Magnetic shielding effect of amine and ammonium groups obtained from proton chemical shifts of androstane derivatives

Article abstract of DOI:10.1016/S0040-4039(03)01486-2

4-Aza-5α-androstanone(1α) and 4-aza-5β-androstanone(1β) were synthesized in order to obtain the NMR shielding parameters for the secondary amine group. A combination of the electric field effect and the anisotropy of the magnetic susceptibility of the C-N bond can successfully reproduce the observed SIS values for these androstanes. Drastic chemical shift change of protons near-by nitrogen atom of ammonium salt was observed and shielding parameter for the secondary ammonium group was also obtained.

Full text of DOI:10.1016/S0040-4039(03)01486-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5975–5978
Magnetic shielding effect of amine and ammonium groups
obtained from proton chemical shifts of androstane derivatives
Hajime Iwamoto, Yoshiaki Kondo, Takefumi Kawatani, Takeharu Haino and
Yoshimasa Fukazawa*
Department of Chemistry, Graduate School of Science, Hiroshima University, Higashi-Hiroshima 739-8526, Japan
Received 21 May 2003; revised 9 June 2003; accepted 16 June 2003
Abstract—4-Aza-5a-androstanone(1a) and 4-aza-5b-androstanone(1b) were synthesized in order to obtain the NMR shielding
parameters for the secondary amine group. A combination of the electric field effect and the anisotropy of the magnetic
susceptibility of the CꢀN bond can successfully reproduce the observed SIS values for these androstanes. Drastic chemical shift
change of protons near-by nitrogen atom of ammonium salt was observed and shielding parameter for the secondary ammonium
group was also obtained.
© 2003 Elsevier Ltd. All rights reserved.
Conformational analysis in solution is very important
for understanding physical and chemical properties of
organic compound. While NMR techniques such as
distance-dependent NOE1 and torsion angle-dependent
3JHH coupling constants2 were used extensively, it is not
always satisfactory. Recently we have developed an
efficient method,3 which utilizes the substituent induced
shifts (SIS) of polar functional groups. In the continu-
ous effort to widen its applicability to a variety of
organic compounds we have succeeded to develop the
induced magnetic shielding parameters, for aromatic
ring,4 ether,5 carbonyl,6 lactone,7 and by using them
succeeded in conformational analysis of flexible
molecules.8 In this paper, we report the induced mag-
netic shielding parameters for the secondary amine
group (CꢀNHꢀC) which is ubiquitous in organic
reduction of the ester group with LiAlH4 in THF gave
compounds.
the corresponding primary alcohol. Tosylation of the
primary alcohol, followed by the treatment of NaN3 in
In order to obtain the reliable magnetic shielding
parameters for this group, the steroid skeleton was
chosen because of its rigidity and well defined geome-
DMF and 1 M HCl afforded primary azide 5. Reduc-
tion of 5 using Pd/C in EtOH under hydrogen, followed
by in situ cyclization gave imime 6. Reduction of 6 with
try. Hence, we synthesized 4-aza-5a- (1a) and 4-aza-5b-
LiAlH4 afforded the corresponding amine 7 as a mix-
androstanone (1b), and compared the chemical shifts of
ture of diastereomer of C-5 position. Protection of
the associated protons with those of the corresponding
secondary amino group of 7 with (Boc)2O in CH2Cl2,
reference compounds (2a, 2b).
followed by tetrapropylammonium perruthenate
(TPAP) oxidation10 gave Boc protected amine 8. HPLC
separation of the mixture afforded 8a and 8b in a ratio
of 5:2. The desired amine 1a (4-aza-5a-androstan-17-
one) and 1b (4-aza-5b-androstan-17-one) was obtained
from deprotection of Boc group, respectively. The
structure of 1a and 1b was determined by X-ray crystal-
lographic analysis (Fig. 1).11
The synthesis of compound 1 is shown in Scheme 1.
Protection of carbonyl groups of keto ester 3,9 which
was obtained from 4-androstene-3,17-dion, followed by
* Corresponding author. Tel.: +81-824-24-7427; fax: +81-824-24-0724;
e-mail: fukazawa@sci.hiroshima-u.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01486-2

5976
H. Iwamoto et al. / Tetrahedron Letters 44 (2003) 5975–5978
Scheme 1. Synthesis of 4-aza-5a-androstanone(1a) and 4-aza-5b-androstanone(1b).
Figure 1. X-Ray crystal structure of (a) 1a and (b) 1b.
1
least-squares regression analysis. The correlation coeffi-
Assignments of the H NMR signals for 1a and 1b in
CDCl3 solution were given using a combination of COSY,
NOESY,HMBCandphase-sensitiveDQF-COSYexperi-
ments. The observed SIS, which is defined as the change
in chemical shift of a proton produced by the substituent,
can be obtained by the chemical shift difference between
1 and 2. The observed SIS values can be correctly
reproduced by calculation if the set of correct shielding
parameters and relative geometry of a proton with respect
to the substituent are known. We utilized the X-ray
structures to obtain such geometrical factor of the
protons. As in the case of CꢀOꢀC group,5 the substituent-
induced chemical shift change of CꢀNHꢀC group can be
described by the classical screening mechanisms,12 with
the sum of the electronic contribution parameters (s1 and
s2), and those of the magnetic susceptibility (D1 and D2)
of CꢀN bond. We used the axis system as shown in Figure
2. The origin of the three axes can be moved along the
CꢀN bond to find the best-fit parameters. The reproduc-
tion of the observed SIS values was achieved by a multiple
cient between the observed and calculated SIS values (R2)
is dependent on the distance (r) of the nitrogen atom from
the origin (assumed center of the electric and induced
magnetic dipole) along the CꢀN bond. The values of the
shielding parameters and the correlation coefficient are
also dependent on the structure.
Figure 2. The axes for calculation.

H. Iwamoto et al. / Tetrahedron Letters 44 (2003) 5975–5978
5977
Table 1. 1H NMR chemical shiftsa for compound 1a and 1b together with their observed and calculated SIS values
Observed chemical shifts
Observed SIS
Calculated SIS
Position
1a
1b
2ab
2bb
Dl1a
Dl1b
Dl1ac
Dl1bd
Dl1ae
Dl1be
1a
1b
2a
2b
3a
3b
5
6a
6b
7a
7b
8
1.00
1.73
1.44
1.65
2.62
3.05
2.22
1.44
1.38
1.05
1.79
1.55
0.73
1.65
1.30
1.82
0.99
1.55
1.31
3.10
2.63
2.45
1.41
1.90
1.34
1.51
1.61
1.80
1.56
1.27
0.89
1.67
1.50
1.41
1.22
1.65
1.07
1.25
1.25
0.97
1.78
1.55
0.72
1.67
1.27
1.75
0.91
1.27
1.37
1.72
1.21
1.31
1.27
1.90
1.18
1.52
1.58
1.47
1.55
1.26
0.11
0.06
−0.06
0.24
1.40
1.40
1.15
0.19
0.13
0.08
0.01
0.00
0.01
−0.02
0.03
0.07
0.08
0.28
−0.06
1.38
1.42
1.14
0
0.14
0.16
−0.01
0.03
0.33
0.01
0.01
0.10
0.05
0.02
0.15
1.38
1.38
1.19
0.20
0.21
−0.02
0.03
0.02
−0.02
0.01
0.01
0.09
0.16
0.20
0.02
1.33
1.39
1.22
0.03
0.25
0.11
0.03
0.00
0.14
0.02
0.04
0.16
0.10
0.02
0.20
1.21
1.75
1.25
0.26
0.26
0.01
0.07
0.06
0.01
0.06
0.06
0.11
0.18
0.22
0.04
1.36
1.41
1.25
0.05
0.27
0.13
0.05
0.02
0.16
0.06
0.04
9
11a
11b
a Measured in CDCl3 at 25°C (500 MHz) and in ppm.
b Ref. 4.
c Calculated with parameters for 1a.
d Calculated with parameters for 1b.
e Calculated with parameters for both 1a and 1b.
Table 2. 1H NMR chemical shiftsa for compound 1a and
1a·HCl together with their observed and calculated SIS
valuesb
While the best-fit values13 for 1a gave excellent correla-
tion (R2=0.991), those for 1b value gave a lesser (R2=
0.978) value. The parameters for the two structures (1a
and 1b) gave a little bit smaller correlation coefficient
[30 data set (range of the observed SIS values −0.06–
1.42 ppm) Dlobs=a·Dlcalcd+b; a=1.003, b=0.036, R2=
0.966].14 In Table 1, are listed the observed and
calculated induced shift for the protons of the aza-
steroids.
Observed
Dl1ab
Calculated SIS
Position
1a
Dl1a
1a
1b
2a
2b
3a
3b
5
6a
6b
7a
7b
8
1.12
1.99
1.73
2.04
3.46
2.82
2.75
2.21
1.76
1.09
1.92
1.62
0.83
1.67
1.36
1.26
1.86
0.23
0.32
0.23
0.63
2.24
1.17
1.68
0.96
0.51
0.12
0.14
0.07
0.11
0.00
0.09
0.03
0.07
0.21
0.33
0.18
0.65
It is known that the induced magnetic shifts for an
ammonium group are larger than those of the corre-
sponding amine.15 The values of the SIS of the sec-
ondary ammonium group can be obtained from the
chemical shift differences of HCl salt of 1a (1a·HCl)
and 2a (Table 2). They are very large when compared
to those of the secondary amines. The values of the
shielding parameters for the secondary ammonium
group were also obtained from 1a·HCl, the structure of
which can be obtained from X-ray crystallographic
analysis (Fig. 3).16 In Table 2, the observed and calcu-
lated induced shift for the protons of 1a·HCl are listed.
Since the protons onto the carbon adjacent to the
ammonium nitrogen suffer severe inductive influence
from the positive charge of the adjacent ammonium
group,15 they are omitted from the shielding parameter
calculation. A good correlation of these data is
obtained in a linear regression analysis: [for 4-aza-5a-
androstan-17-one hydrochloride, 14 data set (range of
c
c
c
0.86
0.68
0.08
0.18
0.13
0.06
0.06
0.11
0.01
0.06
9
11a
11b
12a
12b
a Measured in CDCl3 at 25°C (500 MHz) and in ppm.
b Ref. 4.
c These protons are omitted because of the close proximity to the
substituents.
ing effect for both the secondary amine and ammonium
groups, respectively. Furthermore, it is now clear that
the contribution for the lone pair electrons of the
nitrogen and NꢀH bond(s) is included in these shielding
parameters and no need to add them explicitly.
the observed SIS values 0–0.96 ppm) Dlobs=a·Dlcalcd
+
b; a=0.967, b=0.015, R2=0.943].17
In conclusion, we have succeeded in obtaining new sets
of parameters to estimate the induced magnetic shield-

5978
H. Iwamoto et al. / Tetrahedron Letters 44 (2003) 5975–5978
7. Fukazawa, Y.; Haino, T.; Kondoh, Y. Tetrahedron Lett.
1999, 40, 3591–3594.
8. (a) Okajima, T.; Wang, Z.-H.; Fukazawa, Y. Tetrahedron
Lett. 1989, 30, 1551–1554; (b) Okajima, T.; Wang, Z.-H.;
Fukazawa, Y. Chem. Lett. 1991, 37–40; (c) Wang, Z.-H.;
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11. The crystal data for 1a and 1b are as follows: 1a: C18H29NO,
FW=275.43, orthorhombic, space group P212121 a=
Figure 3. X-Ray crystal structure of 1a·HCl·H2O.
Acknowledgements
This work was supported by Grant-in Aid for Scientific
Research (Nos. 10304053 and 12045248) from the Min-
istry of Education, Science, sports, and culture, Japan,
which is gratefully acknowledged.
,
6.0500(1), b=11.3920(3), c=23.1830(8) A, V=1597.81(7)
3
,
A , and Z=4; of 1818 total unique reflections, 1665 were
considered observed at the level of ꢀFoꢀ>3.0|ꢀFoꢀ. The
structures were solved by the direct method (Sir 92).
Full-matrix least squares refinements converged to a con-
ventional R factor of 0.095, wR=0.101. 1b: C18H29NO,
FW=275.43, orthorhombic; space group P212121 with
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,
a=6.5340(2), b=12.4320(1), c=19.5590(7) A, V=
3
,
1588.79(10) A , and Z=4; of 1895 total unique reflections,
1826 were considered observed at the level of ꢀFoꢀ>3.0|ꢀFoꢀ.
R=0.1235, wR2=0.1176. Supplementary crystallographic
data have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication No.
CCDC 210952 for 1a and No. CCDC 210971 for 1b. Copies
of the data can be obtained, free of charge, on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
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−12
,
13. The values for 1a are: r=1.35 A, s1=–1.80×10
esu,
s2=−0.19×10−12 esu, D1=−3.07×10−30 cm3/molecule,
D2=0.82×10−30 cm3/molecule, Dlothes=2.01×10−8. Those
for 1b are: r=1.30 A, s1=–1.73×10−12 esu, s2=0.18×10−12
,
esu, D1=−3.92×10−30 cm3/molecule, D2=0.70×10−30
cm3/molecule, Dlothes=−0.70×10−8
.
14. The values of amine group for the best fit set are: r=1.30
A, s1=−1.77×10−12 esu, s2=−0.20×10−14 esu, D1=−3.49×
,
10−30 cm3/molecule, D2=−0.76×10−30 cm3/molecule,
Dlothes=0.66×10−8
.
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1698–1706; (b) Sudmeier, J. L.; Reilley, C. N. Anal. Chem.
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16. The crystal data for 1a·HCl·H2O are as follows;
1a·HCl·H2O; C18H32ClNO2, FW=329.91, orthorhombic,
space group P212121 with a=6.7460(2), b=8.7340(2),
3
,
,
c=30.376(1) A, V=1789.74(9) A , and Z=4; of 1953 total
unique reflections, 1894 were considered observed at the
level of ꢀFoꢀ>3.0|ꢀFoꢀ. The structures were solved by the
direct method (Sir 92). Full-matrix least squares refinements
converged to a conventional R factor of 0.047, wR=0.058.
Crystallographic results have been deposited with the
Cambridge Crystallographic Data Centre, UK as supple-
mentary publication number CCDC No. 210972.
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17. The values of ammonium group for the best fit set are:
−12
r=0.40 A, s1=−8.94×10
esu, s2=−6.25×10−12 esu,
,
D1=−8.47×10−30 cm3/molecule, D2=−2.78×10−30 cm3/
molecule, Dlothes=0.92×10−8
.