CHAPTER V SYNTHESIS, RESOLUTION AND VCD ANALYSIS OF THE FIRST
V- 1.2.1 Definition
Thus, nowadays, a lot of powerful techniques are accessible and among all the appealing processes available is the use of substoechiometric or catalytic amounts of enantiopure derivatives as chiral mediators for the synthesis of non-racemic compounds.8,9 Catalytic transformations provide the best “atom economy” because the stoichiometric introduction and removal of the (chiral) auxiliary can be avoided, or at least minimized.10 For a long time, much of the work in this area of stereoselective catalysis has focused on the use of enzymes and organometallic complexes as to catalyze reactions and induce dissymmetry into the products but, since about the year 2000, the interest in asymmetric organocatalysis was renewed and the field has grown rapidly to become one of the most exciting.11
Organocatalysis uses small organic molecules predominantly composed of C, H, O, N, S and P to accelerate chemical reactions. The advantages of organocatalysts include: their lack of sensitivity to moisture and oxygen, their ready availability, low cost and often low toxicity which may confer a direct benefit in the production of pharmaceutical intermediates when compared with some transition metal catalysts.
Further, they offer the appealing prospect of a combined optimization. Synthetic organocatalysts can mimic enzymes but without the restrictive disadvantages they
8 Christmann, M.; Braese, S. Asymmetric Synthesis - The Essentials; Christmann, Mathias.; Braese, Stefan ed.; Wiley-VCH:
Weinheim, Germany, 2007;.
9 Blaser, H. U.; Schmidt, E. In Asymmetric Catalysis on Industrial Scale: Challenges, Approaches and Solutions; Blaser, H.
U.;Schmidt, E., Eds.; Wiley-VCH: Weinheim, Germany, 2004. Ojima, I. Catalytic Asymmetric Synthesis, Second Edition; Iwao Ojima ed.; Wiley-VCH: New York, N. Y., 2000;.
10 Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259-281. Trost, B. M. Science 1991, 254, 1471-1477.
11 Mikami, K.; Lautens, M. New Frontiers in Asymmetric Catalysis; John Wiley & Sons, Inc: Hoboken, N. J., 2007. Pellissier, H. Tetrahedron 2007, 63, 9267-9331. Berkessel, A.; Groeger, H. Organo-Catalysis in Asymmetric Synthesis; Wiley-VCH:
Weinheim, Germany, 2004;.
Chapter IV. Triazatriangulenium Derivatives: Highly Stable Carbocations for PhaseTransfer Catalysis
usually have. Indeed, organocatalysts are low molecular weight organic molecules (enzymes have molecular weights ranging from 10000 to 2000000 Daltons), which can performed reactions in both water and solvents media (the generally unstable nature of enzymes, when removed from their natural environment can be a major drawback to their extensive use and besides the great diversity of enzymes, there are many important organic transformations for which there is no existing biocatalyst).8,9,11,12
IV-1.2.2 History
All in all, organocatalysis started almost one century ago with the studies of Bredig and Fajans (1908), stating that the decomposition of (d)-camphorcarboxylic acid 73 was 13% faster than its (l)-enantiomer when in presence of nicotine. They postulated that "an optically active or asymmetric catalyst may exert a selective action on the decomposition of an asymmetric substance and that in this respect resembles closely to the well-known behavior of enzymes". However, camphor 74 was isolated in racemic form only (Scheme IV-1, (a)).13
O the resulting 2-hydroxy-2-phenylacetonitrile 76 was optically active and of opposite
12 Buchholz, K.; Kasche, V.; Bornscheuer, U. T. Biocatalysts and enzyme technology; Wiley-VCH: Weinheim, Germany, 2006;.
13 Bredig, G.; Fajans, K. Ber. Dtsch. Chem. Ges. 1908, 41, 752-763.
chirality when using quinine or quinidine as catalysts (Scheme IV-1, (b)).14 Amino-acids were also used as chiral organocatalysts, but before the turn of the century, a limited number of useful applications were described.15 One of the first successful applications of organocatalysts in asymmetric organic synthesis was the Hajos-Parrish-Wiechert reaction in 1971.
O
O OH
O O O
NH O OH (L)-Proline, 3 mol%
CH3CN, 23 °C, 100%
93% ee
77 78
Equation IV-1. Hajos-Parrish-Wiechert reaction.
This reaction deals with the desymmetrisation of a prochiral triketone 77 (i.e., the Hajos-Wiechert ketone) by intramolecular aldolisation, catalyzed by (L)-proline and affords an indene dione 78 with excellent yield and enantioselectivity (shown in Equation IV-1).16
IV-1.3 Phase-Transfer Catalysis (PTC)
IV-1.3.1 Introduction
Among all the organocatalytic processes known, one of the most outstanding is phase-transfer catalysis (PTC). Since the pioneering work of Makosza and Brändström almost forty years ago,17,18 as well as the extensive study of Starks in the early 1970s,19 PTC has become a topic of great interest belonging, nowadays, to the burgeoning fields of green chemistry.8-11,20,21,22
14 Bredig, G.; Fiske, P. S. Biochem. Z. 1913, 46, 7-23.
15 Langenbeck, W. Die organischen Katalysatoren und ihre Beziehungen zu den Fermenten, 2nd ed; Springer-Verlag: Berlin, Germany, 1949. Fischer, F. G.; Marschall, A. Ber. Dtsch. Chem. Ges. 1931, 64, 2825-2827.
16 Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615-1621. Eder, U.; Sauer, G.; Weichert, R. Angew. Chem., Int. Ed.
Engl. 1971, 10, 496-497.
17 Brandstrom, A. Adv. Phys. Org. Chem. 1977, 15, 267-330.
18 In this study Makosza showed that PhCH2CN, with EtCl in the presence of catalytic amounts of quaternary ammonium salts in aq. NaOH yields 90% of 2-phenylbutyronitrile. Makosza, M.; Czyzewski, J.; Jawdosiuk, M. Org. Synth. 1976, 55, 99-102.
Makosza, M.; Serafin, B. Rocz. Chem. 1965, 39, 1223-1230.
19 Starks, C. M.; Liotta, C. Phase Transfer Catalysis: Principles and Techniques; Academic Press: New York, N. Y., 1978;.
20 Sasson, Y.; Neumann, R. Handbook of Phase Transfer Catalysis; Blackie Academic and Professional: London, U.K., 1997.
Starks, C. M.; Liotta, C. L.; Halpern, M. Phase-Transfer Catalysis: Fundamentals, Applications, and Industrial Perspectives;
Chapman & Hall: New York, N. Y., 1994;.
21 For a recent review on asymmetric phase-transfer catalysis see Ooi, T.; Maruoka, K. Angew. Chem., Int. Ed. Engl. 2007, 46, 4222-4266. Hashimoto, T.; Maruoka, K. Chem. Rev. 2007, 107, 5656-5682.
22 Yadav, G. D. Top. Catal. 2004, 29, 145-161.
Chapter IV. Triazatriangulenium Derivatives: Highly Stable Carbocations for PhaseTransfer Catalysis
PTC, has many advantages over other catalytic (and stoichiometric) processes:
simple reaction procedure, safe, inexpensive and environmentally friendly reagents (aqueous hydroxides replace alkoxides, sodamide, sodium hydride, or metallic sodium), improved reaction rates and/or lower reaction temperatures, easier work-up in many cases, absence of anhydrous solvents and ease of scale-up. Other special advantages which are also encountered are the occurrence of reactions that would not otherwise proceed, the modification of selectivity, changes in product ratios (e.g., O vs C alkylation), increased yields through suppression of side reactions among others.
Moreover, PTC is compatible with a wide range of solvents (if immiscible with water which contains usually the reactive polar reagents), with microwaves,20,23 ionic liquids,24 and even without any organic solvent if the substrate plays the role of the organic phase itself.25
IV-1.3.2 Principle
Thus, a phase-transfer catalyst is a type of small molecule present in catalytic or substoichiometric amount (i.e., quaternary ammonium or coronands in most cases) which facilitates the migration of a particular reactive and polar reagent from one phase into another in a heterogeneous system.
Br + Na+CN- CN + Na+Cl- (1) organic
substrate
organic product aqueous
reagent
n-BuBr n-BuCN
Equation IV-2. Nucleophilic substitution of 1-bromobutane (RBr) by cyanide anions.
The reactive reagent is soluble in one phase but insoluble in the other unless the phase-transfer catalyst is present.19,20 For example the nucleophilic aliphatic substitution reaction of an aqueous sodium cyanide (NaCN) solution with the alkyl halide 1-bromobutane (n-BuBr) does not ordinarily take place because both solutions will not mix (see Equation IV-2). However, by the addition of 1% of the quaternary ammonium salt tetrahexylammonium bromide (Q+Br-) cyanide ions (CN-) are ferried
23 Loupy, A. Microwaves in Organic Synthesis, 2nde edition; Wiley-VCH: Weinheim, Germany, 2006. Deshayes, S.; Liagre, M.; Loupy, A.; Luche, J.-L.; Petit, A. Tetrahedron 1999, 55, 10851-10870.
24 Dere, R. T.; Pal, R. R.; Patil, P. S.; Salunkhe, M. M. Tetrahedron Lett. 2003, 44, 5351-5353.
25 Mase, N.; Ohno, T.; Morimoto, H.; Nitta, F.; Yoda, H.; Takabe, K. Tetrahedron Lett. 2005, 46, 3213-3216.
from the water phase into the organic phase and 1-cyanobutane (n-BuCN) forms quantitatively in a matter of minutes (vide infra Figure IV-4). Key to this tremendous enhancement in reactivity is the generation of a quaternary ammonium cyanide (Q+CN-), which makes the cyanide anion soluble in organic solvents and sufficiently nucleophilic. The high rate of displacement is mainly due to two characteristic features: high lipophilicity and large ionic radius of the pairing cation (Q+).
[Q+][CN-] + RBr RCN + [Q+][Br-]
Aqueous phase
Organic phase
Q
+ CN-Quaternary onium salt with highlipophilicity and large ionic radius
Interface NaCN + [Q+][Br-]
[Q+][CN-] + NaBr
NaBr NaCN
Figure IV-4. Phase-transfer cyanation of 1-bromobutane.
IV-1.3.3 Asymmetric Phase-Transfer Catalysis
It was not long after the discovery of PTC that the first attempts at enantioselective reactions were performed.21 A typical example of an asymmetric PTC reaction is that of the alkylation of an activated methylene substrate (R1CH2R2) under basic conditions (Equation IV-3). This substrate is deprotonated in the interfacial layer by an inorganic base ([M]+[OH]-) to form a metallic salt [M]+[R1CHR2]- insoluble in the organic layer.
R1CH2R2 MOH
R1CHR2R3 Q+
R3X +
Equation IV-3. Alkylation of activated methylene substrates (R1CH2R2) under PTC conditions.
An exchange of counter-ion with the phase-transfer catalyst, often a quaternary ammonium cation (Q+), leads to a more lipophilic salt [Q]+[R1CHR2]- which can be extracted in the organic layer. Then, the nucleophilic carbanion, associated with Q+ can react with the electrophile (R3-X) contained in the organic layer leading to the desired alkylated product (R1CHR2R3), and thus regenerating the catalyst. If the
Chapter IV. Triazatriangulenium Derivatives: Highly Stable Carbocations for PhaseTransfer Catalysis
catalyst is non-racemic and the substrate prochiral, the in-situ generated reactive intermediate [Q]+[R1CHR2]- has no longer two enantiotopic but two diastereotopic
-Scheme IV-2. Discrimination of the two diastereotopic faces of the carbanion of a methylene substrate during its alkylation under PTC.
The cationic counter-ion Q+ acts as a "chiral auxiliary" linked by non-covalent interactions with the prochiral anionic counter-ion. In the case of the formation of tightly associated contact ion pairs between the two species, large chemical and physical differences among the diastereomeric salts can occur. As a consequence, one diastereomeric ion pair will be selected inducing possibly stereoselectivity in the products.21
Equation IV-4. First efficient enantioselective PTC reaction using N-benzylcinchonium bromide as catalyst.
The enantioselective alkylation of active methylene compounds occupies the central position in the field of asymmetric PTC, and its development was triggered by the pioneering study at Merck (Rahway, N.J.) in 1984. In this study, Dolling and co-workers showed that an efficient enantioselective PTC reaction using the bromide salt
of a N-benzylcinchoninium as catalyst for the methylation of a phenyl-indanone substrate was afforded in high selectivity (95%, 92% ee, see Equation IV-4).26 Since then, the field exploded and many references can be found in a recent review.21
IV-2 Triazatriangulenium Cations: Highly Stable Carbocations for Phase-Transfer Catalysis
IV-2.1 Introduction
As already mentioned, many PTC mediated processes are performed under strongly basic and nucleophilic conditions and the small organic molecules that are used as phase-transfer catalysts need to be stable under these strenuous conditions. If most polyethers, cationic nitrogen- and phosphorus-based catalysts fit the case, it is not so for usual carbocations. These moieties, although interesting due to their charge and subsequent solubility of their salts in both aqueous and organic phases,27 are general electrophiles reacting with strong bases and nucleophiles to form neutral adducts by addition, elimination or fragmentation reactions (this has been highlighted in Chapter I § 2).28 Carbocations have, per se, not been used as catalysts for (asymmetric) PTC purposes and it was questionable whether they would ever be.
Therefore, we wondered whether the very high chemical stability of chiral moieties 18 – translated in quantitative terms by a highly positive pKR+ value (~ 20) – was sufficient to permit their use as chiral auxiliaries in phase-transfer promoted reactions. However, before testing any asymmetric variant, first we decided to study an "achiral" PTC version using triazatriangulenium derivatives 19, these derivatives having almost the same intrinsic chemical stability than dimethoxyquinacridinium salts 18 (pKR+ ~ 24 vs. 20 for 19 and 18 respectively).
IV-2.2 Catalysts preparation
As the efficacy of a phase-transfer catalyst often depends on its partition ability between aqueous and organic phases, and hence on its hydrophilicity/lipophilicity, several triazatriangulenium cations were prepared, 19a to 19d, bearing alkyl side
26 Dolling, U. H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc. 1984, 106, 446-447.
27 Duxbury, D. F. Chem. Rev. 1993, 93, 381-433.
28 Katritzky, A. R.; Taylor, R. J. K. Comprehensive Organic Functional Group Transformations II; Elsevier Ltd.: Oxford, U.K., 2005. Olah, G. A. In Carbocation Chemistry; Olah, G. A. P., G. K. Surya., Ed.; John Wiley & Sons: Hoboken, N. J, 2004; pp 7-41. Olah, G. A.; Prakash, G. K. S. Carbocation Chemistry; John Wiley & Sons: Hoboken, N. J., 2004;.
Chapter IV. Triazatriangulenium Derivatives: Highly Stable Carbocations for PhaseTransfer Catalysis
chains of various length and polar/apolar character (R = CH2CH2OH, n-Pr, n-Hex and n-Oct respectively, Scheme IV-3).
First, purple tris(2,6-dimethoxyphenyl)carbenium tetrafluoroborate salt [11][BF4] was synthesized using a procedure similar to that reported by Wada et al.2930 To a 0-10 °C solution of 79 in toluene under dinitrogen atmosphere was added dropwise a n-butyllithium solution in hexane. Once the addition completed, the reaction mixture was stirred at room temperature (25 °C) during 1.5 h and diphenyl carbonate was added (0.3 equiv.). After 18h at reflux (~ 100 °C), the mixture was evaporated under reduced pressure and 80 was dissolved in CH2Cl2. The phenolic residues released
Scheme IV-3. Synthesis of triazatriangulenium salts [19a][BF4] to [19d][BF4].
After phase separation and evaporation of the solvent under reduced pressure, crude 80 was then directely dissolved in a mixture of EtOH/Et2O (40 mL/400 mL).
Vigorous stirring and subsequent addition of aq. HBF4 solution (50%, 3 equiv.) afforded tris(2,6-dimethoxyphenyl)carbenium tetrafluoroborate [11][BF4] as a
29 To date, the synthesis of cation 11 on large scale was performed using the procedure of J. C. Martin: Martin, J. C.; Smith, R.
G. J. Am. Chem. Soc. 1964, 86, 2252-2256.
30 Wada, M.; Mishima, H.; Watanabe, T.; Natsume, S.; Konishi, H.; Kirishima, K.; Hayase, S.; Erabi, T. Bull. Chem. Soc. Jpn.
1995, 68, 243-249.
blue precipitate which was filtered over Büchner funnel and washed thoroughly with Et2O (300 mL). Multigram quantities of cation [11] can be afforded in excellent yield (e.g., 84% ) and one day only using this modified protocol. Following the already mentioned Laursen and Krebs’s general procedures the triazatriangulenium ions were then synthesized by the simple reaction of salt [11][BF4] with the corresponding primary amines in excess at elevated temperatures (170-180 °C).31,32 Purification of the resulting salts, [19a][BF4] to [19d][BF4], was better afforded by crystallization (e.g., CH3CN/Et2O or MeOH) although, the necessity to perform the purification steps several times, afforded analytically pure samples in reduced yields (40-44%, Scheme IV-3).
To check the lack of reaction of the carbenium ions under strongly basic and nucleophilic conditions, and thus the viability of the PTC approach, care was taken to select test reactions that would associate, as ion pairs along the mechanistic pathways, carbenium ions 19 with reactive bases (e.g., OH–) and nucleophiles (e.g., OOH–, enolates). Three reactions fitting this description (a β-ketoester alkylation, an alkene epoxidation, an olefin dichlorocarbene addition) were selected for the study along with a synthetically useful alkene aziridination. Also the efficacy of the carbenium to behave as PT catalyst was compared to that of tetrabutylammonium (as its bromide salt, TBAB) and/or 18-crown-6 (18-C-6).
IV-2.3 PTC Alkylation of Methyl-1-oxo-2-indanecarboxylate
The generation of tertiary and quaternary centers by C-C bond forming reactions is of great importance for the synthesis of natural and unnatural products.33 For this reason, the alkylation of (α-substituted) β-keto esters has been strongly studied. This reaction is amenable to PTC using strongly basic conditions and biphasic mixture of solvents (e.g., 50% KOH, toluene/water or CH2Cl2/water). The alkylation of methyl-1-oxo-2-indanecarboxylate 81 by benzyl bromide to afford α,α’-disubstituted β-keto ester 82 was chosen as a particular example (Equation IV-5). Halogenated solvents
31 Cations 19a to 19d result from the nucleophilic aromatic substitutions (SNAr) of all six methoxy substituents of 11 by nitrogen containing moieties, see Chapter I, § 4.3.2).
32 Laursen, B. W. Ph. D. Thesis, Univ. Copenhagen 2001, RisØ-R-1275 (EN). Laursen, B. W.; Krebs, F. C. Chem. Eur. J. 2001, 7, 1773-1783. Laursen, B. W.; Krebs, F. C. Angew. Chem., Int. Ed. Engl. 2000, 39, 3432-3434.
33 Trost, B. M.; Jiang, C. H. Synthesis 2006, 369-396. Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A 2004, 101, 5363-5367. Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105-10146. Christoffers, J.; Baro, A. Angew. Chem., Int. Ed.
Engl. 2003, 42, 1688-1690. Shibasaki, M.; Vogl, E. M. J. Organomet. Chem. 1999, 576, 1-15. Corey, E. J.; Guzman-Perez, A.
Angew. Chem., Int. Ed. Engl. 1998, 37, 388-401. Fuji, K. Chem. Rev. 1993, 93, 2037-2066 and references therein.
Chapter IV. Triazatriangulenium Derivatives: Highly Stable Carbocations for PhaseTransfer Catalysis
(CHCl3, CH2Cl2) were selected as organic phases due to the high solubility of salts [19b][BF4] to [19d][BF4] in these media; compound [19a][BF4] being on the contrary highly soluble in water. The results are reported in Table IV-1.
O
CO2Me
catalyst (mol %) PhCH2Br
O
CO2Me 50% KOH aq, 20 °C Ph
81 82
Equation IV-5. PTC alkylation of methyl-1-oxo-2-indanecarboxylate.
Significantly, salts [19b][BF4] to [19d][BF4] behaved as effective catalysts; no reaction being observed in their absence or in the presence of [19a][BF4].
aUnless otherwise specified, the reaction was carried out with 81 (29 mg, 150 µmol), catalyst (10 mol %), benzyl bromide (22 µL, 180 µmol), mesitylene (21 µL, 150 µmol), in a mixture of 50% KOH aq.
(42 µL, 750 µmol) and halogenated solvent (1 mL). b Yield measured by 1H NMR spectroscopy using mesitylene as internal reference. c 85%
isolated yield of 82.
Table IV-1. PTC alkylation of methyl-1-oxo-2-indanecarboxylate.a
Entry Catalysta Mol % Solvent Time (h) Yield (%)b
1 none - CH2Cl2 19 0
2 TBAB 10.0 CHCl3 1 60
3 TBAB 10.0 CH2Cl2 1 50
4 [19a][BF4] 10.0 CHCl3 1 0
5 [19a][BF4] 10.0 CH2Cl2 1 0
6 [19b][BF4] 10.0 CHCl3 1 40
7 [19b][BF4] 10.0 CH2Cl2 1 55
8 [19c][BF4] 10.0 CHCl3 1 60
9 [19c][BF4] 10.0 CH2Cl2 1 65
10 [19d][BF4] 10.0 CHCl3 1 70
11 [19d][BF4] 10.0 CH2Cl2 1 85
12 [19d][BF4] 1.0 CH2Cl2 3 35
13 [19d][BF4] 2.0 CH2Cl2 3 60
14 [19d][BF4] 5.0 CH2Cl2 3 92 c
15 [19d][BF4] 10.0 CH2Cl2 3 99
Whereas salt [19b][BF4] gave slightly lower yields of 82 that TBAB, compounds [19c][BF4] and [19d][BF4] gave similar and better results respectively. With the latter salt, yields could be increased using longer reaction times (3 h vs. 1 h). As well, lower catalyst loading (5 mol %) was amenable. As far as solvent effects are concerned, biphasic CH2Cl2/H2O conditions were better overall than CHCl3/H2O. These lower yields in CHCl3, might be the results of a side reaction – that is the attack of the solvent by the hydroxide anion associated with the carbenium ion 19 (e.g., formation of dichlorocarbenes under PT conditions). In the case of 19a, the effective partitioning of the carbenium ion in the aqueous layer prohibits any reaction of its hydroxide salt with 81 in the organic layer. The difference in the reactions performed in the presence of salts [19b][BF4] to [19d][BF4] is probably due to an increased lipophilicity of the cations. The more lipophilic is the carbenium ion, the better it is a catalyst for this reaction. An attempt at quantifying this effect by measuring the partition coefficients of salts [19b][BF4] to [19d][BF4] indicated that these derivatives are exclusively distributed in the organic layer with no obvious difference. This would tend to indicate that the PTC mechanism is more of an interfacial nature rather than a
"simple" transport.
IV-2.4 PTC Epoxidation of Trans-Chalcone
After this example, the ability of carbenium ions 19 to perform under strongly basic and nucleophilic conditions was tested further in the context of the epoxidation of trans-chalcone 83. For this reaction, a variety of biphasic or triphasic conditions are known using, as stoichiometric oxidants, sodium/potassium hypochlorite, hydrogen peroxide, alkyl hydroperoxide, combinations of urea and H2O2, sodium perborate or percarbonate, as well as trichloroisocyanuric acid.34
Recently, an effective protocol was developed using a co-catalytic amount of surfactant.35 These are the conditions (H2O2 (10 equiv.), 50% KOH aq., iPr2O/H2O, TRITON X-10036 (1 mol %)) that were used to test the efficiency of salts [19a][BF4] to [19d][BF4] as catalysts (Equation IV-6). Results are summarized in Table IV-2.
Interestingly, all four salts [19a][BF4] to [19d][BF4] behaved as catalysts. Whereas
34 Ye, J.; Wang, Y.; Chen, J.; Liang, X. Adv. Synth. Catal. 2004, 346, 691-696. Ye, J.; Wang, Y.; Liu, R.; Zhang, G.; Zhang, Q.;
Chen, J.; Liang, X. Chem. Commun. 2003, 2714-2715 and references therein.
35 Jew, S.; Lee, J. H.; Jeong, B. S.; Yoo, M. S.; Kim, M. J.; Lee, Y. J.; Lee, J.; Choi, S. H.; Lee, K.; Lah, M. S.; Park, H. Angew.
Chem., Int. Ed. Engl. 2005, 44, 1383-1385.
36 t-octylphenoxypolyethoxyethanol.
Chapter IV. Triazatriangulenium Derivatives: Highly Stable Carbocations for PhaseTransfer Catalysis
salts [19a][BF4] to [19c][BF4] gave slightly lower yields of epoxide 84 that TBAB, compound [19d][BF4] gave better results (44 vs. 35% isolated yields).
Ph Ph
O catalyst (10 mol %)
Ph Ph
O O 50% KOH aq
Triton X-100 (1 mol %)
iPr2O, 20 °C
83 84
30% H2O2
Equation IV-6. PTC epoxidation of trans-chalcone.
This example demonstrates further the general aptitude of carbenium ions 19 to act as phase-transfer catalysts for reactions performed under strongly basic and nucleophilic conditions.
Entry Catalyst Time (h) Triton X-100 Conversion (%)b Yield (%)c
1 no 18 yes 0 0
2 TBAB 17 yes 45 35
3 [19a][BF4] 17 yes 21 16
4 [19b][BF4] 17 yes 27 23
5 [19c][BF4] 17 yes 26 22
6 [19d][BF4] 17 yes 50 44
a Aqueous H2O2 (30%, 270 µL; 2.4 mmol) and 50% KOH aq. (27 µL, 0.24 mmol) were added to a mixture of chalcone 83 (50 mg, 0.24 mmol), catalyst (10 mol %), naphthalene (0.24 mmol, reference) and Triton X-100 (1 mol %) in diisopropyl ether (0.8 mL). b Conversion was determined by HPLC analysis (Nucleosil 50-5, hexane : iPrOH 99:1, 0.5 mL·min-1, 23 °C, λ 230 nm; tR: 5.05 min (naphthalene), 6.6 min (trans-chalcone 83), 7.3 min (epoxide 84)). c Isolated yields after flash chromatography (SiO2, hexane:EtOAc 9:1, Rf 0.22).
Table IV-2. PTC epoxidation of trans-chalcone.a
IV-2.5 PTC Addition of Dichlorocarbene to Styrene
Having showed that liquid/liquid PTC reactions can be mediated by carbenium ions 19, a solid/liquid PTC protocol was tested in the context of a cyclopropanation of
styrene 85.37 Previously, Nomura and collaborators have reported a procedure of this type to generate gem-dichlorocyclopropane 86 (Equation IV-7).38
Ph Ph
Cl Cl CHCl3, KOH powder
catalyst (2 mol %) CH2Cl2, 40 °C, 6 h
85 86
Equation IV-7. PTC addition of dichlorocarbene to styrene.
The results of the reactions (KOH powder (5.0 equiv.), CHCl3 (5.0 equiv.), CH2Cl2/H2O) in the presence of salts [19a][BF4] to [19d][BF4] are reported in Table IV-3 and are compared with that of TBAB and 18-C-6 as catalysts. In this case, salts [19a][BF4] to [19d][BF4] performed less efficiently than 18-C-6 or TBAB.
a To a stirred CH2Cl2 (305 µL) solution of styrene (70 µL, 0.60 mmol) with powdered KOH (171 mg, 3.0 mmol, 5 equiv.), catalyst (2 mol %), and mesitylene (73.2 mg, 85 µL, 0.6 mmol) was added CHCl3 (3.0 mmol, 244 µL, 5 equiv.) dropwise at 40 °C. b Conversions and yields determined by 1H NMR using mesitylene as internal reference. c 90%
isolated yield obtained by distillation on a 10 mmol scale of starting material 85. d 65% isolated yield obtained by distillation on a 10 mmol scale of starting material 85.
Table IV-3. PTC addition of dichlorocarbene to styrene.a
37 PTC conditions are particularly important for this reaction for historical and synthetic perspectives: Makosza, M.; Gajos, I.
Rocz. Chem. 1974, 48, 1883-1893. Makosza, M.; Fedorynski, M. Rocz. Chem. 1972, 46, 311-313. Makosza, M.; Wawrzyni.M Tetrahedron Lett. 1969, 4659-4662. Makosza, M.; Serafino.B; Gajos, I. Rocz. Chem. 1969, 43, 671-676.
Rocz. Chem. 1974, 48, 1883-1893. Makosza, M.; Fedorynski, M. Rocz. Chem. 1972, 46, 311-313. Makosza, M.; Wawrzyni.M Tetrahedron Lett. 1969, 4659-4662. Makosza, M.; Serafino.B; Gajos, I. Rocz. Chem. 1969, 43, 671-676.