Improved synthesis of monoprotected 5- and 6-amino-2-azanorbornanes

Article abstract of DOI:10.1080/00397911003707196

(Chemical Equation Presented) An improved synthesis of Boc-monoprotected 5- and 6-amino-2-azanorbornanes is reported. The synthetic scheme consists of five steps and allows multigram quantities of the title compounds to be obtained. The regio- and stereochemistries of the products are established by two-dimensional NMR experiments. Copyright Taylor & Francis Group, LLC.

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Improved Synthesis of Monoprotected 5-
and 6-Amino-2-azanorbornanes
Oleksandr P. Dacenko a , Olga V. Manoylenko a , Oleksandr O.
Grygorenko a b , Pavel K. Mykhailiuk a b , Dmitriy M. Volochnyuk a ,
Oleg V. Shishkin c & Andrey A. Tolmachev a b
a Enamine Ltd., Kyiv, Ukraine
b Department of Chemistry, Kyiv National Taras Shevchenko
University, Kyiv, Ukraine
c STC Institute for Single Crystals, National Academy of Science of
Ukraine, Kharkiv, Ukraine
Version of record first published: 03 Mar 2011.
To cite this article: Oleksandr P. Dacenko , Olga V. Manoylenko , Oleksandr O. Grygorenko , Pavel
K. Mykhailiuk , Dmitriy M. Volochnyuk , Oleg V. Shishkin & Andrey A. Tolmachev (2011): Improved
Synthesis of Monoprotected 5- and 6-Amino-2-azanorbornanes, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 41:7, 981-992
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Synthetic Communications1, 41: 981–992, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911003707196
IMPROVED SYNTHESIS OF MONOPROTECTED 5- AND
6-AMINO-2-AZANORBORNANES
Oleksandr P. Dacenko,1 Olga V. Manoylenko,1
Oleksandr O. Grygorenko,1,2 Pavel K. Mykhailiuk,1,2
Dmitriy M. Volochnyuk,1 Oleg V. Shishkin,3 and
Andrey A. Tolmachev1,2
1Enamine Ltd., Kyiv, Ukraine
2Department of Chemistry, Kyiv National Taras Shevchenko University,
Kyiv, Ukraine
3STC Institute for Single Crystals, National Academy of Science of Ukraine,
Kharkiv, Ukraine
GRAPHICAL ABSTRACT
Abstract An improved synthesis of Boc-monoprotected 5- and 6-amino-2-azanorbornanes is
reported. The synthetic scheme consists of five steps and allows multigram quantities of
the title compounds to be obtained. The regio- and stereochemistries of the products are
established by two-dimensional NMR experiments.
Keywords Bicyclic compounds; cycloadditions; diamines; molecular rigidity; peptidomi-
metics
INTRODUCTION
Aliphatic diamines provide privileged structural functionalities, exemplifying
both molecular diversity and a wide scope of biologic properties for peptidomi-
metics, natural products, and many small molecules of importance to drug
discovery.[1] Mounting the diamine moiety on a conformationally rigid scaffold us
allows to obtain building blocks possessing well-defined spatial arrangements of
amino groups, which could be beneficial for achieving optimal gain in substrate–
receptor binding free energy. Examples of successful use of conformationally rigid
Received December 1, 2009.
Address correspondence to Oleksandr O. Grygorenko, Department of Chemistry, Kyiv National
Taras Shevchenko University, Volodymyrska Street 64, Kyiv 01033, Ukraine. E-mail: gregor@
univ.kiev.ua
981

982
O. P. DACENKO ET AL.
Figure 1. Marketed drugs—derivatives of bicyclic diamines.
diamines in drug design include the CCR-5 antagonist for the treatment of HIV,
maraviroc 1,[2] and the antibiotic trovafloxacin 2[3] (Fig. 1).
Recently, derivatives of 2-azanorbornane 3 and 4 were reported as conforma-
tionally rigid diamine scaffolds in the design of neurokinin receptor antagonists.[4]
Ligands of this biological target are considered to be useful for the treatment or
prevention of various disease states, including emesis, asthma, cardiac disorders,
and neuronal injury.[5]
The scheme for the synthesis of compounds 3 and 4 described in the patent[4]
commenced from hardly achievable precursor 5 (Scheme 1); moreover, toxic and
environmentally unfriendly mercury salts were used at the corresponding steps of
the procedure. Stereochemical outcome of the synthesis was not reported; moreover,
the complete description of spectral and physical data of the novel compounds was
not given.
RESULTS AND DISCUSSION
Unlike the method reported previously,[4] our approach to the synthesis of
monoprotected diamines 3 and 4 includes the construction of azabicycloheptene pre-
cursor 6 by [4 þ 2] cycloaddition (Scheme 2).[6] Transformation of alkene 6 into a
mixture of alcohols 7 and 8 was achieved by a hydroboration–oxidation sequence.[7]
Chromatographic separation of 7 and 8 appeared to be a rather efficient way to
obtain multigram quantities of both isomers, even though the samples of 7 obtained
were of only 81% purity.
Scheme 1. Literature synthesis of 3 and 4.

AMINO AZANORBORNANES
983
Scheme 2. Synthesis of diamines 3 and 4.
Compounds 7 and 8 were oxidized to corresponding ketones 9 and 10 by
2-iodoxybenzoic acid (IBX), which appeared to give the greatest yields among other
oxidizing reagents including dimethylsulfoxide–oxalyl chloride used by previous
authors.[4] Regioisomers 9 and 10 were distinguished by two-dimensional (2D)
NMR experiments. An unexpected by-product 11 was isolated in 12% yield from
the reaction mixture obtained by oxidation of 7. We assume that the fragmentation
occurs at the hydroboration step, as the sample of 7 obtained after the chromato-
graphic separation contains nearly 15% of a compound suspected to be an alcohol
12 based on gas chromatography–mass spectrometry (GS-MS) data. The detailed
mechanism of the formation of the compound 12 is unclear; we propose the fragmen-
tation of an intermediate borane 15 as a key step of the reaction (Scheme 3).[8–10]
The structure of 11 has been established by x-ray diffraction study (Fig. 2,
Tables 1–3). The cyclopentane ring in the molecule of 11 adopts a twist conformation.
The deviations of the C(3) and C(4) atoms from the mean plane of the remaining
˚
˚
atoms of the ring are ꢀ0.20 A and 0.39 A, respectively. The substituent at the C(4)
atom has an equatorial orientation [the C(2)–C(3)–C(4)–C(6) torsion angle is ꢀ
163.6(3)ꢁ]. The carbamide group and the C(8) atom of tert-butyl substituent lie in
˚
the plane within 0.02 A. The planar fragment of the substituent adopts in þsc-confor-
mation relative to the C(3)–C(4) bond, and it is orthogonal to the C(4)–C(6) bond [the
C(3)–C(4)–C(6)–N(1) and C(7)–N(1)–C(6)–C(4) torsion angles are 61.8(4)ꢁ and
96.4(3)ꢁ, respectively]. The molecule 11 exhibits s-trans-conformation with respect
to the amide bond [C(6)–N(1)–C(7)–O(3) dihedral angle is ꢀ173.6(2)ꢁ] in the solid
state. In contrast, both s-trans- and s-cis-conformations are observed in the solution
[1:1 ratio of the conformers in dimethylsulfoxide (DMSO-d6) at 295 K]. The
tert-butyl group is turned in such way that the C(8)–C(9) bond has ap-orientation

984
O. P. DACENKO ET AL.
Scheme 3. Formation of compound 11.
relative to the C(7)–O(3) bond. It can be assumed that such position of the tert-butyl
group is caused by the weak C-H..O hydrogen bonds between two methylꢁsubstituents
˚
and carbonyl group: C(10)–H(10a) . . . O(2) H . . . O 2.35 A C-H . . . O 117 and C(11)–
[11]
ꢁ
˚
˚
H(11b) . . . O(2) H . . . O 2.43 A C-H . . . O 118 (van der Waals radii sum 2.87 A).
Further transformations of the synthetic scheme included formation of oximes
13 and 14 and their subsequent catalytic hydrogenation, which led to the desired
monoprotected amines 3 and 4. Both compounds appeared to be mixtures of diaster-
emers 3a, 3b (1.6:1) and 4a, 4b (1.6:1), respectively. Samples of 3 and 4 were separated
by chromatography to afford pure exo- and endo-isomers. Relative stereochemistry of
the compounds 3 and 4 was assigned using 2D NMR experiments. First of all, assign-
ments of the signals in 1H NMR spectra of the compounds 3a,b and 4a,b were made
using routine H-1H correlation spectroscopy (COSY) experiments. Then, nuclear
1
overhauser effect spectroscopy (NOESY) spectra were recorded for all for isomers.
The main criteria used to assign the stereochemistry of the diamine derivatives 3
and 4 were the correlations between the proton at 5(6)-CH and one of the protons
at 7-CH2, observed only in the case of endo-isomers 3a and 4a. Additional evidence
of the regiochemistry of the compounds was also obtained; namely, correlations
Figure 2. Molecular structure of compound 11.

AMINO AZANORBORNANES
985
˚
Table 1. Bond lengths (A) in the molecule of 11
Bond
Length
N(1)–C(7)
O(1)–C(1)
O(3)–C(7)
C(1)–C(2)
C(2)–C(3)
C(4)–C(6)
C(8)–C(10)
C(8)–C(11)
N(1)–C(6)
O(2)–C(7)
O(3)–C(8)
C(1)–C(5)
C(3)–C(4)
C(4)–C(5)
C(8)–C(9)
1.322(3)
1.226(4)
1.336(3)
1.465(5)
1.534(4)
1.510(3)
1.508(4)
1.517(4)
1.444(3)
1.214(3)
1.460(3)
1.492(5)
1.512(4)
1.520(3)
1.513(3)
between endo-protons at 3-CH2 and 5-CH2 were observed in the case of isomers 4a
and 4b (Fig. 3)
In conclusion, the synthetic scheme described consists of four steps and results
in 37% (3) and 25% (4) total yields of corresponding monoprotected diamines
starting from compound 6. The approach allows multigram quantities of the target
compounds to be obtained.
Table 2. Bond angles (deg) in the molecule of 11
Bond angle
Value
C(7)–N(1)–C(6)
O(1)–C(1)–C(2)
C(2)–C(1)–C(5)
C(4)–C(3)–C(2)
C(6)–C(4)–C(5)
C(1)–C(5)–C(4)
O(2)–C(7)–N(1)
N(1)–C(7)–O(3)
O(3)–C(8)–C(9)
O(3)–C(8)–C(11)
C(9)–C(8)–C(11)
C(7)–O(3)–C(8)
O(1)–C(1)–C(5)
C(1)–C(2)–C(3)
C(6)–C(4)–C(3)
C(3)–C(4)–C(5)
N(1)–C(6)–C(4)
O(2)–C(7)–O(3)
O(3)–C(8)–C(10)
C(10)–C(8)–C(9)
C(10)–C(8)–C(11)
122.4(2)
126.1(4)
110.2(3)
103.9(3)
115.2(3)
104.0(3)
125.1(3)
111.2(2)
102.0(2)
110.0(2)
110.6(4)
121.1(2)
123.7(4)
104.6(3)
114.4(3)
103.3(3)
117.1(2)
123.6(3)
110.6(2)
111.4(3)
111.9(3)

986
O. P. DACENKO ET AL.
Table 3. Torsion angles (deg) in the molecule of 11
Torsion angle
Value
O(1)-C(1)-C(2)-C(3)
C(1)–C(2)–C(3)–C(4)
C(2)–C(3)–C(4)–C(5)
C(2)–C(1)–C(5)–C(4)
C(3)–C(4)–C(5)–C(1)
C(3)–C(4)–C(6)–N(1)
C(6)–N(1)–C(7)–O(2)
C(8)–O(3)–C(7)–O(2)
C(7)–O(3)–C(8)–C(10)
C(7)–O(3)–C(8)–C(11)
C(5)–C(1)–C(2)–C(3)
C(2)–C(3)–C(4)–C(6)
O(1)–C(1)–C(5)–C(4)
C(6)–C(4)–C(5)–C(1)
C(7)–N(1)–C(6)–C(4)
C(5)–C(4)–C(6)–N(1)
C(6)–N(1)–C(7)–O(3)
C(8)–O(3)–C(70–N(1)
C(7)–O(3)–C(8)–C(9)
172.3(4)
28.2(4)
ꢀ37.6(4)
ꢀ15.3(4)
32.5(3)
61.8(4)
ꢀ5.6(4)
ꢀ6.2(4)
62.3(4)
ꢀ61.8(4)
ꢀ7.9(5)
ꢀ163.6(3)
164.4(4)
158.0(3)
96.4(3)
ꢀ57.7(4)
173.6(2)
174.6(2)
ꢀ179.2(3)
EXPERIMENTAL
Solvents were purified according to the standard procedures. All starting
materials were purchased from Acros, Merck, and Fluka. Analytical thin-layer chro-
matography (TLC) was performed using Polychrom SI F254 plates. Column chroma-
tography was performed using Kieselgel Merck 60 (230–400 mesh) as the stationary
phase. 1H NMR, 13C NMR, and all 2D NMR spectra were recorded on a Bruker 170
Avance 500 spectrometer (at 499.9 MHz for protons, 124.9 MHz for carbon-13).
Chemical shifts are reported in parts per million (ppm) downfield from tetramethyl-
silane (TMS) (1H, 13C) as an internal standard. Mass spectra (MS) were recorded on
an Agilent 1100 LCMSD SL instrument (chemical ionization, CI) and Agilent 5890
series II 5972 GC-MS instrument (electron impact ionization, EI). Elemental analyses
were performed on Elementar Vario Micro Cube CHNS=O analyzer.
5-Hydroxy-2-aza-bicyclo[2.2.1]heptane-2-carboxylic Acid tert-Butyl
Ester (7)
A solution of 6 (180 g) in tetrahydrofuran (THF, 750 mL) and finely powdered
sodium borohydride (28.5 g) were placed into a three-necked flask equipped with a
dropping funnel, a thermometer, and inert gas inlet under a nitrogen atmosphere.
After stirring for 10 min, the mixture was warmed to 30 ꢁC, and a solution of
dimethylsulfate (95 g) in THF (200 ml) was added dropwise at 30–40 ꢁC. The resulting
mixture was stirred for 3 h, then cooled to 5 ꢁC and quenched by dropwise addition of
water (30 ml). A solution of potassium hydroxide (31 g) in water (180 ml) was added
at ambient temperature followed by 30% hydrogen peroxide (45 ml) (the temperature
was kept lower than 30 ꢁC). The mixture was stirred for additional 40 min and then

AMINO AZANORBORNANES
987
Figure 3. NOESY spectra of the compounds 3a, 3b, 4a, and 4b.
diluted with diethyl ether (1 L). The organic phase was separated, washed thoroughly
with brine, dried over sodium sulfate, and evaporated in vacuo to give 175 g of a
mixture of alcohols 7 and 8. The latter was subjected to column chromatography
on silica gel [benzene–hexane–acetonitrile (3:1:1) as an eluent; Rf(7) ¼ 0.15,
Rf(8) ¼ 0.18)] to give 7 (11 g, 56%) and 8 (5.8 g, 30%) as colorless oils. A sample of
7 obtained by chromatography contained 81% of the title compound and 4% of its
epimer [m=z 213 (Mþ)], and 15% of alcohol 12 [m=z 159 (Mþ – (CH3)2C CH2)
=
and 142 (Mþ – (CH3)3CO)]. The assumptions on the structure of the contaminants
were made from GC-MS data and are not definitive. The compound was used in
the next step without further purification. MS (m=z): 213 (Mþ), 157, 112, 68, 57,

988
O. P. DACENKO ET AL.
41. 1H NMR (DMSO-d6, d): 4.83 (s, 1H), 4.02 and 3.99 (2 s, 1H), 3.80 (s, 1H), 3.06 (m,
1H), 2.72 (d, J ¼ 10.7 Hz, 1H), 2.30 (s, 1H), 1.83 (m, 1H), 1.68 (d, J ¼ 10.1 Hz, 1H),
1.38 [s, 9H, (CH3)3CO], 1.26–1.45 (m, 2H). 13C NMR (DMSO-d6, d): 154.0
(C¼O), 78.5 [C(CH3)3], 71.6 (5-CH), 56.2 and 55.2, 48.5 and 48.2, 45.1 and 44.5,
43.3 and 42.9, 34.1 and 33.6, 28.7 [C(CH3)3].
6-Hydroxy-2-aza-bicyclo[2.2.1]heptane-2-carboxylic Acid tert-Butyl
Ester (8)
Compound 8 was obtained together with compound 7. MS (m=z): 213 (Mþ),
157, 112, 68, 57, 41. Anal. calcd. for C11H19NO3: C, 62.01; H, 8.76; N, 6.49. Found:
C, 61.87; H, 8.48; N, 6.29. 1H NMR (DMSO-d6, d): 4.94 (dd, J ¼ 11.0 Hz and 3.1 Hz,
1H), 3.82 (s, 0.5H), 3.76 (s, 0.5H), 3.69 (s, 1H), 3.04 (d, J ¼ 8.6 Hz, 0.5H, 3-CHH),
2.99 (d, J ¼ 8.8 Hz, 0.5H, 3-CHH), 2.69 (d, J ¼ 9.0 Hz, 1H, 3-CHH), 2.43 (s, 1H,
4-CH), 1.69 (m, 1H), 1.63 (m, 1H), 1.42 (m, 1H), 1.40 [s, 4.5H, (CH3)3CO], 1.38
[s, 4.5H, (CH3)3CO], 1.28 (d, J ¼ 11.6 Hz, 1H). 13C NMR (DMSO-d6, d): 154.0
and 153.8 (C¼O), 78.6 and 78.5 [(CH3)3CO], 71.7 and 71.4 (6-CH), 61.4 and 60.4
(1-C), 52.0 and 51.6 (3-CH2), 39.8 and 39.7 (CH2), 36.0 and 35.4 (4-CH), 33.7 and
33.1 (CH2), 28.7 and 28.6 [CH3)3CO].
5-Oxo-2-aza-bicyclo[2.2.1]heptane-2-carboxylic Acid tert-Butyl
Ester (9)
Toluene (300 ml) and 2-iodoxybenzoic acid (43 g) were added to a solution of
crude alcohol 7 (24 g, 113 mmol) in dimethylsufoxide (130 ml). The resulting mixture
was warmed to 60 ꢁC over 3 h (TLC control), cooled, poured into saturated aqueous
sodium carbonate (200 ml), and filtered. The filtrate was extracted with dichloro-
methane, and the combined organic extracts were washed with brine, dried over
sodium sulfate, and evaporated in vacuo. The residue was chromatographed
[benzene–hexane–acetonitrile (3:1:1) as an eluent] to give ketone 9 (17.1 g, 81 mmol,
72%) and compound 11 (3.0 g, 14 mmol, 12%). White solid, mp 96 ꢁC. MS (m=z):
211 (Mþ), 155, 138, 68, 57. Anal. calcd. for C11H17NO3: C, 62.54%; H, 8.11%;
1
N, 6.63%. Found: C, 62.28%; H, 7.93%; N, 6.68%. H NMR (DMSO-d6, d): 4.01 (s,
0.4H, 1H, 1-CH), 3.95 (s, 0.6H, 1H, 1-CH), 3.32 (m, 1H), 3.07 (m, 1H), 2.78 (s, 1H,
4-CH), 2.23 (m, 1H), 1.97 (m, 1H), 1.81 (m, 1H), 1.74 (m, 1H), 1.38 [s, 9H, (CH3)3CO].
13C NMR (DMSO-d6, d): 206.4 and 205.9 (5-C¼O), 154.0 and 153.5 (NC¼O), 79.6
[(CH3)3CO], 62.6 and 61.6, 51.0 and 50.6, 41.6, 36.2 and 35.8, 34.9 and 34.2, 28.5.
6-Oxo-2-aza-bicyclo[2.2.1]heptane-2-carboxylic Acid tert-Butyl
Ester (10)
Compound 10 was prepared in 97% yield (25 g) from compound 8 analogously
to 9. White solid, mp 84 ꢁC. MS (m=z): 211 (Mþ), 183, 127, 68, 57. Anal. calcd. for
C11H17NO3: C, 62.54%; H, 8.11%; N, 6.63%. Found: C, 62.50%; H, 8.02%; N,
1
6.89%. H NMR (DMSO-d6, d): 4.44 (s, 0.5H, 1-CH), 4.40 (s, 0.5H, 1-CH), 3.37
(m, 1H, exo-3-CHH), 3.13 (m, 1H, endo-3-CHH), 2.82 (4-CH), 2.27 (m, 1H,
exo-5-CHH), 2.06 (m, 1H, endo-5-CHH), 1.99 (m, 2H, 7-CH2), 1.41 [s, 9H,

AMINO AZANORBORNANES
989
(CH3)3CO]. 13C NMR (DMSO-d6, d): 213.9 and 213.7 (6-C¼O), 154.0 and 153.8
(NC¼O), 79.3 [(CH3)3CO], 56.6 and 55.7, 50.8 and 50.2, 47.9 and 47.6, 45.9 and
45.6, 37.4 and 36.9, 28.6 [(CH3)3CO], 28.8 and 27.8.
tert-Butyl [(3-Oxocyclopentyl)methyl]carbamate (11)
Compound 11 was obtained together witþh compound 9. White solid, mp 80 ꢁC.
þ
þ
=
MS (m=z): 157 [M – (CH3)2C CH2], 140 [M – (CH3)3CO], 96, 83, 57 [(CH3)3C ].
Anal. calcd. for C11H19NO3: C, 61.95; H, 8.98; N, 6.57. Found: C, 61.68; H, 9.13; N,
1
6.31. H NMR (DMSO-d6, d): 6.94 (br. s, 1H, NH), 2.96 (m, 2H, CH2NHBoc),
2.05–2.30 (m, 4H), 1.95 (m, 1H), 1.85 (d, J ¼ 8.7 Hz, 0.5H), 1.81 (d, J ¼ 8.3 Hz,
0.5H), 1.52 (m, 1H), 1.37 [s, 9H, C(CH3)3]. 13C NMR (DMSO-d6, d): 218.7
(C¼O), 156.2 (NC¼O), 78.0 [C(CH3)3], 44.4, 46.2, 37.9, 37.2, 28.7 [C(CH3)3], 26.7.
5-Oximino-2-aza-bicyclo[2.2.1]heptane-2-carboxylic Acid tert-Butyl
Ester (13)
Triethylamine (16 ml, 0.115 mol) and hydroxylamine hydrochloride (6.9 g,
99 mmol) were added to a solution of ketone 9 (15 g, 71 mmol) in ethanol. The result-
ing mixture was refluxed for 2 h, then cooled and evaporated in vacuo. The residue
was triturated with water, filtered, and dried to give oxime 13 in almost quantitative
yield as a white solid, which was used in the next step without further purification.
1
MS (m=z, CI): 227 (MHþ). H NMR (DMSO-d6, d): 10.40 (s, 0.2H, NOH), 10.32
(s, 0.8H, NOH), 4.28 and 4.25 (2 s, 1H, 1-CH), 3.31 (br. m, 1H), 3.05 (m, 2H),
2.25 (m, 2H), 1.79 (m, 1H), 1.66 and 1.64 (2 s, 1H), 1.40 [s, 9H, C(CH3)3]. 13C
NMR (DMSO-d6, d): 161.0, 154.0 and 153.8, 79.0, 56.5 and 55.5, 51.3 and 51.0,
43.0 and 42.4, 38.6 and 38.2, 36.5 and 35.8, 28.6.
6-Oximino-2-aza-bicyclo[2.2.1]heptane-2-carboxylic Acid tert-Butyl
Ester (14)
Compound 14 was obtained in almost quantitative yield from compound 10
analogously to 13 as a white solid, which was used in the next step without further
1
purification. MS (m=z, CI): 227 (MHþ). H NMR (DMSO-d6, d): 10.40 (s, 0.6H,
NOH), 10.36 (s, 0.4H, NOH), 4.38 and 4.33 (2 s, 1H, 1-CH), 3.27 and 3.22 (2d,
J ¼ 7.9 Hz, 1H, 3-CHH), 2.94 and 2.91 (2d, J ¼ 7.9 Hz, 1H, 3-CHH), 2.68 (s, 1H,
4-CH), 2.34 (s, 0.4H), 2.31 (s, 0.6H), 2.08 (s, 0.6H), 2.04 (s, 0.4H), 1.72 (d, J ¼ 8.5 Hz,
Hz, 0.6H), 1.67 (d, J ¼ 8.5 Hz, 0.4H), 1.51 and 1.49 (2d, J ¼ 8.5 Hz, 1H), 1.38 [s, 9H,
C(CH3)3]. 13C NMR (DMSO-d6, d): 159.4 and 159.2, 154.0 and 153.3, 79.0, 59.2 and
58.0, 51.4 and 51.0, 38.4 and 38.0, 35.9 and 35.3, 32.4, 28.6.
5-Amino-2-aza-bicyclo[2.2.1]heptane-2-carboxylic Acid tert-Butyl
Ester (3)
Oxime 13 was dissolved in 10% methanolic ammonia (300 ml) and hydroge-
nated over Raney nickel (3 g) at 40 bars at ambient temperature for 8 h. The reaction
mixture was filtered over celite and evaporated in vacuo. The residue was dissolved in

990
O. P. DACENKO ET AL.
dichloromethane, filtered, and evaporated again. The crude product was distilled
(71 ꢁC=0.1 mmHg) to afford amine 3 (13.8 g, 92%) as a colorless oil. The compound
is a 1.6:1 mixture of diastereomers 3a and 3b, respectively. MS (m=z): 212 (Mþ), 169,
156, 139, 113, 95, 82, 57, 41. A sample of 3 was subjected to flash chromatography
(Combiflash Companion chromatograph, 12 g RediSep column, 2-propanol as an
eluent, 30 ml=min flow, detection at 215 nm) to afford pure diastereomers 3a and
1
3b. Endo-isomer 3a (eluted first): H NMR (CDCl3, d): 4.14 (s, 0.5H, 1-CH), 4.01
(s, 0.5H, 1-CH), 3.52 (t, J ¼ 10.6 Hz, 1H, exo-3-CHH), 3.41 (m, 1H, 5-CH), 3.13 (d,
J ¼ 10.5 Hz, 0.5H, endo-3-CHH), 3.09 (d, J ¼ 10.5 Hz, 0.5H, 3-CHH), 2.37 (s, 1H,
4-CH), 2.02 (m, 1H, 6-CHH), 1.69 (d, J ¼ 10.0 Hz, 0.5H, 7-CHH), 1.64 (d, J ¼ 9.6 Hz,
Hz, 0.5H, 7-CHH), 1.54 (s, 2H, NH2), 1.48 (d, J ¼ 9.8 Hz, 1H, 7-CHH), 1.41 (s, 9H,
C(CH3)3), 1.12 (d, J ¼ 13.2 Hz, 0.5H, 6-CHH), 1.04 (d, J ¼ 13.0 Hz, 0.5H, 6-CHH).
13C NMR (CDCl3, d): 154.4 and 154.2 (C¼O), 79.1 and 79.0 [C(CH3)3], 57.9 and
56.9 (1-CH), 51.0 and 50.9 (5-CH), 45.0 and 44.5 (3-CH2), 44.1 and 43.8 (4-CH),
41.3 and 41.4 (CH2), 38.2 and 37.8 (CH2), 28.7 [C(CH3)3]. exo-Isomer 3b (eluted
1
second): H NMR (CDCl3, d): 4.20 (s, 0.5H, 1-CH), 4.08 (s, 0.5H, 1-CH), 3.17
(m, 1H, 3-CHH), 3.11 (m, 1H, 5-CH), 2.91 (d, J ¼ 10.0 Hz, 0.5H, 3-CHH), 2.84 (d,
J ¼ 9.8 Hz, 0.5H, 3-CHH), 2.22 (s, 1H, 4-CH), 2.10 (m, 0.5H, 6-CHH), 2.01
(m, 0.5H, 6-CHH), 1.70 (d, J ¼ 10.3 Hz, 1H, 7-CHH), 1.58 (s, 2H, NH2), 1.53 (d,
J ¼ 10.2 Hz, 0.5H, 7-CHH), 1.50 (d, J ¼ 10.3 Hz, 0.5H, 7-CHH), 1.42 [s, 9H,
C(CH3)3], 1.16 (d, J ¼ 11.8 Hz, 1H, 6-CHH). 13C NMR (CDCl3, d): 154.6 and
154.3 (C¼O), 79.1 and 79.0 [C(CH3)3], 56.7 and 55.7 (1-CH), 53.4 and 53.3 (6-CH),
50.4 and 49.9 (3-CH2), 45.9 and 45.4 (4-CH), 42.9 and 42.7 (CH2), 33.9 and 33.5
(CH2), 28.6 [C(CH3)3].
6-Amino-2-aza-bicyclo[2.2.1]heptane-2-carboxylic Acid tert-Butyl
Ester (4)
Compound 4 was prepared in 87% yield (20 g) as a colorless oil from oxime 14
analogously to 3. The compound is a 1.6:1 mixture of diastereomers 4a and 4b,
respectively. Bp 73 ꢁC=0.1 mmHg. MS (m=z): 212 (Mþ), 169, 139, 68, 57, 41. A
sample of 4 was subjected to flash chromatography (Combiflash Companion
chromatograph, 12 g RediSep column, 2-propanol as an eluent, 30 ml=min flow,
detection at 215 nm) to afford pure diastereomers 4a and 4b. Endo-isomer 4a (eluted
first): 1H NMR (CDCl3, d): 4.14 (s, 0.5H, 1-CH), 4.01 (s, 0.5H, 1-CH), 3.39 (m, 1H,
6-CH), 3.30 (m, 1H, 3-CHH), 3.00 (d, J ¼ 9.5 Hz, 1H, 3-CHH), 2.97 (s, 2H, NH2),
2.44 (s, 1H, 4-CH), 2.10 (m, 1H, 5-CHH), 1.60 (m, 1H, 7-CHH), 1.50 (d, J ¼ 9.8 Hz,
Hz, 1H, 7-CHH), 1.44 [s, 9H, C(CH3)3], 0.95 (d, J ¼ 11.0 Hz, 0.5H, 5-CHH), 0.86 (d,
J ¼ 11.2 Hz, 0.5H, 5-CHH). 13C NMR (CDCl3, d): 155.7 (C¼O), 79.6 [C(CH3)3],
61.8, 60.6, 55.2, 54.8, 53.8, 53.0, 37.8, 37.4, 37.3, 37.2, 37.1, 36.8, 36.7, 28.6
[C(CH3)3]. Exo-isomer 4b (eluted second): 1H NMR (CDCl3, d): 4.23 (s, 0.5H,
1-CH), 4.13 (br. s, 2H, NH2), 4.10 (s, 0.5H, 1-CH), 3.50 (br. s, 0.5H, 6-CH), 3.46
(br. s, 0.5H, 6-CH), 3.30 (br. s, 1H, 3-CHH), 3.06 (br. s., 1H, 3-CHH), 2.47 (s,
1H, 4-CH), 2.12 (m, 1H, 5-CHH), 1.60 (m, 1H, 7-CHH), 1.52 (d, J ¼ 10.1 Hz, 1H,
7-CHH), 1.44 [s, 9H, C(CH3)3], 1.12 (br. d, J ¼ 10.5 Hz, 0.5H, 5-CHH), 0.99 (br. d,
J ¼ 10.0 Hz, 0.5H, 5-CHH). 13C NMR (CDCl3, d): 155.7 (C¼O), 79.9 [C(CH3)3],
61.2, 59.9, 54.8, 54.4, 53.7, 52.9, 37.7, 37.3, 37.1, 36.3, 35.4, 28.6 [C(CH3)3].

AMINO AZANORBORNANES
991
X-Ray Diffraction Study of 11
Crystals for x-ray diffraction studies were obtained by slow crystallization from
benzene–hexane–acetonitrile (3:1:1) solution. The crystals of 11 (C11H19NO3) are
ꢁ
˚
˚
˚
monoclinic. At 293 K, a ¼ 13.794(3) A, b ¼ 9.567(2) A, c ¼ 9.383(1) A, b ¼ 93.06(2) ,
V ¼ 1236.5(4) A , Mr ¼ 213.27, Z ¼ 4, space group P21=c, dcalc ¼ 1.146 g=cm3,
3
˚
m(MoKa) ¼ 0.083 mmꢀ1, F(000) ¼ 464. Intensity of 6868 reflections (2144 inde-
pendent, Rint ¼ 0.085) were measured on an automatic Xcalibur 3 diffractometer
(graphite monochromated MoKa radiation, CCD detector, x scaning, 2Hmax ¼ 50ꢁ).
The structure was solved by direct method using the Shelxtl package.[12] Posi-
tions of hydrogen atoms were located from electron-density difference maps and
refined using a riding model with Uiso ¼ nUeq (n ¼ 1.5 for methyl groups and 1.2
for other hydrogen atoms), except for the atom involved in the N–H...O hydrogen
bond, which was refined using the isotropic model. Full-matrix least-squares refine-
ment against F2 in anisotropic approximation for nonhydrogen atoms was converged
to wR2 ¼ 0.171 for 2098 reflections (R1 ¼ 0.064 for 912 reflections with F > 4r(F),
S ¼ 0.825). Final atomic coordinates, geometrical parameters, and crystallographic
data have been deposited with the Cambridge Crystallographic Data Centre, 11
Union Road, Cambridge, CB2 1EZ, UK (fax: þ44 1223 336033; e-mail: depos-
it@ccdc.cam.ac.uk) and are available on request (deposition number CCDC 752271).
ACKNOWLEDGMENT
The authors are thankful to Mr. Vitaliy Polovinko for the 2D NMR experiments.
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