Self-promoted nucleophilic addition of hexafluoro-2-propanol to vinyl ethers

Article abstract of DOI:10.1002/adsc.200505260

In spite of its low nucleophilicity, hexafluoro-2-propanol easily adds to vinyl ethers, without catalyst, to afford a range of hexafluoroisopropyloxy acetals. This addition reaction also occurred in the presence of a competitive, more nucleophilic alcohol

Full text of DOI:10.1002/adsc.200505260

FULL PAPERS
DOI: 10.1002/adsc.200505260
Self-Promoted Nucleophilic Additionof Hexafluoro-2-propanol
to Vinyl Ethers
`
Andrea Di Salvo, Marc David, Benoît Crousse, Daniele Bonnet-Delpon*
´
ˆ
Laboratoire BioCIS, FacultØ de Pharmacie-Paris Sud, rue J. B. Clement, 92296 Chatenay-Malabry, France
Fax: (þ33)-1-4683-5739, e-mail: daniele.bonnet-delpon@cep.u-psud.fr
Received: June 29, 2005; Accepted: November 24, 2005
Abstract: In spite of its low nucleophilicity, hexa- bond parameters in the rate and course of the reac-
fluoro-2-propanol easily adds to vinyl ethers, without tion.
catalyst, to afford a range of hexafluoroisopropyloxy
acetals. This addition reaction also occurred in the
presence of a competitive, more nucleophilic alcohol. Keywords: acetals; carbohydrates; fluorine; hexa-
Kinetic studies showed the importance of hydrogen fluoro-2-propanol; protecting groups; solvent effect
Introduction
very useful reaction for the protection of alcohols and
has been widely described in the presence of a variety
In recent years, the importance of fluoro alcohols as me- of Lewis acids or strong protic acids.[3] The achievement
dia for organic synthesis was illustrated by a huge num- of this reaction without the need of any metal or Lewis
ber of articles.[1] The main advantage of these alcohols, acid catalysis would be a great improvement.
for example, hexafluoroisopropanol (HFIP) and tri-
fluoroethanol (TFE), is the possibility to carry out, in
the absence of promoting agents, reactions that usually Results and Discussion
require the aid of Lewis acids or catalysts. In this connec-
tion, we reported the HFIP-promoted preparation of In a preliminary experiment, equimolar amounts of ben-
tetrahydroquinolines in a one-pot procedure from ani- zyl alcohol and HFIP were allowed to stir at room tem-
lines and enol ethers (Scheme 1).[2] In this reaction perature withdyihdrofuran
HFIP facilitates the nucleophilic addition of anilines (Scheme 2).
1a during one day
to vinyl ethers, probably through formation of an inter-
mediate species withcationic character.
Surprisingly it was found that HFIP competed with
the benzyl alcohol for the addition onto the vinyl ether,
In order to extend the scope of this reaction we inves- affording a non-negligible amount of 1,1,1,3,3,3-hexa-
tigated other nucleophiles, such as alcohols. The addi- fluoroisopropoxytetrahydrofuran (3a).
tion of alcohols to 3,4-dihydro-2H-pyran (DHP) is a
The reaction was then investigated in pure HFIP with-
out any other nucleophile. Reaction was carried out by
dissolving dihydrofuran (12 mmol) in a four-fold excess
of HFIP and allowing the mixture to stir at room temper-
ature. The reaction was strikingly very fast (2 h) and, af-
Scheme 1. Formation of tetrahydroquinolines by a domino
reaction in HFIP.
Scheme 2.
118
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Nucleophilic Addition of Hexafluoro-2-propanol to Vinyl Ethers
FULL PAPERS
Table 1.
ter distillation of HFIP, the acetal 3a was isolated in 86%
yield.
Because of its very low nucleophilicity [N (HFIP)¼
ꢀ3.93],[4,5] interference of hexafluoro-2-propanol in re-
actions, when it is used as solvent, is rare. Nevertheless
some nucleophilic additions of fluorinated alcohols to
oxonium intermediates have been reported for the syn-
thesis of fluoro acetals.[6] The acidity of fluorinated alco-
hols has also been exploited in the Mitsunobu reaction
to efficiently synthesize, by nucleophilic substitution,
polyfluoro ethers[7] and fluoroalkyl glycosides.[6b,8]
However, to the best of our knowledge, only two ex-
amples of self-promoted nucleophilic reactions of
HFIP have been reported. They concern oxirane ring
opening. When HFIP was reacted with the 9,10-epoxy
ether derivative of artemisinin, the corresponding 10-
Entry Alcohol Reaction time T [8C] Product Conversion
1
2
3
4
5
HFIP
TFE
BnOH 16 h80
MeOH 16 h80
i-PrOH 16 h80
2 hr.t.
1d
3a
Reflux[a] 4a
8C[a] 2a
100%
30%
100%
54%
8C[a] 5a
8C[a] 6a
47%
[a]
Reaction performed in a bathat 80 8C (after 2 days at
room temperature only starting material was recovered).
hexafluoropropyloxy acetal was obtained after 15 min HFIP, despite of its poor nucleophilicity, can be rational-
at room temperature,[9] whereas the reaction of TFE ized by close associations of HFIP withdihydrofuran
with the same epoxy ether required the presence of p- through hydrogen bonding, as already reported with
toluenesulfonic acid.[10] When styrene was reacted with THF.[13] In an intermediate involving one molecule of
H2O2 in HFIP, a-hexafluoropropyloxy-b-hydroxyethyl- HFIP closely associated to one molecule of dihydrofur-
benzene was formed as a secondary product, probably an, the development of a positive charge makes the dihy-
by HFIP-promoted opening of the intermediate epox- drofuran electrophilic, and the development of a nega-
ide.[11]
tive charge makes HFIP nucleophilic (Scheme 3). The
Despite of these examples showing that HFIP can act, formed ion pair could then collapse to give the fluoro
to some extent, as a nucleophile, the more striking fea- acetal. It is, however, not precluded that such associa-
ture, in the present experiment, is the easy addition of tions involve more than one molecule of HFIP, this latter
HFIP to the enol ether, even in the presence of a more becoming a hydrogen bond acceptor, when its proton is
nucleophilic alcohol.
strongly involved in a hydrogen bond with a good ac-
This prompted us to investigate this reaction in order ceptor.[14]
to evaluate the promoting effect of HFIP and to have a
Competitive experiments have been performed with a
better understanding of the competitive addition to the mixture of HFIP and other alcohols in the view to obtain
enol ether. Reactions were first studied using a range of more information on the mechanism of this reaction.
alcohols alone, and then using mixtures of HFIP and a Taking into account these preliminary results, some
second alcohol.
questions arise. In the competition between benzyl alco-
The reaction of enol ethers with alcohols was first at- hol and HFIP, the acetal 2a could be the result of a sub-
tempted with another fluorinated alcohol, trifluoroetha- stitution reaction of the fluorinated acetal 3a by benzyl
nol (TFE), which is less acidic and a weaker hydrogen alcohol. Indeed, Matsumara reported that in the reac-
bond donor than HFIP (pKa ¼12.3 versus 9.3, and a¼ tion of a nucleophile with the a-trifluoroethoxytetrahy-
1.51 versus 1.96),[5e] but slightly more nucleophilic [N drofuran, the trifluoroethoxide was a better leaving
(TFE)¼ ꢀ2.78]. Reactions were carried out withdihy-
group than the alkoxide.[6d] The reaction with TMSCN
drofuran 1 in excess of TFE (4 equivs.). The adduct 4a provided no ring opening while the same reaction per-
was formed only upon refluxing and in a poor conver- formed withno fluorinated cyclic acetals give a mixture
sion rate (30%) (Table 1). The reaction was then per-
formed withmore nucleophilic non-fluorinated alco-
hols. With BnOH, MeOH and i-PrOH, the addition
also occurred providing acetals, but in long reaction
times and with100%, 54% and 47% conversion, respec-
tively.
These results indicate that the reaction is governed by
several factors. It requires either an easy generation
from the enol ether of an intermediate with a marked
cationic character or a high nucleophilicity of alcohols.
Alcohols have the double role of promoting agent and
of nucleophile.[12] In this reaction, TFE is not able to sat-
isfy any of these requirements and HFIP is the most ef-
ficient reagent. The intriguing easiness of addition of Scheme 3. Mechanism of the addition of HFIP to enol ethers.
Adv. Synth. Catal. 2006, 348, 118 – 124
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Scheme 4.
Scheme 5. Competitive experiments.
of cyclic and non-cyclic substituted compounds
(Scheme 4).[6d,15]
Due to the presence of two CF3 groups, the hexafluor-
oisopropyl moiety should behave as an even better leav-
ing group. Consequently once formed, 3a can easily be
converted into 2a. Alternatively the acetal 2a can also
be formed through a direct addition of benzyl alcohol
on the enol ether activated by HFIP. Nevertheless, it
has been shown that, because of its high hydrogen
bond donor ability, HFIP can deactivate good nucleo-
philes such as aliphatic alcohols or amines, by means
of acid-base interactions.[16]
First, it has been checked than 3a is stable at room
temperature in the presence of 1 equivalent of benzyl al-
cohol, which proves that the formation of acetals 2a and
3a are two competitive pathways. Then kinetic studies of
the competition between HFIP and other alcohols
(MeOH, BnOH, i-PrOH, TFE) were investigated.
HFIP (2 equivs.), the second alcohol (2 equivs.) and di-
Figure 1. Kinetic profile for the competitive addition of HFIP
and BnOH to dihydrofuran 1.
hydrofuran 1a (1 equiv.) were introduced in an NMR tained when the second alcohol is TFE, which is the
1
tube, and the reaction was followed at 308C by H poorest nucleophile. This could be the result, as expect-
NMR, measuring the integration of protons C(H)-O ed, of the deactivation of the competing alcohols by
(Scheme 5). The initial rate of formation of products HFIP. However the addition of trifluoroethanol is dis-
R-Ac (2a,4a–6a) and 3a (evaluated from t0 to time cor- favoured over that of HFIP with a 4a/3a ratio of 0.67,
responding to 10% conversion of 1a), and the R-Ac/3a while the addition of non-fluorinated alcohols is always
ratios at reaction completion, are reported in Table 2. favoured. An examination of the initial rates of reaction
Figure 1 illustrates the kinetic profile of the reaction shows that the rate of formation of 3a is also far slower
withBnOH.
than in the case of the reaction performed in HFIP alone
It appeared that both acetals are stable under these and highly depending on the second alcohol: it is, for ex-
conditions. Reaction times are not reflecting the nucle- ample, 10 times lower with i-PrOH than with TFE (en-
ophilicity of alcohols. The faster reaction (12 h) is ob- tries 3 and 4). This indicates that the competitive path-
Table 2. Initial rate of formation and products ratio in the competitive addition of HFIP and another alcohols to dihydrofuran
1a at 308C.
Entry
ROH
Initial reaction rate·
Initial reaction rate ratio (R-Ac/3a)
Products ratio at completion (time)
kin ꢁ105 (mol/(L·s))
1
2
3
4
BnOH
MeOH
i-PrOH
TFE
kin (2a)¼4.18ꢂ0.08
kin (3a)¼1.73ꢂ0.13
kin (5a)¼1.48ꢂ0.03
kin (3a)¼0.99ꢂ0.02
kin (6a)¼1.10ꢂ0.04
kin (3a)¼0.64ꢂ0.02
kin (4a)¼2.99ꢂ0.04
kin (3a)¼6.93ꢂ0.25
2a/3a¼2.42
5a/3a¼1.49
6a/3a¼1.71
4a/3a¼0.43
2a/3a¼3.2 (30 h)
5a/3a¼2.25 (60 h)
6a/3a¼3.0 (88 h)
4a/3a¼0.67 (12 h)
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Nucleophilic Addition of Hexafluoro-2-propanol to Vinyl Ethers
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Table 3. Initial rates of formation of 3a and values of b.[17]
Alcohol
b
kin (3a)ꢁ105
i-PrOH
0.95
0.64ꢂ0.02
MeOH
BnOH
TFE
0
6.93ꢂ0.25
HFIP
0
0.62[4a,17c]
0.99ꢂ0.02
0.50[17c]
1.73ꢂ0.13
Table 4. Formation of hexafluoropropyloxy acetals.
ways are strongly depending on interactions between
HFIP and the other alcohol. It was found in fact that
one important factor governing the reaction is the hy-
drogen bond acceptor ability of the competing alcohol
(parameter b, Table 3).[17] There is an excellent correla-
tion observed between the logarithm of the initial rates
of formation of 3a and b values (Figure 2). This clearly
indicates that hydrogen bonding between HFIP and
the competing alcohol plays an important role in the re-
action mechanism, both disfavouring the “protonation”
of dihydrofuran and reducing the nucleophilicity of al-
cohols. TFE, which is the weaker hydrogen bond accept-
or, allows the generation by HFIPofthe zwitterion inter-
mediate postulated in Scheme 3, and thus a faster reac-
tion, withnevertheless a predominant formation of
product 3a.
This unexpected and efficient reaction of addition of
HFIP to dihydrofuran could be extended to the syn-
thesis of a range of fluorinated acetals by reaction with
other vinyl ethers in pure HFIP. A solution of the enol
ethers 1b–f (12 mmol) in HFIP (4 equivs.) was stirred
at room temperature and monitored by 19F NMR until
complete reaction. Excess of HFIP was then recovered
by distillation of the reaction mixture, and acetals 3b–
f were isolated pure from the residue in good to excellent
yields (Table 4).
Reaction conditions: vinyl ether (12 mmol) in 5 mL of HFIP
(4 equivs.), room temperature.
[a]
Isolated yields.
Ring opening compounds are observed in the crude reac-
[b]
tion mixture.
The reactions with the enol ethers 1b,c were fast (1 to
2 h) and exothermic. The low isolated yield in acetal 3b
(entry 2) is attributed to its high volatility. With enol from the ring opening of the bis-acetal 3f were present
ethers 1d,e reaction times were muchlonger (1 day)
but yields in acetals were high. In the reaction of HFIP
in the distillation residue.
As an example the reactivity of the acetal 3a towards
with the methoxydihydropyran, products resulting nucleophiles was evaluated with TMSCN. The reaction
was performed at room temperature in presence of
BF3 ·Et2O. The cyclic substitution product 7 was ob-
tained in quantitative yield, withno trace of the ring
opening product (Scheme 6).
This easy preparation of fluorinated acetals was then
applied to the carbohydrate series. When placed in
HFIP, the peracetylated glucal 1g reacted slowly at
room temperature providing in quantitative yields a
3:1 a:b mixture of the allylic fluoroalkyl acetals 3g, re-
sulting from a Ferrier reaction (Scheme 7).[18] When the
reaction was conducted at reflux, the reaction time was
Figure 2. Correlation between the logarithm of the initial rate
of formation of 3 and b. The equation obtained is: log kin ¼
2
ꢀ1.124b–4.20 withR ¼0.97.
Scheme 6. Substitution of hexafluoropropyloxy acetal 3a.
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Scheme 7.
shorter (16 h), but same ratio of stereoisomers was ob- Conclusion
tained. The reaction was also checked in the presence
of a catalytic amount of p-TSA in order to promote In conclusion, this study shows that HFIP, in spite of its
the intermediate formation of an oxonium ion postulat- very low nucleophilicity, easily adds to vinyl ethers with
ed in the Ferrier reaction. The reaction was much faster no need of a catalyst. This reaction also occurred when a
and the only product formed was a-3g (the b isomer was competitive, more nucleophilic alcohol was present. Ki-
not detected by NMR in the crude product). However, netic studies showed the importance of hydrogen bond-
the moderate yield (57%) strongly suggests the degrada- ing in the reaction mechanism, demonstrating that the
tion of the b isomer in the reaction medium.
expected deactivation of nucleophiles by HFIP is also
The mechanism suggested above (see Scheme 3), in- accompanied by the deactivation of HFIP by good hy-
volving hydrogen bond association of HFIP with the glu- drogen bond acceptor solvents. Evidence suggests that
cal, could explain the addition of HFIP with an approach HFIP promotes its own addition reaction by favouring
depending on the steric hindrance of the two faces of the the formation of an intermediate species with a cationic
intermediate. The lost of an acetoxy group instead of a character, with which it is closely associated, thus liber-
proton migration prompted us to investigate the reac- ating the conjugated base with a high degree of anionic
tion from the parent perbenzyloxy compound 1h. No re- character. This reaction was exploited to prepare a
action occurred in HFIP after 16 hat room temperature
or at reflux (Scheme 8).
range of fluorinated acetals, but is efficient for glucals
only when an allylic leaving group is present.
This observation suggests that the addition of HFIP
Starting from the cyclic fluorinated acetals, the hexa-
can only occur through a concerted mechanism where fluoroisopropyloxy moiety being an excellent leaving
the nucleophile entering pushes the double bond to- group, some examples of clean and selective nucleophil-
wards the leaving group. In the absence of a leaving ic substitutions withno ring opening products are re-
group, the postulated ion pair does not collapse. As ex- ported.
pected, glucals are not as reactive towards HFIP than
simple cyclic vinyl ethers.
Experimental Section
1H NMR and 13C NMR spectra were recorded on either a
200 MHz or a 400 MHz multinuclear Bruker spectrometer.
COSY, NOESY, HSQC and HMBC experiments were per-
formed on a 400 MHz multinuclear Bruker spectrometer.
Chemical shifts (d) are given in ppm relative to TMS. Coupling
constants are given in Hz. GC analyses were performed using a
SE 30 capillary column (12 m). All starting materials are com-
mercially available. HFIP was provided by Central Glass Co.
Scheme 8.
Ltd.
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Nucleophilic Addition of Hexafluoro-2-propanol to Vinyl Ethers
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Typical Procedure for the Synthesis of Fluorinated
Acetals 3
Typical Procedure for Acetals 2a, 5a and 6a
2,3-Dihydrofuran (12 mmol) was added to an alcohol (4
equivs.) in a flask and stirred at 808C during 16 h. 1H NMR al-
lowed estimation of the conversion rate. All these acetals were
already described in the literature.[19]
The enol ether (12 mmol) was added to HFIP (5 mL, 4 equivs.)
in a flask and stirred at room temperature for the time indicat-
ed in Table 4. The reaction was followed by 19F NMR and after
completion, distillation allowed us to recover HFIP and pure
products in 52–95% yields.
Fluorinated Acetal 3a: Yield: 2.45 g (86%); 1H NMR
(CDCl3, 200 MHz): d¼5.42 (m, 1H), 4.59 (sept, 1H, J¼
6.2 Hz), 4.12–3.91 (m, 2H), 2.35–1.74 (m, 4H); 13C NMR
(CDCl3, 50 MHz): d¼122.2 (q, J¼282 Hz), 122.0 (q, J¼
282 Hz), 104.5, 70.6 (sept, J¼33 Hz), 68.3, 32.2, 22.3; 19F
(CDCl3, 188 MHz): d¼ ꢀ74.24 (qd, 3F, J¼8.7 Hz, J¼
6.2 Hz), ꢀ74.75 (qd, 3F, J¼8.7 Hz, J¼6.2 Hz, CF3);
IR (neat): n¼1217, 1186, 1100, 1072, 939, 922, 898, 878,
687 cmꢀ1; anal. calcd. for C7H8O2F6: C 35.31, H 3.39; found:
C 35.24, H 3.25.
Typical Procedure for Ferrier-Type Reactions
In pure HFIP: A flask containing 100 mg of tri-O-acetyl-d-glu-
cal and 3 mL of HFIP was heated for 16 h at reflux. Vacuum
evaporation of the solvent and silica gel chromatography (ethyl
acetate/petroleum ether, 2:3) of the crude residue afforded
106 mg of a-3g (76%) and 34 mg of b-3g (24%).
Catalyzed with p-TSA: To a flask containing 100 mg of tri-
O-acetyl-d-glucal and 3 mL of HFIP was added 75 mg (1.07
equivs.) of p-TSA at room temperature. The reaction mixture
turned black within a few minutes and was monitored by
TLC. After 2 h, the reaction mixture was poured into a saturat-
ed solution of sodium hydrogen carbonate (10 mL) and ex-
tracted withdichloromethane (2 ꢁ10 mL). The combined or-
ganic phases were dried on MgSO4, filtrated and evaporated
under vacuum. The crude residue gave after silica gel chroma-
tography (ethyl acetate/petroleum ether, 2:3) 79 mg of a-3g
(57%).
Fluorinated Acetal 3b: Yield: 1.8 g (63%); 1H NMR (CDCl3,
200 MHz): d¼5.07 (q, 1H, J¼5.4 Hz), 4.51 (sept, 1H, J¼
6.1 Hz), 3.85–3.54 (m, 2H), 1.47 (d, 3H, J¼5.4 Hz), 1.26 (t,
3H, J¼7.1 Hz); 13C NMR (CDCl3, 50 MHz): d¼121.3 (q, J¼
282 Hz), 121.2 (q, J¼282 Hz), 101.5, 70.6 (sept, J¼32 Hz),
60.4, 19.0, 14.5; 19F (CDCl3, 188 MHz): d¼ ꢀ74.32–73.92 (m,
6F); IR (neat): n¼1219, 1187, 1100, 1066, 888, 688 cmꢀ1
.
Fluorinated Acetal 3c: Yield: 2.4 g (75%), 1H NMR (CDCl3,
200 MHz): d¼5.06 (q, 1H, J¼5.3 Hz), 4.50 (sept, 1H, J¼
6.2 Hz), 3.76–3.47 (m, 2H), 1.71–1.31 (m, 9H), 0.98 (t, 3H,
J¼7.2 Hz); 13C NMR (CDCl3, 50 MHz): d¼121.7 (q, J¼
287 Hz), 121.4 (q, J¼287 Hz), 101.6, 71.2 (sept, J¼33 Hz),
64.8, 31.4, 19.4, 18.9, 13.5; 19F (CDCl3, 188 MHz): d¼ ꢀ74.40
to ꢀ74.08 (m, 6F); IR (neat): n¼1219, 1194, 1159, 1100, 950,
908, 689 cmꢀ1; anal. calcd. for C9H14O2F6: C 40.30, H 5.72;
found: C 40.05, H 5.60.
Fluorinated Acetal a-3g: 1H NMR (CDCl3, 200 MHz): d¼
6.03 (bd, 1H, J¼11 Hz), 5.86 (ddd, 1H, J¼11 Hz, J¼3 Hz,
J¼1 Hz), 5.34 (ddd, 1H, J¼10 Hz, J¼2 Hz, J¼2 Hz), 5.30–
5.23 (bs, 1H), 4.57 (sept, 1H, J¼6 Hz), 4.21 (d, 2H, J¼4 Hz),
4.13–4.02 (m, 1H), 2.09 (s, 3H), 2.07 (s, 3H); 13C NMR
(CDCl3, 50 MHz): d¼170.6, 170.1, 131.5, 124.9, 121.7 (q, J¼
284 Hz), 121.2 (q, J¼283 Hz), 95.4, 72.0 (sept, J¼33 Hz),
68.1, 64.6, 62.2, 20.8, 20.5; 19F (CDCl3, 376 MHz): d¼ ꢀ73.85
(q, 3F, J¼9 Hz), ꢀ74.03 (q, 3F, J¼9 Hz); IR (neat): n¼2954,
1743, 1371, 1216, 1187, 1101, 1088, 959, 758, 728 cmꢀ1; HR-
MS: calcd. for C13H14F6NaO6þ: 403.0587; found: 403.0586;
anal. calcd. for C13H14F6O6: C 41.06, H 3.71; found: C 41.30,
H 3.85; [a]D: 208.2 (c 0.8, CH2Cl2).
Fluorinated Acetal 3d: Yield: 2.42 g (81%), 1H NMR
(CDCl3, 200 MHz): d¼5.05 (m, 1H), 4.57 (sept, 1H, J¼
6.2 Hz), 3.93 (m, 1H), 3.65 (m, 1H), 1.99–1.54 (m, 6H); 13C
NMR (CDCl3, 50 MHz): d¼121.9 (q, J¼285 Hz), 121.3 (q,
J¼285 Hz), 99.2, 71.2 (sept, J¼33 Hz), 61.7, 29.3, 24.7, 17.5;
19F (CDCl3, 188 MHz): d¼ ꢀ74.15 (m, 3F), ꢀ73.90 (m, 3F);
Fluorinated Acetal b-3g: 1H NMR (CDCl3, 200 MHz): d¼
6.16 (dd, 1H, J¼4 Hz, J¼2 Hz), 6.12 (dd, 1H, J¼4 Hz, J¼
2 Hz), 6.00 (dd, 1H, J¼2 Hz, J¼1 Hz), 5.95 (dd, 1H, J¼
2 Hz, J¼1 Hz), 5.42 (bs, 1H), 5.24 (dd, 1H, J¼4 Hz, J¼
4 Hz), 4.57 (sept, 1H, J¼6 Hz), 4.26–4.18 (m, 2H), 4.16–4.04
(m, 1H), 2.08 (s, 3H), 2.07 (s, 3H); 13C NMR (CDCl3,
50 MHz): d¼170.5, 170.0, 128.1, 127.7, 121.7 (q, J¼290 Hz),
95.7, 73.2, 72.2 (sept, J¼35 Hz), 63.5, 62.5, 20.8, 20.6; 19F
NMR (CDCl3, 376 MHz): d¼ ꢀ73.40 (q, 3F, J¼8.2 Hz),
ꢀ73.50 (q, 3F, J¼8.2 Hz).
IR (neat): n¼1185, 1144, 1099, 953, 904, 687 cmꢀ1
.
Fluorinated Acetal 3e: Yield: 2.75 g (95%), 1H NMR
(CDCl3, 200 MHz): d¼4.56 (sept, 1H, J¼6.1 Hz), 3.33 (s,
3H), 1.49 (s, 6H); 13C NMR (CDCl3, 50 MHz): d¼121,6 (q,
J¼284 Hz), 104.3, 68.5 (sept, J¼33 Hz) 50.3, 30.5, 24.4; 19F
(CDCl3, 188 MHz): d¼ ꢀ73.44 to ꢀ73.20 (m, 6F); IR (neat):
n¼1287, 1217, 1178, 1064, 893, 841, 686 cmꢀ1
.
Fluorinated Acetal 3f: Yield: 1.76 g (52%); two isomers a/b
1
1:1; H NMR (CDCl3, 200 MHz): d¼5.25–5.18 (m, 1Haþ
1Hb), 4.79 (d, 1Ha, J¼1.9 Hz), 4.75 (d, 1Hb, J¼2.6 Hz), 4.6
(sept, 1Haþ1Hb, J¼6.1 Hz), 3.49 (s, 3Haþ3Hb), 1.95–1.44
(m, 6Haþ6Hb); 13C NMR (CDCl3, 50 MHz): d¼121.6 (q,
J¼284 Hz), 121.4 (q, J¼284 Hz), 99.7, 98.7, 71.8 (sept, J¼
33 Hz), 55.5, 29.8, 28.8, 16.3; 19F (CDCl3, 188 MHz): d¼ ꢀ
74.30 (m, 3F), ꢀ73.8 (m, 3F); IR (neat): n¼1264, 1218, 1190,
Typical Procedure for the Nucleophilic Substitutions
Tetrahydrofuran-2-carbonitrile (7): 184 mg (1 mmol) of 3a
were dissolved in 1 mL of dichloromethane in a flask placed
in a water-ice bath. To the resulting solution under argon
were added dropwise 200 mL (1.5 mmol) of TMSCN and
130 mL of BF3 ·Et2O. After 2 h, GC indicated that the reaction
was complete. The solution was then quenchedwith asaturated
solution of NaHCO3 (5 mL) and extracted withdichlorome-
thane (3ꢁ10 ml). The combined organic extracts were washed
1126, 1099, 943, 890, 687 cmꢀ1
.
Fluorinated Acetal 4a: Yield: 450 mg (30%), 1H NMR
(CDCl3, 200 MHz): d¼5.13–5.10 (m, 1H), 4.00–3.55 (m,
4H), 2.07–1.65 (m, 4H); 13C NMR (CDCl3, 50 MHz): d¼
124.0 (q, J¼278 Hz), 103.9, 67.3, 63.4 (q, J¼34 Hz), 32.1,
22.8; 19F (CDCl3, 188 MHz): d¼ ꢀ74.81 (t, 3F, J¼9.4 Hz); IR
(neat): n¼1154, 1116, 1060, 1035, 960, 919, 663 cmꢀ1
.
withbrine and dried withMgSO . Evaporation under reduced
4
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
123

Andrea Di Salvo et al.
FULL PAPERS
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124
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Adv. Synth. Catal. 2006, 348, 118 – 124