Tetrahedron Letters xxx (2014) xxx–xxx

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Tetrahedron Letters

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Cyclisation of benzo[b]thiophen-3(2H)-one 1,1-dioxideand 1,3-indanedione into novel methylene bridged polycyclicdiazocines and their rearrangement into spirocyclic compounds

http://dx.doi.org/10.1016/j.tetlet.2014.06.1060040-4039/� 2014 Elsevier Ltd. All rights reserved.

⇑ Corresponding author. Tel.: +371 67014928; fax: +371 67550338.E-mail address: arkady@osi.lv (A. Sobolev).

Please cite this article in press as: Cekavicus, B.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.06.106

Brigita Cekavicus, Brigita Vigante, Martins Rucins, Aiva Plotniece, Karlis Pajuste, Marina Petrova,Sergey Belyakov, Gunars Duburs, Arkadij Sobolev ⇑Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia

a r t i c l e i n f o

Article history:Received 30 April 2014Revised 4 June 2014Accepted 26 June 2014Available online xxxx

Keywords:Mannich reactionInternal rearrangementStructure revisionSpiroheterocycleMethylene bridged polycyclic diazocine

a b s t r a c t

Methylene bridged polycyclic diazocines 2a and 2b were obtained in reactions of 1,3-indanedione, orbenzo[b]thiophen-3(2H)one-1,1-dioxide, or 2,20-methylene derivatives 3a,b with paraformaldehydeand ammonia or hexamethylenetetramine in acidic medium. A structural revision of methylene bridgedbenzothieno-diazocine 2b based on results of X-ray diffraction analysis is presented. Internalrearrangement of methylene bridged polycyclic diazocines into spiroheterocycles 4a,b is also described.

� 2014 Elsevier Ltd. All rights reserved.

The methylene bridged diazocine scaffold is present in severalimportant classes of compounds such as Tröger’s bases, which havea methylene linkage between two nitrogen atoms, and bispidineswith a methylene bridge between two carbon atoms. Severallupine alkaloids of the sparteine sub-group contain methylenebridged diazocine scaffolds flanked on both sides with cyclic sub-stituents.1,2 Approaches to the 3,7-diazabicyclo[3.3.1]nonane(bispidine) framework are mainly based on double Mannich con-densations,3–5 intramolecular cyclisations3,6 or by ring-opening ofdiazaadamantanes.7 Several literature reviews covering the scopeand limitations of bispidine derivative synthesis have been pub-lished.8,9 The most common synthetic approach to Tröger’s basesincludes condensation of anilines with formaldehyde or a formal-dehyde source such as paraformaldehyde or hexamethylenetetra-mine (HMTA).10 Due to the increasing practical importance ofTröger’s base analogues, further developments of this methodologyhave been elaborated by many research groups.10–13

Benzo[b]thiophen-3(2H)-one 1,1-dioxide (1b), a sulfonyl groupcontaining analogue of 1,3-indanedione (1a), is a versatile reagentin the synthesis of various condensed polycyclic systems. Thus,condensation of benzo[b]thiophen-3(2H)-one 1,1-dioxide (1b)with various aldehydes, followed by Hantzsch cyclisation with

alkyl 3-aminocrotonates furnishes the polycyclic dihydrobenzothi-enopyridine framework.14 Recently, we have described thesynthesis of a novel heterocyclic system, 3H,20H-spiro[benzo[b]thi-eno[3,2-b]pyridine-3,20-benzo[b]thiophene] from benzo[b]thio-phen-3(2H)-one 1,1-dioxide (1b) and hexamethylenetetramine(HMTA) via an intramolecular Mannich reaction.15 On the otherhand, reaction of this b-diketone analogue with aromatic alde-hydes and ammonium acetate led to the formation ofdihydrodibenzothienopyridines.15

It was found previously that the cyclic b-diketone, 1,3-indane-dione, readily formed 2-spirocyclic 1,3-diones with formaldehydeand primary amines,16 whilst N-monosubstituted 3-aminoinde-none led to 2-spirocyclic 1,3-diones with formaldehyde in acidicmedium.17 The Mannich reaction of 1,3-indanedione with second-ary amines and formalin led instead of the Mannich product tobisenamines, which were cyclised to 5,11-dihydrodiindenopyri-dine-10,12-dione on refluxing with ammonium acetate in aceticacid.18

In this Letter, we report the cyclisation of 1,3-indanedione (1a)and benzo[b]thiophen-3(2H)-one 1,1-dioxide (1b) with hexameth-ylenetetramine and ammonium acetate in acidic medium whereinstead of expected unsubstituted (at position 4) 2-spiroderiva-tives 4a,b the unexpected cyclisation products—bridged polycyclicdiazocine derivatives 2a and 2b—flanked on both sides with indenoor benzothieno moieties were obtained (Fig. 1).

N

N

2aN

NS

S

2b

O

O

O O

O O

Figure 1. Methylene bridged polycyclic diazocine derivatives: 6a,13a-methano-diindeno[1,2-b:10 ,20-f][1,5]diazocine-7,16(6H,13H)-dione (2a) and 6,13-dihydro-5a,12a-methanobenzo[4,5]thieno[3,2-b]benzo[4,5]thieno[3,2-f][1,5]diazocine5,5,12,12-tetraoxide (2b).

2 B. Cekavicus et al. / Tetrahedron Letters xxx (2014) xxx–xxx

A structural revision to the bridged polycyclic diazocine 2bflanked on both sides with benzothieno moieties is proposed. Thestructure of benzothieno-diazocine 2b was previously wronglyelucidated as a 1,5-diazabicyclo[3.3.1] heterocyclic analogue of aTröger’s base by our research group.19 X-ray analysis of the reac-tion product 2b has suggested that the previous structural assign-ment for this compound, based mainly on NMR spectroscopicinterpretation was incorrect, and that the correct structure wasbenzothieno-diazocine 2b. Additionally, besides cyclisation reac-tions, the internal rearrangement of these methylene bridged dia-zocine derivatives 2a,b into spirocyclic systems 4a,b is reportedherein. A potential mechanism for cyclisation and rearrangementis also proposed.

Investigation of the cyclisation reaction conditions of 1,3-indan-edione (1a) or its sulfonyl group containing analogue, benzo[b]thiophen-3(2H)one-1,1-dioxide20 (1b) with hexamethylenetet-ramine and ammonium acetate in acetic acid at reflux led to theformation of indeno-diazocine 2a in 87% yield in 0.5 h or in a mix-ture of acetic and trifluoroacetic acids led to benzothieno-diazo-cine 2b in 75% yield in one hour, respectively (Scheme 1, path a).Benzo[b]thiophen-3(2H)-one 1,1-dioxide (1b) also forms benzothi-eno-diazocine 2b in the reaction with paraformaldehyde (PFA) andammonium acetate in a mixture of toluene with acetic acid underazeotropic reflux conditions with the removal of water for threehours in 78% yield (Scheme 1, path b).

Under similar reaction conditions to those used for thesynthesis of diazocine 2a, 1,3-indanedione (1a) with hexamethy-

O

Z

N

NZ

Z

OO

Z

Z

1a,b 2a,b

3a,b4a,b

for a Z = COfor b Z = SO2

a or b

d

j

c

e

f or g

ON

5a

h

O

NH

S SO OOO

6b

i

ZNH

OZ

O

Scheme 1. Synthetic routes for compounds 2–6. Reagents and conditions: (a) for2a: HMTA, AcONH4, AcOH, reflux, 0.5 h, 87%; for 2b: HMTA, AcONH4, AcOH/TFA,reflux, 1 h, 75%; (b) for 2b: PFA, AcONH4, toluene/AcOH, azeotropic removal of H2O,3 h, 78%; (c) for 3a: synthetic procedure was reported in the literature;21 for 3b22:PFA, EtOH, piperidine/AcOH (cat.), rt, 72 h, 70%; (d) for 2a: HMTA, AcONH4, AcOH,90 �C, 0.5 h, 52%; for 2b: HMTA, AcONH4, AcOH, reflux, 1 h, 80%; (e) for 4a HMTA,AcONH4, AcOH/TFA, reflux, 3 h, 75%; (f) for 4a: AcOH/TFA, reflux, 5 min, 88%; for 4b:AcOH/TFA, EtOH, rt, 72 h, 63%; (g) 1 M HCl/EtOH, rt, 72 h, 86%; (h) for 4a: HMTA,AcOH, 4 h reflux, 44%; (i) AcONH4, AcOH, 6 h, reflux, 72%; (j) KOH, MeI, DMF, rt, 4 h,53%.

Please cite this article in press as: Cekavicus, B.; et al. Tetrahedron Lett.

lenetetramine and ammonium acetate in a mixture of acetic acidand trifluoroacetic acid at reflux for three hours gave spirocycliccompound 4a (Scheme 1, path e). Apparently, diazocine 2a appearsto be an intermediate in the formation of spiroindane-1,3,5-trione4a from 1,3-indanedione (1a). The determining factors for the for-mation of spirocyclic compound 4a were the prolonged reactiontime and the presence of strong acid, such as trifluoroacetic acid.In this way (Scheme 1, path e), spirocyclic compound 4b was notobtained from benzo[b]thiophen-3(2H)one-1,1-dioxide (1b) dueto the electronic and steric hindrance of the sufonyl group in com-parison with the carbonyl group of 1,3-indanedione (1a).

The synthesis of the starting 2,20-methylene derivatives 3a,21b22

has already been reported in the literature. Compound 3b wasobtained by a modified procedure which includes reaction of 1bwith paraformaldehyde in ethanol in the presence of a catalyticamount of piperidine and acetic acid (Scheme 1, path c).

Methylene bridged diazocines 2a,b were also obtained from thereaction of 2,20-methylene derivatives 3a,21b22 with hexamethy-lenetetramine and ammonium acetate in acetic acid in 52% or80% yields, respectively (Scheme 1, path d). When the reaction of2,20-methylene derivative 3a was performed with five equivalentsof hexamethylenetetramine and ammonium acetate in acetic acidwith continuous reflux for four hours, the appropriate spirocycle4a was obtained in an yield of 44% (Scheme 1, path h). All ourattempts to obtain suitable crystals of highly insoluble indeno-diazocine 2a were unsuccessful. Moreover, during crystallisationfrom formic acid, bright-coloured crystals of spirocyclic compound4a were formed from 2a. Both these facts serve as further proofthat diazocine 2a is an intermediate in the synthesis of spirocycle4a (Scheme 1, path h). Spirocyclic compound 4b was not obtainedfrom the reaction of 2,20-methylene derivative 3b with hexameth-ylenetetramine and ammonium acetate in acetic acid under thesame reaction conditions where the only product was diazocine2b. The contrasting behaviour of indeno-diazocine 2a and2,20-methylene derivative 3a in comparison with diazocine 2band 2,20-methylene derivative 3b could be due to the fact thatthe indeno group is less hindered than the benzothieno system.

Therefore, another possibility, that is, internal rearrangement ofmethylene bridged diazocine derivatives 2a,b into the correspond-ing spirocyclic compounds 4a,b was investigated under acidic con-ditions (Scheme 1, path f). It was found that the internalrearrangement of diazocine derivative 2a proceeded smoothlyafter only five minutes at reflux in a mixture of acetic and trifluo-roacetic acids, with methyleneimine elimination affording spirocy-clic compound 4a in an yield of 88%. On the other hand, therearrangement of diazocine derivative 2b with the formation ofspirocyclic compound 4b was a rather slow reaction; in a mixtureof acetic and trifluoroacetic acids and ethanol at rt for 72 hours theyield was only 63% (Scheme 1, path f). When the reaction mediumwas changed to 1 M hydrochloric acid and ethanol mixture theyield of spirocycle 4b was improved to 86% at room temperatureafter 72 h (Scheme 1, path g). The difference in reactivity of 2bcompared to 2a can be explained by steric and electronic hin-drance of the sulfonyl group in comparison with the carbonylgroup of 1,3-indanedione.

Symmetric polycyclic dihydropyridine derivative 6b flankedwith benzothieno groups was obtained in 72% yield from the reac-tion of 2,20-methylene derivative 3b with ammonium acetate inacetic acid by refluxing for six hours (Scheme 1, path i). The poly-cyclic bisindeno-substituted analogue of 6b, 5,11-dihydrodiinde-no[1,2-b;20,10-e]pyridine-10,12-dione, was previously obtained inthe reaction of 2,20-methylene derivative 3a with ammoniumacetate in acetic acid.21

The structural elucidation of spirocyclic compound 4a wasbased mainly on NMR spectroscopic interpretation and the synthe-sis of N-methylspirocyclic compound 5a, the structure of which is

(2014), http://dx.doi.org/10.1016/j.tetlet.2014.06.106

Figure 3. ORTEP representation of the structure of diazocine 2b.23

O

Z

1

2a,b

(CH2O)n

ZO

Z

3a,b

Z

HN2

H2C NH2

CH2

OZ

O

NH2

H2N

H2C NH22

H2N

-2H2O -H2O

2H+

N+

N+Z

Z

H

H

N

NZ

Z

O

intermediate Aintermediate B

intermediate C intermediate F

O

O

N+

N+Z

Z

H

H

intermediate D

OH

H2C NH-HO-

4a,b

NH

Z

OZ

N+Z

O

Z

H

O

O

N+Z

O

Z

H

H2N

B. Cekavicus et al. / Tetrahedron Letters xxx (2014) xxx–xxx 3

known.16 Therefore the spiroindan-1,3,5-trione 4a was alkylatedwith iodomethane in DMF in the presence of sodium hydroxide(Scheme 1, path j). The analytical data of 5a were in accordancewith those described earlier by Möhrle.16

The structure determination of compounds 2–4 was accom-plished on the basis of 2D-NMR (1H–1H and 1H–13C) spectrarecorded in CDCl3. The 1H and 13C chemical shifts were in fullagreement with the proposed structures.

The 1H NMR spectra of compounds 2a,b (obtained in CDCl3)showed the methylene group protons as AB-systems at d 3.90and d 4.02 with a coupling constant of 18.8 Hz or at d 4.02 and d4.59 with a coupling constant of 20.2 Hz for indeno-diazocine 2aand benzothieno-diazocine 2b, respectively. For 2,20-methylenederivative 3b, the methylene bridge signals in the 1H NMR spectrawere found to be non-equivalent, and the same was observed forthe carbon signals in the 13C NMR spectra. Comparison of the1H–1H NOESY, 1H–13C HMBC and 1H–13C HSQC spectra led to theconclusion that the assignment and stereoorientation of the pro-tons in compound 4b are as depicted in Figure 2. The assignmentof the relative spatial orientation of the protons at the C2 and C4carbons in compound 4b was based on NOESY spectra wherestrong cross peaks between the protons C4-Ha (d 3.07) andC2-Hd (d 3.76) were observed. This observation defines the orien-tation of these protons in the plane of tetrahydropyridine ring. Theintensive cross-peak between NH (d 5.05) and C2-Hc (d 4.02) indi-cates that these two protons are close in space and probably lie inthe same plane as the pyridine cycle.

For an objective assessment of the structure of compound 2b,an X-ray crystallographic analysis of the crystals of this compoundwas undertaken (see Fig. 3). Both the five-membered thiophenerings are characterised by an envelope conformation. The dihedralangle between the two planes of C10–C6–N7–C22–C20 andC10–C14–N4–C12–C20 is equal to 71.0�. C20–C21–C10 withinthese planes forms a dihedral angle of 54.5�.

A potential mechanism for the formation of diazocines 2a,binvolves a Mannich reaction with subsequent intramolecular imin-ation (Scheme 2, intermediate B). The formation of spirocycliccompounds 4a,b initially proceeds via protonation of diazocines2a,b with strong acids leading to the formation of unstable imineintermediate C. The addition of OH� to intermediate C readilyforms intermediate D. A subsequent ring-opening step leads tothe formation of intermediate E, which undergoes a retro-Mannichreaction to give intermediate F with the elimination of methylenei-mine or formaldehyde and ammonia. Finally, isomerisation ofintermediate F results in the formation of spirocycles 4a,b. Onthe other hand intermediate A also readily forms spirocycle 4a.

In summary, the formation of novel methylene bridged polycy-clic diazocines 2a and 2b was observed in the reactions of thecyclic b-diketone, 1,3-indanedione (1a) and the sulfonyl groupcontaining analogue 1b, as well as 2,20-methylene derivatives, withparaformaldehyde and ammonia or hexamethylenetetramine inacidic medium. X-ray analysis data of the reaction product 2bindicate that the previous structural assignment for this compoundbased mainly on NMR spectra interpretation was incorrect and thecorrect structure is 6,13-dihydro-5a,12a-methanobenzo[4,5]thie-no[3,2-b]benzo[4,5]thieno[3,2-f][1,5]diazocine 5,5,12,12-tetraox-

S

N

S

4b

OO

5 43

2

HbHaO

HdHc

O1'

3'

2'

NOE

4a

7a 7'

6'

NOEH

O6

9

Figure 2. Assignment and stereoorientation of the protons in compound 4b.

for aZ = COfor b Z = SO2

intermediate E

Scheme 2. A potential mechanism for the formation of methylene bridgedpolycyclic diazocines 2a,b and their rearrangement into the spirocyclic compounds4a,b.

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ide (2b). Methylene bridged polycyclic diazocines 2a and 2bundergo internal rearrangement into spirocyclic tetrahydropyri-dines 4a,b under aqueous acidic conditions.

(2014), http://dx.doi.org/10.1016/j.tetlet.2014.06.106

4 B. Cekavicus et al. / Tetrahedron Letters xxx (2014) xxx–xxx

Acknowledgements

This research was supported by the European Social Foundation(ESF), Project Nr. 2013/0002/1DP/1.1.1.2.0/13/APIA/VIAA/005 andESF Project ‘‘Support for Doctoral Studies at the University ofLatvia’’ (for M. Rucins).

Supplementary data

Supplementary data (including experimental procedures, char-acterisation data, 1H and 13C NMR spectra for all the products, asingle crystal X-ray diffraction analysis of 2b) associated with thisarticle can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.06.106.

References and notes

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(2014), http://dx.doi.org/10.1016/j.tetlet.2014.06.106