Combination of gold catalysis and Selectfluor for the synthesis of fluorinated nitrogen heterocycles

Article abstract of DOI:10.3762/bjoc.7.162

We herein report the synthesis of 3-fluoro-2-methylene-pyrrolidine (3a) and -piperidine (3b) from 1,5- and 1,6-aminoalkynes, respectively, using a combination of a gold-catalyzed hydroamination reaction followed by electrophilic trapping of an intermediat

Full text of DOI:10.3762/bjoc.7.162

Combination of gold catalysis and Selectfluor for the
synthesis of fluorinated nitrogen heterocycles
Antoine Simonneau, Pierre Garcia, Jean-Philippe Goddard,
Virginie Mouriès-Mansuy, Max Malacria* and Louis Fensterbank*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1379–1386.
UPMC Univ Paris 06, Sorbonne Universités, Institut Parisien de
Chimie Moléculaire (UMR CNRS 7201), 4 place Jussieu, C. 229,
75005 Paris, France
doi:10.3762/bjoc.7.162
Received: 24 June 2011
Accepted: 14 September 2011
Published: 07 October 2011
Email:
Max Malacria* - max.malacria@upmc.fr; Louis Fensterbank* -
louis.fensterbank@upmc.fr
This article is part of the Thematic Series "Gold catalysis for organic
synthesis".
* Corresponding author
Guest Editor: F. D. Toste
Keywords:
cycloisomerization reactions; fluorinated pyrrolidines; gold catalysis;
Selectfluor
© 2011 Simonneau et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
We herein report the synthesis of 3-fluoro-2-methylene-pyrrolidine (3a) and -piperidine (3b) from 1,5- and 1,6-aminoalkynes, res-
pectively, using a combination of a gold-catalyzed hydroamination reaction followed by electrophilic trapping of an intermediate
cyclic enamine by Selectfluor. Careful attention was paid to the elucidation of the mechanism and Selectfluor was suggested to play
the double role of promoting the oxidation of gold(I) to a gold(III) active species and also the electrophilic fluorination of the
enamine intermediates.
Introduction
The useful properties of fluorinated compounds in medicinal tion of the enamine resulting from the gold-promoted alkyne
chemistry have motivated an intense effort towards the syn- hydroamination or by oxidation of the intermediate vinyl
thesis of new molecules bearing fluorine substituents [1,2]. gold(I) complex by Selectfluor into a gold(III) fluoride species
Therefore, the development of a rapid access to C–F bonds is of followed by a reductive elimination.
great importance. Quite recently, in their study on the synthesis
α-fluoro ketones, Nevado et al. observed the formation Moreover, the formation of C(sp2)–F bonds, either by hydro-
of fluorinated pyrrolidinol obtained by a gold-catalyzed fluorination of alkynes catalyzed by N-heterocyclic carbene
cyclization of a 1,5-aminoalkyne in the presence of Selectfluor gold(I) complexes [4], or by fluorodeauration of transient
(Scheme 1) [3]. These authors proposed that the formation of vinyl gold species [5,6], has been previously reported in the
the C(sp3)–F bond could be explained either by direct fluorina- literature.
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Beilstein J. Org. Chem. 2011, 7, 1379–1386.
Scheme 1: Amino-hydroxyfluorination of alkynes reported by Nevado
et al. [2].
On the basis of our recent results on the gold-catalyzed cycliza-
tion of enynes [7-10] and allenylhydrazones [11], as well as the
studies from Nevado [3], Hammond and Xu [12], Liu and Xu
[13], and Liu [14], we were attracted by the possibility to access
fluorinated nitrogen heterocycles 2a and 2b by performing
subsequently an intramolecular nucleophilic attack of nitrogen
Scheme 2: Proposed access to fluoromethylene pyrrolidines and
piperidines.
onto the gold-activated triple bond on compounds 1a,b in a 5- also, the literature has featured valuable access routes to pyrroli-
and 6-exo-dig manner, respectively, and reductive elimination dine promoted by catalytic systems [18-26].
occurring at a vinyl gold(III) fluoride species or bimolecular
fluorodeauration (Scheme 2). We also anticipated from this Results and Discussion
study to gain more insight into the reactivity of gold catalysts/ Studies on the scope and limitation of the cyclization–fluorina-
Selectfluor combinations [15-17].
tion sequence were carried out with Selectfluor as a source of
electrophilic fluorine. Readily available 4-methyl-N-(pent-4-
Indeed, pyrrolidine and piperidine skeletons are very attractive ynyl)benzenesulfonamide (1a) was used as a model substrate,
ring systems because of their occurrence in numerous bio- and all the reactions were performed in anhydrous acetonitrile
logically active substances, and the design of methodologies as the solvent. Various gold catalysts were screened. The results
allowing the easy introduction of a fluorine atom onto these of the optimization of the cyclization reaction conditions are
skeletons could be attractive for medicinal chemists. Recently summarized in Table 1.
Table 1: Gold catalyst influence on the cyclization of 1a.a
Entry
Catalyst
3a (yield %)
4a (yield %)
5a (yield %)
1b
2c
3b
4
Ph3PAuCl
75
46
14
65
0
17
0
0
AuCl
7
AuCl3
2
2
IPrAuCl
13
0
0
5d
6
(biphenyl)(t-Bu)2PAuCl
(PhO)3PAuCl
(2,4-di-t-BuPhO)3PAuCl
(t-Bu)3PAuCl
dppm(AuCl)2
Ph3PAuNTf2
[Ph3PAu]SbF6
0
35
35
35
43
35
-
7
0
7
5
0
8
6
0
9
0
14
11
-
10
11
0
-
aProducts 3a, 4a and 5a were characterized by 1H, 13C and 19F NMR. Compound 4a was obtained as a single (E)-isomer and the configuration of the
double bond was confirmed by NOE measurements. bWhen the reaction was performed without Selectfluor, the starting material was recovered
unchanged. cReaction time: 5 h.dAn inextricable mixture was obtained.
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Beilstein J. Org. Chem. 2011, 7, 1379–1386.
The reaction of 1a in the presence of commercially available Reaction of a 75 mM solution of 1a with Ph3PAuCl (5 mol %)
Ph3PAuCl (5 mol %) and Selectfluor (1.1 equiv) in acetonitrile and Selectfluor (1.5 equiv) in acetonitrile under reflux (Table 2,
at rt afforded an inseparable mixture of pyrrolidines 3a in 75% entry 1) afforded an inseparable mixture of 3a and 4a
yield and 4a in 17% yield (Table 1, entry 1). Difluoro deriva- both in 25% yield. When the reaction was performed at room
tive 4a was isolated as a single diastereomer, and its relative temperature, 3a could be isolated in 47% yield with 17% of 4a
stereochemistry was determined by F–F NOE measurement. (Table 2, entry 2). Using lower amounts of Selectfluor
The expected fluoromethylene tosylpyrrolidine 2a was not raised the yield of 3a to 54% and 4a to 13% (Table 2, entry 3).
detected. When a AuCl complex was used, product 3a was In the presence of two equivalents of potassium carbonate
obtained in 46% yield with a new monofluorinated 2-pyrroline the cyclization reaction did not occur (Table 2, entry 4).
5a in 7% yield (Table 1, entry 2). In the presence of AuCl3, a Lowering the temperature to 5 °C led to a dramatic decrease of
lower yield of 3a was observed (14%) with trace amounts of 4a the yield of 3a and 4a (Table 2, entry 5). Interestingly, the
and 5a (2% yield each, Table 1, entry 3). The use of the N,N- yield of 3a increased up to 75% when a lower substrate concen-
bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) gold(I) tration was used (25 mM, Table 2, entry 6). Going to an even
chloride as catalyst led to the formation of 3a in 65% yield, more dilute medium resulted in the sole formation of 3a
together with 13% yield of 4a. Under these conditions, the for- (Table 2, entry 7). It is noteworthy that in the absence of either
mation of 5a was not detected (Table 1, entry 4). Gold(I) the gold catalyst or Selectfluor, the starting material was recov-
phosphite catalysts gave 3a and 4a in low yields (Table 1, ered.
entries 6 and 7). A similar result was observed with tri(tert-
butyl)phosphine gold(I) chloride (Table 1, entry 8). The The homologue of 1a, compound 1b, was treated with
dinuclear complex, dppm(AuCl)2, led to 3a and 5a in a manner Ph3PAuCl (5 mol %) and Selectfluor (1.1 equiv) in acetonitrile
comparable to AuCl (Table 1, entry 9). When we used cationic at rt. As expected, the 6-exo-dig cyclization occurred and only
gold(I) catalyst, Ph3PAuNTf2, 3a was obtained in 35% yield led to one compound, 3b, which was isolated in 43% yield
with 11% of 5a (Table 1, entry 10). Finally in the presence (Scheme 3).
of [Ph3PAu]SbF6 a complex mixture of compounds was
obtained (Table 1, entry 11). To the best of our knowledge,
these fluorinated pyrrolidines 3a, 4a and 2-pyrroline 5a are
unknown and could be interesting building blocks for organic
synthesis.
Following the previous catalyst screening, we stuck with the use
of PPh3AuCl as the catalyst and next investigated the effect of
the concentration of 1a and the stoichiometry of Selectfluor
Scheme 3: Cyclization of 1b under standard conditions.
(Table 2).
Table 2: Effects of reaction conditions on the Au(I)-catalyzed cyclization of 1a in the presence of Selectfluor.
Entry
n (equiv)
Substrate concentration (mM)
Temperature
3a (yield %)
4a (yield %)
1a
2
1.5
1.5
1.1
1.1
1.1
1.1
1.1
75
75
75
75
75
25
15
reflux
25
47
54
0
25
17
13
0
rt
3
rt
4b
5
rt
5 °C
rt
17
75
73
2
6
17
0
7
rt
aReaction time: 1 h. b2 equiv of K2CO3 were added.
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Beilstein J. Org. Chem. 2011, 7, 1379–1386.
Our mechanistic proposal for the formation of fluorinated (1 equiv) in acetonitrile at rt during 3 h, led to a mixture of 3a
pyrrolidines is outlined in Scheme 4. Oxidation of the Au(I) and 5a with yields of 74% and 4%, respectively. In the absence
complex by Selectfluor should give the active cationic Au(III) of a gold catalyst, a similar result was obtained (Scheme 5)
species A. Formation of A is consistent with 19F NMR experi- confirming that Selectfluor itself can react with 6 and 7 to give
ments analogous to those previously described in the literature 3a and 5a, which is consistent with Shreeve’s study on the
[12,27]. Thus, upon addition of Selectfluor to PPh3AuCl, a new fluorination of enamines [29].
peak at −181.6 ppm in CD3CN was observed that is character-
istic of Au(III) species A [28]. Coordination of 1a to A would However, the formation of 5a may also be ascribed to the
lead to complex B in which the coordinated triple bond is acti- reductive elimination of C, which leads to 2a, and then further
vated towards a nucleophilic attack by the NH moiety. The isomerization of the double bond of 2a (Scheme 4). As far as
resulting σ-vinyl Au(III) intermediate C could undergo a reduc- the formation of 4a is concerned, we found that treatment
tive elimination of its σ-vinyl and F ligands to give 2a, or a of 3a with one equivalent of Selectfluor in the presence of
protodeauration leading to pyrrolidine 6, which would also Ph3PAuCl (5 mol %), led to 4a in 81% yield. Nevertheless,
rapidly isomerize into 7. Both 6 and 7 under the given reaction in the absence of Au(I) catalyst, 4a was also formed but
conditions would evolve to 3a and 5a.
with a lower yield of 38% (Scheme 5). These results suggest
that the formation of 4a may not exclusively result from the
Selectfluor-mediated fluorination of 3a. These findings are
consistent with Gouverneur's study [5], which showed a compe-
tition between fluorodeauration and protodeauration. In our
case, protodeauration appears to be the major, if not the exclu-
sive, pathway.
Scheme 5: Mechanistic probes.
In a final experiment, 1a was treated with PPh3AuNTf2,
without Selectfluor, and dimer 8 was formed in 63% yield
along with 6 and 7 in low yields of 2% and 8%, respectively.
The formation of 8 could be explained as outlined in Scheme 6.
The cationic Au(I) catalyst would promote the cyclization of 1a
to the mixture of enamines 6 and 7 as previously observed
with cationic Au(III) species (Scheme 4). Activation of the
Scheme 4: Proposed mechanism.
The following experiments were performed to probe the mecha- electron rich double bond of 6 or 7 by the cationic Au(I) com-
nism proposed in Scheme 4. The reaction of a mixture of 6 and plex could finally trigger the dimerization and so the formation
7, in a 2:3 ratio, with PPh3AuCl (5 mol %) and Selectfluor of 8.
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Beilstein J. Org. Chem. 2011, 7, 1379–1386.
Scheme 6: Cationic Au(I)-catalyzed reaction of 1a without Selectfluor.
Conclusion
To a cold solution (0 °C) of the starting alcohol in MeCN, MsCl
In conclusion, we have reported a gold-catalyzed synthesis of and Et3N were successively added, and the mixture was
fluorinated pyrrolidines from 1,ω-aminoalkynes using Select- warmed to rt. After 1 h, K2CO3 and TsNH2 were added and the
fluor as the source of fluorine. This method allows a rapid, effi- mixture was warmed at 80 °C overnight. Once back to rt, the
cient and mild conversion of readily available aminoalkynes mixture was directly purified by flash chromatography being
into valuable nitrogen heterocycles substituted by a fluorine eluted first with petroleum ether and then with petroleum ether/
atom in position 3 of the ring. This could certainly be applied to ethyl acetate 9:1.
the synthesis of biologically relevant substrates. Current efforts
are being made in this direction and a more exemplified study
will be reported in due course.
Spectral data of cyclization precursors
Experimental
General methods
Acetonitrile was distilled over calcium hydride. Other reagents 1a. In agreement with the literature data [30,31].
were commercially available and used without further purifica-
tion. Thin layer chromatography (TLC) was performed on
Merck 60 F254 silica gel. Acros aluminium oxide, basic, Brock-
mann I, 50–200 µm, 60A was used for column chromatography.
NMR spectra (1H, 13C, DEPT, COSY, HMQC, HMBC, NOE)
were recorded at room temperature at 300 or 400 MHz on a 1b. In agreement with the literature data [31,32].
Bruker AVANCE spectrometer. Chemical shifts are given in
ppm, referenced to the residual proton resonance of the solvents General procedure for the cyclization reaction
(δ = 7.26 for CHCl3) or to the residual carbon resonance of the
solvent (δ = 77.16 for CDCl3). Coupling constants (J) are given
in Hertz (Hz). The terms m, s, d, t and q refer to multiplet,
singlet, doublet, triplet and quartet; br means that the signal is
broad. When possible, 1H and 13C signals were assigned on the
basis of DEPT and 2D NMR (COSY, HMBC) experiments.
Low-resolution mass spectra (MS) and high-resolution mass
spectra (HRMS) were measured on a Bruker MicroTOF mass
spectrometer. Infrared spectra (IR) were recorded on a Bruker
Tensor 27 spectrometer and melting points were measured on a
Wagner & Munz HEIZBANK Kofler bench.
Into an oven-dried Schlenk apparatus, the Selectfluor
General procedure for the synthesis of precursors
(0.33 mmol, 117 mg, 1.1 equiv) and the gold catalyst (16 µmol,
0.05 equiv) were loaded under a flow of argon. These solids
were dried under vacuum at 70–80 °C for 2 h. The aminoalkyne
(0.30 mmol, 1 equiv) was then added, followed by anhydrous
MeCN (12 mL), under a flow of argon. The mixture was stirred
at rt until complete consumption of the starting material was
observed by TLC. The reaction was then filtered on a short plug
of basic alumina. After removal of the solvents under reduced
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Beilstein J. Org. Chem. 2011, 7, 1379–1386.
pressure, the crude product was purified by flash column chro- 6.2 Hz, 1H), 2.43 (s, 3H), 2.09 (ddd, J = 17.5, 14.4, 6.1 Hz,
matography on alumina with pentane/ethyl acetate 85:15 as 1H), 1.97–1.76 (m, 1H); 19F NMR (376 MHz, CDCl3) δ −149.5
eluent.
(dd, JH-F = 80.7, JF-F = 8.9 Hz, 1F), −171.6 to −173.7 (m, 1F);
13C NMR (101 MHz, CDCl3) δ 144.8 (C), 142.0 (dd, JC-F =
250.4, 10.1 Hz, CH), 133.3 (C), 129.9 (2CH), 128.2 (C), 127.8
(2CH), 88.1 (dd, JC-F = 178.7, 3.5 Hz, CHF), 48.7 (CH2), 30.4
(d, JC-F = 23.1 Hz, CH2), 21.8 (CH3); IR (neat) 2359, 1597,
1353, 1163, 1133, 1090, 1060, 1011, 964, 814, 664 cm−1;
HRMS (m/z): [M + Na]+ calcd for C12H13F2NO2S, 296.0527;
found, 296.0535.
Spectral data of cyclic products
3a. White solid, mp 102 °C; 1H NMR (400 MHz, CDCl3)
δ 7.73 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 5.38 (d, J =
5.2 Hz, 1H), 5.09 (ddd, JH-F = 54.6, JH-H = 4.2, 1.9 Hz, 1H),
4.76 (d, J = 6.0 Hz, 1H), 3.88–3.82 (m, 1H), 3.63 (td, J = 9.8,
6.5 Hz, 1H), 2.42 (s, 3H), 2.14–1.87 (m, 2H); 19F NMR
(376.5 MHz, CDCl3) δ −168.4 (m, 1F); 13C NMR (101 MHz,
CDCl3) δ 144.5 (C), 143.2 (d, JC-F = 15.4 Hz, C), 134.2 (C), 3b. Colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J =
129.7 (2CH), 127.6 (2CH), 97.2 (d, JC-F = 8.4 Hz, CH2), 93.7 8.3 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 5.35 (s, 1H), 5.16 (s, 1H),
(d, JC-F = 178.5 Hz, CH), 48.6 (CH2), 29.5 (d, JC-F = 22.3 Hz, 4.70 (dt, JH-F = 49.6 Hz, JH-H = 5.3 Hz, 1H), 3.68–3.54 (m,
CH2), 21.7 (CH3); IR (neat) 2358, 1652, 1338, 1251, 1156, 2H), 2.42 (s, 3H), 1.97–1.81 (m, 2H), 1.73 (m, 1H), 1.61–1.48
1085, 1000, 866, 814, 651 cm−1; HRMS (m/z): [M + Na]+ calcd (m, 1H); 19F NMR (376 MHz, CDCl3) δ −173.4 (m, 1F);
for C12H14FNO2S, 278.0621; found, 278.0632.
13C NMR (101 MHz, CDCl3) δ 143.7 (C), 140.5 (d, JC-F =
19.0 Hz, C), 137.3 (C), 129.7 (2CH), 127.7 (2CH), 110.7 (d,
JC-F = 7.7 Hz, CH2), 88.4 (d, JC-F = 178.6 Hz, CHF), 46.9
(CH2), 30.7 (d, JC-F = 21.7 Hz, CH2), 21.7 (CH3), 20.9 (d, JC-F
= 5.4 Hz, CH2); IR (neat) 1647, 1598, 1451, 1340, 1157, 1098,
1057, 950, 908, 814, 690, 653 cm−1; HRMS (m/z): [M + Na]+
calcd for C13H16FNO2S, 292.0778; found, 292.0776.
5a. Isolated as a minor product in mixture with 3a; 1H NMR
(400 MHz, CDCl3) δ 7.71 (d, J = 8.7 Hz, 2H), 7.32 (d, J =
8.7 Hz, 2H), 5.39–5.37 (m, 1H), 5.22 (d, JH-F = 46.8 Hz, 2H),
3.78 (t, J = 8.9 Hz, 2H), 2.43 (s, 3H), 2.33–2.22 (m, 2H);
19F NMR (376 MHz, CDCl3) δ −213.6 to −213.9 (m, 1F);
13C NMR (101 MHz, CDCl3) δ 144.1 (C), 139.5 (d, JC-F =
20.7 Hz, C), 134.1 (C), 130.1 (2CH), 127.8 (2CH), 115.4 (d,
JC-F = 8.1 Hz, CH), 78.5 (d, JC-F = 167.4 Hz, CH2), 50.4 (CH2),
27.7 (CH2), 21.7 (CH3).
8. White solid, mp 66 °C; 1H NMR (300 MHz, CDCl3) δ 7.74
(d, J = 8.2 Hz, 2H), 7.65 (d, J = 8.1 Hz, 2H), 7.30 (d, J =
5.2 Hz, 2H), 7.28 (d, J = 6.3 Hz, 2H), 5.41 (br s, 1H), 3.89–3.69
(m, 2H), 3.54–3.46 (m, 1H), 3.30–3.23 (m, 3H), 2.66–2.52 (m,
1H), 2.44 (s, 3H), 2.42 (s, 3H), 2.01–1.87 (m, 3H), 1.78–1.58
(m, 2H), 1.41 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 143.9 (C),
142.8 (C), 140.9 (C), 138.8 (C), 134.1 (C), 129.7 (2CH), 129.5
(2CH), 127.8 (2CH), 127.3 (2CH), 119.5 (CH), 68.20 (C), 51.3
(CH2), 49.9 (CH2), 39.6 (CH2), 39.2 (CH2), 27.7 (CH2), 26.6
(CH3), 22.7 (CH2), 21.7 (CH3), 21.6 (CH3); IR (neat) 1452,
1332, 1154, 1089, 1000, 811, 655 cm−1; HRMS (m/z):
[M + Na]+ calcd for C24H30N2O4S2, 497.1539; found,
497.1517.
4a. White solid, mp 68 °C; 1H NMR (400 MHz, CDCl3) δ 7.72
(d, J = 8.3 Hz, 2H), 7.39 (dd, JH-F = 80.7, JH-H = 6.1 Hz, 1H),
7.32 (d, J = 8.1 Hz, 2H), 5.63 (dt, JH-F = 53.8 Hz, JH-H =
3.2 Hz, 1H), 3.83 (t, J = 9.2 Hz, 1H), 3.48 (ddd, J = 11.1, 10.1,
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Beilstein J. Org. Chem. 2011, 7, 1379–1386.
Synthesis of cyclic enamines
Supporting Information
Supporting Information File 1
1H, 13C, 19F NMR spectra of products 3a, 4a, 5a, 3b and 8.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-162-S1.pdf]
Cyclic enamines were synthesized in 59% yield (endo/exo 2:3)
according to a literature procedure [32]. Spectral data matched
those reported.
Acknowledgements
We thank UPMC, Ministère de la Recherche et de l'Enseigne-
ment Supérieur, CNRS, IUF (M. M., L. F.). Technical assis-
tance was generously offered by FR 2769 and we are grateful to
Elsa Caytan for the 19F NMR experiments.
General procedure for the fluorination reactions of
the enamines
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(12 mL), under a flow of argon. The mixture was stirred at rt
until complete consumption of the starting material was
observed by TLC. The reaction was then filtered on a short plug
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