating diamine ligands developed by

3866
D. Didier, S. Sergeyev / Tetrahedron 63 (2007) 3864–3869
Buchwald and co-workers18 also remained unsuccessful.
However, we have found the method initially developed
for the cyanation of challenging substrates such as deacti-
vated aryl chlorides to be very useful in the double cyanation
synthesis without further purification or be purified by col-
umn chromatography. However, the purification required
highly polar eluants (CH2Cl2/MeOH/aq NH3). In order to
demonstrate the synthetic utility of these amines, (ꢀ)-2b
was converted to the diamide (ꢀ)-6 by acylation with 2-
nitrobenzoyl chloride in the presence of Et3N (Scheme 3).
In another example, the amino derivative (ꢀ)-1a was trans-
formed to the dithiourea (ꢀ)-7 upon the action of the corre-
sponding isothiocyanate in THF. All synthesized compounds
were characterized by 1H and 13C NMR and by HRMS (see
Supplementary data for original spectra).
€
of the dihalo derivatives of Troger’s base. Air-stable
[Pd2(dba)3] and an activating ligand dppf (1,10-bis(diphenyl-
phosphino)ferrocene) were used as an efficient catalytic sys-
tem. The combination of Zn(CN)2 as a cyanide source with
catalytic amounts of Zn allows to avoid the CNꢂ-induced
deactivation of the catalyst.19 Similar to Pd-catalyzed cross
coupling with Ph2C]NH, iodo derivative (ꢀ)-3b was
more reactive toward Pd-catalyzed cyanation compared to
its bromo analog (ꢀ)-3a. Indeed, (ꢀ)-3b afforded 98% of
(ꢀ)-5b while (ꢀ)-3a gave (ꢀ)-5a in relatively modest yield
(62%) under identical reaction conditions (Scheme 2).
3. Conclusion
In summary, we have demonstrated the efficiency of Pd-cat-
alyzed C–C and C–N forming reactions providing an easy
€
access to amino and aminomethyl derivatives of Troger’s
base. The identity (bromo or iodo) and the position of the
halogen in the aromatic ring of the 6H,12H-5,11-methanodi-
benzo[b,f][1,5]diazocine scaffold have relatively little influ-
ence on the outcome of these coupling reactions. In a similar
€
way, other symmetrical derivatives of Troger’s base bearing
NH2 or CH2NH2 functionalities in the different positions of
the aromatic rings should be easily accessible by this method
starting from known dihalo derivatives. Obviously, these di-
amines can be further elaborated in a variety of ways and
converted into other derivatives such as amides, carbamates,
sulfonamides, ureas, or thioureas. We are currently working
on the studies of the self-assembly of such derivatives into
hydrogen-bonded supramolecular architectures and on their
application in organocatalysis. Furthermore, diamines de-
€
rived from Troger’s base can be interesting as ligands for
transition metal catalysis and for heterotopic metal-medi-
ated self-assemblies, such as recently demonstrated for
enantiomers of 2b and a scissor-like zinc porphyrin.20
€
Scheme 2. Synthesis of aminomethyl derivatives of Troger’s base (ꢀ)-2a,b;
dba¼dibenzylideneacetone, dppf¼1,10-bis(diphenylphosphino)ferrocene,
DMA¼N,N-dimethylacetamide.
4. Experimental section
4.1. General
The reduction of nitriles (ꢀ)-5a and (ꢀ)-5b to diamines (ꢀ)-
2a and (ꢀ)-2b, respectively, with LiAlH4 in THF was
straightforward. 1H NMR spectra showed complete conver-
sion of the starting material and only traces of impurities.
Amines (ꢀ)-2a,b can thus either be used in the subsequent
All chemicals were purchased from Aldrich or Acros and
used without further purification unless stated otherwise.
Scheme 3. Conversion of diamines (ꢀ)-2b and (ꢀ)-1a into diamide and dithiourea derivatives.

D. Didier, S. Sergeyev / Tetrahedron 63 (2007) 3864–3869
3867
2
THF was refluxed over sodium and benzophenone until
a blue-violet color persisted and distilled directly into the re-
action flask. All Pd-catalyzed reactions were performed in
oven-dried glassware under dry Ar atmosphere. Dry N,N-di-
25 ꢁC): d¼3.89 (d, JH,H¼16.5 Hz, 2H), 4.20 (s, 2H), 4.45
2
4
(d, JH,H¼16.5 Hz, 2H), 6.29 (d, JH,H¼2.4 Hz, 2H), 6.49
3
4
3
(dd, JH,H¼8.4 Hz, JH,H¼2.4, 2H), 6.81 (d, JH,H¼8.4 Hz,
2H), 7.00–7.55 (m, 16H), 7.65–7.75 (m, 4H). HREIMS
m/z, calcd for C41H32N4 ([M]+): 580.2627; found: 580.2614.
˚
methylacetamide and toluene were kept over 4 A molecular
sieves. Column chromatography: SiO2 Kieselgel 60
(Macherey–Nagel, particle size 0.04–0.063 mm). TLC: pre-
coated SiO2 plates Kieselgel 60F254 (Merck). 1H (300 MHz)
and 13C (75 MHz) NMR spectra were recorded in CDCl3 on
a Brucker Avance 300 spectrometer; chemical shifts (d) are
given in parts per million relative to Me4Si; coupling con-
stants (J) are given in hertz. Electron impact mass spectra
(EIMS) were recorded on a Waters AutoSpec 6F instrument
and electrospray ionization mass spectra (ESIMS) on a
Waters QToF 2 instrument; m/z with the lowest isotopic
mass are reported. IR spectra were recorded on a Shimadzu
IR-470 instrument. Diiodide (ꢀ)-3b was prepared from
4-iodoaniline as described earlier.6
4.5. ( )-2,8-Dimethyl-6H,12H-5,11-methanodibenzo-
[b,f][1,5]diazocine-4,10-diamine (( )-1a)
A solution of HCl (2 M in water) was added to a solution of
bis-imine (ꢀ)-4a in THF (10 mL) until pH¼2 was reached.
After 2 h of stirring at room temperature the reaction mixture
was partitioned between hexane/AcOEt (2:1, 200 mL) and
the aqueous 0.5 M HCl solution (200 mL). The aqueous
phase was separated, filtered, made alkaline with an aqueous
NaOH solution, and then extracted with CH2Cl2 (2ꢃ
100 mL). The organic layer was dried over MgSO4 and con-
centrated in vacuum to give a pale yellow solid (189 mg,
0.674 mmol). Yield from (ꢀ)-3a: 69%; mp 206 ꢁC (dec);
1H NMR (300 MHz, CDCl3, 25 ꢁC): d¼2.14 (s, 6H), 3.95
4.2. ( )-4,10-Dibromo-2,8-dimethyl-6H,12H-5,11-meth-
anodibenzo[b,f][1,5]diazocine (( )-3a)
2
(br s, 4H), 4.04 (d, JH,H¼16.8 Hz, 2H), 4.26 (s, 2H), 4.35
2
4
(d, JH,H¼16.8 Hz, 2H), 6.16 (d, JH,H¼0.9 Hz, 2H), 6.40
4
2-Bromo-4-methylaniline (25.2 g, 0.135 mol) and then para-
formaldehyde (8.1 g, 0.27 mol) were added in portions to
CF3COOH (250 mL) at ꢂ15 ꢁC. The resulting mixture was
allowed to reach room temperature and stirred for 20 h,
then slowly added upon vigorous stirring to a mixture
of ice and an excess of NH3 solution (25% in water) at
0 ꢁC. The resulting mixture was extracted with CH2Cl2
(3ꢃ200 mL), dried over MgSO4, and concentrated in vac-
uum. The resulting solid was washed with hexane to give
pure (ꢀ)-3a (27.2 g, 98%) as a colorless solid. Analytical
data were identical with those published earlier.21
(d, JH,H¼0.9 Hz, 2H); 13C NMR (75 MHz, CDCl3,
25 ꢁC): d¼21.1, 52.6, 67.9, 113.5, 116.8, 128.3, 131.2,
134.0, 140.6; EIMS: m/z (%)¼280 (100), 265 (14), 146
(16). HREIMS m/z, calcd for C17H20N4 ([M]+): 280.1688;
found: 280.1684.
4.6. ( )-6H,12H-5,11-Methanodibenzo[b,f][1,5]diazo-
cine-2,8-diamine (( )-1b)
Synthesized similar to (ꢀ)-1a from crude (ꢀ)-4b prepared
from (ꢀ)-3b (484 mg, 1.03 mmol). The crude product was
purified by column chromatography (CH2Cl2/MeOH 9:1 to
7:3) to give a pale yellow solid (220 mg). Yield from (ꢀ)-
4.3. ( )-N,N0-Dibenzhydrylidene-2,8-dimethyl-6H,12H-
5,11-methanodibenzo-[b,f][1,5]diazocine-4,10-diamine
(( )-4a)
1
3b: 85%; mp 266 ꢁC (dec); H NMR (300 MHz, DMSO-
2
d6, 25 ꢁC): d¼3.76 (d, JH,H¼16.5 Hz, 2H), 4.04 (s, 2H),
2
4.37 (d, JH,H¼16.5 Hz, 2H), 4.66 (br s, 4H), 6.07 (d,
3
4
A mixture of bromide (ꢀ)-3a (399 mg, 0.977 mmol), Ph2C]
NH (0.423 mL, 2.52 mmol), tBuONa (282 mg, 2.93 mmol),
Pd2(dba)3 (240 mg, 0.262 mmol), (ꢀ)-BINAP (490 mg,
0.787 mmol) and dry toluene (4 mL) were heated at 80 ꢁC
under Ar atmosphere in a Schlenk tube. After 24 h, the reac-
tion mixture was allowed to reach room temperature and
diluted with CH2Cl2 (40 mL). Filtration and evaporation of
the solvent afforded (ꢀ)-5a as a red solid that was used in the
4JH,H¼2.4 Hz, 2H), 6.36 (dd, JH,H¼8.4 Hz, JH,H¼2.4 Hz,
2H), 6.72 (d, JH,H¼8.4 Hz, 2H); 13C NMR (75 MHz,
3
DMSO-d6, 25 ꢁC): d¼58.3, 67.0, 110.8, 113.4, 124.9,
128.3, 137.4, 144.4. HREIMS m/z, calcd for C15H16N4
([M]+): 252.1375; found: 252.1381.
4.7. ( )-2,8-Dimethyl-6H,12H-5,11-methanodibenzo-
[b,f][1,5]diazocine-4,10-dicarbonitrile (( )-5a)
1
next step without further purification. H NMR (300 MHz,
CDCl3, 25 ꢁC): d¼2.02 (s, 6H), 3.94 (s, 2H), 4.17 (d,
Bromide (ꢀ)-3a (5.00 g, 12.2 mmol), Pd2(dba)3 (4.50 g,
4.91 mmol), dppf (5.45 g, 9.83 mmol), Zn powder
(0.192 g, 2.94 mmol), and Zn(CN)2 (1.76 g, 15.0 mmol)
were placed in a dry argon flushed flask. Dry N,N-dimethyl-
acetamide (50 mL) was added via syringe. The resulting
mixture was heated at 150 ꢁC for 18 h. The reaction mixture
was cooled to room temperature and diluted with AcOEt
(150 mL). The organic phase was filtered through Celite,
and then washed with 2 N aqueous NH3 solution (200 mL)
and with water (2ꢃ100 mL). The organic phase was then
dried over MgSO4 and concentrated in vacuum. Hexane
(2 mL) was added to the resulting oil and the mixture was
sonicated for few minutes. The resulting solid was filtered,
dissolved in hexane/AcOEt (8:2), the solution was passed
through a plug of SiO2, and concentrated. Finally, crystalli-
zation of the residue from hexane/AcOEt afforded
2
2JH,H¼17.1 Hz, 2H), 4.33 (d, JH,H¼17.1 Hz, 2H), 6.15 (d,
4
4JH,H¼1.6 Hz, 2H), 6.37 (d, JH,H¼1.6 Hz, 2H), 7.15–7.55
3
4
(m, 16H), 7.82 (dd, JH,H¼8.1 Hz, JH,H¼1.5 Hz, 4H);
EIMS: m/z (%)¼608 (6), 531 (26), 453 (100), 437 (18),
221 (16).
4.4. ( )-N,N0-Dibenzhydrylidene-6H,12H-5,11-meth-
anodibenzo[b,f][1,5]diazocine-2,8-diamine (( )-4b)
Prepared similar to (ꢀ)-4a from (ꢀ)-3b (484 mg,
t
1.03 mmol), Ph2C]NH (0.508 mL, 3.03 mmol), BuONa
(283 mg, 2.94 mmol), Pd2(dba)3 (233 mg, 0.254 mmol),
and (ꢀ)-BINAP (483 mg, 0.776 mmol) in dry toluene
(4 mL). The product was used in the next step without fur-
1
ther purification. Red solid; H NMR (300 MHz, CDCl3,

3868
D. Didier, S. Sergeyev / Tetrahedron 63 (2007) 3864–3869
analytically pure (ꢀ)-5a (2.268 g, 62%) as an off-white
25 ꢁC): d¼42.6, 58.2, 66.1, 124.6, 126.9, 127.2, 127.8,
131.8, 147.6. HREIMS m/z, calcd for C17H20N4 ([M]+):
280.1688; found: 280.1687.
1
solid; mp 258–261 ꢁC (dec); H NMR (300 MHz, CDCl3,
25 ꢁC): d¼2.27 (s, 6H), 4.25–4.40 (m, 4H), 4.73 (d,
2JH,H¼17.7 Hz, 2H), 7.00 (s, 2H), 7.31 (s, 2H); 13C NMR
(75 MHz, CDCl3, 25 ꢁC): d¼20.6, 56.8, 67.0, 108.7,
117.2, 128.9, 132.4, 132.6, 134.5, 148.0; EIMS: m/z
(%)¼300 (100), 285 (15), 272 (9), 180 (9), 170 (15).
HREIMS m/z, calcd for C19H16N4 ([M]+): 300.1375; found:
300.1359.
4.11. ( )-N-(8-[(2-Nitrobenzoylamino)methyl]-6H,12H-
5,11-methanodibenzo[b,f][1,5]diazocin-2-ylmethyl)-2-
nitrobenzamide (( )-6)
Diamine (ꢀ)-2b (0.040 g, 0.143 mmol), 2-nitrobenzoyl
chloride (0.083 g, 0.447 mmol), and Et3N (0.225 mL,
1.61 mmol) in CH2Cl2 (2 mL) were stirred for 5 h at room
temperature, then water (5 mL) and CH2Cl2 (5 mL) were
added. The organic phase was washed with water (20 mL),
dried over MgSO4, and concentrated in vacuum. Column
chromatography (gradient elution from CH2Cl2 to CH2Cl2/
MeOH 95:5) afforded (ꢀ)-6 as a yellow solid (44 mg,
53%); mp 131 ꢁC; IR (KBr) (nmax/cmꢂ1): 3380 (N–H),
3255, 3050, 2910, 1644 (C]O), 1520 (N–H), 1492, 1425,
1346, 1294, 1201, 1106, 1059, 959, 834, 783, 728, 692. 1H
NMR (300 MHz, CDCl3, 25 ꢁC): d¼4.13 (d, 2JH,H¼16.8 Hz,
2H), 4.23 (s, 2H), 4.36–4.44 (m, 4H), 4.63 (d, 2JH,H¼16.8 Hz,
2H), 6.26 (t, 3JH,H¼5.5 Hz, 2H), 6.89 (br, 2H), 7.04–7.16 (m,
4H), 7.41 (dd, 3JH,H¼7.4 Hz, 4JH,H¼1.7 Hz, 2H), 7.46–7.62
4.8. ( )-6H,12H-5,11-Methanodibenzo[b,f][1,5]diazo-
cine-2,8-dicarbonitrile (( )-5b)
Prepared similar to (ꢀ)-5a from (ꢀ)-3b (1.422 g,
3.00 mmol), Pd2(dba)3 (1.106 g, 1.21 mmol), dppf
(1.340 g, 2.42 mmol), Zn powder (47 mg, 0.719 mmol),
and Zn(CN)2 (434 mg, 3.70 mmol) in dry N,N-dimethyl-
acetamide (9 mL). Purification by column chromatography
(hexane/AcOEt gradient from 6:4 to 2:8) afforded (ꢀ)-5b
as an off-white solid (804 mg, 98%); mp 250 ꢁC (lit.15 mp
248–249 ꢁC); 1H NMR (300 MHz, CDCl3, 25 ꢁC):
2
d¼4.21, (d, JH,H¼16.8 Hz, 2H), 4.29 (s, 2H), 4.73 (d,
2JH,H¼16.8 Hz, 2H), 7.16–7.26 (m, 4H), 7.46 (dd,
4
3
4
3JH,H¼8.4 Hz, JH,H¼1.8 Hz, 2H); 13C NMR (75 MHz,
(m, 4H), 7.96 (dd, JH,H¼8.0 Hz, JH,H¼1.3 Hz, 2H); 13C
NMR (75 MHz, CDCl3, 25 ꢁC): d¼43.7, 58.7, 66.8, 124.5,
125.3, 126.5, 127.1, 128.1, 128.6, 130.5, 132.7, 133.1,
133.6, 146.4, 147.5, 166.3. HRESIMS m/z, calcd for
C31H26N6NaO6 ([M+Na]+): 601.1812; found: 601.1805.
CDCl3, 25 ꢁC): d¼58.3, 66.3, 107.7, 118.6, 125.9, 128.6,
131.4, 152.1 (one signal missing because of overlap).
HREIMS m/z, calcd for C17H12N4 ([M]+): 272.1062; found:
272.1065.
4.9. ( )-C-(10-Aminomethyl-2,8-dimethyl-6H,12H-5,11-
methanodibenzo[b,f][1,5]diazocin-4-yl)methylamine
(( )-2a)
4.12. ( )-1-[3,5-Bis(trifluoromethyl)phenyl]-3-[10-
(3-[3,5-bis(trifluoromethyl)phenyl]-thioureido)-2,8-
dimethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]di-
azocin-4-yl]-thiourea (( )-7)
LiAlH4 (0.268 g, 7.06 mmol) was added at 0 ꢁC to a stirred
solution of nitrile (ꢀ)-5a (0.504 g, 1.68 mmol) in dry THF
(25 mL). The reaction mixture was heated to reflux for
24 h, then allowed to reach room temperature, and quenched
with an excess of THF/water (4:1). After 60 min of stirring
the mixture was filtered, the filtrate was dried over
MgSO4, and concentrated in vacuum. The resulting (ꢀ)-2a
(0.488 g, 94%) can be used without further purification.
3,5-Bis(trifluoromethyl)phenyl isothiocyanate (267 mg,
0.985 mmol) was added at 0 ꢁC to a solution of diamine
(ꢀ)-1a (138 mg, 0.492 mmol) in dry THF (5 mL). The mix-
ture was stirred for 10 min at 0 ꢁC, allowed to reach room
temperature, and stirred for further 22 h. Solvent was re-
moved in vacuum and the crude product was crystallized
from CH2Cl2 to give analytically pure (ꢀ)-7 as a colorless
1
Brownish amorphous solid; H NMR (300 MHz, CDCl3,
25 ꢁC): d¼2.0 (br, 4H, NH2), 2.22 (s, 6H), 3.68 (d,
solid (244 mg, 60%); mp 280 ꢁC (dec); IR (KBr) (nmax
/
cmꢂ1): 3345 (N–H), 3175, 3010, 1611, 1524 (br, C]S,
N–H), 1464, 1437, 1383, 1333, 1276, 1180, 1135, 1108,
919, 884, 678.1H NMR (300 MHz, DMSO-d6, 25 ꢁC):
2
2JH,H¼14.4 Hz, 2H), 3.99 (d, JH,H¼16.8 Hz, 2H), 4.24 (d,
2
2JH,H¼14.4 Hz, 2H), 4.25 (s, 2H), 4.57 (d, JH,H¼16.8 Hz,
2H), 6.61 (s, 2H), 6.98 (s, 2H); 13C NMR (75 MHz,
CDCl3, 25 ꢁC): d¼20.9, 42.3, 56.0, 67.2, 125.9, 127.4,
127.9, 133.8, 137.5, 142.9; EIMS: m/z (%)¼308 (15), 274
(35), 205 (100), 174 (33), 158 (55), 130 (70), 91 (46).
HREIMS m/z, calcd for C19H24N4 ([M]+): 308.2001; found:
308.1999.
d¼2.19 (s, 6H), 3.93 (d, JH,H¼16.8 Hz, 2H), 4.32 (s, 2H),
2
2
4.54 (d, JH,H¼16.8 Hz, 2H), 6.67 (s, 2H), 7.48 (s, 2H),
7.82 (s, 2H), 8.40 (s, 4H), 9.64 (s, 2H), 10.64 (s, 2H); 13C
NMR (75 MHz, DMSO-d6, 25 ꢁC): d¼20.5, 54.4, 66.0,
1
116.6–116.9 (m, CCCF3), 123.2 (q, JC,F¼272.8 Hz, CF3),
122.7–123.0 (m, CCCF3), 124.5, 124.7, 128.5, 130.0 (q,
2JC,F¼32.9 Hz, CCF3), 132.0, 132.6, 138.0, 141.7, 179.4.
HRESIMS m/z, calcd for C35H27N6F12S2 ([M+H]+):
823.1547; found: 823.1544.
4.10. ( )-C-(8-Aminomethyl-6H,12H-5,11-methanodi-
benzo[b,f][1,5]diazocin-2-yl)-methylamine (( )-2b)
Prepared similar to (ꢀ)-2a from (ꢀ)-5b (0.276 g,
1.01 mmol) and LiAlH4 (0.248 g, 6.53 mmol) in dry THF
(10 mL). The resulting (ꢀ)-2b (0.283 g, 100%) can be used
without further purification. Brownish amorphous solid; 1H
NMR (300 MHz, DMSO, 25 ꢁC): d¼3.51 (br s, 4H), 3.76
(s, 4H), 4.07 (d, 2JH,H¼16.8 Hz, 2H), 4.23 (s, 2H), 4.62 (d,
Acknowledgements
ꢁ
S.S. is indebted to Prof. Y. Geerts (Universite Libre de
Bruxelles) for the opportunity to conduct an independent
research program in his laboratory and for generous financial
support. We thank Prof. R. Flammang and co-workers
(University of Mons) for the measurement of mass spectra.
3
2JH,H¼16.8 Hz, 2H), 7.00 (s, 2H), 7.12 (d, JH,H¼8.4 Hz,
2H), 7.18–7.22 (m, 2H); 13C NMR (75 MHz, DMSO,

D. Didier, S. Sergeyev / Tetrahedron 63 (2007) 3864–3869
3869
€
9. Jensen, J.; Strozyk, M.; Warnmark, K. Synthesis 2002,
2761–2765; Kiehne, U.; Lutzen, A. Synthesis 2004, 1687–
Supplementary data
€
Original 1H and 13C NMR spectra of (ꢀ)-1a,b, (ꢀ)-2a, (ꢀ)-
5a, (ꢀ)-6, and (ꢀ)-7. Supplementary data associated with
this article can be found in the online version, at doi:
10.1016/j.tet.2007.02.032.
1695.
10. Hof, F.; Schar, M.; Scofield, D. M.; Fischer, F.; Diederich,
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