Novel process for generating useful electrophiles from common anions using Selectfluor fluorination agent

Article abstract of DOI:10.1021/jo020053u

In the present work, the electrophile equivalents C1⁺, Br⁺, SCN⁺, and NO₂⁺ are generated from their respective sodium, potassium, and in some cases ammonium salts (M⁺X^-) by reaction with Selectfluor electrophilic fluorination agent in acetonitrile solution at room temperature. These generated electrophilic species subsequently react in situ with a variety of aromatic substrates containing one or more substituent groups including H, F, C1, CH₃, COOH, C(O)CH₃, NO₂, and OR′ and NR′R″ where R′ and R″ are H or CH₃. The resulting substitution products are, in most cases, isolable as pure compounds in high yield. Variations in the process include the use of other anions, electrophilic fluorination agents, and solvents.

Full text of DOI:10.1021/jo020053u

J . Org. Chem. 2002, 67, 4487-4493
4487
Novel P r ocess for Gen er a tin g Usefu l Electr op h iles fr om Com m on
An ion s Usin g Selectflu or ® F lu or in a tion Agen t†
Robert G. Syvret,* Kathleen M. Butt, Tung P. Nguyen, Victoria L. Bulleck, and
Ryan D. Rieth
Fluorine Technology Center, Air Products and Chemicals, Inc., 7201 Hamilton Blvd.,
Allentown, Pennsylvania 18195
syvretrg@apci.com
Received J anuary 24, 2002
+
In the present work, the electrophile equivalents Cl+, Br+, SCN+, and NO2 are generated from
their respective sodium, potassium, and in some cases ammonium salts (M+X-) by reaction with
Selectfluor electrophilic fluorination agent in acetonitrile solution at room temperature. These
generated electrophilic species subsequently react in situ with a variety of aromatic substrates
containing one or more substituent groups including H, F, Cl, CH3, COOH, C(O)CH3, NO2, and
OR′ and NR′R′′ where R′ and R′′ are H or CH3. The resulting substitution products are, in most
cases, isolable as pure compounds in high yield. Variations in the process include the use of other
anions, electrophilic fluorination agents, and solvents.
In tr od u ction
rite,14 sodium chlorite/(salen)Mn(III) complex,15 chlorine
trifluoromethanesulfonate,16 and triethylammonium tri-
chloride17 for chlorination; N-bromosuccinimide8-12 (NBS)
and alkylammonium tribromide18 for bromination; N-
iodosuccinimide,19 iodine(I) triflate,20 and dichlorohypo-
iodite salts21 for iodination; and various -NF, -XeF, and
-OF agents for fluorination.6,22 In a recent report,23 a new
method for halogenation of activated aromatic substrates
through the dimethyldioxirane oxidation of halide anions
was disclosed.
There is a general need for effective methodologies for
introducing various functional groups into aromatic
systems. In particular, electrophilic methodologies find
widespread applications since these reactions are very
well understood and the product distribution is generally
predictable.1 Despite the importance of synthetic methods
for introducing electrophiles into aromatic systems, in
some cases there are either relatively few reagents
available to accomplish such transformations or the
reagents themselves are difficult to prepare and use.
Reagents for electrophilic halogenation are available
in various forms ranging from the diatomic elements to
some fairly exotic halogen delivery reagents.1-5 Most of
these reagents can be prepared and isolated prior to use;
however, some are available only when generated in situ.
Reagents specifically useful for electrophilic halogenation
include, but are not limited to, N-chlorosuccinimide6-12
(NCS), N-chloroammonium salts,13 tert-butylhypochlo-
Reagents that are known to deliver electrophilic thio-
cyanogen (+SCN) include thiocyanogen,24,25 cyanogen
chloride,26-29 and metal thiocyanates mediated by aryl-
iodite,30 NCS,31,32 and NBS.32,33
(13) Lindsay-Smith, J . R.; McKeer, L. C. Tetrahedron Lett. 1983,
24 (30), 3117.
(14) Lengyel, I.; Cesare, V.; Stephani, R. Synth. Commun. 1998, 28
(10), 1891.
(15) Hirano, M.; Yakabe, S.; Monobe, H.; Morimoto, T. Can. J . Chem.
1997, 75, 1905.
(16) Effenberger, F.; Kussmaul, U.; Huthmacher, K. Chem. Ber.
1979, 112, 1677.
† Presented in part at the 219th National Meeting of the American
Chemical Society, March 2000, San Francisco, CA. See: C&EN, April
17, 2000, p 46.
* To whom correspondence should be addressed. Phone: 610-481-
3536. Fax: 610-706-6586.
(1) March, J . Advanced Organic Chemistry; Wiley: New York, 1985;
pp 447-511; and references therein.
(2) De La Mare, P. B. D.; Ridd, J . H. Aromatic Substitution;
Butterworth: London, 1959; and references therein.
(3) De La Mare, P. B. D.; Electrophilic Halogenation; Cambridge
University Press: London, 1976; and references therein.
(4) Buehler, C. A.; Pearson, D. E. Survey of Organic Synthesis;
Wiley: New York, 1970; and references therein.
(5) Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev. 1996, 96 (5), 1737.
(6) Abushanab, E.; Bindra, A. P.; Lee, D.-Y. J . Org. Chem. 1975, 40
(23), 3373.
(17) Schlama, T.; Gabriel, K.; Gouverneur, V.; Mioskowski, C.
Angew. Chem., Int. Ed. Engl. 1997, 36 (21), 2342.
(18) Kajigaeshi, S.; Moriwaki, M.; Tanaka, T.; Fujisaki, S.; Kaki-
nami, T.; Okamoto, T. J . Chem. Soc., Perkin Trans. 1 1990, 897.
(19) Carren˜o, M. C.; Garc´ıa-Ruano, J . L.; Sanz, G.; Toledo, M. A.;
Urbano, A. Tetrahedron Lett. 1996, 37 (23), 4081.
(20) Olah, G. A.; Wang, Q.; Sandford, G.; Prakash, G. K. S. J . Org.
Chem. 1993, 58, 3194.
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M.; Okamoto, T. Chem. Lett. 1987, 2109.
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Organic Synthesis; Springer-Verlag: Berlin, 1989; and references
therein.
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bari, M. Synth. Commun. 2001, 31 (19), 2955.
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1972, 37 (25), 4078.
10.1021/jo020053u CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/15/2002

4488 J . Org. Chem., Vol. 67, No. 13, 2002
Syvret et al.
Sch em e 1
In the present work, depicted in eq 2, the equivalents
+
to Cl+, Br+, SCN+, and NO2 are generated from their
respective sodium, potassium, and in some cases am-
monium salts (M+X-) by reaction with Selectfluor in ACN
or an equivalent solution, and the generated species
subsequently react in situ with a variety of aromatic
substrates (in eq 2, R1-3 can each represent a strongly
deactivating to strongly activating substituent group,
including H, F, Cl, CH3, COOH, C(O)CH3, NO2, and OR′
and NR′R′′ where R′ and R′′ are H or CH3) yielding the
corresponding substitution products, many times in high
yield and with good purity.
We have evidence also that other anions, e.g., CH3COO-
and CF3COO-, are converted similarly to electrophiles
for some limited examples, that other electrophilic fluo-
rination agents and solvents also show this effect, and
that electrophilic addition reactions with some nonaro-
matic unsaturated moieties can be effected by this
reaction methodology. A discussion of the variations in
this process and some process limitations is provided in
the following subsections.
Electrophilic nitration can be accomplished using a
variety of reagents, some of which include nitronium
salts,34-38 methyl nitrate,39 and sodium nitrite mediated
by trifluoroacetic acid.40
In the present work, we describe a new process for
+
generating electrophiles Cl+, Br+, SCN+, and NO2 and
have applied these in electrophilic aromatic substitution
reactions of various substrates.
Resu lts a n d Discu ssion
In the course of expanding the known reaction chem-
istry of Selectfluor, a commercially available and widely
applicable electrophilic fluorination agent,5,41 we discov-
ered an interesting class of reactions that occur between
various inorganic anions and a number of aromatic
substrates, in the presence of Selectfluor in acetonitrile
(ACN) solution. This process is depicted in general terms
in Scheme 1.
Rea ctivity of Va r iou s An ion s w ith Ar om a tic Su b-
str a tes. The anions that have been investigated in this
general reaction process can be divided into three groups
based on their observed reactivity with aromatic sub-
strates. In the first group of anions, we found that the
sodium, potassium, and in some cases ammonium salts
of chloride (Cl-), bromide (Br-), thiocyanate (-SCN), and
We have found that the combination of Selectfluor,
represented in eq 1a by F+, and various anions, repre-
sented by X-, in acetonitrile solvent at room temperature
produces the equivalent of an X+ electrophile such that,
in the presence of an aromatic substrate (ArH), electro-
philic substitution of X-for-H occurs (eq 1b). We assume
that the reactions proceed via an electrophilic substitu-
tion mechanism; however, this may be an oversimplifica-
tion of the actual mechanism in operation. Nevertheless,
the net effect is the conversion of X- to X+, facilitated by
the fluorine electrophile F+, and subsequent addition of
the resulting X+ electrophile to the aromatic substrate.
There is just one previous report of an electrophilic
fluorination agent functioning as a mediator for effecting
electrophilic reactions.42 In this report, mixtures of ani-
sole 2a , Selectfluor, and I2, KI, Me3SiI, or MeI in solution
were shown to produce iodoanisole derivatives regio-
selectively. This result is not surprising, however, since
it had previously been established43 that Selectfluor
readily and immediately oxidizes iodide to iodine in
solution.
nitrite (NO2-) are very effectively converted to their
+
electrophile equivalents, Cl+, Br+, +SCN, and NO2
,
respectively, in each case, and that these electrophiles
readily add to a wide range of aromatic substrates.
Provided in Table 1 is a summary of experimental
results for electrophilic reactions involving this primary
group of anions with various aromatic substrates. Refer-
ring to Table 1, the reaction between equimolar amounts
of 1a and Br- was ∼90% complete after 3 h of reaction
time, with 1b being the major product. The reaction
between 1a and Cl- was 42% complete after 42 h, with
1e being the major chlorinated product (25%), but also a
significant amount (67%) of 1d was observed. In the
reaction with SCN-, just 4% of 1a was converted after
93 h, with the para-thiocyanate derivative 1f being the
only product. Finally, nearly complete conversion of the
-
1a was observed after 68 h in the reaction with NO2
with 1g being the predominant (81%) product.
,
The difference in reactivity that was observed between
the anions and 1a is representative of all the aromatic
systems that were investigated and supports a general
trend that has been established. That is, the reactivity
of the electrophiles generated from anions with various
aromatic substrates decreases in the order Br+ > Cl+
>
SCN+ > NO2+, with the reactions involving Br+ being,
in general, much more facile than those with NO2+. Thus,
in the reaction involving Br+, 90% conversion of 1a was
achieved after just 3 h, whereas with NO2+, 68 h was
required to achieve the same conversion. The low conver-
(30) Bruno, M.; Margarita, R.; Parlanti, L.; Piancatelli, G.; Trifoni,
M. Tetrahedron Lett. 1998, 39, 3847.
(31) Takagi, K.; Takachi, H.; Hayama, N. Chem. Lett. 1992, 509.
(32) Takagi, K.; Takachi, H.; Sasaki, K. J . Org. Chem. 1995, 60,
6552.
(33) Li, A. L. Chinese Chem. Lett. 1991, 2 (9), 675.
(34) Olah, G. A.; Kuhn, S. J .; Flood, S. H. J . Am. Chem. Soc. 1961,
83, 4571.
(35) Olah, G. A.; Kuhn, S. J .; Flood, S. H. J . Am. Chem. Soc. 1961,
83, 4581.
(36) Olah, G. A.; Kuhn, S. J . J . Am. Chem. Soc. 1962, 84, 3684.
(37) Olah, G. A.; Kuhn, S. J .; Flood, S. H.; Evans, J . C. J . Am. Chem.
Soc. 1962, 84, 3687.
(38) Kuhn, S. J .; Olah, G. A. J . Am. Chem. Soc. 1961, 83, 4564.
(39) Olah, G. A.; Lin, H. C. Synthesis 1973, 488.
(40) Uemura, S.; Toshimitsu, A.; Okano, M. J . Chem. Soc., Perkin
Trans. 1 1978, 1076.
(41) Banks, R. E.; Mohialdin-Khaffaf, S. N.; Lal, G. S.; Sharif, I.;
Syvret, R. G. J . Chem. Soc., Chem. Commun. 1992, 595.
(42) Zupan, M.; Iskra, J .; Stavber, S. Tetrahedron Lett. 1997, 38 (35),
6305.
(43) Gilicinski, A. G.; Pez, G. P.; Syvret, R. G.; Lal, G. S. J . Fluorine
Chem. 1992, 59, 157.

Generating Useful Electrophiles from Common Anions
J . Org. Chem., Vol. 67, No. 13, 2002 4489
Ta ble 1. Resu lts of Exp er im en ts a t Room Tem p er a tu r e in Aceton itr ile Solven t (ACN)
ACN
(mL)
F+a
(mmol)
time conversion
aromatic, mmol
phenol 1a , 10.0
NaX, mmol
NaBr, 15.1
(h)
(%)
product distribution,b,c mol %
80
9.9
3
90
bromophenol 1b, 87; 2,4-dibromophenol 1c, 12;
fluorophenol 1d , 1
phenol 1a , 20.4
phenol 1a , 10.0
phenol 1a , 10.0
80
80
80
NaCl, 25.4
NaSCN, 15.1
NaNO2, 14.5
21.4
9.9
9.9
42
93
68
42
4
98
chlorophenol 1e, 25; 1d , 67; unknown, 8
4-SCN-phenol 1f, 100
nitrophenol 1g, 81; fluoronitrophenol 1h , 16;
unknown, 3
anisole 2a , 19.9
anisole 2a , 21.0
80
80
NaBr, 20.1
NaCl, 22.1
20.9
20.4
21
42
100
58
4-bromoanisole 2b, 100
chloroanisole 2c, 67; fluoroanisole 2d , 31;
unknown, 2
anisole 2a , 20.3
anisole 2a , 10.2
acetanilide 3a , 10.0
acetanilide 3a , 10.0
200
100
80
NaSCN, 19.7
NaNO2, 10.0
NaBr, 17.0
NaCl, 10.3
20.0
9.9
9.9
21
97
3
67
43
87
53
SCN-anisole 2e, 94; unknown, 6
nitroanisole 2f, 13; 2d , 87
bromoacetanilide 3b, 99; fluoroacetanilide 3c, 1
chloroacetanilide 3d , 73;
100
9.9
23
chlorofluoroacetanilide 3e, 5;
3c, 22
acetanilide 3a , 10.0
acetanilide 3a , 20.1
aniline 4a , 24.5
aniline 4a , 21.5
aniline 4a , 21.5
80
80
80
80
80
80
80
NaSCN, 17.3
NaNO2, 27.0
NaBr, 21.4
NaCl, 26.3
NaSCN, 22.4
NaNO2, 19.0
NaBr, 9.7
9.9
9.9
71
27
17
17
17
18
42
0
10
starting material 3a only
nitroacetanilide 3f, 95; 3c, 5
F-aniline 4b, 61; benzophenone 4c, 39
4b, 57; 4c, 43
SCN-aniline 4d , 96; 4b, 4
4c, 60; unknown, 40
bromodimethylaniline 5b, 37;
fluorodimethylaniline 5c, 44;
unknown, 19
20.0
19.8
20.0
20.2
9.9
39d
50e
82f
100g
75
aniline 4a , 29.4
dimethylaniline 5a , 9.9
dimethylaniline 5a , 9.9
dimethylaniline 5a , 18.4
dimethylaniline 5a , 9.9
tolueneh6a , 10.0
80
80
80
NaCl, 9.9
9.9
19.8
9.9
43
18
68
19
66
98
93
39
chlorodimethylaniline 5d , 6; 5c, 54; unknown, 40
4-SCN-dimethylaniline 5e, 100
nitrodimethylaniline 5f, 38; 5c, 43; unknown, 19
bromotoluene 6b, 49; bromomethyltoluene 6c, 36;
unknown, 15
NaSCN, 21.3
NaNO2, 10.1
NaBr, 10.0
100
9.9
tolueneh6a , 19.2
benzene 7a , 10.0
benzene 7a , 10.0
benzene 7a , 10.0
80
80
80
80
NaCl, 20.3
NaBr, 10.5
NaCl, 10.1
NaSCN, 10.4
20.3
10.0
10.0
10.0
66
72
72
72
51
100
100
100
chlorotoluene 6d , 100
bromobenzene 7b, 100
chlorobenzene 7c, 97; dichlorobenzene 7d , 3
no SCN-benzene product, only unidentified
sulfur-containing species present
NO2-benzene 7e, 100
2-bromo-1,4-dimethoxybenzene 8b, 100
2-chloro-1,4-dimethoxybenzene 8c, 100
2-thiocyanato-1,4-dimethoxybenzene 8d , 100
2-nitro-1,4-dimethoxybenzene 8e, 100
3′-Br-p-MAPj 9b, 97;
benzene 7a , 10.0
1,4-DMB 8a , 22.3
1,4-DMB 8a , 17.9
1,4-DMB 8a , 27.6
1,4-DMB 8a , 26.1
p-MAP 9a , 10.0
80
80
80
80
80
80
NaNO2, 10.5
NaBr, 34.7
NaCl, 34.8
NaSCN, 44.1
NaNO2, 33.5
NaBr, 10.1
10.0
30.0
29.7
40.8
31.0
10.0
72
113
113
160
184
95i
100
100
100
60
100
89
2,4-dibromo-1-methoxybenzene 9c, 2;
2b, 1
p-MAP 9a , 10.0
p-MAP 9a , 10.0
p-MAP 9a , 9.9
p-xylene 10a , 10.4
p-xylene 10a , 23.7
p-xylene 10a , 10.4
2-fluoroanisolek11a , 20.0
80
80
80
100
80
100
200
NaCl, 10.2
NaSCN, 10.1
NaNO2, 9.8
NaBr, 10.7
NaCl, 33.7
NaSCN, 10.1
NaCl, 20.1
10.0
10.0
10.0
9.9
21.2
9.9
95
95
95
73
47
≈1
50
52
56
52
3′-chloro-p-MAPj 9d , 97; 2c, 3
3′-SCN-p-MAPj 9e, 100
2f, trace; 2-fluoro-4-methoxynitrobenzene 9f, trace
bromo-p-xylene 10b, 78; unknown, 22
chloro-p-xylene 10c, 100
SCN-p-xylene 10d , 82; unknown, 18
4-chloro-2-fluoroanisole 11b, 96;
2,4-difluoroanisole 11c, 2; 2c, 2
2-chloro-4-fluoroanisole 12b, 91; 11c, 6; unknown, 3
2,4-dinitrophenol, 100
3
162
148
26
42.4
4-fluoroanisolek 12a , 20.1
4-nitrophenoll 13a , 10.1
chloro-p-xylenek 10c, 20.0
200
80
200
NaCl, 20.1
NaNO2, 10.1
NaCl, 20.0
42.3
10.0
42.4
26
45
24
53
95
58
2,5-dichloro-1,4-dimethylbenzene 10e, 95;
2-chloro-5-fluoro-1,4-dimethylbenzene 10f, 2;
unknown, 3
a
F+ is Selectfluor fluorination agent, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate). b Product distribution
is expressed as a normalized % of conversion. c If not specifically stated, the ortho/para isomer ratio was not determined. No brominated
d
products were found. e No chlorinated products were found. f Conversion was increased to 100% after 64 h following the addition of
g
h
Selectfluor (9.8 mmol) and NaSCN (10.3 mmol). No nitrated or fluorinated products were found. Experiments involving 6a and either
NaSCN or NaNO2 failed to show that any reaction had occurred. Conversion did not change from 68 to 95 h. Electrophilic aromatic
i
j
substitution is presumed to occur at the 3′-position due to the directing effects of the acetyl and methoxy groups; however, this has not
k
l
been established analytically. Only experiments with NaCl were performed with these aromatic substrates. Reactions involving 13a
and NaBr, NaCl, and NaSCN proceeded to completion; however, the products could not be unambiguously characterized.
sion (4%) observed in the reaction involving SCN- and
1a in ACN in the presence of Selectfluor is an unresolved
anomaly to the general reactivity trend that has been
established.
In the second group of anions, which includes acetate
(CH3COO-) and trifluoroacetate (CF3COO-) salts, only
some reactions involving these anions were successful,
although conversion of the aromatic substrate was low
(<5%) in each case. For instance, reactions involving
equimolar amounts of Selectfluor, 10a , and either sodium
trifluoroacetate or ammonium acetate, in ACN solution
at ambient temperature, produced only minor amounts
of the trifluoroacyl- and acyl-substituted products, re-
spectively.
Attempted reactions involving the third group of
anions, which include cyanide (-CN), cyanate (-OCN),
methoxide (-OCH3), and thiomethoxide (-SCH3), failed
under all circumstances to show any indication of conver-

4490 J . Org. Chem., Vol. 67, No. 13, 2002
Syvret et al.
Ta ble 2. Com p a r ison of Rea ction Ra tes for Ch lor in a tion of Ar om a tic Su bstr a tes w ith KCl, Na Cl, a n d Selectflu or in
ACN Solven t a t Room Tem p er a tu r e
substrate
reaction time, h
conversion using KCl, mol %
conversion using NaCl, mol %
conversion ratio KCl/NaCl
9a
10a
6a
66
90
66
90
47a
60c
63e
13g
44b
39d
51f
15h
1.1
1.5
1.2
0.9
7a
a
b
9a (24.3 mmol), Selectfluor (20.6 mmol), KCl (21.6 mmol) in 80 mL of ACN. 9a (20.3 mmol), Selectfluor (20.2 mmol), NaCl (26.6
mmol) in 80 mL of ACN. c 10a (26.6 mmol), Selectfluor (20.0 mmol), KCl (21.1 mmol) in 80 mL of ACN. 10a (23.7 mmol), Selectfluor
d
(21.2 mmol), NaCl (33.7 mmol) in 80 mL of ACN. e 6a (21.6 mmol), Selectfluor (21.1 mmol), KCl (20.3 mmol) in 80 mL of ACN. f 6a (19.2
g
mmol), Selectfluor (20.3 mmol), NaCl (20.3 mmol) in 80 mL of ACN. 7a (18.5 mmol), Selectfluor (20.1 mmol), KCl (20.1 mmol) in 80 mL
of ACN. 7a (21.7 mmol), Selectfluor (20.2 mmol), NaCl (20.9 mmol) in 80 mL of ACN.
h
Ta ble 3. Com p a r ison of Rea ction Ra tes for th e
Ch lor in a tion of 2a a n d 10a in ACN Solven t w ith Na Cl
a n d Differ en t F lu or in a tion Agen tsa
sion of the anion to an electrophile or of transfer of the
anticipated electrophile groups “+CN”, “+OCN”, “+OCH3”,
and “+SCH3”, respectively, to the aromatic substrate.
Instead, reactions involving these anions and those
aromatic substrates that are strongly activated toward
electrophilic aromatic substitution, e.g., 2a , resulted in
fluorinated products being formed exclusively, e.g., 2d .
Attempted reactions involving the third group of anions
and weakly activated aromatic substrates, e.g., 6a or 10a ,
failed to show any products in all cases.
product
reaction conversion, distribution
substrate
F+ agentb
time, h
%
(mol %)
2c (80);
2d (20)
2c (63);
2d (37)
2c (80);
2a
Selectfluor
117
84
2a
2a
Accufluor
117
115
76
58
Selectfluor (II)
Qu a lita tive Rea ction Ra tes of K+ vs Na + for M+Cl-
Sa lts. Qualitative reaction rates for the addition of Cl+,
generated from either KCl or NaCl salts, to several
aromatic substrates were determined under similar
conditions, and the results are summarized in Table 2.
Only reactions where chlorination was observed in exclu-
sion of fluorination are included. The rate of reaction,
defined qualitatively as the % conversion of aromatic
substrate achieved in a given time period, using KCl was
found to be marginally faster than that for NaCl for all
aromatic substrates except 7a . The greatest difference
observed was for the chlorination of 10a where 50% more
conversion was achieved in the same time period using
KCl.
2d (20)
2c (100)
10c (78);
10e (14)
10c (90);
10e (6)
2a
10a
SynFluor
Selectfluor
163
121
71
74
10a
Accufluor
121
54
10a
10a
Selectfluor (II)
SynFluor
114
113
42
28
10c (100)
10c (100)
a
For reactions of 10 mmol each of aromatic substrate, NaCl,
and fluorination agent in 100 mL of solvent at room temperature.
F+ agents are: Selectfluor, 1-chloromethyl-4-fluoro-1,4-diazo-
b
niabicyclo[2.2.2]octane bis(tetrafluoroborate); Selectfluor (II), 1-flu-
oro-4-methyl-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluorobo-
rate); Accufluor, 1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate); SynFluor, 1,1′-difluoro-2,2′-bipyridinium
bis(tetrafluoroborate).
Ar om a tic Su bstr a tes In vestiga ted . A wide range of
monosubstituted aromatic substrates has been investi-
gated in this reaction methodology, from highly activated,
e.g., phenol 1a , to nonactivated, e.g., benzene 7a . The
specific monosubstituted aromatic substrates and result-
ing products are depicted in Scheme 2 and summarized
in Table 1. In addition, we also have found several
disubstituted aromatic substrates to be active in this
reaction process; the specific reactants and products are
depicted in Scheme 3 and summarized in Table 1. Not
all of these aromatic substrates respond the same in
terms of which electrophiles will add and which will not.
Moreover, the relative rate of electrophilic addition differs
significantly between substrates; with some of the sub-
strates, the reactions are sluggish, while with others, the
reactions are quite facile. In general, the more activating
the group on the aromatic ring toward electrophilic
aromatic substitution, the more facile the reaction be-
tween the generated electrophile and the aromatic com-
pound. Thus, using the reactions between Br- and the
aromatics for illustration, we found that 1a is nearly fully
converted to 1b within 3 h, conversion of 2a requires 21
h for completion, 7a requires 72 h for complete conver-
sion, and 9a requires 95 h.
reactions performed in the course of this work were
carried out using commercial-grade Selectfluor fluorina-
tion agent, three other fluorination agents, Selectfluor
(II), Accufluor, and SynFluor were also investigated in a
limited subset of examples for their efficacy in this
reaction methodology. The four F+ agents used in this
work are illustrated below.
For all reactions studied in the course of this work,
including those using different electrophile sources M+X-
(M ) Na, K, NH4; X ) Br, Cl, SCN, NO2) with various
aromatic substrates in different solvents, we found that
Selectfluor fluorination agent affords the highest yields
of substituted aromatic products in the shortest reaction
time. Table 3 provides a representative comparison of the
reaction rates, defined as the % conversion of aromatic
Aromatic substrates found to be unreactive in this
reaction methodology include acetophenone, benzoic acid,
benzonitrile, chloro- and fluorobenzene, 2-hydroxy-4-
methyl-quinoline, 2-hydroxyquinoline, and nitrobenzene.
Qu a lita tive Com p a r ison of Rea ction Ra tes Usin g
Differ en t F + Com p ou n d s. While a large majority of the

Generating Useful Electrophiles from Common Anions
Sch em e 2
J . Org. Chem., Vol. 67, No. 13, 2002 4491
substrate achieved in a given time period, for chlorination
of 2a and 10a with equimolar amounts of NaCl, aromatic
substrate, and various fluorination agents, in acetonitrile
solvent at ambient temperature. It is evident from the
data in Table 3 that the highest conversion (of aromatic
substrate) in the shortest period of time is achieved using
Selectfluor, and the conversion then decreases, generally,
in the order Selectfluor > Accufluor > Selectfluor (II) >
SynFluor.
conversion achieved in the shortest period of time) for
reactions performed in DMF and decreases in the order
DMF > ACN ≈ ACN/H2O (50:50 v/v) > propionitrile.
Non a r om a tic Su bstr a tes In vestiga ted . While this
study focused on electrophilic reactions with aromatic
substrates, a few nonaromatic compounds were investi-
gated. For example, the reaction of equimolar amounts
of NaCl, Selectfluor, and 1,3-dimethyluracil, after 94 h
in ACN solvent at room temperature, did result in
complete conversion of the substrate with a product
distribution that included 5-chloro-1,3-dimethyluracil (24
mol %), 5-chloro-6-fluoro-1,3-dimethyluracil (41 mol %),
and 5,6-dichloro-1,3-dimethyluracil (19 mol %).
Qu a lita tive Com p a r ison of Rea ction Ra tes Usin g
Differ en t Solven ts. In general, we have found that ACN
is the best general purpose solvent to use in this elec-
trophilic substitution reaction methodology. We have
qualitatively investigated the effect on the reaction rate
of using different solvents and have found, for each of
the aromatic substrates investigated in this process, that
the rates of reactions with the electrophiles derived from
Br- and Cl- are marginally faster in DMF solvent than
when performed in either ACN or ACN/H2O (50:50). On
the other hand, the rates of reactions with the electro-
Exp er im en ta l Section
Gen er a l. Solvents of HPLC-grade purity and other reagents
were purchased commercially and used as received. Fluorina-
tion agents Selectfluor and Selectfluor (II) (Air Products and
Chemicals, Inc.), Accufluor (Honeywell, Inc.), and SynFluor
(SynQuest Laboratories, Inc.) are commercially available and
were used as received. Unless otherwise specified, all reactions
were carried out in standard glassware, under an N2 atmo-
sphere. Column chromatography was performed on silica gel
philes derived from SCN- and NO2 are considerably
-
faster in ACN than when performed in DMF. In all cases,
the rates are faster for reactions performed in ACN or
DMF when compared to those carried out in propionitrile.
MeOH solvent was found to be inactive in this reaction
methodology. The data in Table 4 are provided as an
illustration of this solvent effect and provide a qualitative
comparison of the reaction rates for the chlorination of
2a and 10a with NaCl and Selectfluor in different
solvents. It is clear from the data in Table 4 that the
reaction rate for chlorination is the greatest (the highest
1
(40-140 mesh). H and 13C{1H} NMR spectra were recorded
at 300.13 and 75.47 MHz, respectively, and referenced inter-
nally to the deuterated solvent. Melting and boiling points are
uncorrected. Galbraith Laboratories, Inc., Knoxville, TN,
performed elemental analyses.
Ch a r a cter iza tion of Rea ction P r od u cts. For all ex-
amples cited in this paper, where appropriate, characterization
was performed on isolated and purified samples of the reaction
products. Combinations of NMR (1H, 13C, 19F), IR, and GC-

4492 J . Org. Chem., Vol. 67, No. 13, 2002
Syvret et al.
Sch em e 3
Ta ble 4. Com p a r ison of Rea ction Ra tes for th e Ch lor in a tion of 2a a n d 10a w ith Na Cl a n d Selectflu or in Differ en t
Solven tsa
solvent
DMF
DMF
ACN
ACN
substrate
reaction time, h
conversion, %
product distribution (%)
2c (100)
10c (100)
2c (67); 2d (31); unknown (2)
10c (100)
2a
10a
2a
23
24
42
76
31
58
6
10a b
18
42
162
68
23
52
68
ACN/H2O
50:50 (v/v
ACN/H2O
50:50 (v/v
propionitrile
propionitrile
MeOH
2a
2c (25); 2d (75)
10a
70
72
10c (69); 10g (6); oxidation product (25)
2a
10a
2a
67
42
93
20
1
0
2c (60); 2d (40)
10g (100)
no reaction products
no reaction products
MeOH
10a
119
0
a
b
For reactions of 10 mmol each of aromatic substrate, NaCl, and Selectfluor in 100 mL of solvent at room temperature. Reaction was
monitored by GC after 18, 42, and 162 h.
MS were employed to effect characterization. Characterization
data for all reaction products were consistent with those found
in the literature except for 5-acetyl-2-methoxyphenyl-1-thio-
cyanate 9e, which apparently is a new composition. Charac-
terization data for 9e can be found later in this Experimental
Section. Because of the established directing effects of the
acetyl and methoxide groups in electrophilic aromatic substi-
tution reactions,1 compounds 9b, 9d , and 9e are presumed to
be the 3′-isomers as indicated in Scheme 3, and not the 2′-
regioisomers, which are also possible for these compounds.
There are no analytical data available that support the latter
assumption.
Gen er a l P r oced u r e. In a typical experiment, Selectfluor
fluorination agent (7.1 g, 20.0 mmol), NaSCN (1.6 g, 19.7
mmol), and 200 mL of ACN were combined in a 500 mL round-
bottom flask containing a magnetic stir bar. Compound 2a (2.2
g, 20.3 mmol) was added, and the contents of the flask were
stirred under nitrogen and sampled periodically to monitor the
reaction progress. After the mixture was stirred for 20 h at
room temperature, analysis by GC and GC-MS indicated that
67% conversion of the 2a had been achieved, with a product
distribution of 1 and 62% ortho- and para-methoxyphenyl-
thiocyanate 2e, respectively. At this point, the solvent was
removed in a vacuum, and the resulting residue was treated
with 200 mL of deionized water. This aqueous mixture was
extracted with 2 × 100 mL portions of methylene chloride; the
methylene chloride extracts were combined, dried (MgSO4),
and then evaporated to a crude product residue. This residue
was purified by chromatography on silica gel using a mixture
of 5% ethyl acetate and 95% hexane. A product fraction was
collected, dried over MgSO4, and then analyzed by NMR, GC-
MS, and GC-IR and shown to be a mixture of ortho and para
isomers of 2e, but predominately the para isomer. 1H NMR
(CDCl3, 25 °C): δ 3.76 (s, 3H), 6.89 (d, 2H, J ) 8.9 Hz), 7.44
(d, 2H, J ) 8.8 Hz). 13C{1H} NMR (CDCl3, 25 °C): δ 55.26
(1C), 111.39 (1C), 113.41 (1C), 115.59 (2C), 133.49 (2C), 161.02
(1C). MS (EI) m/e (relative intensity): 165 (M+, 100), 150 (74),
139(15), 122 (48), 63 (18). IR (KBr): 2173 cm-1
.
5-Acetyl-2-m eth oxyp h en yl-1-th iocya n a te (9e). Follow-
ing the general procedure above, Selectfluor (7.2, 20.3 mmol),

Generating Useful Electrophiles from Common Anions
J . Org. Chem., Vol. 67, No. 13, 2002 4493
9a (3.09 g, 20.6 mmol), and NaSCN (1.69 g, 20.9 mmol) were
combined with 80 mL of ACN and stirred under N2 for 96 h at
room temperature. After the specified time, the solids were
removed by filtration and the filtrate evaporated to near-
dryness. The residue was washed with 50 mL of H2O and
extracted with 3 × 50 mL portions of methylene chloride. The
organic layers were combined, dried (MgSO4), and evaporated
down to an orange solid. The solid was recrystallized from
ethyl acetate/hexane (90/10) to afford an analytically pure
sample. Yield of 9e: 2.4 g, 11.6 mmol, 56.3%. Mp: 107-109
1C). MS (EI) m/z (relative intensity): 207 (M+, 35), 192 (100).
Anal. Calcd for C10H9NO2S: C, 57.95; H, 4.38; N, 6.76; S, 15.47.
Found C, 56.86; H, 4.22; N, 6.94; S, 15.54.
Ack n ow led gm en t. The authors acknowledge the
assistance of Dr. David M. Parees in acquiring the MS
data and Professor Alex J anzen, Dr. Sankar Lal, and
Dr. Bill Casteel, J r., for useful discussions concerning
the content of this paper.
1
°C. H NMR (CDCl3, 25 °C): δ 2.56 (s, 3H), 3.98 (s, 3H), 6.97
1
Su p p or tin g In for m a tion Ava ila ble: GC-MS and H and
(d, 1H, J ) 8.6 Hz), 7.98 (dd, 1H, J ) 8.6, 2.1 Hz), 8.14 (d, 1H,
J ) 2.1 Hz). 13C {1H} (CDCl3, 25 °C): δ 26.30 (s, 1C), 56.64 (s,
1C), 109.67 (s, 1C), 110.92 (s, 1C), 113.90 (s, 1C), 130.76 (s,
1C), 131.38 (s, 1C), 131.48 (s, 1C), 159.94 (s, 1C), 195.32 (s,
13C NMR spectra of compound 9e. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O020053U