Synthesis of cyclic thioethers through tandem C(sp3)-S and C(sp2)-S bond formations from α,β′-dichloro vinyl ketones

Article abstract of DOI:10.1021/jo702457t

(Chemical Equation Presented) The synthesis of 5- to 8-memebered cyclic thioethers 4 has been achieved through a simple two-step sequence. The present methodology utilizes the facile Friedel-Crafts acylation of terminal alkynes 1 with acid chlorides 2 fol

Full text of DOI:10.1021/jo702457t

SCHEME 1. Synthesis of Thiophen-3-one 4a4
Synthesis of Cyclic Thioethers through Tandem
C(sp3)-S and C(sp2)-S Bond Formations from
r,â′-Dichloro Vinyl Ketones
Kyungsoo Oh,* Hyunjung Kim, Francesco Cardelli,
Tamayi Bwititi, and Anna M. Martynow
Department of Chemistry and Chemical Biology,
Indiana UniVersity Purdue UniVersity Indianapolis,
Indianapolis, Indiana 46202
substituent at the C6-position are low yielding (8-36%). Due
to the shortage of synthetic routes to heterocycles containing a
thioether,5 we developed a facile synthesis of thiophen-3-ones
through tandem C(sp3)-S and C(sp2)-S bond formations from
the Friedel-Crafts acylation products, â-chloro vinyl ketones.4
Herein, we report the extension of our methodology to the
synthesis of 6- to 8-membered cyclic thioether derivatives.
oh@chem.iupui.edu
ReceiVed NoVember 15, 2007
From the outset of our synthesis, we reasoned that the “soft”
and “hard” nucleophilic character of sulfur would facilitate the
reaction with R,â′-dichloro vinyl ketones: via the intermolecular
alkylation with a sulfur nucleophile followed by intramolecular
Michael reaction/elimination, or intermolecular Michael reac-
tion/elimination followed by intramolecuar alkylation of the
pendent sulfur nucleophile.
Thus, in order to devise a unified synthetic pathway to access
5- to 8-membered heterocycles, we investigated double C-S
bond formations using R,â′-dichloro vinyl ketones 3a and a
source of sulfur. The generation of the required substrate 3a
was initially investigated by using the Friedel-Crafts acylation
of a chloroacetyl chloride-AlCl3 complex with terminal alkynes
1a.6 The R,â′-dichloro vinyl ketones 3a are routinely obtained
in high yields as a mixture of cis- and trans-stereoisomers (E:Z
) 1:1-20:1) depending on the reaction temperature.7
Next, we turned our attention to the identification of a suitable
sulfur nucleophile to induce the C-S bond formations. Initially
we screened a variety of sulfur nucleophiles (elemental sulfur
S8, thiourea, hydrogen sulfide, sodium sulfide, sodium hydro-
sulfide) in acidic and basic conditions with no success. After
further experimentation, it was found that sodium hydrosulfide
hydrate is the optimal source of sulfur to induce the desired
double C-S bond formation in acetone or in neat form.
The synthesis of 5- to 8-memebered cyclic thioethers 4 has
been achieved through a simple two-step sequence. The
present methodology utilizes the facile Friedel-Crafts acy-
lation of terminal alkynes 1 with acid chlorides 2 followed
by tandem C(sp3)-S and C(sp2)-S bond formations with
NaSH‚xH2O.
While the potential of sulfur heterocycles in synthetic
strategies has been widely recognized, heterocycles containing
a thioenol ether moiety have been a less-studied subject of
investigation. Conjugated cyclic thioenol ethers have been
proven as effective surrogates for unreactive cis-dienes in Diels-
Alder reactions1 as well as precursors for the synthesis of
substituted cyclopentenones through Ramberg-Ba¨cklund reac-
tions.2 More recently, Vedejs reported an internal 1,4-addition
of a tethered amine to dihydrothiopyran-4-one derivatives for
the synthesis of the 8-membered-ring system of the pyrrolizidine
alkaloid octonecine.3 In the course of synthesis of biotin and
its analogues, we utilized thiophen-3-one derivatives, cyclic
â-keto thioenol ethers, to a biotin core.4 Although Lebedev et
al. have described a two-step sequence to thiophen-3-ones from
a 2-(ethylsulfanyl)butanoyl fluoride‚BF3 complex with alkynes,
the preparation of acid fluoride‚BF3 complexes is not trivial.
Christoffers and Rosiak also recently reported the synthesis of
2,6-disubstituted 2,3-dihydrothiopyran-4-ones through double
conjugation of sulfide to enynones; this approach, however, was
confined to 6-membered heterocycles and substrates without a
(5) For selected thiophen-3-one examples, see: (a) Lebedev, M. V.;
Nenajdenko, V. G.; Balenkova, E. S. Synthesis 2001, 2124. (b) Chuburu,
F.; Lacombe, S.; Pfister-Guillouzo, G. J. Org. Chem. 1991, 56, 3445. (c)
Hunter, G. A.; McNab, H. J. Chem. Soc., Chem. Commun. 1990, 375. (d)
Cheikh, A. B.; Dhimane, H.; Pommelet, J. C.; Chuche, J. Tetrahedron Lett.
1988, 29, 5919. (e) Camici, L.; Ricci, A.; Taddei, M. Tetrahedron Lett.
1986, 27, 5155. Selecteted thiopyran-4-one examples, see: (f) Rosiak, A.;
Christoffers, J. Tetrahedron Lett. 2006, 47, 5095. (g) Bi, X.; Dong, D.; Li,
Y.; Liu, Q.; Zhang, Q. J. Org. Chem. 2005, 70, 10886. (h) Samuel, R.;
Nair, S.; Asokan, C. V. Synlett 2000, 1804. (i) Rule, N. G.; Detty, M. R.;
Kaeding, J. E.; Sinicropi, J. A. J. Org. Chem. 1995, 60, 1665. (j) Vedejs,
E.; Eberlein, T. H.; Mazur, D. J.; McClure, C. K.; Perry, D. A.; Ruggeri,
R.; Schwartz, E.; Stults, J. S.; Varie, D. L.; Wilde, R. G.; Wittenberger, S.
J. Org. Chem. 1986, 51, 1556. (k) Vedejs, E.; Perry, D. A.; Wilde, R. G.
J. Am. Chem. Soc. 1986, 108, 2985. (l) Kansal, V. K.; Taylor, R. J. K. J.
Chem. Soc. Perkin Trans. 1, 1984, 703. Selected benzo[b]thiepinone
derivatives, see: (m) Bendorf, H. D.; Colella, C. M.; Dixon, E. C.; Marchetti,
M.; Matukonis, A. N.; Musselman, J. D.; Tiley, T. A. Tetrahedron Lett.
2002, 43, 7031. (n) Tamura, Y.; Takebe, Y.; Mukai, C.; Ikeda, M. J. Chem.
Soc., Perkin Trans. 1 1981, 2978. (o) Kirby, N.; Reid, S. J. Chem. Soc.,
Chem. Commun. 1980, 150.
(1) (a) Ward, D. E.; Gai, Y. Can. J. Chem. 1997, 75, 681. (b) Ward, D.
E.; Nixey, T. E.; Gai, Y.; Hrapchak, M.; Abaee, M. S. Can. J. Chem. 1996,
74, 1418. (c) Ward, D. E.; Nixey, T. E. Tetrahedron Lett. 1993, 34, 947.
(2) (a) Jeffrey, S. M.; Sutherland, A. G.; Pyke, S. M.; Powell, A. K.;
Taylor, R. J. K. J. Chem. Soc., Perkin Trans. 1 1993, 2317. (b) Casy, G.;
Taylor, R. J. K. Tetrahedron 1989, 45, 455.
(3) Vedejs, E.; Galante, R.; Goekjian, P. J. Am. Chem. Soc. 1998, 120,
3613.
(4) Oh, K. Org. Lett. 2007, 9, 2973.
(6) Benson, W. R.; Pohland, A. E. J. Org. Chem. 1964, 29, 385.
(7) Assignment of alkene geometry by NMR, see: Martens, H.;
Hooranaert, G.; Toppet, S. Tetrahedron 1973, 29, 4241.
10.1021/jo702457t CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/16/2008
2432
J. Org. Chem. 2008, 73, 2432-2434

TABLE 1. Synthesis of Cyclic Thioethers
SCHEME 2. Synthesis of 1,2-Dithiin-4(3H)-ones
entry
R1
R2
n
% 3 (Z/E)a
% 4b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
pentyl
pentyl
pentyl
pentyl
pentyl
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
Ph
H
Me
H
H
H
H
Me
H
H
H
H
Me
H
H
H
0
0
1
2
3
0
0
1
2
3
0
0
1
2
3
3a, 85 (1:5)
3b, 62 (1:3)
4a, 67
4b, 64c
4c, 74d
4d, 64
4e, 55
4f, 47
3c, 71 (1:2.3)
3d, 62 (1:1.3)
3e, 77 (1:1.9)
3f, 64 (10:1)
3g, 61 (2.7:1)
3h, 62 (1:2)
3i, 90 (1.2:1)
3j, 70 (1.1:1)
3k, 70 (>20:1)
3l, 73 (2.6:1)
3m, 80 (4.3:1)
3n, 73 (>20:1)
3o, 84 (>20:1)
SCHEME 3. Synthesis of Benzo[b]thiophen-3(2H)-one
4g, 63c
4h, 66d
4i, 64
4j, 51
4k, 50
4l, 64c
4m, 98
4n, 61
4o, 30
Ph
Ph
Ph
Ph
under protic solvents (MeOH and i-PrOH).10 Hydrogen sulfide,
a “soft” nucleophile, would have preferentially reacted in a
Michael fashion rather than alkylation. The formation of 9 could
be explained through an oxidative pathway (7 to 8) due to a
facile isomerization of â-keto thioenol 7 to â-keto thioketone.
Thus, the Michael addition product, (Z)-thioenol ether 7, is prone
to further reactions with either hydrogen sulfide or sodium
hydrosulfide (Scheme 2). The formation of 4 from 7 is probably
deterred due to the geometry of the alkene as a result of
intramolecular H-bonding.11 After some solvent screening, upon
using 2-methoxyethanol5f coupled with sodium hydrosulfide
hydrate we optimized reaction conditions to obtain 1,2-dithiin-
4(3H)-ones 912 (C(sp2)-S to C(sp3)-S) along with the 5-mem-
bered product, thiophen-3-ones 3 (C(sp3)-S to C(sp2)-S), in
good to excellent yields.13 On the basis of these above
observations, we surmised that the alkylated intermediate 5 is
the predominant species under aprotic solvents and subsequently
undergoes faster intramolecular Michael reaction to give 6 than
other oxidative pathways.
a Determined using 1H NMR of crude mixture. b Isolated after silica gel
chromatography. c Isolated yield after O-acetylation. d Reaction performed
at 50 °C.
Having secured a concise synthesis for 5-membered cyclic
â-keto thioenol ether 4a, we explored the substrate and reagent
scope and these results are summarized in Table 1. The reaction
provided good to excellent yields with a wide range of aliphatic
and aromatic alkynes as well as substituted acid chlorides
(entries 2, 7, and 12). Thiophen-3-ones (4a, 4f, 4k) without a
substituent at C5 exist as a stable keto tautomer; however, the
C5-substituted 5-membered heterocycles (4b, 4g, 4l) do not show
the same stability as keto tautomers.8 Although disubstituted
alkyne, 2-octyne, failed to give the corresponding â-chloro vinyl
ketone, the Friedel-Crafts acylation of terminal alkynes pro-
ceeded in modest to excellent yields. The subsequent tandem
C(sp3)-S and C(sp2)-S bond formations was remarkably
efficient and produced 5- to 8-membered cyclic thioethers 4 in
50-98% yield except 4o (30%).9 As expected the efficiency
of ring formation diminished from 5- and 6-membered ring
systems to 7- and 8-membered ring systems.
To gain insight into reaction pathways, we attempted to isolate
two possible intermediates 5 and 6 with no success. Although
the transient intermediates in the reaction have not been
confirmed at the present time, we believe that the reaction
proceeds via a sequence of intermolecular alkylation (C(sp3)-
S) with sodium hydrosulfide hydrate followed by intramolecular
Michael reaction/elimination (C(sp2)-S). We observed that the
reaction in protic solvents (MeOH, EtOH, t-BuOH, and water)
did not proceed to give the desired products, possibly due to
the formation of hydrogen sulfide as well as the solvent cage
surrounding the nucleophile.
The scope and utility of the reaction mechanism was further
extended toward the synthesis of benzo[b]thiophen-3(2H)-one
12 (Scheme 3).14 Careful chlorination of 2′-chloroacetophenone
10 with use of sulfuryl chloride at 0 °C provided 2-chloro-1-
(2-chlorophenyl)ethanone 11 in excellent yield.15 The subsequent
tandem C(sp3)-S and C(sp2)-S bond formations was effected
smoothly with our optimized conditions via a sequence of
intermolecular alkylation (C(sp3)-S) with sodium hydrosulfide
hydrate followed by intramolecular nucleophilic aryl substitution
(C(sp2)-S).16
(10) R′-Methyl-substituted â-chloro vinyl ketones 3b, 3g, and 3l are
expected to enhance the competition between Michael reaction and
alkylation due to the steric hinderance of a methyl group.
(11) We are currently investigating the synthesis of â-keto thioketone
of 7 to confirm the possibility of crossover between 5 and 8, or 6 and 7.
(12) Le Guillanton, G.; Do, Q. T.; Simonet, J. Bull. Soc. Chim. Fr. 1990,
127, 427.
During our investigation, we have also isolated an NMR
quantity of byproducts, 1,2-dithiin-4(3H)-ones 9, upon reactions
(13) Oxidative S-S coupling of 7 followed by intramolecular alkylation
(8) Capon, B.; Kwok, F-C. J. Am. Chem. Soc. 1989, 111, 5346. 2-Methyl
thiophen-3-ones 4b, 4g, and 4l rapidly decomposed at ambient temperature
over 1-24 h, and thus are isolated as their O-acetyl thiophene derivatives,
see the Supporting Information.
(9) cis- and trans-Chloro vinyl ketones 3a undergo cyclization, respec-
tively, thus a mixture of stereoisomers was employed in all other substrates
3b-o.
to 9 cannot be ruled out.
(14) (a) Pradhan, T. K.; De, A.; Mortier, J. Tetrahedron 2005, 61, 9007.
(b) Mukherjee, C.; Kamila, S.; De, A. Tetrahedron 2003, 59, 4767.
(15) Ikemoto, N.; Liu, J.; Brands, K. M. J.; McNamara, J. M.; Reider,
P. Tetrahedron 2003, 59, 1317.
(16) Upon subjecting 2′-chloroacetophenone 10 to our NaSH‚xH2O
conditions, no reaction was observed.
J. Org. Chem, Vol. 73, No. 6, 2008 2433

3.17 (2H, m), 2.65 (2H, m), 2.37 (2H, td, 7.5 Hz, 0.5 Hz), 1.62
(2H, m), 1.35 (4H, m), 0.90 (3H, t, 7 Hz). 13C NMR (125 MHz,
CDCl3) δ 194.4, 165.1, 121.7, 38.3, 36.8, 31.1, 28.4, 27.4, 22.3,
13.8. HRMS calcd for C10H16OS 184.0916, found 184.0903 (M+).
4d: Rf 0.17 (1:5 Et2O/Hex). IR (neat) 2956, 2927, 2857, 1655,
1578 cm-1. 1H NMR (500 MHz, CDCl3) δ 6.04 (1H, s), 2.93 (2H,
t, 6.5 Hz), 2.82 (2H, td, 7 Hz, 0.5 Hz), 2.37 (2H, td, 8 Hz, 0.5 Hz),
2.23 (2H, quintet, 10 Hz), 1.60 (2H, quintet, 7.5 Hz), 1.34 (4H,
m), 0.89 (3H, t, 4.5 Hz). 13C NMR (125 MHz, CDCl3) δ 202.1,
166.6, 127.5, 41.6, 40.1, 37.6, 31.1, 30.7, 28.8, 22.3, 13.9. HRMS
calcd for C11H18OS 198.1073, found 198.1081 (M+).
In conclusion, we have developed a facile synthesis of cyclic
thioethers using iterative intermolecular S-alkylation followed
by intramolecular Michael reaction/elimination. Furthermore,
our methodology can be extended to the synthesis of benzo[b]-
thiophen-3(2H)-one, a useful starting material for dyes.17 We
are currently investigating applications of our methodology as
well as an asymmetric sulfoxidation of the sulfur heterocycles
for the synthesis of biologically relevant compounds, and our
result will be reported in due course.
4e: Rf 0.24 (1:5 Et2O/Hex). IR (neat) 2929, 2857, 1659, 1645,
Experimental Section
1
1633, 1592 cm-1. H NMR (500 MHz, CDCl3) δ 5.93 (1H, s),
General Procedure for Double C-S Bond Formations. To a
stirred sodium hydrosulfide hydrate (68-72% flakes, 89 mg, 1.06
mmol) at ambient temperature, was added the alkenes 3a (200 mg,
0.90 mmol) in acetone (2 mL) dropwise. The reaction was complete
in 5 min as evidenced by thin layer chromatography. The reaction
mixture was diluted with diethyl ether (10 mL) and filtered through
Celite. After solvent removal under reduced pressure, the residue
was purified by flash chromatography on silica gel (eluent 90/10
hexanes/diethyl ether) to give thiophen-3-one 4a as a yellowish
oil (5.47 g, 67%).
2.87 (2H, t, 5.5 Hz), 2.70 (2H, t, 6 Hz, 0.5 Hz), 2.27 (2H, t, 8 Hz,
7.5 Hz), 2.03 (2H, m), 1.90 (2H, m), 1.62 (2H, m), 1.32 (4H, m),
0.90 (3H, t, 6.5 Hz). 13C NMR (125 MHz, CDCl3) δ 206.7, 154.5,
123.1, 42.1, 40.3, 32.8, 31.1, 30.3, 29.1, 22.3, 21.5, 13.9. HRMS
calcd for C12H20OS 212.1229, found 212.1239 (M+).
Acknowledgment. The School of Science (IUPUI) is
acknowledged for start-up funding. This investigation was
supported through a Research Support Funds Grant (RSFG-
IUPUI). The Bruker 500 MHz NMR was purchased via a NSF-
MRI award (CHE-0619254). The authors thank the IUPUI
Undergraduate Research Opportunities Program for fellowships
(A.M.M. and T.B.). A.M.M. and T.B. are recipients of the 2007
Eli Lilly Undergraduate Research Award and the IUPUI
Summer Research Opportunity Program Fellowships, respec-
tively.
4a: Rf 0.20 (1:4 Et2O/Hex). IR (neat) 2957, 2928, 2857, 1656,
1
1564, 1460 cm-1. H NMR (500 MHz, CDCl3) δ 6.00 (1H, s),
3.62 (2H, s), 2.61 (2H, t, 7.6 Hz), 1.65 (2H, m), 1.34 (4H, m),
0.89 (3H, t, 6.6 Hz). 13C NMR (125 MHz, CDCl3) δ 202.8, 185.7,
120.9, 40.8, 33.9, 31.2, 28.3, 22.4, 13.9. HRMS calcd for C9H14O1S1
170.0765, found 170.0759 (M+).
4c: Rf 0.66 (1:1 Et2O/Hex). IR (neat) 2955, 2929, 2858, 1653,
1
1572 cm-1. H NMR (500 MHz, CDCl3) δ 6.07 (1H, d, 1 Hz),
Supporting Information Available: Experimental procedures
and spectral data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(17) Sulfone analogues for cell imaging application, see: Toutchkine,
A.; Nguyen, D.; Hahn, K. M. Org. Lett. 2007, 9, 2775 and references cited
therein.
JO702457T
2434 J. Org. Chem., Vol. 73, No. 6, 2008