New hydrogenated and didehydrogenated 1,2-diamines of quincorine and quincoridine

Article abstract of DOI:10.1016/S0957-4166(02)00320-8

Four new members of the family of 1,2-diamines of quincorine and quincoridine have been synthesized, being hydrogenated and didehydrogenated at the C10-C11 fragment. The alkynes, containing an additional amino group at C9, are potentially useful building blocks for cross-coupling reactions. Additional investigations concerning the chemical properties of the molecules point to a significant impact of the remote C5 substituent on the basicity of the bridgehead nitrogen.

Full text of DOI:10.1016/S0957-4166(02)00320-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1327–1330
New hydrogenated and didehydrogenated 1,2-diamines of
quincorine and quincoridine
a,
a
b
Ion Neda, * Thomas Kaukorat and Christian-George Hrib
a
InnoChemTech GmbH, Leonhardstraße 27, D-38102 Braunschweig, Germany
b
Institut f u¨ r Anorganische und Analytische Chemie der Technischen Universit a¨ t, Postfach 3329, D-38023 Braunschweig, Germany
Received 31 May 2002; accepted 14 June 2002
Abstract—Four new members of the family of 1,2-diamines of quincorine and quincoridine have been synthesized, being
hydrogenated and didehydrogenated at the C10–C11 fragment. The alkynes, containing an additional amino group at C9, are
potentially useful building blocks for cross-coupling reactions. Additional investigations concerning the chemical properties of the
molecules point to a significant impact of the remote C5 substituent on the basicity of the bridgehead nitrogen. © 2002 Elsevier
Science Ltd. All rights reserved.
1
. Introduction
bearing several reactive centers, which can be utilized
for the synthesis of a multitude of new compounds. The
1,2-diamines (1S,2S,4S,5R)-2-(aminomethyl)-5-vinyl-1-
azabicyclo[2.2.2]octane, 2a and (1S,2R,4S,5R)-2-
1
A number of reports have appeared in recent years
about the chemistry of quincorine (QCI) and quin-
coridine (QCD), two pseudo-enantiomeric 1,2-amino
alcohols with four stereogenic centers each, including
the (1S)-configured bridgehead nitrogen. QCI and
QCD represent chemically interesting building blocks,
(
aminomethyl)-5-vinyl-1-azabicyclo[2.2.2]octane,
2b
(
Schemes 1 and 2), derived from QCI and, respectively,
2
QCD, are of special interest, because they seem to be
promising building blocks as vicinal diamines in medic-
3
inal chemistry.
Scheme 1. Reagents and conditions: (i) PPh , DEAD, HN ,
3
3
0
°C“reflux, 2.5 h; (ii) H , Pd/C 10%, THF, rt.
2
Scheme 2. Reagents and conditions: (i) PPh , DEAD, HN ,
THF, 0°C“reflux, 2.5 h.
*
Corresponding author. Tel.: +49(0)531 270 3600; fax: +49(0)531 270
601; e-mail: neda@innochemtech.de
3
3
3
0
957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00320-8

1
328
I. Neda et al. / Tetrahedron: Asymmetry 13 (2002) 1327–1330
Although, research concerning the 1,2-diamines, 2a and
b (Scheme 1) has been very active during the past
couple of years, the existence and chemistry of satu-
rated 5-alkyl- or unsaturated 5-alkynyl-1,2-diamines,
azabicyclic cage affects the basicity of the bridgehead
nitrogen. By X-ray crystal structure determination it
was proved that this distortion in 4a and 4b is less than
2
7
that seen for dihydroquinine and dihydroquinidine.
3
a/b and 5a/b (Schemes 1 and 2) has not yet been
described in the literature.
3
. Conclusions
We herein present the synthesis of two new 1,2-
diamines, derived from QCI and QCD, in two pseudo-
enantiomeric forms that differ in the nature of the
C10–C11 functionality, being one of the reactive centers
in the molecules.
We have described four new members of the family of
quincorine- and quincoridine-1,2-diamines 3a, 3b, 5a
and 5b. The saturated 1,2-diamines, 3a and 3b, could be
synthesized either by reacting the hydrogenated alco-
hols, 1a and 1b with ammonia, or by hydrogenating the
unsaturated 1,2-diamines, 2a and 2b, with H /Pd/C.
2
2
. Results and discussion
The synthesis of the didehydrogenated 1,2-diamines, 5a
and 5b led to two new compounds with two reactive
centers each, useful for either cross-coupling reactions
at C11 or for derivatization at the primary nitrogen
atom. These compounds have huge potential as build-
ing blocks in the development of new and effective
medicinal compounds.
2
.1. Hydrogenated 1,2-diamines of quincorine and
quincoridine
Starting from the known compounds 2a and 2b, we
synthesized the QCI- and QCD-derivatives, 3a and 3b,
according to the usual method (hydrogenation in the
presence of Pd/C) in quantitative yield.
Investigations concerning the basicity of the bridgehead
nitrogen of 5a and 5b suggest that the remote C5
substituent has a significant impact on the chemical
properties of these derivatives.
The same products were obtained, when the saturated
4
derivatives 1a and 1b were reacted with ammonia
1
according to the method of Hoffmann. Compounds 3a
and 3b represent new derivatives of cinchona alkaloids
with a saturated C10–C11 grouping. Our intention for
the preparation of these derivatives was to obtain 1,2-
diamines of QCI and QCD without the vinyl function-
ality, in order to avoid possible side reactions during
the functionalization of the primary amino group.
Compared to 1a/b, the presence of a primary amino
group instead of an alcohol function is advantageous,
because these amines should allow facile syntheses of
new compounds bearing the QCI or QCD moiety.
4
. Experimental
4
.1. General
Experimental conditions and instruments used for the
NMR spectroscopic and mass spectrometric investiga-
tions were identical to those mentioned in Ref. 1.
Starting compounds 1a/b, 2a/b and 4a/b were synthe-
sized according to methods described in the literature.
H and C NMR resonances of compounds 3a/b and
a/b were assigned using the following numbering
1
,4
1
13
2.2. Didehydrogenated 1,2-diamines of quincorine and
5
quincoridine
scheme (Fig. 1):
1
0,11-Didehydro-derivatives of quincorine and quin-
coridine are important precursors for the synthesis of
the corresponding arylalkynes and conjugated enynes
that are formed, e.g. via Pd-catalyzed cross-coupling of
terminal alkynes with aryl or alkenyl halides (known as
the Sonogashira Reaction). They also represent impor-
tant building blocks in medicinal chemistry. Starting
5
6
4
from saturated dihydro-derivatives we have completed
the series of 1,2-diamines of quincorine and quin-
coridine from the fully saturated analogs via the vinylic
1
dehydro-derivatives to alkynic didehydro-derivatives.
Reaction of 4a and 4b with ammonia according to the
4
usual method provided the corresponding acetylenes
5
Figure 1. Numbering scheme for the assignment of the NMR
resonances.
a and 5b in moderate yields (Scheme 2).
The new alkynes 5a/b proved to be more polar and
more basic than the corresponding saturated and
vinylic 1,2-diamines 2a/b and 3a/b (R values from
4.2. Synthesis of diamines 3a,b and 5a,b
f
TLC). Thus, the remote C5-substituent obviously has a
significant impact on chemical properties, i.e. polarity
and basicity. It is assumed that the distortion of the
The diamines 3a,b and 5a,b were prepared according to
two general methods:

I. Neda et al. / Tetrahedron: Asymmetry 13 (2002) 1327–1330
1329
1
4
4
.3. A: General procedure of Hoffmann:
H-9 ), 2.66 (dd, 1H, J=13.0 Hz, J=10.3 Hz, H-9 ),
a b
2
.78–2.88 (m, 3H, H-2, H-6 , H-7 ), 3.22 (dd, 1H,
a b
13
.3.1. (1S,2S,4S,5R)-2-(Aminomethyl)-5-ethyl-1-azabi-
J=13.0 Hz, J=10.0 Hz, H-6b);
C NMR (100
cyclo[2.2.2]octane, 3a. QCI (3.0g, 18 mmol) was
MHz): l 88.16 (CH, C-11), 68.34 (C, C-11), 58.45
allowed to react according to the reported general
(CH, C-2), 57.17 (CH , C-6), 45.17 (CH , C-9), 39.89
2
2
1
procedure to afford the corresponding azide (4.38 g,
(CH , C-7), 27.76 (CH, C-5), 26.93 (CH , C-8), 26.87
2
2
7
6%) as a yellowish solid. A portion of the product
(CH, C-4), 26.49 (CH , C-3); EI-MS: m/z (%): 164
2
(
3.0 g, 15.6 mmol) was, allowed to react according to
(20), 148 (10), 134 (100), 106 (30), 95 (25), 82 (17), 77
(20); C H N (164.25) Calcd.: C 73.13, H 9.82, N
the general procedure to afford the diamine, 3a as a
colourless oil (1.34 g, 52%); [h] −28.1 (c=1, EtOH);
10
16
2
2
0
17.06%; found: C 72.27, H 9.80, N 16.71%.
D
1
H NMR (400 MHz): l 0.75–0.85 (m, 1H, H-10a),
0
.88 (t, 3H, J=7.2 Hz, H-11), 1.29 (s, br, 2H, NH2),
.32–1.51 (m, 5H, H-3, H-8, H-5), 1.53–1.70 (m, 1H,
4.3.4. (1S,2R,4S,5R)-2-(Aminomethyl)-5-ethynyl-1-aza-
bicyclo[2.2.2]octane, 5b. QCD (5.0g, 30 mmol) was
allowed to react according to the general procedure
to afford the corresponding azide (4.49g, 77%) as a
yellowish solid. From this product, 4.0g (20.8 mmol)
was allowed to react according to the general proce-
dure to afford the diamine, 6b as a colourless oil
(2.03g, 59%); [h]D +168.7 (c=1, EtOH); H NMR
(400 MHz): l 1.45–1.70 (m, 4H, H-3, H-8), 1.89 (dq,
1H, J=2.1 Hz, J=1.8 Hz, H-4), 2.09 (d, 1H, J=2.4
Hz, H-11), 2.43–2.48 (m, 1H, H-5), 2.61 (dd, 1H,
1
H-4), 1.75–1.85 (m, 1H, H-10 ), 2.36–2.42 (m, 1H,
b
H-6 ), 2.51–2.64 (m, 2H, H-7 , H-9 ), 2.67–2.76 (m,
a
a
a
2
H, H-2, H-9 ), 2.81–2.94 (m, 1H, H-7 ), 3.17 (dd,
b b
13
1H, J=13.4 Hz, J=9.3 Hz, H-6b); C NMR (100
MHz): l 58.75 (CH, C-2), 57.66 (CH , C-6), 45.60
2
20
1
(
CH , C-9), 40.50 (CH , C-7), 37.59 (CH, C-5), 28.75
2
2
(CH , C-8), 27.51 (CH , C-3), 26.58 (CH , C-10),
2 2 2
2
1
5.30 (CH, C-4), 12.09 (CH , C-11); EI–MS: m/z (%):
3
68 (60), 152 (20), 138 (90), 110 (100), 96 (35), 82
(
60), 70 (25), 55 (50), 42 (40); C H N (168.28)
J=12.8 Hz, J=4.9 Hz, H-7 ), 2.68-2.77 (m, 1H, H-2),
10
20
2
a
Calcd.: C 71.37, H 11.98, N 16.65%; found: C 71.18,
H 11.92, N 16.68%.
2.83–2.94 (m, 4H, H-6, H-7 , H-9 ), 3.00 (dd, 1H,
b
a
13
J=13.6 Hz, J=10.6 Hz, H-9b);
C NMR (100
MHz): l 87.51 (CH, C-11), 68.78 (C, C-10), 58.49
4
.3.2. (1S,2R,4S,5R)-2-(Aminomethyl)-5-ethyl-1-azabi-
(CH, C-2), 48.72 (CH , C-6), 48.02 (CH , C-9), 44.31
2
2
cyclo[2.2.2]octane, 3b. QCD (4.5g, 27 mmol) was
allowed to react according to the general procedure
to afford the corresponding azide (3.93g, 75%) as a
yellowish solid. A portion of this product (2.5 g, 13.0
mmol) was allowed to react according to the general
procedure to afford the diamine, 3b as a colourless
(CH , C-7), 28.28 (CH, C-5), 27.50 (CH, C-4), 26.22
2
(CH , C-8), 25.60 (CH , C-3); EI-MS: m/z (%): 164
2
2
(50), 148 (10), 134 (100), 125 (30), 106 (60), 94 (30),
82 (40), 77 (35), 42 (40); C H N (164.25) Calcd.: C
10
16
2
73.13, H 9.82, N 17.06%; found: C 72.33, H 9.83, N
16.96%.
20
1
oil (1.16g, 54%); [h] +143.3 (c=1, EtOH); H NMR
D
(
(
400 MHz): l 0.86 (t, 3H, J=7.3 Hz, H-11), 1.13
ddt, 1H, J=2.1 Hz, J=8.1 Hz, J=7.6 Hz, H-8a),
4.4. B: Reduction of the vinylic function of 2a and 2b
1
1
.32 (m, 2H, H-10), 1.35–1.40 (m, 1H, H-5), 1.45–
.52 (m, 2H, H-3 , H-8 ), 1.58–1.65 (m, 2H, H-3 ,
A suspension of 2a (and 2b) (3g, 18 mmol) and Pd/C
10% in THF (100 ml) at room temperature was main-
a
b
b
H-4), 2.39 (dd, 1H, J=13.8 Hz, J=7.3 Hz, H-9a),
.53 (dd, 1H, J=12.5 Hz, J=4.7 Hz, H-7 ), 2.62–2.69
tained under H (1 bar) for a period of 8 h. Subse-
2
2
quently, the suspension was filtered through Celite
and the filtrate was evaporated i.v. to give pure 3a
and 3b in 98% yield (for characterization see method
A.).
a
(
3
m, 1H, H-2), 2.72–2.75 (m, 1H, H-7 ), 2.74–2.89 (m,
H, H-6, H-9b); C NMR (100 MHz): l 58.84 (CH,
b
13
C-2), 49.35 (CH , C-6), 48.57 (CH , C-9), 44.55 (CH ,
2
2
2
C-7), 37.75 (CH, C-5), 27.87 (CH , C-3), 25.94 (CH,
2
C-4), 25.86 (CH , C-8), 25.57 (CH , C-10), 11.95
2
2
(
CH , C-11); EI-MS: m/z (%): 168 (70), 152 (20), 138
100), 110 (95), 96 (30), 82 (70), 70 (25), 55 (50), 42
45); C H N (168.28) Calcd.: C 71.37, H 11.98, N
Acknowledgements
3
(
(
1
0
20
2
1
6.65%; found: C 71.25, H 11.87, N 16.66%.
We are grateful to Buchler GmbH for intensive col-
laboration in the field of quincorine and quincoridine
chemistry.
4.3.3. (1S,2S,4S,5R)-2-(Aminomethyl)-5-ethynyl-1-aza-
bicyclo[2.2.2]octane, 5a. QCI (3.0g, 18 mmol) was
allowed to react according to the general procedure
to afford the corresponding azide (4.36g, 75%) as a
yellowish solid. A portion of this product (3.9 g, 20.3
mmol) was allowed to react according to the general
procedure to afford the diamine, 6a as a colourless
References
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20
1
oil (1.91g, 57%); [h] +14.3 (c=1, EtOH); H NMR
D
(
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a
2
3
2
1
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2
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b
H, J=13.1 Hz, J=5.1 Hz, H-7 ), 2.51–2.55 (m, 1H,
a

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