Sep 15, 2005 - 16, 2004. Anhydrous organic ?uoride salts and reagents prepared by a method comprising the nucleophilic substitution of a ?uori. (51) IIlt- Cl-.
US007592486B2
(12) Ulllted States Patent
(10) Patent N0.:
DiMagno et al. (54)
(45) Date of Patent:
ANHYDROUS FLUORIDE SALTS AND REAGENTS AND METHODS FOR THEIR PRODUCTION
6,794,401 B2
_
.
.
_
_
_
_
557726.
Christe, K.O., et al., J. Am. Chem. Soc. 1990, 112, 7619-25.
mm H’
.
( * ) Notice:
_
CheMBloChem Spec1a1 Issue: F1u0r1ne 1n the L1fe Sclences 2004, 5,
.
(73) Asslgnee' £02m ‘l’jR?gentls oiltgiggverslty of 6 “S a’
11/1991
OTHER PUBLICATIONS
(US); Haoran Sun, Lincoln, NE (US) .
9/2004 Nag
2035561
(75) Inventors: Stephen G. DiMagno, Lincoln, NE _
Sep. 22, 2009
FOREIGN PATENT DOCUMENTS CA
_
US 7,592,486 B2
Gnann, R.Z., et al., J. Am. Chem. Soc. 1997, 119,112-115. .
.
Subject‘ to any disclaimer, the term of th1s
K
th, A.,
t
1.1
. Ch
Jig: 199031;, 7I6lir9gi762gn
. 2003,42, 2894-2901.
P211911t 15 extended Or adlusted under 35
.J.Am.Chem.S0c., Bennett, B.K. et a1., 1994, 116, 11165-11166.
U.S.C. 154(b) by 312 days.
JACS, 1997, 119, 112-115. Inorg. Chem., 2003, 42, 2894-2901. Cox, D.P., et al., J. Org. Chem. 1984, 49, 3216-19.
(21)
Appl. N0.: 11/226,277
(22)
Filed:
(65)
Prior Publication Data Us 2006/0089514 A1 Apr' 27, 2006
Sep. 15, 2005
Shannn, R.K., et al., J. Org. Chem. 1983, 48, 2112-14. Pilcher, et al. J. Am. Chem. Soc. 1995, 117, 5166-5167. Akiyama,Y, et 211., S. Synlett 2003, 1530-1532.
Primary ExamineriShailendra Kumar (74) Attorney, Agent, or FirmiThompson Coburn LLP;
Steven M. Ritchey, Esq. Related US. Application Data .
.
.
.
(60) Provisional application No. 60/610,412, ?led on Sep. 16, 2004.
(57)
ABSTRACT
Anhydrous organic ?uoride salts and reagents prepared by a method comprising the nucleophilic substitution of a ?uori nated aromatic or ?uorinated unsaturated organic compound With a salt having the formula:
(51)
IIlt- ClC0 7C 211/63
(52)
US. Cl. ......................................... .. 564/281; 568/9
(58)
Fleld 0f Classl?catlon Search ............... .. 5645/22}
in an inert polar’ aprotic Solvent; wherein M is an atom
See application ?le for complete search history.
Capable Ofsuppomng99111911399913.9999the“ gr.oups Q
References Cited
such that the [QnM] carries at least one formal positive charge, X is an integer de?ning the number of formal positive charge(s), +, carried by the [QnM], A“ is an anionic nucleo phile capable of substituting for F in the ?uorinated com pound and F represents ?uorine or a radioisotope thereof.
(56)
(2006.01)
U.S. PATENT DOCUMENTS 5,369,212 5,854,084 6,156,812 6,451,921
A A A B2
11/1994 12/1998 12/2000 9/2002
Christe Drukier Lau Weisse
[QnMYHAX
are independently vaned organic mo1et1es, n is an integer
16 Claims, 10 Drawing Sheets
US. Patent
Sep. 22, 2009
Sheet 1 0f 10
I
-so
-ao
-1oo
Fig. 1
US 7,592,486 B2
I
4'20
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ppm
US. Patent
Sep. 22, 2009
I
~70
Sheet 2 0f 10
PM Fig. 2
US 7,592,486 B2
I
[
l
410
-120
430
ppm
US. Patent
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Sep. 22, 2009
Sheet 3 0f 10
US 7,592,486 B2
US. Patent
Sep. 22, 2009
Sheet 4 0f 10
US 7,592,486 B2
M e
M M
d
US. Patent
Sep. 22, 2009
Sheet 5 0f 10
US 7,592,486 B2
h l
2 hours
H
9
I
92 min
n
f
l
75 min
H
53 min
H
H
e
I
d
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38 min
C
l
29 min
I
H
b
13 min
n
a‘
before addition of water
u
36 " “ .65
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Fig. 5
4'20
-150
-120 ppm
US. Patent
Sep. 22, 2009
US 7,592,486 B2
h
i
2 hours
9
A
92 min
f
A
9
75 min
i
d
53 min
A
0
I
Sheet 6 0f 10
38 min
A
29 min
b
13 min
a
before addition of water
7'1
1'2
1'3
7[4
7'5
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7'1
7'8
7'9 ppm]
US. Patent
Sep. 22, 2009
Sheet 7 0f 10
US 7,592,486 B2
f
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97 mm
9
JJ
77 min
1
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55 min
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US. Patent
Sep. 22, 2009
Sheet 8 0f 10
US 7,592,486 B2
9
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4.5 hours
i
f
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68 min
I
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62 min
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30 min
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US. Patent
Sep. 22, 2009
Sheet 9 0f 10
US 7,592,486 B2
68 min
66 min
62 min
i
44 min
JL “UL )L W 14 min 442.6
442.8
443.0
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443.8
ppm
US. Patent
Sheet 10 0f 10
9
79 min
d
58 min
0
I
Sep. 22, 2009
l
US 7,592,486 B2
39 min
[L
b
17 min
i
a
before addition of water I
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US 7,592,486 B2 1
2
ANHYDROUS FLUORIDE SALTS AND REAGENTS AND METHODS FOR THEIR PRODUCTION
parative methods for synthesizing these individual salts are not applicable for the preparation of a Wide variety of ?uoride
This application claims bene?t of 60/610,412, ?led Sep. 16, 2004.
salts. Anhydrous ?uoride salts With alkyl groups capable of
beta-elimination (ethyl, propyl, butyl, isopropyl, pentyl, 01
isobutyl, etc.) in particular are not accessible by current meth ods.
Generally, then, these compounds are commonly prepared
FIELD OF THE INVENTION
in a hydrated state and are subsequently dried by heating under dynamic vacuum or by azeotropic distillation. HoW
The invention relates to novel organic ?uorides and meth
ods for their production.
ever, the conditions used to dry these salts are often incom
patible With a variety of desirable cations. For example, dried
BACKGROUND OF THE INVENTION
tetrabutylammonium ?uoride, (TBAF) [Cox, D. P., et al, J. Org. Chem. 1984, 49, 3216-19] is reported to decompose by
Fluorine substitution is a powerful tool to improve the
Hofmann elimination at room temperature. The salt isolated
bioavailability of pharmaceuticals and agrochemicals. Thus,
after dehydration is contaminated With copious amounts of bi?uoride ion (HF2) and tributylamine [Shannn, R. K., et al, J.
an expansive set of nucleophilic and electrophilic reagents have been developed to replace various CiX functional groups With CiF.
Org. Chem. 1983, 48, 2112-14]. These considerations and
[CheMBioChem Special Issue: Fluorine In the Life Sciences 2004, 5, 557726]. Simplest among the nucleophilic ?uori nating reagents are “anhydrous” or “naked” organic ?uo
?ndings have led to the belief among those skilled in the art
20
that “it is very unlikely that pure, anhydrous tetraalkylammo nium ?uoride salts have ever, in fact, been produced in the
ride salts, represented by tetramethylammonium ?uoride (TMAF) [Christe, K. O, et al, J. Am. Chem. Soc. 1990, 112, 761 9-25, 1-methylhexamethylenetetramine ?uoride (MHAF) [Gnann, R. Z., et al, J. Am. Chem. Soc. 1997, 119,
case of ammonium ions susceptible to E2 eliminations”
[Sharma et al, supra]. 25
112-115] and tetramethylphosphonium ?uoride (TMPF) [Kornath, A, et al, Inorg. Chem. 2003, 42, 2894-2901]. Highly soluble anhydrous ?uoride salts possessing a Wide variety of alkyl groups are desirable for synthetic purposes, but these compounds cannot be prepared according to cur
and reagents. It is a further object of the invention to provide novel 30
Typical of prior art methods for preparing such salts are those described in US. Pat. No. 5,369,212 and Canadian
The above and other objects are realized by the present 35
The preparation of absolutely anhydrous ?uoride salts
dynamic high vacuum (.
(CH2)3
CH3
C. to RT] in polar aprotic solvents such as tetrahydrofuran,
diethyl carbonate and hexamethylphosphoric triamide. In
( 2 )3\@/(CH2)3_ N G C=N (H2C)3
The reaction may be carried out at loW temperatures [—35°
dimethyl sulfoxide, diethyl ether, dioxane, dimethoxyethane, methyl tert-butyl ether, acetonitrile, acetone, methylethylke tone, tetrahydrofuran, dimethylformamide, dimethylaceta
CH3
H C
35
6,451,921; 6,156,812 and 5,854,084, inter alia. Thus tetrabutylammonium ?uoride (TBAF) is easily pre pared in one step at loW temperatures by the nucleophilic substitution of the hexa?uorobenZene With tetrabutylammo nium cyanide. Adventitious Water is readily scavenged by the hexacyanobenZene by-product of the reaction. The constraints on a ?uoride-generating synthesis
grounded in nucleophile substitution reactions are quite
preferred embodiments tetrahydrofuran, dimethylsulfoxide,
severe and dictate a careful choice of the nucleophile.
and acetonitrile are the solvents employed. Halogenated sol
Because the enthalpic driving force for ?uoride liberating reaction derives almost exclusively from ion-pairing and ABDE terms, and because the CSPZiF bond in aromatics (as Well as unsaturated compounds) is exceptionally strong (126
vents such as methylene chloride or dichloroethane are
decomposed rapidly by anhydrous ?uoride salts, and are thus generally not useful for this synthetic procedure. In the above-described formulae, Q is an organic moiety capable of undergoing E2 elimination and may be, e.g., alkyl, alkenyl, alkynyl, or form the backbone or sidechain of a
polymer. M may be N, P or any element capable of supporting a formal positive charge. The anion A may any diffusely
40
kcal/mol), only diffusely charged anionic nucleophiles capable of forming strong bonds to carbon are capable of acting in nucleophile substitution reactions reactions at loW 45
hybridized carbon (BDEI133 kcal/mol)_is an excellent can didate. It Will be understood by those skilled in the art, hoW
charged anionic nucleophile capable of forming strong bonds
ever, that any similar diffusely charged anionic nucleophile
to carbon in a nucleophilic substitution reaction, such as, e.g.,
cyanide, isothiocyanate, thiocyanate, alkyl- and arylthiolates,
temperature in polar aprotic solvents. Cyanide ion, a potent, Weakly basic nucleophile that forms strong bonds to sp2
50
may also be employed in the method of the invention, such as,
or aZide. In preferred embodiments cyanide is the nucleophile
e.g., isothiocyanate, isocyanate, cyanate, thiocyanate, alkyl
employed.
and arylthiolates, or aZide.
As illustrated in the examples beloW, treatment of
[QnM]"+Ax_ is preferably a tetraalkylammonium cyanide, a trialkylarylammonium cyanide, a dialkyldiarylammonium cyanide, an alkyltriarylammonium cyanide, or a tetraarylam
55
solvents THF, acetonitrile, or DMSO at or beloW room tem
monium cyanide; Q being an organic moiety capable of
perature gives excellent yields of anhydrous TBAF. 19P NMR
undergoing E2 elimination. The ?uorinated compound nucleophically substituted in the method of the invention is preferably a ?uorinated ben Zene, alkene or alkyne With a large number of ?uorine atoms
60
per unit Weight e. g., hexa?uorobenZene, octa?uoronaphtha
lene, octa?uorotoluene, penta?uorobenZonitrile, penta?uo ropyridine, deca?uorobiphenyl, etc. For the generation of isotopically labeled anhydrous ?uoride salts (i.e., TBA 18F) a singly ?uorinated arene is su?icient, e.g., 4-?uorobenZoni trile.
hexa?uorobenZene With tetrabutylammonium cyanide (TBACN) (in 1:1 to 1:6 molar ratios) in the polar aprotic spectroscopy indicates that the overall yield of TBAF in solu tion in all cases is >95%. Cyano substitution dramatically increases the ?uorinated benZene ring’s susceptibility to fur ther nucleophilic attack, as is evidenced by the observation of pentacyano?uorobenZene and hexa?uorobenZene as the prin
cipal ?uorinated aromatic species in the reaction solution, even if 1:1 TBACN:C6F6 stoichiometry is employed. 65
In THF, colorless to light yelloW anhydrous TBAF precipi tated from cooled (—35° C.) solutions and yields of the iso lated salt ranged from 40% to 70%. Freshly isolated TBAF
US 7,592,486 B2 5
6
displayed one singlet 19P NMR signal at —86 ppm in THF and four 1H NMR signals for the TBA cation. The characteristic doublet of H1324 at 6:447 ppm (JH_F:l28 HZ) Was
of ?uoride ion in polar aprotic solvents, since sloW rates of proton transfer and side reactions may preclude generation of a true equilibrium mixture. An additional complication is that any proton transfer to ?uoride ion is folloWed by a rapid conversion to H1324 under these conditions. The kinetic barriers inherent in the proton transfer from CiH bonds to F“ are apparent in the folloWing example.
observed in freshly prepared solution samples, and in samples precipitated from THE and redissolved. The concentration of TBA H1324 Was generally less than 2% that of TBAF. Solid anhydrous TBAF is stable under nitrogen at —35° C. for Weeks. TBAF decomposes sloWly in THF or in the solid state by E2 elimination if Warmed above 0° C. TBAF can be prepared conveniently in situ in polar aprotic
While (CD3)2SO does not undergo proton exchange With residual HF2 in TBAF solutions, if a (CD3)2SO solution of
solvents at room temperature and used Without isolation or
puri?ed TBAF (precipitated from THE) is spiked With Water (0.08 eq.), a sloW (2 h) conversion of HP; to DE; is
puri?cation. Treatment of (CD)3SO or CD3CN solutions of TBACN With C6136 (at 25° C.) gave highly colored, concen trated (up to 2 M) solutions of TBAF exhibiting the charac
observed. Deuterium exchange occurs Without a detectable
increase in the bi?uoride ion concentration, indicating that deprotonation of Water by TBAF is strongly disfavored under
teristic 19P NMR signals for ion-paired ?uoride (Table 1). Small amounts (generally
