Microwave-assisted synthesis of 2-substituted 4,5,6,7-tetrahydro-1,3-thiazepines from 4-aminobutanol

Article abstract of DOI:10.3762/bjoc.16.5

A general procedure for the synthesis of 2-substituted tetrahydro-1,3-thiazepines by MW-assisted cyclization of 4-thioamidobutanols is presented. The acyclic precursors were prepared in high overall yields by an expeditious three-step diacylation/thionati

Full text of DOI:10.3762/bjoc.16.5

Microwave-assisted synthesis of 2-substituted 4,5,6,7-tetra-
hydro-1,3-thiazepines from 4-aminobutanol
María C. Mollo, Natalia B. Kilimciler, Juan A. Bisceglia and Liliana R. Orelli*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 32–38.
Universidad de Buenos Aires. CONICET. Departamento de Química
Orgánica, Facultad de Farmacia y Bioquímica. Junín 956, (1113)
Buenos Aires, Argentina
doi:10.3762/bjoc.16.5
Received: 26 October 2019
Accepted: 11 December 2019
Published: 06 January 2020
Email:
Liliana R. Orelli* - lorelli@ffyb.uba.ar
Associate Editor: I. Baxendale
*
Corresponding author
©
2020 Mollo et al.; licensee Beilstein-Institut.
Keywords:
License and terms: see end of document.
cyclodehydration; medium-size heterocycles; microwaves; PPSE;
tetrahydrothiazepines
Abstract
A general procedure for the synthesis of 2-substituted tetrahydro-1,3-thiazepines by MW-assisted cyclization of 4-thioamidobu-
tanols is presented. The acyclic precursors were prepared in high overall yields by an expeditious three-step diacylation/thionation/
deprotection sequence from 4-aminobutanol. Microwave-assisted ring closure of 4-thioamido alcohols promoted by trimethylsilyl
polyphosphate (PPSE) in solvent-free conditions allowed for the synthesis of several hitherto unreported seven-membered imino-
thioethers bearing 2-aryl, alkenyl, aralkyl and alkyl substituents. The cyclodehydration reaction is likely to involve an SN2-type dis-
placement and affords good to excellent yields of the desired heterocycles in very short reaction times.
Introduction
Thiazolines (4,5-dihydrothiazoles) are widely studied hetero- their bioactivities [18,19] and as valuable synthetic intermedi-
cycles due to their multiple applications as antibiotics [1], ates [20-22].
antiproliferative agents [2], anti-inflammatories [3] and
antithrombotics [4]. They are also found in many bioactive On the other hand, the seven-membered iminothioethers
natural products [5-8], some of which display anti-HIV-1 [9] (4,5,6,7-tetrahydro-1,3-thiazepines) have remained almost
and antimitotic activities [10], among others. Thiazolines also unexplored. This virtual void is probably due to the known
find use in organic synthesis as building blocks in drug difficulty of the annulation of seven-membered heterocyclic
discovery, and as ligands in metal-catalyzed reactions [11-16]. rings. In fact, ring closure reactions leading to medium-sized
Their six-membered homologues (5,6-dihydro-4H-1,3- heterocycles are hampered by unfavourable entropic and
thiazines) are also compounds of broad interest [17], due to enthalpic factors, and are usually characterized by harsh reac-
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Beilstein J. Org. Chem. 2020, 16, 32–38.
tion conditions, long reaction times, low yields and/or competi- As part of an ongoing program on the applicability of PPE and
tive intermolecular reactions [23-28].
PPSE to the synthesis of nitrogen-containing heterocycles [48-
4], we developed a general method for the preparation of five-
5
In 1963, 2-(2,6-dichlorophenyl)-4,5,6,7-tetrahydro-1,3- and six-membered cyclic iminoethers (2-oxazolines and 5,6-
thiazepine was prepared by a double displacement reaction be- dihydro-4H-1,3-oxazines, respectively), by MW-assisted ring
tween 2,6-dichlorothiobenzamide and 1,4-butylene dibromide closure of amido alcohols promoted by PPA esters [54]. PPE
[
2
29]. In 1970, Mente prepared a dehydro analogue, namely and PPSE were then tested for the synthesis of the more chal-
-(4-chlorophenyl)-4,7-dihydro-1,3-thiazepine, via thermolysis lenging seven-membered heterocycles, namely 4,5,6,7-tetra-
of N-(4-chlorothiobenzoyl)-2-vinylaziridine [30]. No yields hydro-1,3-oxazepines. Instead of the target compounds, the
were reported for these reactions in either case. The synthesis of reactions led to the corresponding N-acylpyrrolidines, as
2
-phenyl-4,5,6,7-tetrahydro-1,3-thiazepine by cyclodehydra- disclosed by Hoogenboom et al. [55]. These results were
tion of N-(4-hydroxybutyl)thiobenzamide was attempted with intriguing, since the synthesis of some seven- and even eight-
different condensing agents: PPA (100 °C, 15 h), Burgess membered 1,3-diheterocycles had already been achieved by our
(
25 °C, 48 h) and PEG-Burgess (80 °C, 2 h) reagents, and under group using the PPA ester/MW system [48,50,52,53].
Mitsunobu conditions. In the first case, the 1H NMR spectrum
of the resulting product contained no signals in the aromatic Considering the lack of efficient methods for 4,5,6,7-tetra-
region [31]. The Burgess reagent led to 58% of the desired hydro-1,3-thiazepines, we decided to explore their synthesis by
product, while the modified PEG-Burgess reagent yielded a microwave-assisted ring closure of N-(4-hydroxybutyl)thio-
mixture of the thiazepine (17%) and the isomeric N-thioben- amides promoted by PPA esters. The preparation of these
zoylpyrrolidine (40%). The use of Mitsunobu conditions led ex- acyclic precursors is not straightforward, as it involves a selec-
clusively to the pyrrolidine derivative (76%) [32]. Therefore, tive thionation step.
the few literature examples reported until now are either
complicated by side reactions or involve long reaction times We present herein a novel method for the synthesis of seven-
and/or modest yields.
membered cyclic iminothioethers from commercially available
-aminobutanol. The sequence allows the preparation of
4
Polyphosphoric acid (PPA) esters PPE (ethyl polyphosphate) 4,5,6,7-tetrahydro-1,3-thiazepines bearing 2-aryl, aralkyl,
and PPSE (trimethylsilyl polyphosphate) are powerful and alkenyl and alkyl substituents.
versatile dehydrating agents that find many applications in
Results and Discussion
organic synthesis [33-42]. Their preparation is operationally
simple and requires readily available and inexpensive starting Synthesis of the acyclic precursors
materials. In addition, they are stable, non-toxic and environ- As previously mentioned, some difficulties were anticipated
mentally safe. These reagents play a dual role, as they enhance regarding the synthesis of 4-thioamidobutanols. In fact, the
the electrophilicity of nitriles, carbonyls and carbinols, and can direct thionation of the corresponding 4-amido alcohols cannot
also react irreversibly with water. Unlike PPA, a Brønsted acid be used, as the OH is almost as reactive as the amide carbonyl
incompatible with some acid-sensitive functionalities, PPE and toward Lawesson's reagent, the most commonly used thion-
PPSE are aprotic and mild reagents, with wide functional group ating agent [56]. Two syntheses of ω-thioamidobutanols were
tolerance. The use of PPA has some operational disadvantages: recently reported by Nguyen et al. The first one afforded
it is an extremely viscous liquid that requires high temperatures N-thiobenzoylaminobutanol in 62% yield [57], and the second
to allow stirring of the reaction mixture, in which organic com- one is not applicable to N-thioaroyl derivatives [58]. Thus, a
pounds do not generally dissolve, while PPA esters are soluble diacylation–thionation–saponification sequence [59] was
in many organic solvents [43].
implemented (Table 1), and the individual steps optimized
using 4-aminobutanol and benzoyl chloride as the starting mate-
Ring closure reactions leading to different heterocyclic cores rials.
are relevant among the synthetic applications of PPA esters.
The use of MW irradiation as the energy source in these The diacylation step using pyridine as the base required 24 h for
reactions [44-47] is of particular interest due to the many completion and gave a disappointingly low yield due to partial
advantages associated with MAOS: very short reaction hydrolysis of the ester moiety, while triethylamine performed
times, minimization of side products and consequent increment comparatively better (80%, 24 h). Finally, addition of 10 mol %
of the yields. To our knowledge, however, PPA esters of DMAP led to a higher yield (95%) in 1 h at room tempera-
had not been tested yet for the synthesis of cyclic iminothio- ture. Using the optimized protocol, compounds 1a–k were syn-
ethers.
thesized in high to excellent yields (Table 1). The more steri-
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Beilstein J. Org. Chem. 2020, 16, 32–38.
Table 1: Synthesis of compounds 3.
Compd.
R
1
2
3
Overall yield [%]a
a
b
c
d
e
f
g
h
i
C6H5
95b
90b
93b
95b
90b
94b
96b
90b
95b
86b
70b
93c,d
77c,d
95
93
95
93
quant.
87
90
92
95
95
87
82
87
91
98
90
83
80
80
93
71e
89e
85
73
72
77
82
80
78
69
72
55
65
56
59
4-ClC6H4
4-CH3C6H4
4-OCH3C6H4
4-NO2C6H4
2,4-Cl2C6H3
2-FC6H4
2-CH3C6H4
C6H5CHCH
C6H5CH2
C5H10
j
k
l
80
quant.
85
isopropyl
tert-butyl
m
87
aYields correspond to pure compounds. bThe reaction was performed with the acid chloride. cThe reaction was performed with the anhydride. dThe
reaction was carried out at reflux for 48 h. eThe reaction was carried out using 10% NaOH/methanol at reflux for 4 h.
cally hindered derivatives 1l,m required significantly longer The overall output of the optimized sequence (Table 1, last
reaction times.
column) ranged from 69 to 85% for thioaroyl derivatives, and
compares favourably with the literature data [57] for 3a (85 vs
Thionation of the resulting amidoester 1a with Lawesson's 62%, respectively). Compounds 3j,l,m afforded slightly lower
reagent (LR) was then examined. Using the reagent in excess, overall yields.
(
LR/substrate 2.5:1, toluene, reflux) the reaction was chemose-
lective toward the amide group, and compound 2a was ob- Synthesis of tetrahydro-1,3-thiazepines
tained in high yield (93%), although the unreacted LR compli- With the required precursors in hand, we examined next the
cated the isolation and purification of the product. Lowering the MW-assisted heterocyclization of N-thiobenzoylaminobutanol
molar ratio of the starting materials to strictly equivalent 0.5:1 promoted by PPA esters. Using PPE/CHCl3, irradiation of pre-
maintained the yield (95%) and considerably simplified the pro- cursor 3a in a closed vessel MW reactor (1 min, 90 °C) afforded
cedure, suppressing collateral products arising from decomposi- tetrahydrothiazepine 4a in 61% yield. The same reaction was
tion of the reagent. Under these conditions, compounds 2a–m then tested with PPSE/CH2Cl2 as the dehydrating agent, leading
were synthesized in excellent yields (Table 1).
to poorer results (30% yield). Based on our previous experi-
ence on related heterocycles, the cyclization was performed
Cleavage of the thioamide-ester 2a with K2CO3 in methanol/ with PPSE under solvent-free conditions (8 min, 90 °C), deliv-
water (30 min, 70 °C) afforded thioamido alcohol 3a (95%). ering 73% of compound 4a as the only product.
Thioaroyl derivatives 3b–k were prepared in high to quantita-
tive yields under these experimental conditions, except for the As already mentioned, Wipf et al. had previously reported that
more sterically hindered 2-methylphenyl derivative 2h, which cyclization of N-thiobenzoylaminobutanol with PEG-linked
required a longer reaction time (1 h) to achieve complete Burgess reagent and under Mitsunobu conditions led to signifi-
conversion to the desired product. Saponification of the less cant amounts of N-thiobenzoylpyrrolidine [32]. In fact, this
reactive isobutyryl and pivaloyl derivatives 2l,m required the kinetically favoured competitive reaction also occurs in the
use of a stronger base, longer reaction times and higher temper- closely related cyclization of N-benzoylaminobutanol with
ature (10% NaOH, reflux, 4 h).
PPSE, which leads exclusively to N-acylpyrrolidines. In order
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Beilstein J. Org. Chem. 2020, 16, 32–38.
to ascertain the structure of compound 4a, we compared its only products (Table 2). Ring closure of the more sterically
NMR spectra with those of N-thiobenzoylpyrrolidine hindered isobutyryl and pivaloyl thioamidoalcohols 3l,m was
(
Scheme 1) [60], confirming further the identity of the tetrahy- also successful, requiring slightly higher temperatures.
drothiazepine by analysis of its 2D NMR spectra (see Support-
ing Information File 1).
Table 2: Synthesis of 4,5,6,7-tetrahydrothiazepines 4.
Compd. 4 R
Time
min)
Temp.
(°C)
Yield
(%)a
(
a
b
c
d
e
f
g
h
i
C6H5
8
1
1
1
2
2
3
4
2
2
2
8
8
90
90
90
90
90
90
90
90
90
90
90
100
100
73
82
72
80
65
70
64
65
65
75
80
95
40
4-ClC6H4
4-CH3C6H4
4-OCH3C6H4
4-NO2C6H4
2,4-Cl2C6H3
2-FC6H4
2-CH3C6H4
C6H5CHCH
C6H5CH2
C5H10
j
k
l
Scheme 1: Chemical shift data for N-thiobenzoylpiperidine and com-
pound 4a.
isopropyl
tert-butyl
m
Using the optimized experimental conditions, several novel
aYields correspond to pure compounds.
2
-aryl-1,4,5,6-tetrahydro-1,3-thiazepines were synthesized in
good to high yields (Table 2). Due to the different reactivity of
each substrate, irradiation times and temperatures were individ-
ually adjusted by monitoring the disappearance of substrate Mechanistic considerations
(
TLC). Derivatives 4f–h, bearing ortho-substituted phenyl The cyclization of 4-amidobutanols promoted by PPA esters
groups afforded slightly lower yields. Our results compare leads exclusively to N-acylpyrrolidines instead of the corre-
favourably with the previously reported data (58% yield of 4a, sponding tetrahydro-1,3-oxazepines. This unexpected reaction
reaction time 48 h) as the method combines the efficiency of path is reasonable considering the relative ease of formation of
PPSE with the advantages of MAOS: very short reaction times five-membered rings as compared to the isomeric seven-mem-
and suppression of collateral products. In view of the encour- bered heterocycles together with the relatively poor nucleophi-
aging results obtained hitherto, we examined next the applica- licity of the carboxamide oxygen. An analogous effect was
bility of the method to the synthesis of derivatives bearing non- sometimes observed even in the sulfur analogues, as previously
aromatic 2-substituents, of which no examples were found in mentioned [32]. The differences between oxygen and sulfur
the literature. Previous studies on related cyclic iminoethers regarding electronegativity and polarizability may explain the
[
54] had shown that 2-alkyl derivatives are comparatively more differential behaviour of the PPSE promoted ring closure of
prone to hydrolysis, require harsher reaction conditions and tetramethylenic amido and thioamido alcohols. In both cases,
afford significantly lower yields. Despite this, and in order to PPSE would activate the OH group for nucleophilic attack, and
extend the scope of the method, we attempted the cyclization of the plausible reaction mechanism would involve an intramolec-
some representative examples of this type of substitution. The ular SN2-type displacement. However, the lower reactivity of
necessary precursors were prepared by the sequence depicted in the carboxamide oxygen (as an O-nucleophile), together with
Table 1. Regarding the cyclodehydration reaction, in the same the comparatively high activation energy associated to the for-
experimental conditions than before (neat PPSE, 1–8 min, mation of a seven-membered heterocycle would favour the
9
0 °C), thioamidoalcohols 3i–k afforded the corresponding competitive ring closure leading to the five-membered ring
tetrahydro-1,3-thiazepines 4i–k in good to high yields as the (Scheme 2, reaction a), which would involve attack of the
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5

Beilstein J. Org. Chem. 2020, 16, 32–38.
Scheme 2: PPSE promoted ring closure reactions of amido- and thioamido alcohols.
carboxamide nitrogen to the ω-carbon. On the other hand, the Funding
higher nucleophilicity of the sulfur in the thioamide would This work was supported by the University of Buenos Aires
overcome the difficulty of the formation of the seven-mem- (20020170100189BA).
bered ring, yielding exclusively the tetrahydrothiazepine
(
Scheme 2, reaction b).
ORCID® iDs
María C. Mollo - https://orcid.org/0000-0001-8040-2533
Liliana R. Orelli - https://orcid.org/0000-0001-7654-7211
Conclusion
We have developed a general method for the synthesis of
2
-aryltetrahydro-1,3-thiazepines, a heterocyclic core with very Preprint
few examples in the literature. The method involves as the key
step the microwave-assisted ring closure of thioamido alcohols
promoted by PPSE, presumably via an intramolecular SN2-type
A non-peer-reviewed version of this article has been previously published
as a preprint doi:10.3762/bxiv.2019.135.v1
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tive and catalyst free. The scope of the method includes the syn-
thesis of unprecedented examples of 2-alkyl, aralkyl and
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