Mg(0)-promoted debromometalation of gem-difluoropropargyl bromides

Article abstract of DOI:10.1016/j.tetlet.2005.01.130

Mg(0)/Me₃SiCl was found to be effective for the preparation of difluoropropargylsilanes. This method, using Me₃SnCl, produced the corresponding propargylstannane.

Full text of DOI:10.1016/j.tetlet.2005.01.130

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1787–1789
Mg(0)-promoted debromometalation of
gem-difluoropropargyl bromides
Masayuki Mae,a Jiyoung A. Hong,a Gerald B. Hammonda,* and Kenji Uneyamab
aDepartment of Chemistry, University of Louisville, Louisville, KY 40292, USA
bDepartment of Applied Chemistry, Faculty of Engineering, Okayama University, Tsushimanaka 3-1-1, Okayama 700-8530, Japan
Received 28December 2004; revised 24 January 2005; accepted 25 January 2005
Abstract—Mg(0)/Me3SiCl was found to be effective for the preparation of difluoropropargylsilanes. This method, using Me3SnCl,
produced the corresponding propargylstannane.
ꢀ 2005 Elsevier Ltd. All rights reserved.
There is a growing interest in developing difluorinated
building blocks for the synthesis of gem-difluoromethyl-
ene-containing compounds because of their interesting
biological activities, such as the anticancer agent gemcit-
abine,1 HIV-1 protease inhibitors,2 phosphotyrosine
(pTyr) mimetics,3 and fluorinated sugars.4 A silylated
and/or stannylated gem-difluoropropargyl synthon,
RC„C–CF2Si(Sn), could be a key synthetic intermedi-
ate in the synthesis of gem-difluoromethylene containing
C-3 synthons because of the rich chemistry of acetyl-
enes. The non-fluorinated propargylsilanes or stann-
anes are stable species,5 and have been converted into
biological active compounds, or have served as pre-
cursor of allenes.6 In stark contrast, there are only
a handful of reports on the generation of gem-
difluoropropargyl organometallic complexes.7 In this
letter, we report a practical synthesis of gem-difluoro-
propargylsilane and gem-difluoropropargylstannane
using Mg(0)-promoted reductive debromometalation8
of 3-bromo-3,3-difluoropropyne as a key reaction (Eq.
1).
As shown in Table 1, the procedure for the selective form-
ation of 2 works well for a diverse group of aromatic
and aliphatic alkynes. No allenyl organometallics were
detected.9 Neither over-reduction nor C–F bond cleav-
age were observed. In the case of aromatic alkynes,
the reactions were completed within 30 min at 0 ꢁC in
THF (entries 1–4). Also, an aliphatic alkyne reacts
smoothly to give the corresponding silylated difluoro-
alkyne at 0 ꢁC in THF (entry 5), as compared with
aliphatic ketones and imines (C–F bond cleavage of ali-
phatic trifluoromethyl ketone and imine) which required
DMF as a solvent and high temperature.8a,g Moreover,
Table 1. Mg(0)-promoted debromometalation of bromodifluoro-
alkyne 1a
Mg (8.0 eq.)
R
R
M-Cl (4.0 eq.)
THF
Br
M
F
F
F F
1
2/3
R
R
R
E, F-
Mg, M-Cl
Br
M
E
Entry
R
M–Cl
Conditions
% Yield of 2/3b
ð1Þ
F
F
F
F
F F
1
p-MeP6H4 TMSCl
o-MeC6H4 TMSCl
p-MeOC6H4 TMSCl
0 ꢁC, 30 min 81 (2a)
0 ꢁC, 30 min 77 (2b)
0 ꢁC, 30 min 90 (2c)
0 ꢁC, 30 min 51 (2d)
0 ꢁC, 30 min 63 (2e)
0 ꢁC, 30 min 82 (2f)
0 ꢁC, 30 min 93 (2g)
2
M = SiR3 ,SnR3
3
4
Ph
TMSCl
TMSCl
TMSCl
TMSCl
5
Hex
TIPS
TES
6
7
8Ph
Keywords: Magnesium; gem-Difluoromethylene; Propargylsilane;
Propargylstannane.
Me
3SnCl 0 ꢁC, 1 h
75 (3)
a The reaction was carried out by the procedure shown in Ref. 10.
b Isolated yield. All compounds gave satisfactory spectral data.
*
Corresponding author. Tel.: +1 502 852 5998; fax: +1 502 852
3899; e-mail: gb.hammond@louisville.edu
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.130

1788
M. Mae et al. / Tetrahedron Letters 46 (2005) 1787–1789
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OH
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PhCHO, TBAF
THF
-100 oC, 30 min.
Ph
F
F
4 (90 %)
Ph
Allyl-Br, KF, CuI
THF
55 oC, 5 h
F
F
Ph
5 (65%)
TMS
F
F
Ph
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2d
Bn-Br, KF, CuI
THF
55 oC, 5 h
Bn
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F
F
6 (36%)
MeI, TBAF
THF
Me
0
oC, 30 min.
F
F
7 (26%)
Scheme 1.
silylated alkynes 1f,g generally gave good yields (entries
6 and 7). Using the same protocol, 1 reacted with trime-
thylstannyl chloride to give the stannane 3 in 75% yield
(entry 8).
Difluorotrimethylsilylmethyl 2 is a promising building
block because it is readily available, can be stored for
long periods of time, and it is highly reactive in the pres-
ence of a fluoride anion.11 To explore the reactivity of
3,3-difluoro-3-trimethylsilyl alkyne, 2d was subjected
to a fluoride anion promoted C–C bond formation with
electrophiles such as aldehydes and halides (Scheme 1).
The reaction of 2d with benzaldehyde proceeded
smoothly to give 4 in excellent yield. Allylation and benz-
ylation of 2d in the presence of KF and CuI gave 5 and 6
in good to moderate yields. Also, methylation of 2d in
the presence of TBAF succeeded to give 7 albeit in
low yield.
In conclusion, the selective metalation of bromodifluo-
ropropargyl 1, using Mg/Me3SiCl or Me3SnCl, allowed
access to difluoropropargylsilanes 2 and difluoropro-
pargylstannane 3 in good yields. The former reacted
with various electrophiles in the presence of fluoride an-
ion to give the corresponding difluoromethylene com-
pounds. Further utilization of difluoropropargylsilanes
and/or -stannanes are in progress in our laboratory.
Acknowledgements
The authors are grateful to the National Science Foun-
dation (CHE-0213502) and the University of Louisville
Research Foundation for their generous support.
9. Allenyl-propargyl organometallics often exist as an equi-
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Kobayashi, S.; Nishio, K. J. Am. Chem. Soc. 1995, 117,
6392; (b) Yamamoto, H. In Comprehensive Organic
Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, 1991;
References and notes
1. Chou, T. S.; Heath, P. C.; Patterson, L. E.; Poteet, L. M.;
Laikin, R. E.; Hunt, A. H. Synthesis 1992, 565.

M. Mae et al. / Tetrahedron Letters 46 (2005) 1787–1789
difluoro-1-(4-methylphenyl)propyne
1789
Vol. 2, p 81; (c) Schuster, H. F.; Coppola, G. M. Allenes in
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(e) Klein, J. In The Chemistry of the Carbon–Carbon Triple
Bond; PatÕai, S., Ed.; Wiley: New York, 1978; p 343.
Although some excellent work has been reported in this
field, the selectivity depends on substrates and metals used.
For example, allenyl organometallics (ÔunsubstitutedÕ
allenyl organometallics) are generated preferentially in
most cases, and there has been no example for the selective
preparation of propargyl organometallics; (f) Zhang, L.-J.;
Mo, X. S.; Huang, Y.-2. J. Organomet. Chem. 1994, 471,
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1a
(238mg,
1.0 mmol) was added dropwise at 0 ꢁC under an argon
atmosphere. The reaction mixture was stirred for 30 min.
at 0 ꢁC. The residual Mg was removed by decantation, and
the THF solution was washed with H2O (5 mL). The
aqueous layer was extracted with hexane (5 mL · 2) and
the combined organic layers were dried over Na2SO4. After
evaporation of the solvent, the crude product was purified
by silica gel treated with Et3N/hexane = 1/9 column chro-
matography (hexane) to afford 2a as an orange oil (187 mg,
81%); IR (neat) 2225 cmꢀ1; 1H NMR (500 MHz, CDCl3) d
0.29 (s, 9H), 2.37 (s, 3H), 7.16 (d, J = 6.5 Hz, 2H), 7.38(d,
J = 7.5 Hz, 2H); 13C NMR (126 MHz, CDCl3) d ꢀ4.9,
21.5, 81.6 (t, J = 30.8Hz), 91.4 (t, J = 8.7 Hz), 111.7, 120.6
(t, J = 253 Hz), 129.2, 131.9, 140.0; 19F NMR (470 MHz,
CDCl3, C6F6 as an internal standard) d 56.8(s, 2F); GC/
MS (CI) m/z (%) 239 (M+1+, 14), 223 (27), 219 (100).
11. (a) Uneyama, K.; Mizutani, G.; Maeda, K.; Kato, T. J.
Org. Chem. 1999, 64, 6717; (b) Prakash, G. K. S.; Yudin,
A. K. Chem. Rev. 1997, 77, 7577.
10. A typical reaction procedure is as follows: To the mixture
of Mg (194 mg, 8.0 mmol) and chlorotrimethylsilane
(0.51 mL, 4.0 mmol) in dry THF (10 mL), 3-bromo-3,3-