Fluorous tagging: An enabling isolation technique for indium-mediated allylation reactions in water

Article abstract of DOI:10.1039/b713244c

An efficient method was developed to allylate aldehydes using an aqueous indium-mediated allylation reaction with fluorous-tagged allyl halides, and to directly purify the products by fluorous solid phase extraction (F-SPE). The Royal Society of Chemistry

Full text of DOI:10.1039/b713244c

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Fluorous tagging: an enabling isolation technique for indium-mediated
allylation reactions in water†
Carolyn S. Reid,a Yuhua Zhanga and Chao-Jun Li*a,b
Received 28th August 2007, Accepted 28th September 2007
First published as an Advance Article on the web 8th October 2007
DOI: 10.1039/b713244c
An efficient method was developed to allylate aldehydes
using an aqueous indium-mediated allylation reaction with
fluorous-tagged allyl halides, and to directly purify the
products by fluorous solid phase extraction (F-SPE).
(1) the elimination of the need for inert atmosphere and anhydrous
organic solvent; (2) allowing direct use of compounds bearing
highly reactive functional groups without the need for protection
and deprotection steps; and (3) the direct use of water-soluble
starting materials without pre-derivatizations. The reaction has
led to the efficient synthesis of various natural products.6
The fluorous technologies recently established by Horva´th,1
Gladysz,2 and Curran3 provide innovative methods for biphasic
catalysis, catalyst recycling, and reaction product purification. In
particular, the concept of fluorous tagging, the attachment of
fluorous fragments to organic substrates, allows simple separation
of organic compounds based on their fluorine content.4
Table 1 Allylation of aldehydes with fluorinated allyl ethers
Entry Aldehyde
1
Product 4
Yield (%)a
98
2
44
3
4
5
6
87
66
81
92
Fig. 1 Fluorous-tag technique for product isolation in aqueous reactions.
7
8
78
39
Indium-mediated Barbier–Grignard-type allylation of aldehy-
des in water5 provides various synthetic advantages including:
aDepartment of Chemistry, Tulane University, New Orleans, Louisiana,
70118, USA
bDepartment of Chemistry, McGill University, 801 Sherbrooke Street West,
Montreal, Quebec, H3A 2K6, Canada. E-mail: cj.li@mcgill.ca
a Isolated yield after F-SPE using water as solvent.
† Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b713244c
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However, there are still some limitations of the reaction at the
current stage: (1) product isolation by extraction with organic
solvent consumes a large amount of organic solvent as well
as leaving a significant amount of solvent residue in aqueous
solution; and (2) for water-soluble products, water has to be
evaporated completely (often by freeze-drying) before further
purification, which is both time-consuming and energy-intensive.
Similar limitations exist in other aqueous reaction systems. Thus,
an innovative method to isolate the products of such aqueous
reactions efficiently avoiding extraction and/or freeze-drying
Table 2 Synthesis of a-methylene-c-butyrolactones by allylation of aldehydes with fluorinated allyl ester 2
Entry
1
Product 5
Yield (%)
86
Product 6
Yield (%)a
88
2
3
4
80
76
85
83
84
Trace
5
74
Trace
6
7
54
90
72
49
20b
91
73
98
89
80
8
9
10
a Isolated yield after F-SPE using water as solvent. b Acetone–water (1 : 1) as solvent.
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techniques is highly desirable. Herein, we wish to report the use
of a shorter fluorous tag in synthesis and purification in aqueous
reaction systems. By using the fluorous-tag chemistry, an isolation
technique was developed for indium-mediated allylation reactions
in water. The corresponding products were isolated readily by
simple filtration through a short plug of fluorous silica gel (Fig. 1).
To begin our study, two different types of fluorous-tagged
allylating reagents 1 and 2 were synthesized.7 With these allylating
reagents in hand, their reactions with various aldehydes were
then examined. We reacted compound 1 (117 mg, 0.30 mmol)
with benzaldehyde (48 mg, 0.45 ◦mmol) and In powder (52 mg,
0.45 mmol) in 4 mL water at 50 C in air for 24 h. The aqueous
4 (a) D. P. Curran, Synlett, 2001, 9, 1488; (b) A.-C. L. Lamer, N. Gouault,
M. David, J. Boustie and P. Uriac, J. Comb. Chem., 2006, 8, 643.
5 C.-J. Li and T. H. Chan, Tetrahedron Lett., 1991, 32, 7017.
6 C.-J. Li and T. H. Chan, Tetrahedron, 1999, 55, 11149; C.-J. Li and
T. H. Chan, Comprehensive Organic Reactions in Aqueous Media, John
Wiley & Sons, New York, 2007; C.-J. Li, in Organic Synthesis in Water,
ed. U. M. Lindstrom, Blackwell, New York, 2007.
7 Synthesis of 1: A solution of 1H,1H-perfluorohexan-1-ol (2.4 g,
8.0 mmol) in dry THF (20 mL) was added slowly over 10 min to a
stirred solution of sodium hydride (0.23 g, 9.7 mmol) in dry THF
(20 mL) at room temperature. The mixture was stirred at rt for 30 min,
then 3-chloro-2-chloromethyl-1-propene (1.5 g, 12 mmol) was added
and stirred for 6 h. The reaction mixture was quenched with ice–water,
extracted with diethyl ether (3 × 20 mL), and the combined extracts
were dried and concentrated in vacuo. Column chromatography of the
residue on silica using hexane–diethyl ether (50 : 1) as eluent gave 1
R
mixture was added to a FluoroFlashꢀ silica gel column (2 cm ×
1
(1.72 g, 55%) as a colorless oil. H NMR (CDCl3, 400 Hz): d (ppm)
30 cm), and 4a was obtained as a pure product by gradient elution
using acetone–water. Subsequently, compound 1 was reacted
with various aldehydes 3 under the standard aqueous indium-
mediated allylation protocol (Table 1).8 Upon simple filtration
through a short plug of fluorous silica gel, the corresponding
allylation products 4 were obtained cleanly without need for
further purification.
Consistent with other studies on Barbier–Grignard-type reac-
tions in water, aromatic aldehydes (Table 1, entries 1, 3–6) generally
gave higher yields of the corresponding allylation products than
aliphatic aldehydes (Table 1, entries 7 and 8), with the exception
of fluorinated aromatic aldehydes (Table 1, entry 2). At the
present time, it is not clear what caused the lower yields of the
fluoroaromatic aldehydes.
On the other hand, the reaction of reagent 2 with various
aldehydes generated the corresponding esters 5 (Table 2).9 Further
treatment of the esters with base generated the a-methylene-c-
butyrolactones 6 in high yields.10 Surprisingly, only trace amounts
of the lactones were obtained with ortho-substituted aryl alde-
hydes, most likely due to steric reasons (Table 2, entries 4 and
5). It should be noted that a water-soluble aldehyde also reacted
to give the desired product (Table 2, entry 10), albeit with a low
conversion, and requiring a modification of the conditions for the
allylation step.
5.30 (s, 1H), 5.21 (s, 1H), 4.17 (s, 2H), 4.03 (s, 2H), 3.88 (t, J = 14 Hz,
2H); 13C NMR (CDCl3, 100 Hz): d (ppm) 140.8, 118.3, 72.8, 67.3
(t, OCH2, JC–F = 26 Hz), 44.8; GC–MS m/z (relative intensity): 388
(M+, 5), 177 (25), 141 (100), 113 (35), 77 (65), 51 (20). Synthesis of
2: To a mixture of 2-(bromomethyl)acrylic acid (5.0 g, 0.03 mol) and
1H,1H-perfluorohexan-1-ol (15.0 g, 0.05 mol), concentrated sulfuric
acid (1.0 g) was added slowly and the mixture then stirred at 50 ◦C for
15 min. The mixture was heated at 130 ◦C for 6 h. After workup,
flash chromatography on silica using hexane–ethyl acetate (20 : 1)
as eluent gave the ester 2 (8.7 g, 65%) as a colorless oil. 1H NMR
(400 MHz, CDCl3, TMS) d (ppm): 6.41 (s, 1H), 6.08 (s, 1H), 4.69
(t, J = 13.6 Hz, 2H), 4.15 (s, 2H); 13C NMR (100 MHz, CDCl3): d
163.4, 136.2, 131.4, 60.4 (t, OCH2 JC–F = 27.5 Hz), 28.5; 19F NMR
(CDCl3, C6F6 −164.9 ppm, 376 MHz): d (ppm) −83.98 (3F), −122.64
(2F), −126.22 (2F), −126.71 (2F), −129.47 (2F); GC–MS m/z (relative
intensity): 447 (M+, 65), 367 (100), 147 (45); IR (liquid film): mmax 3000,
1750 cm−1
.
8 A mixture of benzaldehyde (48 mg, 0.45 mmol), 1 (117 mg, 0.30 mmol)
and indium powder (52 mg, 0.45 mmol) in 4 mL water was stirred at
50 ◦C in air for 24 h. The aqueous mixture was added to a FluoroFlashꢀR
silica gel (FluoroFlashꢀR silica gel bonded with perfluorooctylethylsilyl
˚
chains, 40 lm, 60 A particle size from Fluorous Technologies Inc.)
column (2 cm × 30 cm) and 4a was obtained by gradient eluention
[acetone–water in ratios of 50 : 50 (100 mL), 70 : 30 (20 mL) and 80 :
20] as a colorless oil. 1H NMR (CDCl3, 400 Hz): d (ppm) 7.38–7.26 (m,
5H), 5.20 (s, 1H), 5.12 (s, 1H), 4.84 (dd, J = 5.2, 8.4 Hz, 1H), 4.12 (d,
J = 12 Hz, 1H), 4.03 (d, J = 12.4 Hz, 1H), 3.89 (t, J = 12.4 Hz, 2H),
2.52 (dd, J = 4.8, 14.4 Hz, 1H) 2.47 (dd, J = 8.4 12.4 Hz, 1H), 2.27 (s,
1H); 13C NMR (100 MHz, CDCl3): d (ppm) 144.2, 141.4, 128.7, 127.9,
125.9, 117.3, 75.8, 72.8, 66.9 (t, OCH2, JC–F = 25.9 Hz), 43.5.
9 To a mixture of benzaldehyde (48 mg, 0.45 mmol) and 2 (135 mg,
0.30 mmol) in 4 mL water, indium powder (52 mg, 0.45 mmol) was
added and the mixture was stirred at rt in air for 24 h. The crude
reaction mixture was added to a FluoroFlashꢀR silica gel column, and
washed with 100 mL of acetone–water (50 : 50) and 60 mL acetone–
water (70 : 30). An 80 : 20 mixture of acetone and water eluted the
desired product 5a. 1H NMR (400 MHz, CDCl3, TMS) d (ppm): 7.34–
7.26 (m, 5H), 6.34 (s, 1H), 5.73 (s, 1H), 4.87 (dd, J = 4.4, 8.4 Hz, 1H),
4.68–4.59 (m, 2H), 2.78 (ddd, J = 1.2, 4.4, 14 Hz, 1H), 2.70 (ddd, J =
0.8, 8.4, 14.4 Hz, 1H), 2.60 (s, 1H); 13C NMR (100 MHz, CDCl3): d
165.8, 143.8, 135.6, 130.9, 128.7, 128.0, 125.9, 73.1, 60.2 (O–CH2, t, J =
26.7 Hz), 42.2; 19F NMR (CDCl3, C6F6 −164.9, 376 MHz): d (ppm)
−83.97(3F), −117.98 (1F), −122.62 (2F), −126.20 (2 F), −129.47; IR
In conclusion, an isolation technique has been developed for
directly separating product mixtures of aqueous indium-mediated
allylations by using the fluorous-tag method. Various aldehydes
were transformed into the desired products and isolated in pure
form readily by this method. The fluorous tag regenerated in pure
R
form from the FluoroFlashꢀ silica gel column can be reused for
further reactions.
We thank the US EPA STAR program for support of our
research. CJL is a Canada Research Chair (Tier I) at McGill
University. CSR thanks Professors W. Alworth and G. McPherson
at Tulane University for help.
(liquid film): mmax 3500–3250, 3050, 2900, 1750 cm−1
.
10 Representative example for the preparation of a-methylene-c-
butyrolactones: Diethyl ether (2 mL) was added to 4-hydroxy-2-
methylene-4-phenyl-butyric acid 2,2,3,3,4,4,5,5,6,6,6-undecafluoro-
hexyl ester 5a (139 mg, 0.30 mmol) and K2CO3 (2 mg, 5 mol%) and the
solution was stirred at rt in air for 24 h. The ether was then removed and
the residue was diluted with hexane and transferred on to a column.
The desired product 6a was eluted with hexane–ethyl acetate 10 : 1 to
give a white solid (52 mg, 88%). 1H NMR (400 MHz, CDCl3) d (ppm):
7.39–7.28 (m, 5H), 6.26 (t, J = 3.2 Hz, 1H), 5.67 (t, J = 2.4 Hz, 1H),
5.50 (dd, J = 6.8, 6.8 Hz, 1H), 3.38 (ddt, J = 2.8, 8, 17.2 Hz, 1H), 2.89
(ddt, J = 2.8, 6.4, 17.2 Hz, 1H), 13C NMR (100 MHz, CDCl3): d (ppm):
170.5, 140.0, 134.4, 129.1, 128.8, 125.6, 122.8, 78.2, 36.5.
Notes and references
1 (a) I. T. Horva´th and J. Ra´bai, Science, 1994, 266, 72; (b) I. T. Horva´th,
Acc. Chem. Res., 1998, 31, 641.
2 M. Wende, R. Meier and J. A. Gladysz, J. Am. Chem. Soc., 2001, 123,
11490.
3 (a) M. Matsugi and D. P. Curran, J. Org. Chem., 2005, 70, 1636; (b) D. P.
Curran, K. Fischer and G. Moura-Letts, Synlett, 2004, 1379; W. Zhang
and D. P Curran, Tetrahedron, 2006, 62, 11837; W. Zhang, Curr. Opin.
Drug Discovery Dev., 2004, 7, 784.
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 3589–3591 | 3591
©