Synthesis of C- and N-Substituted 1,5,2,6-Dithiadiazocanes –Electrophilic-Nucleophilic Thioamination (ENTA) Reagents

Article abstract of DOI:10.1002/adsc.202100424

A synthetic method is presented for S?N bond formation starting from cheap and affordable materials. We show that (un)substituted N-protected cyclic eight-membered C₂-symmetric sulfenamides have been prepared in a few steps using this procedure. The synthetic utility of these ambipolar derivatives was demonstrated in a variety of synthetic transformations affording different S,N-heterocyles of pharmaceutical relevance in one or two steps from simple starting materials. (Figure presented.).

Full text of DOI:10.1002/adsc.202100424

RESEARCH ARTICLE
DOI: 10.1002/adsc.202100424
Synthesis of C- and N-Substituted 1,5,2,6-Dithiadiazocanes –
Electrophilic-Nucleophilic Thioamination (ENTA) Reagents
Tomas Javorskis,+a, b Arminas Jurys,+a Gintautas Bagdžiūnas,b, c and
Edvinas Orentasa,*
a
Department of Organic Chemistry, Vilnius University, Naugarduko 24, LT-03225 Vilnius, Lithuania
E-mail: edvinas.orentas@chf.vu.lt
Center for Physical Sciences and Technology, Saulėtekio av. 3, LT-10257 Vilnius, Lithuania
Institute of Biochemistry, Life Sciences Center, Vilnius University, Saulėtekio av. 7, LT-10257 Vilnius, Lithuania
b
c
+
These authors contributed equally to this work.
Manuscript received: April 5, 2021; Revised manuscript received: May 6, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100424
Abstract: A synthetic method is presented for SÀ N bond formation starting from cheap and affordable
materials. We show that (un)substituted N-protected cyclic eight-membered C2-symmetric sulfenamides have
been prepared in a few steps using this procedure. The synthetic utility of these ambipolar derivatives was
demonstrated in a variety of synthetic transformations affording different S,N-heterocyles of pharmaceutical
relevance in one or two steps from simple starting materials.
Keywords: sulfenamide; thiomorpholines; heterocycles; annulation; thiiranium (episulfonium)
Introduction
Saturated heterocyclic compounds comprising two
heteroatoms are ideal scaffolds for various pharma-
ceuticals. Among them, S,N-heterocyclic compounds
have been shown to be very useful in designing potent
anti-inflammatory,[1] antimalarial (Artemisone B),[2]
antitumor (Prinomastat),[3] and antidiabetic[4] agents as
well as antibiotics for the treatment of extensively
resistant tuberculosis (Sutezolid).[5] In fact, three
saturated S,N-heterocyclic systems are listed in the top
one-hundred most frequently found molecular scaf-
folds within FDA approved drugs.[6] The assembly of
these types of heterocycles relies on the reactivity of
sulfur and nitrogen atoms as nucleophiles where the
Scheme 1. Retrosynthetic scheme of C-unsubstituted (a) and C-
substituted (b) 1,5,2,6-dithiadiazocanes.
annulation step is often accomplished by the ring
closure with a suitable bis-electrophile.[7] Recently, we
published a convenient and conceptually different
synthesis route for the formation of thiomorpholines,
benzothiomorpholines and thiazepines, which utilizes synthesized on the gram scale without chromatography.
cyclic C2-symmetric sulfenamide N-tosyl-1,5,2,6-di- However, the synthetic method that has been used to
thiadiazocane 1 (Scheme 1a) as an ambipolar synthon obtain 1 is limited to N-tosyl protected derivatives and
comprised of electrophilic sulfur and nucleophilic further functionalization of the carbon chain is not
nitrogen atoms.[8] The compound 1 is very reactive and easily achievable.
selective towards various nucleophiles and can be
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To broaden the synthetic utility of 1,5,2,6-dithiadia-
zocanes, we sought to develop a new, scalable
procedure that would enable us to freely tune the N-
protecting group and to introduce virtually any sub-
stituent into the carbon chain, preferably, generating
enantiomerically pure derivatives (Scheme 1b).
In the special case of N-tosyl derivative 1, the
ethylene chain can in principle be modified to produce
the chiral intermediate B, however, the presence of a
sulfur atom in the β position might compromise the
enantiomeric purity of the product. The formation of a
diastereomeric mixture of intermediates 3 might also
complicate the purification process. Moreover, the
corresponding β-halo sulfides en route to 3 or B
possesses a potentially genotoxic and hazardous
mustard-gas like structural motif. On the contrary,
intermediates A from a key retrosynthetic SÀ N bond
disconnection do not suffer from these limitations. In
fact, derivatives A can be accessed from abundant
chiral/racemic 1,2-aminoalcohols and are not limited to
any particular N-protecting group.
Results and Discussion
The synthesis of various 1,5,2,6-dithiadiazocanes is
outlined in Scheme 2.
The SÀ N bond formation was accomplished using
an intramolecular nucleophilic substitution reaction on
sulfur in compounds 7, which in turn were easily
obtained from the corresponding amino tosylates or
halides 5 and sodium benzenethiosulfonate (Scheme 2,
Method A). The latter is available in hundred-gram
quantities from the reaction between sodium benzene-
sulfinate and elemental sulfur. Treating compounds 7
with sodium hydride in THF afforded dithiadiazocanes
Scheme 2. Synthesis of 1,5,2,6-dithiadiazocane and isothiazoli-
dine derivatives: [a] gram scale; [b] racemic, mixture of diaster-
eomers; [c] two-step yield; [d] intermediate 7 directly cyclized
into 4.
4 in high yields. Alternatively, in the case of C- lidine) 8 (Scheme 2). Although the formation of 8
unsubstituted or ester functionalized dithiadiazocanes, using Method A was observed by mass spectrometry,
inexpensive cysteamine or cystine derivatives, respec- the majority of the compound was lost during acidic
tively, can be treated with sodium benzenesulfinate and workup as a result of its high reactivity towards
iodine to access intermediates 7 (Scheme 2, Method liberated benzenesulfinic acid. To overcome these
B). In addition to mono-substituted dithiadiazocanes, a difficulties and to cover product types beyond dithia-
collection of more elaborate derivatives having con- diazocanes, Method C based on disulfide activation
densed cyclohexane rings (4e) and benzoannulated with bromine was applied (Scheme 2).[10] This enabled
(4j) scaffolds, was prepared following the same not only the synthesis of elusive 8, but improved the
synthetic methods. Glutamic and aspartic acid derived yield of 1 as well (>10 g scale). On the other hand,
chiral compounds 4c,d, bearing readily transformable amino acid-derived dithiadiazocanes 4a–d could not
pendant ester functionality were also synthesized (from be obtained by this method in high yields highlighting
5, where LG=I).[9] In all cases, the yields of cyclized the broader scope of newly developed methods A and
products were impressive, taking into account the fact B.
that the formation of an eight-membered ring involved
1H NMR spectra of dithiadiazocanes 4 obtained
two distinct steps, namely, the initial intramolecular showed either excessive broadening or, in extreme
cyclization of 7 to form the corresponding unstable cases, two sets of proton resonances. The broadening
four-membered 1,2-thiazetidine and the subsequent of the spectra can be explained by the rather slow
intermolecular dimerization of the latter, as previously equilibration between different conformers of the
shown by us.[8]
eight-membered ring. For instance, the 1H NMR
Methods A and B were, however, not applicable for spectrum of compound 4j displayed two sets of
the synthesis of five-membered sulfenamide (isothiazo-
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resonances, the relative intensities of which changed accomplished simply by subjecting the alkaline sol-
upon prolonged heating (Scheme 3a, S2). ution of 9 to air without any Cu (I) present.
Density-functional theory (DFT) calculations con- Remarkably, in contrast to 4j, the SÀ N bond in 10 was
firmed that two energetic minima corresponding to extremely inert to organolithium or Grignard reagents;
twist-boat and chair conformations separated by rela- it reacted only with n-BuLi at room temperature
tively high activation enthalpy (~80 kJmolÀ 1) can be exclusively forming unusual amide carbonyl 1,2-
identified (Figure S3, see the ESI).[11] The changes in addition product 11 with the strained sulfenamide ring
1H NMR spectrum of 4j upon heating thus corresponds being preserved. The striking difference in reactivity
to the equilibration of two conformers to thermody- and stability in carbamate-amide pair is even more
namic mixture. Interestingly, during the synthesis of 4j surprising considering the well-known high reactivity
we were not able to detect any trace of the four- of acyclic acylated sulfenamides.
membered N-Boc-1,2-thiazetidine[12] despite the fact
With access to gram-scale amounts of dithiadiazo-
that very similar amide derivative 10 is a known canes, we next envision to apply them in one-step
bench-stable compound and can be obtained in high synthesis of 2-aryl and 2,3-diarylthiomorpholines (14,
yield via oxidative Cu(I) catalyzed SÀ N bond forma- 16) from the corresponding styrenes and stilbenes,
tion (Scheme 3b).[13] In fact, we found that the ring respectively (Scheme 4).[14,15] To our delight, model
closure in a precursor 9 is so facile that it could be compound sulfenamide 1 was successfully activated
with methanesulphonic acid in dichloroethane to react
with double bond nucleophiles. Addition of a small
amount of water increased the yield, although the
reaction was slower compared to anhydrous conditions.
Most likely, the use of the biphasic system ensured a
small concentration of acid in the organic phase via
partitioning, thus preventing the polymerization of
sensitive starting materials. Indeed, the extremely
facile polymerization of styrenes with electron donat-
ing substituents limited the scope of our method to
neutral or electron deficient substrates. β-meth-
ylstyrene was also a good substrate providing the
cyclization product 14h in 95% yield.
The analogous condensation of stilbenes 15 pro-
ceeded readily and required no dilution of acid, likely
due to higher stability of the starting materials. The
Scheme 3. (a) Conformational equilibrium of 4j. (b) Synthesis
of N-acyl-benzothiazetidine derivative derivative and its reac-
tivity towards organolithium reagent.
Scheme 4. Sulfenoamidation of styrenes and stilbenes. [a] Mixture of stereoisomers; [b] Mixture of regioisomers.
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reaction also proceeded well with Ms- and Cbz- equilibrium between I and the corresponding Markov-
protected dithiadiazocanes. trans-stilbenes delivered nikov carbonium ion II. Depending on the lifetime of
trans-1,2-diarylthiomorpholines as exclusive products II, the stereochemical integrity of I can be lost if the
(Scheme 4). Interestingly, although mechanistic con- rotation around σ-bond in II is of comparable rate with
siderations (vide infra) and X-ray structure of 16a respect to ring closure. To test this hypothesis, cis-
1
supports trans-stereoselective process, vicinal H-1H stilbene was used as a starting material, producing a
coupling constants were unexpectedly small for all mixture of cis- and trans-thiomorpholines in 1: 0.6
derivatives synthesized. Diaxial arrangement of hydro- ratio. This indicates that σ-bond rotation is competing
gens, seen in X-ray structure of twisted boat conforma- with ring closure, however the latter process is faster
tion of 16a is obviously not realized in solution; the since a large fraction of cis-thiiranium is converted to
1
1
values 6.8–3.2 Hz for HÀ H coupling between ben- thermodynamically less stable cis- product. The
zylic protons (J2,3) are instead suggestive of a possible isomerization of cis-stilbene under reaction
conformation where these hydrogens are located conditions was ruled out by a control experiment.
between the axial and equatorial positions.[16] The Another control experiment with an excess of compet-
energetic profile of various conformers of 16a ing alcohol nucleophile provided no thiiranium open-
obtained by stepwise rotation of Ts group during the ing product, excluding the possibility of the involve-
computational analysis indeed revealed the presence of ment of water nucleophile in the cyclization
two local minima representing twist-boat and chair mechanism of styrenes. Unexpectedly, equilibration of
conformations. The computed chemical shifts and intermediate carbonium ions was also observed during
coupling constants were found to be in perfect agree- the formation of 14h starting from trans-β-meth-
ment with experimental values (see Page S61). ylstyrene. Since calculations indicate that trans-prod-
Deprotection of the Ts group in 16a restored a uct is thermodynamically more stable than cis-product
classical chair conformation and vicinal coupling by 30.4 kJmolÀ 1, the significant amount of the latter
constants (J2,3 =9.6 Hz, see Page S38).
observed might indicate some, yet not fully under-
Mechanistically, the treatment of sulfenamide with stood, stabilization of the cis transition state (for
acid increases sulfur electrophilicity due to protonation instance, by CÀ HÀ π interaction between methyl and
of adjacent nitrogen atom. Ensuing reaction with phenyl groups). Compound 13j with pendant sulfona-
alkene affords thiiranium (episulfonium) ion I with mide nucleophile, on the other hand, formed trans-
ethylene tethered amino group (Scheme 5a).[17,18]
stereoisomer as the sole product (Scheme 5b). This is
The tether, however, is too short for productive in accord with anchimeric assistance in thiirane IV
intramolecular backside attack by sulfonamide nitrogen ring opening. The azetidinium intermediate V formed
nucleophile. In the absence of an external nucleophile, is then opened intramolecularly without the involve-
thiiranium ion I undergoes ring opening-ring closure to ment of acyclic carbocation to form 14j with full
afford thiomorpholine. This process requires the stereo-control. Due to restricted rotation, indene
selectively afforded cis-product 14i, not accessible
using approaches based on classical anti-selective
aminosulfenylation.
The equilibrium between thiiranium and carbonium
ions has also been previously proposed to explain the
lack of full anti-stereospecificity in sulfenylation of
some electron rich alkenes, such as vinylether.[19]
Styrene and stilbene derived benzylic carbocations II
and III are also stabilized and therefore can easily
form via ring opening. This was not the case, however,
when aliphatic alkenes were used as substrates
(Scheme 5c). The corresponding thiomorpholines were
not obtained; the ring opening of VI by external
nucleophile took place instead.[20] The results highlight
the importance of the stability of carbocations in
directing the course of the reaction.
The synthetic utility of 1,5,2,6-dithiadiazocane and
isothiazolidines obtained was further demonstrated in a
series of transformations toward various S,N-hetero-
cycles (Scheme 6). Electron rich aromatic rings served
as reactive nucleophiles in acid-catalysed ring opening
reactions of 1 or 4 to afford products 18 which were
then cyclized into 3,4-dihydro-2H-benzo[b][1,4]
Scheme 5. Mechanistic details.
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group to produce 30. Using ester substituted dithiadia-
zocine 4k in analogous transformation with phenyl
acetylide, the Michael addition step in the oxidized
product required heating with base. Under these
conditions, elimination of the tosyl protecting group
took place to give unprotected thiazine 32.
To complete the full collection of S,N-heterocycles,
we have performed a single step acid-catalyzed trans-
formation of vinyl sulfide 33 into 3,4-dihydro-2H-1,4-
thiazine 34 through intermediate formation of thiomor-
pholine.
Finally, 9- and 10-membered O, S, N-heterocycles
37 were synthesized in two steps by quenching various
cycloalkene derived thiiranium ions with ethylene
glycol and then, performing ring closure using
Mitsunobu alkylation (Scheme 6d).
Conclusion
In summary, we have developed a general method to
access functionalized eight- (dithiadiazocanes) and
five-membered sulfenamides from easily available
starting materials forging SÀ N bond in a key step. The
synthetic utility of the new reagents obtained was
demonstrated in concise synthesis of various saturated
and unsaturated S,N-heterocycles. Significant differ-
ences in reactivity of nucleophile-tethered thiiaranium
ion, derived from styrenes/stilbenes and simple alkenes
were revealed, originating from carbocation-like tran-
sition state.
Experimental Section
General Procedure for the Preparation of
2,3-diarylthiomorpholines (16a as Example)
To an oven-dried reaction tube equipped with a magnetic stir
bar were subsequently added 1 (0.051 g, 0.11 mmol, 1.0 equiv.),
dry 1,2-dichloroethane (2.0 mL) and corresponding styrene
(0.060 g, 0.33 mmol, 3.0 equiv.) under argon atmosphere. The
Scheme 6. Synthetic applications of 1,5,2,6-dithiadiazocanes
and isothiazolidine.
°
reaction mixture was cooled to 0 C and methanesulfonic acid
(0.02 mL, 2.8 equiv.) was added dropwise. Ice bath was
removed and the reaction mixture was stirred at room temper-
ature for 2.5 h. Afterwards, the reaction was quenched with
Et3N (0.05 mL), diluted with dichloromethane, concentrated on
silica gel and purified by column chromatography (9:1 petrol
ether/ethylacetate) to afford 16a as a yellowish solid (0.078 g,
86%).
thiazines (benzomorpholines) 19 under Cu(I) catalysis
(Scheme 6a).[21] Hetero analogues 22–25 can be ac-
cessed in good yields and in a single step from 2-
fluoropyridine or dichloropyrimidine derivative via
ortho metalation and subsequent cyclization (Sche-
me 6b). Subjecting dithiadiazocanes to alkyne anions
The same reaction performed on 1.24 g (trans-stilbene) scale
also afforded ring opening products in good yields using methanesulfonic acid (3.0 equiv.) afforded 16a in 81%
yield.
(Scheme 6c). They were then elaborated into pharma-
ceutically relevant heterosystems. Namely, intermedi-
ate 27 was converted into benzylidene thiazolidine 28
using the acid catalyzed addition of sulfonamide to a
triple bond. One-pot ring-opening of 4j with 2-
bromophenyl acetylide and oxidation afforded 4H-
1
°
Rf =0.42 (5:1 PE/EtOAc). m.p. 94–95 C. H NMR (400 MHz,
CDCl3) δ 7.41 (d, J=6.7 Hz, 2H), 7.32–7.22 (m, 7H), 7.21–
7.15 (m, 3H), 7.04 (d, J=8.1 Hz, 2H), 5.65 (d, J=6.4 Hz, 1H),
4.31 (d, J=6.4 Hz, 1H), 4.09–3.96 (m, 1H), 3.62 (ddd, J=
14.6, 12.0, 3.7 Hz, 1H), 2.91 (td, J=12.2, 5.0 Hz, 1H), 2.74–
benzo[b][1,4]thiazine 29 in 99% yield. Lithiation of 29 2.64 (m, 1H), 2.35 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
143.02, 139.49, 139.41, 137.40, 129.33, 128.77, 128.55, 128.36,
resulted in N to C migration of the tert-butoxycarbonyl
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127.74, 127.69, 127.25, 63.42, 46.38, 41.30, 25.75, 21.58. FT-
IR νmax/cmÀ 1: 2956, 2920, 2855, 1723, 1492, 1450, 1336 (S=O),
1153 (S=O), 1088, 937, 754, 693, 659. HRMS (ESI) m/z: [M+
H]+ Calcd for C23H24NO2S2 410.1243; Found 410.1240.
Acknowledgements
[10] T. P. Shiau, D. A. Erlanson, E. M. Gordon, Org. Lett.
2006, 8, 5697–5699.
This research was funded by the Research Council of Lithuania
(grant no. S-MIP-17-46). We are grateful to Dr. Shannon
Stauffer for valuable comments.
[11] Recently, twisted-boat and chair conformations identical
to the ones described herein, separated by similar
activation heats, have been identified for all-carbon
analogues of dithiadiazocanes using DFT calculations
and IR spectroscopy, see: X. Shen, C. Viney, E. R.
Johnson, C. Wang, J. Q. Lu, Nat. Chem. 2013, 5, 1035–
1041.
[12] Only two 1,2-thiazetidine derivatives, stabilized by
extensive substitution (the corset effect), have been
reported so far: a) T. Otani, J. Takayama, Y. Sugihara, A.
Ishii, J. Nakayama, J. Am. Chem. Soc. 2003, 125, 8255–
8263; b) Y. Sugihara, K. Takeda, J. Zhao, Y. Aoyama, H.
Okuda, J. Nakayama, Chem. Lett. 2008, 37, 1234–1235.
[13] Z. Wang, Y. Kuninobu, M. Kanai, J. Org. Chem. 2013,
78, 7337–7342.
[14] For some synthetic applications of five-membered
sulfenamides: a) C. Spitz, J.-F. Lohier, J. S. O. Santos, V.
Reboul, P. Metzner, J. Org. Chem. 2009, 74, 3936–3939;
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Alom, N. Kaur, F. Wu, S. J. Saluga, W. Li, Chem. Eur. J.
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[16] Unusually small vicinal coupling constants for carbamate
protected 2,3-disubstituted thiomorpholines was also
briefly noted by Eliel in his report, see footnote 20 in:
J. L. Garcia Ruano, M. C. Martinez, J. H. Rodriguez,
E. M. Olefirowicz, E. L. Eliel, J. Org. Chem. 1992, 57,
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[17] Sulfenamide activation with acid: a) T. Hostier, V. Ferey,
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[18] For reviews on thiiranium chemistry, see: a) A. Matviit-
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ruhe Access Structures service www.ccdc.cam.ac.uk/
structures.
[20] For instance, in one experiment, the ppm amount of
methanol present as stabilizer in dichloromethane was
Adv. Synth. Catal. 2021, 363, 1–8
7
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RESEARCH ARTICLE
Synthesis of C- and N-Substituted 1,5,2,6-Dithiadiazocanes –
Electrophilic-Nucleophilic Thioamination (ENTA) Reagents
Adv. Synth. Catal. 2021, 363, 1–8
T. Javorskis, A. Jurys, G. Bagdžiūnas, E. Orentas*