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Abstract

The first palladium-catalyzed cross-coupling of various substituted benzyltitaniums with aryl triflates is presented for the synthesis of diarylmethanes in yields of up to 94% through highly selective C–O bond functionalization. The benzyltitaniums act as nucleophiles to realize the C(sp²)–C(sp³) cross-coupling with high efficiency in short reaction times. The reactions proceed at 60°C and show excellent functional groups tolerance.

Keywords

aryl triflates benzyltitanium reagents cross-coupling diarylmethanes palladium catalysis

Introduce

Palladium-catalyzed cross-coupling plays an important role in the industrial manufacture of pharmaceuticals, fine chemicals, and materials.^1–3 Researchers have found that a significant number of bioactive molecules contain a methylene functional group, which makes research on diarylmethane-containing compounds important (Figure 1).^4,5 The preparation of diarylmethanes is usually accomplished by four common methods: (a) electrophilic substitution of aromatics, which is often referred to as Friedel–Crafts benzylation^6,7 but suffers from poor regioselectivity; (b) nucleophilic aromatic substitution reactions with benzyl derivatives as nucleophiles;⁸ (c) C–H activation of aromatic hydrocarbons;^9–11 and (d) the most commonly used strategy to prepare diarylmethanes through transition metal-catalyzed coupling by employing either electrophilic benzyl derivatives^12,13 or nucleophilic benzyl reagents,^14–16 such as reactions using organoboron derivatives,¹⁷ organozinc,¹⁸ or Grignard reagents.¹⁹ More recently, organotitanium reagents have been used as organometallic partners in C(sp²)–C(sp²) and C(sp²)–C(sp³) cross-coupling reactions.^20–28 Organotitanium reagents have lower nucleophilicity, basicity, and better functional group tolerance compared with Grignard reagents. Moreover, compared with organozinc reagents, organotitanium reagents have higher metal transfer rates. Studies by Dastbaravardeh and Knochel²¹ have shown that the reactivity of organotitanium reagents as nucleophiles is much higher than that of the corresponding organozinc counterparts.

Figure 1.

Examples of the diarylmethane motif in pharmaceuticals.

Interestingly, although many exciting achievements have been made in nucleophilic addition of organotitanium reagents to carbonyl compounds (Scheme 1a),^29,30 by comparison, much less attention has been devoted to the employment of such reagents in C(sp²)–C(sp²) cross-coupling transformations (Scheme 1b).^20–28 Furthermore, there is only one successful example of the employment of such reagents in C(sp²)–C(sp³) cross-coupling transformations (Scheme 1c).²¹ To the best of our knowledge, this is the first example using organotitanium nucleophiles to generate diarylmethane units by C(sp²)–C(sp³) cross-coupling reactions (Scheme 1d).

Scheme 1.

Comparison of reported methods and our design.

Organic halides are commonly the electrophiles,^31–36 which generate halogenated waste after reactions. Also, halides are sometimes limited by reaction conditions, making it difficult to use them in some advanced synthetic intermediates; these shortcomings can be solved using alternative partners, such as C–O electrophiles.^37,38 Aryl triflates are popular as electrophiles in transition metal-catalyzed cross-coupling reactions because they are derived from readily available phenols and carbonyl enolates.³⁹ However, phenolic hydroxy and carbonyl moieties are more common organic functional groups than non-commercially available aryl halides.⁴⁰ Herein, we present the first palladium-mediated cross-coupling of benzyltitanium reagents with aryl triflates to give the corresponding diarylmethanes in yields of up to 94%.

Results and discussion

To develop a new C(sp²)–C(sp³) cross-coupling catalyzed protocol, we initially used phenyl triflate (1a) in a reaction with [(4-(ethoxycarbonyl)benzyl)]triisopropoxytitanium (2a) for optimizing the reaction conditions. The results are given in Table 1. In the absence of a transition metal catalyst and ligand, no product formation was observed (Table 1, Entry 1).

Table 1.

Optimization of the reaction conditions^a.

Entry	Catalyst	Ligand	Pd/ligand	Additive	Solvent	Time (h)	Yield (%)^b
1	–	–	–	–	THF	24	n.d.
2	Pd(OAc)₂	PPh₃	1:2	–	THF	24	n.d.
3	Pd(OAc)₂	PCy₃	1:2	–	THF	24	15
4	Pd(OAc)₂	L1	1:1	–	THF	24	43
5	Pd(OAc)₂	L2	1:1	–	THF	24	49
6	Pd(OAc)₂	L3	1:1	–	THF	24	61
7	Pd(OAc)₂	L4	1:1	–	THF	24	73
8	Pd(OAc)₂	L5	1:1	–	THF	24	64
9	Pd(OAc)₂	L6	1:1	–	THF	24	66
10	Pd(PPh₃)₄	L4	1:1	–	THF	24	25
11	Pd₂(dba)₃	L4	1:1	–	THF	24	41
12	Pd(OAc)₂	L4	1:2	–	THF	24	82
13	Pd(OAc)₂	L4	1:3	–	THF	24	81
14	Pd(OAc)₂	L4	1:2	–	Toluene	24	<5
15	Pd(OAc)₂	L4	1:2	–	1,4-dioxane	24	37
16	Pd(OAc)₂	L4	1:2	–	DME	24	80
17	Pd(OAc)₂	L4	1:2	–	Et₂O	24	32
18	Pd(OAc)₂	L4	1:2	–	THF/DME (1:3)	24	75
19	Pd(OAc)₂	L4	1:2	–	THF/DME (1:2)	24	87
20	Pd(OAc)₂	L4	1:2	–	THF/DME (1:1)	24	79
21^c	Pd(OAc)₂	L4	1:2	LiCl	THF/DME (1:2)	6	85
22^c	Pd(OAc)₂	L4	1:2	LiBr	THF/DME (1:2)	6	61
23^c	Pd(OAc)₂	L4	1:2	LiCl	THF/DME (1:2)	8	92 (89%)^d
24^c	Pd(OAc)₂	L4	1:2	LiCl	THF/DME (1:2)	10	92
25^c	Pd(OAc)₂	L4	1:2	LiCl	THF/DME (1:2)	4	67

Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), solvent (3.0 mL), −10°C.

GC yield calibrated against tridecane as an internal standard, n.d = not detected.

The additive (1.2 equiv.) was added and the reaction was run at 60°C.

Isolated yield is given in parentheses.

The use of various phosphine ligands subsequently tested at a temperature of −10°C using 3 mol% of Pd(OAc)₂ as the catalyst. The results showed that the highest yield of product 3aa was obtained with ligand L4, which afforded 3aa in 73% yield. To increase the amount of the coupling product, other palladium catalysts were studied. The results show that Pd(PPh₃)₄ and Pd₂(dba)₃ gave poor yields in contrast to Pd(OAc)₂ (Table 1, Entries 10 and 11). Further studies with varying ratio of Pd(OAc)₂ and L4 led to a satisfactory yield of 82% when a ratio of 1:2 was employed (Table 1, Entry 12). Next the reaction solvent was screened, and the results showed that the use of a co-solvent of THF/DME (1:2) was the best choice (Table 1, Entry 19), affording product 3aa in 87% yield. While the effects of additives on the coupling reactions were important, LiCl proved to be the additive of choice. Its use increased the reaction activity and shortened the reaction time (Table 1, Entry 21).^41–44 Finally, extending the reaction time to 8 h increased the reaction yield to 92% (Table 1, Entry 23).

On the basis of the optimized reaction conditions, we next investigated the scope and generality of the cross-coupling reactions of a range of aryl triflates with different benzyltitanium lithium chloride species, and the results are given in Table 2. First, we studied the influence of the functional group on the aryl triflate. Reactions with non-activated aryl triflates proceeded satisfactorily. Phenyl triflate (1a) reacted with [(4-(ethoxycarbonyl)benzyl)]triisopropoxytitanium·lithium chloride 2a to give the coupling product 3aa in 89% isolated yield. The result of the reaction with o-tolyltriflate was comparable to those with p- and m-tolyltriflate, and an 81% yield of the coupling product 3da was obtained, indicating that the reaction was not affected by steric hindrance. Conversely, the reactions with deactivated aryl triflates were less efficient and were not ideal with the substituted phenyl triflates 1e and 1f possessing a p-methoxy or p-dimethylamine group giving 74% and 61% yields of products 3ea and 3fc. When the aryl triflate was substituted with an electron-withdrawing group, the reactions proceeded efficiently: trifluoromethyl-, fluoro- and chloro-substituted aryl triflates reacted to give excellent yields of the cross-coupled products 3ga, 3ha, 3ia, and 3ja. The reactions of electron-deficient phenyl triflates substituted with p-cyano (2k), m-cyano (2l), p-N, N-dimethylamine amide (2m), and o- and m-acetyl groups (2n and 2o) produced good-to-excellent isolated yields of the correspounding functionalized diarylmethanes 3ka-oa with benzyltitanium 2a. The reaction of 1-naphthyltriflate with 2a afforded a good yield of the desired product 3pa. Also, screening of heteroaryltriflates (1q, 1r, and 1s) showed that excellent yields were obtained. Similarly, we also examined the cross-coupling reactions of phenyltriflate 2a with different benzyltitaniums and obtained the corresponding cross-coupling products 3ab-3ag in good-to-excellent yields (Table 2). From the results, it can be seen that the reactions with different substituted benzyltitaniums was not affected by changes in the electronic properties of the aryl rings of the benzyltitaniums.

Table 2.

Scope of the cross-coupling of aryl triflates 1 with benzyltitanium·lithium chloride 2^{a, b}.

3aa (89%)	3ba (83%)	3ca (86%)	3da (81%)
3ea (74%)	3fa (61%)	3ga (92%)	3ha (90%)
3ia (92%)	3ja (90%)	3ka (84%)	3la (86%)
3ma (81%)	3na (72%)	3oa (78%)	3pa (89%)
3qa (91%)	3ra (87%)	3sa (85%)	3ab (85%)
3ac (81%)	3ad (88%)	3ae (91%)	3af (90%)
3ag (92%)	3ah (87%)	3ai (93%)	3aj (94%)

Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), Pd(OAc)₂ (3 mol%, with respect to 1), L4 (6 mol%), THF/DME (1:2, 3.0 mL), 60°C, 8 h, Ar atmosphere.

Isolated yields.

Palladium-catalyzed reactions of mixtures of phenyl triflate (1a) and bromobenzene (4) with triisopropoxy(4-methoxybenzyl)titanium·lithium chloride (2g) were also examined (2a). The results showed that bromobenzene showed slightly lower reactivity under the conditions. Furthermore, 2-pyridyl triflate (1q) proved to be more reactive (Scheme 2b). Thus, 2-pyridyl triflate (1q) could be chemoselectively coupled with triisopropoxy(4-methoxybenzyl)titanium reagent in the presence of phenyl triflate (1a).

Scheme 2.

Chemoselective cross-coupling.

We propose the possible reaction mechanism shown in Scheme 3. First, oxidative addition of Pd(0) to the aryl triflate 1 occurs. This is followed by transmetallation of intermediate A with the organotitanium reagent 2, to yield intermediate B. Finally, reductive elimination generates the desired Coupling product 3 and Pd(0), which completes the catalytic cycle.

Scheme 3.

Possible mechanism for the cross-coupling reactions.

Conclusion

In conclusion, we have developed the first examples of the palladium-catalyzed reactions of benzyltitanium reagents with aryl triflates to give diarylmethane derivatives. The procedure demonstrates broad suitability, being useful for the coupling of both electron-deficient and electron-rich aryl triflates. A large variety of functionalized diarylmethanes have been efficiently prepared using this methodology, which is based on the use of the commercially available catalytic system Pd(OAc)₂/L4. Thus, the new coupling protocol involving palladium-catalyzed organotitanium reagents established in this study promises to provide additional opportunities for the development of organic synthesis.

Experimental

General

Anhydrous lithium chloride, Pd(OAc)₂, Pd(PPh₃)₄, and Pd₂(dba)₃ were purchased from Sigma-Aldrich. THF, 1,4-dioxane, and 1,2-dimethoxylethane were purchased from Alfa Aesar. Other reagents are available commercially and were used without further purification, unless otherwise indicated. All reactions were carried out under an argon atmosphere with dry solvents under anhydrous conditions, unless otherwise noted. THF was dried over alumina under N₂ using a Grubbs-type solvent purification system. All benzyltitanium reagents were prepared from the corresponding benzylmagnesium halides. 4-Hydroxy-N,N-dimethylbenzamide was purchased from Alfa Aesar, 4-(dimethylcarbamoyl)phenyltriflate (1m) was prepared by the reported procedures.⁴⁵ Other triflates (1a-l, 1n-s) were obtained from Aldrich. Ligands, L1–L6, were prepared according to literature procedures.^46–49 Spectroscopic data of known compounds matched with data reported in the corresponding references. Reactions were monitored with an Agilent GC Series 6890N and GCMS 7890A. All new compounds were further characterized by High-resolution mass spectra (HRMS) (ESI), and ¹H NMR and ¹³C NMR spectra were measured on a Bruker 400 M spectrometer. ¹H NMR and ¹³C NMR were recorded using tetramethylsilane (TMS) as an internal standard in deuterated chloroform (CDCl₃) or deuterium oxide. Chemical shifts are reported in parts per million (ppm). Multiplicities are indicated as follows: s, singlet; d, doublet; t, triplet; dd, doublet of doublets; dt, doublet of triplets; and m, multiplet. The coupling constants, J, are reported in hertz (Hz). HRMS were recorded on an ESI-Q-TOF mass spectrometer. The products were purified by column chromatography on silica gel (300–400 mesh).

Experimental section

General procedure A: benzyltitanium reagents

The glassware was oven-dried (100°C) and cooled under a stream of argon gas. Aryl Grignard reagents, such as benzylmagnesium chloride and 4-methoxybenzylmagnesium chloride, were prepared according to standard procedures. Functionalized aryl Grignard reagents, including 4-cyanobenzylmagnesium chloride, were prepared by iodine–magnesium exchange using i-PrMgCl•LiCl according to Knochel method.⁵⁰ All of the Grignard reagents were titrated before use.⁵¹

The Grignard reagent (20 mmol) was cooled to 0°C (functionalized Grignard reagents were cooled to −20°C). A solution of Ti(OⁱPr)₄ (4.08 mL, 15.0 mmol in 50 mL THF) and TiCl₄ (0.56 mL, 5.0 mmol) were added at 0°C to a separate two-necked 500 mL round-bottomed flask under a nitrogen atmosphere. The resulting solution was warmed to room temperature and stirred for 30 min to give a solution of ClTi(OⁱPr)₃ (100 mmol). The ClTi(OⁱPr)₃ solution was cooled to 0°C or −20°C and the cold (0°C or −20°C) Grignard solution was added through a cannula. The reaction mixture was warmed to room temperature and stirred for 2 h (functionalized titanium reagents were warmed to −10°C and allowed to react for 4 h). The volatile material was removed completely under reduced pressure, and under a nitrogen atmosphere, the residue was extracted with n-hexane (3 × 40 mL). The combined hexane solution was concentrated and was cooled to −20°C, furnishing the aryltris(2-propoxo)titanium species as a solid product.

General procedure B: palladium-catalyzed cross-coupling of aryl triflates with benzyltitanium reagents

In a glovebox, the aryl triflate 1 (0.50 mmol), Pd(OAc)₂ (3 mol%), and L4 (6 mol%) were added to a dried two-necked round-bottom reaction flask equipped with an addition funnel. ArCH₂Ti(OⁱPr)₃^•LiCl 2 (0.60 mmol) in mixed solvents of DME/THF (2:1, 3 mL) was added at 0°C. The resulting mixture was stirred at 0 ^oC for 15 min and warmed to 60 ^oC and stirred for 8 h. The reaction mixture was quenched with water of 20 mL and extracted with dichloromethane (3 × 30 mL). The combined organic phase was dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to give the coupling product. 3aa, 3ba, 3ca, 3da, 3ea, 3ga, 3ha, 3ia, 3ja, 3ka, 3la, 3na, 3oa, 3pa, 3qa, 3ra, 3sa, 3ab, 3ac, 3ad, 3ae, 3af, 3ag, 3ah, 3ai, 3aj, and 3qg have been reported earlier, and their spectral data matched with those presented in the literature. Products 3fa and 3ma are novel compounds.

Ethyl 4-[(4-(Dimethylamino)benzyl)]benzoate (3fa): Purification using silica gel column chromatography (petroleum ether/EtOAc = 3:1, v/v) afforded the desired product in a 61% yield (70.8 mg), colorless oil, ¹H NMR (400 MHz, CDCl₃): δ: 8.08 (d, J = 7.2 Hz, 2H), 7.15–7.09 (m, 4H), 6.73 (d, J = 7.2 Hz, 2H), 4.38 (q, J = 7.2 Hz, 2H), 4.02 (s, 2H), 2.90 (s, 6H), 1.41 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ: 168.88, 149.44, 146.98, 141.79, 130.88, 130.49, 129.47, 129.36, 126.64, 60.76, 41.05, 40.55, and 13.67. HRMS (ESI) calc. for C₁₈H₂₁NO₂ [M+H]⁺ m/z 284.1572 found 284.1574.

Ethyl 4-[(4-(Dimethylcarbamoyl)benzyl)]benzoate (3ma): Purification using silica gel column chromatography (petroleum ether/EtOAc = 3:1, v/v) afforded the desired product in a 81% yield (126.0 mg), colorless oil, ¹H NMR (400 MHz, CDCl₃): δ: 7.96 (d, J = 7.4 Hz, 2H), 7.20–7.14 (m, 4H), 6.99 (d, J = 7.4 Hz, 2H), 4.40 (q, J = 7.0 Hz, 2H), 3.90 (s, 2H), 3.09 (s, 6H), 1.42 (t, J = 7.0 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ: 169.05, 166.78, 151.54, 147.06, 136.30, 132.15, 130.00, 129.61, 128.81, 128.37, 60.78, 41.05, 38.10, 34.71, and 14.42. HRMS (ESI) calc. for C₁₉H₂₁NO₃ [M+H] ⁺ m/z 312.1521 found 312.1523.

Supplemental Material

sj-doc-1-chl-10.1177_17475198221091941 – Supplemental material for A new protocol for synthesizing diarylmethanes using a benzyltitanium reagent as a nucleophile

Supplemental material, sj-doc-1-chl-10.1177_17475198221091941 for A new protocol for synthesizing diarylmethanes using a benzyltitanium reagent as a nucleophile by He Zhang in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this paper.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this paper: This work was supported by Hebei Chemical and Pharmaceutical College.

ORCID iD

He Zhang

Supplemental material

Supplemental material for this paper is available online.

References

Nicolaou

Bulger

Sarlah

. Angew Chem 2005; 117: 4516.

Corbet

Mignani

. Chem Rev 2006; 106: 2651.

Magano

Dunetz

. Chem Rev 2011; 111: 2177.

Sato

Kawakami

Motomura

, et al. J Med Chem 2009; 52: 4869.

Kofink

Knochel

. Org Lett 2006; 8: 4121.

Mertins

Lovel

Kischel

, et al. Adv Synth Catal 2006; 348: 691.

Rueping

Nachtsheim

. Beilstein J Org Chem 2010; 6: 6.

Duan

Meng

Bao

, et al. Angew Chem 2010; 122: 6531.

Ackermann

Novak

. Org Lett 2009; 11: 4966.

10.

Aihara

Tobisu

Fukumoto

, et al. J Am Chem Soc 2014; 136: 15509.

11.

Paira

Yoshikai

. Org Lett 2015; 17: 4192.

12.

Zhao

Tan

Xiao

, et al. Org Lett 2013; 15: 1520.

13.

Zhou

Srinivas

Dasgupta

, et al. J Am Chem Soc 2013; 135: 3307.

14.

Itami

Mineno

Kamei

, et al. Org Lett 2002; 4: 3635.

15.

Tellis

Primer

Molander

. Science 2014; 345: 433.

16.

Benischke

Knoll

Rerat

, et al. Chem Commun 2016; 52: 3171.

17.

Alacid

Nájera

. J Org Chem 2009; 74: 2321.

18.

Park

Kang

Yie

, et al. Tetrahedron Lett 2005; 46: 2849.

19.

Negishi

King

Okukado

. J Org Chem 1977; 42: 1821.

20.

Han

Tokunaga

Hayashi

. Synlett 2002; 871.

21.

Dastbaravardeh

Knochel

. Synlett 2007; 2077.

22.

Yang

Zhou

Chang

, et al. Organometallics 2009; 28: 5715.

23.

Chen

Zhou

Biradar

, et al. Adv Synth Catal 2010; 352: 1718.

24.

Chang

, et al. Tetrahedron 2012; 68: 3956.

25.

Varenikov

Gandelman

. J Am Chem Soc 2019; 141: 10994.

26.

Varenikov

Shapiro

Gandelman

. Org Lett 2020; 22: 9386.

27.

Lee

Lam

, et al. Angew Chem Int Ed 2009; 48: 7436.

28.

Lee

Yuen

, et al. Org Chem Front 2020; 7: 926.

29.

Yusuke

Toshiro

. Angew Chem Int Ed 2008; 47: 1088.

30.

Yusuke

Toshiro

. Chem Eur J 2008; 14: 10560.

31.

Wang

Dai

Gong

. Top Curr Chem 2016; 2: 374.

32.

Weix

. Acc Chem Res 2015; 48: 1767.

33.

Wang

Xue

, et al. Org Chem Front 2015; 2: 1411.

34.

Tasker

Standley

Jamison

. Nature 2014; 509: 299.

35.

Moragas

Correa

Martin

. Chem Eur J 2014; 20: 8242.

36.

Knappke

CEI

Grupe

Gartner

, et al. Chem Eur J 2014; 20: 6828.

37.

Mesganaw

Garg

. Org Process Res Dev 2013; 17: 29.

38.

Shi

. Acc Chem Res 2010; 43: 1486.

39.

Stang

Hanack

Subramanian

. Synthesis 1982; 25: 85.

40.

de la Mare

PBD

. Electrophilic halogenation. London: Cambridge University Press, 1976.

41.

Ohashi

Doi

Ogoshi

. Chem Eur J 2014; 20: 2040.

42.

Shirakawa

Tamakuni

Kusano

, et al. Angew Chem Int Ed 2014; 53: 521.

43.

Ohashi

Kambara

Hatanaka

, et al. J Am Chem Soc 2011; 133: 3256.

44.

Duan

Meng

Bao

, et al. Angew Chem Int Ed 2010; 49: 6387.

45.

Quesnelle

Snieckus

. Synthesis 2018; 50: 4395.

46.

Bedford

Brenner

Carter

, et al. Organometallics 2014; 33: 5767.

47.

Russ

. Gen Chem 2020; 90: 725.

48.

Zhou

Zhang

Xia

, et al. Asian J Org Chem 2016; 5: 1260.

49.

Han

Buchwald

. J Am Chem Soc 2009; 131: 7532.

50.

Rasovskiy

Knochel

. Angew Chem Int Ed 2004; 43: 3333.

51.

Krasovskiy

Knochel

. Synthesis 2006; 5: 890.

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