One-step synthesis of trger's base hybrids containing at least one halogen atom

Article abstract of DOI:10.1002/ejoc.200900121

The one-step synthesis of a series of hybrid dibenzo Trger's base analogues bearing at least one halogen atom is described. The strategy involves a reaction between two different anilines and affords hybrid compounds in yields as high as 46%, together with the symmetric Trger's base products. This straightforward approach requires only one chromatographic step and has the potential to replace multi-step approaches to hybrid Trger's base compounds. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009.

Full text of DOI:10.1002/ejoc.200900121

FULL PAPER
DOI: 10.1002/ejoc.200900121
One-Step Synthesis of Tröger’s Base Hybrids Containing at Least One
Halogen Atom
Masoud Faroughi,[a] Kai-Xian Zhu,[a] Paul Jensen,[b] Donald C. Craig,[c] and
Andrew C. Try*[a]
Keywords: Tröger’s base / Chirality / Aromatic substitution / Haloanilines / X-ray diffraction
The one-step synthesis of a series of hybrid dibenzo Tröger’s
base analogues bearing at least one halogen atom is de-
scribed. The strategy involves a reaction between two dif-
ferent anilines and affords hybrid compounds in yields as
high as 46%, together with the symmetric Tröger’s base
products. This straightforward approach requires only one
chromatographic step and has the potential to replace multi-
step approaches to hybrid Tröger’s base compounds.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
There have been two long-held beliefs regarding the role
of substituents in the direct synthesis of Tröger’s base ana-
logues from anilines, and these beliefs had limited the de-
sign of new analogues. The first of these beliefs was that
electron-withdrawing substituents are poorly tolerated in
the reaction. The work of Wärnmark’s group on the prepa-
ration of dihalogenated compounds[23] was the first step to
dismantling this misconception. There have been subse-
quent reports of tetrahalo,[24–26] and octafluoro ana-
logues,[27] and diester-,[22,26,28–31] dinitro-[26,32–35] and even
tetranitro-substituted[36] Tröger’s base analogues have now
been prepared. The second belief was that a substituent
must be present in the p-position to prevent polymer forma-
tion, as a result of an additional condensation with formal-
Introduction
Tröger’s base (1, Figure 1) is a chiral cleft-containing
molecule that was first prepared by Tröger in 1887.[1] The
compound is formed as a racemic mixture; however, its
structure was not confirmed until 1935,[2] and it was re-
solved by Prelog in 1944, providing one of the first exam-
ples of chromatography with a chiral stationary phase.[3]
Figure 1. Chemical structure of Tröger’s base (1) and the conven- dehyde at the activated site para to the aniline nitrogen
tional numbering system.
atom. Wärnmark was again the first to show this was not
the case by preparing a series of dihalo Tröger’s base ana-
logues, in yields as high as 59%,[37] from haloanilines un-
substituted para to the aniline amino group. Dinitro-[35] and
diester-substituted[31] Tröger’s bases substituent-free at the
2,8-positions have also been reported, and it has been
shown that aniline itself can be used in the synthesis of un-
substituted Tröger’s base in 78% yield.[38]
The reaction is the result of an acid-catalysed condensa-
tion of formaldehyde with p-toluidine, and involves electro-
philic aromatic substitution and imine formation. In subse-
quent years, numerous researchers have published papers
dealing with the synthesis and structure of Tröger’s base
analogues.[4–8] More recently, potential applications in the
field of supramolecular chemistry provided much of the im-
petus for renewed interest in these compounds.[9–22]
It is sometimes desirable to prepare non-symmetric, or
“hybrid” Tröger’s base analogues. A hybrid material here is
defined as one in which the two aromatic rings are differen-
[a] Department of Chemistry and Biomolecular Sciences, Macqua- tially substituted. These compounds can be synthesised in
rie University,
an unambiguous fashion by a stepwise route that initially
North Ryde, NSW 2109, Australia
involves the formation of a mono-linked compound.[39–43]
Fax: +61-9850-8313
E-mail: andrew.try@mq.edu.au
The use of a single aniline with two unsubstituted and in-
equivalent positions ortho to the amino group can also
theoretically afford a hybrid, as one of three potential
Tröger’s base products. Whilst this has been observed exper-
imentally,[33,35,37] the compounds may be inseparable[13,44]
and with some anilines only a single Tröger’s base com-
[b] Crystal Structure Analysis Facility, School of Chemistry, The
University of Sydney,
Sydney, NSW 2006, Australia
[c] School of Chemistry, University of New South Wales,
Sydney, NSW 2052, Australia
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900121.
4266
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Eur. J. Org. Chem. 2009, 4266–4272

Tröger’s Base Hybrids Containing at Least One Halogen Atom
pound is formed.[31,45] Another strategy is to “desym- other types of functionality (including formyl, carboxy, cy-
metrise” a symmetric Tröger’s base, either by converting ano and imino groups),[46,47,52–55] and hence each of the hy-
one of two symmetrically positioned substituents,[46,47] or brids prepared here have the potential to give rise to other
introducing a substituent through either monobromin- series of hybrid compounds. The hybrids were generally ob-
ation,[38,48] monochlorination[48] or monoiodination reac- tained as pure materials after chromatography (see the Ex-
tions.[38]
perimental Section) in yields ranging from 7% to 41%
Conceptually, hybrids can be formed in a one-step reac- (Scheme 1, Table 1).
tion from a mixed condensation of two different aminoaryl
units. This method has been reported previously; however,
the reactions have involved either an aniline and an amino-
biphenyl (no experimental details were provided),[49] or 5-
aminophenanthroline and 3-aminoacridines.[50,51]
In this paper, we describe our recent efforts to expand
the chemistry of dibenzo Tröger’s base analogues by prepar-
ing a range of new hybrid compounds possessing at least
one halogen atom.
Table 1. Yields of hybrids 2–11.
Compound
R1
R2
R3
Yield[a]
%
2
3
Br
Br
Br
Br
Br
Br
Br
CH3
Br
Br
H
H
H
H
H
H
Cl
Br
Br
H
CH3
CH2(CH2)8CH3
Ph
OCH3
NHCOCH3
NHCOC(CH3)3
Br
35
13
7
23
33
33
25
35
41
14
4
5
6
7
8
9
CH3
CH3
H
10
11
Results and Discussion
[a] Analytically pure material obtained after chromatography.
In the present context, the reaction of two different p-
substituted anilines (Aniline A and Aniline B) affords a
mixture of three possible Tröger’s base products: two sym-
metric compounds and a hybrid (Scheme 1). This approach
yields a range of hybrid compounds in acceptable yields in
a single step from readily available starting materials, pro-
viding that the symmetric product derived from aniline A
has a very different Rf value from the symmetric product
derived from aniline B.
By assuming equal reactivity of both anilines (which is
clearly not the case, as the presence of different substituents
and even the same substituents in different locations will
impart different reactivity on the anilines), the theoretical
yield of hybrids formed in this way is 50%, with each of the
two symmetric compounds formed in 25% yield, based on
a 1:2:1 product distribution (A/A, A/B, B/A, B/B).
Several reactions involving 2,4-substituted anilines were
also performed to afford hybrids 8–10 in 25–41% yields,
and these compounds include examples of hybrids in which
the halogen atoms are present in the 4-, 2,4-, and 2,4,8-
positions.
In each case the homo-coupled products (2,8-dibromo,
2,8-dimethyl Tröger’s base, etc.) were also formed in varying
yields, and in some cases (for example in the synthesis of 3
and 4) fractions were also collected that contained mixtures
of the homo-coupled product and the hybrid material (i.e.,
separation was not complete, and some tailing of the bands
on the column had taken place), and thus the actual yield
of hybrid compound in the crude reaction mixture was
higher than stated in Table 1.
In fact, the poor yield of purified 3 and 4 is indicative of
an insufficient difference in polarity of the symmetric
Scheme 1. Synthesis of Tröger’s base hybrids 2–19.
This requirement was derived empirically from experi- Tröger’s base products. Dibromo and didecyl Tröger’s base,
mental observations. In each case examined thus far, the as well as dibromo and diphenyl Tröger’s base have similar
hybrid, not surprisingly, has an Rf value that lies between Rf values and are therefore difficult to separate (by using
the two symmetric compounds. Thus, if the symmetric conventional column chromatography) from their hybrids 3
products have similar Rf values, the isolation of the hybrid and 4, respectively. In addition, the symmetric 2,8-diphenyl
by chromatographic techniques proves to be problematic.
Tröger’s base is obtained in 29% yield in our hands in a
4-Bromoaniline was chosen as one of the anilines in the reaction involving only 4-aminobiphenyl as the aminoaryl
first series of the reactions as its homo-coupled product, compound (when performed on a 1 g scale with TFA and
2,8-dibromo Tröger’s base, is formed in excellent yield in paraformaldehyde), probably as a result of condensation
the absence of a second aniline. This compound is non- with formaldehyde at the activated 4Ј-site leading to other
polar and is eluted relatively quickly from standard silica products. Hence, a poor yield of hybrid is also expected,
columns with a solvent system consisting of 10% ethyl ace- even in the absence of purification problems.
tate in dichloromethane. In addition, conditions have been
Of course, as is the case in all Tröger’s base reactions,
established that enable the bromo group to be converted to other by-products, such as 3,4-dihydroquinazolines (the
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FULL PAPER
products of a condensation between two anilines and two
formaldehyde equivalents)[28,56–61] and related products (for
example, condensation between three anilines and four
formaldehyde equivalents),[6,62] can also be formed. Clearly,
the use of two different anilines in the reaction can magnify
these types of impurities, which may complicate purification
of the desired hybrids. This appears to be the case in the
synthesis of 11, in which the poor yield is the result of a
significant loss of desired product during purification as it
co-elutes with other (non-Tröger’s base) compounds with
similar Rf values. The preferable route to this compound is
by bromination of unsubstituted Tröger’s base and affords
11 in 44% yield over two steps, as this avoids the problem-
atic impurities formed in the one-step reaction of 11.[38]
However, if the synthesis of a Tröger’s base bearing a single
bromo substituent in the 2-position is desired, the one-step
synthesis of 2 (or 5) is more direct and requires a single
chromatographic step during purification. Compound 2 has
also been prepared by a stepwise procedure (3 steps) from
5-bromoisatoic anhydride in 49% overall yield.[43]
Figure 4. ORTEP diagram of one of the two crystallographically
independent molecules present in the unit cell of 7, with 50% prob-
ability ellipsoids.
A series of reactions were then carried out with iodo-
substituted anilines, by using the same conditions as out-
lined in Scheme 1, and the results are summarised in
Table 2.
Table 2. Yields of hybrids 12–19.
X-ray crystal structures were obtained for compounds 2
and 4 (Figures 2 and 3). The dihedral angle (formed by the
intersection of the least-squares planes that pass through
the aryl rings connected to the diazocine bridge) in these
compounds was measured to be 92.6° and 101.4°, respec-
tively.
Compound
R1
R2
R3
Yield[a]
%
12
13
14
15
16
17
18
19
I
I
H
H
CH3
Br
Cl
Br
CH3
OCH3
I
I
I
I
Br
H
31
46
42
42
20
20
34
15
Br
CH3
Br
Br
I
CH3
H
I
[a] Analytically pure material obtained after chromatography.
The use of iodoanilines was again based on the demon-
strated utility of the halogen atom as a substituent on
Tröger’s base analogues, in which the iodo group has been
used to introduce methoxy,[52] formyl,[63] aryl,[47,63] and al-
kyne[23,52,64,65] substituents.
A reaction involving 4-iodoaniline and 4-aminobiphenyl
yielded an inseparable mixture of the desired hybrid and
the two symmetric compounds, as anticipated, because 2,8-
diiodo and 2,8-diphenyl Tröger’s base have a similar Rf
value. A similar outcome resulted from a reaction with 4-
bromoaniline and 4-iodoaniline, i.e., an inseparable mixture
of the three possible Tröger’s base compounds was formed.
An X-ray structure was obtained of 12 (Figure 5) and the
dihedral angle was found to be 92.3°, essentially the same
as that in 2.
Figure 2. ORTEP diagram of 2 with 50% probability ellipsoids.
Figure 3. ORTEP diagram of 4 with 50% probability ellipsoids.
An X-ray crystal structure of 7 showed the presence of
two crystallographically independent molecules in the unit
cell, with dihedral angles of 94.2° and 99.0° (Figure 4).
Figure 5. ORTEP diagram of 12 with 10% probability ellipsoids.
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Tröger’s Base Hybrids Containing at Least One Halogen Atom
Compounds 12 and 13 may be regarded as analogues of Tröger’s base compounds by TLC analysis. There are clearly
19 in the sense that they are mono-iodo compounds with many other substituted anilines that could be used; how-
the iodo group in the 2- (or 8-)position; however, by using ever, the results detailed here provide a sample of the substi-
this approach the compounds bearing methyl or methoxy tution type and patterns that are possible by using this one-
groups in the 8- (or 2-)positions are available in higher step approach to hybrids. The synthesis of Tröger’s base
yields than those in which the second aryl ring lacks a sub- analogues bearing different halogens presents the opportu-
stituent. As was the case with compound 11, at least part nity to capitalise on their different reactivities in subsequent
of the reason for the poor yield of 19 is the loss of hybrid transformations, and these studies are being actively pur-
material due to co-elution with other (non-Tröger’s base) sued in our laboratory.
compounds with similar Rf values. A more efficient route to
19 involves iodination of unsubstituted Tröger’s base, which
reportedly affords the hybrid in 43% yield over two steps.[38]
In terms of the position of halogen atoms, compounds
14 and 18 may be regarded as equivalent to one another as
they are both essentially “2-bromo-8-iodo Tröger’s base”,
which is available in 29% yield from a three-step process
(that also requires three chromatographic separation
steps).[38] As stated above, the Rf values of 2,8-dibromo and
2,8-diiodo Tröger’s base are similar to one another in a vari-
ety of solvents, and this rendered the attempted isolation
of 2-bromo-8-iodo Tröger’s base unsuccessful by using the
mixed condensation strategy outlined here. However, from
the examination of Table 2 it is apparent that this problem
was readily overcome by incorporating a methyl group at
the 2-position of either 4-bromoaniline or 4-iodoaniline, as
the symmetric Tröger’s base analogues produced in hybrid-
forming reactions exhibit markedly different Rf values to
one another.
Experimental Section
General: All starting materials were commercially available and
were used without further purification or were obtained according
to literature procedures. All solvents were distilled prior to use, with
the exception of trifluoroacetic acid. NMR spectra were measured
with a Bruker 400 MHz spectrometer and referenced to residual
1
protio peaks (CHCl3: δ = 7.26 ppm for H and δ = 77.0 ppm for
13C).
General Procedure for the Synthesis of Hybrids: The two anilines
(5.8 mmol of each) and paraformaldehyde (558 mg, 18.6 mmol,
1.6 equiv. with respect to the total mmol amount of the anilines)
were dissolved in trifluoroacetic acid (25 mL), and the mixture was
stirred under argon in the dark for 60 h. The reaction mixture was
then basified with a solution of concentrated ammonia (30 mL)
in water (60 mL), followed by the addition of a saturated sodium
hydrogen carbonate solution (100 mL) and extracted into dichloro-
methane (3ϫ75 mL). The combined organic layers were washed
with brine (100 mL), dried with anhydrous sodium sulfate, filtered
and the solvents evaporated to dryness. The crude material was
chromatographed (silica gel) to afford the desired hybrid as one of
three Tröger’s base products.
Compound 15 (Figure 6) is an isomer of 14, in which the
bromo group is in the 4-position, rather than the 2-position.
Compounds 16 and 17 are trihalo-substituted analogues.
2-Bromo-8-methyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine
(2): With 4-bromoaniline (1.0 g, 5.8 mmol), p-toluidine (0.62 g,
5.8 mmol) and paraformaldehyde (558 mg, 18.6 mmol),
chromatography (silica gel; ethyl acetate/dichloromethane, 1:9) af-
forded (Ϯ)-2 (647 mg, 35 %) as a pale yellow solid; m.p. 118–
120 °C. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 2.20 (s, 3 H, CH3),
4.05–4.15 (m, 2 H, CH2), 4.22–4.33 (m, 2 H, CH2), 4.63 (d, J =
16.8 Hz, 1 H, CH2), 4.65 (d, J = 16.6 Hz, 1 H, CH2), 6.70–6.72 (m,
1 H, ArH), 6.96–7.05 (m, 4 H, ArH), 7.25 (dd, J = 2.3, 8.6 Hz, 1
H, ArH) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 20.8, 58.3,
58.7, 66.8, 116.5, 124.7, 126.7, 127.1, 127.2, 128.4, 129.7, 130.0,
130.4, 133.8, 144.9, 147.1 ppm. HRMS: calcd. for C16H15BrN2 [M
+ H]+ 315.049138; found 315.049497. C16H15BrN2 (315.21): calcd.
C 60.97, H 4.80, N 8.89; found C 61.10, H 4.85, N 8.91. Crystals
suitable for X-ray diffraction were obtained by recrystallisation
from dichloromethane.
Figure 6. ORTEP diagram of 15 with 10% probability ellipsoids.
All X-ray structures obtained in this work contained
equal numbers of both enantiomers in the unit cell, which
is not surprising as the crystals were grown from racemic
solutions.
2-Bromo-8-decyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine
(3): With 4-bromoaniline (1.0 g, 5.8 mmol), 4-decylaniline (1.35 g,
5.8 mmol) and paraformaldehyde (557 mg, 18.56 mmol),
chromatography (silica gel; ethyl acetate/dichloromethane, 1:9) af-
forded (Ϯ)-3 (300 mg, 13%) as a pale yellow solid; m.p. 44–46 °C.
1H NMR (400 MHz, CDCl3, 25 °C): δ = 0.85–0.90 (m, 3 H, CH3),
1.22–1.31 (m, 14 H, CH2), 1.48–1.58 (m, 2 H, CH2), 2.43–2.50 (m,
2 H, CH2), 4.03–4.13 (m, 2 H, CH2), 4.22–4.34 (m, 2 H, CH2),
4.61–4.70 (m, 2 H, CH2), 6.69–6.73 (m, 1 H, ArH), 6.96–7.06 (m,
4 H, ArH), 7.26 (dd, J = 2.3, 8.6 Hz, 1 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 14.1, 22.7, 29.3, 29.4, 29.5, 29.6,
29.7, 31.5, 31.9, 35.4, 58.2, 58.7, 66.8, 116.5, 120.8, 124.7, 126.5,
Conclusions
We have shown that hybrid Tröger’s base compounds can
be obtained in reasonable yields in a single step from a reac-
tion involving two anilines, negating the need for multistep
syntheses. The reaction works well provided that the two
homo-coupled compounds have significantly different Rf
values. This criterion can be easily assessed qualitatively by
comparing the Rf values of the corresponding symmetric 126.7, 127.0, 127.7, 129.7, 130.0, 130.4, 139.1, 147.1 ppm. HRMS:
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M. Faroughi, K.-X. Zhu, P. Jensen, D. C. Craig, A. C. Try
FULL PAPER
calcd. for C25H33BrN2 [M + Na]+ 463.171933; found 463.172469. 126.7, 128.0, 129.7, 130.5, 134.2, 146.8, 176.5 ppm. HRMS: calcd.
C25H33BrN2 (441.45): calcd. C 68.02, H 7.53, N 6.35; found C for C20H22BrN3O [M + H]+ 400.101901; found 400.100561.
68.46, H 7.60, N 6.33.
C20H22BrN3O (400.31): calcd. C 60.01, H 5.54, N 10.50; found C
59.78, H 5.64, N 10.47. Crystals suitable for X-ray diffraction were
obtained by recrystallisation from dichloromethane.
2-Bromo-8-phenyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine
(4): With 4-bromoaniline (1.00 g, 5.8 mmol), 4-aminobiphenyl
(0.98 g, 5.8) and paraformaldehyde (560 mg, 18.6 mmol),
chromatography (silica gel; ethyl acetate/dichloromethane, 1:9) af-
forded (Ϯ)-4 (158 mg, 7%) as a pale yellow solid; m.p. 142–144 °C.
1H NMR (400 MHz, CDCl3, 25 °C): δ = 4.15–4.23 (m, 2 H, CH2),
4.28–4.38 (m, 2 H, CH2), 4.69 (d, J = 16.8 Hz, 1 H, CH2), 4.75 (d,
J = 16.7 Hz, 1 H, CH2), 7.04 (d, J = 8.6 Hz, 1 H, ArH), 7.06–7.08
(m, 1 H, ArH), 7.11–7.13 (m, 1 H, ArH), 7.19 (d, J = 8.3 Hz, 1 H,
ArH), 7.25–7.33 (m, 2 H, ArH), 7.36–7.42 (m, 3 H, ArH), 7.46–
7.50 (m, 2 H, ArH) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ
= 58.8, 59.2, 67.2, 117.1, 125.8, 125.9, 126.8, 127.2, 127.3, 127.5,
128.2, 129.1, 130.2, 130.4, 130.9, 137.7, 141.0, 147.3, 147.5 ppm.
HRMS: calcd. for C21H17BrN2 [M + H]+ 377.064788, found
377.064504. C21H17BrN2 (377.28): calcd. C 66.85, H 4.54, N 7.43;
found C 66.62, H 4.53, N 7.35. Crystals suitable for X-ray diffrac-
tion were obtained by recrystallisation from dichloromethane.
2,8-Dibromo-4-chloro-6H,12H-5,11-methanodibenzo[b,f][1,5]diazoc-
ine (8): With 4-bromoaniline (505 mg, 2.9 mmol), 4-bromo-2-chlo-
roaniline (605 mg, 2.9 mmol) and paraformaldehyde (560 mg,
18.6 mmol), chromatography (silica gel; dichloromethane) afforded
1
(Ϯ)-8 (298 mg, 25%) as a white solid; m.p. 153–154 °C. H NMR
(400 MHz, CDCl3, 25 °C): δ = 4.10 (d, J = 16.8 Hz, 1 H, CH2),
4.20–4.32 (m, 3 H, CH2), 4.55 (d, J = 17.4 Hz, 1 H, CH2), 4.61 (d,
J = 16.8 Hz, 1 H, CH2), 6.97–7.01 (m, 2 H, ArH), 7.08 (d, J =
2.3 Hz, 1 H, ArH), 7.27 (dd, J = 2.3, 8.6 Hz, 1 H, ArH), 7.39 (d,
J = 2.3 Hz, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3, 25 °C):
δ = 54.3, 58.2, 66.9, 116.8, 117.0, 126.7, 128.3, 129.8, 129.9, 130.1,
130.6, 131.0, 131.6, 142.8, 146.2 ppm. HRMS: calcd. for
C
15H11Br2ClN2 [M + H]+ 412.905028; found 412.906131.
C15H11Br2ClN2 (414.52): calcd. C 43.46, H 2.67, N 6.76; found C
43.57, H 2.70, N 6.96.
2-Bromo-8-methoxy-6H,12H-5,11-methanodibenzo[b,f][1,5]diazoc-
ine (5): With 4-bromoaniline (5.00 g, 29.1 mmol), p-anisidine
(2.58 g, 29.1 mmol) and paraformaldehyde (2.79 g, 93.1 mmol),
chromatography (silica gel; ethyl acetate/dichloromethane, 1:9) af-
forded (Ϯ)-5 (2.18 g, 23%) as a pale orange solid; m.p. 114–117 °C.
1H NMR (400 MHz, CDCl3, 25 °C): δ = 3.71 (s, 3 H, OCH3), 4.07
(d, J = 16.6 Hz, 1 H, CH2), 4.10 (d, J = 16.6 Hz, 1 H, CH2), 4.21–
4.32 (m, 2 H, CH2), 4.57–4.68 (m, 2 H, CH2), 6.42 (d, J = 2.8 Hz,
1 H, ArH), 6.75 (dd, J = 2.8, 8.7 Hz, 1 H, ArH), 7.00–7.06 (m, 3
H, ArH), 7.26 (dd, J = 2.3, 8.7 Hz, 1 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 55.3, 58.3, 58.9, 66.9, 110.8, 114.1,
116.5, 125.9, 126.7, 128.2, 129.7, 130.0, 130.3, 140.4, 147.1,
156.1 ppm. HRMS: calcd. for C1 6H15 BrN2 O [M + Na]+
353.025997; found 353.026771. C16H15BrN2O (331.21): calcd. C
58.02, H 4.56, N 8.46; found C 57.85, H 4.50, N 8.43.
4-Bromo-2,8-dimethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazoc-
ine (9): With 2-bromo-4-methylaniline (1.00 g, 5.37 mmol), p-tolu-
idine (0.58 g, 5.37 mmol) and paraformaldehyde (516 mg,
17.2 mmol), chromatography (silica gel; ethyl acetate/dichlorometh-
ane, 1:9) afforded (Ϯ)-9 (618 mg, 35%) as an off-white solid; m.p.
1
138–139 °C. H NMR (400 MHz, CDCl3, 25 °C): δ = 2.20 (s, 3 H,
CH3), 2.23 (s, 3 H, CH3), 4.11 (d, J = 16.7 Hz, 1 H, CH2), 4.27–
4.39 (m, 3 H, CH2), 4.56 (d, J = 17.2 Hz, 1 H, CH2), 4.62 (d, J =
16.7 Hz, 1 H, CH2), 6.66–6.69 (m, 1 H, ArH), 6.75–6.78 (m, 1 H,
ArH), 6.96–7.00 (m, 1 H, ArH), 7.04 (d, J = 8.2 Hz, 1 H, ArH),
7.24–7.26 (m, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 20.5, 20.9, 55.2, 58.8, 67.4, 119.5, 124.7, 126.7, 127.3,
127.6, 128.2, 130.2, 132.0, 133.8, 135.1, 142.4, 144.8 ppm. HRMS:
calcd. for C17H17BrN2 [M + Na]+ 351.046732; found 351.046953.
C17H17BrN2 (329.23): calcd. C 62.02, H 5.20, N 8.51; found C
62.25, H 5.25, N 8.50.
8-Acetamido-2-bromo-6H,12H-5,11-methanodibenzo[b,f][1,5]diazoc-
ine (6): With 4-bromoaniline (1.0 g, 5.8 mmol), 4-aminoacetanilide
(0.87 g, 5.8 mmol) and paraformaldehyde (558 mg, 18.59 mmol),
chromatography (silica gel; ethanol/dichloromethane, 1:9) afforded
(Ϯ)-6 (680 mg, 33%) as a pale yellow solid; m.p. 132–136 °C. 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 2.10 (s, 3 H, CH3), 4.04–4.12
(m, 2 H, CH2), 4.19–4.29 (m, 2 H, CH2), 4.58–4.66 (m, 2 H, CH2),
6.99 (d, J = 8.6 Hz, 1 H, ArH), 7.02–7.06 (m, 2 H, ArH), 7.10 (dd,
J = 2.2, 8.6 Hz, 1 H, ArH), 7.21–7.25 (m, 2 H, ArH) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 24.4, 58.3, 58.7, 66.7, 116.5,
118.4, 119.6, 125.3, 126.7, 128.1, 129.6, 129.8, 130.4, 133.9, 143.9,
147.0, 168.2 ppm. HRMS: calcd. for C17H16BrN3O [M + Na]+
380.036896; found 380.035812. C17H16BrN3O (358.23): calcd. C
57.00, H 4.50, N 11.73; found C 56.57, H 4.70, N 11.83.
2,4-Dibromo-8-methyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazoc-
ine (10): With 2,4-dibromoaniline (1.00 g, 3.99 mmol), p-toluidine
(0.43 g, 3.99 mmol) and paraformaldehyde (383 mg, 12.8 mmol),
chromatography (silica gel; dichloromethane) afforded (Ϯ)-10
(641 mg, 41%) as an off-white powder; m.p. 156–158 °C. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 2.24 (s, 3 H, CH3), 4.12 (d, J =
16.9 Hz, 1 H, CH2), 4.22–4.38 (m, 3 H, CH2), 4.53–4.64 (m, 2 H,
CH2), 6.74–6.76 (m, 1 H, ArH), 6.89–7.03 (m, 3 H, ArH), 7.56 (d,
J = 2.2 Hz, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3, 25 °C):
δ = 20.8, 55.0, 58.5, 67.2, 117.0, 120.5, 124.7, 127.2, 127.3, 128.4,
129.0, 132.4, 133.7, 134.0, 144.4, 144.5 ppm. HRMS: calcd. for
C16H14Br2N2 [M + Na]+ 414.941560; found 414.941595.
C16H14Br2N2 (394.10): calcd. C 48.76, H 3.58, N 7.11; found C
48.74, H 3.65, N 6.95.
2-Bromo-8-(2Ј,2Ј-dimethylpropionamido)-6H,12H-5,11-methanodi-
benzo[b,f][1,5]diazocine (7): With N-(4-aminophenyl)pivalamide
(8.35 g, 43.44 mmol), 4-bromoaniline (7.47 g, 43.44 mmol) and pa-
2-Bromo-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine (11): With
raformaldehyde (4.17 g, 139 mmol), chromatography (silica gel, 4-bromoaniline (860 mg, 5.0 mmol), aniline (465 mg, 5.0 mmol)
ethyl acetate) afforded (Ϯ)-7 (5.90 g, 33%) as a white solid; m.p. and paraformaldehyde (480 mg, 16 mmol), chromatography (silica
1
190–192 °C. H NMR (400 MHz, CDCl3, 25 °C): δ = 1.26 [s, 9 H, gel; ethyl acetate/dichloromethane, 1:19 then 1:9) afforded (Ϯ)-11
C(CH3)3], 4.06–4.14 (m, 2 H, CH2), 4.22–4.24 (m, 2 H, CH2), 4.62 (217 mg, 14%) as white solid; m.p. 123–124 °C (ref.[38] 119–121 °C;
(d, J = 16.7 Hz, 1 H, CH2), 4.65 (d, J = 16.7 Hz, 1 H, CH2), 7.00
(d, J = 8.6 Hz, 1 H, ArH), 7.03 (d, J = 2.3 Hz, 1 H, ArH), 7.07 (d, (d, J = 16.5 Hz, 1 H, CH2), 4.16 (d, J = 16.5 Hz, 1 H, CH2), 4.23–
ref.[46] 123.5–125 °C). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 4.12
J = 8.6 Hz, 1 H, ArH), 7.13 (dd, J = 2.3, 8.6 Hz, 1 H, ArH), 7.17–
7.21 (br. s, 1 H, NH), 7.25 (dd, J = 2.3, 8.6 Hz, 1 H, ArH), 7.33
(d, J = 2.3 Hz, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 27.5, 39.4, 58.8, 58.7, 66.8, 116.7, 118.4, 119.6, 125.2,
4.35 (m, 2 H, CH2), 4.62–4.73 (m, 2 H, CH2), 6.88–6.92 (m, 1 H,
ArH), 6.96–7.01 (m, 1 H, ArH), 7.00 (d, J = 8.6 Hz, 1 H, ArH),
7.04 (d, J = 2.2 Hz, 1 H, ArH), 7.09–7.13 (m, 1 H, ArH), 7.14–
7.20 (m, 1 H, ArH), 7.25 (dd, J = 2.2, 8.6 Hz, 1 H, ArH) ppm. 13
C
4270
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4266–4272

Tröger’s Base Hybrids Containing at Least One Halogen Atom
NMR (100 MHz, CDCl3, 25 °C): δ = 58.4, 58.7, 66.7, 116.6, 124.2,
125.1, 126.8, 127.0, 127.6, 129.7, 130.1, 130.4, 147.2, 147.7 ppm.
found C 43.82, H 2.83, N 6.18. Crystals suitable for X-ray diffrac-
tion were obtained by recrystallisation from dichloromethane.
2-Bromo-4-chloro-8-iodo-6H,12H-5,11-methanodibenzo[b,f][1,5]di-
azocine (16): With 4-bromo-2-chloroaniline (389 mg, 1.87 mmol),
4-iodoaniline (410 mg, 1.87 mmol) and paraformaldehyde (189 mg,
6.30 mmol), chromatography (silica gel; dichloromethane) afforded
2-Iodo-8-methyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine
(12): With 4-iodoaniline (410 mg, 1.9 mmol), p-toluidine (200 mg,
1.9 mmol) and paraformaldehyde (180 mg, 6.0 mmol), chromatog-
raphy (silica gel; ethyl acetate/dichloromethane, 1:9) afforded (Ϯ)-
12 (204 mg, 31 %) as a white solid; m.p. 171–172 °C. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 2.22 (s, 3 H, CH3), 4.08 (d, J =
16.6 Hz, 1 H, CH2), 4.10 (d, J = 16.4 Hz, 1 H, CH2), 4.21–4.32 (m,
2 H, CH2), 4.61 (d, J = 16.6 Hz, 1 H, CH2), 4.65 (d, J = 16.4 Hz,
1 H, CH2), 6.66–6.72 (m, 1 H, ArH), 6.88 (d, J = 8.5 Hz, 1 H,
ArH), 6.97 (dd, J = 1.6, 8.2 Hz, 1 H, ArH), 7.01 (d, J = 8.2 Hz, 1
H, ArH), 7.23 (d, J = 2.0 Hz, 1 H, ArH), 7.44 (dd, J = 2.0, 8.5 Hz,
1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 20.8,
58.1, 58.7, 66.8, 87.3, 124.8, 126.7, 127.0, 127.1, 127.2, 128.4, 130.6,
133.7, 135.8, 136.2, 145.0 ppm. C16H15IN2 (362.21): calcd. C 53.06,
H 4.17, N 7.73; found C 53.08, H 3.84, N 7.73. Crystals suitable
for X-ray diffraction were obtained by recrystallisation from
dichloromethane.
1
(Ϯ)-16 (168 mg, 20%) as a pale yellow solid; m.p. 142–143 °C. H
NMR (400 MHz, CDCl3, 25 °C): δ = 4.10 (d, J = 16.9 Hz, 1 H,
CH2), 4.21–4.33 (m, 3 H, CH2), 4.52 (d, J = 17.2 Hz, 1 H, CH2),
4.62 (d, J = 16.9 Hz, 1 H, CH2), 6.88 (d, J = 8.5 Hz, 1 H, ArH),
6.99 (d, J = 2.2 Hz, 1 H, ArH), 7.28 (d, J = 2.2 Hz, 1 H, ArH),
7.40 (d, J = 2.2 Hz, 1 H, ArH), 7.47 (dd, J = 2.2, 8.5 Hz, 1 H,
ArH) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 54.2, 58.3,
67.0, 87.9, 116.9, 127.0, 128.3, 130.1, 130.2, 131.0, 131.6, 135.8,
136.5, 142.8, 147.1 ppm. C15H11BrClIN2 (461.52): calcd. C 39.04,
H 2.40, N 6.07; found C 39.25, H 2.23, N 5.85.
2,4-Dibromo-8-iodo-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine
(17): With 4-iodoaniline (410 mg, 1.87 mmol) 2,4-dibromoaniline
(474 mg, 1.87 mmol) and paraformaldehyde (180 mg, 5.98 mmol),
chromatography (silica gel; dichloromethane) afforded (Ϯ)-17
2-Iodo-8-methoxy-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine
(13): With 4-iodoaniline (410 mg, 1.9 mmol), p-anisidine (230 mg,
1.9 mmol) and paraformaldehyde (180 mg, 6.0 mmol), chromatog-
raphy (silica gel; ethyl acetate/dichloromethane, 1:9) afforded (Ϯ)-
13 (315 mg, 46%) as a pale brown solid; m.p. 133–134 °C. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 3.71 (s, 3 H, OCH3), 4.06 (d, J =
16.5 Hz, 1 H, CH2), 4.10 (d, J = 16.5 Hz, 1 H, CH2), 4.23 (d, J =
12.6 Hz, 1 H, CH2), 4.29 (d, J = 12.6 Hz, 1 H, CH2), 4.60 (d, J =
16.5 Hz, 1 H, CH2), 4.66 (d, J = 16.5 Hz, 1 H, CH2), 6.42 (d, J =
2.9 Hz, 1 H, ArH), 6.74 (dd, J = 2.9, 8.8 Hz, 1 H, ArH), 6.88 (d,
J = 8.5 Hz, 1 H, ArH), 7.04 (d, J = 8.8 Hz, 1 H, ArH), 7.23 (d, J
= 2.1 Hz, 1 H, ArH), 7.44 (dd, J = 2.1, 8.5 Hz, 1 H, ArH) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 55.4, 58.1, 58.9, 66.9,
87.4, 110.9, 114.1, 125.9, 127.0, 128.2, 130.5, 135.8, 136.2, 140.5,
148.0, 156.2 ppm. C16H15IN2O (378.21): calcd. C 50.81, H 4.00, N
7.41; found C 50.80, H 4.17, N 7.13.
1
(192 mg, 20%) as a pale yellow solid; m.p. 162–163 °C. H NMR
(400 MHz, CDCl3, 25 °C): δ = 4.09 (d, J = 16.9 Hz, 1 H, CH2),
4.22 (d, J = 12.8 Hz, 1 H, CH2), 4.28 (d, J = 17.4 Hz, 1 H, CH2),
4.30 (d, J = 12.8 Hz, 1 H, CH2), 4.53 (d, J = 17.4 Hz, 1 H, CH2),
4.61 (d, J = 16.9 Hz, 1 H, CH2), 6.88 (d, J = 8.5 Hz, 1 H, ArH),
7.02 (d, J = 2.2 Hz, 1 H, ArH), 7.28 (d, J = 2.0 Hz, 1 H, ArH),
7.46 (dd, J = 2.0, 8.5 Hz, 1 H, ArH), 7.58 (d, J = 2.2 Hz, 1 H,
ArH) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 54.5, 58.5,
66.9, 87.9, 117.3, 120.6, 127.0, 129.0, 130.2, 132.0, 134.0, 135.8,
136.5, 144.0, 147.1 ppm. C15H11Br2IN2 (505.97): calcd. C 35.61, H
2.19, N 5.54; found C 35.77, H 1.97, N 5.35.
8-Bromo-2-iodo-4-methyl-6H,12H-5,11-methanodibenzo[b,f][1,5]di-
azocine (18): With 4-bromoaniline (323 mg, 1.88 mmol), 4-iodo-2-
methylaniline (438 mg, 1.88 mmol) and paraformaldehyde (216 mg,
7.2 mmol), chromatography (silica gel; dichloromethane) afforded
(Ϯ)-18 (281 mg, 34%) as an off-white solid; m.p. 138–139 °C. 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 2.32 (s, 3 H, CH3), 3.90 (d,
J = 16.9 Hz, 1 H, CH2), 4.06 (d, J = 16.9 Hz, 1 H, CH2), 4.22 (d,
J = 17.7 Hz, 1 H, CH2), 4.25 (d, J = 17.7 Hz, 1 H, CH2), 4.51 (d,
J = 16.9 Hz, 1 H, CH2), 4.60 (d, J = 16.9 Hz, 1 H, CH2), 6.99 (d,
J = 8.4 Hz, 1 H, ArH), 7.05 (d, J = 2.3 Hz, 1 H, ArH), 7.07–7.09
(m, 1 H, ArH), 7.27 (dd, J = 2.3, 8.4 Hz, 1 H, ArH), 7.36–7.39 (m,
1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 16.7,
54.5, 58.1, 66.9, 88.0, 116.8, 126.8, 129.7, 130.0, 130.5, 133.2, 135.5,
137.9, 147.0 ppm. C16H14BrIN2 (441.10): calcd. C 43.57, H 3.20,
N 6.35; found C 43.94, H 2.95, N 6.01.
2-Bromo-8-iodo-4-methyl-6H,12H-5,11-methanodibenzo[b,f][1,5]di-
azocine (14): With 4-iodoaniline (410 mg, 1.87 mmol), 4-bromo-2-
methylaniline (347 mg, 1.87 mmol) and paraformaldehyde (180 mg,
5.98 mmol), chromatography (silica gel; dichloromethane) afforded
1
(Ϯ)-14 (347 mg, 42%) as a pale yellow solid; m.p. 149–150 °C. H
NMR (400 MHz, CDCl3, 25 °C): δ = 2.35 (s, 3 H, CH3), 3.89 (d,
J = 16.9 Hz, 1 H, CH2), 4.08 (d, J = 16.9 Hz, 1 H, CH2), 4.21–
4.28 (m, 2 H, CH2), 4.51 (d, J = 16.9 Hz, 1 H, CH2), 4.61 (d, J =
16.9 Hz, 1 H, CH2), 6.85–6.90 (m, 2 H, ArH), 7.16–7.18 (m, 1 H,
ArH), 7.22–7.25 (m, 1 H, ArH), 7.45 (dd, J = 2.0, 8.4 Hz, 1 H,
ArH) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 16.8, 54.3,
58.4, 66.9, 87.6, 116.8, 127.07, 127.11, 129.6, 130.5, 131.9, 135.3,
135.7, 136.2, 144.6, 147.7 ppm. C16H14BrIN2 (441.10): calcd. C
43.57, H 3.20, N 6.35; found C 43.38, H 2.86, N 6.19.
2-Iodo-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine (19): With 4-
iodoaniline (1.09 g, 5.0 mmol), aniline (465 mg, 5.0 mmol) and pa-
raformaldehyde (480 mg, 16 mmol), chromatography (silica gel;
dichloromethane/ethyl acetate, 50:1) afforded (Ϯ)-19 (268 mg,
16%) as a white solid; m.p. 124–125 °C (ref.[38] 121–123 °C). 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 4.12 (d, J = 16.7 Hz, 1 H,
CH2), 4.14 (d, J = 16.7 Hz, 1 H, CH2), 4.23–4.34 (m, 2 H, CH2),
4.64 (d, J = 16.7 Hz, 1 H, CH2), 4.68 (d, J = 16.7 Hz, 1 H, CH2),
6.89 (d, J = 8.5 Hz, 1 H, ArH), 6.90 (d, J = 7.6 Hz, 1 H, ArH),
6.96–7.01 (m, 1 H, ArH), 7.11 (d, J = 7.9 Hz, 1 H, ArH), 7.14–
7.20 (m, 1 H, ArH), 7.22–7.25 (m, 1 H, ArH), 7.44 (dd, J = 2.0,
8.5 Hz, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
58.2, 58.7, 66.7, 87.4, 124.2, 125.1, 127.0, 127.1, 127.6, 130.6, 135.7,
136.3, 147.7, 148.0 ppm.
4-Bromo-8-iodo-2-methyl-6H,12H-5,11-methanodibenzo[b,f][1,5]di-
azocine (15): With 4-iodoaniline (410 mg, 1.87 mmol), 2-bromo-4-
methylaniline (348 mg, 1.87 mmol) and paraformaldehyde (183 mg,
5.98 mmol), chromatography (silica gel; dichloromethane) afforded
(Ϯ)-15 (348 mg, 42%) as an off-white solid; m.p. 176–178 °C. 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 2.21 (s, 3 H, CH3), 4.08 (d,
J = 16.8 Hz, 1 H, CH2), 4.24–4.34 (m, 3 H, CH2), 4.53 (d, J =
17.4 Hz, 1 H, CH2), 4.61 (d, J = 16.8 Hz, 1 H, CH2), 6.66–6.72 (m,
1 H, ArH), 6.89 (d, J = 8.5 Hz, 1 H, ArH), 7.27–7.31 (m, 2 H,
ArH), 7.45 (dd, J = 2.0, 8.5 Hz, 1 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 20.5, 54.6, 58.8, 67.2, 87.6, 119.5,
126.6, 127.0, 129.9, 130.6, 132.2, 135.4, 135.9, 136.3, 142.0, CCDC-713412 (for 2), -713413 (for 4), -713414 (for 7), -713415 (for
147.5 ppm. C16H14BrIN2 (441.10): calcd. C 43.57, H 3.20, N 6.35; 12) and -713416 (for 15), contain the supplementary crystallo-
Eur. J. Org. Chem. 2009, 4266–4272
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4271

M. Faroughi, K.-X. Zhu, P. Jensen, D. C. Craig, A. C. Try
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Received: February 4, 2009
Published Online: July 16, 2009
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