Cross-dehydrogenative coupling of dithiolanes with ketones and indoles under metal-free conditions

Article abstract of DOI:10.1055/s-0033-1339335

A metal-free cross-dehydrogenative coupling of dithiolanes with ketones and indoles has been developed using DDQ as an oxidant. It provides an economical protocol for the synthesis of β-keto dithiolanes and 3-(1,3-dithiolan-2-yl) indoles. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1339335

LETTER
▌1963
lCettreross-Dehydrogenative Coupling of Dithiolanes with Ketones and Indoles
under Metal-Free Conditions
Cross-Dehydrogenative Coupling of Dithiolanes with Ketones
Kamal Nain Singh,* Paramjit Singh, Pushpinder Singh, Yogita Maheshwary, Satinder V. Kessar, Aanchal Batra
Department of Chemistry, Panjab University, Chandigarh 160014, India
E-mail: kns@pu.ac.in
Received: 18.04.2013; Accepted after revision: 10.06.2013
OR1
O
OR1
Abstract: A metal-free cross-dehydrogenative coupling of dithi-
olanes with ketones and indoles has been developed using DDQ as
an oxidant. It provides an economical protocol for the synthesis of
β-keto dithiolanes and 3-(1,3-dithiolan-2-yl) indoles.
O
DDQ
Ar
(1)
+
Ar
1
2
3
Key words: cross-dehydrogenative coupling, dithiolane, metal-
free coupling, C–C bond, DDQ
O
O
Ar
H
O
CN
O
CN
4
O
DDQ
Sulfur-containing compounds are of significant interest
because of their importance in pharmaceutical industry
and in material science.1 β-Keto-1,3-dithiolanes are versa-
tile intermediates,2a and dithiolanes are widely used as
protecting groups in natural and non-natural product syn-
thesis.2b–h These compounds have been synthesized by re-
action of o-silylated enolates with thiocarbocations,3a,b
nucleophilic addition of thioketals to epoxides, followed
by oxidation3c and double Michael addition of dithiol to
electron-deficient acetylenic carbonyl compounds.2a,4
Ar
Ar
O
(2)
(3)
+
O
Cl
O
Cl
Ar
5
2
O
O
O
O
o-chloranil
R1
R2
SMe
+
Ph
SMe
R1
R2
6
7
Ph
8
In recent years, many methods employing transition-met-
al-based catalysts for forming new C–C bonds have been
developed and are used in synthesis.5 Cross-dehydrogena-
tive coupling (CDC) has evolved as an effective alterna-
tive route for the formation of C–C or C–X (X = N, O, S)
bond.6 Owing to its simplicity and nonrequirement of pre-
functionalization, the CDC procedure, with or without us-
ing metal catalyst, has become a useful methodology in
Scheme 1 Previous work
In continuation of our interest in the development of new
CDC reactions of synthetic utility,14 we have now ex-
plored DDQ-promoted reactions of dithiolanes with ke-
tones and indoles under metal-free conditions (Scheme 2,
eq. 1 and 2), and the results are described in this commu-
nication.
synthesis.7–9
2,3-Dichloro-5,6-dicyanobenzoquinone
In our initial study, we heated dithiolane 9a and acetophe-
none (2a) at 100 °C for three hours in the presence of
DDQ (1.2 equiv). After workup and column chromato-
graphic separation, the product 10a was obtained in 25%
(DDQ) has been frequently used as an oxidant in metal-
free CDC reactions.10 DDQ-promoted sp3 C–H function-
alization adjacent to nitrogen and oxygen has been report-
ed,10 but sulfur-containing substrates are less explored.11
For example, Li reported that the reaction of benzyl ether
1 or cyclic ethers with ketones 2 in the presence of DDQ
affords the coupled products 3 (Scheme 1, eq. 1).12 How-
ever, in a similar reaction with acetal 4, DDQ adduct 5
was obtained rather than the desired coupled product
(Scheme 1, eq. 2).13
O
S
S
DDQ
O
Ar
(1)
R1
10
Ar
S
2
o-Chloranil-assisted coupling of thioether 6 and active
methylene substrate 7 has also been investigated (Scheme
1, eq. 3).11c
S
R1
S
S
9
DDQ
NR2
R1
(2)
N
R2
12
SYNLETT 21709013, 2415, 1963–1967
Advanced online publication: 07.08.2013
DOI: 10.1055/s-0033-1339335; Art ID: ST-2013-B0357-L
© Georg Thieme Verlag Stuttgart · New York
11
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Scheme 2 This work

1964
K. N. Singh et al.
LETTER
Table 2 Cross-Dehydrogenative Coupling of 9 with Acetophenonesa
Table 1 Optimization of Reaction Conditionsa
R1
S
O
S
O
S
S
O
R2
R3
DDQ
S
+
S
R4
Ph
+
Ph
9a
2a
10a
9a R1 = R2 = R3 = H
2a R4 = H
9b R1 = H, R2 = H, R3 = OMe
9c R1 = H, R2 = H, R3 = Cl
9d R1 = H, R2 = NO2, R3 = H
2b R4 = 4-OMe
2c R4 = 4-Br
2d R4 = 4-Cl
2e R4 = 4-Me
Entry
2a (equiv)
Time (h)
Temp (°C)
Yield (%)b
1
2
3
5
8
8
8
8
8
8
8
8
3
3
3
6
1
3
3
3
3
3
100
100
100
100
100
100
25
25
30
DDQ, 100 °C
3 h
3
55 (78)c
52
4
R1
O
S
S
R2
R3
5
15
6d
7e
8
23
R4
10a–o
–
O
O
S
S
S
S
130
100
100
<5
9f
10g
50
10p
10q,r
27
Entry
9
2
10
Yield (%)b
a Reaction conditions: dithiolane (1 equiv), DDQ (1.2 equiv).
b Isolated yield.
55 (78)c
45 (64)
58 (82)
55 (80)
65 (88)
45 (65)
60 (85)
55 (82)
62 (88)
56 (80)
50 (83)
50 (85)
60 (80)
65 (78)
50 (82)
41 (73)
45 (66)
40 (68)
c Yield in parenthesis is based on recovered dithiolane.
d Toluene (3 mL) as solvent.
1
2
9a
9a
9a
9a
9a
9b
9b
9b
9b
9c
9c
9c
9c
9c
9d
9a
9a
9a
2a
2b
2c
2d
2e
2a
2c
2d
2e
2a
2c
2d
2e
2b
2a
2fd
2ge
2hf
10a
10b
10c
10d
10e
10f
e CHCl3–CH2Cl2–THF–Et2O–DMF (3 mL) as solvent.
f DDQ (1.5 equiv).
3
g DDQ (3 equiv).
4
Ph
S
S
5
6
S
S
Ph
7
10g
10h
10i
13
8
Figure 1 Homocoupled product
9
yield (Table 1, entry 1). To optimize the yield of the prod-
uct, various changes in experimental conditions were at-
tempted, and the results are summarized in Table 1.
Increasing the amount of acetophenone to five equivalents
led to a slight increase in the yield (30%) (Table 1, entry
2). Further increase in amount of acetophenone (8 equiv)
improved the yield of 10a to 55% (Table 1, entry 3). Pro-
longed reaction time did not affect the yield but shorter re-
action time led to a decrease in the yield of 10a (Table 1,
entries 4 and 5). Using toluene as a solvent in the reaction
also resulted in a decrease in the yield of 10a (Table 1, en-
try 6). In reactions carried out at lower temperature
(25 °C) in different solvents, no product formation was
observed (Table 1, entry 7). At higher reaction tempera-
ture (130 °C) formation of 10a was suppressed (Table 1,
entry 8), instead, the homocoupled product 13 (Figure 1)
was obtained in 28% yield. Moreover, an increase in
amount of DDQ to 1.5 equivalents hardly affected the
yield of the product (Table 1, entry 9), but use of three
equivalents of DDQ drastically reduced the yield (Table
1, entry 10). This may be due to overoxidation and has
10
11
12
13
14
15
16
17
18
10j
10k
10l
10m
10n
10o
10p
10q
10r
a Reaction conditions: dithiolane 9 (1 equiv), acetophenone 2
(8 equiv), DDQ (1.2 equiv), 100 °C, 3 h.
b Isolated yields.
c Yields in parentheses are based on recovered dithiolane.
d Propiophenone.
e Cyclohexanone.
f α-Tetralone.
Synlett 2013, 24, 1963–1967
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cross-Dehydrogenative Coupling of Dithiolanes with Ketones
1965
Table 3 Cross-Dehydrogenative Coupling of 9 with Indolesa
After establishing the optimized reaction conditions, the
substrate scope for both reactants was examined, and the
results are summarized in Table 2.15 It was found that the
reaction is tolerant to electron-donating and electron-
withdrawing groups in both substrates. An increase in the
yield of 10 was observed when p-methyl acetophenone
(2e) was used (Table 2, entries 5, 9, and 13). Also, p-halo-
substituted ketones 2c and 2d gave comparable yields
(Table 2, entries 3, 4, 7, 8, 11, and 12). Use of substituted
dithiolanes did not show any marked difference in the
yield of the product (Table 2, entries 6–15). Other ketones
like propiophenone, cyclohexanone, and α-tetralone also
coupled well under these conditions (Table 2, entries 16–
18).
R1
S
R2
+
S
N
R4
R3
9a R1 = R2 = R3 = H
9b R1 = H, R2 = H, R3 = OMe
9c R1 = H, R2 = H, R3 = Cl
11a R = H
11b R = Me
9d R1 = H, R2 = OMe, R3 = OMe
9e R1 = NO2, R2 = H, R3 =H
DDQ
60 °C, 12 h
R1
S
S
R2
R3
Encouraged by these results, we extended this methodol-
ogy to indole (11a) as the nucleophile, using slightly mod-
ified reaction conditions. Indoles are considered as good
coupling partners6 and C3-functionalized indoles show
many important biological and pharmaceutical activi-
ties.16 Dithiolane-bearing indoles are also of synthetic in-
terest.17 The reaction of 9a (1 equiv) and 11a (2 equiv)
was carried out at 60 °C for 12 hours using DDQ (1.2
equiv). Workup and separation by column chromatogra-
phy gave the coupled product 12a in 35% isolated yield
(Table 3, entry 1). Different dithiolanes 9a–c and 9e–f
coupled smoothly with indole (11a) and N-methyl indole
(11b) to afford the products 12a–g in moderate yields (Ta-
ble 3).
NR4
12
Entry
9
11
12
Yield (%)b,c
1
2
3
4
5
6
7
9a
9a
9b
9b
9c
9e
9f
11a
11b
11a
11b
11a
11a
11a
12a
12b
12c
12d
12e
12f
35 (52)
44 (63)
45 (57)
40 (68)
35 (61)
35 (54)
38 (66)
In accordance with an earlier proposed mechanism in-
volving DDQ,10 a plausible mechanism of reaction of 9a
with (pro)nucleophile is depicted in Scheme 3. Single-
electron transfer (SET) from dithiolane 9a to DDQ gener-
ates the radical cation species I and a DDQ radical anion
II. Abstraction of the H atom by II from I gives the thio-
nium cation III and DDQ anion IV. Further reaction with
Nu–H furnishes the coupled product 10/12 and DDQH2.
12g
a Reaction conditions: dithiolane 9 (1 equiv), indole 11 (2 equiv),
DDQ (1.2 equiv), 60 °C, 12 h.
b Isolated yields.
c Yields in parentheses are based on recovered dithiolane.
been observed in other cases also.10d,11c No reaction oc-
curred in the absence of DDQ. Thus, the best result was
obtained by using eight equivalents of acetophenone and
1.2 equivalents of DDQ at 100 °C (Table 1, entry 3).
Some unreacted dithiolane was always observed (as indi-
cated by TLC analysis) in these reactions.
In conclusion, we have demonstrated that a facile metal-
free coupling at sp3 α-C–H center of dithiolane with ke-
tones and indoles can occur. Proper reaction conditions
are critical for obtaining the cross-coupled product as ma-
jor product because slight variations can result in the for-
mation of homocoupled product. DDQ worked effectively
CN
CN
S
•
O–
S+
NC
NC
O
S
+
S
+
H
•O
Cl
O
Cl
Cl
II
Cl
9a
I
CN
CN
S+
S
NC
HO
O–
NC
HO
OH
Cl
S
S
NuH
+
+
Nu
Cl
Cl
Cl
DDQH2
10/12
III
IV
Scheme 3 Tentative mechanism
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1963–1967

1966
K. N. Singh et al.
LETTER
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Acknowledgment
We acknowledge financial support by grant no. SR/SI/OC-31/2007
from DST, New Delhi. Aanchal Batra, Pushpinder Singh, and Y.
Maheshwary thank UGC and CSIR for research fellowships. NMR
and mass facility from SAIF, Panjab University is gratefully ack-
nowledged.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
References and Notes
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(15) (a) Typical Procedure for Coupling of 9 and 2
To a 10 mL two-necked round-bottom flask charged with
acetophenone 2 (8 equiv) and DDQ (1.2 equiv) was added
dithiolane 9 (1 equiv) under nitrogen atmosphere. The
reaction mixture was heated at 100 °C immediately and
stirred at this temperature for 3 h. The resultant crude
material was directly purified by flash chromatography on
silica gel (EtOAc–hexane, 3:97) to afford the pure product
10.
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Data for Representative Examples
1-Phenyl-2-(2-phenyl-1,3-dithiolan-2-yl)ethanone
(10a)2a,4a
Yield 0.11 g (55%); white solid; mp 129–131 °C (EtOAc–
hexane, 5:95). IR: ν = 3064, 2962, 2921, 2855, 1681, 1659,
1603, 1595, 1529, 1446, 1340, 1242, 1207 cm–1. 1H NMR
[300 MHz, CDCl3–CCl4 (1:1)]: δ = 7.81 (d, J = 1.5 Hz, 2 H),
7.67 (d, J = 1.5 Hz, 2 H), 7.43–7.41 (m, 1 H), 7.35–7.30 (m,
2 H), 7.19–7.14 (m, 2 H), 7.08–7.06 (m, 1 H), 4.17 (s, 2 H),
3.29–3.20 (m, 4 H). 13C NMR [75 MHz, CDCl3–CCl4 (1:1)]:
δ = 195.0, 144.6, 136.7, 133.1, 128.5, 128.1, 127.9, 127.1,
126.9, 69.0, 54.2, 39.4. MS (ES+): m/z = 323.4 [M + Na]+.
(6) For recent reviews on CDC reactions, see: (a) Li, B.-J.; Shi,
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Dong, V. M. Chem. Rev. 2011, 111, 1215. (c) Scheuermann,
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Synlett 2013, 24, 1963–1967
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cross-Dehydrogenative Coupling of Dithiolanes with Ketones
1967
2-[2-(4-Methoxyphenyl)-1,3-dithiolan-2-yl]-1-p-tolyl-
ethanone (10i)
124.8, 122.4, 121.9, 120.7, 119.6, 111.1, 71.1, 40.0.
MS (ES+): m/z = 298.1 [M + H]+.
Yield 0.100g (62%); white solid, mp 110–113 °C (EtOAc–
hexane = 5:95). IR: ν = 3016, 2835, 1682, 1605, 1576, 1505,
1507, 1463, 1414, 1338, 1291, 1249, 1215 cm–1. 1H NMR
[300 MHz, CDCl3–CCl4 (1:1)]: δ = 7.71 (d, J = 8.0 Hz, 2 H),
7.57 (d, J = 8.8 Hz, 2 H), 7.12 (d, J = 8.0 Hz, 2 H), 6.67 (d,
J = 8.8 Hz, 2 H), 4.10 (s, 2 H), 3.67 (s, 3 H), 3.24–3.21 (m,
4 H), 2.32 (s, 3 H). 13C NMR [75 MHz, CDCl3–CCl4 (1:1)]:
δ = 194.7, 158.4, 143.6, 136.7, 134.4, 129.2, 128.4, 128.3,
113.1, 68.9, 55.0, 53.9, 39.3, 21.7. HRMS (ES+): m/z calcd
for C19H20S2O2Na [M + Na]+: 367.0796; found: 367.0780.
2-[2-(4-Chlorophenyl)-1,3-dithiolan-2-yl]-1-phenyl-
ethanone (10j)
Yield 0.086 g (56%); viscous oil. IR: ν = 3018, 2924, 2855,
1687, 1596, 1488, 1448, 1397, 1342, 1260, 1213 cm–1. 1H
NMR [300 MHz, CDCl3–CCl4 (1:1)]: δ = 7.81 (t, J = 7.0 Hz,
2 H), 7.64–7.59 (m, 2 H), 7.48 (t, J = 7.0 Hz, 1 H), 7.36–7.31
(m, 2 H), 7.18–7.12 (m, 2 H), 4.16 (s, 2 H), 3.31–3.16 (m, 4
H). 13C NMR [75 MHz, CDCl3–CCl4 (1:1)]: δ = 195.0,
143.3, 136.4, 133.3, 132.9, 128.6, 128.0, 127.9, 68.4, 54.1,
39.4. HRMS (ES+): m/z calcd for C17H15S2ClONa [M +
Na]+: 357.0145; found: 357.0146.
3-[2-(4-Methoxyphenyl)-1,3-dithiolan-2-yl]-1H-indole
(12c)
Yield 0.069 g (45%); orange solid, mp 125–130 °C (EtOAc–
hexane, 5:95). IR: ν = 3334, 2962, 2923, 1708, 1599, 1504,
1419, 1303, 1244, 1213 cm–1. 1H NMR [300 MHz, CDCl3–
CCl4 (1:1)]: δ = 7.78 (br s, 1 H), 7.52 (d, J = 9.0 Hz, 2 H),
7.35 (d, J = 7.4 Hz, 1 H), 7.19–7.14 (m, 2 H), 7.05–7.00 (m,
1 H), 6.91–6.85 (m, 1 H), 6.68 (d, J = 8.7 Hz, 2 H), 3.70 (s,
3 H), 3.41–3.30 (m, 4 H). 13C NMR [75 MHz, CDCl3–CCl4
(1:1)]: δ = 137.7, 129.6, 124.8, 122.4, 122.3, 119.6, 113.2,
111.0, 71.1, 55.0, 39.9. HRMS (ES+): m/z calcd for
C18H18S2NO [M + H]+: 328.0824; found: 328.0873.
3-[2-(4-Chlorophenyl)-1,3-dithiolan-2-yl]-1H-indole
(12e)
Yield 0.053g (35%); yellow oil. IR: ν = 3407, 2923, 1630,
1589, 1540, 1485, 1445, 1413, 1393, 1331, 1241, 788 cm–1.
1H NMR [300 MHz, CDCl3–CCl4 (1:1)]: δ = 7.80 (br s, 1 H),
7.56 (d, J = 8.7 Hz, 2 H), 7.32 (d, J = 8.1 Hz, 1 H), 7.19–7.11
(m, 4 H), 7.06 (t, J = 7.2 Hz, 1 H), 6.92 (t, J = 7.2 Hz, 1 H),
3.43–3.29 (m, 4 H). 13C NMR [75 MHz, CDCl3–CCl4 (1:1)]:
δ = 142.0, 137.6, 133.3, 129.8, 128.0, 125.5, 124.7, 122.6,
122.0, 120.4, 119.8, 111.1, 70.5, 40.1. HRMS (ES+): m/z
calcd for C17H15S2NCl [M + H]+: 332.0328; found:
332.0341.
2-[2-(4-Chlorophenyl)-1,3-dithiolan-2-yl]-1-p-tolyl-
ethanone (10m)
Yield 0.096 g (60%); viscous oil. IR: ν = 3016, 2922, 2859,
2055, 1682, 1606, 1571, 1488, 1404, 1337, 1216 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 7.72 (d, J = 8.1 Hz, 2 H), 7.64
(d, J = 8.7 Hz, 2 H), 7.18–7.12 (m, 4 H), 4.17 (s, 2 H), 3.32–
3.18 (m, 4 H), 2.31 (s, 3 H). 13C NMR (75 MHz, CDCl3):
δ = 195.2, 144.3, 143.4, 133.8, 132.7, 129.2, 128.4, 128.1,
127.9, 68.2, 53.8, 39.3, 21.6. HRMS (ES+): m/z calcd for
C18H17S2ClONa [M + Na]+: 371.0301; found: 371.0378.
(b) Typical Procedure for Coupling of 9 and 11
To a 10 mL two-necked round-bottom flask charged with
indole 11 (2 equiv) and DDQ (1.2 equiv) was added
dithiolane 9 (1 equiv) under nitrogen atmosphere. The
reaction mixture was heated at 60 °C immediately and
stirred at this temperature for 12 h. The resultant crude
material was directly purified by flash chromatography on
silica gel (EtOAc–hexane, 10:90) to afford the pure product
12.
3-[2-(3,4-Dimethoxyphenyl)-1,3-dithiolan-2-yl]-1H-
indole (12f)
Yield 0.051 g (35%); brown solid, mp 100–103 °C (EtOAc–
hexane, 5:95). IR: ν = 3158, 2917, 2848, 1594, 1565, 1510,
1439, 1379, 1334, 1268, 1201 cm–1. 1H NMR [300 MHz,
CDCl3–CCl4 (1:1)]: δ = 7.83 (br s, 1 H), 7.40 (d, J = 8.1 Hz,
1 H), 7.30 (d, J = 2.2 Hz, 1 H), 7.18 (t, J = 3.6 Hz, 1 H), 7.11
(d, J = 2.2 Hz, 1 H), 7.06 (t, J = 7.2 Hz, 2 H), 6.92 (t, J = 7.2
Hz, 1 H), 6.60 (d, J = 8.1 Hz, 1 H), 3.76 (s, 3 H), 3.73 (s, 3
H), 3.41–3.30 (m, 4 H). 13C NMR [75 MHz, CDCl3–CCl4
(1:1)]: δ = 148.4, 137.6, 135.5, 125.6, 125.0, 122.4, 122.2,
120.9, 119.6, 112.1, 111.0, 110.2, 71.2, 55.8, 55.7, 39.9.
HRMS (ES+): m/z calcd for C19H19S2NO2Na [M + Na]+:
380.0749; found: 380.0750.
(16) (a) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem.
Rev. 2010, 110, 4489. (b) Bandini, M.; Eichholzer, A.
Angew. Chem. Int. Ed. 2009, 48, 9608. (c) Humphrey, G. R.;
Kuethe, J. T. Chem. Rev. 2006, 106, 2875. (d) Cacchi, S.;
Fabrizi, G. Chem. Rev. 2005, 105, 2873. (e) Sundberg, R. J.
Indoles; Academic Press: New York, 1996.
(17) (a) Akgün, E.; Tunali, M.; Pindur, U. Liebigs Ann. Chem.
1986, 9, 1628. (b) Rubiralta, M.; Casamitjana, N.
Tetrahedron 1988, 44, 443. (c) Jo, S.; Tanimoto, S.;
Sugimoto, T.; Okano, M. Bull. Chem. Soc. Jpn. 1981, 54,
2120.
Data for Representative Examples
3-(2-Phenyl-1,3-dithiolan-2-yl)-1H-indole (12a)17a
Yield 0.070 g (35%); yellow reddish solid, mp 91–93 °C
(EtOAc–hexane, 5:95). IR: ν = 3406, 3052, 2921, 1593,
1567, 1517, 1492, 1455, 1443, 1413, 1337, 1241, 1210
cm–1. 1H NMR [300 MHz, CDCl3–CCl4 (1:1)]: δ = 7.84 (br
s, 1 H), 7.64 (d, J = 7.0 Hz, 2 H), 7.35 (d, J = 7.8 Hz, 1 H),
7.21–7.12 (m, 5 H), 7.06 (t, J = 7.0 Hz, 1 H), 6.91 (t, J = 7.2
Hz, 1 H) 3.45–3.30 (m, 4 H). 13C NMR (75 MHz, CDCl3–
CCl4 = 1:1): δ = 143.4, 137.6, 128.2, 127.9, 127.3, 125.6,
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