Tetramethylfluoroformamidinium hexafluorophosphate (TFFH) as a mild deoxofluorination reagent

Article abstract of DOI:10.1055/s-0031-1290336

The solid, air-stable peptide coupling reagent TFFH (tetramethylfluoroformamidinium hexafluorophosphate) was found to activate a variety of alcohols towards deoxofluorination. These conditions are compatible with carbonyl functional groups thus offering interesting possibilities for the application to sensitive molecules. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290336

LETTER
569
Tetramethylfluoroformamidinium Hexafluorophosphate (TFFH) as a Mild
Deoxofluorination Reagent
T
FFH-Mediated D
a
eoxofluorin
b
a
tion of Alc
r
ohols iel Bellavance, Pascal Dubé,* Bao Nguyen
Chemical Research & Development, Pfizer Worldwide Research & Development, Eastern Point Road, Groton, CT 06340, USA
E-mail: pascal.dube@nalasengineering.com
Received 29 August 2011
limited applications of this reagent have been reported de-
spite its remarkable functional group tolerance. We envi-
sioned that TFFH could be used to promote the
deoxofluorination of alcohols under suitable conditions.
Abstract: The solid, air-stable peptide coupling reagent TFFH (tet-
ramethylfluoroformamidinium hexafluorophosphate) was found to
activate a variety of alcohols towards deoxofluorination. These con-
ditions are compatible with carbonyl functional groups thus offer-
ing interesting possibilities for the application to sensitive Our objectives were to identify these conditions and fur-
molecules.
ther underline their limitations in prevision to the use of
this reagent for the deoxofluorination of complex drug
candidates in our pipeline. 2-Phenylpropan-2-ol was thus
chosen as benchmark substrate for the optimization hop-
ing its sensitivity towards elimination would lead us to
identify mild conditions for the desired transformation
(Table 1). As only elimination was observed with TFFH
alone,9 we sought to buffer the HPF6 by-product by the ad-
dition of a base, thus hoping to minimize side reactions.
Interestingly, triethylamine proved ineffective while
modest albeit encouraging results were obtained using
DMAP. Based on this finding we hypothesized that the
presence of exogenous fluoride would enhance the reac-
tivity and favor substitution over elimination. Following
the findings of Couturier et al.,6 decent conversion to the
Key words: deoxofluorination, fluoroformamidinium, fluoride,
TFFH, fluorination
The introduction of fluorine atoms into molecules has re-
ceived an increasing interest in the literature.1 In particu-
lar, the conversion of alcohols to the corresponding
fluorinated analogues via deoxofluorination is now part of
the chemical toolkit.1a,2 If DAST and Deoxo-Fluor have
become the standard reagents for such a transformation
(Figure 1),3 few applications on larger scale have been re-
ported due to their limited chemoselectivity and function-
al group tolerance.4 Moreover, the physical properties of
these fuming liquids further restricts their applicability.5
In response to these limitations, aminodifluorosulfinium
salts offer similar reactivity with enhanced thermal stabil-
ity. These crystalline salts based on the reactivity of the
sulfur–fluorine bond have emerged as novel reagents for
a variety of deoxofluorination reactions.6 Nonetheless, the
discovery of new classes of reagents based on the reactiv-
ity of a different motif is of interest.
Table 1 Optimization of the Additive
TFFH (1.5 equiv)
THF, 60 °C, 2 h
OH
F
+
additive (2 equiv)
1
2
3
Entry Additive
Conv.
(%)
Ratio of 2/3 Yield of 2
(%)a
MeO
OMe
N
N
1
2
–
15
10
23
0
–
0b
0
SF3
SF3
DAST
DeoxoFluor
Et3N
DMAP
KF
–
3
1.3:1
13
F
N
4
–
0
N
N
–
S
F
BF4
PF6
F
5
TBAF
Py–HF
0
–
0
TFFH
XtalFluor-E
6
48
0
–
0b
0
Figure 1 Structures of common deoxofluorination reagents compa-
red with TFFH
7
Et3N–3HF
–
8
Et3N–3HF + Et3N
Et3N–3HF + 2 Et3N
Et3N–3HF + Et3N
55
53
0
4.8:1
4.7:1
–
50
We were thus interested by reports on the use of TFFH, a
stable white crystalline solid,7 to generate acyl fluorides
for the preparation of amide bonds.8 Interestingly, only
9c
10d
43
0
a In situ GC yield based on internal standard (PhCl).
b Only elimination was observed.
SYNLETT 2012, 23, 569–572
Advanced online publication: 08.02.2012
DOI: 10.1055/s-0031-1290336; Art ID: S08411ST
x
x
.
x
x
.
2
0
1
2
c Corresponds to 2 equiv of Et3N–3HF + 4 equiv of Et3N vs. 1.
d Reaction was carried out without TFFH.
© Georg Thieme Verlag Stuttgart · New York

570
G. Bellavance et al.
LETTER
desired tertiary fluoride 2 was finally obtained when using Based on these findings, we screened a variety of halo-
Et3N–3HF10 with additional Et3N (entries 8 and 9).
formamidinium salts in order to identify other potential
activators sharing this motif (Figure 3). This evaluation
rapidly highlighted ability of chloro iminium salts to pro-
mote the incorporation of the chlorine atom in a
deoxochlorination reaction. The evaluation of alternative
fluoroformamidinium salts only supported the superiority
of TFFH to mediate the desired deoxofluorination. Focus
was thus put on the optimization of the reaction featuring
TFFH as the key promoter given its commercial availabil-
ity and stability.14
To gain a better understanding of the reaction and product
ratio a-methylstyrene was submitted to the reaction con-
ditions (Scheme 1). Interestingly, no conversion was ob-
served and the styrene was recovered intact after 48 hours
at 60 °C. This result highlights that under these conditions
the products arising from the deoxofluorination of alco-
hols is of kinetic origin; the reaction does not proceed via
dehydration followed by subsequent hydrofluorination of
the styrene.11
Cl
Cl
Cl
Cl
TFFH (1.5 equiv)
THF, 60 °C
F
+
X
N
N
N
N
N
N
N
N
N
Cl–
–
–
–
Et3N⋅3HF (2 equiv)
Et3N (2 equiv)
BF4
PF6
PF6
3
2
3
F
F
Scheme 1 Reaction of a-methylstyrene under the deoxofluorination
conditions
N
N
–
PF6
N
–
PF6
We then sought to gain understanding of the fate of TFFH
in the presence of additional HF with the rationale that an
equilibrium with the corresponding difluoromethylene
diamine (4) species might be existing in solution
(Equation 1). The exact nature of the active reagent is of
interest given the published ability of such reagents to per-
form deoxofluorination reactions but also in light of po-
tential intellectual property rights governing their use.12
Figure 3 Structures of haloformamidinium reagents evaluated for
the deoxofluorination of alcohols
The optimization of the reaction solvent was examined
next (Table 2). Although conversions were not optimized,
it is interesting that a variety of solvents can produce sim-
ilar ratio of products and in situ yields. The compatibility
of these conditions to such an array of solvents can be ap-
pealing when the solubility of starting alcohols is restrict-
ed. Nonetheless, EtOAc was selected for the remaining of
our study.15
F
F
F
HPF6
+
+
"HF"
N
N
N
N
PF6
Table 2 Solvent Screen
TFFH
4
TFFH (1.5 equiv)
solvent, 60 °C, 2 h
Equation 1 Potential equilibrium of TFFH with the difluoromethy-
lene diamine analogue
OH
F
+
Et3N⋅3HF (2 equiv)
Et3N (2 equiv)
1
2
3
A series of 19F NMR studies were undertaken using the
commercially available 2,2-difluoro-1,3-dimethyl imida-
zolidine (DFI) as reference to monitor the gem-difluoro
moiety. Our data supports the presence of the fluoroform-
amidinium function as resting species of this reaction
mixture and a difluoromethylene diamine unit was not de-
tected (Figure 2).13
Entry
Solvent
THF
Conv. (%) Ratio of 2/3 Yield of 2 (%)a
1
2
3
4
5
6
7
8
55
41
42
56
71
84
73
32
4.8:1
4.3:1
4.6:1
4.7:1
6.2:1
3.7:1
4.3:1
2.1:1
50
33
35
46
62
66
59
22
2-MeTHF
i-PrOAc
MeCN
EtOAc
toluene
CH2Cl2
DMF
a In situ GC yield based on internal standard (PhCl).
We next evaluated the generality of the reaction by exam-
ining a variety of alcohols, again with the intent to under-
stand the limitations of the method (Table 3). The reaction
was found to proceed readily with benzylic alcohols, pro-
viding the corresponding benzylic fluorides in high yields
Figure 2 Comparative 19F NMR of fluorinated species
Synlett 2012, 23, 569–572
© Thieme Stuttgart · New York

LETTER
TFFH-Mediated Deoxofluorination of Alcohols
571
after less than hour at ambient temperature. Allylic alco- after prolonged exposure to the reagents. Given the ability
hols could also be converted under similar conditions to of common reagents based on S–F chemistries to trans-
mixtures of allylic fluorides. In an attempt to define the re- form carbonyl groups to gem-difluoro moieties, the inabil-
activity limits of this system, an aliphatic tertiary alcohol ity of TFFH to promote such a transformation even under
was subjected to the deoxofluorination conditions (entry forcing conditions should open the way for the application
6). Although the reaction required prolonged heating, we of our method to complex systems.16
were delighted to observe the desired tertiary fluoride in
67% in situ yield. Finally, these conditions seem incom-
patible with cyclic secondary alcohols and an ethanol
amine derivative as they were found to favor dehydration
vs. deoxofluorination.
O
F
F
H
H
X
<1% conversion
5
O
F
F
F
Table 3 Scope of Alcohols
TFFH (1.5 equiv)
+
X
EtOAc
R2
R1OH
R1F
+
R3
<1% conversion
Et3N⋅3HF (2 equiv)
Et3N (2 equiv)
6
7
conditions: TFFH (1.5 equiv)
Et3N 3HF (2 equiv)
⋅
Entry ROH
Temp Time Ratioa of Yield
Et3N (2 equiv)
EtOAc
60 °C, 48 h
(°C) (h) RF/elim (%)b
HO
Me
O
Scheme 2 Reactivity of benzylic carbonyl functions
1
2
23
23
1
1
100:0
100:0
83
83
N
Having defined the limitations and some opportunities,
we were particularly interested to apply the method to a
model substrate of a drug candidate in development at
Pfizer. When subjected to our conditions, 8 provided the
corresponding fluorocyclobutane 9 in 79% isolated yield
as a 4:1 mixture of diastereoisomer favoring overall inver-
sion of stereochemistry (Scheme 3). Interestingly, the op-
posite diastereoisomer of 8 (ester and phenyl syn) also
provided the same diastereomeric ratio of 9. This result
suggests the presence of a common carbocationic inter-
mediate accessed by an SN1 mechanism.
Me
OH
Ph
Ph
Ph
Ph
OH
3
4
5
23
23
23
1
1
1
10:1
100:0
8:1
(90)
(>99)c
(51)
Ph
OH
Me
OH
Me
Me
Me Me
OH
OH
OH
6
7
60
23
16
1
2.5:1d (67)
Ph
OH
TFFH (1.5 equiv)
Ph
EtOAc, 60 °C, 2.5 h
F
Ph
1:5
(18)
Et3N⋅3HF (2 equiv)
Et3N (2 equiv)
Cbz
N
i-PrO2C
i-PrO2C
9
8
79%
8e
9
23
23
1
1
0:100
0:100
0
0
dr >20:1
dr = 4:1
t-Bu
Scheme 3 Model study for drug candidate
OH
TsHN
a Ratio of products determined by GC–MS.
In summary, we have developed novel conditions for the
deoxofluorination of alcohols by using the bench-stable
TFFH as a promoter in the presence of added HF reagents
that are commercially available.17 The mildness of these
conditions should allow their application to complex sys-
tems featuring carbonyl functions, offering an alternative
reactivity to existing methods. The application of this
deoxofluorination method to a drug candidate is under-
way and will be reported in due course.
b Isolated yields unless otherwise noted. Yields between parentheses
are in situ GC yields based on an internal standard (PhCl).
c A mixture of fluorinated isomers (1:1) was obtained.
d A mixture of elimination products was obtained.
e Both cis- and trans-isomers gave the same results.
With an understanding of the scope of alcohols, we sought
to evaluate the sensitivity of carbonyl species to these
conditions (Scheme 2). Benzaldehyde and acetophenone
were thus independently subjected to the TFFH-promoted
deoxofluorination conditions at 60 °C to stress any poten-
tial reactivity. We were pleased to find that both com-
pounds could be recovered in high yields (>95%) even
Acknowledgment
We are grateful to David R. Bill of Pfizer for performing the DSC
analysis of TFFH.
© Thieme Stuttgart · New York
Synlett 2012, 23, 569–572

572
G. Bellavance et al.
LETTER
(6) (a) L’Heureux, A.; Beaulieu, F.; Bennett, C.; Bill, D. R.;
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Synthesis 2002, 2561.
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Jiang, Y.; Lee, G. E.; Lienard, P.; Pemberton, C.; Powers, M.
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(7) Differential scanning calorimetry (DSC) analysis of TFFH
revealed a generation of 146 J/g at Tmax of 370 °C. See
reference 6a for comparative data with other reagents.
(8) (a) Carpino, L. A.; El-Faham, A. J. Am. Chem. Soc. 1995,
117, 4101. (b) El-Faham, A.; Khattab, S. N. Synlett 2009,
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handled in borosilicate glassware up to 150 °C without
etching. See: (a) Haufe, G. J. Prakt. Chem. 1996, 338, 99.
(b) Franz, R. J. Fluorine Chem. 1980, 15, 423.
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(11) This conclusion can only be applied to a subset of the
reactions studied as this behavior could be substrate
dependent.
(12) (a) Hayashi, H.; Sonoda, H.; Fukumura, K.; Nagata, T.
Chem. Commun. 2002, 1618. (b) Sonoda, H.; Fukumura,
K.; Takano, Y.; Okada, K.; Hayashi, H.; Takahashi, A.;
Nagata, T. Eur. Patent, EP895991A2, 2001.
(13) 19F NMR experiments were collected using a Bruker-
Biospin 5 mm BBFO probe on Bruker AVANCE III NMR
spectrometer operating at 400 MHz. Limit of detection
evaluated at 0.1%.
(14) The activity of commercial TFFH was found to vary among
suppliers. Material from TCI and Oakwood consistently
provided reproducible results.
(15) Toluene provided slightly better results but the formation of
a gum was deemed undesirable especially in potential scale
up of this reaction.
(16) The mildest of the sulfur fluoride based reagents, XtalFluor,
was found to transform carbonyls into gem-difluoro moieties
at ambient temperatures. This reaction in bifunctional
substrates could be mitigated by using cryogenic
temperatures (–78 °C).
(17) Typical Procedure: The alcohol (1 equiv) was dissolved in
EtOAc (concentration of 0.5 M) at ambient temperature. The
solution was cooled to 5 °C and Et3N⋅3HF (2 equiv) and
Et3N (2 equiv) were successfully added in a dropwise
manner. After stirring for 5 min, TFFH was added in one
portion (1.5 equiv). The solution was then allowed to stir at
the necessary temperature. Upon completion, the reaction
was quenched with sat. NaHCO3 to pH 7 and diluted with
additional EtOAc. Layers were separated and the organic
layer was concentrated to a crude residue. The crude residue
could be purified by flash chromatography or partitioned
between MTBE and H2O to remove the tetramethylurea by-
product.
(5) (a) Cochran, J. Chem. Eng. News 1979, 57 (12), 74.
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Synlett 2012, 23, 569–572
© Thieme Stuttgart · New York

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