Palladium-Catalyzed Selective Five-Fold Cascade Arylation of the 12

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Palladium-Catalyzed Selective Five-Fold Cascade Arylation of the 12-Vertex Monocarborane Anion by B–H Activation Furong Lin, Jing-Lu Yu, Yunjun Shen, Shuo-Qing Zhang, Bernhard Spingler, Jiyong Liu, Xin Hong, and Simon Duttwyler J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b07872 • Publication Date (Web): 19 Sep 2018 Downloaded from http://pubs.acs.org on September 20, 2018

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Palladium-Catalyzed Selective Five-Fold Cascade Arylation of the 12Vertex Monocarborane Anion by B–H Activation Furong Lin,†,§ Jing-Lu Yu,†,§ Yunjun Shen,†,§ Shuo-Qing Zhang,† Bernhard Spingler,‡ Jiyong Liu,† Xin Hong,*,† and Simon Duttwyler*,† †

Department of Chemistry, Zhejiang University, 38 Zheda Road, 310027 Hangzhou, P. R. China Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland

‡

ABSTRACT: A series of cage penta-arylated carboranes have been synthesized by palladium-catalyzed intermolecular coupling of the C-carboxylic acid of the monocarba-closo-dodecaborate anion [CB11H12]– with iodoarenes by direct cage B–H bond functionalization. These transformations set a record in terms of one-pot directing group-mediated activation of inert bonds in a single molecule. The methodology is characterized by high yields, good functional group tolerance and complete cage regioselectivity. The directing group COOH can be easily removed during or after the intermolecular coupling reaction. The mechanistic pathways were probed using density functional theory (DFT) calculations. A Pd(II)–Pd(IV)–Pd(II) catalytic cycle is proposed, in which initial coupling is followed by preferred B–H activation of the adjacent boron vertex, and continuation of this selectivity results in a continuous walking process of the palladium center. The methodology opens a new avenue towards building blocks with five-fold symmetry.

INTRODUCTION 12-Vertex monocarboranes and dicarbaboranes based on the frameworks [CB11H12]– and C2B10H12 are icosahedral clusters in which one or two BH vertices are replaced by a CH unit.[1,2] Their sphere-like delocalization of electron density can be compared to the π system of classical aromatic relatives such as benzene.[2c,d] In general, boron cluster compounds exhibit remarkable chemical and thermal stability as well as low toxicity. These properties have led to applications in diverse areas such as the development of extremely weakly coordinating anions[3] as well as novel ligands,[4] supramolecular structures,[5] medicinal chemistry,[6] fluorescence/phosphorescence[7] and materials science.[8] The progress in all of these fields heavily relies on synthetic procedures that provide access to cage derivatives with a desired substitution pattern in an efficient manner. In order to further explore fundamental aspects of boron clusters and leverage their role as useful building blocks for chemists and materials scientist, new methodologies for their selective preparation are essential. For the introduction of new substituents onto carborane clusters, C– H vertices can in many cases be functionalized by deprotonation and subsequent reaction with electrophiles. The traditional approach to modify B–H bonds relies on electrophilic substitution or halogenation followed by cross coupling reactions.[9] In analogy to the concept of transition metal-catalyzed C–H activation,[10] the directing group-mediated functionalization of B–H vertices of boron cage compounds has emerged as a concept of enormous utility. It allows the construction of B–X bonds (X = C, O, N, halogen) under mild conditions and without prior halogenation. It has become a powerful strategy to prepare otherwise inaccessible cluster derivatives with high selectivity and an overall improved step economy. The majority of the recent reports on catalytic B–H activation have focused on ortho-dicarbaboranes. The research groups of Xie, Yan and Cao, among others, have pioneered methodologies for the selective derivatization of {C2B10}-based starting materials,

Scheme 1. Boron vertex functionalization of {C2B10} and {CB11}based cage compounds. DG = directing group. Previous work a) {C2B10 } Mono- and di-arylation via B−H activation Ar

Ar C

cat. [Pd]

DG

Ar

C

C

I

X C

R

or

C

Ar

X C

R

R

DG = COOH, CHO or CH 2NH 2 R = Me, Ph X = DG or H

b) {CB11 } Functionalization via B−H activation DG C

DG C

B2–6

DG =

Rn

O

N

cat. [Rh] or [Ir] alkynes, alkenes, azides or NCS

B7–11 B12

R n : mono-, di-, or tetrasubstitution of B2–5

c) {CB11 } Arylation by B−I cross coupling Ph

Ph

Ph

C

C

C

ICl

cat. [Pd]

I I

I I I

p-TolMgBr

I

C cat. [Pd] Ar I

Ar Ar

R Ar C

Ar Ar

R C

Ar

Ar = Ar

= B−H

=B


R = H, COOH, COOMe

Tol Tol

Tol I 1 example, 36% yield for the coupling step

This work d) {CB11 } Penta-arylation via B−H activation COOH

Tol Tol

- five-fold one-pot B–H activation Ar - mild conditions - removable directing group - 28 examples, Ar up to 99% yield

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Table 1. Optimization of Penta-arylation Conditions of 1 to 3aa COOH C

COOH

I 2a

C

(6 equiv) [Pd]/Additives

187.2

1

[Et4N]+

1

3a

11B{1H}

ESI-MS

NMR

B7–11

1

B7–11

B2–6 B12

B2–6

567.4

3a

solvent, T, 12 h

[Et4N]+

%

3a

B12

m/z 200

400

600

0

−5

−10

ppm

0

−5

−10

ppm b

Entry

Pd(OAc)2 (mol%)

Additives (equiv)

T (°C)

Solvent

Result

1

10

AgOAc (3), HOAc (6)

80

MeCN

MS: Mixture

2

10

AgOAc (3), HOAc (6)

80

DCE

MS: Mixture

3

10

AgOAc (3), HOAc (6)

80

Tol

N.R.

4

10

AgOAc (3), HOAc (6)

80

(CH3)3CCN

MS: Mixture

5

10

AgOAc (3), HOAc (6)

60

MeCN/DMF (1:1)

MS: 3a + trace tetra

6

10

AgOAc (3), HOAc (6)

60

DMF

68% isolated

7

10

AgOAc (3), HOAc (6)

25

DMF

71% isolated

8

5

AgOAc (3), HOAc (6)

25

DMF

66% isolated

9

2.5

AgOAc (3), HOAc (6)

25

DMF

72% isolated

10

2.5

AgOAc (6), HOAc (6)

25

DMF

86% isolated

11

2.5

AgOAc (1), HOAc (6)

25

DMF

MS: 1:3a = ca. 1:1

12

2.5

NaOAc (3), HOAc (6)

25

DMF

N.R.

13

2.5

Cu(OAc)2 (6), HOAc (6)

25

DMF

N.R.

14

2.5

HOAc (6)

25

DMF

N.R.

15

2.5

AgOAc (6)

25

DMF

22% isolated

16

-

AgOAc (6), HOAc (6)

25

DMF

N.R.

a

Reactions were conducted on a 0.032 mmol (10 mg) scale in 1 mL of solvent in a sealed vial under air; b Results primarily based on ESI-MS; isolated yields are values for purified 3a after silica gel column chromatography.

leading to a variety of new products and materials.[11,12] For example, palladium-catalyzed arylation procedures have been developed that provide access to different types of substitution patterns, depending on the particular directing group and reaction conditions (Scheme 1a). [12f,l,p] In contrast to the progress made in the chemistry of neutral {C2B10} cages, transition metal mediated B–H functionalization of anionic boron clusters is much less precedented.[11c,13–15] In one study, we developed Rh(III)- and Ir(III)-catalyzed derivatization reactions promoted by the pyrrolidine directing group.[13c] These transformations enabled the direct conversion of B–H vertices to B–C, B–N and B–Cl units, occurring regioselectively at the B2–5 positions (Scheme 1b). The [CB11H12]– anion with its C5v symmetry possesses B2–6 and B7–11 positions of equal reactivity, which in principle allows for five-fold substitution of the upper and/or lower boron belt. Until now, reactions in which the five-fold rotational axis is retained have been restricted to electrophilic halogenations or alkylations under harsh conditions. The first position to react is B12, followed by B7–11 and eventually B2–6, based on the decreasing nucleophilicity in this order.[2a,16,17] To the best of our knowledge, there has only been one report on penta-arylation, published by Štíbr and coworkers.[16a] In this case, hexa-iodination of the parent carborane was followed by palladium-mediated cross coupling with tolyl magnesium bromide to afford the B7–11-arylated product (Scheme 1c). Arylation of the [CB11H12]– anion of any degree of substitution by B–H activation has not been accomplished. In the present study, we demonstrate that the carborane-C-carboxylic acid of this anion undergoes selective arylation of the upper boron belt using palladium catalysis and aryl iodides as the coupling partners (Scheme 1d). Under mild conditions, penta-substitution is achieved in high yields and with remarkable functional group tolerance. This is the first demonstration of regioselective catalytic fivefold B–H functionalization of a boron cluster. More generally speaking, it is also the record for directing group-mediated, metal-catalyzed activation of multiple equal inert bonds in a single molecule.[18] DFT calculations indicate that the substitution occurs with a high probability of

consecutive arylation at adjacent boron vertices. Furthermore, the removal of the carboxylate directing group was probed experimentally and computationally.

RESULTS AND DISCUSSION Optimization of Penta-Arylation Reaction Conditions. At the outset of our study, we combined carborane carboxylic acid 1 with iodobenzene in the presence of Pd(OAc)2, AgOAc and HOAc (Table 1). The reactions were monitored by ESI-mass spectrometry and, in some cases, NMR spectroscopy. At 60–80 °C, a solvent screen showed that dimethylformamide gave the desired product 3a relatively cleanly, with a 68% isolated yield (entries 1–6; mass and 11B{1H} NMR spectra are depicted next to the scheme in Table 1). Slightly higher yields were obtained when the temperature and catalyst loading were decreased (entries 7–9). Increasing the amount of AgOAc to 6 equivalents improved the isolated yield to 86% (entry 10), while 1 equivalent of AgOAc did not lead to full conversion (entry 11). Other acetate salts such as NaOAc and Cu(OAc)2 were ineffective as additives (entries 12 and 13). Control experiments revealed that in the absence of Pd(II), Ag(I) or HOAc, the reaction did not proceed in an efficient manner (entries 14–16). Based on these findings, the conditions from entry 10 were chosen to synthesize arylated products 3 and 4 on a preparative scale. Scope of Penta-Arylation with Respect to Iodoarenes. Subsequently, the substrate scope in terms of iodoarenes was investigated, and the results are compiled in Tables 2 and 3. Generally speaking, electronwithdrawing and electron-donating iodo coupling partners allowed the functionalization of B−H bonds at the B2–6 of the carborane cage with complete regioselectivity, affording the corresponding penta-arylated species in good to excellent yields. The products derived from unsubstituted iodobenzene (3a, 86%) and analogues alkylated at the aryl-3–5 positions (3b–g) could all be obtained with comparable high yields of 85– 91%.[19] In contrast, 2-methyliodobenzene did not afford the desired product; primarily, mono-substitution was observed by ESI-MS, and mono-arylated 3h was isolated in low yield and ca. 85% purity (see the



(a)

(b)

Page 4 of 11

(c)

Figure 1. X-ray crystal structures of (a) 3b, (b) 3q and (c) H-3x; cations and H atoms (except for cage C–H and COOH) omitted for clarity; 30% displacement ellipsoids. Selected distances (Å) for (a): C(cage)–C2 1.527(3), C(cage)–B5 1.771(3), B5–C24 1.599(3).; (b): C(cage)–C2 1.507(4), C(cage)–B4 1.779(4), B4–C25 1.586(4); (c): C(cage)–B2 1.723(8), B2–C8 1.583(8). Supporting Information file for details). Furthermore, the transformation was well compatible with fluoro, chloro, and bromo substitution, providing the desired products 3i–3m in yields of 89–94%. In addition, in one case the direction group was transformed to the carboxylic acid ester in a one-pot procedure to furnish 3n in 86% yield. 4Phenyl and 4-benzyl sutbstitution provided access to 3o and 3p in 88% and 78% yield, respectively. Substrates bearing methoxy, NHAc and CH2OH functionalities were tolerated as well to give the five-fold arylated products in 70–80% yield 3q–s); isolation of analytically pure 3q was only achieved after conversion of the directing group to the

Table 2. Synthesis of penta-arylated carboranes 3.a COOH C + [Et4N]+

Ar I (6.0 equiv)

1

Pd(OAc)2, 2.5 mol% AgOAc (6.0 equiv) HOAc (6.0 equiv) DMF, 25 °C or 60 °C

2

Ar Ar

Ar [Et4N]+

3

Entry

R

1

COOH

Ph

86 3a

2

COOH

4-C6H4-Me

91 3b

3

COOH

4-C6H4-Et

87 3c

4

COOH

4-C6H4-n-hex

86 3d

5

COOH

Ar

Ar

R Ar C

4-C6H4-t-Bu

Yield (%)

85 3e

b

d

Table 3. Synthesis of penta-arylated carboranes H-3.a COOH

d

C

6

COOH

3-C6H4-Me

88 3f

7

COOH

3,5-C6H3-Me2

88 3g

8

COOH

2-C6H4-Me

3h

9

COOH

4-C6H4-F

93 3i

10

COOH

3-C6H4-F

92 3j

Entry

+

e

[Et4N]+

1

Ar I (6.0 equiv)

Pd(OAc)2, 2.5 mol% AgOAc (6.0 equiv) HOAc (6.0 equiv) DMF, 60 °C

2

Ar

H Ar C

Ar Ar

Ar [Et4N]+

3 b

Ar

Yield (%)

84 (H-3u)

11

COOH

4-C6H4-Cl

89 3k

1

3-C6H4-Br

12

COOH

3-C6H4-Cl

86 3l

2

4-C6H4-CN

82 (H-3v)

13

COOH

4-C6H4-Br

94 3m

3

4-C6H4-CF3

85 (H-3w)

c

COOMe

4-C6H4-Br

86 3n

4

3,5-C6H3-Cl2

89 (H-3x)

15

COOH

4-C6H4-Ph

88 3o

5

3,4-C6H3-F2

82 (H-3y)

16

COOH

4-C6H4-CH2Ph

78 3p

d

6

4-C6H4-COOMe

94 (H-3z)

COOMe

4-C6H4-OMe

76 3q

7

4-C6H4-COOEt

99 (H-3aa)

14

17

c

18

COOH

4-C6H4-NHAc

70 3r

19

COOH

4-C6H4-CH2OH

80 3s d

20 COOH 2-Nap 59 3t Reactions were conducted on a 0.3 mmol scale in DMF (5 mL) in a 20 b mL vial sealed with a screw cap at 25 °C; yield of the isolated product c after silica gel chromatography; product was separated after methylation d e by using K2CO3 and MeI; reaction conducted at 60 °C; mono-substituted product was observed by ESI-MS, and the product was isolated in 12% yield and ca. 85% purity. a

methyl ester. A moderate yield of 59% was observed for coupling with 2-iodonapthalene (3t). Monitoring the penta-arylation with 1,3-bromoiodobenzene as the substrate at 25 °C indicated formation of ca. 15% of a byproduct that seemed to arise from decarboxylation based on ESI-MS analysis of the reaction. This initial observation encouraged us to develop a one-pot procedure comprising five-fold substitution followed by decarboxylation. Simply raising the temperature to 60 °C under otherwise identical conditions cleanly afforded product H-3u (Table 3, entry 1). This compound with a cage C–H vertex was isolated in 84% yield. Generally, successful combined penta-arylation–decarboxylation occurred with electron-deficient iodoarenes. Cyano, trifluoromethyl, di-chloro, di-fluoro and ester substituents were fully tolerated with this catalytic system, affording the desired products in high yields (H-3v to H-3aa). Notably, the unprotected aldehyde functionality also remained intact during the reaction to give H-3ab in 82% yield. These results demonstrate that the C1–COOH moiety can be used as a traceless directing group, allowing for an even higher number of synthetic steps to be combined in the selective derivatization of carboranes.

8 4-C6H4-CHO 82 (H-3ab) Reactions were conducted on a 0.3 mmol scale in DMF (5 mL) in a 20 b mL vial sealed with a screw cap under 60°C; Yield of the isolated product after silica-gel chromatography.

a

Compounds 3 and H-3 were fully characterized by multinuclear NMR spectroscopy (1H, 1H{11B}, 11B, 11B{1H}, 13C{1H}, 11B-11B COSY for 3a) and mass spectrometry (for characterization details, see the Supporting Information). In the 11B NMR spectra, the resonances


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TSC3 C4 TSC6 C7 TSC8 Figure 2. (a) DFT-computed free energy changes of the Pd-catalyzed arylation of carborane carboxylic acid. (b) DFT-computed free energy changes of concerted metalation-deprotonation of carborane carboxylate anion. Gibbs free energies are in kcal/mol; (c) optimized structures of key catalytic species. of B2–6 were usually observed around –4 ppm and those of B7–11 around –11.5 ppm (–14 ppm and –13 ppm for 1, respectively). The B12 position experienced a slight deshielding from –6.5 ppm in 1 to ca. –5 ppm in the penta-arylated structures. A detailed analysis of cage C–H NMR signals of products H-3 is provided towards the end of this manuscript. Bulk purity of the products, in particular the degree of substitution, could reliably be verified by full-range (m/z = 100–1200) (–)-ESImass spectroscopy because the products carry a negative charge and do not fragment easily. Crystals suitable for X-ray diffraction were obtained for 3a, 3b, 3f, 3q, H-3u and H-3x. Representative molecular structures of the anions of 3b, 3q and H-3x are shown in Figure 1. In the cases with an acid or ester moiety at cage C1, the aryl rings are arranged in a propeller-like geometry (3a, 3f and 3q) or do not exhibit a particular preference in terms of the rotation of the aryl planes (3b). On the other hand, in the solid-state structures of decarboxylated H-3u and H-3x, the aryl rings were found in a perpendicular orientation with respect to the plane defined by B2– 6. Generally speaking, the penta-arylation did not impose a significant strain on the carborane cage, as evidenced by C1–B and B–B bond lengths similar to those of the parent cluster. Additional ORTEP representations are given in the Supporting Information (Figures S4-10). Mechanistic Studies. Based on the above experimental results and previous mechanistic studies, we next explored the reaction mechanism and the origins of regioselectivity and decarboxylation with density functional theory (DFT) calculations.[20] The DFT-computed free energy changes of the most favorable pathway are shown in Figure 2a, and the optimized structures of key catalytic species are shown in Figure 2c. From the [Pd(OAc)2]3 pre-catalyst, the endergonic exchange with carborane carboxylic acid 6 leads to the intermediate 7. From 7, the classic

concerted metalation–deprotonation (CMD) step via TS8 generates the cyclometalated intermediate 9, which requires a barrier of 22.9 kcal/mol compared to the separate [Pd(OAc)2]3 pre-catalyst and carborane carboxylic acid 6. Subsequent oxidative addition of iodobenzene occurs via TS11 and produces the Pd(IV) intermediate 12. This intermediate undergoes C–C reductive elimination through TS13, leading to the B2-mono-arylated species 14. From 14, silver acetate irreversibly abstracts the iodide anion, leading to the intermediate 15. Complex 15 can undergo the same sequence of CMD, oxidative addition, reductive elimination and iodide abstraction for the second arylation at B3, until the penta-arylation cascade is completed (intermediate 16). The oxidative additions with the assistance of carboxylic acid or solvent are less favorable (Supporting Information, Figure S11). Based on the free energy changes of the first arylation, the barriers of oxidative addition and reductive elimination are significantly lower than that of the CMD step, thus the CMD step limits the overall efficiency of the first arylation. The same sequence of the transformations applies to the subsequent four arylations, and the free energy changes of all four arylations are included in the Supporting Information (Figures S12-S15). Figure 2b shows the free energy barriers of the second and third arylations. From 15, the second arylation can in principle occur at the B3 position (adjacent to the first arylation event) via TS17, or at the B4 position (vicinal to the first arylation event) via TS18. Transition state TS17 is 1.9 kcal/mol more favorable than TS18, suggesting that the regioselectivity of the secondary arylation favors the B3 position. Similarly, the third arylation of intermediate S14 also favors the adjacent position by 2.8 kcal/mol (TS19 vs TS20). These computational results indicate that the penta-arylation proceeds through a very specific manner, either clockwise or anticlockwise with a high preference for consecutive adjacent (vs



geminal) bond activation. This regioselectivity is caused by the electronwithdrawing effect of the aryl substituent. Initial arylation at B2 increases the acidity of the adjacent hydrogen atom at B3, making the CMD step at this position more favorable than at the vicinal B4 position. Subsequently, the electron-withdrawing effect by aryl substitution further decreases the CMD barriers for the following coupling events. Therefore, the first arylation has the highest CMD barrier among the five sequential arylations (Figure S16), and the catalytic sequence does not stop until the penta-arylation is completed.

Page 6 of 11

stead, we discovered that deprotonated penta-arylated products can undergo facile decarboxylation without any additional reagent (Table 4). With R = Ph (3a), the decarboxylation barrier is only 13.6 kcal/mol, and the reaction is exergonic with DGsolv = –0.5 kcal/mol (entry 1). With the stronger electron withdrawing 4-CN-C6H4 ring, both the kinetics and thermodynamics of the decarboxylation are energetically more favorable (entry 2). Without the aryl substituents, the generated carborane dianion is much less stable, and the reaction is endergonic by 19.7 kcal/mol (entry 3). Therefore, the charge-stabilizing aryl substituents play key role in facilitating the decarboxylation process, rather than added metal ions.

Table 4. DFT-computed kinetics and thermodynamics of the decarboxylation of selected carborane carboxylate anions.

R

COO R C R

R

R

R

COO R C R

R

R

Figure 3. (a) Formation and reactivity of palladacycle 1-Pd; the NMR yield was inferred by 19F NMR spectroscopy upon addition of 1-fluoro-4-methylbenzene as an internal standard; (b) X-ray crystal structure of 1-Pd; cation and H atoms omitted for clarity. Selected bond distances [Å]:C1–C2 1.511(3), C1–O2 1.237(3), C1–O1 1.279(3), Pd–O1 2.0467(17), Pd–B1 2.016(3), N1–C3 1.132(3), C3– C4 1.454(3); (c) Overlay of computed and experimental structures (RMSD = 0.201 Å). To confirm the computed reaction mechanism, we performed experimental studies to capture the hypothesized cyclometalated species. A stoichiometric reaction of 1 with Pd(OAc)2 in acetonitrile at room temperature was carried out, giving the corresponding palladacycle 1-Pd containing two MeCN ligands (Figure 3a). The structure of this Pd(II) intermediate was confirmed by X-ray diffraction and spectroscopic methods. Single-crystal analysis clearly suggested B2–H bond activation, resulting in a direct B–Pd bond with a B2–Pd distance of 2.016(3) Å (Figure 3b). The computed structure of 1-Pd was in very good agreement with the experimentally determined structure (Figure 3c). Furthermore, 1-Pd, when subjected to the catalytic conditions with 1,4fluoroiodobenzene as the coupling partner, afforded 3i in 60% NMR yield. This finding indicated that formation of a five-membered palladacycle is a key step in the early stages of the catalytic cycle. The somewhat lower yield may be attributed to the presence of MeCN ligands as opposed to conditions where DMF is used as the single solvent. We were not able to isolate the palladacycle intermediate from pure DMF. Additional experiments were carried out in order to probe the preference for consecutive adjacent B–H bond activation. Specifically, 3h was subjected to catalytic conditions with iodobenzene as the coupling partner, and the transformation was monitored by ESI-mass spectrometry. Furthermore, 3h was treated with a stoichiometric amount of Pd(II) in a similar manner to the preparation of 1-Pd. Unfortunately, the results from these experiments did not allow for an unambiguous confirmation of the calculated reaction sequence; details are given in the Supporting Information file on pp. S29–31. Next, we studied the mechanistic details of directing group removal. To our surprise, the palladium- and silver-mediated decarboxylation processes all require unsurmountable barriers (Figure S17-S18).[21] In-

R

R C

R

‡

Entry

R

1

Ph

13.6

–0.5

2

4-C6H4-CN

13.3

–2.0

3

H

--

ΔG

R R

DGsol

DG sol

a

CO2

sol

a

ΔGsol

19.7

Transition state cannot be located.

The above calculations also highlight the distinctive role of initial deprotonation. Only through the deprotonated carboxylate anion, the penta-arylated carborane can undergo facile decarboxylation. Therefore, the acidity of the arylated carborane carboxylic acid is critical for directing group removal, and this explains the effects of specific aryl substitution on the eventual outcome of the cascade, i.e., formation of products 3 vs H-3 (Tables 2 and 3). For 3a, the penta-arylated carborane carboxylic acid has a calculated pKa of 9.8 (Scheme 2, calculated for DMF solvent).[22]The acidity of this carboxylic acid is limited, and thus the corresponding penta-arylation product 3a is inert under the acidic catalytic conditions. With the more electron-withdrawing 4-C6H4-CN substituent, the pKa of the carborane carboxylate acid is 7.3, and acid ionization is significantly more favorable. Therefore, the arylation cascade involving 4-C6H4-CN directly leads to the decarboxylation product H3v, as is the case for other electron-deficient aryl systems shown in Table 3.

Scheme 2. Calculated acid–base equilibria and pKa values of substituted carborane carboxylic acids in DMF.

Decarboxylation of Isolated Penta-Arylated Carborane Carboxylic Acids. To verify the hypothesized decarboxylation process from computations, we next performed experimental studies to explore the possibility of decarboxylation of isolated products 3. We chose 3a as a model compound and subjected it to different conditions for directing group removal. Under typical penta-arylation conditions (DMF solvent, 2.5 mol% Pd(II), 6 equiv AgOAc, 6 equiv HOAc), no decarboxylation product was detected at 25 °C or 60 °C. However, increasing the temperature to 100 °C and screening reaction parameters allowed us to identify suitable decarboxylation conditions (Table 5). Under acidic


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conditions and in the presence of Pd(II) and/or Ag(I), partial formation of H-3a was observed, together with an unknown byproduct (entries 1– 3). In the absence of Brønsted acid and with varying amounts of additives, larger amounts of desired H-3a were obtained, but the transformations still did not occur cleanly (entries 4–8). On the other hand, simple heating of 3a in DMF without any additives caused equally efficient decarboxylation (entry 9). These experimental results were in complete agreement with the conclusions from DFT calculations. Finally directing group removal without formation of unknown byproduts was found to be successful when the reaction was run under N2 atmosphere (entry 10). In this case, H-3a was isolated in 91% yield. Furthermore, a radical trap experiment was conducted with 2 equivalents of TEMPO (2,2,6,6tetramethylpiperdyl-1-oxy radical); ESI-mass spectrometry indicated clean decarboxylation, suggesting that radical intermediates do not play a significant role in this process (entry 11).

with 4-Et and 4-NHAc to afford H-3c and H-3r required the addition of 2 equivalents of potassium acetate, and the corresponding yields were 99% and 93% (entries 4 and 5). The effect of base addition is attributed to facilitated formation of the carboxylate anion of 3. Detailed analytical data for decarboxylated products H-3 enabled the study of substituent effects through the cage on the carborane CH position. To that end, a plot 1H NMR chemical shifts d(C1–H) vs Hammett s constants[24] of the aryl rings was created (Figure 4). A fairly good linear correlation was obtained with a correlation factor of R2 = 0.79, i.e., going from electron-donating to electron-withdrawing systems was associated with increasing d(C1–H). This finding is in agreement with the computational results above and the transformations leading from products 3 to H-3, suggesting that electronic effects of ring substituents are transmitted through the cage onto the remote apical position. R =0.79

a

k

j

2

5.4

Table 5. Optimization of decarboxylation conditionsa

i

g 5.2

Ph C Ph

Ph

Ph

Additives

Ph

[Et 4N]+

DMF, 100 °C, 18 h

Ph C Ph Ph

3a

Additives

1

Pd/Ag/H (0.25/1.1/2.0 equiv)

H-3a c

Pd/H (0.25/2.0 equiv)

3

Ag/H (1.1/2.0 equiv)

H-3a+3a+bpt

4

Pd/Ag (0.25/1.1 equiv)

H-3a+trace 3a+bpt

5

Pd (0.25 equiv)

H-3a+3a+trace bpt

Ag (1.1 equiv)

H-3a+trace 3a+bpt

7

Ag (0.05 equiv)

H-3a+trace bpt

8

Pd (0.025 equiv)

H-3a+trace 3a+trace bpt

9

-

H-3a+trace 3a+trace bpt

d

-

H-3a, 91% isolated yield

d

TEMPO (2.0 equiv)

H-3a

11 a

Reactions were conducted on a 0.01 mmol (7 mg) scale in 0.5 mL DMF in b + a sealed vial under air; Pd = Pd(OAc)2, Ag = AgOAc, H = HOAc, TEMPO c = 2,2,6,6-tetramethylpiperidyl-1-oxy radical; results were inferred by ESId MS, bpt = unknown byproduct(s); under N2 atmosphere.

Applying the conditions from Table 5, entry 10, we investigated the decarboxylation of selected isolated acids 3.[23] Aryl rings bearing groups with different electronic properties were all converted cleanly to the corresponding decarboxylated penta-aryl-carboranes H-3 in consistently excellent yields (Table 6). Starting from 3a, the product H-3a was obtained in identical yield to the reaction on a smaller scale (entry 1). Substituents such as 4-F and 4-Br quantitatively gave the decarboxylated products H-3i and H-3n (entries 2 and 3). Complete decarboxylation

Table 6. Decarboxylation of penta-arylated carboranes 3.

Ar

COOH Ar C Ar Ar

Ar [Et 4N]+

Entry

Ar DMF, 100 °C, 18 h

H Ar C

Ar

d

Br

F

-0.2

0.0

0.2

0.4

0.6

3

4-C6H4-Br

99 (H-3n)

4-C6H4-Et

c

Additional transformations. Subsequent reactions were performed to probe the opportunity for late-stage modification of penta-arylated products. Bromination of 3a and also H-3v with N-bromosuccinimide in acetonitrile proceeded smoothly to afford the corresponding B12-brominated compounds 4a and 4b in 98% and 91% yield, respectively (Scheme 3a). Successful palladium-catalyzed cross coupling of Bbrominated carboranes has been demonstrated by Spokoyny and coworkers[25], such that 4a and 4b are anticipated to present molecules Scheme 3. (a and b) Subsequent transformations of 3a, H-3v and H3n and (c) gram-scale synthesis of 3a. Ar

a)

R Ar C

Ar

Ar

Ar

NBS (1.1 equiv) 25 °C or 80 °C

3a R = COOH, Ar = Ph H-3v R = H, Ar = 4-C6H 4-CN

Ar

R Ar C

Ar

Ar

Ar

[Et 4N]+ Br

NHAc

C

b)

99 (H-3c)

c

4a R = COOH, Ar = Ph 98% 4b R = H, Ar = 4-C6H 4-CN 91%

H 2N

H

AcHN

H

H 2N

NHAc

NH 2CH 2CH 2NH 2 MW, 80 °C H 2N

NH 2 [Et 4N]+ 5 99%

COOH C

c)

+ [Et 4N]+

NH 2

C

NH 4Br (6.0 equiv)

H-3n

c

5 4-C6H4-NHAc 93 (H-3r) a Reactions were conducted on a 0.05 mmol scale in DMF (2.5 mL) under b N2 in a 20 mL round-bottom flask at 100°C; yield of the purified product; c with the addition of KOAc (2 equiv).

0.8

Figure 4. H NMR shifts of carborane cage CH positions of decarboxylated products H-3 vs Hammett s constant of the aryl substituents (NMR conditions: DMSO-d6, 23 °C).

b

91 (H-3a)

CN

σ (Hammett)

H-3

99 (H-3i)

CF3

1

[Et 4N]+

Ph

COOEt

m

-0.4

AcHN

4-C6H4-F

j k Cl

AcHN

2

CHO

Cl

Ar

Yield (%)

i

l

c

b

[Et 4N]+

1

4

a

-0.6

a

Ar

Ar [Et 4N]+

3

F

f g Br

e

4.2

H-3a+3a+bpt

6

10

e

h

4.4

2

+

NHAc

h

4.8

H-3a+3a+bpt

+

Et

c d

m

5.0

4.6

Result

+

NH2

b

F

b

Entry

Ph Ph

[Et 4N]+

l

f

H

COOH

δ (ppm)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1 2 mmol


I

2a 6.0 equiv

Pd(OAc) 2, 2.5 mol% AgOAc (6.0 equiv) HOAc (6.0 equiv) DMF, 25 °C

Ph

COOH Ph C Ph Ph

Ph [Et 4N]+

3a 92% 1.28 g


en route to even more highly functionalized boron clusters. Furthermore, deacylation of H-3n furnished deprotected 5 with free amino groups in 99% yield (Scheme 3b). This product is a rare example of a C5-symmetrical ligand for the construction of frameworks involving transition metals or serving as a building block in covalent supramolecular chemistry. Finally, we tested the scalability of our catalytic protocol. When the penta-arylation of 1 and with iodobenzene was run on a 2 mmol scale, the desired product 3a was isolated in 92% yield (1.28 g), matching that of the reactions on a smaller scale (Scheme 3c).

CONCLUSION In conclusion, we have synthesized a series of cage penta-arylated carboranes by palladium-catalyzed intermolecular coupling of monocarborane carboxylic acid with iodoarenes by direct cage B–H bond functionalization in high yields and with complete regioselectivity. For the first time, directing group-mediated, metal-catalyzed activation of five equivalent inert bonds within a single molecule has been accomplished. The directing group can easily be removed during or after the intermolecular coupling reaction. The mechanistic manifold was investigated in detail using DFT calculations, which strongly suggest consecutive B–C bond formation at adjacent B2–6 vertices. Relevant transition states and intermediates were calculated for each part of the cascade. The decarboxylation was additionally related to the electronic properties of the substituents, indicating more facile directing group removal in the case of electron-deficient aryl systems. The above-described functionalized penta-aryl carborane derivatives represent attractive building blocks that have unique 5-fold symmetry for the synthesis of supramolecular structures by subcomponent assembly, setting the stage for the construction of novel types of molecular architectures.

ASSOCIATED CONTENT Supporting Information The Supporting Information containing experimental details, computational methods, compound characterizations and X-ray data in CIF format for 3a, 3b, 3f, 3q, H-3u, H-3x and 1-Pd (CCDC numbers: 18547931854799). This material is available free of charge on the ACS Publications website: http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Authors *Simon Duttwyler: [email protected] *Xin Hong: [email protected]

ORCID Simon Duttwyler: 0000-0001-9851-4920 Xin Hong: 0000-0003-4717-2814

Author Contributions §

F. L., J.–L. Y. and Y. S. contributed equally.

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This research was supported by the Natural Science Foundation of China (grant 21472166, S. D.; 21702182, X. H.), the National Basic Research Program of China (973 Project 2015CB856500, S. D.), and the Chinese “1000 Young Talents Plan” (S. D. and X. H.). Calculations were

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performed on the high-performance computing system at the Department of Chemistry, Zhejiang University.

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Palladium-Catalyzed Selective Five-Fold Cascade Arylation of the 12

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