Regioselective synthesis of dimethylamino- or arylalkylamino- "crowned" troeger's base analogues under Vilsmeier-Haack conditions

Article abstract of DOI:10.1002/ejoc.201100804

Under typical Vilsmeier-Haack conditions, Troeger's base undergoes regioselective dimethylamino or arylalkylamino substitution on the methano bridge of the dibenzo[b,f][1,5]diazocine system, revealing a hitherto unknown reactivity pattern. The regioselect

Full text of DOI:10.1002/ejoc.201100804

FULL PAPER
DOI: 10.1002/ejoc.201100804
Regioselective Synthesis of Dimethylamino- or Arylalkylamino-‘‘Crowned”
Tröger’s Base Analogues Under Vilsmeier–Haack Conditions
Manda Bhaskar Reddy,[a] Alla Manjula,*[a] Bommena Vittal Rao,[a] and
Balasubramanian Sridhar[b]
Dedicated to Professor Madhavarao Nagarajan on the occasion of his 60th birthday
Keywords: Tröger’s base / Amination / Regioselectivity
Under typical Vilsmeier–Haack conditions, Tröger’s base un-
dergoes regioselective dimethylamino or arylalkylamino sub-
this reaction is its generality; it is compatible with different
substitution patterns on the Tröger’s base and can be per-
stitution on the methano bridge of the dibenzo[b,f][1,5]diazo- formed with DMF as well as with other formamides. The
cine system, revealing a hitherto unknown reactivity pattern.
The regioselectivity of the reaction was established by NMR
spectroscopy and X-ray crystallography. The key feature of
wide scope of the reaction has been applied in the synthesis
of several uncommon Tröger’s base analogues.
ground, there is an immense demand for the construction
of unusual Tröger’s base analogues.
Introduction
Tröger’s base[1] [Figure 1(a)] is a fascinating molecule
with a unique concave conformation and C2-symmetric chi-
rality arising from its two stereogenic nitrogen centres.[2]
Owing to its rigid V-shaped geometry, Tröger’s base has be-
come a valued building block for the creation of novel sup-
ramolecular frameworks[3] and exploration of molecular re-
cognition phenomena.[4] Tröger’s base analogues have also
found applications in other fields such as in asymmetric ca-
talysis,[5] in stereoselective synthesis as chiral solvating
agents[6] and in bioorganic chemistry.[7] Given this back-
Classically, Tröger’s base is produced by acid-catalysed
condensation of 4-methylaniline with formaldehyde (or its
equivalents).[8] For many years the presence of the electron-
donating substituent on the aniline ring was thought to be
a prerequisite for this condensation. However, Warnmark
et al. reported that the presence of electron-withdrawing
groups such as halogen atoms in almost any position on
the aniline aromatic ring also resulted in good substrates
for the synthesis of Tröger’s base analogues.[9] This facili-
tates the introduction of any group by substitution of halo-
gen on the aromatic core. The same group reported the li-
thiation of dihalogenated Tröger’s base analogues followed
by substitutions on the aromatic core,[10] as well as direct
functionalization on the aromatic core of Tröger’s base
through Pd-catalysed cross-coupling reactions,[11] facilita-
ting the introduction of acid-sensitive groups. Subsequently
there were reports on the synthesis of Tröger’s base ana-
logues bearing other electron-withdrawing substituents such
Figure 1. a) Tröger’s base. b) Target dialkyl/arylalkyl-crowned as ester[12] and nitro groups.[13] C-Alkylation of the Tröger’s
Tröger’s base analogues.
base-saturated component has been carried out through
benzylic carbon lithiation.[14] The bicyclic methanodibenzo-
[a] Organic Chemistry Division-II,
diazocene, which is known to racemize in the presence of
Indian Institute of Chemical Technology,
dilute acids,[15] was restricted to N-alkylations, N-acylations,
Hyderabad 500607, India
Fax: +91-40-27160387
N-nitrosylations[16] and conversion into ethano-bridged
Tröger’s base analogues.[17]
E-mail: manjula@iict.res.in
manjula_alla@yahoo.com
Our interest in the utility of Tröger’s base analogues as
hosts in supramolecular chemistry[18] led us to design strate-
gies for the general synthesis of Tröger’s base analogues
with variation of substitution both on the aromatic ring and
[b] Laboratory of X-ray Crystallography,
Indian Institute of Chemical Technology,
Hyderabad 500607, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100804.
312
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“Crowned” Tröger’s Base Analogues
on the methylene bridge. In this context we were interested stituted Tröger’s base analogues 1a–1f in order to investi-
in electrophilic substitutions of Tröger’s base and report gate the generality of the method for constructing new ana-
here the reactions of Tröger’s base and its analogues under logues. The reactions were regioselective in all cases and
Vilsmeier–Haack conditions[19] for the first time [Figure 1 products were obtained in 53 to 72% yields. Various func-
(b)].
tionalities and multiple substitution patterns on the Tröger’s
base aromatic core appear to be compatible for substitution
at the methano bridge under classic Vilsmeier–Haack con-
ditions as shown in Table 1.
Results and Discussion
A thorough search for methylene bridge substitution on
the Tröger’s base diazocine unit revealed that a few “meth-
ano strap” modified Tröger’s base analogues have been re-
ported.[21] However, they were synthesized from a 5,6,11,12-
tetrahydrodibenzodiazocine unit (cyclic diamine) generated
by removing the methylene unit from the corresponding
Tröger’s base. An attempt to synthesize Tröger’s base ana-
logues containing spiro[4.5]lactone straps by direct substitu-
tion of the methano bridge were fruitful only when the aro-
matic core substituents were electron-donating.[22] Electron-
withdrawing substituents were detrimental and the corre-
sponding spiro[4.5]lactone analogues were synthesized from
the cyclic diamines. Unusually modified Tröger’s base ana-
logues produced by Michael addition to dimethyl acetylene-
dicarboxylate and leading to methylene-bridged vinyl carb-
2,8-Dimethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]di-
azocine (1a) was subjected to classical Vilsmeier–Haack
conditions with DMF and POCl3. The product of this reac-
1
tion was identified by H NMR analysis as N,N,2,8-tet-
ramethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocin-
13-amine (2a, Table 1). The substitution had taken place
not on the aromatic core of the Tröger’s base but on the
methano bridge of the saturated bicyclic component. A lit-
erature review revealed that similar methylene bridge substi-
tutions occurred in triphenylcorroles,[20] with excess DMF
believed to trigger the unusual substitution. In our reaction,
it was further found that the substitution occurred only at
the methylene bridge whether the reaction was carried out
either with the optimum concentration of Vilsmeier–Haack
reagent (3 equiv.) or with an excess (10 equiv.). The opti- oxylate derivatives have been described.[23] This work, how-
mized Vilsmeier–Haack conditions were applied to the sub- ever, has no such limitations. The methano bridge substitu-
Table 1. Synthesis of dimethylamine-crowned Tröger’s base analogues under Vilsmeier–Haack conditions.[a]
[a] All the reactions were carried out with the Tröger’s base or analogue (1 mmol), POCl3 (3 mmol) and formamide (3 mmol). [b] Isolated
yields.
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M. B. Reddy, A. Manjula, B. V. Rao, B. Sridhar
FULL PAPER
tion under Vilsmeier–Haack conditions occurs both in sub- with one molecule in the asymmetric unit. Figure 2 (a)
stituted and in unsubstituted Tröger’s base analogues 1a– shows the molecular structure, with the expected overall V-
1f.
shape and the crowning of the methano bridge with the
In order to establish the structures of the products unam- dimethylamino functionality. Although the crystal con-
biguously, the crystal structure of N-(2,8-dibromo-6H,12H- tained only one enantiomer, a solution made from bulk so-
5,11-methanodibenzo[b,f][1,5]diazocin-13-yl)dimethylamine lid showed no optical rotation: the reaction is not stereose-
(2c, Table 1) was determined by X-ray crystallography. The lective and this crystallization of enantiomers into separate
compound crystallized in the chiral P212121 space group, chiral crystals is an example of spontaneous resolution. The
two bromine atoms in the crystal are in different environ-
ments. Together they form short, polarization-induced,
type-II Br···Br contacts with the two bromine atoms sepa-
rated by 3.70 Å.[24] An interesting feature of this structure
is that one of the bromine atoms forms Br···π contacts with
the aromatic ring such that the C–Br bond is pointing
towards the carbon of another C–Br bond (C–Br···C angle
is 170.6°; distance of 3.53 Å) as opposed to the centre of
the aromatic ring (C–Br···π angle is 151.9°). Figure 2 (b)
shows the network of Br···Br and C–Br···C contacts in the
crystal. The angle between the planes of aromatic rings
within the molecule is 81.05°.
A plausible mechanism based on the observed results is
shown in Scheme 1. The nitrogen atoms are more nucleo-
Figure 2. a) The molecular structure of 2c, with the atom number-
ing scheme. Displacement ellipsoids are drawn at the 30% prob-
ability level and H atoms are shown as small spheres of arbitrary
radius. b) Crystal structure of 2c showing a network of Br···Br and
Br···C contacts.
Table 2. Synthesis of arylalkyl-crowned Tröger’s base analogues under typical Vilsmeier–Haack conditions.[a]
[a] All the reactions were carried out with the Tröger’s base or analogue (1 mmol), POCl3 (3 mmol) and the formamide derivative
1
(3 mmol). [b] Isolated yields. [c] Only a trace of product was observed in the crude H NMR spectrum.
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“Crowned” Tröger’s Base Analogues
philic than the aromatic ring, probably due to the fact that
their lone pairs are not involved in conjugation, leading to
substitution at the bridgehead. However, the other equally
important driving force is the lability of the methano
bridge. This is substantiated by the fact that the ethano-
bridged Tröger’s base analogue does not undergo for-
mylation at all, neither at the bridgehead nor on the aro-
matic ring. Ethano-bridged Tröger’s base analogues are
known to be resistant to the conventional racemization via
iminium ions that occurs in methano-bridged Tröger’s base
analogues. The mechanism involves nucleophilic attack by
the bridgehead nitrogen on the Vilsmeier–Haack reagent
and proceeds via an iminium intermediate. Closure of the
methano bridge followed by elimination of dichlorometh-
ane leads to the formation of product.
Figure 3. a) The molecular structure of 3d, with the atom number-
ing scheme. Displacement ellipsoids are drawn at the 30% prob-
ability level and H atoms are shown as small spheres of arbitrary
radius. b) Crystal structure of 3d showing enantiomer dimer.
Treatment of 1a with the heterocyclic formamides piperi-
dine-1-carbaldehyde
and
morpholine-1-carbaldehyde
(Scheme 2) under Vilsmeier–Haack conditions results in the
formation of 2,8-dimethyl-13-piperidin-1-yl-6H,12H-5,11-
methanodibenzo[b,f][1,5]diazocine (4) and 13-(morpholin-
4-yl)-2,8-dimethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]di-
azocine (5) in 81% and 72% yields, respectively. However,
the Vilsmeier–Haack reagent had to be formed at 70 °C in
this case.
Scheme 1. Plausible mechanism for the synthesis of dialkylamino/
arylalkylamino-crowned Tröger’s base analogues under typical
Vilsmeier–Haack conditions.
Scheme 2. Treatment of 1a with heterocyclic formamides and
POCl3.
Furthermore, the generality and scope of this reaction
were investigated by replacing the DMF with other for-
mylating agents such as N-phenylformamide, N,N-diphenyl-
formamide, N-methyl-N-phenylformamide, piperidine-1-
carbaldehyde, morpholine-1-carbaldehyde[25] and DCM as
solvent. Whereas N-phenylformamide did not react as ex-
Conclusions
In summary, treatment of Tröger’s base analogues under
pected, N,N-diphenylformamide gave trace amounts of the Vilsmeier–Haack conditions illustrates the distinctive reac-
corresponding products. Under Vilsmeier–Haack condi- tivity pattern of the molecule. The wide scope and general-
tions, the reactions between various Tröger’s base analogues ity of the Vilsmeier reaction has been utilized to generate
and N-methyl-N-phenylformamide were facile, affording some unusual Tröger’s base scaffolds. Normally, in the
68–83% yields of products (Table 2).
sharply folded V-shape geometry of Tröger’s base ana-
Interestingly, the X-ray crystal structure of N-(2,3,8,9-tet- logues, the angle between two aromatic planes is in the
ramethoxy-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocin- range of 90–100°. The crowning of the methylene bridge
13-yl)methylphenylamine (3d, Table 2), shown in Figure 3, results in the two aromatic planes in the molecule being
was different from that of N-(2,8-dibromo-6H,12H-5,11- brought closer, as evidenced by the smaller angles between
methanodibenzo[b,f][1,5]diazocin-13-yl)dimethylamine (2c, the planes (81° and 79°). Methylene unit substitutions have
Table 1). The compound crystallized in the centrosymmet- been known to affect the overall geometries of Tröger’s base
ric P21/c space group with one molecule in the asymmetric analogues through variation of the dihedral angles. These
unit. This is an example of a true racemate, with the two findings are consistent with this. These structurally diverse
enantiomers forming a dimer across an inversion centre and Tröger’s base analogues represent new building blocks for
lead to a staircase-like framework of molecules. The angle generation of supramolecular frameworks. Further studies
between the planes of aromatic rings within the molecule is on their applicability in recognition phenomena and cataly-
79°.
sis are being actively pursued.
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M. B. Reddy, A. Manjula, B. V. Rao, B. Sridhar
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41.6 ppm. IR (KBr): ν = 2937, 1494 cm–1. MS (ESI): m/z (%) =
326 (100) [M + H]. HRMS (ESI) calcd. for C19H24N3O2 326.1868;
found 326.1882.
˜
Experimental Section
General Methods: All starting materials were obtained from com-
mercial sources and used without further purification. All reactions
were carried out under anhydrous conditions. Organic fractions
were dried with anhydrous Na2SO4. TLC analyses were performed
on glass plates coated with silica gel (60 F254). Plates were visual-
ized with the aid of UV light (254 nm) and/or iodine. Column
chromatography was performed on silica gel (60ϫ120 mesh) on a
glass column. Melting points (m.p.s) were determined in capillary
tubes and are uncorrected.
(؎)-2,8-Dibromo-N,N-dimethyl-6H,12H-5,11-methanodibenzo[b,f]-
[1,5]diazocin-13-amine (2c): 2,8-Dibromo-6H,12H-5,11-methanodi-
benzo[b,f][1,5]diazocine (1c, 200 mg, 0.52 mmol) in DMF (5 mL)
was added to Vilsmeier–Haack reagent prepared from DMF
(120 μL, 1.57 mmol) and POCl3 (147 μL, 1.57 mmol). The crude
product was purified by column chromatography with EtOAc in
hexane (5%) as eluent to afford 2c (146 mg, 66%) as a white solid;
1
m.p. 190–191 °C. H NMR (300 MHz, CDCl3): δ = 7.27–7.18 (m,
1H and 13C NMR spectra (300 and 75 MHz, respectively) were
recorded with use of TMS as an internal standard (δ = 0 ppm).
Mass data (ESI) were recorded by quadruple mass spectrometry.
HRMS data were obtained with the ESI ionization sources. IR
spectra were recorded as KBr pellets or neat with a FTIR spec-
trometer. All Tröger’s base analogues were synthesized by the
method developed by Warnmark et al.[9] and were completely char-
acterized before their subjection to Vilsmeier–Haack conditions.
2 H), 7.03 (d, J = 2.1 Hz, 1 H), 6.99–6.85 (m, 3 H), 4.56 (dd, J =
16.6, 7.7 Hz, 2 H), 4.11 (d, J = 16.6 Hz, 1 H), 3.77 (t, J = 16.4 Hz,
2 H), 2.34 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 147.6,
143.5, 130.6, 130.5, 130.3, 130.1, 129.3, 127.3, 127.0, 116.8, 116.6,
89.7, 59.0, 51.3, 41.3 ppm. IR (KBr): ν = 2950, 1473 cm–1. MS
˜
(ESI): m/z (%) = 424 (100) [M + H]. HRMS (ESI) calcd. for
C17H18N3Br2 421.9867; found 421.9848.
Crystals were obtained from 100 mg of (Ϯ)-2c in dilute EtOAc
(25 mL) at room temp. after 48 h. A well shaped crystal was picked
for XRD studies.
Synthesis of Dimethylamino-Crowned Tröger’s Base Analogues Un-
der Vilsmeier–Haack Conditions. General Procedure 1: Dimethyl-
formamide (3 mmol) was cooled in an ice bath and phosphorus
oxychloride (3 mmol) was added dropwise. After formation of a
yellow-coloured paste, the reaction mixture was allowed to warm
to room temperature. Tröger’s base or an analogue (1 mmol), dis-
solved in dry dimethylformamide (10 mL), was added and the reac-
tion mixture was stirred at room temperature for 2–6 h. After com-
pletion of the reaction (monitored by TLC), the reaction mixture
was poured into cold saturated NaHCO3 solution and stirred at
room temperature for 1 h. The aqueous layer was extracted with
dichloromethane (3ϫ 10 mL) and the combined organic extracts
were washed with water (3ϫ 10 mL), dried and concentrated in
vacuo. The crude product was purified by column chromatography
with EtOAc/hexane as eluent.
(؎)-2,3,8,9-Tetramethoxy-N,N-dimethyl-6H,12H-5,11-methano-
dibenzo[b,f][1,5]diazocin-13-amine (2d): 2,3,8,9-Tetramethoxy-
6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine (1d, 300 mg,
0.87 mmol) in DMF (8 mL) was added to Vilsmeier–Haack reagent
prepared from DMF (204 μL, 2.63 mmol) and POCl3 (246 μL,
2.63 mmol). The crude product was purified by column chromatog-
raphy with EtOAc in hexane (10%) as eluent to afford 2d (236 mg,
1
70%) as a pale yellow solid; m.p. 67–68 °C. H NMR (300 MHz,
CDCl3): δ = 6.55 (d, J = 9.1 Hz, 2 H), 6.31 (d, J = 6.4 Hz, 2 H),
4.47 (t, J = 15.9 Hz, 2 H), 4.06 (d, J = 16.2 Hz, 1 H), 3.84 (s, 3 H),
3.83 (s, 3 H), 3.77–3.67 (m, 8 H), 2.37 (s, 6 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 148.3, 148.1, 146.0, 145.8, 141.4, 137.0,
119.6, 119.2, 108.9, 108.6, 108.4, 90.3, 58.9, 55.8, 55.7, 51.0,
41.5 ppm. IR (KBr): ν = 2935, 1506 cm–1. MS (ESI): m/z (%) =
˜
(؎)-N,N,2,8-Tetramethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]-
diazocin-13-amine (2a): 2,8-Dimethyl-6H,12H-5,11-methanodi-
benzo[b,f][1,5]diazocine (1a, 180 mg, 0.72 mmol) in DMF (4 mL)
was added to Vilsmeier–Haack reagent prepared from DMF
(168 μL, 2.16 mmol) and POCl3 (202 μL, 2.16 mmol). The crude
product was purified by column chromatography with EtOAc in
hexane (5%) as eluent to afford 2a (151 mg, 72%) as a pale brown
385 (100) [M + H]. HRMS (ESI) calcd. for C21H28N3O4 386.2079;
found 386.2096.
(؎)-2,8-Diisopropyl-N,N-dimethyl-6H,12H-5,11-methanodibenzo-
[b,f][1,5]diazocin-13-amine (2e): 2,8-Diisopropyl-6H,12H-5,11-
methanodibenzo[b,f][1,5]diazocine (1e, 90 mg, 0.29 mmol) in DMF
(4 mL) was added to Vilsmeier–Haack reagent prepared from
DMF (68 μL, 0.88 mmol) and POCl3 (82 μL, 0.88 mmol). The
crude product was purified by column chromatography with EtOAc
in hexane (5%) as eluent to afford 2e (54 mg, 53%) as a pale yellow
1
solid; m.p. 95–96 °C. H NMR (300 MHz, CDCl3): δ = 6.96–6.82
(m, 4 H), 6.62 (d, J = 13.6 Hz, 2 H), 4.53 (dd, J = 16.6, 6.8 Hz, 2
H), 4.09 (d, J = 16.6 Hz, 1 H), 3.75 (d, J = 15.9 Hz, 2 H), 2.36 (s,
6 H), 2.19 (s, 3 H), 2.17 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 146.2, 142.0, 132.8, 132.6, 128.0, 127.8, 127.6, 126.7, 126.6,
1
gummy compound. H NMR (300 MHz, CDCl3): δ = 6.94 (d, J =
15.9 Hz, 4 H), 6.67 (d, J = 15.9 Hz, 2 H), 4.55 (dd, J = 16.6,
13.6 Hz, 2 H), 4.13 (d, J = 16.6 Hz, 1 H), 3.80 (d, J = 17.4 Hz, 2
125.1, 124.9, 90.1, 59.2, 51.4, 41.3, 20.7, 20.6 ppm. IR (KBr): ν =
˜
2947, 1494 cm–1. MS (ESI): m/z (%) = 294 (100) [M + H]. HRMS
H), 2.37 (s, 6 H), 1.25 (s, 2 H), 1.18 (s, 6 H), 1.15 (s, 6 H) ppm. 13
C
(ESI) calcd. for C19H24N3 294.1970; found 294.1969.
NMR (75 MHz, CDCl3): δ = 146.8, 144.0, 143.6, 142.5, 128.1,
128.0, 125.5, 125.3, 125.1, 124.3, 124.1, 90.3, 59.6, 51.7, 41.7, 33.6,
(؎)-2,8-Dimethoxy-N,N-dimethyl-6H,12H-5,11-methanodibenzo-
[b,f][1,5]diazocin-13-amine (2b): 2,8-Dimethoxy-6H,12H-5,11-meth-
anodibenzo[b,f][1,5]diazocine (1b, 123 mg, 0.43 mmol) in DMF
(4 mL) was added to Vilsmeier–Haack reagent prepared from
DMF (101 μL, 1.3 mmol) and POCl3 (120 μL, 1.3 mmol). The
crude product was purified by column chromatography with EtOAc
in hexane (5%) as eluent to afford 2b (98 mg, 69%) as a pale yellow
solid; m.p. 75–76 °C. 1H NMR (300 MHz, CDCl3): δ = 6.94 (dd, J
= 14.9, 8.7 Hz, 2 H), 6.69 (td, J = 8.7, 2.6 Hz, 2 H), 6.35 (dd, J =
8.7, 2.6 Hz, 2 H), 4.53 (dd, J = 16.6, 10.0 Hz, 2 H), 4.08 (d, J =
29.8, 24.1 ppm. IR (neat): ν = 2955, 1493 cm–1. MS (ESI): m/z (%)
˜
= 350 (100) [M + H]. HRMS (ESI) calcd. for C23H32N3 350.2596
found 350.2586.
(؎)-N,N-Dimethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocin-
13-amine (2f): 6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine (1f,
250 mg, 1.12 mmol) in DMF (6 mL) was added to Vilsmeier–
Haack reagent prepared from DMF (262 μL, 3.37 mmol) and
POCl3 (316 μL, 3.37 mmol). The crude product was purified by
column chromatography with EtOAc in hexane (5%) as eluent to
16.6 Hz, 1 H), 3.79–3.63 (m, 8 H), 2.36 (s, 6 H) ppm. 13C NMR afford 2f (191 mg, 64 %) as a white solid; m.p. 135–136 °C. 1H
(75 MHz, CDCl3): δ = 156.0, 155.8, 141.9, 137.6, 129.3, 128.9, NMR (300 MHz, CDCl3): δ = 7.14–6.78 (m, 8 H), 4.61 (dd, J =
126.5, 126.0, 113.9, 113.6, 110.6, 110.3, 90.4, 59.7, 55.0, 52.0,
16.6, 9.2 Hz, 2 H), 4.19 (d, J = 16.6 Hz, 1 H), 3.85 (d, J = 17.2 Hz,
316
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“Crowned” Tröger’s Base Analogues
1
2 H), 2.38 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 148.9,
to afford 3c (126 mg, 72%) as a white solid; m.p. 130–131 °C. H
144.7, 128.6, 128.3, 127.1, 126.9, 126.5, 126.4, 125.6, 125.3, 123.7,
NMR (300 MHz, CDCl3): δ = 7.30–7.15 (m, 4 H), 7.08–6.89 (m, 7
H), 5.01 (s, 1 H), 4.71 (d, J = 16.6 Hz, 1 H), 4.40 (d, J = 16.6 Hz,
1 H), 4.21 (d, J = 16.6 Hz, 1 H), 3.74 (d, J = 16.6 Hz, 1 H), 2.81
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 148.9, 146.9, 143.7,
130.5, 130.0, 129.3, 128.5, 127.2, 126.8, 121.1, 119.6, 116.8, 116.7,
123.6, 90.1, 59.4, 51.5, 41.5 ppm. IR (KBr): ν = 2939, 1444 cm–1.
˜
MS (ESI): m/z (%) = 266 (100) [M + H]. HRMS (ESI) calcd. for
C17H20N3 266.1657; found 266.1651.
Synthesis of Arylalkylamino-Crowned Tröger’s Base Analogues Un-
der Typical Vilsmeier–Haack Conditions. General Procedure 2: N-
Methyl-N-phenylformamide (3 mmol) was cooled in an ice bath
and phosphorus oxychloride (3 mmol) was added dropwise. After
formation of a yellow coloured paste, the reaction mixture was al-
lowed to warm to room temperature. Tröger’s base (1 mmol) dis-
solved in dry dichloromethane (10 mL) was added to the Vilsme-
ier–Haack reagent and the reaction mixture was stirred at room
temperature for 2–4 h. After completion of the reaction (monitor-
ing by TLC), the reaction mixture was poured into saturated
NaHCO3 solution and stirred at room temperature for 1 h. The
aqueous layer was extracted with dichloromethane (3ϫ 10 mL) and
the combined organic extracts were washed with water (3 ϫ
10 mL), dried and concentrated in vacuo. The crude product was
purified by column chromatography with EtOAc/hexane as eluent.
84.4, 59.6, 50.5, 37.8 ppm. IR (KBr): ν = 2923, 1473 cm–1. MS
˜
(ESI): m/z (%) = 486 (100) [M + H]. HRMS (ESI) calcd. for
C22H20N3Br2 484.0023; found 484.0012.
(؎)-N-(2,3,8,9-Tetramethoxy-N,2,8-trimethyl-N-phenyl-6H,12H-
5,11-methanodibenzo[b,f][1,5]diazocin-13-amine (3d): 2,3,8,9-Tetra-
methoxy-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine (1d,
300 mg, 0.87 mmol) in dry CH2Cl2 (8 mL) was added to the
Vilsmeier–Haack reagent prepared from N-methyl-N-phenylfor-
mamide (355 mg, 2.63 mmol) and POCl3 (246 μL, 2.63 mmol). The
crude product was purified by column chromatography with EtOAc
in hexane (10%) as eluent to afford 3d (325 mg, 83%) as a white
1
solid; m.p. 177–178 °C. H NMR (300 MHz, CDCl3): δ = 7.19 (t,
J = 8.2 Hz, 2 H), 7.0 (d, J = 8.2 Hz, 2 H) 6.85 (t, J = 6.8 Hz, 1 H),
6.58 (d, J = 3.6 Hz, 2 H), 6.36 (s, 1 H), 6.29 (s, 1 H), 5.06 (s, 1 H),
4.65 (d, J = 15.5 Hz, 1 H), 4.28 (d, J = 15.5 Hz, 1 H), 4.17 (d, J =
16.4 Hz, 1 H), 3.85 (s, 3 H), 3.83 (s, 3 H), 3.76 (s, 3 H), 3.75 (s, 3
H), 3.70 (d, J = 16.4 Hz, 1 H), 2.83 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 149.0, 148.4, 146.2, 146.0, 140.8, 137.4,
128.3, 120.0, 119.6, 119.1, 118.2, 108.7, 108.5, 108.4, 108.0, 84.7,
(؎)-N,2,8-Trimethyl-N-phenyl-6H,12H-5,11-methanodibenzo[b,f]-
[1,5]diazocin-13-amine (3a): 2,8-Dimethyl-6H,12H-5,11-methanodi-
benzo[b,f][1,5]diazocine (1a, 250 mg, 1 mmol) in dry CH2Cl2
(8 mL) was added to the Vilsmeier–Haack reagent prepared from
N-methyl-N-phenylformamide (405 mg, 3 mmol) and POCl3
(280 μL, 3 mmol). The crude product was purified by column
chromatography with EtOAc in hexane (5%) as eluent to afford 3a
59.8, 55.8, 55.7, 55.6, 50.2, 36.6 ppm. IR (KBr): ν = 2908,
˜
1503 cm–1. MS (ESI): m/z (%) = 443 (100) [M + H]. HRMS (ESI)
calcd. for C26H30N3O4 448.2236; found 448.2256.
1
(255 mg, 72%) as a pale brown solid; m.p. 135–136 °C. H NMR
(300 MHz, CDCl3): δ = 7.17 (t, J = 7.9 Hz, 2 H), 7.05–6.88 (m, 6
H), 6.84 (t, J = 7.2 Hz, 1 H), 6.69 (s, 1 H), 6.60 (s, 1 H), 5.09 (s, 1
H), 4.70 (d, J = 16.6 Hz, 1 H), 4.34 (d, J = 16.6 Hz, 1 H), 4.22 (d,
J = 15.9 Hz, 1 H), 3.75 (d, J = 16.6 Hz, 1 H), 2.83 (s, 3 H), 2.22
(s, 3 H), 2.20 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 149.0,
145.6, 142.6, 133.3, 133.2, 128.4, 128.1, 128.0, 127.0, 126.8, 125.3,
Crystals were obtained from 200 mg of (Ϯ)-3d in dilute EtOAc
(40 mL) at room temp. after 72 h. A well shaped crystal was picked
for XRD studies.
(؎)-2,8-Dimethyl-13-(piperidin-1-yl)-6H,12H-5,11-methanodi-
benzo[b,f][1,5]diazocine (4): Piperidine-1-carbaldehyde (135 mg,
1.2 mmol) was cooled in an ice bath and phosphorus oxychloride
(112 μL, 1.2 mmol) was added dropwise. The reaction mixture was
then heated to 70 °C and stirred for 1 h to give a yellow coloured
paste. It was then allowed to cool to room temperature, 2,8-di-
methyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine (1a,
100 mg, 0.4 mmol) in dry CH2Cl2 (5 mL) was added, and the mix-
ture was stirred at room temperature for 3 h. After completion of
124.8, 119.8, 118.1, 84.6, 60.5, 50.7, 36.5, 20.8 ppm. IR (KBr): ν =
˜
2915, 1494 cm–1. MS (ESI): m/z (%) = 356 (100) [M + H]. HRMS
(ESI) calcd. for C24H26N3 356.2126; found 356.2122.
(؎)-2,8-Dimethoxy-N,2,8-trimethyl-N-(p-tolyl)-6H,12H-5,11-
methanodibenzo[b,f][1,5]diazocin-13-amine (3b): 2,8-Dimethoxy-
6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine (1b, 120 mg,
0.42 mmol) in CH2Cl2 (4 mL) was added to the Vilsmeier–Haack the reaction (monitoring by TLC), the reaction mixture was poured
reagent prepared from N-methyl-N-p-tolylformamide (0.190 mg,
1.27 mmol) and POCl3 (119 μL, 1.27 mmol). The crude product
was purified by column chromatography with EtOAc in hexane
into saturated NaHCO3 solution and stirred at room temp. for 1 h.
The aqueous layer was extracted with dichloromethane (3 ϫ
10 mL) and the combined organic extracts were washed with water
(3ϫ 10 mL), dried and concentrated in vacuo. The crude product
(10%) as eluent to afford 3b (115 mg, 68%) as a pale yellow gummy
1
compound. H NMR (300 MHz, CDCl3): δ = 7.01–6.87 (m, 6 H), was purified by column chromatography with EtOAc in hexane
6.67 (dt, J = 8.7, 2.6 Hz, 2 H), 6.39 (d, J = 2.6 Hz, 1 H), 6.32 (d,
J = 2.8 Hz, 1 H), 4.96 (s, 1 H), 4.67 (d, J = 16.4 Hz, 1 H), 4.36 (d,
J = 16.6 Hz, 1 H), 4.15 (d, J = 16.8 Hz, 1 H), 3.72–3.64 (m, 7 H)
(5%) as eluent to afford 4 (108 mg, 81%) as a pale yellow gummy
compound. H NMR (300 MHz, CDCl3): δ = 6.87–6.73 (m, 4 H),
1
6.53 (d, J = 16.0 Hz, 2 H), 4.44 (d, J = 16.2 Hz, 2 H), 4.01 (d, J =
2.79 (s, 3 H), 2.28 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.4 Hz, 1 H), 3.83 (s, 1 H), 3.64 (d, J = 16.0 Hz, 1 H), 2.10 (s, 3
156.0, 155.8, 147.1, 141.2, 137.9, 130.1, 129.5, 129.0, 126.5, 126.1,
119.7, 113.9, 113.8, 110.5, 110.4, 85.2, 60.3, 55.3, 55.2, 51.2, 38.0,
H), 2.01 (s, 3 H), 1.43–1.17 (m, 10 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 146.3, 142.2, 132.6, 132.2, 128.5, 127.9, 127.7, 127.4,
126.6, 125.2, 124.7, 119.1, 88.7, 59.6, 51.5, 49.7, 29.6, 25.6, 24.9,
20.6 ppm. IR (neat): ν = 2922, 1496 cm–1. MS (ESI): m/z (%) = 402
˜
(100) [M + H]. HRMS (ESI) calcd. for C25H28N3O2 402.2181;
found 402.2196.
20.8, 20.7 ppm. IR (neat): ν = 2925, 1493 cm–1. MS (ESI): m/z (%)
˜
= 334 (100) [M + H]. HRMS (ESI) calcd. for C22H28N3 334.2283;
found 334.2295.
(؎)-2,8-Dibromo-N,2,8-trimethyl-N-phenyl-6H,12H-5,11-methano-
dibenzo[b,f][1,5]diazocin-13-amine (3c): 2,8-Dibromo-6H,12H-5,11-
methanodibenzo[b,f][1,5]diazocine (1c, 138 mg, 0.36 mmol) in dry
CH2Cl2 (8 mL) was added to the Vilsmeier–Haack reagent pre-
pared from N-methyl-N-phenylformamide (147 mg, 1.08 mmol)
and POCl3 (101 μL, 1.08 mmol). The crude product was purified
by column chromatography with EtOAc in hexane (5%) as eluent
(؎)-13-(Morpholin-4-yl)-2,8-dimethyl-6H,12H-5,11-methanodi-
benzo[b,f][1,5]diazocine (5): Morpholine-1-carbaldehyde (248 mg,
2.16 mmol) was cooled in an ice bath and phosphorus oxychloride
(202 μL, 2.16 mmol) was added dropwise. The reaction mixture was
then heated to 70 °C and stirred for 1 h to give a yellow coloured
paste. It was cooled to room temperature, 2,8-dimethyl-6H,12H-
Eur. J. Org. Chem. 2012, 312–319
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
317

M. B. Reddy, A. Manjula, B. V. Rao, B. Sridhar
FULL PAPER
5,11-methanodibenzo[b,f][1,5]diazocine (1a, 180 mg, 0.72 mmol) in
dry CH2Cl2 (6 mL) was then added, and the mixture was stirred at
room temperature for 2 h. After completion of the reaction (moni-
toring by TLC), the reaction mixture was poured into saturated
NaHCO3 solution and stirred at room temp. for 1 h. The aqueous
layer was extracted with dichloromethane (3 ϫ 10 mL) and the
combined organic extracts were washed with water (3ϫ 10 mL),
dried and concentrated in vacuo. The crude product was purified
by column chromatography with EtOAc in hexane (5%) as eluent
[1]
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[3]
[4]
1
to afford 5 (173 mg, 72%) as a pale yellow gummy compound. H
NMR (300 MHz, CDCl3): δ = 6.88 (d, J = 13.8 Hz, 4 H), 6.63 (d,
J = 15.3 Hz, 2 H), 4.52 (dd, J = 16.4, 11.1 Hz, 2 H), 4.37 (d, J =
16.4 Hz, 1 H), 3.96 (s, 1 H), 3.74 (d, J = 16.2 Hz, 1 H), 3.66–3.54
(m, 4 H), 2.85–2.60 (m, 4 H), 2.20 (s, 6 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 146.0, 142.0, 133.3, 132.8, 128.5, 128.0,
127.7, 126.9, 126.7, 125.3, 124.9, 88.7, 66.9, 59.6, 51.5, 49.5, 20.9,
20.8 ppm. IR (neat): ν = 2913, 1494, 1178 cm–1. MS (ESI): m/z (%)
˜
= 336 (100) [M + H]. HRMS (ESI) calcd. for C21H26N3O 336.2075;
found 336.2082.
X-Ray Crystallography Data for 2c and 3d: X-ray data for com-
pounds 2c and 3d were collected at room temperature with use of
a Bruker Smart Apex CCD diffractometer and graphite monochro-
mated Mo-Kα radiation (λ = 0.71073 Å) by the ω-scan method.[26]
Preliminary lattice parameters and orientation matrices were ob-
tained from four sets of frames. Unit cell dimensions were deter-
mined by use of 7640 reflections for 2c and 7047 for 3d.
[5]
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isotropic displacement parameters were included for all non-hydro-
gen atoms. All H atoms were positioned geometrically and treated
as riding on their parent C atoms, with C–H distances of 0.93–
0.96 Å and with Uiso(H) = 1.2Ueq (C) or 1.5Ueq for methyl atoms.
For 2c, the absolute configuration was confirmed by unambiguous
refinement of the absolute structure parameters [0.018(13) for the
S configuration of the C(13) atom].
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Data for 2c: Formula C17H17Br2N3, M = 423.16, orthorhombic,
space group P212121, a = 8.6149(9) Å, b = 9.9174(10) Å, c =
19.7154(13) Å, V = 1644.9(3) Å3, Z = 4, Dc = 1.709 gcm–3, μ(Mo-
K) = 4.928 mm–1, F(000) = 840, T = 294(2) K, R1(I Ͼ 2σ) = 0.0303,
wR2(all data) = 0.0855 for 2893 independent reflections with a
goodness-of-fit of 1.072.
[10]
Data for 3d: Formula C26H29N3O4, M = 447.52, monoclinic, space
group P21/c,
a = 9.9850(9) Å, b = 15.6080(14) Å, c =
15.4194(14) Å, β = 104.797(2)°, V = 2323.4(4) Å3, Z = 4, Dc =
1.279 gcm–3, μ(Mo-K) = 0.087 mm–1, F(000) = 952, T = 294(2) K,
R1(I Ͼ 2σ) = 0.0486, wR2(all data) = 0.1263 for 4083 independent
reflections with a goodness-of-fit of 1.079.
[11]
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H and 13C spectra for all compounds, crystallo-
graphic data for 2c and 3d (CIF files).
Acknowledgments
The authors wish to thank Dr. Venkat R. Thalladi and Dr. A. An-
thony for support and valuable discussions. M. B. R. thanks the
Council of Scientific and Industrial Research (CSIR) for a fellow-
ship. We thank the Indian Institute of Chemical Technology (IICT)
for facilities.
318
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 312–319

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Received: June 6, 2011
Published Online: November 8, 2011
Eur. J. Org. Chem. 2012, 312–319
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
319