Synthesis of functionalized dihydrothiophenes from doubly activated cyclopropanes using tetrathiomolybdate as the sulfur transfer reagent

Article abstract of DOI:10.1021/jo102059p

A number of doubly activated cyclopropanes were synthesized starting from various substituted bromosulfonium bromides in good yield. Regioselective ring-opening of cyclopropanes with tetrathiomolybdate as the sulfur transfer reagent gave dihydrothiophenes

Full text of DOI:10.1021/jo102059p

pubs.acs.org/joc
Although a large number of publications have appeared on
Synthesis of Functionalized Dihydrothiophenes from
Doubly Activated Cyclopropanes Using
Tetrathiomolybdate as the Sulfur Transfer Reagent
the synthesis and study of thiophenes,5 there are fewer reports
on the chemistry of dihydrothiophenes and their derivatives.
Dotsenko et al. has shown that 2-amino-4,5-dihydrothiophenes
can be synthesized by base-catalyzed condensation of phenacyl
thiocyanate with substituted thioamides.6 They are also synthe-
sized by a three-component condensation reaction involving
aldehydes, cyanothioacetamide, and pyridinium or sulfo-
nium ylides.7
Purushothaman Gopinath and Srinivasan Chandrasekaran*
Department of Organic Chemistry, Indian Institute of Science,
Bangalore 560012, India
More recently, Yan and co-workers have reported the
synthesis of 2-amino-4,5-dihydrothiophenes through a dom-
ino reaction involving 1,3-thiazolidinedione, malononitrile,
and aromatic aldehydes.8 In general, most of the methods used
for the synthesis of 2-amino-4,5-dihydrothiophenes involve
multiple steps and suffer from lower yields.
scn@orgchem.iisc.ernet.in
Received October 24, 2010
Doubly activated cyclopropanes9 are known to be valuable
synthetic intermediates for the synthesis of a wide variety of
1,3 bifunctionalized molecules. Thus, we conceived a simple
protocol for the synthesis of 2-amino-4,5-dihydrothiophenes
starting from doubly activated cyclopropanes using benzyl-
triethylammonium tetrathiomolybdate, 1,10 as the sulfur
transfer reagent. Doubly activated cyclopropanes are gener-
ally synthesized by the reaction of an alkene with a diazo com-
pound11 or an iodonium ylide12 and a transition metal catalyst
(mostly rhodium or copper complexes). Development of hy-
pervalent iodine(III) reagents12 as synthetic equivalents of
diazo compounds have also been reported.13
A number of doubly activated cyclopropanes were synthe-
sized starting from various substituted bromosulfonium
bromides in good yield. Regioselective ring-opening of
cyclopropanes with tetrathiomolybdate as the sulfur trans-
fer reagent gave dihydrothiophenes in excellent yield.
However, there is no general method for the synthesis of
all the doubly activated cyclopropanes using a single proto-
col. Since we were interested in studying the ring-opening of
a variety of doubly activated cyclopropanes, we decided to
modify the work reported by Chow involving the use of
substituted bromosulfonium bromides14 as precursors for
the synthesis of doubly activated cyclopropanes (Scheme 1).
Accordingly, wesynthesized the bromosulfoniumbromides
2a-e from the corresponding styrenes (Table 1). Reaction of
bromosulfonium bromide 2a with various active methylene
compounds 3a-h led to the corresponding doubly activated
cyclopropanes 4-11, respectively, in good to excellent yields.
The results of this study are summarized in Table 2.
Dihydrothiophenes1 and their derivatives are key compo-
nents present in many natural products, bioactive compounds,
and synthetic intermediates (Figure 1).2 They contain a reac-
tive double bond and a sulfur atom that accounts for many of
their interesting ring-opening reactions. In particular, 2-amino-
4,5-dihydrothiophenes have great synthetic value as they are
used as starting materials for the synthesis of partially hydro-
genated thieno[2,3-b]pyridines3 and pyrimidines.4
(5) (a) Gewald, K. Angew. Chem. 1961, 73, 114. (b) Gewald, K. Chem.
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V. V. Synthesis 1997, 623.
FIGURE 1. Structures of pharmacologically important thioesters.
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700 J. Org. Chem. 2011, 76, 700–703
Published on Web 12/23/2010
DOI: 10.1021/jo102059p
r
2010 American Chemical Society

Gopinath and Chandrasekaran
JOCNote
SCHEME 1. General Reaction Scheme
TABLE 2. Synthesis of Styrene-Derived Doubly Activated
Cyclopropanes
TABLE 1. Synthesis of Various Bromosulfonium Bromides
the second molecule of 4 to form intermediate Y. This inter-
mediate then undergoes an internal redox process10,16 with
the formation of a disulfide bond to give product 20 and
MoS2 as the byproduct.
We then attempted the ring-opening of doubly activated
cyclopropane 5 containing a cyano group with tetrathiomo-
lybdate 1(1.2equiv,MeOH,28°C, 1 h). Interestingly, the reaction
led to the formation of the dihydrothiophene derivative 21 in 88%
yield. The structure of 21 was unambiguously proved by single
crystal X-ray analysis (see the Supporting Information).
The formation of dihydrothiophene 21 from cyclopropane
derivative 5 in the reaction with 1 may be visualized to take
place initially via the formation of disulfide intermediate, which
undergoes reductive cleavage with 117 to form the thiolate
anion that can undergo intramolecular Gewald cyclization18
to give product 21 (Scheme 3).
When the reaction was carried out in CH3CN as solvent,
the reaction was slow and hence we were able to isolate the
disulfide intermediate, which again on treatment with tetra-
thiomolybdate 1 gave the corresponding dihydrothiophene
derivative, thereby proving the reaction mechanism.
The reaction was then carried out with other substituted
bromosulfonium bromides 2b-e and various active methy-
lene compounds to show the generality and synthetic utility
of the reaction. The results of this study are summarized in
Table 3.
After successfully synthesizing the doubly activated cyclo-
propanes, we then attempted the ring-opening of diester
cyclopropane 4 with reagent 1 (MeOH, reflux, 5 h) to form
the corresponding disulfide 20 regioselectively (1:1 diastere-
omeric ratio) in 70% yield (Scheme 2).15
The formation of product 20 from cyclopropane 4 with 1
can be visualized to take place via the initial nucleophilic
attack of tetrathiomolybdate 1 to open the cyclopropane
ring to form the intermediate “X”, which then can react with
(16) Ramesha, A. R.; Chandrasekaran, S. Synth. Commun. 1992, 22,
3277.
(17) (a) Pan, W. H.; Harmer, M. A.; Halbert, T. R.; Stiefel, E. I. J. Am.
Chem. Soc. 1984, 106, 459. (b) Prabhu, K. R.; Sivanand, P.; Chandrasekaran,
S. Angew. Chem., Int. Ed. 2000, 39, 4316. (c) Sureshkumar, D.; Ganesh, V.;
Vidyarini, R. S.; Chandrasekaran, S. J. Org. Chem. 2009, 74, 7958.
(18) (a) Puterova, Z.; Krutosikova, A.; Vegh, D. Arkivoc 2010, 209 and
references cited therein. (b) Jacoby, D.; Celerier, J. P.; Haviari, G.; Petit, H.;
Lhommet, G. Synthesis 1992, 884.
(15) The reaction does not work efficiently with ammonium tetrathio-
molybdate, which is commercially available, and hence reagent 1 is used.
Other sulfur transfer reagents like NaSH and Na2S give a mixture of mono-
and disulfides as products.
J. Org. Chem. Vol. 76, No. 2, 2011 701

Gopinath and Chandrasekaran
SCHEME 3. Synthesis of Dihydrothiophene 21
JOCNote
TABLE 3. Synthesis of Various Doubly Activated Cyclopropanes
the 2-position (compound 22) the reaction was slower (2 h) and
gave moderate yield of the corresponding dihydrothiophene 32.
Substituted 2-aminothiophenes are also important syn-
thetic intermediates in organic synthesis as they find broad
applications18,19 in pharmaceuticals, dyes, and agrochem-
icals. Thus, compound 23 on treatment with DDQ gave the
corresponding 2-amino thiophene derivative 33 in 71% yield
(Scheme 4).
Cyclopropane derivative 8 on treatment with reagent 1
gave the corresponding dihydrothiophene derivative 34 in
75% yield, which on further treatment with ethyl chlorofor-
mate and NaOMe gave compound 35, a potential precursor
of HIV-1 reverse transcriptase inhibitor,2d,20 (HEPT analogue)
in 70% yield (Scheme 5).
In conclusion, we have presented an alternative protocol
for the synthesis of doubly activated cyclopropanes from a
single intermediate. Also we have demonstrated the synthetic
utility of benzyltriethylammonium tetrathiomolybdate 1 toward
the synthesis of 2-amino-4,5-dihydrothiophenes from doubly
activated cyclopropane derivatives in excellent yield under
mild reaction conditions without any Lewis acid activation.
Additionally we have presented a simple route for the synthesis
of 2-amino thiophene 33 and a potential HIV-1 RT inhibitor,
35 (HEPT analogue).
SCHEME 2. Synthesis of Disulfide 20 from Cyclopropane 4
Experimental Section
Synthesis of Substituted Bromosulfonium Bromides. To a solu-
tion of dimethyl sulfide (2.7 mL, 35 mmol) in CH3CN (20 mL)
kept at 0 °C was added a solution of bromine (0.51 mL, 10 mmol)
in CCl4 (3 mL) to give a yellow precipitate. The corresponding
styrene derivative (20 mmol) was then added and stirring was
continued for 30 min at the same temperature. The solution was
then brought to room temperature and diethyl ether (30 mL)
was added to it to give a white precipitate that was then filtered
and washed with diethyl ether to give the corresponding bro-
mosulfonium bromide in good yield.
Bromosulfonium bromide, 2b: white solid; yield 2.72 g, 80%;
1
mp 139.5 °C; IR (KBr) 2977, 1514, 1052, 829 cm-1; H NMR
(300 MHz, D2O) δ 7.37-7.36 (m, 4H), 5.06 (dd, J1 = 6.3 Hz, J2 =
8.7 Hz, 1H), 4.22-4.09 (m, 2H), 2.84 (s, 3H), 2.57 (s, 3H), 2.35 (s,
3H); 13C NMR (100 MHz, D2O) δ 142.1, 130.3, 129.4, 125.6, 60.9,
29.2, 24.2, 20.4. Anal. Calcd for C11H16Br2S: C, 38.84; H, 4.74; S,
9.43. Found: C, 38.72; H, 4.56; S, 9.69.
Synthesis of Doubly Activated Cyclopropanes from Bromosul-
fonium Bromides. Potassium carbonate (0.414 g, 3 mmol) was
added to a solution containing the required bromosulfonium
bromide (1 mmol) in CH2Cl2:H2O (1:1) mixture (20 mL). The
To test the generality of this reaction a number of doubly
activated cyclopropane derivatives substituted with a cyano
group were treated with tetrathiomolybdate 1 (MeOH, 28 °C,
10 min-2 h) to give the corresponding dihydrothiophenes in
very good yields (Table 4). In the absence of a phenyl group at
(19) (a) Lutjens, H.; Zickgraft, A.; Figler, H.; Linden, J.; Olsson, R. A.;
Scammels, P. J. J. Med. Chem. 2003, 46, 1870. (b) Nikolakopoulos, G.;
Figler, H.; Linden, J.; Scammels, P. J. Bioorg. Med. Chem. 2006, 14, 2358.
(20) (a) Arakawa, M.; Hasegawa, K.; Funatsu, K. Chemom. Intell. Lab.
Syst. 2006, 83, 91. (b) Gaudio, A. C.; Montanari, C. A. J. Comput.-Aided
Mol. Des. 2002, 16, 287.
702 J. Org. Chem. Vol. 76, No. 2, 2011

Gopinath and Chandrasekaran
JOCNote
TABLE 4. Synthesis of Dihydrothiophenes
SCHEME 5. Synthesis of Potential HIV-1 RT Inhibitor 35
on silica gel to give the corresponding doubly activated cyclo-
propanes in moderate to good yields.
1,10-(2-Phenylcyclopropane-1,1-diyl)diethanone, 11: light yel-
low solid; yield 0.131 g, 65%; mp 58.0 °C; IR (neat) 1683, 1356
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.30-7.11 (m, 5H), 3.29 (t,
J = 8.4 Hz, 1H), 2.25 (dd, J1 = 5.4 Hz, J2 = 7.5 Hz, 1H), 2.27 (s,
3H), 1.80 (s, 3H), 6.65 (dd, J1 = 5.4 Hz, J2 = 9.0 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) δ 202.6, 202.0, 134.1, 128.4, 128.3,
127.4, 52.6, 35.5, 30.3, 27.5, 18.9; HR-MS m/z calcd for
C13H14O2Naþ [M þ Naþ] 225.0891, found 225.0881.
General Procedure for the Synthesis of Dihydrothiophenes. To
a well-stirred solution of the corresponding cyclopropane derivative
(1 mmol) in MeOH (4 mL) was added benzyltriethylammonium
tetrathiomolybdate, 1 (0.731 g, 1.2 mmol). The reaction mixture
was then stirred until the disappearance of the starting cyclopro-
pane. The solvent was removed; the residue was extracted with
CH2Cl2 (5 mL) and diethyl ether (20 mL) and filtered through a
Celite pad. The residue was again extracted with CH2Cl2 (5 mL)
followed by extraction with diethyl ether (20 mL) and filtered
again through a Celitepad. The combinedextractwas evaporated
and the residue was purified by column chromatography on silica
gel to give the corresponding dihydrothiophene derivative.
Ethyl 2-amino-5-phenyl-4,5-dihydrothiophene-3-carboxylate,
21: white crystalline solid (0.219 g, 88%); mp 107.5 °C; IR (neat)
1
3407, 3309, 1650, 1603, 1516, 1271 cm-1; H NMR (400 MHz,
CDCl3) δ 7.42 (d, J = 7.6 Hz, 2H), 7.34-7.25 (m, 3H), 6.08 (br s,
2H), 4.86 (t, J= 8.0 Hz, 1H), 4.18-4.11 (m, 2H), 3.40 (dd, J1 =8.4
Hz, J2 = 14.4 Hz, 1H), 3.15 (dd, J1 = 7.6 Hz, J2 = 14.4 Hz, 1H),
1.26 (t, J = 5.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.3,
162.0, 141.5, 128.6, 127.7, 127.2, 91.0, 59.0, 51.4, 41.6, 14.6; HR-
MS m/z calcd for C13H15NO2SNaþ [M þ Naþ] 272.0721, found
272.0723.
SCHEME 4. Synthesis of 2-Amino Thiophene 33
Acknowledgment. P.G. thanks the Council of Scientific
and Industrial Research (CSIR), New Delhi for a Senior
Research Fellowship.
corresponding activate methylene compound (2 mmol) was
added to it and the reaction mixture was stirred for 8 h at room
temperature. The CH2Cl2 layer was then separated and the
aqueous layer was washed three times with dichloromethane
(10 mL) and added to the organic layer. The combined organic
layer was dried over anhydrous sodium sulfate and then evapo-
rated. The residue was then purified by column chromatography
Supporting Information Available: Experimental proce-
1
dures, full characterization, H NMR spectra, and 13C NMR
spectra for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 76, No. 2, 2011 703