3,5-Bis(n-perfluorooctyl)benzyltriethylammonium bromide (F-TEBA): An efficient, easily recoverable fluorous catalyst for solid-liquid PTC reactions

Article abstract of DOI:10.1002/adsc.200900631

A readily available 3,5-bis(perfluorooctyl)benzyl bromide and triethylamine were reacted under mild conditions to give 3,5-bis(n-perfluorooctyl) benzyltriethylammonium bromide (F-TEBA), an analogue of the versatile phase-transfer catalyst, benzyltriethyla

Full text of DOI:10.1002/adsc.200900631

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DOI: 10.1002/adsc.200900631
3,5-Bis(n-perfluorooctyl)benzyltriethylammonium Bromide
A
for Solid-Liquid PTC Reactions
Gianluca Pozzi,a,* Voichit¸a Mihali,a Francesca Foschi,a Michele Penso,a
Silvio Quici,a and Richard H. Fishb
a
Istituto di Scienze e Tecnologie Molecolari del CNR, via Golgi 19, 20133 Milano, Italy
Fax : (+39)-2-5031-4159; phone: (+39)-2-5031-4163; e-mail: gianluca.pozzi@istm.cnr.it
Lawrence Berkeley National Laboratory, University of California, Berkeley, CA 94720 (USA)
b
Received: September 11, 2009; Revised: November 2, 2009; Published online: December 2, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900631.
Abstract: A readily available 3,5-bis(perfluorooc-
tyl)benzyl bromide and triethylamine were reacted
under mild conditions to give 3,5-bis(n-perfluorooc-
tyl)benzyltriethylammonium bromide (F-TEBA),
an analogue of the versatile phase-transfer catalyst,
benzyltriethylammonium chloride (TEBA), contain-
ing two fluorous ponytails. This perfluoroalkylated
quaternary ammonium salt was successfully em-
ployed as a catalyst in a variety of reactions run
under solid-liquid phase-transfer catalysis (SL-PTC)
conditions. Thus, being both hydrophobic and lipo-
phobic, F-TEBA could be quickly recovered in
quantitative yields, and reused without loss of activ-
ity over several reaction cycles.
covery and the recycling efficiency of PT fluorous cat-
alysts were thus demonstrated. In addition, reactivi-
ties and selectivities comparable to those observed
with classical PT agents could be achieved through
careful design of the fluorous catalysts, even in the
case of reactions run in extremely non-polar per-
A
.
The true potential of fluorous catalysts in PTC re-
actions; however, has not been fully discovered. This
was particularly the case for polyfluorinated quater-
nary ammonium salts, which have not been extensive-
ly investigated as PT catalysts, in spite of the wide
utility and versatility of their standard counterparts.
In an early, remarkable example, due to Maruoka and
co-workers, an enantiopure perfluoroalkylated quater-
nary ammonium bromide was applied to the asym-
metric synthesis of both natural and unnatural a-
amino acids through enantioselective liquid-liquid
PTC alkylation of a protected glycine derivative in a
toluene-water system.[4] Similar non-fluorous PT cata-
lysts provided faster reactions, and afforded the alky-
Keywords: alkylation; amino acids; fluorous cataly-
sis; onium salts; phase-transfer catalysis
Polyfluorinated phase-transfer (PT) catalysts, such as lated products in slightly better yields and ee val-
quaternary phosphonium salts RF R1P+YÀ (RF = ues.[4b] Nevertheless, the fluorous ammonium salt
3
CnF
N
derivatives with typical light or heavy fluorous charac- tional runs. A restricted number of structurally simple
teristics, and yet having retained the ability to transfer fluorous ammonium salts were also used by others in
reactive anionic species from water or from a solid catalytic reactions, though not strictly speaking as PT
surface into a second distinct organic or perfluorocar- agents.[5]
bon phase, have recently emerged on the fluorous
Herein, we report the convenient synthesis of the
chemistry scene.[1] These initial studies were mainly perfluoroalkylated quaternary ammonium salt F-
focused on proving the viability of the fluorous ap- TEBA (Scheme 1), which could be thought of as the
proach in some well known phase-transfer catalysis analogue of the multipurpose PT catalyst, benzyltri-
(PTC) reactions, such as Finkelstein-type ionic dis-
placement reactions of simple fluorous alkyl halides this salt in solid-liquid phase-transfer catalysis (SL-
RF(CH2)nX,[2] and analogous nucleophilic substitu- PTC) reactions of synthetic relevance will also be re-
tions on purely organic substrates.[3] The ease of re- ported.
ACHTUNGTRENeNGNU thylammonium chloride (TEBA). The application of
ACHTUNGTRENNUNG
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3,5-Bis(n-perfluorooctyl)benzyltriethylammonium Bromide (F-TEBA)
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+
À
Various synthetic methods were reported to gener-
NEt3 polar head of F-TEBA, which was instrumen-
ate polyfluorinated ammonium salts, RF(4Àm)R1 N+YÀ tal for its use as a PT agent, was likely to be responsi-
m
[RF =CnF
(CH2)n-, R1 =RF or alkyl], which could ble for this particular behaviour. Indeed, related am-
be potentially useful as PT catalysts,[1] but because of monium salts, 3,[5b] 4,[2c] and 5 (Supporting Informa-
+
À
the considerably lower reactivity of tertiary amines tion) with a NH3 polar head attached to a 3,5-bis
bearing RF substituents,[6] the final N-quaternarization (perfluoroalkylated)aryl ring (Figure 1) were found to
step often proved to be challenging. This drawback be soluble in perfluorocarbons. Unfortunately, the re-
+
À
was avoided in the case of F-TEBA, which was readi- active nature of the NH3 group imposes serious
ly obtained in 92% yield by N-alkylation of Et3N with limitations on the applicability of such salts in many
the highly reactive fluoroponytailed benzyl bromide, relevant PTC processes, especially those involving
2, a valuable building block in the synthesis of fluo- basic reagents.
rous molecules.[7] The preparation of 2 from the cor-
To evaluate the efficiency of F-TEBA, we focused
responding benzyl alcohol, 1, was also improved with our attention on solid-liquid phase-transfer catalysis
respect to the original procedure, thus providing this (SL-PTC), another neglected facet of fluorous PTC.
alkylating agent on a multigram scale in 90% yield Indeed, most fluorous PT catalysts described thus far
(see the Supporting Information).
were tested under liquid-liquid (water-organic solvent
F-TEBA was found to be highly soluble in polar or- or water-perfluorocarbon) conditions, or in triphasic
ganic solvents, such as MeOH and CH3CN, while it systems, consisting of a fluorous, organic, and an inor-
was found to be insoluble in water and in lipophilic ganic phase,[1] while in just one case, simple SL-PTC
organic solvents, such as toluene and hexane. In other nucleophilic substitutions were described.[3a] Three
media with higher affinity for fluorous substances, representative reactions (Scheme 2, Scheme 3, and
such as CF3C6H5 (BTF) or ethers, it exhibited highly Scheme 4) were thus chosen, in which a reactive
temperature-dependent solubility profiles. As an ex- anion was generated on the surface of solid K2CO3
ample, F-TEBA was poorly soluble in dioxane at suspended in an anhydrous organic solution contain-
room temperature (1.3 mgmLÀ1). However, by raising ing the reagents and F-TEBA. The latter transferred
the temperature from 25 to 808C, its solubility in- the anion, as a reactive ion-pair, from the surface of
creased more than ten times. Analogously, these same the solid base into the organic phase.
thermomorphic properties were previously observed
The epoxide ring-opening reaction, shown in
in the case of quaternary phosphonium salts Scheme 2, was selected for its versatility in the prepa-
RF R1P+YÀ.[2] As far as non-polar perfluorocarbon ration of aziridines and 2,6-substituted morpholines,[8]
3
phases were concerned, F-TEBA has no appreciable both used in stereoselective synthesis as chiral auxilia-
solubilities at room temperature, but stable colloidal ries and ligands, while N-alkylation of trifluoroacet-
dispersions were formed upon refluxing and subse-
quent cooling (see the Supporting Information). The
ACHTUNGTRENaNGNU mide with 2-bromo esters, such as ethyl 2-bromopro-
panoate (Scheme 3), provided access to a large
number of natural and unnatural a-amino acids.[9] In
both cases, F-TEBA gave results identical to those
Scheme 2. Ring-opening reaction of phenyl glycidyl epoxide
under SL-PTC conditions.
Figure 1. Ammonium salts soluble in perfluorocarbons.
Scheme 1. Synthesis of F-TEBA.
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Gianluca Pozzi et al.
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Table 1. N-Alkylation
of
N-(2-nitrobenzenesulfonyl)-a-
amino acid ester 6a with R2X=CH2=CHCH2Br, solvent=
CH3CN.
Entry Catalyst
mol%[a] T [8C] t [h] Yield[b] [%]
Scheme 3. N-Alkylation of trifluoroacetamide with ethyl 2-
bromopropanoate under SL-PTC conditions.
1
–
–
5
30
30
30
30
80
80
80
80
80
80
80
80
10
10
10
10
1.5
12
7
traces[c]
75
2
F-TEBA
3
F-TEBA 10
86
4
TEBA
10
87
obtained with TEBA, the catalyst of choice for these
reactions, thus showing that the introduction of the
fluorous substituents had no adverse effects on the
catalytic activity of these types of ammonium salts
(for reaction details see the Supporting Information).
There has been considerable interest in the devel-
opment of efficient procedures for the synthesis of
enantiomerically pure N-alkyl amino acids and esters,
due to their importance as intermediates in the syn-
thesis of biologically active products. A functional
methodology, amenable to large-scale applications,
was reported by one of us, and was based on the se-
lective N-monoalkylation of N-(2-nitrobenzenesulfon-
yl)-a-amino acid esters, 6, under mild SL-PTC condi-
tions to give compounds of the general formula, 7
(Scheme 4).[10] The same reaction applied to N-(4-ni-
trobenzenesulfonyl)-a-amino esters, 8, allowed a con-
5
TEBA
10
98
6[d]
7[e]
8
F-TEBA 10
F-TEBA 10
F-TEBA 10
98
97
1.5
1.5
1.5
1.5
1.5
98
99
98
98
9[f]
10
11
12
98
[a]
[b]
[c]
[d]
[e]
[f]
With respect to 6a.
Isolated yields.
1
Detected by H NMR.
Solvent=toluene.
Solvent=BTF.
Entries 9–12=subsequent reaction runs performed with
recovered F-TEBA.
venient access to compounds, 9, the starting materials change between F-TEBA and the deprotonated sub-
for the synthesis of a-4-nitrobenzene-a-amino strate, was equally soluble in toluene. This reinforced
acids,[11] which have attracted considerable attention the idea, which first emerged in the case of fluorous
for the design of new oligopeptidic fragments. F- crown ethers,[3b] that the choice of the solvent in SL-
TEBA proved to be a suitable catalyst for this PTC PTC reactions cannot only be dictated by its affinity
process, as shown by the results collected in Table 1 for the fluorous PT agents.
and Table 2.
The work-up of the reaction mixture and the sepa-
The reaction between the l-phenylalanine deriva- ration of F-TEBA were operationally simple. For ex-
tive, 6a, and a slight excess of allyl bromide (1.1 mol ample, fluorous solid-phase extraction, without using
equiv.), in the presence of anhydrous K2CO3 (1.5 mol any fluorous solvent, allowed us to obtain the reaction
equiv.), was chosen in order to determine the suitable product, 7a, in excellent yields and purity without any
conditions for the use of F-TEBA (Table 1).
additional purification step. The catalyst could also be
In both the case of TEBA (entry 5) and F-TEBA conveniently recovered by washing the cartridge with
(entry 8), the best results were obtained with a cata- MeOH, with no apparent degradation, and was
lyst loading of 10 mol% with respect to the substrate, reused. However, F-TEBA was partly retained on flu-
in refluxing CH3CN (entry 8). The reaction with F- orous silica (see the Supporting Information), and the
TEBA was considerably slower in other solvents, such optimal work-up method found entailed the evapora-
as toluene (entry 6) and BTF (entry 7). Solubility tion of the clear CH3CN phase, followed by the addi-
issues were not a convincing explanation for this find- tion of toluene. The solid catalyst was then quantita-
ing. Indeed, at 808C, F-TEBA readily dissolved in tively recovered by filtration, and was reused.[12] Five
BTF, and the lipophilic ion-pair formed by anion ex-
Scheme 4. N-alkylation of N-[2-(4-nitrobenzenesulfonyl)]-a-amino acid esters.
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3,5-Bis(n-perfluorooctyl)benzyltriethylammonium Bromide (F-TEBA)
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Table 2. N-Alkylation
amino acid esters 6 and 8 (Scheme 4) catalyzed by F-TEBA.
of
N-(2-nitrobenzenesulfonyl)-a-
[C29H20F34N]Br (1108.33): C 31.43, H 1.82, N 1.26; found C
31.01, H 1.95, N 1.22%.
Entry[a] Substrate R2X t [h] Yield[b] [%]
N-Alkylation of N-(n-Nitrobenzenesulfonyl)-a-amino
Acid Esters 6, 8, and Catalyst Recycling: Typical
Procedure
1
2
3
4
5
6
7
8
9
6a
6a
6a
6a
6a
6a
6b
8a
8b
CH2=CHCH2Br 1.5
98
98
94
93
89
84
95
91
98
MeI
1.5
1.5
12
24
40
4
ꢀ
HC CCH2Br
n-PrI
In an oven-dried screw-cap vial, anhydrous potassium car-
bonate (104 mg, 0.75 mmol) was added to a solution of start-
ing sulfonamide 6a (183 mg, 0.50 mmol), F-TEBA (55 mg,
0.05 mmol), and allyl bromide (67 mg, 0.55 mmol) in anhy-
drous acetonitrile (3 mL). The heterogeneous reaction mix-
ture was magnetically stirred at 808C and the consumption
of 6a was followed by TLC analysis (PE/AcOEt, 2/1). After
cooling to room temperature, the mixture was filtered on
Celite to remove the inorganic salts. The filtrate was evapo-
rated under reduced pressure and the catalyst was removed
by addition of cold toluene (2 mL) followed by filtration.
The solid catalyst was washed with 2ꢁ0.5 mL of toluene,
dried at 408C under vacuum for 5 h and then reused. The
combined filtrate and washing phases were evaporated
under reduced pressure affording 7a (R2 =allyl) in quantita-
tive yield.
n-BuBr
n-C10H21I
CH2=CHCH2Br
CH2=CHCH2Br
3
CH2=CHCH2Br 1.5
[a]
[b]
Reaction conditions: see Experimental Section.
Isolated yields.
subsequent reaction runs (entries 8–12) were conduct-
ed with no apparent loss of activity.
The scope of the SL-PTC N-alkylation catalyzed by
F-TEBA was also briefly investigated (Table 2). The
reaction was very sensitive to the steric hindrance of
the alkylating agent (entries 1–5), and to a lesser
extent, the nature of the protected a-amino acid
esters (entries 6 and 7). In any event, the correspond-
ing N-alkylated products were obtained in excellent
isolated yields (84–98%), after a minimal work-up
procedure.
The N-alkylation reactions summarized in Table 2 were
similarly performed. Spectroscopic data for 7a and all previ-
ously reported compounds were identical to those reported
in ref.[10] For all other compounds (Table 2, entries 6, 8, 9)
see the Supporting Information.
In conclusion, we have shown, for the first time,
that a readily accessible perfluorolakylated ammoni-
um salt, F-TEBA, could be conveniently employed as
a recyclable PT catalyst in a series of synthetically
useful reactions that were conducted under SL-PTC
conditions. Further investigations on the use of fluo-
rous ammonium salts in PTC are underway in our
laboratories, and will be reported in the future.
References
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Preparation of F-TEBA
To a stirred suspension of 3,5-bis(n-perfluorooctyl)benzyl
bromide 2 (2.01 g, 2.00 mmol) in dry EtOH (20 mL) a solu-
tion of freshly distilled Et3N (1.62 g, 2.23 mmol) in dry
EtOH (5 mL) was added dropwise. The reaction mixture
was heated to reflux until 2 was completely consumed (6 h,
TLC monitoring: PE/Et2O, 9/1). The solvent was then
evaporated under reduced pressure, and the solid residue
was washed with cold Et2O and dried overnight in a vacuum
oven at 408C to give pure F-TEBA, as a white solid; yield:
2.01 g (90.7%); mp 168–1708C; 1H NMR (400 MHz,
CD3OD): d=1.45 (t, J=7.2 Hz, 9H), 3.35 (q, J=7.2 Hz,
6H), 4.81 (s, 2H), 8.09 (br s, 1H), 8.21 (br s, 2H); 13C NMR
(100.8 MHz, CD3OD): d=9.0, 55.4, 61.4, 105.0–121.8 (m,
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2
RF), 129.50, 133.0 (t, JC,F =24.5 Hz), 133.1, 137.1; 19F NMR
(282 MHz, CD3OD): d=À78.9 (t, JF,F =10.5 Hz, 6F), À108.5
(t, JF,F =14.2 Hz, 4F), À118.4 (br s, 4F), À119.2 (m, 12F),
À120.2 (br s, 4F), À123.7 (br s, 4F); anal. calcd. for
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2À
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