Synthesis of 11-methyl-13-azabicyclo[7.3.1]trideca-3,10-diene, a macrobicycle with the 9b-azaphenalene carbon framework, based on the combination of allylboration and intramolecular metathesis

Article abstract of DOI:10.1007/s11172-014-0768-3

A four-step synthesis of 11-methyl-13-azabicyclo[7.3.1]trideca-3,10-diene, a potential precursor of the ladybugs defensive alkaloids precoccinelline and mirrhine, has been accom-plished. Treatment of 4-picoline with 5-hexenyl-1-lithium, triallylborane, and methanol led to the synthesis of trans-6-allyl-2-(hex-5-enyl)-4-methyl-1,2,3,6-tetrahydropyridine, which reacted with triallylborane upon heating to be converted to the cis-isomer. A subsequent cyclization of the cis-isomer of N-Boc derivative via the intramolecular metathesis using Grubbs II and Hoveyda - Grubbs II ruthenium catalysts furnished the target bridged macrobicycle. The structure of its hydrochloride was confirmed by single crystal X-ray diffraction studies. The optimal conditions for the metathesis reaction and the isolation of the macrobicyclic product were selected.

Full text of DOI:10.1007/s11172-014-0768-3

Russian Chemical Bulletin, International Edition, Vol. 63, No. 11, pp. 2502—2508, November, 2014
2502
Synthesis of 11ꢀmethylꢀ13ꢀazabicyclo[7.3.1]tridecaꢀ3,10ꢀdiene,
a macrobicycle with the 9bꢀazaphenalene carbon framework, based
on the combination of allylboration and intramolecular metathesis*
N. Yu. Kuznetsov,a,b V. N. Khrustalev,a T. V. Strelkova,a and Yu. N. Bubnova,b
aA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5085. Eꢀmail: bubnov@ineos.ac.ru, nkuznff@ineos.ac.ru
bN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation
A fourꢀstep synthesis of 11ꢀmethylꢀ13ꢀazabicyclo[7.3.1]tridecaꢀ3,10ꢀdiene, a potential preꢀ
cursor of the ladybugs´ defensive alkaloids precoccinelline and mirrhine, has been accomꢀ
plished. Treatment of 4ꢀpicoline with 5ꢀhexenylꢀ1ꢀlithium, triallylborane, and methanol led to
the synthesis of transꢀ6ꢀallylꢀ2ꢀ(hexꢀ5ꢀenyl)ꢀ4ꢀmethylꢀ1,2,3,6ꢀtetrahydropyridine, which reꢀ
acted with triallylborane upon heating to be converted to the cisꢀisomer. A subsequent cyclizaꢀ
tion of the cisꢀisomer of NꢀBoc derivative via the intramolecular metathesis using Grubbs II
and Hoveyda—Grubbs II ruthenium catalysts furnished the target bridged macrobicycle. The
structure of its hydrochloride was confirmed by single crystal Xꢀray diffraction studies. The
optimal conditions for the metathesis reaction and the isolation of the macrobicyclic product
were selected.
Key words: mirrhine, precoccinelline, allylboranes, allylboration, bridged azabicycles,
macrocyclization, metathesis.
Bridged azabicycles in which one of the heterocyclic
reliably carry out the metathesis with the maximal effiꢀ
ciency, since due to the A1,3ꢀeffect4 the alkenyl substituents
are oriented axially and are in close proximity, whereas
the nucleophilic properties of the amino group are supꢀ
pressed and do not deactivate the catalyst.
This methodology (allylboration—metathesis) was sucꢀ
cessfully used for the synthesis from 4ꢀpicoline of hippoꢀ
casine (one of the components of a mixture of the ladyꢀ
bugs´ defensive alkaloids) and nonnatural isomer of epiꢀ
hippodamine,5 which are the hydrogenated derivatives of
9bꢀazaphenalene (Scheme 2). These compounds have the
transꢀorientation of 2,6ꢀsubstituents of the main piperiꢀ
dine ring. In this case, a required stereochemistry of
substituents was preset in the first stage of the synthesis of
compound transꢀ1.
Attempted application of this methodology for the synꢀ
thesis of another two ladybugs´ tricyclic alkaloids, preꢀ
coccinelline and mirrhine, with the cisꢀarrangement of
ꢀhydrogen atoms in the main cycle was unsuccessful.
The "standard" trans—cisꢀisomerization of the key piperiꢀ
dine derivative transꢀ1 via heating with triallylborane led
to a mixture of cis—transꢀisomers and a considerable
amount of side products, that resulted from the decompoꢀ
sition of the diethyl acetal group6 (see Scheme 2). Thereꢀ
fore, we decided to change the synthetic scheme and asꢀ
fragments is represented by a piperidine heterocycle are
a unique class of compounds exhibiting a wide range of bioꢀ
logical activity.1 Therefore, the search for and developꢀ
ment of efficient approaches to the construction of such
bicyclic system is an important direction of synthetic
chemistry.2 One of the most powerful instruments in the
design of cyclic systems of virtually any size is the ring
closing metathesis (RCM) reaction.2 Recently, we have
developed a convenient and efficient methodology for the
synthesis of bridged azabicycles (with fiveꢀ, sixꢀ, and sevenꢀ
membered rings in the molecule) from simple aromatic
heterocycles, such as pyridines, isoquinolines, and pyrrole
using a combination of reductive allylboration and intraꢀ
molecular metathesis in the presence of Grubbs I and II
catalysts (Scheme 1).3
It should be noted that the required conditions for the
metathesis cyclization to be successful are the cisꢀarrangeꢀ
ment of the alkene substituents and the presence at the
nitrogen atom of an acylꢀtype protecting group (the Boc
protection is most preferred).3 This makes it possible to
* Dedicated to the 60th anniversary of the foundation A. N.
Nesmeyanov Institute of Organoelement Compounds of the Rusꢀ
sian Academy of Sciences.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2502—2508, November, 2014.
1066ꢀ5285/14/6311ꢀ2502 © 2014 Springer Science+Business Media, Inc.

Azamacrobicycles via allylboration—RCM
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 11, November, 2014 2503
Scheme 1
GꢀI, GꢀII, HGꢀII stand for the Grubbs I, II and Hoveyda—Grubbs II catalysts; Cy is cyclohexyl; n = 0, 1.
semble the 9bꢀazaphenalene framework using the metꢀ
athesis reaction (Scheme 3). In this case, the key intermeꢀ
diate product should be the azamacrobicyclic compound 4
containing sixꢀ and tenꢀmembered rings. The bromoꢀ
cyclocarbamation reaction, successfully used by us earlier
for different transformations of homoallylamine fragment,7
in particular, for desymmetrization of 1ꢀazaspirobicycles,7d
was accomplished by treatment with the source of cationꢀ
ic bromine (or iodine).
The synthesis of the diene derivative of transꢀ2 was
carried out according to the developed method8 by
1,2ꢀorganolithiation of 4ꢀpicoline and allylboration of the
intermediate lithium amide (Scheme 4). Initially, 5ꢀhexenꢀ
ylꢀ1ꢀlithium was synthesized by the reaction of 6ꢀiodoꢀ
hexene9c with ButLi. It should be noted that 5ꢀhexenylꢀ1ꢀ
lithium is extremely unstable compound, which underꢀ
goes intramolecular carbolithiation with a halfꢀlife of
23 min at 0 C.9 Therefore, after carrying out the exchange
reaction at –78 C and addition of 4ꢀpicoline to the lithiꢀ
um derivative formed, the reaction mixture was stirred at
–40 C for 1.5 h (usually the reaction is carried out at
0 C), followed by a sequential addition of triallylborane
and MeOH. transꢀIsomer 2 was isolated by distillation
(43%) and converted afterwards to cisꢀisomer 2 by heating
with triallylborane at 180 C for 12 h.
catalysts. Initially, we studied the influence of the conꢀ
centration of diene 3 on the course of the cyclization.
As it turned out, when a 1.5ꢀfold diluted solution
(C = 0.01 mol L–1) was used compared to the cyclization
of cisꢀ2,5ꢀdiallylpyrrolidine3a in the presence of the Grubbs II
catalyst in toluene at 80 C, the diene was completely
converted within 1.5 h. However, a considerable amount
of oligomeric products appeared on the chromatographic
pattern besides the target bicycle 4, whereas attempted
isolation of compound 4 failed. The dilution of the soluꢀ
tion of compound 3 to 5 mmol L–1 did not lead to a conꢀ
siderable drop in the yield of oligomeric products either.
Only for the concentration of 2.5 mmol L–1, no formation
of oligomers was observed. We finally found that the metaꢀ
thesis in CH2Cl2 at 40 C proceeds slowly and even when
30 mol.% of the Grubbs II catalyst was used, the complete
conversion was reached within 10 days (Table 1).
It should be emphasize that if the reaction mixtures
were concentrated (on a rotary evaporator), oligomers were
the only reaction products. Since the metathesis process
consists of several equilibrium steps, the increase of the
concentration in the course of the synthesis of thermodyꢀ
namically unstable macrocycles leads to the shift of the
equilibrium to the side of more stable oligomers.10 It is
obvious that in this case azabicycle 4 readily undergoes
polymerization through the ring opening metathesis polyꢀ
merization (ROMP) (Scheme 5).
Thus obtained cisꢀisomer 2 (4% of transꢀisomer 2) was
converted to NꢀBoc derivative 3 (94%) by reflux with
Boc2O in THF and purified by chromatography. Then,
diene 3 was used as the starting compound in the syntheꢀ
sis of macrobicycle 4 upon treatment with the Grubbs
This problem was successfully solved by the dilution of
the reaction mixture with hexane with subsequent removꢀ
al of CH2Cl2 at reduced pressure, that led to a precipitaꢀ

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Russ.Chem.Bull., Int.Ed., Vol. 63, No. 11, November, 2014
Kuznetsov et al.
Scheme 2
i. See Ref. 5; ii. A possibility to accomplish this transformation is not yet confirmed, no required isomer was yet obtained.
Scheme 3

Azamacrobicycles via allylboration—RCM
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 11, November, 2014 2505
Scheme 4
i.
, –40 C, 1.5 h; ii. 1)
; 2) MeOH; iii.
, 180 C, 12 h.
Scheme 5
tion of the catalyst from the solution. Then, the hexane
solution was applied to silica gel and subjected to chromatoꢀ
graphy to obtain pure azabicycle 4. This procedure was
selected as the optimal for the separation from the Grubbs II
catalyst when the reaction was carried out in CH2Cl2.
Another method consisting of the addition of vinyl acetate
(isonitriles can also be used for the deactivation) allowed
us to deactivate not only the Grubbs II catalyst, but also
the very stable Hoveyda—Grubbs II catalyst, which are
converted to inactive Fischer´s carbene complexes.11 The
metathesis of diene 3 (C = 2 mmol L–1) at 80 C in toluꢀ
ene with the Grubbs II catalyst after deactivation with
vinyl acetate gives product 4 in 65% yield (see Table 1).
The use of the Hoveyda—Grubbs II catalyst reduces the
reaction time to 8 h at 80 C and to 5 h at 110 C.
It should be noted that we planned to convert comꢀ
pound 4 to allylic alcohol 6 and the latter to mirrhine and/or
precoccinelline (see Scheme 3). A close analog of comꢀ
pound 6, but with transꢀconfiguration of substituents at
the piperidine ring, has been earlier used in the synthesis
of azaphenalene alkaloids.12 However, treatment of macꢀ
robicycle 4 with Nꢀbromosuccinimide in different solvents
(CH2Cl2, CHCl3, 1,2ꢀdichloroethane, or MeCN) did not
lead to bromourethane 5 (only unidentified products conꢀ
taining the Boc group were rather identified). Therefore,
this synthetic scheme was abandoned.
i. Ruꢀcatalyst, solvent; ii. Ruꢀcatalyst; iii. HCl, dioxane.
removal of the Boc group) and crystallization from CHCl3,
its structure was established by Xꢀray diffraction studꢀ
ies (Fig. 1).
Compound 7 crystallizes with two solvent molecules
of chloroform, i.e., the complex in crystal has the formula
7•2CHCl3. The chloroform molecules in crystal form
strong hydrogen bonds C—H...Cl with chlorine anions (see
Fig. 1, a, Table 2).
Azabicycle hydrochloride 7 was isolated after treatꢀ
ment of compound 4 with HCl (4 mol L–1) in dioxane (for
The azabicyclic molecule 7 has a crownꢀlike conformaꢀ
tion, which includes a boat—boat conformation of the tenꢀ
membered ring and a halfꢀchair conformation of the sixꢀ
membered tetrahydropyridine ring (see Fig. 1, b). The cation
contains two asymmetric carbon atoms C(1) and C(9). The
crystal is a racemate with the 1R* and 9S* relative configꢀ
Table 1. Ringꢀclosing metathesis of diene 3 (0.5 mmol,
c = 2.5 mmol L–1
)
Ru catalyst
(mol.%)
Solvent,
T/C
t
Yield of
compound 4 (%)
urations of the chiral centers. In crystal, the complex
7•2CHCl3 forms the centrosymmetric Hꢀbonded dimeric
associates (Fig. 2) separated by the van der Waals distances.
In conclusion, we have developed an approach to the
synthesis of macroazabicyclic compounds containing
GꢀII (30)
GꢀII (7)
HGꢀII (6)
HGꢀII (6)
CH2Cl2, 40
PhMe, 80
PhMe, 80
PhMe, 110
10 days
15 h
8 h
78
65
85
60
5 h

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Russ.Chem.Bull., Int.Ed., Vol. 63, No. 11, November, 2014
Kuznetsov et al.
C(13)
a "large" azaphenalene carbon skeleton. Bicycles with other
substituents in the piperidine ring can be obtained similarꢀ
ly. Such bridged macroazabicyclic compounds are promꢀ
ising for the search of new biologically active substances,
since they include a rigid sixꢀmembered ring and a flexible
lipophilic tenꢀmembered ring.
a
C(11)
Cl(6)
Cl(7)
C(10)
C(9)
C(12)
C(1)
Cl(4)
Cl(5)
C(15)
N(13)
C(2)
C(8)
Experimental
C(14)
Cl(3)
C(3)
C(7)
C(6)
Reactions were carried out under dry argon. Solvents were
purified according to the standard procedures.13 NMR spectra
were recorded on Bruker Avance spectrometer (300, 400, and
600 MHz) using residual signals of CHCl3 as a reference. Colꢀ
umn chromatography was carried out on Merck silica gel
(60—230 mesh). Ruthenium catalysts Grubbs II and Hoveyꢀ
da—Grubbs II were purchased from Materia Inc. Mass spectra
were recorded on a Finnigan Polaris Q Ion Trap instrument.
transꢀ2ꢀAllylꢀ6ꢀ(5ꢀhexenyl)ꢀ4ꢀmethylꢀ1,2,3,6ꢀtetrahydroꢀ
pyridine (transꢀ2). tertꢀButyllithium (1.6 mol L–1, 39 mL,
63 mmol) was added to a solution of iodide (6.27 g, 29.8 mmol)
in a mixture of nꢀhexane—Et2O (220 mL, 7 : 4) at –78 C, this
was accompanied by the formation of a white precipitate of
5ꢀhexenylꢀ1ꢀlithium, which was stirred for 30 min at this temꢀ
perature. Then, THF (55 mL) and 4ꢀpicoline (2.8 g, 30 mmol)
were added to the reaction mixture, which was stirred at –40 C
for 1 h, then the temperature was elevated to –10 C. Triallylboꢀ
rane (4.7 g, 6.05 mL, 35 mmol) was added to the mixture obꢀ
tained and after 10 min it was treated with MeOH (20 mL),
refluxed for 30 min, followed by the addition of 10% aqueous
NaOH (50 mL) and refluxed for another 1 h. After cooling to
room temperature, the organic layer was separated, washed with
water, dried with К2CO3, and concentrated. The residue was
distilled in vacuo to collect the fraction with b.p. 84—86 C
(0.5 Torr). The yield was 2.84 g (43%). 1H NMR (CDCl3,
300 MHz), : 5.84—5.70 (m, 2 H, 2 CH=, chain); 5.35 (s, 1 H,
CH=, cycle); 5.10—4.89 (m, 4 H, 2 CH2=); 3.31—3.24 (br.s,
1 H, CHN); 2.96—2.87 (m, 1 H, CHN); 2.22—2.08 (m, 2 H,
CH2, hexenyl); 2.04—2.01 (m, 2 H, CH2, All); 1.91 (dd, 1 H,
CHaHb, cycle, J = 4.1 Hz, J = 16.9 Hz); 1.71 (dd, 1 H, CHaHb,
cycle, J = 8.0 Hz, J = 16.7 Hz); 1.64 (s, 3 H, Me); 1.45—1.28
(m, 6 H, 3 CH2). 13C NMR (CDCl3, 75 MHz), : 138.83, 135.69,
131.72, 124.11, 117.11, 114.30, 52.08, 47.07, 40.27, 36.40, 35.42,
33.67, 28.91, 25.97, 23.45. Found (%): C, 82.06; H, 11.54;
N, 6.28. C15H25N. Calculated (%): C, 82.13; H, 11.49; N, 6.39.
cisꢀ2ꢀAllylꢀ6ꢀ(5ꢀhexenyl)ꢀ4ꢀmethylꢀ1,2,3,6ꢀtetrahydropyrꢀ
idine (cisꢀ2). Compound transꢀ2 (3.0 g, 13.7 mmol) was mixed
with triallylborane (2.0 g, 2.6 mL, 15.1 mmol) and heated at 180 C
for 12 h. The reaction progress was monitored by 1H NMR
spectroscopy. The reaction mixture was quenched with MeOH
(5 mL) upon reflux for 1 h. Then it was treated with 10% aqueous
NaOH (10 mL) and diluted with hexane (20 mL). The organic
layer was separated, washed with water, dried, and concentrated
to obtain cisꢀ2 (the impurity of transꢀ2 was 4%). The yield was
92%. 1H NMR (CDCl3, 300 MHz), : 5.88—5.74 (m, 2 H,
2 CH=, chain); 5.29 (s, 1 H, CH=, cycle); 5.17—4.92 (m, 4 H,
2 CH2=); 3.34—3.26 (br.s, 1 H, CHN); 2.82—2.73 (m, 1 H, CHN);
2.31—2.12 (m, 2 H, CH2, hexenyl); 2.07—2.03 (m, 2 H, CH2,
All); 1.85—1.82 (m, 2 H, CH2, cycle); 1.67 (s, 3 H, Me); 1.45—1.35
(m, 6 H, 3 CH2). 13C NMR (CDCl3, 100 MHz), : 138.94,
135.34, 132.65, 124.68, 117.49, 114.33, 55.00, 52.64, 41.05,
Cl(1)
C(4)
C(5)
C(5)
Cl(2)
b
C(13)
C(11)
C(10)
C(8)
C(2)
C(6)
C(9)
C(7)
C(12)
C(1)
C(4)
C(3)
N(13)
Fig. 1. The structure of hydrochloride 7: a general view (a) and
the azabicycle conformation (b).
Table 2. Parameters of hydrogen bonding in the structure of
7•2CHCl3 (d/Å and /deg)
...
...
Bond
d(D—H) d(H A) d(D A) (DHA)
...
N(13)—H(13A) Cl(1) 0.92
[–x + 2, –y, –z + 1]
N(13)—H(13B) Cl(1) 0.92
[x, y, z + 1]
2.38
2.15
3.126(2)
3.064(2)
139
173
...
...
C(14)—H(14) Cl(1)
...
1.00
1.00
2.41
2.39
3.404(2)
3.349(2)
171
160
C(15)—H(15) Cl(1)
Note. D is a proton donor, A is a proton acceptor.
Cl(4A)
Cl(2A)
Cl(7)
Cl(5)
N(13)
Cl(6A)
Cl(5A)
Cl(1)
Cl(2)
Cl(3A)
Cl(3)
Cl(1A)
N(13A)
Cl(6)
Cl(4)
Cl(7A)
Fig. 2. Centrosymmetric Hꢀbonded dimeric associates in the
structure 7•2CHCl3.

Azamacrobicycles via allylboration—RCM
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 11, November, 2014 2507
37.16, 36.61, 33.70, 29.04, 25.38, 23.17. MS (EI, 70 eV), m/z
(Irel (%)): 220 [MH]+ (8), 219 [M]+ (4), 218 [M – H]+ (17), 202
(14), 190 (25), 178 (40), 176 (70), 163 (65), 147 (22), 136 (30),
134 (29), 120 (30), 108 (20), 107 (22), 105 (24), 94 (100), 93 (20),
91 (24), 79 (27), 77 (29). Found (%): C, 82.10; H, 11.41; N, 6.32.
C15H25N. Calculated (%): C, 82.13; H, 11.49; N, 6.39.
residue was dried on a rotary evaporator in vacuo. The oil obꢀ
tained was dissolved in chloroform and left to crystallize. Comꢀ
pound 7 (0.13 g, 83%) was obtained as white plates after drying
of the formed crystals in vacuo, m.p. 237—238 C (CHCl3).
1H NMR (CDCl3, 300 MHz), : 10.83 (br.s, 1 H, NH2+); 7.30
(br.s, 1 H, NH2+); 5.73—5.62 (m, 2 H, CH=CH); 2.39 (s, 1 H,
CH=); 3.94—3.79 (m, 2 H, 2 CHN); 3.12 (dd, 1 H, CHaHb, sixꢀ
membered ring, J = 7.7 Hz, J = 17.9 Hz); 2.86 (dd, 1 H,
C(5)HaHb, J = 14.1 Hz, J = 24.7 Hz); 2.43—2.31 (m, 1 H,
C(5)HaHb); 2.13—2.00 (m, 2 H, C(2)H2); 1.91 (d, 1 H, CHaHb,
sixꢀmembered ring, J = 18.0 Hz); 1.76 (s, 3 H, Me); 1.73—1.58
(m, 5 H, 2 CH2 and C(7)HaHb); 1.53—1.42 (m, 1 H, C(7)HaHb).
13C NMR (CDCl3, 75 MHz), : 133.09, 130.08, 126.23, 118.62,
50.56, 49.64, 32.56, 31.60, 29.17, 23.90, 23.70, 22.85, 19.28. MS
(EI, 70 eV), m/z (Irel (%)): 191 [M]+ (12), 190 [M – H]+ (82),
134 (16), 120 (23), 107 (18), 95 (10), 94 (100). Found (%):
C, 68.55; H, 9.74; N, 6.15; Cl, 15.56. C13H22NCl. Calculated (%):
C, 68.48; H, 9.82; N, 6.17; Cl, 15.67.
tertꢀButyl cisꢀ2ꢀallylꢀ6ꢀ(5ꢀhexenyl)ꢀ4ꢀmethylꢀ3,6ꢀdihydroꢀ
1(2H)ꢀpyridinecarboxylate (3). The reactant Boc2O (2.83 g,
13 mmol) was added to a solution of compound cisꢀ2 (2.57 g,
11.7 mmol) in THF (15 mL) and the reaction mixture was reꢀ
fluxed for 1 h. The reaction progress was monitored by TLC
(hexane—EtOAc = 2 : 1). Then, the reaction mixture was conꢀ
centrated at reduced pressure, the residue was subjected to chroꢀ
matography on silica gel in the hexane—EtOAc (40 : 1) to obtain
compound 3 (3.51 g, 94%) (Rf 0.2, hexane—EtOAc, 40 : 1) as
a dense oil. 1H NMR (CDCl3, 300 MHz), : 5.85—5.67 (m, 2 H,
2 CH=, chain); 5.47 and 5.41 (both br.s, 1 H, CH=, cycle);
5.04—4.90 (br.m, 4 H, 2 CH2=); 4.45 (br.s, 1 H, CHN); 4.20—4.12
(br.m, 1 H, CHN); 2.24—2.04 (br.m, 5 H, CH2 (hexenyl),
CH2 (All), CHaHb (cycle)); 1.82 (d, 1 H, CHaHb, cycle,
J = 17.1 Hz); 1.69 (s, 3 H, Me); 1.69—1.58 (br.m, 1 H); 1.45 and
1.44 (both br.s, 9 H, But); 1.39 (br.m, 5 H). 13C NMR (CDCl3,
75 MHz), : 154.76 br, 138.80, 139.29, 128.93 br, 120.21, 116.66,
114.35, 79.22, 51.72, 47.40 br, 39.20, 36.91 br, 33.78, 32.17 br,
28.95, 28.47 (3 C), 26.50, 23.71. MS (EI, 70 eV), m/z (Irel (%)):
320 [MH]+ (4), 264 (7), 236 (8), 222 (43), 192 (8), 180 (91), 178 (47),
176 (45), 140 (25), 138 (28), 96 (19), 94 (100), 93 (51), 88 (26),
41 (26), 39 (20). Found (%): C, 75.16; H, 10.43; N, 4.37.
C20H33NO2. Calculated (%): C, 75.19; H, 10.41; N, 4.38.
tertꢀButyl 11ꢀmethylꢀ13ꢀazabicyclo[7.3.1]tridecaꢀ3,10ꢀdiꢀ
eneꢀ13ꢀcarboxylate (4). A Grubbs II catalyst (30 mol.%, 0.127 g,
0.15 mmol) was added to a degassed solution of compound 3
(0.16 g, 0.5 mmol) in CH2Cl2 (250 mL) and the mixture was
refluxed with stirring for 10 days. The reaction progress was
monitored by TLC (hexane—EtOAc, 25 : 1). Then, the reaction
mixture was diluted with hexane (250 mL), CH2Cl2 was evapoꢀ
rated at reduced pressure. The solution in hexane was applied to
silica gel and purified by column chromatography (hexane—
EtOAc, 40 : 1) to obtain compound 4 (0.11 g, 78%) as a dense oil.
In the NMR spectrum, the signals are doubled and broadened
because of the hindered rotation around the N—Boc amide bond.
1H NMR (CDCl3, 300 MHz), : 5.67 and 5.57 (both td, total 1 H,
sixꢀmembered ring, J = 3.7 Hz, J = 11.3 Hz); 5.42—5.29 (br.m,
2 H, 2 CH=, macrocycle); 4.85 and 4.67 (both ddd, total 1 H,
=CHCHN, sixꢀmembered ring, J = 3.5 Hz, J = 8.0 Hz, J =
= 12.8 Hz); 4.59—4.55 and 4.43—4.40 (both br.m, total 1 H,
CH2CHN, sixꢀmembered ring); 2.87—2.70 (m, 1 H, CHaHb, sixꢀ
membered ring); 2.59—2.38 (br.m, 2 H, =CHCH2CHN, macꢀ
rocycle); 1.95—1.78 (br.m, 3 H, =CHCH2CH2 (macrocycle)
and CHaHb (sixꢀmembered ring)); 1.75 (br.s, 3 H, Me); 1.65—1.40
(m, 6 H, 3 CH2); 1.52 and 1.48 (both s, total 9 H, But). MS (EI,
70 eV), m/z (Irel (%)): 292 [MH]+ (0.5), 264 (4), 236 (8), 194 (5),
181 (12), 180 (100), 140 (9), 138 (12), 136 (28), 119 (20), 94 (39),
91 (10), 41 (8). Found (%): C, 74.17; H, 10.05; N, 4.87.
C18H29NO2. Calculated (%): C, 74.18; H, 10.03; N, 4.81.
11ꢀMethylꢀ13ꢀazabicyclo[7.3.1]tridecaꢀ3,10ꢀdiene hydroꢀ
chloride (7). Bicyclic NꢀBoc derivative 4 (0.2 g, 0.69 mmol) was
dissolved in dioxane (0.5 mL), followed by the addition of 4 M
solution of HCl in dioxane (0.5 mL, 2.0 mmol) and heating of
the reaction mixture at 70 C for 30 min3 until the starting comꢀ
pound 4 disappeared Then, the mixture was concentrated, the
Xꢀray diffraction studies of compound 7•2CHCl3. Crystals
–
C15H24Cl7N (M = 466.50) are triclinic, space group P1 , at
T = 100.0(2) K a = 9.6266(4) Å, b = 10.7701(5) Å, c = 11.4395(5) Å,
 = 69.769(1),  = 79.375(1),  = 79.796(1), V = 1085.49(8) Å3,
Z = 2, dcalc = 1.427 g cm–3, F(000) = 480,  = 0.913 mm–1. The
unit cell parameters and intensities of 12389 reflections (5201
independent reflections, Rint = 0.018) were measured on a Brukꢀ
er SMART APEXꢀII CCD automated threeꢀcircle diffractometer
((MoꢀK) radiation, graphite monochromator, ꢀ and ꢀscan
techniques, 2 = 56). The structure was solved by direct methꢀ
ods and refined by the fullꢀmatrix least squares method on F2 in
anisotropic approximation for nonhydrogen atoms. The crystal
contains two solvent molecules of chloroform per one molecule
of compound. The hydrogen atoms of the amino group were
found objectively in the difference Fourierꢀsyntheses and
included in the refinement with the fixed positional paraꢀ
meters and the isotropic displacement parameters Uiso(H) =
= 1.2Ueq(N). Position of other hydrogen atoms were calculatꢀ
ed geometrically and included in the refinement with the fixed
positional parameters (a riding model) and isotropic displaceꢀ
ment parameters (Uiso(H) = 1.5Ueq(C) for the Me group and
Uiso(H) = 1.2Ueq(C) for other groups). The final divergence
factors are R1 = 0.035 for 4507 independent reflections with
I  2(I) and wR2 = 0.086 for all the independent reflections.
The maximal and minimal values of the residual electron density
peaks are 0.828 and –0.868 e Å3, respectively. All the calculaꢀ
tions were performed using the SHELXTL software.14 Tables
of atomic coordinates, bond distances, bond and torsional anꢀ
gles, and anisotropic temperature parameters for compound
7•2CHCl3 were deposited with the Cambridge Crystallographic
Data Center (CCDC 1006121).
This work was financially supported by the Council on
Grants at the President of the Russian Federation (Program
of State Support for Leading Scientific Schools of the
Russian Federation, Grant NShꢀ69.2014.3) and the Preꢀ
sidium of the Russian Academy of Sciences (Program Pꢀ8).
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Received June 3, 2014;
in revised form July 18, 2014