Expedient synthesis of α,α-difluorohomopropargylic alcohols from TIPS- difluorobromopropyne via a Zn-mediated propargylation of aldehydes and ketones

Article abstract of DOI:10.1016/S0040-4039(00)00196-9

The synthesis of α,α-difluorohomopropargyl alcohols containing an alkynyl silane moiety is reported. The title compound was prepared by the reaction of the organozinc derivative of TIPS-bromodifluoropropyne with aldehydes or ketones under mild conditions and in good yields. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00196-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2339–2342
Expedient synthesis of α,α-difluorohomopropargylic alcohols
from TIPS-difluorobromopropyne via a Zn-mediated
propargylation of aldehydes and ketones
ZhiGang Wang and Gerald B. Hammond ∗
Department of Chemistry and Biochemistry, The University of Massachusetts Dartmouth, North Dartmouth,
Massachusetts 02747, USA
Received 24 November 1999; revised 26 January 2000; accepted 27 January 2000
Abstract
The synthesis of α,α-difluorohomopropargyl alcohols containing an alkynyl silane moiety is reported. The
title compound was prepared by the reaction of the organozinc derivative of TIPS-bromodifluoropropyne with
aldehydes or ketones under mild conditions and in good yields. © 2000 Elsevier Science Ltd. All rights reserved.
The search for new methods for the introduction of the CF2 group in organic molecules is an area of
much current interest.1 The unique stereoelectronic properties of the gem-difluoromethylene group, in
which the CF2 carbon is sp3 hybridized, have fostered its widespread utilization in pharmacologically
active substances. For example, the presence of a CF2 has aided in the formation of stable hydrates
and hemiketals capable of inhibiting proteases and esterases;2 CF2 has been employed as an isoelec-
tronic–isosteric replacement for the oxygen atom in phosphate analogues;3 and in the synthesis of β,β-
difluoro-α-amino acids,4 and fluorinated arachidonic acid,5 among other uses.
As part of our ongoing research on fluorinated building blocks, we speculated that TIPS-α,α-
difluorohomopropargyl alcohol 2, could be an efficient conduit for fluorine incorporation in an organic
compound. Compound 2 is equipped with two synthetic handles on both ends of the CF2 group:
an alkynyl silane and a hydroxyl group. To our knowledge, the only reported6 synthesis of α,α-
difluoropropargylic alcohols was provided by Kobayashi et al.,7 who used zinc activated with HgCl2
in the reaction of aryl- or alkyl-substituted bromodifluoroacetylenes with aldehydes (R2=H) to give α,α-
difluoropropargylic alcohols. Kobayashi obtained his bromodifluoroacetylenes following Wakselman’s
procedure,8 in disappointingly low yields by the reaction of an alkyl- or aryl-substituted acetylene with
CF2Br2, under strongly basic conditions.
Our strategy for the preparation of 2 makes use of a highly efficient synthesis of TIPS-
bromodifluoropropyne 1, recently discovered in our laboratory.9 Compound 1 was assembled in
∗
Corresponding author. Tel: 508-999-8865; fax: 508-910-6918; e-mail: ghammond@umassd.edu (G. B. Hammond)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00196-9
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one step (92% GC–MS, 81% isolated) by the reaction of CF2Br2 with lithium TIPS-acetylide. We
attributed the success of this reaction to the presence of the TIPS group, which possesses remarkably
different properties compared to other alkylsilyl groups.10 Treatment of 1 with zinc at room temperature
using Methods A or B forms an organozinc intermediate capable of reacting with a wide variety of
aldehydes and ketones at room temperature to give the desired α,α-difluorohomopropargylic alcohol 2 in
good yield (see Table 1). Aldehydes, being more electrophilic than ketones, furnished the corresponding
alcohols in higher yields. Method B provided a higher yield of 2 because the organozinc intermediate
could be trapped by the aldehyde as soon as it was formed. Dimer 3 is the only observable by-product
of this reaction and was easily removed during chromatography due to its very low polarity. The ratio of
2:3 ranged from approximately 3:1 to 5:1.
Method A (two-step procedure): To a solution of 1 (824 mg, 2.3 mmol) in THF (7 mL) was added zinc
dust (208 mg, 1.2 equiv.). The mixture was sonicated for 10 min and stirred at room temperature until
the absence of starting material was observed (about 1 h). 2-Octynal (389 µL, 1.0 equiv.) was added and
the resulting mixture was stirred for 20 h. Solvent removal, standard work-up (saturated NH4Cl, ethyl
acetate extraction) and purification (silica gel flash chromatography), furnished 2 (entry 4).11
Method B (one-step procedure): To a solution of 1 (907 mg, 2.91 mmol) and 3-methyl-2-butenal (290
µL, 1.0 equiv.) in THF (10 mL) was added zinc dust (229 mg, 1.2 equiv.). The mixture was sonicated for
15 min and stirred at room temperature for 18 h. Standard work-up followed by flash chromatography
gave 2 (entry 2).12
When needed, the TIPS-protecting group in 2 can be easily removed, as demonstrated by the
conversion of 2 (entry 7) to 4 (Eq. (1)) under mild conditions and in excellent yield. This result will
allow an easy access to other propargylic, and possibly allylic α,α-difluorocarbonyl compounds, after
oxidation of the alcohol and hydrogenation of the triple bond.
(1)
Other organometallic applications of 1 to the synthesis of organofluoro compounds are under investi-
gation.
Acknowledgements
The generous support of the National Science Foundation (CHE-9711062) and the Camille and Henry
Dreyfus Foundation (TH-96-012) is gratefully appreciated.
References
1. For a recent review, see: Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619–8683. See also: Percy, J. M. Top. Curr. Chem.
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Organic Chemistry; Thieme: Stuttgart, 1999; Vol. E 10a. Elegant new approaches that include the Claisen rearrangement,
and electroreductive defluorination have appeared recently. See: Uneyama, K.; Mizutani, G.; Maeda, K.; Kato, K. J. Org.
Chem. 1999, 64, 6717–6723. Qing, F.-L.; Wan, D.-P. Tetrahedron 1998, 54, 14 189–14 200. Ishihara, T.; Takahashi, A.;
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2. Altenburger, J. M.; Schirlin, D. Tetrahedron Lett. 1991, 32, 7255–7258.

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Table 1

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8413–8418. For leading references, see: O’Hagan, D.; Rzepa, H. S. J. Chem. Soc., Chem. Commun. 1997, 645–652.
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and ketones via the in situ reaction of 3-bromo-3,3-difluoropropene with acid-washed zinc powder: Yang, Z.-Y.; Burton, D.
J. J. Org. Chem. 1991, 56, 1037–1041.
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1
11. H NMR δ 4.54 (m, 1H), 2.21 (dt, 2H, 3JHH=7.1 Hz, 5JHH=2.0 Hz), 2.04 (s, 1H), 1.52–1.26 (m, 6H), 1.12 (s, 21H), 0.90 (t,
3H, 3JHH=7.1 Hz). 13C NMR δ 111.57 (t, 1JFC=239 Hz), 96.08 (t, 2JFC=37 Hz), 93.02 (t, 3JFC=6 Hz), 89.03, 74.03 (t, 3JFC=4
Hz), 66.52 (t, 2JFC=33 Hz), 30.99, 27.89, 22.13, 18.66, 18.07, 14.00, 10.88. EI-MS m/e 355 (M+, 3), 304 (12), 261 (2), 241
(15), 157 (17), 109 (18), 77 (100). Anal. calcd for C20H34SiF2O: C, 68.13; H, 9.64. Found: C, 68.08; H, 9.74.
1
12. H NMR δ 5.30 (m, 1H, 4JFH=9.0 Hz), 4.56 (m, 1H, 3JFH=11.6 Hz, 3JFH=8.9 Hz, 3JHH=6.4 Hz), 2.05 (s, 1H), 1.79 (d, 3H,
4JHH=1.4 Hz), 1.76 (d, 3H, 4JHH=1.3 Hz), 1.09 (s, 21H). 13C NMR δ 141.6, 119.2 (t, 3JFC=2 Hz), 113.2 (t, 1JFC=238 Hz),
2
3
2
2
96.9 (t, JFC=38 Hz), 92.44 (t, JFC=6 Hz), 71.3 (t, JFC=30 Hz, JFC=27 Hz), 26.00, 18.73, 18.38, 10.87. EI-MS m/e 273
(M+−43, 3), 253 (4), 203 (3), 169 (8), 131 (4), 105 (20), 85 (100).