Fluorocyanation of enamines

Article abstract of DOI:10.1021/jo1008993

(Figure presented) A method for the fluorocyanation of enamines has been described. The reaction involves fluorination of the electron rich double bond with N-F reagent (Selectfluor or NFSI) accompanied by trapping of β-fluoroiminium cationic intermediate with cyanide nucleophile.

Full text of DOI:10.1021/jo1008993

pubs.acs.org/joc
In particular, reagents with a N-F bond can be considered as
Fluorocyanation of Enamines
equivalents of positive fluorine and can be employed in reac-
tions with many organic and organometallic nucleophiles.6-8
Typical N-F reagents such as Selectfluor, N-fluorobenzene-
sulfonimide (NFSI), and N-fluoropyridinium triflate are com-
mercially available (Figure 1).
The interaction of alkenes with fluorinating reagent gene-
rates labile β-fluorocarbocations,9 which are either trapped by
oxygen or nitrogen nucleophile10 (eq 1) or stabilized by elimi-
nation of an adjacent proton or silyl group.11 Herein we report
the first example of a process involving electrophilic fluorina-
tion accompanied by addition of a carbon nucleophile.
Alexander D. Dilman,*,† Pavel A. Belyakov,†
Marina I. Struchkova,† Dmitry E. Arkhipov,‡
Alexander A. Korlyukov,‡ and Vladimir A. Tartakovsky†
†N. D. Zelinsky Institute of Organic Chemistry, 119991 Moscow,
Leninsky prosp. 47, Russian Federation, and ‡A. N. Nesmeyanov
Institute of Organoelement Compounds, 119991 Moscow,
Vavilov str. 28, Russian Federation
adil25@mail.ru
Received May 7, 2010
To realize this process in a three-component manner, a
fluorinating reagent should react with alkene faster than with
carbon nucleophile. At the same time, intermediate β-fluoro-
carbocation should react faster with nucleophile than with
the starting alkene. To satisfy these criteria we selected enamines
as electron rich alkenes readily susceptible to fluorination,12,13
and trimethylsilyl cyanide (TMSCN) as terminating nucleophile.
A method for the fluorocyanation of enamines has been
described. The reaction involves fluorination of the elec-
tron rich double bond with N-F reagent (Selectfluor or
NFSI) accompanied by trapping of β-fluoroiminium
cationic intermediate with cyanide nucleophile.
(6) (a) Baudoux, J.; Cahard, D. Org. React. (N.Y.) 2007, 69, 347–672.
(b) Brunet, V., A.; O’Hagan, D. Angew. Chem., Int. Ed. 2008, 47, 1179–1182.
(c) Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev. 1996, 96, 1737–1756.
(d) Taylor, S. D.; Kotoris, C. C.; Hum, G. Tetrahedron 1999, 55, 12431–
12477.
(7) For reviews on Selectfluor, see: (a) Nyffeler, P. T.; Duryn, S. G.;
Burkart, M. D.; Vincent, S. P.; Wong, C.-H. Angew. Chem., Int. Ed. 2005, 44,
192–212. (b) Singh, R. P.; Shreeve, J. M. Acc. Chem. Res. 2003, 37, 31–44.
(c) Banks, R. E. J. Fluorine Chem. 1998, 87, 1–17.
(8) For transition metal catalyzed electrophilic fluorination, see: Hull,
K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 7134–7135.
(b) Wang, X.; Mei, T.-S.; Yu, J. Q. J. Am. Chem. Soc. 2009, 131, 7520–7521.
(c) Furuya, T.; Kaiser, H. M.; Ritter, T. Angew. Chem., Int. Ed. 2008, 47,
5993–5996.
(9) The mechanism of electrophilic fluorination is a matter of debate.
Though one-step transfer of “Fþ” is usually proposed, the ion-radical
mechanisms have also been suggested. For discussion, see refs 6a, 6c, and 7a.
(10) (a) Lal, G. S. J. Org. Chem. 2002, 58, 2791–2796. (b) Stavber, S.;
Sotler, T.; Zupan, M. Tetrahedron Lett. 1994, 35, 1105–1108. (c) Stavber, S.;
Pecan, T. S.; Pape, M.; Zupan, M. Chem. Commun. 1996, 2247–2248.
(d) Vincent, S. P.; Burkart, M. D.; Tsai, C.-Y.; Zhang, Z.; Wong, C.-H.
J. Org. Chem. 1999, 64, 5264–5279. (e) Zhou, C.; Li, J.; Lu, B.; Fu, C.; Ma, S.
Org. Lett. 2008, 10, 581–583. (f) Wilkinson, S. C.; Lozano, O.; Schuler, M.;
Pacheco, M. C.; Salmon, R.; Gouverneur, V. Angew. Chem., Int. Ed. 2009,
48, 7083–7086.
(11) (a) Tredwell, M.; Gouverneur, V. Org. Biomol. Chem. 2006, 4, 26–32.
(b) Greedy, B.; Paris, J.-M.; Vidal, T.; Gouverneur, V. Angew. Chem., Int. Ed.
2003, 42, 3291–3294. (c) Gouverneur, V.; Greedy, B. Chem.;Eur. J. 2002, 8,
766–772. (d) Greedy, B.; Gouverneur, V. Chem. Commun. 2001, 233–234.
(12) With N-F reagents: (a) Peng, W.; Shreeve, J. M. J. Org. Chem. 2005,
70, 5760–5763. (b) Stanton, M. G.; Hubbs, J.; Sloman, D.; Hamblett, C.;
Andrade, P.; Angagaw, M.; Bi, G.; Black, R. M.; Crispino, J.; Cruz, J. C.;
Fan, E.; Farris, G.; Hughes, B. L.; Kenific, C. M.; Middleton, R. E.; Nikov,
G.; Sajonz, P.; Shah, S.; Shomer, N.; Szewczak, A. A.; Tanga, F.; Tudge,
M. T.; Shearman, M.; Munoz, B. Bioorg. Med. Chem. Lett. 2010, 20, 755–
758. (c) Banks, R. E.; Mohialdin-Khaffaf, S. N.; Lal, G. S.; Sharif, I.; Syvret,
R. G. J. Chem. Soc., Chem. Commun. 1992, 595–596. (d) Poss, A. J.; Van der
Puy, M.; Nalewajek, D.; Shia, G. A.; Wagner, W. J.; Frenette, R. L. J. Org.
Chem. 1991, 56, 5962–5964. (e) Umemoto, T.; Fukami, S.; Tomizawa, G.;
Harasawa, K.; Kawada, K.; Tomita, K. J. Am. Chem. Soc. 1992, 112, 8563–
8575. (f) Purrington, S. T.; Jones, W. A. J. Fluorine Chem. 1984, 26, 43–46.
(g) Alkhathlan, H. Z. Tetrahedron 2003, 59, 8163-8170. With O-F reagnets:
(h) Barton, D. H. R.; Godinho, L. S.; Hesse, R. H.; Pechet, M. M. Chem. Commun.
1968, 804–806. (i) Njar, V. C. O.; Arunachalam, T.; Caspi, E. J. Org. Chem. 1983,
48, 1007–1011.
Due to the unique properties of fluorinated compounds,1 as
well as their importance in pharmaceutical research,2 methods
for the direct introduction of a single fluorine atom into organic
molecule have attracted considerable attention.3 While pro-
cesses involving introduction of nucleophilic fluoride have been
studied for decades,4,5 reactions in which the fluorine is intro-
duced electrophilically have come to the fore only in recent
times after the advent of convenient fluorinating reagents.6-8
(1) (a) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308–319. (b) Organofluorine
Chemistry; Uneyama, K., Ed.; Blackwell: Oxford, U.K., 2006. (c) Fluorine in
Organic Chemistry; Chambers, R., Ed.; Blackwell: Oxford, U.K., 2004.
€
(2) (a) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881–1886.
(b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev.
2008, 37, 320–330. (c) Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013–1029.
(d) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359–4369.
(3) (a) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305–321. (b) Furuya, T.;
Kuttruff, C. A.; Ritter, T. Curr. Opin. Drug Discovery Dev. 2008, 11, 803–819.
(4) (a) Singh, R. P.; Shreeve, J. M. Synthesis 2002, 2561–2578. (b) Adams,
D. J.; Clark, J. H. Chem. Soc. Rev. 1999, 28, 225–231. (c) Gerstenberger,
M. R. C.; Haas, A. Angew. Chem., Int. Ed. Engl. 1981, 20, 647–667.
(d) Mascaretti, O. A. Aldrichim. Acta 1993, 26, 47-58. For recent works, see:
(e) Lee, J. W.; Yan, H.; Jang, H. B.; Kim, H. K.; Park, S.-W.; Lee, S.; Chi, D. Y.;
Song, C. E. Angew. Chem., Int. Ed. 2009, 48, 7683–7686. (f) Sun, H.; DiMagno,
S., G. Angew. Chem., Int. Ed. 2006, 45, 2720–2725. (g) Sun, H.; DiMagno, S. G.
J. Am. Chem. Soc. 2005, 127, 2050–2051. (h) Kim, K.-Y.; Kim, B. C.; Lee, H. B.;
Shin, H. J. Org. Chem. 2008, 73, 8106–8108.
(5) For transition metal catalyzed nucleophilic fluorination, see: (a) Watson,
D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; Garcia-Fortanet, J.; Kinzel, T.;
Buchwald, S. L. Science 2009, 325, 1661–1664. (b) Grushin, V. V. Acc. Chem.
Res. 2009, 43, 160–171.
DOI: 10.1021/jo1008993
r
Published on Web 07/02/2010
J. Org. Chem. 2010, 75, 5367–5370 5367
2010 American Chemical Society

Dilman et al.
JOCNote
TABLE 2. Reaction of Enamine 1b
FIGURE 1. Fluorinating reagents.
yield of 2b,
% (dr)
TABLE 1. Reaction of Enamine 1a.a
no.
reagent
Nu
conditions ratioa 2b:3
1
2
3
4
Selectfluor/Py TMSCN
-30f0 °C
0 °C
1:15
1:9
NFSI/Py
Selectfluor
NFSI
TMSCN
BnNEt3CN -30f0 °C >20:1
BnNEt3CN -30f0 °C >20:1
85 (3.2: 1)
36 (1.8: 1)
aDetermined by NMR spectroscopy of crude product.
entry
reagent
additive
yield of 2a,b %
SCHEME 1. Mechanism of Difluorination
1
2
3
4
5
6
7
8
Selectfluor
NFSI
Py-F
Selectfluor
Selectfluor
Selectfluor
NFSI
50-75
79c
35d
89
Py
NEt3
dabco
Py
41d
23d
89
NFSI
NEt3
70d
aConditions: for Selectfluor, -30 °C, 30 min, then 15 min at 0 °C; for
NFSI and Py-F, 1 h at 0 °C. bIsolated yield unless mentioned otherwise.
cByproduct 3-methyl-2-[methyl(phenyl)amino]butanenitrile (ca. 10%)
was formed. dDetermined by NMR spectroscopy with trichloroethylene
as internal standard.
the formation of N-fluoropyridinium cation seems unlikely due
to its decreased activity as fluorinating reagent toward enamine
1a (entry 3).
When enamine 1b was subjected to optimized conditions
for fluorocyanation, which required only 1.1 equiv of fluori-
nating reagent, the desired product 2b was formed in less
than 10% yields, with the major product being difluorinated
amine 3 (entries 1 and 2, Table 2). The formation of product 3
likely occurs through the deprotonation of initially formed
fluoroiminium intermediate 4b to generate fluoroenamine
followed by a second fluorination step17 (Scheme 1).
To avoid this side reaction it is necessary to increase the
rate of trapping of iminium ion 4b by the cyanide nucleo-
phile. Indeed, addition of Selectfluor to a mixture of enamine
1b and benzyltriethylammonium cyanide cleanly gave amine
2b as the sole product, the difluorinated amine 3 was not
detected in the crude sample. The amine 2b was isolated in
85% yield as a mixture of diastereoisomers (entry 3). A
similar experiment with NFSI also afforded only mono-
fluorinated compound in reduced yield, while significant
amounts of starting 1b remained unreacted. We tested the
combination Selectfluor/cyanide anion for the reaction with
enamine 1a, and found only 36% conversion to the fluoro-
cyantion product.
The overall result of this stepwise reaction corresponds to
fluorocyantion of the CdC bond. It should be pointed out
that in the literature addition reactions of cyanogen fluoride to
alkenes have not been reported.14
Fluorinating reagents shown in Figure 1 were used in
initial experiments. Thus, a mixture of enamine 1a and TMSCN
was treated with the fluorinating reagent either at -30 to 0 °C
(for most reactive Selectfluor) or at 0 °C (for NFSI and Py-F)
(entries 1-3, Table 1). Though the product 2a was formed in
good yields with Selectfluor and NFSI, the reactions with
the former provided irreproducible yields, while with the latter
the formation of up to 10% of byproduct originating from the
addition of HCN to the enamine was noted. It was observed
that these reactions proceed much cleaner when pyridine (1.2 equiv)
was added, whereas triethylamine and dabco were ineffective.
Pyridine may serve for the stabilization of intermediate fluoro-
iminium carbocation15 and/or as a scavenger of trimethylsilyl
cation arising after consumption of TMSCN.16 At the same time,
(13) Organocatalytic fluorination reactions proceeding through enamine
intermediates: (a) Beeson, T. D.; MacMillan, D. W. C. J. Am. Chem. Soc.
2005, 127, 8826–8828. (b) Marigo, M.; Fielenbach, D.; Braunton, A.;
Kjærsgaard, A.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 3703–
3706. (c) Steiner, D. D.; Mase, N.; Barbas, C. F., III. Angew. Chem., Int. Ed.
Various enamines were subjected to fluorocyantion reac-
tions (Table 3). For enamines 1c-f bearing two substituents
at the β-position, reactions were performed with Selectfluor
or NFSI and TMSCN (entries 1-6). Reasonable yields of
products were achieved, though for compounds 1e,f the use of
triethylamine instead of pyridine gave better results. For the
enamines 1g-j containing a β-hydrogen atom the combination
Selectfluor/BnNEt3CN was used affording fluorocyanation
€
2005, 44, 3706–3710. (d) Enders, D.; Huttl, M. R. M. Synlett 2005, 991–0993.
(e) Jiang, H.; Falcicchio, A.; Jensen, K. L.; Paixao, M. W.; Bertelsen, S.;
~
Jørgensen, K. A. J. Am. Chem. Soc. 2009, 131, 7153–7157.
(14) At the same time, the interaction of enamines with bromocyane, as
well as with bromine followed by potassium cyanide, has been described, see:
De Kimpe, N.; Verhe, R.; De Buyck, L.; Schamp, N. Chem. Ber. 1983, 116,
3846–3857.
(15) Earlier, upon the interaction of glycals with Selectfluor the stabiliza-
tion of β-fluorooxocarbenium ion with the bicyclic nitrogen base, which is
formed from Selectfluor, was observed; see ref 10d.
(16) (a) Arshadi, M.; Johnels, D.; Edlund, U.; Ottosson, C.-H.; Cremer,
D. J. Am. Chem. Soc. 1996, 118, 5120–5131. (b) Bassindale, A. R.; Stout, T.
Tetrahedron Lett. 1985, 26, 3403–3406.
(17) The difluorination of enamines followed by hydrolysis of iminum
cation to give either dilfuoroketones or difluorosemiaminals was described;
see refs 12a and 12b.
5368 J. Org. Chem. Vol. 75, No. 15, 2010

Dilman et al.
JOCNote
TABLE 3. Fluorocyanation of Enamines
solution of enamine 1a and pyridine was treated with either
Selectfluor or NFSI, a major cationic species was observed
corresponding to the pyridinium salt 4a according to 1H, 19F,
and 13C NMR spectroscopy19 (eq 2).
However, in a similar experiment with enamine 1e, the
β-fluoroiminium ion 5 was observed along with 23% of
iminium cation 620 (eq 3). The proton signals of pyridine
remained unshifted, but broadening may suggest the equi-
librium interaction with the iminium carbocation. Notably,
in 1H and 13C spectra of 5 and 6, the sp2-CH iminium frag-
ment contains splitting with the 14N nucleus, which is char-
acteristic of complete involvement of the nitrogen lone pair
in conjugation with the adjacent carbocationic center.21
It was also interesting to evaluate the compatibility of
fluorinating reagents with nucleophilic reagents. No reaction
between NFSI and TMSCN in CD3CN was noted at room
temperature for 1 h. In contrast, treatment of Selectfluor with
1.2 equiv of TMSCN caused rapid decomposition of TMSCN
to form TMS-fluoride (40% conversion in 15 min at rt), with
the fluoroammonium dication being mostly untouched (ca.
95%). In 1 h no TMSCN was observed, whereas 75% of fluoro-
ammonium dication remained unreacted. Conversion of TMSCN
to TMS-fluoride (confirmed by 1Hand19FNMR) likelyoccurs
with the participation of tetrafluoroborate anion.22
After mixing of Selectfluor or NFSI with BnNEt3CN in
CD3CN no signals of initial N-F species were detected even
upon the first NMR measurements (a few minutes after mixing).
These results suggest that fluorocyanation of the alkene substrate
may be successful only if fluorination of the substrate is faster
than the decomposition of the fluorinating reagent.
aIsolated yield. bThe structure of the major isomer is shown.
In summary, an approach for the fluorocyantion of en-
amines has been described. The reaction involves convenient
fluorinating reagents along with silylcyanide or cyanide
anion, and proceeds through the intermediacy of β-fluoro-
iminium cationic intermediates. Further studies will be focused
products in good to moderate yields (entries 5-8). It may be
proposed that the efficiency of the reaction decreases with
the decrease of nucleophilicity of the enamine substrate.18
The products 2g-j were formed as mixtures of diastereo-
isomers. For compound 2h, the structure of the major isomer
was studied by X-ray diffraction analysis that showed trans
arrangement of fluorine atom and cyano group (see the
Supporting Information for details).
(19) The distinction between aminal (CH-sp3) or iminium (CH-sp2)
structures can be made based on chemical shifts in 1H and 13C NMR spectra,
see the Supporting Information for details.
(20) The proton required for the formation of iminium ion 6 may arise
from adventitious water contained in Selectfluor or solvent.
To gain insight on the nature of reaction intermediates and
understand the role of pyridine additive, several experiments
were performed in an NMR tube in CD3CN. Thus, when a
€
(21) Mayr, H.; Ofial, A. R.; Wurthwein, E.-U.; Aust, N. C. J. Am. Chem.
Soc. 1997, 119, 12727–12733.
(22) However, when TMSCN was combined with Me4N BF4 in CD3CN,
3
no formation of TMS-fluoride was observed and TMSCN remained un-
affected. This means that the fluoroammonium dication of Selectfluor
somehow activates TMSCN for the interaction with tetrafluoroborate anion.
We thank a reviewer for suggesting this control experiment.
(18) Kempf, B.; Hampel, N.; Ofial, A. R.; Mayr, H. Chem.;Eur. J. 2003,
9, 2209–2218.
J. Org. Chem. Vol. 75, No. 15, 2010 5369

Dilman et al.
JOCNote
on employing other terminating nucleophiles and extending the
scope of this process to other alkene substrates.
mixture was stirred for 30 min at -30 °C, the cooling bath was
replaced by an ice/water bath, and the mixture was stirred for
15 min at 0 °C. The mixture was diluted with an excess of water
and extracted with ether (3 ꢀ 5 mL), then the combined organic
phase was washed with brine, filtered through Na2SO4, con-
centrated, and azeotropically dried with acetonitrile. The resi-
due was purified by flash chromatography.
3-Fluoro-3-methyl-2-[methyl(phenyl)amino]butanenitrile (2a):
Rf 0.27 (hexanes/EtOAc, 9:1). Mp 30-32 °C. 1H NMR (300 MHz,
CDCl3) δ 1.55 (d, 3H, J = 22.3 Hz), 1.62 (d, 3H, J = 22.3 Hz), 3.06
(s, 3H), 4.52 (d, 1H, J = 22.3 Hz), 6.89-7.00 (m, 3H), 7.28-7.36
(m, 2H). 13C NMR (75 MHz, CDCl3) δ 23.5 (d, J = 24.2 Hz), 25.1
(d, J = 24.2 Hz), 35.9 (d, J = 6.3 Hz), 62.0 (d, J = 20.7 Hz), 96.3
(d, J = 180.6 Hz), 114.7 (d, J = 2.3 Hz), 115.8, 120.7, 129.4, 149.8.
19F NMR (282 MHz, CDCl3) δ -144.0 (octet, J = 22.3). Calcd for
C12H15FN2 (206.26): C, 69.88; H, 7.33; N, 13.58. Found: C, 69.97;
H, 7.29; N, 13.41.
Experimental Section
General Procedures for Fluorocyantion of Enamines. Method A.
Pyridine (40 μL, 0.42 mmol) and enamine (0.35 mmol) were
successively added to a solution of TMSCN (70 μL, 0.53 mmol)
and NFSI (121.3 mg, 0.39 mmol) in acetonitrile (1.4 mL) at 0 °C.
The mixture was stirred for 1 h at 0 °C, and quenched with saturated
aqueous NaHCO3 (1.0 mL). The resulting mixture was diluted with
an excess of water and extracted with ether (3 ꢀ 5 mL), then the
combined organic phase was washed with brine, filtered through
Na2SO4, concentrated, and azeotropically dried with acetonitrile.
The residue was purified by flash chromatography.
Method B. Enamine (0.5 mmol) and Selectfluor (194.7 mg,
0.55 mmol) were successively added to a solution of TMSCN
(100 μL, 0.75 mmol) and base (pyridine or NEt3, 0.6 mmol) in
acetonitrile (2.0 mL) at -30 °C. The mixture was stirred for
30 min at -30 °C, the cooling bath was replaced by an ice/water
bath, and the mixture was stirred for 15 min at 0 °C. The mixture
was quenched with saturated aqueous NaHCO3 (1.0 mL),
diluted with an excess of water, and extracted with ether (3 ꢀ
5 mL), then the combined organic phase was washed with brine,
filtered through Na2SO4, concentrated, and azeotropically dried
with acetonitrile. The residue was purified by flash chromatography.
Method C. Enamine (0.5 mmol) and Selectfluor (194.7 mg,
0.55 mmol) were successively added to a solution of BnNEt3CN
(163.5 mg, 0.75 mmol) in acetonitrile (2.0 mL) at -30 °C. The
Acknowledgment. This work was supported by the Russian
Academy of Sciences (program no. 7) and the Federal program
“Scientific and educational personnel of innovative Russia”
(project 02.740.11.0258).
Supporting Information Available: Experimental procedures
and spectroscopic, analytical, and X-ray data for the products.
This material is available free of charge via the Internet at http://
pubs.acs.org.
5370 J. Org. Chem. Vol. 75, No. 15, 2010