Iron-Catalyzed Benzylation Reaction of Arenes with Benzyl Thiocyanates

Abstract

A novel, regioselective protocol for the synthesis of diphenylmethane derivatives has been developed by using iron-­catalyzed Friedel-Crafts reaction of arenes with benzyl thiocyanates. In the presence of FeBr₃, a variety of benzyl thiocyanates underwent the reaction with arenes to selectively afford the corresponding diarylmethane derivatives in moderate to high yields.

The diarylmethane moiety is a valuable structural unit in numerous biological compounds. [¹] For this reason, considerable effort has been devoted to the synthesis of diarylmethane derivatives. [²-8] Among the developed approaches, the Friedel-Crafts reaction is one of the most efficient methods for the formation of diarylmethane derivatives. [²] Although the Friedel-Crafts method can provide efficient access to substituted diarylmethane derivatives, there are noticeable drawbacks associated with this approach; it usually requires stoichiometric amounts of Lewis acids, high temperatures, and/or a large excess of arene for the relatively low nucleophilic aromatic compounds. [³-5] To overcome these limitations, palladium- or ruthenium-catalyzed C-H bond activation strategies for direct benzylation of aromatic compounds were developed recently. [6] However, both palladium and ruthenium catalysts are highly expensive. Thus, development of some new protocols using inexpensive and more environmentally benign catalysts is interesting. Here, we wish to report a novel Friedel-Crafts-type reaction for direct benzylation of arenes with benzyl thiocyanate catalyzed by inexpensive iron salts (Scheme  [¹] ). To the best of our knowledge, this is the first example of direct benzylation of aromatic compounds with benzyl thiocyanate using a catalytic amount of iron salts.

The reaction between (thiocyanatomethyl)benzene (1a) and p-xylene (2a) was investigated to optimize the reaction conditions; the results are summarized in Table  [¹] . Initially, three iron salts, FeCl₃, FeBr₃ and FeF₃, were examined (Table  [¹] , entries 1-3). Both FeCl₃ and FeBr₃ were suitable catalysts for the reaction, affording the target product 3 in 25% and 29% yields, respectively (Table  [¹] , entries 1 and 2). However, FeF₃ had no effect on this reaction (Table  [¹] , entry 3). Further screening revealed that the amount of FeBr₃ did not affect the reaction significantly (Table  [¹] , entries 4 and 5). Upon studying the effect of reaction temperature, it turned out that the reaction performed at 80 ˚C gave the best results (Table  [¹] , entries 2 and 6-8). In light of these results, a number of other solvents, including N,N-dimethylformamide (DMF), tetrahydrofuran (THF), toluene and MeCN, were tested, but they were not suitable for this reaction (Table  [¹] , entries 9-12). We were pleased to find that the amount of p-xylene (2a) affected the yield of 3: the yield was enhanced sharply to 63% when four equivalents p-xylene (2a) was added (Table  [¹] , entry 13), and to 75% at 10 equivalents p-xylene (2a; Table  [¹] , entry 14). Notably, in the presence of 20 equivalents p-xylene (2a) the target product 3 was obtained in 85% yield under solvent-free conditions (Table  [¹] , entry 15). The results demonstrated that, in the presence of 2,6-di-tert-butylpyridine or NaHCO₃, the reaction did not take place, and substrate 1a was almost completely recovered (Table  [¹] , entries 16 and 17).

Table 1 Screening Optimal Conditions^a

Entry	[Fe] (mol%)	Solvent	Temp (˚C)	Yield (%)b
1	FeCl3 (20)	DCE	120	25
2	FeBr3 (20)	DCE	120	29
3	FeF3 (20)	DCE	120	trace
4	FeBr3 (50)	DCE	120	27
5	FeBr3 (100)	DCE	120	34
6	FeBr3 (20)	DCE	100	32
7	FeBr3 (20)	DCE	80	31
8	FeBr3 (20)	DCE	60	15
9	FeBr3 (20)	DMF	80	trace
10	FeBr3 (20)	THF	80	trace
11	FeBr3 (20)	toluene	80	trace
12	FeBr3 (20)	MeCN	80	trace
13c	FeBr3 (20)	DCE	80	63
14d	FeBr3 (20)	DCE	80	75
15e	FeBr3 (20)	neat	80	85
16e f	FeBr3 (20)	neat	80	0
17e g	FeBr3 (20)	neat	80	0
a Reagents and conditions: 1a (0.4 mmol), 2a (0.4 mmol), [Fe] and solvent (3 mL), 24 h. b Isolated yield. c 2a (4 equiv). d 2a (10 equiv). e 2a (20 equiv). f 2,6-di-tert-butylpyridine (2 equiv) was added. g NaHCO3 (2 equiv) was added.

With the optimal conditions in hand, the reaction scope was explored (Table  [²] ). In the presence of FeBr₃, a variety of (thiocyanatomethyl)benzenes 1b-h were first examined by reacting with p-xylene (2a; Table  [²] , entries 1-7). The results demonstrated that several substituents, including Me, MeO, F and Br, on the aromatic ring of (thio­cyanatomethyl)benzenes were well-tolerated (Table  [²] , entries 1-6). Substrate 1c, with an ortho-methyl group, for instance, was treated with p-xylene (2a) and FeBr₃ to afford the desired product 5 in good yield (Table  [²] , entry 2). A 23% yield was still isolated from methoxy-substituted substrate 1e (Table  [²] , entry 4). Interestingly, substrates 1f and 1g, with a fluorine or bromine group, were compatible with the optimal conditions (Table  [²] , entries 5 and 6). For example, treatment of substrate 1g (with a Br group) with p-xylene (2a) and FeBr₃ furnished the corresponding product 9 in 67% yield (Table  [²] , entry 6). Gratifyingly, 3-(thiocyanatomethyl)thiophene (1h), a heterocyclic compound, was also suitable for the reaction (Table  [²] , entry 7). Subsequently, a range of arenes 2 were investigated under the optimal conditions (Table  [²] , entries 8-14). The results showed that electron-rich arenes were compatible with the optimal conditions. Notably, several substituents, such as Me, MeO, Cl or OH, on the aryl ring in substrates 2 were perfectly tolerated. 1-Chloro-4-methoxybenzene (2e), for instance, selectively reacted with (thiocyanato­methyl)benzene (1a) and FeBr₃ to give the desired product 15 in 89% yield (Table  [²] , entry 11). It was noted that substrates 2d, 2f and 2g gave a mixture of para- and ortho-products in moderate yields (Table  [²] , entries 10, 12 and 13). Phenol (2h) was also a suitable substrate for the reaction with 1a, selectively giving the para-substituted benzylation product 20 in 55% yield (Table  [²] , entry 14). However, electron-deficient nitrobenzene did not undergo the reaction (Table  [²] , entry 15).

Surprisingly, the reaction of 1,3,5-trimethoxybenzene (2i) with (thiocyanatomethyl)benzene (1a) and FeBr₃ afforded a thiocyanation product 21 in 85% yield, and not the desired diarylmethane (Scheme  [²] ). [9]

A possible mechanism, outlined in Scheme  [³] , was proposed. [²] [³] Initially, the reaction of 1a with FeBr₃ affords a cation intermediate A and an anion intermediate B. Intermediate A subsequently undergoes electrophilic alkylation with substrate 2a to form intermediate C. Finally, deprotonation of intermediate C gives the target product 3.

In summary, we have developed a novel protocol for the synthesis of diarylmethanes using inexpensive and environmentally benign iron catalysts. [¹0] This method allows direct benzylation of aromatic compounds with numerous thiocyanates with high regioselectivity under neat conditions.

Supporting Information for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synlett.

Table 2 Synthesis of Diarylmethanes by Fe-Catalyzed Friedel-Crafts-Type Reaction^a (continued)

Entry	Compound 1	Compound 2	Product	Isolated yield (%)
1	1b	2a	4	71
2	1c	2a	5	73
3	1d	2a	6	77
4	1e	2a	7	23
5	1f	2a	8	81
6	1g	2a	9	67
7	1h	2a	10	35
8	1a	2b	11	75
9b	1a	2c	12	95
10b	1a	2d	13/14 (10:1)c	70
11b	1a	2e	15	89
12	1a	2f	16/17 (1.6:1)c	36
13	1a	2g	18/19 (1.8:1)c	35
14b	1a	2h	20	55
15 b	1a	2i	-	0
a Reagents and conditions: 1 (0.4 mmol), 2 (20 equiv), FeBr3 (20 mol%), 80 ˚C, 24 h. b 1 (0.4 mmol), 2 (10 equiv) in DCE (3 mL) for 24 h. c The products were determined by ¹H NMR analysis.

Acknowledgment

We thank the National Natural Science Foundation of China (Nos. 20872112 and 21002010), Zhejiang Provincial Natural Science Foundation of China (Nos. Y407116, Y4080169 and Y4100307).

References and Notes

• For representative examples, see:
• 1a McPhail KL. Rivett DEA. Lack DE. Davies-Coleman MT. Tetrahedron  2000,  56:  9391 
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• 1d Rose C. Vtoraya O. Pluzanska A. Davidson N. Gershanovich M. Thomas R. Johnson S. Caicedo JJ. Gervasio H. Manikhas G. Ben AyedF. Burdette-Radoux S. Chaudri-Ross HA. Lang R. Eur. J. Cancer  2003,  39:  2318 
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• 1e Forsch RA. Queener SF. Rosowsky A. Bioorg. Med. Chem. Lett.  2004,  14:  1811 
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• 2b Friedel C. Crafts JMCR. Hebd. Seances Acad. Sci.  1877,  84:  1450 
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• 3b Olah GA. Friedel-Crafts Chemistry   Wiley; New York: 1973. 
• 3c Roberts RM. Khalaf AA. Friedel-Crafts Alkylation Chemistry   Marcel Dekker; New York: 1984. 
• 3d Olah GA. Krishnamurti R. Surya Prakash GK. In Comprehensive Organic Synthesis   1st ed., Vol. 3:  Pergamon; New York: 1991.  p.293-339 
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• 3e Bandini M. Melloni A. Umani-Ronchi A. Angew. Chem. Int. Ed.  2004,  43:  550 
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• 6b Lapointe D. Fagnou K. Org. Lett.  2009,  11:  4160 
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• 6d Ackermann L. Chem. Commun.  2010,  46:  4866 
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• 6e Ackermann L. Barfusser S. Kornhaass C. Kapdi AR. Org. Lett.  2011,  13:  3082 
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• 6f Sahnoun S. Messaoudi S. Brion J.-D. Alami M. ChemCatChem  2011,  3:  893 
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• For cross-coupling reactions of organometallic reagents with benzyl halides, see:
• 8a Bedford RB. Huwe M. Wilkinson MC. Chem. Commun.  2009,  600 
• 8b Chen Y.-H. Sun M. Knochel P. Angew. Chem. Int. Ed.  2009,  48:  2236 
  Search in Google Scholar
• 8c Chupak LS. Wolkowski JP. Chantigny YA. J. Org. Chem.  2009,  74:  1388 
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• 8d Burns MJ. Fairlamb IJS. Kapdi AR. Sehnal P. Taylor RJK. Org. Lett.  2007,  9:  5397 
  Search in Google Scholar
• 8e Molander GA. Elia MD. J. Org. Chem.  2006,  71:  9198 
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• 8f McLaughlin M. Org. Lett.  2005,  7:  4875 ; and references cited therein
  Search in Google Scholar
• 8g Liegault B. Renaud J.-L. Bruneau C. Chem. Soc. Rev.  2008,  37:  290 
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• 8h Kuwano R. Synthesis  2009,  1049 
• 9a Yadav JS. Reddy BVS. Krishna AD. Reddy . Suresh C. Narsaiah AV. Synthesis  2005,  961 
• 9b Chakrabarty M. Sarkar S. Tetrahedron Lett.  2003,  44:  8131 
  Search in Google Scholar

Typical Procedure: A mixture of benzyl thiocyanate (1a; 0.4 mmol), substrate (2a; 20 equiv), and FeBr₃ (23.4 mg, 20 mol%) was stirred in a Schlenk tube at 80 ˚C (oil bath temperature) until complete consumption of starting material was observed (reaction monitored by TLC and GC-MS analyses). The mixture was filtered through a crude column, washed with ethyl acetate, and evaporated under vacuum. The residue was purified by flash column chroma-tography (hexane/ethyl acetate) to afford the product 3.
Benzyl-1,4-dimethylbenzene (3): Yellow oil; ^¹H NMR (500 MHz, CDCl₃): δ = 7.25 (t, J = 7.5 Hz, 2 H), 7.19-7.15 (m, 1 H), 7.11 (d, J = 7.5 Hz, 2 H), 7.04 (d, J = 7.6 Hz, 1 H), 6.95 (d, J = 7.7 Hz, 1 H), 6.92 (s, 1 H), 3.94 (s, 2 H), 2.28 (s, 3 H), 2.18 (s, 3 H); ^¹³C NMR (125 MHz, CDCl₃): δ = 140.5, 138.7, 135.3, 133.4, 130.8, 130.2, 128.7, 128.3, 127.1, 125.8, 39.4, 21.0, 19.2; MS (EI, 70 eV): m/z (%) = 196 (90) [M]⁺, 181 (100), 118 (43).
Typical Procedure: A mixture of benzyl thiocyanate (1a; 0.4 mmol), 1,3,5-trimethoxybenzene (2i; 10 equiv), FeBr₃ (23.4 mg, 20 mol%) and DCE (3 mL) was stirred in a Schlenk tube at 80 ˚C (oil bath temperature) until complete consumption of starting material was observed (reaction monitored by TLC and GC-MS analyses). The mixture was filtered through a crude column, washed with ethyl acetate, and evaporated under vacuum. The residue was purified by flash column chromatography (hexane/ethyl acetate) to afford the product 21. 1,3,5-Trimethoxy-2-thiocyanatobenzene (21): Yellow soild; mp 159.3-160.5 ˚C; ^¹H NMR (500 MHz, CDCl₃): δ = 6.15 (s, 2 H), 3.92 (s, 6 H), 3.84 (s, 3 H); ^¹³C NMR (125 MHz, CDCl₃): δ = 164.2, 161.3, 111.8, 91.3, 89.7, 56.3, 55.6; LRMS (EI, 70 eV): m/z (%) = 225 (100) [M]⁺, 179 (34).

References and Notes

• For representative examples, see:
• 1a McPhail KL. Rivett DEA. Lack DE. Davies-Coleman MT. Tetrahedron  2000,  56:  9391 
  Search in Google Scholar
• 1b Graffner-Nordberg M. Kolmodin K. Aqvist J. Queener SF. Hallberg A. J. Med. Chem.  2001,  44:  2391 
  Search in Google Scholar
• 1c Manzoni C. Lovati MR. Bonelli A. Galli G. Sirtori CR. Eur. J. Pharmacol.  1990,  190:  39 
  Search in Google Scholar
• 1d Rose C. Vtoraya O. Pluzanska A. Davidson N. Gershanovich M. Thomas R. Johnson S. Caicedo JJ. Gervasio H. Manikhas G. Ben AyedF. Burdette-Radoux S. Chaudri-Ross HA. Lang R. Eur. J. Cancer  2003,  39:  2318 
  Search in Google Scholar
• 1e Forsch RA. Queener SF. Rosowsky A. Bioorg. Med. Chem. Lett.  2004,  14:  1811 
  Search in Google Scholar
• 2a Friedel C. Crafts JMCR. Hebd. Seances Acad. Sci.  1877,  84:  1392 
  Search in Google Scholar
• 2b Friedel C. Crafts JMCR. Hebd. Seances Acad. Sci.  1877,  84:  1450 
  Search in Google Scholar
• 3a Olah GA. Friedel-Crafts and Related Reactions   Wiley; New York: 1963. 
• 3b Olah GA. Friedel-Crafts Chemistry   Wiley; New York: 1973. 
• 3c Roberts RM. Khalaf AA. Friedel-Crafts Alkylation Chemistry   Marcel Dekker; New York: 1984. 
• 3d Olah GA. Krishnamurti R. Surya Prakash GK. In Comprehensive Organic Synthesis   1st ed., Vol. 3:  Pergamon; New York: 1991.  p.293-339 
  Search in Google Scholar
• 3e Bandini M. Melloni A. Umani-Ronchi A. Angew. Chem. Int. Ed.  2004,  43:  550 
  Search in Google Scholar
• 3f Bandini M. Emer E. Tommasi S. Umani-Ronchi A. Eur. J. Org. Chem.  2006,  3527 
• 4a Olah GA. Lee CS. Prakash GKS. Moriarty RM. Rao MSC. J. Am. Chem. Soc.  1993,  115:  10728 
  Search in Google Scholar
• 4b Olah GA. Lee CS. Prakash GKS. J. Org. Chem.  1994,  59:  2590 
  Search in Google Scholar
• 5a Ichihara J. Chem. Commun.  1997,  1921 
• 5b Kaneko M. Hayashi R. Cook GR. Tetrahedron Lett.  2007,  48:  7085 
  Search in Google Scholar
• 6a Verrier C. Hoarau C. Marsais F. Org. Biomol. Chem.  2009,  7:  647 
  Search in Google Scholar
• 6b Lapointe D. Fagnou K. Org. Lett.  2009,  11:  4160 
  Search in Google Scholar
• 6c Ackermann L. Novák P. Org. Lett.  2009,  11:  4966 
  Search in Google Scholar
• 6d Ackermann L. Chem. Commun.  2010,  46:  4866 
  Search in Google Scholar
• 6e Ackermann L. Barfusser S. Kornhaass C. Kapdi AR. Org. Lett.  2011,  13:  3082 
  Search in Google Scholar
• 6f Sahnoun S. Messaoudi S. Brion J.-D. Alami M. ChemCatChem  2011,  3:  893 
  Search in Google Scholar
• 7a L′Hermite N. Giraud A. Provot O. Peyrat J.-F. Alami M. Brion J.-D. Tetrahedron  2006,  62:  11994 
  Search in Google Scholar
• 7b Long Y.-Q. Jiang X.-H. Dayam R. Sanchez T. Shoemaker R. Sei S. Neamati N. J. Med. Chem.  2004,  47:  2561 ; and references cited therein
  Search in Google Scholar
• For cross-coupling reactions of organometallic reagents with benzyl halides, see:
• 8a Bedford RB. Huwe M. Wilkinson MC. Chem. Commun.  2009,  600 
• 8b Chen Y.-H. Sun M. Knochel P. Angew. Chem. Int. Ed.  2009,  48:  2236 
  Search in Google Scholar
• 8c Chupak LS. Wolkowski JP. Chantigny YA. J. Org. Chem.  2009,  74:  1388 
  Search in Google Scholar
• 8d Burns MJ. Fairlamb IJS. Kapdi AR. Sehnal P. Taylor RJK. Org. Lett.  2007,  9:  5397 
  Search in Google Scholar
• 8e Molander GA. Elia MD. J. Org. Chem.  2006,  71:  9198 
  Search in Google Scholar
• 8f McLaughlin M. Org. Lett.  2005,  7:  4875 ; and references cited therein
  Search in Google Scholar
• 8g Liegault B. Renaud J.-L. Bruneau C. Chem. Soc. Rev.  2008,  37:  290 
  Search in Google Scholar
• 8h Kuwano R. Synthesis  2009,  1049 
• 9a Yadav JS. Reddy BVS. Krishna AD. Reddy . Suresh C. Narsaiah AV. Synthesis  2005,  961 
• 9b Chakrabarty M. Sarkar S. Tetrahedron Lett.  2003,  44:  8131 
  Search in Google Scholar

Typical Procedure: A mixture of benzyl thiocyanate (1a; 0.4 mmol), substrate (2a; 20 equiv), and FeBr₃ (23.4 mg, 20 mol%) was stirred in a Schlenk tube at 80 ˚C (oil bath temperature) until complete consumption of starting material was observed (reaction monitored by TLC and GC-MS analyses). The mixture was filtered through a crude column, washed with ethyl acetate, and evaporated under vacuum. The residue was purified by flash column chroma-tography (hexane/ethyl acetate) to afford the product 3.
Benzyl-1,4-dimethylbenzene (3): Yellow oil; ^¹H NMR (500 MHz, CDCl₃): δ = 7.25 (t, J = 7.5 Hz, 2 H), 7.19-7.15 (m, 1 H), 7.11 (d, J = 7.5 Hz, 2 H), 7.04 (d, J = 7.6 Hz, 1 H), 6.95 (d, J = 7.7 Hz, 1 H), 6.92 (s, 1 H), 3.94 (s, 2 H), 2.28 (s, 3 H), 2.18 (s, 3 H); ^¹³C NMR (125 MHz, CDCl₃): δ = 140.5, 138.7, 135.3, 133.4, 130.8, 130.2, 128.7, 128.3, 127.1, 125.8, 39.4, 21.0, 19.2; MS (EI, 70 eV): m/z (%) = 196 (90) [M]⁺, 181 (100), 118 (43).
Typical Procedure: A mixture of benzyl thiocyanate (1a; 0.4 mmol), 1,3,5-trimethoxybenzene (2i; 10 equiv), FeBr₃ (23.4 mg, 20 mol%) and DCE (3 mL) was stirred in a Schlenk tube at 80 ˚C (oil bath temperature) until complete consumption of starting material was observed (reaction monitored by TLC and GC-MS analyses). The mixture was filtered through a crude column, washed with ethyl acetate, and evaporated under vacuum. The residue was purified by flash column chromatography (hexane/ethyl acetate) to afford the product 21. 1,3,5-Trimethoxy-2-thiocyanatobenzene (21): Yellow soild; mp 159.3-160.5 ˚C; ^¹H NMR (500 MHz, CDCl₃): δ = 6.15 (s, 2 H), 3.92 (s, 6 H), 3.84 (s, 3 H); ^¹³C NMR (125 MHz, CDCl₃): δ = 164.2, 161.3, 111.8, 91.3, 89.7, 56.3, 55.6; LRMS (EI, 70 eV): m/z (%) = 225 (100) [M]⁺, 179 (34).

• Supplementary Material