H Arylation of Primary and Secondary Benzylamines - American

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Carbon Dioxide-Mediated C(sp2)–H Arylation of Primary and Secondary Benzylamines Mohit Kapoor, Pratibha Chand-Thakuri, and Michael C. Young J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 29 Apr 2019 Downloaded from http://pubs.acs.org on April 29, 2019

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Journal of the American Chemical Society

Carbon Dioxide-Mediated C(sp2)–H Arylation of Primary and Secondary Benzylamines Mohit Kapoor,‡ Pratibha Chand-Thakuri,‡ and Michael C. Young* Department of Chemistry and Biochemistry, School of Green Chemistry and Engineering, University of Toledo, Toledo, OH, 43606. ABSTRACT: C–C bond formation by transition metal-catalyzed C–H activation has become an important strategy to fabricate new bonds in a rapid fashion. Despite the pharmacological importance of ortho-arylbenzylamines, however, effective ortho-C–C bond formation of free primary and secondary benzylamines using PdII remains an outstanding challenge. Presented herein is a new strategy for constructing ortho-arylated primary and secondary benzylamines mediated by carbon dioxide (CO2). The use of CO2 with Pd is critical to allowing this transformation to proceed under relatively mild conditions, and mechanistic studies indicate that it (CO2) is directly involved in the rate determining step. Furthermore, the milder temperatures furnish free amine products that can be directly used or elaborated without the need for deprotection. In cases where diarylation is possible, an interesting chelate effect is shown to facilitate selective monoarylation.

■ INTRODUCTION Amines are a ubiquitous functional group, being especially important in polymers1-3 and pharmaceuticals.4, 5 Despite many classical6-8 and modern9-12 approaches to their synthesis, however, new methods are still in demand to access new chemical space surrounding these functional groups.13 One strategy for preparing amines that has recently been gaining traction has been to functionalize C–H bonds through C–H activation14-17 and C–H functionalization18-20 methods. These approaches can allow rapid access to compounds that were either inaccessible with conventional synthetic methods, or required more lengthy synthetic routes, thereby expediting and improving drug library synthesis.21 Although primary and secondary aliphatic amines often require pre-functionalization with static directing groups to facilitate C–H bond activation and prevent undesirable substrate oxidation under palladiumcatalyzed protocols,22-29 aromatic C–H bonds have generally been more easily targeted. For this reason free homobenzylamines30, 31 have been widely used as substrates for a variety of palladium-catalyzed C–H activation reactions without the need to pre-functionalize the amine. It is therefore interesting to note that there was until recently no example in the literature whereby free primary ortho-aryl benzylamines could be directly accessed via C–H arylation,32 and there is still no method for the same transformation on free secondary benzylamine substrates. Because of the importance of the biaryl moiety in a number of biologically-active molecules (Figure 1),33-35 we considered that the ability to directly access free primary and secondary ortho-aryl benzylamines directly under milder conditions would have utility to the synthetic community. Ortho-aryl benzylamines are generally prepared directly from biaryl nitriles via reduction36, 37 or an azidation/reduction sequence, also from a pre-formed biaryl species.38 Alternatively, they can be prepared from protected benzylamines via Suzuki-Miyaura cross-coupling39, 40 or directed C–H arylation.41 However, it was not until 2006 that Daugulis was able to show the first example of Pd-catalyzed

ortho-arylation utilizing free primary and secondary benzylamines as substrates.42 Though the arylation strategy was successful, the harsh conditions led to partial protection of the substrate and product as acetamides, which led to the need to fully protect the amines for isolation. Furthermore, the substrate scope of secondary amines was only demonstrated for Nmethylbenzylamines. Subsequent strategies have emerged for C–H arylation,43, 44 carbonylation,45 olefination,46 and even a Catellani-type reaction47 of tertiary benzylamines using Pd as a catalyst, as well as one example of the carbonylation/lactamization of free primary benzylamines,48 yet no improvements have been made on C–H arylation of secondary benzylamines, and only one report has improved on the arylation of primary benzylamines.32 Notably, while this manuscript was under review, two reports were published demonstrating minimal examples of ortho-C(sp2)–H arylation of benzylamines, albeit at higher temperatures49 or requiring a more exotic Ar+ reagent.50 Figure 1. Examples of Biologically Active ortho-Aryl Benzylamines.

N O MeO O

H O

O

MeO N

F 3C

N

O

OH

Dalomycin T

O

MeO

CF3

O

HO

MeO

HOOC

HO O

-Secretase Modulators

O

(-)-Steganacin aza-analogue

Present efforts in the field of C–H activation field have moved towards use of transient directing groups that can be formed in situ.51 Though more frequently applied to aldehyde5254 and ketone55-57-based substrates, this has also been achieved more recently using amine substrates combined with aldehyde-

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based directing groups.32, 58-63 Inspired by this and the use of CO2 as a traceless directing group for C–H activation of phenols,64, 65 we recently developed a different approach, and showed that γ-arylation of aliphatic amines could be achieved in the presence of carbon dioxide.66 Mechanistic experiments surrounding that work supported the idea of a transient carbamate serving as a directing as well as protecting group, thereby facilitating the desired C–H activation step. We therefore considered that carbon dioxide might facilitate the realization of a milder C–H activation strategy towards free primary and secondary ortho-arylbenzylamines. ■ RESULTS AND DISCUSSION To investigate the feasibility of utilizing carbon dioxide to facilitate the γ-C(sp2)–H arylation of benzylamines, we focused on the substrate 2-(2-fluorophenyl)butan-2-amine. We were delighted to find that our previously reported conditions for aliphatic amines, using Pd(OAc)2 as pre-catalyst, AgTFA as an additive, and acetic acid as solvent, gave product albeit in only modest yield (Table 1, Entry 1). The reaction was performed in a 2 dram reaction vial by combination of the reagents and solvent, followed by addition of carbon dioxide in the form of dry ice.67 Despite numerous examples in our previous report where C(sp3)‒H arylation was exclusively observed for secondary benzylamines (presumably due to possessing a more favorable conformation),68 only C(sp2)‒H arylation was observed in the current examples. We examined other less Lewis acidic Ag salts (Entries 2 and 3), but found them to give poorer results. Increasing the halide loading to 3 equivalents gave improved yield, with only marginal improvement when the reaction time was extended to 24 h (Entries 4 and 5). Changing the solvent to HFIP (1,1,1,3,3,3hexafluoroisopropanol) gave a dramatic increase in yield, with the optimal temperature to perform the reaction being 100 ºC (Entries 6 – 8). Table 1. Optimization of the C–H Arylation of 2-(2Fluorophenyl)butan-2-amine with Ethyl 4-Iodobenzoate. F

F

I

NH2

Pd-catalyst (10 mol%) Ag-salt (2.0 equiv.)

+ CO2Et

Solvent

Halide (equiv.) Pd-catalyst

AcOH AcOH AcOH AcOH AcOH HFIP HFIP HFIP HFIP/AcOH(1:1)

2.0 1.5 1.5 3.0

Pd(OAc)2 Pd(OAc)2

3.0 3.0 3.0 3.0 3.0

10 11 12 13 14 15 16e 17 18f 19

HFIP/AcOH(6:4) HFIP/AcOH(7:3) HFIP/AcOH (8:2) HFIP/AcOH (9:1) HFIP/AcOH (7:3) HFIP/AcOH (7:3) HFIP/AcOH (7:3) HFIP/AcOH (7:3) HFIP/AcOH (7:3) HFIP/AcOH (7:3)

3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0

Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2

Pd(OAc)2 Pd(OAc)2

Pd(OAc)2 PdCl2 Pd(TFA)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 --

Reactions set-up using amine (0.15 mmol), halide (0.45 mmol), Pd precatalyst (0.015 mmol), CO2 (~0.75 mmol), H2O (0.60 mmol), 1 mL of solvent, followed by running at 100 ºC for 12h. a NMR yields determined using 1,1,2,2-tetrachloroethane as an internal standard. b 24 h reaction time. c 110 ºC reaction temperature. d 90 ºC reaction temperature. e 1.5 equiv. of Ag additive used. f No dry ice added.

We next explored whether the relative acidity of the solution was important, and began testing different mixtures of AcOH and HFIP (Entries 9 – 13). Although higher amounts of AcOH seemed detrimental to the reaction, a mixture of HFIP and AcOH was found to improve the overall yield, with the best coming from a mixture of 7:3 HFIP/AcOH (Entry 11). Despite the potential for ion exchange, the palladium precursor is important to the reaction, with the dichloride or bis(trifluoroacetate) salts performing poorly (Entries 14 and 15). Although Ag salts are sometimes used simply as halide scavengers,69 the yield was decreased when only 1.5 equivalents of silver trifluoroacetate was added (Entry 16), and less than one turnover was achieved when silver trifluoroacetate was omitted (Entry 17), suggesting more than one role in this transformation. Consistent with our hypothesis, the reaction is greatly enhanced by CO2, and only 9% yield was obtained in the absence of additional CO2 (Entry 18), while omission of palladium completely shut down the reaction (Entry 19). Table 2. Aryl Iodide Scope of the γ-C(sp2)‒H Arylation of 2(2-Fluorophenyl)butan-2-amine. F

I

NH2

+

F

Pd(OAc)2 (10 mol%) AgTFA (2.0 equiv.) R CO2, H2O HFIP/AcOH

NH2

R

1a-z

CF3

F F

1a, 71%

1c, 63%

1b, 64%

1d, 69%

CO2Et

F

NH2

CO2Et

CF3

CO2, H2O Solvent

Entry 1 2 3 4 5b 6 7c 8d 9

Page 2 of 11

F 1f, 55%

1e, 61% CO2Et

Ag-salt Yield (%)a 27 AgTFA 5 Ag2CO3 17 AgOAc 34 AgTFA 38 AgTFA 71 AgTFA 66 AgTFA 59 AgTFA 52 AgTFA AgTFA AgTFA AgTFA AgTFA AgTFA AgTFA AgTFA -AgTFA AgTFA

63 78 77 75 22 29 57 5 9 0

1g, 73%

1h, 77% CO2Me

NO2

Me

NO2

1i, 57%

O

CO2Me

1k, 64%

1j, 51%

1l, 64% Me

Br

N Ts

I

1m, 72%

1n, 70%

1o, 49%

1p, 75% OCHF2

OMe OMe

Me

1q, 81%

1s, 59%

1r, 61%

1t, 57% N H N

1u, 57%

OCHF2


1v, 59%

OCF3

Ph 1w, 66%

O 1x, 34%

H H

O

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Reactions set-up using amine (0.15 mmol), halide (0.45 mmol), Pd(OAc)2 (0.015 mmol), AgTFA (0.30 mmol), CO2 (~0.75 mmol), H2O (0.60 mmol), 1 mL of HFIP/AcOH (7:3), followed by running at 100 ºC for 12-15h. Reactions were run in duplicate and the average yield reported.


With the optimized conditions in hand, we next set-out to explore the substrate scope of the transformation with regard to aryl halides (Table 2). Using the optimized conditions, phenyl iodide could be coupled with 2-(2-fluorophenyl)butan-2-amine in 71% isolated yield (1a). The reaction could be performed on a number of fluorinated aryl iodides (1b – 1f), as well as those with more electron deficient groups such as esters (1g and 1h), nitro groups (1i and 1j), ketones (1k), and even multiple electron deficient groups (1l). It is noteworthy that neither the ketone nor the isophthalate groups show signs of condensation or substitution with the amine under the reaction conditions. Reactions with either bromoiodobenzene (1m) or diiodobenzene (1n) could be performed without reactivity at the second halogen. Electron rich aryl iodides bearing indole rings (1o), methyl groups (1p and 1q), methoxy groups (1r and 1s), both difluoro and trifluoromethoxy groups (1t – 1v), and even an arene with extended conjugation (1w) were also tolerated during the reaction. Surprisingly, 2-iodostrychnine70 can be used in the reaction (1x) despite the presence of a tertiary amine that can also react with CO2. Furthermore, the conditions are mild enough to preserve both the amide and allylic ether groups. Although the alkene is preserved in the case of 1x, many other alkene-containing substrates were unsuitable for the reaction.71 It is worth noting that N-heterocyclic substrates, including 3iodopyridine and 2-iodoquinoline, did not give any identifiable product under these reaction conditions, most likely due to competitive binding or poisoning of the palladium catalyst.72 Table 3. Primary Benzylamine Scope of the γ-C(sp2)‒H Arylation with Aryl Halides.

We next focused on the scope of the reaction with respect to the amine substrates. A common issue in the intermolecular o-C(sp2)‒H activation literature is the challenge of achieving selective monofunctionalization, and so we initially focused on examples that would be unlikely to undergo diarylation by positioning a group at either the 2 or 3 position of the benzylamine.73 Short to medium length aliphatic chains could be tolerated, all with excellent selectivity for C(sp2)‒H arylation (Table 3, 2a – 2d). Moving the position of the fluoro substituent on the benzylamine (2e) as well as using substrates bearing either an o- or m-chloro group (2f and 2g) all gave good yields. More electron rich benzylamines with methyl (2h) and methoxy (2i) substituents were also tolerated in the reaction. Amines with both benzylic and homobenzylic sites showed complete selectivity for γ-arylation on the benzyl rather than δ-arylation on the homobenzylic chain (2j and 2k), presumably due to a faster rate of C‒H activation. Gratifyingly, no changes were necessary to apply this protocol to more oxidatively-sensitive α-primary benzylamines, and the corresponding o-biaryls could be prepared without concomitant oxidation of the benzylamine (2l and 2m). Even αsecondary benzylamines, which could be expected to undergo β-hydride elimination to generate imines during the reaction,42 gave the unoxidized amine products in excellent yields (2n – 2p). It is noteworthy that in cases where the yields are moderate, a significant part of the mass balance is actually unreacted amine, suggesting that the catalyst eventually dies in the reaction before all of the substrate is consumed. We tried circumventing this by opening the reaction vessels mid-reaction and adding a second portion of catalyst and re-pressurizing, but found this did not have an appreciable benefit on the reaction. The difference in polarity between starting materials and products is also low, and in some examples the yield is hampered by the inability to achieve complete baseline separation during purification by column chromatography. Based on our previous success applying carbon dioxide to the functionalization of secondary amines, we considered that it might help prevent oxidation problems.74 The optimized conditions were found to indeed promote the C‒H arylation of secondary benzylamines while preventing deleterious oxidation pathways. Substrates bearing linear (Table 4, 3a) and branched (3b – 3d) chains added to the benzylamine were able to participate in the reaction. Amines bearing various carbocycles (3e – 3g) were also viable under the standard reaction conditions. Aryl groups could be added to the benzylamine via either a β (3h) or γ (3i) linkage without degraded regioselectivity for arylation of the γ-C(sp2)‒H bond. We were delighted to find that unsaturated (3j) as well as saturated (3k – 3o) heterocycles appended to the benzylamine could also survive the reaction conditions, although it is worth noting that appending an N-methylpyrrole moiety to the benzylamine failed to give product under these conditions, presumably due to its increased nucleophilicity. The presence of two potentially competitive γ-C(sp2)–H bonds on 3j made us wonder if activation on a five-membered heterocycle might be possible.75 However, when the reaction was performed on N,N-bis-(2furylmethyl)amine under the standard conditions nearly

I R3

Pd(OAc)2 (10 mol%) AgTFA (2.0 equiv.) CO2, H2O CO2Et HFIP/AcOH

R1+

R2

F

NH2

R3

NH2

F

NH2

F

NH2

R2

NH2

Ar

2a, 72% NH2

2b, 70% Cl

F

2d, 59% NH2

NH2 Me

Ar

F

Hex

Ar

2c, 63% NH2

Ar

2f, 61% NH2

n

Bu

Cl

Ar

NH2

Ar

F

2e, 66%

CO2Et

2a-p

n

Ar

R1

Ar 2h, 82% F NH2 F

2g, 75% F

NH2

NH2

Ph

MeO

Ar 2i, 77% NH2

Ar 2j, 68% NH2 F

Ar 2k, 71% NH2 Cl

MeO

Ar 2l, 70% NH2 Br

Ar 2m, 68%

Ar

Ar 2n, 81%

2o, 84%

Ar 2p, 80%


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quantitative recovery of the starting amine was observed (Scheme 1). At this point it is unclear whether the reaction fails to functionalize the heterocycle for an electronic reason or because of the difference in ring size and shape. Table 4. Secondary Benzylamine Scope of the γ-C(sp2)‒H Arylation with Aryl Halides. Ar1 = 4-Ester Ar2 = 2-Ester R1 I HN Pd(OAc)2 (10 mol%) AgTFA (2.0 equiv.) 2 + R CO2, H2O HFIP/AcOH CO Et

R3

2

F

F n

N H

Ar1 3a, 71% i

Ar 3d, 51%

N H

1

Ar 3e, 57%

Cl

Ar 3f, 72%

N H

Cy F3C

N H

Ar1 3g, 84%

Ar 3j, 43%

N H

N H

1

1

Ar 3k, 64% O

F3C

Ar 3m, 88%

N H 1

Ar 3n, 52%

CO2Et

NO2

NH2

F 3C

NO2

CO2Et 4b,70%, >96% es 4c, 47% >96% ee CO2Et

CO2Et

Ar1 3i, 66%

NH2

NH2

O N H

CO2Et

1

4d, 61%

O

CO2Et

Ph

N H

R3

O

4a, 68%

O

2

R1

4a-4j

NH2

NH2

1

F

Ar 3l, 86%

NO2

R2

Cy

N H

O

F

NH2

O

Ar1 3h, 57%

O

F

2

Pd(OAc)2 (10 mol%) AgTFA (2.0 equiv.) CO2, H2O HFIP/AcOH CO2Et

CO2Et N H

Ph MeO

1+ 2R

R3

ad

1

R3

I

NH2

CO2Et

Ar1 3c, 71% Cl

Pr

CO2Et ~Quantitative Recovery of Amine SM

3 equiv.

N H

Ar1 3b, 67% F N H

0.15 mmol

R

N H

CO2, H2O HFIP/AcOH

CO2Et

O

Table 5. Scope of the Di-γ-C(sp2)‒H Arylation of StericallyAccessible Benzylamines.

R1

3a-o

Pd(OAc)2 (10 mol%) AgTFA (2.0 equiv.)

+

O

O

HN

I

HN

F

Bu

MeO

R

R1

HN

3

O

Page 4 of 11

O2 N

4e, 72% CO2Et

CO2Et

N H

Ar 3o, 60%

1


Unsurprisingly, we found that in the absence of a substituent at the 2 or 3-position, diarylation products were afforded with great selectivity when excess aryl halide was used (Table 5), although dropping the ratio to less than six equivalents of halide led to a mixture of mono and di-arylation products. The rationale for this is that although the reactive C‒H bond is not forced towards the catalyst during the initial reaction, after arylation the aromatic ring will adopt a conformation where the second o-C‒H bond becomes more accessible, leading to faster C–H activation of the monosubstituted benzylamines compared to the unsubstituted starting material. Scheme 1. Attempted Arylation of N,N-Bis-(2furfurylmethyl)amine.

NH2

NH2

NH2

F

Ph 4f, 81%, >96% es >96% ee

4g, 71%

CO2Et

4h, 62%

CO2Et

CO2Et

NH2

NH2

CO2Me

4i, 66%

4j, 68%

CO2Et

Reactions set-up using amine (0.15 mmol), halide (0.75 mmol), Pd(OAc)2 (0.015 mmol), AgTFA (0.30 mmol), CO2 (~0.75 mmol), H2O (0.60 mmol), 1 mL of HFIP/AcOH (7:3), followed by running at 100 ºC for 12-15h. Reactions were run in duplicate and the average yield reported. The ee was determined by preparation of the Mosher amides and comparison of the diastereomers by 1H NMR.


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The m-terphenyl products could be achieved with αtertiary and secondary benzylamines (4a – 4c). Notably, using an enantioenriched starting material, the configuration was retained with no erosion in the enantiomeric excess (ee) (4b) (determined by preparing the Mosher amide, see SI for details). α-Primary benzylamines are also viable substrates in the reaction (4d and 4e). By using 4-phenyl iodobenzene as the electrophile, it is even possible to rapidly access a highly conjugated m-pentaphenyl with an amine moiety (4f), again with no erosion in ee. Substrates containing both benzylic and homobenzylic positions also still gave complete selective for diarylation of solely the benzylic ring (4g and 4h). Given the ability to potentially synthesize highly conjugated substrates, we next targeted a bis-fluorene (4i), although this was not particularly emissive. Finally, use of a β-phenylalanine ester also led to the diarylation products in good yield with no observable α-arylation (4j) of either the amine or ester carbonyl. While exploring the diarylation of benzylamines, we discovered an interesting outlier: subjecting methyl phenylglycine to the reaction conditions led to selective monoarylation (Table 6, 5a), even without utilizing the blocking method. We assumed there might be a chelation effect from the pendant ester that leads to the unusual selectivity. Encouraged by this result, we explored a number of other substrates with chelating groups: replacing the ester with an amide (5b – 5d) still led to monoarylation when only three equivalents of aryl halide were utilized. The relatively acidic α-proton in substrates 5a – 5c led to significant erosion of ee during the reaction. Notably, the free amide required a slight modification to the conditions (5d), and gave the almost completely racemized product after the reaction. While the presence of a β-carbonyl was clearly effective in achieving monoarylation, we wondered if other groups might facilitate this selectivity, and found that placing an alcohol β to the amine could also prevent diarylation (5e). Protection of the alcohol as an ester was also effective in the selective monoarylation (5f). The es for 5e and 5f was much higher than for the more acidic substrates, at 90% and 88% respectively. To our surprise, even an α-phosphonate ester could be used to achieve selective monoarylation (5g). Table 6. Scope of the Selective Mono-γ-C(sp2)‒H Arylation of Sterically-Accessible Benzylamines.

R

+ 1 2R

O

NH2

I

NH2

Pd(OAc)2 (10 mol%) AgTFA (2.0 equiv.) CO2, H2O HFIP/AcOH CO2Et O

OMe

R2 5a-g

O

NEt2

5a, 69% 15% es, 15% ee

5b, 65% 50% es 50% ee

NH2

Ar

5c, 57% 61% es 60% ee

5d, 47%a

H Arylation of Primary and Secondary Benzylamines - American

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