Platinum-Catalyzed Substitution of Allylic Fluorides - American


Jan 20, 2012 - Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, U.K.. •S Supporting ... by Kurosawa and then ...
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Platinum-Catalyzed Substitution of Allylic Fluorides Elena Benedetto, Massaba Keita, Matthew Tredwell, Charlotte Hollingworth, John M. Brown,* and Véronique Gouverneur* Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, U.K. S Supporting Information *

ABSTRACT: Allyl fluorides are reactive toward Pt-catalyzed alkylation with malonate and likewise toward N- and Onucleophiles under mild conditions. The reactivity of fluoride as a leaving group equals or exceeds that of the esters and carbonates commonly employed in allylic alkylation. The order of leaving-group ability with Pt catalysts was found to be F ≥ OCO2Me ≫ OBz ≥ OAc. This discouraged the application of platinum catalysts for the reverse reaction, fluorination of allylic substrates. Fluoride displacement involves predominant or complete retention of configuration in all the observed cases, and this was confirmed as a general feature of Pt catalysis, the stereochemical integrity being as high or higher as in Pd catalysis for the examples chosen. C(sp3)−F bonds6 complement the burgeoning activity in catalyzed syntheses of C(sp2)−F bonds.7 The vast majority of allylic substitutions are carried out with palladium or iridium catalysts.8 Many other metals are also active,9 and we were encouraged to diversify in order to extend the scope of allyl fluoride chemistry. Despite the close similarities of many aspects of palladium and platinum organometallic chemistry, Pt-catalyzed allylic sustitutions are far less well developed and have never been applied to organofluorine substrates. The earliest examples were provided by Kurosawa and then Brown.10 An in-depth analysis of Ptcatalyzed allylic substitution has been conducted by Williams and co-workers, in which enantioselectivities comparable to those for palladium catalysis were demonstrated.11 Their work was conducted with rac-1,3-diphenylallyl acetate, and the optimal conditions are shown in Scheme 2. More recently, platinum-catalyzed allylic amination (86% ee) and allylation of aldehydes (up to 83% ee) have been reported.12,13 Using XantphosPtCl2 as the precatalyst, direct amination of allylic alcohols has been achieved,14 in line with the high efficiency of platinum complexes as catalysts for allylic amination.15 These scattered results highlight the unrealized potential for further examples of Pt catalysis via allylic intermediates. Differences between Pd allyl and Pt allyl chemistry have been noted. The stability of platinacyclobutanes is well-known,16 and consequently nucleophilic attack at the central carbon of Pt allyls with displacement of a 2-halo substituent has been observed in several cases.17 Similar reactions have been observed in palladium catalysis and, where comparable, the Pd and Pt cases show distinct behavior.18 Catalytic allylic

1. INTRODUCTION Our longstanding interest in the synthesis and chemistry of allylic fluorides provided the impetus for our recent studies centered around palladium catalysis.1 First, we demonstrated that acyclic and cyclic allyl fluorides are reactive under conditions for malonate substitution and that fluoride is a better leaving group than acetate but inferior to benzoate or carbonate (Scheme 1).2 Second, the reverse reaction whereby Scheme 1. Palladium-Catalyzed Activation and Alkylation of Allyl Fluorides2

allyl fluorides are themselves synthesized by Pd-catalyzed allylic substitution was achieved. This reaction works well with pnitrobenzoates of primary allylic alcohols under mild conditions.3 An enantioselective variant for cyclic substrates employing AgF as fluoride source has been reported by Doyle4 and extended recently to acyclic cases.5 These and other related developments in the catalytic formation or activation of © 2012 American Chemical Society

Special Issue: Fluorine in Organometallic Chemistry Received: October 24, 2011 Published: January 20, 2012 1408

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Scheme 2. Prior Work on the Enantioselective Pt-Catalyzed Allylic Alkylation11

alkylation involves both η2 and η3 ligation of the reacting fragment (and in some cases also κ1); the relative stability of intermediate states is distinct for Pd and Pt and will also depend on electronic factors introduced by the residual ligands of the catalyst. With some exceptions,19 most of the computational work to date on catalytic allylic substitution has been directed toward Pd rather than Pt, reflecting the respective synthetic input. Herein, we report the result of a detailed study aimed on investigating the reactivity of allylic fluorides under Pt catalysis.

Scheme 4. A Further Stereochemical Test in Pt-Catalyzed Allylic Alkylation

2. RESULTS AND DISCUSSION A. Stereochemical Study of Pt-Catalyzed Allylic Alkylation. At the onset of this study we were surprised to discover the absence of a critical piece of information. Several authors had suggested a double-inversion mechanism for Ptcatalyzed allylic substitution with soft nucleophiles, in accordance with the corresponding Pd-catalyzed transformation, but formal verification was lacking. We therefore applied the classical stereochemical probe 1 to platinum catalysis.20 For a direct comparison, the reaction was also performed with the corresponding palladium catalyst under the same reaction conditions. Lactone 1 was subjected to the conditions of Scheme 3. Pd and Pt catalysts showed comparable reactivity

entry

3

dr of 3 (syn:anti)

M

time (h)

yield of 4 (%)a

dr of 4b (syn:anti)

1 2 3 4

syn-3 syn-3 anti-3 anti-3

>98:2 >98:2 4:96 4:96

Pt Pd Pt Pd

0.5 1 16 1

86 71 68 78

>98:2 97:3 4:96 11:89

Table 2

a Isolated yields. mixture.

Table 1 M

yield of 2 (%)a

dr of 2b (syn:anti)

1 2

Pt Pd

79 >99

>98:2 >98:2

dr determined by 1H NMR of crude reaction

transformation was much slower than for palladium, affording anti-4 in 68% yield within 16 h (Table 2, entry 3). Pd-catalyzed substitution of anti-3 was complete in 1 h, yielding 78% of anti4. However, a partial loss of configuration occurred from the starting material (anti-4, dr 89:11), in contrast to the case for platinum, where the diastereomeric ratio was unchanged. Two features that contrast Pd and Pt catalysis are apparent from these results. First, the turnover rate is retarded in the platinum case for anti-3. Second, there is a diminution of stereoselectivity under palladium catalysis for anti-3. A thorough study of the mechanism of cyclohexenyl acetate allylation with Trost’s catalyst21 shows by DFT calculations that the leaving group departs anti to palladium along an axial trajectory. The TS structures derived in the same work by DFT show that the ring conformation resembles the Pd allyl intermediate. On this basis the first observation could be explained if formation of the η3-allyl is the turnover-limiting stage for platinum with anti-3, but trapping of this allyl complex is turnover-limiting for palladium, as is normally observed. In Pd catalysis, it was shown that with more reactive leaving groups (such as carbonate) the rate-limiting step of the reaction is normally the attack of the nucleophile on the π-allyl intermediate (Scheme 5).22 The partial loss in stereoselectivity exhibited by Pd(PPh3)4 may be due to its propensity for epimerization at the allyl stage promoted by a second Pd(0) species, according to the proposals of Bäckvall and co-workers.23 In further work from the same group, conformational and stability differences between the diastereomeric η3-allyls formed from syn- and anti-3 were noted.24 This would clearly affect their lifetime and hence the relative ease of epimerization. We have thus demonstrated, for the first time, that Ptcatalyzed allylic alkylation follows the same stereochemical pathway as Pd catalysis. The two metals show substratedependent reactivity and selectivity; platinum gives higher

Scheme 3. Initial Test for the Stereochemical Course of PtCatalyzed Allylic Alkylation

entry

b

a Isolated yields. bdr determined by 1H NMR of the crude reaction mixture.

and stereoselectivity, affording 2 in high yields within 30 min, with complete retention of configuration (Table 1). This result confirms that Pt-catalyzed allylic substitutions with soft nucleophiles proceed with overall retention of configuration at the reactive center. Scheme 4 reports a more detailed analysis using both the syn and anti diastereomers of ester 3. Under standard conditions, the substitution of the diastereomerically pure syn-3 occurred in comparable reaction times for Pt(PPh3)4 and Pd(PPh3)4, giving syn-4 with complete retention of configuration, in 86% and 71% yields, respectively (Table 2, entries 1 and 2). When the reaction was carried out with anti-3, employed as a diastereomeric mixture (dr 96:4), the platinum-catalyzed 1409

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Scheme 5. Analysis of the Stereochemical Course of Pd- and Pt-Catalyzed Allylic Alkylation

Scheme 6. Internal Test for Relative Leaving Group Ability with anti-5

Table 3 entry

substrate anti-5

dr of anti-5 (anti:syn)

amt of Nu (equiv)

time (h)

yield of anti6a (%)

dr of anti-6 (anti:syn)b

yield of anti7a (%)

dr of anti-7 (anti:syn)b

yield of anti8a (%)

dr of anti-8 (anti:syn)b

1 2 3 4 5 6

anti-5a anti-5ac anti-5b anti-5b anti-5c anti-5cd

93:7 91:9 96:4 96:4 97:3 90:10

2 1.2 2 1.2 2 1.2

24 4 24 24 24 3

40 31 38 28 25 12

86:14 91:9 75:25 83:17 83:17 86:14

5 14 11 13 11 8

>98:2 94:6 83:17 95:5 >98:2 >98:2

9 6 21 4 64 12

67:33 33:67 91:9 67:33 94:6 75:25

a

Isolated yields. bdr determined by 1H NMR of isolated products. canti-5a was recovered in 6% yield (dr >98:2). danti-5c was recovered in 25% yield (dr 75:25).

fluorinated product 7 resulting from displacement of acetate was isolated in 5% yield, entirely as the anti diastereoisomer. The product anti-8 was obtained in 9% yield as a mixture of diastereomers (dr 67:33 anti:syn). The reaction with anti-5a was repeated, employing 1.2 equiv of sodium dimethyl malonate and a shorter reaction time, in an attempt to avoid the formation of the disubstituted product anti-8 so as to have better understanding of the diastereoselectivity of the first step (Table 3, entry 2). The reaction was quenched after 4 h, with the starting material recovered in 6% yield as a single diastereoisomer (dr >98:2). However, it was not possible to stop the reaction at the first substitution step, and 6% of 8 was also formed. The product 8 was isolated mainly as the syn isomer with a diastereomeric ratio of 67:33. This result proved our hypothesis of the higher reactivity of the syn isomer of intermediates 6 and 7 with respect to the anti counterparts. anti-6a was isolated in 31% yield, with the same diastereomeric ratio as the reactant. The 14% yield of intermediate anti-7 was afforded with an increased diastereomeric ratio with respect to anti-5a, as previously observed in entry 1. Overall, the retention pathway is less compromised than in Pd catalysis, albeit under different conditions (CH2Cl2 vs THF and (allyl)Pd(PPh3)2BF4 as catalyst in the earlier work).2 Similar results were obtained with 5b and 5c, but in contrast to the Pd case both benzoate

levels of diastereoselectivity than palladium catalysis with anti derivatives. B. Reactivity of the Cyclohexenyl Fluoride anti-5 under Pt Catalysis. We now turn our attention to the leavinggroup ability of fluoride vis-à-vis commonly used alternatives under platinum catalysis. For this purpose, allylic fluoride 5, carrying competing anti-disposed leaving groups (OAc, anti-5a; OBz, anti-5b; OCO2Me, anti-5c) was selected, on the basis of the earlier work involving Pd catalysis.2 The reactions were carried out under catalytic conditions similar to those described above and run to complete conversion (as determined by TLC) or for a maximum of 24 h (Scheme 6; Table 3). When the reaction was carried out with the acetate anti-5a and 2 equiv of nucleophile, after 24 h the major product isolated was the intermediate anti-6a, derived by the displacement of the fluoride, in 40% yield, with predominant retention of configuration (Table 3, entry 1). Complete analysis of the stereochemical course is complicated by the fact that the first intermediate is reactive, and in both the first and second steps the syn isomer is more reactive. This parallels the results in Pd chemistry.2 Since the syn isomer in both intermediate products 6 and 7 is more reactive than the anti isomer, the diastereomeric ratio (Table 3) understates the extent of stereochemical leakage along the inversion route. The minor 1410

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Scheme 7. Internal Test for Relative Leaving Group Ability with syn-5

Table 4 entry

substrate syn-5

dr of 5 (syn:anti)

amt of Nu (equiv)

time (h)

yield of syn-5a (%)

dr of 5 (syn:anti)b

yield of syn-8a (%)

dr of syn-8 (syn:anti)c

1 2 3 4

syn-5a syn-5b syn-5c syn-5b

88:12 94:6 97:3 67:33

2 2 2 1.2

24 24 10 3

6 19 19 34

88:12 80:20 >98:2 33:67

39 38 69 27

>98:2 >98:2 98:2 >98:2

a

yield of byproducts(%) (9:10)a 7 9 6 4

(1:1) (1:1) (1:1) (1:1)

Isolated yields. bdr determined by 1H NMR of recovered starting material. cdr determined by 1H NMR of isolated products.

entry 4). However, the outcome was unchanged with respect to the previous results (Table 4, entry 2). The disubstituted product syn-8 was recovered in 27% yield as a single diastereoisomer, and unreacted syn-5b (34%) was isolated mainly as the anti diastereoisomer. Use of a decreased amount of nucleophile and shorter reaction time for syn-5b did not avoid the formation of byproducts 9 and 10 (4%). Due to the high reactivity of intermediates syn-6 and syn-7, the study carried out on syn-5 derivatives was unable to validate the leaving group propensity established for anti-5 (Table 3). Intermediate 6b was synthesized independently in both syn and anti diastereomeric forms27 and subjected to Pt(PPh3)4 catalyst with 1.7 equiv of nucleophile in THF at room temperature (Scheme 8). As expected, it was found that syn-6b

and carbonate were inferior leaving groups to fluoride, with anti-6 being the predominant product. It was noted that more of the double-substitution product 8 was obtained with carbonate as leaving group. The relative reactivity of the leaving groups under study is less clear-cut for Pt, compared to Pd catalysis for anti-5 as reactants. It was, however, possible to determine a scale of reactivity: F ≥ OCO2Me ≫ OBz ≥ OAc. Preliminary experiments indicate that the conditions employed here, with Pd(PPh3)4 instead of Pt(PPh3)4 as catalyst, in THF and using 5a−c as substrate provide lower levels of the anomalous inversion pathway than was previously observed.21,25 C. Reactivity of the Cyclohexenyl Fluoride syn-5 under Pt Catalysis. Both in Pd-catalyzed and now in Ptcatalyzed allylic alkylation, the minor syn isomer of 5 was the more reactive of the pair, encouraging a separate analysis. The synthetic strategy for the preparation of derivatives syn-5a−c was identical with that for their anti counterparts, employing the syn-γ-hydroxyallylsilane precursor.26 Electrophilic fluorodesilylation of the anti-allylsilane was significantly less stereoselective, affording the final products with low diastereomeric purity and requiring careful chromatography prior to isolation. The outcomes of Pt-catalyzed reactions of syn-5a−c under the optimized conditions were similar to one another, when an excess of sodium dimethyl malonate (2 equiv) was used (Table 4, entries 1−3). In all three cases, syn-8 was the only isolable product, resulting from the substitution of both groups with retention of configuration. There was no loss in diastereoselectivity, showing that both substitutions occurred with complete stereocontrol. A small amount of starting material was also recovered in each case; interestingly, substrates syn-5a and syn-5c were recovered without detectable stereochemical leakage (Table 4, entries 1 and 3), whereas syn-5b (Table 4, entry 2) had epimerized to an extent (4:1). Two inseparable byproducts were also isolated from the reaction mixtures, tentatively assigned as diene 9 and ether 10 by MS (Scheme 7). The intermediate compounds syn-6a−c and syn-7 were not seen and were presumed to be too reactive. In an attempt to isolate these intermediates, the substitution of syn-5b was repeated with a decreased quantity of sodium dimethyl malonate (1.2 equiv) and quenched within 3 h, when TLC showed complete consumption of starting material (Table 4,

Scheme 8. Stereoselectivity in Allylic Alkylation of Intermediate 6

Table 5 entry

6b

dr of 6b (syn:anti)

time (h)

yield of 8 (%)a

dr of 8a (syn:anti)

1 2

syn-6b anti-6bb

>98:2 99 37

>98:2 98:2).

is more reactive than the anti-6b and is fully converted into the final product syn-8 as a single diastereoisomer after 24 h (Table 5, entry 1). anti-6b, isolated in 37% yield with unchanged diastereomeric ratio, was recovered after 30 h when the reaction with anti-6b was carried out under the same catalytic conditions. This control experiment also demonstrated the absence of epimerization of anti-6b (Table 5, entry 2). These results confirm that substitution of the benzoate leaving group 1411

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Chart 1. Relative Concentrations of syn-5b and anti-5b Determined by 19F NMRa

occurs with complete retention of configuration under platinum catalysis, in line with previous results (Schemes 3 and 4). D. Tests for Competing Epimerization. Allylic fluorides anti-5b and syn-5b were subjected to catalytic conditions in the absence of malonate anion. The 1H NMR of the crude mixture indicated that with the derivative anti-5b no epimerization occurred under the reaction conditions after stirring the solution for 24 h (Table 6, entry 1). However, syn-5b does epimerize to a measurable extent (Table 6, entry 2). Table 6. Epimerization Test for anti- and syn-5b, anti- and syn-6b, and anti- and syn-7 entry substrate 1 2 3 4 5 6

anti-5b syn-5b anti-6b syn-6b anti-7 syn-7

substrate dr (anti:syn)

recovered substrate yield (%)a

recovered substrate dr (anti:syn)

96:4 20:80 >98:2 98:2 8:92

>99 >99 >99 86b >99 0b

96:4 25:75 >98:2 17:83 >98:2

a Reaction carried out on 5b (syn:anti 80:20) under the reaction conditions of entry 4, Table 4.

a Ratio determined by 1H NMR of the crude reaction mixture. bThe rest of the substrate was converted into diene 9 (Scheme 7).

Scheme 9. Probe for the Generality of Pt-Catalyzed Allylic Substitutions

When anti-6b was subjected to these conditions, the substrate was recovered with an unchanged diastereomeric ratio (Table 6, entry 3). However, when the reaction was carried out with syn-6b, 86% of substrate was detected with a significant erosion of dr and 14% of diene 9 was also formed by β-hydride elimination at the π-allyl platinum complex intermediate (Table 6, entry 4). For syn-7, elimination to 9 was complete (Table 6, entry 6). Hence, the formation of the byproduct 9 observed in the reactions of derivatives syn-5a−c (Table 4) is likely the result of β-hydride elimination from the intermediates syn-6b and syn-7. E. Kinetic Study by 19F NMR. The Pt-catalyzed reaction of 5b (syn:anti 80:20) was followed in situ by 19F NMR under the conditions shown in Scheme 7. Spectra were recorded every 5 min over 1.5 h, and 1H NMR spectra were recorded early and late in the sequence. Under these conditions the syn isomer peak at −171.6 ppm disappeared far more rapidly than the anti isomer peak at −173.0 ppm (Chart 1), consistent with the experimental observations described above (Tables 3 and 4). The only other observed change was the appearance of a new peak at −165.8 ppm, consistent with the formation of syn-7 during the course of the reaction. This peak was never more intense than 1% of the total integral. During the reaction a weak shoulder appears and then disappears on the high-field side of the main syn-5 peak at −171.6 ppm; this is close to the observed chemical shift of anti-7. F. Survey of the Scope of Pt-Catalyzed Substitution of Allyl Fluoride 11. As a test of the generality of Pt-catalyzed substitution of fluorides, the reactivity of 11 with various nucleophiles was studied under standard conditions (Scheme 9). In each case good yields were obtained without complications (Table 7). A control reaction was run in the absence of catalyst with C-, N- and O-nucleophiles, proving that the transformation proceeds only through Pt catalysis. In fact, after 16 h at room temperature neither product 12a nor 12b was detected, but full recovery of starting material was realized (Table 7, entries 1 and 2). Similarly, when the reaction was carried out with phenoxide as nucleophile in the absence of

Table 7. Results of C−F Activation with Different Nucleophiles

a

At reflux for 16 h. bAt reflux for 4 h.

Pt(PPh3)4, after 7 h at reflux only unreacted allylic fluoride was recovered (Table 7, entry 6).

3. CONCLUSIONS In conclusion, we have confirmed that Pt-catalyzed allylic alkylation occurs with overall retention of configuration, with somewhat higher stereochemical integrity than for palladium. For the main part of the work, we have determined the relative leaving ability of a variety of commonly used anionic leaving groups in Pt-catalyzed allylic alkylation. Under optimized conditions, we found the relative reactivity to be F ≥ OCO2Me ≫ OBz ≥ OAc. This stands in contrast to the palladium1412

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A solution of sodium dimethyl malonate (0.34 mmol) in THF (1 mL), prepared from dimethyl malonate (51.6 mL, 0.34 mmol) and NaH (60% in mineral oil, 13.6 mg, 0.34 mmol), was added to a stirred solution of Pt(PPh3)4 (0.01 mmol, 5%) in THF (1 mL), followed by the addition of the allylic substrate (0.2 mmol). The reaction mixture was stirred at room temperature and monitored by TLC. The reaction was quenched by addition of distilled water and the aqueous layer extracted two times with Et2O. The combined organic layers were dried over MgSO4, and the solvent was removed in vacuo. Procedure for Pd-Catalyzed Allylic Alkylation. A solution of sodium dimethyl malonate (0.34 mmol) in THF (1 mL), prepared from dimethyl malonate (51.6 mL, 0.34 mmol) and NaH (60% in mineral oil, 13.6 mg, 0.34 mmol), was added to a stirred solution of Pd(PPh3)4 (0.01 mmol, 5%) in THF (1 mL), followed by the addition of the allylic substrate (0.2 mmol). The reaction mixture was stirred at room temperature and monitored by TLC. The reaction was quenched by addition of distilled water and the aqueous layer extracted two times with Et2O. The combined organic layers were dried over MgSO4, and the solvent was removed in vacuo. The reactions carried out on 1, syn-3, and anti-3 gave the desired products 2, syn-4, and anti-4, respectively, presented in Tables 1 and 2. syn-5-(1,3-Dimethoxy-1,3-dioxopropan-2-yl)cyclohex-3-ene-1carboxylic acid (2). 1H NMR (400 MHz, CDCl3): δ 5.81−5.76 (1H, m), 5.55 (1H, dm, J = 10 Hz), 3.75 (6H, s), 3.30 (1H, d, J = 9 Hz), 3.06−3.00 (1H, m), 2.71−2.63 (1H, m), 2.35 (1H, dm, J = 18 Hz), 2.26−2.19 (1H, m), 2.16 (1H, dm, J = 12 Hz), 1.49 (1H, dd J = 12 Hz, 24 Hz). 13C NMR (100 MHz, CDCl3): δ 180.9, 168.5, 127.4, 127.1, 56.3, 52.5, 39.2, 35.9, 29.1, 27.4. IR (CH2Cl2) ν 2954.8, 1731.9, 1253.8, 1157.5. HRMS: m/z calcd for C12H16O6 [M + Na]+ 279.0839, found 279.0843. Dimethyl syn-[5-(Methoxycarbonyl)cyclohex-2-en-1-yl]malonate (syn-4). 1H NMR (400 MHz, CDCl3): δ 5.79−5.74 (1H, m), 5.53 (1H, dm, J = 10.1 Hz), 3.74 (6H, s), 3.68 (3H, s), 3.28 (1H, d, J = 5.6 Hz), 3.04−2.96 (1H, m), 2.29 (1H, dm, J = 15.9 Hz), 2.23−2.14 (1H, m), 2.10 (1H, dm, J = 12.6 Hz), 1.46 (1H, dd, J = 24.0, 12.6 Hz). 13C NMR (100 MHz, CDCl3): δ 175.5, 168.5, 127.4, 127.3, 56.4, 52.5, 51.7, 39.3, 36.0, 29.3, 27.6. Data are in agreement with those in the literature.20 Dimethyl anti-[5-(Methoxycarbonyl)cyclohex-2-en-1-yl]malonate (anti-4). 1H NMR (400 MHz, CDCl3): δ 5.80−5.75 (1H, m), 5.58 (1H, dm, J = 10.1 Hz), 3.73 (6H, s), 3.67 (3H, s), 3.32 (1H, d, J = 9.6 Hz), 3.04−2.96 (1H, m), 2.65−2.58 (1H, m), 2.27−2.25 (2H, m), 1.97−1.89 (1H, m), 1.77 (1H, dm, J = 14.4 Hz). 13C NMR (100 MHz, CDCl3): δ 175.4, 168.4, 127.9, 126.7, 56.3, 52.5, 51.8, 35.7, 33.2, 28.0, 27.1. Data are in agreement with those in the literature.20 Procedure for the Electrophilic Fluorodesilylation of Allylsilanes.2 A solution of the allylsilane (1 equiv) and sodium bicarbonate (1.2 equiv) in acetonitrile (c = 0.1 M) was treated with Selectfluor (1.1 equiv) and the mixture stirred at room temperature for 24 h. Distilled water was added and the aqueous layer extracted three times with diethyl ether. The combined organic layers were washed with brine and dried over MgSO4, and the solvent was removed in vacuo. anti-4-Fluorocyclohex-2-en-1-yl Acetate (anti-5a). 1H NMR (400 MHz, CDCl3): δ 6.05−6.00 (1H, m), 5.94 (1H, dm, J = 10.4 Hz), 5.34−5.30 (1H, m), 5.08 (1H, dm, J = 48.5 Hz), 2.22−2.09 (2H, m), 2.05 (3H, s), 1.93−1.81 (1H, m), 1.72−1.62 (1H, m);. 13C NMR (100 MHz, CDCl3) δ 170.5, 130.9 (d, J = 9.6 Hz), 130.1 (d, J = 19.2 Hz), 85.4 (d, J = 164.6 Hz), 67.3 (d, J = 2.4 Hz), 26.5 (d, J = 20.0 Hz), 25.1 (d, J = 4.8 Hz), 21.2. 19F{1H} NMR (376 MHz, CDCl3) δ −172.1. Data are in agreement with those in the literature.2 anti-4-Fluorocyclohex-2-en-1-yl Benzoate (anti-5b). 1H NMR (400 MHz, CDCl3): δ 8.05−8.03 (2H, m), 7.59−7.55 (1H, m), 7.48− 7.41 (2H, m) 6.12−6.06 (2H, m), 5.61−5.56 (1H, m), 5.15 (1H, dm, J = 48.5 Hz), 2.33−2.19 (2H, m), 2.04−1.91 (1H, m), 1.88−1.81 (1H, m). 13C NMR (100 MHz, CDCl3) δ 166.0, 133.0, 131.0 (d, J = 9.6 Hz), 130.2 (d, J = 19.2 Hz), 130.2, 129.6, 128.4, 85.5 (d, J = 165.4 Hz), 67.8 (d, J = 20.0 Hz), 26.6 (d, J = 4.8 Hz), 25.2 (d, J = 9.6 Hz). 19 1 F{ H} NMR (376 MHz, CDCl3): δ −172.2. Data are in agreement with those in the literature.2

catalyzed transformation, where carbonate is the best leaving group and fluoride more reactive only than acetate.2 A study on the stereochemical outcome of the fluoride displacement was made, and it was found that overall retention of configuration is favored with Pt(PPh3)4 as catalyst in THF. Less of the competing inversion pathway was observed than previously reported for palladium catalysis in CH2Cl2.2 For the Ptcatalyzed transformation the levels of diastereoselectivity were found to be dependent on the starting geometry, affording better results with syn-3 and syn-5 than with their anti isomers. On the basis of the high reactivity of allylic fluorides under Pt catalysis, we conclude that platinum-catalyzed allylic fluorination will be highly challenging, in contrast to what has been achieved with palladium catalysis.3 Some preliminary experiments with allylic p-nitrobenzoates under palladium optimized reaction conditions reinforced this view, and the desired fluoride was not detected. In addition to being a contribution to allyl fluoride chemistry, this work reinforces and extends our knowledge of the distinct chemistry of palladium and platinum as applied to allylic alkylation. By comparison, the initial and final η2-bound states are more highly stabilized for Pt than for Pd; indeed, simple alkene complexes are commonplace in Pt chemistry but are far less common in Pd chemistry. Under catalytic turnover conditions, the alkene product from allylic alkylation forms an observable complex with Pt.10b Applying these observations, together with the Hammond postulate, suggests that the transition state for η3-allyl formation from the reactant η2 complex is later for Pt than for Pd. This factor could well be responsible for the striking change in the order of leaving-group reactivity between the two metals.

4. EXPERIMENTAL SECTION General Procedures. Solvents were purchased from Fisher or Rathburn. When dry solvents were required, they were purified by expression through an activated alumina column built according to the procedures described by Pangborn and Grubbs.29 Glassware was ovendried or heated in vacuo, where required. Chemicals were purchased from Aldrich, Lancaster Synthesis, Fisher, Acros, BDH, Eastman, or Alfa Aesar and used as received. Reactions involving air-sensitive reagents or intermediates were performed under a dry nitrogen atmosphere using standard vacuum line techniques. Reactions were monitored by thin-layer chromatography (TLC) carried out on Merck Kiesegel 60 F254 plates, using UV light (254 nm) as a visualizing agent and KMnO4 stain and heat as developing agent. Column chromatography was carried out on Merck silica gel C60 (40−60 mm). 1 H NMR spectra and 13C NMR spectra were recorded on Bruker DPX400 (400 MHz) or AVC500 (500 MHz) spectrometers. 19F spectra were recorded on a Bruker DPX400 (376 MHz) spectrometer. Proton and carbon-13 NMR spectra are reported as chemical shifts (δ) in parts per million (ppm) relative to the solvent peak using the Bruker internal referencing procedure (edlock). Fluorine-19 NMR spectra are referenced relative to CFCl3 in CDCl3. Coupling constants (J) are reported in units of hertz (Hz) to the nearest 0.1 Hz. Data are reported as follows: chemical shift, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz). Assignments were aided by the use of COSY, HMQC, HMBC, HOESY and NOESY experiments as required. Mass spectra were recorded on Micromass GCT (CI+), and Bruker MicroTof (ESI+) instruments. Infrared spectra were recorded as liquid films on NaCl disks using a Bruker Tensor 27 FT-IR spectrometer. Absorptions are reported in wavenumbers (cm−1). All known compounds are quoted with two points of reference and are in agreement with the literature. Stereochemical Study of Pt-Catalyzed Allylic Alkylation (Schemes 3 and 4). Procedure for Pt-Catalyzed Allylic Alkylation. 1413

dx.doi.org/10.1021/om201029m | Organometallics 2012, 31, 1408−1416

Organometallics

Article

anti-4-Fluorocyclohex-2-en-1-yl Methyl Carbonate (anti-5c). 1H NMR (400 MHz, CDCl3): δ 6.08−5.98 (2H, m), 5.22−5.16 (1H, m), 5.06 (1H, dm, J = 48.3 Hz), 3.79 (3H, s), 2.23−2.10 (2H, m), 1.95− 1.82 (1H, m), 1.80−1.72 (1H, m). 13C NMR (100 MHz, CDCl3): δ 155.2, 130.5 (d, J = 19.2 Hz), 130.1 (d, J = 9.6 Hz), 85.1 (d, J = 164.6 Hz), 71.0 (d, J = 2.4 Hz), 54.8, 26.3 (d, J = 20.8 Hz) 25.0 (d, J = 4.8 Hz). 19F{1H} NMR (376 MHz, CDCl3) δ −172.5. Data are in agreement with those in the literature.2 syn-4-Fluorocyclohex-2-en-1-yl Acetate (syn-5a). 1H NMR (400 MHz, CDCl3): δ 6.03−5.98 (1H, m), 5.95−5.91 (1H, m), 5.24−5.19 (1H, m), 4.96 (1H, dm, J = 51.5 Hz), 2.07 (3H, s), 2.04−1.92 (1H, m), 1.90−1.84 (3H, m). 13C NMR (100 MHz, CDCl3): δ 170.6, 131.7 (d, J = 9.6 Hz), 129.3 (d, J = 19.2 Hz), 84.8 (d, J = 164.6 Hz), 67.7 (d, J = 3.2 Hz), 25.9 (d, J = 21.6 Hz), 24.0 (d, J = 4.0 Hz), 21.2. 19F{1H} NMR (376 MHz, CDCl3): δ −170.5. IR (CH2Cl2): ν 3055, 2987, 1732, 1422, 1265. HRMS: m/z calcd for C8H15FNO2 [M + NH4]+ 176.1087, found 176.1087. syn-4-Fluorocyclohex-2-en-1-yl Benzoate (syn-5b). 1H NMR (400 MHz, CDCl3): δ 8.08−8.05 (2H, m), 7.60−7.56 (1H, m), 7.47−7.44 (2H, m) 6.10−6.05 (2H, m), 5.52−5.48 (1H, m), 5.03 (1H, dm, J = 47.3 Hz), 2.19−2.11 (1H, m), 2.06−1.94 (3H, m). 13C NMR (100 MHz, CDCl3): δ 166.0, 133.1, 131.8 (d, J = 9.5 Hz), 130.2, 129.7, 129.5 (d, J = 19.1 Hz), 128.4, 84.9 (d, J = 164.0 Hz), 68.1 (d, J = 1.9 Hz), 26.0 (d, J = 21.0 Hz), 24.2 (d, J = 3.8 Hz). 19F{1H} NMR (376 MHz, CDCl3): δ −170.4. IR (CH2Cl2): ν 3055, 2987, 1715, 1421, 1265. HRMS: m/z calcd for C13H13FNaO2 [M + Na]+ 243.0792, found 243.0792. syn-4-Fluorocyclohex-2-en-1-yl Methyl Carbonate (syn-5c). 1H NMR (400 MHz, CDCl3): δ 6.05−5.97 (2H, m), 5.11−5.06 (1H, m), 4.97 (1H, dm, J = 48 Hz), 3.80 (3H, s), 2.11−2.02 (1H, m), 1.98−1.85 (3H, m). 13C NMR (100 MHz, CDCl3): δ 155.3, 130.8 (d, J = 9.6 Hz), 129.9 (d, J = 20.0 Hz), 84.7 (d, J = 164.6 Hz), 71.4 (d, J = 2.4 Hz), 54.8, 25.7 (d, J = 20.8 Hz,) 24.0 (d, J = 4.8 Hz). 19F{1H} NMR (376 MHz, CDCl3): δ −171.2. IR (CH2Cl2): ν 3055, 2987, 1746, 1422, 1265. HRMS: m/z calcd for C8H11FNaO3 [M + Na]+ 197.0584, found 197.0589. 1-tert-Butyl-4-(3-fluoroprop-1-en-2-yl)benzene (11). 1H NMR (400 MHz, CDCl3): δ 7.40 (4H, s), 5.60 (1H, s), 5.39 (1H, s), 5.25 (2H, d, JH−F = 47.2 Hz), 1.34 (9H, s). 13C NMR (100 MHz, CDCl3): δ 151.3, 142.7 (d, J = 14.4 Hz), 134.3, 128.2, 125.5 (4H, d, J = 8.0), 114.5 (d, J = 10.4 Hz), 84.4 (d, J = 168.6 Hz), 34.6, 31.2. 19F{1H} NMR (376 MHz, CDCl3): δ −212.8. Data are in agreement with those in the literature.3 Reactivity of Cyclohexenyl Fluorides anti- and syn-5 and anti- and syn-6 under Pt Catalysis (Schemes 6−8). Procedure for Pt-Catalyzed Allylic Alkylation of 5a−c and 6b. A solution of sodium dimethyl malonate (2, 1.2, or 1.7 equiv) in THF (0.1 M), prepared from dimethyl malonate (2, 1.2, or 1.7 equiv) and NaH (2, 1.2, or 1.7 equiv), was added to a stirred solution of Pt(PPh3)4 (5 mol %) in THF (0.1 M), followed by the addition of the allylic substrate (1 equiv). The reaction mixture was stirred at room temperature, until TLC indicated complete conversion of the starting material (in any case, not over 24 h). The reaction was quenched by addition of distilled water and the aqueous layer extracted two times with Et2O. The combined organic layers were dried over MgSO4, and the solvent was removed in vacuo. The reactions carried out on anti-5a−c and syn-5a−c gave the products anti-6a−c, anti-7, anti-8, and syn-8 as indicated in Tables 3−5. When the reaction was carried out with syn-5a−c, an inseparable mixture of 9 and 10 (1:1) was isolated. 9 has been identified by 1H NMR and 13C NMR; data are in agreement with those in the literature.28 Meanwhile, 10 was tentatively assigned by MS-GCT (m/z [M + NH4]+ 260.15). Dimethyl [anti-4-Acetoxycyclohex-2-en-1-yl]malonate (anti-6a). 1 H NMR (400 MHz, CDCl3): δ 5.78−5.70 (2H, m), 5.27 (1H, m) 3.74 (6H, s) 3.28 (1H, d, J = 8.8 Hz), 2.97 (1H, m), 2.08−2.04 (1H, m) 2.04 (3H, s), 1.89 (1H, m), 1.66−1.57 (1H, m) 1.50−1.42 (1H, m). 13C NMR (100 MHz, CDCl3): δ 170.7, 168.4, 131.6, 128.7, 68.7, 56.0, 52.5, 35.1, 27.2, 24.2, 21.3. Data are in agreement with those in the literature.2

Dimethyl [anti-4-(Benzoyloxy)cyclohex-2-en-1-yl]malonate (anti6b). 1H NMR (400 MHz, CDCl3): δ 8.04 (2H, br d, J = 7.3 Hz), 7.55 (1H, br t, J = 7.3 Hz), 7.43 (2H, br t, J = 7.6 Hz), 5.88−5.81 (2H, m), 5.54 (1H, m), 3.76 (6H, s), 3.33 (1H, d, J = 8.8 Hz), 3.04 (1H, m), 2.23−2.17 (1H, m), 2.01−1.97 (1H, m), 1.83−1.74 (1H, m), 1.60− 1.54 (1H, m). 13C NMR (100 MHz, CDCl3): δ 168.5, 166.2, 132.9, 131.8, 130.4, 129.6, 128.8, 128.3, 69.2, 56.0, 52.5, 35.2, 27.3, 24.3. IR (CH2Cl2): ν 3055, 2987, 1735, 1265. HRMS: m/z calcd for C18H20NaO6 [M + Na]+ 355.1152, found 355.1153. Dimethyl {anti-4-[(Methoxycarbonyl)oxy]cyclohex-2-en-1-yl}malonate (anti-6c). 1H NMR (500 MHz, CDCl3): δ 5.80 (2H, s), 5.17−5.13 (1H, m) 3.78 (3H, s), 3.75 (6H, s), 3.30 (1H, d, J = 8.8 Hz), 2.99−2.97 (1H, m), 2.14−2.10 (1H, m), 1.95−1.92 (1H, m), 1.75−1.69 (1H, m), 1.52−1.44 (1H, m). 13C NMR (100 MHz, CDCl3): δ 168.4, 155.4, 132.1, 128.0, 72.5, 55.9, 54.7, 52.6, 35.0, 27.1, 24.0. IR (CH2Cl2): ν 3055, 2987, 1742, 1265. HRMS: m/z calcd for C13H18NaO7 [M + Na]+ 309.0945, found 309.0944. The relative stereochemistry of anti-6c has been determined by NOESY studies. anti-Dimethyl (4-Fluorocyclohex-2-en-1-yl)malonate (anti-7). 1H NMR (400 MHz, CDCl3): δ 5.92−5.87 (1H, m), 5.83−5.81 (1H, m), 5.04 (1H, dm, J = 49.0 Hz), 3.75 (6H, s), 3.30 (1H, d, J = 8.8 Hz), 2.99 (1H, m), 2.13−2.06 (1H, m), 1.94 (1H, m), 1.85−1.74 (1H, m), 1.45 (1H, q, J = 10.9, 22.2 Hz). 13C NMR (100 MHz, CDCl3): δ 168.4 (d, J = 4.0 Hz), 132.3 (d, J = 8.8 Hz), 128.6 (d, J = 20.8 Hz), 86.5 (d, J = 163.8 Hz), 55.7 (d, J = 2.4 Hz), 52.6 (d, J = 1.6 Hz), 35.1 (d, J = 3.2 Hz), 27.9 (d, J = 19.2 Hz), 23.4 (d, J = 6.4 Hz). 19F{1H} NMR (376 MHz, CDCl3): δ −170.6. Data are in agreement with those in the literature.2 anti-1,4-Bis(dicarboxymethyl)cyclohex-2-ene (anti-8). 1H NMR (400 MHz, CDCl3): δ 5.62 (2H, s), 3.74 (6H, s), 3.73 (6H, s), 3.27 (2H, d, J = 8.6 Hz), 2.92−2.89 (2H, m), 1.87−1.85 (2H, m), 1.43− 1.38 (2H, m). 13C NMR (100 MHz, CDCl3): δ 169.0, 130.1, 56.9, 52.9, 36.1, 26.5. Data are in agreement with those in the literature.2,30 cis-1,4-Bis(dicarbomethoxymethyl)cyclohex-2-ene (syn-8). 1H NMR (400 MHz, CDCl3): δ 5.67 (2H, s), 3.72 (12H, s), 3.31 (2H, d, J = 9.6 Hz), 2.91−2.86 (2H, m), 1.75−1.69 (2H, m), 1.51−1.44 (2H, m). 13C NMR (100 MHz, CDCl3): δ 168.5, 129.8, 56.2, 52.4, 34.6, 23.6. Data are in agreement with those in the literature.2,30 Tests for Competing Epimerization. To a solution of Pt(PPh3)4 (6 mg, 5 mol %) in THF (1 mL) was added the substrate (0.1 mmol), and the mixture was stirred at room temperature for 24 h. The solution was diluted with Et2O and filtered through Celite. The solvent was then removed in vacuo. The reactions carried out on anti-5b and syn-5b, anti-6b and syn-6b, anti-7 and syn-7 gave the results indicated in Table 6. cis-Dimethyl(4-fluorocyclohex-2-en-1-yl) malonate (syn-7). Substrate syn-7 was prepared by palladium-catalyzed allylic alkylation of syn-5c.25 1H NMR (400 MHz, CDCl3): δ 5.96−5.90 (2H, m), 4.92 (1H, dm, J = 50.0 Hz), 3.76 (6H, s), 3.36 (1H, d, J= 9.1 Hz), 2.91− 2.82 (1H, m), 2.14−2.03 (1H, m), 1.85−1.67 (2H, m), 1.62−1.52 (1H, m); 13C NMR (100 MHz, CDCl3): δ 168.5 (d, J = 10.4 Hz), 134.9 (d, J = 10.4 Hz), 126.3 (d, J = 16.8 Hz), 83.7 (d, J = 163.0 Hz), 55.8 (d, J = 4.0 Hz), 52.5 (d, J = 1.6 Hz), 35.7 (d, J = 3.2 Hz), 28.1 (d, J = 21.6 Hz), 21.6; 19F{1H} NMR (376 MHz, CDCl3): δ −165.0; IR (CH2Cl2): ν 3055, 2987, 1735, 1422, 1266. Data are in agreement with those in the literature.4 Kinetic Study by 19F NMR. Following the general procedure, the reaction was carried out in an NMR tube in d8-THF on 16 mg (0.1 mmol) of 5a (syn:anti 80:20) for 24 h. 19F NMR spectra were recorded every 5 min over 1.5 h, and 1H NMR spectra were recorded early and late in the sequence. Relative concentrations of syn-5b and anti-5b, calculated by integration of their fluorine peaks (at −171.6 and −173.0 ppm, respectively) against time, are reported in Chart 1. Pt-Catalyzed Substitution of Allyl Fluoride 11. Dimethyl [2(4-tert-Butylphenyl)prop-2-en-1-yl]malonate (12a). A solution of sodium dimethyl malonate (0.34 mmol) in THF (1 mL), prepared from dimethyl malonate (39 μL, 0.34 mmol) and NaH (60% in mineral oil, 13.6 mg, 0.34 mmol), was added to a stirred solution of Pt(PPh3)4 (0.01 mmol, 5 mol %) in THF (1 mL), followed by the addition of 11 (38 mg, 0.2 mmol). The reaction mixture was stirred at 1414

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Organometallics

Article

(3H, td, J = 7.3, 2.0), 5.67 (1H, s), 5.46 (1H, s), 4.95 (2H, s), 1.36 (9H, s). 13C NMR (100 MHz, CDCl3): δ 158.7, 151.1, 142.6, 135.4, 129.5, 128.5, 125.4, 121.0, 114.8, 114.0, 69.8, 34.6, 31.3. IR (CH2Cl2): ν 1599, 1240, 1015. HRMS: m/z calcd for C19H22O [M + Na]+ 289.1563, found 289.1563.

room temperature for 1 h. The reaction was quenched by addition of distilled water and the aqueous layer extracted two times with Et2O. The combined organic layers were dried over MgSO4 and solvent removed in vacuo. Silica gel column chromatography (hexane−diethyl ether, 7:3) yielded 12a (56 mg, 91%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.38−7.31 (4H, m), 5.31 (1H, d, J = 1.0 Hz), 5.10 (1H, d, J = 1.0 Hz), 3.70 (6H, s), 3.57 (1H, t, J = 7.6 Hz), 3.13 (2H, dd, J = 7.6, 0.9 Hz), 1.33 (9H, s). 13C NMR (100 MHz, CDCl3): δ 169.4, 153.7, 150.8, 144.4, 136.8, 125.9, 125.4, 114.1, 52.5, 50.8, 34.6, 31.3. IR (CH2Cl2): ν 3055, 2966, 1736, 1266. HRMS: m/z calcd for C18H24NaO4 [M + Na]+ 327.1567, found 327.1567. Pt-Catalyzed Allylic Amination of 11. A solution of amine (0.34 mmol) and 11 (38 mg, 0.2 mmol) in THF (1 mL) was added to a stirred solution of Pt(PPh3)4 (0.01 mmol, 5%) in THF (1 mL). The reaction was stirred at room temperature for 1 h. Distilled water was added and the aqueous layer extracted two times with Et2O. The combined layers were dried over MgSO4, and the solvent was removed in vacuo. 2-(4-tert-Butylphenyl)-N,N-diethylprop-2-en-1-amine (12b). Following the procedure of platinum-catalyzed amination of 11, the reaction was carried out with 35 μL of diethylamine. Silica gel column chromatography (hexane−diethyl ether, 1:1) yielded 12b (45 mg, 92%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.48 (2H, d, J = 8.5 Hz), 7.36 (2H, d, J = 8.5 Hz), 5.44 (1H, s), 5.26 (1H, s), 3.42 (2H, s), 2.56 (4H, q, J = 7.0 Hz), 1.35 (9H, s), 1.02 (6H, t, J = 7.0 Hz). 13C NMR (100 MHz, CDCl3): δ 150.2, 145.5, 137.7, 125.9, 125.1, 114.1, 57.6, 46.8, 34.5, 31.3, 11.5. IR (CH2Cl2): ν 1265. HRMS: m/z calcd for C17H27N [M + H]+ 246.2216 found 246.2215. 1-(2-(4-tert-Butylphenyl)allyl)pyrrolidine (12c). Following the procedure of platinum-catalyzed amination of 11, the reaction was carried out with 28 μL of pyrrolidine. Silica gel column chromatography (hexane−diethyl ether, 1:1) yielded 12c (44 mg, 90%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.50 (2H, d, J = 8.5 Hz), 7.32 (2H, d, J = 8.5 Hz), 5.42 (1H, s), 5.26 (1H, s), 3.48 (2H, s), 2.56 (4H, m), 1.78 (4H, m), 1.33 (9H, s). 13C NMR (100 MHz, CDCl3): δ 150.3, 145.2, 137.6, 125.8, 125.1, 113.7, 60.7, 54.2, 34.5, 31.3, 23.6. IR (CH2Cl2): ν 1265. HRMS: m/z calcd for [M + H]+ 244.2060, found 244.2062. 4-(2-(4-tert-Butylphenyl)allyl)morpholine (12d). Following the procedure of platinum-catalyzed amination of 11, the reaction was carried out on 30 μL of morpholine. Silica gel column chromatography (hexane−diethyl ether, 6:4) yielded 12d (43 mg, 83%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.52 (2H, d, J = 8.0 Hz), 7.37 (2H, d, J = 8.0 Hz), 5.31 (1H, s), 5.24 (1H, s), 3.72 (4H, t, J = 4.7 Hz), 3.33 (2H, s), 2.51 (4H, m), 1.35 (9H, s). 13C NMR (100 MHz, CDCl3): δ 150.5, 143.0, 137.3, 125.8, 125.0, 114.9, 67.1, 63.6, 53.6, 34.5, 31.3. IR (CH2Cl2): ν 1266, 1116. HRMS: m/z calcd for [M + H]+ 260.2009, found 260.2006. N-(2-(4-tert-Butylphenyl)allyl)benzenamine (12e). Following the procedure of platinum-catalyzed amination of 11, the reaction was carried out on 32 mg of aniline for 16 h at reflux. Silica gel column chromatography (hexane) yielded 12e (38 mg, 72%) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 7.47 (2H, d, J = 7.3 Hz), 7.41 (2H, d, J = 7.3 Hz), 7.03 (2H, m), 6.74 (1H, t, J = 7.0 Hz), 6.67 (2H, d, J = 8.5 Hz), 5.53 (1H, s), 5.33 (1H, s), 4.19 (2H, s), 3.95 (1H, NH), 1.37 (9H, s). 13C NMR (100 MHz, CDCl3): δ 151.0, 148.1, 144.3, 136.2, 129.2, 125.7, 125.4, 117.5, 113.0, 112.9, 48.0, 34.6, 31.3. IR (CH2Cl2): ν 1603, 1265; HRMS: m/z calcd for [M + Na]+ 288.1723 found 288.1723. 1-tert-Butyl-4(3-phenoxyprop-1-en-2-yl)benzene (12f). A solution of sodium phenoxide (0.34 mmol) in THF (1 mL), prepared from phenol (30 μL, 0.34 mmol) and NaH (60% in mineral oil, 13.6 mg, 0.34 mmol), was added to a stirred solution of Pt(PPh3)4 (0.01 mmol, 5%) in THF (1 mL), followed by the addition of 11 (38 mg, 0.2 mmol). The reaction mixture was stirred for 4 h at reflux. Distilled water was added and the aqueous layer extracted two times with Et2O. The combined layers were dried over MgSO4, and the solvent was removed in vacuo. Silica gel column chromatography (hexane) yielded 12f (54 mg, 99%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.48 (2H, d, J = 8.3 Hz), 7.43 (2H, d, J = 8.3 Hz), 7.34 (2H, m), 7.02



ASSOCIATED CONTENT

* Supporting Information S

Text and figures giving additional synthetic procedures, characterization data, and NMR spectra of novel compounds. This material is available free of charge via the Internet at http://pubs.acs.org.



AUTHOR INFORMATION

Corresponding Author

*Fax: (+ 44) 1865-275-644. E-mail: [email protected] uk (J.M.B.); [email protected] (V.G.).



ACKNOWLEDGMENTS We gratefully acknowledge funding from the European Union (No. FP7-ITN-238434), MNSER, CRUK, EPSRC, and the Leverhulme Trust. In addition, we thank Dr. Barbara Odell for the NMR studies on the relative stereochemistry of novel compounds described herein.



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