Synthesis of new cyano-substituted analogues of Tr?ger's bases from bromo-derivatives. A stereochemical dependence of long-range (nJHH, n?=?4, 5, and 6) proton–proton and proton–carbon (nJCH, n?=?1, 2, 3, 4, and 5) coupling constants of these compounds

Article abstract of DOI:10.1002/mrc.4872

A free-catalyst microwave-assisted cyanation of brominated Tr?ger's base derivatives (2a-f) is reported. The procedure is simple, efficient, and clean affording the nitrile compounds (3a-e, I) in very good yields. Complete assignment of ¹H and ¹³C chemical shifts of 2a-f, I and 3a-d, I was achieved using gradient selected 1D nuclear magnetic resonance (NMR) techniques (1D zTOCSY, PSYCHE, DPFGSE NOE, and DEPT), homonuclear 2D NMR techniques (gCOSY and zTOCSY), and heteronuclear 2D NMR techniques (gHSQCAD/or pure-shift gHSQCAD, gHMBCAD, bsHSQCNOESY, and gHSQCAD-TOCSY) with adiabatic pulses. Determination of the long-range proton–proton coupling constants ⁿJ_HH (n?=?4, 5, 6) was accomplished by simultaneous irradiation of two protons at appropriate power levels. In turn, determined coupling constants were tested by an iterative simulation program by calculating the ¹H NMR spectrum and comparing it to the experimental spectrum. The excitation-sculptured indirect-detection experiment (EXSIDE) and ¹H-¹⁵N CIGARAD-HMBC (constant time inverse-detection gradient accordion rescaled heteronuclear multiple bond correlation) were applied for determination of long-range carbon–proton coupling constants ⁿJ_CH (n?=?2, 3, and 4) and for assignment of ¹⁵N chemical shift at natural abundance, respectively. DFT/B3LYP optimization studies were performed in order to determine the geometry of 2c using 6-31G(d,p), 6-311G(d,p), and 6–311?+?G(d,p) basis sets. For calculation of ¹H and ¹³C chemical shifts, ⁿJ_HH (n?=?2, 3, 4, 5, and 6), and ⁿJ_CH (n?=?1, 2, 3, and 4) coupling constants, the GIAO method was employed at the B3LYP/6-31G(d,p), B3LYP/6-31+G(d,p), B3LYP/6-311+G(d,p), B3LYP/6-311++G(2d,2p), B3LYP/cc-pVTZ), and B3LYP/aug-cc-pVTZ) levels of theory. For the first time, a stereochemical dependence magnitude of the long-range ⁿJ_HH (n?=?4, 5, and 6) and ⁿJ_CH (n?=?1, 2, 3, 4, and 5) have been found in bromo-substituted analogues of Tr?ger's bases.

Full text of DOI:10.1002/mrc.4872

Akhmedov Novruz (Orcid ID: 0000-0002-4586-2304)
Parella Teodor (Orcid ID: 0000-0002-1914-2709)
Synthesis of new cyano-substituted analogues of Tröger’s bases from bromo-
n
derivatives. A stereochemical dependence of long-range ( JHH, n = 4, 5, and 6) proton-
n
proton and proton-carbon ( JCH, n = 1, 2, 3, 4, and 5) coupling constants of these
compounds
a,b
c
c
c
c
Diego Dusso , Cristina Ramirez , Alejandro Parise , P. Lanza , D. Mariano Vera , Carlos
b
a
d*
Chesta , E. Laura Moyano , Novruz G. Akhmedov
a
INFIQC-Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad
Nacional de Córdoba, Ciudad Universitaria, Córdoba, Argentina.
b
Facultad de Ciencias Exactas Fisicoquímicas y Naturales, Universidad Nacional de Río
Cuarto, Córdoba, Argentina.
c
QUIAMM-INBIOTEC- Departamento de Química, Facultad de Ciencias Exactas y Naturales,
Universidad Nacional de Mar del Plata, Mar del Plata, Buenos Aires, Argentina.
a
E. L. Moyano, INFIQC-Departamento de Química Orgánica, Facultad de Ciencias Químicas,
Universidad Nacional de Córdoba, Ciudad Universitaria, Córdoba, 5000, Argentina.
*
d
West Virginia University, Eugene Bennett Department of Chemistry, Morgantown, WV
6506-6045, USA.
2
*
Correspondence to: Novruz G. Akhmedov, Eugene Bennett Department of Chemistry,
West Virginia University, Morgantown, WV 26506-6045, USA. Email:
Novruz.Akhmedov@mail.wvu.edu, Phone: 304 2930918, Fax: 304 293 4904.
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1002/mrc.4872
This article is protected by copyright. All rights reserved.

Abstract
A free-catalyst microwave-assisted cyanation of brominated Tröger’s base derivatives (2a-f)
is reported. The procedure is simple, efficient and clean affording the nitrile compounds (3a-e,
1
13
I) in very good yields. Complete assignment of H and C chemical shifts of 2a-f, I and 3a-d,
I was achieved using gradient selected 1D NMR techniques (1D zTOCSY, PSYCHE, DPFGSE
NOE and DEPT), homonuclear 2D NMR techniques (gCOSY, zTOCSY), and heteronuclear
2
D NMR techniques (gHSQCAD/or pure-shift gHSQCAD, gHMBCAD, bsHSQCNOESY,
and gHSQCAD-TOCSY) with adiabatic pulses. Determination of the long-range proton-proton
coupling constants n
HH (n = 4, 5, 6) was accomplished by simultaneous irradiation of two
J
protons at appropriate power levels. In turn, determined coupling constants were tested by an
1
iterative simulation program by calculating the H NMR spectrum and comparing it to the
experimental spectrum.
1
15
The excitation-sculptured indirect-detection experiment (EXSIDE) and H- N CIGARAD-
HMBC (constant time inverse-detection gradient accordion rescaled heteronuclear multiple
bond correlation) were applied for determination of long-range carbon-proton coupling
constants n
J
CH (n = 2, 3, and 4) and for assignment of N chemical shift at natural abundance,
15
respectively.
DFT/B3LYP optimization studies were performed in order to determine the geometry of
1
2
c
using 6-31G(d,p), 6-311G(d,p), and 6-311+G(d,p) basis sets. For calculation of H
and C chemical shifts, JHH (n = 2, 3, 4, 5, and 6), and nJCH (n = 1, 2, 3, and 4)
coupling constants, the GIAO method was employed at the B3LYP/6-31G(d,p),
B3LYP/6-31+G(d,p), B3LYP/6-311+G(d,p), B3LYP/6-311++G(2d,2p), B3LYP/cc-
pVTZ), and B3LYP/aug-cc-pVTZ) levels of theory. For the first time, a stereochemical
1
3
n
dependence magnitude of the long-range n
J
HH (n = 4, 5, and 6) and nJCH (n = 1, 2, 3, 4, and
5) have been found in bromo-substituted analogues of Tröger’s bases
.
Keywords: bsHSQCNOESY, EXSIDE, PSYCHE, CIGARAD, GIAO, microwaves,
cyanation, Tröger’s bases
This article is protected by copyright. All rights reserved.

INTRODUCTION
Troger’s base (TB) is a chiral V-shaped compound whose chirality is the result of two
stereogenic nitrogen centres being unable to invert due to the presence of a methylene strap.
[
1,2]
TB analogues have exhibited outstanding applications in supramolecular chemistry, [3,4]
DNA recognition, [5] optical and optoelectronic materials, [6] among others. Chiral TBs have
also been proven as promising catalyst in asymmetric reactions [7] and chiral auxiliary in
stereoselective syntheses. [8] For several reasons, the preparation of asymmetric TB
compounds, where one of the two aromatic rings is differentially substituted, has been
explored. One of the synthetic possibility is through a stepwise route that initially involves the
formation of a mono-linked compound.[9-11] Using different anilines with two unsubstituted
positions ortho to the amino group as starting materials a non-symmetrical derivative can be
formed, as one of three potential Tröger’s base products,[12-14] and with some anilines only a
single Tröger’s base is obtained.[15] Another route is the transformation of a symmetric TB in
another asymmetric one using different approaches.[16-18]
On the other hand, the synthesis of aryl and heteroaryl nitriles became of great
importance because esters, amides, amines, aldehydes, and nitrogen-containing heterocycles
can be formed from nitrile precursors.[19] For cyanation of aryl halides, the Rosenmund-von
Braun reaction mediated by copper (I) cyanide, has been widely used.[20,21] Recent
methodologies have been developed for this reaction using palladium as catalyst,[22] and
different sources of nitriles as malononitrile,[23] potassium hexacyanoferrate (II) [24] and
ammonium bicarbonate.[25]
Microwave dielectric heating has been used to perform organic reactions since decades
giving rise to the field of microwave-assisted organic synthesis. [26,27] By using microwave
irradiation, higher yields and different product distributions have been reported in several
organic transformations reducing reaction times from many hours to a few minutes. Some
This article is protected by copyright. All rights reserved.

authors have described the microwave promoted Rosenmund-von Braun cyanation of aryl
iodides/bromides as a green methodology for the synthesis of simple cyano-aryl derivatives.
[
28,29]
In this work, we describe our recent efforts to expand the chemistry of dibenzo Tröger’s
base analogues by preparing new asymmetric compounds possessing one cyano substituent
using a simple microwave-assisted protocol mediated by CuCN without additional catalysts.
The incorporation of the nitrile function in one of the aromatic ring of the dibenzo-diazocines
can enable precursors of many derivatives as aldehydes, acids, esters and imines, among others,
expanding the chemistry of these Tröger’s bases.
The structures of these new novel compounds of 2a-f, I and 3a-d, I were elucidated by
1
D and 2D NMR techniques. The observed complex NMR spin system of Tröger’s bases
makes NMR characterization particularly challenging to determine accurate values of long-
1
1
13
1
range coupling constants ( H- H and C- H). Consequently, the focus of this paper involves
1
1
13
1
the complete assignment of H- H and C- H coupling constants by utilizing advanced 1D and
2
D NMR techniques in combination with theoretical DFT/GIAO calculations. The accuracy of
the experimentally determined coupling constants was then compared to the simulated spectra.
RESULTS and DISCUSSION
1
. Synthesis of Tröger’s base (TB) derivatives
Bromine-containing TB derivatives 2a-e were prepared by the reaction of two different
anilines, p-bromine anilines 1a, b and anilines 1c-f as it is depicted in the Scheme 1. This
reaction affords a mixture of the three possible TB products, the expected asymmetric nuclei
(2a-e) and two symmetrically substituted compounds (2f, g and 2h-k). This approach yielded
brominated-asymmetric compounds in acceptable yields after a meticulous purification process
(Table 1). In the case of 2c and 2d yields were better probably due to the electron donor effect
This article is protected by copyright. All rights reserved.

of methoxy and dimethyl-amino substituents in the starting anilines. The TB derivative 2f was
synthesized using only 4-bromo-2-methylaniline as the starting material. In addition, the
presence of a methyl substituent on ortho position of the starting bromoaniline considerably
diminished (~ 5 times) the time required for the reaction is completed. In addition, from 2f the
asymmetric TB 2l was prepared using 4,4'-dimethoxydiphenylamine and palladium acetate as
catalyst (Scheme 1). Compounds 2h-k were detected in the reaction mixture but were not
isolated because only the bromo-derivatives are useful for the next step of the synthetic
sequence.
For the cyanation reaction, the experimental conditions were optimized using in the first
place and for testing, the brominated anilines 1a and 1b. This way, a mixture of the brominated
precursor and CuCN in DMF was irradiated (850 W) during 30 minutes at 250 °C and 1200
rpm. After this irradiation period, the crude was extracted with ethyl acetate and water to
eliminate the remaining solvent and catalyst. Different ratios of aryl bromide: CuCN were
tested (1:2, 1:3 and 1:4) and the optimal value was 1:4. These experimental conditions allowed
the complete conversion of substrates 1a,b giving very good yields of 4-aminobenzonitrile
(from 1a, 85%) and 4-amino-3-methylbenzonitrile (from 1b, 75%) associated with a clean
work-up of the reaction. It is worthy to mention that the reaction of anilines 1a-b in DMF and
CuCN using conventional heating for many hours did not allow the formation of cyano-
derivatives.
Next, when cyanation of TB compounds (2a-e, l) was performed using the same conditions
that for anilines 1a,b and nitrile products 3a-e, l were obtained in very good to excellent yields
(Scheme 1). Scaling of synthesis of 3d was carried out and yields were also quantitative (> 95
%
yield).
This article is protected by copyright. All rights reserved.

2
. NMR analysis
1
13
15
Although most published NMR data includes complete assignment of H, C, and N NMR
1
1
13
1
chemicals shifts, the determination of long-range H- H and C- H couplings has received
little attention for the Tröger’ s bases.[30-35] Recently, an interesting NMR study has been
reported for the EE, EZ, and ZZ photoisomerization of disazo Tröger’s base analogs.[36] In
general, review of the literature pertaining to multiplicity patterns of various types of Tröger’s
bases shows that the multiplicity of protons was generally over-simplified. The methylene
protons of the benzylic and methanodiazocine units were reported as a doublet, thus ignoring
the small, long-range couplings (4JHH, JHH, and 6JHH).
5
1
13
15
Herein, we report the complete and unambiguous assignment of the H, C, and N
NMR spectra of newly synthesized compounds, 2a-f, l and 3a-d, l, with the prospect that the
assigned NMR parameters (proton and carbon chemical shifts and coupling constants) will
serve as a reference for structural confirmation of novel members of the Tröger’s bases family.
1
1
1
The H- H coupling constants were obtained from the first-order analysis of the H NMR
1
3
1
spectrum, along with simulated spectra. The C- H coupling constants were obtained from the
proton-coupled 13C NMR and H- C EXSIDE spectra. Among the bromo-substituted
analogues of Tröger’s bases, 2a-f, the compound 2c was chosen to demonstrate the NMR
analysis.
1
13
2
.1. Structural features of Bromo- and Cyano-Substituted Analogues of Tröger’s Bases 2a-f
and 3a-d, l
The key structural feature of Tröger’s bases is the 1, 5-diazabicyclo[3.3.1]nonane skeletal
subunit fused with two benzene rings. The synthesized di- (2a, 3a), tri- (2b-2d) / 3b-d, or tetra-
substituted (2f, 2I, and 3l) compounds (Scheme 2) are analogous of Tröger’s base (2,8-
dimethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine). The structure of all compounds
contains the same 6, 12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine central framework.
This article is protected by copyright. All rights reserved.

The molecular geometry of 2a-f, l and 3a-d, l is asymmetric, whereas only compound 2f
possess a C2-symmetry. Moreover, one of the fused benzene ring carbons (C1-C2-C3-C4) in
2
a and 3a is not substituted. The following substituents were installed at the C2 and C8 position
of the fused benzene rings for compounds 2a-2f and 3a-d, l: H, Br, CN, CH , OCH , N(CH
N (p-OCH Ph)
3
3
3
2
) ,
3
2
.
2
.2.Spin system designation for the methylene protons of the 6, 12, and 13-CH
protons of the two fused benzene rings
2
groups and
1
The H NMR spectra of asymmetric analogous of Tröger’s bases 2a-f, l and 3a-d, l display a
characteristic pattern for the two aryl and methanodiazocine protons. The most noticeable
aspect of the non-planar molecular framework of 2a-f, l – 3a-d, l with a concave V-shape is
that one of the benzylic-type protons of the 6-CH
2
and 12-CH groups is in a syn and anti-
2
position to the bridgehead protons (13-CH ) and are labeled as an exo and endo protons,
2
respectfully (see Scheme 2, the expanded structural formula of 2c). Consequently, these
1
methylene protons became diastereotopic, and they appear in the H NMR spectrum as two
AB-type doublets. Similarly, the methylene bridgehead protons (13-CH
2
) also are displayed as
an AB-type of spin system in 2a-d and 3a-e, l; this is compared to 2f where the chemically and
a
b
magnetically equivalent protons are labeled as H13 /H13 . Only in 2f do these methylene
protons (benzylic, metanodiazocine, and bridgehead) display as a singlets due to V-shaped C2
symmetry, and constitute an AA’BB”CC’ type of spin system.
1
The H NMR spectra of 2a acquired in CDCl
3
and C
6
6
D reveals a first order four-spin
system for the unsubstituted benzene ring protons (H1, H2, H3, and H4). This spin system is
1
described as an ABMX. However, the H NMR spectrum of 2a acquired in acetone-d
6
shows
very strongly pronounced, non-first order multiplicity patterns for these aromatic protons due
to the ratio (/J<10) established for high order NMR spectra, where () is the difference in
chemical shift between interacting protons (H1 and H2, H3 and H4) and J is the magnitude of
coupling constants between them. The calculated values of the /J ratio, 0.5 and 1.9,
This article is protected by copyright. All rights reserved.

1
respectively, satisfy the ratio (/J<10). Similarly, the H NMR spectrum of 3a in CDCl
3
exhibited an ABMX spin system for H1, H2, H3, and H4.
For all compounds 2a-f, 3a-d, l, the H7 and H9 protons shows an AX spin system; the
three-spin systems ABX and AMX were revealed for the H1, H3, and H4 in 2b-d and 3b-d,
respectively. The AX spin system for H1 and H3 protons were revealed for compounds 2I and
2
f. The di-substituted benzene ring protons of the N(p-OCH Ph)2 groups in 2l and 3l display
3
non-first order AA’BB’ splitting patterns.
1
1
13
2
.3. H NMR spectral features, the strategies for measurements, assignments of H/ C NMR
1
1
13
1
chemical shifts, and coupling constants ( H- H) / ( C- H) of 2a-f and 3a-d, l
1
The 400 and 600 MHz H NMR spectra of 2a-d, I and 3a-d, l are rather well dispersed in
CDCl
3
and display similar multiplicity patterns for the aromatic ring and methanodiazocine
1
13
ring protons. Complete and unequivocally assigned H and C NMR chemical shifts of bromo-
and cyano-substituted analogues of Tröger’s base (2a-d and 3a-d, l) in CDCl are given in
3
1
Tables 2 and 3, respectively. Additionally, the H NMR spectra of 2a, 2c, 2f, and 3b were
1
acquired in polar (CD
3
)
2
CO and anisotropic (C
6
D
6
) in order to explore solvent-induced H and
1
3
1
13
C NMR chemical shifts and long-range coupling constants. The assigned H and C NMR
chemical shifts in these solvents are summarized in Tables 4 and 5, respectively. Better
resolution of the proton resonances was observed in (CD CO, resulting in the use of this
deuterated solvent for the complete analysis of H and C NMR spectra. The use of (CD CO
)
3 2
1
13
)
3 2
allowed for easier determination of the long-range proton-proton (nJHH) coupling constants and
carbon-proton coupling constants (nJCH), which will be discussed in this paper for compound
2
c. The assigned coupling constants, along with the calculated values, are presented in Table
1
0.
1
13
Examination of the H and C NMR chemical shifts (see Tables 4 and 5) in these
different solvents (isotropic, polar, and anisotropic) revealed that peak separations of the
This article is protected by copyright. All rights reserved.

bridgehead methylene protons of 6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine are
greater in benzene-d than in chloroform-d and acetone-d . It must be emphasized that due to
6
6
long-range inter-ring proton-proton couplings, the bridgehead protons and all other peaks
1
exhibited in the H NMR spectrum for 2a-d, I and 3a-d, l show broad resonance patterns. The
splitting patterns arising from geminal (2JHH), vicinal (3JHH), and long-range couplings (4JHH
)
are readily recognizable and were determined directly from the experimental splitting patterns
versus the small long-range couplings of 5JHH and 6JHH
.
The structures of 2a-d, I and 3a-d, l contain one or two singlet methyl groups, which
are potentially good starting points for the assignment of remaining proton and carbon
1
frequencies. The H NMR chemical shifts of the CH
3
resonances are readily recognized by
) and 2.23-2.27
are somewhat broadened
their appearances as singlets in the high field region: 2.32-2.41 ppm (10-CH
3
(
2/4-CH
3
) (see Table 2). In fact, the peaks of the peripheral 4/10-CH
3
due to unresolved small coupling (4JHH, JHH) to H7/H9 and to the methylene protons of the
6
6
/12-CH
Since the assignment of 10-CH
the proton-proton and carbon-carbon connectivities within the structural fragments of CH
2
groups.
3
resonances in 2a-d, I and 3a-e, l are straightforward,
3
-
C10-C9-C8-C7-C6a(C6)-C10a, C1-C2-C3-C4-C4a-C12a-C12, and also within inter ring
structural fragments such as C10a-N-11(C13)-C12a-C12 and C4a-N-5(C13)-C6-C6a, were
1
15
established based upon long-range gHMBC, H- N CIGAR-HMBC, gHSQC, and
gHSQCTOCSY. These correlations are agreement with gCOSY, 1D zTOCSY, and
DPFGSENOE spectra. Assigned chemical shifts and nOe’s were supported also by the
selective gHSQC-NOESY correlations.
1
The H NMR spectra of 2a and 3a exhibit similar spectral features for both aromatic
1
and methylene protons, and a fragmentary analysis of the H NMR spectrum is given only for
1
13
compound 2a. Details on the assignment of H/ C NMR chemical shifts and determination of
This article is protected by copyright. All rights reserved.

1
1
13
1
H- H and C- H coupling constants for 2a will not be discussed. However, in this paper, a
comprehensive description of the results obtained from the application of advanced 1D and 2D
NMR techniques for compound 2c will be described in the subsequent section.
1
2
.4. H NMR spectrum of 2a
(2-bromo-4-methyl-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine) in (CD
3
2
) CO
1
The H NMR spectrum of 2a in CDCl
3
or C
6
D
6
vs. (CD
3
2
) CO displays six complex first-order
multiplets in the region of 6.55 – 7.25 ppm (H1, H2, H3, H4, H7, and H9) and six AB doublets
for the methylene protons of the 6-CH , 12-CH , and 13-CH groups. Assignment of these
aromatic and stereospecific methylene proton frequencies were based on a series of
DPFGSENOE spectra. For instance, in CDCl solution, the bridgehead methylene protons of
the 13-CH group are well differentiated based upon through-space correlations observed
2
2
2
3
2
between H6exo (4.64) and H13 ( 4.25) and between H12 (4.58) and H13 ( 4.33). Based
a
exo
b
endo
on the nOe, the upfield doublets at  3.94 and  4.15 were assigned to the endo protons (H12
and H6endo, respectively) and the AB doublets at lower fields were assigned to the H6 (4.64)
exo
exo
1
13
and H12  4.58) protons. All assigned H and C NMR chemical shifts for 2a are readily
supported by one-bond HSQC/HMBC correlations.
1
It is worth mentioning that the H NMR spectrum of 2a acquired in (CD
3
2
) CO shows
a smaller chemical shift dispersion for the aromatic protons, thereby revealing strong line
distortions. The second-order appearances are greatly pronounced for each aromatic proton
(H1, H2, H3, and H4) resonance. The high-order splitting patterns of these protons analyzed
by simulation allowed for determination of three bond (3JHH), and long-range (nJHH, n = 4, 5,
and 6) couplings. Unresolved long-range couplings between the methylene protons of the 12-
CH
2
group were detected by the gradient selected gCOSY experiments (see Supplementary
Fig. 1. gCOSY spectrum of 2a).
This article is protected by copyright. All rights reserved.

1
Figure 1 shows the expanded portions of the experimental and calculated H NMR
spectrum that reveals a very good match between calculated and experimental multiplicity
pattern for each aromatic proton signal in 2a, providing accurate values of vicinal (3J1,2 = 7. 6
Hz, 3J2,3 = 7.4 Hz, and 3J3,4 = 8.1 Hz) and all long-range coupling constants (4J1,3 = 1.5 Hz, 4J2,4
=
1.5 Hz, 4J1,12endo = 0.7 Hz, 4J1,12exo = 0.9 Hz, 5J2,12endo = 0.2 Hz, 5J2,12exo = 0.3 Hz, 5J4,12endo
=
0
.5 Hz, 5J4,12exo = 0.3 Hz, 6J3,12endo = 0.7 Hz, 6J3,12exo = 0.7 Hz). Assignment of experimental
and theoretical lines of the multiplet for the aromatic protons H1 and H2 was challenging due
to difficulties in finding exact chemical shifts of these protons. The obstacle in determination
of these shifts is strongly caused by second order effects and the partial overlap with the H7
proton peak.
1
In order to establish exact H NMR chemical shifts of H1 and H2, the proton broad
band decoupled PSYCHE (Pure Shift Yielded by Chirp Excitation) experiment was performed.
Consequently, the obtained PSYCHE spectrum (Fig. 2b) revealed chemical shifts of heavily
1
1
overlapped H1 and H2 and as well as other protons due to elimination of H- H coupling
constants between them.
1
The H NMR spectrum of 2a in C
6
D
6
accidentally showed very similar chemical shifts
exo
exo
(
 4.1452 and  4.1420) for the H6 and H12 and were differentiated by PSYCHE spectrum.
1
The Supplementary Figure 2 shows the expanded portions of the H NMR and PSYCHE
spectra.
1
1
n
2
.5. Detection of long-range coupling H- H couplings ( JHH, n = 4, 5, and 6) by gCOSY and
simultaneous irradiation of one or two proton frequencies of 2c
The unambiguous assignment of coupling constants (nJHH, n = 4, 5, and 6) was achieved by the
1
combined use of selective proton-decoupled and calculated H NMR spectra together with
homonuclear gCOSY spectra (see Supplementary gCOSY spectrum of 2c). Considering the
This article is protected by copyright. All rights reserved.

1
similar spectral features of the H NMR spectra of 2b-2f, l and 3a-d, l simultaneous irradiation
of one or two proton frequencies were conducted only for compound 2c using a 400 MHz JEOL
NMR instrument.
As mentioned above the first order multiplicity patterns for the methylene protons of
the 6-CH
2
, 12-CH
2
, and 13-CH groups and the aromatic protons are too complex due to
2
exhibiting long-range (nJHH, n = 4, 5, and 6) coupling constants. The gCOSY spectrum (see
Supplementary Fig. 1) reveals the long-range correlations between protons within each
-H9-H7-H6endo-H6 ) and (H1-OCH
exo
-H3-H4-H12endo-H12 ) of 2c
exo
benzylic segment (10-CH
3
3
1
1
and H12endo and between H4 and H6endo
and an inter-ring H- H correlation between 10-CH
3
.
The observed long-range (5JHH / JHH) correlations between the H6endo and H4/H7 and between
4
the H12endo and H1/10-CH
protons (4JHH / JHH) conclusively confirms the two benzene rings
6
3
are fused to the central methanodiazocine structural unit.
It is important to recognize that the task of extracting the accurate values of coupling
constants from first order multiplets such as doublets, triplets, quartets and doublet of doublets
is most decipherable. From the complex first order multiplicity patterns, the complete set of
JHH values cannot be deduced precisely without involving a simulation procedure. The JHH
1
values extracted from the experimental spin decoupled H NMR spectra were verified by
simulation procedure.
The protons of the CH )
O group are coupled with the H1/ H3 (5JHH), and H4 (6JHH
3
protons of the benzene ring in 2c, which is confirmed by the long-range gCOSY correlations.
1
A series of selective decoupled H NMR spectra (Figures 3-7) were acquired by simultaneous
irradiation of two proton resonances and as well as by irradiation of an individual CH
3
and
OCH
3
resonances at the appropriate power level to determine long-range coupling constants
(n
J
HH, n = 4, 5, and 6). The decoupler power is precisely adjusted to avoid intensity distortions
of the lines.
This article is protected by copyright. All rights reserved.

The magnitude of these long-range (5JHH/ JHH) coupling constants were comparable
with intrinsic line width (< 0.3 Hz) of the peaks, which could not be resolved. This resulted in
somewhat broadening of H1, H3, and H4 multiplicity lines. The Figure 3b shows a
6
simplification of the multiplicity patterns for H1, H3, and H4 when the OCH frequency at 3.68
3
ppm was selectively irradiated. By simultaneously irradiating the methylene protons of the 12-
CH
group (Fig. 3c) at 3.98 ppm (H12endo) and 4.53 ppm (H12 ) the multiplicity pattern of
exo
2
protons H1, H3, and H4 become simplified, as their long-range spin-spin interactions to
methylene protons (4JHH, JHH, and 6JHH) of the 12-CH
5
group disappear.
2
The peaks of the diastereotopic methylene protons of 6/12-CH groups are broadened
2
due to unresolved small long-range coupling constants (4JHH, JHH, and 6JHH) to the protons of
5
the aromatic rings as well as to methylene protons of the13-CH
2
group. The subspectrum (b)
of the Figure 4 shows an expanded splitting patterns of the H6exo and H6endo protons of the 6-
CH
2
group when the CH protons were selectively irradiated at 2.37 ppm. The subspectrum
3
(
c) represents the simplification of H6endo and H6exo when two proton frequencies were
simultaneously irradiated (CH
3
at 2.37 ppm and H7 at 6.95 ppm). Similarly, the subspectra (d)
and (e) show the expanded multiplicity patterns of H6exo and H6endo when simultaneous
irradiation of the two proton frequencies were conducted at  2.37 (CH
.95 (H7) /  7.18 (H9), respectively.
Figure 6 shows an expanded part of the methylene protons (H13 /H13 ) of the 13-CH
3
)/ 7.18 (H9) and 
6
a
b
2
group
(subspectrum 6a). The subspectra (b-c) show the changes of multiplicity patterns when a
simultaneous irradiation of the two proton (endo and exo) frequencies of the 6/12-CH groups
2
was performed, respectively. The subspectra (b) and (c) show a relatively large coupling
between H12endo and H13 and between H6 and H13b.
a
endo
The simultaneous irradiation of two proton frequencies was performed to determine coupling
values between H7/H9 and the exo and endo protons of the 6-CH group.
2
This article is protected by copyright. All rights reserved.

The assigned proton chemical shifts and determined values of coupling constants (4JHH, JHH
and 6JHH) from spin decoupling spectra were used as the input data to the simulation program,
gNMR. Figures 8 and 9 shows expanded regions of the experimental and calculated splitting
patterns for each proton resonances in 2c. The experimental and calculated spectra showed
excellent matching of intensity and frequency of the peaks. The magnitude of (4JHH) coupling
5
,
1
constants (commonly referred to as “W” coupling), derived from the selective decoupled H
NMR spectra and calculated splitting patterns, revealed a stereochemical dependence of 4JHH
values between methylene protons of the 6/12-CH groups and bridgehead methylene protons
2
(
13-CH
2
). The values of coupling constants are as follows: 4JH6endo, H13a = 0.65 Hz, 4JH6endo, H13b
1.75 Hz, 4JH6exo, H13a = = < 0.3 Hz Hz, 4JH6exo, H13b = < 0.3 Hz, 4JH12endo, H13a = 1.81 Hz, 4JH12endo,
=
H13b = 0.74 Hz, 4JH12exo, H13a = < 0.3 Hz, 4JH12exo-H13b = 0.3 Hz. A stereochemical dependence of
the long-range proton-proton coupling constants were found between protons of the aromatic
rings and H6endo/H12endo and H6 /H1
exo
2exo
protons (see Table 9), which is consistent with the
predicted values by DFT/GIAO calculations.
2
.6.gHSQCAD-TOCSY spectrum of 2c in acetone-d
6
The Figure 10 shows an expanded region of the gHSQCAD-TOCSY spectrum of 2c.
1
3
Instead of traces on the F1 (carbon) and F2 (proton) dimensions, the high-resolution C and
1H NMR spectra are presented herein. The proton-bearing carbon on the F1 dimension reveals
one-bond correlation peaks (1JHC) and an important correlation to other protons that are coupled
with its proton. Thus, proton-proton and carbon-carbon connectivity can be effectively
established within a fragment of molecule. For example, the CH carbon at 17.02 ppm shows
3
correlation to the protons H7, H9, H6endo, and H6exo at 6.95 ppm, 7.18 ppm, 4.09 ppm, and 4.58
ppm, respectively. These protons are in the same spin-system via couplings and belong to the
N-5-C6-C6a-C7-C8-C9-C10(10-CH
)-C10a structural fragment. The 13C chemical shift
3
assignment of quaternary carbons C10, C8, C6a, and C10a was derived from the gHMBCAD
This article is protected by copyright. All rights reserved.

spectrum. Similarly, in the F1 dimension, all other proton-bearing carbons such as C12, C6,
C13, C1, C3, C4, C7, and C8 reveal a correlation with the protons that are coupled with its
respective attached proton. The observed HSQC-TOCSY, in addition to the long-range HMBC
correlations, confirms both proton-proton and carbon-carbon connectivities for different
segments of the molecule. It can also exclusively map carbon-carbon skeletal connectivities
within the entire molecular framework of 2c.
2
.7.gHMBCAD spectrum of 2c in acetone-d
6
Figure 11 shows the selected expansions of the gHMBCAD spectrum of 2c. In Supplementary
Table 1 summarizes all observed long-range HMBC along with one-bond HSQC correlations.
The explanation of how the four cyclic units in 2c are connected through long-range
correlations (nJHC, n = 2, 3, 4, and 5) is described below.
Hypothetically, the tetracyclic structure of 2c (Scheme 3) can be divided into three
different segments: two fused benzene rings and a 1,5-diazabicyclo[3.3.1] nonane central unit,
which share the same C6a-C10a and C4a-C12a bond connections.
The 10-CH
the structural fragment CH
between the 10-CH proton and the inter-ring carbons C6 and C12 at 59.07 and 55.83 ppm,
respectively. Similarly, the carbon- carbon connectivities within the structural fragment C1-C2
OCH )-C3-C4-C4a-C12a-C12 is established by the long-range correlations observed between
H1/or H4 and those carbons. An inter-ring correlation is also observed between H4 and C6 at
3
protons at 2.37 ppm shows long-range correlations to all 7 carbons within
3
-C10-C9-C8-C7-C6a-C10a. There are also long-range corrections
3
(
3
5
9.07 ppm.
Thus, the two segments of the compound [CH -C10-C9-C8-C7-C6a(C6)-C10a and C1-C2
3
(
OCH )-C3-C4-C4a-C12a-C12] are connected via the N-11 and N-5 atoms of the central unit.
3
a
b
The bridgehead protons (H13 /H13 ) reveal long-range correlations to the C6, C12, C4a, and
C10a at 59.07, 55.83, 141.99, and 146.58 ppm, respectively. This correlation confirms carbon-
This article is protected by copyright. All rights reserved.

carbon connectivities within this subunit. It is interesting to note that methylene protons of the
group reveals a long-range, five bond (5JHC) correlation to the carbon of the 12-CH
6
-CH
2
2
group (Fig. 12). Similarly, the methylene protons of the 12-CH
2
group reveals the same long-
group. To conclude, all the
range, five bond (5JHC) correlation to the carbon of the 6-CH
2
observed long-range HMBC (nJHC, n = 2, 3, 4, and 5) and one-bond (1JHC) HSQC correlations
confirmed the carbon-carbon connectivities in 2c.
2
.8.Gradient-selected gHSQCAD-NOESY spectrum of 2-bromo-8-methoxy-4-methyl-6,12-
dihydro-5,11-methanodibenzo [b,f][1,5]diazocine 2c in (CD CO
)
3 2
The gradient-selected gHSQCAD-NOESY with an adiabatic pulse is a hybrid experiment that
can be also useful for mapping out through-space nOe connectivity between protons of
different segments of a given molecule. Figure 13 shows expanded portions (a-b) of the
gHSQCAD-NOESY spectrum of 2c in acetone-d
6
acquired on a 600 MHz NMR instrument
(
INOVAUnity) using an inverse multinuclear z-gradient probe-head. In the contour plot of the
gHSQCAD-NOESY spectrum two types of correlation peaks appear: first, the cross peak
between carbons and protons directly attached (1JHC); the 2 type of correlation peaks results
from the NOESY part of the gHSQCAD-NOESY experiment. All proton-bearing carbons on
the F1 dimension show NOESY-type cross peaks appearing at the chemical shifts of the
directly bonded protons and of other protons to which it displays nOe’s.
nd
For example, the carbon signal of the MeO group at 55.4 ppm shows a correlation to the
H1 and H3, since protons of the MeO group have nOes to H1 and H4 at 6.51 ppm and 7.63
ppm, respectively. The C6 at 59.1 ppm shows a correlation to H4 at 7.04 ppm and H7 at 6.95
ppm, and also H13 /H13 at 4.21/4.26 ppm due to observed nOe’s between H6endo/H6exo and
a
b
a
exo
exo
H4/H7 and H13 . As a result of the observed stronger nOe’s between H6 /H12 and
a
b
bridgehead methylene protons (H13 /H13 ), the C13 reveals a correlation to these exo protons.
The C1 at 111.1 ppm shows a cross peak to the peak at 3.98 ppm (H12endo) because it has an
nOe to H1 at 6.51 ppm. Similarly, both carbons C4 and C7 at 127.9 and 128.0 ppm, respectively
This article is protected by copyright. All rights reserved.

reveal correlations to the H6endo at 4.09 ppm due to observed nOe’s between H6endo and H4 at
.04 ppm and between H6endo and H7 at 6.95 ppm.
7
2
.9. Similar geometric characteristics of Tröger’s base [2,8-dimethyl-6H,12H-5,11-
methanodibenzo[b,f][1,5]diazocine] and its analogue 2c based on DFT / B3LYP/6-
3
1G(d,p) optimization
The methanodibenzo[b,f][1,5]diazocine framework of Tröger’s base contains only two
identical methyl groups at C2 and C8, whereas the methanodibenzo[b,f][1,5]diazocine unit of
2
c bears three substituents: 2-OMe, 8-Br, and 10-CH .
3
The geometry optimization was performed at the B3LYP/6-31G(d,p) level of theory for 2c and
Tröger’s base in order to compare geometric parameters such as bond angles and lengths
obtained from the X-ray structure.[37] It is important to note that optimized structures of
Tröger’s base and 2c exhibit a non-planar molecular framework with a concave V-shape (Fig.
1
4, 2c – A, B are different representations of the optimized geometry), which is consistent
with the X-Ray structure of Tröger’s base reported by Wilcox in 1986.[37] The X-ray structure
o
of Tröger’s base revealed a dihedral angle of 92.85 between the planes of the two aromatic
rings. The DFT/B3LYP optimized structure (2c - B) shows that the 1,5-diazocine binds the two
fused aromatic rings, which appear to be nearly perpendicular to each other. The calculated
inter-proton distance between H3 and H9 is about 9.05 Å (~ 1nm), which is comparable to the
inter-methyl distance (8.75 Å) reported for Tröger’s base.
The selected bond lengths and angles of Tröger’s base and 2c are listed in Table 6. After
examination of the data it is clearly observed that there is good agreement in bond lengths and
angles for Tröger’s base and the unsymmetrical analogous of Tröger’s base 2c. The difference
between experimental (X-ray) and calculated bond lengths for Tröger’s base are in the range
of 0.0012 - 0.0276 Å, whereas the difference between experimental (X-ray) and calculated
This article is protected by copyright. All rights reserved.

bond lengths of 2c are 0.0010 - 0.0250 Å. This is a bit larger than the range 0.0002 - 0.0134 Å
which is obtained between calculated bond lengths of 2c and Tröger’s base.
The calculated values of bond angles for 2c and Tröger’s base are also in good agreement
with values obtained from the X-ray structure of Tröger’s base. The difference between
experimental and calculated bond angles for Tröger’s base are in the range of 0.00-0.03
degrees, which is smaller than the range of 0.0-1.84 degrees, obtained between experimental
(X-ray) bond angles of Tröger’s base and 2c. The calculated bond angles 117.8 and 122.2
degrees between C7-C8-C9 and C6a-C7-C8, respectively, is very close to values obtained from
the X-ray structure of Tröger’s base (see Table 6).
However, the difference between calculated values of bond angles for the same atoms of
2
c and Tröger’s base (X-ray) is larger by 4 and 3.5 degrees, respectively. This significant
change in bond angles can be explained by the nature of the substituents of 2c.
Comparison of the experimental (X-ray) and calculated results indicates that the DFT/B3LYP
method with the 6-31G(d,p) basis set is in good agreement with the experimental data for
predicting geometric properties.
2
.10. Selected proton-proton distances based on DFT/B3LYP optimized structure of 2c.
A series of DPFGSE NOE (Double Pulsed Field Gradient Spin Echo Nuclear Overhauser
Enhancement) spectra
Selected proton-proton distances (Figure 15) through space are given on the geometry
optimized structure of 2c at the B3LYP/6-31G(d,p) level of theory. Since the nOe build-up rate
–
6
depends on the interproton distance with r dependence, the selected calculated distances
support consistency of the observed nOe enhancements. Optimization revealed that the
geometry of the molecular framework of 2c is a non-coplanar concave-V-shape, which is
consistent with the observed strong nOe’s between H4 and H6endo and between 10-CH
H12endo. The stereochemical differentiation of the methylene protons of the 6-CH
and
3
2
, 12-CH ,
2
and 13-CH groups are established on a series of DPFGSENOE spectra, which are given below.
2
This article is protected by copyright. All rights reserved.

Figure 16 displays a series of DPFGSENOE experimental subspectra (b-i) and the
1
control H NMR spectrum (a) of 2c in (CD
3
2
) CO with a concentration of 10mg/0.7mL using a
5
00 ms mixing time. Selectively excited peaks are shown as inverted. The DPGSENOE
subspectrum (Fig.16d) with selective excitation of H6endo at 4.09 ppm convincingly shows
direct positive transannular nOe enhancements between H6endo and H4 at 7.04 ppm and
between H6endo and H7 at 6.95 ppm. This data confirms that the molecule of 2c exhibits a V-
type shape molecular framework, yielding close-space proximity between these protons. The
calculated distances are 2.63 Å (H6endo - H4) and 2.61 Å (H6endo - H7). DPFGSENOE
subspectra (Figs. 16b-c) show a transannular and mutual nOe between H12endo and 10-CH
where the calculated distance is 2.98 Å. Moreover, the lack of nOe’s between peripheral
protons (10-CH and H1, H4 and H7) of the two different segments of 2c are consistent with
the calculated distances between them (10-CH --H1 = 5.45 Å, H4--H7 = 5.19 Å). It should be
mentioned that selective excitation of 10-CH at 2.37 ppm with a mixing time of 0.3s exhibits
a very weak nOe to the H1 proton at 6.51ppm (see Supplementary Fig. 3). The average distance
between 10-CH and H1 is 5.45 Å, which is out of limit (the inter-proton distance for nOe
,
3
3
3
3
3
observation should be less than 5 Å). Thus, the observed nOe cannot be explained by through-
space interaction between them. One possible explanation could be due to the spin diffusion
(
nOe transfer pathway from 10-CH
3
to H12endo and from H12endo to H1), even though the
DPFGSENOE experiment was run with a small mixing time to avoid occurrence of it. The
exo
exo
optimized structure of 2c effectively illustrates the syn relationships between the H6 /H12
a
b
and H13 /H13 , which is confirmed by observed nOe’s between them (Fig. 16e and Fig. 16g).
For the calculated distances, see Figure 15. The calculated distance between H6endo and H13a,
and between H12endo and H13 are equal (3.58 Å), which is less than the calculated distances
b
between H6endo and H13 and between H12
b
endo
and H13a, which is 3.58 Å. Surprisingly, the
This article is protected by copyright. All rights reserved.

DPFGSE NOE subspectra does not reveal a positive nOe between them while the inter proton
distances is less than 5 Å.
2
.11. The stereochemical differentiation of methylene protons of the 6-CH
2
and 12-CH
2
1
15
groups by the H- N CIGAR-HMBC (constant time inverse-detected gradient accordion
rescaled long-range heteronuclear multiple bond correlation) spectrum at natural
1
5
abundance of N
1
15
The H- N CIGARAD-HMBC spectrum confirms assigned stereospecific methylene proton
1
15
chemical shifts derived from the DPFGSENOE spectra The contour plot of the H- N CIGAR-
HMBC spectrum (Fig. 17) with adiabatic pulses reveals a correlation peaks (2JHN) between
only exo methylene protons and two nitrogen atoms (labeled as N-5 and N-11). In addition, a
correlation peak (3JHN) is observed between H4 and N-5 at -341.6 ppm. The relatively more
upfield nitrogen was assigned to the N-11 at -343.6 ppm. It was found that the magnitude of
2
1
15
J( H- N) coupling constants are dependent on the nitrogen lone pair orientation in
oxaziridines.[38] The cis arrangement between nitrogen lone-pair electrons and the proton in
2
1
oxaziridines was attributed to the large coupling constant in the range 4.8 - 5.3 Hz of J( H-
15N). For trans oxaziridines, the 2JHN values were reported as nearly zero. Based on this data,
in 2c the lone pair electrons on N-5 and N-11 share a cis relationship with H6exo and H12exo vs.
H6endo and H12endo and, consequently, the contour plot of the H - N CIGARAD-HMBC
1
15
exo
exo
spectrum reveals a correlation peak only from H6 /H12 to N5 and N-11, respectively.
1
2
.12. The stereochemical dependence of the magnitude of one-bond ( JCH) and long-range
n
carbon-proton ( JCH, n = 2, 3, 4, 5, and 6) coupling constants in 2c
The one-bond 1JCH coupling constants were extracted from the high-resolution proton-coupled
13C NMR spectrum of 2c in acetone-d
6
. The magnitude of long-range carbon-proton couplings
1
3
were obtained from the simulated proton-coupled C NMR spectrum (Figures 18b-20b). The
multiplicity patterns of proton-bearing carbons were essentially complex first order. The
multiplicity of quaternary carbons (C10, C9, C8, and C7) is complicated due to splitting to the
1
0-CH
3
protons, resulting in a broadening of lines to some extent (Figure 19a). However, the
This article is protected by copyright. All rights reserved.

broadband proton-decoupling during the acquisition time of the 13C NMR spectrum was
applied to simplify multiplicity patterns of those carbons. Thus, application of this old
experiment known as selective heteronuclear decoupling at low power levels (5 or 10 dB) on
CH
3
protons was successfully applied. A selective decoupling removed all long-range
protons and resulted in relatively simplified splitting patterns for the C10,
couplings to CH
3
C10a, C9, C8, C7 and C6a carbons (Figure 20a). In addition, for measurements of long-range
nJCH (n = 2, 3, 4, and 5) coupling constants, the EXSIDE (Excitation-Sculptured Indirect-
Detection Experiment) NMR technique was applied. It has been found that the magnitude of
long-range nJCH constants are not the same between carbons of the two benzene rings and
stereospecific methylene protons of the 6/12-CH
2
and bridgehead 13-CH groups. The
2
magnitude of one-bond couplings 1JC6, H6endo and 1JC6, H6exo, JC12, H12exo and 1JC12, H12endo, 1JC13,
H13a and 1JC13, H13b are somewhat different (Table 10). A stereochemical dependence of the long-
range coupling constants (nJCH) was found and supported by DFT/GIAO calculations.
1
2
.13. Excitation Sculptured Indirect-Detection Experiment (EXSIDE) for measurement of
n
long-range JCH coupling constants in 2c
A series of EXSIDE spectra were acquired with a J-scaling factor of 15. For example, selected
expansions of the EXSIDE spectrum (Fig. 21) of 2c allows for the measurement of the long-
range proton-carbon coupling constants between the endo and exo protons of the 6-CH
2
/ 12-
CH
2
groups and carbons that are two or three bonds away. Extracted values of nJCH on F1
(carbon dimension) are given in Table 10.
It should be noted that a detailed description of the EXSIDE pulse sequence is given by
Krishnamurthy. [39] The inherent limitation of the EXSIDE experiment is that it cannot be run
with all proton resonances at the same time. If two proton frequencies were selected for
1
1
excitation, then there should not be a homonuclear coupling constant ( H- H) between them.
For example, the expansions of the EXSIDE spectrum (Fig. 21) show selected H6endo/H12endo
exo
exo
and H6 /H12 .
This article is protected by copyright. All rights reserved.

1
13
n
2
.14. DFT/GIAO calculated H / C NMR chemical shifts and proton-proton ( JHH, n = 2, 3,
n
4
, 5, and 6) and carbon-proton coupling constants ( JCH, n = 1, 2, 3, 4, and 5) in 2c
For calculation of H and C chemical shifts, JHH (n = 2, 3, 4, 5, and 6), and nJCH (n
1
13
n
=
1, 2, 3, 4, and 5) coupling constants, the GIAO method at the B3LYP/6-31G(d,p),
B3LYP/6-31+G(d,p), B3LYP/6-311+G(d,p), B3LYP/6-311++G(2d,2p), B3LYP/cc-
pVTZ), and B3LYP/aug-cc-pVTZ) levels of theory was employed in order to explore
the effect of geometry on predicted chemical shifts and coupling constants.
The predicted values are listed in Tables 7-10. Examination of these values show that
1
the prediction of H NMR chemicals shifts employing any of these methods is in good
agreement with experimental values. An essential finding is that DFT/GIAO
1
calculation differentiates the H chemical shifts of the stereospecific exo and endo
methylene protons of the 6-CH
2
, 12-CH
2
, and 13-CH groups in the following order:
2
exo
endo
exo
endo
a
b

(H6 ) >  (H6 ),  (H12 ) >  (H12 ),  (H13 ) <  (H13 ) (Table 7). In fact,
1
the assigned H NMR chemical shifts based DFT/GIAO calculation are consistent with
assignment based on the DPFGSENOE spectra.
1
3
Checking of the calculated C NMR chemical shifts of 2c given in Table 8 shows that use of
any of the methods does not offer precise prediction of all carbons. The calculated chemical
shifts of C1 employing any of methods are in excellent agreement with experimental data. A
good match between experimental and calculated values of (C3) was found using the
B3LYP/6-31G(d,p) // B3LYP /6-31G(d,p) (gas and solution phases), and B3LYP/6-
31+G(d,p) // B3LYP/6-31G(d,p) levels of theory. The chemical shift of C2 is fairly
predicted using only the B3LYP/6-31+G(d,p) // B3LYP/6-31G(d,p) method.
Upon examination of the predicted values of JHH and JCH listed in Tables 9 and 10, the use of
the DFT/GIAO method gives a clear indication of which different basis set should be used in
the prediction of certain types of long-range coupling constants. In general, neither of the
This article is protected by copyright. All rights reserved.

applied methods is well reproduced in the experimental values of coupling constants.
Calculations of long-range proton-proton and carbon-proton coupling constants using the
valence-oriented basis sets such as 6-311 + G(d,p), 6-311 ++G(2d,2p), cc-pVTZ, aug-cc-pVTZ
showed reasonable agreement with the experimental values. For example, geminal coupling
constants (2JHH) were predicted well using all applied methods. One-bond carbon-proton
couplings (1JCH) for the benzene rings are reproduced better using aug-cc-pVTZ basis sets,
whereas the experimental values of 1JCH for the aliphatic carbons of the 6, 12, and 13-CH
groups are not well predicted. Only by using both the B3LYP/6-31G(d,p) // B3LYP /6-
2
31G(d,p) (gas and solution phases) and B3LYP/6-31+G(d,p) // B3LYP/6-31G(d,p)
methods are the best agreement between calculated and experimental 1JCH values
achieved.
Supplementary Figures 4-8 show a good linear correlation between theoretical and
experimental NMR parameters (proton and carbon chemical shifts and coupling constants).
1
1
The major result obtained by GIAO calculations is that the magnitude of long-range H- H
coupling constants observed between the benzylic (exo and endo) and aromatic types of protons
are different. The calculations also reveal that the ‘W’ type coupling constants between
methylene protons of the 6-CH
2
/12-CH
2
groups and the bridgehead methylene protons
a
b
(
H13 /H13 ) are distinctive. Similarly, the predicted values of carbon-proton coupling
constants listed in Table 10 confirms a stereochemical dependence of (nJCH). In other words,
the carbons of the benzene ring reveal different magnitude of long-range (nJCH) to the
stereospecific protons of the 6, 12, and 13-CH
2
groups. Similarly, the carbons (C6, C12, and
C13) of these methylene groups showed different magnitude of 1JCH and 3JCH to the
stereospecific methylene protons: 1JC6,H6endo, 1JC6,H6exo
,
3JC6,H13a, 3JC6,H13b, 1JC12,H12endo
,
1JC12,H12exo, 3JC12,H13a, 3JC12,H13b, 1JC13,H13a, 1JC13,H13b, 3JC13,H6endo, 3JC13,H6exo, 3JC13,H12endo
,
3JC13,H12exo (see Table 10).
This article is protected by copyright. All rights reserved.

3
. EXPERIMENTAL
NMR measurements
The NMR spectra were acquired at 25 C on a Varian INOVAUnity 600 MHz spectrometer
equipped with a 5 mm inverse broadband PFG Probe. The operating frequencies at 599.67
MHz and 150.79 MHz are for proton and carbon, respectively. Simultaneous irradiation of
two proton frequencies were performed on a JEOL ECZ 400 MHz spectrometer operating at
o
3
99.78 MHz for proton. Sample concentrations were 5–15 mg/0.7 mL. The FIDs of the one-
and two-dimensional NMR spectra were processed using the commercially available NMR
software package ACD/Spectrus Processor 2017.2 (Advanced Chemistry Development, Inc;
1
http://, File Version S70S41, Build 98721, 19 Dec 2017). H NMR chemical shifts are reported
relative to the internal residual solvent peaks at  7.26, 2.05, 7.16 for CDCl
3
, (CD
relative to the central peak
of the triplet was set to 77 ppm. The central peak of the septet resonance for (CD CO was set
, the C NMR chemical shifts are reported relative to the central peak of
3
) CO, and
2
1
3
C
6
D
6
, respectively. C NMR chemical shifts are reported in CDCl
3
)
3 2
1
3
to 29.9 ppm. In C
the triplet was set to 128 ppm. The N NMR chemical shifts are referenced relative to CH
15N = 0). The typical NMR parameters for the applied 1D and 2D NMR experiments were
6
D
6
15
3
NO
2
(

similar as described in references 40-44.
COMPUTATIONAL PROCEDURES
The geometry optimizations were carried out with GAUSSIAN G09 program. [45] The H and
13C chemical shifts, along with coupling constants (nJHH and nJCH), were calculated by the
DFT/GIAO method. Detailed description of applied basis sets, methods for geometry
optimization, and chemical shifts / coupling constants calculations were similar as described in
previously published papers. [41-43]
1
This article is protected by copyright. All rights reserved.

ACKNOWLEGMENTS
The project was supported by AGENCIA- FONCYT (PICT-2013-1439), SECyT-UNC
(05/C690), CONICET (PIP11220090101030).
CONCLUSION
We have reported a highly efficient microwave assisted-synthesis of dibenzo Tröger’s bases
containing a nitrile function in one of the phenyl rings, which is susceptible for further
modifications extending the chemistry of these compounds. This cyanation protocol is
advantageous, does not need additional catalyst as most reported processes and yields are very
good from bromine precursors.
The DFT/GIAO method was employed at the B3LYP/6-31G(d,p), B3LYP/6-
31+G(d,p), B3LYP/6-311+G(d,p), B3LYP/6-311++G(2d,2p), B3LYP/cc-pVTZ), and
B3LYP/aug-cc-pVTZ) levels of theory for prediction of chemical shifts and coupling
constants. It has been found that the values of nJHH and nJCH coupling constants are
excellent agreement using the more extended basis sets such as 6-311+ G(2d,2p) and
aug-cc-pVTZ.
Authors Contributions
D.D, C. R, A.P, P.L, D. M. V, C. C, and E.L. M co-developed the initial idea of a microwave
synthesis of bromo and cyano derivatives of TBs. Each compound was characterized by HRMS
and melting point determination. The general experimental procedures and synthetic part of
manuscript was written by the corresponding authors, along with editing of the manuscript.
N.A. performed all NMR and computational studies, along with analysis, and described the
data for NMR and computational parts of the manuscript.
This article is protected by copyright. All rights reserved.

REFERENCES
1] J. J. Troger, J. Prakt. Chem. 1887, 36, 225.
[
[
[
[
2] V. Prelog, P. Wieland, Helv. Chim. Acta. 1944, 27, 1127.
3] W. Li, T. Michinobu, Macromol. Chem. Phys. 2016, 217, 863.
4] B. Dolensky, J. Elguero, V. Kral, C. Pardo, M. Valik, Adv. Heterocycl. Chem. 2007, 93,
1
.
[
5] N. Classens, F. Perard, C. Bresson, C. Moucheron, A. K-D. Mesmaeker, J. Inorg.
Biochem. 2007, 101, 987.
6] R. Yuan, M. Li, J. Xu, S. Huang, S. Zhou, P. Zhang, J. Liu, H. Wu, Tetrahedron 2016,
2, 4081.
7] H. Wu, X.-C. Chen, Y. Wan, L. Ye, H. Xin, H. Xu, C. Yue, L. Pang, R. Ma, D. Shi,
Tetrahedron Lett. 2009, 50, 1062.
[
7
[
[
[
[
8] M. S. Sigman, D. R. Jensen, Acc. Chem. Res. 2006, 39, 221.
9] T. H. Webb, C. S. Wilcox, J. Org. Chem. 1990, 55, 363.
10] C. Pardo, E. Sesmilo, E. Gutiérrez-Puebla, A. Monge, J. Elguero, A. Fruchier, J. Org.
Chem. 2001, 66, 1607.
11] F. Hof, D. M. Scofield, W. B. Schweizer, F. Diederich, Angew. Chem. Int. Ed. 2004,
3, 5056.
12] M. D. H. Bhuiyan, A. B. Mahon, J. Jensen, J. K. Clegg, A. C. Try, Eur. J. Org. Chem.
009, 687.
[
4
[
2
[
[
[
[
13] A. P. Hansson, J. Jensen, O. F. Wendt, K. Wärnmark, Eur. J. Org. Chem. 2003, 3179.
14] I. Sucholeiki, V. Lynch, L. Phan, C. S. Wilcox, J. Org. Chem. 1988, 53, 98.
15] M. D. H. Bhuiyan, J. K. Clegg, A. C. Try, Acta Crystallogr. Sect. E 2009, 65, 187.
16] J. Jensen, J. Tejler, K. Wärnmark, J. Org. Chem. 2002, 67, 6008.
This article is protected by copyright. All rights reserved.

[
17] F. Hof, M. Schar, D. M. Scofield, F. Fischer, F. Diederich, S. Sergeyev, Helv. Chim.
Acta 2005, 88, 2333.
[
[
[
[
[
[
[
[
[
18] D. Didier, S. Sergeyev, Eur. J. Org. Chem. 2007, 35, 3905.
19] P. Y. Yeung, C. P. Tsang, F. Y. Kwong, Tetrahedron Lett. 2011, 52, 7038.
20] K. W. Rosemund, E. Stuck, Chem. Ber. 1919, 52, 1749.
21] J. Xin Wu, B. Beck, R. X. Ren, Tetrahedron Lett. 2002, 43, 387.
22] M. Gholinejad, A. Aminianfar, J. Mol. Catal. A-Chem. 2015, 397, 106.
23] Z. Jiang, Q. Huang, S. Chen, L. Long, X. Zhou, Adv. Synth. Catal. 2012, 354, 589.
24] C. De Blase, N. Leadbeater, Tetrahedron 2010, 66, 1098.
25] A. Pawar, S. Chang, Chem. Comm. 2014, 50, 448.
26] D. P. Mingos, in Microwave Assisted Organic Synthesis, J. P. Tierney, P. Lidström,
Eds.; Blackwell Publishing Ltd: Oxford, UK, 2005, 12.
27] C. O. Kappe, D. Dallinger, S. S. Murphree, in Practical Microwave Synthesis for
Organic Chemists, Wiley-VCH: Weinheim, Germany 2009, 11.
[
[
[
28] L. Cai, X. Liu, X. Tao, D. Shen, Synthetic Commun. 2004, 34, 1215.
29] R. K. Arvela, N. E. Leadbeater, H. M. Torenius, H. Tye, Org. Biomol. Chem. 2003, 1,
1
119.
30] J. Cudero, P. Jimenez, C. Marcos, C. Pardo, M. Ramos, J. Elguero, Magn. Reson. Chem.
996, 34, 318.
31] F. Salort, C. Pardo, J. Elguero, Magn. Reson. Chem. 2002, 40, 743.
[
1
[
[
[
[
32] C. Pardo, M. Ramos, A. Fruchier, J. Elguero, Magn. Reson. Chem. 1996, 34, 708.
33] M. Demeunynck, C. Fontaine, J. Lhomme, Magn. Reson. Chem. 1999, 37, 73.
34] I. Alkorta, J. Elguero, Magn. Reson. Chem. 2004, 42, 955.
[
35] C. Pardo, I. Alkorta, J. Elguero, Tetrahedron: Assymetry. 2006, 17, 191.
[
36] M. Kazem-Rostami, N. G. Akhmedov, S. Faramazi S, J. Mol. Struct. 2019, 1178, 538.
This article is protected by copyright. All rights reserved.

[
[
[
37] S. B. Larson, C. S. Wilcox, Acta. Cryst. 1986, C42, 224.
38] D. M. Jerina, D. R. Boyd, L. Paolillo, E.D. Becker, Tetrahedron Lett. 1970, 18, 1483.
39] V.V. Krishnamurthy, J. Magn. Reson. Ser. A 1996, 121, 33.
[
40] A. R. Katritzky, N. G. Akhmedov, Z. Wang, V. A. Roznyatovsky, A. A. Shestopalov,
C. D. Hall, Magn. Reson. Chem. 2003, 41, 908.
[
41] A. R. Katritzky, N. G. Akhmedov, A. Gȕven, J. Doskocz, R. G. Akhmedova, S.
Majumdar, C. D. Hall, J. Mol. Struct. 2006, 787, 131.
[
[
[
42] A. R. Katritzky, N. G. Akhmedov, J. Doskocz, P. P. Mohapatra, C. D. Hall, A. Gȕven,
Magn. Reson. Chem. 2007, 45, 532.
43] N. G. Akhmedov, C. A. Dacko, A. Gȕven, B. C. G. Söderberg, Magn. Reson. Chem.
2
010, 48, 134.
44] N. G. Akhmedov, P. M. Gannett, B. Wu, M. M. Cummings, B. C. Train, Magn. Reson.
Chem. 2013, 51, 156.
[
45] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman,
G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H.
P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T.
Vreven, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers,
K. N. Kudin, V. N. Staroverov, T. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A.
Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J.
E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O.
Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V.
G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, O.
Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian, Inc., Wallingford CT,
2
013, ES64L-G09RevD.01 24-Apr-2013 / 15-Oct-2018.
This article is protected by copyright. All rights reserved.

Figure 1. Expanded downfield region (aromatic) of the experimental (a) and calculated (b)
1
H NMR spectrum of 2a in acetone-d6.
This article is protected by copyright. All rights reserved.

1
Figure 2. Selected regions (aromatic) of the PSYCHE (b) and H NMR spectrum (a) in
acetone-d6.
This article is protected by copyright. All rights reserved.