Hiroki
Andoh
,
Ryo
Nakagawa
,
Tatsuya
Akutagawa
,
Eiko
Katata
and
Teruhisa
Tsuchimoto
*
Department of Applied Chemistry, School of Science and Technology, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki 214-8571, Japan. E-mail: tsuchimo@meiji.ac.jp
First published on 10th April 2025
We developed practical reaction conditions and a procedure for the direct Suzuki–Miyaura cross-coupling (SMCC) of C(sp2)–B(dan) bonds. Below are important notes to successfully execute the direct SMCC: (1) dehydrated conditions that exclude as much H2O as possible are required, (2) LiOH is the base of choice, (3) dppf is the ligand of choice when using electron-deficient (hetero)aryl halides [(Het)ArX], (4) P(t-Bu)3 is the ligand of choice when using electron-rich (Het)ArX, and (5) COD is the ligand of choice when using (Het)ArX with a protic functional group such as NH2 and OH. Taking heed of these notes enables the direct SMCC of the C(sp2)–B(dan) bond by using a wide range of substrates with diverse functional groups, affording the following series of coupling products: Ar–Ar, Ar–HetAr, HetAr–HetAr, alkenyl–Ar, and alkenyl–alkenyl. Sequentially executing distinct types of palladium-catalyzed CCs, such as Buchwald–Hartwig CC + SMCC, Mizoroki–Heck reaction + SMCC, and Sonogashira–Hagihara CC + SMCC, allows access to complex π-conjugated molecules. The B(dan) moiety also exhibits outstanding compatibility with Wittig olefination and Sc(OTf)3-catalyzed acetal-forming reactions, enabling molecular transformations that are otherwise impracticable when using ArB(OH)2. Mechanistic studies suggest the involvement of both path A, wherein a boronate species reacts with an arylpalladium halide, and path B, wherein a boron compound reacts with an arylpalladium hydroxide, at the stage of the transmetalation.
Among the three masked boryl groups, B(dan) is reportedly the most resistant to hydrolysis8 and used for the SMCC after the conversion to B(OH)2 or B(pin) under strongly acidic conditions.4 This B(dan) technology is now recognized as a boron-masking–unmasking strategy. Despite its robustness, we envisioned that the direct use of B(dan) in the SMCC would contribute to the further progress of CC chemistry in terms of the step economy and substrate scope. The former reduces time, cost, and waste by avoiding the unmasking step. The latter leads to, for instance, solving the 2-pyridyl problem; 2-pyridylB(OH)2 is infamously unstable due to rapid protodeboronation,9 in contrast to 2-pyridylB(dan) (Fig. 2).10 Due to the same reason, the SMCC of 2-heteroarylB(OH)29 and perfluoroarylB(OH)2
9,11 is also challenging. These issues partly apply to their B(pin) variants.12 Accordingly, the SMCC, a Nobel Prize-winning reaction, will be much more practical and reliable by directly utilizing B(dan).
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Fig. 2 Stability of 2-pyridylB(OH)2 and 2-pyridylB(dan). a![]() |
Since 2007, it has been believed that B(dan) is inert under SMCC conditions. Despite this preconception, we disclosed for the first time that the C–B(dan) bond of alkynylB(dan) can be directly activated in the SMCC (Scheme 2a).13 More recently, the Yoshida–Tsuchimoto10 and Mutoh–Saito14 teams independently achieved the direct SMCC of aryl/alkenylB(dan) with more robust C(sp2)–B(dan) bonds (Scheme 2b).15 Both teams employed KOt-Bu as a base, which is crucial for providing the transmetalation-active boronate salt, [(dan)B(Ot-Bu)–Ar]− (conditions A in Scheme 2b).16 However, base-sensitive functional groups are difficult to apply thereto. Ba(OH)2 is an effective alternative in such cases but unsatisfactory in terms of product yields: 33–64% (conditions B in Scheme 2b).10 We have since endeavoured to ensure more practical and reliable direct SMCC of the C(sp2)–B(dan) bond. In this context, we have preliminarily confirmed and reported that one of the reaction conditions presented in this study is effective for the synthesis of optoelectronic molecules.13d After this, the Tsui group reported unique, base-free direct SMCC of fluorinated alkenylB(dan).17 The Yoshida group recently reported a palladium/copper co-catalyzed system for base-sensitive (Het)ArB(dan).18 Herein, we report the details of the direct SMCC catalyzed solely by palladium, using three sets of reaction conditions applicable to couplings of a wide variety of substrate combinations.
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Scheme 2 Previous work on direct SMCC of C–B(dan) bonds. Ar covers 5- and 6-membered heteroaryls. DMF = HCONMe2. Cy = cyclohexyl. |
Entry | x | y | Proc. | Conv. (%) | Yield (%) of | ||
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of 1a | 3aa | 4a | 5 | ||||
a Reagents: 1a (0.20 mmol), 2a (0.30 mmol), Pd(OAc)2 (10 μmol), dppf (15 μmol), Ba(OH)2 (0.40 or 0.60 mmol), and DMF (0.40 or 0.80 mL). See Fig. 3 for procedures A and B. Conversions and yields were determined by 1H NMR. Proc. = procedure. Conv. = conversion. b Isolated yield: 57%. c Performed for 6 h. d Pd(OAc)2 (20 μmol, 10 mol%) and dppf (30 μmol, 15 mol%) were used. | |||||||
1 | 2 | 0.4 | A | 68 | 68b | 3 | <1 |
2c | 3 | 0.4 | A | 41 | 35 | 7 | <1 |
3 | 3 | 0.8 | A | 76 | 69 | 10 | 15 |
4d | 3 | 0.8 | A | 77 | 70 | 32 | 17 |
5 | 3 | 0.8 | B | 76 | 72 | 10 | 8 |
With procedure B, we continuously examined the effect of other bases (Table 2). Bases that have shown relatively good performance in the preceding study were selected here (see Table S4 in the ESI of ref. 10). The results of entry 5 of Table 1 are presented again in entry 7 of Table 2 for comparison. As a result, LiOH emerged as the most promising option, increasing the yield of 3aa to 85% while remarkably restricting the two side reactions (entries 1–7). Since LiOH (pKb = 0.18) has comparable basicity to Ba(OH)2 (pKb = 0.15),19 the reduction in the side reactions is unlikely to be due to the lower basicity of LiOH, but it could be due, in part, to the lower nucleophilicity of OH− bound to Li+ (73 pm) with a much smaller ionic radius than Ba2+ (149 pm).20,21 However, using LiOH caused poor reproducibility in the yield of 3aa (entries 1 and 8). This could be improved by increasing the loading of Pd(OAc)2 and dppf: using 10/15 mol% of Pd(OAc)2/dppf delivered 3aa in the highest yield of 94% without producing 4a and 5 (entries 9 and 10). Reverting procedure B back to A again caused the side reactions, showing the validity of procedure B irrespective of the base used (entry 11). Entry 12 revealed that dppf is necessary as a ligand. The final tuning of the reaction time indicated that the reaction reaches completion in 8 h (entry 13).
Entry | Base | Conv. (%) | Yield. (%) of | ||
---|---|---|---|---|---|
of 1a | 3aa | 4a | 5 | ||
a Reagents: 1a (0.20 mmol), 2a (0.30 mmol), Pd(OAc)2/dppf (10/15 μmol) for entries 1–8 or (20/30 μmol) for entries 9–13, base (0.60 mmol), and DMF (0.80 mL). Conversions and yields were determined by 1H NMR. Reactions were performed through procedure B. b Performed through procedure A. c Without dppf. d Performed for 8 h. | |||||
1 | LiOH | 93 | 85 | 2 | <1 |
2 | KF | 4 | <1 | <1 | <1 |
3 | KOAc | 13 | <1 | <1 | <1 |
4 | KHCO3 | 30 | 17 | <1 | <1 |
5 | K3PO4 | 33 | 11 | <1 | <1 |
6 | Cs2CO3 | 35 | 10 | <1 | <1 |
7 | Ba(OH)2 | 76 | 72 | 10 | 8 |
8 | LiOH | 97 | 71 | 1 | <1 |
9 | LiOH | >99 | 94 | <1 | <1 |
10 | LiOH | >99 | 93 | <1 | <1 |
11b | LiOH | 90 | 89 | 1 | 3 |
12c | LiOH | 62 | 25 | <1 | <1 |
13d | LiOH | >99 | 93 | <1 | <1 |
Our strategic framework to clarify the usability of this reaction is depicted in Fig. 4, which is divided into four areas I–IV based on the electronic properties of the two substrates: ArB(dan) 1 and XAr 2 with an EDG or EWG. We expected that filling the four areas with enough coupling products should be a good demonstration of the broad substrate scope of this reaction.
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Fig. 4 A strategic framework for the substrate scope. EDG = electron-donating group. EWG = electron-withdrawing group. |
We started with the conquest of the area I: EDG–ArB(dan) × XAr–EWG (Table 3). Under conditions C (see the reaction scheme in Table 3) established in the exploration of Tables 1 and 2 and Fig. 3, 1a reacted with 2 bearing CN, Cl, CF3, NO2, COR (R = H, Bu, Ph, indanonyl), and CCPh groups,22 affording 3aa–3ai in good to high yields. Several important notes are as follows: (1) the careful pre-drying using procedure B may suppress base-mediated hydrolysis of the CN group,23 (2) the Cl–C(sp2) bond of 2′′a participated in the SMCC, but that of 2b remained unreacted by the chemoselective SMCC of the I–C(sp2) bond, (3) the CHO group of 2e was tolerated without undergoing the Cannizzaro side reaction,24 and (4) no aldol side reaction of the COBu group in 2f was observed.25 In area I, ArB(dan) with the sterically congested o-MeO (1b) as well as with p-(i-Pr)S (1c), p-(i-Pr) (1d) and p-(N-carbazolyl) (1e) groups can also be used to obtain 3ba–3ea.
a Reagents for conditions C and D (unless otherwise noted): 1 (0.20 mmol), 2 (0.30 mmol), Pd(OAc)2 (20 μmol), dppf (30 μmol) or P(t-Bu)3 (40 μmol), LiOH (0.60 mmol), and DMF (0.80 mL). Reagents for conditions E (unless otherwise noted): 1 (0.30 mmol), 2 (0.20 mmol), Pd(OAc)2 (20 μmol), COD (30 μmol), LiOH (0.60 mmol), and DMF (0.80 mL). Conditions used are shown in parentheses. Yields of isolated products are shown here.
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Inspired by the above results, we worked on capturing area II: EWG–ArB(dan) × XAr–EWG. We conducted the SMCC of p-F3CC6H4B(dan) (1f) with a series of XAr–EWG 2a–2n to obtain 3fa–3fn. The functional groups, F (2j), SO2Me (2k), COMe (2l), and CO2Et (2n), newly proved to be compatible with conditions C. Of note is the tolerance of COMe with higher acidic α-protons than COBu of 2f (see area I). No serious observation of the base-mediated saponification of the CO2Et in 2n is also noteworthy. In addition, the SMCC of 2i selectively occurred to yield 3fi without causing palladium-catalyzed cyclotrimerization of the CC part.26 Like other ArB(dan) compounds, 1h was chemoselectively cross-coupled with the I–C(sp2) bond of 2a without losing the Br functionality. Due to the instability of 2,4,5-F3C6H2B(OH)2 [t1/2 = 1 h at 70 °C in H2O/1,4-dioxane (1/1)],11 the compatibility of 1g is an advantage of the dan-protected boronic acid. The uracil framework that is crucial as a pharmacophore is also introducible from non-aromatic 5-iodo-1,3-dimethyluracil (2o).27
The next concern is area III for the synthesis of biaryls with an EDG on each aryl unit. We carried out the SMCC of 1a with p-BrC6H4NMe2 (2p) under conditions C, but the conditions C were ineffective, providing the desired product 3ap in a low yield of 19% (Scheme 3). GC-MS and 1H NMR analysis of the crude reaction mixture exhibited the formation of some by-products, mainly including p-MeOC6H4–Ph (1a + dppf–Ph) in 24% yield, along with a small amount of Ph–C6H4–p-NMe2 (dppf–Ph + 2p).28 The Ph group of the by-products was considered to come from dppf.29 We therefore explored an appropriate ligand for this case (Scheme 4). Replacing dppf with DPEPhos and XantPhos, both of which still contain the Ph group, did not result in any improvements. With JohnPhos and SPhos, coupling products incorporating the bulky biaryl units were not detected, but the yields of 3ap were still low to moderate. In sharp contrast, P(t-Bu)3 with no aryl group exhibited outstanding performance, affording 3ap in 91% yield; Table 3 shows the isolated yield thereof. Interestingly, COD also worked as a ligand to afford 3ap in a good yield of 72%. These results showed that P(t-Bu)3 is the ligand of choice for the SMCC of 2p. Hereinafter, the reaction conditions using P(t-Bu)3 as a ligand are referred to as conditions D,30 and their generality in area III was examined. However, disappointingly, the SMCC of 1a with 2q having the NH2 group under conditions D resulted in a low yield of 3aq (Scheme 5). Besides 3aq, anisole and a trace amount of its dimer were produced from 1a. As a major by-product, insoluble black materials were obtained quantitatively from 2q. FT-IR analysis implied the generation of polymers probably via the self-Buchwald–Hartwig coupling of 2q.31 Here, the observation in Scheme 4 reminded us that COD may be a good option for 2q, which is also an XAr–EDG. To our delight, switching the ligand to COD prevented the polymerization of 2q, delivering 3aq in a dramatically improved yield of 86% (Table 3).32 Thus, the ligand COD was found to be effective in preventing the 2q-based self-Buchwald–Hartwig coupling that directly lowers the yield of 3aq. Hereinafter, the reaction conditions using COD as a ligand are referred to as conditions E, which also worked well for the SMCC of XAr with NHMe (2r) and OH (2s) groups. These results reveal that COD is a suitable ligand for XAr–YH (Y = NR", O), in which the YH potentially cross-couples with X–Ar. On the other hand, P(t-Bu)3 was again effective in the SMCC of 2t and 2u, indicating that conditions D should be selected for XAr–EDG without the YH.
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Scheme 3 Direct SMCC of p-MeOC6H4B(dan) with p-BrC6H4NMe2 under conditions C. Yields determined by 1H NMR are shown here. |
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Scheme 4 Screening of ligands for direct SMCC of p-MeOC6H4B(dan) with p-BrC6H4NMe2. Yields determined by 1H NMR are shown here. a![]() |
At the last corner of area IV, the purpose is the achievement of the SMCC of EWG–ArB(dan) with XAr–EDG. Here as well, conditions D and E established for XAr–EDG and XAr–YH, respectively, in area III remain useful. Thus, 1f was cross-coupled with 2p, 2u, 2v, and 2w under conditions D and with 2x, 2r, and 2y under conditions E to afford the corresponding products in good to high yields. These results show that the functional groups, NHCOMe, N-morpholino, and CH2OH, can also participate in this protocol. The compatibility of NHCOMe without undergoing hydrolysis is noted. Besides 1f, ArB(dan) with m-NO2 (1j) or 2,4,5-F3 (1g) was converted to the respective coupling product 3jp or 3gu in a high yield.
As depicted in the center of Fig. 4, the simplest coupling product, biphenyl (3kz), can also be prepared in an excellent yield under conditions C (Scheme 6).
As Table 4 shows, ArB(dan) 1 can also react with heteroaryl halides (XHetAr) 2, which are classified into two groups of electron-deficient and electron-rich, based on the electron density of the reaction site compared to that of the carbon atom of benzene.33p-MeOC6H4B(dan) (1a) and p-CF3C6H4B(dan) (1f) were used in the SMCC with 3-I–pyridine (2aa), 2-Br–thiophene (2ab), and 3-Br–furan (2ac) under conditions C, affording the corresponding Ar–HetAr 3 in good to high yields. Note that a higher loading is required for the coupling of 2ac due to its rapid consumption (see also the coupling of 2ac in area III of Table 5). It should also be noted that distinct from the couplings of electron-rich XAr–EDG in areas III and IV of Table 3, conditions C with the ligand dppf could be applied to those of electron-rich XHetAr 2ab and 2ac because no incorporation of the dppf-based Ph group into the product was observed (refer to Scheme 3).
a Reagents (unless otherwise noted): 1 (0.20 mmol), 2 (0.30 mmol), Pd(OAc)2 (20 μmol), dppf (30 μmol) for conditions C or P(t-Bu)3 (40 μmol) for conditions D, LiOH (0.60 mmol), and DMF (0.80 mL). Conditions used are shown in parentheses. b 2a (0.34 mmol), 2ae (0.36 mmol), or 2ac (0.60 mmol) was used, respectively. c1 (0.40 mmol) and 2 (0.20 mmol) were used. dLiOH (0.40 mmol) was used. eAt 70 °C. fPd(OAc)2 (30 μmol) and dppf (45 μmol) were used. g1 (0.30 mmol) and 2 (0.20 mmol) were used. hAt 60 °C. |
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Through the investigation conducted so far, we realized 47 reactions, and areas I–IV of Tables 3 and 4 were filled with coupling products to a significant extent. To further expand the scope of this method, we continuously studied the direct SMCC for HetArB(dan) (Table 5) and alkenylB(dan) (Table 6).
a Reagents (unless otherwise noted): 1 (0.20 mmol), 2 (0.30 mmol), Pd(OAc)2 (20 μmol), dppf (30 μmol) for conditions C or P(t-Bu)3 (40 μmol) for conditions D, LiOH (0.60 mmol), and DMF (0.80 mL). Conditions used are shown in parentheses. b Performed with 1v (0.30 mmol) and 2c (0.20 mmol) at 80 °C. cDetermined by 1H NMR. dDetermined by GC and GC-MS. |
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Table 5 summarizing the SMCC of HetArB(dan) with X(Het)Ar also consists of areas I–IV,33 and conditions C and D work well here as well. In area I, we first realized the SMCC of electron-rich benzofuranylB(dan) 1l and carbazolylB(dan) 1m with p-IC6H4CN (2a), affording 3la and 3ma in high yields, respectively. Besides the HetAr–Ar structure, the HetAr–HetAr structure, including benzofuranyl (from 1l), pyridyl (from 2aa), pyrazyl (from 2ad), thienyl (from 1n) or benzothiazolyl (from 2ae) ring, could be constructed. A pharmacologically active antipyrinyl nucleus can also be selected, affording 3laf in a high yield.34
The results from area II in Table 5 reveal that the current protocol is at a satisfactory level to address the 2-pyridyl problem.9 Thus, 2-pyridylB(dan) compounds containing a 6-MeO (1o) or 6-F (1q) group as well as 2-pyridylB(dan) itself (1p) were cross-coupled with electron-deficient X–(Het)Ar. These reactions produced pyridines connected with C6H4–p-CN (3oa, 3pa, and 3qa), 2-benzothiazolyl (3oae), imidazo[1,2-b]pyridazinyl (3oag), and 4-pyridyl (3qah) units in moderate to high yields. Due to the low yield (33%) of a 1q-derived product in a previous study,10 which was attributed to the propensity of 1q for more readily undergoing protodeboronation,9 the results from area II signify that the present method is greatly refined.
A range of HetAr–(Het)Ar molecules were also constructed in areas III and IV, where 1r and 1s as HetArB(dan) and 2ai, 2aj, 2ak, and 2al as X(Het)Ar could be employed as new substrates.
The use of alkenylB(dan) enables access to 1,2-diarylalkenes (3ta and 3tu) and 1,2-alkylarylalkenes (3ua and 3um) as well as 1,1-alkylarylalkenes (3vc and 3vh) in good to high yields (Table 6). With an 87:
13 E/Z mixture of commercially supplied β-bromostyrene (2am), product 3tam also consisted of a mixture of stereoisomers, albeit with higher E selectivity (E/Z = 97
:
3). We therefore expected that starting with a single isomer of (E)-2am would afford only (E,E)-3tam and that the classical method of treating (E/Z)-2am with NaOH would be useful to selectively destruct the Z-isomer (Scheme 7a).35 Due to the similar characteristics of NaOH and LiOH, we further expected that, if LiOH can serve as a base for the destruction reaction as well as for the SMCC, the two reactions may be conveniently performed in one pot. This idea worked out nicely (Scheme 7b), and (E,E)-3tam was stereoselectively constructed in a good yield of 76% by the treatment of (E/Z)-2am with LiOH in DMF at 100 °C for 1 h followed by the SMCC with 1t under conditions D.36 This stereoselective one-pot procedure can also be applied to 1-cyclohexenylB(dan) (1w) and p-CF3C6H4B(dan) (1f).
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Scheme 7 [a] Selective destruction of (Z)-β-bromostyrene [(Z)-2am].35 [b] One-pot SMCC starting with an 87![]() ![]() |
We further expected that iterative palladium-catalyzed CCs, including the current direct SMCC, would enable rapid access to complex π-conjugated molecules (Scheme 8). Showing the compatibility of the B(dan) group with other palladium-catalyzed CCs would be one of the advantages of B(dan) chemistry. m-/p-BrC6H4B(dan) 1x and 1h were selected as substrates. Upon the treatment of 1x with benzamide under palladium catalysis, the Buchwald–Hartwig amidation first occurred selectively at the Br group to afford 6 in 80% yield.37 No self-SMCC of 1x was observed under the reaction conditions, showing that the B(dan) group was in the switch-off mode. On the other hand, treating 6 with 2an under conditions C switched the B(dan) group to the "on" mode, providing 7 in 97% yield without an extra step for unmasking B(dan). Moreover, 9 was obtained from 1xvia the sequence of Mizoroki–Heck and SMCC. The iterative CCs starting with the Sonogashira–Hagihara CC38 of 1h followed by the SMCC of 10 yielded 11.
In contrast to ArB(OH)2, ArB(dan) indicates unique adaptability to other organic transformations (Scheme 9). For example, the Wittig olefination of 1′y having the B(OH)2 group under the reaction conditions using t-BuOK yielded no desired product 12′, despite the complete consumption of 1′y.39 Instead, base-promoted protodeboronation occurred as a major side reaction.11a In marked contrast to this, using 1y with the B(dan) group delivered an excellent yield of 12, which was then used for the direct SMCC with 2p to yield 13. Due to the significance of chiral diols as chiral inducers in organic chemistry,40 we attempted to synthesize an arylboron compound having a chiral acetal moiety. The acetalization of boronic acid 1′z with (R,R)-2,3-butanediol in the presence of the acid catalyst Sc(OTf)3 (Tf = SO2CF3) resulted in a complex mixture of products.41 Unlike the B(OH)2 case, the chiral acetal formation of 1z occurred to yield 14, which was then directly reacted with 2h to furnish chiral acetal 15.
Distinct from the successful direct SMCC demonstrated thus far, (Het)ArB(dan) and (Het)ArBr collected in Fig. 5 did not work as substrates: a possible or plausible reason is stated below each substrate.
Some experimental observations are available for mechanistic studies. The absence of H2dan (5), already shown in Table 2, can actually be confirmed by the 1H NMR spectrum of the crude reaction mixture after the aqueous work-up of the SMCC of 1a with 2a (Fig. 6a); the 1H NMR spectrum of 5 as an authentic sample is shown in Fig. 6b. Alternatively, a mixture of HOB(dan) and O[B(dan)]2 that retains the B(dan) unit was obtained in 86% yield, close to 90% yield of product 3aa (Fig. 6).42 The formation of this mixture, YOB(dan) [Y = H, B(dan)], in the crude reaction mixture (Fig. 6c) was also confirmed by 11B NMR analysis; the 11B NMR spectrum of isolated YOB(dan) is given in Fig. 6d for comparison. YOB(dan) is considered to form via transmetalation43 followed by partial dehydration,44 as depicted in Fig. 6, supporting the direct SMCC of ArB(dan) 1.
Currently, two distinct courses are recognized to exist prior to the transmetalation event: the boronate pathway A and the oxo-palladium pathway B, as simply illustrated in Scheme 10. There have been studies in support of either path A45 or path B.46 On the other hand, the Denmark group has demonstrated that both path A and path B, including transmetalation-active pre-intermediates, are operative, with path B being faster.47 These earlier studies reveal that whether path A or B is involved depends on the substrates and reaction conditions.
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Scheme 10 Simplified generic mechanisms for SMCC. L = ligand; R = H, alkyl; Y = OH, Oalkyl, NHaryl, etc. |
To gain insights into the transmetalation, we first examined the possibility of path A via the formation of boronate salts 17. Prior to investigating the above, whether the strongly coordinating solvent DMF interacts with ArB(dan) 1 for enhancing the nucleophilicity of the Ar moiety was examined. The 11B signal of PhB(dan) (1k) was observed at 29 ppm in the non-coordinating solvent CDCl3 (Fig. 7a); a 11B signal of 1 appears at approximately 29 ppm, irrespective of a substituent in the Ar part and a solvent. Adding DMF (5 equiv.) to this solution did not cause any spectral change, showing no formation of a DMF–1k complex (Fig. 7b). Next, a 1/1 mixture of 1k and LiOH was stirred in DMF at 30 °C for 2 h and then monitored by 11B NMR spectroscopy, but no boronate salt 17k–OH was observed (Fig. 7c). The extremely low solubility of LiOH in DMF was assumed to be the reason for the absence of 17k–OH. To improve this, switching from LiOH to LiOEt caused a 5% upfield shift in the 1k signal into the typical range of ArB(dan)-based boronate species (17k–OEt, Fig. 7d).10,14b Replacing 1k with 1f having the CF3 group, which should enhance the Lewis acidity of the boron center, resulted in a higher rate of boronate salt 17f–OEt (Fig. 7e). It was then confirmed that yet untested LiOEt as a base can also promote the direct SMCC of 1k with 2z effectively (Scheme 11). Encouraged by these results, we devoted much effort to purifying 17–OEt for a stoichiometric control reaction with the oxidative adduct BrPd(dppf)Ar2 (16a: Ar2 = C6H4–p-F) but could not purify 17–OEt because 17–OEt readily reverted to its original species, 17 and −OEt. Meanwhile, of note is that, unlike in DMF, 17f–OEt was not formed in toluene (Fig. 7f). This result was consistent with the fact that the direct SMCC of 1f with 2j did not occur in toluene, regardless of whether LiOH or LiOEt was used (Scheme 12), suggesting that the boronate formation is one of the important factors for the progress of the present direct SMCC. Moreover, the Mutoh–Saito group has demonstrated that a stoichiometric reaction between the boronate salt K[PhB(dan)(Ot-Bu)] and the oxidative adduct IPd[(PPh3)2]C6H4–p-OMe successfully yields the coupling product Ph–C6H4–p-OMe.14b Consequently, all the findings collected in this section suggest that path A involving borate salt 17 is a viable option in the current direct SMCC.
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Scheme 11 Direct SMCC of PhB(dan) with IPh using LiOEt as a base. The yield of isolated 3kz is shown here. |
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Scheme 12 Direct SMCC of p-F3CC6H4B(dan) with p-BrC6H4F in toluene. Yields of 3fj determined by 1H NMR are shown here. |
The Yoshida group has reported that the H–N moieties of PhB(dan) undergo deprotonation by a Grignard reagent working as a base, followed by methylation with MeOTs (Ts = SO2–p-tolyl).15a Hence, it was assumed that, like 17 in path A, lithium amides 19 possibly produced by LiOH-mediated deprotonation of 1 could be another activated form transmetalating with XPd(Ln)Ar216 (path A′ in Scheme 13a). To verify the possibility of path A′, methylation of 1k under the reaction conditions shown in Scheme 13b was attempted, but 1k was not methylated. In addition, 1kMe2 prepared by a different method was subjected to the direct SMCC with 2a under the standard reaction conditions, delivering 3ka successfully (Scheme 13c). These results clearly indicate that path A′ involving 19 is improbable and thus support path A, in which the reaction partner of 16 is 17.
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Scheme 13 Validation of ArB(dan)-based lithium amides as possible activated species in SMCC. Yields of PhB(Medan) and/or PhB(Me2dan) determined by 1H NMR and of isolated 3ka are shown here. |
Subsequently, we looked into the feasibility of path B in which the 6-electron, 3-coordinate boron compound Y2BAr1 reacts with ROPd(Ln)Ar218. Upon the treatment of a stoichiometric mixture of p-F3CC6H4B(dan) (1f) and cis-Pd(OH)(C6H4–p-F)(dppf)(thf)2 [18j(thf)2]47 in DMF at 90 °C for 8 h, the transmetalation occurred to furnish 3fj in 72% yield (Scheme 14).48 This result supports the likelihood of path B.
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Scheme 14 Stoichiometric control experiment by reacting p-F3CC6H4B(dan) with cis-Pd(OH)(C6H4–p-F)(dppf)(thf)2. The yield of 3fj determined by 1H NMR is shown here. |
There is an additional note in relation to the results of Scheme 14. As shown in Table 3 or Scheme 15, the SMCC of 1f with 2j using LiOH or LiOEt as a base, respectively, was completed in 8 h at 90 °C. These two reactions were thus completed within the same reaction time and at the same reaction temperature as the reaction in Scheme 14, where 1f reacted with intermediate 18j(thf)2 for the subsequent transmetalation. Accordingly, the rate-determining step of the present direct SMCC may be the transmetalation, as proposed in most SMCCs.49
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Scheme 15 Direct SMCC of p-F3CC6H4B(dan) with p-BrC6H4F. The yield of 3fj determined by 1H NMR is shown here. |
Considering all the experimental results pertaining to the mechanistic studies, we currently regard both path A and path B as possible courses of involvement in the direct SMCC of ArB(dan).
With conditions C, D, and E and procedure B, we carried out 84 SMCCs using a wide variety of substrates with various functional groups. Not only is it merely feasible to conduct the direct SMCC, but also to construct complex aromatic architectures by combining the current direct SMCC with other organic transformations. For example, Buchwald–Hartwig CC, Mizoroki–Heck reaction, Sonogashira–Hagihara CC, Wittig olefination, and Lewis-acid-catalyzed chiral acetal formation can first be used to transform a functional group on the Ar moiety of ArB(dan), followed by the direct SMCC of the remaining B(dan) unit.
Mechanistic studies showed that C(sp2)–B(dan) is directly activated under the reaction conditions established here. At present, both path A and path B illustrated in Scheme 10 are likely the catalytic cycles.
Footnote |
† Electronic supplementary information (ESI) available: Experimental procedures, analytical data, characterization data and NMR spectra of compounds. See DOI: https://doi.org/10.1039/d5qo00230c |
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