A convenient synthesis of propargylic dithioacetals

Article abstract of DOI:10.1055/s-2006-948169

Treatment of trimethylsilyl-substituted alkynyl ketones with 1,2-ethanedithiol in the presence of BF₃·OEt₂ in methanol afforded the corresponding dithioacetal. Removal of the silyl group under basic conditions followed by palladium-catalyzed coupling reactions with aryl iodides yielded the corresponding propargylic dithioacetals in excellent yield. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-948169

LETTER
3173
A Convenient Synthesis of Propargylic Dithioacetals
A
Convenient
S
i
ynthes
-
F
a
rgylic
D
ithio
u
acetals Huang, Chin-Fa Lee, Jui-Chang Tseng, Tien-Yau Luh*
Department of Chemistry, National Taiwan University, Taipei, Taiwan 106
Fax +886(2)23644971; E-mail: tyluh@ntu.edu.tw
Received 12 April 2006
Dedicated to Professor Richard F. Heck in recognition of his outstanding contributions to modern organic synthesis
moved to generate the corresponding terminal alkynes,8
further coupling reactions9 may provide a general proce-
dure for the synthesis of 1 bearing different kinds of
substituents R2.
Abstract: Treatment of trimethylsilyl-substituted alkynyl ketones
with 1,2-ethanedithiol in the presence of BF3·OEt2 in methanol af-
forded the corresponding dithioacetal. Removal of the silyl group
under basic conditions followed by palladium-catalyzed coupling
reactions with aryl iodides yielded the corresponding propargylic
dithioacetals in excellent yield.
Palladium catalysts have been shown to be particularly
useful for the alkynylation of various electrophiles.10–12
We recently reported that palladium-catalyzed Kumada–
Corriu cross-couplings of alkynyl Grignard reagents with
alkyl iodides or bromides in the presence of triphen-
ylphosphine.12 It is envisaged that this protocol might be
applicable to the synthesis of a variety of substituted
propargylic dithioacetals 6 (Equation 2).
Key words: propargylic dithioacetals, alkynyl Grignard, cross-
coupling reactions, desilylation
There has been an ever burgeoning interest in the use of
propargylic systems in organic synthesis.1,2 Depending on
the nature of the substrates and reactions, a range of prod-
ucts with fascinating structures can be conveniently ob-
tained. We recently reported that propargylic dithioacetals
1 are useful starting materials for the synthesis2 of substi-
tuted allenes,3 enynes,4 pyrroles and tri- or tetrasubstituted
furans5,6 (Scheme 1). The reaction is particularly attrac-
tive for the regioregular synthesis of furan- or pyrrole-
containing oligoaryls.5 At the beginning of this research,
the starting material 1 was prepared by the BF3-catalyzed
reaction of propargylic ketone 2 with 1,2-ethanedithiol in
methanol.7 However, a significant amount of the bis-
Michael adduct 3 was also obtained as a side product in
12–48% yield (Equation 1). Tedious chromatographic
separation is required to afford pure 1.
O
HSCH2CH2SH
S
S
O
S
S
R2
R1
R1
+
R1
BF3·OEt2, MeOH
R2
R2
2
1
3
Equation 1 Dithioacetalization of propargyl ketone 2
Treatment of 4 with 1,2-ethanedithiol in the presence of
BF3·OEt2 in methanol followed by addition of aqueous
NaOH and K2CO3 afforded 5 in good to excellent yields
(Table 1). Alkyne 5 was allowed to react with MeMgI (2
M solution, Et2O) at ambient temperature for 30 minutes
to give the corresponding alkynyl Grignard reagent,
which was then added dropwise to a THF solution of aryl
iodide and a catalytic amount of Pd2(dba)3 (2.5 mol%) and
Ph3P (10 mol%). The mixture was refluxed for 10–12
hours followed by usual workup to yield 6 (Table 1).13,14
Aryl iodides bearing different functional groups, such as
methyl, methoxy, bromo, and methoxycarbonyl, afforded
the corresponding dithioacetals 6 in excellent yield. Aryl
bromides were, however, not suitable for these coupling
reactions. It is interesting to note that the coupling
reaction could also proceed at ambient temperature with
similar results but a longer reaction time was necessary.
As can be seen from Table 1, the substituent at C-2 of
dithiolane can be aryl or alkyl groups. Sterically bulky
substituents such as tert-butyl or adamantyl groups did not
affect the yield of the coupling reactions.
EtO2C
R3
R3
R1
C
R1
R2
R2
S
S
R1
R2
R4
R2
X = O or NR5
R1
1
S
E
S
R1
R3
C
R2
R3
X
Scheme 1 Synthetic applications of propargylic dithioacetals 1
It is interesting to note that, when R2 was a trimethylsilyl
group, the reaction became regioselective, giving 1
(R1 = Ph, R2 = Me3Si) exclusively in 95% isolated yield.
Since the silyl moiety in alkynylsilanes can be easily re-
A Sonogashira reaction can also be employed for the syn-
thesis of 6 from 5. Thus, treatment of 5 (R1 = Ph) with PhI
in the presence of 5 mol% of PdCl2(PPh3)2 and 10 mol%
each of CuI and Ph3P in DMF at 90 °C for 12 hours afford-
ed 6 (R1 = Ph) in 73% yield.
SYNLETT 2006, No. 18, pp 3173–3175
0
3
.1
1
.2
0
0
6
Advanced online publication: 04.08.2006
DOI: 10.1055/s-2006-948169; Art ID: S07206ST
© Georg Thieme Verlag Stuttgart · New York

3174
L.-F. Huang et al.
LETTER
1. HSCH2CH2SH
BF3·OEt2
O
S
R1
S
1. MeMgI
2. ArI
Pd2(dba)3
PPh3
S
R1
S
R1
2. K2CO3,
10% NaOH
SiMe3
H
Ar
4
5
6
Equation 2 Two-step synthesis of substituted propargylic dithioacetal 6
Table 1 Synthesis of Propargylic Dithioacetals from 4
avoided. This protocol provides a large-scale synthesis of
a range of useful starting propargylic dithioacetals for
synthetic applications.2–6
R1
Ph
Yield of 5
5a, 97%
Ar
Yield of 6a
6a, 94% (90%)
6b, 91% (85%)
6c, 94% (88%)
6d, 91% (90%)
6e, 92%
Ph
Acknowledgment
4-MeC6H4
4-MeO2CC6H4
4-BrC6H4
4-MeOC6H4
Ph
We thank the National Science Council and the Ministry of Educa-
tion of the Republic of China for financial support.
References and Notes
(1) Selected recent reviews: (a) Amemiya, R.; Yamaguchi, M.
Eur. J. Org. Chem. 2005, 5145. (b) Ma, S. Eur. J. Org.
Chem. 2004, 1175. (c) Gung, B. W. Org. React. (N. Y.)
2004, 64, 1. (d) Teobald, B. J. Tetrahedron 2002, 58, 4133.
(e) Prakesch, M.; Gree, D.; Gree, R. Acc. Chem. Res. 2002,
35, 175. (f) Green, J. R. Curr. Org. Chem. 2001, 5, 809.
(g) Müller, T. J. J. Eur. J. Org. Chem. 2001, 2021. (h) Li,
C.-L.; Liu, R.-S. Chem. Rev . 2000, 100, 3127. (i) Bruneau,
C.; Darcel, C.; Dixneuf, P. H. Curr. Org. Chem. 1997, 1,
197. (j) Tsuji, J.; Mandai, T. Synthesis 1996, 1. (k) Tsuji, J.;
Mandai, T. Angew. Chem. Int. Ed. 1996, 34, 2589.
(l) Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207.
(m) Overman, L. E. Acc. Chem. Res. 1980, 13, 218.
(2) For a recent review, see: Luh, T.-Y.; Lee, C.-F. Eur. J. Org.
Chem. 2005, 3875.
n-Pr
5b, 92%
6f, 96%
4-MeO2CC6H4
4-BrC6H4
4-MeOC6H4
4-MeO2CC6H4
4-BrC6H4
4-MeO2CC6H4
4-BrC6H4
4-MeO2CC6H4
6g, 95%
6h, 89%
6i, 95%
t-Bu
5c, 94%
5d, 64%
5e, 98
6j, 87%
6k, 90%
1-Ad
6l, 85%
6m, 83%
c-Hex
6n, 93%
(3) (a) Tseng, H.-R.; Luh, T.-Y. J. Org. Chem. 1996, 61, 8685.
(b) Tseng, H.-R.; Luh, T.-Y. J. Org. Chem. 1997, 62, 4568.
(c) Tseng, H.-R.; Lee, C.-F.; Yang, L.-M.; Luh, T.-Y. J. Org.
Chem. 1999, 64, 8582.
(4) Tu, H.-Y.; Liu, Y.-H.; Wang, Y.; Luh, T.-Y. Tetrahedron
Lett. 2005, 46, 771.
a The yields in parentheses are for reactions carried out at r.t. for 15 h.
Attempts to couple alkyl iodides with the Grignard re-
agent prepared from 5 under various conditions were un-
successful. Under mild conditions (e.g. refluxing THF),
starting 5 was recovered. On the other hand, when more
drastic conditions were employed (e.g in refluxing toluene
or dioxane), decomposition of 5 occurred. Presumably,
the alkyl iodide was too unreactive under mild conditions,
whereas the propargylic dithioacetal moiety was too labile
under more vigorous conditions.
(5) (a) Lee, C.-F.; Yang, L.-M.; Hwu, T.-Y.; Feng, A.-H.;
Tseng, J.-C.; Luh, T.-Y. J. Am. Chem. Soc. 2000, 122, 4992.
(b) Zhang, L.-Z.; Chen, C.-W.; Lee, C.-F.; Wu, C.-C.; Luh,
T.-Y. Chem. Commun. 2002, 2336. (c) Lee, C.-F.; Liu, C.-
Y.; Song, H.-C.; Luo, S.-J.; Tseng, J.-C.; Tso, H.-H.; Luh,
T.-Y. Chem. Commun. 2002, 2824. (d) Liu, C.-Y.; Luh, T.-
Y. Org. Lett. 2002, 4, 4305. (e) Tseng, J.-C.; Lin, H.-C.;
Huang, S.-L.; Lin, C.-L.; Jin, B.-Y.; Chen, C.-Y.; Yu, J.-K.;
Chou, P.-T.; Luh, T.-Y. Org. Lett. 2003, 5, 4381. (f) Chou,
C.-M.; Chen, W.-Q.; Chen, J.-H.; Lin, C.-L.; Tseng, J.-C.;
Lee, C.-F.; Luh, T.-Y. Chem. Asian J. 2006, 1, in press.
(6) Tseng, J.-C.; Chen, J.-H.; Luh, T.-Y. Synlett 2006, 1209.
(7) Williams, J. R.; Sarkisian, G. M. Synthesis 1974, 32.
(8) (a) Sabourin, E. T.; Onopchenko, A. J. Org. Chem. 1983, 48,
5135. (b) Bakthavachalam, V.; d’Alarco, M.; Leonard, N. J.
J. Org. Chem. 1984, 49, 289. (c) Havens, S. J.;
Organolithium or Grignard reagents obtained from 5 can
react with carbonyl compounds to give the corresponding
propargylic alcohols in good yield (Equation 3).
S
S
1. n-BuLi, THF, –78 °C
S
S
or MeMgI, THF, r.t.
OH
2. cyclohexanone
85–87%
Hergenrother, P. M. J. Org. Chem. 1985, 50, 1763.
(d) Magnus, P.; Annoura, H.; Harling, J. J. Org. Chem. 1990,
55, 1709. (e) Semmelhack, M. F.; Neu, T.; Foubelo, F.
Tetrahedron Lett. 1992, 33, 3277.
H
5a
7
Equation 3 Reaction of 5a with a carbonyl compound
(9) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich,
F.; Stang, P. J., Eds.; Wiley-VCH: New York, 1998.
(b) Cross-Coupling Reactions: A Practical Guide; Miyaura,
N., Ed.; Springer-Verlag: New York, 2002.
(10) For a recent review, see: Negishi, E.-i.; Anastasia, L. Chem.
Rev. 2003, 103, 1979.
In summary, we have demonstrated a convenient synthe-
sis of propargylic dithioacetals by coupling reactions. Al-
though the procedure requires extra steps, tedious
chromatographic separation from by product(s) can be
Synlett 2006, No. 18, 3173–3175 © Thieme Stuttgart · New York

LETTER
A Convenient Synthesis of Propargylic Dithioacetals
3175
(11) (a) Du, F. C.-J.; Hart, H. J. Org. Chem. 1987, 52, 4311.
(b) Katz, H. E. J. Org. Chem. 1989, 54, 2179.
H), 7.47 (d, J = 6.7 Hz, 2 H), 7.96 (d, J = 6.7 Hz, 2 H). 13
C
NMR (CDCl3, 100 MHz): d = 14.0, 22.0, 39.8, 45.8, 52.2,
59.8, 83.3, 95.0, 127.6, 129.3, 129.4, 131.5, 166.5. 6h: 1H
NMR (CDCl3, 400 MHz): d = 1.03 (t, J = 7.3 Hz, 3 H),
1.60–1.82 (m, 2 H), 2.10–2.26 (m, 2 H), 3.35–3.66 (m, 4 H),
7.28 (d, J = 7.8 Hz, 2 H), 7.43 (d, J = 7.8 Hz, 2 H). 13C NMR
(CDCl3, 100 MHz): d = 14.0, 22.0, 39.8, 46.0, 59.9, 83.0,
93.1, 121.8, 122.4, 131.4, 133.1. 6i: 1H NMR (CDCl3, 300
MHz): d = 1.02 (t, J = 7.3 Hz, 3 H), 1.68–1.85 (m, 2 H),
2.15–2.25 (m, 2 H), 3.48–3.65 (m, 4 H), 3.80 (s, 3 H), 6.81
(d, J = 7.3 Hz, 2 H), 7.34 (d, J = 7.3 Hz, 2 H). 13C NMR
(CDCl3, 100 MHz): d = 14.0, 22.0, 39.7, 46.3, 55.2, 60.3,
84.0, 90.4, 113.7, 114.9, 133.0, 159.5. 6j: Mp 93–94 °C. 1H
NMR (CDCl3, 300 MHz): d = 1.33 (s, 9 H), 3.45–3.65 (m, 4
H), 3.91 (s, 3 H), 7.47 (d, J = 8.2 Hz, 2 H), 7.96 (d, J = 8.2
Hz, 2 H). 13C NMR (CDCl3, 100 MHz): d = 27.6, 40.2, 40.4,
52.2, 71.6, 83.9, 95.8, 128.0, 129.2, 129.3, 131.4, 166.6. 6k:
Mp 52–54 °C. 1H NMR (CDCl3, 300 MHz): d = 1.31 (s, 9
H), 3.35–3.48 (m, 2 H), 3.50–3.62 (m, 2 H), 7.27 (d, J = 8.3
Hz, 2 H), 7.42 (d, J = 8.3 Hz, 2 H). 13C NMR (CDCl3, 100
MHz): d = 27.6, 40.3, 40.4, 71.6, 83.5, 93.9, 122.1, 122.2,
131.4, 132.9. 6l: Mp 160–161 °C. 1H NMR (CDCl3, 300
MHz): d = 1.60–1.80 (m, 6 H), 1.99 (br s, 6 H), 2.08 (br s, 3
H), 3.26–3.40 (m, 2 H), 3.45–3.60 (m, 2 H), 3.91 (s, 3 H),
7.48 (d, J = 8.3 Hz, 2 H), 7.96 (d, J = 8.3 Hz, 2 H). 13C NMR
(CDCl3, 100 MHz): d = 28.7, 36.6, 39.1, 39.8, 41.1, 52.2,
72.1, 84.5, 95.2, 128.1, 129.2, 129.3, 131.5, 166.6. 6m: Mp
66–68 °C. 1H NMR (CDCl3, 300 MHz): d = 1.60–1.80 (m, 6
H), 1.90–2.04 (m, 6 H), 2.06 (br s, 3 H), 3.30–3.42 (m, 2 H),
3.45–3.60 (m, 2 H), 7.28 (d, J = 8.4 Hz, 2 H), 7.42 (d, J = 8.4
Hz, 2 H). 13C NMR (CDCl3, 100 MHz): d = 37.4, 39.8, 40.5,
41.9, 72.7, 73.9, 84.5, 93.6, 122.2, 122.4, 131.4, 133.0. 6n:
Mp 97–98 °C. 1H NMR (CDCl3, 300 MHz): d = 1.40–1.58
(m, 5 H), 1.65–2.20 (m, 6 H), 3.40–3.64 (m, 4 H), 3.91 (s, 3
(c) Kamikawa, T.; Hayashi, T. J. Org. Chem. 1998, 63,
8922. (d) Brettar, J.; Gisselbrecht, J.-P.; Gross, M.; Solladié,
N. Chem. Commun. 2001, 733. (e) Rein, R.; Gross, M.;
Solladié, N. Chem. Commun. 2004, 1992. (f) Cheng, Y.-J.;
Luh, T.-Y. Chem. Eur. J. 2004, 10, 5361. (g) Toyota, S.;
Goichi, M.; Kotani, M. Angew. Chem. Int. Ed. 2004, 43,
2248.
(12) Yang, L.-M.; Huang, L.-F.; Luh, T.-Y. Org. Lett. 2004, 6,
1461.
(13) Synthesis of 5; General Procedure: To a solution of 4 (50
mmol) in MeOH (100 mL) cooled to – 78 °C were added
BF3·OEt2 (60 mmol) and 1,2-ethanedithiol (51 mmol). The
mixture was gradually warmed to r.t. and stirred for 12 h.
After quenching with a 10% aq solution of NaOH, the
organic layer was separated. The aqueous layer was
extracted with CH2Cl2. The combined organic layers were
washed with a 10% aq solution of NaOH, brine, dried
(MgSO4), filtered, and concentrated in vacuo to give the
crude propargylic dithioacetal which was dissolved in
MeOH (100 mL). To this methanolic solution was added
K2CO3 (200 mmol) and a 10% aq solution of NaOH (25
mL).14 The mixture was stirred at r.t. overnight and then
quenched with dilute HCl. CH2Cl2 was added and the
aqueous layer was extracted with CH2Cl2. The combined
organic solution was washed with brine, dried (MgSO4), and
filtered. The filtrate was concentrated in vacuo and the
residue was chromatographed on silica gel (hexane–EtOAc,
20:1) to give 5.
Synthesis of 6; General Procedure A solution of Pd2(dba)3
(2.5–5.0 mol%) in THF (15 mL), PPh3 (10–20 mol%), and
aryl iodide (1.0 mmol) were heated at 65–70 °C under an Ar
atmosphere; a solution of the Grignard reagent (1.0 mmol) in
THF (15 mL) was added dropwise [prepared from the
corresponding 5 (1 equiv) and MeMgI (2.0 M, Et2O; 1.1
equiv)]. The mixture was refluxed for 10–12 h. After cooling
to r.t., the mixture was quenched with a sat. solution of
NH4Cl. Et2O was added and the organic layer was washed
with brine, dried (MgSO4), and filtered. The filtrate was
evaporated in vacuo, and the residue was chromatographed
on silica gel (hexane–EtOAc, 20–30:1) to give 6.
H), 7.47 (d, J = 7.1 Hz, 2 H), 7.96 (d, J = 7.1 Hz, 2 H). 13
C
NMR (CDCl3, 100 MHz): d = 25.8, 26.2, 31.7, 39.3, 50.0,
52.2, 66.1, 84.3, 94.3, 127.8, 129.3, 131.5, 166.5.
Sonogashira Reaction of 5a A solution of 5a (206 mg, 1
mmol) in DMF (20 mL), iodobenzene (0.11 mL, 1 mmol),
PdCl2 (PPh3) 2 (35 mg, 5 mol%), Ph3P (26 mg, 10 mol%), CuI
(19 mg, 10 mol%), and Et3N (0.42 mL, 3 mmol) was stirred
under an Ar atmosphere at 90 °C for 12 h. After cooling to
r.t., the mixture was filtered (silica gel–celite,1:1) and the
solvent was removed in vacuo to give the residue which was
chromatographed on silica gel (hexane–EtOAc, 3:1) to give
6a as a white solid (205 mg, 73%).
6b: 1H NMR (CDCl3, 300 MHz): d = 2.36 (s, 3 H), 3.65–
3.90 (m, 4 H), 7.14 (d, J = 8.0 Hz, 2 H), 7.30–7.45 (m, 5 H),
8.02 (d, J = 8.0 Hz, 2 H). 13C NMR (CDCl3, 100 MHz):
d = 21.5, 41.3, 62.4, 87.1, 90.3, 119.6, 127.7, 128.2, 128.3,
129.0, 131.5, 138.5, 138.8. 6c: Mp 107–109 °C. 1H NMR
(CDCl3, 300 MHz): d = 3.65–3.90 (m, 4 H), 3.93 (s, 3 H),
7.30–7.42 (m, 3 H), 7.56 (d, J = 8.2 Hz, 2 H), 7.95–8.10 (m,
4 H). 13C NMR (CDCl3, 100 MHz): d = 41.4, 52.2, 62.0,
86.0, 94.1, 127.4, 128.3, 128.5, 129.4, 129.6, 131.5, 138.3,
166.5. 6d: Mp 56–58 °C. 1H NMR (CDCl3, 400 MHz):
d = 3.65–3.90 (m, 4 H), 7.30–7.55 (m, 7 H), 7.90–8.10 (m, 2
H). 13C (CDCl3, 100 MHz): d = 41.4, 62.1, 85.7, 92.3, 121.7,
122.7, 127.6, 128.3, 128.4, 131.5, 133.1, 138.5. 6e: Mp 66–
68 °C. 1H NMR (CDCl3, 300 MHz): d = 3.65–3.80 (m, 4 H),
3.82 (s, 3 H), 6.86 (d, J = 7.3 Hz, 2 H), 7.28–7.50 (m, 5 H),
8.02 (d, J = 7.3 Hz, 2 H). 13C NMR (CDCl3, 100 MHz):
d = 41.3, 55.3, 62.4, 86.8, 89.6, 113.8, 114.8, 127.6, 128.2,
128.3, 133.1, 139.0, 159.7. 6f: 1H NMR (CDCl3, 400 MHz):
d = 1.03 (t, J = 7.3 Hz, 3 H), 1.70–1.90 (m, 2 H), 2.15–2.35
(m, 2 H), 3.38–3.70 (m, 4 H), 7.28–7.55 (m, 5 H). 13C NMR
(CDCl3, 100 MHz): d = 14.0, 22.0, 39.7, 46.0, 60.0, 84.1,
91.8, 122.8, 128.1, 131.5. 6g: Mp 68–70 °C. 1H NMR
(CDCl3, 300 MHz): d = 1.03 (t, J = 7.3 Hz, 3 H), 1.70–1.86
(m, 2 H), 2.15–2.30 (m, 2 H), 3.44–3.70 (m, 4 H), 3.91 (s, 3
1-[(2-Phenyl-1,3-dithiolan-2-yl)ethynyl]cyclohexanol (7)
n-BuLi (2.5 M, hexane; 0.84 mL, 2.2 mmol) was added
dropwise to a solution of 5a (412 mg, 2 mmol) in THF (30
mL) at –78 °C, and the resulting mixture was stirred for 30
min. Cyclohexanone (0.20 mL, 2 mmol) was then added, the
dry-ice bath was removed, and the mixture was stirred at r.t.
for 2 h. The reaction was quenched with a sat. solution of
NH4Cl, Et2O was added, and the organic layer was washed
with brine, dried (MgSO4), and filtered. The filtrate was
concentrated in vacuo and the residue was chromatographed
on silica gel (hexane–EtOAc, 3:1) to give 7 as a white
powder (527 mg, 87%); mp 72–74 °C. IR (KBr): 3403 cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.15–1.34 (m, 2 H), 1.48–
1.65 (m, 4 H), 1.68–1.80 (m, 4 H), 1.97 (br s, 1 H), 3.62–3.80
(m, 4 H), 7.28–7.40 (m, 3 H), 7.94 (d, J = 8.0 Hz, 2 H). 13
C
NMR (CDCl3, 100 MHz): d = 23.9, 25.6, 40.4, 41.6, 62.1,
69.3, 86.8, 90.9, 127.7, 128.4, 128.5, 138..8
(14) The reaction can also be carried out without NaOH,
however, a higher reaction temperature (40–45 °C) was
required.
Synlett 2006, No. 18, 3173–3175 © Thieme Stuttgart · New York