gem-Difluoropropargylation of aldehydes using cat. In/Zn in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2006.12.134

Zn (0.9 equiv) in combination with catalytic amounts of In (0.1 equiv) and I₂ (0.1 equiv) was found to effect the reaction of several difluoropropargyl bromide derivatives with aldehydes to produce gem-difluorohomopropargyl alcohols in aqueous

Full text of DOI:10.1016/j.tetlet.2006.12.134

Tetrahedron Letters 48 (2007) 1625–1627
gem-Difluoropropargylation of aldehydes using cat.
In/Zn in aqueous media
Satoru Arimitsu, Jesse M. Jacobsen and Gerald B. Hammond*
Department of Chemistry, University of Louisville, Louisville, KY 40292, USA
Received 25 October 2006; revised 22 December 2006; accepted 22 December 2006
Available online 23 January 2007
Abstract—Zn (0.9 equiv) in combination with catalytic amounts of In (0.1 equiv) and I2 (0.1 equiv) was found to effect the reaction
of several difluoropropargyl bromide derivatives with aldehydes to produce gem-difluorohomopropargyl alcohols in aqueous media
under conditions suitable for large scale applications.
ꢀ 2007 Published by Elsevier Ltd.
The formation of C–C bonds in aqueous media is an
important goal of environmentally friendly synthetic
methodologies.1 Indium has shown potential for such
reactions; notable examples include Reformatsky
reaction,2 Barbier type alkylation,3 allylation,4 and
propargylation5 of carbonyl compounds. An intrinsic
Table 1. Screening of the bimetallic system of Barbier type reaction
In (X eq.), Met (Y eq.)
Eu(OTf) (5 mol%)
O
F
F
F
F
3
+
TES
TES
Ph
H
Br
Ph
H O/THF (4/1, 0.3 M)
2
2a
(1.1 eq.)
o
1a
3aa
HO
40 C, 12 h, )))
Entry
In (X equiv)
Metal (Y equiv)
Yields of producta (%)
1a:3aa:4b
1
2
3
4
5
1.0
0.5
0.1
0.05
0
—
0:78:8
0:73:9
0:61:12
0:55:15
0:12:23
Zn (0.5)
Zn (0.9)
Zn (0.95)
Zn (1.0)
6
7
8
0.05
0.05
0.05
0.05
0.05
0.05
0.05
Mg (0.95)
Cu (0.95)
Fe (0.95)
Al (0.95)
Mo (0.95)
Sb (0.95)
Sn (0.95)
46:4:Trace
No reaction
Decomposed
0:28:4
No reaction
54:3:Trace
4:28:4
9
10
11
12
a Yield was determined by 19F NMR.
b Dimer 4.
TES
CF2
2
4
Keywords: Cat. indium; Zinc; Aqueous media; gem-Difluorohomopropargyl alcohols.
*
Corresponding author. Tel.: +1 502 852 5998; fax: +1 502 852 3899; e-mail: gb.hammond@louisville.edu
0040-4039/$ - see front matter ꢀ 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.12.134

1626
S. Arimitsu et al. / Tetrahedron Letters 48 (2007) 1625–1627
drawback of indium is the need for almost stoichiometric
amounts of this relatively expensive metal. In response to
the cost factor, various combinations containing cata-
lytic amounts of indium and a secondary cheaper metal
(such as Al, Zn, Sn or Mn) have been developed,6 but
these protocols are still limited to few reactions, chiefly,
the allylation of carbonyl compounds. Our interest in
the synthesis of gem-difluorohomopropargyl alcohol 3
led us recently to its synthesis using indium and a cata-
lytic amount of Eu(OTf)3 (5 mol %) as a water tolerant
Lewis acid.7 In our continuous search for new cost-effec-
tive methods, we are now pleased to report an economi-
cal synthesis of 3 that relies on the utilization of zinc
combined with the catalytic amounts of indium and
iodine.
Although Eu(OTf)3 is an effective catalyst in the reac-
tion above, it is costly. Some metal halide complexes,
on the other hand, are also well known water tolerant
Lewis acid catalysts but available at a fraction of the
cost.8 Thus, a more economical solution would be the
in situ generation of a metal halide complex by the addi-
tion of iodine to the reaction of 1 with 2. As depicted in
Table 2, iodine addition (entries 3–7) has a positive effect
on the reaction outcome. When used in similar propor-
tions, either iodine or Eu(OTf)3 produced analogous
results (compare entries 1 and 3, also 2 and 4). It is clear
that the lack of either indium or iodine give low yields
(entries 6 and 7).
The optimized reaction conditions (entry 4) were applied
to the synthesis of 3 using various aldehyde substrates
(Table 3).10
First, we studied the effects of varying the ratio of zinc
and indium, using Eu(OTf)3 as a catalyst. The results,
shown in Table 1, indicated that the yield of product
3aa decreases as lesser amounts of indium are employed
(entries 1–5); zinc alone gave a very low yield of 3aa
accompanied by relatively large amounts of the dimeric
byproduct 4 (entry 5). We then screened the effects of
other readily available metals (entries 6–12), none of
which matched zinc’s performance.
With the triethylsilyl (TES) group as a convenient syn-
thetic handle, alcohols 3aa–ai were obtained in good
NMR yields, albeit moderate isolated yields (entries
1–5, 7–9). Only fluorinated propargyl alcohols were
observed under the reaction conditions. In contrast,
nonfluorinated propargyl bromides yield both allenyl
and propargyl alcohols under similar conditions.9 Inter-
estingly, no reaction took place with 4-nitrobenzalde-
hyde, a normally reactive electrophile (entry 6). The
type of substituent on the acetylenic moiety in 1 had a
noticeable effect on the yield of product. Whereas the
n-hexyl group (1b) did not have a deleterious effect on
the yield of 3ba (entry 10), a phenyl substituent (1c) fur-
nished 3ca in a very low yield, and always accompanied
by unidentified nonfluorinated byproducts (entry 11).
Table 2. Effects of Eu(OTf)3 versus I2
Entry In
Zn
Additive
Yields of
producta (%)
3aa:4
(X equiv) (Y equiv)
1
2
0.05
0.1
0.95
0.9
Eu(OTf)3 (5 mol %) 55:15
Eu(OTf)3 (5 mol %) 61:12
3
4
5
6
7
0.05
0.1
0.1
0.1
—
0.95
0.9
1.1
0.9
0.9
I2 (5 mol %)
I2 (10 mol %)
I2 (10 mol %)
—
52:8
66:6
55:9
43:12
24:16
In summary, the combination of zinc (0.9 equiv)/indium
(0.1 equiv) and I2 (0.1 equiv) is a cost-effective alterna-
tive to the use of Eu(OTf)3. Although the resulting
gem-difluorohomopropargyl alcohols are obtained in
moderate yields, this reaction is highly regioselective as
I2 (10 mol %)
a Yield was determined by 19F NMR.
Table 3. Barbier type reaction of 1 and several aldehydes 2
In (0.1 eq.), Zn (0.9 eq.),
(0.1 eq.)
F
O
F
I
2
F
F
+
R
R
R'
H
H O/ THF (4/1, 0.3 M)
2
Br
R'
o
40 C, 12 h, )))
2
3
1
HO
(1.1 eq.)
Entry
R
R0
Isolate yield of 3a (%)
1
2
3
4
5
6
7
8
9
TES (1a)
Ph (2a)
55 (66) [3aa]
48 (55) [3ab]
48 (60) [3ac]
53 (67) [3ad]
42 (61) [3ae]
No reaction
56 (81) [3ag]
47 (55) [3ah]
53 (64) [3ai]
4-Me–C6H4 (2b)
3-MeO–C6H4 (2c)
2,4-(MeO)2–C6H3 (2d)
4-Cl–C6H4 (2e)
4-NO2–C6H4 (2f)
4-CF3C6H4 (2g)
2-F–C6H4 (2h)
4-OH–C6H4 (2i)
10
11
n-Hex (1b)
Ph (1c)
Ph (2a)
41 (42) [3ba]
0 (26) [3ca]b
a The values in parentheses are 19F NMR yields. These were determined using trifluorotoluene (entries 1–6 and 8–11) and hexafluorobenzene (entry 7)
as the internal standard.
b Product could not be isolated from the complex mixture.

S. Arimitsu et al. / Tetrahedron Letters 48 (2007) 1625–1627
1627
2002, 35, 209–217; (b) Kobayashi, S.; Nagayama, S.;
Busujima, T. J. Am. Chem. Soc. 1998, 120, 8287–8288; For
In3+: (c) Loh, T.-P.; Chua, G.-L. Chem. Commun. 2006,
2739–2749.
the corresponding fluoroallenyl alcohols were not
detected.
9. (a) Alcaide, B.; Almendros, P.; Mart, T. Angew. Chem., Int.
Ed. 2006, 45, 4501–4504; (b) Miao, W.; Chung, L. W.; Wu,
Y. D. J. Am. Chem. Soc. 2004, 126, 13326–13334; (c) Lin,
M. J.; Loh, T. P. J. Am. Chem. Soc. 2003, 125, 13042–13043.
10. A typical reaction procedure is as follows: To a flask were
added indium (0.2 mmol, 0.1 equiv), zinc powder
(1.8 mmol, 0.9 equiv), and I2 (0.2 mmol, 10 mol %) then
triethylsilyl difluoropropargylbromide (1a) (2.0 mmol) and
4-(trifluoromethyl)benzaldehyde (2g) (2.2 mmol, 1.1 equiv)
with rinsing by THF/H2O solution (1/4) (6.7 mL, 0.3 M).
The reaction was sonicated at 40 ꢁC for 12 h. The reaction
was quenched with 10% HCl (10 mL), extracted by ethyl
acetate (10 mL · 3) and the combined organic layers were
washed with brine and dried over anhydrous MgSO4. After
evaporation of the solvent, the residue was purified by
silica gel with hexane/EtOAc (40:1) to afford 3ag (408 mg,
Acknowledgment
The generous financial support of the National Science
Foundation (CHE 0513483) is appreciated.
References and notes
1. (a) Li, C.-J. Chem. Rev. 2005, 105, 3095–3165; (b) Li, C.-J.;
Chan, T.-H. Organic Reactions in Aqueous Media; John
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1993, 93, 2023–2035.
2. Chao, L.-C.; Rieke, R. D. J. Org. Chem. 1975, 40, 2253–
2255.
3. Keh, C. C. K.; Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2003,
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5. Lin, M.-J.; Loh, T.-P. J. Am. Chem. Soc. 2003, 125,
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1
56%). H NMR (CDCl3): d 0.62 (q, J = 7.8 Hz, 6H), 0.95
(t, J = 7.8 Hz, 9H), 2.97 (br s, 1H), 5.01 (t, J = 8.3 Hz, 1H),
7.65 (s, 4H); 19F NMR (CDCl3):
d
ꢀ93.23 (d,
J = 277.3 Hz, 1F), ꢀ95.04 (d, J = 277.3 Hz, 1F); 13C
NMR (CDCl3): d 3.7, 7.1, 75.7 (dt, J = 29.3, 12.1 Hz),
94.8 (t, J = 37.4 Hz), 112.8 (t, J = 238.6 Hz), 123.9 (q,
J = 271.8 Hz), 125.0, 128.2, 131.2 (q, J = 32.2 Hz), 139.0;
IR (neat) cmꢀ1: 3610, 3410, 2960, 2881, 2187, 1927, 1623,
1166; MS m/z (%): 364 (2, M+), 346 (17), 326 (13), 290 (27),
224 (100), 183 (29), 155 (78), 68 (15); Anal. Calcd: C, 56.03;
H, 5.81. Found: C, 56.25; H, 5.95.
6. Podlech, J.; Maier, T. C. Synthesis 2003, 5, 633–655, and
references cited therein.
7. Arimitsu, S.; Hammond, G. B. J. Org. Chem. 2006, 71,
8865–8868.
8. Both Zn2+ and In3+ might perform as a water tolerant
Lewis acid. For a comprehensive discussion, see: For
Zn2+: (a) Kobayashi, S.; Manabe, K. Acc. Chem. Res.