Nucleophilic and electrophilic substitutions of difluoropropargyl bromides

Journal of Fluorine Chemistry 127 (2006) 476–488

www.elsevier.com/locate/ﬂuor

Nucleophilic and electrophilic substitutions

of diﬂuoropropargyl bromides

*

Gerald B. Hammond

Department of Chemistry, University of Louisville, Louisville, KY 40292, USA

Received 19 December 2005; accepted 20 December 2005

Available online 28 February 2006

Abstract

Fundamental organic reactions like nucleophilic and electrophilic substitutions have seldom been studied on ﬂuorinated propargyl or allenyl

modules, when the carbon atom undergoing substitution is bonded to two ﬂuorine atoms. Herein we report a practical synthesis of

diﬂuoropropargyl bromides from substituted acetylenes and dibromodiﬂuorometane using a wide variety of alkyl, aryl or silyl substrates.

The synthesis of O-, S- and carboxylic acid derivatives of diﬂuoropropargyl bromide is also described. These compounds are suitable starting

materials for the synthesis of electrophilically substituted diﬂuoropropargyl derivatives via magnesium and ﬂuoride promoted reactions. An

indium-mediated reaction of silyldiﬂuoropropargyl bromide, followed by electrophilic trapping with bromine led to a very useful bromoallene,

which was then used in reactions with nucleophiles (C, O, N, P, S, Hal) to yield a de facto bimolecular nucleophilic substitution of a

diﬂuoropropargyl bromide.

Keywords: Diﬂuoropropargyl; Fluorinated allenes; Nucleophilic substitution; Electrophilic substitution; Indium; Magnesium; TIPS

1. Introduction

organometallic S_N2⁰displacement (e.g. Grignard reaction). In

this case, the initial bromine–magnesium exchange would lead

to a magnesium carbenoid intermediate [7], which then

undergoes a facile loss of ﬂuorine through a-elimination, thus

forming complex mixtures. In this paper we will examine the

effects of ﬂuorine activation on S_N2⁰, S_E2 and S_E2⁰reactions,

that is, the substitution of a bromine in 1 by a nucleophile or an

electrophile, namely 3 or 2; and the preparation of an

electrophilically substituted allene 4 (Scheme 1).

It is well known that alkynes and allenes are of paramount

importance in organic chemistry, both as synthetic building

blocks, and targets [1–4]. Conceptually, the substitution of two

ﬂuorine atoms on an allenic or propargylic carbons could lead

to the discovery of novel reactions and provide potential targets

of biological importance [5]. Traditional synthetic approaches

to functionalized allenes or alkynes involve S_Nand S_E

substitutions. However, even though these types of reactions

are essential part of the arsenal of organic reactions, they have

seldom been studied on ﬂuorinated propargyl or allenyl

modules, when the carbon atom undergoing substitution is

bonded to ﬂuorine atoms. Indeed, R–CBBC–CF₂Nu (3) cannot

be synthesized from R–CBBC–CF₂Br (1) under normal

conditions using S_N2-type reactions. This lack of reactivity

is attributed to the shielding of the carbon atom by the

surrounding ﬂuorine atoms [6]. Another synthetic challenge is

the preparation of substituted diﬂuoroallene 5 through a

2. Results and discussion

2.1. Synthesis of substituted diﬂuoropropargyl bromide 1

The starting material used in this work, diﬂuoropropargyl

bromide 1, has been utilized by other workers in the synthesis of

diﬂuorosugars [8], substituted ﬂuorofurans, [9], ﬂuorinated

diynes [10], intermediates in the preparation of HIV proteins

inhibitors [11], diﬂuorohomopropargyl alcohols [12], and

diﬂuoroaldonic acids [13]. Wakselman and coworkers [14],

reported the ﬁrst preparation of 1, which consisted in

alkynylation of a lithium acetylide derived from 6 with CF₂Br₂

(Eq. (1)). Both, ionic [10,14] and SET [15] mechanisms have

* Tel.: +1 502 852 5998.

E-mail address: gb.hammond@louisville.edu.

doi:10.1016/j.jﬂuchem.2005.12.024

G.B. Hammond / Journal of Fluorine Chemistry 127 (2006) 476–488

477

(1)

In stark contrast to the modest yields described above, we

obtained the silyl substituted 1a (R = TIPS) in 82% yield [18].

We surmised that this high yield was associated with the

distinctive properties of the TIPS group [19]. Similar results

were obtained with other bulky silyl substituents [20].

However, with R = TMS the yield was disappointingly low

(19%) under the same conditions. By reducing the number of

equivalents of CF₂Br₂, n-butyllithium, and the concentration of

the solution, and at the same time controlling the temperature of

the reaction mixture (rather than the cooling bath), we

increased the yields signiﬁcantly (Table 1).

The TIPS substituent produced the highest yield of 1 (entry

1). The triethylsilyl (TES) group in 1d was a better alternative

to the TMS group (compare entries 2 and 4). The yield of the

phenyl analog 1c (entry 3) was higher than substituted benzenes

(compare with entries 5 and 6). An electron-withdrawing

substituent on the benzene ring increased the yield of 1 in

comparison with an electron-donating substituent (compare

entries 7 and 8). Notably, our procedure proved highly effective

for the synthesis of alkyl substituents 1i and 1j (entries 9 and

10). These reactions were conducted at submolar scale. In our

experience, large-scale reactions tend to give better yields of 1

because of diminished losses associated with the column hold

up of the distillation apparatus.

Scheme 1. Transformation of 1 using nucleophilic and electrophilic substitu-

tions.

been postulated for this reaction. The major side product in the

preparation of 1 is bromoalkyne 7 (Eq. (1)). A new method for

preparing aryl derivatives of 1 (R = Ar) in two steps from

CBrF₂–CBrF₂was reported recently [16]. However, the yields

were not signiﬁcantly better. For example, for Ar = p-Cl–

C₆H₄, p-MeO–C₆H₄, p-Br–C₆H₄, o-Cl–C₆H₄, and o,p-diCl–

C₆H₃, the yields ranged between 15 and 35%. In view of the

low yields and scarce diversity of substituents on the acetylenic

carbon of 1 reported thus far, we set out to develop a more

efﬁcient protocol, the results of which have been recently

published [17].

We also investigated the feasibility of synthesizing

heteroatom substituted diﬂuoropropargyl bromides 1k, 1l,

1m and the carboxylic acid derivative 1n. The preparation of S-

and O-substituted diﬂuoropropargyl precursors 1k (Eq. (2)) and

1l (Eq. (3)) involved multi-step syntheses of the corresponding

precursors 6a and 6b:

(2)

(3)

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G.B. Hammond / Journal of Fluorine Chemistry 127 (2006) 476–488

To our disappointment, the synthesis of the acetylenic amine

analog 1m could not be accomplished despite repeated attempts

using various basic conditions (Eq. (4)):

Table 2). As shown in Table 2, the procedure for the selective

formation of 2 works well for a diverse group of aromatic and

aliphatic alkynes.

(4)

The carboxylic acid derivative 1n could be obtained in one

step from the commercially available propiolic acid 6d, albeit

in moderate yield (Eq. (5)):

Neither over-reduction nor C–F bond cleavage were

observed. In the case of aromatic alkynes, the reactions were

completed within 30 min at 0 8C in THF (entries 1–4). Also, an

aliphatic alkyne reacts smoothly to give the corresponding

silylated diﬂuoroalkyne at 0 8C in THF (entry 5), as compared

with aliphatic ketones and imines which required DMF as a

solvent and high temperature. Moreover, silylated alkynes 1a,

1d generally give good yields (entries 6, 7). Using the same

protocol, 1c reacted with trimethylstannyl chloride to give the

stannane 2h in 75% (entry 8). Silylated or stannylated gem-

diﬂuoropropargyl 2 could act as key intermediates in the

synthesis of gem-diﬂuoromethylene containing modules

(5)

2.2. S_E2 substitution of gem-diﬂuoropropargyl bromide 1

via Mg(0)-promoted debromometalation (Eq. (6))

(6)

The gem-diﬂuoromethylene group (–CF₂–), where the

carbon atom is sp³hybridized, has received much attention

for its protease inhibition, phosphate mimicry, or metabolic

oxidation blocking properties, and as enzyme inactivator

when substituted on the b-position of aminoacids [21–23].

Similarly, the gem-diﬂuoroethylidene group (CF₂C ), with

a sp²hybridized carbon-bearing ﬂuorine, is a well known

synthetic building block, whose carbonyl mimicking prop-

erty has aroused interest recently, because of the apparent

reversal effect in the regioselectivity of NAD(P)H-depen-

dent hydride transfer in sugars [24]. Methods for the

introduction of ﬂuorine in –CF₂– include electrophilic and

nucleophilic ﬂuorinating agents [22] or building blocks

[25].

because of the rich chemistry of acetylenes. To demonstrate

their synthetic utility, we reacted 2d with benzaldehyde to give

8a in excellent yield (Scheme 2). Allylation and benzylation

produced 8b and 8c, respectively, in satisfactory yields.

During our investigations on the preparation of silylated or

stannylated gem-diﬂuoropropargyl synthons, RCBBC–

CF₂Si(Sn), we noticed that the analysis of 2 using mass

spectrometry did not yield the expected M + 1 peak under

conditions of methane chemical ionization (methane-CI).

When methane-CI ionization was employed, all gem-diﬂuor-

opropargyl synthons produced ions at [M ꢀ 19]⁺. These

presented as base peaks in the CI spectra of all compounds

in which the opposing alkyne substituent was aromatic. Taken

together, the CI spectra of gem-diﬂuoropropargyl compounds

indicate cleavage of the C–F bond is a likely event under

conditions of methane chemical ionization. However such C–F

bond cleavage is not common in spectra of ﬂuorinated carbon

structures due to the strength of the C–F bond. Consequently,

We recently reported [26] a practical S_E2 synthesis of gem-

diﬂuoropropargylsilanes 2a–g and gem-diﬂuoropropargyl

stannane 2h using a Mg(0)-promoted reductive debromome-

talation of 3-bromo-3,3-diﬂuoropropyne 1 (Eq. (6) and

G.B. Hammond / Journal of Fluorine Chemistry 127 (2006) 476–488

479

Table 1

An efﬁcient synthesis of diﬂuoropropargyl bromide 1

Table 2

Mg(0)-promoted debromometalation of diﬂuorobromoalkyne 1^a

Entry

R

Method

% yield of 2^a

Entry

R

M-CI

Conditions

% yield of 2^b

1

2

TIPS (1a)

TMS (1b)

phenyl (1c)

TES (1d)

p-MeC₆H₄(1e)

o-MeC₆H₄(1f)

p-MeOC₆H₄(1g)

p-CF₃C₆H₄(1h)

hexyl (1i)

B

A

B

A

92

52

82

74

61

42

53

78

81^b

71

1

2

3

4

5

6

7

8

p-MeP₆H₄

o-MeC₆H₄

p-MeOC₆H₄

Ph

TMSCl

Me₃SnCl

0 8C, 30 min

0 8C 1 h

81 (2a)

77 (2b)

90 (2c)

51 (2d)

63 (2e)

82 (2f)

93 (2g)

75 (2h)

3

4

5

Hex

6

TIPS

7

TES

8

Ph

9

a

The reaction was carried out by the procedure shown in experimental

10

(3-Me)butyl (1j)

section.

b

a

Yield after distillation.

Isolated yield.

b

The only other reported yield of an alkyl substituted derivative (pentyl) is

46%.

Whereas potent methodologies exist for S_E2-type

electrophilic substitution using a diﬂuoromethylene dianion

equivalent [28], the shielding of carbon by the surrounding

ﬂuorine atoms impedes substitution by a nucleophile, except

under exceptional circumstances [10,15]. In principle, RCF₂Nu

could be synthesized by a nucleophilic reaction on gem-

diﬂuorooleﬁns (Scheme 3a), taking advantage of the prefer-

ential attack of nucleophiles at the terminal sp²diﬂuoromethy-

lene carbon. However, this approach usually yields addition–

these [M ꢀ 19]⁺ions offer reliable information with respect to

the molecular weights of these gem-diﬂuoropropargyl struc-

tures. The phenomenon of C–F bond cleavage under methane-

CI conditions has recently been disclosed by us [27].

2.3. De facto S_N2 substitution of diﬂuoropropargyl bromide

1 using a sequence of S_E2⁰and S_N2⁰reactions (Eq. (7))

(7)

elimination products arising from the facile b-elimination of

ﬂuoride ion. The elimination of ﬂuoride has been avoided only

in exceptional cases (Scheme 3b) [29,30].

On the basis of ab initio calculations we postulated that a

vinylogous gem-diﬂuorooleﬁn, such as ﬂuoroallene 4 (Fig. 1),

would be ideally suited to the task of acting as a

diﬂuoromethylene cation-equivalent because of the opposite

NBO (natural bond orbital) charges in 4 (+0.765 versus

ꢀ0.449).

This charge distribution would favor a S_N2⁰nucleophile

attack on the CF₂center, with concomitant bromide elimina-

tion, the driving force being the favorable allene to propargyl

isomerization. Conversely, its non-ﬂuorinated counterpart has

the electronic charge concentrated on both carbon termini, a

deterrent towards nucleophilic attack. To synthesize 4 we relied

on a procedure reported by our group a few years ago [32],

Scheme 2. Synthetic utility of 2d as a nucleophilic 3-C synthon.

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G.B. Hammond / Journal of Fluorine Chemistry 127 (2006) 476–488

Scheme 3. (a) Nucleophilic substitution on a sp²ﬂuorinated carbon. (b) Synthesis of ﬂuorinated pyrethroids and propargyl alcohols through nucleophilic addition to a

sp²CF₂group.

whereby a preformed indium propargyl complex reacted with a

reactive electrophile such as aqueous formaldehyde, to furnish a

ﬂuoroallenyl alcohol. A similar reaction with a reactive

electrophile such as Br₂should produce the desired g-

bromodiﬂuoroallene 4. Indeed, the indium-mediated S_E2⁰

bromide substitution converted 1a to 4 in 81% yield (Eq. (7)).

To our satisfaction, 4 reacted easily with a wide range of weak

and strong nucleophiles (P, O, S, C, N, Br), in a S_N2⁰manner,

producing 3 in good to excellent yields (Table 3) [33].

Although the reaction of amines with 4 produced complex

mixtures, this problem was circumvented by using sodium azide

as a nitrogen nucleophile. This reaction produced a stable

Fig. 1. Ab initio calculation of gem-diﬂuorinated allene 4 and its non-ﬂuori-

nated counterpart. Numbers refer to NBO (natural bond order) charge densities.

propargyl diﬂuoroazide 3h in close to 70% yield. Notably, our

new methodology also allowed the synthesis of hydroﬂuoroether

Computational analysis was carried out using Gaussian 03, Revision C.02 at the

HF/6-311++g level of theory [31].

3c using triﬂuoroethanol as the nucleophile under very mild

Table 3

S_N2 synthesis of diﬂuoropropargyl 3 from diﬂuoroallene 4

Nucleophile/conditions

Entry (yield)³

Nucleophile/conditions

Entry (yield)³

3a (61%)

3f (92%)

3b (70%)

3g (78%)

3c (68%)

3d (70%)

3h (68%)

3i (70%)

3e (53%)

3j (55%)

G.B. Hammond / Journal of Fluorine Chemistry 127 (2006) 476–488

481

Scheme 4. Deprotection and functionalization of 3i using TBAF.

conditions, in 68% yield. Prior to our disclosure, the synthesis of

hydroﬂuoroethers could only be achieved under strongly basic

conditions – that led to vinyl ether by-products – or through the

veryrecentlyreported [34]Pd(0)-catalyzed hydroalkoxylationof

hexaﬂuoropropene. In addition to the alkyne functionality

present in 3, the TIPS group is also a useful synthetic handle. It

can be cleaved in excellent yield, without loss of ﬂuorine, to yield

9a, using TBAF. Alternatively, it can be further functionalized

using an electrophilic trap, such as p-chlorobenzaldehyde, to

produce 9b, as demonstrated in Scheme 4.

measured amount of the product with the signal integration

corresponding to a 0.3 equivalent of a,a,a-triﬂuoromethyl-

benzene, used as internal reference. Products were puriﬁed

using a Biotage ﬂash+ system or Chromatotron apparatus.

Column chromatography was performed using #R12030B,

SiliaFlash¹P60, 40–63 mm obtained from SiliCycle Inc. TLC

was developed on Merck silica gel 60 F254 Aluminum sheets.

Prep. TLC was conducted on DC-fertigplatten SIL RP-18W/

UV₂₅₄by Alltech associates Inc. Elemental analysis was

performed at Atlantic Microlabs Inc., Norcross, Georgia

30091. Accurate mass determinations were performed either

at the Nebraska Center for Mass Spectrometry, University of

Nebraska-Lincoln, Nebraska 68588 or Mass Spectrometry &

Proteomics Facility, Ohio State University, Columbus, OH

43210.

3. Conclusion

We have found a practical preparation of diﬂuoropropargyl

bromide and have used this compound in wide-ranging

nucleophilic and electrophilic substitutions (S_E2, S_E2⁰and

S_N2⁰) that led to the synthesis of novel CF₂-substituted-alkynes

and -allenes. In addition, we have discovered a sequence of S_E2⁰

and S_N2⁰substitutions that accomplished a de facto S_N2

displacement of bromide. Overall, these results have increased

our understanding on the effects of two ﬂuorine atoms on a

carbon undergoing nucleophilic or electrophilic substitutions—

two benchmark organic reactions. Synthetic applications are

ongoing in our laboratory.

4.2. Method A (for the synthesis of TMS and alkyl

diﬂuoropropargyl bromides 1b, 1i and 1j)

To a solution of trimethylsilylacetylene (4.91 g, 50 mmol) in

dry THF (250 mL), a 2.5 M hexane solution of n-butyllithium

(20 mL, 50 mmol) was added dropwise at approximately

ꢀ90 8C (liquid N₂/EtOH bath) under an argon atmosphere.

After the reaction mixture was stirred for 30 min at that

temperature, the reaction mixture was cooled to ꢀ110 8C

(because the solvent along the wall of reaction ﬂask froze at

ꢀ110 8C, it is important to maintain good stirring throughout).

Cold dibromodiﬂuoromethane (ꢀ78 8C) (5.5 mL, 60 mmol)

was added to the mixture by cannulation. The temperature of

the reaction mixture has to be controlled very carefully during

the addition of CF₂Br₂using a thermometer immersed in the

reaction mixture (very important!). The reaction temperature

may raise to ꢀ90 8C or even higher even if CF₂Br₂is

introduced slowly. After the addition is completed, the mixture

is allowed to warm up to ꢀ50 8C with stirring during the

course of 1 h and quenched with sat. aq. NH₄Cl (50 mL). The

aqueous layer was extracted with ether (100 mL) and the

organic layer was washed by water (3ꢁ 100 mL). The organic

layer was dried over Na₂SO₄. After evaporation of the solvent,

the crude product was puriﬁed by distillation (110–125 8C/

760 mmHg) to afford 1b (7.0 g, 52%, >92% purity) as a

colorless oil.

4. Experimental

4.1. General

¹H, ¹³C and ¹⁹F NMR spectra were recorded on Varian

Inova 500 instrument at 500, 126 and 470 MHz, respectively,

using CDCl₃as a solvent. The chemical shifts are reported in d

(ppm) values relative to CHCl₃(d 7.26 ppm for ¹H NMR and d

77.0 ppm for ¹³C NMR) and CFCl₃(d 0 ppm for ¹⁹F NMR).

Coupling constants are reported in hertz (Hz). GC/MS

analyses were performed on a Varian Saturn 2000 system.

Infrared spectra were recorded using either a Mattson Inﬁnity

Series FTIR or Mattson Galaxy Series FTIR 5000 spectro-

meter. All air and/or moisture sensitive reactions were carried

out under argon atmosphere. Solvents (tetrahydrofuran, ether,

dichloromethane and DMF) were dried using a PureSolv PS-

400-4 puriﬁcation system (Innovative Technology, Inc.). All

other commercial reagents were obtained from Sigma–

Aldrich Chemical Co. Progress of the reactions was monitored

by ¹⁹F NMR and the mixture yield was obtained using a,a,a-

triﬂuoromethylbenzene as internal reference. The percentage

purity of the isolated product was determined by comparing

the integration of the ¹⁹F NMR signal corresponding to a

IR (neat) 2193 cm^ꢀ1; ¹H NMR (500 MHz, CDCl₃), d: 0.26

(s, 9H); ¹³C NMR (126 MHz, CDCl₃), d: ꢀ1.13, 95.0 (t,

J = 36.0 Hz), 97.0 (t, J = 4.3 Hz), 100.9 (t, J = 290 Hz); ¹⁹F

NMR (470 MHz, CDCl₃), d: ꢀ33.8 (s, 2F). Satisfactory

elemental analysis could not be obtained due to slight

contamination with 7 which co-eluted and co-distilled with 1b.

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G.B. Hammond / Journal of Fluorine Chemistry 127 (2006) 476–488

4.2.1. 1-Bromo-1,1-diﬂuoronon-2-yne (1i)

132.1, 141.4; ¹⁹F NMR (470 MHz, CDCl₃), d: ꢀ32.1 (s, 2F);

HRMS (EI) m/z calcd. for C₁₀H₇F₂Br, 243.9699. Found:

243.9690.

Colorless oil; 81% yield; bp. 67–70 8C/8 mmHg; this

compound was contaminated by 7% compound 3. IR (neat)

2242 cm^ꢀ1; ¹H NMR (500 MHz, CDCl₃), d: 0.92 (t, J = 7.0 Hz,

3H), 1.27–1.37 (m, 4H), 1.42–1.45(m, 2H), 1.54–1.63(m, 2H),

2.34–2.38(m, 2H); ¹³C NMR (126 MHz, CDCl₃), d: 14.13,

18.69, 22.64, 27.43, 28.61, 31.34, 74.17 (t, J = 38.1 Hz), 93.36

(t, J = 5.8 Hz), 101.69 (t, J = 287 Hz); ¹⁹F NMR (470 MHz,

CDCl₃), d: ꢀ30.4 (s, 2F); GC/MS (EI) m/z: 177, 159, 139, 117,

97, 79.

4.3.3. 3-Bromo-3,3-diﬂuoro-1-(2-methyl)phenylpropyne

(1f)

Colorless oil; 42% yield; bp. 75 8C/4.4 mmHg; IR (neat)

2224, 2247 cm^ꢀ1; ¹H NMR (500 MHz, CDCl₃), d: 2.47 (s, 3H),

7.19–7.50 (m, 4H); ¹³C NMR (126 MHz, CDCl₃), d: 20.3, 84.6

(t, J = 38.6 Hz), 89.4 (t, J = 5.8 Hz), 102.1 (t, J = 290 Hz),

118.6, 125.8, 129.9, 130.8, 132.5, 141.7; ¹⁹F NMR (470 MHz,

CDCl₃), d: ꢀ32.2 (s, 2F); HRMS (EI) m/z calcd. for C₁₀H₇F₂Br,

243.9699. Found: 243.9696.

4.2.2. 1-Bromo-1,1-diﬂuoro-6-methylhept-2-yne (1j)

Colorless oil; 71% yield; bp. 65–70 8C/10 mmHg; this

compound was contaminated by 5% compound 3. IR (neat)

2252 cm^ꢀ1

;

¹H NMR (500 MHz, CDCl₃), d: 0.93 (d,

4.3.4. 3-Bromo-3,3-diﬂuoro-1-(4-methoxy)phenylpropyne

(1g)

J = 7.0 Hz, 6H), 1.49 (q, J = 7.0 Hz, 2H), 1.67–1.71(m, 1H),

2.34–2.39(m, 2H); ¹³C NMR (126 MHz, CDCl₃), d: 16.72,

22.16, 27.50, 36.26, 74.05 (t, J = 37.3 Hz), 93.42 (t,

J = 5.7 Hz), 101.68 (t, J = 287 Hz); ¹⁹F NMR (470 MHz,

CDCl₃), d: ꢀ30.4 (s, 2F); GC/MS (EI) m/z: 189, 163, 125, 79,

57. Satisfactory elemental analysis could not be obtained for 1i,

and 1j due to slight contamination with 7 which co-eluted and

co-distilled with the product.

Yellow oil; 53% yield; bp. 105 8C/2.2 mmHg; IR (neat)

2218, 2252 cm^ꢀ1; ¹H NMR (500 MHz, CDCl₃), d: 3.84 (s, 3H),

6.90 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H); ¹³C NMR

(126 MHz, CDCl₃), d: 55.4, 80.2 (t, J = 37.4 Hz), 90.6 (t,

J = 5.8 Hz), 102.2 (t, J = 289 Hz), 110.6, 114.3, 134.0, 161.5;

¹⁹F NMR (470 MHz), d: ꢀ33.5 (s, 2F); Anal. Calcd. for

C₁₀H₇BrF₂O: C, 64.01; H, 2.70. Found: C, 64.02; H, 2.66.

4.3. Method B (for the synthesis of 3,3-diﬂuoropropargyl

bromides 1a, 1c–h)

4.3.5. 3-Bromo-3,3-diﬂuoro-1-(4-triﬂuoromethyl)

phenylpropyne (1h)

Colorless oil; 78% yield; bp. 68 8C/3.8 mmHg; IR (neat)

2225, 2263 cm^ꢀ1; ¹H NMR (500 MHz, CDCl₃), d: 7.67 (s, 4H);

¹³C NMR (126 MHz, CDCl₃), d: 82.5 (t, J = 38.6 Hz), 87.7 (t,

J = 5.7 Hz), 101.7 (t, J = 291 Hz), 122.6, 123.4 (q, J = 273 Hz),

125.6 (q, J = 3.8 Hz), 132.6, 132.5 (q, J = 16.5 Hz); ¹⁹F NMR

(470 MHz, CDCl₃), d: ꢀ64.4 (s, 3F), ꢀ33.8 (s, 2F); HRMS (EI)

m/z calcd. for C₁₀H₄BrF₅, 247.9417. Found: 247.9414.

To a solution of 4-ethynyltoluene (1.6 g, 14.6 mmol) in dry

THF (30 mL), a 2.5 M hexane solution of n-butyllithium

(6.1 mL, 15.3 mmol) was added dropwise at ꢀ78 8C under an

argon atmosphere. After the reaction mixture was stirred for

30 min at ꢀ78 8C, cold (ꢀ78 8C) dibromodiﬂuoromethane

(4.6 g, 21.9 mmol) was added to the reaction mixture at

ꢀ100 8C. After stirring for 16 h at rt., the THF solution was

washed with sat. aq. NH₄Cl (10 mL). The aqueous layer was

extracted with hexane (2ꢁ 20 mL) and the combined organic

layer was dried over Na₂SO₄. After evaporation of the solvent,

the crude product was puriﬁed by distillation under reduced

pressure (75 8C/4.4 mmHg) to afford 1e (2.2 g, 61%) as a

colorless oil. Note: the spectral data of 1a [18] and 1c [10] have

been previously published.

4.3.6. 3-Bromo-3,3-diﬂuoroprop-1-ynyl

diisopropylcarbamate (1k)

2,2,2-Tribromoethanol (5.66 g, 20 mmol) and carbamoyl

chloride 2 (4 g, 24 mmol) in pyridine (20 mL) were heated to

70 8C for 16 h under argon. After cooling, HCl and ether were

added, the mixture was extracted with ether (3ꢁ 50 mL) and the

combined organic phase was washed with saturated aqueous

NaHCO₃, dried (MgSO₄). After concentrated in vacuo, the

crude product was puriﬁed by ﬂash column chromatography

(20/1 hexane/ethyl acetate) to afford product 2,2,2-tribro-

moethyl diisopropylcarbamate (6.08 g, 74%) as a white solid.

An aliquot (2.05 g, 5 mmol) was dissolved in THF (50 mL),

and LDA (14 mL, 1.8 M in THF, 25 mmol) was added to the

solution at ꢀ85 8C. The mixture was stirred for another 4 h.

MeOH (2 mL) was added and stirred for another 2 h, and then

warmed to rt. Afterwards, H₂O (30 mL) were added and the

mixture was extracted with ether. The combined organic layers

were dried (MgSO₄) and concentrated in vacuo. The crude

product was puriﬁed by ﬂash column chromatography (30/1

hexane/ethyl acetate) to afford ethynyl diisopropylcarbamate

6a (414 mg, 49%) as a yellow solid. To a solution of 6a (85 mg,

0.5 mmol) in THF (3 mL), LiHMDS (1 M in THF, 0.6 mL) was

added slowly at ꢀ90 8C and stirred for 15 min. CF₂Br₂was

4.3.1. 3-Bromo-3,3-diﬂuoro-1-triethylsilylpropyne (1d)

Colorless oil; 74% yield; bp. 60 8C/4.8 mmHg; IR (neat)

2191 cm^ꢀ1

;

¹H NMR (500 MHz, CDCl₃), d: 0.69 (q,

J = 8.0 Hz, 6H), 1.02 (t, J = 8.0 Hz, 9H); ¹³C NMR

(126 MHz, CDCl₃), d: 3.6, 7.2 95.6 (t, J = 4.8 Hz), 96.2 (t,

J = 36.5 Hz), 100.7 (t, J = 290 Hz); ¹⁹F NMR (470 MHz,

CDCl₃), d: ꢀ33.5 (s, 2F); Anal. Calcd. for C₉H₁₅BrF₂Si: C,

40.15; H, 5.62. Found: C, 40.46; H, 6.04.

4.3.2. 3-Bromo-3,3-diﬂuoro-1-(4-methyl)phenylpropyne

(1e)

IR (neat) 2223, 2247 cm^ꢀ1; ¹H NMR (500 MHz, CDCl₃), d:

2.40 (s, 3H), 7.20 (d, J = 7.5 Hz, 2H), 7.44 (d, J = 7.5 Hz, 2H);

¹³C NMR (126 MHz, CDCl₃), d: 21.7, 80.5 (t, J = 38.4 Hz),

90.4 (t, J = 5.8 Hz), 102.1 (t, J = 290 Hz), 115.7, 129.4, 129.6,

G.B. Hammond / Journal of Fluorine Chemistry 127 (2006) 476–488

483

added to the mixture and stirred for 1 h then warmed to rt.

Saturated aqueous NH₄Cl was added and the mixture was

extracted with ether. The combined organic layers were dried

(MgSO₄) and concentrated in vacuo. Flash column chromato-

graphy afforded 1k (78 mg, 55%). ¹H NMR (500 MHz,

CDCl₃): 3.69 (s, 1H), 1.10–1.03 (m, 14H); ¹⁹F NMR

(470 MHz, CDCl₃): ꢀ53.97; GC/MS: 298/300.

the mixture was warmed to rt. for 2 h and heated to 70 8C for

4 h. After cooling down to rt., the mixture was poured onto 1 M

HCl. The aqueous phase was extracted with ethyl acetate and

washed with 1 M HCl (2ꢁ 80 mL), water (3ꢁ 80 mL) and dried

(MgSO₄). Removal of the solvent afforded N-benzyl-N-

tosylamine (25.4 g, 97%). To a solution of ethynyltriisopro-

pylsilane (3.64 g, 20 mmol) in THF (30 mL) butyl lithium

(2.5 M in hexane, 10 mL, 25 mmol) was syringed in at ꢀ80 8C.

After stirring for 0.5 h, iodine (5.59 g, 22 mmol) was added to

quench the reaction. Ether (100 mL) was added to dilute the

mixture and the organic phase was washed with water (3ꢁ

50 mL). After drying (MgSO₄) and solvent removal, the crude

product was puriﬁed by ﬂash column chromatography

(hexane) to afford 1-iodo-2-trisopropylsilyethyne (5.87 g,

95%) as a yellow liquid. A mixture of N-benzyl-N-tosylamine

(1.148 g, 4.4 mmol), potassium carbonate (1.104 g, 8 mmol),

CuSO₄ꢂ5H₂O (100 mg, 0.4 mmol), phenanthrene (148 mg,

0.8 mmol), 1-iodo-2-trisopropylsilyethyne (1.232 g, 4 mmol)

in toluene (10 mL), was heated to 70 8C for 24 h. After cooling

down the mixture was diluted with ether (20 mL) and ﬁltered.

Flash column chromatography afforded N-benzyl-2-(triisopro-

pylsilyl)-N-tosylethynamine (720 mg, 68%). An aliquot of N-

benzyl-2-(triisopropylsilyl)-N-tosylethynamine (220 mg, 0.5

mmol) was dissolved in THF (2 mL), and cooled to ꢀ80 8C.

TBAF was added slowly. After stirring for 5 min, saturated

aqueous NH₄Cl was added to the mixture. The aqueous phase

was extracted with ether (2ꢁ 30 mL) and dried (MgSO₄). The

crude product was puriﬁed by ﬂash column chromatography to

afford product 6c (112 mg, 79%) as a white solid. Treatment of

6c with strong bases such as n-BuLi, LDA, LiHMDS, or

NaHMDS followed by reaction with CF₂Br₂failed to produce

1m.

4.3.7. 3-Bromo-3,3-diﬂuoroprop-1-ynyl-p-tolylsulﬁde (1l)

A mixture of 4-methylbenzenethiol (6.2 g, 50 mmol), 2-

bromo-1,1-diethoxyethane (10.8 g, 55 mmol), and sodium

ethoxide (3.74 g, 55 mmol) in ethanol (50 mL) was reﬂuxed

for 5 h. Saturated aqueous NH₄Cl was added to the mixture then

extracted with ethyl acetate (3ꢁ 80 mL). The organic phase was

dried (MgSO₄). After removal of the solvent, distillation

(110 8C) afforded 2-p-tolylsulﬁnyl-1,1-diethoxyethane (11.5 g,

96%). To a solution of diisopropylamine (8.4 mL, 60 mmol) in

ether (100 mL), butyl lithium (2.5 M in hexane, 24 mL,

60 mmol) was added at ꢀ80 8C. After stirring for 30 min at

0 8C, the reaction mixture was cooled down to ꢀ80 8C and 2-p-

tolylsulﬁnyl-1,1-diethoxyethane was syringed into the mixture.

A milky solution was observed as the reaction was warmed to

0 8C. After stirring for 15 min the reaction was quenched with

saturated aqueous NH₄Cl and neutralized with 1 M HCl. The

aqueous phase was extracted (ether, 2ꢁ 100 mL) and the

combined organic phase was dried (MgSO₄), concentrated in

vacuo to afford 6b (2.55 g, 86%). To a solution of 6b (2.37 g,

16 mmol) in THF (100 mL) butyl lithium (2.5 M in hexane,

7.2 mL, 18 mmol) was added dropwise at ꢀ100 8C and stirred

for 0.5 h. CF₂Br₂(6.72 g, 32 mmol) was added and warmed to

ꢀ70 8C for 0.5 h. Saturated aqueous NH₄Cl was added and the

mixture was extracted (ether, 3ꢁ 80 mL). The combined organic

phase was washed with water (3ꢁ 100 mL) and dried (MgSO₄).

After concentrated in vacuo, the crude product was puriﬁed by

column chromatography to afford 1l (1.77 g, 40%) as yellow

liquid. The product was unstable even if kept in a refrigerator. ¹H

NMR (500 MHz, CDCl₃): 7.36–7.34 (m, 2H), 7.23–7.21 (m,

2H), 2.38 (s, 3H); ¹⁹F NMR (470 MHz, CDCl₃): ꢀ31.71 (s, 2F).

4.3.10. A typical procedure for the synthesis of 3,3-

diﬂuoropropargylsilanes (2)

To the mixture of Mg (194 mg, 8.0 mmol) and chloro-

trimethylsilane (0.51 mL, 4.0 mmol) in dry THF (10 mL), 3-

bromo-3,3-diﬂuoro-1-(4-methylphenyl)propyne (1e) (245 mg,

1.0 mmol) was added dropwise at 0 8C under an argon

atmosphere. The reaction mixture was stirred for 30 min at

0 8C. The residual Mg was removed by decantation, the THF

solution was washed with H₂O (5 mL). The aqueous layer was

extracted with hexane (2ꢁ 5 mL) and the combined organic

layer was dried over Na₂SO₄. After evaporation of the solvent,

the crude product was puriﬁed by silica gel treated with Et₃N/

hexane = 1/9 column chromatography (hexane) to afford 2a

(193 mg, 81%) as a colorless oil.

4.3.8. 4-Bromo-4,4-diﬂuorobut-2-ynoic acid (1n)

To a solution of propiolic acid 6d (1.35 g, 19.3 mmol) in

THF (100 mL) was added butyl lithium (2.5 M in hexane,

16 mL, 40 mmol) slowly at ꢀ100 8C and stirred for 0.5 h.

CF₂Br₂(5 mL, dissolved in 10 mL THF) was cannulated to the

mixture. After warming to rt. for 1 h, the reaction mixture was

quenched with saturated aqueous NH₄Cl and acidiﬁed with

HCl. The aqueous phase was extracted with ether (3ꢁ 80 mL)

and the combined organic phase was washed with 1 M HCl (do

not use water to wash!) and dried (MgSO₄). After removal of

the solvent, distillation gave 1n (1.725 g, 45%). ¹⁹F NMR

(470 MHz, CDCl₃): ꢀ37.35; GC/MS: 198/200.

4.3.11. 3,3-Diﬂuoro-1-(4-methyl)phenyl-3-

trimethylsilylpropyne (2a)

IR (neat) 2225 cm^ꢀ1; ¹H NMR (500 MHz, CDCl₃), d: 0.29

(s, 9H), 2.37 (s, 3H), 7.16 (d, J = 7.0 Hz, 2H), 7.38 (d,

J = 7.0 Hz, 2H); ¹³C NMR (126 MHz, CDCl₃), d: ꢀ4.9, 21.6,

81.6 (t, J = 30.6 Hz), 91.4 (t, J = 9.6 Hz), 111.7, 120.6 (t,

J = 254 Hz), 129.2, 131.9, 140.0; ¹⁹F NMR (470 MHz, CDCl₃,

C₆F₆as an internal standard), d: 56.8 (s, 2F); Anal. Calcd. for

C₁₃H₁₆F₂Si: C, 65.51; H, 6.77. Found: C, 65.24; H, 6.94.

Note: treatment of ethyl ester of 6d with LDA followed by

CF₂Br₂; or 6d with LDA followed by CF₂Br₂failed.

4.3.9. Attempted synthesis of 1m

Tosyl chloride (20 g, 0.105 mol) was added to a solution of

benzylamine (11 mL, 0.1 mol) in pyridine (35 mL) at 0 8C, and

484

G.B. Hammond / Journal of Fluorine Chemistry 127 (2006) 476–488

4.3.12. 3,3-Diﬂuoro-1-(2-methyl)phenyl-3-

3.98, 7.29, 95.3 (t, J = 7.7 Hz) 98.9 (t, J = 29.7 Hz), 119.8 (t,

J = 255 Hz); ¹⁹F NMR (470 MHz, CDCl₃, C₆F₆as an internal

standard), d: 56.7 (s, 2F); Anal. Calcd. for C₁₂H₂₄F₂Si₂: C,

54.91; H, 9.22. Found: C, 55.18; H, 9.31.

trimethylsilylpropyne (2b)

Colorless oil; 77% yield; IR (neat) 2222 cm^ꢀ1; H NMR

(500 MHz, CDCl₃), d: 0.29 (s, 9H), 2.38 (s, 3H), 7.16 (d,

J = 7.5 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H); ¹³C NMR (126 MHz,

CDCl₃), d: ꢀ5.0, 21.5, 81.6 (t, J = 31.8 Hz), 91.4 (t,

J = 9.7 Hz), 111.7, 120.6 (t, J = 255 Hz), 129.2, 131.9,

140.0; ¹⁹F NMR (470 MHz, CDCl₃, C₆F₆as an internal

standard), d: 57.5 (s, 2F); Anal. Calcd. for C₁₃H₁₆F₂Si: C,

65.51; H, 6.77. Found: C, 65.52; H, 6.69.

1

4.3.18. 3,3-Diﬂuoro-1-phenyl-3-trimethylstannylpropyne

(2h)

To the mixture of Mg (194 mg, 8.0 mmol) and chloro-

trimethyltin (4.0 mL of 1.0 M solution) in dry THF (10 mL),

1c (231 mg, 1.0 mmol) was added dropwise at 0 8C under an

argon atmosphere. The reaction mixture was stirred for 1 h at

0 8C. The residual Mg was removed by decantation. After

evaporation of the solvent and removal of excess amount of

chrolotrimethyltin in vacuo (<0.1 mmHg, rt.), the hexane

solution was washed with H₂O (5 mL), aqueous layer was

extracted with hexane (2ꢁ 5 mL) and combined organic

layer was dried over Na₂SO₄. The crude product was

chromatographed on silica gel (hexane) treated with Et₃N/

hexane = 1/9 to afford 2h (236 mg, 75%) as a colorless

oil.

IR (neat) 2223 cm^ꢀ1; ¹H NMR (500 MHz, CDCl₃), d: 0.41

(s, 9H), 7.33–7.49 (m, 5H); ¹³C NMR (126 MHz, CDCl₃), d:

ꢀ9.5, 83.9 (t, J = 27.8 Hz), 92.5 (t, J = 10.6 Hz), 121.0, 124.0

(t, J = 279 Hz), 128.4, 129.5, 131.8; ¹⁹F NMR (470 MHz,

CDCl₃, C₆F₆as an internal standard), d: 68.0 (s, 2F); Anal.

Calcd. for C₁₂H₁₄F₂Sn: C, 45.76; H, 4.48. Found: C, 46.24; H,

4.42.

4.3.13. 3,3-Diﬂuoro-1-(4-methoxy)phenyl-3-trimethylsilyl-

1-propyne (2c)

Yellow oil; 90% yield; IR (neat) 2221 cm^ꢀ^{1 1}H NMR

;

(500 MHz, CDCl₃), d: 0.28 (s, 9H), 3.83 (s, 3H), 6.87 (d,

J = 8.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H); ¹³C NMR (126 MHz,

CDCl₃), d: ꢀ4.9, 55.3, 81.0 (t, J = 31.8 Hz), 91.3 (t,

J = 9.6 Hz), 122.8, 114.1, 120.7 (t, J = 254 Hz), 133.6,

160.6; ¹⁹F NMR (470 MHz, CDCl₃, C₆F₆as an internal

standard), d: 57.8 (s, 2F); Anal. Calcd. for C₁₃H₁₆F₂OSi: C,

61.39; H, 6.34. Found: C, 61.31; H, 6.25.

4.3.14. 3,3-Diﬂuoro-1-phenyl-3-trimethylsilylpropyne (2d)

1

Colorless oil; 51% yield; IR (neat) 2225 cm^ꢀ1; H NMR

(500 MHz, CDCl₃), d: 0.29 (s, 9H), 7.34–7.50 (m, 5H); ¹³C

NMR (126 MHz, CDCl₃), d: ꢀ5.0, 82.2 (t, J = 31.8 Hz), 91.0 (t,

J = 9.6 Hz), 120.5 (t, J = 255 Hz), 120.8 (t, J = 3.5 Hz), 128.4,

129.6 132.0; ¹⁹F NMR (470 MHz, CDCl₃, C₆F₆as an internal

standard), d: 57.1 (s, 2F); Anal. Calcd. for C₁₂H₁₄F₂Si: C,

64.25; H, 6.29. Found: C, 64.60; H, 6.23.

4.3.19. Fluoride ion promoted addition of 2d to

benzaldehyde

To a solution of 2d (224 mg, 1.0 mmol) and benzaldehyde

(1.09 mg, 1.5 mmol) in THF (1.5 mL) at ꢀ78 8C was added

TBAF (1.0 mL of 1.0 M solution in THF) dropwise under an

argon atmosphere. After the mixture was stirred for 1 h at

ꢀ78 8C, the reaction mixture was washed with water (5 mL).

The aqueous layer was extracted with EtOAc (2ꢁ 5 mL). The

combined organic layer was dried over MgSO₄. After removal

of solvent, the crude product was puriﬁed by silica gel column

chromatography (ether/hexane = 1/9) to furnish 8a [8]

(232 mg, 90%) as a colorless oil.

4.3.15. 1,1-Diﬂuoro-1-trimethylsilyl-2-nonyne (2e)

1

Colorless oil; 63% yield; IR (neat) 2234 cm^ꢀ1; H NMR

(500 MHz, CDCl₃), d: 0.22 (s, 9H), 0.89 (t, J = 7.0 Hz, 3H),

1.26–1.33 (m, 4H), 1.40 (q, J = 7.0 Hz, 2H), 1.55 (q, J = 7.0 Hz,

2H), 2.31 (q, J = 7.0 H, 2H); ¹³C NMR (126 MHz, CDCl₃), d:

ꢀ5.1, 14.0, 18.7, 22.5, 28.0, 28,4, 31.2, 74.4 (t, J = 31.8 Hz),

93.0 (t, J = 8.7 Hz), 120.4 (t, J = 253 Hz); ¹⁹F NMR (470 MHz,

CDCl₃, C₆F₆as an internal standard), d: 58.8 (t, J = 7.0 Hz, 2F);

Anal. Calcd. for C₁₂H₂₂F₂Si: C, 62.02; H, 9.54. Found: C,

62.40; H, 9.44.

4.3.20. 4,4-Diﬂuoro-6-phenyl-1-hexen-5-yne (8b)

4.3.16. 3,3-Diﬂuoro-1-triisopropylsilyl-3-

trimethylsilylpropyne (2f)

A solution of 2d (224 mg, 1.0 mmol), allyl bromide

(605 mg, 5.0 mmol), KF (70 mg, 1.2 mmol), and CuI

(286 mg, 1.5 mmol) in DMF (1.5 mL) under an argon

atmosphere was stirred for 5 h at 55 8C. The usual workup

procedure of the mixture provided the crude product. The crude

mixture was chromatographed on silica gel (hexane) to give 8b

(125 mg, 65%) as a colorless oil.

IR (neat) 2243, 1230 cm^ꢀ1; ¹H NMR (500 MHz, CDCl₃), d:

2.87–2.94 (m, 2H), 5.30–5.33 (m, 2H), 5.85–5.94 (m, 1H),

7.34–7.51 (m, 5H); ¹³C NMR (126 MHz, CDCl₃), d: 44.1 (t,

J = 27.8 Hz), 81.4(t, J = 40.6 Hz), 87.3 (t, J = 6.7 Hz), 114.0 (t,

J = 234 Hz), 120.2, 121.1, 128.5, 129.9, 132.1; ¹⁹F NMR

(470 MHz, CDCl₃, C₆F₆as an internal standard), d: 79.1 (t,

J = 15.5 Hz, 2F); HRMS (EI) m/z calcd. for C₁₀H₁₀F₂,

192.0751. Found: 192.0744.

1

Colorless oil; 82% yield; IR (neat) 1863 cm^ꢀ1; H NMR

(500 MHz, CDCl₃), d: 0.24 (s, 9H), 1.08–1.11 (m, 21H); ¹³C

NMR (126 MHz, CDCl₃), d: ꢀ5.0, 11.0, 18.5, 94.0 (t,

J = 7.1 Hz), 99.8 (t, J = 28.9 Hz), 119.8 (t, J = 254 Hz); ¹⁹F

NMR (470 MHz, CDCl₃, C₆F₆as an internal standard), d: 56.7

(s, 2F); Anal. Calcd. for C₁₅H₃₀F₂Si₂: C, 59.15; H, 9.93. Found:

C, 59.22; H, 10.09.

4.3.17. 3,3-Diﬂuoro-1-trietylsilyl-3-trimethylsilyl-1-

propyne (2g)

Yellow oil; 93% yield; IR (neat) 1884 cm^ꢀ^{1 1}H NMR

;

(500 MHz, CDCl₃), d: 0.23 (s, 9H), 0.65 (q, J = 8.0 Hz, 6H),

1.01 (t, J = 8.0 Hz, 9H); ¹³C NMR (126 MHz, CDCl₃), d: ꢀ5.1,

G.B. Hammond / Journal of Fluorine Chemistry 127 (2006) 476–488

485

4.3.21. 3,3-Diﬂuoro-1,4-diphenylbutyne (8c)

the unstable nature of diﬂuoroallene for long periods at room

temperature that prevent it from being shipped.)

A solution of 2d (224 mg, 1.0 mmol), benzylbromide

(513 mg, 3.0 mmol), KF (70 mg, 1.2 mmol), and CuI (286

mg, 1.5 mmol) in DMF (1.5 mL) under an argon atmospherewas

stirred for 8 h at 70 8C. The usual workup procedure of the

mixture provided the crude product. The crude mixture was

chromatographed on silica gel (hexane) to give 8c (87 mg, 36%)

as a colorless oil.

4.3.23. (3,3-Diﬂuoro-3-methoxyprop-1-

ynyl)triisopropylsilane (3a)

At 0 8C, to a mixture of K₂CO₃(212 mg, 2 mmol) and

MeOH (2 mL), the solution of bromoallene 4 (311 mg, 1 mmol)

in 1 mL THF was introduced through a syringe, the reaction

mixture was stirred for 3 h at 0 8C. Then 10 ml saturated NH₄Cl

solution was added to quench the reaction. After stirring for

5 min at about 0 8C, the resulting aqueous mixture was

extracted with ether (three times); the extract washed with brine

(three times) and then dried over Na₂SO₄. The solvent was

removed under reduced pressure, and the crude product was

puriﬁed by ﬂash silica gel chromatography (pure hexane to 10%

ethyl acetate in hexane) to give 3a (158 mg, 61%) as a colorless

oil.

1

IR (neat) 2244 cm^ꢀ1; H NMR (500 MHz, CDCl₃), d: 3.44

(t, J = 14.0 Hz, 2H), 7.33–7.42 (m, 10H); ¹³C NMR (126 MHz,

CDCl₃), d: 45.8 (t, J = 27.0 Hz), 81.4 (t, J = 40.3 Hz) 88.0 (t,

J = 6.7 Hz), 114.2 (t, J = 235 Hz), 120.2, 127.7, 128.3, 128.4,

129.8, 130.7, 132.0, 132.1; ¹⁹F NMR (470 MHz, CDCl₃, C₆F₆

as an internal standard), d: 79.9 (t, J = 14.0 Hz, 2F); HRMS (EI)

m/z calcd. for C₁₀H₁₂F₂, 242.0907. Found: 242.0905.

4.3.22. Synthesis of (1-bromo-3,3-diﬂuoropropa-1,2-

dienyl)triisopropylsilane 4

IR (neat) 2846, 2868, 1463, 1265, 1172, 1026, 882,

;

679 cm^ꢀ^{1 1}H NMR (500 MHz, CDCl₃), d: 1.04–1.14 (m,

To a 0.15 M solution of (3-bromo-3,3-diﬂuoroprop-1-

ynyl)triisopropylsilane 1a in a mixture of 2% NH₄Cl aqueous

solution and THF (4:1) is added indium (1 equiv.). This mixture

was sonicated at 5–10 8C for 6–8 h. The temperature in the

ultrasound bath was adjusted by addition of ice periodically. An

aliquot was analyzed in CDCl₃by ¹⁹F NMR to monitor the

completion of the reaction. After the starting material was

consumed, the reaction mixture was extracted by ether and the

organic layer was washed by brine and dried over MgSO₄. Then

the most solvent was removed in reduced pressure to give the

crude indium complex. (Not evaporation to complete dryness,

because the indium complex is not stable when solvent was

removed completely.) The crude indium complex was used in

next step directly without further puriﬁcation. Although this

indium complex can be kept in freezer for several days, using of

the complex for next step immediately give better yield. The

freshly prepared indium complex (prepared from compound 1a

(3.20 g, 9.7 mmol)) was dissolved in THF (50 ml), then

reaction mixture was cooled to ꢀ78 8C, then a solution of Br₂

(3.10 g, 19.4 mmol) in THF (10 mL) was added dropwise to the

reaction mixture under stirring. The reaction mixture was

warmed to ꢀ20 8C and was stirring for another 0.5 h at ꢀ20 8C.

Then saturated Na₂S₂O₃solution (10 mL) was added to quench

the reaction. After stirring for 5 min at about 0 8C, the resulting

aqueous mixture was extracted with ether (three times); the

extract washed with brine (three times) and then dried over

Na₂SO₄. The solvent was removed by rotavapor, and the crude

product was puriﬁed by ﬂash silica gel chromatography (pure

hexane) to give 4 (2.44 g, 76%) as colorless oil. The yield

varied from 67 to 81%, the obtained ﬂuoroallene 4 is not stable

in solution, but neat 4 can be stored in freezer for more than 1

month.

21H), 3.16 (s, 3H); ¹³C NMR (125 MHz, CDCl₃), d: 11.08,

18.53, 52.40, 88.63, 95.36 (t, J = 51 Hz), 114.14 (t,

J = 241 Hz); ¹⁹F NMR (470 MHz, CDCl₃), d: ꢀ57.9 (s);

GC/MS (EI) m/z: 243 (M⁺ꢀ F), 219, 191, 163, 81; Anal. Calcd.

for C₁₃H₂₄F₂OSi: C, 59.50; H, 9.22. Found: C, 59.31; H, 9.21.

4.3.24. (3-(Allyloxy)-3,3-diﬂuoroprop-1-

ynyl)triisopropylsilane (3b)

At 0 8C, to a mixture of K₂CO₃(212 mg, 2 mmol) and allylic

alcohol (2 mL), the solution of bromoallene 4 (311 mg,

1 mmol) in THF (1 mL) was introduced through a syringe,

the reaction mixture was stirred for 4 h at 0 8C. Then saturated

NH₄Cl solution (10 ml) was added to quench the reaction. After

stirring for 5 min at about 0 8C, the resulting aqueous mixture

was extracted with ether (three times); the extract washed with

brine (three times) and then dried over Na₂SO₄. The solvent

was removed under reduced pressure, and the crude product

was puriﬁed by ﬂash silica gel chromatography (pure hexane to

10% ethyl acetate in hexane) to give 3b (200 mg, 70%) as a

colorless oil.

IR (neat) 2946, 2868, 1463, 1256, 1162, 1025, 882 cm^ꢀ1; ¹H

NMR (500 MHz, CDCl₃), d: 1.07–1.19 (m, 21H), 4.41–4.43 (m,

2H), 5.26 (d, J = 10 Hz, 1H), 5.38 (d, J = 17 Hz, 1H), 5.91–5.97

(m, 1H); ¹³C NMR (125 MHz, CDCl₃), d: 11.09, 18.58, 66.68,

88.61 (t, J = 5.3 Hz), 95.60 (t, J = 52 Hz), 113.84 (t,

J = 242 Hz), 118.62, 132.15; ¹⁹F NMR (470 MHz, CDCl₃),

d: ꢀ55.0 (s); GC/MS (EI) m/z: 269 (M⁺ꢀ F), 227, 209, 185, 93;

Anal. Calcd. for C₁₅H₂₆F₂OSi: C, 62.46; H, 9.09. Found: C,

62.44; H, 9.20.

4.3.25. (3,3-Diﬂuoro-3-(2,2,2-triﬂuoroethoxy)prop-1-

ynyl)triisopropylsilane (3c)

IR (neat) 2947, 2869, 1986, 1716, 1397, 1218, 1114,

882 cm^ꢀ1; ¹H NMR (500 MHz, CDCl₃), d: 1.08–1.13 (m, 18H),

1.29–1.34 (m, 3H); ¹³C NMR (125 MHz, CDCl₃), d: 11.39,

At 0 8C, to a mixture of K₂CO₃(212 mg, 2 mmol) and

triﬂuoroethanol (2 mL), the solution of bromoallene 4 (311 mg,

1 mmol) in 1 mL THF was introduced through a syringe, the

reaction mixture was stirred for 4 h at 0 8C. Then saturated

NH₄Cl (10 mL) solution was added to quench the reaction.

After stirring for 5 min at about 0 8C, the resulting aqueous

18.11, 111.80, 154.40 (t, J = 268 Hz), 179.14 (t, J = 36 Hz); ¹⁹

F

NMR (470 MHz, CDCl₃), d: ꢀ97.9 (s); Anal. Calcd. for

C₁₂H₂₁F₂Si: C, 46.30; H, 6.80. Found: C, 48.88; H, 7.36.

(Satisfactory EA and MS data couldn’t be obtained because of

486

G.B. Hammond / Journal of Fluorine Chemistry 127 (2006) 476–488

mixture was extracted with ether (three times); the extract

washed with brine (three times) and then dried over Na₂SO₄.

The solvent was removed under reduced pressure, and the crude

product was puriﬁed by ﬂash silica gel chromatography (pure

hexane) to give 3c (224 mg, 68%) as colorless oil.

IR (neat) 2948, 2871, 2200, 1463, 1294, 1257, 1172,

883 cm^ꢀ1; ¹H NMR (500 MHz, CDCl₃), d: 1.08–1.18 (m, 21H),

4.22 (q, J = 8.0 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃), d:

11.02, 18.50, 62.24 (q, J = 37.0 Hz), 90.96 (t, J = 5.7 Hz),

93.77 (t, J = 49.6 Hz), 113.19 (t, J = 246 Hz), 122.60 (t,

J = 276 Hz); ¹⁹F NMR (470 MHz, CDCl₃), d: ꢀ56.69 (s, 2F),

ꢀ74.75 (t, J = 8 Hz, 3F); GC/MS (EI) m/z: 330 (M⁺), 204, 177,

131, 111, 91; Anal. Calcd. for C₁₄H₂₃F₅OSi: C, 50.89; H, 7.02.

Found: C, 51.38; H, 7.20.

4.16 (s, 2H), 6.88 (d, J = 6.5 Hz, 2H), 7.29 (d, J = 6.5 Hz, 2H);

¹³C NMR (125 MHz, CDCl₃), d: 11.16, 18.68, 34.31, 55.48,

94.01, 97.03 (t, J = 38 Hz), 114.42, 117.43 (t, J = 263 Hz),

127.62, 130.55, 159.40; ¹⁹F NMR (470 MHz, CDCl₃), d: ꢀ59.8

(s); GC/MS (EI) m/z: 383 (M⁺ꢀ H), 341, 121; Anal. Calcd. for

C₂₀H₃₀F₂OSSi: C, 62.46; H, 7.86. Found: C, 62.52; H, 7.97.

4.3.28. (1,1-Diﬂuoro-3-(triisopropylsilyl)prop-2-

ynyl)triphenylphosphonium bromide (3f)

At room temperature, to a mixture of PPh₃(394 mg,

1.5 mmol) in ether (4 mL), the solution of bromoallene 4

(311 mg, 1 mmol) in 1 mL ether was introduced through a

syringe, the reaction mixture was stirred for 12 h at room

temperature. Then reaction mixture was ﬁltered and the solid

was washed with ether, and the white solid obtained was dried

in vacuum (526 mg, 92%).

4.3.26. 1,1-Diﬂuoro-3-(triisopropylsilyl)prop-2-ynyl

acetate (3d)

IR (CHCl₃solution) 2946, 2866, 2166, 1584, 1438, 1158,

1

At room temperature, to a mixture of AgOAc (334 mg,

2 mmol) and acetic acid (2 mL), the solution of bromoallene 4

(311mg, 1 mmol) in 1 mL acetic acid was introduced through a

syringe, the reaction mixture was stirred for 12 h at room

temperature. Then saturated NH₄Cl solution (10 ml) was added

to quench the reaction. After stirring for 5 min at rt., the

reaction mixture was ﬁltered and the solid collected was

washed by ether. The resulting ﬁltrate was extracted with ether

(three times); the extract was washed by brine (three times) and

then dried over Na₂SO₄. The solvent was removed under

reduced pressure, and the crude product was puriﬁed by ﬂash

silica gel chromatography (pure hexane to 10% ethyl acetate in

hexane) to give 3d (188 mg, 70%) as a colorless oil.

IR (neat) 2946, 2868, 2193, 1799, 1464, 1131, 882 cm^ꢀ1; ¹H

NMR (500 MHz, CDCl₃), d: 1.09–1.12 (m, 21H), 2.17 (s, 3H);

¹³C NMR (125 MHz, CDCl₃), d: 11.04, 18.53, 21.18, 91.24,

93.98 (t, J = 46 Hz), 110.38 (t, J = 246 Hz), 165.02; ¹⁹F NMR

(470 MHz, CDCl₃), d: ꢀ56.6 (s); GC/MS (EI) m/z: 247

(M⁺ꢀ AcO), 209, 173, 149, 81; HRMS (EI): calcd. for

C₁₅H₂₆F₂OSi (M⁺): 290.1514. Found: 290.1513.

1108, 730, 686 cm^ꢀ1; H NMR (500 MHz, CDCl₃), d: 0.83–

0.95 (m, 21H), 7.71–7.74 (m, 2H), 7.79–7.83 (m, 2H), 7.87–

8.01 (m, 1H); ¹³C NMR (125 MHz, CDCl₃), d: 10.81, 18.38,

92.52–92.68 (m), 107.68, 108.58–112.79 (m), 112.00 (d,

J = 84 Hz), 131.60 (t, J = 13 Hz), 134.85 (t, J = 10 Hz), 137.87;

¹⁹F NMR (470 MHz, CDCl₃), d: ꢀ82.2 (d, J = 102 Hz); Anal.

Calcd. for C₃₀H₃₆BrF₂PSi: C, 62.82; H, 6.33. Found: C, 62.71;

H, 6.63.

4.3.29. (3-Bromo-3,3-diﬂuoroprop-1-

ynyl)triisopropylsilane (3g)

At 0 8C, to a mixture of NaBr (212 mg, 2 mmol) and DMF

2 mL, the solution of bromoallene 4 (311 mg, 1 mmol) in DMF

(1 mL) was introduced through a syringe, the reaction mixture

was stirred for 12 h at room temperature. Then saturated NH₄Cl

solution (10 mL) was added to quench the reaction. After

stirring for 5 min at about 0 8C the resulting aqueous mixture

was extracted with ether (three times); the extract washed with

brine (three times) and then dried over Na₂SO₄. The solvent

was removed under reduced pressure, and the crude product

was puriﬁed by ﬂash silica gel chromatography (pure hexane)

to give 3g (242 mg, 78%) as colorless oil. The spectral data is

the same as 1a.

4.3.27. (3-(4-Methoxybenzylthio)-3,3-diﬂuoroprop-1-

ynyl)triisopropylsilane (3e)

At ꢀ78 8C, to a solution of (4-methoxyphenyl)methanethiol

(308 mg, 278 mL, 2 mmol) in THF (2 mL), 2.5 M solution of

butyllithium in hexane (0.64 mL, 1.6 mmol) was added under

argon, the reaction mixture was stirred for about 0.5 h at

ꢀ78 8C, and then the solution of bromoallene 4 (311 mg,

1 mmol) in THF (1 mL) was introduced through a syringe, the

reaction mixture was allow to be warmed to 0 8C slowly. Then

saturated NH₄Cl solution (10 mL) was added to quench the

reaction. After stirring for 5 min at about 0 8C, the resulting

aqueous mixture was extracted with ether (three times); the

extract washed with brine (three times) and then dried over

Na₂SO₄. The solvent was removed under reduced pressure, and

the crude product was puriﬁed by ﬂash silica gel chromato-

graphy (hexane to 10% ethyl acetate in hexane) to give 3e

(202 mg, 53%) as a colorless oil.

4.3.30. (3-Azido-3,3-diﬂuoroprop-1-ynyl)triisopropylsilane

(3h)

At 0 8C, to a mixture of NaN₃(130 mg, 2 mmol) and

CH₃CN (2 mL), the solution of bromoallene 4 (311 mg,

1 mmol) in CH₃CN (1 mL) was introduced through a syringe,

the reaction mixture was stirred for 12 h at room temperature.

Then 10 mL saturated NH₄Cl solution was added to quench the

reaction. After stirring for 5 min at rt., the reaction mixture was

extracted with ether (three times); the extract washed with brine

(three times) and then dried over Na₂SO₄. The solvent was

removed under reduced pressure, and the crude product was

puriﬁed by ﬂash silica gel chromatography (pure hexane to 10%

ethyl acetate in hexane) to give 3h (212 mg, 68%) as a colorless

oil.

1

IR (neat) 2945, 2866, 1513, 1463, 1250, 1154 cm^ꢀ1; H

IR (neat) 2948, 2869, 2148, 1465, 1247, 1207, 1045,

883 cm^ꢀ1; ¹H NMR (500 MHz, CDCl₃), d: 1.11–1.13 (m, 21H);

NMR (500 MHz, CDCl₃), d: 1.13–1.19 (m, 21H), 3.82 (s, 3H),

G.B. Hammond / Journal of Fluorine Chemistry 127 (2006) 476–488

487

¹³C NMR (125 MHz, CDCl₃), d: 10.99, 18.50, 93.13 (t,

4.3.33. Diethyl 2-(1,1-diﬂuoroprop-2-ynyl)-2-

methylmalonate (9a)

J = 47 Hz), 93.79 (s), 111.93 (t, J = 239 Hz); ¹⁹F NMR

(470 MHz, CDCl₃), d: ꢀ58.18 (s); GC/MS (EI) m/z: 193,

178, 166, 151, 126, 97, 82, 67, 55;

At ꢀ78 8C, to a solution of diethyl 2-(1,1-diﬂuoro-3-

(triisopropylsilyl)prop-2-ynyl)-2-methylmalonate 3i (104 mg,

0.257 mmol) in THF (2.5 mL), 1.0 M solution of TBAF in THF

(0.3 mL, 0.3 mmol) was added under argon, the reaction

mixture was stirred for about 0.5 h at ꢀ78 8C, the reaction

mixture was allow to be warmed to ꢀ20 8C slowly. Then

saturated NH₄Cl solution (10 mL) was added to quench the

reaction. After stirring for 5 min at about 0 8C, the resulting

aqueous mixture was extracted with ether (three times); the

extract washed with brine (three times) and then dried over

Na₂SO₄. The solvent was removed under reduced pressure, and

the crude product was puriﬁed by ﬂash silica gel chromato-

graphy (10% AcOEt in hexane) to give 9a (68 mg, 92%) as

colorless oil.

4.3.31. Diethyl 2-(1,1-diﬂuoro-3-(triisopropylsilyl)prop-2-

ynyl)-2-methylmalonate (3i)

At 0 8C, to a solution of methyl diethyl malonate (348 mg,

2 mmol) in THF (2 mL), NaH (60% suspension in mineral oil)

(72 mg, 1.8 mmol) was added under argon, the reaction mixture

was stirred for about 0.5 h at 0 8C, and then the solution of

bromoallene 4 (311 mg, 1 mmol) in THF (1 mL) was

introduced through a syringe, the reaction mixture was stirred

for 4 h at 0 8C. Then saturated NH₄Cl solution (10 mL) was

added to quench the reaction. After stirring for 5 min at about

0 8C, the resulting aqueous mixture was extracted with ether

(three times); the extract washed with brine (three times) and

then dried over Na₂SO₄. The solvent was removed under

reduced pressure, and the crude product was puriﬁed by ﬂash

silica gel chromatography (10% ethyl acetate in hexane to 50%

ethyl acetate in hexane) to give 3i (282 mg, 70%) as a colorless

oil.

IR (neat) 3264, 2943, 2866, 2133, 1742, 1459, 1275, 1099,

645 cm^ꢀ1; ¹H NMR (500 MHz, CDCl₃), d: 1.26 (t, J = 5.5 Hz,

1H), 4.21–4.28 (m, 4H); ¹³C NMR (125 MHz, CDCl₃), d:

14.02, 16.96, 61.72 (t, J = 25 Hz), 62.53, 74.76 (t, J = 38 Hz),

111.89 (t, J = 241 Hz), 166.76; ¹⁹F NMR (470 MHz, CDCl₃), d:

ꢀ89.4 (s); GC/MS (EI) m/z: 248 (M⁺), 203, 111.

IR (neat) 2954, 2866, 1745, 1463, 1271, 1046, 883,

¹H NMR (500 MHz, CDCl₃), d: 1.08–1.10 (m,

679 cm^ꢀ1

;

4.3.34. Diethyl-2-(4-(4-chlorophenyl)-1,1-diﬂuoro-4-

hydroxybut-2-ynyl)-2-methylmalonate (9b)

21H), 1.27 (t, J = 7.1 Hz, 6H), 1.69 (s, 3H), 4.24 (q, J = 7.1 Hz);

¹³C NMR (125 MHz, CDCl₃), d: 11.10, 14.05, 17.50, 18.56,

61.97 (t, J = 25 Hz), 62.30, 92.31, 96.82 (t, J = 38 Hz), 111.64

(t, J = 240 Hz), 52.40, 88.63, 95.36 (t, J = 51 Hz), 114.14 (t,

J = 241 Hz); ¹⁹F NMR (470 MHz, CDCl₃), d: ꢀ87.6 (s); GC/

MS (EI) m/z: 404 (M⁺), 385, 361, 269, 241, 225; Anal. Calcd.

for C₂₀H₃₄F₂O₄Si: C, 59.38; H, 8.47. Found: C, 59.11; H, 8.48.

At ꢀ78 8C, to a solution of diethyl 2-(1,1-diﬂuoro-

3-(triisopropylsilyl)prop-2-ynyl)-2-methylmalonate (104 mg,

0.257 mmol) and p-Cl–PhCHO (75.5 mg, 0.514 mmol) in

THF (2.5 mL), 1.0 M solution of TBAF in THF (0.257 mL,

0.257 mmol) was added under argon, the reaction mixture was

stirred for about 0.5 h at ꢀ78 8C, the reaction mixture was

allow to be warmed to ꢀ20 8C slowly. Then saturated NH₄Cl

solution (10 mL) was added to quench the reaction. After

stirring for 5 min at about 0 8C, the resulting aqueous mixture

was extracted with ether (three times); the extract washed with

brine (three times) and then dried over Na₂SO₄. The solvent

was removed under reduced pressure, and the crude product

was puriﬁed by ﬂash silica gel chromatography (10–30%

AcOEt in hexane) to give 9b (56 mg, 57%) as colorless oil.

4.3.32. (3,3-Diﬂuoro-5-phenylpenta-1,4-

diynyl)triisopropylsilane (3j)

At ꢀ78 8C, to a solution of 1-ethynylbenzene (204 mg,

2 mmol) in THF (2 mL), a 2.5 M solution of butyllithium in

hexane (0.64 mL, 1.6 mmol) was added under argon, the

reaction mixture was stirred for about 0.5 h at ꢀ78 8C, and then

the solution of bromoallene 4 (311 mg, 1 mmol) in THF (1 mL)

was introduced through a syringe, the reaction mixture was

allow to be warmed to 0 8C slowly. Then saturated NH₄Cl

solution (10 ml) was added to quench the reaction. After

stirring for 5 min at about 0 8C, the resulting aqueous mixture

was extracted with ether (three times); the extract washed with

brine (three times) and then dried over Na₂SO₄. The solvent

was removed under reduced pressure, and the crude product

was puriﬁed by ﬂash silica gel chromatography (hexane) to give

3j (183 mg, 55%) as colorless oil.

IR (neat) 3482, 2985, 2258, 1734, 1276, 1054 cm^ꢀ1; H

1

NMR (500 MHz, CDCl₃), d: 1.16 (t, J = 7.5 Hz, 3H), 1.17 (t,

J = 7.5 Hz, 3H), 1.60 (s, 3H), 4.14 (q, J = 7.5 Hz, 2H), 4.15 (1,

J = 7.5 Hz, 2H), 5.44 (s, 3H), 7.28 (d, J = 8.0 Hz, 2H), 7.38 (d,

J = 8.0 Hz); ¹³C NMR (125 MHz, CDCl₃), d: 13.79, 16.62,

62.00 (t, J = 25.7 Hz), 62.36, 63.35, 77.75 (t, J = 39.1 Hz),

87.93 (t, J = 6.7 Hz), 111.00 (t, J = 240 Hz), 166.69; ¹⁹F NMR

(470 MHz, CDCl₃), d: ꢀ89.06 (s); GC/MS (EI) m/z: 388 (M⁺),

370, 321, 295, 267, 249, 225, 176, 139, 111, 75; Anal. Calcd.

for C₁₈H₁₉ClF₂O₅: C, 55.61; H, 4.93. Found: C, 55.42; H, 5.04.

IR (neat) 2945, 2867, 2241, 1463, 1281, 1152, 1106, 1025,

;

756 cm^ꢀ^{1 1}H NMR (500 MHz, CDCl₃), d: 1.14–1.22 (m,

21H), 7.40–7.44(m, 3H), 7.55–7.56 (m, 2H); ¹³C NMR

(125 MHz, CDCl₃), d: 11.21, 18.66, 81.56 (t, J = 43 Hz),

86.81, 91.58, 98.24 (t, J = 41 Hz), 100.85 (t, J = 222 Hz),

120.06, 128.77, 130.47, 132.50; ¹⁹F NMR (470 MHz, CDCl₃),

d: ꢀ65.3 (s); GC/MS (EI) m/z: 312 (M⁺ꢀ F), 289, 219, 165,

103; HRMS (EI): calcd. for C₂₀H₂₆F₂Si (M⁺): 332.1772.

Found: 332.1777.

Acknowledgements

The author is grateful to the National Science Foundation

(CHE-0513483) and the University of Louisville Vice-Provost

Ofﬁce for Research for their generous support. Special

recognition is due to Mr. Bo Xu, Drs. Masayuki Mae and

Youhua Li, and Ms. Jiyoung A. Hong for their contribution to

488

G.B. Hammond / Journal of Fluorine Chemistry 127 (2006) 476–488

[20] S. Arimitsu, B. Xu, T.L.S. Kishbaugh, L. Grifﬁn, G.B. Hammond, J.

Fluorine Chem. 125 (2004) 641–645.

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references cited herein.

[21] P. Kirsch, Modern Fluoroorganic Chemistry, Wiley–VCH, Weinheim,

2004.

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Nucleophilic and electrophilic substitutions of difluoropropargyl bromides

DOI: 10.1016/j.jfluchem.2005.12.024

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Article abstract of DOI:10.1016/j.jfluchem.2005.12.024

Full text of DOI:10.1016/j.jfluchem.2005.12.024

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