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Synlett 2015; 26(08): 1045-1048
DOI: 10.1055/s-0034-1380164
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Sulfur-Rich Crown Ethers via Azide–Alkyne Macrocyclization of α,ω-Diazido- and α,ω-Dipropargyl Sulfide Derivatives

Monika Stefaniak
Department of Organic and Applied Chemistry, University of Łódź, Tamka 12, 91-403 Łódź, Poland   Email: romanski@uni.lodz.pl
,
Marcin Jasiński
Department of Organic and Applied Chemistry, University of Łódź, Tamka 12, 91-403 Łódź, Poland   Email: romanski@uni.lodz.pl
,
Jarosław Romański*
Department of Organic and Applied Chemistry, University of Łódź, Tamka 12, 91-403 Łódź, Poland   Email: romanski@uni.lodz.pl
› Author Affiliations
Further Information

Publication History

Received: 09 December 2014

Accepted after revision: 22 January 2015

Publication Date:
27 February 2015 (online)

 
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Abstract

A series of diazides and dithiols were prepared in a one-pot protocol from commercially available alcohols by a modified Appel reaction. Selected dithiols were converted into α,ω-dipropargyl sulfides and combined with thioglycol-derived diazides under Huisgen–Sharpless–Meldal reaction conditions to give a new class of 1,2,3-triazole-linked sulfur-rich crown ethers.


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Key words

Appel reaction - click [3+2] cycloaddition - macrocycles - crown thioethers - thiiranium salt

Huisgen–Sharpless–Meldal (HSM)[1] reaction belongs to one of the most reliable protocols of unprecedented selectivity and scope in joining small organic molecules together. Numerous applications of the HSM cycloaddition covering such areas as natural products and drug discovery,[2] bioconjugates,[3] supramolecular scaffolds,[4] polymers,[5] and also other special materials[6] has been demonstrated during last decades. Although HSM reaction has been shown as an efficient tool in the context of intramolecular macrocyclization processes, the syntheses of crown ethers via intermolecular fashion are explored in a limited extent.[7] More recently, we successfully applied the azide–alkyne click protocol for the synthesis of a series of macrocyclic systems containing one or two sulfur atoms,[8] including highly lipophilic derivatives with built-in Cookson’s birdcage motif. In continuation, we turned our attention to sulfur-enriched analogues, which, however, required the use of much lesser-known thioglycol-derived building blocks, particularly terminal dithiols[9] and diazides.[10]

Initial experiments were performed using di-, tri-, and tetraethylene glycols selected as model substrates. Following classical protocols,[11] starting materials were reacted with sulfonyl chlorides (mesyl or tosyl) to give, after standard chromatographic purification, corresponding sulfonates in moderate yields of 20–50%. Subsequent SN2-type substitution with azide anion provided expected diazides 1a–c, however, in overall 10–35% yield, only. Attempted synthesis of analogous sulfur-containing derivatives 2a,b failed; treatment of thioglycols with sulfonyl chloride led to complex mixtures of unidentified products, presumably due to subsequent intramolecular substitution processes. In search for a more reliable protocol, modified ‘one-pot’ approach described for aryl sulfones was implemented.[12] Thus, starting model glycols were converted into the respective dibromides under Appel reaction conditions (Ph3P, NBS). As shown in Scheme [1], primarily formed halides were treated without isolation with NaN3 in the presence of catalytic amounts of KI to afford, after standard workup, compounds 1a–c in acceptable yields of 57–75% (Table [1]).[10] [13] Gratifyingly, the use of thiourea as a nuclophile towards in situ generated dibromides provided expected isothiouronium salts, which after basic hydrolysis delivered dithiols 3a–c in moderate yields (Table [1]).[13]

Zoom Image
Scheme 1 One-pot transformation of primary alcohols into thiols and azides

Table 1 Azides and Thiols Prepared via Modified Appel Reaction

Entry

Substitution product

Compd 1–12

Conditionsa

Yield (%)b

1

 1a n = 1
 1b n = 2
 1c n = 3

A
A
A

71
75
57

2

 2a n = 1
 2b n = 2

A
A

75
86

3

 3a n = 1
 3b n = 2
 3c n = 3

B
B
B

54
44
44

4

 4a n = 1
 4b n = 2

B
B

45
58

5

 5 X = N3
 6 X = SH

A
B

53
41

6

 7 X = N3
 8 X = SH

A
B

60
41

7

 9

A

52

8

10 X = N3
11 X = SH

A
B

49
35

9

12

A

 0

a Conditions A: i. Ph3P (1.5 equiv/OH group), NBS (1.5 equiv/OH group), DMF, 0 °C to r.t., 30 min; ii. KI (0.1 equiv), NaN3 (2.0 equiv/OH group), 1 d, 90 °C. Conditions B: i. Ph3P (1.5 equiv/OH group), NBS (1.5 equiv/OH group), DMF, 0 °C to r.t., 30 min; ii. KI (0.1 equiv), CS(NH2)2 (2.0 equiv/OH group), 1 d, 75 °C; iii. 3% aq NaOH.

b Isolated yield.

Prompted by the efficient synthesis of 1 and 3 series, two thioglycols were tested to give fairly stable diazides 2a,b and dithiols 4a,b in high yields. In contrast to oxo analogues, the NMR-tube experiments evidenced more complex reaction pathway (see Supporting Information), apparently due to anchimeric assistance of the neighboring sulfur atom. For example, treatment of 3-thiapentane-1,5-diol with NBS resulted in the formation of two intermediates, designated as 1-(2-hydroxyethyl)- and 1-(2-bromoethyl)thiiranium bromides of type A (Figure [1]).[14] These are assumed to undergo ring opening via nucleophilic attack to afford compounds 2 and 4.

Zoom Image
Figure 1 The diagnostic part of the 1H NMR spectra indicating the formation of thiiranium salts (signals of intermediates A are marked with arrows)

In order to test the scope of the method developed, N-Boc-prolinol was selected as a model chiral substrate, and was converted into the respective azide 5 (53%) and thiol 6 (41%). As expected, optical rotation values of the isolated products nicely matched to those reported for enantiomerically pure samples.[15] Similar moderate chemical yields (41–60%) were noticed for two polycyclic diols containing pentacycloundecane and adamantane moieties (Table [1], products 7–9). Next, taking into account the importance of the furan ring as an active element of both macrocyclic core[16] and side-chain pendant group,[17] two furan-derived alcohols were also tested (Table [1], entries 8 and 9). Thus, the reactions of furfuryl alcohol delivered target azide 10 (49%), and 2-furfurylthiol (11, 35%), a known odorant of roasted coffee.[18] However, attempted synthesis of diazide 12 derived from 2,5-bis(hydroxymethyl)furan led to a complex mixture of unidentified products indicating some limitations of the applied methodology.

As shown in Scheme [2], diazides 2a,b and dithiols 3a,b, and also fully sulfurated derivative 4b were selected for further studies. The latter compounds were first alkylated under standard reaction conditions[19] using propargyl bromide as an electrophile to give α,ω-disubstituted products 13a–c (Table [2], entries 1–3). Final macrocyclization step was conducted under nonaqueous reaction conditions similarly to the recently described procedure[8] to give the target 1,2,3-triazole-linked crown ethers of type 14 in acceptable yields of 31–47% (Table [2], entries 4–6).[20] For example, treatment of diazide 2b with 13a in the presence of CuI and N,N-diisopropylethylamine (DIPEA), in acetonitrile (1 mg/mL), at 40 °C, provided after 24 hours the expected macrocycle 14b as a major component of the reaction mixture. Standard single column chromatography provided crude material contaminated with small amounts of unconsumed azide. Subsequent preparative TLC enabled isolation of analytically pure sample of 14a in satisfactory 47% yield. Two other macrocycles of type 14 were prepared and purified in a similar manner. The structure of the isolated materials was confirmed on the basis of spectroscopic (NMR/IR) and MS methods. For example, in the NMR spectra of 14c (CDCl3) a set of diagnostic signals attributed to triazole ring at δ = 7.81 ppm (1H) and at δ = 145.7 and 123.4 ppm (13C) were found.

Zoom Image
Scheme 2 Synthesis of thiacrown ethers 14 via Huisgen–Sharpless–Meldal macrocyclization of α,ω-diazides 2 and bispropargyl podands 13. Reagents and conditions: (a) K2CO3, propargyl bromide, acetone, 24 h, r.t.; (b) CuI (0.06 equiv), DIPEA (2.3 equiv) MeCN, 40 °C, 24 h, 1 mg/mL.

Table 2 α,ω-Dipropargyl Sulfide Derivatives 13a–c and Sulfur-Rich Macrocycles 14a–c

Entry

Product

m

n

X

Yield (%)

1

13a

–

1

O

79

2

13b

–

2

O

88

3

13c

–

2

S

47

4

14a

1

1

O

47

5

14b

2

1

O

31

6

14c

2

2

O

43

In conclusion, a series of organic diazides and dithiols were prepared by modified Appel reaction and applied for the construction of a new class of sulfur-rich macrocycles 14 decorated with 1,2,3-triazole as an adjuvant complexing moiety.[8] [21] Although some of the key substrates 1–4 are known in the literature,[22] the presented one-pot protocol nicely supplement multistep syntheses described thus far. The final macrocyclic compounds are of our interest in the context of their potential complexing properties towards heavy-metal ions evidenced for other sulfurated crown ethers.[23]


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Acknowledgment

The authors acknowledge financial support from National Science Center in Cracow (NCN, OPUS Grant No. DEC-2011/01/B/ST5/06613). M.J. also thanks the University of Łódź Foundation.

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org.accesdistant.sorbonne-universite.fr/10.1055/s-0034-1380164.
  • Supporting Information

  • References and Notes

  • 4 Assali M, Cid J.-J, Fernandez I, Khiar N. Chem. Mater. 2013; 25: 4250
    CrossrefSearch in Google Scholar
  • 5 Golas PL, Matyjaszewski K. Chem. Soc. Rev. 2010; 39: 1338
    CrossrefSearch in Google Scholar
  • 6 Click Chemistry for Biotechnology and Material Science. Lahann J. John Wiley and Sons; Chichester: 2009
    CrossrefSearch in Google Scholar
  • 8 Stefaniak M, Jasiński M, Romański J. Synthesis 2013; 45: 2245
    Thieme ConnectSearch in Google Scholar
  • 9 Meadow RJ, Reid EE. J. Chem. Soc. 1934; 56: 2177
    CrossrefSearch in Google Scholar
  • 10 Stefaniak M, Jasiński M, Urbaniak K, Romański J, Seliger P, Gutowska N. Chemik 2014; 68: 592
    Search in Google Scholar
  • 12 Murakami T, Furusawa K. Synthesis 2002; 479
  • 13 General Procedure for the Synthesis of Diazides and Dithiols To a mixture of alcohol (1.0 mmol) and Ph3P (1.5 equiv*) in anhydrous DMF (5.0 mL) was added portionwise during 15 min NBS (1.5 equiv*) at 0 °C under inert atmosphere. The resulting mixture was stirred at r.t. for 30 min, followed by addition of solid KI (0.1 equiv*) and NaN3 or thiourea (2.0 equiv*). The resulting solution was heated for 24 h at 90 °C or 75 °C, respectively. In the case of thiol synthesis, crude isothiouronium salt was treated with 3% NaOH (aq), and the mixture was acidified using 3% HClaq to ca. pH 7. The mixture was diluted with EtOAc (25 mL), excess of 3% NaS2O3 (aq) solution was added (ca. 10 mL), and the layers were separated. The organic layer was washed with H2O, then with brine, and dried over MgSO4. The solvents were removed in vacuo to give crude products that were purified chromatographically; (*per OH group). 3-Thiapentane-1,5-diazide (2a) Colorless liquid, 129 mg (75%). 1H NMR (600 MHz, CDCl3): δ = 2.79 (t, 4 H, J = 7.2 Hz), 3.51 (t, 4 H, J = 7.2 Hz) ppm. 13C NMR (600 MHz, CDCl3): δ = 31.8; 51.3 ppm. IR (film): ν = 2926 (m), 2101 (s, N3), 1451 (m), 1349 (m), 1258 (m) cm–1. Anal. Calcd for C4H8N6S: C, 27.91; H, 4.65; N, 48.84. Found: C, 28.03; H, 4.81; N, 48.57.

      • Diagnostic signals in 1H NMR spectra located at δ = 2.81–2.84, 2.93–2.98, and 3.76–3.78 ppm could be attributed to the methylene groups neighboring sulfur atom of the intermediates A according to the literature data:
    • 14a Henkel JG, Amato GS. J. Med. Chem. 1988; 31: 1279
      CrossrefSearch in Google Scholar
    • 14b Olah GA, Szilagyi PJ. J. Org. Chem. 1971; 36: 1121
      CrossrefSearch in Google Scholar
  • 17 Georghiou G, Kleiner RE, Pulkoski-Gross M, Liu DR, Seeliger MA. Nat. Chem. Biol. 2012; 8: 366
    CrossrefSearch in Google Scholar
  • 18 Blank I, Sen A, Grosch W. Z. Lebensm.-Unters. Forsch. 1992; 195: 239
    Search in Google Scholar
  • 19 Hill AF, Neiss B, Schultz M, White AJ. P, Williams DJ. Organometallics 2010; 29: 6488
    Search in Google Scholar
  • 20 General Macrocyclization Procedure To a vigorously stirred mixture of solid CuI (12 mg) and diisopropylethylamine (DIPEA, 0.4 mL) in anhydrous MeCN (100 mL) an equimolar mixture (in the range of 0.4–0.6 mmol) of diazide 2 and α,ω-dipropargyl derivative 13 in MeCN (100 mL) was added dropwise within 6 h at 40 °C, under argon atmosphere. The stirring was continued at 40 °C overnight. The mixture was extracted with CH2Cl2 (2 × 40 mL), the combined organic layers were dried over MgSO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography using neutral Al2O3 and 1% MeOH in CH2Cl2 as an eluent. Data for Compound 14a Compound 14a was obtained from diazide 2a (0.58 mmol) and dipropargyl derivative 13a (0.58 mmol); yield 86 mg (47%); pale-yellow solid. 1H NMR (600 MHz, CDCl3): δ = 2.73 (t, J = 6.2 Hz, 4 H), 2.98 (t, J = 6.7 Hz, 4 H), 3.65 (t, J = 6.2 Hz, 4 H), 3.93 (s, 4 H), 4.51 (t, J = 6.7 Hz, 4 H), 7.70 (s, 2 H) ppm. 13C NMR (600 MHz, CDCl3): δ = 26.7, 31.4, 32.2, 50.1, 70.8, 123.0, 145.8 ppm. IR (KBr): ν = 2961, 2921, 2855, 1459, 1361, 1262, 1102, 1051 cm–1. ESI-HRMS: m/z [M + Na]+ calcd for C14H22N6S3ONa: 409.0915; found: 409.0910.
    • 21a Liao W, Chen Y, Liu Y, Duan H, Petersen JL, Shi X. Chem. Commun. 2009; 6436
    • 21b Schweinfurth D, Pattacini R, Strobel S, Sarkar B. Dalton Trans. 2009; 9291
    • 21c Li Y, Flood AH. Angew. Chem. Int. Ed. 2008; 47: 2649
      CrossrefSearch in Google Scholar
    • 21d Suijkerbuijk BM. J. M, Aerts BN. H, Dijkstra HP, Lutz M, Spek AL, van Koten G, Klein Gebbink RJ. M. Dalton Trans. 2007; 1273
  • 22 Slaitas A, Yeheskiely E. Eur. J. Org. Chem. 2002; 67: 2391 ; see also ref. 9, 10, and 14
    Search in Google Scholar

  • References and Notes

  • 4 Assali M, Cid J.-J, Fernandez I, Khiar N. Chem. Mater. 2013; 25: 4250
    CrossrefSearch in Google Scholar
  • 5 Golas PL, Matyjaszewski K. Chem. Soc. Rev. 2010; 39: 1338
    CrossrefSearch in Google Scholar
  • 6 Click Chemistry for Biotechnology and Material Science. Lahann J. John Wiley and Sons; Chichester: 2009
    CrossrefSearch in Google Scholar
  • 8 Stefaniak M, Jasiński M, Romański J. Synthesis 2013; 45: 2245
    Thieme ConnectSearch in Google Scholar
  • 9 Meadow RJ, Reid EE. J. Chem. Soc. 1934; 56: 2177
    CrossrefSearch in Google Scholar
  • 10 Stefaniak M, Jasiński M, Urbaniak K, Romański J, Seliger P, Gutowska N. Chemik 2014; 68: 592
    Search in Google Scholar
  • 12 Murakami T, Furusawa K. Synthesis 2002; 479
  • 13 General Procedure for the Synthesis of Diazides and Dithiols To a mixture of alcohol (1.0 mmol) and Ph3P (1.5 equiv*) in anhydrous DMF (5.0 mL) was added portionwise during 15 min NBS (1.5 equiv*) at 0 °C under inert atmosphere. The resulting mixture was stirred at r.t. for 30 min, followed by addition of solid KI (0.1 equiv*) and NaN3 or thiourea (2.0 equiv*). The resulting solution was heated for 24 h at 90 °C or 75 °C, respectively. In the case of thiol synthesis, crude isothiouronium salt was treated with 3% NaOH (aq), and the mixture was acidified using 3% HClaq to ca. pH 7. The mixture was diluted with EtOAc (25 mL), excess of 3% NaS2O3 (aq) solution was added (ca. 10 mL), and the layers were separated. The organic layer was washed with H2O, then with brine, and dried over MgSO4. The solvents were removed in vacuo to give crude products that were purified chromatographically; (*per OH group). 3-Thiapentane-1,5-diazide (2a) Colorless liquid, 129 mg (75%). 1H NMR (600 MHz, CDCl3): δ = 2.79 (t, 4 H, J = 7.2 Hz), 3.51 (t, 4 H, J = 7.2 Hz) ppm. 13C NMR (600 MHz, CDCl3): δ = 31.8; 51.3 ppm. IR (film): ν = 2926 (m), 2101 (s, N3), 1451 (m), 1349 (m), 1258 (m) cm–1. Anal. Calcd for C4H8N6S: C, 27.91; H, 4.65; N, 48.84. Found: C, 28.03; H, 4.81; N, 48.57.

      • Diagnostic signals in 1H NMR spectra located at δ = 2.81–2.84, 2.93–2.98, and 3.76–3.78 ppm could be attributed to the methylene groups neighboring sulfur atom of the intermediates A according to the literature data:
    • 14a Henkel JG, Amato GS. J. Med. Chem. 1988; 31: 1279
      CrossrefSearch in Google Scholar
    • 14b Olah GA, Szilagyi PJ. J. Org. Chem. 1971; 36: 1121
      CrossrefSearch in Google Scholar
  • 17 Georghiou G, Kleiner RE, Pulkoski-Gross M, Liu DR, Seeliger MA. Nat. Chem. Biol. 2012; 8: 366
    CrossrefSearch in Google Scholar
  • 18 Blank I, Sen A, Grosch W. Z. Lebensm.-Unters. Forsch. 1992; 195: 239
    Search in Google Scholar
  • 19 Hill AF, Neiss B, Schultz M, White AJ. P, Williams DJ. Organometallics 2010; 29: 6488
    Search in Google Scholar
  • 20 General Macrocyclization Procedure To a vigorously stirred mixture of solid CuI (12 mg) and diisopropylethylamine (DIPEA, 0.4 mL) in anhydrous MeCN (100 mL) an equimolar mixture (in the range of 0.4–0.6 mmol) of diazide 2 and α,ω-dipropargyl derivative 13 in MeCN (100 mL) was added dropwise within 6 h at 40 °C, under argon atmosphere. The stirring was continued at 40 °C overnight. The mixture was extracted with CH2Cl2 (2 × 40 mL), the combined organic layers were dried over MgSO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography using neutral Al2O3 and 1% MeOH in CH2Cl2 as an eluent. Data for Compound 14a Compound 14a was obtained from diazide 2a (0.58 mmol) and dipropargyl derivative 13a (0.58 mmol); yield 86 mg (47%); pale-yellow solid. 1H NMR (600 MHz, CDCl3): δ = 2.73 (t, J = 6.2 Hz, 4 H), 2.98 (t, J = 6.7 Hz, 4 H), 3.65 (t, J = 6.2 Hz, 4 H), 3.93 (s, 4 H), 4.51 (t, J = 6.7 Hz, 4 H), 7.70 (s, 2 H) ppm. 13C NMR (600 MHz, CDCl3): δ = 26.7, 31.4, 32.2, 50.1, 70.8, 123.0, 145.8 ppm. IR (KBr): ν = 2961, 2921, 2855, 1459, 1361, 1262, 1102, 1051 cm–1. ESI-HRMS: m/z [M + Na]+ calcd for C14H22N6S3ONa: 409.0915; found: 409.0910.
    • 21a Liao W, Chen Y, Liu Y, Duan H, Petersen JL, Shi X. Chem. Commun. 2009; 6436
    • 21b Schweinfurth D, Pattacini R, Strobel S, Sarkar B. Dalton Trans. 2009; 9291
    • 21c Li Y, Flood AH. Angew. Chem. Int. Ed. 2008; 47: 2649
      CrossrefSearch in Google Scholar
    • 21d Suijkerbuijk BM. J. M, Aerts BN. H, Dijkstra HP, Lutz M, Spek AL, van Koten G, Klein Gebbink RJ. M. Dalton Trans. 2007; 1273
  • 22 Slaitas A, Yeheskiely E. Eur. J. Org. Chem. 2002; 67: 2391 ; see also ref. 9, 10, and 14
    Search in Google Scholar

   Permissions and Reprints All articles of this category
Zoom Image
Scheme 1 One-pot transformation of primary alcohols into thiols and azides
Zoom Image
Figure 1 The diagnostic part of the 1H NMR spectra indicating the formation of thiiranium salts (signals of intermediates A are marked with arrows)
Zoom Image
Scheme 2 Synthesis of thiacrown ethers 14 via Huisgen–Sharpless–Meldal macrocyclization of α,ω-diazides 2 and bispropargyl podands 13. Reagents and conditions: (a) K2CO3, propargyl bromide, acetone, 24 h, r.t.; (b) CuI (0.06 equiv), DIPEA (2.3 equiv) MeCN, 40 °C, 24 h, 1 mg/mL.