1

This is the pre-peer reviewed version of the following article: Carbocations as Lewis Acid Catalysts in Diels–Alder and Michael Addition Reactions. Bah, J.; Franzén J. Chem.-Eur. J. 2014, 20, 1066, which has been published in final form at: http://onlinelibrary.wiley.com/doi/10.1002/chem.201304160/abstract

Carbocations as Lewis Acid Catalysts in Diels-Alder and Michael Addition Reactions

Juho Bah[a] and Johan Franzén*[a]

Abstract: In general, Lewis acid catalysts are metal-based compounds that owe their reactivity to a low-lying empty orbital. However, one potential Lewis acid that has received negligible attention as a catalyst is the carbocation. Here we show the potential of the carbocation as a highly powerful Lewis

Acid catalyst for organic reactions. The stable and easily available trityl cation was found to be a highly efficient catalyst for the Diels-Alder reaction with a range of substrates, catalyst loadings as low as 500 ppm, excellent yields and endo:exo selectivities. Furthermore, by changing the

electronic properties of the substituents on the tritylium ion, reactivity, i.e. the Lewis acidity, of the catalyst could be tuned to control the outcome of the reaction. The ability of the carbocation as a Lewis acid catalyst was also further extended to the Michael reaction.

Introduction

Chemistry is one of the fundamental research areas needed to preserve a sustainable future. This holds a profound challenge for chemists – from understanding the molecular basis of the natural and human-impacted environment to the design of novel catalytic processes that are highly selective and neither energy nor materials intensive. The utilization of Lewis Acids is one of the most versatile and applicable ways to facilitate catalysis. By definition, a Lewis acid has a low-lying LUMO that can accept an electron pair. The most common Lewis acids employed in catalysis today are based on metals like lithium, boron, zinc, aluminum, tin, magnesium and titanium.[1] However, one potential and easy available Lewis acid that has been almost completely neglected in the field of catalysis is the carbocation.[2] In elementary textbooks first year chemistry students are taught that carbocations are relatively common but generally unstable, non-isolable intermediates in several fundamental reactions.[3] However, this is only part of the truth: carbocations can be stable enough to be isolated and handled without employing inert conditions and some carbocations are even stable in water solution.[4] In fact, on a scale developed by Mayr et al., trityl cations display a range of 1021 orders of magnitude in reactivity (and stability) towards nucleophilic attack, depending on the substitution around the carbocationic center and its ability to stabilize the positive charge (Figure 1).[5] These properties of the carbocation open up unique opportunities for tuning stability and reactivity in a range unseen for traditional metal-based Lewis acids as far as we know.

Figure 1. Tuning of the Lewis acidity of trityl-cations.

Surprisingly, reports on the use of carbocations as Lewis acid catalysts are very sparsely reported in literature and the few mechanistic studies that are done are contradictory.[2,6,7] Mukaiyama and co-workers were pioneers in the quest to use carbocations as Lewis Acids and employed trityl-salts and N-acyliminium ions as catalysts for Mukaiyama aldol reactions,[8] Sakurai allylations[9] and Michael additions of silyl enol ethers to α,β-unsaturated ketones.[10] In all cases they reported fast and efficient reactions under mild conditions. In Mukaiyama’s first proposed catalytic cycle the aldehyde reacts with the trityl-cation 1 forming an intermediate oxonium ion 3 that will lower the LUMO of the electrophile enabling nucleophilic attack by the silyl enol ether giving intermediate 4 (Scheme 1, Tr-route). An intramolecular transfer of the silyl-group to the aldolate position (via 5) is then required to release the product and regenerate the catalyst. However, two additional mechanistic pathways have been suggested: 1) Trityl-cation initiated formation of a silyl-cation 6, which is a stronger

Scheme 1. Trityl v.s. silyl-cation catalyzed Mukaiyama aldol reaction.

OMe NMe2

MeO

MeO

Me2N

Me2N

Increased Lewis acidity / Increased Reactivity

Decreased Lewis Acidity / Increased Stability

1 (Tr+) 2 Crystal violet

Ar

O

Ar

O

PhPhPh

PhPhPh

OTMS

Ar

OOTMS

Ph

Ph Ph

Ar

OO Ph

Ph PhSiMe3

Ar

OOTMS

Tr-route Si

TMS-route

Ar

OO Ph

Ph Ph

Ar

OTMS

Ar

O OTMS

Ar

OTMS

OTMS

Ar

OTMS

O

1

3

4

5

6

2

Lewis acid than the trityl-cation, providing a purely silyl-mediated pathway that does not involve trityl-cation catalysis (Scheme 1, TMS-route). This route is also favored by a degenerated catalytic cycle. In fact, silyl-based Lewis acids, e.g. TMSOTf, are frequently used as catalysts and the application of silyl-cations as powerful catalysts for Diels-Alder reactions has recently gained attention, as demonstrated by the groups of Sawamura[11] and Oestreich. [12] 2) Decomposition of the trityl-cation to form a Brønsted acid that catalyzes the reaction. In a kinetic study, Denmark et al. found support for the carbocationic mechanism (Scheme 1, Tr-route).[13] However, a later thorough mechanistic study by Bosnich et al. contradicts Denmark results.[14] Their investigation excludes the possibility of a Brønsted acid catalyzed pathway and points toward a silyl-cation catalyzed mechanism (Scheme 1, TMS-route). In 1997, Chen et al. reported on attempts toward an asymmetric Mukaiyama aldol reaction, mediated by stoichiometric amounts of a chiral trityl-carbocation.[15] The aldol additions product was isolated with 3-50 % ee depending on the counterion and aromatic groups. However, when catalytic amounts of the chiral carbocation were used no enantioselectivity was observed. These results also support catalysis through a trityl-cation initiated formation of a silyl-cation (e.g. Scheme 1, TMS-route). In contradiction, Mukaiyama et al. reported a trityl-catalyzed aldol addition of vinyl acetate to aldehydes.[16] Thus, removal of the silyl-groups from the system points towards trityl cation catalysis, although no control experiments were done to exclude Brønsted acid catalysis. Kagan and coworkers developed a chiral ferrocenyl carbocation that was used as a catalyst in an attempted asymmetric Diels-Alder reaction.[17] However, absence of enantioselectivity and further mechanistic investigations verified that in situ degradation of the carbocation led to formation of a Brønsted acid, which proved to be the actual catalyst.[18]

Despite the previously reported, non-conclusive results on the application of carbocations as Lewis Acid catalysts, we set out to verify this concept by designing conditions that would exclude involvement of competing silyl-based Lewis acid or Brønsted acid catalysis. The Diels-Alder reaction was chosen as model reaction to test the catalytic activity of the trityl-carbocations.[17,19] This would avoid the problem of possible silyl cation catalysis. In our proposed catalytic cycle the dienophile, e.g. the free electron pair on the α,β-unsaturated aldehyde, will react with carbocation 1 forming an intermediate oxonium ion 7 that will lower the LUMO of the dienophile enabling the pericyclic reaction with the diene giving intermediate 8 (Scheme 2). Decomposition of intermediate 8 will release the Diels-Alder adduct and regenerate catalyst 1. Here we report the application of carbocations as extremely efficient, mild and selective Lewis acid catalysts for the Diels-Alder reaction with catalyst loadings down to ppm-levels. We demonstrate how reactivity and selectivity of the reaction can be tuned by tuning the Lewis acidity of the carbocation. We have also solid support for carbocationic catalysis by being able to exclude the involvement of competing Brønsted acid catalysis.

Scheme 2. Trityl-cation catalyzed Diels-Alder reaction.

Results and Discussion

Diels-Alder reactions: The triphenylcarbenium tetrafluoroborate or trityl tetrafluoroborate (TrBF4) is a cheap, commercially available carbocation that is stable enough to handle without any special precautions. It also constitutes a rather unique mode of carbon-centered Lewis acidity with extensive possibilities for relatively easy tuning of the electronic properties of the carbocation through variation of the electronic properties of the aromatic groups.[5] To our satisfaction we found that TrBF4 is an extremely efficient catalyst in the Diels-Alder reaction between acrolein and cyclohexadiene in DCM and addition of only 0.5 mol% gave full conversion in less than 1 h to selectively give the endo-product in quantitative yields (Table 1, entry 3). After further optimization we found that the catalyst loading could be decreased down to 0.1 mol% and still uphold good activity (Table 1, entry 2). However, turnover stopped after 48 h and 85 % conversion, most likely due to catalyst decomposition or inhibition. The optimal catalyst loading was found to be 0.2 mol% giving the endo-adduct as the only observable isomer in 94 % isolated yield after 48 h (Table 1 entry 2).20 It is important to stress the addition order of the starting materials and the catalyst: When only cyclohexadiene was added to a solution of TrBF4 in DCM the reaction mixture turned black immediately and complete decomposition/polymerization of the diene was observed by 1H-NMR. However, adding the dienophile to a solution of TrBF4 prior to cyclohexadiene or adding the catalyst to a solution of the starting materials completely suppressed polymerization of the diene and only formation of the Diels-Alder adduct was observed.[21] As expected, the reaction of both crotonal and methacrolein with cyclohexadiene in the presence of TrBF4 was much slower compared to acrolein and the reactions stopped due to polymerization of cyclohexadiene resulting in low yields in both cases. However, diene polymerization could be suppressed to some extent by performing the reaction at low temperature and the products could be isolated in moderate 45 and 60% yield, respectively (Table 1, entries 4 and 5). On the other hand, methyl vinyl ketone was comparable with acrolein in reactivity and the product was isolated in 75 % yield using as low as 0.2 mol% of the catalyst (Table 1, Entry 6).

Ph PhPh O

OPh

PhPhOPh

PhPh

O 1

78

3

Table 1. TrBF4 catalyzed Diels-Alder reactions of cyclohexadiene.[a,b]

Entry Dieno-

phile

Cat.

[mol%]

t

[h]

Conv.

[%]

Endo

/Exo[c]

Yield

[%][d]

1 9 0.1 48 85 50:1 --

2 9 0.2 48 100 >99:1 94

3 9 0.5 1 100 >99:1 Quant.

4[e,f] 10 5.0 36 60 33:1 45

5[f] 11 5.0 36 95 10:1 60

6 12 0.2 72 88 7:1 75

[a] The dienophile (1 equiv.) and diene (1.2 equiv.) was added to a solution of TrBF4

(C=0.3 M) and stirred for the indicated time. [b] No blank reaction was observed for

any dienophile after 72 h. [c] Determined by 1H NMR spectroscopy on the crude

reaction mixture. [d] Isolated yield. [e] Dienophile (2 equiv.) and diene (1 equiv.). [f]

Performed at -78 and slowly allowed to reach -20 °C over 36 h.

The more reactive cyclopentadiene slowly formed the Diels-Alder adduct with acrolein and methyl vinyl ketone in the absent of catalyst (Table 2, entries 1 and 9). However, addition of 0.1 mol% TrBF4 resulted in a distinct increased rate of the reaction and the corresponding products could be isolated in quantitative yield (Table 2, entries 2 and 10). Crotonal and methacrolein showed no background reaction with cyclopentadiene and addition of 0.1 mol% TrBF4 resulted in an efficient reaction to give the corresponding products in quantitative yield (Table 2, entries 4 and 8). For the Diels-Alder reaction of crotonal and cyclopentadiene the catalyst loading could be decreased to 500 ppm with excellent results and even at 200 ppm catalyst loading activity was observed, with 63 % conversion to the product before catalyst deactivation (Table 2, entries 5-6). The open diene 2,3-dimethylbutadiene and acrolein, required 0.1 mol% catalyst loading to obtain full conversion and the product was isolated in quantitative yield (Table 3, entry 1). At 500 ppm catalyst loading, TrBF4 gave 62 % conversion over 3 days. (Table 3, entry 2). As for cyclohexadiene, the reaction of 2,3-dimethylbutadiene with crotonal required higher catalyst loading to reach full conversion but the product was isolated in excellent yield (Table 3, entry 3). Methacrolein and methyl vinyl ketone were smoothly converted to the corresponding Diels-Alder adducts with 0.1 mol% and 0.2 mol% TrBF4, respectively, again in excellent yields (Table 3, entries 4-5). It is essential to highlight the excellent yields and exceptionally low catalyst loadings observed for the majority of these reactions. Although catalyst loadings at these levels are reported for transition metal catalyzed reactions[22] it is unusual and it is very rarely reported for non-metal catalysis.[23]

Table 2. TrBF4 catalyzed Diels-Alder reactions of cyclopentadiene.[a]

Entry Dieno-

phile

Cat.

[mol%]

t

[h]

Conv.

[%]

Endo

/Exo[b]

Yield

[%][c]

1

2

9

9

Blank

0.1

16

16

50

100

4:1

>99:1

--

Quant.

3

4

5

6

10

10

10

10

Blank

0.1

0.05

0.02

16

16

72

72

0

100%

95

63

---

49:1

49:1

49:1

--

Quant.

91

--

7

8

11

11

Blank

0.1

16

16

0

100

--

1:5

--

Quant.

9

10

12

12

Blank

0.1

16

16

50

100

6:1

13:1

--

Quant.

[a] The dienophile (1 equiv.) and diene (1.2 equiv.) was added to a solution of TrBF4

(C=0.3 M) and stirred for the indicated time. [b] Determined by 1H NMR spectroscopy

on the crude reaction mixture. [c] Isolated yield. [d] Reaction performed at -20 °C. [e]

Dienophile (2 equiv.) and diene (1 equiv.).

Table 3. TrBF4 catalyzed Diels-Alder reactions of 2,3-dimethylbutadiene.[a,b]

Entry Dieno-

phile

Cat.

[mol%]

t

[h]

Conv.

[%]

Yield

[%][c]

1

2

9

9

0.1

0.05

48

72

100

100

Quant.

--

3[d] 10 1.0 16 100 94

4[e] 11 0.1 16 100 87

5 12 0.2 16 100 94

[a] The dienophile (1 equiv.) and diene (1.2 equiv.) was added to a solution of TrBF4

(C=0.3 M) and stirred for the indicated time. [b] No blank reaction was observed for any dienophile after 72 h. [c] Isolated yield. [d] Reaction performed at -20 °C. [e]

Dienophile (2 equiv.) and diene (1 equiv.).

Cinnamic aldehydes and other dienophiles: When going through the literature, the Diels-Alder reaction between cinnamaldehyde and cyclohexadiene has proven to be a highly demanding reaction. Unsuccessful attempts involves the application of ultra-high pressures in the presence of different Lewis Acids that merely led to intractable mixtures and no isolated product.[24,25] In our initial attempts at this challenging reaction we used 20 mol% TrBF4 at

OR2

R3

R1

TrBF4

DCM, r.t.

R1

R2

R3O

O OO O

9 10 11 12

OR2

R3

R1

TrBF4

DCM, r.t.

R1

R2

R3O

O OO O

9 10 11 12

OR2

R3

R1

TrBF4

DCM, r.t.

O OO O

9 10 11 12

R1

R2

OR3

4

room temperature and could only observe 4 % conversion to the corresponding Diels-Alder adduct accompanied by substantial consumption of cyclohexadiene through polymerization (Table 4, entry 1). Heating of the reaction at 40 °C increased conversion to the Diels-Alder adduct to 7 % but likewise increased diene polymerization and at 60 °C in CDCl3 selective diene polymerization was observed (Table 4, entries 2-3). However, in accordance with the previously discussed tunable Lewis acidity of the trityl-cation (vide supra), we reasoned that variation of the substituents on the carbocation could suppress diene polymerization and favor the cycloaddition.[26] Gratifyingly, conversion was vastly improved when using 5.0 mol% of the less active and more stable catalyst (p-MeOPh)3CBF4 in chloroform at 40 °C (Table 4, entry 5). After 18 h, 56 % of the cinnamaldehyde was converted to the Diels-Alder product without any significant amount of cyclohexadiene decomposition. Unfortunately, the product was not completely stable under the reaction conditions and the prolonged heating led to product decomposition and low isolated yields. Although encouraged by these results we turned our attention to the Diels-Alder reaction of cinnamaldehyde and cyclopentadiene.As was the case for the TrBF4 catalyzed reaction of cinnamaldehyde and cyclohexadiene, the corresponding reaction with cyclopentadiene only led to trace amounts of product with full consumption of the diene through polymerization (Table 4, entry 7). Again, applying (p-MeOPh)3CBF4 as the catalyst led to a smooth conversion to the Diels-Alder product, without any observable diene decomposition (Table 4, entry 8). The catalyst load could be decreased to 0.25 mol% and the product was isolated in high yield and with 93:7 endo:exo selectivity. Furthermore, 1.0 mol% of (p-MeOPh)3CBF4 successfully converted p-MeO-cinnamaldehyde and o-NO2-

cinnamaldehyde to the corresponding Diels-Alder products in 78% and 73% yield respectively and with 94:6 endo:exo selectivity in both cases (Table 4, entries 9-10). In line with previous observations, the Diels-Alder reaction of 2,3-dimethylbutadiene and cinnamaldehyde turned out to be poorly catalyzed by TrBF4 with polymerization of the diene as the result (Table 4, entry 11). Again, (p-MeOPh)3CBF4 turned out to be successful and 1.0 mol% catalyst at 40 °C overnight gave 82 % conversion and 74 % isolated yield after flash chromatography (Table 4, entry 12).

All attempts to use acrylonitrile and methyl acrylate as dienophiles in the Diels-Alder reaction with both cyclohexadiene and cyclopentadiene, catalyzed by TrBF4 and (4-MeOPh)3CBF4

failed after repeated attempts (Scheme 3, eq a and b). However, one interesting observation was made: In the case of acrylonitrile, the diene underwent instant decomposition through polymerization (Scheme 3, eq a). On the other hand, when methylacrylate was employed as dienophile, all reagents remained unreacted (Scheme 3, eq b). This can be interpreted as an insufficient interaction between the empty p-orbital of the carbocation and the lone pairs of the nitrile, which allows the diene to attack the carbocation, thus leading to polymerization. For methyl acrylate, it is assumed that the ester carbonyl interacts strongly enough with the empty p-orbital of the carbocation to prevent the diene from attacking and thereby suppressing diene polymerization. However, the interaction of the ester-group with the catalyst do not lower the LUMO of methylacrylate enough to allow for the Diels-Alder reaction to occur.

Table 4. Carbocation catalyzed Diels-Alder reactions with cinnamic aldehydes.[a]

Entry Ar Diene T

[°C]

Cat.

[mol%]

t

[h]

Product Conv.

[%]

Endo

/Exo[b]

Yield

[%][c]

1

2

3

4

5

6

Ph

Ph

Ph

Ph

Ph

Ph

r.t.

40

60

r.t.

40

80

1 (20)

1 (20)

1 (20)

2 (20)

2 (5.0)

2 (1.0)

24

24

24

120

16

16

4

7

0

0

56

10

--

--

--

--

>99:1

--

--[e]

--[e]

--[e]

--

22 (29)[d]

--[e]

7

8[d]

9[d]

10[d]

Ph

Ph

4-MeO-Ph

2-NO2-Ph

r.t.

r.t.

r.t.

r.t.

1 (1-10)

2 (0.25)

2 (1.0)

2 (1.0)

72

96

96

168

0

100

92

78

--

13:1

16:1

16:1

--[e]

85

78

73

11

12

Ph

Ph r.t.

40

1 (1.0)

2 (1.0)

18

18 14

82

--

--

--[e]

74 (86)[f]

[a] The catalyst was added to a CH2Cl2 solution (0.3 M) of the diene (3 equiv.) and the cinnamic aldehyde (1 equiv.). [b] Determined by 1H NMR spectroscopy on the crude reaction

mixture. [c] Isolated yield. [d] 2 eq. cyclopentadiene was used. [e] Decomposition of diene. [f] Based on recovered starting material.

O

Ar

R1

R2

R3O

( )n

( )n Ph PhPh BF4

R=H, n=1 or 2(cyclic)R=Me (acyclic)

Cat.

CH2Cl2,T, t

endo

Ph-OMe-pPh-OMe-p

BF4p-MeO-Ph

1 2

Cat.

Ph

O

Ar

O

Ph

O

5

Scheme 3. Eq. a and b: Unsuccessful trityl-ion catalyzed Diels-Alder of methyl acrylate and acrylonitrile i) TrBF4 (10 mol%), DCM, r.t. ii) (MeOPh)3CBF4 (10 mol%), DCE, r.t. or 80 °C.

Danger of Hidden proton catalysis: A competing catalytic pathway can involve reaction of the carbocation with traces of water or decomposition of the carbocation to form a Brønsted acid that could be the actual catalyst of the Diels-Alder reaction. This was the case observed by Kagan et al. in their attempts to use chiral ferrocene based carbocations as catalysts for asymmetric Diels-Alder ractions.[17] It is also highlighted as a competing mechanistic pathway for the silyl cation-catalyzed Diels-Alder reactions studied by Oestreich et al.[12] In fact, when a mixture of acrolein and cyclohexadiene was treated with just 1.0 mol% of HBF4 as catalyst, full conversion to the Diels-Alder adduct was obtained in one hour, which is compatible to the result obtained from corresponding reaction catalyzed by 1.0 mol% TrBF4. The most straightforward way to exclude Brønsted acid catalysis is to perform the reaction with the sterically hindered base DBPy as a proton scavenger. Thus, when the reaction between cyclohexadiene and acrolein was conducted in presence of TrBF4 (1.0 mol%) and DBPy (2.0 mol%) no reaction was observed and we started to suspect a mechanistic pathway proceeding through proton catalysis. However, further investigations revealed that a 1:1 mixture of DBPy and TrBF4 instantly reacted to give an unidentified adduct(s) that had no catalytic activity (Scheme 4, eq. a). Interestingly it could be undoubtedly concluded by 1H-NMR that the formed adduct(s) was not protonated DBPy (Scheme 4). Therefore, DBPy cannot be used as a proton scavenger under these reaction conditions since it leads to decomposition of the catalyst.

Scheme 4. Eq. a: The reaction of DBPy and TrBF4. Eq. b: Comparison experiment between TrBF4 and HBF4.

In order to exclude Brønsted acid catalysis comparative experiments between the carbocation and the Brønsted acid was performed: 0.1 mol% HBF4 in CH2Cl2 gave 8% conversion in the Diels Alder reaction between cyclopentadiene and acrolein after 72 h at r.t. (Scheme 4, eq. b). On the other hand, the corresponding reaction using 0.1 mol% TrBF4 gave 85% conversion after 48 h.[27] Following this, it is unlikely that the trityl cation-catalyzed reactions should proceed through initial carbocation decomposition and Brønsted acid catalysis. However, in order to fully exclude Brønsted acid catalysis we designed the more steric hindered indenylium tetrafluoroborate 13. We anticipated that the increased steric bulk of

the quaternary α-carbon on 13 would prevent reaction between the catalyst and DBPy. At -20 °C, no background reaction between cyclopentadiene and acrolein was observed (cf. Table 5, entry1 and Table 2, entry 1). However, addition of catalyst 13 (20 mol%) to the reaction gave 81% conversion to the product in one hour (Table 5, entry 2). In contradiction to the trityl cation 1, indenylium ion 13 and DBPy did not react with each other and gratifyingly; indenylium ion 13 catalyzed the Diels Alder even in the presence of 50 mol% DBPy. These results exclude the possibility of Brønsted acid catalysis and we interpret these findings as proof of an active carbocation being responsible for the catalysis.

Table 5: Indenylium ion 13 catalyzed Diels-Alder reaction.[a]

Entry Cat.

[mol%]

Additive

[mol%]

Conv.

[%]

Endo /Exo[b]

1 Blank -- 0 --

2 13 (20) -- 81 8:1

3 13 (20) DBPy (50) 48 6:1

[a] The dienophile (1 equiv., C=0.3 M) and diene (1.2 equiv.) was added to a solution of catalyst and additive at -20 °C. [b] Determined by 1H NMR spectroscopy on the crude

reaction mixture.

Michael addition reactions: After the successful results from the Diels-Alder reaction we sought to further expand the Lewis acid catalyzed reactions of the carbocation. The tritylium-ion catalyzed Michael reaction was previously reported by Mukaiyama et al. using silyl enol ethers as nucleophiles to α,β-unsaturated ketones.[10] We intended to repeat this reaction under silyl-free conditions in order to exclude competing silyl-cation catalysis and we identified activated aromatic and methylene compounds as potential nucleophiles. Unfortunately, the reaction of crotonal or cinnamic aldehyde with N,N’-dimethylaniline or indole in the presence of 5 mol% TrBF4 gave no reaction and the starting materials were recovered. However, the more activated ethyl 4-oxo-2-butenoate 8 reacted smoothly with N,N’-dimethylaniline to afford the corresponding adduct 9 in 81 % yield over 3 days in the presence of only 1.0 mol% TrBF4 (Table 5, entries 1-2). The more sterically hindered 3-methyl-N,N’-diethylaniline required 10 mol% catalyst loading to go to full conversion and was isolated in 76 % yield after work-up (Table 5, entries 3-5). The reaction of indole and ethyl 4-oxo-2-butenoate 8 turned out to be efficiently catalyzed by 1.0 mol% TrBF4 and the product was isolated in high yield after only 90 minuets. N-methylindole was more reactive and gave substantial amount of the corresponding Michael adducts in the absence of catalyst (Table 5, entry 8). However, with 1.0 mol% TrBF4 full conversion was observed after 90 minutes and the product could be isolated in 56 % yield (Table 5, entries 6-9). The more acid labile N-methylpyrrolidine and pyrrolidine immediately decomposed in the presence of TrBF4 (Table 5, entries 3-4) and 1,3-diketones and β-ketoesters turned out to be to weak nucleophiles and gave no conversion under these reaction conditions (Table 5, entries 5-6).

+

CN ( )n

n=1 or 2

i or ii DieneDecomposition (a)

+( )n

n=1 or 2

O

OMe No Reaction (b)i or ii

O Cat. (0.1 mol%)

DCM, r.t.O

Cat. = HBF4 x OEt2: 8% conversion (72 h)Cat. =TrBF4: 85% conversion (48 h)

N t-But-BuDBPy

Ph Ph

PhBF4

DCM, r.t.UnidentifiedProduct(s)

(b)

(a)

O Cat.Additive

DCM -20, 1 h O

Ph

MeO 13

BF4 N t-But-BuDBPy

6

TABLE 5. TrBF4 catalyzed Michael additions.[a]

Entry Nu-H Cat. load

[mol%]

Time

[h]

Product Conv.

[%]

Yield

[%][b]

1

2

Blank

1.0

72

72

19

100

--

81

3

4

5

Blank

1.0

10

24

24

72

8

15

100

--

--

76

6

7

Blank

1.0

24

1.5

14

100

--

87

8

9

blank

1.0

1.5

1.5

15

100

--

56

10

10 -- -- --[c] --

11

10 72 -- 0 --

[a] TrBF4 was added to a CH2Cl2 solution (C = 0.3 M) of (E)-Ethyl 4-oxobut-2-enoate

(1 equiv.) and the corresponding nucleophile (1.5 equiv.). [b] Isolated yield. [c] Instant

decomposition of the pyrrole.

Conclusion

In summary, we have demonstrated that carbocations are highly active and versatile Lewis acids catalysts for the Diels-Alder reaction. The catalyst loadings are in most cases exceptionally low (‰), and for some examples they may even be reduced down to ppm-levels. The products are isolated in good to quantitative yields often in a very clean and selective manner. The high yields and the rare ppm-level catalyst loadings have an obvious potential for developing novel sustainable processes both in industry and academia. Furthermore, we have shown that tuning the electronic properties e.g. the Lewis acidity/reactivity of the carbocation can control the outcome of a reaction (diene polymerization vs. Diels-Alder). In contradiction to previous reports we also have very strong mechanistic support for carbocation catalysis by being able to unambiguously exclude Brønsted acid catalysis. In addition we also preliminary results that the trityl cation is an efficient catalyst for the Michael reaction of activated aromatic compounds. The application of carbocations in catalysis has not been previously systematically investigated and the knowledge of their behavior is extremely limited. Thus, it is likely that carbocations will have unique properties compared to those found for metal based Lewis acids so there is a challenging potential to discover completely new reactivity and selectivity that is not accessible through traditional Lewis acid catalysis. At the present we are continuing to explore the

scope and limitation of carbocation catalysis by tuning the Lewis acidity in order to gain more understanding of reactivity and to further extend the reaction scope. These results will be reported in due course.

Experimental Section

Bicyclo[2.2.2]oct-5-ene-2-carboxaldehyde: To a solution of the catalyst in CH2Cl2 (c=0.3 M with respect to the dieneophile) was added the dienophile (1 equiv.) followed by the diene (1.2 equiv.). After completion, determent by 1H NMR, the reaction mixture was passed through a small plug of SiO2 (CH2Cl2) and carefully concentrated under reduced pressure to give the pure product in quantitative yield. No further purification was required unless otherwise noted.

Acknowledgements ((optional))

This work was made possible by grants from the Swedish Research Council (VR) and the Royal Swedish Academy of Sciences (KVA). J.F. thanks the Stenbäcks Foundation and Lars Hiertas Minne for a grant.

[1] Lewis Acids in Organic Synthesis. (Ed: H. Yamamoto) WILEY-VCH, 2000.

[2] O. Sereda, S. Tabassum, R. Wilhelm, Lewis Acid Organocatalysts. (Ed: B. List) Top. Curr. Chem. 2010, 291, 349.

[3] J. Clayden, N. Greeves, S. Warren, Organic Chemistry (2nd ed.) Oxford Press. ISBN: 9780199270293. (2012).

[4] Carbocation Chemistry (Eds: G. A. Olah, G. K. S. Prakash) Wiley, Hoboken, NJ, 2004.

[5] See: M. Horn, H. Mayr J. Phys. Org. Chem. 2012, 25, 979 and references therein.

[6] a) S. Kobayashi, S.-L. Shoda, T. A. Mukaiyama Chem. Lett. 1984, 13, 907. b) T. A. Mukaiyama, S. Kobayashi, S.-I. Shoda Chem. Lett. 1984, 1529. c) M. Ohshima, M. Murakami, T. A. Mukaiyama Chem. Lett. 1985, 1871. d) M. Yanagisawa, T. A. Mukaiyama Chem. Lett. 2001, 224.

[7] C. Nicolas, J. Lacour Org. Lett. 2006, 8, 4343.

[8] a) T. Mukaiyama, S. Kobayashi, M. Murakami Chem. Lett. 1984, 1759. b) S. Kobayashi, S. Murakami. T. A. Mukaiyama Chem. Lett. 1985, 447. c) S. Kobayashi, M. Murakami, T. Mukaiyama Chem. Lett. 1985, 1535. d) S. Kobayashi, S. Matsui, T. A. Mukaiyama, Chem. Lett. 1988, 1491. e) J. S. Han, H. Akamatsu, T. A. Mukaiyama Chem. Lett. 1990, 889.

[9] T. Mukaiyama, H. Nagaoka, M. Murakami, M. Ohshima Chem. Lett. 1985, 997.

[10] S. Kobayashi, M. Murakami, T. Mukaiyama Chem. Lett. 1985, 953.

[11] R. Akiyama, K. Hara, M. Sawamura Org. Lett. 2005, 7, 5621.

[12] a) R. Schmidt, K. Müther, C. Mück-Lichtenfeld, S. Grimme, M. Oestreich J. Am. Chem. Soc. 2012, 134, 4421. b) H. F. T. Klare, K. Bergander, M. Oestreich Angew. Chem. Int. Ed. 2009, 48, 9077.

[13] C.-T. Chen, S. Denmark Tetrahedron Lett. 1994, 35, 4327.

[14] T. K. Hollis, B. Bosnich J. Am. Chem. Soc. 1995, 117, 4570.

[15] a) S.-D. Chao, K.-C. Yen, C. Chien-Tien Synlett. 1998, 924. b) S.-D. Chao, K.-C. Yen, C.-H. Chen, I.-C. Chou, S.-W. Hon, C.-T. Chen J. Am. Chem. Soc. 1997, 119, 11341.

[16] M. Yanagisawa, T. Shimamura, D. Iida, J.-I. Matsuo, T. A. Mukaiyama Chem. Pharm. Bull. 2000, 48, 1838.

[17] a) O. Riant, O. Samuel, H. B. Kagan J. Am. Chem. Soc. 1993, 115, 5835. b) A. Brunner, S. Taudien, O. Riant, H. Kagan Chirality 1997, 9, 478. c) S. Taudien, O. Riant, H. Kagan Tetrahedron Lett. 1995, 36, 3513.

[18] H. Latham, T. Sammakia Tetrahedron Lett. 1995, 36, 6867.

[19] K. Ishihara, A. Sakakura [4+2]-Cycloaddition Reactions. (Eds: J. G. De Vries, G. A. Molander, P. A. Evans) Science of Synthesis, Stereoselective Synthesis (2011), 3, 67-123.

[20] For optimization see supporting information.

EtO

O

EtO

ONu

TrBF4

CH2Cl2, rt

O O

Nu H

8 9

NEtO

O

O

N

NEt

Et

EtO

O

O

N Et

Et

NH

EtO

O

O

NH

N EtO

O

O

N

NR

R=Hor Me

O O

RR = Me, OMe, CF3

7

[21] Other solvents were evaluated yet proved unsuccessful. Screening of the different trityl salts (BF4

-, ClO4-, PF6

-, B[(C6F5)4]- revealed that altering the anion

has limited effect on the reactivity.[11,15] Fur full optimization see Supporting info.

[22] For some selected examples see: a) R. M. Thomas, B. K. Keitz, T. M. Champagne, R. H. Grubbs J. Am. Chem. Soc. 2011, 133, 7490. b) Z. Wang, X. Feng, W. Fang, T. Tu Synlett 2011, 951. c) Y. Schrodi, T. Ung, A. Vargas, G. Mkrtumyan, C. W. Lee, T. M. Champagne, R. L. Pederson, S. H. Hong, Clean 2008, 36, 669. d) Q. Shen, S. Shekhar, J. P. Stambuli, J. F. Hartwig Angew. Chem. Int. Ed. 2005, 44, 1371.

[23] For some recent selected examples see: a) S. Shirakawa, A. Kasai, T. Tokuda, K. Maruoka Chem. Sci. 2013, 4, 2248. b) M. Rueping, A. P. Antonchick, T. Theissmann Angew. Chem. Int. Ed. 2006, 45, 6751. c) M. Kotke, P. R. Schreiner Synthesis 2007, 779.

[24] A. C. Kinsman, M. Kerr Org. Lett. 2000, 2, 3517.

[25] To our knowledge, no successful Diels-Alder reaction between cinnamaldehyde and cyclohexadiene has been reported in literature.

[26] The (p-MeOPh)3CBF4 (1 mol%) catalyzed reaction of cyclohexadiene and acrolein proceeded to 81% conversion to the corresponding adduct over 9 days before catalyst deactivation without any observable diene polymerization. The observed decrease in reactivity is due to the lower Lewis acidity originating from the stabilization of the positive charge by the methoxy-groups.

[27] In the Diels-Alder reaction of crotonal and cyclopentadiene at room temperature, TrBF4, showed higher conversions than the corresponding reactions catalyzed by HBF4 (See supporting information).

8

Entry for the Table of Contents (Please choose one layout only)

Carbocation Catalysis

J. Bah, J. Franzén* ………..… Page – Page

Carbocations as Lewis Acid Catalysts in Diels-Alder and Michael Addition Reactions

The Quest for the forgotten Lewis Acid: In general, Lewis acid catalysts are metal-based compounds. However, one potential Lewis acid catalyst that has received negligible attention is the carbocation.

Here we show the ability of the stable and easily available trityl cation as a highly powerful catalyst for the Diels Alder reaction with a range of substrates, catalyst loadings down to 500 ppm, excellent yields and endo:exo selectivity.

OR2

R3

R1

R1

R2

R3O

( )n

( )n0.05 - 5 mol%

17 examplesQuantitative - 22 % yield>99:1 to 4:1 endo/exo

Ar ArAr BF4

S1

Carbocations as Lewis Acid Catalysts in Diels-Alder and

Michael Addition Reactions

Juho Bah and Johan Franzén*

Department of Chemistry, Organic Chemistry, Royal Institute of Technology (KTH), Teknikringen 30, SE-100 44 Stockholm, Sweden.

jfranze@kth.se

Supporting Information Table of Contents Optimization of the TrBF4 catalyzed Diels-Alder reaction: S2 Comparison experiment between TrBF4 and HBF4: S3 Experimental Section: S4 NMR-Spectra: S9

S2

TABLE 1: Optimization of the carbocation catalyzed Diels-Alder reactions of acrolein with cyclohexadiene.[a]

+ Catalyst +Solvent, r.t., T

endo-1 exo-1O

O

O

Entry Catalyst Cat.load

[mol%] Solvent Time

[h] Conv. [%]

Endo /Exo[b]

Yield [%][c]

1 Blank Blank CH2Cl2 72 h 0 -- -- 2 TrBF4 1.0 CH2Cl2 1 h 100 33:1 95

3 TrBF4 0.5 CH2Cl2 1 h 100 100:0 Quant.

4 TrBF4 0.2 CH2Cl2 1 h 59 100:0 --

5 TrBF4 0.2 CH2Cl2 48 h 100 100:0 94

6 TrBF4 0.1 CH2Cl2 48 h 85 50:1 -- 7 TrBF4 0.05 CH2Cl2 48 h 0 -- -- 8 TrBF4 0.2 CH3CN 1 h 14 -- -- 9 TrBF4 0.2 THF 1 h 0 -- -- 10 TrBF4 0.2 Toluene 1 h 3 -- -- 11 (4-MeOPh)3CBF4 1.0 CH2Cl2 9 d 81 99:1 -- 12 TrClO4 0.5 CH2Cl2 48 h 100 23:1 93 13 TrClO4 0.2 CH2Cl2 48 h 81 38:1 93 14 Tr[B(C6F5)4] 0.2 CH2Cl2 72 h 75 23:1 --

15 TrPF6 0.2 CH2Cl2 48 h 77 36:1 -- [a] The catalyst was added to a solution (0.3 M) of cyclohexadiene (1.2 equiv.) and acrolein (1 equiv.) and stirred for the indicated time. [b] Determined by 1H NMR spectroscopy on the crude reaction mixture. [c] Isolated yield. [d] Ratio of dienophile:diene 2:1.

S3

Table 4: Comparison experiment between TrBF4 and HBF4.[a]

+R

OR

CH2Cl2, rtCatalyst

O( )n

( )n

Entry R n Catalyst

Cat.load [mol%]

Time [h]

Conv. [%]

Endo /Exo[b]

1 H 2 HBF4 1.0 1 100 >99:1

2 H 2 TrBF4 1.0 1 100 >99:1

3[c] H 2 TrBF4 1.0 18 0[d] --

4 H 2 HBF4 0.2 0.4 4 --

5 H 2 TrBF4 0.2 0.4 37 50:1

6 H 2 HBF4 0.1 72 8 --

7 H 2 TrBF4 0.1 48 85 50:1

8 H 2 TrBF4 1.0 18 100 99:1

9 Me 1 HBF4 0.05 72 80 5:1

10 Me 1 TrBF4 0.05 72 95 10:1

11 Me 1 HBF4 0.02 72 50 10:1

12 Me 1 TrBF4 0.02 72 63 10:1

[a] TrBF4 was added to a CH2Cl2 solution (0.3 M) of the diene (1.2 equiv) and the dienophile (1 equiv.) and stirred for the indicated time. [b] Determined by 1H NMR spectroscopy on the crude reaction mixture. [c] 2.0 mol% DBPy was added to the reaction. [d] Catalyst decomposition.

S4

Experimental Section

General. The 1H NMR and 13C NMR spectra were recorded at 500 or 400 MHz and 125 or 100 MHz, respectively. The chemical shifts are reported in ppm relative to CHCl3 (δ = 7.26) for 1H NMR and relative to the central CDCl3 resonance (δ = 77.0) for 13C NMR. Flash chromatography (FC) and column chromatography were carried out using Merck silica gel 60 (230-400 mesh). Materials. TrBF4 and TrPF6 are commercially available and used as received. TrClO4, Tr[B(C6F5)4] and TrPF6 were prepared according to literature procedures.1,2,3 Acrolein, crotonaldehyde, methacrolein and methyl vinyl ketone are commercially available and were distilled prior to use. Cyclopentadiene was cracked from dicyclopentadiene prior to use and stored in freezer. Other reagents are commercially available and used as received. All reactions are preformed in pre-dried solvents under nitrogen atmosphere unless otherwise noticed Standard procedure A – (dienophile excess 2:1): To a solution of the catalyst in CH2Cl2 (c=0.3 M with respect to the diene) was added the dienophile (2 equiv.) followed by the diene (1 equiv.). After completion, determent by 1H NMR, the reaction mixture was passed through a small plug of SiO2 (CH2Cl2) and carefully concentrated under reduced pressure to give the pure product. No further purification was required unless otherwise noted. Standard procedure B (diene excess 1.2:1): To a solution of the catalyst in CH2Cl2 (c=0.3 M with respect to the dieneophile) was added the dienophile (1 equiv.) followed by the diene (1.2 equiv.). After completion, determent by 1H NMR, the reaction mixture was passed through a small plug of SiO2 (CH2Cl2) and carefully concentrated under reduced pressure to give the pure product. No further purification was required unless otherwise noted.

O Bicyclo[2.2.2]oct-5-ene-2-carboxaldehyde: The title compound was prepared according to Standard Procedure A or B from acrolein and 1,3-dimethylbutadiene using 0.5 mol% TrBF4 in quantitative yield. Spectral data were in accordance with those previously reported.4

O 3-methyl-bicyclo[2.2.2]oct-5-ene-2-carbaldehyde: The title compound was prepared according to Standard Procedure A from crotonaldehyde and 1,3-cyclohexadiene using 5.0 mol% TrBF4 in 39% yield. Spectral data were in accordance with those previously reported.5

O 2-methylbicyclo[2.2.2]oct-5-ene-2-carbaldehyde: The title compound was prepared according to Standard Procedure B from methacrolein and 1,3-cyclohexadiene using 5.0

1 Hao, W.; Parker, V.D. J. Org. Chem. 2008, 73, 48. 2 Lambert, J.B.; Schulz, W. J. J.; McConnell, JA.; Schilf, W. J. Am. Chem. Soc. 1988, 110, 2201. 3 Ihara, E.; Young, V.G.; Jordan, R.F. J. Am. Chem. Soc. 1998, 120, 8277. 4 Ahrendt, K.A; Borths, C.J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243. 5 Klare, H.F.T.; Bergander, K.; Oestreich, M. Angew. Chem., Int. Ed. 2009, 48, 9241.

S5

mol% TrBF4 with the exception that the reaction was performed at -20°C. The pure product was isolated in 50 % yield. Spectral data were in accordance with those previously reported.9

O 1-(Bicyclo[2.2.2]oct-5-en-2-yl)ethanone: The title compound was prepared according to Standard Procedure B from methyl vinyl ketone and 1,3-cyclohexadiene using 0.2 mol% TrBF4 in 75 % yield. Spectral data were in accordance with those previously reported.9

O Bicyclo[2.2.1]hept-5-ene-2-carbaldehyde: The title compound was prepared from acrolein and 1,3-cyclopentadiene using 0.1 mol% TrBF4 in quantitative yield according to Standard Procedure B. Spectral data were in accordance with those previously reported.6

O 3-Methylbicyclo[2.2.1]hept-5-ene-2-carbaldehyde: The title compound was prepared according to Standard Procedure B from crotonaldehyd and 1,3-cyclopentadiene using 0.05 mol% TrBF4 in 91 % yield. Spectral data were in accordance with those previously reported.6

O 2-Methylbicyclo[2.2.1]hept-5-ene-2-carbaldehyde: The title compound was prepared according to Standard Procedure B from methacrolein and 1,3-cyclopentadiene using 0.1 mol% TrBF4 in quantitative yield. Spectral data were in accordance with those previously reported.7

O 1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone: The title compound was prepared according to Standard Procedure B from methyl vinyl ketone and 1,3-cyclopentadiene using 0.1 mol% TrBF4 in quantitative yield. Spectral data were in accordance with those previously reported.8

O 3,4-Dimethyl-3-cyclohexene-1-carbaldehyde: The title compound was prepared according to Standard Procedure B from freshly distilled acrolein and 2,3-dimethylbutadiene using 0.1 mol% TrBF4 in quantitative yield. Spectral data were in accordance with those previously reported.9

O 3,4,6-Trimethyl-3-cyclohexene-1-carbaldehyde: The title compound was prepared according to Standard Procedure A from crotonaldehyde and 3,4-dimethylbutadiene using1.0 mol% catalyst loading. The pure product was isolated in 94 % yield Spectral data were in accordance with those previously reported.10 6 Ishihara, K.; Kurihara, H.; Matsumoto, M.; Yamamoto, H. J. Am. Chem. Soc. 1998, 120, 6920. 7 Hatano, M.; Mizuno, T.; Izumiseki, A.; Usami, R.; Asai, T.; Akakura, M.; Ishihara, K. Angew. Chem. Int. Ed.

2011, 50, 12189. 8 Schmidt, R., Munther, K., Münck-Lichtenfeld, C., Grimme, S. & Oestreich, M. J. Am. Chem. Soc. 2012, 134,

4421. 9 Nakashima, D.; Yamamoto, H. Org. Lett. 2005, 7, 1251. 10 Taarning, E.; Madsen, R. Chem. Eur. J. 2009, 48, 9241.

S6

O 1,3,4-trimethyl-3-cyclohexene-1-carbaldehyde: The title compound was prepared according to Standard Procedure A from methacrolein and 3,4-dimethylbutadiene using 0.2 mol% TrBF4. The pure product was isolated in 87 % yield. Spectral data were in accordance with those previously reported.10

O 1-(3,4-dimethylcyclohex-3-en-1-yl)ethanone: The title compound was prepared according to Standard Procedure A from methacrolein and 3,4-dimethylbutadiene using 0.5 mol% TrBF4. The pure product was isolated in 58 % yield. Spectral data were in accordance with those previously reported.10

O 3-phenyl-bicyclo[2.2.2]oct-5-ene-2-carbaldehyde: Cinnamaldehyde (33 µl, 0.50 mmol) followed by 1,3-cyclohexadiene (142 µl, 1.5 mmol) was added to a solution of (4-MeOPh)3CBF4 (10 mg, 0.025 mmol) in CDCl3 (1,2 ml). The solution was heated in a closed vial at 60°C for 16 h. The reaction mixture was cooled to ambient temperature and quenched with Na2CO3 (aq.), extracted with CH2Cl2 and concentrated in vacuo. The resulting oil was purified by FC (SiO2, Pentane:Et2O) to give 25 mg (22%) of the product (29 % yield based on recovered starting material). Spectral data were in accordance with those previously reported.11

O 3-Phenylbicyclo[2.2.1]hept-5-ene-2-carbaldehyde: The title compound was prepared according to Standard Procedure A from cinnamaldehyde and 1,3-cyclopentadiene (2 equiv.) using 0.25 mol% (4-MeOPh)3CBF4 in 96 % yield. Spectral data were in accordance with those previously reported.12

O

O

3-(4-Methoxyphenyl)bicyclo[2.2.1]hept-5-ene-2-carbaldehyde: The title compound was prepared according to Standard Procedure A from cinnamaldehyde and 1,3-cyclopentadiene (2 equiv.) using 1.0 mol% (4-MeOPh)3CBF4 in 96 % yield. Spectral data were in accordance with those previously reported.12

O

O2N

3-(2-Nitrophenyl)bicyclo[2.2.1]hept-5-ene-2-carbaldehyde: The title compound was prepared according to Standard Procedure A from cinnamaldehyde and 1,3-cyclopentadiene (2 equiv.) using 1.0 mol% (4-MeOPh)3CBF4 in 68 % yield. Spectral data were in accordance with those previously reported.13

11 Gomez-Bengpa, E.; Oiarbide, M.; Palomo, C.; Banuelos, P.; Garcia, J. M.; Herrero, A.; Odriozola, J M.;

Razkin, J. J. Org. Chem., 2010, 75, 1458. 12 He, H.; Pei, B.-J.; Chou, H.-H.; Tian, T.; Chan, W.-H.; Lee, A. W. M. Org. Lett. 2008, 10, 2421. 13 Lemay, M.; Ogilvie, W. W. Org. Lett. 2005, 7, 4141.

S7

O 3,4-dimethyl-6-phenyl-3-cyclohexene-1-carbaldehyde: Cinnamaldehyde (25 µl, 0.38 mmol) followed by 3,4-dimethylbutadiene (225 µl, 1.14 mmol) was added to a solution of (4-MeO)3CBF4 (1.5 mg, 0.0038 mmol) in CH2Cl2 (1 ml). The resulting mixture was heated in a closed vial at 40°C for 48 h. The reaction mixture was then cooled to ambient temperature and passed through a small plug of SiO2 and evaporated in vacuo. The resulting oil was purified by FC (SiO2, Pentane:Et2O) to give 60 mg (74%) of the product (86 % yield based on recovered starting material). Spectral data were in accordance with those previously reported.14 General Procedure for the TrBF4-catalyzed Michael addition: (E)-Ethyl 4-oxobut-2-enoate (1 equiv.) and the corresponding nucleophile (1.5 equiv.) was added to a solution of TrBF4 (1.0 mol%) in dichloromethane (c = 1 M). After full conversion of the starting material (determined by 1H NMR), the reaction mixture was passed through a short plug of SiO2 and the solvent removed under vacuum. The crude product was purified by flash column (SiO2, Et2O/Pentane).

EtO

O

O

NEthyl 2-(4-(dimethylamino)phenyl)-4-oxobutanoate: The title compound was

prepared from N,N’-dimethylaniline in 81 % yield according to the general procedure described above. Full conversion was obtained after 3 days. Spectral data were in accordance with those previously reported.15

EtO

O

O

N Et

Et Ethyl 2-(4-(diethylamino)-2-methylphenyl)-4-oxobutanoate: The title compound was prepared from N,N-diethyl-3-methylaniline in 76 % yield according to the general procedure described above with the exception that 10 mol% TrBF4 was used. Full conversion was obtained after 3 days. 1H NMR (500 MHz, CDCl3): δ9.79 (s, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.49 (d, J=8.4 Hz, 1H), 6.48 (s, 1H), 4.26 (dd, J=9.9, 4.9 Hz, 1H), 4.18 (dq, J=10.9, 7.2 Hz, 1H), 4.06 (dq, J=10.9, 7.2 Hz, 1H), 3.36-3.06 (overlapping peaks, including a q, J=7.1 Hz, total 5H), 2.69 (dd, J=18.7, 4.5 Hz, 1H), 2.36 (s, 3H), 1.21 (t, J=7.2 Hz, 1H), 7.08 (t, J=7.08 Hz, 6H). 13C NMR (125 MHz, CDCl3): 200.5, 173.8, 147.0, 136.9, 127.7, 122.8, 113.6, 109.9, 61.0, 47.1, 44.2, 40.0, 20.4, 14.1, 12.7.

EtO

O

O

NH Ethyl 2-(1H-indol-3-yl)-4-oxobutanoate: The title compound was prepared from indole in 87 % yield according to the general procedure described above. Full conversion was obtained after 1.5 h. Spectral data were in accordance with those previously reported.16

14 Asenjo, A.; Lahoz, F.J.; García-Orduña, P.; Oro, A. L.; Carmona, D.; Viguri, F. Organometallics 2012, 31,

4551. 15 Paras, N.A., MacMillan, D.W.C. J. Am. Chem. Soc. 2002, 124, 7894. 16 Jin, S.; Li, C.; Ma, Y.; Kan, Y.; Zhang, Y. J.; Zhang, W. Org. Biomol. Chem., 2010, 8, 4011.

S8

EtO

O

O

N Ethyl 2-(1-methyl-1H-indol-3-yl)-4-oxobutanoate: The title compound was prepared from N-methylindole in 55 % yield according to the general procedure described above. Full conversion was obtained after 1.5 h. Spectral data were in accordance with those previously reported.17

17 Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172.

S9

EtO

O

O

N Et

Et