An efficient preparation of TIPS - Halofluoropropyne and its application to the diastereoselective synthesis of propargylic fluorohydrins

Full text of DOI:10.1021/jo000243+

J . Org. Chem. 2000, 65, 4217-4221
4217
to unsaturated R-fluorophosphononucleosides and R-fluo-
roenaminophosphonates. In addition, the Diels-Alder
cyclization of 2 provided a diastereoselective route to
exocyclic R-fluoromethylidene phosphonates.9
An Efficien t P r ep a r a tion of
TIP S-Ha loflu or op r op yn e a n d Its
Ap p lica tion to th e Dia ster eoselective
Syn th esis of P r op a r gylic F lu or oh yd r in s
Yunfeng Lan and Gerald B. Hammond*,1
Department of Chemistry and Biochemistry,
University of Massachusetts Dartmouth,
North Dartmouth, Massachusetts 02747
Received February 22, 2000
With the exception of enynes and enediynessobtained
from 1 via HWE olefinationsthe sluggish reactivity of
the phosphonyl group in 1 and 2 will circumscribe their
usefulness mainly to the synthesis of other R-fluorophos-
phonates. To enhance the building block potential of the
R-fluoropropargyl motif present in 1, we sought the
substitution of the phosphorus atom with a halogen. This
paper reports an efficient one-step synthesis of 3 from
halofluoromethane and the diastereoselective synthesis
of propargylic fluorohydrins 6 via a Zn-mediated pro-
pargylation of aldehydes and acetone.
In tr od u ction
The replacement of CH2 by CHFsan area of much
research activity2shas been fueled by the continuous
expansion of the role played by fluorine in fields as
diverse as pharmaceuticals, molecular imaging, and
polymers.3 The increased repertoire of asymmetric fluo-
rination reactions4 and improvements in the design of
fluorine-containing building block,5 are examples of a
synthetic response to new and challenging demands for
site-specific fluorine substitution. R-Fluorophosphonates
are important mimics of biological phosphates.6 Our
earlier work focused on developing highly functional
monofluorophosphonate building blocks. This resulted in
the synthesis of R-fluoropropargyl phosphonates 17-8 and
R-fluoroallene phosphonate 2.8 The latter was used to
generate a cascade of diastereospecific reactions leading
Resu lts a n d Discu ssion
Despite its synthetic potential, only a single previous
report of the γ-silyl-R-fluorohalopropargyl synthon exists.
Krantz and Castelhano10 prepared the TMS analogue of
3a in moderate yields (40-50%) by the reaction of
CHFCl2 with the requisite acetylide in THF, at very low
temperatures (-100 to -70 °C). The preparation of 3a ,b
followed our recently discovered synthesis of 1-TIPS-3-
bromo-3,3-difluoropropyne.11 Chloride 3a was assembled
by the alkylation of CHFCl2 with lithium TIPS-acetylide
in 76% after distillation (Scheme 1).
The only byproduct detected in this reaction was
TIPS-CtC-CHCl2 according to the GC-MS of the
reaction mixture. Substitution of chlorine by bromine in
the starting halofluoromethane led to 3b in slightly lower
yield (64%). Reaction byproducts included TIPS-CtC-
Br (GC-MS analysis) and TIPS-CtC-CFH2. An at-
tempted SN2 displacement of chloride from 3a using KBr
in refluxing methyl ethyl ketone (MEK) failed to produce
the desired 3b. The starting material remained un-
changed. However, nucleophilic substitution of 3a or 3b
using NaI in refluxing MEK (reaction time was 40 h in
the case of 3a , and 1 h in the case of 3b) produced the
iodo analogue 3c quantitatively, according to the 19F
NMR spectrum of the crude product. The purification of
3c was hampered by its gradual decomposition (even
under darkness) at room temperature to give TIPS-Ct
C-CHO. Dechlorination of 3a using tri(n-butyl)tin hy-
dride12 (1.0 equiv) with a radical initiator, in refluxing
toluene, afforded TIPS-fluoropropyne 4a in 60-70% yield.
This compound could also be prepared, albeit in lower
yield (37%), using Zn (1 equiv) in DMF at 100 °C.
(1) E-mail: ghammond@umassd.edu. Tel.: 508-999-8865. Fax: 508-
910-6918.
(2) Selected recent examples include: Bainbridge, J . M.; Corr, S.;
Kanai, M.; Percy, J . M. Tetrahedron Lett. 2000, 41, 971-974. Huang,
X.; He, P.; Shi, G. J . Org. Chem. 2000, 65, 627-629. Funabiki, K.;
Fukushima, Y.; Matsui, M.; Shibata, K. J . Org. Chem. 2000, 65, 606-
609. Shimizu, M.; Hata, T.; Hiyama, T. Tetrahedron Lett. 1999, 40,
7375-7378. Narisano, E.; Riva, R. Tetrahedron: Asymmetry 1999, 10,
1223-1242. Narisano, E.; Riva, R. Tetrahedron: Asymmetry 1999, 10,
1223-1242. Laue, K. W.; Haufe, G. Synthesis 1998, 1453-1456. Davis,
F. A.; Kasu, P. V. N.; Sundarababu, G.; Qi, H. J . Org. Chem. 1997, 62,
7546-7547.
(3) Hudlicky, M.; Pavlath, A. E. Chemistry of Organic Fluorine
Compounds II; American Chemical Society: Washington, DC, 1995.
Fluorine-containing Molecules. Structure, Reactivity, Synthesis, and
Applications; Liebman, J . F., Greenberg, A., Dolbier, W. R., Eds.; VCH
Publishers: New York, 1988. Fluoroorganic Chemistry: Synthetic
Challenges and Biomedicinal Rewards; Resnati, G., Soloshonok, V. A.,
Eds.; Tetrahedron Symposia-In-Print No. 58, Elsevier: Amsterdam,
1996; pp1-330. Ojima, I.; McCarthy, J . R.; Welch, J . T. Biomedical
Frontiers of Fluorine Chemistry; Ojima, I., McCarthy, J . R., Welch, J .
T., Eds.; American Chemical Society: Washington, DC, 1996; Vol. 639,
p 356. Fluorine-Containing Amino Acids: Synthesis and Properties;
Kukhar, V. P.; Soloshonok, V. A., Ed.; Wiley: Chichester, 1994.
Biomedicinal Aspects of Fluorine Chemistry; Filler, R., Kobayashi, Y.,
Yagupolskii, L. M. Eds; Elsevier: Amsterdam, 1993. Organofluorine
Chemistry. Principles and Commercial Applications; Banks, R. E.,
Smart, B. E., Tatlow, J . C., Eds.; Plenum Press: New York, 1994; p
644. For a comprehensive list, up to 1993, of books and reviews on
fluoroorganic chemistry see: Resnati, G. Tetrahedron 1993, 49, 9385-
9445.
(4) Enantiocontrolled Synthesis of Fluoro-Organic Compounds;
Soloshonok, V. A., Ed.; Wiley & Sons: West Sussex, 1999,
(5) For an excellent review and an updated compilation of references,
see: Percy, J . M. Top. Curr. Chem. 1997, 193, 131-195.
(6) Recent review: O’Hagan, D.; Rzepa, H. S. J . Chem. Soc., Chem.
Commun. 1997, 645-652.
(7) Benayoud, F.; deMendonca, D. J .; Digits, C. A.; Moniz, G. A.;
Sanders, T. C.; Hammond, G. B. J . Org. Chem. 1996, 61, 5159-5164.
Benayoud, F.; Hammond, G. B. J . C. S. Chem. Commun. 1996, 1447-
1448.
(9) Gu, Y.; Hama, T.; Hammond, G. B. J . Chem. Soc., Chem.
Commun. 2000, 395-396.
(10) Castelhano, A. L.; Krantz, A. J . Am. Chem. Soc. 1987, 109,
3491-3493.
(11) Wang, Z.; Hammond, G. B. J . Chem. Soc., Chem. Commun.
1999, 2545-2546.
(8) Zapata, A.; Gu, Y.; Hammond, G. B. J . Org. Chem. 2000, 65,
227-234.
(12) Reviews: Curran, D. P. Synthesis 1988, 417-439. Neumann,
W. P. Synthesis 1987, 665-683.
10.1021/jo000243+ CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/18/2000

4218 J . Org. Chem., Vol. 65, No. 13, 2000
Notes
Sch em e 1
Changing the solvent (THF instead of DMF), and soni-
cating a mixture of activated zinc13 and bromide 3b at
room temperature, furnished dimer 4b, as a 1:1 mixture
of diastereoisomers. This reaction also produced small
amounts of 4a and TIPS-CtC-CH3. Chloride 3a failed
to undergo a similar reaction. Dimer 4b could also be
obtained by the reaction of triethyl phosphite with 3a or
3b.14
The alkynylsilane moiety present in 3 is a convenient
handle for new C-C bond formation. With this in mind,
we probed the deprotection of the TIPS group with TBAF
and in situ trapping with an electrophile (benzaldehyde).
The reaction afforded the desired propargyl alcohol 5a ,b,
in moderate isolated yields (45%). Substituting the
halogen atom before TBAF deprotection greatly improved
the yield of desilylated product (see eq 1 below).
from 60% to 90% (Table 1). The only byproduct detected
in this reaction was dimer 4b (10-20% according to GC-
MS), easily removed during chromatography due to its
low polarity.
The yield of 6 appeared to increase with the electro-
philic character of the carbonyl compound (e.g., entry b).
Furthermore, this reaction favored the preferential for-
mation of the erythro diastereomer. The diastereomeric
ratio was determined by 1H and/or 19F NMR spectroscopy
in the crude mixture. The erythro and threo isomers were
3
identified by their J HH coupling constants (Table 2).17
This ratio appears to be dependent on steric hindrance,
at least in the case of aliphatic aldehydes (compare entry
f vs entry e in Table 1). The preference for the erythro
isomer in Zn-mediated additions to aldehydes has also
been reported by Chemla and co-workers.18
The published preparation of 1a is relatively laborious.8
Our synthesis of 3 offered an opportunity to synthesize
1a in one step provided suitable conditions for the
phosphorus substitution of the halide in either 3a , 3b,
or 3c could be found. Unfortunately, our attempts, using
a nucleophilic or electrophilic phosphorus reagent, did
not provide the desired result (see ref 14).
When needed, the TIPS-protecting group in 6 can be
easily removed using TBAF, as demonstrated by the
conversion of 6a to 7 (eq 1), under mild conditions and
in good yield.
We have recently reported the synthesis of R,R-difluo-
rohomopropargylic alcohols starting from TIPS-CtC-
CF2Br, via a Zn-mediated propargylation of aldehydes
and ketones.15 Propargylic fluorohydrin 6 can be regarded
as a monofluoro counterpart to R,R-difluorohomopropar-
gylic alcohols, with the potential to deliver a -CHF-
group into an organic compound, by way of a silyl
propargyl scaffold. To our surprise, with the exception
of 13-fluoro-14-hydroxyhexadec-11-ynyl acetate,16 pro-
pargylic fluorohydrins have not been reported in the
literature. Premixing the aldehyde in THF with activated
zinc dust and 3b (sonication at room temperature, or
reflux) carried out the synthesis of 6 in yields ranging
This result may allow access to allylic fluorohydrins
as well as R-fluorocarbonyl compounds, after hydrogena-
tion of the triple bond, and oxidation of the alcohol,
respectively. These and other organometallic applications
of 3 are under investigation.
Exp er im en ta l Section
All moisture-sensitive reactions were done using flame-dried
glassware flushed with argon, magnetic stirring, and dry, freshly
distilled solvents. THF was distilled from Na/benzophenone.
Toluene was distilled from calcium hydride. Other solvents were
HPLC grade and were used without purification. CHFCl2
(HCFC-21, 97%) and CHFBr2 (Halon 1102, 98%) were purchased
from SynQuest Laboratories, Inc. (Alachua, FL) and used
without further purification. Other commercial reagents were
purchased from Aldrich and used as received. All reactions were
(13) For a zinc activation procedure, see: Branda¨nge, S.; Dahlman,
O.; Mo¨rch, L. J . Am. Chem. Soc. 1981, 103, 4452-4458.
(14) An Arbuzov reaction with triethyl phosphite (Bhattacharya, A.
K.; Thyagarajan, G. Chem. Rev. 1981, 81, 415-430) accompanied by
either n-Bu4NI or (NH4)2Ce(NO3]6 (Kottmann, H.; Skarzewski, J .;
Effenberger, F. Synthesis 1987, 1987, 797-801) produced a mixture
of 4b, and TIPS-CtC-CHO. Use of n-BuLi in 3a , or b, followed by
the addition of diethyl chlorophosphate or diethyl chlorophosphite led
to complex mixtures or unreacted starting material.
(15) Wang, Z.; Hammond, G. B. Tetrahedron Lett. 2000, 41, 2339-
2342.
(16) This compound, prepared in low yield after several steps, was
an intermediate in a pheromone synthesis: Camps, F.; Fabrias, G.;
Guerrero, A. Tetrahedron 1986, 42, 3623-3629.
(17) Al-Badri, H.; About-J audet, E.; Collignon, N. Synthesis 1994,
1072-1078. Buss, A. D.; Cruse, W. B.; Kennard, O.; Warren, S. J .
Chem. Soc., Perkin Trans. 1 1984, 243-247.
(18) Chemla, F.; Hebbe, V.; Normant, J . F. Tetrahedron Lett. 1999,
40, 8093-8096. Chemla, F.; Bernard, N.; Normant, J . F. Tetrahedron
Lett. 1999, 40, 75-78.

Notes
J . Org. Chem., Vol. 65, No. 13, 2000 4219
Ta ble 1
a
b
Isolated yields of pure product after chromatography. Determined by 1H and/or 19F NMR spectroscopy in the crude product. c Acetone
was used as solvent.
2
monitored using one of the following techniques: TLC, GC-MS,
and/or 19F NMR. Analytical TLC was performed using Macherey-
Nagel Polygram Sil G/UV254 precoated plastic plates and visual-
ized using phosphomolybdic acid (5% in methanol). Flash
chromatography was performed using silica gel 230-400 mesh,
40-63 µm (Lagand Chemicals). 1H, 19F, and 13C NMR spectra
were recorded in CDCl3 at 300, 282, and 75 MHz, respectively.
19F NMR spectra were referenced against external CFCl3. 19F
NMR spectra were broadband decoupled from hydrogen nuclei.
Elemental analyses were performed by Atlantic Microlab, Inc.,
Norcross, GA.
Gen er a l P r oced u r e for th e Syn th esis of 1-(Tr iisop r o-
p ylsilyl)-3-ch lor o-3-flu or op r op yn e 3a . To a solution of (tri-
isopropylsilyl)acetylene19 (8.480 g, 46.6 mmol) in THF (35 mL)
at -80 °C was added n-BuLi (1.6M in hexane, 32 mL, 51.2
mmol), and then the mixture was warmed to room temperature
and stirred for 30 min. At -80 °C, dichlorofluoromethane (d25
) 1.366, 5 mL, 6.83 g, 66.4 mmol) was added dropwise by
cannula. The dark brown solution was stirred at 0 °C for 1 h
and quenched with saturated NH4Cl. THF was removed in
vacuo, and the residue was extracted by diethyl ether and
washed with saturated NH4Cl and brine. The combined organic
layers were dried (MgSO4) and concentrated. Vacuum distillation
afforded 3a (50-52 °C/0.1 mmHg, 8.806 g, 76%): 1H NMR δ
1.11 (s, 21H), 6.56 (d, 1H, J HF ) 50.6 Hz); 13C NMR δ 11.2,
1
3
2
18.2, 85.8 (d, J CF ) 236 Hz), 94.4 (d, J CF ) 4 Hz), 99.0 (d, J CF
) 27 Hz); 19F NMR δ -121. Anal. Calcd for C12H22ClFSi: C,
57.92; H, 8.91. Found: C, 57.70; H, 8.83.
1-(Tr iisop r op ylsilyl)-3-br om o-3-flu or op r op yn e 3b. Di-
bromofluoromethane (5.230 g, 27.26 mmol) was added to TIPS-
acetylene (4.536 g, 24.92 mmol) in THF according to the above
general procedure. The ratio of the reagents was as follows:
TIPS-acetylene/n-BuLi/CHBr2F ) 1:1.1:1.1. Vacuum distillation
provided 3b (bp 67 °C/0.1 mmHg, 4.661 g, 64%): 1H NMR δ 1.11
(s, 21H), 6.79 (d, 1H, J HF ) 51.5 Hz); 13C NMR δ 11.0, 18.4,
73.5 (d, J CF ) 246 Hz), 96.7 (d, J CF ) 6 Hz), 99.5 (d, J CF ) 26
Hz); 19F NMR δ -125. Anal. Calcd for C12H22BrFSi: C, 49.14;
H, 7.56. Found: C, 48.64; H, 7.42.
2
1
3
2
1-(Tr iisop r op ylsilyl)-3-flu or op r op yn e 4a . A mixture of
1,1′-azobis(cyclohexanecarbonitrile) (0.0432 g, 0.177 mmol),
tributyltin hydride (0.515 g, 1.77 mmol), and TIPS-chlorofluo-
ropropyne 3a (0.438 g, 1.77 mmol) was refluxed in toluene for 1
h. After cooling, the solvent was removed in vacuo. The residue
was dissolved in diethyl ether and then treated with 1 g/mL of
KF solution. After the mixture was stirred 30 min, the white
precipitate of n-Bu3SnF was filtrated off at reduced pressure,
the ethereal filtrate was dried (MgSO4) and concentrated. Flash
column chromatography on silica gel (hexane/CH2Cl2 ) 98:2)
yielded 4a (0.265 g, 70%): 1H NMR δ 1.08 (s, 21H), 5.98 (d, 2H,
(19) TIPS-CtC-H was purchased from GFS Chemicals, Inc.
(Columbus, OH). The company assay showed that 70% contained TIPS-
acetylene. The impurities present corresponded to propyl isomers of
TIPS: diisopropylpropylsilylacetylene (17%) and diisopropylpropenyl-
silylacetylene (12%). Fractional distillation failed to separate the TIPS
isomers but this did not affect the outcome of the reactions.
2J HF ) 47.5 Hz); 13C NMR δ 11.0, 18.3, 71.0 (d, J CF ) 165 Hz),
1
91.9 (d, 3J CF ) 10 Hz), 100.5 (d, 2J CF ) 21 Hz); 19F NMR δ -189.
Anal. Calcd for C12H23FSi: C, 67.23; H, 10.81. Found: C, 67.15;
H, 10.74.

4220 J . Org. Chem., Vol. 65, No. 13, 2000
Notes
Ta ble 2
a
Coupling between the two protons (HA and HB), on the main carbon skeleton, is greater for the threo than for the erythro isomers.
See ref 17. The only exception was 6f. Further signal splitting due to long-range coupling with aromatic fluorines was observed. c Unable
to determine. Degenerate erythro and threo signals.
b
d
1,6-Bis(tr iisopr opyl)-3,4-diflu or o-1,5-h exadiyn e 4b. Freshly
activated zinc dust (0.130 g, 1.99 mmol) was added to TIPS-
bromofluoropropyne 3b (0.580 g, 1.99 mmol) in THF. The
mixture was sonicated for 30 min and stirred at room temper-
ature until the absence of starting material. Standard workup
(saturated NH4Cl, brine, ether extraction, drying, and concen-
tration) and purification by flash chromatography (pentane/
cyclohexane ) 1:1) afforded 4b (0.186 g, 44%). Erythro or
aldehyde (0.278 g, 2.62 mmol) yielded 6a (0.636 g, 76%).
Erythro: 1H NMR δ 1.04 (s, 21H), 2.52 (s, 1H), 4.97 (dd, 1H,
3
2
3J HF ) 12.3 Hz, J HH ) 3.8 Hz), 5.23 (dd, 1H, J HF ) 47.7 Hz,
3J HH ) 4.1 Hz), 7.25-7.46 (m, 5H); 13C NMR δ 11.0, 18.5, 75.0
2
1
3
(d, J CF ) 24 Hz), 86.2 (d, J CF ) 175 Hz), 93.5 (d, J CF ) 8 Hz),
99.5 (d, J CF ) 25 Hz), 126.8, 128.3, 128.4, 137.6; 19F NMR δ
2
-178. Anal. Calcd for C19H29FSiO: C, 71.20; H, 9.12. Found:
C, 71.26; H, 9.18.
2
threo: 1H NMR δ 1.08 (s, 21H), 5.26 (dm, 2H, J HF ) 62.5 Hz);
1-(Tr iisop r op ylsilyl)-5-en e-3-flu or oh ep t yn -4-ol 6d . Zn
(0.100 g, 1.53 mmol), 3b (0.447 g, 1.53 mmol) and trans-
crotonaldehyde (0.107 g, 1.53 mmol) yielded 6d (0.244 g, 56%).
1
2
13C NMR δ 11.0, 18.5, 82.5 (dd, J CF ) 183 Hz, J CF ) 29 Hz),
93.4 (t, J CF ) 4.6 Hz), 97.5 (t, J CF ) 16 Hz); 19F NMR δ -180.
3
2
Threo or erythro: 1H NMR δ 1.08 (s, 21H), 5.18 (dm, 2H, 2J HF
)
)
Erythro: H NMR δ 1.08 (s, 21H), 1.75 (d, 3H, J HH ) 6.3 Hz),
2 3
1
3
58.9 Hz); 13C NMR δ 11.0, 18.5, 82.3 (dd, J CF ) 184 Hz, J CF
2.03 (s, 1H), 4.29 (m, 1H), 5.08 (dd, 1H, J HF ) 48.5 Hz, J HH
)
1
2
29 Hz), 93.8 (t, J CF ) 4.7 Hz), 98.0 (t, J CF ) 16 Hz); 19F NMR
δ -177. Anal. Calcd for C24H44F2Si2: C, 67.54; H, 10.39. Found:
C, 67.80; H, 10.39.
3.6 Hz), 5.57 (m, 1H), 5.87 (m, 1H); 13C NMR δ 11.0, 17.8, 18.5,
3
2
2
1
3
74.1 (d, J CF ) 23 Hz), 85.4 (d, J CF ) 173 Hz), 92.7 (d, J CF ) 8
Hz), 100.0 (d, J CF ) 25 Hz), 127.0 (d, J CF ) 5 Hz), 130.8; 19F
NMR δ -183. Anal. Calcd for C16H29FSiO: C, 67.55; H, 10.27.
Found: C, 67.46; H, 10.24.
2
3
4-Ch lor o-4-flu or o-1-p h en yl-2-bu tyn -1-ol 5a . At -80 °C,
TBAF (1.28 mL 1.0 M) was added into the solution of TIPS-
chlorofluoropropyne 3a (0.276 g, 1.11 mmol) in THF mixed with
benzaldehyde (0.120 g, 1.11 mmol). The reaction was quenched
at -50 °C within 1 h. Standard workup and purification using
flash column chromatography on silica gel (hexane/EtOAc ) 9:1)
gave 5a (0.100 g, 45%): 1H NMR δ 2.30 (s, 1H), 5.58 (d, 1H,
1-(Tr iisop r op ylsilyl)-3-flu or o-1-d ecyn -4-ol 6e. Zn (0.061
g, 0.94 mmol), 3b (0.274 g, 0.94 mmol), and heptanal (0.107 g,
1
0.94 mmol) yielded 6e (0.216 g, 70%). Erythro: H NMR δ 0.89
(t, 3H), 1.09 (s, 21H), 1.29 (s, 6H), 1.56 (m, 2H), 1.67 (m, 1H),
1.90 (m, 1H), 3.82 (m, 1H), 5.06 (dd, 1H, 2J HF ) 48.3 Hz, 3J HH
)
2
5
5J HF ) 4.8 Hz), 6.65 (dd, 1H, J HF ) 50.5 Hz, J HH ) 1.4 Hz),
3.8 Hz); 13C NMR δ 11.0, 14.0, 18.5, 22.6, 25.3, 29.1, 31.6, 31.8
2 1
7.35-7.5 (m, 5H); 13C NMR δ 64.4, 79.5 (d, J CF ) 29 Hz), 86.2
(d, J CF ) 236 Hz), 90.3 (d, J CF ) 7 Hz), 126.6, 128.9, 129.0,
138.8; 19F NMR δ -123. Anal. Calcd for C10H8ClFO: C, 60.47;
H, 4.06. Found: C, 60.71; H, 4.19.
(3J CF ) 3 Hz), 73.0 (d, J CF ) 22 Hz), 86.0 (d, J CF ) 171 Hz),
3 2
2
1
3
92.6 (d, J CF ) 8 Hz), 100.3 (d, J CF ) 25 Hz); 19F NMR δ -183.
Anal. Calcd for C19H37FSiO: C, 69.45; H, 11.35. Found: C, 69.72;
H, 11.22.
Gen er a l P r oced u r e for th e P r ep a r a tion of P r op a r gylic
F lu or oh yd r in s 6a ,b,d ,e. Freshly activated zinc dust was added
to 3b in THF mixed with the aldehyde. The mixture was
sonicated for 30 min and stirred at room temperature until the
absence of starting material was observed in 19F NMR or GC-
MS. Standard workup (saturated NH4Cl, brine, ether extraction,
drying, and concentration) and purification by flash chromatog-
raphy (hexane/EtOAc ) 98:2) afforded TIPS-propargylic fluoro-
hydrin.
Gen er a l P r oced u r e for th e P r ep a r a tion of P r op a r gylic
F lu or oh yd r in s 6c,f,g. The mixture of TIPS-bromofluoropro-
pyne, fleshly activated zinc dust, and aldehyde (1:1:1) was
vigorously stirred at the refluxing temperature of THF.
1-(Tr iisop r op ylsilyl)-3-flu or o-1,5-u n d eca d iyn e-4-ol 6c.
Zn (0.058 g, 0.89 mmol), 3b (0.259 g, 0.89 mmol), and 2-octynal
(0.110 g, 0.89 mmol) yielded 6c (0.208 g, 69%). Threo: 1H NMR
δ 0.9 (m, 3H), 1.11 (s, 21H), 1.22 (m, 4H), 1.53 (m, 2H), 2.20 (td,
2H, 3J HH ) 7.2 Hz, 5J HH ) 2.0 Hz), 4.57 (ddt, 1H, 3J HF ) 9.2 Hz,
5
2
4-(Tr iisop r op ylsilyl-2-flu or o-1-p h en yl-3-b u t yn -1-ol 6a .
Zn (0.171 g, 2.62 mmol), 3b (0.764 g, 2.62 mmol), and benz-
3J HH ) 7.1 Hz, J HH ) 2.1 Hz), 5.01 (dd, 1H, J HF ) 49.3 Hz,
3J HH ) 7.1 Hz); 13C NMR δ 11.0, 13.9, 18.5, 18.7, 22.2, 28.1, 31.0,

Notes
J . Org. Chem., Vol. 65, No. 13, 2000 4221
2
3
1
65.2 (d, J CF ) 27 Hz), 75.5 (d, J CF ) 7 Hz), 84.7 (d, J CF ) 176
Hz), 88.5, 92.5 (d, 3J CF ) 8 Hz), 99.8 (d, 2J CF ) 24 Hz); 19F NMR
δ -178. Anal. Calcd for C20H35FSiO: C, 70.95; H, 10.42. Found:
C, 71.18; H, 10.47.
silica gel (hexane/EtOAc ) 9:1) afforded 7 (0.136 g, 74%).
4
Erythro: 1H NMR δ 2.55 (s, 1H), 2.73 (dd, 1H, J HF ) 5.6 Hz,
3
3
4J HH ) 2.2 Hz), 5.00 (dd, 1H, J HF ) 11.9 Hz, J HH ) 4.5 Hz),
2
3
4
5.20 (ddd, 1H, J HF ) 47.2 Hz, J HH ) 4.4 Hz, J HH ) 2.2 Hz),
2
6-(Tr iisop r op ylsilyl)-4-flu or o-2,2-d im et h yl-5-h exyn -3-
ol 6f. Zn (0.067 g, 1.03 mmol), 3b (0.3 g, 1.03 mmol), and
trimethylacetaldehyde (0.089 g, 1.03 mmol) yielded 6f (0.22 g,
72%). Erythro: 1H NMR δ 1.03 (d, 9H), 1.09 (s, 21H), 2.15 (s,
7.34-7.47 (m, 5H); 13C NMR δ 74.7 (d, J CF ) 24 Hz), 78.9 (d,
3J CF ) 9.9 Hz), 85.5 (d, 1J CF ) 175 Hz), 126.8, 128.4, 128.6, 137.3;
19F NMR δ -180. Anal. Calcd for C10H9FO: C, 73.16; H, 5.53.
Found C, 73.15; H, 5.63. Threo: 1H NMR 2.66 (dd, 1H, J HF
)
)
)
4
3
3
4
3
1H), 3.52 (dd, 1H, J HF ) 16.0 Hz, J HH ) 4.1 Hz), 5.20 (dd, 1H,
5.8 Hz, J HH ) 2.1 Hz), δ 2.92 (s, 1H), 4.89 (ddd, 1H, J HF
3 2 3
2J HF ) 47.5 Hz, 3J HH ) 4.2 Hz); 13C NMR δ 11.0, 18.5, 26.2, 26.6,
12.3 Hz, J HH ) 7.4 Hz), 5.11 (ddd, 1H, J HF ) 48.7 Hz, J HH
2
1
3
4
79.4 (d, J CF ) 22 Hz), 84.2 (d, J CF ) 169 Hz), 94.1 (d, J CF ) 9
7.3 Hz, J HH ) 2.1 Hz), 7.36-7.47 (m, 5H); 19F NMR δ -181.
Hz), 100.8 (d, J CF ) 25 Hz); 19F NMR δ -172. Anal. Calcd for
2
C
17H33FSiO: C, 67.94; H, 11.07. Found: C, 68.39; H, 10.97.
Ack n ow led gm en t. This work has been made pos-
sible by the generous financial support of the National
Science Foundation (CHE-9711062) and the Camille
and Henry Dreyfus Foundation (TH-96-012). The au-
thors thank Mr. ZhiGang Wang for helpful discussions
and experimental advice.
5-(Tr iisop r op ylsilyl)-3-flu or o-2-m eth yl-4-p en tyn -2-ol 6g.
Zn (0.269 g, 4.11 mmol) and 3b (1.201 g, 4.11 mmol), refluxing
in 5 mL of anhydrous acetone, yielded 6g (0.753 g, 67%): 1H
4
4
NMR δ 1.09 (s, 21H), 1.34 (dd, 6H, J HF ) 10.3 Hz, J HH ) 1.3
2
3
Hz), 2.05 (s, 1H), 4.87 (dd, 1H, J HF ) 48.9 Hz, J HH ) 3.3 Hz);
13C NMR δ 11.0, 18.5, 23.9 (d, J CF ) 2 Hz), 24.4 (d, J CF ) 2
3
3
Hz), 72.6 (d, 2J CF ) 21 Hz), 89.0 (d, 1J CF ) 175 Hz), 91.9 (d, 3J CF
) 8 Hz), 101.0 (d, J CF ) 24 Hz); 19F NMR δ -182. Anal. Calcd
2
Su p p or tin g In for m a tion Ava ila ble: Mass spectral data
for compounds 3a -c, 4a ,b, 5a ,b, 6a -g, and 7. NMR data for
3c, 5b, and 6b. This material is available free of charge via
the Internet at http://pubs.acs.org.
for C15H29FSiO: C, 66.12; H, 10.73. Found: C, 66.00; H, 10.78.
2-F lu or o-1-p h en yl-3-bu tyn -1-ol 7. At -80 °C, TBAF (1.13
mL 1.0M in THF) was added to the solution of 6a (0.36 g, 1.13
mmol) in THF. The reaction was quenched within 1 h. Standard
workup and purification using flash column chromatography on
J O000243+