Comparative study of TmI2, SmI2, and SmI 2/HMPA in the cross-coupling reactions of 2-acetylthiophene and thiophene-2-carboxylate with carbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2004.01.130

The cross-coupling reactions of acetylthiophene or ethyl thiophene-2-carboxylate with aldehydes or ketones were achieved in a regioselective manner by using thulium diiodide in THF solution. Similar coupling reactions were also realized by using samarium diiodide together with excess amounts of hexamethylphosphoramide (HMPA). However, ethyl thiophene-2-carboxylate was inert in SmI₂/THF solution, and acetylthiophene was simply reduced to thienylethanol by SmI₂ in the absence of HMPA.

Full text of DOI:10.1016/j.tetlet.2004.01.130

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2703–2707
Comparative study of TmI2, SmI2, and SmI2/HMPA in the
cross-coupling reactions of 2-acetylthiophene and thiophene-
2-carboxylate with carbonyl compounds
Jiun-Jie Shie,a Penny S. Workman,b William J. Evansb,* and Jim-Min Fanga,*
aDepartment of Chemistry, National Taiwan University, Taipei 106, Taiwan
bDepartment of Chemistry, University of California Irvine, CA 92697-2025, USA
Received 24 September 2003; revised 2 January 2004; accepted 12 January 2004
Abstract—The cross-coupling reactions of acetylthiophene or ethyl thiophene-2-carboxylate with aldehydes or ketones were
achieved in a regioselective manner by using thulium diiodide in THF solution. Similar coupling reactions were also realized by
using samarium diiodide together with excess amounts of hexamethylphosphoramide (HMPA). However, ethyl thiophene-2-car-
boxylate was inert in SmI2/THF solution, and acetylthiophene was simply reduced to thienylethanol by SmI2 in the absence of
HMPA.
Ó 2004 Published by Elsevier Ltd.
Samarium diiodide (SmI2) has become a popular one-
electron-transfer reducing agent in organic synthesis.1;2
Hexamethylphosphoramide (HMPA) is a reagent gen-
erally used to enhance the reduction potential of SmI2 in
THF solution.3 Although this protocol is successful in
a variety of organic reactions, one should take caution
in using HMPA due to its suspected cancer inducing
property.4 It is thus desirable to have an HMPA-free
reagent that can behave similarly as SmI2/HMPA in
organic synthesis. Along this line, thulium diiodide
(TmI2)5 and dysprosium diiodide (DyI2)6 having higher
reduction potential than SmI2 are considered good can-
didates.7 Evans et al. have shown that TmI2 exhibits a
reactivity equivalent or even superior to SmI2/HMPA in
the coupling reactions of ketones with alkyl halides.5 For
example, treatment of cyclohexanone and 2-phenylethyl
iodide by TmI2 or SmI2/HMPA at room temperature in
THF solutions affords the coupling product, 1-(2-phen-
ylethyl)-1-cyclohexanol, in high yields (>80%). Without
the assistance of HMPA, SmI2 can only reduces phen-
ylethyl iodide in the refluxing THF solution.1b
compounds.1;2 The extraordinary effect of HMPA has
been observed. For example, benzaldehyde generally
undergoes a pinacol coupling reaction on treatment with
SmI2 in THF solution.1 However, Fang and co-workers
have found a phenyl–carbonyl coupling product, 4-(1-
hydroxybenzyl)benzaldehyde, when benzaldehyde is
treated with SmI2 in the presence of HMPA.8 In the
latter reaction, coordination of several HMPA mole-
cules on samarium ion exerts a severe steric hindrance
around the ketyl center to prevent the pinacol coupling
between two ketyl sites. Instead, the benzaldehyde ketyl
undergoes electron delocalization, and reacts at the
remote para-position to furnish the phenyl–carbonyl
coupling product. The crucial role of HMPA is also
found in various self- and cross-aryl–carbonyl coupling
reactions of acetophenones,8 indolecarbaldehydes,9
thiophenecarbaldehydes,10 and thiophenecarboxylates.11
In order to make a comparison of TmI2 with SmI2 in the
presence or absence of HMPA, we investigated the
function of TmI2 in the cross-coupling reactions of
2-acetylthiophene (1) and ethyl thiophene-2-carboxylate
(2) with carbonyl compounds. The similarity and dif-
ference in the chemo-, regio-, and stereoselectivities are
demonstrated in these reactions using SmI2, SmI2/
HMPA, or TmI2.
Due to its oxophilic nature, SmI2 is also extensively
utilized to effect the coupling reactions of carbonyl
Keywords: Thulium diiodide; Samarium diiodide; Hexamethylphos-
phoramide; Coupling reaction.
Depending on the reaction conditions, there are several
possible reaction pathways when acetylthiophene was
* Corresponding authors. Tel.: +886-2-23637812; fax: +886-2-23636-
359; e-mail addresses: wevans@uci.edu; jmfang@ccms.ntu.edu.tw
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.01.130

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J.-J. Shie et al. / Tetrahedron Letters 45 (2004) 2703–2707
treated with SmI2 or TmI2 (Scheme 1). The first one-
electron transfer from MI2 (M represents Tm or Sm)
could generate the ketyl intermediate A. Abstraction of
a hydrogen atom from THF solvent could give a
reduction product, 1-(thien-2-yl)ethanol (3) (reaction
type i). Indeed, the reduction product was obtained
when 2-acetylthiophene was treated with SmI2 in the
absence of HMPA (Table 1, entries 1 and 4). No cross-
coupling product 4 (reaction type ii) was observed in any
case. The ketyl intermediate A might be further reduced
by a second equivalent of MI2 to give the organometallic
intermediates B and C.12 The intermediate B might be
stabilized by chelation, whereas the adjacent sulfur atom
with empty d-orbitals might stabilize the intermediate C.
The cross-coupling reaction of B with another carbonyl
compound would give a C-3 coupling product 5 (reac-
tion type iii), whereas the reaction of C would afford a
C-5 coupling product 6 (reaction type iv). Our study
revealed the effective formation of C-5 coupling prod-
ucts under appropriate reaction conditions, while no C-3
coupling product was observed.
(method B),11b and using TmI2 in the absence of HMPA
(method C). The following procedure for the TmI2
promoted coupling reactions is typical.
Method C: Under an atmosphere of argon, a greenish
solution of TmI2 was prepared by dissolving
TmI2(THF)2:8 (756 mg, 1.2 mmol) in THF (10 mL) at
room temperature (25 °C). To the cooled TmI2 solution
(in an ice bath) was added a THF solution (3 mL) of
ethyl thiophene-2-carboxylate (73 mg, 0.5 mmol) and
cyclohexanone (109 mg, 1.1 mmol). The reaction
mixture was stirred at 0 °C for 20 min, and then at
room temperature for 5 h. The resulting yellow mixture
was then quenched by adding saturated aqueous NH4Cl
solution (1 mL). The reaction mixture was filtered
through a short silica gel column, and rinsed with
EtOAc/hexane (1:1). The filtrate was concentrated,
and chromatographed on
a
silica gel column
by elution with EtOAc/hexane 2:8 to give the
desired three-component coupling product 9 (144 mg,
82%).13
HO
HO
O
O
O
O
S
S
S
CH3
S
OEt
OH
CH3
OEt
2
6a
7
8a
MeO
MeO
H3C
O
OH
H
O
OH
S
H3C
H3C
OEt
H
O
O
S
S
OH
8b
OEt
MeO
OH
10
OEt
9
H3C
OMe
OMe
MeO
MeO
OH
H
H
O
O
MeO
S
11b
MeO
S
OH
OEt
OEt
11a
MeO
MeO
OMe
OH
CH3
OH
OH
R
H3C
MeO
14
13 R = OH
15 R = H
12
The results for the SmI2 and TmI2 promoted reactions
of 2-acetylthiophene and ethyl thiophene-2-carboxylate
with carbonyl compounds are compiled in Table 1. In
order to make a precise comparison, each set of reac-
tions was conducted under three different conditions:
using SmI2 in the absence of HMPA (method A), using
SmI2 in the presence of excess amounts of HMPA
In the absence of HMPA (entries 1, 10, 13, and 16),
SmI2 generally reduced ketones to the corresponding
alcohols, such as thienylethanol 3, cyclohexanol 12, 1-(p-
tolyl)ethanol 14, and 1,2-bis(4-methoxyphenyl)ethanol
15. The reductive coupling reaction of 4-methoxybenz-
aldehyde also occurred under such reaction conditions
to give pinacol 13 (entries 4 and 7). Without HMPA,

J.-J. Shie et al. / Tetrahedron Letters 45 (2004) 2703–2707
2705
MI2
MI2(L)x
OMI2(L)x
MI2(L)x
O
3
MI2(L)x
O
MI2, THF
MI2
O
5
S
S
S
HMPA (L)
(L)xI2M
S
CH3
CH3
CH3
CH3
A
B
C
1
H atom
R1R2CO
(type ii)
R1R2CO
(type iii)
R1R2CO
(type iv)
abstraction
(type i)
R2
OH
O
R1
OH
OH
R2
R2
R1
OH
O
S
S
S
CH3
H
R1
CH3
OH
H3C
S
CH3
3
4
5
6
Reduction
Pinacol coupling
Coupling at C-3
Coupling at C-5
Scheme 1. The possible reactions of 2-acetylthiophene by the promotion of SmI2 or TmI2: (i) reduction to alcohol 3, (ii) coupling with a carbonyl to
pinacol 4, (iii) coupling at C-3 with a carbonyl to hydroxyketone 5, and (iv) coupling at C-5 with a carbonyl to hydroxyketone 6.
Table 1. Comparison of TmI2 and SmI2 in the cross-coupling reactions of 2-acetylthiophene (1) and ethyl thiophene-2-carboxylate (2) with carbonyl
compounds
Entry Reactants (equiv)
Methoda
Reaction time (h) Coupling products
Other products
Recovered substrate
(yields, %)
(yields, %; ratio of isomers) (yields, %)
1
1 (1)+Cyclohexanone (1)
A
B
10
10
10
2
3 (87); 12 (77)
3 (35); 12 (20)
3 (23); 12 (29)
3 (24); 13 (81)
2
1 (1)+Cyclohexanone (1)
1 (1)+Cyclohexanone (1)
1 (1)+4-MeOC6H4CHO (1)
1 (1)+4-MeOC6H4CHO (1)
1 (1)+4-MeOC6H4CHO (1)
2 (1)+4-MeOC6H4CHO (1)
2 (1)+4-MeOC6H4CHO (1)
2 (1)+4-MeOC6H4CHO (1)
2 (1)+Cyclohexanone (2)
2 (1)+Cyclohexanone (2)
2 (1)+Cyclohexanone (2)
2 (1)+4-MeC6H4COMe (2)
2 (1)+4-MeC6H4COMe (2)
2 (1)+4-MeC6H4COMe (2)
2 (1)+ArCOCH2Ar (2)e
2 (1)+ArCOCH2Ar (2)e
2 (1)+ArCOCH2Ar (2)e
6a (41; 55:45)
6a (41; 55:45)
3
C
A
Bb
Cb
A
B
4
5
2
7 (61)
7 (60)c
6
2
13 (21)
13 (85)
1 (45)
2 (88)
7
2
8
2
8a (75; 19:30:15:36)d
8a (74; 20:32:15:33)d
9
C
A
B
2
10
11
12
13
14
15
16
17
18
10
10
5
12 (69)
14 (71)
15 (89)
2 (87)
2 (80)
2 (84)
9 (89)
9 (82)
C
A
B
10
10
10
24
24
24
10 (63; 61:39)
10 (53; 58:42)
C
A
B
11a (48; 57:43)
11a (31; 55:45)
C
a Method A: SmI2 (2.4 equiv) in THF. Method B: SmI2 (2.4 equiv) and HMPA (16 equiv) in THF. Method C: TmI2 (2.4 equiv) in THF. All the
reactions were conducted by dropwise addition of a mixture of 2-acetylthiophene (0.5–1.0 mmol) (or ethyl thiophene-2-carboxylate) and carbonyl
compound (0.6–2.2 mmol as indicated) in THF (1–3 mL) to the freshly prepared lanthanide diiodide solution in THF (10–20 mL) at 0 °C. The
reaction mixture was stirred at 0–25 °C for the indicated period, and then quenched by addition of aqueous NH4Cl solution.
b The product was obtained by exposure of the reaction mixture to air for 2 h before workup.
c The yield of 7 was calculated based on the consumed acetylthiophene.
d The mixture of four isomers was oxidized by PDC to give a single product 8b.
e Ar represents 4-methoxyphenyl.
SmI2 could not reduce thiophenecarboxylate; more than
80% of ester 2 was recovered under such conditions
(method A, entries 7, 10, 13, and 16).
matization product 7 in 61% yield.13 Using the HMPA-
free TmI2 reagent induced the thienyl–carbonyl coupling
reactions in a similar fashion to afford products 6a and 7
in comparable yields (entries 3 and 6), as from the SmI2/
HMPA promoted reactions. Some reduction products (3
and 12) of 2-acetylthiophene and cyclohexanone as well
as the pinacol 13 derived from p-methoxybenzaldehyde
were also observed in the reactions using TmI2 or SmI2/
HMPA.
By the assistance of HMPA, SmI2 promoted a cross-
coupling reaction (Scheme 1, type iv) between 2-acetyl-
thiophene and cyclohexanone to give product 6a in 41%
yield (entry 2). Compound 6a consisted of two isomers
(55:45), which were partially separated and character-
1
ized by their H NMR spectra.13 The combined reagent
SmI2/HMPA also effected the cross-thienyl–carbonyl
coupling reaction between acetylthiophene and p-meth-
oxybenzaldehyde (entry 5); after which the reaction
mixture was stirred in air to furnish an oxidative aro-
Although ester 2 was inert to SmI2 in THF solution,
using TmI2 or SmI2/HMPA successfully effected the
coupling reactions of ester 2 with various carbonyl
compounds. The coupling reaction with p-methoxy-

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J.-J. Shie et al. / Tetrahedron Letters 45 (2004) 2703–2707
benzaldehyde (1 equiv) occurred at the C-5 position of
ester 2, and the subsequent protonation at the C-2
position of the dienolate intermediate (analogous to
intermediate C) furnished the 2,5-dihydrothiophene
product 8a (entries 8 and 9). Compound 8a existed as a
mixture of four isomers, which was oxidized by pyridi-
nium dichromate to give a single product 8b.11a On the
other hand, the double electrophilic reaction of ester 2
with 2 equiv of cyclohexanone was realized by using
SmI2/HMPA or TmI2 to give diol 9 in high yields
(entries 11 and 12). Attack of the dienolate intermediate
by the second cyclohexanone molecule should occur at
the less hindered face to produce diol 9 with the 4,5-
trans configuration, which was established by NMR
analysis and X-ray diffraction method.11b Similarly, the
three-component coupling reaction of ester 2 with
2 equiv of p-methylacetophenone was carried out by
using SmI2/HMPA or TmI2, giving the diol product 10
as a mixture of two isomers13 (entries 14 and 15).
Because lanthanide ion is more oxophilic but less basic
than alkali and alkaline metal ions,14 the three-compo-
nent coupling reaction of ester 2 with 1,2-bis(4-meth-
oxyphenyl)ethanone, a highly enolizable ketone, was
also realized by using SmI2/HMPA or TmI2 to afford the
diol product 11a (entries 17 and 18). The acid-catalyzed
dehydration of 11a (as a mixture of two isomers), fol-
lowed by treatment with DDQ, furnished the oxidative
cyclization product 11b.11b
References and notes
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Chem. Eur. J. 2001, 7, 3558–3563, Aqueous Ln(III)/Ln(II)
reduction potentials (vs NHE): Dy ()2.5 V), Tm ()2.3 V),
and Sm ()1.55 V).
8. (a) Shiue, J.-S.; Lin, C.-C.; Fang, J.-M. Tetrahedron Lett.
1993, 34, 335–338; (b) Shiue, J.-S.; Lin, M.-H.; Fang,
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1278; (b) Lin, S.-C.; Yang, F.-D.; Shiue, J.-S.; Yang,
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1 1995, 2669–2671; (b) Yang, S.-M.; Fang, J.-M. J. Org.
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Chem. 2002, 67, 5208–5215.
Through this study we found that TmI2 and SmI2
exhibited distinct reaction modes with 2-acetylthioph-
ene. Using TmI2 favored the thienyl–carbonyl coupling
reaction, whereas using SmI2 caused the reduction of the
acetyl group. Thiophene-2-carboxylate was reactive with
TmI2, but inert to SmI2 because it has a lower reduction
potential than TmI2.7 By ligation with HMPA mole-
cules, the reduction potential of SmI2/HMPA was
enhanced14 to exhibit reactivity toward thiophene-2-
carboxylate. Our study not only revealed the difference
of TmI2 from SmI2, but also clearly indicated the simi-
larity between TmI2 and SmI2/HMPA in promotion of
the cross-coupling reactions of 2-acetylthiophene and
thiophene-2-carboxylate with other carbonyl com-
pounds. As shown in Table 1, TmI2 and SmI2/HMPA
behave similarly in terms of chemo-, regio-, and stereo-
selectivities in the reaction protocols. Our finding
showing the similarity of TmI2 to SmI2/HMPA but
discrepancy from SmI2 is remarkable. The detailed
mechanism for these results is not fully understood,
however, the effective size and inherent electronic nature
of thulium and samarium ions may be important factors
to account for the reaction modes.3;15
12. Nakayama, J.; Sugino, M.; Ishii, A.; Hoshino, M. Chem.
Lett. 1992, 703–706.
13. The products were characterized by their physical and
spectroscopic properties (mp, IR, MS, HRMS, 1H, and 13
C
NMR). Some pertinent data are listed. 6a-major isomer: dH
5.97 (1H, dd, J ¼ 5:8, 2.6 Hz, H-3), 5.66 (1H, dd, J ¼ 5:8,
2.8 Hz, H-4), 4.52 (1H, d, J ¼ 2:8 Hz, H-2), 4.29 (1H, d,
J ¼ 2:6 Hz, H-5), 2.53 (1H, br s, OH), 2.32 (3H, s), 1.69–
1.46 (10H, m). 6a-minor isomer: dH 6.22 (1H, dd, J ¼ 5:8,
2.5 Hz), 5.75 (1H, dd, J ¼ 5:8, 2.9 Hz), 4.89 (1H, d,
J ¼ 2:9 Hz), 4.80 (1H, d, J ¼ 2:5 Hz), 2.97 (1 H, br s,
OH), 2.86 (3H, s), 2.17–1.46 (10H, m). 7: dH 7.16 (2H, d,
J ¼ 9:0 Hz), 7.09 (1H, dd, J ¼ 6:8, 1.9 Hz), 6.87 (2H, d,
J ¼ 9:0 Hz), 6.76 (1H, dd, J ¼ 6:8, 1.9 Hz), 5.86 (1H, s),
3.77 (3H, s), 2.27 (3H, s). 10-major isomer: dH 7.21 (2H, d,
J ¼ 8:2 Hz), 7.09 (2H, d, J ¼ 8:2 Hz), 7.06 (2H, d, J ¼
8:2 Hz), 6.97 (2H, d, J ¼ 8:2 Hz), 6.20 (1H, d, J ¼ 3:4 Hz),
4.20 (2H, q, J ¼ 6:8 Hz), 3.98 (1H, dd, J ¼ 5:6, 3.9 Hz),
3.60 (1H, dd, J ¼ 3:9, 3.7 Hz), 2.33 (3H, s), 2.31 (3H, s),
2.00 (1H, br s, OH), 1.64 (1H, br s, OH), 1.46 (3H, s), 1.29
(3H, t, J ¼ 6:8 Hz), 1.29 (3H, s). 10-minor isomer: dH 7.26–
7.04 (8H, m), 6.32 (1H, d, J ¼ 3:4 Hz), 4.31 (2H, q,
J ¼ 6:8 Hz), 3.99 (1H, dd, J ¼ 4:2, 3.0 Hz), 3.78 (1H, dd,
J ¼ 4:2, 3.5 Hz), 3.02 (2H, br s, OH), 2.31 (6H, s), 1.40 (3H,
s), 1.33 (3H, t, J ¼ 6:8 Hz), 1.32 (3H, s). Two isomers of
Acknowledgements
We thank the National Science Council (Republic of
China) and the US National Science Foundation for
financial support.

J.-J. Shie et al. / Tetrahedron Letters 45 (2004) 2703–2707
2707
11a showed the diagnostic olefin proton (H-3, d,
J ¼ 3:4 Hz) at dH 6.27 and 6.24, respectively.
15. (a) Miller, R. S.; Sealy, J. M.; Shabangi, M.; Kuhlman,
M. L.; Fuchs, J. R.; Flowers, R. A., II. J. Am. Chem. Soc.
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Skrydstrup, T.; Daasbjerg, K. Chem. Eur. J. 2000, 6,
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Chem. Soc. 2002, 124, 6895–6899.
14. (a) Imamoto, T. Lanthanides in Organic Synthesis; Aca-
demic: New York, 1994; (b) Kagan, H. B.; Namy, J.-L. In
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