Synthesis of 8-oxa-2-azaspiro[4.5]decane

Article abstract of DOI:10.1007/s11172-020-2994-1

A convenient synthesis of new 8-oxa-2-azaspiro[4.5]decane from commercially available reagents based on tetrahydropyran-4-carbonitrile and 1-bromo-2-fluoroethane has been developed. This compound is promising for the production of important biologically active compounds.

Full text of DOI:10.1007/s11172-020-2994-1

Russian Chemical Bulletin, International Edition, Vol. 69, No. 10, pp. 2017—2019, October, 2020
2017
Synthesis of 8-oxa-2-azaspiro[4.5]decane
V. А. Оgurtsov and О. А. Rakitin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Е-mail: orakitin@ioc.ac.ru
A convenient synthesis of new 8-oxa-2-azaspiro[4.5]decane from commercially available
reagents based on tetrahydropyran-4-carbonitrile and 1-bromo-2-fluoroethane has been de-
veloped. This compound is promising for the production of important biologically active
compounds.
Key words: spiro compounds, 8-oxa-2-azaspiro[4.5]decane, synthesis, alkylation, hetero-
cyclization.
Spiro derivatives are bicyclic organic compounds
formed by two rings linked by one carbon atom. The
originality of spiro compounds lies in the fact that they
simultaneously possess 3D structural properties and inher-
ent rigidity.1 Spiro derivatives of heterocyclic compounds
are widely applied in the synthesis of biologically active
compounds and are met within natural compounds.
Currently, spiro compounds are attracting attention as
scaffolds in the search for modern drugs.2—9 The combina-
tion of the intrinsic complexity and, more importantly,
the rigidity of these scaffolds offer a number of advantages
for programmed drug discovery.
The introduction of at least one heterocycle into spiro
compounds significantly increases the value of this scaffold
as a precursor for the production of drugs. In particular,
spiro compounds containing saturated pyrrolidine ring are
intensively studied in reactions with compounds contain-
ing pharmacophoric groups, for example, 2,8-diaza-
spiro[4.5]decane (1),10 2,7-diazaspiro[4.5]decane (2),11
2,7-diazaspiro[4.4]nonane (3),12 2-oxa-7-azaspiro[4.4]-
nonane (4),13 8-oxa-2-azaspiro[4.5]decane (5), and
a number of others.
tors in the treatment or prevention of diseases or disorders
associated with steroid hormones or requiring concentra-
tion reduction of endogenous estradiol,16 as NO-in-
dependent and heme-dependent sGC stimulants that are
useful in the treatment of a variety of diseases.17,18 At the
same time, there were no data on the preparation methods,
properties, and spectral characteristics of 8-oxa-2-aza-
spiro[4.5]decane (5) itself. This work is devoted to the
development of the synthesis of spiro compound 5 and to
the proof of its structure.
Analysis of the literature on methods for the formation
of the pyrrolidine ring in 3,3-disubstituted derivatives
showed that the general approach is the reduction of
4-halogenobutanonitrile derivatives of the type 6 with
lithium aluminum hydride19 or hydrogen in the presence
of Raney nickel and aqueous ammonia in methanol,20
which leads to the closure of the pyrrolidine ring into
heterocycles 7 (Scheme 1). In turn, compounds 6 can be
easily obtained by alkylation of cyano derivatives 8 with
1,2-dihalogenoethanes in the presence of strong bases.
Scheme 1
Analysis of the literature found in the Reaxys and
SciFinder databases showed that synthesized 8-oxa-2-
azaspiro[4.5]decane derivatives (5) exhibited biological
activity. They are used as an FGFR4 inhibitor for the
treatment of hepatocellular carcinoma,14 as inhibitors of
the vanin-1 enzyme, which plays an important role in
metabolism and in inflammation,15 as 17β-HSD1 inhibi-
R1 + R2
=
,
R1 = R2 = Ph; X, Y = Cl, Br
We have shown that the generation of carbanion 9 from
commercially available tetrahydro-2H-pyran-4-carboni-
trile with lithium diisopropylamide followed by treatment
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2017—2019, October, 2020.
1066-5285/20/6910-2017 © 2020 Springer Science+Business Media LLC

Оgurtsov and Rakitin
2018
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 10, October, 2020
with 1-bromo-2-fluoroethane leads to C(1)-alkylated
tetrahydropyran ring at 1100 cm–1 in the IR spectra. The
1H NMR spectrum of nitrile 10 exhibits characteristic
signals for the protons of the CH2F group at δ 4.66 and
4.81 (J = 5.5 Hz), and its 13С NMR spectrum contains
two series of characteristic doublets of carbon atoms of
the —CH2CH2F fragment at δ 40.4 (J = 19.8 Hz) and
80.3 ppm (J = 168.4 Hz). At the same time, the IR spec-
trum of compound 10 also contains absorption bands
characteristic of the CH2F group at 2966 and 1028—
product 10 in high yield (Scheme 2).
Scheme 2
1011 cm–1, as well as the cyano group at 2236 cm–1
.
To conclude, we have developed an effective single
step synthesis of 8-oxa-2-azaspiro[4.5]decane (5) from
commercially available reagents. Note that nucleophilic
substitution of an inactivated aliphatic fluorine is a rather
rare case.
Experimental
1Н and 13С NMR spectra were registered for compounds 5
and 10 in CDCl3, for compound 5•HCl in DMSO-d6 using
a Bruker AM-300 spectrometer with working frequencies 300
and 75 MHz, respectively. Chemical shifts are presented in δ
using SiMe4 as standard. Melting points were determined using
a Kofler device and were not corrected. Mass spectra were reg-
istered using a Finnigan MAT INCOS 50 spectrometer with
electron impact (70 eV). High-resolution mass spectra were
registered using a Bruker micrOTOF II spectrometer with
electrospray ionization. IR spectra were registered using UR-20
spectrometer in KBr pellets. The reaction was monitored by TLC
using TLC Silica gel 60 F254 plates developed under UV lamp
and I2 vapors.
Reagents and conditions: i. BunLi, PriNH, THF, –78 °С; ii. THF.
The reduction of 4-(2-fluoroethyl)tetrahydro-2H-
pyran-4-carbonitrile (10) required a more detailed study.
It was found that during the reduction with hydrogen in
the presence of Raney nickel and aqueous ammonia in
methanol at 50 °C for 10 h or with a borane-tetrahydro-
furan complex in THF at 25 °C for 20 h a hard to separate
mixture of products is formed and a significant part of the
initial nitrile 10 remains (60—70%). The reduction did
not proceed when 10% Pd/C in 80% aqueous ethanol at
130 atm H2 was used as a catalyst. The target 8-oxa-2-
azaspiro[4.5]decane (5) was obtained in moderate yield
by treating compound 10 with lithium aluminum hydride
in THF. We found that the preparation of spiro compound
5 could be carried out in a single step from nitrile 9 in THF
without isolation of intermediate 10, and the yield of the
final product was higher (69%) than in the case of a two-
steps synthesis (54%). The free amine was converted into
hydrochloride 5•HCl. In this form the compound can be
stored at room temperature for a long time.
4-(2-Fluoroethyl)tetrahydro-2H-pyran-4-carbonitrile (10).
Solution of BunLi in hexane (15%, 30.8 mL, 49.2 mmol) was
added dropwise to the solution of diisopropylamine (6.3 g,
45.4 mmol) in THF (65 mL) at –30 °С. The mixture was kept
at this temperature for 30 min, cooled down to –78 °С, and
a solution of nitrile 9 (4.2 g, 37.8 mmol) in THF (8 mL) was
added dropwise. The solution was kept at –78 °С for another
hour, then a solution of 1-bromo-2-fluoroethane (3.4 mL,
45.4 mmol) in THF (8 mL) was added dropwise. The cooling
was removed, and the mixture was left at room temperature
for 16 h. Then, a saturated solution of ammonium chloride
(20 mL) was added dropwise, the aqueous layer was sepa-
rated, and the organic layer was dried over anhydrous mag-
nesium sulfate. The solvent was distilled off, and the residue
was distilled in vacuo. Yield 4.9 g (83%) of product 10. Light
yellow liquid, b.p. 130—132 °С (20 Torr), n 20 1.4533, Rf 0.39
D
(ethyl acetate—chloroform, 1 : 3). Found (%): C, 61.23; H, 7.56;
N, 8.78. С8H12FNO. Calculated (157.18): C, 61.13; H, 7.69;
N, 8.91. MS, m/z (Irel (%)): 157 [M]+ (52), 130 (16), 113 (62),
100 (45), 93 (56), 83 (95), 80 (100), 67 (83), 53 (58), 33 (45),
27 (75), 18 (63). 1H NMR, δ: 1.70 (m, 2 H, CH2—С—СH2);
1.95 (m, 3 H, CH2—С—СH2—CH2F); 2.05 (t, 1 H, CH2—С—
СH2—CH2F, J = 5.5 Hz); 3.72 (t, 2 H, CH2—O—СH2,
J = 12.1 Hz); 3.95 (m, 2 H, CH2—O—СH2); 4.66 (t, 1 H, CH2F,
J = 5.5 Hz); 4.81 (t, 1 H, CH2F, J = 5.5 Hz). 13C NMR, δ: 35.5
(2 С, CH2—С—СH2); 36.8 (1 С, CH2—С—СH2); 40.4 (1 С,
CH2—СH2F, J = 19.8 Hz); 64.5 (2 С, CH2—O—СH2); 80.3
The structure of new compounds 5 and 10 was proved
using high-resolution mass spectrometry, mass spectro-
metry, IR spectroscopy, and 1Н and 13С NMR spectroscopy.
Note that the mass spectra of 4-(2-fluoroethyl)tetra-
hydro-2H-pyran-4-carbonitrile (10) and 8-oxa-2-aza-
spiro[4.5]decane (5) exhibit signals of the molecular ion
[М]+, and there is a strong band characteristic of the

8-Oxa-2-azaspiro[4.5]decane
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 10, October, 2020
2019
(1 С, CH2—СH2F, J = 168.4 Hz); 121.8 (1 С, CN). IR (KBr),
ν/cm–1: 2966 (CF—H), 2928, 2856 (C—H), 2236 (CN), 1470,
1439, 1393, 1245, 1145, 1110 (CH2—O—СH2), 1028, 1011
(CH2—F), 915, 841, 733. HRMS, found m/z: 180.0798; cal-
culated for C8H12FNO [M + Na]+ 180.0795.
References
1. R. Rios, Chem. Soc. Rev., 2012, 41, 1060.
2. A. S. Ding, M. Meazza, H. Guo, J. W. Yang, R. Rios, Chem.
Soc. Rev., 2018, 47, 5946.
3. A. Yu. Barkov, N. S. Zimnitskiy, I. B. Kutyashev, V. Yu.
Korotaev, V. Ya. Sosnovskikh, Chem. Heterocycl. Compd.
(Engl. Transl.), 2018, 54, 43.
4. L M. Saliyeva, N. Yu. Slyvka, D. A. Mel´nyk, E. B. Rusanov,
R. I. Vas´kevich, M. V. Vovk, Chem. Heterocycl. Compd.
(Engl. Transl.), 2018, 54, 130.
5. I. B. Kutyashev, A. Yu. Barkov, V. Yu. Korotaev, V. Ya.
Sosnovskikh, Chem. Heterocycl. Compd. (Engl. Transl.), 2019,
55, 529.
6. I. B. Kutyashev, A. Yu. Barkov, N. S. Zimnitskiy, V. Yu.
Korotaev, V. Ya. Sosnovskikh, Chem. Heterocycl. Compd.
(Engl. Transl.), 2019, 55, 861.
7. V. Yu. Korotaev, N. S. Zimnitskiy, A. Yu. Barkov, I. B.
Kutyashev, V. Ya. Sosnovskikh, Chem. Heterocycl. Compd.
(Engl. Transl.), 2018, 54, 905.
8. E. V. Suslov, K. Yu. Ponomarev, D. V. Korchagina, K. P.
Volcho, N. F. Salakhutdinov, Russ. Chem. Bull., 2019, 68, 601.
9. V. D. Gvozdev, K. N. Shavrin, O. M. Nefedov, Russ. Chem.
Bull., 2019, 68, 2108.
10. J. Gunzner-Toste, G. Zhao, P. Bauer, T. Baumeister, A. J.
Buckmelter, M. Caligiuri, K. H. Clodfelter, B. Fu, B. Han,
Y.-C. Ho, N. Kley, X. Liang, B. M. Liederer, J. Lin, S. Mu-
kadam, T. O´Brien, A. Oh, D. J. Reynolds, G. Sharma,
N. Skelton, C. C. Smith, J. Sodhi, W. Wanga, Z. Wang,
Y. Xiao, P.-w. Yuen, M. Zak, L. Zhang, X. Zheng, K. W. Bair,
P. S. Dragovich, Bioorg. Med. Chem. Lett., 2013, 23, 3531.
11. K. Weinberg, A. Stoit, C. G. Kruse, M. F. Haddowa,
T. Gallagher, Tetrahedron Lett., 2013, 69, 4694.
8-Oxa-2-azaspiro[4.5]decane (5). А. A solution of nitrile
10 (4.71 g, 30 mmol) in THF (10 mL) was added dropwise to
a suspension of lithium aluminum hydride (1.4 g, 36 mmol) in
THF (40 mL), and the mixture was refluxed for 2 h. The solution
was cooled to 20 °C and neutralized with 20% NaOH solution.
The aqueous layer was separated, the organic one was dried
over anhydrous magnesium sulfate, and the solvent was
distilled off. Yield 2.75 g (65%) of product 5. Light yellow liq-
20
uid, n
1.4938, Rf 0.12 (ethyl acetate—chloroform, 1 : 3).
D
Found (%): C, 68.21; H, 10.32; N, 9.61. С8H15NO. Calculated
(%): C, 68.04; H, 10.71; N, 9.92. MS, m/z (Irel (%)): 141 [M]+
(30), 111(5), 84 (58), 43 (100), 35 (16), 28 (25). 1H NMR, δ:
1.59 (m, 4 H, CH2—С—СH2); 1.69 (t, 2 H, HN—CH2—СH2—C,
J = 7.3 Hz); 2.83 (s, 2 H, —HN—CH2—С); 3.06 (t, 2 H, С—CH2—
СH2—NH, J = 7.3 Hz); 3.36 (s, 1 H, NH); 3.68 (m, 4 H,
CH2—O—СH2). 13C NMR, δ: 36.9 (2 С, CH2—С—СH2); 37.9
(1 С, CH2—С—СH2); 40.7 (1 С, CH2—СH2—C); 45.8 (1 С,
CH2—СH2—NH); 58.4 (1 С, CH2—N—СH2—C); 65.6 (2 С,
CH2—O—СH2). IR (KBr), ν/cm–1: 3308 (N—H), 2923, 2848
(C−H), 1466, 1438, 1390, 1230, 1108 (CH2—O—СH2), 1060,
1019, 839, 564. HRMS, found m/z: 142.1228; calculated for
C8H15NO [M + H]+ 142.1226.
B. A solution of BunLi in hexane (15%, 6.9 mL, 11 mmol)
was added dropwise to a solution of diisopropylamine (1.11 g,
11 mmol) in THF (65 mL) at –30 °С. The reaction mixture was
maintained at this temperature for 30 min, cooled down to
–78 °С, and a solution of nitrile 9 (1.11 g, 10 mmol) in THF
(5 mL) was added dropwise. The solution was kept at –78 °С for
another hour, then solution of 1-bromo-2-fluoroethane (0.74 mL,
10 mmol) in THF (3 mL) was added dropwise. The cooling was
removed and the mixture was left at room temperature for
16 h. Then, a saturated solution of ammonium chloride
(10 mL) was added dropwise, the aqueous layer was sepa-
rated, and dried with anhydrous magnesium sulfate. The
obtained solution was added dropwise to the suspension of
lithium aluminum hydride (0.42 g, 11 mmol) in THF (10 mL),
the reaction mixture was refluxed for 2 h, cooled to 20 °С, and
neutralized with 20% NaOH solution. The aqueous layer was
separated, and the organic one was dried over anhydrous
magnesium sulfate, the solvent was distilled off. Yield 0.97 g
(69%) of spiro compound 5.
8-Oxa-2-azaspiro[4.5]decane hydrochloride (5•HCl).
Hydrogen chloride solution in 1,4-dioxane (4 М) was added
dropwise to a solution of 8-oxa-2-azaspiro[4.5]decane 5 (1.41 g,
10 mmol) in diethyl ether (15 mL) until pH 5 was reached. The
mixture was stirred for 15 min, the precipitate was filtrated,
washed with ether, and dried in air. Yield 1.64 g (93%) of salt
5•HCl. White crystals, m.p. 124—125 оС. Found (%): C, 53.93;
H, 9.15; N, 7.62. С8H16ClNO. Calculated (%): C, 54.08; H, 9.08;
N, 7.88. 1H NMR, δ: 1.55 (m, 4 H, CH2—С—СH2); 1.80 (t, 2 H,
CH2—СH2—C—, J = 7.7 Hz); 2.98 (t, 2 H, HN—CH2—С,
J = 5.9 Hz); 3.19 (m, 2 H, CH2—СH2—NH); 3.54 (t, 4 H,
CH2—O—СH2, J = 5.1 Hz); 9.57 (br.s, 2 H, NH•HCl). 13C NMR,
δ: 35.1 (2 С, CH2—С—СH2); 35.2 (1 С, CH2—С—СH2); 43.6
(1 С, CH2—СH2—C); 53.9 (2 С, CH2—N—СH2); 64.7 (2 С,
CH2—O—СH2).
12.C. G. Overberger, D. W. Wang, R. K. Hill, G. R. Krow, D. W.
Ladner, J. Org. Chem., 1981, 46, 2757.
13. Z. Cheng, X. Han, M. Jiang, J. Wang, Y. Wang, S. Yang, Pat.
WO2018/19521, 2018.
14. W. Yong, Z. Liwen, W. Zhanguo, J. Jianfeng, D. Peng, L. Kun-
zhi, W. Dongdong, W. Hui, T. Ying, Pat. CN109422760,
2019.
15. A. Casimiro-Garcia, J. W. Strohbach, D. Hepworth,
F. E. Lovering, C. Choi, C. P. Allais, S. W. Wright, Pat.
WO2018/11681, 2018.
16. L. Hirvelä, M. Hakola, T. Linnanen, P. Koskimies, C. Stjern-
schantz, Pat. WO2018/224736, 2018.
17. T. Akai, J. Moore, N. R. Perl, R. R. Iyengar, A. Mermerian,
G-Y. J. Im, T. W.-H. Lee, T. C. Hudson, G. R. Rennie,
J. Jia, P. A. Renhowe, T. C. Barden, X. Y. Yu, J. E. Sheppeck,
K. Iyer, J. Jung, Pat. WO2014/144100, 2014.
18. N. Galapagos, N. Desroy, B. Heckmann, R. C. X. Brys, A. M.
Joncour, C. Peixoto, X. M. Bock, C. G. Housseman, Pat.
WO2014/202458, 2014.
19. B. Mathys, C. Müller, M. Scherz, T. Weller, M. Clozel,
J. Velker, D. Bur, Pat. WO2005/30209, 2005.
20. Q. Tang, M. Xu, S.-H. Chen, G. Li, Synth. Commun., 2007,
37, 3793.
Received February 18, 2020;
in revised form March 17, 2020;
accepted March 23, 2020