Efficient synthesis of 6-amino-2-thiaspiro[3,3]heptane hydrochloride

Article abstract of DOI:10.1515/hc-2014-0210

A novel compound 6-amino-2-thiaspiro[3,3]heptane hydrochloride was synthesized in nine steps using 2,2-bis(bromomethyl)-1,3-propanediol as starting material, with an overall yield of 31%.

Full text of DOI:10.1515/hc-2014-0210

Heterocycl. Commun. 2015; 21(1): 1–4
Preliminary Communication
Yan Lu, Jin Wang, Jianyu Guo*, Yihong Tang, Suxia Zhang, Jianwei Tao, Lei Xiong, Xiujie Li
aEnfdfJiincgiyei Lnuot synthesis of 6-amino-2-thiaspiro[3,3]
heptane hydrochloride
Abstract: A novel compound 6-amino-2-thiaspiro[3,3]hep- acid, which are analogues of natural ornithine and
tane hydrochloride was synthesized in nine steps using γ-aminobutyric acid. These amino acids are sterically
2,2-bis(bromomethyl)-1,3-propanediol as starting mate- constrained compounds and can be selective ligands for
rial, with an overall yield of 31%.
various biological targets that are especially popular in the
design of peptidomimetic drugs. The sterically constrained
2,2-bis- cyclobutane diamine derivative 6-amino-3-azaspiro[3,3]
heptane has been evaluated as inhibitor of kinases CDK1,
CDK2, CDK5, GSK-3, and PLK and can be used as insecti-
cides and acaricides [14]. Fang et al. [15] have reported a
new class of indole spiro compounds, which can be used
for the treatment and prophylaxis of respiratory syncytial
virus infection. Rice and Gorgan [16] have reported that the
bismethonium salt derivatives of spiro[3,3]heptane have a
weak hypotensive and curarimimetic activity. Therefore,
design and synthesis of new spiro[3,3]heptane compounds,
especially the spiro heterocyclic compounds, with better
Keywords:
6-amino-2-thiaspiro[3,3]heptane;
(bromomethyl)-1,3-propanediol; synthesis.
DOI 10.1515/hc-2014-0210
Received December 22, 2014; accepted December 23, 2014
Introduction
Unique properties of spiro heterocyclic compounds are
spiroconjugation, spirohyperconjugation, and anomeric
effect. Because their special space configurations can
usually match different spatial structures of macromol-
ecules in organisms, these compounds can show sig-
nificant biological activity [1]. The spiro compounds are
widely used as a pharmacophore unit in the synthesis of
antineoplastic [2], antidepressant [3, 4], antiviral [5], anti-
bacterial [6], and antianxiety [7–9] drugs.
biocompatibility are of great significance for the develop-
ment and efficacy of new drug screening.
In this paper, the short and efficient synthesis of a
novel compound 6-amino-2-thia-spiro[3,3]heptane hydro-
chloride (10in Scheme 1) is reported. The cheap compound
2,2-bis(bromomethyl)-1,3-propanediol (1) was used as the
starting material. To protect the two exposed hydroxyls in
1, as originally proposed by Allinger and Tushaus [17], its
dioxane dibromo derivative 2 was used in the synthesis.
The treatment of dibromide 2 with malonic ester under
basic conditions gave a diester derivative 3 with a cyclob-
utane structure. Similar syntheses have been reported
[18]. This diester was hydrolyzed to the dicarboxylic acid
4. After a subsequent decarboxylation process [19], the
monocarboxylic acid 5 was obtained. The resultant mono-
carboxylic acid derivative 5 was efficiently converted into
N-Boc-protected amino derivative 6 by treatment with
diphenylphosphoryl azide (DPPA) and triethylamine
Spiro[3,3]heptane and its derivatives has recently been
used as the surrogates of piperazines, piperidines, morpho-
lines, and thiomorpholines, which display pharmacologi-
cal activity [10–12]. For example, Radchenko et al. [13] have
reported the synthesis of 6-amino-2-azaspiro[3,3]heptane-
6-carboxylic acid and 2-azaspiro[3,3]heptane-6-carboxylic
*Corresponding author: Jianyu Guo, Department of Chemistry,
Shanghai Normal University, Shanghai 200234, China,
e-mail: luuyann@sit.edu.cn
Yan Lu: School of Engineering and Innovation, Shanghai Institute
of Technology, Shanghai 201418, China; and School of Chemical
and Environmental, Shanghai Institute of Technology, Shanghai
201418, China
Jin Wang, Yihong Tang, Suxia Zhang, Jianwei Tao, Lei Xiong,
Xiujie Li and Jingyi Luo: School of Chemical and Environmental,
Shanghai Institute of Technology, Shanghai 201418, China
(Et
3N) in tert-butanol (t-BuOH). There are two ways of con-
verting carboxylic acid to amine reported in the literature.
In the first method, carboxylic acid is allowed to react
with thionyl chloride or ethyl chloroformate to give an acyl
chloride or ester, the treatment of which with ammonium
hydroxide produces an amide. The amide can then be
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ꢀY. Lu et al.: 6-Amino-2-thiaspiro[3,3]heptane hydrochloride
2ꢀ
Br
Br
CHO
HO
O
O
Br
CO Et
diethyl malonate
2
O
Ph
Br
CO Et
NaH, DMF, 78.7%
TsOH, 91.6%
2
Ph
O
OH
1
3
2
O
O
DPPA, N(Et)
CO H
KOH, EtOH
81.3%
3
2
Py
Ph
Ph
O
CO H
2
t-BuOH, 76.4%
heat, 98.5%
CO H
2
O
4
5
O
OMs
OMs
OH
H , Pd/C
N(Et)
2
3
Ph
O
NHBoc
BocHN
BocHN
MsCl, 100%
100%
OH
6
7
8
Na S
2
HCl/EA
87.5%
S
NHBoc
S
NH ·HCl
2
DMSO, 81%
9
10
Scheme 1ꢀTotal synthesis of 6-amino-2-thiaspiro[3,3]heptane hydrochloride (10).
1
points were measured on a WRS-2A apparatus. H NMR (400 MHz)
and 13C NMR (100 MHz) spectra were recorded on a Bruker AVANCE
400 spectrometer at room temperature. FT-IR spectra were obtained
in KBr pellets on Avatar360 spectrometer. Mass spectra were acquired
using a Waters Acquity-Quaptro Premier spectrometer equipped
with electrospray ionization (ESI) source or chemical ionization (CI)
source.
converted into an amino derivative [20, 21]. This method is
complex and the yield is low. The superior second method
[22–24] is shown in Scheme 1. Then, the protected diol
moiety in 6 is deprotected by reduction with hydrogen to
give the diol 7. This reaction was followed by mesylation,
which yielded the bis-methanesulfonate ester 8, the bis-
sulfonate functionality of which was transformed into a
thiaspiro derivative 9 by reaction with sodium sulfide. In
principle, the introduction of the sulfur atom in 9 could be
accomplished starting with the bis-halomethyl analogues
of 8. Such preparations are common in the literature
[25–28]. However, compound 7 proved to be difficult to
convert to a halide derivative. By contrast, the sulfonyla-
tion of 7 was efficient, and the resultant bis-ester 8 was
easily cyclized into the thia derivative 9. As can be seen
in Scheme 1, the desired product 10 was obtained by acid
hydrolysis of the Boc-protected 2-thiaspiro[3,3]heptane 9.
In summary, 6-amino-2-thia-spiro[3,3]heptane (10)
was successfully prepared in nine steps from commercially
available starting materials, with an overall yield of 31%.
The efficient synthetic procedures were designed based on
a critical evaluation of analogous literature preparations.
5,5-Bis(bromomethyl)-2-phenyl-1,3-dioxane (2)
To a four-neck flask equipped with a thermometer, water segregator,
and condenser, 1,3-dibromo-2,2-dihydroxymethylpropane (1, 164.9 g,
0.63 mol), benzene (250 mL), benzaldehyde (73.5 g, 0.69 mol), and
p-toluenesulfonic acid (1.1 g, 5.78 mmol) were added. The mixture
was heated under reflux until water removal was completed, then
cooled to ambient temperature, washed with aqueous sodium car-
bonate, dried with anhydrous potassium carbonate, and concen-
trated under reduced pressure, and the residue was crystallized from
methanol at -10°C to give product 2 (202 g, 92%) as a white solid; mp
70.8–71.0°C; IR: 3095, 3030, 3017, 2863, 2834, 2749, 2714, 1960, 1495,
1450, 1259, 1121, 1029, 832, 743, 694, 683, 667, 643 cm-1; CI-MS: m/z
350.85 [(M+H) ]; 1H NMR (CDCl3): δ 7.48–7.24 (5H, m), 5.39 (1H, s), 4.24
+
(2H, d, J ꢀ=ꢀ 12 Hz), 3.97 (2H, s), 3.84 (2H, d, J ꢀ=ꢀ 12 Hz), 3.30 (2H, s);
13C NMR (CDCl3): δ 137.5, 129.5, 128.6, 126.3, 102.5, 72.2, 37.6, 36.3, 34.7.
Anal. Calcd for C12H14Br2O2: C, 41.17; H, 4.03; Br, 45.65. Found: C, 41.19;
H, 4.00; Br, 45.64.
Experimental details
Reactions were monitored by thin-layer chromatography (TLC) using
Sanpont Silica gel GF254 plates. In addition, preparative chromatog-
raphy (flash chromatography) was performed on silica gel (200–300
mesh) column, eluting with pentane/ethyl acetate (9:1). Melting
7-Phenyl-6,8-dioxa-spiro[3,5]nonane-2,2-dicarboxylic
acid diethyl ester (3)
Diethyl malonate (22.3 g, 0.14 mol) was added dropwise to a sus-
pension of sodium hydride (5.4 g, 60%) in DMF (230 mL). Then,
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Y. Lu et al.: 6-Amino-2-thiaspiro[3,3]heptane hydrochlorideꢀ
5,5-bis-(bromomethyl)-2-phenyl-1,3-dioxane (2, 24.0 g, 0.07 mol) was additional 17 h, concentrated under reduced pressure, and treated
added, and the mixture was heated at 140°C for 4 h under N2 atmos- with potassium hydroxide (40 mL, 10%). The product was extracted
phere, cooled, and extracted with aqueous ammonium chloride and with ethyl acetate (3 ꢀ×ꢀ 50 mL), and the combined organic extracts
methyl tert-butyl ether. The organic layer was concentrated, and the were washed with water and saturated sodium chloride, dried with
residue was crystallized from petroleum ether to give 18.8 g (79%) of anhydrous sodium sulfate, and concentrated under reduced pressure
compound 3; mp 82.5–83.3°C; IR: 3092, 3037, 2855, 1962, 1724, 1498, to give a pink solid. The crude product was purified by column chro-
+
1478, 1458, 1274, 1172, 1098, 761, 702 cm-1; CI-MS: m/z 349.10 [(M+H) ] ; matography to obtain 6 (6.1 g, 76%); mp 137.6–137.9°C; IR: 3337, 2980,
1H NMR (CDCl3): δ 7.38–7.18 (5H, m), 5.36 (1H, s), 4.18 (4H, q, J ꢀ=ꢀ 7 Hz), 2926, 2851, 1682, 1651, 1533, 1389, 1368, 1345, 1313, 1109, 748 cm-1; ESI-
+
1
4.07 (2H, d, J ꢀ=ꢀ 12 Hz), 3.68 (2H, d, J ꢀ=ꢀ 12 Hz), 2.71 (2H, s), 2.14 (2H, s), MS: m/z 342.15 [(M+Na) ]; H NMR (CDCl ): δ 7.43–7.22 (5H, m), 5.38
1.22 (6H, t, J ꢀ=ꢀ 7 Hz); 13C NMR (CDCl3): δ 172.0, 138.2, 129.2, 128.5, 126.2, (1H, s), 4.68 (1H, s), 4.07–4.10 (2H, m), 3.913(1H, m), 3.78–3.74 (2H, m),
101.6, 75.5, 62.0, 47.4, 37.8, 31.8, 14.3. Anal. Calcd for C19H24O6: C: 65.50; 2.72 (1H, m), 2.00 (1H, m), 1.84 (1H, m), 1.51 (1H, m), 1.47 (9H, s); 13C
H: 6.94. Found: C: 65.51; H: 6.95.
NMR (CDCl3): δ 138.3, 129.2, 128.5, 126.3, 101.7, 74.9, 39.3, 35.1, 31.7, 28.6.
Anal. Calcd for C18H25NO4: C: 67.69; H: 7.89, N: 4.39. Found: C: 67.71; H:
7.88, N: 4.36.
7-Phenyl-6,8-dioxa-spiro[3,5]nonane-2,2-dicarboxylic
acid (4)
1-tert-Butoxycarbonylamino-3,3-bis(hydroxymethyl)
cyclobutane (7)
Compound 3 (39.7 g, 0.11 mol) was added to a solution of potassium
hydroxide 20.0 g, 0.30 mol) in ethanol (440 mL). The mixture was
heated for 30 min at 80°C and then cooled to 0°C, and the precipitate A solution of compound 6 (3.2 g, 10 mmol) in methanol (50 mL) was
of dipotassium salt of the title compound was filtered. This salt was treated with Pd (10% on charcoal, 0.6 g). The mixture was heated
then acidified with HCl to pH 4, and the mixture was extracted with to 45°C under a hydrogen atmosphere (balloon) and stirred for 17 h,
ethyl acetate. The organic layer was dried and concentrated, and the until the TLC results indicated the absence of compound 6. The mix-
residue was crystallized from petroleum ether to give compound 4 ture was then cooled to room temperature and filtrated. The filtrate
(27.1 g, 81%) as a white solid; mp 168.5–169.6°C; IR: 3047, 2717, 2683, was concentrated under reduced pressure. The crude product was
1741, 1709, 1459, 1309, 1101, 932, 902, 696; ESI-MS: m/z 291.05 [(M-H)-]; crystallized from petroleum ether to give 7 (2.3 g, 100%) as a white
1H NMR [dimethyl sulfoxide (DMSO)-d6]: δ 12.61 (2H, s), 7.34–7.28 (5H, solid; mp 113.0–113.4°C; IR: 3373, 2977, 2932, 1682, 1526, 1390, 1366,
+
m), 5.36 (1H, s), 3.92 (2H, d, J ꢀ=ꢀ 12.0 Hz), 3.70 (2H, d, J ꢀ=ꢀ 12.0 Hz), 2.47 1171, 1042, 1026; ESI-MS: m/z 254.00 [(M+Na) ]; 1H NMR (DMSO-d6): δ
(2H, d, J ꢀ=ꢀ 20 Hz), 2.06 (2H, s). 13C NMR (DMSO-d6): δ 173.6, 139.2, 129.2, 6.92 (1H, d, J ꢀ=ꢀ 7.6 Hz), 4.45 (1H, t, J ꢀ=ꢀ 5.2 Hz), 4.33 (1H, d, J ꢀ=ꢀ 5.2 Hz),
128.6, 126.8, 101.0, 75.2, 47.6, 38.1, 32.2, 31.7. Anal. Calcd for C15H16O6: C: 3.78 (1H, q, J ꢀ=ꢀ 8.0 Hz), 3.29 (2H, d, J ꢀ=ꢀ 5.2 Hz), 3.21 (2H, d, J ꢀ=ꢀ 5.2 Hz),
61.64; H: 5.52. Found: C: 61.63; H: 5.52.
1.91–1.88 (2H, m), 1.59–1.54 (2H, m), 1.30 (9H, s); 13C NMR (DMSO-d6):
δ 155.2, 78.0, 66.6, 64.8, 34.5, 28.9. Anal. Calcd for C11H21NO4: C: 57.12;
H: 9.15, N: 6.06. Found: C: 57.13; H: 9.17, N: 6.09.
7-Phenyl-6,8-dioxaspiro[3,5]nonane-2-carboxylic acid
(5)
3-(tert-Butoxycarbonylamino)cyclobutane-1,1-diyl
bis(methanesulfonate) (8)
A solution of dicarboxylic acid 4 (8.0 g, 27.3 mmol) in pyridine
(80 mL) was heated under reflux for 15 h and then concentrated
in vacuo, and the residue was adjusted to pH 6 with 3 n hydrochloric Et3N (2.09 mL, 15 mmol) was added to a solution of compound 7 (1.2 g,
acid. The product was extracted with ethyl acetate (3 ꢀ×ꢀ 100 mL), and 5 mmol) in chloroform (10 mL). The mixture was cooled to -10°C,
the organic extracts were dried with anhydrous sodium sulfate and treated dropwise with mesyl chloride (0.93 mL, 12 mmol), returned to
concentrated under reduced pressure to give 5 (6.7 g, 98%) as a white ambient temperature, stirred for 16 h, washed with water (1ꢀ×ꢀ20 mL),
solid; mp 139.8–140.0°C; IR: 3067, 2955, 2939, 2769, 2676, 1693, 1497, and extracted with dichloromethane (3 ꢀ×ꢀ 20 mL). The extract was
+
1
1454, 1090, 698 cm-1; ESI-MS: m/z 249.05 [(M+H) ]; H NMR (DMSO- washed with brine (1 ꢀ×ꢀ 20 mL), dried with sodium sulfate, and then
d6): δ 11.90 (1H, s), 7.36–7.30 (5H, m), 5.38 (1H, s), 4.08 (1H, m), 3.91 concentrated under reduced pressure to give dimesylate 8 (2.0 g,
(1H, m), 3.70–3.63 (2H, m), 3.03 (1H, t, J ꢀ=ꢀ 8.4 Hz), 2.44–2.30 (1H, m), 100%) as a white solid; mp 100.1–100.8°C; IR: 3345, 2988, 2944, 1681,
1
2.27–2.09 (1H, m), 1.77–1.74 (2H, m); 13C NMR (DMSO-d6): δ 176.9, 139.3, 1646, 1539, 1353, 1287, 953, 814; ESI-MS: m/z 410.05 [(M-H)-]; H NMR
129.2, 128.6, 126.7, 101.0, 75.8, 74.9, 34.2, 33.8, 32.2, 28.3. Anal. Calcd for (CDCl3): δ 4.86 (1H, m), 4.24 (2H, s), 4.15 (2H, s), 4.10 (1H, s), 3.00 (6H,
C14H16O4: C: 67.73; H: 6.50. Found: C: 67.73; H: 6.51.
s), 2.34–2.29 (2H, m), 1.92–1.94 (2H, m), 1.37 (9H, s); 13C NMR (CDCl3):
δ 155.1, 72.3, 70.6, 37.6, 35.8, 34.8, 28.6. Anal. Calcd for C13H25NO4S2: C:
40.30; H: 6.50, N: 3.61, S: 16.55. Found: C: 40.30; H: 6.50, N: 3.62: S:
16.51.
2-tert-Butoxycarbonylamino-7-phenyl-6,8-
dioxaspiro[3,5]nonane (6)
6-tert-Butoxycarbonylamino-2-thiaspiro[3,3]heptane (9)
A solution of compound 5 (6.2 g, 0.025 mol) and Et3N (3.02 g, 0.03 mol)
in toluene (75 mL) was treated dropwise with DPPA (7.5 g, 27.5 mmol),
and the mixture was heated at 95°C for 1 h. Then, tertiary butyl alco- A solution of compound 8 (2.4 g, 6.19 mmol) and Na2S·9H2O (1.62 g,
hol (5.5 g, 0.075 mol) was added, and the mixture was stirred for an 6.75 mmol) in DMSO (50 mL) was stirred at 80°C for 16 h, diluted with
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4ꢀ
ation in drug discovery. Angew. Chem. Int. Ed. 2010, 49,
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petroleum ether, and the mixture was washed with water (1 ꢀ×ꢀ 20 mL)
and brine (1ꢀ ×ꢀ 20 mL). The organic layer was dried with sodium sul-
fate and concentrated under reduced pressure. The residue was puri-
fied by column chromatography to give compound 9 (1.15 g, 81%) as
a white solid; mp 93.8–94.6°C; IR: 3375, 2977, 2936, 1683, 1646, 1514,
1368, 1161, 624; ESI-MS: m/z 227.0 [(M-H)-]; 1H NMR (CDCl3): δ 4.52 (1H,
s), 3.90 (1H, s), 3.21 (2H, s), 3.11 (2H, s), 2.61 (2H, t, J ꢀ=ꢀ 8.0 Hz), 1.79 (2H,
t, J ꢀ=ꢀ 9.6 Hz), 1.39 (9H, s); 13C NMR (CDCl3): δ 45.3, 42.0, 39.1, 38.1, 28.6.
Anal. Calcd for C11H19NO2S: C: 57.61; H: 8.35, N: 6.11, S: 13.98. Found: C:
57.62; H: 8.35, N: 6.13, S: 13.95.
6-Amino-2-thiaspiro[3,3]heptane hydrochloride (10)
A solution of compound 9 (0.9 g, 3.9 mmol) in a solution of HCl in
ethyl acetate (2.5 m, 17 mL) was stirred at ambient temperature for
17 h, then concentrated under reduced pressure, washed with ether,
and filtered. Concentration gave the title compound 10 (0.58 g, 87%)
as a white solid; mp 241.7–243.8°C; IR: 2936, 2669, 2623, 2527, 2036,
+
1604, 1594, 1517, 1456, 1380, 1279; ESI-MS: m/z 129.90 [(M-HCl+H) ]; 1H
NMR (DMSO-d6): δ 8.3 (3H, s), 3.48–3.40 (1H, m), 3.16 (2H, s), 3.09 (2H,
s), 2.47–2.42 (2H, m), 2.21–2.16 (2H, m); 13C NMR (DMSO-d6); δ 42.8,
41.4, 38.9, 38.3. Anal. Calcd for C6H12ClNS: C: 43.49; H: 7.30, N: 8.45, S:
19.35. Found: C: 43.48; H: 7.31, N: 8.44, S: 19.31.
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