Organotin reagents supported on ionic liquid: highly efficient catalytic free radical reduction of alkyl halides

Article abstract of DOI:10.1016/j.tetlet.2009.04.059

Ionic liquid-supported organotin reagents were prepared in good yield and demonstrated a convenient catalytic free radical reduction of alkyl halides. A variety of alkyl and aryl halides could be reduced in high to excellent yields and selectively to afford the desired products with simple work-up procedure.

Full text of DOI:10.1016/j.tetlet.2009.04.059

Tetrahedron Letters 50 (2009) 3780–3782
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Organotin reagents supported on ionic liquid: highly efficient catalytic free
radical reduction of alkyl halides
*
Phuoc Dien Pham, Stéphanie Legoupy
Laboratoire de Synthèse Organique, UCO2M, UMR CNRS 6011, Université du Maine, Avenue Olivier Messiaen, 72085 Le Mans Cedex 9, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Ionic liquid-supported organotin reagents were prepared in good yield and demonstrated a convenient
catalytic free radical reduction of alkyl halides. A variety of alkyl and aryl halides could be reduced in high
to excellent yields and selectively to afford the desired products with simple work-up procedure.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 30 January 2009
Revised 30 March 2009
Accepted 1 April 2009
Available online 20 April 2009
Keywords:
Ionic liquid
Organotin
Radical dehalogenation
1. Introduction
ple extraction and filtration, the desired product could be easily
isolated.
During the past decades, a number of reactions using organotin
compounds1 (Stille coupling, radical dehalogenation, etc.) have
emerged as a result of the increasing demand to develop more ver-
satile and efficient synthetic methods. However, despite that such
impressive synthetic potential, organotin reagents have been
avoided for the synthesis of health care products and pharmaco-
logically active substances. They have undoubtedly a bad reputa-
tion because of their toxicity and the difficulties of removing
organotin residues2 from reaction products. Recently, efforts have
been done to overcome these problems, leading, for example, to
the use of solid-phase synthetic methods,3 phosphonium grafted
organotins,4 and other modified organotin reagents.5
As a part of our ongoing research program on the discovery of
potentialities of TSILs (task-specific ionic liquids) by supporting
organotin reagents on ionic liquid,6 we examined the activity of
organotin hydride in the reduction of alkyl halide7—one of the
important applications of organotin reagents. One approach to
minimize the pollution of organotin residue is with free radical cat-
alytic organotin hydride reactions, employing only a catalytic
amount of organotin hydride. For example, the in situ regeneration
of an organotin hydride is possible by employing hydrogenosilanes
or with sodium borohydride.8 Herein, we would like to report a
very simple method to reduce selectively alkyl halide. Moreover,
thanks to the organotin reagents supported on ionic liquid, by sim-
Typically, classical dehalogenation reaction using trialkyl hy-
dride requires an excess amount of the organotin reagent. During
the purification, some precautions must be taken to avoid the con-
tamination of the product by organotin residue. If organotin hy-
dride could be immobilized in an ionic liquid and used in a
catalytic amount (recycled by an external reducing agent), this
contamination could be limited (Fig. 1).
The organotin reagents incorporated on ionic liquid are con-
structed as shown in Scheme 1. Initially, treatment of the imidaz-
ole with 1-bromo-6-chlorohexane gave 1, which was stannylated
with Bu2SnPhH6 to afford 26 which was methylated by methyl io-
dide to give the ionic liquid 3.6 Conversion of 3 into 49 was
achieved by treatment with HCl in ether. Finally, NaBH4 reduction
of 4 in the presence of methanol led to the organotin hydride 5.10
We showed that the reductions of alkyl and aryl halides by 4
were very efficient with 65–97% good yield of isolated product.
After a standard work-up procedure,11 the pure products were iso-
lated in good yields.
I
N
R-H
SnBu2Cl
N
( )
6
R=alkyl, aryl.
catalytic amount 1-25 mol%
NaBH4
I
X=Cl, Br.
R-X
N
SnBu2H
6
N
( )
* Corresponding author. Tel.: +33 0 2 43 83 30 96; fax: +33 0 2 43 83 39 02.
E-mail address: stephanie.legoupy@univ-lemans.fr (S. Legoupy).
Figure 1. Organotin hydride in catalytic amount catalyzed dehalogenation reaction.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.059

P. D. Pham, S. Legoupy / Tetrahedron Letters 50 (2009) 3780–3782
3781
N
Bu2SnPhH
tained. In the presence of 4, 6a, 6b could be easily reduced in
excellent yield (Table 1, entries 2 and 4). As an extension, aryl
bromides of different structures (2-fluorenyl, 9-anthracenyl, and
3,4-dimethoxy-2-methylphenyl) could be also reduced but re-
quired higher organotin catalyst charge and longer reaction times
(entries 5, 6, and 10). Interestingly, in the case of 9-anthracenyl
bromide (entry 6), the formation of dimerized product 9,90-
bianthracenyl was observed as the result of a coupling reaction.
Furthermore, the hexadecylchloride could also be reduced with
long-reaction time to afford the pure product in high yield (entry
8). Despite, total and clean conversion of the reduction of ada-
mantyl bromide (entry 9), the product was isolated in moderate
yield (65%) possibly due to high volatility. Taking advantage of
the reactivity difference between an aryl and a benzyl bromide
by applying an appropriated reaction time (3 h), we could reduce
selectively the more reactive one by employing 1 mol % of
organotin reagent 4 (entry 7) to yield 7e (70%). Surprisingly, with-
out AIBN (entries 5 and 8), the conversion into the dehalogenated
product is 5% (entry 5), and 30% (entry 8). It is plausible that
organotin radical could be formed by thermal homolysis but in
very low concentration. Although AIBN is not so stable at 80 °C,
it could promote the formation of organotin radical that is more
stable at high concentration than under purely thermal condi-
tions. In addition, the role of the counter anion (Iꢀ) was also
tested. As demonstrated in our recent trials, dehalogenation of
N
Cl
( )6
SnBu2Ph
N
N
CH3I, 45°C
( )6
LDA, THF
-78°C - rt, 73%
1
2
I
quant.
N
SnBu2Ph
( )6
3
N
85%
I
HCl / Et2O rt
I
NaBH4, CH2Cl2
rt, 80%
N
N
SnBu2H
SnBu2Cl
N
N
( )6
( )6
5
4
Scheme 1. Preparation of organotin reagents supported on ionic liquid.
In an initial study, without organotin reagent 4 and AIBN,
NaBH4 (1.5 equiv) could not reduce the aryl halides as shown in
Table 1, entries 1 and 3. No trace of the desired product was ob-
Table 1
Catalytic reduction of halides with organotin hydride in situ supported on ionic liquid
I
AIBN, CH3CN
N
SnBu2Cl
R
X
+
N
R
H
( )6
NaBH4, MeOH, 80°C
1 - 25 mol%
4
7
6
Entry
4
Substrate
Time Product12
(h)
Yielda
(%)
(equiv)
hexadecylchloride was carried out in the presence of BF4 vs Iꢀ
ꢀ
counter anion (conversion 55% vs 100% (81% yield) (Table 1, entry
8)). I/Br,Cl exchange is strongly possible under these reaction con-
ditions (CH3CN, MeOH, 80 °C) and could result in an enhanced
reactivity. Besides, in the case of 6c, counter anion exchange
could not be carried out ðBF4ꢀ=IꢀÞ because the same reduction
rate of 2-fluorenylbromide was observed (entry 5) (91% yield
(100% conversion) vs 93% yield (100% conversion)). Analysis by
ICP-AES13 of the 7h (entry 10) showed that the concentration in
residual tin was <5 ppm. In all reactions (Table 1, entries 2, 4–
10), 1H NMR and 119Sn NMR analyses showed no contamination
by organotin byproducts.
Furthermore, by employing directly the organotin hydride 5 in
the radical dehalogenation reaction, the aryl halides could be re-
duced chemoselectively to afford 9a, 9b in good yield without
touching the ester function (Table 2). Analysis by ICP-AES13 of
9a indicated that the concentration in residual tin was <8 ppm.
In all reactions (Table 2, entries 1 and 2), 1H NMR and 119Sn
NMR analyses showed no contamination by organotin
byproducts.
1b
2
0
6a 14
—
0
Br
0.1
6a
8
7a 95
Br
Br
Br
3b
0
6b 24
6b 24
6c 24
—
0
4
0.25
7b 96
Br
5
6
7
0.25
0.25
0.01
7c 93c (91)d
Br
e
6d
6e
4
3
7d —
Br
7e 70
Br
Br
( )
Table 2
Reduction of halides with organotin hydride supported on ionic liquid15
I
8
9
0.15
0.25
6f 36
7f 81f (55)g
7g 65
( )
14
AIBN, CH3CN
Cl
14
Br
N
SnBu2H
R
X
+
N
R
H
( )6
80 °C
1.2 equiv
8
5
9
6g
3
Entry
1
Substrate
Time (h)
24
Product14
Yielda (%)
Br
OMe
OMe
OMe
OMe
O
10
0.1
6h 22
7h 83
O
62
80
O
Br
O
a
Isolated yield.
In the absence of 4 and AIBN.
b
c
8a
9a
Without AIBN under the same condition (5% conversion by 1H NMR).
d
e
ꢀ
91% yield by utilizing 4 with the counter anion BF4
.
H3COOC
H3COOC
( )
10
( )
10
Br
Isolated product as unseparable mixture of anthracene (21% yield) and 9,90-
2
6
bianthracene (50% yield)
8b
9b
Without AIBN under the same conditions (30% conversion by 1H NMR).
f
a
By utilizing 4 with the counter anion BF4 (55% conversion by 1H NMR).
g
ꢀ
Isolated yield.

3782
P. D. Pham, S. Legoupy / Tetrahedron Letters 50 (2009) 3780–3782
6. Vitz, J.; Mac, D. H.; Legoupy, S. Green Chem. 2007, 9, 431.
2. Conclusion
7. Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2002, 102, 4009.
8. (a) Lipowitz, J.; Bowman, S. A. J. Org. Chem. 1973, 38, 162; (b) Corey, E. J.; Suggs,
J. W. J. Org. Chem. 1975, 40, 2554; (c) Stork, G.; Sher, P. M. J. Am. Chem. Soc. 1986,
108, 303; (d) Hays, D. S.; Fu, G. C. Tetrahedron 1999, 55, 8815; (e) Gallagher, W.
P.; Terstiege, I.; Maleczka, R. E., Jr. J. Am. Chem. Soc. 2001, 123, 3194; (f)
Gallagher, W. P.; Maleczka, R. E., Jr. J. Org. Chem. 2005, 70, 841.
In conclusion, the new ionic liquid-supported organotin re-
agents 4 and 5 were prepared in very high yield and demonstrated
a convenient catalytic free radical reduction of alkyl halides. A vari-
ety of alkyl and aryl halides could be reduced in high to excellent
yields and selectively to afford the desired product with simple
work-up procedure.
9. 1-((Dibutylchlorostannyl)hexyl)-3-methyl-1H-imidazol-3-ium iodide (4): To
a
solution of 3 (1.25 g, 2.07 mmol) in CH2Cl2 (10 mL) was added dropwise a
solution of HCl 2 M in ether (1.1 mL, 2.2 mmol) at 0–5 °C over a period of 5 min.
The mixture was stirred for 2 h at rt, then treated with H2O (10 mL). To this
mixture CH2Cl2 (20 mL) was added and the organic phase was washed with
H2O (3 ꢁ 20 mL), and the aqueous phase was washed with CH2Cl2 (3 ꢁ 10 mL),
the combined organic phase was then dried over MgSO4, filtered, and
concentrated under reduced pressure to yield 4 (988 mg, 85%) as a yellow
viscous oil. 1H NMR (CDCl3, 400 MHz): d 10.10 (s, 1H), 7.42–7.40 (m, 2H), 4.34
(t, J = 7.3 Hz, 2H), 4.12 (s, 3H), 1.31–1.99 (m, 22 H), 0.92 (t, J = 7.3 Hz, 6H); 13C
NMR (CDCl3, 100 MHz): d 136.6, 123.7, 123.4, 50.2, 37.1, 32.6, 29.9, 28.6, 26.8,
25.9, 25.4, 18.5, 18.1, 13.7; 119Sn NMR (149 MHz, CDCl3): d +105.7; IR (neat):
3082, 2953, 2920, 2853, 1579, 1462, 1166, 678, 519 cmꢀ1. HRMS calcd. for
C18H36N2Cl120Sn 435.1589. Found: 435.1595.
Acknowledgments
We thank CNRS, the Université du Maine, the Agence Nationale
de la Recherche (Grant No. ANR-07-JCJC-0026-01), and French
MENRT for a fellowship to P.D.P. We also acknowledge Dr. A.-S.
Castanet for the generous gift 8a.
10. 1-((Dibutylstannyl)hexyl)-3-methyl-1H-imidazol-3-ium
suspension of NaBH4 (25 mg, 0.65 mmol) in CH2Cl2 (5 mL), a solution of 4
(122 mg, 0.22 mmol) in mixture of CH2Cl2 (5 mL) and MeOH (20 L) was added
iodide
(5)To
a
References and notes
l
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M. Angew. Chem., Int. Ed. 2004, 43, 4704; (f) Su, W.; Urgaonkar, S.; McLaughlin,
P. A.; Verkade, J. G. J. Am. Chem. Soc. 2004, 126, 16433; (g) Organotin Chemistry;
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Liang, Y.; Wang, D.-P.; Liu, W.-J.; Xie, Y.-X.; Yin, D.-L. J. Org. Chem. 2005, 70,
2832; (i) Calo, V.; Nacci, A.; Monopoli, A.; Montingelli, F. J. Org. Chem. 2005, 70,
6040; (j) Garcia-Martinez, J. C.; Lezutekong, R.; Crooks, R. M. J. Am. Chem. Soc.
2005, 127, 5097; (k) Lee, K.; Gallagher, W. P.; Toskey, E. A.; Chong, W.;
Maleczka, R. E., Jr. J. Organomet. Chem. 2006, 691, 1462; (l) Chiappe, C.;
Pieraccini, D.; Zhao, D.; Fei, Z.; Dyson, P. J. Adv. Synth. Catal. 2006, 348, 68.
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Org. Chem. 1979, 44, 449; (c) Curran, D. P.; Chang, C. T. J. Org. Chem. 1989, 54,
3140; (d) Farina, V. J. Org. Chem. 1991, 56, 4985; (e) Crich, D.; Sun, S. X. J. Org.
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1998, 39, 2123; (g) Edelson, B. S.; Stoltz, B. M.; Corey, E. J. Tetrahedron Lett.
1999, 40, 6729; (h) Salomon, C. J.; Danelon, G. O.; Mascaretti, O. A. J. Org. Chem.
2000, 65, 9220; (i) Studer, A.; Amreim, S. Synthesis 2002, 835; (j) Bergbreiter, D.
E.; Walker, S. A. J. Org. Chem. 1989, 54, 5138; (k) Light, J.; Breslow, R.
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Chem. 1993, 58, 3046; (m) Rai, R.; Collum, D. B. Tetrahedron Lett. 1994, 35, 6221;
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Yoshida, J.-I. Chem. Commun. 1999, 1237; (p) Han, X.; Hartmann, G. A.; Brazzale,
A.; Gaston, R. D. Tetrahedron Lett. 2001, 42, 583; (q) Clive, D. L. J.; Wang, J. J. Org.
Chem. 2002, 67, 1192; (r) Stien, D.; Gastaldi, S. J. Org. Chem. 2004, 69, 4464.
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5971; (b) Dumarin, G.; Ruel, G.; Kharboutli, J.; Delmond, B.; Connil, M.-F.;
Jousseaume, B.; Pereyre, M. Synlett 1994, 952; (c) Enholm, E. J.; Schulte, J. P., II
Org. Lett. 1999, 1, 1275; (d) Zhu, X.; Blough, B. E.; Carroll, F. I. Tetrahedron Lett.
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slowly at 0 °C. The resulting mixture was stirred for 1 h at rt. To this mixture
CH2Cl2 (10 mL) was added and the organic phase was washed with H2O
(3 ꢁ 10 mL), and the aqueous phase was washed with CH2Cl2 (3 ꢁ 10 mL), the
combined organic phase was then dried over MgSO4, filtered, and concentrated
under reduced pressure to yield 5 (92 mg, 80%) as a yellow viscous oil. 1H NMR
(CDCl3, 400 MHz): d 10.11 (s, 1H), 7.39–7.42 (m, 2H), 5.29 (m, 1H), 4.33 (t,
J = 7.6 Hz, 2H), 4.11 (s, 3H), 1.28–1.99 (m, 22 H), 0.92 (t, J = 7.3 Hz, 6H); 13C
NMR (CDCl3, 100 MHz): d 138.2, 123.2, 121.6, 50.2, 36.7, 33.4, 30.2, 29.8, 27.5,
27.1, 25.8, 13.7, 8.2, 8.1; IR (neat): 2954, 2925, 2852, 1806, 1463, 1376, 1169,
676 cmꢀ1
;
119Sn NMR (149 MHz, CDCl3):
d
ꢀ88.3; HRMS calcd. for
C18H37N2120Sn 401.1979. Found: 401.1975.
11. Representative procedure for the reduction of halides using organotin hydride 4
(Table 1). 1-(Bromomethyl)-4-methylbenzene 6e (Table 1, entry 7).A mixture
of 6e (472 mg, 1.89 mmol, 1 equiv), organotin chloride 4 (10.6 mg, 0.019 mmol,
0.01 equiv), NaBH4 (107 mg, 2.84 mmol, 1.5 equiv), AIBN (3 mg, 0.019 mmol,
0.01 equiv), CH3CN (2 mL), and MeOH (20 lL) was placed in a Schlenk tube
which was then evacuated and back filled with nitrogen five times. The
solution was heated under reflux for required time, the conversion was
checked by 1H NMR. The mixture was cooled to room temperature and
concentrated under reduced pressure. The residue was dissolved in Et2O
(10 mL) and filtered over a short pad of silica gel to afford the desired product
(70%).
12. 1H NMR of 7a–h and the corresponding commercially available product were
identical.
13. ICP-AES measurements were carried out at UT2A (Ultra Traces Analyses
Chimiques), Hélioparc Pau—Pyrénées 2, avenue du président Angot F-64053
PAU Cedex 9, France.
14. 1H NMR of 9a, 9b and the corresponding commercially available product were
identical.
15. Representative procedure for the reduction of halides using tin hydride 5 (Table 2).
3,5-dimethylphenyl 2-bromobenzoate 8a (Table 2, entry 1).A mixture of
methyl 3,5-dimethylphenyl 2-bromobenzoate 8a (48 mg, 0.16 mmol,
1.0 equiv), organotin hydride
5 (100 mg, 0.19 mmol, 1.2 equiv), AIBN
(0.016 mmol, 2.6 mg, 0.1 equiv), and CH3CN (1 mL) was placed in a Schlenk
tube which was then evacuated and back filled with nitrogen five times. The
solution was heated under reflux for required time, the conversion was
checked by 1H NMR. The mixture was cooled to room temperature and
concentrated under reduced pressure. The residue was dissolved in Et2O
(10 mL) and filtered over a short pad of silica gel to give a pure product in 62%.
4. Poupon, J. C.; Marcoux, D.; Cloarec, J. M.; Charette, A. B. Org. Lett. 2007, 9, 3591.
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1999, 64, 4539; (b) Fouquet, E.; Pereyre, M.; Rodriguez, A. L. J. Org. Chem. 1997,
62, 5242; (c) Fouquet, E.; Pereyre, M.; Roulet, T. J. Chem. Soc., Chem. Commun.
1995, 2387.